PT95704A - Process for the preparation of 17&beta-acyl-4-aza-5&alpha- androst-1-en-3-ones which are useful as 5&alpha-reductase inhibitors - Google Patents

Abstract

The present invention relates to a process for the preparation of 17β-acyl-4-aza-5α-androst-1-en-3- ones of the formula: <IMAGE> in which R is selected from hydrogen, methyl and ethyl and R3 is cycloalkyl of 4 to 8 carbon atoms. Said process involves starting from the steroid ester of the formula: <IMAGE> 17β-(carbomethoxy)-4-aza-5α-androstan-3-one, in which R', R'' and R''' are hydrogen, and performing the following steps: (1) dehydrogenation of said starting material in order to produce the corresponding compound containing a double bond in position 1,2 of the ring A; (2) conversion of the 17-carbomethoxy substituent into the 17β-acyl substituent; and, if desired, (3) alkylation of the nitrogen ring A in order to introduce the substituents 4-methyl and 4-ethyl into ring A. The pharmaceutical formulations of the aforesaid compounds are active as testerone 5α-reductase inhibitors and are thus useful for the treatment of acne, seborrhoea, hirsutism in women, androgenetic alopecia, prostate carcinoma and benign prostatic hyperplasia.

Description

CROSS REFERENCE TO FACTORY REQUESTS

This patent application is a continuation in part of US Serial No. 363,567, filed June 8, 1989, which is a continuation in part of US Serial No. 129 335, filed December 3, 1987, pending, which in turn is a continuation in part of US Serial No. 624, filed November 21, 1985, now abandoned, which is hereby incorporated by reference. in turn a continuation in part of US Serial No. 'No' 584 061, filed February 27, 1984, now abamdonado *

BACKGROUND OF THE INVENTION The present invention relates to novel 17β-acyl-4-aza-5Î ± -androst-1-en-3-one compounds and to the use of such compounds as testosterone-5β-reductase inhibitors.

Description of the Antenor Technique It is well known in the art that certain undesirable physiological manifestations, such as acne vulgaris, seborrhoea, hirsutism of the female, and male pattern baldness and benign prostatic hypertrophy are α resulting from hyperandrogenic stimulation caused by excessive accumulation of testosterone or analogous androgenic hormones in the metabolic system. Initial attempts to provide a chemotherapeutic agent to address the undesirable effects of hyperandrogenicity have led to the discovery of various steroidal steroids having undesirable hormonal activities themselves. Estrogens, for example,

D example, not only against attack the effect of androgens but also has a feminizing effect. Non-steroidal anti-steroids have also been developed, such as, for example,

Endo., Vol. 91, Vol. 2 (1972). However, these products, although without hormonal effects, are peripherally active, competing with the natural androgens for the receptor sites, and thus have a tendency to feminize a male host or the male fetus of a host female.

More recently it has become known in the art that the main mediator of androgenic activity in some target organs is &amp; 5'-hydrotestosterone, which is formed locally in the target organ by the action of testosterone-5α-reductase. It has therefore been postulated and demonstrated that inhidroids of testerone-5 &lt; a-reductase will serve to prevent or lessen the symptoms of hyperandrogenic stimulation. Nayfeh et al., Steroids, 4, 269 &lt; 199) have been shown to inhibit 4-androsten-3-one-17β-methyl ester. a testosterone-S-reductase inhibitor. ft follow

Voigt and Hsia, Endocrinol. 92, 1216 (19/3), Canadian Pat 970,692, have shown that the foregoing ester and parent acid, 4-androsten-3-one-17β-carbocyclic acid are active inhibitors of testosterone-β-reductase in vitro.

»S * 4d. They both further demonstrated that topical application of both testosterone and 5'-dihydrotestosterone caused the enlargement of the hamster's flank organ &quot; female, or androgen-dependent sebaceous structure. However, concomitant administration of 4-androsten-3-one-17β-carboxylic acid or its methyl ester inhibits the response caused by testosterone but does not inhibit the response caused by 5α-dihydrotestosterone. These results were interpreted as indicating that the compounds were antiandrogenic by virtue of their ability to inhibit testosterone-5α-reductase. A number of 4-α-steroid compounds are known. See, for example, U.S. Pat. 2 227 876? 3,239,417? 3,264,301; &amp; 3,285,918? U.S. Pat. Doorenbos and Bolomons, J, Fharm, Sci, 62, 4, ρρ = 638-640 (1973)? Doorenbos and Broun, J. Fharm. Sci, 6-Q, 8, pp. 1234-1235 (1971); and Doorenbos and Kim, J., Fharm, Sci, 63, 4, pp. 62, 622 (1974),

In addition, U.S. Patents 4,377,584 and 4,217,754 to Rasmusson et al. Describe a group of 4-aza-5Î ± -17H-substituted-5Î ± -androsten-3-ones which are useful in the treatment of hyperandrogenic conditions However, none of the foregoing references suggests that any of the novel 17β-1,4Î ± -aza-5Î ± -androst-1-en-3-ones of the present invention will have utility as highly potent inhibitors of testosterone- reductase »

The present invention relates to novel 17B-acyl-4-aza-5a-androst-1-en-3-one compounds, processes for their preparation, pharmaceutical formulations comprising the novel compounds as active ingredients and methods of inhibition The present invention relates to novel 17β-acyl-4-aza-5α-androst-1-en-3-one compounds of the formula ?

0. p2 <5 · x ® c

wherein R is selected from hydrogen, methyl and ethyl; and ··? R é is a monovalent radical selected from straight or branched chain alkyl having 1-12 carbon atoms, or monocyclic aryl optionally containing one or more substituents; lower alkyl of 1-2 carbon atoms and / or 1 or 2; more halo (Cl or Br) substituents, aralkyl selected from benzyl are phenethyl and heterocyclyl selected from 2- or 4-pyridyl, 2-pyrrolyl, 2-furyl or thiophenyl at R ', R &quot; and R !! ' are each selected from hydrogen and methyl.

A preferred embodiment of the novel compounds of our invention is represented by the formula &quot; (i.e.

R is hydrogen, methyl or ethyl, s

 € ƒâ € ƒâ € ƒF1 is branched chain alkyl, or cycloalkyl of 4-8, carbuno. c 1 tten

Representative compounds of the present invention are listed below in the following examples: - (t-butylcarbonyl) -4-aza-4-methyl-5Î ± -androst-1-en-3-

J 17β- &lt; isobutylcarbamoyl) -4-aza-4-methyl-1-aza-androst-1-en-3-one (B) -cyclohexanecarboxylate 4-methyl-1-propen-1-en-3-one a. ^ 1713- < 4-methyl-5Î ± -androst-3-one â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ17β- (1,1-Diethylbutylcarbonyl) -4- 17β-Neopentylcarbonyl) -4-aza-4-methyl-5α-androst-1-en-3-one =

(Tert-butoxycarbonyl) -4-aza-4-methyl-5Î ± -androst-1-ene-3-ones 1Î ± - (5-butylcarbonyl) -4- With the corresponding compounds in which the 4-methyl substituent is substituted in each of the above compounds by a hydrogen radical or by a radical.

Also included as representative compounds are any of the aforementioned compounds having the alkyl of the alkyl carbonyl substituent substituted by a methyl, ethyl, propyl-s-propyl, butyl-phenyl, 2-, 3- or 4-substituent 2-β-dichloro- or a 2,6-dibromophenyl carbonyl substituent or a heterocyclic substituent selected from 2 or 4-p-2-pyrrolyl, 2-bromophenyl- furyl or 2-thiophenyl)

Additional representative compounds are 170 - (cyclobutylcarbonyl) -? - aza-S-androst-1-en-4-one;

4-azas-5α-androst-1-en- 4-aza-5Î ± -androst-1-ol-17β- (cycloheptyl) carbonyl-4-aza-b-androst-6β- (4-azabicyclo [4.4.0] octane-4-az-5a-androst-1-ene) and the above compounds wherein the substituent is replaced by a 4-methyl-4 - [[

The novel compounds of the invention are prepared by a known route of the formulas of the present invention.

H 1 / S- (carbamoyloxy) -4-aza-5α-anthracen-cv-one

which comprises the steps (i) of dehydrogenating said starting material to produce the corresponding compound containing a double bond in the. ring position A, 12> conversion of the 17-carbomethoxy substituent into the 17B-acyl substituent and, if desired &lt; 3 &gt; alkylation of the ring A nitrogen to. introducing the 4-methyl or 4-ethyl substituents on ring A * In carrying out the process of the present invention, it is essential that the dehydrogenation step (1) of the 1,2-position of the ring A steroid is carried out using a 4-aβ-5Î ± -androst-3-one compound having no substituents other than hydrogen attached to the nitrogen of ring A. Step (2) may consist of one or more chemical steps and if it is can take place before step Π.) or after step & &gt; or step C3K

According to the process of the present invention, the products of our invention are formed by the heating of the compound III 17β-acyloxycarbonyl-4-aza-5Î ± -androstan-3-one with a dehydrogenating agent such as anhydride (2) is reacted in chlorobenzene at reflux to form a 17β-alkoxycarbonyl-4-aza-5Î ± -androst-3β-en-3-one (ΣV), (2) 5a-androst-1-en-3-one formed in step (1) with sodium hydride and anhydrous conditions in an n-aural solvent such as dimethylformamide, (2) the resulting reagent mixture is contacted with a methyl or ethyl alkyl) to form the corresponding 17β-cycloalkyl-4-aza-4-aza-5α-androst-1-en-3-one with a strong base such as aqueous methanolic potassium hydroxide at the reflux temperature, followed by acidification and isolation of the resulting steroidal acid, 70-carboxy-4-alkyl-4-aza-5a-an-dost-1-en-3-one (VI), (4) followed by refe 2-thiopyridyl ester was prepared by refluxing with triphenylphosphine and 2,2'-dipyridyl disulfide in an inert solvent and the 17Râ € ²-pyridylthiacarbonyl) -4-akyl-4-aza-5α- androst-3-one (VII) by chromatography on silica, 5 g. the pyridylthio ester 9b is then reacted with a compound R1-Li or RTigX (X = Cl, Br) such as sec-butylmagnesium chloride in tetrahydrofuran to give the desired product 17β- (4-methoxy-4-azabicyclo [2.2.1] oct-3-one (VIII) which is isolated by silica gel chromatography. When the above reaction is carried out using a compound of the formula R 1 MgX or a R 1 -L instead of sec-butylmagnesium chloride, the corresponding 17β- (acyl) -4-alkyl- 4-aza-5Î ± -androst-1-en-3-one wherein the acyl is Râ, " carbonyl "

According to the process of our invention, the corresponding 17β-acyl-4-as-5Î ± -androst-1-en-3-one is readily prepared from 4β- (4-alkoxycarbonyl) -4 "aza-5Î ± -androsten -3-one (IV) by repeating the above series of reaction steps but omitting step 2 above, i.e., the treatment of 4-aza-5α-androst-1-en-3-one with sodium iodide followed by methyl or ethyl iodide. X,; ' The* - .

According to a further alternative process of preparation of the compounds of our invention having only hydrogen as the single substituent on ring A nitrogen, the double bond A 'in ring A is introduced in the last step of the process. (III) is hydrolyzed to the corresponding steroid acid, 17β-carboxy-4-aza-5Î ± -androstenan-3-one, (IX) which , is converted to the corresponding pyridyl ester, 17B- <2-pyridylthiocarbonyl> -4-aza-5α-androstan-1-one (X) followed by treatment of the ester with a pyridine. 2 wherein R1 is as defined above to form a 17β-acyl} -4-aza-5Î ± -androstan-3-one (XI) which is dehydrogenated as previously described for. yield Compound XIV, 17Î ± - [acyl] -4-aza-5Î ± -androst-1-sn-3-one

In a further alternative process for the manufacture of compounds of formula I and II, when the starting material is an ester, e.g. In particular the methyl ester as shown in formula III-V of the scheme, reaction with a Brignard reagent gives the corresponding ketone associated with the Brignard reagent. The methyl 16 derivative wherein R1 is methyl is prepared from 4-aza-5Î ± -androstan-3-ones, e.g., 4β, 16β-dimethyl-17β-acetyl-4-aza-5Î ± -androst- 3-one by the known dehydrogenation procedures for the 4-methyl-4-aza compounds to give 4,4apos; -dimethyl-17β-acetyl-4-aza-5Î ± -androst-1-en-3 -one said

The foregoing reactions are schematically represented in the following structural scheme

X &amp; 2-pyridylthio. wherein X is a 2-pyridylthio substituent and is defined as

The compounds of the present invention prepared according to the above-described method are potent anti-androgens by virtue of their ability to specifically inhibit testosterone-S-reductase.

Accordingly, the present invention relates in particular to the provision of a method of treating hyperandrogenic conditions of acne vulgaris, breasts, and hirsutism of the female by topical administration, and a method of treating all of the above conditions as well as benign prostatic hypertrophy by the parenteral administration of the novel compounds of the present invention. The present invention thus also relates to the provision of appropriate topical and parenteral pharmaceutical formulations for use in novel methods of treatment of the present invention, the compounds of the present for use in the treatment in

The compositions containing the invention as the active ingredient, benign prostatic hypertrophy, may be administered in a wide variety of therapeutic dosage forms in conventional carriers for systemic administration, such as, for example, by oral administration in the form of tablets, capsules, solutions, or suspensions, or by intravenous injection. The daily dosage of the products may vary over a wide range of 5Θ to 2ΦΘΘ mg. Preferably the compositions are supplied in the form of 5,12,25,25, ;? 15, 250, and 50 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the drug to be treated. An effective amount of the drug is usually provided at a dosage level of about 5, mg to about 5 mg / kg body weight per day. Preferably the gamma is about 1 mg to 5 mg / kg body weight per day. These dosages are well below the toxic dose of the product Capsules containing the product of this invention may be prepared by mixing an active compound of the present invention with lactose and magnesium stearate, calcium stearate, starch, or other carriers and placing the mixture into gelatin capsules. can be prepared by mixing the active ingredient with conventional tablet ingredients such as calcium phosphate, lactose, corn starch or magnesium stearate. The liquid forms are used in suitably flavored suspending or dispersing agents s, such as natural and synthetic gums, for example, tragacanth, acacia, methylcellulose and the like. Other dispersing agents which may be employed include glycerin and the like. Suspensions or sterile solutions are desirable for parenteral administration. Isotonic preparations are generally employed which generally contain suitable preservatives when intravenous administration is desired,

For the treatment of acne vulgaris, seborrhoea, hirsutism of the female, the compounds of the present invention are admited in the pharmaceutical composition formulation comprising the active compound in combination with a pharmacologically acceptable carrier adapted for topical administration. These topical pharmaceutical compositions may be in the form of a cream, ointment, gel or aerosol formulation adapted for application to the skin. These topical pharmaceutical compositions containing the compounds of the present invention usually comprise about 0.1% to 15%, preferably about 5%, of the active compound, in admixture with about 95% of the carrier. The method of preparing the novel compounds of the present invention, already described in general terms, may be further illustrated by the following examples. EXAMPLE 1 22-Heti-4 2a-nor-Sa-chol-4-ene-5,20-dione

HA-A solution of 7.2 g of S- (2-pyridyl) -3-oxo-4a-androst-1-ene-17β-thiocarbutyrylate in 2-38 ml of tetrahydrofuran are added, at -79 ° C, 33.6 ml of 1.3M 5-butylmagnesium chloride. After 3 minutes at -78 ° C the solution returned to temperature

NaCl t. The solution was cooled to room temperature and treated with saturated aqueous product. The product was extracted into dichloromethane and washed with saturated aqueous NaCl and aqueous NaOH solution. then dried and concentrated. The residue was eluted through silica gel dichloromethanesacetone 9: 1 to provide 4.5 g of product, mp = 246-249 ° C.

When the procedure is repeated as follows, the indicated product is obtained. (2-pyridyl) -3-oxo-4-aza-5α-androstane-17α-thiocarboxylate hydrochloride The title compound was prepared from 2-pyrrolo [2,1-c] [1,4] benzoxazepin-2-yl) 8-oxo-4-methyl-5β-androst-1-ene-17β-carboxylic acid (sec -butyl) 4-aza-21-ene-5α-androstane-3,20-dione mp 134-136 ° C 8- <2-pi 3-oxo-4-methyl-4-aza-5Î ± -androstane-7-ene-7-carboxylic acid 2-pyrrolyl magnesium chloride 2-pyrrolidin-1-yl) -4-aza-2-androst-1-ol-3, -0- (i.e. 3-oxo-4-methyl-4-aza-5β-anza-7β-androstane-7β-carboxylate 23-methyl-4-aza-21-nor-5-oxo-1H-imidazo [4,3-b] 220-222 ° C: m.p. 22 ° -Hetyl-4-aza-2β-Ânaphth-5Î ± -hydroxy-3β-dione

A solution of 21 g of 22Î ± -ethyl-4-aza-21-nor-5-aza-3β-dione (Step 1) and 29.49 g of benzene seleninic anhydride in 552 ml of chlorobenzene , was refluxed with water separation for 4 hours. The mixture was concentrated and the residue redissolved in dichloromethane. After washing with 10% aqueous sodium hydroxide, then 10% hydrochloric acid and saturated aqueous sodium chloride, the solution was dried and concentrated to 45 g of yellow residue. This was chromatographed on 1.5 kg of silica gel packed in dichloromethane and eluted with ethyl acetate to give 1 6 g of the product, m.p. 248-251 ° C.

J COCHCH3

H

When the procedure is repeated using 23-methyl-4Î ± -aza-21-nor-5β-cholane-3,20-dione as the starting material, 23-methyl-4-aza-2-nor 5a-eol-1-ene-3,2-dione, mp 283-286 ° C.

EXAMPLE 3 1α-Cyclohexylcarbamoyl) -4-azabicyclo [3.3.0] hept-1-en-3-one 500 ml anhydrous THF was added rometane * the phases were bleached with charcoal; filtered and concentrated to give a residue, gua1 was crystallized from ethyl acetate to give 28.2 g of the title compound, m.p. 271.5-277 ° C. EXAMPLE 3a

, And 34.8 g of the triphenylmethyl ester were added at -65 DEG C. to 30 ml of a solution of hexane-magnesium sulfate for a period of -70 ° C 60 minutes at 1 ° C for 60 minutes. The Π x x s tur a was ometan O Θ; in 1OS; g g O 4 · * ·. '-•W! , s of di I ution. o com. 100 ml of &quot; 4 &lt; RTI ID = 0.0 &gt; (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) S. The solution is obtained by chromatography on silica gel. was the title compound of Example 3, it was also prepared by the following procedure. A mixture of 150 g of methyl 3-oxo-4-aza-5Î ± -androst-1-ene-17β-carboxylate in 2800 ml of fHF was added with stirring at less than at 0 ° C internal temperature, 678 ml of a 2 N solution in cyclohexyl magnesium chloride ether. The solution was then refluxed for 6 hours. The cooled reaction mixture (less than 10 ° C) was acidified with 10% HCl solution and extracted with dichloromethane. The organic layer was washed sequentially with water,

solution (MgSO4). Recrystallized NaOH and evaporation of the catalyst to part-NaOH and saturated NaCl solution. 163 g of cyclohexyl ether-dichloromethane / ethyl acetate were collected and dried, yielding 131 g of the pure material.

269-270 ° C a 1 c (.%) Sj fcf l Ί 3.61 3.61 C * 7 **? EXAMPLE 4 4-Amino-4-methoxy-2-oxo-1

Exemp1 η 3 with

J

When the procedure of the appropriate steps was repeated, the compound was obtained. %) Found: C 3.66% N Found: 70.07% C; 4. * 1 74.89 IU Π S, 60 9.54

(4-methoxyphenyl) -1H-indole-4-carboxylic acid (1-methanesulfonyl-phenyl) -amide; The title compound, mp 288-283 ° C, was obtained.

Ca.lc (%) Found (%) N 3.34 3.87 C 77; 71 70; 06 H 3.36 O iT * 5 Λ

J

Claims (1)

&gt; A process for the preparation of a compound of the formula; P3c Wherein R is selected from hydrogen, methyl and ethyl and R 'is cycloalkyl of from 4 to 8 carbon atoms; characterized in that the steroid ester of formula fc! R &quot; Carbonyloxy) -4-a2a-5Î ± -androstane wherein H ', R' and R² are hydrogen, which is subjected to the following steps (1) dehydrogenation of said starting material to produce the corresponding compound containing a double bond in the Î ±, β-position of the ring A, (2) converting the β-carnoxy substituent at the 17Î ± -cyclic substituent and if desired, (3) alkylating the introducing the 4-methyl and 4-ethyl substituents on the Aβ ring for preparing? (5-cyclohexylcarbamoyl) -4-azabicyclo [2.2.1] hept-1-en-d-ones, 17β- (cyclopropylcarbamoyl) -4-aza-5α- rost-1-en-3-bnaρ 17 β- < 4-azabicyclo [2.2.1] hept-1-one-3-one; 17 | 5 &lt; cycloheptyl-1-carboxylate &lt; / RTI &gt; -4-aza-5α-andros-1-en-3-one. Γ-. s * '17β- &lt; cyclohexyl) carbonyl) -4-aza-5-oxazolidinecarboxamide. 3â. The process according to Claim 2, wherein the 4-hydrogen member is substituted by a 4-methyl substituent. The title compound was prepared according to Claim 2, which was synthesized according to the procedure described in Claim 2, which was synthesized. by preparing the -androst-1-en-S-one. Method for the treatment of hyperandrogenic conditions of acne vulgaris, seborrhoea, female hirsutism, androgenic alopecia, prostatic carcinoma and benign prostatic hypertrophy, comprising administering to a patient having such treatment a the therapeutically effective amount of a compound prepared according to Claim 1, the dosage range ranging from 0.006 mg to about 50 mg / kg of body weight per day. Sã. A method for inhibiting testosterone S-reductase in a patient in need of such inhibition treatment, comprising administering to said patient a therapeutically effective amount of a compound prepared according to Rexvxndation 1, varying the range of dosage of from and 0.005 mg to about 50 mg / kg of body weight per day. 9a. A pharmaceutical composition for the inhibition of testosterone is characterized by mixing a pharmaceutically acceptable carrier and a pharmaceutically acceptable carrier. ! -4 The compounds of formula (I) are the same as those of the compound of formula (I): ## STR4 ## Replication. r.i JU ΐϊί ** 3 L. x sboa f L'October 6, 1990 RUA VK3T0R CORDON, 10-A 3 "1200 USBOA