USOO6329416B1 (12) United States Patent (10) Patent No.: US 6,329,416 B1 Grubb et al. (45) Date of Patent: Dec. 11, 2001

(54) COMBINATION REGIMENS USING FOREIGN PATENT DOCUMENTS 3,3-SUBSTITUTED INDOLINE DERIVATIVES 363.3861 4/1988 (DE). (75) Inventors: Gary S. Grubb, Newtown Square; 3. 3.1995/1995 (DE). John W. Ullrich, Exton; Andrew O22.317 1/1981 (EP). Fensome, Wayne, all of PA (US); Jay O 208 510 1/1987 (EP) E. Wrobel, Lawrenceville, NJ (US); 311135 4/1989 (EP). James P. Edwards, San Diego, CA 3858SO 9/1990 (EP). (US); Todd K. Jones, Solana Beach, 483077 9/1991 (EP). CA (US); Christopher M. Tegley, 454330 10/1991 (EP). SSS CA (US); Lin Zhi, San (List continued on next page.) OTHER PUBLICATIONS (73) Assignees: American Home Products Corporation, Madison, NJ (US); R. M. Evans, “The and Thyroid Hormone Receptor Ligand Pharmaceuticals, Inc., San Superfamily”, Science, 240:889 (May 13, 1988). Diego, CA (US) A. Ulmann et al., “Clinical Uses of (MFP)”, s Ann. N.Y. Acad. Sci., 261:248 (Jun. 12, 1995). Notice: Subject to any disclaimer, the term of this Li patent is extended or adjusteds under 35 (Listt continuedt d on nextt page.) U.S.C. 154(b) by 0 days. Primary Examiner Minna Moezie Assistant Examiner Mojdeh Bahar (21) Appl. No.: 09/552,631 (74) Attorney, Agent, or Firm Howson and Howson (22) Filed: Apr. 19, 2000 (57) ABSTRACT Related U.S. Application Data This invention relates to cyclic combination therapies and Provisional a fication No. 60/183,057, filed on May 4 regimens utilizing Substituted indoline derivative com (60) 1999. pp 2Y- - y 4, pounds that are antagonists of the receptor having the general Structure: (51) Int. Cl...... A01N 43/38 (52) U.S. Cl...... 514/415; 514/409; 514/411 R R I (58) Field of Search ...... 514/409, 411, R 1 TV2 514/415 5 N R 6 (56) References Cited A 21NN R7 U.S. PATENT DOCUMENTS R4 Y, 3,635,964 1/1972 Skorcz et al...... 260/247.1 3. 'E Shina ------: wherein: R, and R are chosen independently from each 4446785 4/1984 Walsh. 237 other from H, OH, OAc; alkylaryl; alkylheteroaryl; 4,666,913 5/1987 Kubla et al. 514/259 1-propynyl; 3-propynyl; and optionally Substituted alkyl, 4,670,566 6/1987 Walsh ...... 548/485 O(alkyl); aryl; or heteroaryl groups, or R and R2 are joined 4,721,721 1/1988 Kuhla ...... 514/312 to FORM a ring comprising -CH (CH),CH- where 4,822,794 4/1989 Spada ...... 514/230 n=0-5; -CHCHCMeCHCH-, -O(CH), CH 4,831,027 5/1989 Narret al...... S1212 where m = 1-4; O(CH), O - where p = 1-4; 4,853,473 8/1989 Fischer et al. . ... 549/326 -CHCHOCHCH-; —CHCHN(H O alkyl) 5,007,952 4/1991 Kume et al...... 71/73 CHCH 5,171,851 12/1992 Kim et al...... 544/50 2Y- 2 3 5,414,088 5/1995 Von Der Saal et al. ... 546/158 or R, and R together comprise a double bond to CMe, 5,453,516 9/1995 Fischer et al. . ... 548/543 C(cycloalkyl), O, or C(cycloether); 5,475,020 12/1995 Johnson et al. ... 548/466 R is H, OH, NH, COR; or optionally Substituted 5,521,166 5/1996 Grubb ...... 514/170 alkenyl or alkynyl groups, is . g al...... sis. R'=H or optionally substituted alkyl, alkoxy, or ami 5688.810 11/1997 Jones et al... 514/311 noalkyl groups, 5,693,646 12/1997 Jones et al...... 514/285 R=H, halo, CN, NH, or optionally substituted alkyl, 5,693,647 12/1997 Jones et al...... 514/285 alkoxy, or aminoalkyl, 5,696,127 12/1997 Jones et al...... 514/285 Rs is selected from optionally Substituted benzene ring; a E. 1:32 IS et Fa ------SE five or six membered heterocyclic ring; a 4 or 5.716.136 2/1998 GW. cal ------514/170 7-substituted indole or a substituted benzothiophene; or 5,733,902 3/1998 Schneider. . 514/177 pharmaceutically acceptable Salt thereof. These meth

5,808 139 9/1998 Pathirana ...... 560/138 ods of treatment may be used for contraception. 5,874,430 2/1999 Christ ..... 514/229.8 6,077,840 6/2000 Kurihara ...... 514/232.8 16 Claims, No Drawings US 6,329,416 B1 Page 2

FOREIGN PATENT DOCUMENTS B. Narr et al., “Preparation, Testing, and Formulation of O 535 529 9/1992 (EP). Imidazobenzoxazinones as Cardiotonics', Chemical 510235 10/1992 (EP). Abstracts, 109:22973 (1988). 947 507 10/1999 (EP). R. J. Hartmann et al., “Effects of Brofoxine, A New Anxi 978 279 2/2000 (EP). olytic on Experimentally Induced Conflict in Rats', Proc. 63112584 5/1988 (JP). West Pharmacol. Soc., 21:51-55 (1978). WO 86/03749 7/1986 (WO). B. Singh et al., “Novel cAMP PDE III Inhibitor: Imidazo WO 91/04974 4/1991 (WO). 4,5-b]pyridin-2(3H)-ones and Thiazolo 4,5-b] WO 91/06545 5/1991 (WO). pyridin-2(3H)-ones and Their Analogs”, J. Med Chem., WO 93/12085 6/1993 (WO). 37:248 (Jan. 21, 1994). WO 94/14434 7/1994 (WO). WO 94/29272 12/1994 (WO). A. Andreani et al., “Potential Antitumor Agents XVII (1). WO95/11013 4/1995 (WO). Cytotoxic Agents from Indole Derivatives and Their Inter WO95/20389 8/1995 (WO). mediates”, Acta. Pharm. Nord, 2(6):407 (1990). WO95/20972 8/1995 (WO). Sakata et al., “Silver Halide Photographic Materials Useful WO95/33746 12/1995 (WO). for Platemaking", Chemical Abstracts, 123:30.1431 (1993). WO 96/15794 5/1996 (WO). P. Pflegel et al., “Polarografie CO WO 96/19458 6/1996 (WO). 7-Chlor-5-phenyl-2-thioxo-1H-2,3-dihydro-1,3,4-ben WO 96/19997 7/1996 (WO). zotriazenpinen”, Pharmazie, 37(10): 714-717 (1982). WO 97/13767 4/1997 (WO). E. I. Barengolts et al., “Progesterone Antagonist RU486 Has WO 97/494O7 12/1997 (WO). Bone-Sparing Effects in Ovariectomized Rats', Bone, WO 98/14436 4/1998 (WO). WO 98/27059 6/1998 (WO). 17(1):21 (Jul 1995). WO 98/55116 12/1998 (WO). E. V. Gromachevskaya et al., “Studies of 4H-3, 1-Benzox WO 99/10325 3/1999 (WO). azines”, Chem. Heterocycl. Cmpds. 33(10): 1209–1214 WO 99/11264 3/1999 (WO). (1997). WO 99/15500 4/1999 (WO). D. Chiarino et al., “2, 1-Benzisothiazoline 2, 2-Dioxide and WO 99/44608 9/1999 (WO). Derivatives”, J. Heterocycl. Chem., 23(6):1645-1649 (Nov.-Dec. 1986). OTHER PUBLICATIONS A. Turck et al., “On the Metabolism of 3-Substituted and R. Kekkonen et al., “Sequential Regiment of the Antiproges 3,6-Diisubstituted Pyridazines”, Tetrahedron, terone RU486 and Synthetic Progestin for Contraception”, 49(3):599–606 (1993). Fertility and Sterility, 60(4):610 (Oct. 1993). V. Kumar et al., “Synthesis of 7-AZaindole and 7-AZaox indole Derivatives through a Palladium-Catalyzed Cross K. Horwitz et al., “Progestin, Progesterone Receptors, and Coupling Reaction”, J. Org. Chem., 57(25):6995-6998 Breast Cancer”, “Horm. Cancer', publisher: Birkhaeuser, (1992). Boston, Mass., ed. Vedeckis, p. 283-306 (1996) abstract P. Canonne et al., “Spirocyclization of 1-(o-Aminophenyl only. )cycloalkanols and A. A. Murphy et al., “Regression of Uterine Leiomyomata in 1-(2'Amino-3-pyridinyl)cycloalkanols”, J. Heterocyclic Response to the Antiprogesterone RU 486, J. Clin. Endo. Chem., 26:113 (Jan.-Feb. 1989). Metab., 76(2):513 (Feb. 1993). M-C. Forest et al., “A Novel Class of Cardiotonic Agents: L. M. Kettel et al., “Endocrine Responses to Long-Term Synthesis and Biological Evaluation of 5-Substituted Administration of the Antiprogesterone RU486 in Patients 3,6-Dihydrothiadiazin-2-ones with Cyclic AMP Phos with Pelvic Endometriosis”, Fertility and Sterility, phodiesterase Inhibiting and Myofibrillar Sensitiz 56(3):402 (Sep.1991). ing Properties”, J. Med. Chem., 35:163–172 (Jan. 1992). H. Michna et al., “Differentiation Therapy with Progesterone D. W. Combs et al., “Heteroatom Analogues of Bemoradan: Antagonists”, Ann. N.Y. Acad. Sci., 761:224 (Jun. 1995). Chemistry and Cardiotonic Activity of 1,4-Benzothiazi L. Zhi et al., “5-Aryl-1,2-Dihydrochromeno3,4-fcuino nylpyridazinones”, J. Med. Chem., 35:172-176 (Jan. 1992). lines: A Novel Class of Human Progesterone Kurihari et al., “Synthesis of (+)-PF1092A, B, and C; New Receptor Agonists”, J. Med Chem., 41(3):291 (Oct. 22, Nonsteroidal Ligands”, J. Antibiot 1998). ics, 50(4):360 (Apr. 1997). D. W. Combs et al., “Nonsteroidal . Kende et al., “Regioselective C-3 Alkylation of Oxindole Ligands. 2. High-Affinity Ligands with Selectivity for Bone Dianion”, Synth. Commun. 12(1):1 (1982). T. Tucker et al., “Synthesis of a Series of Cell Progesterone Receptors”, J. Med. Chem., 38:4880 (Dec. 4-(Arylethylnyl)-6-Chloro-4-Cyclopropyl-3, 8, 1995). 4-dihydroquinazolin-2(1H)-ones as Novel Non-Nucleo K.L. Perlman et al., “20-Oxopregnacalciferols: Vitamin D side HIV-1 Reverse Transcriptase Inhibitors”, J. Med. Compounds that Bind the Progesterone Receptor”, Tet. Chem., 37:2347–2444 (Jul 22, 1994). Letters, 35(15):2295 (1994). J. P. Edwards et al., “5-Aryl-1,2-Dihydro-5H-Chromeno L. G. Hamann et al., “Synthesis and Biological Activity of 3,4-fCuinolines as Potent, Orally Active, Nonsteroidal Novel Nonsteroidal Progesterone Receptor Antagonists”, Progesterone Receptor Agonists: The Effect of D-Ring Ann. N.Y. Acad. Sci., 761:383 (Jun. 12, 1995). Substituents”, J. Med. Chem., 41:303-310 (Jan. 29, 1998). R. H. K. Chen et al., “Synthesis and SAR of a Novel Series Derwent WPI abstract, “New Imidazo-Pyridine Deriva of Spirobenzothlzaepine Derivatives with Antiprogestin tives-Useful as Platelet Agglutination Inhibitor, Antialler Activity", POI-37, 16" Int. Cong. Het. Chem., Montana gic, Antiinflammatory Sedative, Cardiac, and Cardiovascu (1997). lar Vasodilators”, JP 63112584, May 17, 1988. US 6,329,416 B1 Page 3

Derwent WPI abstract, N. Brumagniez et al., “Benzimida Kolasa, K., et al., “Preliminary Pharmacological Studies of Zole and AZabenzimidazole(s)-Having Cardiotonic, the Central Action of Phenyl and Piperidinomethyl Deriva Vasodilating, Anti-Hypertensive, Anti-Aggregation, and tives of 2-Benzoxazolone.” Chemical Abstracts, vol. 99, Anti-Ulcer Activity”, EP 385850, Sep. 5, 1990. No. 1, Abst. No. 157a, Jul. 4, 1983. Derwent WPI abstract, F. Arndt et al., “New Heterocycle Substituted Benzo-Fused Azine and Azole Derivatives Meanwell N.A., et al., “Regiospecific Functionalization of Useful as Selective Herbicides for Pre or Post-Emergence 1,3-dihydro-2H-Benzimidazol-2-One and Structurally Application”, EP311135, Apr. 12, 1989. Related Cyclic Urea Derivatives”. J. Organic Chem.,60(6): Mamaev, V.P., et al., “Synthesis of 4H-Thieno 3.2-B 1565–82 (Mar. 24, 1995). Pyrrol-5 (6H)-One” Bulletin of the Academy of Sciences on Singh, B., et al., “An Efficient and Novel Synthesis of Fused the USSR. Division of Chemical Science, US, Consultants Thiazol-2(3H)-ones” Heterocycles, 36(1): 133-134, p. 136, Bureau. New York. Vol. 9, pp. 1549-1553, 1966. compounds 16a, 18a, Jan. 1993. Derwent WPI Abstract, Chwalisz, K., et al. “Female Con traceptive Method Comprises Gestation Treatment with Vernin, G., et al., “Etude Dans la Serie des Radicaux Intermittent Progesterone Antagonist Administration., DE Heterocycliques. Partie XV. Decomposition aprotique de 4,330,234, Mar. 9, 1995. 1'amino-6-ethyl-2-benzothiazole dans des substrats aro Derwent WPI Abstract, Chwalisz, K., et al. “Contraceptive matiques et heteroaromatiques: preparation des Pack for Implantation Inhibition-Contains Competitive mesityl-6-et furyl-6-ethyl-2-benzothiazoles, des Sels qua Progesterone Antagonist and Gestagen for Sequential Oral ternaires et des Spiropyrannes correspondants' Helvetica Administration.”, DE 4,344,463, Jun. 29, 1995. Chimica Acta, 62(1/3):21–30 Jan. 24, 1979. US 6,329,416 B1 1 COMBINATION REGIMENS USING 3,3- SUBSTITUTED INDOLINE DERVATIVES

CROSS-REFERENCE TO RELATED APPLICATIONS s Me This application claims the benefit of the priority of U.S. S Provisional patent application No. 60/183,057, filed May 4, le N 1999. Me

N Me FIELD OF THE INVENTION H This invention relates to regimens of administering compounds, which are antagonists of the progesterone 15 receptor in combination with a progestin, an estrogen, or Jones, et al, described the enol ether B (U.S. Pat. No. both. 5,693,646) as a PR ligand.

BACKGROUND OF THE INVENTION B Me Intracellular receptors (IR) form a class of structurally related gene regulators known as “ligand dependent tran scription factors” (R. M. Evans, Science, 240, 889, 1988). The steroid receptor family is a subset of the IR family, including progesterone receptor (PR), estrogen receptor 25 O 2 Me (ER), receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR). F N The natural hormone, or ligand, for the PR is the steroid Me progesterone, but Synthetic compounds, Such as medroX N Me yprogesterone or , have been made H which also serve as ligands. Once a ligand is present in the fluid Surrounding a cell, it passes through the membrane Via passive diffusion, and binds to the IR to create a receptor/ ligand complex. This complex binds to specific gene pro 35 moters present in the cells DNA. Once bound to the DNA Jones, et al, described compound C (U.S. Pat. No. 5,696, the complex modulates the production of mRNA and protein 127) as a PR ligand. encoded by that gene.

A compound that binds to an IR and mimics the action of 40 the natural hormone is termed an agonist, whilst a compound which inhibits the effect of the hormone is an antagonist. PR antagonists may be used in contraception. In this context they may be administered alone (Ulmann, et al., Ann. N. Y. Acad. Sci., 261,248, 1995), in combination with a PR 45 agonist (Kekkonen, et al, Fertility and Sterility, 60, 610, 1993) or in combination with a partial ER antagonist such as tamoxifen (WO 96/19997, published Jul. 4, 1996). PR antagonists may also be useful for the treatment of hormone 50 dependent breast cancers (Horwitz, et al., Horm. Cancer, 283), pub: Birkhaeuser, Boston, Mass., ed. Vedeckis) as well as uterine and ovarian cancers. PR antagonists may also be useful for the treatment of non-malignant chronic conditions such as fibroids (Murphy, et al., J. Clin. Endo. Metab., 76, 55 513, 1993) and endometriosis (Kettel, et al., Fertility and Zhi, et al, described lactones D, E and F as PR antagonists Sterility, 56, 402, 1991). PR antagonists may also be useful (J. Med. Chem., 41, 291, 1998). in hormone replacement therapy for post menopausal

patients in combination with a partial ER antagonist Such as tamoxifen (U.S. Pat. No. 5,719,136). PR antagonists, such as 60 mifepristone and , have been shown to be effec tive in a model of hormone dependent prostate cancer, which may indicate their utility in the treatment of this condition in men (Michna, et al, Ann. N.Y. Acad. Sci., 761, 224, 1995). 65 Jones, et al., (U.S. Pat. No. 5,688,810) describe the PR antagonist dihydroquinoline A. US 6,329,416 B1 3 4 -continued

E I O 5 O CH CH O Me

N Me 1O

N Me H CH2

F 15 Ho

2O Hamann, et al, described the PR antagonist J (Ann. N.Y. Acad. Sci., 761, 383, 1995).

J 25 OCH Zhi, et al, described the ether G as a PR antagonist (J. Br HC CH Med. Chem., 41, 291, 1998).

3O G OAc HC CH

35 Chen, et al, described the PR antagonist K (Chen, et al., POI-37, 16' Int. Cong. Het. Chem., Montana, 1997). O Me K N 40 Cl Me N Me S in N Cl H H

N H Combs, et al., disclosed the amide H as a ligand for the PR (J. Med. Chem., 38, 4880, 1995). 50 Kurihari, et. al., described the PR ligand L (J. Antibiotics, 50, 360, 1997).

H L 55 CH F HC CH 3 OAc N -N S N1 Br O O 60 O OH

Elliott (SmithKline Beecham) claimed the generic indo 65 line M as potential endothelin receptor antagonists (WO Perlman, et. al., described the vitamin D analog I as a PR 94/14434). The patent does not claim indolines and lacks the ligand (Tet. Letters, 35, 2295, 1994). appropriate 5-aryl substitution, i.e. CN and NO. US 6,329,416 B1 6 ous administration or periodic discontinuation of adminis M tration of the invention to allow for minimization of effective R1 R10 dose or minimization of Side effects or cyclic menstrual R bleeding. C N P The use of this invention for contraception includes P administration, preferably orally, to a female of child bear R4A-4N M P. ing age an antiprogestin in combination with an estrogen or (CH2)2-R2 progestin or both. These administration regimens are pref R1, R10, P1 and P2 = H, 1-8 Calkyl, Ph erably carried out over 28 consecutive days, with a terminal n = 0 portion of the cycle containing administration of no R3 = H R = H progestins, estrogens or anti-progestins. R4 = Ar (substituted) The progestins of these combinations may be adminis tered alone or in combination with an estrogen for the first 14 to 24 days of the cycle, the progestins being administered wherein: R=H, Ar, R1, OH, 1-5 Calkoxy (opt. Substd. by 15 OH, OMe or halogen), -S(O).R., N(R), XR1, halogen at a dosage range equal in progestational activity to about 35 or NHCOR; X=(CH), O, NRs or S(O), n=0–6; q=0–2; tug to about 150 lug levonorgestrel per day, preferably equal Re=H or 1-4C alkyl; R =1-8 Calkyl, 2-8 Calkenyl or 2-8 in activity to from about 35 lug to about 100 ug levonorg C alkynyl (all optionally substituted); Ar=(i) optionally estrel per day. An antiprogestin may then be administered Substituted phenyl or benzo-fused group of (a) or (b); or (ii) alone or in combination with an estrogen for a period of 1 napthyl, indoyl, pyridyl, thienyl, oxazolindyl, oxazolyl, to 11 days to begin on any cycle day between day 14 and 24. thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, The anti-progestin in these combinations may be adminis imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, tered at a dose of from about 2 ug to about 50 ug per day and oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, pyrrolyl the estrogen may be administered at a dose of from about 10 tug to about 35 lug per day. In an oral administration, a or pyrimidyl, all optionally Substituted by one or more R or 25 package or kit containing 28 tablets will include a placebo R2 groupS. tablet on those days when the antiprogestin or progestin or estrogen is not administered. (a) In a preferred embodiment of this invention, the R progestins of this invention may be administered alone or in Sé combination with an estrogen for the initial 18 to 21 days of a 28-day cycle, followed by administration of an ex R. antiprogestin, alone or in combination with an estrogen, for R3 from 1 to 7 days. (b) The estrogen to be used in the combinations and formu R 35 lations of this invention is preferably ethinyl . NS-B ProgeStational agents useful with this invention include, Y S \, but are not limited to, levonorgestrel, , , 44 1/ 3-ketodesogestrel, norethindrone, , norethindrone 40 acetate, , , acetate, A = CO or (C(R6)2) , , droSpire none, , or (17 B = CH2 or O deacetyl)norgestimate. Among the preferred progestins for use in the combinations of this invention are levonorgestrel, gestodene and trimegestone. U.S Pat. No. 5,521,166 (Grubb) teaches cyclophasic hormonal regimens comprising an antiprogestin and a 45 Examples of orally administered regimens of this inven progestin wherein the progestin is administered in the alter tion over a 28 day cycle include administration of a proges nating presence and absence of an antiprogestin. The dis tational agent Solely for the first 21 days at a daily dose equal closed regimens also provide for use of an estrogen for a in progestational activity to from about 35 to about 100 lug period of from 2 to 4 days to prevent breakthrough bleeding. of levonorgestrel. An antiprogestin compound of this inven 50 tion may then be administered at a daily dose of from about DESCRIPTION OF THE INVENTION 2 to 50 mg from day 22 to day 24, followed by no administration or administration of a placebo for days 25 to This invention provides combination therapies and dosing 28. It is most preferred that the daily dosages of each regimens utilizing antiprogestational agents in combination relevant active ingredient be incorporated into a combined, with one or more progestational agents. This invention 55 Single daily dosage unit, totaling 28 daily units per 28-day further provides methods of treatment and dosing regimens cycle. further utilizing in combination with these antiprogestins In another regimen, a progestational agent may be coad and progestins, an estrogen, Such as ethinyl estradiol. ministered for the first 21 days at a daily dose equal in These regimens and combinations may be administered to progestational activity to from about 35 to about 150 ug a mammal to induce contraception or for the treatment 60 levonorgestrel, preferably equal in activity to from about 35 and/or prevention of Secondary amenorrhea, dysfunctional to about 100 lug levonorgestrel, with an estrogen, Such as bleeding, uterine leiomyomata, endometriosis, polycystic ethinyl estradiol, at a daily dose range of from about 10 to ovary Syndrome, carcinomas and adenocarcinomas of the about 35 lug. This may be followed as described above with endometrium, ovary, breast, colon, and prostate. Additional an antiprogestin administered at a daily dose of from about uses of the invention include stimulation of food intake. The 65 2 to 50 mg from day 22 to day 24, followed by no uses herein for the treatment and/or prevention of the administration or administration of a placebo for days 25 to conditions or diseases described above includes the continu 28. US 6,329,416 B1 7 8 Still another regimen within the scope of this invention A preferred embodiment of the kit described above may will include coadministration from dayS 1 to 21 of a proges comprise: tational agent, the progestational agent, preferably a) a first phase of 21 daily dosage units of a progestational levonorgestrel, being administered at a daily dose equal in agent equal in progestational activity to about 35 to progestational activity to from about 35 to about 100 ug about 150 lug levonorgestrel, preferably equal in activ levonorgestrel, and an estrogen, Such as ethinyl estradiol, at ity to from about 35 to about 100 lug levonorgestrel, a daily dose range of from about 10 to about 35ug. This will and, as an estrogen, ethinyl estradiol at a daily dose be followed on days 22 to 24 by coadministration of an range of from about 10 to about 35 lug; and antiprogestin (2 to 50 mg/day) and an estrogen, Such as b) a second phase of 3 daily dosage units for days 22 to ethinyl estradiol, at a daily dose of from about 10 to about 1O 24 of an antiprogestin administered at a daily dose of 35 ug. From day 25 to day 28, this regimen may be followed from about 2 to 50 mg; and by no administration or administration of a placebo. c) optionally, a third phase of 4 daily dose units of an This invention also provides kits or packages of pharma orally and pharmaceutically acceptable placebo for ceutical formulations designed for use in the regimens each of days 25 to 28. described herein. These kits are preferably designed for 15 A further 28-day packaged regimen or kit of this invention daily oral administration over a 28-day cycle, preferably for comprises: one oral administration per day, and organized So as to a) a first phase of from 18 to 21 daily dosage units, each indicate a Single oral formulation or combination of oral containing a progestational agent of this invention at a formulations to be taken on each day of the 28-day cycle. daily dose equal in progestational activity to about 35 Preferably each kit will include oral tablets to be taken on to about 150 lug levonorgestrel, preferably equal in each the days Specified, preferably one oral tablet will activity to from about 35 to about 100 lug contain each of the combined daily dosages indicated. levonorgestrel, and ethinyl estradiol at a daily dose According to the regimens described above, one 28-day range of from about 10 to about 35 lug; kit may comprise: b) a second phase of from 1 to 7 daily dose units, each a) an initial phase of from 14 to 21 daily dosage units of 25 daily dose unit containing an antiprogestin of this a progestational agent equal in progestational activity invention at a concentration of from 2 to 50 mg, and to from about 35 to about 150 lug levonorgestrel, ethinyl estradiol at a concentration of from about 10 to preferably equal in progestational activity to about 35 about 35 lug; and to about 100 ug levonorgestrel; c) optionally, an orally and pharmaceutically acceptable b) a second phase of from 1 to 11 daily dosage units of an placebo for each of the remaining 0-9 days in the antiprogestin compound of this invention, each daily 28-day cycle in which no progestational agent, estrogen dosage unit containing an antiprogestin compound at a or antiprogestin is administered. daily dosage of from about 2 to 50 mg, and A preferred embodiment of the package or kit just c) optionally, a third phase of an orally and pharmaceu 35 described comprises: tically acceptable placebo for the remaining days of the a) a first phase of 21 daily dosage units, each containing cycle in which no antiprogestin, progestin or estrogen a progestational agent of this invention at a daily dose is administered. equal in progestational activity to about 35 to about 150 A preferred embodiment of this kit may comprise: tug levonorgestrel, preferably from about 35 to about a) an initial phase of 21 daily dosage units of a proges 40 100 ug levonorgestrel, and ethinyl estradiol at a daily tational agent equal in progestational activity to about dose range of from about 10 to about 35 u; 35 to about 150 lug levonorgestrel, preferably equal in b) a second phase of 3 daily dose units for days 22 to 24, progestational activity to about 35 to about 100 ug each dose unit containing an antiprogestin of this levonorgestrel; invention at a concentration of from 2 to 50 mg, and 45 ethinyl estradiol at a concentration of from about 10 to b) a Second phase of 3 daily dosage units for days 22 to about 35 lug; and 24 of an antiprogestin compound of this invention, each c) optionally, a third phase of 4 daily units of an orally and daily dosage unit containing an antiprogestin com pharmaceutically acceptable placebo for each of days pound at a daily dosage of from about 2 to 50 mg, and 25 to 28. c) optionally, a third phase of 4 daily units of an orally and 50 In each of the regimens and kits just described, it is pharmaceutically acceptable placebo for each of days preferred that the daily dosage of each pharmaceutically 25 to 28. active component of the regimen remain fixed in each Another 28-day cycle packaging regimen or kit of this particular phase in which it is administered. It is also invention comprises: understood that the daily dose units described are to be a) a first phase of from 18 to 21 daily dosage units of a 55 administered in the order described, with the first phase progestational agent equal in progestational activity to followed in order by the second and third phases. To help about 35 to about 150 ug levonorgestrel, preferably facilitate compliance with each regimen, it is also preferred equal in activity to from about 35 to about 100 tug that the kits contain the placebo described for the final days levonorgestrel, and, as an estrogen, ethinyl estradiol at of the cycle. It is further preferred that each package or kit a daily dose range of from about 10 to about 35 lug; and 60 comprise a pharmaceutically acceptable package having b) a second phase of from 1 to 7 daily dosage units of an indicators for each day of the 28-day cycle, Such as a labeled antiprogestin of this invention at a daily dose of from blister package or dial dispenser packages known in the art. about 2 to 50 mg; and In this disclosure, the terms anti-progestational agents, c) optionally, an orally and pharmaceutically acceptable anti-progestins and progesterone receptor antagonists are placebo for each of the remaining 0-9 days in the 65 understood to be Synonymous. Similarly, progestins, proges 28-day cycle in which no progestational agent, estrogen tational agents and progesterone receptor agonists arc under or antiprogestin is administered. stood to refer to compounds of the same activity. US 6,329,416 B1 9 10 These dosage regimens may be adjusted to provide the aminoalkyl, NO, C to C perfluoroalkyl, 5 or 6 optimal therapeutic response. For example, Several divided membered heterocyclic ring containing 1 to 3 doses of each component may be administered daily or the dose may be proportionally increased or reduced as indi heteroatoms, COR, OCOR, or NRCCOR; cated by the exigencies of the therapeutic Situation. In the R’ is H, C, to C alkyl, substituted C, to C, alkyl, descriptions herein, reference to a daily dosage unit may also aryl, Substituted aryl, C to C alkoxy, Substituted include divided units which are administered over the course C to C alkoxy, C to C aminoalkyl, or Substi of each day of the cycle contemplated. tuted C to C aminoalkyl, Compounds of this invention that may be used as the R is H, C, to C, alkyl, or substituted C, to C, alkyl: anti-progestational agents in the kits, methods and regimens Y and Z are independent substituents taken from the herein are those of the Formula I: group including H, halogen, CN, NO, C to C. alkoxy, C to C alkyl, or C to C thioalkyl, or b) Rs is a five or six membered ring with 1, 2, or 3 R1 R2 heteroatoms from the group including O, S, SO, SO R5 15 or NR and containing one or two independent ry Substituents from the group including H, halogen, A. 21 NN R7 CN, NO and C to C alkyl, C to C alkoxy, C to R4 Y. C, aminoalkyl, CORP, or NRCORP; 3 R’ is H, C, to C, alkyl, substituted C, to C, alkyl, aryl, Substituted aryl, C to C alkoxy, Substituted wherein: C to C alkoxy, C to C aminoalkyl, or Substi R and R are chosen independently from H, alkyl, tuted C to C aminoalkyl, Substituted alkyl, OH, O(alkyl); O(substituted alkyl); R’ is H, C, to C, alkyl, or substituted C, to C, alkyl; OAc, aryl, optionally Substituted aryl; heteroaryl; 25 R is H or C to C alkyl; optionally Substituted heteroaryl; alkylaryl; alkylhet O eroaryl, 1-propynyl; or 3-propynyl, c) R is an indol-4-yl, indol-7-yl or benzo-2-thiophene or R and R2 are joined to form a ring comprising one of moiety, the moiety being optionally Substituted by the following: -CH (CH), CH -; from 1 to 3 substituents selected from halogen, lower -CHCHCMe CHCH-, -O(CH2)CH-; alkyl, CN, NO, lower alkoxy, or CF; wherein R O(CH), O-; - CHCHO CHCH-; and R7 are independently chosen from H, methyl, -CHCH-N(H or alkyl)CHCH-; ethyl, propyl, butyl, iso-propyl, iso-butyl, n is an integer from 0 to 5; cyclohexyl, aryl, Substituted aryl, heteroaryl, or Sub m is an integer from 1 to 4, Stituted heteroaryl; p is an integer from 1 to 4, 35 or pharmaceutically acceptable Salt thereof. or R and R together comprise a double bond to A preferred Set of antiprogestin compounds of this inven =C(CH); = C(C-C cycloalkyl), =O, or tion is depicted by structure II: =C(cycloether), wherein cycloether is selected from tetrahydrofuranyl or hexahydropyranyl; II R is H, OH, NH, C, to C alkyl, Substituted C to C 40 alkyl, C. to Calkenyl, alkynyl or Substituted alkynyl, or CORA; R is H, C, to C, alkyl, substituted C, to C, alkyl, C, to Me Calkoxy, Substituted C to C alkoxy, C to Caminoalkyl, or Substituted C to C aminoalkyl, 45 R is H, halogen, CN, NH, C to C alkyl, Substituted C. to C alkyl, C to C alkoxy, Substituted C to C wherein: alkoxy, C to C aminoalkyl, or Substituted C to C aminoalkyl, Rs is a disubstituted benzene ring containing the Substitu Rs is selected from the groups a), b) or c): 50 ents X, and Y as shown below: a) Rs is a trisubstituted benzene ring containing the Substituents X, Y and Z as shown below:

Z. e/ 55 S

60 X is Selected from halogen, CN, C to C alkoxy, C to X is selected from halogen, OH, CN, C to C alkyl, C. alkyl, NO, C, to C perfluoroalkyl, 5-membered Substituted C to C alkyl, C to C alkoxy, heterocyclic ring containing 1 to 3 heteroatoms, or Substituted C to C alkoxy, C to C thioalkyl, C to C thioalkoxy, Substituted C to C thioalkyl, S(O)alkyl, 65 Y is a substituent on the 4' or 5' position selected from H, S(O)-alkyl, C to Caminoalkyl, Substituted C to halogen, CN, NO, C to C alkoxy, C to C alkyl, or C to Cs C. thioalkyl, or US 6,329,416 B1 11 12 Rs is a five membered ring having the Structure: alkoxy, aryloxy, Substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio. X The term “heterocyclic” is used herein to describe a stable 4-to 7-membered monocyclic or a stable multicyclic hetero ray cyclic ring which is Saturated, partially unsaturated, or unsaturated, and which consists of carbon atoms and from one to four heteroatoms Selected from the group including is. N, O, and Satoms. The N and Satoms may be oxidized. The heterocyclic ring also includes any multicyclic ring in which U is O, S, or NR, any of above defined heterocyclic rings is fused to an aryl R is H, or C to C alkyl, or C to C, CO-alkyl, ring. The heterocyclic ring may be attached at any heteroa X is selected from halogen, CN, NO, C to C alkyl tom or carbon atom provided the resultant Structure is or C to C alkoxy; chemically Stable. Such heterocyclic groups include, for Y is selected from the group H, F, CN, NO or C to example, tetrahydrofuran, piperidinyl, piperaZinyl, C. alkyl, or 15 2-oxopiperidinyl, azepinyl, pyrrollidinyl, imidazolyl, Rs is a six-membered ring with the Structure: pyridyl, pyrazinyl, pyrimidinyl, pyridaZinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl, furyl, benzofuranyl, benzothienyl, thiamorpholinyl, thiamorpholi nyl Sulfoxide, and isoquinolinyl. The term “substituted heterocyclic” is used herein to describe the heterocyclic just defined having 1 to 4 Substitu ents Selected from the group which includes halogen, CN, OH, NO, amino, alkyl, Substituted alkyl, cycloalkyl, alkenyl, Substituted alkenyl, alkynyl, alkoxy, aryloxy, Sub X is N or CX; 25 Stituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, X is halogen, CN or NO; or arylthio. The term “thioalkyl is used herein to refer to the or pharmaceutically acceptable Salt thereof. SR group, where R is alkyl or Substituted alkyl, containing The antiprogestin compounds of the formulations and 1 to 8 carbon atoms. The term “alkoxy' refers to the OR regimens of this invention may contain an asymmetric group, where R is alkyl or Substituted alkyl, containing 1 to carbon atom and Some of the compounds of this invention 8 carbon atoms. The term “aryloxy” refers to the OR group, may contain one or more asymmetric centers and may thus where R is aryl or substituted aryl, as defined above. The give rise to optical isomers and diastereomers. While shown term “alkylcarbonyl refers to the RCO group, where R is without respect to Stereochemistry in Formula I and II the alkyl or Substituted alkyl, containing 1 to 8 carbon atoms, present invention includes Such optical isomers and diaste preferably 1 to 6 carbon atoms. The term “alkylcarboxy” reomers, as well as the racemic and resolved, enantiomeri 35 indicates the COOR group, where R is alkyl or substituted cally pure R and S Stereoisomers, as well as other mixtures alkyl, containing 1 to 8 carbon atoms, preferably 1 to 6 of the R and S Stereoisomers and pharmaceutically accept carbon atoms. The term “aminoalkyl” refers to both second able salts thereof. ary and tertiary amines wherein the alkyl or Substituted alkyl The term “alkyl” is used herein to refer to both straight groups, containing 1 to 8 carbon atoms, which may be either and branched-chain Saturated aliphatic hydrocarbon groups 40 the same or different and the point of attachment is on the having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, nitrogen atom. The term “halogen” refers to Cl, Br, F, or I. “alkenyl' is intended to include both straight- and branched The antiprogestational compounds of the present inven chain alkyl group with 1 or 2 carbon-carbon double bonds tion can be used in the form of Salts derived from pharma and containing 2 to 8 carbon atoms, preferably 2 to 6 carbon ceutically or physiologically acceptable acids or bases. atoms; “alkynyl group is intended to cover both Straight 45 These Salts include, but are not limited to, the following Salts and branched-chain alkyl group with at least 1 or 2 carbon with inorganic acids Such as hydrochloric acid, Sulfuric acid, carbon triple bonds and containing 2 to 8 carbon atoms, nitric acid, phosphoric acid and, as the case may be, Such preferably 2 to 6 carbon atoms. organic acids as acetic acid, Oxalic acid, Succinic acid, and The terms “substituted alkyl”, “substituted alkenyl', and maleic acid. Other Salts include Salts with alkali metals or “substituted alkynyl' refer to alkyl, alkenyl, and alkynyl as 50 alkaline earth metals, Such as Sodium, potassium, calcium or just described having one or more Substituents from the in the form of esters, carbamates and other group including halogen, CN, OH, NO, amino, aryl, conventional “pro-drug forms, which, when administered heterocyclic, Substituted aryl, Substituted heterocyclic, in Such form, convert to the active moiety in Vivo. alkoxy, aryloxy, Substituted alkyloxy, alkylcarbonyl, When the active compounds of these regimens are alkylcarboxy, alkylamino, arylthio. These Substituents may 55 employed for the above utilities, they may be combined with be attached to any carbon of alkyl, alkenyl, or alkynyl group one or more pharmaceutically acceptable carriers or provided that the attachment constitutes a stable chemical excipients, for example, Solvents, diluents and the like, and moiety. may be administered orally in Such forms as tablets, The term “aryl' is used herein to refer to an aromatic capsules, dispersible powders, granules, or Suspensions System which may be a single ring or multiple aromatic rings 60 containing, for example, from about 0.05 to 5% of suspend fused or linked together as Such that at least one part of the ing agent, Syrups containing, for example, from about 10 to fused or linked rings forms the conjugated aromatic System. 50% of Sugar, and elixirs containing, for example, from The aryl groups include but not limited to phenyl, naphthyl, about 20 to 50% ethanol, and the like, or parenterally in the biphenyl, anthryl, tetrahydronaphthyl, and phenanthryl. form of Sterile injectable Solutions or Suspensions containing The term “substituted aryl” refers to an aryl as just defined 65 from about 0.05 to 5% suspending agent in an isotonic having 1 to 4 Substituents from the group including halogen, medium. Such pharmaceutical preparations may contain, for CN, OH, NO, amino, alkyl, cycloalkyl, alkenyl, alkynyl, example, from about 25 to about 90% of the active ingre US 6,329,416 B1 13 14 dient in combination with the carrier, more usually between -continued about 5% and 60% by weight. R2 R3. The pharmacologically active agents of this invention YQA R1 may be administered orally as well as by intravenous, \ intramuscular, or Subcutaneous routes. Solid carriers include x(– N Starch, lactose, dicalcium phosphate, microcrystalline H cellulose, Sucrose and kaolin, while liquid carriers include Y R2 R3. Sterile water, polyethylene glycols, non-ionic Surfactants and Z. edible oils. Such as corn, peanut and Sesame oils, as are 2xe Pd(O) appropriate to the nature of the active ingredient and the X- -- R1 N N particular form of administration desired. Adjuvants cus Z. H tomarily employed in the preparation of pharmaceutical Z = I, Br, or B(OH)2 compositions may be advantageously included, Such as R2 R3. flavoring agents, coloring agents, preserving agents, and 15 antioxidants, for example, Vitamin E, ascorbic acid, BHT YCA R1 and BHA. \ x(– N The preferred pharmaceutical compositions from the H Standpoint of ease of preparation and administration are Solid compositions, particularly tablets and hard-filled or As outlined in Scheme 2, the “right side' of the anti liquid-filled capsules. Oral administration of the compounds progestin compounds of this invention may be prepared by is preferred. following the procedure described of Letcher, R. M. et. al., These active compounds may also be administered J. Chem. Soc. Perkin Trans., 1993, Vol. 1, pp. 939–944. parenterally or intraperitoneally. Solutions or Suspensions of 25 these active compounds as a free base or pharmacologically Scheme 2 acceptable Salt can be prepared in water Suitably mixed with a Surfactant Such as hydroxypropylcellulose. Dispersions Y HCI O can also be prepared in glycerol, liquid, polyethylene glycols \ N AcOH(cat) and mixtures thereof in oils. Under ordinary conditions of X -- R2 benzene, reflux 2n -NH2 Ri Storage and use, these preparations contain a preservative to N prevent the growth of microorganisms. H R3 The pharmaceutical forms Suitable for injectable use R2 35 Y R include Sterile aqueous Solutions or dispersions and Sterile 1. powders for the extemporaneous preparation of Sterile X \ N R A.cCH injectable Solutions or dispersions. In all cases, the form 2n-N 120 degrees C. must be sterile and must be fluid to the extent that easy Syringe ability exits. It must be stable under conditions of 40 H manufacture and Storage and must be preserved against the contaminating action of microorganisms. Such as bacterial Y R2 R3. and fungi. The carrier can be a Solvent or dispersion medium 1.X^n NaBH4 containing, for example, Water, ethanol (e.g., glycerol, pro X- 7 R1 THE-MeOH(6-1) pylene glycol and liquid polyethylene glycol), Suitable mix 45 21 N tures thereof, and vegetable oil. Y R2 R3. The compounds of this invention can be prepared by the \ N procedures outlined in the Schemes illustrated below: x- R1 Typically the antiprogestin compounds of this invention 50 21 N are prepared in a convergent manner as shown is Scheme 1, by a Suitable coupling reaction. For example, a palladium 2 mediated coupling of an aryl halide with an arylboronic acid provides the desired bi-aryl Substituted target. The choice of AS an example the right Side template, 2, is prepared by the aryl halide-arylboronic acid combination is established 55 condensing an appropriately Substituted phenyl hydrazine experimentally. and a Suitable ketone to give the corresponding hydraZone. This material is cyclized to an imine in refluxing acetic acid and then reduced to the desired indoline template 2. Scheme 1 Examples 1-7 and 10-20 were prepared by this route using 60 the appropriate ketone. Alternatively the right Side template may be prepared as x outlined in Scheme 3. The commercially available oxindole Xf Pd(O) is di-alkylated at C-3 by using an appropriate base and the S N corresponding alkyl halide to give the 3,3-dialky-OXindole, 65 8, or the spiro-cyclic oxindole 9. These oxindoles are then brominated under Standard conditions and the carbonyl group is reduced to the desired methylene using a hydride US 6,329,416 B1 15 mediated reduction. The timing of the aryl coupling and the -continued reduction of the 2-position carbonyl are established experi mentally.

Scheme 3 O R2 R3. 1. nBuLi(1.6M/Hex) ON O N R1 TMEDA, THF H -20 degrees, C. O He 11 2. CHI ) HC Dioxane N O H H(CH2)s-I 11 (HCl salt) -20 degrees C. to RT R2 R3. The compounds of this invention, are stable Semi-Solids 15 and are conveniently converted into their corresponding Br, NaOAc Salts by treatment with acid. Example 1, compound 11 O HeAcOH (R=R=R=Me), when treated with HCl in dioxane affords N the HCl salt (Example 2) as a white solid. The racemic H indolines can be separated into their enantiomers by Chiral 8 HPLC, to provide the individual enantiomers in >98% EE. 9 R2 R -(CH2) This invention may be further understood by the follow R2 R3. ing non-limiting examples. Br 1. BH-DMS EXAMPLE 1. O THF 2. TEA-N-oxide 25 2,3,3-Trimethyl-5-(3-nitro-phenyl)-2,3-dihydro-1H N indole H 5-Bromo-2,3,3-trimethyl-2,3-dilyhydro-1H-indole R2 R3. This compound was prepared by the procedure of Letcher, Br R. M. et. al., J. Chem. Soc. Perlcin Trais., 1:939–944, 1993. Pd(O) To a solution of 4-bromo-phenyl hydrazine hydrochloride Y (2.59g, 11.6 mmol) and 3-methyl-2-butanone (1.0 g, 11.6 mmol) in 20 mL benzene was added acetic acid (catalytic X amount) and the resulting Solution was refluxed with azeo 21 tropic removal of HO for 14 h. The reaction mixture was B(OH)2 35 cooled to room temperature and concentrated. The resulting Y Semi-Solid was extracted in acetic acid and refluxed for 12 \ N hours. The reaction mixture was cooled to room temperature X- R2 R3 and concentrated. The Semi-Solid residue was extracted in 2 ether and neutralized with KCO. The ether layer was dried 40 and concentrated. The resulting Solid imine was dissolved in THF-MeOH (6:1), cooled to 0° C. and sodium borohydride N (0.5 g., 13.2 mmol) was added. The solution was allowed to H warm to room temperature and stirred for 0.5 hours. The reaction mixture was poured into 15% aqueous HCl and then The right Side templates are coupled with an appropriate 45 made basic with KCO. The organic layer was separated, washed with brine, dried (NaSO), and concentrated. The aryl boronic acid using an appropriate palladium (O) crude product was purified by column chromatography catalyst, Scheme 4. For example compound 10 is coupled (SiO, hexane-ethyl acetate 9:1). The product was isolated under Standard Suzuki conditions with an appropriately as an orange liquid (2.1 g, 75%): 'H-NMR (CDCl3)6 1.03 (s, substituted aryl-boronic acid to afford compound 11. 50 3H), 1.15 (d.J=6.6 Hz, 3H), 1.25 (s, 3H), 3.50 (q, J=6.6 Hz, 1H), 3.70 (br. S, 1H), 6.45 (d.J=8.7 Hz, 1H), 7.09 (m, 2H); 'C-NMR (CDC1)ö 15.10, 22.25, 26.11 (q), 43.72 (s), 65.47 (d), 110.32 (s), 110.70, 125.47, 129.75 (d), 141.48, 148.33 Scheme 4 (s); MS (EI) m/z 240, 242 (M+H)". 55 A solution of 5-bromo-2,3,3-trimethyl-2,3-dihydro-1H Y indole (0.5g, 2.1 mmol) and tetrakis-(triphenylphosphine) \ N palladium (0.14g, 0.12 mmol) in dimethoxyethane (10 mL) x- -- 2 was cycled under Na-vacuum (4x) and then Stirred under N B(OH)2 for 0.5 hours. To this mixture was then added 60 3-nitrophenylboronic acid (0.42 g, 2.5 mmol) followed by a R2 R3. solution of NaCO (0.36 g., 3.4 mmol) in 5 mL water cycled Br under Na-vacuum (3x). The solution was brought to reflux Pd(Ph3P)4 for 6 hours then cooled to room temperature, poured into R1 Na2CO3 water and extracted with EtOAc. The combined organic N DME-HO H 85 degrees C. 65 extracts were washed with water, brine, dried (Na2SO), and 1O evaporated. The residue was purified by column chroma tography (SiO, methylenechloride:hexane 1:3) to afford the

US 6,329,416 B1 19 20 6.47 (d.J=8.2 Hz, 1H), 7.09, dd.J=8.2, 2.0 Hz, 1H), 7.19 dimethoxyethane (5 mL) with 3-nitrophenylboronic acid (d.J-2.0 Hz, 1H); 'C-NMR (CDC1)& 17.22 (q), 23.19, (0.22g, 1.3 mmol) and sodium carbonate (0.35 g, 3.3 mmol) 23.44, 26.16, 30.17, 36.70 (t), 47.99 (s), 62.34 (d), 110.08 in 5 mL water. The title compound (0.17 g. 60%) was (s), 111.07, 126.83, 130.08 (d), 139.98, 148.49 (s); MS (EI) obtained as a brown semi-solid: "H NMR (CDC1)ö 1.38 (s, m/z 280, 282 (M+H)". 3H), 3.40 (s, 2H), 6.72 (d.J=8.0 Hz, 1H), 7.29-7.34 (m, 2H), Using the Standard coupling conditions given in Example 7.54 (dd.J=8.0, 8.0 Hz, 1H), 7.86 (d.J=7.8 Hz, 1H), 8.09 1 the title compound was prepared from 5-bromo- 1,2- (dd.J=8.0, 1.5 Hz, 1H), 8.40 (dd.J=2.0, 2.0 Hz, 1H); 'C- dihydro-2-methylspirocyclohexane-1,3-3H indole (0.5 NMR (CDC1)& 27.89 (q), 41.93 (s), 62.05 (d), 109.78, g, 1.65 mmol), tetrakis(triphenylphosphine)palladium (0.08 12087, 121.02, 121.23, 126.87 (d), 129.19 (s), 129.69, g, 0.07 mmol) in dimethoxy-ethane (5 mL) with 132.52 (d), 139.64, 143.75, 148.94, 151.17 (s); MS (EI) m/z. 3-nitrophenylboronic acid (0.33 g, 1.98 mmol) and sodium 268 (M)". carbonate (0.53 g, 4.95 mmol) in 5 mL water. The pure material (0.35 g, 55%) was obtained as an orange brown EXAMPLE 9 semi-solid: "H NMR (CDC1)ö 1.16 (d.J=6.4 Hz, 3H), 5'-(3-Chlorophenyl)-1,2-dihydrospiro 1.38–1.83 (m, 10H), 3.7 (brs, 1H), 3.8 (qJ=6.4 Hz, 1H), 15 cyclohexane-1,3'-3Hindole 6.69 (d.J=8.0 Hz, 1H), 7.31 (dd.J=8.0, 1.8 Hz, 1H), 7.53 Spiro cyclohexane-1,3'-3Hindol-2'-(1"H) one (dd.J=8.0, 8.0 Hz, 1H), 7.86 (d.J=7.3 Hz, 1H), 8.09 (d.J=8.0 A solution of the oxindole (25g, 190 mmol) in 800 mL of Hz, 1H), 8.39 (dd.J=1.9, 19 Hz, 1H); 'C-NMR (CDC1)ö anhydrous THF was cooled to -20°C., n-butyllithium (2.5M 17.45 (q), 23.32, 23.70, 26.21, 30.31, 37.07 (t), 47.77 (s), in hexanes, 152 mL, 0.38 mol) slowly added, followed by 62.11 (d), 109.81, 120.78, 121.23, 122.40, 126.92 (d), the addition of N.N,N',N'-tetramethylenediamine (51 mL, 128.96 (s), 129.66, 132.51 (d), 138.63, 143.92, 148.94, 0.38 mol). After 15 minutes, 1,5-diiodopentane (174g., 0.54 150.1 (s); MS (EI) m/z 322 (M)". mol) was added slowly and the mixture was allowed to warm to room temperature. After Stirring for 16 hours EXAMPLE 8 Saturated aqueous ammonium chloride Solution (1L) and 3,3-Dimethyl-5-(3-nitro-phenyl)-2,3-dihydro-1H 25 ethylacetate (1L) were added. After 15 minutes, the layers indole (WAY-160655) were Separated and the aqueous phase was extracted with 3,3-dimethyl-1,3-dihydro-2H-indol-2-one ethyl acetate. The combined organic layers were extracted This compound was prepared using the general method with hydrochloric acid (1N, 500 mL), then washed with described by A. Kende, Synth. Commun., 1:12 (1982). The brine, dried (MgSO), and concentrated to obtain an oil. The crude material was purified by column chromatography oil was triturated with hexane (200 mL) and benzene (20 (SiO, methylenechloride:hexane 1:3) to afford the subtitled mL). The precipitate was collected and dried in vacuo to compound which was consistent with the reported Spectral provide Spiro cyclohexane-1,3'-3Hindol-2'-(1"H) one data. (26.3g, 69.6%) as colorless crystals: mp 110-114 C.; H The above oxindole (0.65 g, 4.03 mmol) and sodium NMR (DMSO-d)ö 1.67 (m, 10H),6.84 (d. 1H.J-8 Hz), 6.94 acetate (0.334g, 4.07 mmol) were stirred in acetic acid (5.0 35 (t, 1H.J=Hz), 7.17 (t, 1H.J=8 Hz) 7.44 (d. 1H.J=8 Hz), 10.3 mL). Bromine (0.66 g., 0.00413 mol) in acetic acid (5.0 mL) (s, 1H). was added drop-wise to the reaction mixture. The reaction To a solution of the above oxindole (17.6 g., 90.0 mmol) was stirred for 50 minutes, and then poured into water (10 in acetic acid (300 mL) was added Sodium acetate (8.0 g, mL). The mixture was made basic with Sodium carbonate, 100.0 mmol) and bromine (14.6g, 91.0 mmol) with stirring. extracted with ethyl acetate, dried (MgSO), filtered, and 40 After 30 minutes at room temperature, the reaction mixture evaporated to give 5-bromo-1,3-dihydro-3,3-dimethyl-2H was partitioned between water and ethylacetate. The aque indol-2-one (0.89 g, 92%); H NMR (DMSO-d) 1.21 (s, 6 ouS phase was extracted with ethylacetate. The combined H), 6.76 (d.J=8.22 Hz, 1H), 7.29 (dd.J=2.1, 8.2 Hz, 1H), organic layers were washed with water, dried (MgSO) and 7.49 (d.J=2.0 Hz, 1H), 10.4 (s, 1H). evaporated. The residue was triturated with hexane. The To a solution of the 5-bromo-1,3-dihydro-3,3-dimethyl 45 precipitate was collected, and dried in vacuo to provide 2H-indol-2-one (0.9 g, 3.7 mmol) in 20 mLTHF at 0°C. was 5-Bromo-spirocyclohexane-1,3'-3H]indol-2'(1"H)-one added aborane-methylsulfide complex (2M in THF, 38 mL, (16.5g, 67%) as off-white crystals: m.p. 196–199° C.; H 75 mmol). The reaction mixture was warmed to room NMR (DMSO-d)ö 1.62 (m, 10H), 6.8 (d. 1H.J=6.8 Hz), temperature then brought to reflux for 4 hours. The mixture 7.36 (d. 1H, J=8.2, 1.8 Hz), 7.58 (dd, 1H, J=8.2, 1.8 Hz), was cooled to room temperature and poured into H2O/ 50 10.44 (s, 1H). CHCl and washed with 5% NaHCO. The organic layer Using the Standard coupling conditions given in Example was washed with brine, dried (Na2SO) and concentrated. 1, the title compound was prepared from the above bromo The crude product was extracted in MeOH, trimethylamine OXindole (0.32 g, 1.14 mmol) tetrakis(triphenylphosphine) N-oxide (2.0g, 26.6 mmol) was added, and the solution was palladium (0.08g, 0.07 mmol) and 3-chlorophenylboronic brought to reflux for 2 hours. The reaction mixture was 55 acid (0.21 g, 1.37 mmol), and sodium carbonate (0.36 g., 3.4 cooled, concentrated and the crude residue purified by mmol) in water (3 mL). 5-(3-chloroplhenyl)-spiro column chromatography (SiO2, methylene chloride) to cyclohexane-1,3-3H]indol-2(1H)-one (0.28 g., 80%) was afford 5-bromo-3,3-dimethyl-2,3-dihydro-1H-indole (0.074 obtained as a yellow solid: m.p. 164–165° C.; H NMR g, 87%) as a yellow oil: "H NMR (CDC1)ö 1.29 (s, 6H), (CDC1)ö 1.60–1.78 (m, 6H), 1.81–1.99 (m, 4H), 7.04 3.30 (s, 2H), 3.5 (brs, 1H), 6.49 (d.J=8.8 Hz, 1H), 7.08-7.12 60 (d.J=8.1 Hz, 1H), 7.22–7.47 (m, 4H), 7.53 (s, 1H).7.71 (m, 2H); ' C-NMR (CDC1)ö 27.69 (q), 42.21 (s), 62.01 (s.1H), 9.28 (brs, 1H); 'C-NMR (CDC1)ö 20.17, 24.12, (d), 110.38(s), 111.09, 125.46, 130.09(d), 141.03, 149.52(s); 31.92 (t), 47.22 (s), 109.21, 121.94, 124.06, 125.50, 125.79, MS (EI) m/z 225, 227 (M)". 125.97, 126.38, 128.96 (d), 132.88, 133.59, 135.60, 139.14, Using the Standard coupling conditions given in Example 142.17, 182.89 (s); MS (EI) m/z. 310, 312 (M-H)". 1, the title compound was prepared from 5-bromo-3,3- 65 To a solution of 5-(3-chlorophenyl)-spirocyclohexane dimethyl-2,3-dihydro-1H-indole (0.25 g, 1.1 mmol), tetrakis 1,3-3H]indol-2(1H)-one (0.42g, 1.4 mmol) in 20 mL THF (triphenylphosphine) palladium (0.08 g., 0.07 mmol) in at 0° C. is added borane-dimethylsulfide complex, (2M in US 6,329,416 B1 21 22 THF, 14 mL, 28 mmol). The reaction mixture was warmed below. In-vitro potencies lie in the range 0.01 nM-10,000 to room temperature then brought to reflux for 4 hours. The nM, and in-vivo potencies in the range 1 lug/kg to 100 mixture was cooled to room temperature and poured into mg/kg. HO with CHCl and washed with 5% NaHCO. The The in-vitro biology is determined by (1) competitive organic layer was washed with brine, dried over NaSO and radioligand Binding: using the A-form of the human proges concentrated. The crude product was extracted in MeOH and terone receptor with progesterone as the radioligand; (2) trimethylamine N-oxide (1.0 g, 9.0 mmol) was added. The co-transfection assay, which provides functional activity Solution was brought to reflux for 2 hours, the mixture was expressed as agonist EC50 and Antagonist IC50 values, and cooled, concentrated and the crude residue purified by (3) a T47D cell proliferation, which is a further functional column chromatography (SiO, methylene chloride) to assay which also provides agonist and antagonist data. afford the title compound (0.25 g, 63%) as a yellow oil: "H 1. hPR Binding assay NMR (CDC1)& 1.3–1.55 (m,3H), 1.6–1.85 (m, 7H), 3.1 (br This assay is carried out in accordance with: Pathirana, s, 1H). 3.5 (s, 2H), 6.6 (d, J=8.0 Hz, 1H), 7.18-7.32 (m, 4H), C.; Stein, R. B.; Berger, T. S.; Fenical, W.; laniro, T.; Mais, 7.4 (dd.J=7.7, 1.5 Hz, 1H), 7.5 (s, 1H); C-NMR (CDC1)ö D. E.; Torres, A., Glodman, M. E., Nonsteroidal human 23.65, 26.24, 37.00 (t), 46.58 (s), 57.49 (t), 109.95, 12182, progesterone receptor modulators from the marine alga 125.07, 126.36, 126.98, 127.08, 130.29 (d), 130.64, 134.91, 15 cymoplia barbata, J. Steroid Biochem. Mol. Biol., 1992, 41, 139.65, 144.29, 151.09 (s); MS (EI) m/z 298,300 (M+H)". 733–738. 2. PRE-luciferase assay in CV-1 cells EXAMPLE 10 The object of this assay is to determine a compounds 3-(2',3',3'-trimethyl-2,3-dihydro-1H-indol-5-yl) progestational or antiprogestational potency based on its benzonitrile effect on PRE-luciferase reporter activity in CV-1 cells To a solution of 5-bromo-2,3,3-trimethyl-2,3-dihydro co-transfected with human PR and PRE-luciferase plasmids. 1H-indole (2.03 g, 8.45 mmol) in dimethoxyethane (50 mL), The materials methods used in the assay are as follows. under nitrogen was added tetrakis(triphenylphosphine) a. Medium palladium (0.47 g., 0.4 mmol). After 20 minutes at room The growth medium was as follows: DMEM temperature, 3-formylphenylboronic acid (2.36 g, 16.4 25 (BioWhittaker) containing 10% (v/v) fetal bovine serum mmol) and potassium carbonate (6.80 g, 55 mmol) in water (heat inactivated), 0.1 mM MEM non-essential amino acids, (25 mL) was added, and the mixture was heated under 100 U/ml penicillin, 100 mg/ml streptomycin, and 2 mM reflux. After 2 hours, the mixture was cooled, poured into GlutaMax (GIBCO, BRL). The experimental medium was brine and extracted with EtOAc (x2). The combined organic as follows: DMEM (BioWhittaker), phenol red-free, con extracts were washed with brine, dried (MgSO) and evapo taining 10% (v/v) charcoal-stripped fetal bovine serum rated. The residue was then Subjected to column chroma (heat-inactivated), 0.1 mM MEM non-essential amino acids, tography (SiO2, EtOAc: hexane, 1:8) to afford 3-(2,3,3'- 100 U/ml penicillin, 100 mg/ml streptomycin, and 2 mM trimethyl-2,3-dihydro-1H-indol-5-yl) benzaldehyde (0.96 GlutaMax (GIBCO, BRL). g, 3.62 mmol, 43%) as a slightly impure Solid that was used b. Cell culture, transfection, treatment, and luciferase without further purification: "H NMR (CDC1)ö 1.11 (s, 35 asSay 3H), 1.22 (d,3H, J=6.5 Hz), 1.35 (s, 3H), 3.59 (dd, 1H.J=13, Stock CV-1 cells are maintained in growth medium. 7 Hz), 6.69 (d. 1H,J-1Hz), 7.25 (s, 1H), 7.32(s, 1H), 7.55 (t, Co-transfection is done using 1.2x10" cells, 5 mg plEM 1H.J=7.6 Hz), 7.80 (d. 1 H.J-1 Hz), 7.82 (d. 1H.J=1Hz), 8.05 plasmid with hPR-B inserted at Sph 1 and BamH 1 sites, 10 (s, 1H), 10.07 (s, 1H). mg pGL3 plasmid with two PREs upstream of the luciferase To a solution of the above compound (0.96 g., 3.62 mmol) 40 Sequence, and 50 mg Sonicated calf thymus DNA as carrier in MeCN/HO (20 mL, 95:5) was added hydroxylamine DNA in 250 ml. Electroporation is carried out at 260 V and hydrochloride (0.82g, 7.25 mmol). After 1 hour, the mixture 1,000 m F in a Biorad Gene Pulser II. After electroporation, was poured into a Saturated Sodium hydrogen carbonate cells are resuspended in growth medium and plated in solution and extracted with EtOAc (x2). The combined 96-well plate at 40,000 cells/well in 200 ul. Following organic extracts were washed with water, dried (MgSO) 45 overnight incubation, the medium is changed to experimen and evaporated. The residue was then dissolved in dichlo tal medium. Cells are then treated with reference or test romethane (20 mL) and treated with thionyl chloride (0.53 compounds in experimental medium. Compounds are tested mL, 7.25 mmol). After 16 hours, the mixture was quenched for antiprogestational activity in the presence of 3 nM with Saturated Sodium hydrogen carbonate Solution and progesterone. Twenty-four hr. after treatment, the medium is concentrated, partitioned between water and EtOAc, and 50 discarded, cells are washed three times with D-PBS re-extracted with EtOAc. The combined organic extracts (GIBCO, BRL). Fifty ul of cell lysis buffer (Promega, were washed with brine, dried (MgSO) and evaporated. Madison, Wis.) is added to each well and the plates are Purification by column chromatography (EtOAc: hexane, shaken for 15 min in a Titer Plate Shaker (Lab Line 1:8) afforded a yellow oil (0.31 g) which was dissolved in Instrument, Inc.). Luciferase activity is measured using methanol (5 mL) and treated with ethereal hydrogen chlo 55 luciferase reagents from Promega. ride (1M, 1.3 mL, 1.3 mmol) and evaporated. Recrystalli c. Analysis of Results zation from MeOH/EtO then afforded the title compound Each treatment consists of at least 4 replicates. Log (0.20 g, 0.60 mmol, 18%); mp >235°C. (decomp); H NMR transformed data are used for analysis of variance and (CDC1)ö 1.57 (s, 3H), 1.36 (d. 3H.J=6.7 Hz), 1.40 (s, 3H), nonlinear dose response curve fitting for both agonist and 3.72–3.76 (m, 1H), 7.30 (d. 1H.J-8 Hz), 7.67 (t, 2H.J-7 Hz), 60 antagonist modes. Huber weighting is used to downweight 7.79–7.84 (m, 2H), 8.03 (d. 1H, J=8 Hz), (8.2, s, 1H); MS the effects of outliers. ECso or ICso values are calculated (EI) m/z 262 (M)". from the retransformed values. JMP software (SAS Institute, EXAMPLE 11 Inc.) is used for both one-way analysis of variance and non-linear response analyses. Pharmacology 65 d. Reference Compounds The biological activity for the compounds of the current Progesterone and tr