United States Patent (10) Patent No.: US 7,863,261 B2 Frincke (45) Date of Patent: Jan

USOO786.3261 B2

(12) United States Patent (10) Patent No.: US 7,863,261 B2 Frincke (45) Date of Patent: Jan. 4, 2011

(54) BREAST AND PROSTATE CANCER 2,308,834. A 1/1943 Ruzicka et al. TREATMENT METHOD 2,318, 105 A 5, 1943 Ruzicka 2,357,364 A 9/1944 Stavely (75) Inventor: James M. Frincke, Carlsbad, CA (US) 3,029.263 A 4/1962 Campbell et al. 3,210,249 A 10, 1965 BeerStecher et al. (73) Assignee: Hah Biosciences, Inc., San Diego, 3,336,347 A 8/1967 Engelfried et al. (US) 3.459,739 A 8/1969 Borrevang et al. (*) Notice: Subject to any disclaimer, the term of this 3,654,320 A 4/1972 Ayer et al. patent is extended or adjusted under 35 3,734,935 A 5.1973 Husbands et al. U.S.C. 154(b) by 543 days. 3,869,467 A 3, 1975 Guthrie et al. 3,935,245 A 1/1976 Engelfried et al. (21) Appl. No.: 11/835,397

(22) Filed: Aug. 7, 2007 (Continued)Ont1nue (65) Prior Publication Data FOREIGN PATENT DOCUMENTS US 2008/O176823 A1 Jul. 24, 2008 CA 1054143 5, 1979 Related U.S. Application Data (63) Continuation of application No. 09/675,323, filed on Sep. 28, 2000, now abandoned. (Continued) (60) Provisional application No. 60/157.275, filed on Sep. OTHER PUBLICATIONS 30, 1999, now abandoned, provisional application No. 60/157.347, filed on Sep. 30, 1999, now abandoned, Ben-David et al., Anti-hypocholterolemic effects of provisional application No. 60/166,116, filed on Nov. yspiandersterone in rats Proc. Soc. Exp. Biol. Med., 125:1136 16, 1999, now abandoned. (51) Int. Cl. (Continued) A6 IK3I/56 (2006.01) Primary Examiner San-ming Hui C07 L/00 (2006.01) (74) Attorney, Agent, or Firm Daryl D. Muenchau (52) U.S. Cl...... 514/182:552/502 (58) Field of Classification Search ...... 514/182; (57) ABSTRACT 552/5O2 See application file for complete search history. The invention provides methods to treating conditions such as (56) References Cited prostate cancer, or for ameliorating one or more symptoms U.S. PATENT DOCUMENTS associated with prostate cancer, or for agents that modulate the biological activity of the androgen receptor. The invention 2,243,887 A 6, 1941 Serini et al. also provides methods and compositions suitable for thera 2,251,939 A 8, 1941 Kathol peutic applications. 2,266,778 A 12/1941 Logemann et al. 2,267,257 A 12/1941 Ruzicka 2,308,833. A 1, 1943 Ruzicka et al. 24 Claims, 6 Drawing Sheets

Ethanol DHT (1 nM) No.4 1,3,5(10)-Estratriene-17o-ethynyl-3,17-diol No.6 17o-Ethynyl-androstene-diol No.8 3,3,17B-Dihydroxy-androst-5-en-16-one No. 10 3-Methylcarbonate-androst-5-en-7,17-dione No.18 17-Methyl-marrianotic acid No.15 3B-Methoxy-17B-hydroxyandrost-5-en-7-one No.22 7-oxo-androstene-diol No.13 3,3,17B-Acetoxy-androst-5-ene-7o, 173-diol No.O 7-oxo-dehydroepiandrosterone No.5 Androst-5-ene-3B, 11B,173-triol No.18 33-Methoxy-androst-5-ene-73, 173-diol No.11 3B,173-Dihydroxy-androst-5-en-11-one No. 17 173-Methoxy-androst-3,5-dien-7-One No.19 17-Hydroxy-androst-3,5-dien-7-one No.2 17a-Ethynyl-17B-hydroxy-4-estren-3-one No.7 17o-Ethynyl-17B-hydroxy-4-androsten-3-one No. 14 33,17B-Diacetoxy-androst-5-en-7-one No. 1 17o-Ethynyl-17B-hydroxy-4-estren-3-one No.3 17o-Ethynyl-7-hydroxy-5(1-0)-estren-3-one No.9 33,173-Dihydroxy-androst-4-ene No.23 19-nor-Androst-5-ene-3,17-diol No.21 5o-Androstane-3c, 173-diol US 7,863,261 B2 Page 2

U.S. PATENT DOCUMENTS WO WO99.63.973 12/1999 3,944,576 A 3, 1976 Van den Broek OTHER PUBLICATIONS 3,962,275 A 6, 1976 Guthrie et al. 4,898,694 A 2f1990 Schwartz et al. Clinton, et al., Esters of 17o-Ethinylandrostane-3?,17B-diol and 5,028,631 A 7, 1991 Schwartz et al. 17o-ethinylandrost-5-ene-3?,17B-diol, J. Org. Chem. 22:473-475 5,075,464 A 12/1991 Blohm 1957. 5,206,008 A 4, 1993 Loria Gatto, et al., Dehydroepiandrosterone inhibits the growth of DMBA 5,237,064 A 8, 1993 Bakshi et al. induced rat mammary carcinoma via the androgen receptor Oncol. 5,292,730 A 3/1994 Lardy Rep. 5(1): 241-3 1998. 5,296.481 A 3/1994 Partridge et al. Irmsher, et al. Preparation of 7o-Hydroxy- and 5,372,996 A 12/1994 Labrie 7o-Methoxytestosterone Derivatives Chem. Ber. 97:3363-3373 5,387,583 A 2f1995 Loria 1964 (translated from German). 5,424,463 A 6/1995 Lardy et al. Marshall, et al, 7-Keto steroids. II. Steroidal 3-f-hydroxy-A-ones 5,461,042 A 10/1995 Loria and A-7-ones.J. Amer: Chem. Soc. 79:6308-6313 1957. 5,478,566 A 12/1995 Loria Moore, et al. Concentration of dihydrotestosterone and 5,506,223. A 4/1996 Lardy et al. 3O-androstanediol in naturally occurring and androgen-induced 5,532,230 A 7, 1996 Daynes et al...... 514,178 prostatic hyperplasia in the dog J. Clin. Invest. 64: 1003-1010 1979. 5,567,830 A 10/1996 Upasani Ranney et al Hypocholesterolemic effect of an androsterone analog 5,593.981 A 1, 1997 Labrie Proc. Soc. Exp. Biol. Med. 166:569-9 1964. 5,656,621 A 8, 1997 Schwartz et al. Rao, et al., Chemoprevention of rat prostate carcinogenesis by early 5,686,438 A 1 1/1997 Daynes et al. and delayed administration of dehydroepiandrosterone, Cancer Res. 5,744.462 A 4, 1998 Schwartz et al. 59(13):3084-3089, 1999. 5,763.433 A 6, 1998 Morfin Schwarz, Concerning Steroid Derivatives XIV Preparation of 5,859,000 A 1/1999 Dowell et al. Methylandrostenediol Derivatives with an Oxygen Function at the 7 5,912,240 A 6, 1999 Loria Position Coll. Czech. Chem. Comm. 26:1958-1966 1961 (translated 5,922,701 A 7, 1999 Araneo from German). 5,925,630 A 7/1999 Upasani et al. Chang, et al., Suppression of Al-Androstenediol-induced androgen 5,981,744 A 1 1/1999 Ng et al. receptor transactlvation by selective steroids in human prostate can 5,994,335 A 11/1999 Brodie et al. cer cells, Proc. Natl. Acad. Sci. USA., 96(20): 11173-11177, Sep. 28, 6,440,966 B1 8/2002 Barrett et al. 1999. 6,573.289 B1 6/2003 Tasaka et al. Hackenberg et al., Estrogen and androgen receptor mediated Stimu 6,667,299 B1 12/2003 Ahlem et al. lation and inhibition of proliferation by androst-5-ene-3B,17B-diol in 6,696.459 B1 2/2004 Jones et al. human mammary cancer cells, J. Steroid Biochem. Molec. Biol. 6,767,903 B1 7/2004 Cleve et al. 46(5):597-603 1993. 6,770,639 B2 8, 2004 Snow et al. Henderson, Dehydroepiandrosterone and 16O-bromo 6,770,641 B2 8/2004 Hayakawa et al. epiandrosterone: Inhibitors of Epstein-Barr virus-induced transfor 6,790,842 B1 9, 2004 Bohlmann et al. mation of human lymphocytes, Carcinogenesis, 2(7):683-686 1981. 6,962.923 B2 11/2005 Banks et al. Lardy, et al., Ergosteroids. II: Biologically active metabolites and 7,482,334 B2 1/2009 Frincke et al. synthetic derivatives of dehydroepiandrosterone, Steroids, 63:158 7,524,835 B2 4/2009 Frincke 165 1998. 2003/0060425 A1 3/2003 Ahlem et al. Miyamoto, et al., A-androstenediol is a natural hormone with andro 2004.0043973 A1 3, 2004 Ahlem et al. genic activity in human prostate cancer cells, Proc. Natl. Acad. Sci. U. 2004/00974.06 A1 5/2004 Ahlem et al. S.A. 95(19): 11083-1 1088 1998. 2004/O116359 A1 6, 2004 Ahlem et al. Miyamoto, et al.,3B-Acetoxyandrost-1,5-diene-17-ethylene ketal 2004/022O114 A1 11/2004 Ahlem et al. functions as a potent antiandrogen with marginal agonist activity, 2004/0242618 A1 12/2004 Lardy et al. Proc. Natl. Acad. Sci. USA, 100:4440-4444, 2003. 2005/O159366 A1 7/2005 Ahlem et al. Pashko, et al., Dehydroepiandrosterone (DHEA) and 3 beta 2005/0256095 A1 11, 2005 Ahlem et al. methylandrost-5-en-17-one: inhibitors of 7, 12 2005/0282732 A1 12, 2005 Ahlem et al. dimethylbenzalanthracene (DMBA)-initiated and 12-O- 2006, OO63749 A1 3, 2006 Ahlem et al. tetradecanoylphorbol-13-acetate (TPA)-promoted skin papilloma 2006, OO73099 A1 4/2006 Frincke et al. formation in mice, Carcinogenesis 5(4):463-466 1984. 2006, OO79492 A1 4/2006 Ahlem et al. Segaloff, et al. Hormonal therapy in cancer of the breast II. Effect of 2006, OO88473 A1 4/2006 Dowding et al. methylandrostenediol on clinical course and hormonal excretion, 2007/00 14719 A1 1/2007 Reading et al. Cancer, 5(2):271-74 1952. 2007/00772O1 A1 4/2007 Reading et al. Segaloff, et al, Hormonal therapy in cancer of the breast IV. Effect of 2007/01292.82 A1 6, 2007 Ahlem etal androstenediol on clinical course and hormonal excretion, Cancer, 5(6):271-74 1952. 2008.0004250 A1 1/2008 Lardy et al. Segaloff, etal, Hormonal therapy in cancer of the breast. V. The effect 2008, OOO9472 A1 1/2008 Lardy et al. of methyltestosterone on clinical course and hormonal excretion, 2008, 0021006 A1 1/2008 Lardy et al. Cancer, 6(3):483-487 1953. 2008, OO58301 A1 3/2008 Lardy et al. Segaloff, et al. Testosterone and miscellaneous steroids in the treat 2008/007088. A 32008 Lardy et al. ment of advanced mammary cancer, Cancer, 10(4):808-812 1957. 20080153792 Al 6 2008 Frincke et al. U.S. Appl. No. 1 1/835,394, filed Aug. 7, 2007, Frincke, et al. 2008. O176823 A1 7/2008 Frincke et al. Chambaz, et al., Urinary steroids in neonates: Characterization of 2008. O176824 A1 7/2008 Frincke et al. four androstenetetrols by gas chromatography and mass spectrom etry. Proceedings of Acad. Sc. Paris, Series D, 268: 2817-??? 1969. FOREIGN PATENT DOCUMENTS Chang, et al., Suppression of AS -Androstenediol-induced androgen receptor transactivation by selective steroids in human prostate can EP O 363 128 4f1990 cer cells, Proc. Natl. Acad. Sci. USA. 96(20): 11173-11177, Sep. 28, WO WO95/07926 3, 1995 1999. WO WO95/10527 4f1995 Kroboth, et al DHEA and DHEA-S: A review, J. Clin. Pharm. WO WO97,37662 10, 1997 39:327-348, 1999. US 7,863,261 B2 Page 3

Lardy, et al., Ergosteroids. II: Biologically active metabolites and Labaree, et all 7a-iodo and 7a-fluotro steroids as androgen receptor synthetic derivatives of dehydroepiandrosterone Steroids 63:158-165 mediated imaging agents.J. Med Chem. 1999, 42:2021-2034. 1998. Marshall, et al, 7-Keto steroids. II. Steroidal 3-f-hydroxy-A-ones Marwah, et al., C19-Steroids as androgen receptor modulators: and A-7-ones.J. Amer: Chem. Soc. 1957, 79:6308-6313. Design, discovery, and structure-activity relationship of new steroi Siemann, Steroids: Synthesis of derivatives of 5-androsten-7-one dal androgen receptor antagonists, Bioorg. Med. Chem., 14:5933 Zeitschrifi Chem. 1971, 11:15-16. (translated from German). 5947 2006. Siemann, Steroids: Preparation of C-17-substituted derivatives of Morfin, et al. Pregnenolone and dehydroepiandersterone as precur 3.5-androstadien-7-one, Zeitschrift Chem. 1971, 11:235-236. (trans sors of native 7-hydroxylated metabolites which increases the lated from German). immune response in mice.J. Steroid Biochem. Mol. Biol. 50:91-100 Ben-David et al Anti-hypocholterolemic effects of 1994. dihydroepiandersterone in rats Proc. Soc. Exp. Biol. Med. 1967. Segaloff, et al., Hormonal therapy in cancer of the breast II. Effect of 125:1136-40. methylandrostenediol on clinical course and hormonal excretion, Fink, etal Peripheral serum corticosteroid concentrations in relation Cancer 5(2):271-74 1952. to the rat adrenal cortical circadian rhythm in androgen-induced Segaloff, et al., Hormonal therapy in cancer of the breast IV. Effect of hypertension, Hypertension 1980, 2:617-622. androstenediol on clinical course and hormonal excretion, Cancer Gaunt, et al. Antagonists to cortisone: an ACTH-like action of Ste 5(6):271-74 1952. roids Endocrinol. 1953, 52:407-423. Segaloff, et al., Hormonal therapy in cancer of the breast. V. The Irmsher, et al. Preparation of 7o-Hydroxy- and effect of methyltestosterone on clinical course and hormonal excre 7o-Methoxytestosterone Derivatives Chem. Ber. 1964, 97:3363 tion Cancer, 6(3):483-487 1953. 3373 (translated from German). Segaloff, et al., Testosterone and miscellaneous steroids in the treat Kroboth, et al DHEA and DHEA-S: a review J. Clin. Pharm. 1999, ment of advanced mammary cancer, Cancer, 10(4):808-812 1957. 39:327-348. Shackleton, et al., Metabolism of fetal and neonatal adrenal steroids, Lee, et al. Effect of steroid structure on the inhibition of lanosterol J. Steroid. Biochem. 11:523-529, 1979. demethylation by steroid hormones Steroids 1968, 11:699-702. Siemann, Steroids: Synthesis of derivatives of 5-androsten-7-one Morfin, et al. Pregnenolone and dehydroepiandersterone as precur Zeitschrifi Chem. 11:15-16 1971 (translated from German). sors of native 7-hydroxylated metabolites which increases the Siemann, Steroids: Preparation of C-17-substituted derivatives of immune response in mice.J. Steroid Biochem. Mol. Biol. 1994, 50:91 3.5-androstadien-7-one, Zeitschrifi Chem. 11:235-236 1971 (trans 100. lated from German). Ranney et al Hypocholesterolemic effect of an androsterone analog Tummala, et al., Correlation between the administrated dose of Proc. Soc. Exp. Biol. Med. 1964, 166:569-9. DHEA and serum levels of DHEA and DHEA-Sinhuman volunteers Schwarz, Concerning Steroid Derivatives XIV Preparation of Clin. Biochen. 32:355-361 1999. Methylandrostenediol Derivatives with an Oxygen Function at the 7 Bloch, et al. Optical rotatory dispersion and circular dichroism stud Position Coll. Czech. Chem. Comm. 1961 26:1958-1966 (translated ies. Part XXXIX. Cotton effects of halogen-substituted O?3-unsatur from German). ated ketones J. Chem. Soc. (B) 1966, pp. 1177-1183. Tummala, etal Correlation between the administrated dose of DHEA Campbell, et al The synthesis of some 7o- and 73-methyl steroid and serum levels of DHEA and DHEA-S in human volunteers Clin. hormones, J. Amer: Chem. Soc. 1959, 81:4069-4074. Biochem. 1999, 32:355-361. Dorfman, et al. Biological activity of various steroids including Copending U.S. Appl. No. 1 1/835.394, allowed claims. B-nor steroids 1964, 3:675-686. Copending U.S. Appl. No. 1 1/835,334, publication No. 2008 Gatto, etal, Dehydroepiandrosterone inhibits the growth of DMBA 0021006, pending claims. induced rat mammary carcinoma via the androgen receptor, Oncol U.S. Appl. No. 60/124,087, filed Nov. 3, 1999, Prendergast et al. Rep. 5(1), pp. 241-243, 1998. U.S. Appl. No. 60/126,056, filed Mar. 23, 1999, Ahlem et al. Guthrie, et al. Preparation of Some 7-Oxaandrostane derivatives J. Med. Chem. 1973, 16:257-262. * cited by examiner U.S. Patent Jan. 4, 2011 Sheet 1 of 6 US 7,863,261 B2

Ethanol DHT (1 nM) Aaaaaaaaaa No.4 1,3,5(10)-Estratriene-17o-ethynyl-3,17B-diol NO.6 17o-Ethynyl-androstene-diol No.8 3,3,173-Dihydroxy-androst-5-en-16-one No. 10 33-Methylcarbonate-androst-5-en-7,17-dione No. 18 17-Methyl-marrianolic acid No.15 3B-Methoxy-17B-hydroxyandrost-5-en-7-one No.22 7-Oxo-androstene-diol No.13 33,17B-Acetoxy-androst-5-ene-7o, 17B-diol NO.O 7-oxo-dehydroepiandrosterone NO.5 Androst-5-ene-33, 11B, 173-triol No.16 3B-Methoxy-androst-5-ene-7B, 173-diol No. 11 33,173-Dihydroxy-androst-5-en-11-one No. 17 17B-Methoxy-androst-3,5-dien-7-one NO.19 17B-Hydroxy-androst-3,5-dien-7-one No.2 17o-Ethynyl-17B-hydroxy-4-estren-3-one No.7 17o-Ethynyl-17B-hydroxy-4-androsten-3-one No. 14 36,17B-Diacetoxy-androst-5-en-7-one NO.1 17o-Ethynyl-17B-hydroxy-4-estren-3-one No.3 17o-Ethynyl-7(5-hydroxy-5(10)-estren-3-one No.9 33,173-Dihydroxy-androst-4-ene No.23 19-nor-Androst-5-ene-36,17B-diol No.21 5o-Androstane-30, 17B-diol

Figure 1

U.S. Patent Jan. 4, 2011 Sheet 3 of 6 US 7,863,261 B2

200 s se SO R e 2 M 2 E22 SSS w %2 N. R

OCC 33%2 R3 NNNI, E 2D R 2%%2 NN RS d5 30 I SS 222 N. NN 88R 4. O 3222%. 2 NN R.

Adiol ------(50 nM) - - 8 7 6 8 7 6 8 7 6.8 7 6 8686 8686 8686 log(con. L------centration) EtOH No.4 No.6 No.8 No. 10 No. 18 No. 15 No.22 No. 13 No.0 No.5 Figure 2B U.S. Patent Jan. 4, 2011 Sheet 4 of 6 US 7,863,261 B2

O H-? +|ZZZZZZZZZZZZ H-IZZZZZZZZZ H-ZZZZZZZZZ DHT (1 nM) -log(Concen tration)(M) U.S. Patent Jan. 4, 2011 Sheet 5 of 6 US 7,863,261 B2

OO s > 5 CC 5 N g 5O N N (2 N ups N -, N N o

Adiol (50 nM) - + + H. H. H. - - - H ------HF (1 uM) ------H ------log(concen- + + + 8 7 6 8 7 6 8 7 6 8 7 6 trati" M - EtOH No. 4 No. 6 No. 8 NO. 10

Figure 4 U.S. Patent Jan. 4, 2011 Sheet 6 of 6 US 7,863,261 B2

E2 (1 nM) E R ap N N N N Progesterone (1 nM) PR

Dexamethasone (1 nM) GR

-log (ConCen- EtOH 6 7 8 6 7 8 6 7 8 6 7 8 tration)(M) No.4 No.6 No.8 No. 10

Figure 5 US 7,863,261 B2 1. 2 BREAST AND PROSTATE CANCER synthesis inhibitors such as 5C. reductase inhibitors to inhibit TREATMENT METHOD production of sex hormones Such as testosterone or dihy drotestosterone, or administering Naftopidil for dysuria. CROSS-REFERENCE TO RELATED Treatment with 5C. reductase inhibitors has been combined APPLICATIONS with other treatments such as anti-estrogens, aromatase (es This application is a continuation application of abandoned trogen synthetase) inhibitors, inhibitors of 17 B-hydroxys U.S. application Ser. No. 09/675,323, filed Sep. 28, 2000, teroid dehydrogenase or luteinizinq hormone releasing hor which claims priority of U.S. provisional application Ser. No. mone agonists or antagonists. Other proposed treatments 60/157.275, filed Sep. 30, 1999, U.S. provisional application 10 include administering aromatase inhibitors such as 4-hy Ser. No. 60/157.347, filed Sep. 30, 1999, and U.S. provisional droxyandrostene-3,17-dione. Chemotherapy typically has application Ser. No. 60/166,116, filed Nov. 16, 1999, all of drawbacks. It can have unwanted side effects, particularly in which are incorporated herein by reference. older patients or it can become ineffective over time. Various treatments and their limitations have been described, see, e.g., BACKGROUND OF THE INVENTION 15 U.S. Pat. Nos. 4,059,630, 4,310,523, 4,659,695, 4,970,204, The invention provides methods and compositions com 5,137,882, 5,372,996, 5,494,914, 5,561,124, 5,593.981, prising steroids or analogs, such as analogs of androst-5-ene 5,994,334, 5,994,335, 5,998.377, 6,015,806, 6,093,722, 3 B, 17 B-diol (AED) or 1,3,5(10)-estratriene-17o-ethynyl 6,110,906 and European publication EP 0401 653. 3f3, 17 B-diol (“EED) for use as agents to modulate the Biological properties of AED and related steroid com biological activity of the androgen receptor (“AR”) or to treat pounds have been disclosed, see, e.g., U.S. Pat. Nos. 2,833, androgen responsive or related conditions such as prostate 793, 2,911,418, 3,148,198, 3,471,480, 3,710,795, 3,711,606 cancer and benign prostatic hypertrophy (“BPH'). 3,976,691, 4,268,441, 4,427,649, 4,542,129, 4,666,898, Prostate cancer represents the most commonly diagnosed 4,898,694, 4,956,355, 4,978,532, 5,001,119, 5,043,165, non-cutaneous malignancy in aging males and is the second 25 5,077,284, 5,028,631, 5,110,810, 5,157,031, 5,162,198, leading cause of cancer-related death in North American men. 5,175,154, 5,206,008, 5,277,907, 5,292,730, 5,296.481, Androgen ablation has been the cornerstone of treatment for 5,372,996, 5,387,583, 5,407,684, 5,424,463, 5,461,042, advanced forms of this disease, typically by a combination of 5,478,566, 5,506,223, 5,518,725, 5,527,788, 5,527,789, Surgical or medical antiandrogen therapy. Antiandrogens that 30 5,532,230, 5,559,107, 5,562,910, 5,583,126, 5,585,371, are commonly used include hydroxyflutamide (HF), cyprot 5,587,369, 5,591,736, 5,593.981, 5,610,150, 5,635,496, erone acetate and bicalutamide (casodex). Androgen ablation 5,641,766, 5,641,768, 5,656,621, 5,660,835, 5,677,366, treatments are used to reduce the level of endogenous andro 5,686,438, 5,696,106, 5,700,793, 5,707,983, 5,709,878, gens. However, most androgen-dependent prostate cancer 5,710,143, 5,714,481, 5,728,688, 5,736,537, 5,744,462, cases appear to progress to androgen-independent malignan 35 5,753,237, 5,756.482, 5,776,921, 5,776,923, 5,780.460, cies. Limiting the availability of androgens to regional or 5,795,880, 5,798,347, 5,798,348, 5,804,576, 5,807,848, metastatic prostate cancers usually induces remission, but 5,807,849, 5,811,418, 5,824,313, 5,824,668, 5,824,671, after sometime the cancer often becomes refractory to andro 5,827,841, 5,837,269, 5,837,700, 5,843,932, 5,846,963, gen ablation treatments. It has been Suggested that genetic 5,856,340, 5,859,000, 5,869,090, 5,863,910, 5,872,114, 40 5,872,147 and 5,910.407; German patent numbers 2035738 changes of the AR gene may contribute to a short response to and 2705917; PCT publication numbers WO95/21617, WO anti-androgen therapy. However, the mechanisms respon 97/48367, WO 98/05338, WO 98/50040, WO 98/50041, WO sible for conversion of prostate cancer cells to an androgen 98/58650; European publication number 0020029. independent condition are not fully characterized. The androgen receptor and co-activators such as ARA, BPH is a disease that affects approximately 60% of males 45 ARA, ARAs, ARAss and Rb, and methods to use them older than about 60 years of age. An elevated accumulation of have been described, e.g., U.S. Pat. Nos. 5,789,170, 5,614, male hormones such as dihydrotestosterone (“DHT”) in pros 620; International publication number WO 00/04152. tate tissue may contribute to prostate enlargement. The accu mulation of DHT appears to result from elevated intracellular The invention methods and compositions accomplish one 50 or more of several objects. Invention objects include provid DHT receptor levels. The increase is associated with an eleva ing methods and compositions to inhibit proliferation of pros tion of estrogen levels relative to androgen levels, which tate cancer cells a subject. Other objects are to provide meth decrease with age. The urological symptoms consist in an ods to make and use compositions and formulations elevated frequency of miction due to elevated residual urine. comprising EED analogs or other compounds disclosed This is typically accompanied by a weak flow of urine, a 55 herein. Additional objects will be apparent from the disclo time-delayed start of miction, and repeated infections of the SUC. bladder and kidneys. BPH treatment includes surgery to remove the obstruction, but this is not always effective or has SUMMARY OF THE INVENTION unwanted side-effects, e.g., incontinence or decreased libido. 60 Other treatments such as androgen ablation by bilateral In accordance with the objects, the invention provides a orchiectomy orandrogen ablation chemotherapy are too inva method to treat or prevent an androgen responsive disease sive or have unwanted side-effects. Less invasive methods Such as prostate cancer, benign prostatic hyperplasia or breast exist, e.g. balloon dilatation. treatment with hyperthermia or cancer in a Subject, or to ameliorate one or more symptoms microwaves, but they can have limited efficacy. 65 thereof, comprising administering to a Subject, or delivering Chemotherapy for conditions such as prostate cancer and to the Subjects tissues, an effective amount of a compound of BPH, or their symptoms, include administering androgen formula 1 or 2 US 7,863,261 B2 4 BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 The effects of various DHEA metabolites on the transcriptional activity of AR. FIG. 2 The structures of DHEA derivatives and effects on the Adiol-induced AR transcriptional activity. (A) The struc tures of compounds No. 4, 6, 8 & 10, DHEA, Adiol, and testosterone. (B) CAT activity determined in PC-3 cells tran siently co-transfected with WtAR and MMTV-CAT. 10 FIG.3 The suppression effects of No. 4, 6, 8 & 10 DHEA derivatives on the DHT induced AR transcriptional activity. FIG. 4 The effects No. 4, 6, 8 & 10 DHEA derivatives on the Adiol-induced and HF-blocked AR transcriptional activ ity. 15 FIG.5 The effects No. 4, 6, 8 & 10 DHEA derivatives on the ER, PR, or GR transcriptional activity. DETAILED DESCRIPTION OF THE INVENTION As used herein and unless otherwise stated or implied by context, the following terms have the meanings defined here. A 'subject’ means a human or animal. Usually the animal is a vertebrate Such as a primate, rodent, domestic animal or game animal. Primates include chimpanzees, cynomoldus 25 monkeys, spider monkeys, and macaques, e.g., Rhesus. Rodents include mice, rats, woodchucks, ferrets, rabbits and wherein, R-R independently are -H, -OR*. —SR*, hamsters. Domestic and game animals include cows, horses, -N(R), —O Si (R), —CN, NO, OSOH, pigs, deer, bison, buffalo, felines, e.g., domestic cat, dogs, —OPOH, an ester, a phosphoester, a phosphonoester, a e.g., domestic dog, wolf, birds, e.g., chicken, turkey, emu, 30 ostrich, and fish, e.g., trout, catfish and salmon. Subject Sulfite ester, a Sulfate ester, an amide, an amino acid, a pep includes any Subset of the foregoing, e.g., all of the above, but tide, an ether, a thioether, an acyl group, a carbonate, a car excluding one or more groups or species Such as humans, bamate, a slufonamide, a halogen, an optionally substituted primates or rodents. alkyl group, an optionally Substituted alkenyl group, an Expressions that refer to “a formula 1 compound”, “a com optionally Substituted alkynyl group, an optionally Substi 35 pound of formula 1”, “a formula 2 compound' or the like tuted aryl moiety, an optionally substituted heterocycle, an means compounds, compositions or formulations where one or more than one formula 1 (or formula 2) compound is optionally Substituted heteroaryl moiety, an optionally Sub present, typically 1, 2, 3 or 4, usually 1. stituted monosaccharide, an optionally Substituted oligosac A "mimetic of a formula 1 or 2 compound' or a “mimetic charide, a nucleoside, a nucleotide, an oligonucleotide, a 40 ofEED' means any compound, steroid or non-steroid (e.g., a polymer, or, when two of R'-R are linked to the same compound disclosed in one or more of the references cited carbon atom (e.g., RandR or R'' and R'), they indepen herein), that qualitatively or quantitatively induces the same dently comprise a double bond, such as =O. —S, —CH or or similar biological responses to any significant degree that —N OH, at one or more ring carbons, and provided that one or more formula 1 compounds or EED induces. Biologi 45 cal responses include modulation of AR-mediated transcrip when one or more of the rings comprises a double bond, one tion or inhibition of replication of cells, e.g., prostate cancer of the variable groups that is bonded to the double bonded cells. In general, a mimetic of a formula 1 or 2 compound, e.g. ring carbon is absent; each R" independently is Cls alkyl; EED, will induce at least about 35%, preferably at least about each R* independently is Hora protecting group; and the 50%, of the biological response that the formula 1 or 2 com dotted lines are optional double bonds, provided that 2, 3, 4 or 50 pound induces as optionally compared to suitably controlled more of R'-R are not hydrogen, and provided that com and untreated reference cells, cell populations (in vitro or in pound is not 17O-ethynyl-17 3-hydroxy-4-estrene-3-one, vivo) or subjects. Typically the biological response will be defined by measuring one, two, three or more parameters, 17O-ethynyl-17 3-hydroxy-5(10)-estrene-3-one, 1,3,5(10)- e.g., modulation of the synthesis of one or more gene products estratriene-17? 3-ethynyl-3?,17B-diol, 17O-ethynyl-androst 55 or modulation of cell replication. 5-ene-3?,17? 3-diol, 17O-ethynyl-17B-hydroxy-4-androsten Alkyl as used here means linked normal, secondary, ter 3-one, 3B, 17 B-dihydroxy-androst-5-en-16-one, 3 B, 17 B tiary or cyclic carbon atoms, i.e., linear, branched or cyclic. dihydroxy-androst-4-en, 3B,-methylcarbonate-androst-5-en The number of carbon atoms in an alkyl group or moiety is 1 7,17-dione, 3f3, 17(3-dihydroxy-androst-5-en-11-one, to about 20, unless otherwise specified, e.g., C.s alkyl means 3f3, 17 B-diacetoxy-androst-5-ene-7C, 17 B-diol. 3 B, 17 B-diac 60 an alkyl moiety containing 1,2,3,4, 5, 6, 7 or 8 carbonatoms. etoxy-androst-5-ene-7-one, 3.f3-methoxy-androst-5-ene-7C. Examples include methyl, ethyl, 1-propyl (n-propyl), 2-pro pyl (i-propyl, —CH(CH)), 1-butyl (n-butyl), 2-methyl-1- 17 B-diol, 17(3-methoxy-androst-3,5-diene-7-one, 17 B-hy propyl (i-butyl, —CHCH(CH)), 2-butyl (s-butyl, -CH droxy-androst-3,5-diene-7-one, 5C.-androstane-3C, 17 B-diol (CH)CHCH), 2-methyl-2-propyl (t-butyl, —C(CH)), or an ester, ether or salt of any of these compounds. 65 1-pentyl (n-pentyl), 2-pentyl ( CH(CH)CHCHCH), Other objects will become apparent on reading the disclo 3-pentyl ( CH(CHCH)), 2-methyl-2-butyl ( C(CH) SUC. CHCH), 3-methyl-2-butyl ( CH(CH)CH(CH)), US 7,863,261 B2 5 6 3-methyl-1-butyl ( CHCH-CH(CH)), 2-methyl-1-butyl groups comprise one, two, three or more Substituents, and ( CHCH(CH)CHCH), 1-hexyl, 2-hexyl ( CH(CH) Such substituents are optionally bonded to a carbon atom that CHCHCHCH), 3-hexyl (-CH(CHCH.) is one or more methylene moiety removed from the double (CH2CHCH)), 2-methyl-2-pentyl (—C(CH) bond, i.e., the substituent is separated at least by 1, 2, 3 or CHCHCH), 3-methyl-2-pentyl ( CH(CH)CH(CH) more —CH2— moieties from a double bond. CHCH), 4-methyl-2-pentyl ( CH(CH)CH-CH(CH)), Heterocycle. “Heterocycle' or "heterocyclic” includes by 3-methyl-3-pentyl ( C(CH)(CHCH)), 2-methyl-3-pen way of example and not limitation these heterocycles tyl ( CH(CHCH)CH(CH)), 2,3-dimethyl-2-butyl ( C described in Paquette, Leo A.: “Principles of Modern Hetero (CH),CH(CH)), 3.3-dimethyl-2-butyl ( CH(CH)C cyclic Chemistry” (W. A. Benjamin, New York, 1968), par (CH)), cyclopropyl, cyclobutyl, cyclopentyl and 10 ticularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of cyclohexyl. Heterocyclic Compounds. A series of Monographs” (John Alkenyl' means linked normal, secondary, tertiary or Wiley & Sons, New York, 1950 to present), in particular cyclic carbon atoms where one or more double bonds (e.g., Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. 1960, —CH=CH-) are present, typically 1, 2 or 3, usually 1 or 2. 82:5566. The number of carbonatoms in an alkenyl group or moiety is 15 Examples of heterocycles include by way of example and 2 to about 20, unless otherwise specified, e.g., C.s alkenyl not limitation pyridyl, thiazolyl, tetrahydrothiophenyl, sulfur means an alkenyl moiety containing 2, 3, 4, 5, 6, 7 or 8 carbon oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, atOmS. pyrrolyl pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl. Alkynyl means linked normal, secondary, tertiary or thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinoli cyclic carbon atoms where one or more triple bonds nyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, ( C=C ) are present, typically 1, 2 or 3, usually 1. The 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydro number of carbonatoms in an alkynyl group or moiety is 2 to quinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, about 20, unless otherwise specified, e.g., C.s alkynyl means octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadi an alkynyl moiety containing 2,3,4, 5, 6, 7 or 8 carbonatoms. azinyl, 2H,6H-1.5.2-dithiazinyl, thienyl, thianthrenyl, pyra Aryl means phenyl or naphthyl. 25 nyl, isobenzofuranyl, chromenyl, Xanthenyl, phenoxathiinyl, Aryl-alkyl, aryl-alkenyl and aryl-alkynyl respectively 2H-pyrrolyl, isothiazolyl, isoxazolyl pyrazinyl, pyridazinyl, mean an aryl moiety bonded to an alkyl, alkenyl or alkynyl indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl, group, wherein aryl, alkyl, alkenyl and alkynyl have the 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, meanings defined above. Exemplary aryl-alkyl moieties have quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carba the structure aryl-Co alkyl- or aryl-Coalkenyl-, e.g., 30 Zolyl, B-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, aryl-CH , phenyl-CH , phenyl-CH-CH=CH phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phe CH-. Typically the alkyl groups will comprise 1-8 carbon noxazinyl, isochromanyl, chromanyl, imidazolidinyl, imida atoms that are linear or branched and typical alkenyl and Zolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, alkynyl groups will comprise 1-8 carbonatoms that are linear isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, ben or branched. 35 Zotriazolyl, benzisoxazolyl, OXindolyl, benzoxazolinyl, and “Substituted alkyl”, “substituted alkenyl', “substituted isatinoyl. alkynyl” “substituted aryl-alkyl”, “substituted aryl-alkenyl By way of example and not limitation, carbon bonded and “substituted aryl-alkynyl' mean an alkyl, alkenyl, alky heterocycles are bonded at position 2, 3, 4, 5, or 6 of a nyl, aryl-alkyl, aryl-alkenyl or aryl-alkynyl group respec pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, tively, that comprises 1, 2, 3 or more independently selected 40 or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, substituents bonded to a carbon atom or 1, 2, 3 or more position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, independently selected substituents that replace or interrupt thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of any carbon atom chain or ring. Substituents include ethers an oxazole, imidazole or thiazole, position 3, 4, or 5 of an ( O ), ketones ( C(O) ), —OR* (including —OH), isoxazole, pyrazole, or isothiazole, position 2 or 3 of an —C(O)OR* (including –C(O)OH), C(O)O-, -C(S) 45 aziridine, position 2, 3, or 4 of anaZetidine, position 2, 3, 4, 5, OR*, C(S)O , —OC(O) , —C(O)H, OCH , 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an —OCHCH , —OCHO , –OCHCH-O-, isoquinoline. Still more typically, carbon bonded hetero NR* , N(R), NHR, NHC(O) , cycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, -CH NR* , CH, NHR, -CH NHC(O) , 6-pyridyl, 3-pyridazinyl, 4-pyridaZinyl, 5-pyridazinyl, 6-py C(O)NH , C(O)NHR, OC(O)NR OC(O) 50 ridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-py NHR, NRC(O)NR NRC(O)NHR'. rimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, NRCH, NRCHCH, , S: , SR, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl. S(O) , S(O)(O) , S(O)OR, S(O)H, CN, By way of example and not limitation, nitrogen bonded —NO, - O CH, O C(O) OR (including heterocycles are bonded at position 1 of an aziridine, aZeti O CH-O C(O) OH), O CH-O-C(O) 55 dine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imida SRPR (including —O CH-O C(O)—SH), Zole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, —O CH-C(O) NHR* (including —O CH-C pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, pipera (O) NH), - O CH, C(O) R' (including Zine, indole, indoline, 1H-indazole, position 2 of a isoindole, O CH C(O) OH), O CH, C(O)—SR* (in or isoindoline, position 4 of a morpholine, and position 9 of a cluding —O CH, C(O)—SH), —O CH, OR* (in 60 carbazole, or B-carboline. Typically, nitrogen bonded hetero cluding —O CH, OH), —O CH, CH, OR* (in cycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imida cluding —O CH, CH, OH), —O—CH2—CH2—O Zolyl, 1-pyrazolyl, and 1-piperidinyl. CH, CH, OR* (including —O CH-CH “Heteroaryl' or "heteroaromatic' means an aromatic ring OCH CH-OH), halogen, and combinations of these or two or more fused rings that contain one or more aromatic moieties where R* independently is hydrogen, a protecting 65 rings where the ring or fused rings comprise 1, 2, 3 or more group or both R* together are a protecting group. In some heteroatoms, usually oxygen (-O-), nitrogen ( NR'' ) embodiments, alkenyl, alkynyl, aryl-alkenyland aryl-alkynyl or sulfur ( S ) where R is -H, a protecting group, US 7,863,261 B2 7 8 optionally Substituted Cls alkyl, optionally substituted Cs by, e.g. hydrolysis, elimination or aminolysis. Thus, simple alkenyl or optionally substituted Cls alkynyl, usually —H. functional considerations will suffice to guide the selection of Examples are as described for heterocycle and heteroaryl or a reversible oran irreversible protecting group at a given locus heteroaromatic groups comprise a Subset of heterocycles. on the invention compounds. Suitable protecting groups and Alcohol as used herein means an alcohol that comprises criteria for their selection are described in T. W. Greene and P. a Coalkyl moiety Substituted at one, two or more hydrogen G. M. Wuts, Eds. “Protective Groups in Organic Synthesis' atoms with one, two or more hydroxyl groups. Alcohols 2nd edition, Wiley Press, at pps. 10-142, 143-174, 175-223, include ethanol, n-propanol, i-propanol, n-butanol, i-butanol, 224-276, 277-308, 309-405 and 406-454. S-butanol, t-butanol, n-pentanol, i-pentanol, n-hexanol, Determination of whether a group is a protecting group is cyclohexanol, n-heptanol, n-octanol, n-nonanol, n-decanol, 10 made in the conventional manner, e.g., as illustrated by ethylene glycol and glycerol. The carbon atoms in alcohols Kocienski, Philip J.; “Protecting Groups' (Georg Thieme can be straight, branched or cyclic. Alcohol includes any Verlag Stuttgart, New York, 1994) (hereafter “Kocienski'), Subset of the foregoing, e.g., Calcohols (alcohols having 1. Section 1.1, page 2, and Greene Chapter 1, pages 1-9. In 2, 3, 4, 5 or 6 carbon atoms). particular, a group is a protecting group if when, based on "Halogen' means fluorine, chlorine, bromine or iodine. 15 mole ratio, 90% of that protecting group has been removed by “Protecting group' or “R” means a moiety that prevents a deprotection reaction, no more than 50%, preferably no the atom to which it is linked from participating in unwanted more than 25%, more preferably no more than 10%, of the reactions, or it limits such reactions. For example, for deprotected product molecules have undergone changes to —OR*. R* may be hydrogen or a protecting group for the their covalent bond structure or oxidation/reduction state oxygen atom found in a hydroxyl. For –C(O) OR*. R* other than those occasioned by the removal of the protecting may behydrogen or a carboxyl protecting group, for—SR*, group. When multiple protecting groups of the same type are R* may behydrogenora protecting group for sulfur in thiols present in the molecule, the mole ratios are determined when for instance, and for NHR or - N(R)-, R* may be all of the groups of that type are removed. When multiple hydrogen or a nitrogen atom protecting group for primary or protecting groups of different types are present in the mol secondary amines. One or more hydroxyl, thiol, amine or 25 ecule, each type of protecting group is treated (and the mole other reactive groups may be found in formula 1 or formula 2 ratios are determined) independently or together with others compounds. These groups may require protection against depending on whether the deprotection reaction conditions reactions taking place elsewhere in the molecule. The pro pertinent to one type are also pertinent to the other types tecting groups for oxygen, Sulfur or nitrogen atoms, or for present. In one embodiment of the invention, a group is a reactive groups containing heteroatoms, are used, for 30 protecting group if when, based on mole ratio determined by example, to prevent unwanted reactions with electrophilic conventional techniques, 90% of that protecting group has compounds. Such as acylating used, e.g., in Steroid chemistry. been removed by a conventional deprotection reaction, no “Protecting groups' as used herein comprise noncyclic or more than 50%, preferably 25%, more preferably 10%, of the cyclic protecting groups, which have been extensively deprotected product molecules of the invention have under described, e.g., “Protective Groups in Organic Chemistry’. 35 gone irreversible changes to their covalent bond structure or Theodora W. Greene (John Wiley & Sons, Inc., New York, oxidation/reduction state other than those occasioned by the 1991, ISBN 0-471-62301-6) (hereafter “Greene') and will removal of the protecting group. Irreversible changes require not be detailed here. The corresponding cleavage reactions chemical reactions (beyond those resulting from aqueous have also been described, e.g., Greene. In the context of the hydrolysis, acid/base neutralization or conventional separa present invention, these protecting groups are groups that can 40 tion, isolation or purification) to restore the covalent bond be removed from the molecule of the invention without irre structure or oxidation/reduction state of the deprotected mol versibly changing the covalent bond structure or oxidation/ ecule of the invention. reduction state of the remainder of the molecule. For “Ester” means a moiety that comprises a —C(O)—O— example, when -R is a removable protecting group that is structure. Typically, esters as used here, comprise an organic bonded to a —O— or —NH group, it is removed to form 45 moiety containing about 1-50 carbon atoms, usually about —OH or —NH, respectively, without affecting other cova 2-18 carbon atoms, and 0 to about 10 independently selected lent bonds in the molecule. In some embodiments, the pro heteroatoms (e.g., O.S.N. P. Si, F, Cl, Br, I), usually about 1-6 tecting group will not be removable without affecting other heteroatoms, linked to a formula 1 or formula 2 steroid covalent bonds in the molecule. More than one protecting nucleus at 1,2,3,4 or more of R'-R through the C(O)— group can be removed at a time, or they can be removed 50 O— structure, e.g., organic moiety-C(O)—O-steroid or sequentially. The formula 1 or 2 compounds may contain one organic moiety-O—C(O)-steroid. When more than one ester or more than one protecting group, which may be the same or is present, e.g., 2, 3 or 4 esters, eachester moiety is indepen different. dently selected. The organic moiety usually comprises one or Removable protecting groups are usually removed by more of any of the organic groups described above, e.g., Co known procedures, although it will be understood that the 55 alkyl moieties, Coalkenyl moieties, Coalkynyl moieties, protected intermediates fall within the scope of this invention. aryl moieties, C. heterocycles, an ester moiety or substi The removal of the protecting group may require several steps tuted derivatives of any of these. Typical substitutions for or removal may be straight-forward, depending upon the these organic groups include 1, 2, 3, 4 or more, usually 1 or 2 economics and nature of the conversions involved. In general, independently selected, —O , —S , —NR* , one will use a protecting group with exocyclic amines or with 60 C(O) , N(R), C(O)OR, OC(O)R*, carboxyl groups during synthesis of a formula 1 or 2 com OR, BSR, NO =O, =S, CN, NHC(O) , pound. For most therapeutic applications protected groups will be deprotected, unless the protecting group is one that - C(O)-A8, OC(O)-A8, C(O)O-A8, -N , N=, can be removed under physiological conditions. Protecting —OPO.(R), —OSOH, or halogen moieties or atoms, groups commonly are employed to protect against covalent 65 where R* independently is -H, a protecting group or both modification of a sensitive group in reactions such as alkyla R* together are a protecting group and A8 is Cisalkyl, Cs tion or acylation. Ordinarily, protecting groups are removed alkenyl, Cs alkynyl, Co alkyl-C-9 aryl (e.g., benzyl), aryl US 7,863,261 B2 9 10 (e.g. phenyl) or Co. alkyl-C-7 heterocycle. Substitutions are esters. In some embodiments, the Sulfite ester is unsubsti independently chosen. The organic moieties exclude obvi tuted, i.e., HO S(O)—O-steroid. ously unstable moieties, e.g., -O-O-, except where Such "Sulfonamide' means a moiety that comprises 1, 2, 3, 4 or unstable moieties are transient species that one can use to more –S(O)(O) N(R)(R) or -S(O)(O) N(R)- make a compound with sufficient chemical stability for the structures, usually 1, where R and R independently are one or more of the uses described herein. The substitutions —H, a protecting group, an organic moiety (as described for listed above are typically Substituents that one can use to esters), or both R and R together comprise a protecting replace a one or more carbon atoms, e.g., —O— or group. Typically, Sulfonamides as used here comprise an —C(O)—, or one or more hydrogen atom, e.g., halogen, organic moiety containing about 1-50 carbon atoms and 0 to —NH or —OH. In some embodiments, the ester is unsub 10 about 10 independently selected heteroatoms (e.g., O.S.N. P. stituted, i.e., H C(O)—O-steroid. Si) linked to a formula 1 or 2 steroid nucleus at 1, 2, 3, 4 or “Thioester’ means a moiety that comprises a C(S)— more of R'-R through the O S(O)—O—structure, e.g., O— structure. Typically, thioesters as used here comprise a organic moiety-S(O)(O) NH-steroid or N(R)(R) S(O) hydrogen atom or an organic moiety containing about 1-50 (O)-steroid. The organic moieties are as described above for carbon atoms and 0 to about 10 independently selected het 15 esters, e.g., moieties that comprise 1 to about 22 carbonatoms eroatoms (e.g., O.S.N. P. Si) linked to a formula 1 or 2 steroid and up to about 10 independently selected heteroatoms. In nucleus at 1, 2, 3, 4 or more of R'-R through the C(S)— Some embodiments, the Sulfonamide is unsubstituted, e.g., O— structure, e.g., organic moiety-C(S)—O-steroid or HN S(O)(O)-steroid. organic moiety-O—C(S)-steroid. The organic moiety is as Amide' means an organic moiety as described for ester described above for esters. In some embodiments, the that comprises 1, 2, 3, 4 or more —C(O)NR' moieties, thioester is unsubstituted, i.e., H C(S)—O-steroid. usually 1 or 2, where R is Hora protecting group, R* is “Phosphoester” or “phosphate ester” means a moiety that usually H. In some embodiments, the C(O)NR' group comprises a-O-P(OR)(O) O-structure where R is is linked to the steroid nucleus at 1, 2, 3, 4 or more of R'-R hydrogen (—H), a protecting group or an organic moiety as through the NR*— moiety, e.g., organic moiety-C(O)— described for esters. Typically, phosphoesters as used here 25 NR-steroid or steroid-C(O) NR*-organic moiety. The comprise a hydrogen atom, a protecting group or an organic organic moiety is as described above for esters. In some moiety containing about 1-50 carbon atoms and 0 to about 10 embodiments, the amide is unsubstituted, i.e., H.N. C(O)- independently selected heteroatoms (e.g., O, S. N. P. Si) steroid or HC(O) NH-steroid. linked to a formula 1 or 2 steroid nucleus at 1, 2, 3, 4 or more “Ether means an organic moiety as described forester that of R'-R through the -O-P(OR)(O) O— structure, 30 comprises 1, 2, 3, 4 or more —O— moieties, usually 1 or 2. i.e., organic moiety-O-P(OR)(O)—O— steroid. The In some embodiments, the —O— group is linked to the organic moiety is as described above for esters. In some steroid nucleus at 1, 2, 3, 4 or more of R'-R through the embodiments, the phosphate ester is unsubstituted, e.g., —O— moiety, e.g., organic moiety-O-steroid. The organic HO P(OR)(O) O-steroid. moiety is as described above for esters. “Phosphonoester’ means a moiety that comprises 1, 2, 3, 4 35 “Thioether means an organic moiety as described forester or more, typically only 1, -P(OR)(O)—O structure that comprises 1, 2, 3, 4 or more —S— moieties, usually 1 or where R is -H, a protecting group or an organic moiety as 2. In some embodiments, the —S— group is linked to the described foresters. Typically, phosphonoesters as used here steroid nucleus at 1, 2, 3, 4 or more of R'-R through the comprise a hydrogen atom, a protecting group or an organic —S— moiety, e.g., organic moiety-5-steroid. The organic 40 moiety is as described above for esters. moiety containing about 1-50 carbon atoms and 0 to about 10 Acyl group” means an organic moiety as described for independently selected heteroatoms (e.g., O, S. N. P. Si) ester that comprises 1, 2, 3, 4 or more —C(O)—groups. In linked to a formula 1 or 2 steroid nucleus at 1, 2, 3, 4 or more Some embodiments, the -CO)— group is linked to the of R'-R through the -P(OR)(O) O— structure, i.e., steroid nucleus at 1, 2, 3, 4 or more of R'-R, e.g., organic organic moiety-P(OR)(O) O-steroid or steroid-P(OR) 45 moiety-C(O)-steroid. The organic moiety is as described (O)—O-organic moiety. The organic moiety is as described above for esters. An unsubstituted acyl group comprises a above foresters. In some embodiments, the phosphonoesteris HC(O)— moiety, e.g., linked to the steroid nucleus. unsubstituted, e.g., H-P(OR)(O)—O-steroid. “Carbonate’ means an organic moiety as described for "Sulfate ester” means a moiety that comprises 1, 2, 3, 4 or ester that comprises 1, 2, 3, 4 or more —O C(O)—O— more —O—S(O)(O)—O-structure, usually 1. Typically, sul 50 structures. Typically, carbonate groups as used here comprise fate esters as used here comprise a hydrogen atom, a protect an organic moiety containing about 1-50 carbon atoms and 0 ing group or an organic moiety containing about 1-50 carbon to about 10 independently selected heteroatoms (e.g., O, S, N, atoms and 0 to about 10 independently selected heteroatoms P. Si) linked to a formula 1 or formula 2 steroid nucleus at 1, (e.g., O.S. N. P. Si) linked to a formula 1 or 2 steroid nucleus 2, 3, 4 or more of R'-R through the —O C(O)—O-struc at 1, 2, 3, 4 or more of R'-R through the -O-S(O)(O)— 55 ture, e.g., organic moiety-O-C(O)—O-steroid. The organic O— structure, e.g., organic moiety-O—S(O)(O)—O-steroid. moiety is as described above for esters. An unsubstituted The organic moiety is as described above for esters. In some carbonate group comprises a HO—C(O)—O-moiety, e.g., embodiments, the sulfate ester is unsubstituted, i.e., HO S linked to the steroid nucleus. (O)(O)—O-steroid. “Carbamate” means an organic moiety as described for "Sulfite ester” means a moiety that comprises 1, 2, 3, 4 or 60 ester that comprises 1, 2, 3, 4 or more —O C(O)NR' more —O S(O)—O-structures, usually 1. Typically, sulfite structures where R is -H, a protecting group or an organic esters as used here comprise an organic moiety containing moiety as described forester. Typically, carbamate groups as about 1-50 carbon atoms and 0 to about 10 independently used here comprise an organic moiety containing about 1-50 selected heteroatoms (e.g., O, S, N. P. Si) linked to a formula carbon atoms and 0 to about 10 independently selected het 1 or 2 steroid nucleus at 1,2,3,4 or more of R'-R through 65 eroatoms (e.g., O.S.N. P. Si) linked to a formula 1 or formula the -O-S(O)—O— structure, e.g., organic moiety-O—S 2 steroid nucleus at one or more of R'-R through the (O) O-steroid. The organic moiety is as described above for —O C(O) NR*-structure, e.g., organic moiety-O C US 7,863,261 B2 11 12 (O) NR-steroid or steroid-O-C(O) NR*-organic tected thiol or substituents as described for substituted alkyl moiety. The organic moiety is as described above for esters. groups. The linkage between the monosaccharide the steroid An unsubstituted carbamate group comprises a HO C(O)— is C. or f3. NH or HN C(O)—O— moiety, e.g., linked to the steroid Optionally substituted "oligosaccharide' comprises two, nucleus. 5 three, four or more of any C3-C7 sugars that are covalently As used herein, "monosaccharide' means a polyhydroxy linked to each other. The linked Sugars may have D-, L- or aldehyde or ketone having the empirical formula (CHO), DL-configurations. Suitable Sugars and Substitutions are as where n is 3, 4, 5, 6 or 7. Monosaccharide includes open chain described for monosaccharides. The linkage between the oli and closed chain forms, but will usually be closed chain gosaccharide and the steroid is C. or B, as are the linkages forms. Monosaccharide includes hexofuranose and pento 10 between the monosaccharides that comprise the oligosaccha furanose Sugars such as 2'-deoxyribose, ribose, arabinose, ride. xylose, their 2'-deoxy and 3'-deoxy derivatives and their 2',3'- Nucleoside includes 3TC, AZT, D4T, ddI, ddC, G, A, U, C, dideoxy derivatives. Monosaccharide also includes the 2',3' T, dG, dA, dT and dC. dideoxydidehydro derivative of ribose. Monosaccharides Polymer includes biocompatible organic polymers, e.g., include the D-, L- and DL-isomers of glucose, fructose, man 15 PEGs and polyhydroxyalkyl polymers. PEG means an ethyl nose, idose, galactose, allose, gulose, altrose, talose, fucose, ene glycol polymer that contains about 20 to about 2000000 erythrose, threose, lyxose, erythrulose, ribulose, Xylulose, linked monomers, typically about 50-1000 linked monomers, ribose, arabinose, Xylose, psicose, Sorbose, tagatose, glycer usually about 100-300. Polyethylene glycols include PEGs aldehyde, dihydroxyacetone and their monodeoxy deriva containing various numbers of linked monomers, e.g., PEG tives such as rhamnose. Monosaccharides are optionally pro 20, PEG 30, PEG40, PEG 60, PEG 80, PEG 100, PEG 115, tected or partially protected. The formula 1 and formula 2 PEG 200, PEG 300, PEG400, PEG 500, PEG 600, PEG 1000, compounds may comprise 1, 2, 3 or more independently PEG 1500, PEG 2000, PEG 3350, PEG 4000, PEG 4600, selected monosaccharides at one or more of R'-R. PEG 5000, PEG 6000, PEG 8000, PEG 11000, PEG 12000, PEG 2000000 and any mixtures thereof. Disaccharide and oligosaccharide mean a moiety that com 25 Amino acid. “Amino acid means an amino acid moiety prises respectively two or more linked monosaccharides. that comprises any naturally-occurring or synthetic amino Substituted disaccharide or substituted oligosaccharide acid residue, i.e., any moiety comprising at least one carboxyl means a moiety that comprises two or more linked monosac and at least one amino residue directly linked by one, two charides, at least one of which is a Substituted monosaccha three or more carbon atoms, typically one (C) carbon atom. ride. The formula 1 and formula 2 compounds may comprise 30 The nature and identity of the intervening structure located 1, 2, 3 or more independently selected disaccharides or oli between the carboxyl and amino groups can have a variety of gosaccharides at one or more of R'-R. structures including those described herein. Typically, amino Optionally substituted alkyl group, optionally substituted acids linked to the steroid through the amine group have alkenyl group, optionally Substituted alkynyl group, option Sufficient conformation and length to be capable of autocata ally substituted aryl moiety and optionally substituted hetero 35 lytic hydrolysis of the amino acid-steroid bond and release of cycle mean Substitutions of Co alkyl moieties, Coalk the steroid. This can occur when the free carboxyl is gener enyl moieties, Co alkynyl moieties, aryl moieties, C ated in vivo by deesterification, deamidation or peptidolytic heterocycles or substituted derivatives of any of these. Typical cleavage of the precursor containing a linkage between the Substitutions for these organic groups include 1, 2, 3, 4 or amino acids amine group and the steroid. Hydrolysis of the more, usually 1 or 2 independently chosen, —O— —S , 40 bond between an amino acids carboxyl or amino group and NR* , C(O) , N(R), C(O)CR, OC(O) the steroid can also occur by chemical or enzymatic activity, R*,--OR* (including-OH), SR (including—SH), e.g., esterase cleavage or non-enzymatic hydrolysis. In general, the amino acids corresponding to the residues employed in the invention compounds are naturally occurring 45 and have no significant pharmacological activity perse. How halogen moieties or atoms, where R* independently is H. ever, optimal pharmacokinetic activity, (Substantially com a protecting group or both R* together are a protecting group plete hydrolysis upon hydrolysis of the distal amide or ester and A8 is Cls alkyl, Csalkenyl, Cs alkynyl, Calkyl-aryl bond) may be achieved by using non-naturally occurring (e.g., benzyl), aryl (e.g. phenyl) or C. alkyl-Cls hetero amino acid residues. The intervening structure may be as cycle. Substitutions are independently chosen. The organic 50 simple as methylene when the amino acid residue is glycyl, or moieties as described here, and for other any other moieties substituted methylene for other C. amino acids. The structure described herein, exclude obviously unstable moieties, e.g., ordinarily contains up to about 5 carbon or heteroatoms in the —O-O-, except where such unstable moieties are transient direct linkage between the amino acids carboxyl carbon and species that one can use, for example, to make a compound the amine nitrogen. Thus, amino acids can comprise interven with sufficient chemical stability for the one or more of the 55 ing ethylene, propylene, butylene, or pentylene groups or uses described herein. their substituted analogs, such as for example, oxyesters or Optionally substituted “monosaccharide' comprise any ethers in which oxygen replaces carbon and, as appropriate, C3-C7 Sugar, in the D-, L- or DL-configurations, e.g., eryth hydrogen. An example of such an intervening structure would rose, glycerol, ribose, deoxyribose, arabinose, glucose, man be CH-O-C(R)(R) , where R’ and R’ are inde nose, galactose, fucose, mannose, glucosamine, N-acetyl 60 pendently selected hydrogen or organic moieties as described neuraminic acid, N-acetylglucosamine, above for esters. In some embodiments one of R and R is N-acetylgalactosamine or glucuronic acid, that is optionally hydrogen and the other is a Co organic moiety. Typically substituted at one or more hydroxyl groups. Suitable substi the organic moieties contain about 1-20 carbonatoms and 0. tutions include hydrogen, protected hydroxyl, carboxyl, 1, 2, 3, 4 or 5 independently selected heteroatoms, which are azido, cyano, acetyl. —O—C alkyl, —S-C alkyl, 65 typically selected from oxygen, nitrogen, Sulfur and phospho —O—Coalkenyl, -S Coalkenyl, optionally protected rus. In general, fewer intervening atoms are used when more amine, optionally protected carboxyl, halogen, thiol, pro rapid hydrolysis is desired, although larger structures are US 7,863,261 B2 13 14 suitable if, e.g., they possess sufficient flexibility or have proline, pipecolic acid, 5-hydroxypipecolic acid, conformations to allow positioning of the carboxyl group in - N(CHCOOR), whereinn is 1,2,3,4, 5 or 6 and R* proximity to the amino acid-steroid bond. is —Hora protecting group, and azetidine-2-carboxylic acid Ordinarily, R’ is H. methyl or hydroxymethyl, usually residues; a mono- or di-alkyl (typically C-C branched or —H, and R is a side chain or group of a naturally occurring normal) amino acid Such as alanine, Valine, leucine, allylgly amino acid. Amino acid side chains include analogs where the cine, butyrine, norvaline, norleucine, heptyline, C.-meth side chain is a Cls homolog of the corresponding natural ylserine, C.-amino-C.-methyl-y-hydroxyvaleric acid, compound, e.g., methylene, ethylene, propylene, butylene or C.-amino-C.-methyl-6-hydroxyvaleric acid, C.-amino-C.-me a Substituted derivative thereof, e.g., an alkyl, ether oralkoxy thyl-e-hydroxycaproic acid, isovaline, C.-methylglutamic (e.g., methoxy, ethoxy, propoxy) Substituted derivative. In 10 acid, C-aminoisobutyric acid, C-aminodiethylacetic acid, general, for carboxyl-containing side chains, if the C atom of C.-aminodiisopropylacetic acid, C.-aminodi-n-propylacetic the side chain carboxyl is linked by 5 or less atoms to the N acid, C.-aminodiisobutylacetic acid, C.-aminodi-n-butylacetic then the carboxyl optionally will be blocked, e.g. by esterifi acid, C.-aminoethylisopropylacetic acid, C.-amino-n-propy cation or amidation wherein the ester or amide bonds are lacetic acid, C.-aminodiisoamyacetic acid, C.-methylaspartic hydrolyzable in vivo. R’ also is taken together with R" to 15 acid, C.-methylglutamic acid, 1-aminocyclopropane-1-car form a proline residue (-CH ). Thus, R is generally a boxylic acid; isoleucine, alloisoleucine, tert-leucine, B-meth side group Such as —H, —CH, —CH(CH), —CH2—CH yltryptophan and C.-amino-B-ethyl-3-phenylpropionic acid (CH), —CHCH-CH CH, —CH2—CHs. residues; 3-phenylserinyl; aliphatic C-amino-3-hydroxy —CHCH, S CH, -CHOH, -CH(OH)–CH, acids such as serine, B-hydroxyleucine, 3-hydroxynorleu —CH2—SH, —CH CH-OH, —CH CO. NH2, cine, 3-hydroxynorvaline, and C.-amino-B-hydroxy Stearic CH-CH CO. NH, CH-COOH, -CH acid residues; C.-Amino, C.-, y-, 6- or e-hydroxy acids such as CH-COOH, -(CH2). NH and —(CH). NH C homoserine, Y-hydroxynorvaline, 8-hydroxynorvaline and (NH) NH. R also includes 1-guanidinoprop-3-yl, ben epsilon-hydroxynorleucine residues; canavinyl and canali Zyl. 4-hydroxybenzyl, imidazol-4-yl, indol-3-yl, nyl: Y-hydroxyornithinyl, 2-Hexosaminic acids such as methoxyphenyl and ethoxyphenyl. The optimal R'group is 25 D-glucosaminic acid or D-galactosaminic acid residues; readily selected using routine assays. C.-amino-B-thiols such as penicillamine, B-thiolnorvaline or In general, the amino acid residue has the structure shown B-thiolbutyrine residues; other Sulfur containing amino acid in the formulas below. Ordinarily, n is 1 or 2, R’ is —Hand residues including cysteine; homocystine; 3-phenylmethion R’ is a moiety containing one or more of the following ine; methionine: S-allyl-L-cysteine sulfoxide: 2-thiolhisti groups: amino, carboxyl, amide, carboxyl ester, hydroxyl, 30 dine; cystathionine; and thiol ethers of cysteine or homocys C-C, aryl, ether (—O—), thioether ( -S ), n-, s- or t-alkyl teine; phenylalanine, tryptophan and ring-Substituted C. (C-C), guanidinyl, imidazolyl, indolyl, sulfhydryl, sulfox amino acids such as the phenyl- or cyclohexylamino acids ide, and phosphoryl. The RandR substituents can have a C.-aminophenylacetic acid, C.-aminocyclohexylacetic acid wide variety of structures including those disclosed herein, and C-amino-B-cyclohexylpropionic acid; phenylalanine e.g., esters, ethers or carbonates. 35 analogues and derivatives comprising aryl, lower alkyl, When the amino acid residues contain one or more chiral hydroxy, guanidino, oxyalkylether, nitro, Sulfur or halo-Sub centers, any of the D. L. meso, threo or erythro (as appropri stituted phenyl (e.g., tyrosine, methyltyrosine and o-chloro-, ate) racemates or mixtures thereof, fall within the scope of p-chloro-3,4-dichloro, o-, m- or p-methyl-, 2,4,6-trimethyl-, this invention. In general, if it is desired to rely on non 2-ethoxy-5-nitro, 2-hydroxy-5-nitro and p-nitro-phenylala enzymatic means of hydrolysis, D isomers should be used. 40 nine); furyl-, thienyl-, pyridyl-, pyrimidinyl-, purine or naph On the other hand, L isomers may be more versatile since they thylalanines; and tryptophan analogues and derivatives can be susceptible to both non-enzymatic as well as potential including kynurenine, 3-hydroxykynurenine, 2-hydroxytryp targeted enzymatic hydrolysis, and are more efficiently trans tophan and 4-carboxytryptophan residues; C.-amino Substi ported by amino acid or dipeptidyl transport systems in the tuted amino acid residues including sarcosine (N-methylgly gastrointestinal tract. 45 cine), N-benzylglycine, N-methylalanine, N-benzylalanine, Examples of suitable amino acid residues include the fol N-methylphenylalanine, N-benzylphenylalanine, N-meth lowing: Glycyl; aminopolycarboxylic acids, e.g., aspartic ylvaline and N-benzylvaline; and C.-Hydroxy and substituted acid, B-hydroxyaspartic acid, glutamic acid, B-hydroxy C-hydroxy amino acid residues including serine, threonine, glutamic acid, B-methylaspartic acid, 3-methylglutamic acid, allothreonine, phosphoserine and phosphothreonine resi B.f3-dimethylaspartic acid, Y-hydroxyglutamic acid, B.Y-dihy 50 dues. droxyglutamic acid, B-phenylglutamic acid, Y-methylene Any one of the foregoing or other known amino acids are glutamic acid, 3-aminoadipic acid, 2-aminopimelic acid, Suitably employed in this invention. Typically amino acids 2-aminoSuberic acid and 2-aminosebacic acid residues; are capable of autocatalytically hydrolyzing the amino acid amino acid amides such as glutaminyl and asparaginyl: steroid bond. Thus, they typically contain, or upon being polyamino- or polybasic-monocarboxylic acids such as argi 55 hydrolyzed in Vivo, contain a free carboxyl group or amine nine, lysine, 3-aminoalanine, Y-aminobutyrine, ornithine, cit group. ruline, homoarginine, homocitrulline, 5-hydroxy-2,6-diami Also of interest are hydrophobic amino acids such as nohexanoic acid (commonly, hydroxylysine, including mono- or di-alkyl orarylamino acids, cycloalkylamino acids allohydroxylysine) and diaminobutyric acid residues; other and the like. These residues, together with R’-R (R-R basic amino acid residues such as histidinyl; diaminodicar 60 are defined below) can contribute to cell permeability by boxylic acids Such as C.C.'-diaminosuccinic acid, C.C.'-diami modulating the lipophilicity of a formula 1 or formula 2 noglutaric acid, C.C.'-diaminoadipic acid, C.C.'-diami compound. Typically, the residue does not contain a sulfhy nopimelic acid, C.C.'-diamino-3-hydroxypimelic acid, C.C.'- dryl or guanidino Substituent. diaminoSuberic acid, C.C.'-diaminoaZelaic acid, and C.C.'- Peptide. One, 2, 3 or more of R'-R can comprise a "pep diaminosebacic acid residues; imino acids such as proline, 4 65 tide', i.e., two or more amino acids as defined above. Typi or 3-hydroxy-2-pyrrolidinecarboxylic acid (commonly, cally the amino acids are linked through normal peptide hydroxyproline, including allohydroxyproline), Y-methyl bonds, i.e., —CO—NH-, between adjacentamino acid resi US 7,863,261 B2 15 16 dues. Peptides comprise dipeptides (dimers), tripeptides (tri mers), short peptides of 4, 5, 6, 8, 10 or 15 residues, and longer -continued peptides or proteins having about 100 or more residues. Invention compounds that comprise a peptide can be used as Dipeptides immunogens, prodrugs or as synthetic precursors for other MA, MR, MN, MD, MC, ME, MQ, MG, MH, MI, ML, MK, MM, MF, steroid derivatives. In one embodiment, the peptide will con MP, MS, MT, MW, MY, MV, FA, FR, FN, FD, FC, FE, FQ, FG, FH, FI, tain a peptidolytic enzyme cleavage site at the peptide bond FL, FK, FM, FF, FP, FS, FT, FW, FY, FV, PA, PR, PN, PD, PC, PE, PQ, PG, PH, PI, PL, PK, PM, PF, PP, PS, PT, PW, PY, PV, SA, SR, SN, SD, linking the first residue and the next residue distal to the SC, SE, SQ, SG, SH, SI, SL, SK, SM, SF, SP, SS, ST, SW, SY, SV, TA, steroid residue. Such cleavage sites are optionally flanked by TR, TN, TD, TC, TE, TO, TG, TH, TI, TL, TK, TM, TF, TP. TS, TT, TW, enzymatic recognition structures, e.g. particular residues rec 10 TY, TV, WA, WR, WN, WD, WC, WE, WQ, WG, WH, WI, WLWK, ognized by a hydrolytic enzyme, e.g., a peptidase located in WM, WF, WP, WS, WT, WW, WY, WV, YAYR,YN,YD,YC,YE, the serum or in cells. YQ, YG, YH,YI,YL,YK, YM,YF,YPYS, YT,YW, YY.YV, VA, VR, VN, VD, VC, VE, VQ, VG, VH, VI, VL, VK, VM, VF, VP, VS, Peptidolytic enzymes are well known, and in particular VT, VW, VY. VV include carboxypeptidases. Carboxypeptidases digest polypeptides by removing C-terminal residues, and are spe 15 cific in many instances for particular C-terminal sequences. Such dipeptides include species where both amino acids Such enzymes and their Substrate requirements in general are are in the L configuration, the D configuration or mixtures of well known. For example, a dipeptide having a given pair of configurations. residues and a free carboxyl terminus is covalently bonded Tripeptides, i.e., 3 linked amino acid residues, are also through its C.-amino group to the steroid nucleus. It is useful embodiments. Tripeptides include those where A, C, expected that the peptide will be cleaved by the appropriate D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, WorY is linked dipeptidase, protease or by chemical hydrolysis, leaving the by a standard peptide bond to the amino or the carboxyl carboxyl of the proximal amino acid residue to autocatalyti terminus of any of the dipeptides listed above. The sequence cally cleave the amidate bond. —X1-pro-X2-(where X1 is any amino acid and X2 is hydro Examples of Suitable dipeptidyl groups (designated by 25 gen, any amino acid residue or a carboxyl ester of proline) will be cleaved by luminal carboxypeptidase to yield X1 with their single letter symbols) are shown in the table below. a free carboxyl, which in turn autocatalytically cleaves the amidate bond. X2usually will be a benzyl ester of the carboxy group of X2. Other embodiments include tetrapeptides such SYMBOL 30 as ones where any two of the dipeptides listed above, which may be the same or different dipeptides (e.g., AA and AA 1-Letter 3-Letter AMINO ACID linked together or, e.g., AA and GI linked together), are linked Y Tyr tyrosine to each other by a peptide bond through the amino terminus or G Gly glycine carboxyl terminus. One, 2 or more tetrapeptides may be Phe phenylalanine 35 bonded to the formula 1 or formula 2 compound through the M Met methionine A. Ala alanine tetrapeptide's amino or carboxyl terminus. S Ser serine In some embodiments, the formula 1 or formula 2 com Ile isoleucine pound comprises one or more amino acids or peptides having Leu eucine Thr hreonine the structure (A), (B) or (C); (A) R' NH-C(R) V Wall valine 40 (R), C(O) N(R)}, C(R)(R), C(O) O-ste C Pro proline roid, (B), R O (C(O)-C(R)(R), N(R)} C K Lys ysine H His histidine (O)-C(R)(R)). N(R)-O-steroid, or (C) R O-C Q Gln glutamine (O)-C(R)(R)) N(R), C(O)-C(R)(R). N E Glu glutamic acid (R')—C(O)—O-steroid, wherein (A), (B) or (C) are W Trp tryptophan 45 independently selected and they are bonded to 1, 2, 3 or more R Arg arginine of R' through R', where each R’-R is independently D Asp aspartic acid N ASn asparagine selected; Rindependently are —Hora Coorganic moiety C Cys cysteine (e.g., C. alkyl, e.g. —CH or -CH3); R' independently are the side chain of an amino acid, including the side chain of 50 naturally occurring amino acids as described above, e.g., —H, —CH, -CH2CHs; R is —H or a protecting group; RandR independently comprise-H, a protecting group, Dipeptides an ester or an amide where each atom or group is indepen dently chosen: a, b, c and d independently are 1, 2, 3, 4 or 5. AA, AR, AN, AD, AC, AE, AQ, AG, AH, AI, AL, AK, AM, AF, AP, AS, 55 usually 1, e. f and g independently are an integer from 0 to AT, AW, AY, AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH, RI, RL, RK, about 1000, typically they independently are 0, 1,2,3,4, 5, 6, RM, RF, RP, RS, RT, RW, RY, RV, NA, NR, NN, ND, NC, NE, NQ, NG, NH, NI, NL, NK, NM, NF, NP, NS, NT, NW, NY, NV, DA, DR, DN, DD, 7 or 8; a, b, c and d independently are 1 or 2; e. f and g DC, DE, DQ, DG, DH, DI, DL, DK, DM, DF, DP, DS, DT, DW, DY, DV, independently are 0, 1, 2, 3, 4 or 5. CA, CR, CN, CD, CC, CE, CQ, CG, CH, CI, CL, CK, CM, CF, CP, CS, If the amino acid(s) or residue(s) has 2 or more amine CT, CW, CY, CV, EA, ER, EN, ED, EC, EE, EQ, EG, EH, EI, EL, EK, EM, EF, EP, ES, ET, EW, EY, EV, QA, QR, QN, QD, QC, QE, QQ, QG, 60 groups, e.g., a lysinyl or arginyl, or ornithinyl residue, then QH, QI, QL, QK, QM, QF, QP, QS, QT, QW, QY, QV, GA, GR, GN, R’ is usually —H and R' may comprise —C(R), IN GD, GC, GE, GQ, GG, GH, GI, GL, GK, GM, GF, GP, GS, GT, GW, (R) - where n2 is 0, 1, 2, 3, 4, 5 or 6, R* is - H or a GY, GV, HA, HR, HN, HD, HC, HE, HQ, HG, HH, HI, HL, HK, HM, protecting group and each R' independently is -H, C, -Co HF, HP, HS, HT, HW, HY, HV, IA, IR, IN, ID, IC, IE, IQ, IG, IH, II, IL, IK, IM, IF, IP, IS, IT, IW, IY, IV, LA, LR, LN, LD, LC, LE, LO, LG, LH, optionally Substituted alkyl, Co-Co optionally Substituted LI, L.L., LK LM, LF, LP, LS, LT, LW, LY, LV, KA, KR, KN, KD, KC, 65 aryl, C7-Co optionally Substituted alkylaryl, C7-Co option KE, KQ, KG, KH, KI, KL, KK, KM, KF, KP, KS, KT, KW, KY, KV, ally Substituted arylalkyl, C-Co optionally Substituted alkoxy, Co-Co optionally substituted aryloxy or hydroxyl. US 7,863,261 B2 17 18 Such compounds will contain a plurality of steroid moieties. Zoic, hydroxybenzoic, phenylacetic, cinnamic, Salicylic, For example when both the epsilon (e) or delta (8) and alpha nicotinic and 2-phenoxybenzoic. (C) amino groups of lysine or ornithine are substituted with Invention salts include those made from inorganic acids, steroid moieties the amidate is believed to be capable of e.g., HF, HCl, HBr, H., HSO, HPO, NaCO, KCO, releasing two molecules of active drug, each expected to CaCO, MgCO and NaClO. Suitable anions, which are emerge under different pharmacokinetics and therefore fur optionally present with a cation such a Ca", Mg", Li, Na' ther Sustaining the drug release. or K", include formate, Sorbate, glycodeoxycholate, cholate, Salt. Invention embodiments include Salts and complexes deoxycholate, desoxycholate, taurocholate, taurodeoxycho of formula 1 compounds, including pharmaceutically accept late, taurolithocholate, tetraborate, nitrate, nitrite, sulfite, able or salts that are relatively non-toxic. Some of the com 10 sulfamate, hyposulfite, bisulfite, metabisulfite, thiosulfate, pounds have one or more moieties that carry at least a partial silicate, metasilicate, gluconate, gulcuronate, hippurate, positive or negative charge in aqueous Solutions, typically at hydrosulfite, borate, metaborate and urate. a pH of about 4-10, that can participate in forming a salt, a Salts also include the invention compound salts with one or complex, a composition with partial salt and partial complex more amino acids. Many amino acids are Suitable, especially properties or other noncovalent interactions, all of which we 15 the naturally-occurring amino acids found as protein compo refer to as a “salt(s)'. Salts are usually biologically compat nents, although the amino acid typically is one bearing a side ible orpharmaceutically acceptable or non-toxic, particularly chain with a basic or acidic group, e.g., lysine, arginine, for mammalian cells. Salts that are biologically toxic are histidine or glutamic acid, or a neutral group Such as glycine, optionally used with synthetic intermediates of invention serine, threonine, alanine, isoleucine, or leucine. compounds. When a water-soluble composition is desired, The invention compositions include compounds in their monovalent salts are usually preferred. un-ionized, as well as Zwitterionic form, and combinations Metal salts typically are prepared by reacting the metal with Stoiochiometric amounts of water as in hydrates. hydroxide with a compound of this invention. Examples of Stereoisomers. The formula 1 compounds include metal salts which are optionally prepared in this way are salts enriched or resolved optical isomers at any or all asymmetric containing Li, Na', and K". A less soluble metal salt can be 25 atoms as are apparent from the depictions. Both racemic and precipitated from the solution of a more soluble salt by adding diasteromeric mixtures, as well as the individual optical iso a suitable metal compound. Invention salts may be formed mers can be isolated or synthesized so as to be substantially from acid addition of certain organic acids, such as organic free of their enantiomeric or diastereomeric partners, and carboxylic acids, and inorganic acids, such as alkylsulfonic these are all within the scope of the invention. Chiral centers acids or hydrogen halide acids, to acidic or basic centers on 30 may be foundin invention compounds at, for example, R. R. invention compounds, such as basic centers on the invention R, R, R or R. pyrimidine base analogs. Metal salts include ones containing One or more of the following methods are used to prepare Na", Li, K, Ca" or Mg". Other metal salts may contain the enantiomerically enriched or pure isomers herein. The aluminum, barium, strontium, cadmium, bismuth, arsenic or methods are listed in approximately their order of preference, Zinc ion. 35 i.e., one ordinarily should employ stereospecific synthesis Salt(s) of compounds may comprise a combination of from chiral precursors before chromatographic resolution or appropriate cations such as alkali and alkaline earth metal before spontaneous crystallization. ions or ammonium and quaternary ammonium ions with the Stereospecific synthesis is conveniently used when the acid anion moiety of the phosphoric acid or phosphonic acid appropriate chiral starting material is available and reaction group, which may be present in invention polymers or mono 40 steps are chosen that do not result in undesired racemization CS. at chiral sites. One advantage of Stereospecific synthesis is Salts are produced by Standard methods, including dissolv that it does not produce undesired enantiomers that must be ing free base in an aqueous, aqueous-alcohol or aqueous removed from the final product, thereby lowering overall organic Solution containing the selected acid, optionally fol synthetic yield. In general, those skilled in the art would lowed by evaporating the solution. The free base is reacted in 45 understand what starting materials and reaction conditions an organic solution containing the acid, in which case the salt should be used to obtain the desired enantiomerically usually separates directly or one can concentrate the solution. enriched or pure isomers by Stereospecific synthesis. Suitable amine salts include amines having Sufficient Another synthesis method of general utility is chromato basicity to form a stable salt, preferably amines of low toxic graphic resolution of enantiomers on chiral chromatography ity including trialkyl amines (tripropylamine, triethylamine, 50 resins. These resins are packed in columns, commonly called trimethylamine), procaine, dibenzylamine, N-benzyl-be Pirkle columns, and are commercially available. The columns taphenethylamine, ephenamine, N,N'-dibenzylethylenedi contain a chiral stationary phase. The racemate is placed in amine, N-ethylpiperidine, benzylamine and dicyclohexy Solution and loaded onto the column, and thereafter separated lamine. by HPLC. See for example, Proceedings Chromatographic Salts include organic Sulfonic acid or organic carboxylic 55 Society—International Symposium on Chiral Separations, acid salts, made for example by addition of the acids to basic Sep. 3-4, 1987. Examples of chiral columns that could be centers, typically amines. Exemplary Sulfonic acids include used to Screen for the optimal separation technique would Caryl Sulfonic acids, C. heteroaryl Sulfonic acids and include Diacel Chriacel OD, Regis Pirkle Covalent D-phe C. alkyl Sulfonic acids such as phenyl Sulfonic acid, nylglycine, Regis Pirkle Type 1A, Astec Cyclobond II, Astec a-naphthalene Sulfonic acid, B-naphthalene Sulfonic acid, 60 Cyclobond III, Serva Chiral D-DL=Daltosil 100, Bakerbond (S)-camphorsulfonic acid, methyl (CHSOH), ethyl DNBLeu, Sumipax OA-1000, Merck Cellulose Triacetate (CHSSOH), n-propyl, i-propyl. n-butyl, S-butyl, i-butyl, column, Astec Cyclobond I-Beta, or Regis Pirkle Covalent t-butyl, penty1 and hexyl Sulfonic acids. Exemplary organic D-Naphthylalanine. Not all of these columns are likely to be carboxylic acids include C. alkyl, C-aryl carboxylic effective with every racemic mixture. However, those skilled acids and C. heteroaryl carboxylic acids such as acetic, 65 in the art understand that a certain amount of routine Screen glycolic, lactic, pyruvic, malonic, glutaric, tartaric, citric, ing may be required to identify the most effective stationary fumaric, succinic, malic, maleic, oxalic, hydroxymaleic, ben phase. When using Such columns it is desirable to employ US 7,863,261 B2 19 20 embodiments of the compounds of this invention in which the monosaccharide or disaccharide derivative or prodrug of any charges are not neutralized, e.g., where acidic functionalities of these compounds or 3 B-methylcarbonate-androst-5-ene-7, Such as carboxyl are not esterified or amidated. 17 dione, are useful to treat conditions that areassociated with Another method entails converting the enantiomers in the or that respond to modulation of AR activity, including pros mixture to diasteriomers with chiral auxiliaries and then sepa 5 tate cancer, acne, male pattern baldness, hirsutism, hypogo rating the conjugates by ordinary column chromatography. nadism and breast cancer. These compounds may be option This is a very suitable method, particularly when the embodi ally be used in combination therapies to treat any of these ment contains free carboxyl, amino or hydroxyl that will form diseases or conditions. The combinations include a formula 1 a salt or covalent bond to a chiral auxiliary. Chirally pure or 2 compound(s) combined with Surgery, radiation therapy, amino acids, organic acids or organosulfonic acids are all 10 cytotoxic agents, cytostatic agents or hormone therapies, worthwhile exploring as chiral auxiliaries, all of which are including any of the therapies or treatments disclosed herein well known in the art. Salts with such auxiliaries can be or in any of the references cited herein. formed, or they can be covalently (but reversibly) bonded to The formula 1 or 2 compounds are also useful to determine the functional group. For example, pure D or Lamino acids if the AR or another steroid receptor, e.g., an orphan receptor, can be used to amidate the carboxyl group of invention 15 are present in a cell population or cell extract. In these appli embodiments that comprise a carboxyl group and then sepa cations, the compounds will typically be labeled, e.g., radio rated by chromatography. labels (''C, H, °P S or a radioactive iodine isotope) or Enzymatic resolution is another method of potential value. labeled with a crosslinking moiety. In related applications, In such methods one prepares covalent derivatives of the the compounds are useful as reference standards to compare enantiomers in the racemic mixture, generally lower alkyl their capacity to modulate AR activity with the capacity of esters (for example of carboxyl), and then exposes the deriva known AR modulators, such as AED. In these applications, a tive to enzymatic cleavage, generally hydrolysis. For this formula 1 or 2 compound is used in a Suitable assay system, method to be successful an enzyme must be chosen that is e.g., one that comprises cells (in vitro or in vivo) that contain capable of stereospecific cleavage. So it is frequently neces functional AR, an AR-responsive gene, e.g., ornithine car sary to routinely screen several enzymes. If esters are to be 25 boxylase, that can be conveniently assayed, a formula 1 or 2 cleaved, then one selects a group of esterases, phosphatases, compound and a test compound. In such methods, the effect and lipases and determines their activity on the derivative. of the formula 1 or 2 compound on the capacity of the test Typical esterases are from liver, pancreas or other animal compound to modulate the AR is examined, usually using a organs, and include porcine liver esterase. Suitably controlled system, e.g., with varying concentrations If the enantiomeric mixture separates from Solution or a 30 of the formula 1 or 2 compound, or varying concentrations of melt as a conglomerate, i.e., a mixture of enantiomerically the test compound. Assay systems, or components thereof pure crystals, then the crystals can be mechanically separated, that comprise the Ar have been described, see, e.g., U.S. Pat. thereby producing the enantiomerically enriched preparation. Nos. 4,981,784 and 5,071,773, Evans, et al., Science 240: This method, however, is not practical for large scale prepa 889-895 1988, T. Berger et al., J. Steriod Biochem. Molec. rations and is of limited value for true racemic compounds. 35 Biol. 41:773-778 1992, J. Simenthal, et al., J. Biol. Chem. Asymmetric synthesis is another technique for achieving 266:510-514 1991, G. Scalabrino et al., Mol. Cell. Endo enantiomeric enrichment. For example, a chiral protecting crinol. 77:1-35 1991, O. Janne, et al., Ann. N.Y. Acad. Sci. group is reacted with the group to be protected and the reac 438:72-84 1984, and R. Djurhuus, Anal. Biochem. 113:352 tion mixture allowed to equilibrate. If the reaction is enantio 355 1981. merically specific then the product will be enriched in that 40 An effective dose of a formula 1 or formula 2 compound, or enantiomer. the “active ingredient’, for use in therapeutic applications, Further guidance in the separation of enantiomeric mix e.g., prostate cancer treatment, will depend to a certain extent tures can be found, by way of example and not limitation, in at least on factors such as the status of the condition being "Enantiomers, Racemates, and resolutions”, Jean Jacques, treated, whether the compound(s) is being used prophylacti Andre Collet, and Samuel H. Wilen (Krieger Publishing 45 cally (lower doses) or the severity of the malignancy, the Company, Malabar, Fla., 1991, ISBN 0-89464-618-4): Part 2, method of delivery, and the pharmaceutical formulation. Resolution of Enantiomer Mixture, pages 217-435: more par These factors will be determined by the clinician using con ticularly, section 4, Resolution by Direct Crystallization, ventional dose escalation studies. Typically the dose admin pages 217-251, section 5. Formation and Separation of Dias istered to the subject will be from about 0.03 to about 30 tereomers, pages 251-369, section 6, Crystallization-induced 50 mg/kg body weight per day, generally about 0.1 to about 10 Asymmetric Transformations, pages 369-378, and section 7. mg/kg body weight per day. For example, for topical delivery Experimental Aspects and Art of Resolutions, pages 378-435: the daily candidate dose for an adult human of approximately still more particularly, section 5.1.4, Resolution of Alcohols, 70 kg body weight will range from about 1 mg to about 750 Transformation of Alcohols into Salt-Forming Derivatives, mg, generally between about 5 mg and about 300 mg, usually pages 263-266, section 5.2.3, Covalent Derivatives of Alco 55 between about 30 mg and about 250 mg. A daily dose may hols. Thiols, and Phenols, pages 332-335, section 5.1.1, take the form of single or multiple doses or administration Resolution of Acids, pages 257-259, section 5.1.2, Resolu sites. For a formula 1 or 2 compound that is delivered tion of Bases, pages 259-260, section 5.1.3, Resolution of parenterally, e.g., i.v., s.c. or i.m., the dose will generally be Amino Acids, page 261-263, section 5.2.1. Covalent Deriva lower (e.g., about 0.02 to about 6 mg/kg) than a dose admin tives of Acids, page 329, section5.2.2, Covalent derivatives of 60 istered orally. Amines, pages 330-331, section 5.2.4, Covalent Derivatives Pharmaceutical formulations that comprise a formula 1 or of Aldehydes, Ketones, and Sulfoxides, pages 335-339, and 2 compound will typically comprise one or more carriers or section 5.2.7. Chromatographic Behavior of Covalent Dias excipients and optionally other therapeutic ingredients. The tereomers, pages 348-354. carrier(s) will generally be “acceptable' in the sense of being The formula 1 and 2 compounds, e.g., EED, 17O-ethynyl 65 compatible with the other ingredients of the formulation and androst-5-ene-3B,17-diol, 33,17b-dihydroxy-androst-5-ene physiologically innocuous to the recipient thereof. Such car 16-one or an amino acid, peptide, carbonate, ester, thioester, riers or excipients are known, e.g., fillers, lubricants, binders US 7,863,261 B2 21 22 and various liquid excipients for liquid formulations. Suitable regard to the type of formulation in question, for example carriers include those disclosed in the references cited herein. those Suitable for oral administration may include flavoring or Suitable formulations include aqueous or oily Solutions of coloring agents. the active ingredient. Formulations suitable for parenteral The invention further provides veterinary compositions delivery of the active ingredient include aqueous and non comprising at least one active ingredient together with a vet erinary carrier therefor. aqueous compositions where the active ingredient is dis Veterinary carriers are materials useful for the purpose of solved or suspended in solution. Such formulations will typi administering the composition and may be solid, liquid or cally comprise about 25-300 mg/mL of the active ingredient, gaseous materials which are otherwise inert or acceptable in usually about 40-200 mg/mL. Formulations suitable for 10 the veterinary art and are compatible with the active ingredi parenteral administration include aqueous and non-aqueous ent. These veterinary compositions may be administered sterile injection Solutions which may contain anti-oxidants, orally, parenterally or by any other desired route. buffers, bacteriostats or solutes that render the formulation The active ingredients may be used to provide controlled isotonic with the blood of the intended recipient. Other parenteral formulations may comprise aqueous and non release pharmaceutical formulations containing an active 15 ingredient ("controlled release formulations”) in which the aqueous sterile Suspensions which may include Suspending release of the active ingredient is controlled and regulated to agents and thickening agents. allow less frequency dosing or to improve the pharmacoki Formulations suitable for topical administration include netic or toxicity profile of a given active ingredient. creams or ointments wherein the formula 1 or 2 compound is The formulations include those suitable for any of the dissolved or Suspended in a suitable carrier, especially a non foregoing administration routes. The formulations may con aqueous solvent or carrier for the active ingredient. The active Veniently be presented in unit dosage form and may be pre ingredient is typically present in Such formulations in a con pared by any of the methods well known in the art of phar centration of 0.5 to 20% w/w, often 0.5 to 10% w/w. Such macy. Techniques and formulations generally are found in formulations are suitable for use in applications such as treat Remington’s Pharmaceutical Sciences (Mack Publishing ing male pattern baldness or acne. 25 Co., Easton, Pa.). Such methods include the step of bringing Formulations suitable for buccal or sublingual administra into association the active ingredient with the carrier which tion include lozenges comprising the active ingredient, which constitutes one or more accessory ingredients or excipients. is optionally present in a flavored basis Such as Sucrose and In general, the formulations are prepared by uniformly and acacia or tragacanth. Pastilles may comprise the active ingre intimately bringing into association the active ingredient with dient in an inert basis such as gelatin and glycerin, or Sucrose 30 liquid carriers or finely divided solid carriers or both, and and acacia, and mouthwashes may comprise the active ingre then, if necessary, shaping the product. dient in a suitable liquid carrier. Formulations of the invention suitable for oral administra Formulations for rectal administration may be presented as tion are prepared as discrete units such as capsules, cachets or a Suppository with a Suitable base comprising for example tablets each containing a predetermined amount of the active cocoa butter or a salicylate. 35 ingredient; as a powder or granules; as solution or a Suspen Formulations suitable for intrapulmonary or nasal admin sion in an aqueous liquid or a non-aqueous liquid; or as an istration will have a particle size for example in the range of oil-in-water liquid emulsion ora water-in-oil liquid emulsion. 0.01 to 200 microns (including particle sizes in a range The active ingredient may also be presented as a bolus, elec between 0.01 and 500 microns in increments of 0.1 microns tuary or paste. such as 0.1, 0.2,0.3, 0.4,0.5, 1, 2, 5, 30 microns, 35 microns, 40 A tablet is made by compression or molding, optionally etc.), which is administered by inhalation through the nasal with one or more accessory ingredients. Compressed tablets passage or by inhalation through the mouth so as to reach the may be prepared by compressing in a Suitable machine the various bronchi or alveolar sacs. Formulations suitable for active ingredient in a free-flowing form such as a powder or aerosol or dry powder administration may be prepared granules, optionally mixed with a binder, lubricant, inert dilu according to conventional methods and may be delivered with 45 ent, preservative, Surface active or dispersing agent. Molded other therapeutic agents such as compounds heretofore used tablets may be made by molding in a Suitable machine a mixture of the powdered active ingredient moistened with an in the treatment or prophylaxis of prostate cancer. inert liquid diluent. The tablets may optionally be coated or Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams scored and optionally are formulated so as to provide slow or 50 controlled release of the active ingredient therefrom. or spray formulations containing in addition to the active If desired, the aqueous phase of a cream base may include, ingredient such carriers as are known in the art to be appro for example, polyhydric alcohol, i.e. an alcohol having two or priate. more hydroxyl groups such as propylene glycol, butane 1,3- Formulations comprising an active ingredient are pre diol, mannitol, Sorbitol, glycerol and polyethylene glycol and sented in unit-dose or multi-dose containers, for example 55 mixtures thereof. The topical formulations may desirably sealed ampoules and vials, and may be stored in a freeze include a compound which enhances absorption or penetra dried (lyophilized) condition requiring only the addition of tion of the active ingredient through the skin or other affected the sterile liquid carrier, for example water for injection, areas. Examples of Such dermal penetration enhancers immediately prior to use. Extemporaneous injection solu include dimethyl Sulphoxide and related analogs. tions and Suspensions are prepared from Sterile powders, 60 The oily phase of the emulsions of this invention may be granules and tablets of the kind previously described. Pre constituted from known ingredients in a known manner. ferred unit dosage formulations are those containing a daily While the phase may comprise merely an emulsifier (other dose or unit daily Sub-dose, as described herein, or an appro wise known as an emulgent), it desirably comprises a mixture priate fraction thereof, of the active ingredient. of at least one emulsifier with a fat or an oil or with both a fat It should be understood that in addition to the ingredients 65 and an oil. Preferably, a hydrophilic emulsifier is included particularly mentioned above the formulations of this inven together with a lipophilic emulsifier which acts as a stabilizer. tion may include other agents conventional in the art having It is also preferred to include both an oil and a fat. Together, US 7,863,261 B2 23 24 the emulsifier(s) with or without stabilizer(s) make up the 4 double bonds will be present. Thus, if a double bond is so-called emulsifying wax, and the wax together with the oil present at the 5-6-positions, Randone of R'' and R' will be and fat make up the so-called emulsifying ointment base absent. Or, if one or both of the variable groups that are which forms the oily dispersed phase of the cream formula bonded to the ring atoms comprises a double bond, e.g., tions. =CH=CHCH =N. NH =O or =S, there will be no Emulgents and emulsion stabilizers suitable for use in the double bond in the ring at those ring atom positions. The A formulation of the invention include TweenTM 60, SpanTM 80, ring may comprise 0, 1, 2 or 3 double bonds and that ring may cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyc thus be aromatic. The B and D rings may independently eryl mono-stearate and sodium lauryl Sulfate. comprise 0, 1 or 2 double bonds and the Cring may comprise The choice of suitable oils or fats for the formulation is 10 1 double bond. When one or both of R and Rare present, based on achieving the desired cosmetic properties. The they independently are in the Cl- or B-configurations, and in cream should preferably be a non-greasy, non-staining and Some embodiments, they are independently —CH or washable product with Suitable consistency to avoid leakage —CH-OH in the B-configuration. from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl 15 Compounds of formula 2 have the structure Stearate, propylene glycol diester of coconut fatty acids, iso propyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in com bination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils are used. In some embodiments, the methods or compositions described herein will utilize, in lieu of a formula 1 or 2 25 compound, one or more steroid or non-steroid compounds that are disclosed in U.S. Pat. Nos. 2,833,793, 2,911,418, 3,148,198, 3,471,480, 3,710,795, 3,711,606 3,976,691, 4,268,441, 4,427,649, 4,542,129, 4,666,898, 4,693,999, 4,978,532, 5,001,119, 5,043,165, 5,077,284, 5,028,631, 30 wherein R-R independently comprise -H, -OR*, 5,110,810, 5,157,031, 5,162,198, 5,175,154, 5,277,907, —SR, N(R) -O-Si-(R'), —CN, NO, an 5,292,730, 5,296,481, 5,372,996, 5,387,583, 5,407,684, ester, a phosphoester, a phosphonoester, a sulfite ester, a Sul 5,424,463, 5,461,042, 5,478,566, 5,506,223, 5,518,725, fate ester, an amide, an amino acid, a peptide, an ether, a 5,527,788, 5,527,789, 5,532,230, 5,559,107, 5,562,910, 35 thioether, an acyl group, a carbonate, a carbamate, a carboxyl, 5,583,126, 5,585,371, 5,587,369, 5,591,736, 5,593,981, a halogen, an optionally Substituted alkyl group, an optionally 5,610,150, 5,635,496, 5,641,766, 5,641,768, 5,656,621, Substituted alkenyl group, an optionally Substituted alkynyl 5,660,835, 5,677,336, 5,681,835 5,686,438, 5,696,106, group, an optionally Substituted aryl moiety, an optionally 5,696, 127, 5,696,130, 5,700,793, 5,707,983, 5,709,878, substituted heteroaryl moiety, an optionally substituted 5,710,143, 5,714,481, 5,728,688, 5,736,537, 5,744,462, 40 monosaccharide, an optionally Substituted oligosaccharide, a 5,753,237, 5,756,482, 5,776,921, 5,776,923, 5,780,460, nucleoside, a nucleotide, an oligonucleotide, a polymer, or, 5,780,676, 5,795,880, 5,798,347, 5,798,348, 5,804,576, R’ and R7 or R and R taken together independently 5,807,848, 5,807,849, 5,811,418, 5,824,313, 5,824,668, comprise =O or =S. 5,824,671, 5,827,841, 5,837,269, 5,837,700, 5,843,932, 5,846,963, 5,856,340, 5,859,000, 5,869,090, 5,863,910, In some embodiments, one, two, three, four or more of 5,872,114, 5,872,147, 5,886,005, 5,889,042, 5,891,865, 45 R'-R independently comprise –OH, =O, -SH, =S, 5,892,069, 5,945,404 or 5,945,412 or in PCT publication - NH, halogen, —CH=NOH, -NOC(O)CH-O C number 97/49709. (O)—(CH) (CF), CH, —O—C(O)—(CH), The positions in the rings of formula 1 compounds are (CF), CFs, O—C(O)—(CH), (CF), CHF. numbered as shown below. O—C(O)—O—(CH), (CF), CH, O C(O) 50 O—(CH2) (CF), CF O C(O) O—(CH), (CF), CHF. O C(O) NH (CH), (CF), CH, —O C(O) NH (CH), (CF), CF, —O—C (O) NH-(CH2) (CF), CHF (where m is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, n is 0, 1,2,3,4, 5, 6, 7, 8, 9 or 10, usually 55 n is 0), —CH(CH)–(CH), C(O)NH-CHCOOH, —CH(CH)–(CH), C(O)NH-CHSOH, —OSi(CH),C(CH), C(OH)—CHCH =CH(CH2)CH, -(CH2). CHF, -(CH2) - CHCl, —(CH2). CHBr, —(CH2). CHI, 60 (CH)-o-O-(CH2). CH, —(CH)-o-S- (CH) CHs. —(CH). NH-(CH2). CH, —O-(CH2). CHF. —O-(CH2). CHCl, —O— (CH). CHBr, —O—(CH). CHI, —O— (CH)-o-O-(CH2). CH, —O—(CH)-o-S- More than one double bond may be present in formula 1 65 (CH2). CH, —O—(CH)-o NH-(CH2). CH, compounds, but no carbon atom will carry a charge due to the —O—C(O)—(CH2). CHF. —O—C(O)—(CH2) - presence of excess bonds or Valences. Typically, 0, 1, 2, 3 or CHCl, —O C(O)—(CH). CHBr, —O—C(O)—

US 7,863,261 B2 27 28

TABLE 2 .1.1.1, .1.1.2, 1.1.1.3, 1.1.1.4, 1.1.1.5.1.1.1.6, .1.1.7.1.1.1.8, 1.1.1.9, 1.1.1.10, 1.1.2.1.1.1.2.2, 1.1.2.3, 1.1.2.4. .1.2.5. .1.2.6, 1.1.2.7.1.1.2.8, 1.1.2.9, 1.1.2.10, .1.3.1, 1.1.3.2.1.1.3.3, 1.1.3.4.1.1.3.5, 1.1.3.6., 1.1.3.7, 1.1.3.8, .1.3.9, .1.3.10, 1.1.4.1, 1.1.4.2, 1.1.4.3, 1.1.4.4, .1.4.5, 1.1.4.6., 1.1.4.7, 1.1.4.8, 1.1.4.9, 1.1.4.10, 1.1.5.1, 1.1.5.2, .1.5.3, .1.5.4, 1.1.5.5, 1.1.5.6, 1.1.5.7.1.1.5.8. .1.5.9, 1.1.5.10, 1.1.6.1, 1.1.6.2, 1.1.6.3, 1.1.6.4, 1.1.6.5, 1.1.6.6, .1.6.7. .1.6.8, 1.1.6.9, 1.1.6.10, 1.1.7.1.1.1.7.2, 1.7.3, 1.1.7.4, 1.1.7.5, 1.1.7.6, 1.1.7.7, 1.1.7.8, 1.1.7.9, 1.1.7.10, .1.8.1, .1.8.2, 1.1.8.3, 1.1.8.4, 1.1.8.5, 1.1.8.6. .1.8.7, 1.1.8.8, 1.1.8.9, 1.1.8.10, 1.1.9.1, 1.1.9.2, 1.1.9.3, 1.1.9.4, .1.9.5, .1.9.6, 1.1.9.7, 1.1.9.8, 1.1.9.9, 1.1.9.10, .1.10.1, 1.1.10.2, 1.1.10.3, 1.1.10.4, 1.1.10.5, 1.1.10.6, 1.1.10.7, .1.10.8, 1.1.10.9, 1.1.10.10, 1.2.1.1, 1.2.1.2, 1.2. 1.3, 1.2.1.4, 1.2.1.5, 1.2.1.6., 1.2.1.7, 1.2.1.8, 1.2.1.9, 1.2.1.10, .2.2.1, .2.2.2, 1.2.2.3, 1.2.2.4, 1.2.2.5.1.2.2.6, .2.2.7.1.2.2.8, 1.2.2.9, 1.2.2.10, 1.2.3.1, 1.2.3.2.1.2.3.3, 1.2.3.4. 2.3.5, .2.3.6., 1.2.3.7, 1.2.3.8, 1.2.3.9, 1.2.3.10, .2.4.1, 1.2.4.2, 1.2.4.3, 1.2.4.4, 1.2.4.5, 1.2.4.6., 1.2.4.7, 1.2.4.8, .2.4.9, .2.4.10, 1.2.5.1, 1.2.5.2, 1.2.5.3, 1.2.5.4, .2.5.5, 1.2.5.6, 1.2.5.7.1.2.5.8.1.2.5.9, 1.2.5.10, 1.2.6.1, 1.2.6.2, .2.6.3, .2.6.4, 1.2.6.5, 1.2.6.6, 1.2.6.7.1.2.6.8, .2.6.9, 1.2.6.10, 1.2.7.1.1.2.7.2, 1.2.7.3, 1.2.7.4, 1.2.7.5, 1.2.7.6, .2.7.7, .2.7.8, 1.2.7.9, 1.2.7.10, 1.2.8.1, 1.2.8.2, .2.8.3, 1.2.8.4, 1.2.8.5, 1.2.8.6., 1.2.8.7, 1.2.8.8, 1.2.8.9, 1.2.8.10, .2.9.1, .2.9.2, 1.2.9.3, 1.2.9.4, 1.2.9.5, 1.2.9.6, .2.9.7, 1.2.9.8, 1.2.9.9, 1.2.9.10, 1.2.10.1, 1.2.10.2, 1.2.10.3 .2.10.4, 1.2.10.5, 1.2.10.6, 1.2.10.7.1.2.10.8, 1.2.10.9, 1.2.10.10, 1.3.1.1, 1.3.1.2, 1.3.1.3, 1.3.1.4, 1.3.1.5, 1.3.1.6, .3.1.7, .3.1.8, 1.3.1.9, 1.3.1.10, 1.3.2.1, 1.3.2.2, .3.2.3, 1.3.2.4, 1.3.2.5, 1.3.2.6, 1.3.2.7.1.3.2.8, 1.3.2.9, 1.3.2.10, .3.3.1, .3.3.2.1.3.3.3, 1.3.3.4, 1.3.3.5, 1.3.3.6. .3.3.7, 1.3.3.8, 1.3.3.9, 1.3.3.10, 1.3.4.1, 1.3.4.2, 1.3.4.3, 1.3.4.4, .3.4.5, .3.4.6., 1.3.4.7, 1.3.4.8, 1.3.4.9, 1.3.4.10, 3.5.1, 1.3.5.2, 1.3.5.3, 1.3.5.4, 1.3.5.5, 1.3.5.6, 1.3.5.7., 1.3.5.8, 3.5.9, .3.5.10, 1.3.6.1, 1.3.6.2, 1.3.6.3, 1.3.6.4, .3.6.5, 1.3.6.6, 1.3.6.7.1.3.6.8, 1.3.6.9, 1.3.6.10, 1.3.7.1.1.3.7.2, .3.7.3, .3.7.4, 1.3.7.5, 1.3.7.6, 1.3.7.7, 1.3.7.8, .3.7.9, 1.3.7.10, 1.3.8.1, 1.3.8.2, 1.3.8.3, 1.3.8.4, 1.3.8.5, 1.3.8.6. 3.8.7, 3.8.8, 1.3.8.9, 1.3.8.10, 1.3.9.1, 1.3.9.2, 3.9.3, 1.3.9.4, 1.3.9.5, 1.3.9.6, 1.3.9.7, 1.3.9.8, 1.3.9.9, 1.3.9.10, .3.10.1, 1.3.10.2, 1.3.10.3, 1.3.10.4, 1.3.10.5, 1.3.10.6, 1.3.10.7, 1.3.10.8, 1.3.10.9, 1.3.10.10, 1.4.1.1, 1.4.1.2 4.1.3, .4.1.4, 1.4.1.5, 1.4.1.6., 1.4.1.7, 1.4.1.8, 4.1.9, 1.4.1.10, 1.4.2.1, 1.4.2.2, 1.4.2.3, 1.4.2.4, 1.4.2.5, 1.4.2.6, 4.2.7. .4.2.8, 1.4.2.9, 1.4.2.10, 1.4.3.1, 1.4.3.2. 4.3.3, 1.4.3.4, 1.4.3.5, 1.4.3.6., 1.4.3.7, 1.4.3.8, 1.4.3.9, 1.4.3.10, .4.4.1, .4.4.2, 1.4.4.3, 1.4.4.4, 1.4.4.5, 1.4.4.6. .4.4.7, 1.4.4.8, 1.4.4.9, 1.4.4.10, 1.4.5.1, 1.4.5.2, 1.4.5.3, 1.4.5.4, 4.5.5, .4.5.6, 1.4.5.7., 1.4.5.8, 1.4.5.9, 1.4.5.10, .4.6.1, 1.4.6.2, 1.4.6.3, 1.4.6.4, 1.4.6.5, 1.4.6.6, 1.4.6.7., 1.4.6.8, .4.6.9, .4.6.10, 1.4.7.1, 1.4.7.2, 1.4.7.3, 1.4.7.4, 4.7.5, 1.4.7.6, 1.4.7.7, 1.4.7.8, 1.4.7.9, 1.4.7.10, 14.8.1, 1.4.8.2, 4.8.3, .4.8.4, 1.4.8.5, 1.4.8.6., 14.8.7, 14.8.8, 4.8.9, 14.8.10, 1.4.9.1, 1.4.9.2, 1.4.9.3, 1.4.9.4, 1.4.9.5, 1.4.9.6, .4.9.7, .4.9.8, 1.4.9.9, 1.4.9.10, 1.4.10.1, 1.4.10. 2, 1.4.10.3, 1.4.10.4, 1.4.10.5, 1.4.10.6, 1.4.10.7, 1.4.10.8, .4.10.9, 1.4.10.10, 1.5.1.1, 1.5.1.2, 1.5.1.3, 1.5.1 4, 1.5.1.5, 1.5.1.6., 1.5.1.7, 1.5.1.8, 1.5.1.9, 1.5.1.10, 1.5.2.1, .5.2.2, .5.2.3, 1.5.2.4, 1.5.2.5, 1.5.2.6, 1.5.2.7, .5.2.8, 1.5.2.9, 1.5.2.10, 1.5.3.1, 1.5.3.2, 1.5.3.3, 1.5.3.4, 1.5.3.5, .5.3.6, .5.3.7, 1.5.3.8, 1.5.3.9, 1.5.3.10, 1.5.4.1, .5.4.2, 1.5.4.3, 1.5.4.4, 1.5.4.5, 1.5.4.6., 1.5.4.7, 1.5.4.8, 1.5.4.9, .5.4.10, 1.5.5.1, 1.5.5.2, 1.5.5.3, 1.5.5.4, 1.5.5.5, .5.5.6, 1.5.5.7., 1.5.5.8, 1.5.5.9, 1.5.5.10, 1.5.6.1, 1.5.6.2, 1.5.6.3, .5.6.4, .5.6.5, 1.5.6.6, 1.5.6.7, 1.5.6.8, 1.5.6.9, .5.6.10, 1.5.7.1, 1.5.7.2, 1.5.7.3, 1.5.7.4, 1.5.7.5, 1.5.7.6, 1.5.7.7, .5.7.8, .5.7.9, 1.5.7.10, 1.5.8.1, 1.5.8.2, 1.5.8.3, .5.8.4, 1.5.8.5, 1.5.8.6., 1.5.8.7, 1.5.8.8, 1.5.8.9, 1.5.8.10, 1.5.9.1, .5.9.2, .5.9.3, 1.5.9.4, 1.5.9.5, 1.5.9.6, 1.5.9.7, .5.9.8, 1.5.9.9, 1.5.9.10, 1.5.10.1, 1.5.10.2, 1.5.10.3, 1.5.10.4, .5.10.5, 1.5.10.6, 1.5.10.7.1.5.10.8, 1.5.10.9, 1.5.10.10, 1.6.1.1, 1.6.1.2, 1.6.1.3, 1.6.1.4, 1.6.1.5, 1.6.1.6., 1.6.1.7, .6.1.8, .6.1.9, 1.6.1.10, 1.6.2.1, 1.6.2.2, 1.6.2.3, .6.2.4, 1.6.2.5, 1.6.2.6, 1.6.2.7.1.6.2.8, 1.6.2.9, 1.6.2.10, 1.6.3.1, .6.3.2. .6.3.3.1.6.3.4, 1.6.3.5, 1.6.3.6., 1.6.3.7, .6.3.8, 1.6.3.9, 1.6.3.10, 1.6.4.1, 1.6.4.2, 1.6.4.3, 1.6.4.4, 1.6.4.5, .6.4.6. .6.4.7, 1.6.4.8, 1.6.4.9, 1.6.4.10, 1.6.5.1, .6.5.2, 1.6.5.3, 1.6.5.4, 1.6.5.5, 1.6.5.6, 1.6.5.7., 1.6.5.8, 1.6.5.9, .6.5.10, 1.6.6.1, 1.6.6.2, 1.6.6.3, 1.6.6.4, 1.6.6.5, .6.6.6, 1.6.6.7.1.6.6.8, 1.6.6.9, 1.6.6.10, 1.6.7.1.1.6.7.2, 1.6.7.3, .6.7.4, .6.7.5, 1.6.7.6, 1.6.7.7, 1.6.7.8, 1.6.7.9, .6.7.10, 1.6.8.1, 1.6.8.2, 1.6.8.3, 1.6.8.4, 1.6.8.5, 1.6.8.6., 1.6.8.7, .6.8.8, .6.8.9, 1.6.8.10, 1.6.9.1, 1.6.9.2, 1.6.9.3, .6.9.4, 1.6.9.5, 1.6.9.6, 1.6.9.7, 1.6.9.8, 1.6.9.9, 1.6.9.10, 1.6.10.1, .6.10.2, 1.6.10.3, 1.6.10.4, 1.6.10.5, 1.6.10.6, 1.6.10.7, 1.6.10.8, 1.6.10.9, 1.6.10.10, 1.7.1.1, 1.7.1.2, 1.7.1.3 .7.1.4, .7.1.5, 1.7.1.6., 1.7.1.7, 1.7.1.8, 1.7.1.9, .7.1.10, 1.7.2.1, 1.7.2.2, 1.7.2.3, 1.7.2.4, 1.7.2.5, 1.7.2.6., 1.7.2.7. 7.2.8, .7.2.9, 1.7.2.10, 1.7.3.1, 1.7.3.2, 1.7.3.3, .7.3.4, 1.7.3.5, 1.7.3.6., 1.7.3.7, 1.7.3.8, 1.7.3.9, 1.7.3.10, 1.7.4.1, .7.4.2, .7.4.3, 1.7.4.4, 1.7.4.5, 1.7.4.6., 1.7.4.7, .7.4.8, 1.7.4.9, 1.7.4.10, 1.7.5.1, 1.7.5.2, 1.7.5.3, 1.7.5.4, 1.7.5.5, 7.5.6, 7.5.7., 1.7.5.8, 1.7.5.9, 1.7.5.10, 1.7.6.1, 7.6.2, 1.7.6.3, 1.7.6.4, 1.7.6.5, 1.7.6.6, 1.7.6.7, 1.7.6.8, 1.7.6.9, 7.6.10, 1.7.7.1, 1.7.7.2, 1.7.7.3, 1.7.7.4, 1.7.7.5, .7.7.6, 1.7.7.7, 1.7.7.8, 1.7.7.9, 1.7.7.10, 1.7.8.1, 1.7.8.2, 1.7.8.3, .7.8.4, .7.8.5, 1.7.8.6., 1.7.8.7, 1.7.8.8, 1.7.89, .7.8.10, 1.7.9.1, 1.7.9.2, 1.7.9.3, 1.7.9.4, 1.7.9.5, 1.7.9.6, 1.7.9.7, .7.9.8, .7.9.9, 1.7.9.10, 1.7.10.1, 1.7.10.2, 1.7.1 0.3, 1.7.10.4, 1.7.10.5, 1.7.10.6, 1.7.10.7, 1.7.10.8, 1.7.10.9 .7.10.10, 1.8.1.1, 1.8.1.2, 1.8.1.3, 1.8.1.4, 1.8.1.5, 1.8.1.6., 1.8.1.7, 1.8.1.8, 1.8.1.9, 1.8.1.10, 1.8.2.1, 1.8.2.2, 1.8.2.3, .8.2.4, .8.2.5, 1.8.2. 6, 1.8.2.7, 1.8.2.8, 1.8.2.9, .8.2.10, 1.8.3.1, 1.8.3.2, 1.8.3.3, 1.8.3.4, 1.8.3.5, 1.8.3.6., 1.8.3.7, .8.3.8, .8.3.9, 1.8.3.10, 1.8.4.1, 1.8.4.2, 1.8.4.3, .8.4.4, 1.8.4.5, 1.8.4.6., 1.8.4.7, 1.8-4.8, 1.8.4.9, 1.8.4.10, 1.8.5.1, .8.5.2, .8.5.3, 1.8.5.4, 1.8.5.5, 1.8.5.6, 1.8.5.7., .8.5.8, 1.8.5.9, 1.8.5.10, 1.8.6.1, 1.8.6.2, 1.8.6.3, 1.8.6.4, 1.8.6.5, .8.6.6, .8.6.7, 1.8.6.8, 1.8.6.9, 1.8.6.10, 1.8.7.1, .8.7.2, 1.8.7.3, 1.8.7.4, 1.8.7.5, 1.8.7.6, 1.8.7.7, 1.8.7.8, 1.8.7.9, .8.7.10, .8.8.1, 1.8.8.2, 1.8.8.3, 1.8.8.4, 1.8.8.5, .8.8.6., 1.8.8.7, 1.8.8.8, 1.8.8.9, 1.8.8.10, 1.8.9.1, 1.8.9.2, 1.8.9.3, .8.9.4, .8.9.5, 1.8.9.6, 1.8.9.7, 1.8.9.8, 1.8.99, .8.9.10, 1.8.10.1, 1.8.10.2, 1.8.10.3, 1.8.10.4, 1.8.10.5, 1.8.10.6, .8.10.7, .8.10.8, 1.8.10.9, 1.8.10.10, 1.9.1.1, 1.9.1.2, 1.9.1.3, 1.9.1.4, 1.9.1.5, 1.9.1.6., 1.9.1.7, 1.9.1.8, 1.9.1.9, .9.1.10, .9.2.1, 1.9.2.2, 1.9.2.3, 1.9.2.4, 1.9.2.5. .9.2. 6, 1.9.2.7.1.9.2.8, 1.9.2.9, 1.9.2.10, 1.9.3.1, 1.9.3.2, 1.9.3.3, .9.3.4. 9.3.5, 19.3.6., 1.9.3.7, 19.3.8, 19.3.9, .9.3.10, 1.9.4.1, 1.9.4.2, 1.9.4.3, 1.9.4.4, 1.9.4.5, 1.9.4.6., 1.9.4.7, .9.4.8, 9.4.9, 19.4.10, 1.9.5.1, 1.9.5.2, 1.9.5.3, 9.5.4, 1.9.5.5, 1.9.5.6, 1.9.5.7., 1.9.5.8, 1.9.5.9, 1.9.5.10, 1.9.6.1, .9.6.2, .9.6.3, 1.9.6.4, 1.9.6.5, 1.9.6.6, 1.9.6.7. 9.6.8, 1.9.6.9, 1.9.6.10, 1.9.7.1, 19.7.2, 19.7.3, 19.7.4, 19.7.5, 9.7.6, 9.7.7, 19.7.8, 1.9.7.9, 19.7.10, 1.9.8.1, 9.8.2, 1.9.8.3, 19.8.4, 1.9.8.5, 19.8.6., 1.9.8.7, 19.8.8, 1.9.8.9, 9.8.10, 9.9.1, 1.9.9.2, 19.9.3, 1.9.94, 19.9.5, 9.9.6, 1.99.7, 19.9.8, 1.9.9.9, 19.9.10, 1.9.10.1, 1.9.10.2, .9.10.3, .9.10.4, 1.9.10.5, 1.9.10.6, 1.9.10.7, 1.9.10.8, 1.9.10.9, 1.9.10.10, 1.10.1.1, 1.10.1.2, 1.10.1.3, 1.10.1.4, .10.1.5, .10.1.6., 1.10.1.7, 1.10.1.8, 1.10.1.9, 1. 0.1.10, 1.10.2.1, 1.10.2.2, 1.10.2.3, 1.10.2.4, 1.10.2.5, 1.10.2.6, .10.2.7, .10.2.8, 1.10.2.9, 1.10.2.10, 1.10.3.1, 1. 0.3.2, 1.10.3.3, 1.10.3.4, 1.10.3.5, 1.10.3.6., 1.10.3.7, 1.10.3.8, .10.3.9, .10.3.10, 1.10.4.1, 1.10.4.2, 1.10.4.3, 1. 0.4.4, 1.10.4.5, 1.10.4.6., 1.10.4.7, 1.10.4.8, 1.10.4.9, 1.10.4.10, .10.5.1, .10.5.2, 1.10.5.3, 1.10.5.4, 1.10.5.5, 1. 0.5.6, 1.10.5.7., 1.10.5.8, 1.10.5.9, 1.10.5.10, 1.10.6.1, 1.10.6.2, .10.6.3, .10.6.4, 1.10.6.5, 1.10.6.6, 1.10.6.7.1. 0.6.8, 1.10.6.9, 1.10.6.10, 1.10.7.1, 1.10.7.2, 1.10.7.3, 1.10.7.4, .10.7.5, .10.7.6, 1.10.7.7, 1.10.7.8, 1.10.7.9, 1. 0.7.10, 1.10.8.1, 1.10.8.2, 1.10.8.3, 1.10.8.4, 1.10.8.5, 1.10.8.6. .10.8.7, .10.8.8, 1.10.8.9, 1.10.8.10, 1.10.9.1, 1 .10.9.2, 1.10.9.3, 1.10.9.4, 1.10.9.5, 1.10.9.6, 1.10.9.7, 1.10.9.8, .10.9.9, .10.9.10, 1.10.10.1, 1.10.10.2, 1.10.10. 3, 1.10.10.4, 1.10.10.5, 1.10.10.6, 1.10.10.7, 1.10.10.8, 1.10.10.9, .10.10.10, 2.1.1.1, 2.1.1.2, 2.1.1.3.2.1.1.4, 2.1.1.5.2.1.1.6.2.1.1.7, 2.1.1.8, 2.1.1.9, 2.1.1.10, 2.1.2.1.2.1.2.2, 2.1.2.3, 2.1.2.4, 2.1.2.5.2.1.2.6, 2.1.2.7., 2.1.2.8, 2.1.2.9, 2.1.2.10, 2.1.3.1, 2.1.3.2, 2.1.3.3.2.1.3.4, 2.1.3.5.2.1.3.6. 2.1.3.7, 2.1.3.8, 2.1.3.9, 2.1.3.10, 2.1.4.1, 2.1.4.2, 2.1.4.3, 2.1.4.4, 2.1.4.5, 2.1.4.6.2.1.4.7, 2.1.4.8, 2.1.4.9, 2.1.4.10, 2.1.5.1, 2.1.5.2, 2.1.5.3, 2.1.5.4, 2.1.5.5, 2.1.5.6, 2.1.5.7., 2.1.5.8.2.1.5.9, 2.1.5.10, 2.1.6.1, 2.1.6.2, 2.1.6.3, 2.1.6.4, 2.1.6.5, 2.1.6.6, 2.1.6.7., 2.1.6.8, 2.1.6.9, 2.1.6.10, 2.1.7.1.2.1.7.2, 2.1.7.3, 2.1.7.4, 2.1.7.5, 2.1.7.6, 2.1.7.7, 2.1.7.8, US 7,863,261 B2 29 30

TABLE 2-continued 2.1.7.9, 2.1.7.10, 2.1.8.1.2.1.8.2, 2.1.8.3, 2.1.8.4, 2.1.8.5, 2.1.8.6.2.1.8.7, 2.1.8.8, 2.1.8.9, 2.1.8.10, 2.1.9.1, 2.1.9.2, 2.1.9.3, 2.1.9.4, 2.1.9.5, 2.1.9.6, 2.1.9.7, 2.1.9.8, 2.1.9.9, 2.1.9.10, 2.1.10.1, 2.1.10.2, 2.1.10.3, 2.1.10.4, 2.1.10.5, 2.1.10.6, 2.1.10.7, 2.1.10.8, 2.1.10.9, 2.1.10.10, 2.2.1.1, 2.2.1.2, 2.2.1.3, 2.2.1.4, 2.2.1.5, 2.2.1.6., 2.2.1.7, 2.2.1.8, 2.2.1.9, 2.2.1.10, 2.2.2.1.2.2.2.2, 2.2.2.3, 2.2.2.4, 2.2.2.5.2.2.2.6, 2.2.2.7., 2.2.2.8, 2.2.2.9, 2.2.2.10, 2.2.3.1, 2.2.3.2, 2.2.3.3. 2.2.3.4, 2.2.3.5, 2.2.3.6., 2.2.3.7, 2.2.3.8, 2.2.3.9, 2.2.3.10, 2.2.4.1, 2.2.4.2, 2.2.4.3, 2.2.4.4, 2.2.4.5, 2.2.4.6. 2.2.4.7, 2.2.4.8, 2.2.4.9, 2.2.4.10, 2.2.5.1, 2.2.5.2, 2.2.5.3, 2.2.5.4, 2.2.5.5, 2.2.5.6, 2.2.5.7., 2.2.5.8.2.2.5.9, 2.2.5.10, 2.2.6.1, 2.2.6.2, 2.2.6.3, 2.2.6.4, 2.2.6.5, 2.2. 6.6, 2.2.6.7., 2.2.6.8, 2.2.6.9, 2.2.6.10, 2.2.7.1.2.2.7.2, 2.2.7.3, 2.2.7.4, 2.2.7.5, 2.2.7.6, 2.2.7.7, 2.2.7.8, 2.2.7.9, 2.2.7.10, 2.2.8.1, 2.2.8.2, 2.2.8.3, 2.2.8.4, 2.2.8.5, 2.2.8.6., 2.2.8.7, 2.2.8.8, 2.2.8.9, 2.2.8.10, 2.2.9.1, 2.2.9.2, 2.2.9.3, 2.2.9.4, 2.2.9.5, 2.2.9.6, 2.2.9.7, 2.2.9.8, 2.2.9.9, 2.2.9.10, 2.2.10.1, 2.2.10.2, 2.2.10.3, 2.2.10.4, 2.2.10.5, 2.2.10.6, 2.2.10.7, 2.2.10.8, 2.2.10.9, 2.2.10.10, 2.3.1.1, 2.3.1.2, 2.3.1.3, 2.3.1.4, 2.3.1.5, 2.3.1.6., 2.3.1.7, 2.3.1.8, 2.3.1.9, 2.3.1.10, 2.3.2.1, 2.3.2.2, 2.3.2.3, 2.3.2.4, 2.3.2.5. 2.3.2.6, 2.3.2.7. 2.3.2.8, 2.3.2.9, 2.3.2.10, 2.3.3.1, 2.3.3.2, 2.3.3.3, 2.3.3.4, 2.3.3.5, 2.3.3.6., 2.3.3.7, 2.3.3.8, 2.3.3.9, 2.3.3.10, 2.3.4.1, 2.3.4.2, 2.3.4.3, 2.3.4.4, 2.3.4.5, 2.3.4.6., 2.3.4.7, 2.3.4.8, 2.3.4.9, 2.3.4.10, 2.3.5.1, 2.3.5.2, 2.3.5.3, 2.3.5.4, 2.3.5.5, 2.3.5.6, 2.3.5.7., 2.3.5.8, 2.3.5.9, 2.3.5.10, 2.3.6.1, 2.3.6.2, 2.3.6.3, 2.3.6.4, 2.3.6.5, 2.3.6.6, 2.3.6.7., 2.3.6.8, 2.3.6.9, 2.3.6.10, 2.3.7.1, 2.3.7.2, 2.3.7.3, 2.3.7.4, 2.3.7.5, 2.3.7.6, 2.3.7.7, 2.3.7.8, 2.3.7.9, 2.3.7.10, 2.3.8.1, 2.3.8.2, 2.3.8.3, 2.3.8.4, 2.3.8.5, 2.3.8.6., 2.3.8.7, 2.3.8.8, 2.3.8.9, 2.3.8.10, 2.3.9.1, 2.3.9.2, 2.3.9.3, 2.3.9.4, 2.3.9.5, 2.3.9.6, 2.3.9.7, 2.3.9.8, 2.3.9.9, 2.3.9.10, 2.3.10.1, 2.3.10.2, 2.3.10.3, 2.3.10.4, 2.3.10.5, 2.3.10.6, 2.3.10.7, 2.3.10.8, 2.3.10.9, 2.3.10.10, 2.4.1.1, 2.4.1.2, 2.4.1.3, 2.4.1.4, 2.4.1.5, 2.4.1.6., 2.4.1.7, 2.4.1.8, 2.4.1.9, 2.4.1.10, 2.4.2.1, 2.4.2.2, 2.4.2.3, 2.4.2.4, 2.4.2.5., 2.4.2.6, 2.4.2.7., 2.4.2.8, 2.4.2.9, 2.4.2.10, 2.4.3.1, 2.4.3.2, 2.4.3.3, 2.4.3.4, 2.4.3.5, 2.4.3.6., 2.4.3.7, 2.4.3.8, 2.4.3.9, 2.4.3.10, 2.4.4.1, 2.4.4.2, 2.4.4.3, 2.4.4.4, 2.4.4.5, 2.4.4.6., 2.4.4.7, 2.4.4.8, 2.4.4.9, 2.4.4.10, 2.4.5.1, 2.4.5.2, 2.4.5.3, 2.4.5.4, 2.4.5.5, 2.4.5.6, 2.4.5.7., 2.4.5.8, 2.4.5.9, 2.4.5.10, 2.4.6.1, 2.4.6.2, 2.4.6.3, 2.4.6.4, 2.4.6.5, 2.4.6.6, 2.4.6.7., 2.4.6.8, 2.4.6.9, 2.4.6.10, 2.4.7.1, 2.4.7.2, 2.4.7.3, 2.4.7.4, 2.4.7.5, 2.4.7.6, 2.4.7.7, 2.4.7.8, 2.4.7.9, 2.4.7.10, 2.4.8.1, 2.4.8.2, 2.4.8.3, 2.4.8.4, 2.4.8.5, 2.4.8.6., 2.4.8.7, 2.4.8.8, 2.4.8.9, 2.4.8.10, 2.4.9.1, 2.4.9.2, 2.4.9.3, 2.4.9.4, 2.4.9.5, 2.4.9.6, 2.4.9.7, 2.4.9.8, 2.4.9.9, 2.4.9.10, 2.4.10.1, 2.4.10.2, 2.4.10.3, 2.4.10.4, 2.4.10.5, 2.4.10.6, 2.4.10.7, 2.4.10.8, 2.4.10.9, 2.4.10.10, 2.5.1.1, 2.5.1.2, 2.5.1.3, 2.5.1.4, 2.5.1.5, 2.5.1.6., 2.5.1.7, 2.5.1.8, 2.5.1.9, 2.5.1.10, 2.5.2.1, 2.5.2.2, 2.5.2.3, 2.5.24, 2.5.2.5, 2.5.2.6, 2.5.2.7, 2.5.2.8, 2.5.2.9, 2.5.2.10, 2.5.3.1, 2.5.3.2, 2.5.3.3, 2.5.3.4, 2.5.3.5, 2.5.3.6, 2.5.3.7, 2.5.3.8, 2.5.3.9, 2.5.3.10, 2.5.4.1, 2.5.4.2, 2.5.4.3, 2.5.44, 2.5.4.5, 2.5.4.6, 2.5.4.7, 2.5.48, 2.5.4.9, 2.5.4.10, 2.5.5.1, 2.5.5.2, 2.5.5.3, 2.5.5.4, 2.5.5.5, 2.5.5.6, 2.5.5.7., 2.5.5.8, 2.5.5.9, 2.5.5.10, 2.5.6.1, 2.5.6.2, 2.5.6.3, 2.5.6.4, 2.5.6.5, 2.5.6.6, 2.5.6.7, 2.5.6.8, 2.5.6.9, 2.5.6.10, 2.5.7.1, 2.5.7.2, 2.5.7.3, 2.5.7.4, 2.5.7.5, 2.5.7.6, 2.5.7.7, 2.5.7.8, 2.5.7.9, 2.5.7.10, 2.5.8.1, 2.5.8.2, 2.5.8.3, 2.5.8.4, 2.5.8.5, 2.5.8.6., 2.5.8.7, 2.5.8.8, 2.5.8.9, 2.5.8.10, 2.5.9.1, 2.5.9.2, 2.5.9.3, 2.5.94, 2.5.9.5, 2.5.9.6, 2.5.9.7, 2.5.9.8, 2.5.9.9, 2.5.9.10, 2.5.10.1, 2.5.10.2, 2.5.10.3, 2.5.10.4, 2.5.10.5, 2.5.10.6, 2.5.10.7, 2.5.10.8, 2.5.10.9, 2.5.10.10, 2.6.1.1, 2.6.1.2, 2.6.1.3, 2.6.1.4, 2.6.1.5, 2.6.1.6., 2.6.1.7, 2.6.1.8, 2.6.1.9, 2.6.1.10, 2.6.2.1, 2.6.2.2, 2.6.2.3, 2.6.2.4, 2.6.2.5. 2.6.2.6, 2.6.2.7., 2.6.2.8, 2.6.2.9, 2.6.2.10, 2.6.3.1, 2.6.3.2, 2.6.3.3. 2.6.3.4, 2.6.3.5, 2.6.3.6., 2.6.3.7, 2.6.3.8, 2.6.3.9, 2.6.3.10, 2.6.4.1, 2.6.4.2, 2.6.4.3, 2.6.4.4, 2.6.4.5, 2.6.4.6., 2.6.4.7, 2.6.4.8, 2.6.4.9, 2.6.4.10, 2.6.5.1, 2.6.5.2, 2.6.5.3, 2.6.5.4, 2.6.5.5, 2.6.5.6, 2.6.5.7., 2.6.5.8, 2.6.5.9, 2.6.5.10, 2.6.6.1, 2.6.6.2, 2.6.6.3, 2.6.6.4, 2.6.6.5, 2.6.6.6, 2.6.6.7., 2.6.6.8, 2.6.6.9, 2.6.6.10, 2.6.7.1, 2.6.7.2, 2.6.7.3, 2.6.7.4, 2.6.7.5, 2.6.7.6, 2.6.7.7, 2.6.7.8, 2.6.7.9, 2.6.7.10, 2.6.8.1, 2.6.8.2, 2.6.8.3, 2.6.8.4, 2.6.8.5, 2.6.8.6., 2.6.8.7, 2.6.8.8, 2.6.8.9, 2.6.8.10, 2.6.9.1, 2.6.9.2, 2.6.9.3, 2.6.9.4, 2.6.9.5, 2.6.9.6, 2.6.9.7, 2.6.9.8, 2.6.9.9, 2.6.9.10, 2.6.10.1, 2.6.10.2, 2.6.10.3, 2.6.10.4, 2.6.10.5, 2.6.10.6, 2.6.10.7, 2.6.10.8, 2.6.10.9, 2.6.10.10, 2.7.1.1, 2.7.1.2, 2.7.1.3, 2.7.1.4, 2.7.1.5, 2.7.1.6, 2.7.1.7, 2.7.1.8, 2.7.1.9, 2.7.1.10, 2.7.2.1, 2.7.2.2, 2.7.2.3, 2.7.2.4, 2.7.2.5, 2.7.2.6, 2.7.2.7, 2.7.2.8, 2.7.2.9, 2.7.2.10, 2.7.3.1, 2.7.3.2, 2.7.3.3, 2.7.34, 2.7.3.5, 2.7.3.6, 2.7.3.7, 2.7.3.8, 2.7.3.9, 2.7.3.10, 2.7.4.1, 2.74.2, 2.7.4.3, 2.7.44, 2.7.4.5, 2.74.6, 2.74.7, 2.74.8, 2.7.4.9, 2.74.10, 2.7.5.1, 2.7.5.2, 2.7.5.3, 2.7.5.4, 2.7.5.5, 2.7.5.6, 2.7.5.7., 2.7.5.8, 2.7.5.9, 2.7.5.10, 2.7.6.1, 2.7.6.2, 2.7.6.3, 2.7.6.4, 2.7.6.5, 2.7.6.6, 2.7.6.7, 2.7.6.8, 2.7.6.9, 2.7.6.10, 2.7.7.1, 2.7.7.2, 2.7.7.3, 2.7.7.4, 2.7.7.5, 2.7.7.6, 2.7.7.7, 2.7.7.8, 2.7.7.9, 2.7.7.10, 2.7.8.1, 2.7.8.2, 2.7.8.3, 2.7.8.4, 2.7.8.5, 2.7.8.6., 2.7.8.7, 2.7.8.8, 2.7.8.9, 2.7.8.10, 2.7.9.1, 2.7.9.2, 2.7.9.3, 2.79.4, 2.7.9.5, 2.7.9.6, 2.7.9.7, 2.7.9.8, 2.7.9.9, 2.7.9.10, 2.7.10.1, 2.7.10.2, 2.7.10.3, 2.7.10.4, 2.7.10.5, 2.7.10.6, 2.7.10.7, 2.7.10.8, 2.7.10.9, 2.7.10.10, 2.8.1.1, 2.8.1.2, 2.8.1.3, 2.8.1.4, 2.8.1.5.2.8.1.6., 2.8.1.7, 2.8.1.8, 2.8.1.9, 2.8.1.10, 2.8.2.1, 2.8.2.2, 2.8.2.3, 2.8.2.4, 2.8.2.5.2.8.2.6, 2.8.2.7., 2.8.2.8, 2.8.2.9, 2.8.2.10, 2.8.3.1, 2.8.3.2, 2.8.3.3, 2.8.3.4, 2.8.3.5, 2.8.3.6., 2.8.3.7, 2.8.3.8, 2.8.3.9, 2.8.3.10, 2.8.4.1, 2.8.4.2, 2.8.4.3, 2.8.4.4, 2.8.4.5, 2.8.4.6.2.8.4.7, 2.8-4.8, 2.8.4.9, 2.8.4.10, 2.8.5.1, 2.8.5.2, 2.8.5.3, 2.8.5.4, 2.8.5.5, 2.8.5.6, 2.8.5.7., 2.8.5.8, 2.8.5.9, 2.8.5.10, 2.8.6.1, 2.8.6.2, 2.8.6.3, 2.8.6.4, 2.8.6.5, 2.8.6.6, 2.8.6.7, 2.8.6.8, 2.8.6.9, 2.8.6.10, 2.8.7.1, 2.8.7.2, 2.8.7.3, 2.8.7.4, 2.8.7.5, 2.8.7.6, 2.8.7.7, 2.8.7.8, 2.8.7.9, 2.8.7.10, 2.8.8.1, 2.8.8.2, 2.8.8.3, 2.8.8.4, 2.8.8.5, 2.8.8.6., 2.8.8.7, 2.8.8.8, 2.8.8.9, 2.8.8.10, 2.89.1, 2.8.9.2, 2.89.3, 2.8.9.4, 2.89.5, 2.8.9.6, 2.8.9.7, 2.8.9.8, 2.8.9.9, 2.8.9.10, 2.8.10.1, 2.8.10.2, 2.8.10.3, 2.8.10.4, 2.8.10.5, 2.8.10.6, 2.8.10.7, 2.8.10.8, 2.8.10.9, 2.8.10.10, 2.9.1.1, 2.9.1.2, 2.9.1.3, 2.9.1.4, 2.9.1.5, 2.9.1.6., 2.9.1.7, 2.9.1.8, 2.9.1.9, 2.9.1.10, 2.9.2.1, 2.9.2.2, 2.9.2.3, 2.9.2.4, 2.9.2.5, 2.9.2.6, 2.9.2.7., 2.9.2.8, 2.9.2.9, 2.9.2.10, 2.9.3.1, 2.9.3.2, 2.9.3.3, 2.9.3.4, 2.9.3.5, 2.9.3.6, 2.9.3.7, 2.9.3.8, 2.9.3.9, 2.9.3.10, 2.9.4.1, 2.9.4.2, 2.9.4.3, 2.9.44, 2.9.45, 2.9.4.6, 2.94.7, 2.9.4.8, 2.9.4.9, 2.9.4.10, 2.9.5.1, 2.9.5.2, 2.9.5.3, 2.9.5.4, 2.9.5.5, 2.9.5.6, 2.9.5.7., 2.9.5.8, 2.9.5.9, 2.9.5.10, 2.9.6.1, 2.9.6.2, 2.9.6.3, 2.9.6.4, 2.9.6.5, 2.9.6.6, 2.9.6.7, 2.9.6.8, 2.9.6.9, 2.9.6.10, 2.9.7.1, 2.9.7.2, 2.9.7.3, 2.9.7.4, 2.9.7.5, 2.9.7.6, 2.9.7.7, 2.9.7.8, 2.9.7.9, 2.9.7.10, 2.9.8.1, 2.9.8.2, 2.9.8.3, 2.9.8.4, 2.9.8.5, 2.9.8.6., 2.9.8.7, 2.9.8.8, 2.9.8.9, 2.9.8.10, 2.9.9.1, 2.9.9.2, 2.9.9.3, 2.9.9.4, 2.99.5, 2.9.9.6, 2.9.9.7, 2.9.9.8, 2.9.9.9, 2.9.9.10, 2.9.10.1, 2.9.10.2, 2.9.10.3, 2.9.10.4, 2.9.10.5, 2.9.10.6, 2.9.10.7, 2.9.10.8, 2.9.10.9, 2.9.10.10, 2.10.1.1, 2.10.1.2, 2.10.1.3, 2.10.1.4, 2.10.1.5.2.10.1.6., 2.10.1.7, 2.10.1.8, 2.10.1.9, 2.10.1.10, 2.10.2.1, 2.10.2.2, 2.10.2.3, 2.10.2.4, 2.10.2.5, 0.2.6, 2.10.2.7., 2.10.2.8, 2.10.2.9, 2.10.2.10, 2.10.3.1, 2.10.3.2, 2.10.3.3.2.10.3.4, 2.10.3.5, 2.10.3.6., 2.10.3.7, 0.3.8, 2.10.3.9, 2.10.3.10, 2.10.4.1, 2.10.4.2, 2.10.4.3, 2.10.4.4, 2.10.4.5, 2.10.4.6., 2.10.4.7, 2.10.4.8, 2.10.4.9, 0.4.10, 2.10.5.1, 2.10.5.2, 2.10.5.3, 2.10.5.4, 2.10.5.5, 2.10.5.6, 2.10.5.7., 2.10.5.8, 2.10.5.9, 2.10.5.10, 2.10.6.1, 0.6.2, 2.10.6.3, 2.10.6.4, 2.10.6.5.2.10.6.6, 2.10.6.7., 2.10.6.8, 2.10.6.9, 2.10.6.10, 2.10.7.1, 2.10.7.2, 2.10.7.3, 0.7.4, 2.10.7.5, 2.10.7.6, 2.10.7.7, 2.10.7.8, 2.10.7.9, 2.10.7.10, 2.10.8.1, 2.10.8.2, 2.10.8.3, 2.10.8.4, 2.10.8.5, 0.8.6., 2.10.8.7, 2.10.8.8, 2.10.8.9, 2.10.8.10, 2.10.9.1, 2.10.9.2, 2.10.9.3, 2.10.9.4, 2.10.9.5, 2.10.9.6, 2.10.9.7, 0.9.8, 2.10.9.9, 2.10.9.10, 2.10.10.1, 2.10.10.2, 2.10.10.3, 2.10.10.4, 2.10.10.5, 2.10.10.6, 2.10.10.7, 2.10.10.8, 0.10.9, 2.10.10.10, 3.1.1.1, 3.1.1.2, 3.1.1.3.3.1.1.4, 3.1.1.5, 3.1.1.6, 3.1.1.7, 3.1.1.8, 3.1.1.9, 3.1.1.10, 3.1.2.1. .2.2, 3.1.2.3, 3.1.2.4, 3.1.2.5.3.1.2.6, 3.1.2.7, 3.1.2.8, 3.1.2.9, 3.1.2.10, 3.1.3.1, 3.1.3.2, 3.1.3.3.3.1.3.4.3.1.3.5, .3.6, 3.1.3.7, 3.1.3.8, 3.1.3.9, 3.1.3.10, 3.1.4.1, 3.1.4.2, 3.1.4.3, 3.1.4.4, 3.1.4.5, 3.1.4.6, 3.1.4.7, 3.14.8, 3.1.4.9, 4.10, 3.1.5.1, 3.1.5.2, 3.1.5.3, 3.1.5.4, 3.1.5.5, 3.1.5.6, 3.1.5.7., 3.1.5.8, 3.1.5.9, 3.1.5.10, 3.1.6.1, 3.1.6.2, 3.1.6.3, .6.4, 3.1.6.5, 3.1.6.6, 3.1.6.7, 3.1.6.8, 3.1.6.9, 3.1.6.10, 3.1.7.1, 3.17.2, 3.1.7.3, 3.17.4, 3.1.7.5, 3.1.7.6, 3.1.7.7, .7.8, 3.1.7.9, 3.1.7.10, 3.1.8.1, 3.1.8.2, 3.1.8.3, 3.1.8.4, 3.1.8.5, 3.1.8.6, 3.1.8.7, 3.1.8.8, 3.1.8.9, 3.1.8.10, 3.19.1, .9.2, 3.19.3, 3.19.4, 3.1.9.5, 3.19.6, 3.1.9.7, 3.19.8, 3.19.9, 3.1.9.10, 3.1.10.1, 3.1.10.2, 3.1.10.3, 3.1.10.4, 3.1.10.5, 3.1.10.6, 3.1.10.7, 3.1.10.8, 3.1.10.9, 3.1.10.10, 3.2.1.1, 3.2.1.2, 3.2.1.3.3.2.1.4, 3.2.1.5.3.2.1.6, 3.2.1.7, 3.2.1.8, 3.2.1.9, 3.2.1.10, 3.2.2.1, 3.2.2.2, 3.2.2.3, 3.2.2.4, 3.2.2.5.3.2.2.6, 3.2.2.7, 3.2.2.8, 3.2.2.9, 3.2.2.10, 3.2.3.1, 3.2.3.2, 3.2.3.3.3.2.3.4.3.2.3.5, 3.2.3.6, 3.2.3.7, 3.2.3.8, 3.2.3.9, 3.2.3.10, 3.2.4.1, 3.2.4.2, 3.2.4.3, 3.2.4.4, 3.2.4.5, US 7,863,261 B2 31 32

TABLE 2-continued 3.2.4.6, 3.24.7, 3.24.8, 3.2.4.9, 3.24.10, 3.2.5.1, 3.2.5.2, 3.2.5.3, 3.2.5.4, 3.2.5.5, 3.2.5.6, 3.2.5.7., 3.2.5.8, 3.2.5.9, 3.2.5.10, 3.2.6.1, 3.2.6.2, 3.2.6.3, 3.2.6.4, 3.2.6.5, 3.2.6.6, 3.2.6.7.3.2.6.8, 3.2.6.9, 3.2.6.10, 3.2.7.1.3.2.7.2, 3.2.7.3, 3.2.7.4, 3.2.7.5, 3.2.7.6, 3.2.7.7, 3.2.7.8, 3.2.7.9, 3.2.7.10, 3.2.8.1, 3.2.8.2, 3.2.8.3, 3.2.8.4, 3.2.8.5, 3.2.8.6, 3.2.8.7, 3.2.8.8, 3.2.8.9, 3.2.8.10, 3.2.9.1, 3.2.9.2, 3.2.9.3, 3.2.9.4, 3.2.9.5, 3.2.9.6, 3.2.9.7, 3.2.9.8, 3.2.9.9, 3.2.9.10, 3.2.10.1, 3.2.10.2, 3.2.10.3, 3.2.10.4, 3.2.10.5, 3.2.10.6, 3.2.10.7, 3.2.10.8, 3.2.10.9, 3.2.10.10, 3.3.1.1, 3.3.1.2, 3.3.1.3, 3.3.1.4, 3.3.1.5, 3.3.1.6, 3.3.1.7, 3.3.1.8, 3.3.1.9, 3.3.1.10, 3.3.2.1, 3.3.2.2, 3.3.2.3, 3.3.2.4, 3.3.2.5, 3.3.2.6, 3.3.2.7, 3.3.2.8, 3.3.2.9, 3.3.2.10, 3.3.3.1, 3.3.3.2, 3.3.3.3, 3.3.3.4, 3.3.3.5, 3.3.3.6, 3.3.3.7, 3.3.3.8, 3.3.3.9, 3.3.3.10, 3.3.4.1, 3.3.4.2, 3.3.4.3, 3.3.4.4, 3.3.4.5, 3.34.6, 3.3.4.7, 3.34.8, 3.3.4.9, 3.3.4.10, 3.3.5.1, 3.3.5.2, 3.3.5.3, 3.3.5.4, 3.3.5.5, 3.3.5.6, 3.3.5.7., 3.3.5.8, 3.3.5.9, 3.3.5.10, 3.3.6.1, 3.3.6.2, 3.3.6.3, 3.3.6.4, 3.3.6.5, 3.3.6.6, 3.3.6.7, 3.3.6.8, 3.3.6.9, 3.3.6.10, 3.3.7.1, 3.3.7.2, 3.3.7.3, 3.3.7.4, 3.3.7.5, 3.3.7.6, 3.3.7.7, 3.3.7.8, 3.3.7.9, 3.3.7.10, 3.3.8.1, 3.3.8.2, 3.3.8.3, 3.3.8.4, 3.3.8.5, 3.3.8.6, 3.3.8.7, 3.3.8.8, 3.3.8.9, 3.3.8.10, 3.3.9.1, 3.3.9.2, 3.3.9.3, 3.3.9.4, 3.3.9.5, 3.3.9.6, 3.3.9.7, 3.3.9.8, 3.3.9.9, 3.3.9.10, 3.3.10.1, 3.3.10.2, 3.3.10.3, 3.3.10.4, 3.3.10.5, 3.3.10.6, 3.3.10.7, 3.3.10.8, 3.3.10.9, 3.3.10.10, 3.4.1.1, 3.4.1.2, 3.4.1.3.3.4.1.4, 3.4.1.5, 3.4.1.6.3.4.1.7, 3.4.1.8, 3.4.1.9, 3.4.1.10, 3.4.2.1, 3.4.2.2, 3.4.2.3, 3.4.2.4, 3.4.2.5.3.4.2.6, 3.4.2.7.3.4.2.8, 3.4.2.9, 3.4.2.10, 3.4.3.1, 3.4.3.2, 3.4.3.3.3.4.3.4.3.4.3.5, 3.4.3.6.3.4.3.7, 3.4.3.8, 3.4.3.9, 3.4.3.10, 3.4.4.1, 3.4.4.2, 3.4.4.3, 3.4.4.4, 3.4.4.5, 3.4.4.6, 3.4.4.7, 3.4.4.8, 3.4.4.9, 3.4.4.10, 3.4.5.1, 3.4.5.2, 3.4.5.3, 3.4.5.4, 3.4.5.5, 3.4.5.6, 3.4.5.7., 3.4.5.8, 3.4.5.9, 3.4.5.10, 3.4.6.1, 3.4.6.2, 3.4.6.3.3.4.6.4, 3.4.6.5, 3.4.6.6, 3.4.6.7, 3.4.6.8, 3.4.6.9, 3.4.6.10, 34.7.1, 34.7.2, 3.4.7.3, 34.74, 3.4.7.5, 3.47.6, 34.7.7, 3.4.7.8, 34.7.9, 3.4.7.10, 3.4.8.1, 3.4.8.2, 3.4.8.3, 3.4.8.4, 3.4.8.5, 3.4.8.6.3.4.8.7, 3.4.8.8, 3.4.8.9, 3.4.8.10, 3.4.9.1, 3.4.9.2, 3.4.9.3, 3.4.9.4, 3.4.9.5, 3.4.9.6, 3.4.9.7, 3.4.9.8, 3.4.9.9, 3.4.9.10, 3.4.10.1, 3.4.10.2, 3.4.10.3, 3.4.10.4, 3.4.10.5, 3.4.10.6, 3.4.10.7, 34.10.8, 3.4.10.9, 3.4.10.10, 3.5.1.1, 3.5.1.2, 3.5.1.3, 3.5.1.4, 3.5.1.5, 3.5.1.6, 3.5.1.7, 3.5.1.8, 3.5.1.9, 3.5.1.10, 3.5.2.1, 3.5.2.2, 3.5.2.3, 3.5.2.4, 3.5.2.5, 3.5.2.6, 3.5.2.7, 3.5.2.8, 3.5.2.9, 3.5.2.10, 3.5.3.1, 3.5.3.2, 3.5.3.3, 3.5.3.4, 3.5.3.5, 3.5.3.6, 3.5.3.7, 3.5.3.8, 3.5.3.9, 3.5.3.10, 3.5.4.1, 3.5.4.2, 3.5.4.3, 3.5.44, 3.5.4.5, 3.5.4.6, 3.5.4.7, 3.5.48, 3.5.4.9, 3.5.4.10, 3.5.5.1, 3.5.5.2, 3.5.5.3, 3.5.5.4, 3.5.5.5, 3.5.5.6, 3.5.5.7., 3.5.5.8, 3.5.5.9, 3.5.5.10, 3.5.6.1, 3.5.6.2, 3.5.6.3, 3.5.6.4, 3.5.6.5, 3.5.6.6, 3.5.6.7, 3.5.6.8, 3.5.6.9, 3.5.6.10, 3.5.7.1, 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3.6.8.1, 3.6.8.2, 3.6.8.3, 3.6.8.4, 3.6.8.5, 3.6.8.6, 3.6.8.7, 3.6.8.8, 3.6.8.9, 3.6.8.10, 3.6.9.1, 3.6.9.2, 3.6.9.3, 3.6.9.4, 3.6.9.5, 3.6.9.6, 3.6.9.7, 3.6.9.8, 3.6.9.9, 3.6.9.10, 3.6.10.1, 3.6.10.2, 3.6.10.3, 3.6.10.4, 3.6.10.5, 3.6.10.6, 3.6.10.7, 3.6.10.8, 3.6.10.9, 3.6.10.10, 3.7.1.1, 3.7.1.2, 3.7.1.3, 3.7.1.4, 3.7.1.5, 3.7.1.6, 3.7.1.7, 3.7.1.8, 3.7.1.9, 3.7.1.10, 3.7.2.1, 3.7.2.2, 3.7.2.3, 3.7.2.4, 3.7.2.5, 3.7.2.6, 3.7.2.7, 3.7.2.8, 3.7.2.9, 3.7.2.10, 3.7.3.1, 3.7.3.2, 3.7.3.3.3.7.34, 3.7.3.5, 3.7.3.6, 3.7.3.7, 3.7.3.8, 3.7.3.9, 3.7.3.10, 3.7.4.1, 3.74.2, 3.7.4.3, 3.7.44, 3.7.4.5, 3.74.6, 3.74.7, 3.74.8, 3.7.4.9, 3.74.10, 3.7.5.1, 3.7.5.2, 3.7.5.3, 3.7.5.4, 3.7.5.5, 3.7.5.6, 3.7.5.7., 3.7.5.8, 3.7.5.9, 3.7.5.10, 3.7.6.1, 3.7.6.2, 3.7.6.3, 3.7.6.4, 3.7.6.5, 3.7.6.6, 3.7.6.7, 3.7.6.8, 3.7.6.9, 3.7.6.10, 3.7.7.1, 3.7.7.2, 3.7.7.3, 3.7.7.4, 3.7.7.5, 3.7.7.6, 3.7.7.7, 3.7.7.8, 3.7.7.9, 3.7.7.10, 3.7.8.1, 3.7.8.2, 3.7.8.3, 3.7.8.4, 3.7.8.5, 3.7.8.6, 3.7.8.7, 3.7.8.8, 3.7.8.9, 3.7.8.10, 3.7.9.1, 3.7.9.2, 3.7.9.3, 3.79.4, 3.7.9.5, 3.7.9.6, 3.7.9.7, 3.7.9.8, 3.7.9.9, 3.7.9.10, 3.7.10.1, 3.7.10.2, 3.7.10.3, 3.7.10.4, 3.7.10.5, 3.7.10.6, 3.7.10.7, 3.7.10.8, 3.7.10.9, 3.7.10.10, 3.8.1.1, 3.8.1.2, 3.8.1.3, 3.8.1.4, 3.8.1.5, 3.8.1.6, 3.8.1.7, 3.8.1.8, 3.8.1.9, 3.8.1.10, 3.8.2.1, 3.8.2.2, 3.8.2.3, 3.8.2.4, 3.8.2.5, 3.8.2.6, 3.8.2.7, 3.8.2.8, 3.8.2.9, 3.8.2.10, 3.8.3.1, 3.8.3.2, 3.8.3.3, 3.8.34, 3.8.3.5, 3.8.3.6, 3.8.3.7, 3.8.3.8, 3.8.3.9, 3.8.3.10, 3.8.4.1, 3.8-4.2, 3.8.4.3, 3.8.4.4, 3.8.4.5, 3.84.6, 3.8.47, 3.8-4.8, 3.8.4.9, 3.8.4.10, 3.8.5.1, 3.8.5.2, 3.8.5.3, 3.8.5.4, 3.8.5.5, 3.8.5.6, 3.8.5.7., 3.8.5.8, 3.8.5.9, 3.8.5.10, 3.8.6.1, 3.8.6.2, 3.8.6.3, 3.8.6.4, 3.8.6.5, 3.8.6.6, 3.8.6.7, 3.8.6.8, 3.8.6.9, 3.8.6.10, 3.8.7.1, 3.8.7.2, 3.8.7.3, 3.8.7.4, 3.8.7.5, 3.8.7.6, 3.8.7.7, 3.8.7.8, 3.8.7.9, 3.8.7.10, 3.8.8.1, 3.8.8.2, 3.8.8.3, 3.8.8.4, 3.8.8.5, 3.8.8.6, 3.8.8.7, 3.8.8.8, 3.8.8.9, 3.8.8.10, 3.8.9.1, 3.8.9.2, 3.89.3, 3.8.9.4, 3.8.9.5, 3.8.9.6, 3.8.9.7, 3.8.9.8, 3.8.9.9, 3.8.9.10, 3.8.10.1, 3.8.10.2, 3.8.10.3, 3.8.10.4, 3.8.10.5, 3.8.10.6, 3.8.10.7, 3.8.10.8, 3.8.10.9, 3.8.10.10, 3.9.1.1, 3.9.1.2, 3.9.1.3, 3.9.1.4, 3.9.1.5, 3.9.1.6, 3.9.1.7, 3.9.1.8, 3.9.1.9, 3.9.1.10, 3.9.2.1, 3.9.2.2, 3.9.2.3, 3.9.2.4, 3.9.2.5, 3.9.2.6, 3.9.2.7, 3.9.2.8, 3.9.2.9, 3.9.2.10, 3.9.3.1, 3.9.3.2, 3.9.3.3, 3.9.3.4, 3.9.3.5, 3.9.3.6, 3.9.3.7, 3.9.3.8, 3.9.3.9, 3.9.3.10, 3.9.4.1, 3.9.4.2, 3.9.4.3, 3.9.44, 3.9.45, 3.9.4.6, 3.94.7, 3.9.4.8, 3.9.4.9, 3.9.4.10, 3.9.5.1, 3.9.5.2, 3.9.5.3, 3.9.5.4, 3.9.5.5, 3.9.5.6, 3.9.5.7., 3.9.5.8, 3.9.5.9, 3.9.5.10, 3.9.6.1, 3.9.6.2, 3.9.6.3, 3.9.6.4, 3.9.6.5, 3.9.6.6, 3.9.6.7, 3.9.6.8, 3.9.6.9, 3.9.6.10, 3.9.7.1, 3.9.7.2, 3.9.7.3, 3.9.7.4, 3.9.7.5, 3.9.7.6, 3.9.7.7, 3.9.7.8, 3.9.7.9, 3.9.7.10, 3.9.8.1, 3.9.8.2, 3.9.8.3, 3.9.8.4, 3.9.8.5, 3.9.8.6, 3.9.8.7, 3.9.8.8, 3.9.8.9, 3.9.8.10, 3.9.9.1, 3.9.9.2, 3.9.9.3, 3.9.9.4, 3.9.9.5, 3.9.9.6, 3.9.9.7, 3.9.9.8, 3.9.9.9, 3.9.9.10, 3.9.10.1, 3.9.10.2, 3.9.10.3, 3.9.10.4, 3.9.10.5, 3.9.10.6, 3.9.10.7, 3.9.10.8, 3.9.10.9, 3.9.10.10, 3.10.1.1, 3.10.1.2, 3.10.1.3, 3.10.1.4, 3.10.1.5, 3.10.1.6, 3.10.1.7, 3.10.1.8, 3.10.1.9, 3.10.1.10, 3.10.2.1, 3.10.2.2, 3.10.2.3, 3.10.2.4, 3.10.2.5, 0.2.6, 3.10.2.7, 3.10.2.8, 3.10.2.9, 3.10.2.10, 3.10.3.1, 3.10.3.2, 3.10.3.3, 3.10.3.4, 3.10.3.5, 3.10.3.6, 3.10.3.7, 0.3.8, 3.10.3.9, 3.10.3.10, 3.10.4.1, 3.10.4.2, 3.10.4.3, 3.10.4.4, 3.10.4.5, 3.10.4.6, 3.10.4.7, 3.10.4.8, 3.10.4.9, 0.4.10, 3.10.5.1, 3.10.5.2, 3.10.5.3, 3.10.5.4, 3.10.5.5, 3.10.5.6, 3.10.5.7., 3.10.5.8, 3.10.5.9, 3.10.5.10, 3.10.6.1, 0.6.2, 3.10.6.3, 3.10.6.4, 3.10.6.5, 3.10.6.6, 3.10.6.7, 3.10.6.8, 3.10.6.9, 3.10.6.10, 3.10.7.1, 3.10.7.2, 3.10.7.3, 0.7.4, 3.10.7.5, 3.10.7.6, 3.10.7.7, 3.10.7.8, 3.10.7.9, 3.10.7.10, 3.10.8.1, 3.10.8.2, 3.10.8.3, 3.10.8.4, 3.10.8.5, 0.8.6, 3.10.8.7, 3.10.8.8, 3.10.8.9, 3.10.8.10, 3.10.9.1, 3.10.9.2, 3.10.9.3, 3.10.9.4, 3.10.9.5, 3.10.9.6, 3.10.9.7, 0.9.8, 3.10.9.9, 3.10.9.10, 3.10.10.1, 3.10.10.2, 3.10.10.3, 3.10.10.4, 3.10.10.5, 3.10.10.6, 3.10.10.7, 3.10.10.8, 0.10.9, 3.10.10.10, 4.1.1.1, 4.1.1.2, 4.1.1.3, 4.1.1.4, 4.1.1.5, 4.1.1.6, 4.1.1.7, 4.1.1.8, 4.1.1.9, 4.1.1.10, 4.1.2.1, .2.2, 4.1.2.3, 4.1.2.4, 4.1.2.5, 4.1.2.6, 4.1.2.7. 4.1.2.8, 4.1.2.9, 4.1.2.10, 4.1.3.1, 4.1.3.2, 4.1.3.3, 4.1.3.4. 4.1.3.5, .3.6, 4.1.3.7, 4.1.3.8, 4.1.3.9, 4.1.3.10, 4.1.4.1, 4.1.4.2, 4.1.4.3, 4.1.4.4, 4.1.4.5, 4.1.4.6, 4.1.4.7, 4.1.4.8, 4.1.4.9, .4.10, 4.1.5.1, 4.1.5.2, 4.1.5.3, 4.1.5.4, 4.1.5.5, 4.1.5.6, 4.1.5.7., 4.1.5.8, 4.1.5.9, 4.1.5.10, 4.1.6.1, 4.1.6.2, 4.1.6.3, .6.4, 4.1.6.5, 4.1.6.6, 4.1.6.7. 4.1.6.8, 4.1.6.9, 4.1.6.10, 4.1.7.1, 4.1.7.2, 4.1.7.3, 4.1.7.4, 4.1.7.5, 4.1.7.6, 4.1.7.7, .7.8, 4.1.7.9, 4.1.7.10, 4.1.8.1, 4.1.8.2, 4.1.8.3, 4.1.8.4, 4.1.8.5, 4.1.8.6, 4.1.8.7, 4.1.8.8, 4.1.8.9, 4.1.8.10, 4.1.9.1, .9.2, 4.1.9.3, 4.1.9.4, 4.1.9.5, 4.1.9.6, 4.1.9.7, 4.1.9.8, 4.1.9.9, 4.1.9.10, 4.1.10.1, 4.1.10.2, 4.1.10.3, 4.1.10.4, .10.5, 4.1.10.6, 4.1.10.7, 4.1.10.8, 4.1.10.9, 4.1.10.10, 4.2.1.1, 4.2.1.2, 4.2.1.3, 4.2.1.4, 4.2.1.5, 4.2.1.6, 4.2.1.7, 4.2.1.8, 4.2.1.9, 4.2.1.10, 4.2.2.1, 4.2.2.2, 4.2.2.3, 4.2.2.4, 4.2.2.5, 4.2.2.6, 4.2.2.7., 4.2.2.8, 4.2.2.9, 4.2.2.10, 4.2.3.1, 4.2.3.2, 4.2.3.3, 4.2.3.4. 4.2.3.5, 4.2.3.6, 4.2.3.7, 4.2.3.8, 4.2.3.9, 4.2.3.10, 4.2.4.1, 4.2.4.2, 4.2.4.3, 4.2.4.4, 4.2.4.5, 4.2.4.6, 4.2.4.7, 4.2.4.8, 4.2.4.9, 4.2.4.10, 4.2.5.1, 4.2.5.2, 4.2.5.3, 4.2.5.4, 4.2.5.5, 4.2.5.6, 4.2.5.7., 4.2.5.8, 4.2.5.9, 4.2.5.10, 4.2.6.1, 4.2.6.2, 4.2.6.3, 4.2.6.4, 4.2.6.5, 4.2.6.6, 4.2.6.7., 4.2.6.8, 4.2.6.9, 4.2.6.10, 4.2.7.1, 4.2.7.2, 4.2.7.3, 4.2.7.4, 4.2.7.5, 4.2.7.6, 4.2.7.7, 4.2.7.8, 4.2.7.9, 4.2.7.10, 4.2.8.1, 4.2.8.2, 4.2.8.3, 4.2.8.4, 4.2.8.5, 4.2.8.6, 4.2.8.7, 4.2.8.8, 4.2.8.9, 4.2.8.10, 4.2.9.1, 4.2.9.2, 4.2.9.3, 4.2.9.4, 4.2.9.5, 4.2.9.6, 4.2.9.7, 4.2.9.8, 4.2.9.9, 4.2.9.10, 4.2.10.1, 4.2.10.2, 4.2.10.3, 4.2.10.4, 4.2.10.5, 4.2.10.6, 4.2.10.7, 4.2.10.8, 4.2.10.9, 4.2.10.10, 4.3.1.1, 4.3.1.2, 4.3.1.3, US 7,863,261 B2 33 34

TABLE 2-continued 4.3.1.4, 4.3.1.5, 4.3.1.6, 4.3.1.7, 4.3.1.8, 4.3.1.9, 4.3.1.10, 4.3.2.1, 4.3.2.2, 4.3.2.3, 4.3.2.4, 4.3.2.5, 4.3.2.6, 4.3.2.7. 4.3.2.8, 4.3.2.9, 4.3.2.10, 4.3.3.1, 4.3.3.2, 4.3.3.3, 4.3.3.4. 4.3.3.5, 4.3.3.6, 4.3.3.7, 4.3.3.8, 4.3.3.9, 4.3.3.10, 4.3.4.1, 4.3.4.2, 4.3.4.3, 4.3.4.4, 4.3.4.5, 4.3.4.6, 4.3.4.7, 4.3.4.8, 4.3.4.9, 4.3.4.10, 4.3.5.1, 4.3.5.2, 4.3.5.3, 4.3.5.4, 4.3.5.5, 4.3.5.6, 4.3.5.7., 4.3.5.8, 4.3.5.9, 4.3.5.10, 4.3.6.1, 4.3.6.2, 4.3.6.3, 4.3.6.4, 4.3.6.5, 4.3.6.6, 4.3.6.7. 4.3.6.8, 4.3.6.9, 4.3.6.10, 4.3.7.1, 4.3.7.2, 4.3.7.3, 4.3.7.4, 4.3.7.5, 4.3.7.6, 4.3.7.7, 4.3.7.8, 4.3.7.9, 4.3.7.10, 43.8.1, 4.3.8.2, 43.8.3, 4.3.8.4, 4.3.8.5, 4.3.8.6, 4.3.8.7, 4.3.8.8, 4.3.8.9, 4.3.8.10, 4.3.9.1, 4.3.9.2, 4.3.9.3, 4.3.9.4, 4.3.9.5, 4.3.9.6, 4.3.9.7, 4.3.9.8, 4.3.9.9, 4.3.9.10, 4.3.10.1, 4.3.10.2, 4.3.10.3, 4.3.10.4, 4.3.10.5, 4.3.10.6, 4.3.10.7, 4.3.10.8, 4.3.10.9, 4.3.10.10, 4.4.1.1, 4.4.1.2, 4.4.1.3, 4.4.1.4, 4.4.1.5, 4.4.1.6, 4.4.1.7, 4.4.1.8, 4.4.1.9, 4.4.1.10, 4.4.2.1, 4.4.2.2, 4.4.2.3, 4.4.2.4, 4.4.2.5, 4.4.2.6, 4.4.2.7, 4.4.2.8, 4.4.2.9, 4.4.2.10, 4.4.3.1, 4.4.3.2, 4.4.3.3, 4.4.3.4.4.4.3.5, 4.4.3.6, 4.4.3.7, 4.4.3.8, 4.4.3.9, 4.4.3.10, 4.4.4.1, 4.4.4.2, 4.4.4.3, 4.4.4.4, 4.4.4.5, 4.4.4.6, 4.4.4.7, 4.4.4.8, 4.4.4.9, 4.4.4.10, 4.4.5.1, 4.4.5.2, 4.4.5.3, 4.4.5.4, 4.4.5.5, 4.4.5.6, 4.4.5.7., 4.4.5.8, 4.4.5.9, 4.4.5.10, 4.4.6.1, 4.4.6.2, 4.4.6.3, 4.4.6.4.4.4.6.5, 4.4.6.6, 4.4.6.7. 4.4.6.8, 4.4.6.9, 4.4.6.10, 4.4.7.1, 4.4.7.2, 4.4.7.3, 4.4.7.4, 4.4.7.5, 4.4.7.6, 4.4.7.7, 4.4.7.8, 4.4.7.9, 4.4.7.10, 4.4.8.1, 4.4.8.2, 4.4.8.3, 4.4.8.4, 4.4.8.5, 4.4.8.6, 4.4.8.7, 4.4.8.8, 4.4.8.9, 4.4.8.10, 4.4.9.1, 4.4.9.2, 4.4.9.3, 4.4.9.4, 4.4.9.5, 4.4.9.6, 4.4.9.7, 4.4.9.8, 4.4.9.9, 4.4.9.10, 4.4.10.1, 4.4.10.2, 4.4.10.3, 4.4.10.4, 4.4.10.5, 4.4.10.6, 4.4.10.7, 4.4.10.8, 4.4.10.9, 4.4.10.10, 4.5.1.1, 4.5.1.2, 4.5.1.3, 4.5.1.4, 4.5.1.5, 4.5.1.6, 4.5.1.7, 4.5.1.8, 4.5.1.9, 4.5.1.10, 4.5.2.1, 4.5.2.2, 4.5.2.3, 4.5.2.4, 4.5.2.5, 4.5.2.6, 4.5.2.7. 4.5.2.8, 4.5.2.9, 4.5.2.10, 4.5.3.1, 4.5.3.2, 4.5.3.3, 4.5.3.4. 4.5.3.5, 4.5.3.6, 4.5.3.7, 4.5.3.8, 4.5.3.9, 4.5.3.10, 4.5.4.1, 4.5.4.2, 4.5.4.3, 4.5.44, 4.5.4.5, 4.5.4.6, 4.5.4.7, 4.5.48, 4.5.4.9, 4.5.4.10, 4.5.5.1, 4.5.5.2, 4.5.5.3, 4.5.5.4, 4.5.5.5, 4.5.5.6, 4.5.5.7., 4.5.5.8, 4.5.5.9, 4.5.5.10, 4.5.6.1, 4.5.6.2, 4.5.6.3, 4.5.6.4, 4.5.6.5, 4.5.6.6, 4.5.6.7, 4.5.6.8, 4.5.6.9, 4.5.6.10, 4.5.7.1, 4.5.7.2, 4.5.7.3, 4.5.7.4, 4.5.7.5 4.5.7.6, 4.5.7.7, 4.5.7.8, 4.5.7.9, 4.5.7.10, 4.5.8.1, 4.5.8.2, 4.5.8.3, 4.5.8.4, 4.5.8.5, 4.5.8.6, 4.5.8.7, 4.5.8.8, 4.5.8.9, 4.5.8.10, 4.5.9.1, 4.5.9.2, 4.5.9.3, 4.5.9.4, 4.5.9.5, 4.5.9.6, 4.5.9.7, 4.5.9.8, 4.5.9.9, 4.5.9.10, 4.5.10.1, 4.5.10.2, 4.5.10.3, 4.5.10.4, 4.5.10.5, 4.5.10.6, 4.5.10.7, 4.5.10.8, 4.5.10.9, 4.5.10.10, 4.6.1.1, 4.6.1.2, 4.6.1.3, 4.6.1.4, 4.6.1.5. 4.6.1.6, 4.6.1.7, 4.6.1.8, 4.6.1.9, 4.6.1.10, 4.6.2.1.4.6.2.2, 4.6.2.3, 4.6.2.4, 4.6.2.5, 4.6.2.6, 4.6.2.7. 4.6.2.8, 4.6.2.9, 4.6.2.10, 4.6.3.1, 4.6.3.2, 4.6.3.3, 4.6.3.4.4.6.3.5, 4.6.3.6, 4.6.3.7, 4.6.3.8, 4.6.3.9, 4.6.3.10, 4.6.4.1, 4.6.4.2, 4.6.4.3, 4.6.4.4, 4.6.4.5, 4.6.4.6, 4.6.4.7, 4.6.4.8, 4.6.4.9, 4.6.4.10, 4.6.5.1, 4.6.5.2, 4.6.5.3, 4.6.5.4, 4.6.5.5, 4.6.5.6, 4.6.5.7., 4.6.5.8, 4.6.5.9, 4.6.5.10, 4.6.6.1, 4.6.6.2, 4.6.6.3, 4.6.6.4, 4.6.6.5, 4.6.6.6, 4.6.6.7. 4.6.6.8, 4.6.6.9, 4.6.6.10, 4.6.7.1, 4.6.7.2, 4.6.7.3, 4.6.7.4, 4.6.7.5, 4.6.7.6, 4.6.7.7, 4.6.7.8, 4.6.7.9, 4.6.7.10, 4.6.8.1, 4.6.8.2, 4.6.8.3, 4.6.8.4, 4.6.8.5, 4.6.8.6, 4.6.8.7, 4.6.8.8, 4.6.8.9, 4.6.8.10, 4.6.9.1, 4.6.9.2, 4.6.9.3, 4.6.9.4, 4.6.9.5, 4.6.9.6, 4.6.9.7, 4.6.9.8, 4.6.9.9, 4.6.9.10, 4.6.10.1, 4.6.10.2, 4.6.10.3, 4.6.10.4, 4.6.10.5, 4.6.10.6, 4.6.10.7, 4.6.10.8, 4.6.10.9, 4.6.10.10, 4.7.1.1, 4.7.1.2, 4.7.1.3, 4.7.1.4, 4.7.1.5, 4.7.1.6, 4.7.1.7, 4.7.1.8, 4.7.1.9, 4.7.1.10, 4.7.2.1, 4.7.2.2, 4.7.2.3, 4.7.2.4, 4.7.2.5. 4.7.2.6, 4.7.2.7, 4.7.2.8, 4.7.2.9, 4.7.2.10, 4.7.3.1, 4.7.3.2, 4.7.3.3, 4.7.34, 4.7.3.5, 4.7.3.6, 4.7.3.7, 4.7.3.8, 4.7.3.9, 4.7.3.10, 4.7.4.1, 4.7.4.2, 4.7.4.3, 4.7.4.4, 4.7.4.5, 4.7.4.6, 4.7.4.7, 4.7.4.8, 4.7.4.9, 4.7.4.10, 4.7.5.1, 4.7.5.2, 4.7.5.3, 4.7.5.4, 4.7.5.5, 4.7.5.6, 4.7.5.7., 4.7.5.8, 4.7.5.9, 4.7.5.10, 4.7.6.1, 4.7.6.2, 4.7.6.3, 4.7.6.4, 4.7.6.5, 4.7.6.6, 4.7.6.7, 4.7.6.8, 4.7.6.9, 4.7.6.10, 4.7.7.1, 4.7.7.2, 4.7.7.3, 4.7.7.4, 4.7.7.5, 4.7.7.6, 4.7.7.7, 4.7.7.8, 4.7.7.9, 47.7.10, 4.7.8.1, 4.7.8.2, 4.7.8.3, 4.7.8.4, 4.7.8.5, 4.7.8.6, 4.7.8.7, 4.7.8.8, 4.7.8.9, 4.7.8.10, 4.7.9.1, 4.7.9.2, 4.7.9.3, 4.7.9.4, 4.7.9.5, 4.7.9.6, 4.7.9.7, 4.7.9.8, 4.7.9.9, 4.7.9.10, 4.7.10.1, 4.7.10.2, 4.7.10.3, 4.7.10.4, 4.7.10.5, 4.7.10.6, 4.7.10.7, 4.7.10.8, 4.7.10.9, 4.7.10.10, 4.8.1.1, 4.8.1.2, 4.8.1.3, 4.8.1.4, 4.8.1.5, 4.8.1.6, 4.8.1.7, 4.8.1.8, 4.8.1.9, 4.8.1.10, 4.8.2.1, 4.8.2.2, 4.8.2.3, 4.8.2.4, 4.8.2.5, 4.8.2.6, 4.8.2.7, 4.8.2.8, 4.8.2.9, 4.8.2.10, 4.8.3.1, 4.8.3.2, 4.8.3.3, 4.8.3.4, 4.8.3.5, 4.8.3.6, 4.8.3.7, 4.8.3.8, 4.8.3.9, 4.8.3.10, 4.8.4.1, 4.8.4.2, 4.8.4.3, 4.8.4.4, 4.8.4.5, 4.8.4.6, 4.8.4.7, 4.8-4.8, 4.8.4.9, 4.8.4.10, 4.8.5.1, 4.8.5.2, 4.8.5.3, 4.8.5.4, 4.8.5.5, 4.8.5.6, 4.8.5.7., 4.8.5.8, 4.8.5.9, 4.8.5.10, 4.8.6.1, 4.8.6.2, 4.8.6.3, 4.8.6.4, 4.8.6.5, 4.8.6.6, 4.8.6.7., 4.8.6.8, 4.8.6.9, 4.8.6.10, 4.8.7.1, 4.8.7.2, 4.8.7.3, 4.8.7.4, 4.8.7.5, 4.8.7.6, 4.8.7.7, 4.8.7.8, 4.8.7.9, 4.8.7.10, 4.8.8.1, 4.8.8.2, 4.8.8.3, 4.8.8.4, 4.8.8.5, 4.8.8.6, 4.8.8.7, 4.8.8.8, 4.8.8.9, 4.8.8.10, 4.8.9.1, 4.8.9.2, 4.8.9.3, 4.8.9.4, 4.8.9.5, 4.8.9.6, 4.8.9.7, 4.8.9.8, 4.8.9.9, 4.8.9.10, 4.8.10.1, 4.8.10.2, 4.8.10.3, 4.8.10.4, 4.8.10.5, 4.8.10.6, 4.8.10.7, 4.8.10.8, 4.8.10.9, 4.8.10.10, 4.9.1.1, 4.9.1.2, 4.9.1.3, 4.9.1.4, 4.9.1.5, 4.9.1.6, 4.9.1.7, 4.9.1.8, 4.9.1.9, 4.9.1.10, 4.9.2.1, 4.9.2.2, 4.9.2.3, 4.9.2.4, 4.9.2.5, 4.9.2.6, 4.9.2.7, 4.9.2.8, 4.9.2.9, 4.9.2.10, 4.9.3.1, 4.9.3.2, 4.9.3.3, 4.9.3.4.4.9.3.5, 4.9.3.6, 4.9.3.7, 4.9.3.8, 4.9.3.9, 4.9.3.10, 4.9.4.1, 4.9.4.2, 4.9.4.3, 4.9.4.4.4.9.4.5, 49.4.6, 49.4.7, 49.4.8, 4.9.4.9, 49.4.10, 49.5.1, 4.9.5.2, 4.9.5.3, 4.9.5.4, 49.5.5, 49.5.6, 4.9.5.7., 49.5.8, 4.9.5.9, 4.9.5.10, 4.9.6.1, 4.9.6.2, 4.9.6.3, 4.9.6.4, 4.9.6.5, 4.9.6.6, 4.9.6.7., 4.9.6.8, 4.9.6.9, 4.9.6.10, 4.9.7.1, 4.9.7.2, 4.9.7.3, 4.9.7.4, 4.9.7.5, 49.7.6, 4.9.7.7, 4.9.7.8, 4.9.7.9, 49.7.10, 49.8.1, 4.9.8.2, 4.9.8.3, 49.8.4, 4.9.8.5, 49.8.6, 4.9.8.7, 49.8.8, 4.9.8.9, 49.8.10, 4.9.9.1, 4.9.9.2, 49.9.3, 4.9.9.4, 4.99.5, 4.9.9.6, 49.9.7, 4.9.9.8, 4.9.9.9, 49.9.10, 4.9.10.1, 4.9.10.2, 4.9.10.3, 4.9.10.4, 4.9.10.5, 4.9.10.6, 4.9.10.7, 4.9.10.8, 4.9.10.9, 4.9.10.10, 4.10.1.1, 4.10.1.2, 4.10.1.3, 0.1.4, 4.10.1.5, 4.10.1.6, 4.10.1.7, 4.10.1.8, 4.10.1.9, 4.10.1.10, 4.10.2.1, 4.10.2.2, 4.10.2.3, 4.10.2.4, 4.10.2.5, 0.2.6, 4.10.2.7. 4.10.2.8, 4.10.2.9, 4.10.2.10, 4.10.3.1, 4.10.3.2, 4.10.3.3, 4.10.3.4. 4.10.3.5, 4.10.3.6, 4.10.3.7, 0.3.8, 4.10.3.9, 4.10.3.10, 4.10.4.1, 4.10.4.2, 4.10.4.3, 4.10.4.4, 4.10.4.5, 4.10.4.6, 4.10.4.7, 4.10.4.8, 4.10.4.9, 0.4.10, 4.10.5.1, 4.10.5.2, 4.10.5.3, 4.10.5.4, 4.10.5.5, 4.10.5.6, 4.10.5.7., 4.10.5.8, 4.10.5.9, 4.10.5.10, 4.10.6.1, 0.6.2, 4.10.6.3, 4.10.6.4, 4.10.6.5, 4.10.6.6, 4.10.6.7. 4.10.6.8, 4.10.6.9, 4.10.6.10, 4.10.7.1, 4.10.7.2, 4.10.7.3, 0.7.4, 4.10.7.5, 4.10.7.6, 4.10.7.7, 4.10.7.8, 4.10.7.9, 4.10.7.10, 4.10.8.1, 4.10.8.2, 4.10.8.3, 4.10.8.4, 4.10.8.5, 0.8.6, 4.10.8.7, 4.10.8.8, 4.10.8.9, 4.10.8.10, 4.10.9.1, 4.10.9.2, 4.10.9.3, 4.10.9.4, 4.10.9.5, 4.10.9.6, 4.10.9.7, 0.9.8, 4.10.9.9, 4.10.9.10, 4.10.10.1, 4.10.10.2, 4.10.10.3, 4.10.10.4, 4.10.10.5, 4.10.10.6, 4.10.10.7, 4.10.10.8, 0.10.9, 4.10.10.10, 5.1.1.1, 5.1.1.2, 5.1.1.3, 5.1.1.4, 5.1.1.5, 5.1.1.6, 5.1.1.7, 5.1.1.8, 5.1.1.9, 5.1.1.10, 5.1.2.1. .2.2, 5.1.2.3, 5.1.2.4, 5.1.2.5, 5.1.2.6, 5.1.2.7, 5.1.2.8, 5.1.2.9, 5.1.2.10, 5.1.3.1, 5.1.3.2, 5.1.3.3, 5.1.3.4, 5.1.3.5 .3.6, 5.1.3.7, 5.1.3.8, 5.1.3.9, 5.1.3.10, 5.1.4.1, 5.1.4.2, 5.1.4.3, 5.1.4.4, 5.1.4.5, 5.1.4.6., 5.1.4.7, 5.1.4.8, 5.1.4.9, 4.10, 5.1.5.1, 5.1.5.2, 5.1.5.3, 5.1.5.4, 5.1.5.5, 5.1.5.6, 5.1.5.7., 5.1.5.8, 5.1.5.9, 5.1.5.10, 5.1.6.1, 5.1.6.2, 5.1.6.3, .6.4, 5.1.6.5, 5.1.6.6, 5.1.6.7, 5.1.6.8, 5.1.6.9, 5.1.6.10, 5.1.7.1, 5.1.7.2, 5.1.7.3, 5.1.7.4, 5.1.7.5, 5.1.7.6, 5.1.7.7, .7.8, 5.1.7.9, 5.1.7.10, 5.1.8.1, 5.1.8.2, 5.1.8.3, 5.1.8.4, 5.1.8.5, 5.1.8.6., 5.1.8.7, 5.1.8.8, 5.1.8.9, 5.1.8.10, 5.1.9.1, .9.2, 5.1.9.3, 5.19.4, 5.1.9.5, 5.1.9.6, 5.1.9.7, 5.19.8, 5.1.9.9, 5.1.9.10, 5.1.10.1, 5.1.10.2, 5.1.10.3, 5.1.10.4, .10.5, 5.1.10.6, 5.1.10.7, 5.1.10.8, 5.1.10.9, 5.1.10.10, 5.2.1.1, 5.2.1.2, 5.2.1.3, 5.2.1.4, 5.2.1.5, 5.2.1.6, 5.2.1.7, 5.2.1.8, 5.2.1.9, 5.2.1.10, 5.2.2.1, 5.2.2.2, 5.2.2.3, 5.2.2.4, 5.2.2.5, 5.2.2.6, 5.2.2.7, 5.2.2.8, 5.2.2.9, 5.2.2.10, 5.2.3.1, 5.2.3.2, 5.2.3.3, 5.2.3.4, 5.2.3.5, 5.2.3.6, 5.2.3.7, 5.2.3.8, 5.2.3.9, 5.2.3.10, 5.2.4.1, 5.24.2, 5.2.4.3, 5.2.4.4, 5.24.5, 5.2.4.6, 5.24.7, 5.24.8, 5.2.4.9, 5.24.10, 5.2.5.1, 5.2.5.2, 5.2.5.3, 5.2.5.4, 5.2.5.5, 5.2.5.6, 5.2.5.7., 5.2.5.8, 5.2.5.9, 5.2.5.10, 5.2.6.1, 5.2.6.2, 5.2.6.3, 5.2.6.4, 5.2.6.5, 5.2.6.6, 5.2.6.7, 5.2.6.8, 5.2.6.9, 5.2.6.10, 5.2.7.1, 5.2.7.2, 5.2.7.3, 5.2.7.4, 5.2.7.5, 5.2.7.6, 5.2.7.7, 5.2.7.8, 5.2.7.9, 5.2.7.10, 5.2.8.1, 5.2.8.2, 5.2.8.3, 5.2.8.4, 5.2.8.5, 5.2.8.6., 5.2.8.7, 5.2.8.8, 5.2.8.9, 5.2.8.10, 5.2.9.1, 5.2.9.2, 5.2.9.3, 5.2.9.4, 5.2.9.5, 5.2.9.6, 5.2.9.7, 5.2.9.8, 5.2.9.9, 5.2.9.10, 5.2.10.1, 5.2.10.2, 5.2.10.3, 5.2.10.4, 5.2.10.5, 5.2.10.6, 5.2.10.7, 5.2.10.8, 5.2.10.9, 5.2.10.10, 5.3.1.1, 5.3.1.2, 5.3.1.3, 5.3.1.4, 5.3.1.5, 5.3.1.6, 5.3.1.7, 5.3.1.8, 5.3.1.9, 5.3.1.10, 5.3.2.1, 5.3.2.2, 5.3.2.3, 5.3.2.4, 5.3.2.5, 5.3.2.6, 5.3.2.7, 5.3.2.8, 5.3.2.9, 5.3.2.10, 5.3.3.1, 5.3.3.2, 5.3.3.3, 5.3.3.4, 5.3.3.5, 5.3.3.6., 5.3.3.7, 5.3.3.8, 5.3.3.9, 5.3.3.10, 5.3.4.1, 5.3.4.2, 5.3.4.3, 5.3.4.4, 5.3.4.5, 5.3.4.6, 5.3.4.7, 5.3.4.8, 5.3.4.9, 5.3.4.10, 5.3.5.1, 5.3.5.2, 5.3.5.3, 5.3.5.4, 5.3.5.5, 5.3.5.6, 5.3.5.7., 5.3.5.8, 5.3.5.9, 5.3.5.10, 5.3.6.1, 5.3.6.2, 5.3.6.3, 5.3.6.4, 5.3.6.5, 5.3.6.6, 5.3.6.7, 5.3.6.8, 5.3.6.9, 5.3.6.10, 5.3.7.1, 5.3.7.2, 5.3.7.3, 5.3.7.4, 5.3.7.5, 5.3.7.6, 5.3.7.7, 5.3.7.8, 5.3.7.9, 5.3.7.10, 5.3.8.1, 5.3.8.2, 5.3.8.3 US 7,863,261 B2 35 36

TABLE 2-continued 5.3.8.4, 5.3.8.5, 5.3.8.6., 5.3.8.7, 5.3.8.8, 5.3.8.9, 5.3.8.10, 5.3.9.1, 5.3.9.2, 5.3.9.3, 5.3.9.4, 5.3.9.5, 5.3.9.6, 5.3.9.7, 5.3.9.8, 5.3.9.9, 5.3.9.10, 5.3.10.1, 5.3.10.2, 5.3.10.3, 5.3.10.4, 5.3.10.5, 5.3.10.6, 5.3.10.7, 5.3.10.8, 5.3.10.9, 5.3.10.10, 5.4.1.1, 5.4.1.2, 5.4.1.3, 5.4.1.4, 5.4.1.5, 5.4.1.6, 5.4.1.7, 5.4.1.8, 5.4.1.9, 5.4.1.10, 5.4.2.1, 5.4.2.2, 5.4.2.3, 5.4.2.4, 5.4.2.5, 5.4.2.6, 5.4.2.7, 5.4.2.8, 5.4.2.9, 5.4.2.10, 5.4.3.1, 5.4.3.2, 5.4.3.3, 5.4.34, 5.4.3.5, 5.4.3.6, 5.4.3.7, 5.4.3.8, 5.4.3.9, 5.4.3.10, 5.4.4.1, 5.4.4.2, 5.4.4.3, 5.4.4.4, 5.4.4.5, 5.4.4.6, 5.4.4.7, 5.4.4.8, 5.4.4.9, 5.4.4.10, 5.4.5.1, 5.4.5.2, 5.4.5.3, 5.4.5.4, 5.4.5.5, 5.4.5.6, 5.4.5.7., 5.4.5.8, 5.4.5.9, 5.4.5.10, 5.4.6.1, 5.4.6.2, 5.4.6.3, 5.4.6.4, 5.4.6.5, 5.4.6.6, 5.4.6.7, 5.4.6.8, 5.4.6.9, 5.4.6.10, 5.4.7.1, 5.4.7.2, 5.4.7.3, 5.4.74, 5.4.7.5, 5.4.7.6, 5.4.7.7, 5.4.7.8, 5.4.7.9, 5.4.7.10, 5.4.8.1, 5.4.8.2, 5.4.8.3, 5.4.84, 5.4.8.5, 5.4.8.6., 5.4.8.7, 5.4.8.8, 5.4.8.9, 5.4.8.10, 5.4.9.1, 5.4.9.2, 5.4.9.3, 5.4.9.4, 5.4.9.5, 5.4.9.6, 5.4.9.7, 5.4.9.8, 5.4.9.9, 5.4.9.10, 5.4.10.1, 5.4.10.2, 5.4.10.3, 5.4.10.4, 5.4.10.5, 5.4.10.6, 5.4.10.7, 5.4.10.8, 5.4.10.9, 5.4.10.10, 5.5.1.1, 5.5.1.2, 5.5.1.3, 5.5.1.4, 5.5.1.5, 5.5.1.6, 5.5.1.7, 5.5.1.8, 5.5.1.9, 5.5.1.10, 5.5.2.1, 5.5.2.2, 5.5.2.3, 5.5.2.4, 5.5.2.5, 5.5.2.6, 5.5.2.7, 5.5.2.8, 5.5.2.9, 5.5.2.10, 5.5.3.1, 5.5.3.2, 5.5.3.3, 5.5.3.4, 5.5.3.5, 5.5.3.6, 5.5.3.7, 5.5.3.8, 5.5.3.9, 5.5.3.10, 5.5.4.1, 5.5.4.2, 5.5.4.3, 5.5.44, 5.5.4.5, 5.5.4.6, 5.5.4.7, 5.5.48, 5.5.4.9, 5.5.4.10, 5.5.5.1, 5.5.5.2, 5.5.5.3, 5.5.5.4, 5.5.5.5, 5.5.5.6, 5.5.5.7., 5.5.5.8, 5.5.5.9, 5.5.5.10, 5.5.6.1, 5.5.6.2, 5.5.6.3, 5.5.6.4, 5.5.6.5, 5.5.6.6, 5.5.6.7, 5.5.6.8, 5.5.6.9, 5.5.6.10, 5.5.7.1, 5.5.7.2, 5.5.7.3, 5.5.7.4, 5.5.7.5, 5.5.7.6, 5.5.7.7, 5.5.7.8, 5.5.7.9, 5.5.7.10, 5.5.8.1, 5.5.8.2, 5.5.8.3, 5.5.8.4, 5.5.8.5, 5.5.8.6., 5.5.8.7, 5.5.8.8, 5.5.8.9, 5.5.8.10, 5.5.9.1, 5.5.9.2, 5.5.9.3, 5.5.9.4, 5.5.9.5, 5.5.9.6, 5.5.9.7, 5.5.9.8, 5.5.9.9, 5.5.9.10, 5.5.10.1, 5.5.10.2, 5.5.10.3, 5.5.10.4, 5.5.10.5, 5.5.10.6, 5.5.10.7, 5.5.10.8, 5.5.10.9, 5.5.10.10, 5.6.1.1, 5.6.1.2, 5.6.1.3, 5.6.1.4, 5.6.1.5, 5.6.1.6, 5.6.1.7, 5.6.1.8, 5.6.1.9, 5.6.1.10, 5.6.2.1, 5.6.2.2, 5.6.2.3, 5.6.2.4, 5.6.2.5, 5.6.2.6, 5.6.2.7, 5.6.2.8, 5.6.2.9, 5.6.2.10, 5.6.3.1, 5.6.3.2, 5.6.3.3, 5.6.3.4, 5.6.3.5, 5.6.3.6., 5.6.3.7, 5.6.3.8, 5.6.3.9, 5.6.3.10, 5.6.4.1, 5.6.4.2, 5.6.4.3, 5.6.4.4, 5.6.4.5, 5.6.46, 5.6.4.7, 5.6.4.8, 5.6.4.9, 5.6.4.10, 5.6.5.1, 5.6.5.2, 5.6.5.3, 5.6.5.4, 5.6.5.5, 5.6.5.6, 5.6.5.7., 5.6.5.8, 5.6.5.9, 5.6.5.10, 5.6.6.1, 5.6.6.2, 5.6.6.3, 5.6.6.4, 5.6.6.5, 5.6.6.6, 5.6.6.7, 5.6.6.8, 5.6.6.9, 5.6.6.10, 5.6.7.1, 5.6.7.2, 5.6.7.3, 5.6.7.4, 5.6.7.5, 5.6.7.6, 5.6.7.7, 5.6.7.8, 5.6.7.9, 5.6.7.10, 5.6.8.1, 5.6.8.2, 5.6.8.3, 5.6.8.4, 5.6.8.5, 5.6.8.6., 5.6.8.7, 5.6.8.8, 5.6.8.9, 5.6.8.10, 5.6.9.1, 5.6.9.2, 5.6.9.3, 5.6.9.4, 5.6.9.5, 5.6.9.6, 5.6.9.7, 5.6.9.8, 5.6.9.9, 5.6.9.10, 5.6.10.1, 5.6.10.2, 5.6.10.3, 5.6.10.4, 5.6.10.5, 5.6.10.6, 5.6.10.7, 5.6.10.8, 5.6.10.9, 5.6.10.10, 5.7.1.1, 5.7.1.2, 5.7.1.3, 5.7.1.4, 5.7.1.5, 5.7.1.6, 5.7.1.7, 5.7.1.8, 5.7.1.9, 5.7.1.10, 5.7.2.1, 5.7.2.2, 5.7.2.3, 5.7.2.4, 5.7.2.5, 5.7.2.6, 5.7.2.7, 5.7.2.8, 5.7.2.9, 5.7.2.10, 5.7.3.1, 5.7.3.2, 5.7.3.3, 5.7.3,4, 5.7.3.5, 5.7.3.6, 5.7.3.7, 5.7.3.8, 5.7.3.9, 5.7.3.10, 5.7.4.1, 5.7.4.2, 5.7.4.3, 5.7.44, 5.7.4.5, 5.7.4.6, 5.7.4.7, 5.7.4.8, 5.7.4.9, 5.7.4.10, 5.7.5.1, 5.7.5.2, 5.7.5.3, 5.7.5.4, 5.7.5.5, 5.7.5.6, 5.7.5.7., 5.7.5.8, 5.7.5.9, 5.7.5.10, 5.7.6.1, 5.7.6.2, 5.7.6.3, 5.7.6.4, 5.7.6.5, 5.7.6.6, 5.7.6.7, 5.7.6.8, 5.7.6.9, 5.7.6.10, 5.7.7.1, 5.7.7.2, 5.7.7.3, 5.7.7.4, 5.7.7.5, 5.7.7.6, 5.7.7.7, 5.7.7.8, 5.7.7.9, 5.7.7.10, 5.7.8.1, 5.7.8.2, 5.7.8.3, 5.7.8.4, 5.7.8.5, 5.7.8.6, 5.7.8.7, 5.7.8.8, 5.7.8.9, 5.7.8.10, 5.7.9.1, 5.7.9.2, 5.7.9.3, 5.7.9.4, 5.7.9.5, 5.7.9.6, 5.7.9.7, 5.7.9.8, 5.7.9.9, 5.7.9.10, 5.7.10.1, 5.7.10.2, 5.7.10.3, 5.7.10.4, 5.7.10.5, 5.7.10.6, 5.7.10.7, 5.7.10.8, 5.7.10.9, 5.7.10.10, 5.8.1.1, 5.8.1.2, 5.8.1.3, 5.8.1.4, 5.8.1.5, 5.8.1.6, 5.8.1.7, 5.8.1.8, 5.8.1.9, 5.8.1.10, 5.8.2.1, 5.8.2.2, 5.8.2.3, 5.8.2.4, 5.8.2.5, 5.8.2.6, 5.8.2.7, 5.8.2.8, 5.8.2.9, 5.8.2.10, 5.8.3.1, 5.8.3.2, 5.8.3.3, 5.8.34, 5.8.3.5, 5.8.3.6, 5.8.3.7, 5.8.3.8, 5.8.3.9, 5.8.3.10, 5.8.4.1, 5.8.4.2, 5.8.4.3, 5.8.4.4, 5.8.4.5, 5.8.4.6, 5.8.47, 5.8.4.8, 5.8.4.9, 5.8.4.10, 5.8.5.1, 5.8.5.2, 5.8.5.3, 5.8.5.4, 5.8.5.5, 5.8.5.6, 5.8.5.7., 5.8.5.8, 5.8.5.9, 5.8.5.10, 5.8.6.1, 5.8.6.2, 5.8.6.3, 5.8.6.4, 5.8.6.5, 5.8.6.6, 5.8.6.7. 5.8.6.8, 5.8.6.9, 5.8.6.10, 5.8.7.1, 5.8.7.2, 5.8.7.3, 5.8.7.4, 5.8.7.5, 5.8.7.6, 5.8.7.7, 5.8.7.8, 5.8.7.9, 5.8.7.10, 5.8.8.1, 5.8.8.2, 5.8.8.3, 5.8.8.4, 5.8.8.5, 5.8.8.6., 5.8.8.7, 5.8.8.8, 5.8.8.9, 5.8.8.10, 5.8.9.1, 5.8.9.2, 5.8.9.3, 5.8.9.4, 5.8.9.5, 5.8.9.6, 5.8.9.7, 5.8.9.8, 5.8.9.9, 5.8.9.10, 5.8.10.1, 5.8.10.2, 5.8.10.3, 5.8.10.4, 5.8.10.5, 5.8.10.6, 5.8.10.7, 5.8.10.8, 5.8.10.9, 5.8.10.10, 5.9.1.1, 5.9.1.2, 5.9.1.3, 5.9.1.4, 5.9.1.5, 5.9.1.6, 5.9.1.7, 5.9.1.8, 5.9.1.9, 5.9.1.10, 5.9.2.1, 5.9.2.2, 5.9.2.3, 5.9.2.4, 5.9.2.5, 5.9.2.6, 5.9.2.7, 5.9.2.8, 5.9.2.9, 5.9.2.10, 5.9.3.1, 5.9.3.2, 5.9.3.3, 5.9.3.4, 5.9.3.5, 5.9.3.6, 5.9.3.7, 5.9.3.8, 5.9.3.9, 5.9.3.10, 5.9.4.1, 5.9.4.2, 5.9.4.3, 5.9.44, 5.9.45, 5.9.4.6, 5.94.7, 5.9.4.8, 5.9.4.9, 5.9.4.10, 5.9.5.1, 5.9.5.2, 5.9.5.3, 5.9.5.4, 5.9.5.5, 5.9.5.6, 5.9.5.7., 5.9.5.8, 5.9.5.9, 5.9.5.10, 5.9.6.1, 5.9.6.2, 5.9.6.3, 5.9.6.4, 5.9.6.5, 5.9.6.6, 5.9.6.7, 5.9.6.8, 5.9.6.9, 5.9.6.10, 5.9.7.1, 5.9.7.2, 5.9.7.3, 5.9.7.4, 5.9.7.5, 5.9.7.6, 5.9.7.7, 5.9.7.8, 5.9.7.9, 5.9.7.10, 5.9.8.1, 5.9.8.2, 5.9.8.3, 5.9.8.4, 5.9.8.5, 5.9.8.6., 5.9.8.7, 5.9.8.8, 5.9.8.9, 5.9.8.10, 5.9.9.1, 5.9.9.2, 5.9.9.3, 5.9.9.4, 5.99.5, 5.9.9.6, 5.9.9.7, 5.9.9.8, 5.9.9.9, 5.9.9.10, 5.9.10.1, 5.9.10.2, 5.9.10.3, 5.9.10.4, 5.9.10.5, 5.9.10.6, 5.9.10.7, 5.9.10.8, 5.9.10.9, 5.9.10.10, 5.10.1.1, 5.10.1.2, 5.10.1.3, 5.10.1.4, 5.10.1.5, 5.10.1.6, 5.10.1.7, 5.10.1.8, 5.10.1.9, 5.10.1.10, 5.10.2.1, 5.10.2.2, 5.10.2.3, 5.10.2.4, 5.10.2.5, 0.2.6, 5.10.2.7, 5.10.2.8, 5.10.2.9, 5.10.2.10, 5.10.3.1, 5.10.3.2, 5.10.3.3, 5.10.3.4, 5.10.3.5, 5.10.3.6, 5.10.3.7, 0.3.8, 5.10.3.9, 5.10.3.10, 5.10.4.1, 5.10.4.2, 5.10.4.3, 5.10.4.4, 5.10.4.5, 5.10.4.6, 5.10.4.7, 5.10.4.8, 5.10.4.9, 0.4.10, 5.10.5.1, 5.10.5.2, 5.10.5.3, 5.10.5.4, 5.10.5.5, 5.10.5.6, 5.10.5.7., 5.10.5.8, 5.10.5.9, 5.10.5.10, 5.10.6.1, 0.6.2, 5.10.6.3, 5.10.6.4, 5.10.6.5, 5.10.6.6, 5.10.6.7, 5.10.6.8, 5.10.6.9, 5.10.6.10, 5.10.7.1, 5.10.7.2, 5.10.7.3, 0.7.4, 5.10.7.5, 5.10.7.6, 5.10.7.7, 5.10.7.8, 5.10.7.9, 5.10.7.10, 5.10.8.1, 5.10.8.2, 5.10.8.3, 5.10.8.4, 5.10.8.5, 0.8.6., 5.10.8.7, 5.10.8.8, 5.10.8.9, 5.10.8.10, 5.10.9.1, 5.10.9.2, 5.10.9.3, 5.10.9.4, 5.10.9.5, 5.10.9.6, 5.10.9.7, 0.9.8, 5.10.9.9, 5.10.9.10, 5.10.10.1, 5.10.10.2, 5.10.10.3, 5.10.10.4, 5.10.10.5, 5.10.10.6, 5.10.10.7, 5.10.10.8, 0.10.9, 5.10.10.10, 6.1.1.1, 6.1.1.2, 6.1.1.3, 6.1.1.4, 6.1.1.5, 6.1.1.6., 6.1.1.7, 6.1.1.8, 6.1.1.9, 6.1.1.10, 6.1.2.1. .2.2, 6.1.2.3, 6.1.2.4, 6.1.2.5, 6.1.2.6, 6.1.2.7., 6.1.2.8, 6.1.2.9, 6.1.2.10, 6.1.3.1, 6.1.3.2, 6.1.3.3, 6.1.3.4., 6.1.3.5, .3.6., 6.1.3.7, 6.1.3.8, 6.1.3.9, 6.1.3.10, 6.1.4.1, 6.1.4.2, 6.1.4.3, 6.1.4.4, 6.1.4.5, 6.1.4.6., 6.1.4.7, 6.1.4.8, 6.1.4.9, .4.10, 6.1.5.1, 6.1.5.2, 6.1.5.3, 6.1.5.4, 6.1.5.5, 6.1.5.6, 6.1.5.7., 6.1.5.8, 6.1.5.9, 6.1.5.10, 6.1.6.1, 6.1.6.2, 6.1.6.3, .6.4, 6.1.6.5, 6.1.6.6, 6.1.6.7., 6.1.6.8, 6.1.6.9, 6.1.6.10, 6.1.7.1, 6.1.7.2, 6.1.7.3, 6.1.7.4, 6.1.7.5, 6.1.7.6, 6.1.7.7, .7.8, 6.1.7.9, 6.1.7.10, 6.1.8.1, 6.1.8.2, 6.1.8.3, 6.1.8.4, 6.1.8.5, 6.1.8.6., 6.1.8.7, 6.1.8.8, 6.1.8.9, 6.1.8.10, 6.1.9.1, .9.2, 6.1.9.3, 6.1.9.4, 6.1.9.5, 6.1.9.6, 6.1.9.7, 6.1.9.8, 6.1.9.9, 6.1.9.10, 6.1.10.1, 6.1.10.2, 6.1.10.3, 6.1.10.4, 6.1.10.5, 6.1.10.6, 6.1.10.7, 6.1.10.8, 6.1.10.9, 6.1.10.10, 6.2.1.1, 6.2.1.2, 6.2.1.3, 6.2.1.4, 6.2.1.5, 6.2.1.6, 6.2.1.7, 6.2.1.8, 6.2.1.9, 6.2.1.10, 6.2.2.1, 6.2.2.2, 6.2.2.3, 6.2.2.4, 6.2.2.5, 6.2.2.6, 6.2.2.7., 6.2.2.8, 6.2.2.9, 6.2.2.10, 6.2.3.1, 6.2.3.2, 6.2.3.3, 6.2.3.4., 6.2.3.5, 6.2.3.6., 6.2.3.7, 6.2.3.8, 6.2.3.9, 6.2.3.10, 6.2.4.1, 6.2.4.2, 6.2.4.3, 6.2.4.4, 6.2.4.5, 6.2.4.6, 6.2.4.7, 6.2.4.8, 6.2.4.9, 6.2.4.10, 6.2.5.1, 6.2.5.2, 6.2.5.3, 6.2.5.4, 6.2.5.5, 6.2.5.6, 6.2.5.7., 6.2.5.8, 6.2.5.9, 6.2.5.10, 6.2.6.1, 6.2.6.2, 6.2.6.3, 6.2. 6.4., 6.2.6.5, 6.2.6.6, 6.2.6.7., 6.2.6.8, 6.2.6.9, 6.2.6.10, 6.2.7.1, 6.2.7.2, 6.2.7.3, 6.2.7.4, 6.2.7.5, 6.2.7.6, 6.2.7.7, 6.2.7.8, 6.2.7.9, 6.2.7.10, 6.2.8.1, 6.2.8.2, 6.2.8.3, 6.2.8.4, 6.2.8.5, 6.2.8.6., 6.2.8.7, 6.2.8.8, 6.2.8.9, 6.2.8.10, 6.2.9.1, 6.2.9.2, 6.2.9.3, 6.2.9.4, 6.2.9.5, 6.2.9.6, 6.2.9.7, 6.2.9.8, 6.2.9.9, 6.2.9.10, 6.2.10.1, 6.2.10.2, 6.2.10.3, 6.2.10.4, 6.2.10.5, 6.2.10.6, 6.2.10.7, 6.2.10.8, 6.2.10.9, 6.2.10.10, 6.3.1.1, 6.3.1.2, 6.3.1.3, 6.3.1.4, 6.3.1.5, 6.3.1.6, 6.3.1.7, 6.3.1.8, 6.3.1.9, 6.3.1.10, 6.3.2.1, 6.3.2.2, 6.3.2.3, 6.3.2.4, 6.3.2.5, 6.3.2.6, 6.3.2.7. 6.3.2.8, 6.3.2.9, 6.3.2.10, 6.3.3.1, 6.3.3.2, 6.3.3.3, 6.3.3.4., 6.3.3.5, 6.3.3.6, 6.3.3.7, 6.3.3.8, 6.3.3.9, 6.3.3.10, 6.3.4.1, 6.3.4.2, 6.3.4.3, 6.3.4.4, 6.3.4.5, 6.3.4.6, 6.3.4.7, 6.3.4.8, 6.3.4.9, 6.3.4.10, 6.3.5.1, 6.3.5.2, 6.3.5.3, 6.3.5.4, 6.3.5.5, 6.3.5.6, 6.3.5.7., 6.3.5.8, 6.3.5.9, 6.3.5.10, 6.3.6.1, 6.3.6.2, 6.3.6.3, 6.3.6.4, 6.3.6.5, 6.3.6.6, 6.3.6.7., 6.3.6.8, 6.3.6.9, 6.3.6.10, 6.3.7.1, 6.3.7.2, 6.3.7.3, 6.3.7.4, 6.3.7.5, 6.3.7.6, 6.3.7.7, 6.3.7.8, 6.3.7.9, 6.3.7.10, 6.3.8.1, 6.3.8.2, 6.3.8.3, 6.3.8.4, 6.3.8.5, 6.3.8.6., 6.3.8.7, 6.3.8.8, 6.3.8.9, 6.3.8.10, 6.3.9.1, 6.3.9.2, 6.3.9.3, 6.3.9.4, 6.3.9.5, 6.3.9.6, 6.3.9.7, 6.3.9.8, 6.3.9.9, 6.3.9.10, 6.3.10.1, 6.3.10.2, 6.3.10.3, 6.3.10.4, 6.3.10.5, 6.3.10.6, 6.3.10.7, 6.3.10.8, 6.3.10.9, 6.3.10.10, 6.4.1.1, 6.4.1.2, 6.4.1.3, 6.4.1.4, 6.4.1.5, 6.4.1.6., 6.4.1.7, 6.4.1.8, 6.4.1.9, 6.4.1.10, 6.4.2.1, 6.4.2.2, 6.4.2.3, 6.4.2.4, 6.4.2.5, 6.4.2.6, 6.4.2.7., 6.4.2.8, 6.4.2.9, 6.4.2.10, 6.4.3.1, 6.4.3.2, 6.4.3.3, 6.4.3.4., 6.4.3.5, 6.4.3.6., 6.4.3.7, 6.4.3.8, 6.4.3.9, 6.4.3.10, 6.4.4.1, 6.4.4.2, 6.4.4.3, 6.4.4.4, 6.4.4.5, 6.4.4.6, 6.4.4.7, 6.4.4.8, 6.4.4.9, 6.4.4.10, 6.4.5.1, US 7,863,261 B2 37 38

TABLE 2-continued 6.4.5.2, 6.4.5.3, 6.4.5.4, 6.4.5.5, 6.4.5.6, 6.4.5.7., 6.4.5.8, 6.4.5.9, 6.4.5.10, 6.4.6.1, 6.4.6.2, 6.4.6.3, 6.4.6.4, 6.4.6.5, 6.4.6.6, 6.4.6.7., 6.4.6.8, 6.4.6.9, 6.4.6.10, 6.4.7.1, 6.4.7.2, 6.4.7.3, 6.4.7.4, 6.4.7.5, 6.4.7.6, 6.4.7.7, 6.4.7.8, 6.4.7.9, 6.4.7.10, 6.4.8.1, 6.4.8.2, 6.4.8.3, 6.4.8.4, 6.4.8.5, 6.4.8.6., 6.4.8.7, 6.4.8.8, 6.4.8.9, 6.4.8.10, 6.4.9.1, 6.4.9.2, 6.4.9.3, 6.4.9.4, 6.4.9.5, 6.4.9.6, 6.4.9.7, 6.4.9.8, 6.4.9.9, 6.4.9.10, 6.4.10.1, 6.4.10.2, 6.4.10.3, 6.4.10.4, 6.4.10.5, 6.4.10.6, 6.4.10.7, 6.4.10.8, 6.4.10.9, 6.4.10.10, 6.5.1.1, 6.5.1.2, 6.5.1.3, 6.5.1.4, 6.5.1.5, 6.5.1.6., 6.5.1.7, 6.5.1.8, 6.5.1.9, 6.5.1.10, 6.5.2.1, 6.5.2.2, 6.5.2.3, 6.5.2.4, 6.5.2.5, 6.5.2.6, 6.5.2.7., 6.5.2.8, 6.5.2.9, 6.5.2.10, 6.5.3.1, 6.5.3.2, 6.5.3.3, 6.5.3.4., 6.5.3.5, 6.5.3.6, 6.5.3.7, 6.5.3.8, 6.5.3.9, 6.5.3.10, 6.5.4.1, 6.5.4.2, 6.5.4.3, 6.5.44, 6.5.4.5, 6.5.4.6, 6.5.4.7, 6.5.48, 6.5.4.9, 6.5.4.10, 6.5.5.1, 6.5.5.2, 6.5.5.3, 6.5.5.4, 6.5.5.5, 6.5.5.6, 6.5.5.7., 6.5.5.8, 6.5.5.9, 6.5.5.10, 6.5.6.1, 6.5.6.2, 6.5.6.3, 6.5.6.4, 6.5.6.5, 6.5.6.6, 6.5.6.7., 6.5.6.8, 6.5.6.9, 6.5.6.10, 6.5.7.1, 6.5.7.2, 6.5.7.3, 6.5.7.4, 6.5.7.5, 6.5.7.6, 6.5.7.7, 6.5.7.8, 6.5.7.9, 6.5.7.10, 6.5.8.1, 6.5.8.2, 6.5.8.3, 6.5.8.4, 6.5.8.5, 6.5.8.6., 6.5.8.7, 6.5.8.8, 6.5.8.9, 6.5.8.10, 6.5.9.1, 6.5.9.2, 6.5.9.3, 6.5.94, 6.5.9.5, 6.5.9.6, 6.5.9.7, 6.5.9.8, 6.5.99, 6.5.9.10, 6.5.10.1, 6.5.10.2, 6.5.10.3, 6.5.10.4, 6.5.10.5, 6.5.10.6, 6.5.10.7, 6.5.10.8, 6.5.10.9, 6.5.10.10, 6.6.1.1, 6.6.1.2, 6.6.1.3, 6.6.1.4, 6.6.1.5, 6.6.1.6, 6.6.1.7, 6.6.1.8, 6.6.1.9, 6.6.1.10, 6.6.2.1, 6.6.2.2, 6.6.2.3, 6.6.2.4, 6.6.2.5, 6.6.2.6, 6.6.2.7. 6.6.2.8, 6.6.2.9, 6.6.2.10, 6.6.3.1, 6.6.3.2, 6.6.3.3, 6.6.3.4., 6.6.3.5, 6.6.3.6., 6.6.3.7, 6.6.3.8, 6.6.3.9, 6.6.3.10, 6.6.4.1, 6.6.4.2, 6.6.4.3, 6.6.4.4, 6.6.4.5, 6.6.4.6, 6.6.4.7, 6.6.4.8, 6.6.4.9, 6.6.4.10, 6.6.5.1, 6.6.5.2, 6.6.5.3, 6.6.5.4, 6.6.5.5, 6.6.5.6, 6.6.5.7., 6.6.5.8, 6.6.5.9, 6.6.5.10, 6.6.6.1, 6.6.6.2, 6.6.6.3, 6.6.6.4, 6.6.6.5, 6.6.6.6, 6.6.6.7., 6.6.6.8, 6.6.6.9, 6.6.6.10, 6.6.7.1, 6.6.7.2, 6.6.7.3, 6.6.7.4, 6.6.7.5, 6.6.7.6, 6.6.7.7, 6.6.7.8, 6.6.7.9, 6.6.7.10, 6.6.8.1, 6.6.8.2, 6.6.8.3, 6.6.8.4, 6.6.8.5, 6.6.8.6., 6.6.8.7, 6.6.8.8, 6.6.8.9, 6.6.8.10, 6.6.9.1, 6.6.9.2, 6.6.9.3, 6.6.9.4, 6.6.9.5, 6.6.9.6, 6.6.9.7, 6.6.9.8, 6.6.9.9, 6.6.9.10, 6.6.10.1, 6.6.10.2, 6.6.10.3, 6.6.10.4, 6.6.10.5, 6.6.10.6, 6.6.10.7, 6.6.10.8, 6.6.10.9, 6.6.10.10, 6.7.1.1, 6.7.1.2, 6.7.1.3, 6.7.1.4, 6.7.1.5, 6.7.1.6, 6.7.1.7, 6.7.1.8, 6.7.1.9, 6.7.1.10, 6.7.2.1, 6.7.2.2, 6.7.2.3, 6.7.2.4, 6.7.2.5, 6.7.2.6, 6.7.2.7., 6.7.2.8, 6.7.2.9, 6.7.2.10, 6.7.3.1, 6.7.3.2, 6.7.3.3, 6.7.34, 6.7.3.5, 6.7.3.6, 6.7.3.7, 6.7.3.8, 6.7.3.9, 6.7.3.10, 6.7.4.1, 6.7.4.2, 6.7.4.3, 6.7.44, 6.7.4.5, 6.7.4.6, 6.7.4.7, 6.7.4.8, 6.7.4.9, 6.7.4.10, 6.7.5.1, 6.7.5.2, 6.7.5.3, 6.7.5.4, 6.7.5.5, 6.7.5.6, 6.7.5.7., 6.7.5.8, 6.7.5.9, 6.7.5.10, 6.7.6.1, 6.7.6.2, 6.7.6.3, 6.7.6.4, 6.7.6.5, 6.7.6.6, 6.7.6.7, 6.7.6.8, 6.7.6.9, 6.7.6.10, 6.7.7.1, 6.7.7.2, 6.7.7.3, 6.7.7.4, 6.7.7.5, 6.7.7.6, 6.7.7.7, 6.7.7.8, 6.7.7.9, 6.7.7.10, 6.7.8.1, 6.7.8.2, 6.7.8.3, 6.7.8.4, 6.7.8.5, 6.7.8.6., 6.7.8.7, 6.7.8.8, 6.7.8.9, 6.7.8.10, 6.7.9.1, 6.7.9.2, 6.7.9.3, 6.7.9.4, 6.7.9.5, 6.7.9.6, 6.7.9.7, 6.7.9.8, 6.7.9.9, 6.7.9.10, 6.7.10.1, 6.7.10.2, 6.7.10.3, 6.7.10.4, 6.7.10.5, 6.7.10.6, 6.7.10.7, 6.7.10.8, 6.7.10.9, 6.7.10.10, 6.8.1.1, 6.8.1.2, 6.8.1.3, 6.8.1.4, 6.8.1.5, 6.8.1.6., 6.8.1.7, 6.8.1.8, 6.8.1.9, 6.8.1.10, 6.8.2.1. 6.8.2.2, 6.8.2.3, 6.8.2.4, 6.8.2.5, 6.8.2.6, 6.8.2.7., 6.8.2.8, 6.8.2.9, 6.8.2.10, 6.8.3.1, 6.8.3.2, 6.8.3.3, 6.8.3.4., 6.8.3.5, 6.8.3.6., 6.8.3.7, 6.8.3.8, 6.8.3.9, 6.8.3.10, 6.8.4.1, 6.8.4.2, 6.8.4.3, 6.8.4.4, 6.8.4.5, 6.8.4.6., 6.8.4.7, 6.8.4.8, 6.8.4.9, 6.8.4.10, 6.8.5.1, 6.8.5.2, 6.8.5.3, 6.8.5.4, 6.8.5.5, 6.8.5.6, 6.8.5.7., 6.8.5.8, 6.8.5.9, 6.8.5.10, 6.8.6.1, 6.8.6.2, 6.8.6.3, 6.8.6.4, 6.8.6.5, 6.8.6.6, 6.8.6.7., 6.8.6.8, 6.8.6.9, 6.8.6.10, 6.8.7.1, 6.8.7.2, 6.8.7.3, 6.8.7.4, 6.8.7.5, 6.8.7.6, 6.8.7.7, 6.8.7.8, 6.8.7.9, 6.8.7.10, 6.8.8.1, 6.8.8.2, 6.8.8.3, 6.8.8.4, 6.8.8.5, 6.8.8.6., 6.8.8.7, 6.8.8.8, 6.8.8.9, 6.8.8.10, 6.8.9.1, 6.8.9.2, 6.8.9.3, 6.8.9.4, 6.8.9.5, 6.8.9.6, 6.8.9.7, 6.8.9.8, 6.8.9.9, 6.8.9.10, 6.8.10.1, 6.8.10.2, 6.8.10.3, 6.8.10.4, 6.8.10.5, 6.8.10.6, 6.8.10.7, 6.8.10.8, 6.8.10.9, 6.8.10.10, 6.9.1.1, 6.9.1.2, 6.9.1.3, 6.9.1.4, 6.9.1.5, 6.9.1.6, 6.9.1.7, 6.9.1.8, 6.9.19, 6.9.1.10, 6.9.2.1, 6.9.2.2, 6.9.2.3, 6.9.2.4, 6.9.2.5, 6.9.2.6, 6.9.2.7., 6.9.2.8, 6.9.2.9, 6.9.2.10, 6.9.3.1, 6.9.3.2, 6.9.3.3, 6.9.3.4., 6.9.3.5, 6.9.3.6., 6.9.3.7, 6.9.3.8, 6.9.3.9, 6.9.3.10, 6.9.4.1, 6.9.4.2, 6.9.4.3, 6.9.4.4, 6.9.45, 6.9.4.6, 6.9.4.7, 6.9.4.8, 6.9.4.9, 6.9.4.10, 6.9.5.1, 6.9.5.2, 6.9.5.3, 6.9.5.4, 6.9.5.5, 6.9.5.6, 6.9.5.7., 6.9.5.8, 6.9.5.9, 6.9.5.10, 6.9.6.1, 6.9.6.2, 6.9.6.3, 6.9.6.4, 6.9.6.5, 6.9.6.6, 6.9.6.7., 6.9.6.8, 6.9.6.9, 6.9.6.10, 6.9.7.1, 6.9.7.2, 6.9.7.3, 6.9.7.4, 6.9.7.5, 6.9.7.6, 6.9.7.7, 6.9.7.8, 6.9.7.9, 6.9.7.10, 6.9.8.1, 6.9.8.2, 6.9.8.3, 6.9.8.4, 6.9.8.5, 6.9.8.6., 6.9.8.7, 6.9.8.8, 6.9.8.9, 6.9.8.10, 6.9.9.1, 6.9.9.2, 6.9.9.3, 6.9.9.4, 6.9.9.5, 6.9.9.6, 6.9.9.7, 6.9.9.8, 6.9.9.9, 6.9.9.10, 6.9.10.1, 6.9.10.2, 6.9.10.3, 6.9.10.4, 6.9.10.5, 6.9.10.6, 6.9.10.7, 6.9.10.8, 6.9.10.9, 6.9.10.10, 6.10.1.1, 6.10.1.2, 6.10.1.3, 6.10.1.4, 6.10.1.5, 6.10.1.6., 6.10.1.7, 6.10.1.8, 6.10.1.9, 6.10.1.10, 6.10.2.1, 6.10.2.2, 6.10.2.3, 6.10.2.4, 6.10.2.5. 0.2.6, 6.10.2.7., 6.10.2.8, 6.10.2.9, 6.10.2.10, 6.10.3.1, 6.10.3.2, 6.10.3.3, 6.10.3.4., 6.10.3.5, 6.10.3.6, 6.10.3.7, 0.3.8, 6.10.3.9, 6.10.3.10, 6.10.4.1, 6.10.4.2, 6.10.4.3, 6.10.4.4, 6.10.4.5, 6.10.4.6., 6.10.4.7, 6.10.4.8, 6.10.4.9, 0.4.10, 6.10.5.1, 6.10.5.2, 6.10.5.3, 6.10.5.4, 6.10.5.5, 6.10.5.6, 6.10.5.7., 6.10.5.8, 6.10.5.9, 6.10.5.10, 6.10.6.1, 0.6.2, 6.10.6.3, 6.10.6.4, 6.10.6.5, 6.10.6.6, 6.10.6.7., 6.10.6.8, 6.10.6.9, 6.10.6.10, 6.10.7.1, 6.10.7.2, 6.10.7.3, 0.7.4, 6.10.7.5, 6.10.7.6, 6.10.7.7, 6.10.7.8, 6.10.7.9, 6.10.7.10, 6.10.8.1, 6.10.8.2, 6.10.8.3, 6.10.8.4, 6.10.8.5, 0.8.6., 6.10.8.7, 6.10.8.8, 6.10.8.9, 6.10.8.10, 6.10.9.1, 6.10.9.2, 6.10.9.3, 6.10.9.4, 6.10.9.5, 6.10.9.6, 6.10.9.7, 0.9.8, 6.10.9.9, 6.10.9.10, 6.10.10.1, 6.10.10.2, 6.10.10.3, 6.10.10.4, 6.10.10.5, 6.10.10.6, 6.10.10.7, 6.10.10.8, 0.10.9, 6.10.10.10, 7.1.1.1, 7.1.1.2.7.1.1.3, 7.1.1.4, 7.1.1.5, 7.1.1.6.7.1.1.7, 7.1.1.8, 7.1.1.9, 7.1.1.10, 7.1.2.1. .2.2, 7.1.2.3, 7.1.2.4, 7.1.2.5, 7.1.2.6, 7.1.2.7, 7.1.2.8, 7.1.2.9, 7.1.2.10, 7.1.3.1, 7.1.3.2, 7.1.3.3, 7.1.3.4, 7.1.3.5, .3.6.7.1.3.7, 7.1.3.8, 7.1.3.9, 7.1.3.10, 7.1.4.1, 7.1.4.2.7.1.4.3, 7.1.4.4, 7.1.4.5, 7.1.4.6.7.1.4.7, 7.1.4.8, 7.1.4.9, 4.10, 7.1.5.1, 7.1.5.2, 7.1.5.3, 7.1.5.4, 7.1.5.5, 7.1.5.6, 7.1.5.7., 7.1.5.8, 7.1.5.9, 7.1.5.10, 7.1.6.1, 7.1.6.2, 7.1.6.3, .6.4, 7.1.6.5, 7.1.6.6, 7.1.6.7, 7.1.6.8, 7.1.6.9, 7.1.6.10, 7.1.7.1, 7.1.7.2, 7.1.7.3, 7.1.7.4, 7.1.7.5, 7.1.7.6, 7.1.7.7, .7.8, 7.1.7.9, 7.1.7.10, 7.1.8.1, 7.1.8.2, 7.1.8.3, 7.1.8.4, 7.1.8.5, 7.1.8.6.7.1.8.7, 7.1.8.8, 7.1.8.9, 7.1.8.10, 7.1.9.1, .9.2, 7.1.9.3, 7.1.9.4, 7.1.9.5, 7.1.9.6, 7.1.9.7, 7.19.8, 7.1.9.9, 7.1.9.10, 7.1.10.1, 7.1.10.2, 7.1.10.3, 7.1.10.4, 7. .10.5, 7.1.10.6, 7.1.10.7, 7.1.10.8, 7.1.10.9, 7.1.10.10, 7.2.1.1, 7.2.1.2, 7.2.1.3, 7.2.1.4, 7.2.1.5, 7.2.1.6, 7.2.1.7, 7.2.1.8, 7.2.1.9, 7.2.1.10, 7.2.2.1, 7.2.2.2, 7.2.2.3, 7.2.2.4, 7.2.2.5, 7.2.2.6, 7.2.2.7, 7.2.2.8, 7.2.2.9, 7.2.2.10, 7.2.3.1, 7.2.3.2, 7.2.3.3, 7.2.3.4, 7.2.3.5, 7.2.3.6, 7.2.3.7, 7.2.3.8, 7.2.3.9, 7.2.3.10, 7.2.4.1, 7.2.4.2, 7.2.4.3, 7.2.4.4, 7.2.45, 7.2.4.6, 7.2.4.7, 7.2.4.8, 7.2.4.9, 7.2.4.10, 7.2.5.1, 7.2.5.2, 7.2.5.3, 7.2.5.4, 7.2.5.5, 7.2.5.6, 7.2.5.7., 7.2.5.8, 7.2.5.9, 7.2.5.10, 7.2.6.1, 7.2.6.2, 7.2.6.3, 7.2.6.4, 7.2.6.5, 7.2.6.6, 7.2.6.7, 7.2.6.8, 7.2.6.9, 7.2.6.10, 7.2.7.1, 7.2.7.2, 7.2.7.3, 7.2.7.4, 7.2.7.5, 7.2.7.6, 7.2.7.7, 7.2.7.8, 7.2.7.9, 7.2.7.10, 7.2.8.1, 7.2.8.2, 7.2.8.3, 7.2.8.4, 7.2.8.5, 7.2.8.6, 7.2.8.7, 7.2.8.8, 7.2.8.9, 7.2.8.10, 7.2.9.1, 7.2.9.2, 7.2.9.3, 7.2.9.4, 7.2.9.5, 7.2.9.6, 7.2.9.7, 7.2.9.8, 7.2.9.9, 7.2.9.10, 7.2.10.1, 7.2.10.2, 7.2.10.3, 7.2.10.4, 7.2.10.5, 7.2.10.6, 7.2.10.7, 7.2.10.8, 7.2.10.9, 7.2.10.10, 7.3.1.1, 7.3.1.2, 7.3.1.3, 7.3.1.4, 7.3.1.5, 7.3.1.6, 7.3.1.7, 7.3.1.8, 7.3.1.9, 7.3.1.10, 7.3.2.1, 7.3.2.2, 7.3.2.3, 7.3.2.4, 7.3.2.5, 7.3.2.6, 7.3.2.7, 7.3.2.8, 7.3.2.9, 7.3.2.10, 7.3.3.1, 7.3.3.2, 7.3.3.3, 7.3.3.4, 7.3.3.5, 7.3.3.6, 7.3.3.7, 7.3.3.8, 7.3.3.9, 7.3.3.10, 7.3.4.1, 7.3.4.2, 7.3.4.3, 7.3.4.4, 7.3.4.5, 7.3.4.6, 7.3.4.7, 7.3.4.8, 7.3.4.9, 7.3.4.10, 7.3.5.1, 7.3.5.2, 7.3.5.3, 7.3.5.4, 7.3.5.5, 7.3.5.6, 7.3.5.7., 7.3.5.8, 7.3.5.9, 7.3.5.10, 7.3.6.1, 7.3.6.2, 7.3.6.3, 7.3.6.4, 7.3.6.5, 7.3.6.6, 7.3.6.7, 7.3.6.8, 7.3.6.9, 7.3.6.10, 7.3.7.1, 7.3.7.2, 7.3.7.3, 7.3.7.4, 7.3.7.5, 7.3.7.6, 7.3.7.7, 7.3.7.8, 7.3.7.9, 7.3.7.10, 7.3.8.1, 7.3.8.2, 7.3.8.3, 7.3.8.4, 7.3.8.5, 7.3.8.6., 7.3.8.7, 7.3.8.8, 7.3.8.9, 7.3.8.10, 7.3.9.1, 7.3.9.2, 7.3.9.3, 7.3.9.4, 7.3.9.5, 7.3.9.6, 7.3.9.7, 7.3.9.8, 7.3.9.9, 7.3.9.10, 7.3.10.1, 7.3.10.2, 7.3.10.3, 7.3.10.4, 7.3.10.5, 7.3.10.6, 7.3.10.7, 7.3.10.8, 7.3.10.9, 7.3.10.10, 7.4.1.1, 7.4.1.2, 7.4.1.3, 7.4.1.4, 7.4.1.5, 7.4.1.6, 7.4.1.7, 7.4.1.8, 7.4.1.9, 7.4.1.10, 7.4.2.1, 7.4.2.2, 7.4.2.3, 7.4.2.4, 7.4.2.5, 7.4.2.6, 7.4.2.7, 7.4.2.8, 7.4.2.9, 7.4.2.10, 7.4.3.1, 7.4.3.2, 7.4.3.3, 7.4.34, 7.4.3.5, 7.4.3.6, 7.4.3.7, 7.4.3.8, 7.4.3.9, 7.4.3.10, 7.4.4.1, 7.4.4.2, 7.4.4.3, 7.4.4.4, 7.4.4.5, 7.4.4.6, 7.4.4.7, 7.4.4.8, 7.4.4.9, 7.4.4.10, 7.4.5.1, 7.4.5.2, 7.4.5.3, 7.4.5.4, 7.4.5.5, 7.4.5.6, 7.4.5.7., 7.4.5.8, 7.4.5.9, 7.4.5.10, 7.4.6.1, 7.4.6.2, 7.4.6.3, 7.4.6.4, 7.4.6.5, 7.4.6.6, 7.4.6.7, 7.4.6.8, 7.4.6.9, 7.4.6.10, 74.7.1, 7.4.7.2, 7.4.7.3, 7.4.7.4, 7.4.7.5, 74.7.6, 74.7.7, 7.4.7.8, 7.4.7.9, 74.7.10, 74.8.1, 7.4.8.2, 7.4.8.3, 7.4.84, 7.4.8.5, 7.4.8.6., 7.4.8.7, 7.4.8.8, 7.4.89, 7.4.8.10, 7.4.9.1, 7.4.9.2, 7.4.9.3, 7.4.9.4, 7.4.9.5, 7.4.9.6, 7.4.9.7, 7.4.9.8, 7.4.9.9, 7.4.9.10, 7.4.10.1, 7.4.10.2, 7.4.10.3, 7.4.10.4, 7.4.10.5, 7.4.10.6, 74.10.7, 7.4.10.8, 7.4.10.9, 7.4.10.10, 7.5.1.1, 7.5.1.2, 7.5.1.3, 7.5.1.4, 7.5.1.5, 7.5.1.6, 7.5.1.7, 7.5.1.8, 7.5.1.9, US 7,863,261 B2 39 40

TABLE 2-continued 7.5.1.10, 7.5.2.1, 7.5.2.2, 7.5.2.3, 7.5.2.4, 7.5.2.5, 7.5.2.6, 7.5.2.7, 7.5.2.8, 7.5.2.9, 7.5.2.10, 7.5.3.1, 7.5.3.2, 7.5.3.3, 7.5.3.4, 7.5.3.5, 7.5.3.6, 7.5.3.7, 7.5.3.8, 7.5.3.9, 7.5.3.10, 7.5.4.1, 7.5.4.2, 7.5.4.3, 7.5.44, 7.5.4.5, 7.5.4.6, 7.5.4.7, 7.5.48, 7.5.4.9, 7.5.4.10, 7.5.5.1, 7.5.5.2, 7.5.5.3, 7.5.5.4, 7.5.5.5, 7.5.5.6, 7.5.5.7, 7.5.5.8, 7.5.5.9, 7.5.5.10, 7.5.6.1, 7.5.6.2, 7.5.6.3, 7.5.6.4, 7.5.6.5, 7.5.6.6, 7.5.6.7, 7.5.6.8, 7.5.6.9, 7.5.6.10, 7.5.7.1, 7.5.7.2, 7.5.7.3, 7.5.7.4, 7.5.7.5, 7.5.7.6, 7.5.7.7, 7.5.7.8, 7.5.7.9, 7.5.7.10, 7.5.8.1, 7.5.8.2, 7.5.8.3, 7.5.8.4, 7.5.8.5, 7.5.8.6, 7.5.8.7, 7.5.8.8, 7.5.8.9, 7.5.8.10, 7.5.9.1, 7.5.9.2, 7.5.9.3, 7.5.94, 7.5.9.5, 7.5.9.6, 7.5.9.7, 7.5.9.8, 7.5.9.9, 7.5.9.10, 7.5.10.1, 7.5.10.2, 7.5.10.3, 7.5.10.4, 7.5.10.5, 7.5.10.6, 7.5.10.7, 7.5.10.8, 7.5.10.9, 7.5.10.10, 7.6.1.1, 7.6.1.2, 7.6.1.3, 7.6.1.4, 7.6.1.5, 7.6.1.6, 7.6.1.7, 7.6.1.8, 7.6.19, 7.6.1.10, 7.6.2.1, 7.6.2.2, 7.6.2.3, 7.6.2.4, 7.6.2.5, 7.6.2.6, 7.6.2.7, 7.6.2.8, 7.6.2.9, 7.6.2.10, 7.6.3.1, 7.6.3.2, 7.6.3.3, 7.6.3.4, 7.6.3.5, 7.6.3.6, 7.6.3.7, 7.6.3.8, 7.6.3.9, 7.6.3.10, 7.6.4.1, 7.6.4.2, 7.6.4.3, 7.6.4.4, 7.6.4.5, 7.6.46, 7.6.4.7, 7.6.4.8, 7.6.4.9, 7.6.4.10, 7.6.5.1, 7.6.5.2, 7.6.5.3, 7.6.5.4, 7.6.5.5, 7.6.5.6, 7.6.5.7., 7.6.5.8, 7.6.5.9, 7.6.5.10, 7.6.6.1, 7.6.6.2, 7.6.6.3, 7.6.6.4, 7.6.6.5, 7.6.6.6, 7.6.6.7, 7.6.6.8, 7.6.6.9, 7.6.6.10, 7.6.7.1, 7.6.7.2, 7.6.7.3, 7.6.7.4, 7.6.7.5, 7.6.7.6, 7.6.7.7, 7.6.7.8, 7.6.7.9, 7.6.7.10, 7.6.8.1, 7.6.8.2, 7.6.8.3, 7.6.8.4, 7.6.8.5, 7.6.8.6., 7.6.8.7, 7.6.8.8, 7.6.8.9, 7.6.8.10, 7.6.9.1, 7.6.9.2, 7.6.9.3, 7.6.9.4, 7.6.9.5, 7.6.9.6, 7.6.9.7, 7.6.9.8, 7.6.9.9, 7.6.9.10, 7.6.10.1, 7.6.10.2, 7.6.10.3, 7.6.10.4, 7.6.10.5, 7.6.10.6, 7.6.10.7, 7.6.10.8, 7.6.10.9, 7.6.10.10, 7.7.1.1, 7.7.1.2, 7.7.1.3, 7.7.1.4, 7.7.1.5, 7.7.1.6, 7.7.1.7, 7.7.1.8, 7.7.1.9, 7.7.1.10, 7.7.2.1, 7.7.2.2, 7.7.2.3, 7.7.2.4, 7.7.2.5, 7.7.2.6, 7.7.2.7, 7.7.2.8, 7.7.2.9, 7.7.2.10, 7.7.3.1, 7.7.3.2, 7.7.3.3, 7.7.3.4, 7.7.3.5, 7.7.3.6, 7.7.3.7, 7.7.3.8, 7.7.3.9, 7.7.3.10, 7.7.4.1, 7.7.4.2, 7.7.4.3, 7.7.44, 7.7.4.5, 7.7.4.6, 7.7.4.7, 7.7.4.8, 7.7.4.9, 7.7.4.10, 7.7.5.1, 7.7.5.2, 7.7.5.3, 7.7.5.4, 7.7.5.5, 7.7.5.6, 7.7.5.7, 7.7.5.8, 7.7.5.9, 7.7.5.10, 7.7.6.1, 7.7.6.2, 7.7.6.3, 7.7.6.4, 7.7.6.5, 7.7.6.6, 7.7.6.7, 7.7.6.8, 7.7.6.9, 7.7.6.10, 7.7.7.1, 7.7.7.2, 7.7.7.3, 7.7.7.4, 7.7.7.5, 7.7.7.6, 7.7.7.7, 7.7.7.8, 7.7.7.9, 7.7.7.10, 7.7.8.1, 7.7.8.2, 7.7.8.3, 7.7.8.4, 7.7.8.5, 7.7.8.6, 7.7.8.7, 7.7.8.8, 7.7.8.9, 7.7.8.10, 7.7.9.1, 7.7.9.2, 7.7.9.3, 7.7.9.4, 7.7.9.5, 7.7.9.6, 7.7.9.7, 7.7.9.8, 7.7.9.9, 7.7.9.10, 7.7.10.1, 7.7.10.2, 7.7.10.3, 7.7.10.4, 7.7.10.5, 7.7.10.6, 7.7.10.7, 7.7.10.8, 7.7.10.9, 7.7.10.10, 7.8.1.1, 7.8.1.2, 7.8.1.3, 7.8.1.4, 7.8.1.5, 7.8.1.6, 7.8.1.7, 7.8.1.8, 7.8.1.9, 7.8.1.10, 7.8.2.1, 7.8.2.2, 7.8.2.3, 7.8.2.4, 7.8.2.5, 7.8.2.6, 7.8.2.7, 7.8.2.8, 7.8.2.9, 7.8.2.10, 7.8.3.1, 7.8.3.2, 7.8.3.3, 7.8.34, 7.8.3.5, 7.8.3.6, 7.8.3.7, 7.8.3.8, 7.8.3.9, 7.8.3.10, 7.8.4.1, 7.8.4.2, 7.8.4.3, 7.8.4.4, 7.8.4.5, 7.8.4.6, 7.8.47, 7.8.4.8, 7.8.4.9, 7.8.4.10, 7.8.5.1, 7.8.5.2, 7.8.5.3, 7.8.5.4, 7.8.5.5, 7.8.5.6, 7.8.5.7., 7.8.5.8, 7.8.5.9, 7.8.5.10, 7.8.6.1, 7.8.6.2, 7.8.6.3, 7.8.6.4, 7.8.6.5, 7.8.6.6, 7.8.6.7, 7.8.6.8, 7.8.6.9, 7.8.6.10, 7.8.7.1, 7.8.7.2, 7.8.7.3, 7.8.7.4, 7.8.7.5, 7.8.7.6, 7.8.7.7, 7.8.7.8, 7.8.7.9, 7.8.7.10, 7.8.8.1, 7.8.8.2, 7.8.8.3, 7.8.8.4, 7.8.8.5, 7.8.8.6., 7.8.8.7, 7.8.8.8, 7.8.8.9, 7.8.8.10, 7.8.9.1, 7.8.9.2, 7.8.9.3, 7.8.9.4, 7.8.9.5, 7.8.9.6, 7.8.9.7, 7.8.9.8, 7.8.9.9, 7.8.9.10, 7.8.10.1, 7.8.10.2, 7.8.10.3, 7.8.10.4, 7.8.10.5, 7.8.10.6, 7.8.10.7, 7.8.10.8, 7.8.10.9, 7.8.10.10, 7.9.1.1, 7.9.1.2, 7.9.1.3, 7.9.1.4, 7.9.1.5, 7.9.1.6, 7.9.1.7, 7.9.1.8, 7.9.19, 7.9.1.10, 7.9.2.1, 7.9.2.2, 7.9.2.3, 7.9.2.4, 7.9.2.5, 7.9.2.6, 7.9.2.7, 7.9.2.8, 7.9.2.9, 7.9.2.10, 7.9.3.1, 7.9.3.2, 7.9.3.3, 7.9.3.4, 7.9.3.5, 79.3.6, 7.9.3.7, 7.9.3.8, 7.9.3.9, 7.9.3.10, 7.9.4.1, 7.9.4.2, 7.9.4.3, 7.9.44, 7.9.45, 7.9.4.6, 7.94.7, 7.9.4.8, 7.9.4.9, 7.9.4.10, 7.9.5.1, 7.9.5.2, 7.9.5.3, 7.9.5.4, 7.9.5.5, 7.9.5.6, 7.9.5.7., 7.9.5.8, 7.9.5.9, 79.5.10, 7.9.6.1, 7.9.6.2, 7.9.6.3, 7.9.6.4, 7.9.6.5, 7.9.6.6, 7.9.6.7, 7.9.6.8, 7.9.6.9, 7.9.6.10, 7.9.7.1, 7.9.7.2, 7.9.7.3, 7.9.7.4, 7.9.7.5, 7.9.7.6, 7.9.7.7, 7.9.7.8, 7.9.7.9, 7.9.7.10, 7.9.8.1, 7.9.8.2, 7.9.8.3, 7.9.8.4, 7.9.8.5, 7.9.8.6, 7.9.8.7, 7.9.8.8, 7.9.8.9, 7.9.8.10, 7.9.9.1, 7.9.9.2, 7.9.9.3, 7.9.9.4, 7.99.5, 7.9.9.6, 7.9.9.7, 7.9.9.8, 7.9.9.9, 7.9.9.10, 7.9.10.1, 7.9.10.2, 7.9.10.3, 7.9.10.4, 7.9.10.5, 7.9.10.6, 7.9.10.7, 7.9.10.8, 7.9.10.9, 7.9.10.10, 7.10.1.1, 7.10.1.2, 7.10.1.3, 7.10.1.4, 7.10.1.5, 7.10.1.6, 7.10.1.7, 7.10.1.8, 7.10.1.9, 7.10.1.10, 7.10.2.1, 7.10.2.2, 7.10.2.3, 7.10.2.4, 7.10.2.5, 0.2.6, 7.10.2.7, 7.10.2.8, 7.10.2.9, 7.10.2.10, 7.10.3.1, 7.10.3.2, 7.10.3.3, 7.10.3.4, 7.10.3.5, 7.10.3.6, 7.10.3.7, 0.3.8, 7.10.3.9, 7.10.3.10, 7.10.4.1, 7.10.4.2, 7.10.4.3, 7.10.4.4, 7.10.4.5, 7.10.4.6, 7.10.4.7, 7.10.4.8, 7.10.4.9, 0.4.10, 7.10.5.1, 7.10.5.2, 7.10.5.3, 7.10.5.4, 7.10.5.5, 7.10.5.6, 7.10.5.7., 7.10.5.8, 7.10.5.9, 7.10.5.10, 7.10.6.1, 0.6.2, 7.10.6.3, 7.10.6.4, 7.10.6.5, 7.10.6.6, 7.10.6.7, 7.10.6.8, 7.10.6.9, 7.10.6.10, 7.10.7.1, 7.10.7.2, 7.10.7.3, 0.7.4, 7.10.7.5, 7.10.7.6, 7.10.7.7, 7.10.7.8, 7.10.7.9, 7.10.7.10, 7.10.8.1, 7.10.8.2, 7.10.8.3, 7.10.8.4, 7.10.8.5, 0.8.6.7.10.8.7, 7.10.8.8, 7.10.8.9, 7.10.8.10, 7.10.9.1, 7.10.9.2, 7.10.9.3, 7.10.9.4, 7.10.9.5, 7.10.9.6, 7.10.9.7, 0.9.8, 7.10.9.9, 7.10.9.10, 7.10.10.1, 7.10.10.2, 7.10.10.3, 7.10.10.4, 7.10.10.5, 7.10.10.6, 7.10.10.7, 7.10.10.8, 0.10.9, 7.10.10.10, 8.1.1.1, 8.1.1.2, 8.1.1.3, 8.1.1.4, 8.1.1.5, 8.1.1.6, 8.1.1.7, 8.1.1.8, 8.1.1.9, 8.1.1.10, 8.1.2.1. .2.2, 8.1.2.3, 8.1.2.4, 8.1.2.5, 8.1.2.6, 8.1.2.7, 8.1.2.8, 8.1.2.9, 8.1.2.10, 8.1.3.1, 8.1.3.2, 8.1.3.3, 8.1.3.4, 8.1.3.5, .3.6, 8.1.3.7, 8.1.3.8, 8.1.3.9, 8.1.3.10, 8.1.4.1, 8.1.4.2, 8.1.4.3, 8.1.4.4, 8.1.4.5, 8.1.4.6, 8.1.4.7, 8.1.4.8, 8.1.4.9, 4.1.0, 8.1.5.1, 8.1.5.2, 8.1.5.3, 8.1.5.4, 8.1.5.5, 8.1.5.6, 8.1.5.7., 8.1.5.8, 8.1.5.9, 8.1.5.10, 8.1.6.1, 8.1.6.2, 8.1.6.3, .6.4, 8.1.6.5, 8.1.6.6, 8.1.6.7, 8.1.6.8, 8.1.6.9, 8.1.6.10, 8.1.7.1, 8.1.7.2, 8.1.7.3, 8.1.7.4, 8.1.7.5, 8.1.7.6, 8.1.7.7, .7.8, 8.1.7.9, 8.1.7.10, 8.1.8.1, 8.1.8.2, 8.1.8.3, 8.1.8.4, 8.1.8.5, 8.1.8.6, 8.1.8.7, 8.1.8.8, 8.1.8.9, 8.1.8.10, 8.1.9.1, .9.2, 8.1.9.3, 8.1.9.4, 8.1.9.5, 8.1.9.6, 8.1.9.7, 8.19.8, 8.1.9.9, 8.1.9.10, 8.1.10.1, 8.1.10.2, 8.1.10.3, 8.1.10.4, 8.1.10.5, 8.1.10.6, 8.1.10.7, 8.1.10.8, 8.1.10.9, 8.1.10.10, 8.2.1.1, 8.2.1.2, 8.2.1.3, 8.2.1.4, 8.2.1.5.8.2.1.6, 8.2.1.7, 8.2.1.8, 8.2.1.9, 8.2.1.10, 8.2.2.1, 8.2.2.2, 8.2.2.3, 8.2.2.4, 8.2.2.5.8.2.2.6, 8.2.2.7, 8.2.2.8, 8.2.2.9, 8.2.2.10, 8.2.3.1, 8.2.3.2, 8.2.3.3, 8.2.3.4, 8.2.3.5, 8.2.3.6, 8.2.3.7, 8.2.3.8, 8.2.3.9, 8.2.3.10, 8.2.4.1, 8.2.4.2, 8.2.4.3, 8.2.4.4, 8.2.4.5, 8.2.4.6, 8.2.4.7, 8.24.8, 8.2.4.9, 8.2.4.10, 8.2.5.1, 8.2.5.2, 8.2.5.3, 8.2.5.4, 8.2.5.5, 8.2.5.6, 8.2.5.7., 8.2.5.8, 8.2.5.9, 8.2.5.10, 8.2.6.1, 8.2.6.2, 8.2.6.3, 8.2.6.4, 8.2.6.5, 8.2.6.6, 8.2.6.7.8.2.6.8, 8.2.6.9, 8.2.6.10, 8.2.7.1, 8.2.7.2, 8.2.7.3, 8.2.7.4, 8.2.7.5, 8.2.7.6, 8.2.7.7, 8.2.7.8, 8.2.7.9, 8.2.7.10, 8.2.8.1, 8.2.8.2, 8.2.8.3, 8.2.8.4, 8.2.8.5, 8.2.8.6, 8.2.8.7, 8.2.8.8, 8.2.8.9, 8.2.8.10, 8.2.9.1, 8.2.9.2, 8.2.9.3, 8.2.9.4, 8.2.9.5, 8.2.9.6, 8.2.9.7, 8.2.9.8, 8.2.9.9, 8.2.9.10, 8.2.10.1, 8.2.10.2, 8.2.10.3, 8.2.10.4, 8.2.10.5, 8.2.10.6, 8.2.10.7, 8.2.10.8, 8.2.10.9, 8.2.10.10, 8.3.1.1, 8.3.1.2, 8.3.1.3, 8.3.1.4, 8.3.1.5, 8.3.1.6, 8.3.1.7, 8.3.1.8, 8.3.1.9, 8.3.1.10, 8.3.2.1, 8.3.2.2, 8.3.2.3, 8.3.2.4, 8.3.2.5, 8.3.2.6, 8.3.2.7, 8.3.2.8, 8.3.2.9, 8.3.2.10, 8.3.3.1, 8.3.3.2, 8.3.3.3, 8.3.3.4, 8.3.3.5, 8.3.3.6, 8.3.3.7, 8.3.3.8, 8.3.3.9, 8.3.3.10, 8.3.4.1, 8.3.4.2, 8.3.4.3, 8.3.4.4, 8.3.4.5, 8.3.4.6, 8.3.4.7, 8.3.4.8, 8.3.4.9, 8.3.4.10, 8.3.5.1, 8.3.5.2, 8.3.5.3, 8.3.5.4, 8.3.5.5, 8.3.5.6, 8.3.5.7., 8.3.5.8, 8.3.5.9, 8.3.5.10, 8.3.6.1, 8.3.6.2, 8.3.6.3, 8.3.6.4, 8.3.6.5, 8.3.6.6, 8.3.6.7, 8.3.6.8, 8.3.6.9, 8.3.6.10, 8.3.7.1, 8.3.7.2, 8.3.7.3, 8.3.7.4, 8.3.7.5, 8.3.7.6, 8.3.7.7, 8.3.7.8, 8.3.7.9, 8.3.7.10, 8.3.8.1, 8.3.8.2, 8.3.8.3, 8.3.8.4, 8.3.8.5, 8.3.8.6, 8.3.8.7, 8.3.8.8, 8.3.8.9, 8.3.8.10, 8.3.9.1, 8.3.9.2, 8.3.9.3, 8.3.9.4, 8.3.9.5, 8.3.9.6, 8.3.9.7, 8.3.9.8, 8.3.9.9, 8.3.9.10, 8.3.10.1, 8.3.10.2, 8.3.10.3, 8.3.10.4, 8.3.10.5, 8.3.10.6, 8.3.10.7, 8.3.10.8, 8.3.10.9, 8.3.10.10, 8.4.1.1, 8.4.1.2, 8.4.1.3, 8.4.1.4, 8.4.1.5, 8.4.1.6, 8.4.1.7, 8.4.1.8, 8.4.1.9, 8.4.1.10, 8.4.2.1, 8.4.2.2, 8.4.2.3, 8.4.2.4, 8.4.2.5, 8.4.2.6, 8.4.2.7, 8.4.2.8, 8.4.2.9, 8.4.2.10, 8.4.3.1, 8.4.3.2, 8.4.3.3, 8.4.3.4, 8.4.3.5, 8.4.3.6, 8.4.3.7, 8.4.3.8, 8.4.3.9, 8.4.3.10, 8.4.4.1, 8.4.4.2, 8.4.4.3, 8.4.4.4, 8.4.4.5, 8.4.4.6, 8.4.4.7, 8.4.4.8, 8.4.4.9, 8.4.4.10, 8.4.5.1, 8.4.5.2, 8.4.5.3, 8.4.5.4, 8.4.5.5, 8.4.5.6, 8.4.5.7., 8.4.5.8, 8.4.5.9, 8.4.5.10, 8.4.6.1, 8.4.6.2, 8.4.6.3, 8.4.6.4, 8.4.6.5, 8.4.6.6, 8.4.6.7, 8.4.6.8, 8.4.6.9, 8.4.6.10, 84.7.1, 8.4.7.2, 8.4.7.3, 84.74, 8.4.7.5, 8.4.7.6, 84.7.7, 8.4.7.8, 8.4.7.9, 8.4.7.10, 8.4.8.1, 8.4.8.2, 8.4.8.3, 8.4.8.4, 8.4.8.5, 8.4.8.6, 8.4.8.7, 8.4.8.8, 8.4.8.9, 8.4.8.10, 8.4.9.1, 8.4.9.2, 8.4.9.3, 8.4.9.4, 8.4.9.5, 8.4.9.6, 8.4.9.7, 8.4.9.8, 8.4.9.9, 8.4.9.10, 8.4.10.1, 8.4.10.2, 8.4.10.3, 8.4.10.4, 8.4.10.5, 8.4.10.6, 8.4.10.7, 8.4.10.8, 8.4.10.9, 8.4.10.10, 8.5.1.1, 8.5.1.2, 8.5.1.3, 8.5.1.4, 8.5.1.5, 8.5.1.6, 8.5.1.7, 8.5.1.8, 8.5.1.9, 8.5.1.10, 8.5.2.1, 8.5.2.2, 8.5.2.3, 8.5.2.4, 8.5.2.5, 8.5.2.6, 8.5.2.7, 8.5.2.8, 8.5.2.9, 8.5.2.10, 8.5.3.1, 8.5.3.2, 8.5.3.3, 8.5.3.4, 8.5.3.5, 8.5.3.6, 8.5.3.7, 8.5.3.8, 8.5.3.9, 8.5.3.10, 8.5.4.1, 8.5.4.2, 8.5.4.3, 8.5.4.4, 8.5.4.5, 8.5.4.6, 8.5.4.7, 8.5.48, 8.5.4.9, 8.5.4.10, 8.5.5.1, 8.5.5.2, 8.5.5.3, 8.5.5.4, 8.5.5.5, 8.5.5.6, 8.5.5.7., 8.5.5.8, 8.5.5.9, 8.5.5.10, 8.5.6.1, 8.5.6.2, 8.5.6.3, 8.5.6.4, 8.5.6.5, 8.5.6.6, 8.5.6.7, 8.5.6.8, 8.5.6.9, 8.5.6.10, 8.5.7.1, 8.5.7.2, 8.5.7.3, 8.5.7.4, 8.5.7.5, 8.5.7.6, 8.5.7.7, 8.5.7.8, 8.5.7.9, 8.5.7.10, 8.5.8.1, 8.5.8.2, 8.5.8.3, 8.5.8.4, 8.5.8.5, 8.5.8.6, 8.5.8.7, 8.5.8.8, 8.5.8.9, US 7,863,261 B2 41 42

TABLE 2-continued 8.5.8.10, 8.5.9.1, 8.5.9.2, 8.5.9.3, 8.5.9.4, 8.5.9.5, 8.5.9.6, 8.5.9.7, 8.5.9.8, 8.5.99, 8.5.9.10, 8.5.10.1, 8.5.10.2, 8.5.10.3, 8.5.10.4, 8.5.10.5, 8.5.10.6, 8.5.10.7, 8.5.10.8, 8.5.10.9, 8.5.10.10, 8.6.1.1, 8.6.1.2, 8.6.1.3, 8.6.1.4, 8.6.1.5, 8.6.1.6, 8.6.1.7, 8.6.1.8, 8.6.1.9, 8.6.1.10, 8.6.2.1, 8.6.2.2, 8.6.2.3, 8.6.2.4, 8.6.2.5, 8.6.2.6, 8.6.2.7, 8.6.2.8, 8.6.2.9, 8.6.2.10, 8.6.3.1, 8.6.3.2, 8.6.3.3, 8.6.3.4, 8.6.3.5, 8.6.3.6, 8.6.3.7, 8.6.3.8, 8.6.3.9, 8.6.3.10.8.6.4.1, 8.6.4.2, 8.6.4.3, 8.6.4.4, 8.6.4.5, 8.6.46, 8.6.4.7, 8.6.4.8, 8.6.4.9, 8.6.4.10, 8.6.5.1, 8.6.5.2, 8.6.5.3, 8.6.5.4, 8.6.5.5, 8.6.5.6, 8.6.5.7., 8.6.5.8, 8.6.5.9, 8.6.5.10, 8.6.6.1, 8.6.6.2, 8.6.6.3, 8.6.6.4, 8.6.6.5, 8.6.6.6, 8.6.6.7, 8.6.6.8, 8.6.6.9, 8.6.6.10, 8.6.7.1, 8.6.7.2, 8.6.7.3, 8.6.7.4, 8.6.7.5, 8.6.7.6, 8.6.7.7, 8.6.7.8, 8.6.7.9, 8.6.7.10, 8.6.8.1, 8.6.8.2, 8.6.8.3, 8.6.8.4, 8.6.8.5, 8.6.8.6, 8.6.8.7, 8.6.8.8, 8.6.8.9, 8.6.8.10, 8.6.9.1, 8.6.9.2, 8.6.9.3, 8.6.9.4, 8.6.9.5, 8.6.9.6, 8.6.9.7, 8.6.9.8, 8.6.9.9, 8.6.9.10, 8.6.10.1, 8.6.10.2, 8.6.10.3, 8.6.10.4, 8.6.10.5, 8.6.10.6, 8.6.10.7, 8.6.10.8, 8.6.10.9, 8.6.10.10, 8.7.1.1, 8.7.1.2, 8.7.1.3, 8.7.1.4, 8.7.1.5, 8.7.1.6, 8.7.1.7, 8.7.1.8, 8.7.1.9, 8.7.1.10, 8.7.2.1, 8.7.2.2, 8.7.2.3, 8.7.2.4, 8.7.2.5, 8.7.2.6, 8.7.2.7, 8.7.2.8, 8.7.2.9, 8.7.2.10, 8.7.3.1, 8.7.3.2, 8.7.3.3, 8.7.34, 8.7.3.5, 8.7.3.6, 8.7.3.7, 8.7.3.8, 8.7.3.9, 8.7.3.10, 8.7.4.1, 8.7.4.2, 8.7.4.3, 8.7.4.4, 8.74.5, 8.74.6, 8.74.7, 8.74.8, 8.7.4.9, 8.74.10, 8.7.5.1, 8.7.5.2, 8.7.5.3, 8.7.5.4, 8.7.5.5, 8.7.5.6, 8.7.5.7., 8.7.5.8, 8.7.5.9, 8.7.5.10, 8.7.6.1, 8.7.6.2, 8.7.6.3, 8.7.6.4, 8.7.6.5, 8.7.6.6, 8.7.6.7, 8.7.6.8, 8.7.6.9, 8.7.6.10, 8.7.7.1, 8.7.7.2, 8.7.7.3, 8.7.7.4, 8.7.7.5, 8.7.7.6, 8.7.7.7, 8.7.7.8, 8.7.7.9, 8.7.7.10, 8.7.8.1, 8.7.8.2, 8.7.8.3, 8.7.8.4, 8.7.8.5, 8.7.8.6, 8.7.8.7, 8.7.8.8, 8.7.8.9, 8.7.8.10, 8.7.9.1, 8.7.9.2, 8.7.9.3, 8.7.9.4, 8.7.9.5, 8.7.9.6, 8.7.9.7, 8.7.9.8, 8.7.9.9, 8.7.9.10, 8.7.10.1, 8.7.10.2, 8.7.10.3, 8.7.10.4, 8.7.10.5, 8.7.10.6, 8.7.10.7, 8.7.10.8, 8.7.10.9, 8.7.10.10, 8.8.1.1, 8.8.1.2, 8.8.1.3, 8.8.1.4, 8.8.1.5, 8.8.1.6, 8.8.1.7, 8.8.1.8, 8.8.1.9, 8.8.1.10, 8.8.2.1, 8.8.2.2, 8.8.2.3, 8.8.2.4, 8.8.2.5, 8.8.2.6, 8.8.2.7, 8.8.2.8, 8.8.2.9, 8.8.2.10, 8.8.3.1, 8.8.3.2, 8.8.3.3, 8.8.34, 8.8.3.5, 8.8.3.6, 8.8.3.7, 8.8.3.8, 8.8.3.9, 8.8.3.10, 8.8.4.1, 8.8.4.2, 8.8.4.3, 8.84.4, 8.8.4.5, 8.84.6, 8.8.47, 8.84.8, 8.8.4.9, 8.8.4.10, 8.8.5.1, 8.8.5.2, 8.8.5.3, 8.8.5.4, 8.8.5.5, 8.8.5.6, 8.8.5.7., 8.8.5.8, 8.8.5.9, 8.8.5.10, 8.8.6.1, 8.8.6.2, 8.8.6.3, 8.8.6.4, 8.8.6.5, 8.8.6.6, 8.8.6.7, 8.8.6.8, 8.8.6.9, 8.8.6.10, 8.8.7.1, 8.8.7.2, 8.8.7.3, 8.8.7.4, 8.8.7.5, 8.8.7.6, 8.8.7.7, 8.8.7.8, 8.8.7.9, 8.8.7.10, 8.8.8.1, 8.8.8.2, 8.8.8.3, 8.8.8.4, 8.8.8.5, 8.8.8.6, 8.8.8.7, 8.8.8.8, 8.8.8.9, 8.8.8.10, 8.8.9.1, 8.8.9.2, 8.8.9.3, 8.8.9.4, 8.8.9.5, 8.8.9.6, 8.8.9.7, 8.8.9.8, 8.8.9.9, 8.8.9.10, 8.8.10.1, 8.8.10.2, 8.8.10.3, 8.8.10.4, 8.8.10.5, 8.8.10.6, 8.8.10.7, 8.8.10.8, 8.8.10.9, 8.8.10.10, 8.9.1.1, 8.9.1.2, 8.9.1.3, 8.9.1.4, 8.9.1.5, 8.9.1.6, 8.9.1.7, 8.9.1.8, 8.9.19, 8.9.1.10, 8.9.2.1, 8.9.2.2, 8.9.2.3, 8.9.2.4, 8.9.2.5, 8.9.2.6, 8.9.2.7, 8.9.2.8, 8.9.2.9, 8.9.2.10, 8.9.3.1, 8.9.3.2, 8.9.3.3, 8.9.3.4, 8.9.3.5, 8.9.3.6, 8.9.3.7, 8.9.3.8, 8.9.3.9, 8.9.3.10, 8.9.4.1, 8.9.4.2, 8.9.4.3, 8.9.4.4, 8.9.45, 8.9.4.6, 8.9.4.7, 8.9.4.8, 8.9.4.9, 8.9.4.10, 8.9.5.1, 8.9.5.2, 8.9.5.3, 8.9.5.4, 8.9.5.5, 8.9.5.6, 8.9.5.7., 8.9.5.8, 8.9.5.9, 8.9.5.10, 8.9.6.1, 8.9.6.2, 8.9.6.3, 8.9.6.4, 8.9.6.5, 8.9.6.6, 8.9.6.7, 8.9.6.8, 8.9.6.9, 8.9.6.10, 8.9.7.1, 8.9.7.2, 8.9.7.3, 8.9.7.4, 8.9.7.5, 8.9.7.6, 8.9.7.7, 8.9.7.8, 8.9.7.9, 8.9.7.10, 8.9.8.1, 8.9.8.2, 8.9.8.3, 8.9.8.4, 8.9.8.5, 8.9.8.6, 8.9.8.7, 8.9.8.8, 8.9.8.9, 8.9.8.10, 8.9.9.1, 8.9.9.2, 8.9.9.3, 8.9.9.4, 8.9.9.5, 8.9.9.6, 8.9.9.7, 8.9.9.8, 8.9.9.9, 8.9.9.10, 8.9.10.1, 8.9.10.2, 8.9.10.3, 8.9.10.4, 8.9.10.5, 8.9.10.6, 8.9.10.7, 8.9.10.8, 8.9.10.9, 8.9.10.10, 8.10.1.1, 8.10.1.2, 8.10.1.3, 8.10.1.4, 8.10.1.5, 8.10.1.6, 8.10.1.7, 8.10.1.8, 8.10.1.9, 8.10.1.10, 8.10.2.1, 8.10.2.2, 8.10.2.3, 8.10.2.4, 8.10.2.5. 0.2.6, 8.10.2.7, 8.10.2.8, 8.10.2.9, 8.10.2.10, 8.10.3.1, 8.10.3.2, 8.10.3.3, 8.10.3.4, 8.10.3.5, 8.10.3.6, 8.10.3.7, 0.3.8, 8.10.3.9, 8.10.3.10, 8.10.4.1, 8.10.4.2, 8.10.4.3, 8.10.4.4, 8.10.4.5, 8.10.4.6, 8.10.4.7, 8.10.4.8, 8.10.4.9, 0.4.10, 8.10.5.1, 8.10.5.2, 8.10.5.3, 8.10.5.4, 8.10.5.5, 8.10.5.6, 8.10.5.7., 8.10.5.8, 8.10.5.9, 8.10.5.10, 8.10.6.1, 0.6.2, 8.10.6.3, 8.10.6.4, 8.10.6.5, 8.10.6.6, 8.10.6.7, 8.10.6.8, 8.10.6.9, 8.10.6.10, 8.10.7.1, 8.10.7.2, 8.10.7.3, 0.7.4, 8.10.7.5, 8.10.7.6, 8.10.7.7, 8.10.7.8, 8.10.7.9, 8.10.7.10, 8.10.8.1, 8.10.8.2, 8.10.8.3, 8.10.8.4, 8.10.8.5, 0.8.6, 8.10.8.7, 8.10.8.8, 8.10.8.9, 8.10.8.10, 8.10.9.1, 8.10.9.2, 8.10.9.3, 8.10.9.4, 8.10.9.5, 8.10.9.6, 8.10.9.7, 0.9.8, 8.10.9.9, 8.10.9.10, 8.10.10.1, 8.10.10.2, 8.10.10.3, 8.10.10.4, 8.10.10.5, 8.10.10.6, 8.10.10.7, 8.10.10.8, 0.10.9, 8.10.10.10, 9.1.1.1, 9.1.1.2, 9.1.1.3, 9.1.1.4, 9.1.1.5, 9.1.1.6, 9.1.1.7, 9.1.1.8, 9.1.1.9, 9.1.1.10, 9.1.2.1. .2.2, 9.1.2.3, 9.1.2.4, 9.1.2.5, 9.1.2.6, 9.1.2.7. 9.1.2.8, 9.1.2.9, 9.1.2.10, 9.1.3.1, 9.1.3.29.1.3.3, 9.1.3.4.9.1.3.5, .3.6, 9.1.3.7, 9.1.3.8, 9.1.3.9, 9.1.3.10, 9.1.4.1, 9.1.4.2, 9.1.4.3, 9.1.4.4, 9.1.4.5, 9.1.4.6, 9.1.4.7, 9.1.4.8, 9.1.4.9, 4.10, 9.1.5.1, 9.1.5.2,9.1.5.3, 9.1.5.4, 9.1.5.5, 9.1.5.6, 9.1.5.7., 9.1.5.8, 9.1.5.9, 9.1.5.10, 9.1.6.19.1.6.2, 9.1.6.3, .6.4, 9.1.6.5, 9.1.6.6, 9.1.6.7, 9.1.6.8, 9.1.6.9, 9.1.6.10, 9.1.7.1, 9.1.7.2, 9.1.7.3, 9.1.7.4, 9.1.7.5, 9.1.7.6, 9.1.7.7, .7.8, 9.1.7.9, 9.1.7.10, 9.1.8.1, 9.1.8.2, 9.1.8.3, 9.1.8.4, 9.1.8.5, 9.1.8.6, 9.1.8.7, 9.1.8.8, 9.1.8.9, 9.1.8.10, 9.19.1, .9.2, 9.19.3, 9.19.4, 9.1.9.5, 9.1.9.6, 9.1.9.7, 9.19.8, 9.1.9.9, 9.1.9.10, 9.1.10.1, 9.1.10.2, 9.1.10.3, 9.1.10.4, 9.1.10.5, 9.1.10.6, 9.1.10.7, 9.1.10.8, 9.1.10.9, 9.1.10.10, 9.2.1.1, 9.2.1.2, 9.2.1.3, 9.2.1.4, 9.2.1.5, 9.2.1.6, 9.2.1.7, 9.2.1.8, 9.2.1.9, 9.2.1.10, 9.2.2.1, 9.2.2.2, 9.2.2.3, 9.2.2.4, 9.2.2.5, 9.2.2.6, 9.2.2.7. 9.2.2.8, 9.2.2.9, 9.2.2.10, 9.2.3.1, 9.2.3.2, 9.2.3.3, 9.2.3.4, 9.2.3.5, 9.2.3.6, 9.2.3.7, 9.2.3.8, 9.2.3.9, 9.2.3.10, 9.2.4.1, 9.2.4.2, 9.2.4.3, 9.2.4.4, 9.2.45, 9.2.4.6, 9.2.4.7, 9.2.4.8, 9.2.4.9, 9.2.4.10, 9.2.5.1, 9.2.5.2, 9.2.5.3, 9.2.5.4, 9.2.5.5, 9.2.5.6, 9.2.5.7., 9.2.5.8, 9.2.5.9, 9.2.5.10, 9.2.6.1, 9.2.6.2, 9.2.6.3, 9.2.6.4, 9.2.6.5, 9.2.6.6, 9.2.6.7, 9.2.6.8, 9.2.6.9, 9.2.6.10, 9.2.7.1, 9.2.7.2, 9.2.7.3, 9.2.7.4, 9.2.7.5, 9.2.7.6, 9.2.7.7, 9.2.7.8, 9.2.7.9, 9.2.7.10, 9.2.8.1, 9.2.8.2, 9.2.8.3, 9.2.8.4, 9.2.8.5, 9.2.8.6, 9.2.8.7, 9.2.8.8, 9.2.8.9, 9.2.8.10, 9.2.9.1, 9.2.9.2, 9.2.9.3, 9.2.9.4, 9.2.9.5, 9.2.9.6, 9.2.9.7, 9.2.9.8, 9.2.9.9, 9.2.9.10, 9.2.10.1, 9.2.10.2, 9.2.10.3, 9.2.10.4, 9.2.10.5, 9.2.10.6, 9.2.10.7, 9.2.10.8, 9.2.10.9, 9.2.10.10, 9.3.1.1,9.3.1.2, 9.3.1.3, 9.3.1.4, 9.3.1.5, 9.3.1.6, 9.3.1.7,9.3.1.8, 9.3.1.9, 9.3.1.10, 9.3.2.1,9.3.2.2, 9.3.2.3, 9.3.2.4, 9.3.2.5, 9.3.2.6, 9.3.2.7, 9.3.2.8, 9.3.2.9, 9.3.2.10, 9.3.3.1, 9.3.3.2, 9.3.3.3, 9.3.3.4, 9.3.3.5, 9.3.3.6, 9.3.3.7, 9.3.3.8, 9.3.3.9, 9.3.3.10, 9.3.4.1, 9.3.4.2, 9.3.4.3,9.3.4.4, 9.3.4.5, 9.3.4.6, 9.3.4.7, 9.3.4.8, 9.3.4.9, 9.3.4.10, 9.3.5.1, 9.3.5.2,9.3.5.3, 9.3.5.4, 9.3.5.5, 9.3.5.6, 9.3.5.7., 9.3.5.8, 9.3.5.9,9.3.5.10, 9.3.6.1,9.3.6.2, 9.3.6.3, 9.3.6.4, 9.3.6.5, 9.3.6.6, 9.3.6.7, 9.3.6.8, 9.3.6.9, 9.3.6.10, 9.3.7.1, 9.3.7.2,9.3.7.3, 9.3.7.4, 9.3.7.5, 9.3.7.6, 9.3.7.7,9.3.7.8, 9.3.7.9, 9.3.7.10, 9.3.8.1,9.3.8.2, 9.3.8.3, 9.3.8.4, 9.3.8.5, 9.3.8.6, 9.3.8.7,9.3.8.8, 9.3.8.9, 9.3.8.10, 9.3.9.19.3.9.2, 9.3.9.3, 9.3.9.4, 9.3.9.5, 9.3.9.6, 9.3.9.7, 9.3.9.8, 9.3.9.9, 9.3.9.10, 9.3.10.1, 9.3.10.2, 9.3.10.3, 9.3.10.4, 9.3.10.5, 9.3.10.6, 9.3.10.7,9.3.10.8, 9.3.10.9, 9.3.10.10, 9.4.1.1, 9.4.1.2, 9.4.1.3, 9.4.1.4, 9.4.1.5, 9.4.1.6, 9.4.1.7, 9.4.1.8, 9.4.1.9, 9.4.1.10, 9.4.2.1, 9.4.2.2, 9.4.2.3, 9.4.2.4, 9.4.2.5, 9.4.2.6, 9.4.2.7. 9.4.2.8, 9.4.2.9, 9.4.2.10, 9.4.3.1, 9.4.3.2, 9.4.3.3, 9.4.3.4.9.4.3.5, 9.4.3.6, 9.4.3.7, 9.4.3.8, 9.4.3.9, 9.4.3.10, 9.4.4.1, 9.4.4.2, 9.4.4.3, 9.4.4.4, 9.4.4.5, 9.4.4.6, 9.4.4.7, 9.4.4.8, 9.4.4.9, 9.4.4.10, 9.4.5.1, 9.4.5.2, 9.4.5.3, 9.4.5.4, 9.4.5.5, 9.4.5.6, 9.4.5.7., 94.5.8, 9.4.5.9, 9.4.5.10, 9.4.6.1, 9.4.6.2, 9.4.6.3, 9.4.6.4, 9.4.6.5, 9.4.6.6, 9.4.6.7,9.4.6.8, 9.4.6.9, 9.4.6.10, 94.7.1, 9.4.7.2, 9.4.7.3, 9.4.74, 9.4.7.5, 9.4.7.6, 9.4.7.7, 9.4.7.8, 9.4.7.9, 9.4.7.10, 9.4.8.1, 9.4.8.2, 9.4.8.3, 9.4.8.4, 9.4.8.5, 9.4.8.6, 9.4.8.7, 9.4.8.8, 9.4.8.9, 9.4.8.10, 9.4.9.19.4.9.2, 9.4.9.3, 9.4.9.4, 9.4.9.5, 9.4.9.6, 9.4.9.7, 9.4.9.8, 9.4.9.9, 9.4.9.10, 9.4.10.1, 9.4.10.2, 9.4.10.3, 9.4.10.4, 9.4.10.5, 9.4.10.6, 9.4.10.7, 9.4.10.8, 9.4.10.9, 9.4.10.10, 9.5.1.1, 9.5.1.2,9.5.1.3, 9.5.1.4, 9.5.1.5, 9.5.1.6, 9.5.1.7, 9.5.1.8, 9.5.1.9, 9.5.1.10, 9.5.2.1, 9.5.2.2,9.5.2.3, 9.5.2.4, 9.5.2.5, 9.5.2.6, 9.5.2.7, 9.5.2.8, 9.5.2.9, 9.5.2.10, 9.5.3.1,9.5.3.2, 9.5.3.3, 9.5.3.4, 9.5.3.5, 9.5.3.6, 9.5.3.7, 9.5.3.8, 9.5.3.9, 9.5.3.10, 9.5.4.1, 9.5.4.2, 9.5.4.3, 9.5.44, 9.5.4.5, 9.5.4.6, 9.5.4.7, 9.5.48, 9.5.4.9, 9.5.4.10, 9.5.5.1, 9.5.5.2, 9.5.5.3, 9.5.5.4, 9.5.5.5, 9.5.5.6, 9.5.5.7., 9.5.5.8, 9.5.5.9, 9.5.5.10, 9.5.6.1, 9.5.6.2, 9.5.6.3, 9.5.6.4, 9.5.6.5, 9.5.6.6, 9.5.6.7, 9.5.6.8, 9.5.6.9, 9.5.6.10, 9.5.7.1, 9.5.7.2, 9.5.7.3, 9.5.7.4, 9.5.7.5, 9.5.7.6, 9.5.7.7,9.5.7.8, 9.5.7.9, 9.5.7.10, 9.5.8.1, 9.5.8.2, 9.5.8.3, 9.5.8.4, 9.5.8.5, 9.5.8.6, 9.5.8.7, 9.5.8.8, 9.5.8.9, 9.5.8.10, 9.5.9.1, 9.5.9.2, 9.5.9.3, 9.5.94, 9.5.9.5, 9.5.9.6, 9.5.9.7, 9.5.9.8, 9.5.99, 9.5.9.10, 9.5.10.1, 9.5.10.2, 9.5.10.3, 9.5.10.4, 9.5.10.5, 9.5.10.6, 9.5.10.7, 9.5.10.8, 9.5.10.9, 9.5.10.10, 9.6.1.1, 9.6.1.2, 9.6.1.3, 9.6.1.4, 9.6.1.5, 9.6.1.6, 9.6.1.7, 9.6.1.8, 9.6.19, 9.6.1.10, 9.6.2.1, 9.6.2.2, 9.6.2.3, 9.6.2.4, 9.6.2.5, 9.6.2.6, 9.6.2.7, 9.6.2.8, 9.6.2.9, 9.6.2.10, 9.6.3.1, 9.6.3.2, 9.6.3.3, 9.6.3.4, 9.6.3.5, 9.6.3.6, 9.6.3.7, 9.6.3.8, 9.6.3.9, 9.6.3.10, 9.6.4.1, 9.6.4.2, 9.6.4.3, 9.6.4.4, 9.6.4.5, 9.6.46, 9.6.4.7, 9.6.4.8, 9.6.4.9, 9.6.4.10, 9.6.5.1, 9.6.5.2, 9.6.5.3, 9.6.5.4, 9.6.5.5, 9.6.5.6, 9.6.5.7., US 7,863,261 B2 43 44

TABLE 2-continued 9.6.5.8, 9.6.5.9, 9.6.5.10, 9.6.6.1, 9.6.6.2, 9.6.6.3, 9.6.6.4, 9.6.6.5, 9.6.6.6, 9.6.6.7, 9.6.6.8, 9.6.6.9, 9.6.6.10, 9.6.7.1, 9.6.7.2, 9.6.7.3, 9.6.7.4, 9.6.7.5, 9.6.7.6, 9.6.7.7, 9.6.7.8, 9.6.7.9, 9.6.7.10, 9.6.8.1, 9.6.8.2, 9.6.8.3, 9.6.84, 9.6.8.5, 9.6.8.6, 9.6.8.7, 9.6.8.8, 9.6.8.9, 9.6.8.10, 9.6.9.1, 9.6.9.2, 9.6.9.3, 9.6.9.4, 9.6.9.5, 9.6.9.6, 9.6.9.7, 9.6.9.8, 9.6.9.9, 9.6.9.10, 9.6.10.1, 9.6.10.2, 9.6.10.3, 9.6.10.4, 9.6.10.5, 9.6.10.6, 9.6.10.7, 9.6.10.8, 9.6.10.9, 9.6.10.10, 9.7.1.1, 9.7.1.2, 9.7.1.3, 9.7.1.4, 9.7.1.5, 9.7.1.6, 9.7.1.7, 9.7.1.8, 9.7.1.9, 9.7.1.10, 9.7.2.1, 9.7.2.2, 9.7.2.3, 9.7.2.4, 9.7.2.5, 9.7.2.6, 9.7.2.7,9.7.2.8, 9.7.2.9, 9.7.2.10, 9.7.3.1,9.7.3.2, 9.7.3.3, 9.7.34, 9.7.3.5, 9.7.3.6, 9.7.3.7, 9.7.3.8, 9.7.3.9, 9.7.3.10, 9.7.4.1, 9.7.4.2,9.7.4.3, 9.7.44, 9.7.4.5, 9.7.4.6, 9.7.4.7, 9.7.4.8, 9.7.4.9, 9.7.4.10, 9.7.5.1,9.7.5.2, 9.7.5.3, 9.7.5.4, 9.7.5.5, 9.7.5.6, 9.7.5.7., 9.7.5.8, 9.7.5.9, 9.7.5.10, 9.7.6.1,9.7.6.2, 9.7.6.3, 9.7.6.4, 9.7.6.5, 9.7.6.6, 9.7.6.7, 9.7.6.8, 9.7.6.9, 9.7.6.10, 9.7.7.1, 9.7.7.2, 9.7.7.3, 9.7.7.4, 9.7.7.5, 9.7.7.6, 9.7.7.7, 9.7.7.8, 9.7.7.9, 9.7.7.10, 9.7.8.1, 9.7.8.2, 9.7.8.3, 9.7.8.4, 9.7.8.5, 9.7.8.6, 9.7.8.7, 9.7.8.8, 9.7.8.9, 9.7.8.10, 9.7.9.1, 9.7.9.2, 9.7.9.3, 9.7.9.4, 9.7.9.5, 9.7.9.6, 9.7.9.7,9.7.9.8, 9.7.9.9, 9.7.9.10, 9.7.10.1, 9.7.10.2, 9.7.10.3, 9.7.10.4, 9.7.10.5, 9.7.10.6, 9.7.10.7, 9.7.10.8, 9.7.10.9, 9.7.10.10, 9.8.1.1,9.8.1.2,9.8.1.3, 9.8.1.4, 9.8.1.5, 9.8.1.6, 9.8.1.7, 9.8.1.8, 9.8.1.9, 9.8.1.10, 9.8.2.1, 9.8.2.2, 9.8.2.3, 9.8.2.4, 9.8.2.5, 9.8.2.6, 9.8.2.7, 9.8.2.8, 9.8.2.9, 9.8.2.10, 9.8.3.1, 9.8.3.2, 9.8.3.3, 9.8.34, 9.8.3.5, 9.8.3.6, 9.8.3.7, 9.8.3.8, 9.8.3.9, 9.8.3.10, 9.8.4.1,9.8.4.2, 9.8.4.3, 9.8.4.4, 9.8.4.5, 9.8.4.6, 9.8.47, 9.8.4.8, 9.8.4.9, 9.8.4.10, 9.8.5.1, 9.8.5.2,9.8.5.3, 9.8.5.4, 9.8.5.5, 9.8.5.6, 9.8.5.7., 9.8.5.8, 9.8.5.9, 9.8.5.10, 9.8.6.1,9.8.6.2, 9.8.6.3, 9.8.6.4, 9.8.6.5, 9.8.6.6, 9.8.6.7,9.8.6.8, 9.8.6.9, 9.8.6.10, 9.8.7.1,9.8.7.2, 9.8.7.3, 9.8.7.4, 9.8.7.5, 9.8.7.6, 9.8.7.7, 9.8.7.8, 9.8.7.9, 9.8.7.10, 9.8.8.1, 9.8.8.2, 9.8.8.3, 9.8.8.4, 9.8.8.5, 9.8.8.6, 9.8.8.7, 9.8.8.8, 9.8.8.9, 9.8.8.10, 9.8.9.1, 9.8.9.2, 9.8.9.3, 9.8.9.4, 9.8.9.5, 9.8.9.6, 9.8.9.7, 9.8.9.8, 9.8.9.9, 9.8.9.10, 9.8.10.1, 9.8.10.2,9.8.10.3, 9.8.10.4, 9.8.10.5, 9.8.10.6, 9.8.10.7, 9.8.10.8, 9.8.10.9, 9.8.10.10, 9.9.1.1, 9.9.1.2, 99.1.3, 9.9.1.4, 9.9.1.5, 9.9.1.6, 9.9.1.7, 9.9.1.8, 9.9.19,9.9.1.10, 9.9.2.1, 9.9.2.2, 9.9.2.3,9.9.2.4, 9.9.2.5, 9.9.2.6, 9.9.2.7, 9.9.2.8, 9.9.2.9, 9.9.2.10, 9.9.3.1, 9.9.3.2, 9.9.3.3,9.9.3.4, 9.9.3.5, 9.9.3.6, 9.9.3.7, 99.3.8, 9.9.3.9, 9.9.3.10, 9.9.4.1, 9.94.2,9.9.4.3, 9.9.44, 9.9.45, 9.9.4.6, 9.94.7,9.9.4.8, 9.94.9, 9.94.10, 9.9.5.1,9.9.5.2, 9.9.5.3,9.9.5.4, 9.9.5.5, 9.9.5.6, 9.9.5.7., 9.9.5.8, 9.9.5.9, 9.9.5.10, 9.9.6.1, 9.9.6.2,9.9.6.3, 9.9.6.4, 99.6.5, 9.9.6.6, 9.9.6.7,9.9.6.8, 9.9.6.9, 9.9.6.10, 9.9.7.1,9.9.7.2, 9.9.7.3, 9.9.7.4, 9.9.7.5, 9.9.7.6, 9.9.7.7,9.9.7.8, 9.9.7.9, 9.9.7.10, 9.9.8.1,9.9.8.2, 9.9.8.3, 9.9.8.4, 9.9.8.5, 9.9.8.6, 9.9.8.7, 9.9.8.8, 9.9.8.9,9.9.8.10, 9.9.9.1, 9.9.9.2, 99.9.3, 9.9.9.4, 9.99.5, 9.9.9.6, 9.9.9.7, 9.9.9.8, 9.9.9.9, 9.9.9.10, 9.9.10.1, 9.9.10.2,9.9.10.3, 9.9.10.4, 9.9.10.5, 9.9.10.6, 9.9.10.7, 9.9.10.8, 9.9.10.9,9.9.10.10, 9.10.1.1, 9.10.1.2,9.10.1.3, 9.10.1.4, 9.10.1.5, 9.10.1.6, 9.10.1.7, 9.10.1.8, 9.10.1.9, 9.10.1.10, 9.10.2.1, 9.10.2.2, 9.10.2.3, 9.10.24, 9.10.2.5, 9.10.2.6, 9.10.2.7, 9.10.2.8, 9.10.2.9, 9.10.2.10, 9.10.3.1, 9.10.3.2, 9.10.3.3, 9.10.3.4.9.10.3.5, 9.10.3.6, 9.10.3.7, 9.10.3.8, 9.10.3.9, 9.10.3.10, 9.10.4.1,9.10.4.2, 9.10.4.3, 9.10.4.4, 9.10.4.5, 9.10.4.6, 9.10.4.7, 9.10.4.8, 9.10.4.9, 9.10.4.10, 9.10.5.1, 9.10.5.2, 9.10.5.3, 9.10.5.4.9.10.5.5, 9.10.5.6, 9.10.5.7., 9.10.5.8, 9.10.5.9, 9.10.5.10, 9.10.6.1, 9.10.6.2, 9.10.6.3, 9.10.6.4, 9.10.6.5, 9.10.6.6, 9.10.6.7, 9.10.6.8, 9.10.6.9, 9.10.6.10, 9.10.7.1, 9.10.7.2, 9.10.7.3, 9.10.7.4, 9.10.7.5, 9.10.7.6, 9.10.7.7, 9.10.7.8, 9.10.7.9, 9.10.7.10, 9.10.8.1, 9.10.8.2, 9.10.8.3, 9.10.8.4, 9.10.8.5, 9.10.8.6, 9.10.8.7, 9.10.8.8, 9.10.8.9, 9.10.8.10, 9.10.9.19.10.9.2, 9.10.9.3, 9.10.9.4, 9.10.9.5, 9.10.9.6, 9.10.9.7, 9.10.9.8, 9.10.9.9, 9.10.9.10, 9.10.10.1, 9.10.10.2, 9.10.10.3, 9.10.10.4, 9.10.10.5, 9.10.10.6, 9.10.10.7, 9.10.10.8, 9.10.10.9, 9.10.10.10, 10.1.1.1, 10.1.1.2, 10.1.1.3, 10.1.1.4, 10.1.1.5, 10.1.1.6., 10.1.1.7, 10.1.1.8, 10.1.1.9, 10.1.1.10, 0.1.2.1, 10.1.2.2, 10.1.2.3, 10.1.2.4, 10.1.2.5, 10.1.2.6., 10.1.2.7, 10.1.2.8, 10.1.2.9, 10.1.2.10, 10.1.3.1, 10.1.3.2. 0.1.3.3.10.1.3.4, 10.1.3.5, 10.1.3.6., 10.1.3.7, 10.1.3.8, 10.1.3.9, 10.1.3.10, 10.1.4.1, 10.1.4.2, 10.1.4.3, 10.1.4.4, 0.1.4.5, 10.1.4.6., 10.1.4.7, 10.1.4.8, 10.1.4.9, 10.1.4.10, 10.1.5.1, 10.1.5.2, 10.1.5.3, 10.1.5.4, 10.1.5.5, 10.1.5.6, 0.1.5.7., 10.1.5.8, 10.1.5.9, 10.1.5.10, 10.1.6.1, 10.1.6.2, 10.1.6.3, 10.1.6.4, 10.1.6.5, 10.1.6.6, 10.1.6.7, 10.1.6.8, 0.1.6.9, 10.1.6.10, 10.1.7.1, 10.1.7.2, 10.1.7.3, 10.1.7.4, 10.1.7.5, 10.1.7.6, 10.1.7.7, 10.1.7.8, 10.1.7.9, 10.1.7.10, 0.1.8.1. 10.1.8.2, 10.1.8.3, 10.1.8.4, 10.1.8.5, 10.1.8.6., 10.1.8.7, 10.1.8.8, 10.1.8.9, 10.1.8.10, 10.1.9.1, 10.1.9.2, 0.19.3, 10.1.9.4, 10.1.9.5, 10.1.9.6, 10.1.9.7, 10.19.8, 10.1.9.9, 10.1.9.10, 10.1.10.1, 10.1.10.2, 10.1.10.3 0.1.10.4, 10.1.10.5, 10.1.10.6, 10.1.10.7, 10.1.10.8, 10.1.10.9, 10.1.10.10, 10.2.1.1, 10.2.1.2, 10.2.1.3, 10.2.1.4, 0.2.1.5, 10.2.1.6., 10.2.1.7, 10.2.1.8, 10.2.1.9, 10.2.1.10, 10.2.2.1, 10.2.2.2, 10.2.2.3, 10.2.2.4, 10.2.2.5, 10.2.2.6, 0.2.2.7, 10.2.2.8, 10.2.2.9, 10.2.2.10, 10.2.3.1, 10.2.3.2, 10.2.3.3, 10.2.3.4, 10.2.3.5, 10.2.3.6., 10.2.3.7, 10.2.3.8, 0.2.3.9, 10.2.3.10, 10.2.4.1, 10.2.4.2, 10.2.4.3, 10.2.4.4, 10.2.4.5, 10.2.4.6., 10.2.4.7, 10.2.4.8, 10.2.4.9, 10.2.4.10, 0.2.5.1, 10.2.5.2, 10.2.5.3, 10.2.5.4, 10.2.5.5, 10.2.5.6, 10.2.5.7., 10.2.5.8, 10.2.5.9, 10.2.5.10, 10.2.6.1, 10.2.6.2, 0.2.6.3, 10.2.6.4, 10.2. 6.5, 10.2. 6.6, 10.2.6.7, 10.2.6.8, 10.2.6.9, 10.2.6.10, 10.2.7.1, 10.2.7.2, 10.2.7.3, 10.2.7.4, 0.2.7.5, 10.2.7.6, 10.2.7.7, 10.2.7.8, 10.2.7.9, 10.2.7.10, 10.2.8.1, 10.2.8.2, 10.2.8.3, 10.2.8.4, 10.2.8.5, 10.2.8.6. 0.2.8.7, 10.2.8.8, 10.2.8.9, 10.2.8.10, 10.2.9.1, 10.2.9.2, 10.2.9.3, 10.2.9.4, 10.2.9.5, 10.2.9.6, 10.2.9.7, 10.2.9.8, 0.2.9.9, 10.2.9.10, 10.2.10.1, 10.2.10.2, 10.2.10.3, 10.2.10.4, 10.2.10.5, 10.2.10.6, 10.2.10.7, 10.2.10.8, 10.2.10.9, 0.2.10.10, 10.3.1.1, 10.3.1.2, 10.3.1.3, 10.3.1.4, 10.3.1.5, 10.3.1.6., 10.3.1.7, 10.3.1.8, 10.3.1.9, 10.3.1.10, 10.3.2.1. 0.3.2.2, 10.3.2.3, 10.3.2.4, 10.3.2.5, 10.3.2.6, 10.3.2.7, 10.3.2.8, 10.3.2.9, 10.3.2.10, 10.3.3.1, 10.3.3.2, 10.3.3.3, 0.3.3.4, 10.3.3.5, 10.3.3.6., 10.3.3.7, 10.3.3.8, 10.3.3.9, 10.3.3.10, 10.3.4.1, 10.3.4.2, 10.3.4.3, 10.3.4.4, 10.3.4.5, 0.3.4.6., 10.3.4.7, 10.3.4.8, 10.3.4.9, 10.3.4.10, 10.3.5.1, 10.3.5.2, 10.3.5.3, 10.3.5.4, 10.3.5.5, 10.3.5.6, 10.3.5.7., 0.3.5.8, 10.3.5.9, 10.3.5.10, 10.3.6.1, 10.3.6.2, 10.3.6.3, 10.3.6.4, 10.3.6.5, 10.3.6.6, 10.3.6.7, 10.3.6.8, 10.3.6.9, 0.3.6.10, 10.3.7.1, 10.3.7.2, 10.3.7.3, 10.3.7.4, 10.3.7.5, 10.3.7.6, 10.3.7.7, 10.3.7.8, 10.3.7.9, 10.3.7.10, 10.3.8.1, 0.3.8.2, 10.3.8.3, 10.3.8.4, 10.3.8.5, 10.3.8.6., 10.3.8.7, 10.3.8.8, 10.3.8.9, 10.3.8.10, 10.3.9.1, 10.3.9.2, 10.3.9.3, 0.3.9.4, 10.3.9.5, 10.3.9.6, 10.3.9.7, 10.3.9.8, 10.3.9.9, 10.3.9.10, 10.3.10.1, 10.3.10.2, 10.3.10.3, 10.3.10.4, 0.3.10.5, 10.3.10.6, 10.3.10.7, 10.3.10.8, 10.3.10.9, 10.3.10.10, 10.4.1.1, 10.4.1.2, 10.4.1.3, 10.4.1.4, 10.4.1.5, 0.4.1.6., 10.4.1.7, 10.4.1.8, 10.4.1.9, 10.4.1.10, 10.4.2.1, 10.4.2.2, 10.4.2.3, 10.4.2.4, 10.4.2.5, 10.4.2.6, 10.4.2.7, 0.4.2.8, 10.4.2.9, 10.4.2.10, 10.4.3.1, 10.4.3.2, 10.4.3.3, 10.4.3.4, 10.4.3.5, 10.4.3.6., 10.4.3.7, 10.4.3.8, 10.4.3.9, 0.4.3.10, 10.4.4.1, 10.4.4.2, 10.4.4.3, 10.4.4.4, 10.4.4.5, 10.4.4.6., 10.4.4.7, 10.4.4.8, 10.4.4.9, 10.4.4.10, 10.4.5.1, 0.4.5.2, 10.4.5.3, 10.4.5.4, 10.4.5.5, 10.4.5.6, 10.4.5.7., 10.4.5.8, 10.4.5.9, 10.4.5.10, 10.4.6.1, 10.4.6.2, 10.4.6.3, 0.4.6.4, 10.4.6.5, 10.4.6.6, 10.4.6.7, 10.4.6.8, 10.4.6.9, 10.4.6.10, 10.4.7.1, 10.4.7.2, 10.4.7.3, 10.4.7.4, 10.4.7.5, 0.4.7.6, 10.4.7.7, 10.4.7.8, 10.4.7.9, 10.4.7.10, 10.4.8.1, 10.4.8.2, 10.4.8.3, 10.4.8.4, 10.4.8.5, 10.4.8.6., 10.4.8.7, 0.4.8.8, 10.4.8.9, 10.4.8.10, 10.4.9.1, 10.4.9.2, 10.4.9.3, 10.4.9.4, 10.4.9.5, 10.4.9.6, 10.4.9.7, 10.4.9.8, 10.4.9.9, 0.4.9.10, 10.4.10.1, 10.4.10.2, 10.4.10.3, 10.4.10.4, 10.4.10.5, 10.4.10.6, 10.4.10.7, 10.4.10.8, 10.4.10.9, 0.4.10.10, 10.5.1.1, 10.5.1.2, 10.5.1.3, 10.5.1.4, 10.5.1.5, 10.5.1.6., 10.5.1.7, 10.5.1.8, 10.5.1.9, 10.5.1.10, 10.5.2.1, 0.5.2.2, 10.5.2.3, 10.5.24, 10.5.2.5, 10.5.2.6, 10.5.2.7, 10.5.2.8, 10.5.2.9, 10.5.2.10, 10.5.3.1, 10.5.3.2, 10.5.3.3, 0.5.3.4, 10.5.3.5, 10.5.3.6., 10.5.3.7, 10.5.3.8, 10.5.3.9, 10.5.3.10, 10.5.4.1, 10.5.4.2, 10.5.4.3, 10.5.44, 10.5.4.5, 0.5.4.6., 10.5.4.7, 10.5.48, 10.5.4.9, 10.5.4.10, 10.5.5.1, 10.5.5.2, 10.5.5.3, 10.5.5.4, 10.5.5.5, 10.5.5.6, 10.5.5.7., 0.5.5.8, 10.5.5.9, 10.5.5.10, 10.5.6.1, 10.5.6.2, 10.5.6.3, 10.5.6.4, 10.5.6.5, 10.5.6.6, 10.5.6.7, 10.5.6.8, 10.5.6.9, 0.5.6.10, 10.5.7.1, 10.5.7.2, 10.5.7.3, 10.5.7.4, 10.5.7.5, 10.5.7.6, 10.5.7.7, 10.5.7.8, 10.5.7.9, 10.5.7.10, 10.5.8.1, 0.5.8.2, 10.5.8.3, 10.5.8.4, 10.5.8.5, 10.5.8.6., 10.5.8.7, 10.5.8.8, 10.5.8.9, 10.5.8.10, 10.5.9.1, 10.5.9.2, 10.5.9.3, 0.5.9.4, 10.5.9.5, 10.5.9.6, 10.5.9.7, 10.5.9.8, 10.5.9.9, 10.5.9.10, 10.5.10.1, 10.5.10.2, 10.5.10.3, 10.5.10.4, 0.5.10.5, 10.5.10.6, 10.5.10.7, 10.5.10.8, 10.5.10.9, 10.5.10.10, 10.6.1.1, 10.6.1.2, 10.6.1.3, 10.6.1.4, 10.6.1.5, 0.6.1.6., 10.6.1.7, 10.6.1.8, 10.6.1.9, 10.6.1.10, 10.6.2.1, 10.6.2.2, 10.6.2.3, 10.6.2.4, 10.6.2.5, 10.6.2.6, 10.6.2.7, 0.6.2.8, 10.6.2.9, 10.6.2.10, 10.6.3.1, 10.6.3.2, 10.6.3.3, 10.6.3.4, 10.6.3.5, 10.6.3.6., 10.6.3.7, 10.6.3.8, 10.6.3.9, US 7,863,261 B2 45 46

TABLE 2-continued 0.6.3.10, 10.6.4.1, 10.6.4.2, 10.6.4.3, 10.6.4.4, 10.6.4.5, 10.6.4.6., 10.6.4.7, 10.6.4.8, 10.6.4.9, 10.6.4.10, 10.6.5.1, 0.6.5.2, 10.6.5.3, 10.6.5.4, 10.6.5.5, 10.6.5.6, 10.6.5.7., 10.6.5.8, 10.6.5.9, 10.6.5.10, 10.6.6.1, 10.6.6.2, 10.6.6.3, 0.6.64, 10.6.6.5, 10.6.6.6, 10.6.6.7, 10.6.6.8, 10.6.6.9, 10.6.6.10, 10.6.7.1, 10.6.7.2, 10.6.7.3, 10.6.7.4, 10.6.7.5, 0.6.7.6, 10.6.7.7, 10.6.7.8, 10.6.7.9, 10.6.7.10, 10.6.8.1, 10.6.8.2, 10.6.8.3, 10.6.8.4, 10.6.8.5, 10.6.8.6., 10.6.8.7, 0.6.8.8, 10.6.8.9, 10.6.8.10, 10.6.9.1, 10.6.9.2, 10.6.9.3, 10.6.9.4, 10.6.9.5, 10.6.9.6, 10.6.9.7, 10.6.9.8, 10.6.9.9, 0.6.9.10, 10.6.10.1, 10.6.10.2, 10.6.10.3, 10.6.10.4, 10.6.10.5, 10.6.10.6, 10.6.10.7, 10.6.10.8, 10.6.10.9, 0.6.10.10, 10.7.1.1, 10.7.1.2, 10.7.1.3, 10.7.1.4, 10.7.1.5, 10.7.1.6., 10.7.1.7, 10.7.1.8, 10.7.1.9, 10.7.1.10, 10.7.2.1, 0.7.2.2, 10.7.2.3, 10.7.24, 10.7.2.5, 10.7.2.6, 10.7.2.7, 10.7.2.8, 10.7.2.9, 10.7.2.10, 10.7.3.1, 10.7.3.2, 10.7.3.3, 0.7.34, 10.7.3.5, 10.7.3.6., 10.7.3.7, 10.7.3.8, 10.7.3.9, 10.7.3.10, 10.7.4.1, 10.7.4.2, 10.7.4.3, 10.7.4.4, 10.7.4.5, 0.7.4.6., 10.7.4.7, 10.7.4.8, 10.7.4.9, 10.7.4.10, 10.7.5.1, 10.7.5.2, 10.7.5.3, 10.7.5.4, 10.7.5.5, 10.7.5.6, 10.7.5.7., 0.7.5.8, 10.7.5.9, 10.7.5.10, 10.7.6.1, 10.7.6.2, 10.7.6.3, 10.7.6.4, 10.7.6.5, 10.7.6.6, 10.7.6.7, 10.7.6.8, 10.7.6.9, 0.7.6.10, 10.7.7.1, 10.7.7.2, 10.7.7.3, 10.7.7.4, 10.7.7.5, 10.7.7.6, 10.7.7.7, 10.7.7.8, 10.7.7.9, 10.7.7.10, 10.7.8.1, 0.7.8.2, 10.7.8.3, 10.7.84, 10.7.8.5, 10.7.8.6., 10.7.8.7, 10.7.8.8, 10.7.8.9, 10.7.8.10, 10.7.9.1, 10.7.9.2, 10.7.9.3, 0.7.9.4, 10.7.9.5, 10.7.9.6, 10.7.9.7, 10.7.9.8, 10.7.9.9, 10.7.9.10, 10.7.10.1, 10.7.10.2, 10.7.10.3, 10.7.10.4, 0.7.10.5, 10.7.10.6, 10.7.10.7, 10.7.10.8, 10.7.10.9, 10.7.10.10, 10.8.1.1, 10.8.1.2, 10.8.1.3, 10.8.1.4, 10.8.1.5, 0.8.1.6., 10.8.1.7, 10.8.1.8, 10.8.1.9, 10.8.1.10, 10.8.2.1, 10.8.2.2, 10.8.2.3, 10.8.2.4, 10.8.2.5, 10.8.2.6, 10.8.2.7, 0.8.2.8, 10.8.2.9, 10.8.2.10, 10.8.3.1, 10.8.3.2, 10.8.3.3, 10.8.34, 10.8.3.5, 10.8.3.6., 10.8.3.7, 10.8.3.8, 10.8.3.9, 0.8.3.10, 10.8.4.1, 10.8.4.2, 10.8.4.3, 10.8.4.4, 10.8.4.5, 10.8.4.6., 10.8.4.7, 10.8.4.8, 10.8.4.9, 10.8.4.10, 10.8.5.1, 0.8.5.2, 10.8.5.3, 10.8.5.4, 10.8.5.5, 10.8.5.6, 10.8.5.7., 10.8.5.8, 10.8.5.9, 10.8.5.10, 10.8.6.1, 10.8.6.2, 10.8.6.3, 0.8.6.4, 10.8.6.5, 10.8.6.6, 10.8.6.7, 10.8.6.8, 10.8.6.9, 10.8.6.10, 10.8.7.1, 10.8.7.2, 10.8.7.3, 10.8.7.4, 10.8.7.5, 0.8.7.6, 10.8.7.7, 10.8.7.8, 10.8.7.9, 10.8.7.10, 10.8.8.1, 10.8.8.2, 10.8.8.3, 10.8.8.4, 10.8.8.5, 10.8.8.6., 10.8.8.7, 0.8.8.8, 10.8.8.9, 10.8.8.10, 10.8.9.1, 10.8.9.2, 10.8.9.3, 10.8.9.4, 10.8.9.5, 10.8.9.6, 10.8.9.7, 10.8.9.8, 10.8.9.9, 0.8.9.10, 10.8.10.1, 10.8.10.2, 10.8.10.3, 10.8.10.4, 10.8.10.5, 10.8.10.6, 10.8.10.7, 10.8.10.8, 10.8.10.9, 0.8.10.10, 10.9.1.1, 10.9.1.2, 10.9.1.3, 10.9.1.4, 10.9.1.5, 10.9.1.6., 10.9.1.7, 10.9.1.8, 10.9.19, 10.9.1.10, 10.9.2.1, 0.9.2.2, 10.9.2.3, 10.9.24, 10.9.2.5, 10.9.2.6, 10.9.2.7, 10.9.2.8, 10.9.2.9, 10.9.2.10, 10.9.3.1, 10.9.3.2, 10.9.3.3, 0.9.34, 10.9.3.5, 10.9.3.6., 10.9.3.7, 10.9.3.8, 10.9.3.9, 10.9.3.10, 10.9.4.1, 10.9.4.2, 10.9.4.3, 10.9.44, 10.9.45, 0.9.4.6., 10.94.7, 10.9.4.8, 10.9.4.9, 10.9.4.10, 10.9.5.1, 10.9.5.2, 10.9.5.3, 10.9.5.4, 10.9.5.5, 10.9.5.6, 10.9.5.7., 0.9.5.8, 10.9.5.9, 10.9.5.10, 10.9.6.1, 10.9.6.2, 10.9.6.3, 10.9.6.4, 10.9.6.5, 10.9.6.6, 10.9.6.7, 10.9.6.8, 10.9.6.9, 0.9.6.10, 10.9.7.1, 10.9.7.2, 10.9.7.3, 10.9.7.4, 10.9.7.5, 10.9.7.6, 10.9.7.7, 10.9.7.8, 10.9.7.9, 10.9.7.10, 10.9.8.1, 0.9.8.2, 10.9.8.3, 10.9.84, 10.9.8.5, 10.9.8.6., 10.9.8.7, 10.9.8.8, 10.9.8.9, 10.9.8.10, 10.9.9.1, 10.9.9.2, 10.9.9.3, 0.9.9.4, 10.9.9.5, 10.9.9.6, 10.9.9.7, 10.9.9.8, 10.9.9.9, 10.9.9.10, 10.9.10.1, 10.9.10.2, 10.9.10.3, 10.9.10.4, 0.9.10.5, 10.9.10.6, 10.9.10.7, 10.9.10.8, 10.9.10.9, 10.9.10.10, 10.10.1.1, 10.10.1.2, 10.10.1.3, 10.10.1.4, 0.10.1.5, 10.10.1.6., 10.10.1.7, 10.10.1.8, 10.10.1.9, 10.10.1.10, 10.10.2.1, 10.10.2.2, 10.10.2.3, 10.10.2.4, 0.10.2.5, 10.10.2.6, 10.10.2.7, 10.10.2.8, 10.10.2.9, 10.10.2.10, 10.10.3.1, 10.10.3.2, 10.10.3.3, 10.10.3.4, 0.10.3.5, 10.10.3.6., 10.10.3.7, 10.10.3.8, 10.10.3.9, 10.10.3.10, 10.10.4.1, 10.10.4.2, 10.10.4.3, 10.10.4.4, 0.10.4.5, 10.10.4.6., 10.10.4.7, 10.10.4.8, 10.10.4.9, 10.10.4.10, 10.10.5.1, 10.10.5.2, 10.10.5.3, 10.10.5.4, 0.10.5.5, 10.10.5.6, 10.10.5.7., 10.10.5.8, 10.10.5.9, 10.10.5.10, 10.10.6.1, 10.10.6.2, 10.10.6.3, 10.10.6.4, 0.10.6.5, 10.10.6.6, 10.10.6.7, 10.10.6.8, 10.10.6.9, 10.10.6.10, 10.10.7.1, 10.10.7.2, 10.10.7.3, 10.10.7.4, 0.10.7.5, 10.10.7.6, 10.10.7.7, 10.10.7.8, 10.10.7.9, 10.10.7.10, 10.10.8.1, 10.10.8.2, 10.10.8.3, 10.10.8.4, 0.10.8.5, 10.10.8.6., 10.10.8.7, 10.10.8.8, 10.10.8.9, 10.10.8.10, 10.10.9.1, 10.10.9.2, 10.10.9.3, 10.10.9.4, 0.10.9.5, 10.10.9.6, 10.10.9.7, 10.10.9.8, 10.10.9.9, 10.10.9.10, 10.10.10.1, 10.10.10.2, 10.10.10.3, 10.10.10.4, 0.10.10.5, 10.10.10.6, 10.10.10.7, 10.10.10.8, 10.10.10.9, 10.10.10.10

Additional exemplary formula 1 compound groups include a compounds or genera of compounds named in the groups disclosed below. The configurations of all hydrogenatoms for the following groups are as defined for the group 1 com pounds above. Group 2 compounds. These compounds are named as 45 defined for group 1 compounds, except that R'' informula 3 is —OH and R' is H. Thus, the group 2 compound named 4.2.2.3 has the structure

50 Group 4 compounds. These compounds are named as defined for group 1 compounds, except that R'' and R' in formula 3 are both —OH. Thus, the group 4 compound named 4.2.2.3 has the structure 55

Group 3 compounds. These compounds are named as defined for group 1 compounds, except that R'' informula 3 65 is —Hand R' is OH. Thus, the group 3 compound named 4.2.2.3 has the structure US 7,863,261 B2 47 48 Group 5 compounds. These compounds are named as defined for group 1 compounds, except that R'' and R' in formula 3 together comprise =O. Thus, the group 5 com pound named 4.2.2.3 has the structure

Group 9 compounds. These compounds are named as 15 defined for group 1 compounds, except that the double bond at the 5-6 position is absent, R. R'' and R'' (as defined for formula 1) are present and are all hydrogen, and R is in the B-configuration. Thus, the group 9 compound named 4.2.2.3 Group 6 compounds. These compounds are named as has the structure defined for group 1 compounds, except that R' informula 3 4.2.2.3

is -H, -CHOH, -CHOC(O)CH, OC(O)CH or —CHOC(O)OCH. Thus, the group 6 compound named CH. 4.2.2.3 has the structure

25 4.2.2.3

30 Group 10 compounds. These compounds are named as defined for group 1 compounds, except that R'' is —O-C O O (O)—CH-NH —O C(O)—O CH, O C(O)—CH or—SH. Thus, the group 10 compound named 4.2.2.3 has the her Structure O 35 4.2.2.3

where R is -H, -CHOH, -CHOC(O)CH, OC(O) CH, or -CHOC(O)OCH. Group 7 compounds. These compounds are named as 40 defined for group 1 compounds, except that R in formula 3 is -H, -CHOH, -CHOC(O)CH, OC(O)CH or O O —CHOC(O)OCH. Thus, the group 7 compound named 4.2.2.3 has the structure her 45 O where R'' is —O C(O) CH-NH —O C(O)-O- CH-O C(O)-CH or -SH. Group 11 compounds. These compounds are named as 50 defined for group 1 compounds, except that R' is —OH, O—C(O)—O CH, —O—C(O)—CH or —SH. Thus, the group 11 compound named 4.2.2.3 has the structure

O O 4.2.2.3 55 her O

where R is -H, -CHOH, -CHOC(O)CH, OC(O) 60 CH or -CHOC(O)OCH. O O Group 8 compounds. These compounds are named as defined for group 1 compounds, except that the double bond her at the 5-6 position is absent, R. R'' and R' (as defined for O H formula 1) are present and are all hydrogen, and R is in the 65 C-configuration. Thus, the group 8 compound named 4.2.2.3 where R' is —O C(O) CH-NH. has the structure CH-O C(O)-CH or -SH. US 7,863,261 B2 49 50 Group 12 compounds. Group 12 comprises 11 Subgroups Other embodiments of the formula 1 and 2 compounds of compounds, Subgroups 12-1 through group 12-11. These include compounds having the formulas 3 and 4 compounds are named as defined for any compound or genus in any of group 1 through group 11 compounds, except that 3 the RandR structures in Table 1 have the following struc 5 tures. 1-C1, —H; 2-H, —Cl: 3-H, —Br: 4-Br, —H; 5-O- CH-CH OCH —H; 6-H, -O-CH-CH - OCH; 7-O CH. C.H. F. —H; 8-H, - O CH C.H. F. 9-O C(O)—CH2—CHs. OH: 10-OH, —O—C(O)—CH2—CHs. Thus, the Subgroup 12-1 and 12-2 compounds named 4.2.2.3 have the structure 10

25 wherein, R-R7 are independently chosen and have the defi nitions given herein. Exemplary formula 3 and 4 compounds have 0, 1, 2 or 3 double bonds and a non- ydrogen Substituent at 2,3,4 or more of R,R,R,R,R,R7, R, R and R. When three double bonds are present in the A ring, then R’ 30 is absent. Such embodiments include each of the compounds groups described above wherein the A ring is aromatic and in Subgroup 12-2, compound 4.2.2.3. Such compounds, only one variable group is present at each carbon atom in the A ring, and the R. R. Rand R7 variable Group 13 compounds. Group 13 comprises 11 Subgroups groups are as defined in the compound groups given above. of compounds, Subgroups 13-1 through group 13-11. These Substituents include methylat RandR and independently compounds are named as defined for any compound or genus 35 selected —OR* (e.g., OH), O. —SR* (e.g., SH) or in any of group 1 through group 11 compounds, except that halogen at 2, 3 or more of R. R.R. R'', R', R7 and R', the Rand R structures in Table 1 have the following struc with remaining positions being hydrogen. tures. 1-H, - H; 2-H, -CCH: 3-CCH —H: 4-OH, In other embodiments the formula 3 compound shown in —CCH; 5-CCH-OH: 6-H, -CH; 7-CH, H; 8-CH, compound group 1 comprises (1) a double bond at the 16-17 —CH; 9-CHs —CHs; 10-CHs —H. Thus, the group 40 position and only R'7 and Rare present at 16 and 17. (2) a 13-1 and 13-2 compounds named 4.2.2.3 have the structure double bond at the 16-17 position and only R'' and Rare OH present at 16 and 17, (3) a double bond at the 16-17 position CH3 H and only R'' and R'' are present at 16 and 17, (4) a double a bond at the 16-17 position and only R'' and R'' are present at 45 16 and 17, (5) a double bond at the 5-6 and 16-17 positions and only R'' and R' are present at 16 and 17, (6) a double bond at the 5-6 and 16-17 positions and only R'' and Rare present at 16 and 17, (7) a double bond at the 5-6 and 16-17 positions 5-6 and 16-17 positions and only R'' and R'' are present at 16 and 17, (8) a double bond at the 5-6 and 16-17 50 positions and only R'' and R'' are present at 16 and 17. (9) a double bond at the 4-5 and 16-17 positions and only R'7 and Rarepresent at 16 and 17. (10) a double bond at the 4-5 and 16-17 positions and only R'' and Rarepresent at 16 and 17. (11) a double bond at the 4-5 and 16-17 positions 4-5 and 55 16-17 positions and only R'' and Rare present at 16 and 17, (12) a double bond at the 5-6 and 16-17 positions and only R' and R' are present at 16 and 17, (13) a double bond at the 1-2 and 16-17 positions and only R'' and Rarepresent at 16 and 17, (14) a double bond at the 1-2 and 16-17 positions and only R" and Rare present at 16 and 17, (15) a double bond at the 60 1-2 and 16-17 positions 5-6 and 16-17 positions and only R' and R' are present at 16 and 17, or (16) a double bond at the 1-2 and 16-17 positions and only RandR'' are present at 16 and 17. In any of these embodiments, a single variable group is bonded to ring carbon atoms and the variable group can be 65 as described in any of the compound groups described above. For these compounds, the variable groups at the 1, 2, 4, 6, 11 Subgroup 13-2, compound 4.2.2.3. and 12 positions may comprise one, two or three moieties US 7,863,261 B2 51 52 other than hydrogen, e.g., optionally Substituted alkyl, optionally protected thiol, NH-, optionally protected optionally Substituted alkoxy, optionally Substituted alky —NH, optionally protected —C(O)OH, —C(O)—NH . laryl, an ester, an ether, a thioether, a thioester, an optionally substituted heterocycle, or an optionally substituted C(O) NH NH, C(O) H, NH, C(O) monosaccharide, while the remainder of the variable groups CoHo. —NH CO)—O—CoHo. —CN. —NO, at the 1, 2, 4, 6, 11 and 12 positions are hydrogen. —N or halogen. Reactive groups are protected as needed, In some embodiments, when one or more of R'-R is a e.g., =O would usually be protected in the LiCR reaction that protected moiety, e.g., OR, SR*, N(R*), the R* is used to generate compound 1 in Scheme 1 below. protecting group, together with the atom to which it is linked, Scheme 1 comprises an ester, a thioester, a phosphoester, a phospho 10 noester, a sulfite ester, a Sulfate ester, an amide, anamino acid, R24 O a peptide, an ether, a thioether, an acyl group, a carbonate, a LDA, -78° C. carbamate, a Sulfonamide, an optionally substituted alkyl 25 He group, an optionally substituted alkenyl group, an optionally R TMSC Substituted alkynyl group, an optionally Substituted aryl moi ety, an optionally Substituted heteroaryl moiety, an optionally 15 Substituted monosaccharide, an optionally Substituted oli gosaccharide, a nucleoside, a nucleotide, an oligonucleotide AcO or a polymer. A R24 OSiMe3 In all of the embodiments of the formula 1 or formula 2 compounds described herein, the variable groups are in the C. 1. MCPBA B or CB configuration, unless otherwise specified. Esters and He thioesters at one, two or more variable groups, e.g., at 1, 3, 6, 2. HCI 7 or 17, may comprise a Saturated or unsaturated, normal or branched fatty acid, typically comprising about 4 to about 20 25 carbon atoms. Such fatty acids, if unsaturated may comprise AcO one, two or more double bonds or one or two triple bonds. Exemplary fatty acids include one having the structure CH (CH) is COOH, CH (CH), CH=CH III IOH Ac2O (CH) is COOH, CH (CH) CH=CH 30 ---pyridine (CH) COOH and CH (CH) is CH=CH DMAP (CH) CH=CH-(CH2)5-COOH. The double bond in the fatty acids can be in the cis, trans or cis and trans configurations and they are optionally Substituted with one, AcO two or more substituents as described for esters, e.g., with 35 —O— —OH, —S– or —SH. 1. Dibromantin Exemplary synthesis methods. By way of exemplification He and not limitation, the following methods are used to prepare 2. LiBir the one or more of the compounds disclosed herein. Starting materials or straightforward variations of the schemes are found, e.g., in the following citations, which are all incorpo 40 rated herein by reference: U.S. Pat. Nos. 4,602,008, 4,989, AcO 694, 5,001,119, 5,175,154, 5,571,795, 5,627,270, 5,681,964, 5,714,481, 5,744,453, 5,939,545, 5,939,570, 5,962,442, 5,962,443, 5,994,568; international publication numbers WO 9408588, WO 9508558, WO 9508559, WO 963.8466, WO 45 9809450; and European patent applications EP 232788, EP 43OO78. Scheme 1. Exemplary formula 1 compounds are prepared AcO as shown in the schemes below. For the structures shown in scheme 1, R-R are as defined for formula 1 compounds. 50 Thus, when R and Rare both —CH in the B-configura tion, H at the 9 and 14 positions are in the C-configuration, acetate at the 3-position is in the B-configuration, and H at the III iOAc 8 position is in the B-configuration, the first compound in scheme 1 is DHEA acetate. The acetate groups at the 3, 7, 16, 17 or other positions in this scheme and in other schemes 55 disclosed herein may independently be otherester moieties as AcO described herein, e.g., Clso esters including —C(O)— (CH2)oa (CF2)o a CFs. including —C(O)—CF, 1 —C(O)—C optionally substituted alkyl, -C(O)— Abbreviations: CH-C-2s optionally substituted alkenyl, —C(O)—CH2— 60 LDA = lithium diisopropylamide; MCPBA = m-chloroperbenzoic acid; C-2s optionally Substituted alkynyl. —C(O)—(CH)-op TMSC1 = trimethychlorosilane; DMAP = 4-dimethylaminopyridine; tionally Substituted phenyl, or—C(O)—(CH2)o-optionally Dibromantin = 1,3-dibromo-44-dimethylhydantoin. R = CR4, R3 = Hora C1-C50 organic moiety as described herein, e.g., H, Substituted heterocycle or other organic moieties as disclosed C1-20 optionally substituted alkyl, C1-20 optionally substituted herein or in the cited references. alkenyl, C1-20 optionally substituted alkynyl, (CH2)0-6- Typical Substituents for these organic moieties are as 65 optionally substituted phenyl or (CH2)06 - optionally substituted described herein, e.g., one, two, three or more independently heterocycle, selected —O— =O, optionally protected hydroxyl. —S , US 7,863,261 B2 53 54 Scheme 2. Compounds of formula 2A are prepared from Scheme 4. The addition of lithium reagent (lithium acetyl structure A compounds shown in Scheme 1 using the last two ide when R is —CH) to the 17-position >C=O in the pres steps of Scheme 1: (1) dibromantin, (2) LiBr, (3) Li C R. ence of the bromide at C-16 results in epoxide formation or in where R is CR" and R' is —H or - C, optionally substi a pinacol rearrangement. Alternatively, compounds without tuted alkyl. When H at the 9 and 14 positions are in the 1-configuration and H at the 8 position is in the B-configura ofstructure 3 can be dehydrated by mild acid catalysis to form tion the first compound in scheme 1 is DHEA acetate. Typical compounds of formula 4 by treatment of the alkene with Br, substituents for the Ralkyl moiety includes one, two or more H.O.R and Rare as defined in Schemes 1 and 2. independently selected —O—, optionally protected =O. Scheme 4 optionally protected hydroxyl. —S-, optionally protected thiol, NH , optionally protected NH, optionally pro 10 R24 O tected –C(O)OH, -C(O) NH-, -C(O) NH, NH, CCO)—H. —NH CO) COH, -NH C 25 (O)—O—CoHo. —CN. —NO —N or halogen. R CuBr2 He

AcO

R24 O

R25 Br LCER ---

AcO 25 AcO

AcO Scheme 3. The allylic bromination at C-7 is accomplished essentially as shown in Scheme 1. RandR are as defined in Schemes 1 and 2.

Scheme 3

Ag2O --- H2O, acetOne

AcO AcO

Ac2O pyridine DMAP

LCER Her

AcO AcO US 7,863,261 B2

-continued R 24 PHCER

R25 HO"3

AcO 10 R24 CER Br AcO R 25 - HO - 4

15 Scheme 6. Formula 6 compounds are prepared by treat ment of the acetate with lithium acetylideas in Schemes 1, 2, AcO 3 or 4. Rand Rare as defined in Schemes 1 and 2. Scheme 7. Formula 7 compounds are prepared from the Scheme 5. Sodium borohydride gives a mixture of epimers at C-7, which may be separated by Standard methods, e.g., 3-acetate with reagents described in Schemes 1 and 4. Rand HPLC, TLC or column chromatography. To obtain the pure Rare as defined in Schemes 1 and 2. 7C -OH compound, allylic bromination followed by hydroly sis is accomplished, e.g., essentially as described in Schemes 1 and 3.

Scheme 5 25 R24 O

-e- c NaBH4 30 AcO 'Br HO O R24 OH Scheme 8. Formula 8 compounds are prepared from the 35 formula A compounds by sodium borohydride reduction at R25 Ac2O C-17 followed by acetylation. --pyridine DMAP

HO OH 40 R24 OAc

R25 45

AcO AcO OAc

50 5 Scheme 9. The starting material is made using reactions described in Schemes 1 and 3. Scheme 9 R24 O R24 OH

R25

AcO 'OH HO 'OH

NaBH4 US 7,863,261 B2 57

-continued OH

II iOH II IOAc Ac2O Hepyridine DMAP

AcO

15 Scheme 10. Reduction and acetylation at C-3 and hydroly (R” I). Thionoesters, R. C(S)-O , are prepared by sis and oxidation at C-17 will allow formula 10a and 10b treating the R' C(O)—O— ester with Lawesson's reagent. compounds to undergo functionalization as shown in Sulfates, NaO S(O)(O)-O-, R O S(O)(O) Schemes 1-9 at C-3, C-16 and C-17. The 7-oxoacetate can be O—, e.g., CH (CH2)os S(O)(O)—O— are prepared by substituted for the formula A compound 3-acetate and func tionalization at C-3, C-16 and C-17 is achieved similarly for treatment of alcohols with chlorosulfonic acid followed by 7-Oxo compounds using the reactions shown in schemes 1-9. NaOH or alternatively by oxidation of sulfites using KMnO. Treatment of 10a with LDA, followed by alkylation of the If the alkyl (e.g., methyl) ester is desired alkylchloro-sul enolate allows introduction of side chains, which may be, fonate (methylchloro-sulfonate) can be used. Sulfites HO S e.g., C1-C20 alkyl (methyl, ethyl), C1-C20 alkenyl 25 (O) O and ammonium saltsNHO S(O)—O, or RO— (CH2=CH-(CH2) ). benzyl, —(CH2). O— S(O)—O— esters (e.g., CHO S(O)—O ) are prepared (CH) CH. by standard methods. The ammonium salts are prepared by

Scheme 10 R24 OAc R24 OAc

R25 H R25 PoC

O O H 10a R = -CHR 10 (PhSeO)2O 1. PhSeC R9 = CHR 10 PhIO 2. H2O2

R24 OAc R24 OAc

R25 R25

O O H 10c 1Ob 55 Schemes 1-9 show the introduction of the hydroxyl func treatment of alcohols with ammonia and sulfur dioxide. The tion at the positions shown. Methods to convert hydroxyl to esters such as alkyl, alkenyl and alkynyl esters (e.g., methyl other functional groups are accomplished essentially as ester) are obtained when alcohols are treated with alkylchlo rosulfite (e.g., methycholorosulfite), alkenylchlorosulfite or described, e.g., in the references cited herein. For example, 60 alkynylchlorosulfite in the presence of a suitable base such as esters, of formula 1-10c compounds, such as —O—C(O)— triethylamine. Phosphoesters, RO-P(OR)(O) O— are R° where R is a Clso organic moiety, are prepared from the prepared by treating the alcohol with diethylchlorophosphate steroid alcohol by treatment with the appropriate acid anhy in the presence of NaCO. Alternatively, if the alcohol is dride or acid chloride (R' C(O)—Cl) to form any desired treated with phosphoric acid diesters in the presence of triph ester. Ethers, such as —O R', are prepared from alcohols 65 enylphospine (PPh) and diethylazodicarboxylate (DEAD) by formation of the alkaline metal alkoxide (Na" or K") the corresponding triesters are formed with inversion (Mit followed by treatment with a primary or secondary iodide Sunobu reaction). US 7,863,261 B2 59 60 Phosphothioesters, RO-P(SR*)(O) O— are gener fonamide (R' S(O)(O) NH-steroid). Alternatively, ated by treatment of alcohols with the monothio analog of Sodium napthalenide deprotects to give the N-Boc com diethylchlorophosphate as described for phosphoesters yield ing the phosphothioesters. Carbonates, RO-C(O)-O- pound. Amines (NH-steroid) can be converted to amides are generated from the corresponding steroid alcohol using (R'NH-C(O)-steroid) using acyl chlorides (R' C(O)— the chloroformate (R-C(O)—Cl), e.g., Coalkyl, alkenyl Cl). Treatment with ethyl chloroformate gives the N-carbam oralkynyl chloroformates (e.g. CH (CH) is C(O)Cl). Car ate (RO-C(O) NH-steroid). The amine (NH-steroid) bamates, R NH C(O)—O are made from steroid alco can be alkylated with an O-bromoester (R C(O)—CHY hols by treatment with isocyanates (R'N=C=O) or NaOCN NH) to yield the amino acid substituted steroid (R O C in the presence of trifluroroacetic acid. Amino acid esters, 10 (O) CHY NH-steroid). ZNX—CHY C(O)—O— are generated by coupling the Where reactions such as Substitutions give a product mix steroid alcohol with the acid chloride of the N protected ture, the desired intermediate is optionally separated from amino acid. other products or at least partially enriched (e.g., enriched at Oxidation of hydroxyl groups that are linked to the steroid least about 10-fold, usually at least about 50-100-fold) from nucleus is used to obtain ketones and related functionalities. 15 For example, conversion of alcohols to ketones can be other products before Subsequent reactions are conducted. achieved using a variety of oxidizing agents such as CrO in Substitution at steroid carbon atoms will generally proceed AcOH, or pyridinium chlorochromate, pyridinium dichro with greatest efficiency at the 3-position, which is relatively mate or oxalyl chloride with triethylamine (Swern oxidation). sterically unhindered and C-17 is generally somewhat less Thioketones (—S) are prepared by treating ketones with accessible than the C-3 position. The relative reactivities of Lawesson’s reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4- the C-3, C-7, C-17 and C-16 positions allows one to use their dithiadiphosphetane-2,4-disulfide; commercially available reactivities to control the sequential introduction of different from Aldrich). Thioacetals, —C(SR)(SR) , are prepared functional groups into the same steroid molecule. Also, from ketones ( C(O) ) by treatment with R SH thiols groups, such as hydroxyl at more reactive positions, C-3 or under acid catalysis conditions (e.g., HCl). Phosphonoesters, 25 RO P(OR)(O) , are generated by addition of the phos C-17, may be sequentially protected or deprotected to allow phorus acid diester to ketones in the presence of KF to yield introduction of functional groups at other positions, such as hydroxy phosphonoesters. One may optionally remove the C-7 or C-16. hydroxy group using a dehydration and hydrogenation Polymers such as PEG are linked to the compounds essen Sequence. 30 tially as described above. For example, PEG 200 or PEG 300 Substitution of hydroxyl groups is used to generate a num is linked to the steroid at the 3, 7, 16, 17 or other positions by ber of functionalities. For example, thiols, SH, are prepared an ether linkage (PEG-O-steroid) using a PEG alkoxide from alcohols by conversion of the alcohol with inversion to (PEG-ONa), to displace the steroid bromide. Alternatively, the bromide using PBr. Treatment of the bromide with thio PEG-Br can be treated with the steroid alkoxide. Polyethyl urea followed by NaOH gives the thiol. Thioethers, R S , 35 ene glycol esters such as those described in U.S. Pat. No. are prepared from thiols by treatment with NaOH and the 5,681.964 can also be prepared using a suitable formula 1 required halide, e.g., alkyl halide. Alternatively, alcohol compound and the methods described therein. Monosaccha derivatives like tosylates or mesylates can be displaced by rides or polysaccharides and oligonucleotides are linked to thiolate anions, R S , to yield the thioether. Thioesters, steroid hydroxyl groups using known methods, see e.g., U.S. R—C(O)—S—, are prepared by treating the tosylate (mesy 40 late) of the alcohol with the sodium salt of the thioacid. Pat. No. 5,627,270. Substitution of hydroxyl groups can be used to generate Scheme 1 1. Formula 1 or 2 compounds that contain an both esters, RO C(O)—, and amides, NHR'. C(O) , organic moiety that is linked to the 1 position are prepared linked to the steroid at carbonatoms. Foramides and amines, essentially as follows. The allylic bromination reaction to Ris-H, a protecting group or a Clso organic moiety. These 45 generate 11 may utilize any Suitable reagent, e.g., N-bromo are synthesized from the steroid bromide with inversion by succinimide (“NBS) to yield the 1-bromo derivative. This displacement with NaCN. The cyanide group can be hydro intermediate is treated with zinc to yield the alkylated deriva lyzed to the amide or the acid. The acid is esterified or treated tive 12. Organic moieties are introduced into the 1 position by standard peptide coupling reactions with an O-protected using a corresponding reagent, e.g., (R),Culi, where R is amino acid in the presence of a suitable carboxyl activating 50 a C1-C25 organic moiety that may comprise 1,2,3,4 or more agents such as dicyclohexylcarbodiimide (DCC) to form ste substituents, e.g., -O-, -S , -NH-, -OR, pro roid - C(O) NH-CHY C(O) OR, where Y is the side tected ketone (e.g., ethylene ketal), SR' or N(R'). In chain of an amino acid or a C1-C10 organic moiety and R is other embodiments, R is R'. Thus, when R is methyl, a a protecting group (or hydrogen when deprotected). methyl group is introduced into the 1 position, or when R is Amines and derivatives of amines, e.g., RNH , R. C 55 (O)NH ROC(O) NH or RO C(O) CHR —CH, OR, the -CH, OR group is introduced into NH linked to steroid carbon atoms, are typically prepared the 1 position. Compound 12 is converted to the 17 hydroxyl by standard methods. For example, amines (NH-steroid) are derivative 13 by hydrolysis using standard methods, e.g., generally prepared using the Hoffmann rearrangement (Br, treatment with sodium carbonate in methanol. The compound NaOH) from the amide (NH CO)-steroid) or the Curtius 60 15 is converted to the 17-hydroxy derivative by reduction of rearrangement (NaNs) from the acid chloride of the steroid. the ketone, e.g., using LiBH or NaBH4 in ethanol or by The R substituent can subsequently be introduced by alky catalytic hydrogenation with H/Ni, H/Ptor H/Pd. Catalytic lation. Steroid alcohols can be used as starting materials hydrogenation will also result in reduction of the double bond understandard Mitsunobu conditions (PPh. DEAD) to yield in 12, 13, 14 or 15. Alternatively, a hydroxylat both the 3 and N-Boc sulfonamides using N-(t-butoxycarbonyl)-p-toluene 65 17 positions is obtained by reducing the ketone in compound Sulfonamide. One can selectively remove either protecting 12 and removing the acetate group or by directly reducing the group. Treatment with trifluoroacetic acid affords the sul 3 ketone in compound 13. US 7,863,261 B2 62 alkaline hydrogen peroxide to obtain the epoxide 16. The compound 16 is converted to the 1-hydroxyl derivative by Scheme 11 treatment, e.g., with excess lithium metal and excess ammo R24 OC(O)CH nium chloride in NH-THF (1:1) at reflux to give 17. The ketal group is hydrolyzed to give the 17 ketone. The hydroxyl group at 1 is optionally further converted to other moieties R25 essentially as described above. He1) NBS 2) Zn 10 Scheme 12 O 10c R24 O) R24 OC(O)CH O R25 15 H2O2, base --- R25

O 16

11 R24 OC(O)CH R35 25 R25 1 (R35),Culli Hess

O 30 17

12 R24 OH Scheme 13. Formula 1 or 2 compounds that contain an an organic moiety that is linked to the 2 position are prepared R35 35 essentially as follows. Organic moieties are introduced into Na2CO3, R25 12 methanol the 2 position using a corresponding reagent, e.g., (R), -- Culi, where R is a C-C2s organic moiety that may com prise 1, 2, 3, 4 or more Substituents, e.g., —O— —S—, NH , —OR*, protected ketone (e.g., ethylene ketal), O 40 —SR or - N(R). In other embodiments, R is R. Thus, when R is methyl, a methyl group is introduced into 13 the 2 position, or when R is —CH, OR, the CH R24 OH OR* group is introduced into the 2 position. The starting R35 material 18 is testosterone when RandR are both methyl. R25 45 The compound 18 is alkylated using an alkylating agent such ethylene as the iodide R1 in the presence of a strong base such as 13 glycol lithium diisopropylamide (“LDA), n-butyllithium sodium O t-pentoxide or (CHS)-Ni to give Ribonded to the steroid in the C. and B configurations. The 2B-R group is epimerized to Kl 50 the 2C. configuration using a strong base, e.g., a sodium alkox 14 ide Such as Sodium methoxide in an alcohol Such as methanol. R24 O Alternatively the two epimers are at least Substantially sepa rated by routine methods. R35 25 CrO3, R 55 14 pyridine --- O

Cl 60 R25 15 R36I, LDA

Scheme 12. Formula 1 or 2 compounds that contain a hydroxyl or ether that is linked to the 1 position are prepared 65 essentially as follows. A hydroxyl is introduced into the 1 18 position by oxidation of a suitable starting material using

US 7,863,261 B2 65 66 together are —O. —S, —CH2—CHCH =NOH, -NOC 18. A product produced by the process of contacting a (O)CH, or they are both —OH, or a halogen, or (m) R' is formula 1 compound, e.g., a compound in any compound —OH, -SH, NH, a halogen, —O—C(O)—CH, or group or embodiment disclosed herein, and an excipient. —O C(O)—CHs, or (n) R' and R'' together are =O, 19. The method of embodiment 1 wherein the compound of =S, —CH =CHCH =NOH, -NOC(O)CH, or they formula 1 or 2 is administered to the subject on an intermittent are both -OH, or a halogen, or (o) R' is -OH, -SH, basis, e.g., dosing for 1, 2, 4, 5, 7, 10 or more consecutive —NH, a halogen, —O—C(O)—CH, or —O—C(O)— days, followed by no dosing for at least about 5-180 days, CHs, or (p) R' and R together are =O, =S, =CH2. followed by dosing again. =CHCH =NOH, =NOC(O)CH, or they are both -OH, 20. The method of embodiment 20 herein the compound of or a halogen, or (q) R is -OH, -SH, -NH2, a halogen, 10 formula 1 or 2 is administered every other day for at least O C(O)—CH, or - O C(O)—CHs, or (r) R' and about 3-45 days, followed by at least about 3-180 days of not R° together are —O. —S, —CH =CHCH =NOH, dosing the subject, optionally followed by another course of —NOC(O)CH, or they are both —OH, or a halogen, or (s) administration. R’ is —OH, -SH, NH, a halogen, —O C(O)—CH, All references cited herein are incorporated herein by ref or —O C(O) CHs, or (t) R' and R together are =O, 15 erence in their entirety. =S, —CH, —CHCH =NOH, -NOC(O)CH, or they The following examples further illustrate the invention and are both -OH, or a halogen, or (u) R' is -OH, -SH, are not intended to limit it in any manner. —NH, a halogen, —O—C(O)—CH, or —O—C(O)— CHs, or (v) R' and R7 together are —O. —S, —CH, EXAMPLE 1. =CHCH=NOH, -NOC(O)CH, or they are both -OH, or a halogen. AR Activity Assay 9. A product produced by the process of contacting a for mula 1 or a formula 2 compound with one or more carriers One biological function of the AR is to act as a transcription and storing the product for at least about 3 months under factor, which can modulate transcription of target genes. ambient conditions in a sealed container. 25 AED, 5C.-dihydrotestosterone (DHT), 17 B-estradiol (E2), 10. A kit comprising a formula 1 or a formula 2 compound, and progesterone were purchased from Sigma. Ethynyl a container comprising unit dosage or multiple dosage forms derivatized steroids were purchased from Steraloids. The of the formula 1 or 2 compound and a label comprising one or plasmid pSG5-wild-type AR (pSG5) and mouse mammalian more of (1) directions for therapeutic use of the formula 1 or tumor virus (MMTV)-chloramphenicol acetyltransferase 2 compound, (2) counterindications or toxicities for the for 30 (CAT) were constructed as described (6). The numbers in mula 1 or 2 compound and (3) information about the formula parentheses, e.g., (6) in the preceding sentence, refer to the 1 or 2 compounds structure or the formulation that contains references listed in the reference section below. Other steroid the formula 1 or 2 compound. compounds, were synthesized using routine protocols and 11. A method comprising administering to a subject having others have been described (19, 20). The human prostate an androgen responsive condition Such as benign prostatic 35 cancer cell line, PC-3, and human breast cancer cell line, hyperplasia, prostate cancer or breast cancer an effective MCF-7, were maintained in Dulbecco's modified eagles amount of a compound selected from the compounds or medium (DMEM) containing 10% fetal calf serum. DNA groups of compounds selected from compounds named in transfection and CAT assays were performed essentially as any compound groups described herein. described (4, 6, 7). Briefly, 4x10 cells were plated on 60 mm 12. The method of embodiment 11, wherein one or more of 40 dishes 24h before transfection, and the medium was changed the symptoms of benign prostatic hyperplasia, prostate can to DMEM (without phenol red) with 10% charcoal-stripped cer or breast cancer are ameliorated or wherein any undesired fetal calf serum 1 hour before transfection. The cells were cell proliferation or disease progression associated with transfected using the calcium phosphate precipitation benign prostatic hyperplasia, prostate cancer or breast cancer method. The total amount of DNA was adjusted to 8.5ug with is reduced or delayed. 45 pSG5 in each transfection assay. After transfecting the cells 13. A compound having formula 1 or formula 2. for 24 hours, the transfection medium was removed, fresh 14. A composition comprising a formula 1 or formula 2 DMEM was added and steroids were added. The cells were compound and a pharmaceutically acceptable carrier. then incubated in DMEM with steroids for 24 hours. After 15. Use of a compound of formula 1 or 2 for the manufac incubation, the cells were harvested and whole cell extracts ture of a medicament for use to treat or prevent an androgen 50 were used for CAT assay. Transfection efficiency was nor responsive disease in a Subject, or to ameliorate one or more malized by cotransfection with a B-galactosidase vector, symptoms thereof, e.g., in a mammal or a human. which acted as an internal control. The CAT enzyme activity 16. The method of embodiment 15 wherein the androgen was quantitated by phosphor imager according to the manu responsive disease is prostate cancer, benign prostatic hyper facturer's instructions (Molecular Dynamics). plasia or breast cancer. 55 17. A kit comprising a formulation that comprises a unit dosage or a multiple dosage comprising a formula 1 or a formula 2 compound, e.g., a compound in any compound compound compound group or embodiment disclosed herein, and one or more number l8le excipients wherein the formulation is dispensed in a Suitable 60 O 7-oxo-dehydroepiandrosterone container, wherein the kit further comprises a label that pro 1 17C-ethynyl-17B-hydroxy-4-estrene-3-one vides information about one or more of (1) the formula 1 or 2 2 17C-ethynyl-17B-hydroxy-4-estrene-3-one 3 17C-ethynyl-17B-hydroxy-5(10)-estrene-3-one compounds chemical structure, (2) any recommended dos 4 1,3,5(10)-estratriene-17C-ethynyl-3?,17B-diol ing regimen, (3) any adverse effects of administering the 5 androst-5-ene-3?,11B,17B-triol formula 1 or 2 compound to a subject that are required to be 65 6 17C-ethynyl-androst-5-ene-3?,17B-diol disclosed and (4) the amount of the formula 1 or 2 compound 7 17C-ethynyl-17B-hydroxy-4-androsten-3-one that is present in each unit dose or in the entire container. US 7,863,261 B2 67 68 13, 15, 16, 18, and 22 had little androgenic activity but they -continued did induce a low level of AR-mediated CAT gene transacti Vation. AED (compound 21) had about the same capacity as compound compound number l8le DHT to stimulate AR-mediated CAT gene transcription. 8 3f,17B-dihydroxy-androst-5-en-16-one EXAMPLE 3 9 3f,17B-dihydroxy-androst-4-en 10 3f.-methylcarbonate-androst-5-en-7,17-dione 11 3f,17B-dihydroxy-androst-5-en-11-one Identification of Anti-Adiol Activity of Steroids with 13 3f,17B-diacetoxy-androst-5-ene-7C,17B-diol Low Androgenic Effects 14 3f,17B-diacetoxy-androst-5-ene-7-one 10 15 3f-methoxy-17B-hydroxy-androst-5-ene-7-one 16 3f-methoxy-androst-5-ene-2,17B-diol Several compounds were screened for their capacity to 17 17B-methoxy-androst-3,5-diene-7-one modulate AED’s effects on AR-mediated activation of gene 18 17-methyl-marrianolic acid transcription in PC-3 cells. The chemical structures of com 19 17B-hydroxy-androst-3,5-diene-7-one pounds 4, 6, 8 and 10 are shown in FIG. 2A. The PC-3 cells 21 5C-androstane-3C,17B-diol 15 were co-transfected with pSG5 and the MMTV-CAT reporter 22 7-oxo-androstene-3?,17B-diol vector in the presence of 50 nM AED and each compound at a concentration of 10, 100, or 1000 nM. As shown in FIG. 2B, compounds 4, 6, 8 and 10 antagonized AED-mediated AR transcriptional activity. At concentrations of 0.1 uM and 1 compound 4 uM, compounds 4 and 6 suppressed the AED-induced AR transactivation to less than 30%. Compounds 0, 5, 13, 15, 18 e and 22 show either activation of AED-mediated AR transcrip tional activity or they have no effect.

25 EXAMPLE 4

Identification of Anti-DHT Effects of Steroids compound 6 Compounds 4, 6, 8 and 10 were examined to determine e' 30 whether these AED antagonists had the ability to repress DHT-induced AR transactivation. PC-3 cells were co-trans fected with pSG5 and the MMTV-CAT reporter plasmid in the presence of 1 nM DHT and each compound at 10, 100, or 1000 nM. Compound 4 repressed the DHT-induced AR trans 35 activation to less than 40% at 1 uM (FIG. 3). compound 8 CH3 OH EXAMPLE 5 Suppression of the AED-Induced ARTranscriptional CH3 O 40 Activity in the Presence of HF To mimic the in vivo condition of total androgen blockage in prostate cancer patients, compounds 4, 6, 8 and 10 were HO compound 10 examined for their capacity to antagonize AED-induced AR 45 transactivation in the presence of HF. In the presence of 1 uM CH, HF, 50 nM AED, and each compound at 0.01, 0.1 or 1 uM, PC-3 cells were transiently transfected with pSG5 and the MMTV-CAT reporter plasmid. As shown in FIG. 4, HF Sup CH3 pressed AED-mediated AR transcription activity by about 50 40%. The compounds tested decreased AED-mediated AR transcription activity by about 75%. HCO-(O)C-O O EXAMPLE 6

55 Steroid Hormone Specificity of DHEA Metabolites EXAMPLE 2 (No. 4, 6, 8, & 10) Induction of AR-Mediated Transcriptional Activity The estrogen receptor (ER)-positive MCF-7 cell line was transfected with a CAT reporter plasmid containing an estro Steroid compounds were screened for their ability to 60 genresponse element linked to the CAT gene. PC-3 cells were induce AR transcriptional activity in the AR-negative PC-3 transfected with MMTV-CAT reporter and progesterone cell line. The results of the CAT assay were obtained by receptor (PR) or glucocorticoid receptor (GR) to test the transient co-transfection of AR plasmid and a reporter plas steroid hormone specificity of compounds 4, 6, 8 and 10. All mid (MMTVCAT) containing the CAT gene linked to the 4 compounds have some estrogenic activity and only com androgen response element (ARE). After transfection, the 65 pound 4, which has a 173-ethynyl group, shows some weak cells were treated with various DHEA derivatives at 1000, 10, PR activity. None of these four compounds showed any GR and 0.1 nM. As shown in FIG. 1, compounds 0, 4, 5, 6, 8, 10. activity. US 7,863,261 B2 69 70 REFERENCES -continued The following citations describe various aspects of prostate cancer and related Subject matter. 1. Landis, S. H. Murray, T., Bolden, S. & Wingo, P. A. (1999) Canadian Cancer J. Clin. 49:8-31; 2. Garnick, M. B. (1997) Urology 49:5-15; 3. Gad dipati, J. P. McLeod, D.G., Heidenberg, H. B., Sesterhenn, I. A., Finger, M.J., Moul, J. W. & Srivastava, S. (1994) Cancer Res. 54:2861-2864; 4. Miyamoto, H., Yeh, S. Lardy, H., Messing, E. & Chang, C, (1998) Proc. Nad. Acad. Sci. USA 10 95:11083-1 1088; 5. Adams, J. B. (1985) Mol. Cell. Endo crinol. 41:1-17; 6. Yeh, S. & Chang, C. (1996) Proc. Natl. Acad. Sci. USA 93:5517-5521; 7. Yeh, S., Miyamoto, H., Shima, H. & Chang, C. (1998) Proc. Natl. Acad. Sci. USA 95:5527-5532; 8. Kang, H.-Y., Yeh, S., Fujimoto, N., & 15 Chang, C. (1999).J. Biol. Chem. 274:8570-8576:9. Fujimoto, N., Yeh, S., Kang, H.-Y., Inui, S., Chang, H.-C., Mizokami, CH3 ... iR17 O A., & Chang, C. (1999).J. Biol. Chem. 274:8316-8321; 10. Yeh, S., Miyamoto, H., Nishimura, K. Kang, H., Ludlow, J., Hsiao, P. Wang, C., Su, C., & Chang, C. (1998) Biochem. Biophys. Res. Commun. 248:361-367; 11. Hslao, P-W, Lin, D-L., Nakao, R. & Chang, C, (1999) J. Biol. Chem. 274:

20229-20234; 12. Hsiao, P.-W. & Chang, C. (1999).J. Biol. Chem. 274:22373-22379; 13. Belanger, A., Brochu, M. & Cliche, J. (1986).J. Clin. Endocrinol. Metab. 62:812-815; 14. 25 Hirschmann, H., de Courcy, C., Levy, R. P. & Miller, K. L. (1960).J. Biol. Chem. 235:PC48-PC49; 15. Kirschner, M.A., Sinhamahapatra, S., Zucker, 1. R. Lorlaux, L. & Nieschiag, E. (1973).J. Clin. Endocrinol. Metab. 37:183-189; 16. Bon ney, R. C., Scanlon, M.J., Jones, D. L., Beranek, P. A., Reed, 30 M. J. & James, V. H (1984) J. Steroid Biochem. 20:1353 1355; 17. Mills, 1. H. (1967) Proc. Royal Soc. Med. 60:905 906; 18. Labrie, F. Dupont, A., Giguere, M., Borsanyi, J. P. Lacourclere. Y., Monfette, G., Emond, J. & Bergeron, N. (1988) Br. J. Urol. 61:341-346; 19. Lardy, H., Kneer, N., Wei, 35 wherein Y., Partridge, B., & Marwah, P. (1998) Steroids 63:158-165; 20. Reich, I., Lardy, H., Wei. Y., Marwah, P., Kneer, N., R is -OH or - O C(O)-CH: Powell, D., & Reich, H. J. (1998) Steroids 63:542-553; 21. R7 is -OH or - O C(O) CH: Kelly, W. K., Slovin, S. & Scher, H. 1. (1997) Urol. Clin. R" is -OH or - O C(O) CH: North Am. 24:421-431; 22. Veldscholte, J., Ris-Stalpers, C., 40 Kuiper, G. G. J. M., Jenster, G., Berrevoets, C., Claassen, E., R" is H; and van Rooij. H. C., Trapman, J., Brinkmann, A.O. & Mulder, E. R is —CH, or —CH2OH, wherein the compound is a (1990) Biochem. Biophys. Res. Commun. 173:534-540; 23. purified and isolated solid. Suzuki, H., Akakura, K. Komiya, A., Aida, S., Akimoto, S. & 2. The compound of claim 1 wherein the compound has the Shimazaki, J. (1996) Prostate 29:153-158; 24. Kuil, C. W., 45 Structure Berrevoets, C. A. & Mulder E. (1995) J. Biol. Chem. 270: 27569-27576; 25. Wong, C., Kelce, W. R., Sar, M. & Wilson, E. M. (1995) J. Biol. Chem. 70: 19998-20003; 26. Yeh, S., OH CH3 Miyamoto, H. & Chang, C. (1997) Lancet 349:852-853; 27. R19 Miyamoto, H., Yeh, S., Wilding, G. & Chang, C. (1998) Proc. 50 Natl. Acad. Sci. USA 95:7379-7984; 28. Chang, H. C. et al., CH3 III.iiOH or Proc. Natl. Acad. Sci. USA 96:11173-11177 1999.

What is claimed is: 1. A compound having the structure 55 HO OH

OH CH3

... I iOH. 60

“oH

65 3. The compound of claim 2 wherein the solid is a powder or granules. US 7,863,261 B2 71 72 4. The compound of claim 2 wherein the compound has the Structure -continued

R18 CH, 9

CH3 III IOH.

HO OH

5. The compound of claim 4 wherein the solid is a powder or granules. 15 6. The compound of claim 1 wherein the compound has the Structure

... I iOH O 25 Ho

CH3 OH

IIIOH. 35 i '''OH 40 7. The compound of claim 6 wherein the solid is a powder or granules. 8. A compound having the structure 45

60 wherein R is -OH or - O C(O)-CH: R" is -OH or - O C(O) CH: R" is -OH or - O C(O) CH: 65 R" is CCH; and R’ is CH. US 7,863,261 B2 73 74 9. The compound of claim 8 wherein the compound has the Structure -continued CH, 9 19 AR

O 10 HO Ho 14. The compound of claim 8 wherein the compound has the structure 15

CH, 9

OH.

i '''OH

25 10. The compound of claim 9 wherein the compound is a solid. 11. The compound of claim 8 wherein the compound has the structure

12. The compound of claim 11 wherein the compound is a solid. 13. The compound of claim 8 wherein the compound has 5 5 the structure

65 US 7,863,261 B2 75 76

-continued -continued R24 R' R24 R18

15. A pharmaceutical formulation comprising one or more 2O excipients and a compound having the structure

18 R24 S 25

wherein 30 R is OH or O C(O) CH: R" is -OH or - O C(O) CH: R" is -OH or - O C(O) CH: R" is CCH; and

R is CH, 16. The pharmaceutical formulation of claim 15 wherein the pharmaceutical formulation is a formulation for oral, parenteral, aerosol or topical administration.

40 17. The pharmaceutical formulation of claim 15 wherein the compound has the structure

How

as 18. The pharmaceutical formulation of claim 15 wherein the pharmaceutical formulation is a formulation for oral, parenteral, aerosol or topical administration. US 7,863,261 B2 77 78 19. The pharmaceutical formulation of claim 15 wherein the compound has the structure -continued CH, 9 A.R.19

OH.

HOS OH 10 22. The pharmaceutical formulation of claim 21 wherein

the pharmaceutical formulation is a formulation for oral, parenteral, aerosol or topical administration. is 23. The pharmaceutical formulation of claim 15 wherein the compound has the structure

20. The pharmaceutical formulation of claim 19 wherein the pharmaceutical formulation is a formulation for oral, 25 parenteral, aerosol or topical administration. 21. The pharmaceutical formulation of claim 15 wherein the compound has the structure

How O 35 24. The pharmaceutical formulation of claim 23 wherein the pharmaceutical formulation is a formulation for oral, parenteral, aerosol or topical administration.

k k k k k