||||||III US005578599A United States Patent (19) 11 Patent Number: 5,578,599 Diani et al. (45) Date of Patent: Nov. 26, 1996 54). STIMULATION OF HAIR GROWTH WITH 5,026,691 6/1991 Kligman et al. ........................ 514/171 NNE AND A SOREDUCTASE FOREIGN PATENT DOCUMENTS 0285382A2 10/1988 European Pat. Off. ....... A61K 31/58 T5 Inventors: Arthur R. Diani, Mattawan; Allen E. 3615396A 11/1987 Germany ....................... A61K 07/06 Buhl; Heinrich J. Schostarez, both of 1305017A 12/1989 Japan ....... ... A61K 07/06 Portage, all of Mich. WO87/00427 1/1987 WIPO ............................ A16K 07/06 73) Assignee: The Upjohn Company, Kalamazoo, Primary Examiner-Marianne M. Cintins Mich. Assistant Examiner-M. Moezie Attorney, Agent, or Firm-Donald L. Corneglio 22 Filed: Jan. 20, 1995 An improved method and composition for promoting hair growth in mammals for treating various forms of alopecia or Related U.S. Application Data male pattern baldness comprising the concomitant adminis 63 continuation of set No. 9451, filed as PCTus91.05170, ration of potassium channel openers, such asninoxidl, Jul. 29, 1991, abandoned, which is a continuation of Ser. No. cromakalim, pinacidil, or a compound selected frown the 565,777, Aug. 10, 1990, abandoned. classes of s-triazine, thiane-1-oxide, benzopyran and pyri dinopyran compounds; and a 50-reductase inhibitors, 173 51) Int. Cl.6 ......................... A61K 31/505; Alk 31/44 (N-tert-butylcarbamoyl)-4-aza-5-O-androst-1-en-3-one. The (52) U.S. Cl. ............................................. 514/275; 514/284 method comprises administering an effective amount of the 58) Field of Search ...................................... 514/284, 275 potassium channel opener and administering an effective O amount of the 173-(N-tert-butylcarbamoyl)-4-aza-5-O-an 56) References Cited drost-1-en-3-one whereby the promotion of hair growth is U.S. PATENT DOCUMENTS increase over the sole administration of the potassium chan nel opener. 4,139,619 2/1979 Chidsey, III .............................. 424/45 4,596,812 6/1986 Chidsey, III et al. .. ... 54/256 4,684,635 8/1987 Orentreich et al. ..................... 514/170 4 Claims, No Drawings 5,578,599 1 2 STIMULATION OF HAIR GROWTH WITH 50-reductase inhibitors. Androgen receptor blockers inter MINOXOL AND A SO-REDUCTASE fere with the binding of androgens, testosterone and dihy INHIBITOR drotestosterone (DHT), to their receptors, while 50-reduc tase inhibitors prevent the conversion of testosterone into DHT. The clinical use of androgen blockers, such as cypro CROSS-REFERENCE TO RELATED terone acetate, in men is complicated with systemic effects APPLICATIONS on normal sexual function. This is not the case in women, where these agents are utilized. Burke, B.M., Cunliff, W.J., This application is a continuation of U.S. Ser. No. 08/009, Br. J. Dermatol., 112, 124 (1985); Dawber, R. P. R., Sonnex, 451, filed 27 Jan. 1993, abandoned; which was a continua T., Ralfs, I., Br. J. Dermatol, Suppl. 107, 20 (1982). The tion of International Patent Application No. PCT/US91/ 10 other class of antiandrogens are the 5o-reductase inhibitors. 05170, filed 29 Jul. 1991; which was a continuation of U.S. These compounds block action of 5o-reductase and thus Ser. No. 07/565,777, filed 10 Aug. 1990, abandoned. reduce the level of DHT in the peripheral tissue. Rittmaster, BACKGROUND OF THE INVENTION R. S, Stoner, E., Thompson, D. L., Nance, D., Lasseter, K. The present invention relates to improved methods and C., J. Androl., 10, 259 (1989). Brooks, J. R., Berman, C., compositions for promoting hair growth by the concomitant 15 Primka, R. L., Reynolds, G. F., Rasmusson, G. H., Steroids, administration of a potassium channel opener such as 47, 1 (1986). Rittmaster, R. S., Uno, H., Povar, M. L., J. minoxidil, cromakalim, pinacidil, or a compound selected Clin, Endocrinol. Metab., 65, 188 (1987) have shown that from the classes of potassium channel openers such as topical treatment of periadolescent stumptail macaque mon S-triazine derivatives, benzopyran derivatives, pyridinopy eys with the 50-reductase inhibitor 4-MA prevented the ran derivatives and thiane-1-oxide compounds; and a 5o-re 20 progression of baldness normally observed in this species. ductase inhibitors, 173-(N-tert-butylcarbamoyl)-4-aza-5-o- Similar studies in humans have not been reported. androst-1-en-3-one. The coupling of hair growth stimulation with potassium Since the discovery that minoxidil could promote hair channel activation has been inferred from literature reports growth and was useful in the treatment of androgenetic 25 of several vasodilators, minoxidil (through its metabolite alopecia commonly known as "male pattern baldness' (U.S. minoxidil sulfate), pinacidil, and diazoxide, which cause Pat. Nos. 4,596,812; 4,139,619), alopecia areata, and bald varying degrees of hypertrichosis upon oral administration. ing in females, effort has been directed toward attempts to Zins, G. R., Clin. Dermatoll, 6, 132 (1988); Goldberg, M.R., improve upon the sole use of a topical minoxidil composi J. Cardiovasc. Pharmacol., 12(Suppl. 2), S41 (1988); Okun, tion by incorporating other active ingredients, for example 30 R., Russell, R. P., Wilkson, W. R., Arch Inter. Meal., 112, the combinations of minoxidil/hydrocortisone and minoxi 886 (1963). It is also known in the an that topical minoxidil dil/retinoids (DE 3827467-A). is an effective treatment for andogentic alopecia. The Another approach has been to attempt to identify and mechanism by which these compounds, minoxidil (through quantify the biological mechanisms responsible for the its metabolite minoxidil sulfate), pinacidil, and diazoxide, initiating and controlling hair growth at the follicular level 35 dilate vascular smooth muscle has been reported to be via and intervening with therapeutic agents which stimulate hair the opening (activation) of potassium channels. Robertson, growth. It is well known in the an that the onset of puberty D. W., Steinberg, M. I., J. Med. Chem., 33, 1529 (1990). results in changes in endocrine levels which result in, among Thus potassium channel openers are useful in the treatment other changes, the stimulation of facial hair growth (males), of androgenetic alopecia. axillary hair growth (males and females), and pubic hair The surprising and unexpected result, and the subject of growth (males and females). One class of compounds impli this invention, is the synergistic effect observed when both cated in these effects are the androgens. 17B-(N-tert-butylcarbamoyl)-4-aza-5-o-androst-1-en-3-one Androgens appear to play a major role in the development and minoxidil, a potassium channel opener, are utilized to and progression of androgenetic alopecia (male pattem stimulate or promote hair growth in a statistically significant baldness). Rittmaster, R. S., Clin. Dermatol, 6, 122 (1988). 45 fashion when compared to each drug alone. This was demonstrated in humans, in that prepubertally INFORMATION DISCLOSURE STATEMENT castrated men do not develop male pattern baldness. Hamil ton, J. B., Am. J. Anat, 71, 451 (1942). In the skin, and Topical minoxidil has been shown to be an effective presumably in the follicle, the effector androgen is dihyr treatment for male pattern baldness as described in U.S. Pat. dotestosterone (DHT), the product of the enzymatic conver 50 Nos. 4,596,812 and 4,139,619. The utilization of 17B-(N- sion of testosterone to DHT by the enzyme 5o-reductase. tert-butylcarbamoyl)-4-aza-5-O-androst-1-en-3-one for the Ebling, F. J. Clin. Endocrinol. Metab., 15,319 (1986); Price, treatment of androgenetic alopecia has been disclosed in V. H. Arch. Dermatol., 111, 1496 (1975). Additional evi European Patent Application 285382 A2. The use of com dence for DHT's role stems from reports that men with male binations of androgen receptor blocking agent (antiandro pattern baldness have elevated 5o-reductase levels in the 55 gen) and 5o-reductase inhibitors (not 17 B-(N-tert-butylcar hair follicles and skin of the frontal scalp and that men with bamoyl)-4-aza-5-O-androst-1-en-3-one) has been disclosed a 50-reductase deficiency do not develop male pattern in U.S. Pat. No. 4,684,635. The combination of minoxidil baldness. Bingham, K. D., Shaw, D. A., J. Endocrinol, 57, and an androgen receptor blocking agent for the treatment of 111 (1973); Schweikert, H. U., Wilson, J. D., J. Clin. male pattern baldness has also been disclosed in Patent Endocrinol. Metab., 385, 811 (1974). Antiandrogen therapy 60 Applications DE 3615-396-A and WO 8700-427-A. The offers a potential intervention to the treatment of male combination of minoxidil and a 50-reductase inhibitor for pattern baldness in men, and in women where it has been the treatment of male pattern baldness has also been dis suggested that elevated androgen levels are responsible for closed in Japanese Patent Application JA 1305-017-A. the appearance of male pattern baldness. Rittmaster, R. S., SUMMARY OF THE INVENTION Lofiaux, D. L., Ann. Intern. Med., 106, 95 (1987). This class 65 of compounds, the antiandrogens, have been subdivided into In one aspect, the subject invention is directed toward an two major catagories, the androgen receptor blockers and the improved method for promoting hair growth in mammals 5,578,599 3 4 comprising the administration of a potassium channel et al., J. Org. Chem, 40,3304 (1975). Related compounds opener in an effective amount and the administration of are sulfoxypyrimidinium, -pyridinium, and -triazinium 173-(N-tert-butylcarbamoyl)-4-aza-5-O-androst-1-en-3-one which are described in U.S. Pat. No. 4,287,338 herein in an effective amount whereby hair growth is increased over incorporated by reference. Hereinafter, the term "minoxidil' the sole administration of the potassium channel opener. The means any of the various forms of 6-amino-1,2-dihydro routes of administration for either component can be by any hydroxy-2-imino-4-pipefidinopyrimidine, derivatives and of various means, preferably orally, topically or any com analogs thereof.