Substituted 3-phenanthridinone derivatives as 5-alpha-reductase inhibitors

United States Patent     5,621,104

Graham, et al.     Apr. 15, 1997

Useful in the prevention and treatment of hyper-androgenic disorders.

 

Inventors:

Donald W. Graham, William K. Hagmann

 

Assignee:

Merck & Co., Inc. (Rahway, NJ).

Appl. No:

522,350

 

Filed:

Sept. 5, 1995

 

Related U.S. Application Data:

Continuation of (including streamline cont.) Ser. No. 36,645, Mar. 24, 1993, abandoned.

Intl. Cl.: C07D 221/12, C07D 401/12

Current U.S. Cl.: 546/108; 514/298; 546/109

Field of Search: 546/108, 109; 514/298

 

Abstract:

The present invention provides for the preparation of compounds,namely, 3-phenanthridiNones and their derivatives and their unique ability to inhibit 5-alpha-reductase or their isozymes thereof in mammals enabling said compounds for treating hyperandrogenic conditions of acne, androgenicalopecia, male pattern baldness,female hirsutism,benign prostatic hyperplasia, prostatitis and prostatic cancer.

1 Claim, No Drawings

References Cited:

U.S. Patent Documents

2,227,876      Jan., 1941      Bolt      546/77

3,239,417      Mar., 1966      Ditullio et al.      514/284

3,264,301      Aug., 1966      Doorenboos et al.      546/77

3,285,918      Nov., 1966      Doorenboos et al.      544/245

3,567,733      Mar., 1971      Nomine et al.      546/79

4,220,775      Sept., 1980      Rasmusson et al.      546/77

4,317,817      Mar., 1982      Blohm et al.      514/150

4,377,584      Mar., 1983      Rasmusson et al.      514/284

4,596,812      Jun., 1986      Chidsey, III et al.      514/256

4,732,897      Mar., 1988      Cainelli et al.      514/228.2

4,760,071      Jul., 1988      Rasmusson et al.      514/284

4,845,104      Jul., 1989      Carlin et al.      514/284

4,859,681      Aug., 1989      Rasmusson et al.      514/284

4,882,319      Nov., 1989      Holt et al.      514/119

4,910,226      Mar., 1990      Holt et al.      514/573

5,247,091      Sept., 1993      Mueller-Lehar      546/105

Foreign Patent Documents

970692      Jul., 1975      CA

0004949      Oct., 1979      EP

0155096      Sept., 1985      EP

0200859      Nov., 1986      EP

0277002      Jun., 1988      EP

0289327      Nov., 1988      EP

0314199      May, 1989      EP

0343954      Nov., 1989      EP

0375344      Jun., 1990      EP

0375345      Jun., 1990      EP

0375347      Jun., 1990      EP

0375349      Jun., 1990      EP

1465544      Nov., 1965      FR

WO91/12261      Aug., 1991      WO

Other References

Campbell et al., Syn. Commun. (1979), vol. 9, pp. 471-476, “A Novel Synthesis . . . : An Intermediate Useful in Terpene Synthesis”.

Vila et al., Tet. Letters (1989), vol. 45, pp. 4951-4960, “Conformational Analysis of the 4a-Methyl Octahydrophenanthrene System”.

Iida et al., Heterocycles (1983), vol. 20, pp.227-230, “A New Synthesis of Phenanthridine Derivatives”.

Schultz et al., J. Am. Chem. Soc. (1978), vol. 100, pp. 2140-2149, “Heteroatom Directed Photoarylation. Synthetic Potential of the Heteroatom Sulfur”.

Neri et al., Endo. (1972), vol. 91, No. 2, pp. 427-437, “A Biological Profile of a Non-steroidal Antiandrogen, SCH 13521 . . . “.

Nayfeh et al., Steroids, vol. 14 (1969), pp. 269-283, “Metabolism of Progesterone by Rat Testicular Homogenates-III”.

Voight et al., Endo., vol. 92 (1973), p.1216, “The Antiandrogenic Action of 4-Androsten-3-one-17beta-Carboxylic Acid and its Methyl Ester on Hamster Flank Organ”.

Doorenbos et al., J. Pharm. Sci., vol. 62, No. 4 (1973), pp. 638-640, “Synthesis & Antimicrobial Properties of 17Beta-Isopentyloxy-4-Aza-5 Alpha-Androstane and the 4-Methyl Derivative”.

Doorenbos et al., J. Pharm. Sci., vol. 60, No. 8 (1971), pp. 1234-1235, “4,17 Alpha-Dimethyl-4-Aza-5 Alpha-Androstan-17 beta-ol Acetate & Related Azasteroids”.

Doorenbos et al., J. Pharm. Sci., vol. 63, No. 4 (1974), pp. 620-622, “Synthesis & Evaluation of Antimicrobial Properties of Amidinoazaandrostanes and Guanidinoazaandrostanes”.

Rasmusson et al., J. Med. Chem., vol. 29, No.11 (1986), pp. 2298-3115, “Aza Steroids: Structure-Activity Relationships . . . “.

Brooks et al., Prostate, vol. 9, No. 1 (1986), pp. 65-75, “Prostatic Effects Induced in Dogs by . . . 5 alpha-Reductase Inhibitors”.

Brooks et al., Steroids, vol. 47, No. 1 (1986), pp. 1-19, “5 Alpha-Reductase Inhibitory . . . Activities of Some 4-Aza-Steroids in the Rat”.

Liang et al., Endo., vol. 117, No. 2, (1986), pp. 571-579, “Species Differences in Prostatic Steroidal 5 Alpha-Reductases of Rat, Dog and Human”.

Rasmusson et al., J. Med. Chem., vol. 27, No. 12 (1984), pp. 1690-1701, “Azasteroids as Inhibitors of Rat Prostatic 5 Alpha-Reductase”.

Back et al., J. Org. Chem, vol. 46, No. 7 (1981), pp. 1442-1446, “N-Chloroazasteroids . . . “.

Liang et al., Chem. Abstracts, vol. 95, 109055j, “Inhibition of 5-Alpha-Receptor Binding . . . by a 4-Methyl-4-Aza-Steroid” (1985).

Kadohama et al., JNCL, vol. 74, No. 2 (Feb. 1985), pp. 475-481, “Retardation of Prostate Tumor Progression in the Noble Rat by 4-Methyl-4-Aza-Steroidal Inhibitors of 5 Alpha-Reductase”.

Andriole et al., The Prostate, vol. 10 (1987), pp. 189-197, “The Effect of 4MA . . . on the Growth of . . . Human Tumors . . . “.

Bingham et al., J. Endocr., vol. 57 (1973), pp. 111-121, “The Metabolism of Testosterone by Human Male Scalp Skin”.

Kedderis et al., Toxicol. Appl. Pharmacol., vol. 103 (1990), pp. 222-227, “Studies with Nitrogen-Containing Steroids . . . “.

Metcalf et al., Bioinorganic Chemistry, vol. 17 (1986), pp. 372-376, “Patent Inhibition of Human Steroid . . . by 3-Androstene-3-Carboxylic Acid”.

Levy et al., Biochemistry, vol. 29 (1990), pp. 2815-2824, “Inhibition of Rat Liver Steroid 5 Alpha-Reductase . . . “.

Holt et al., J. Med. Chem., vol. 33 (1990), pp. 943-950, “Steroidal A Ring Carboxylic Acids . . . “.

Levy et al., J. Steroid Biochem., vol. 34, No. 1-6 (1989), pp. 571-575, “Interaction Between Rat Prostatic 5 Alpha-Reductase . . . “.

Holt et al., J. Med. Chem., vol. 33 (1990), pp. 937-942, “Steroidal A Ring Aryl Carboxylic Acids . . . “.

Metcalf et al., TIPS (Dec. 1989), vol. 10, pp. 491-495, “Inhibitors of . . . 5 Alpha-Reductase in Benign Prostatic Hyperplasia . . . “.

Murphy et al., Steroids, vol. 35, No. 3 (Mar. 1980), pp. 1-7, “Effect of Estradiol on a . . . Binding Protein in the Uterus of the Mouse”.

Stone et al., Prostate, vol. 9 (1986), pp. 311-318, “Estrogen Formation in Human Prostatic Tissue . . . “.

Brooks et al., Steroids, vol. 47, No. 1 (1986), pp. 1-19, “5 Alpha-Reductase Inhibitory . . . Activities of Some 4-Azasteroids . . . “.

Labrie et al., Lancet, No. 8515 (1986), pp. 1095-1096, “Combination Therapy in Prostate Cancer”.

Rittmaster et al., J. Clin. Endocrin & Metab., vol. 55, No. 1 (1987), pp. 188-193, “The Effects of . . . a 5 Alpha-Reductase Inhibitor . . . “.

Diani et al., J. Clin. Endoc. & Metab., vol. 74, No. 2 (1990), pp. 345-350, “Hair Growth Effects of Oral Administration of Finasteride . . . “.

Bruchovsky et al., J. Clin. Endoc. Metab., vol. 67, No. 4 (1988), pp. 808-816, “Kinetic Parameters of 5 Alpha-Reductase Activity in Stroma & Epithelium of Normal, Hyperplastic & Carcinomatous Human Prostates”.

Hudson, J. Steroid Biochem., vol. 26, No. 3 (1987), pp. 349-353, “Comparison of Nuclear 5 Alpha-Reductase Activities in the Stromal and Epithelial Fractions of Human Prostatic Tissue”.

Moore et al., J. Biol. Chem., vol. 251, No. 19 (1976), pp. 5895-5900, “Steroid 5 Alpha-Reductase in Cultured Human Fibroblasts”.

Andersson et al., J. Biol. Chem., vol. 264, No. 27 (1989), pp. 16249-16255, “Expession Cloning & Regulation of Steroid 5 Alpha-Reductase, an Enzyme Essential for Male Sexual Differentiation”.

Andersson et al., Proc. Nat’l Acad. Science, vol. 87 (1990), pp. 3640-3644, “Structural & Biochemical Properties of Cloned and Expressed Human and Rat Steroid 5 Alpha-Reductases”.

Andersson et al., Nature, vol. 354 (Nov. 14, 1991), pp. 159-161, “Deletion of Steroid 5 Alpha-Reductase-2 Gene in Male Pseudohermaphroditism”.

Wilson, Biol. of Reproduction, vol. 46 (1992), pp. 168-173, “Syndromes of Androgen Resistance”.

Geldolf et al., Eur. J. Cancer, vol. 26, No. 2 (1990), pp. 188, “Enzyme Inhibitors in Hormone Dependent Prostate Cancer Growth”.

Geldolf et al., J. Cancer Res. Clin. Oncol., vol. 118 (1992), pp. 50-55, “Consideration of the Use of . . . 4MA . . . in Prostate Cancer Research”.

Brooks et al., The Prostate, vol. 18 (1991), pp. 215-227, “Effect of Castration, DES, Flutamide, and MK-906 on Growth of the Dunning Rat Prostatic Carcinoma”.

Jones et al., J. Med. Chem., vol. 36 (1993), pp. 421-423, “Nonsteroidal Inhibitors of Human Type 1 Steroid 5alpha-Reductase”.

Masubuchi et al., Eur. J. Pharm., vol. 183, No. 5 (1990), p. 1757, “Lack of DHT Inhibition . . . by Treatment of 4MA . . . “.
Primary Examiner: Rotman; Alan L.
Assistant Examiner: Rotman; A.
Attorney, Agent or Firm: Fitch; Catherine D., Winokur; Melvin