|||||||||||III US005183815A United States Patent (19) (1) Patent Number: 5,183,815 Saari Et Al
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|||||||||||III US005183815A United States Patent (19) (1) Patent Number: 5,183,815 Saari et al. (45) Date of Patent: Feb. 2, 1993 (54) NOVEL BONE ACTING AGENTS OTHER PUBLICATIONS 75 Inventors: Walfred S. Saari, Lansdale; Gideon A. Rodan, Bryn Mawr; Thorsten E. J. Am. Chem. Soc. 78; 4.450-4452 (1956). Fisher; Paul S. Anderson, both of Synthesis (2): 135-137 (1990). Lansdale, all of Pa. Derwent Abstract 90-161 353/21 of Fujisawa's JO 2104-593A. 73) Assignee: Merck & Co., Inc., Rahway, N.J. Adzamli, et al., Development of Phosphonate Derivatives 21 Appl. No.: 839,741 of Gadolinium Chelates for NMR Imaging of Calcified 22 Filed: Feb. 19, 1992 Soft Tissues, J. Med. Chem., vol. 32, pp. 139-144 (1989). Primary Examiner-Howard T. Mars Related U.S. Application Data Assistant Examiner-Kimberly J. Kestler Attorney, Agent, or Firm-Robert J. North; Charles M. (63) Continuation of Ser. No. 644,178, Jan. 22, 1991, aban Caruso doned. 57 ABSTRACT 51) int. Cl. ...................... A61K 31/56; A61K 31/58 52) U.S.C. .................................... 514/172; 514/174; Described are new agents for treating bone disorders 514/176; 514/178; 514/181; 514/182; 540/5; associated with a reduction in bone mass and abnormali 552/506,552/507 ties in bone resportion or bone formation including 58) Field of Search ................ 552/506, 507; 514/178, osteoporosis. Paget's disease, bone metastases and ma 514/181, 182, 172, 174, 176; 540/5 lignant hypercalcemia. The agents are hydroxyl con taining steroidal hormones, having bone resportion 56) References Cited antagonist or bone formation stimulatory activity, cova U.S. PATENT DOCUMENTS lently linked through the hydroxyl group via a bond 3,664,975 5/1972 Kerst .................................... 260/2.5 hydrolyzable in the human body, e.g. carbamate or 3,957,858 5/1976 Kerst.... ... 260/502.4 carbonate, which is further covalently linked to an 3,962,318 6/1976 Kerst ........ ... 260/SO2.4 amino, or hydroxy substituted alkylidene-1,1-bisphos 4,407,761 10/1983 Blum et al. ... ... 260/502.5 phonate, through the respective amino or hydroxy 4,621,077 11/1986 Rosini et al. ........................ 514/108 group. The alkyl bisphosphonate moiety confers bone 4,705,651 ll/1987 Staibano ........... 260/.502.5 affinity. The agent acts by delivering the steroidal hor 4,992,007 5/1990 Kieczykowski ...................... S62/13 mone directly to the bone target site where it is released FOREIGN PATENT DOCUMENTS for bone resorption antagonist or bone formation stimu 0.088462 9/1983 European Pat. Off. latory action by hydrolysis of the hydrolyzable cova 201057 11/1986 European Pat. Off................ 31/65 lent bond. 0341961 5/1989 European Pat. Off. WO91/05791 5/1991 PCT Int'l Appl. 15 Claims, No Drawings 5, 183,815 1 2 amino or hydroxyl moiety, which linkage can hy NOVEL BONE ACTING AGENTS drolyze in the human body in the vicinity of bone This is a continuation of application Ser. No. to release steroidal hormone A, and pharmaceuti 07/644,178, filed on Jan. 22, 1991, now abandoned. 5 cally acceptable salts or esters thereof. Further provided is a compound of the formula: BACKGROUND OF THE INVENTION 1. Field of the Invention I The present invention relates to novel substituted OH: amino or hydroxy alkyl-1,1-bisphosphonic acid com O O-C-Y-(CH2)-C-R2 pounds, processes for their preparation, pharmaceutical CH3 compositions containing them, and methods for their PO3H2 use as bone-affinity agents for delivering bone resorp tion or formation active drugs directly to the bone tar get site. 15 2. Brief Description of Disclosures in the Art It is known that certain compounds exhibit an affinity for bone. In this context, an affinity for bone relates to HO the ability of the compound to bind to mineralized bone matrix with a tendency to accumulate in bone and to where bind into the crystalline apatite structure. Tetracyclines, 20 X is O, S; polymalonates and diphosphonates are representative Y is NH, O, NRI, wherein R1 is H or C1-C4 alkyl; compounds known to have an affinity for bone. n is 1-4; See, for example, U.S. Pat. No. 4,705,651 (assigned to R2 is H, OH, Gentili) and U.S. Pat. No. 4,922,007 (assigned to Merck 25 and pharmaceutically acceptable salts or thereof. & Co. Inc.) which disclose the bone affinity agent, 4 amino-1-hydroxybutylidene-1,1-bisphosphonic acid and Also provided is a compound of the formula: processes for its production. It has previously been proposed to join a bone-seek O I ing agent, such as tetracyline, to a carbonic anhydrase CH3 inhibitor through a bridging agent to provide com 30 pounds for the treatment or prophylaxis of degenerative CH3 bone diseases. See EP 201,057 (published Nov. 12, 1986). Further, it is taught in Fujisawa's JO 2104-593A to OH. link a hormone, e.g., calcitonin or insulin-like growth 35 R-i-CH)-yeo h factor to an amino methylene bisphosphonic acid. PO3H2 However, it is not taught or suggested in either refer- - ence that a hydroxyl containing steroidal hormone, where such as 17-beta estradiol, norethandrolone, androster one, norethindrone, or nandrolone, can be linked to an 40 X is O, S; amino or hydroxy alkylidene bisphosphonic acid to Y is NH, O, NRI, wherein R1 is H or C1-C4-alkyl; produce an agent effective in treating bone disorders. n is 1-4; R2 is H, OH: SUMMARY OF THE INVENTION and pharmaceutically acceptable salts thereof. The present invention is based on discoveries related 45 Furthermore, there is provided a compound of the to the greater relative bone affinities of 1,1-bisphos formula: phonates versus polymalonates described in the art. We have found that compounds having a hydroxyl contain ing steroidal hormone, which are linked through the I hydroxyl to an amino or hydroxyl alkyl-1,1-bisphos 50 OH: phonic acid, through the respective amino or hydroxyl O-C-Y-(CH2)-C-R2 group, via a carbanate or carbonate type linkage, have CH3 an affinity for bone, where hydrolysis of the linkage PO3H2 occurs to liberate the steroidal hormone which can then H exhibit a localized therapeutic effect on bone. 55 By this invention there is provided compounds of the formula: O 60 where wherein: X is O, S; A is a residue of a hydroxyl containing steroidal hor mone possessing human bone resorption antagonist Y is NH, O, NR, wherein R1 is H or C1-C4-alkyl; activity or bone formation stimulatory activity; n is 1-4; C is a residue of an amino or hydroxy alkyl-1,1-bis 65 R2 is H, OH: phosphonate, possessing human bone affinity; and and pharmaceutically acceptable salts thereof. B is a covalent linkage, connecting A through the Additionally there is provided a compound being of hydroxyl moiety and C through the respective the formula: 3 5,183,815 4. -continued oh, V O II O-C-Y-(CH2)-C-R2 CH3 CH -C=CH PO3H2 5 CH3 H oh, O 10 R2-r- f (CH2) -v-n-y CO H PO3H2 where III X is O, S; X PO3H2 Y is NH, O, NR, wherein R is H or C-C-alkyl, 1s o-l-y-CH)--R n is 1-4; ls-C=CH R2 is H, OH: as PO3H2 and pharmaceutically acceptable salts thereof. Also being provided are intermediates useful for pro ducing the compounds of formula I, of the following 20 formulas; o O V V I 25 oh, -OR). CH -e-Y-CH2--R NEC-a-CH2CH2CH2 2 g 3 PO3H2 P-(OR3)2 H 30 a. O VI -OR), 35 where H2N-CH2CHCH-CH X is OS; Y is NH, O, NR1, wherein R1 is H or C1-C4 alkyl; -OR). n is 1-4; O R2 is H, OH: and pharmaceutically acceptable salts or esters thereof. wherein R3 is linear/branched C1-C4 alkyl. In the main embodiment of the invention, the bone Also provided is a pharmaceutical composition affinity properties of the alkyl-1,1-bisphosphonic acid which comprises a compound described above and a portion of the compound of formulas I-IV can be ad pharmaceutically acceptable carrier. vantageously used as a drug delivery agent. Application Further provided is a method for treating bone dis 45 of 1,1-bisphosphonic acids as drug delivery agents re sults in use of reduced amounts of the bone resorption eases in a human host which comprises administering to or formation active drugs, thus lowering toxicity and said host a therapeutically effective amount of a com other unwanted side effects related to these drugs. pound described above. The steroid drugs or agents which modulate bone BRIEF DESCRIPTION OF THE INVENTION 50 resorption or stimulate bone formation in this invention AND PREFERRED EMBOOMENTS may be drugs which act as either bone resorption inhib iting or bone formation stimulating agents such as bone The scope of the compounds of the present invention active steroids. Representative examples of hydroxy is defined above by the formula A-B-C and includes containing steroidal hormones known in the art inclose those characterized by the following structural formu 55 those listed in the MERCK INDEX, Eleventh Edition lae: (1989) as follows (the therapeutic category and respec tive compound number are given for each): ANABOLC 60 Androisoxazole, 667 Androstenediol, 670 Bolandiol, 1325 Bolasterone, 1326 Clostebol, 2409 65 Ethylestrenol, 3761 Formyldienolone, 4161 HO 4-Hydroxy-9-nortestosterone, 4768 Methandrio, 5861 5, 183,815 6 Methenolone, 5887 Fluocinolone Acetonide, 4076 Methyltrienolone, 6049 Fluocinonide, 4077 Nandrolone, 6280 Fluocortin Butyl, 4078 Norbolethone, 6603 Fluocortolone, 4079 Oxymesterone, 698 5 Fluorometholone, 4104 Stenbolone, 8763 Fluperolone Acetate, 4115 Trenbolone, 9499 Fluprednidene Acetate, 4118 Fluprednisolone, 4119 ANDROGEN Flurandrenolide, 4122 Boldenone, 1327 10 Formocortal, 4156 Fluoxymesterone, 41 13 Halcinonide, 4504 Mestanolone, 5816 Halometasone, 4510 Mesterolone, 5817 Halopredone Acetate, 4512 Methandrostenolone,