EP0724440A1

EP0724440A1 - Di- and tetra-hydrobenzo f]quinolin-3-ones

Info

Publication number: EP0724440A1
Application number: EP94926534A
Authority: EP
Inventors: Dennis Alan Holt; Dennis Shinji Yamashita; Hwa-Kwo Yen
Original assignee: SmithKline Beecham Corp
Current assignee: SmithKline Beecham Corp
Priority date: 1993-08-20
Filing date: 1994-08-19
Publication date: 1996-08-07
Also published as: EP0724440A4; ZA946308B; GB9317314D0; CA2169750A1; WO1995005821A1; AU7634194A; JPH09501695A; CN1133007A

Abstract

Invented are di- and tetra-hydrobenzo[f]quinolin-3-one compounds, pharmaceutical compositions containing these compounds, and methods for using these compounds to inhibit steroid 5-α-reductase. Also invented are processes used in preparing these compounds.

Description

DI- AND TETRA- HYDR0BENZ0[F]QUIN0LIN-3-0NES

FIELD OF THE INVENTION The present invention relates to certain novel di and tetra- hydrobenzo[f]quniolin-3-one compounds, pharmaceutical compositions containing these compounds, and methods for using these compounds to inhibit steroid 5-α- reductase. Also invented are novel processes useful in preparing these compounds.

DESCRIPTION OF RELATED ART

The class of steroidal hormones known as androgens is responsible for the physical characteristics that differentiate males from females. Of the several organs that produce androgens, the testes produce these hormones in the greatest amounts. Centers in the brain exert primary control over the level of androgen production. Numerous physical manifestations and disease states result when ineffective control results in excessive androgen hormone production. For example, acne vulgaris, seborrhea, female hirsutism, male pattern baldness and prostate diseases such as benign prostatic hypertropy are correlated with elevated androgen levels. Additionally, the reduction of androgen levels has been shown to have a therapeutic effect on prostate cancer.

Testosterone is the principal androgen secreted by the testes and is the primary androgenic steroid in the plasma of males. It now is known that 5-α- reduced androgens are the active hormones in some tissues such as the prostate and sebaceous gland. Circulating testosterone thus serves as a prohormone for dihydrotestosterone (DHT), its 5-α-reduced analogue, in these tissues but not in others such as muscle and testes. Steroid 5-α-reductase is a nicotinamide adenine dinucleotide phosphate (NADPH) dependent enzyme that converts testosterone to DHT. The importance of this enzyme in male development was dramatically underscored by the discovery of a genetic steroid 5-α-reductase deficiency in male pseudohermaphrodites. Imperato-McGinley, J., et al., (1979), J. Steroid Biochem. 11:637-648.

Recognition of the importance of elevated DHT levels in various disease states has stimulated many efforts to synthesize inhibitors of this enzyme.

A number of 5-α-reductase inhibiting compounds are known in the art. For example, 1. J. Steroid Biochem., Vol. 34, Nos. 1-6 pp. 571-575(1989), by M.A. Levy, et al., describes the interaction mechanism between rat prostatic steroid 5- alpha reductase and 3-carboxy-17β-substituted steroids;

2. J. Med. Chem. (1990) Vol. 33, pp. 937-942, by D.A. Holt, et al., describes the new steroid class of A ring aryl carboxylic acids;

3. TIPS (December 1989) Vol. 10, pp. 491-495, by B.W. Metcalf, et al., describes the effect of inhibitors of steroid 5α -reductase in benign prostatic hyperplasia, male pattern baldness and acne; and

4. EPO Publn. No. 0 343 954 A3, to D. A. Holt, et al., (SmithKline Beckmann) describes steroidal 3-carboxylic acid derivatives as useful 5-α-reductase inhibitors.

5. EPO Publn. No. 0531026 Al, to K.S. Hirsch, et al., describes hexahydrobenzo[f]quinolin-3-ones as 5-α-reductase inhibitors.

However, none of the above references specifically suggests that any of the novel di and tetra-hydrobenzo[f]quinolin-3-one compounds of the present invention would have utility as potent testosterone 5-α-reductase inhibitors.

SUMMARY OF THE INVENTION The present invention resides in the discovery that steroid 5-α-reductase is inhibited by certain di and tetra-hydrobenzo[f]quinolin-3-one compounds. The compounds are potent enzyme inhibitors.

Presently preferred compounds of the invention and compounds used in the invented pharmaceutical compositions and the invented methods include: 8-chloro-4-methyl-3,4-dihydrobenzo[fJquinolin-3-one, 8-chloro-l,2,3,4-tetrahydrobenzo[f]quinolin-3-one, 8-methoxy-4-methyl- 1 ,2,3,4-tetrahydrobenzo[f]quinolin-3-one, 4-methyl-3,4-dihydrobenzo[f|quinolin-3-one, 8-chloro-4-methyl- 1 ,2,3,4-tetrahydrobenzo[f]quinolin-3-one and 8-chloro-4-methyl-3,4,5,6-tetrahydrobenzo[f]quinolin-3-one.

The invention also is a method for inhibiting 5-α -reductase activity in mammals, including humans, that comprises administering to a subject an effective amount of a pharmaceutically active compound of the invention. In a further aspect of the invention there are provided novel processes useful in preparing the presently invented 5-α-reductase inhibiting compounds. Included in the present invention are pharmaceutical compositions comprising a pharmaceutical carrier and compounds useful in the methods of the invention. Also included in the present invention are methods of co-administering the pharmaceutically active compounds of the invention with further active ingredients.

DETAILED DESCRIPTION OF THE INVENTION The presently invented compounds that inhibit 5-α-reductase have the following Formula (I):

in which the A and B rings have optional double bonds where indicated by the broken lines, provided that the A ring or the B ring or both the A and B rings have a double bond where indicated by the broken lines; R! is hydrogen or -CH3; and R* is halogen, or methoxy; and pharmaceutically acceptable salts, hydrates and solvates thereof.

Preferred among the presently invented compounds are those having the following formula (la)

in which the A and B rings have optional double bonds where indicated by the broken llines, provied that the A ring or the B ring or both the A and B rings have a double bond where indicated by the broken lines; R! is hydrogen or -CH3; and R2 is halogen or methoxy; and pharmaceutically acceptable salts, hydrates and solvates thereof.

Particularly preferred among Formula (la) compounds are those in which R2 is chloro or methoxy, preferably chloro.

Preferred among the presently invented Formula I compounds are 8-chloro-4-methyl-3,4-dihydrobenzo[f]quinolin-3-one, 8-chloro- 1 ,2,3,4- tetrahy d_obenzo[f]quinolin-3-one, 8-me thoxy-4-methyl- 1 ,2,3,4-tetrahydrobenzo[f]quinolin-3-one 8-chloro-4-methyl-l,2,3,4-tetrahydrobenzo[f]quinolin-3-one and 8-chloro-4-methyl-3,4,5,6-tetrahydrobenzo[f]quinolin-3-one and pharmaceutically acceptable salts, hydrates and solvates thereof.

Compounds of Formula (II) are included in the pharmaceutical compositions of the invention and used in the methods of the invention.

in which: the A and B rings have optional double bonds where indicated by the broken lines, provided that the A ring or the B ring or both the A and B rings have a double bond where indicated by the broken lines; R! is hydrogen or -CH3; and R3 is hydrogen, methoxy or halogen; and pharmaceutically acceptable salts, hydrates and solvates thereof; except compounds in which R and R3 are both hydrogen.

Preferred among the presently invented Formula II compounds are: 8-chloro-4-methyl-3,4-dihydrobenzo[f]quinolin-3-one, 8-chloro- 1 ,2,3,4-tetrahydrobenzo[f]quinolin-3-one, 8-methoxy-4-methyl- 1 ,2,3,4- tetrahydrobenzo[f]quinolin-3-one 4-methyl-3,4-dihydrobenzo[f]quinolin-3-one,

8-chlor o-4-methyl- 1 ,2,3,4-tetrahy drobenzo[f]quinolin-3-one and

8-chloro-4-methyl-3,4,5,6-tetrahydrobenzo[f]quinolin-3-one and pharmaceutically acceptable salts, hydrates and solvates thereof.

The term "α-receptor antagonist", as used herein, refers to a known class of alpha-andrenergic receptor antagonist comounds, such as described in Lafferty, et al. U.S. Patent No. 4,963,547, which are utilized in treating vascular disorders such as diabetes, cardiovascular disease, benign prostatic hypertrophy and ocular hypertension.

Preferred alpha-andrenergic receptor antagonists for use in the compositions and methods of the invention include amsulosin, terazosin, doxazosin, alfuzosin, indoramin, prazosin, 7-chloro-2-ethyl-3,4,5,6-tetrahydro-4-methylthieno[4,3,2- ef][3]-benzazepine and 8-{3-[4-(2-methoxyphenyl)-l-piperazinyl)- propylcarbamoyl } -3-methyl-4-oxo-2-phenyl-4H- 1 -benzopyran. By the term "amsulosin" as used herein is meant a compound of the structure

and salts, hydrates and solvates thereof.

Chemically, amsulosin is designated as (-)-(R)-5-[2-[[2-(O- ethoxyphenoxy)ethyl] amino]propyl] -2-methoxybenzenesulfona___.de.

Amsulosin is disclosed in U.S. Patent Number 4,703,063 and claimed in

U.S. Patent Number 4,987,125 as being useful in treating lower urinary tract dysfunction.

By the term "terazosin" as used herein is meant a compound of the structure

and salts, hydrates and solvates thereof.

Chemically, terazosin is designated as l-(4-amino-6,7-dimethoxy-2 quinazolinyl)-4-[(tetrahydro-2-furoyl)carbonyl]piperazine. Terazosin is disclosed in U.S. Patent Number 4,251,532.

By the term doxazosin as used herein is meant a compound of the structure

and salts, hydrates and solvates thereof.

Chemically "doxazosin" is designated as l-(4-amino-6,7-dimethoxy-2- quinazolinyl)-4- [(2,3-dihydro- 1 ,4-benzodioxin-2-yl)carbonyl]-piperazine. Doxazosin is disclosed in U.S. Patent Number 4,188,390. By the term "alfuzosin" as used herein is meant a compound of the structure and salts, hydrates and solvates thereof.

Chemically alfuzosin is designated as N-[3-[(4-amino-6,7-dimethoxy-2- quina___linyl)methyla_mno]propyl]tetrahydxo-2-furancarboxamide.

Alfuzosin is disclosed in U.S. Patent Number 4,315,007.

By the term "indoramin" as used herein is meant a compound of the structure

H

and salts, hydrates and solvates thereof. Chemically indoramin as designated N-[[l-[2-(lH-indol-3-yl)ethyl]-4- piperidinyl]benzamine.

Indoramin is disclosed in U.S. Patent Number 3,527,761.

By the term "prazosin" as used herein is meant a compound of the structure

and salts, hydrates and solvates thereof.

Chemically prazosin is designated as l-(4-amino-6,7-dimethoxy-2- quinazolinyl)-4-(2-furanylcarbonyl)piperazine.

Prazosin is disclosed in U.S. Patent Number 3,511,836.

"7-chloro-2-ethyl-3,4,5,6-tetrahydro-4-methylthieno[4,3,2-ef]- [3]benzazepine" as used herein is meant a compound of the structure

and salts, hydrates and solvates thereof. 7-chloro-2-ethyl-3,4,5,6-tetrahydro-4-methylthieno[4,3,2-ef]-[3]benzazepine is disclosed in U.S. Patent No. 5,006,521. Additionally, all compounds disclosed in U.S. Patent No. 5,006,521 as alpha-adrenergic receptor antagonist are prefened alpha-adrenergic receptor antagonist as used herein.

"8- { 3- [4-(2-methoxyphenyl)- 1 -piperazinyl)-propylcar b amoy 1 } -3-methyl-4-oxo-2- phenyl-4H-l-benzopyran" as used herein is meant a compound of the structure

and salts, hydrates and solvates thereof.

8- { 3-[4-(2-methoxyphenyl)- l-piperazinyl]-propylcarbamoyl } -3-methyl-4- oxo-2-phenyl-4H-l-benzopyran is disclosed in EPO Publn. No. 0558245 Al, to Leonardi, et al., (Recordati S.A.).

Additionally all compounds disclosed in EPO Publn. No. 0558245 Al, as alpha-adrenergic receptor antagonists are preferred alpha-adrenergic receptor antagonists as used herein.

Persons skilled in the art can readily determine if a compound other than one specifically referred to herein is a alpha-andrenergic receptor antagonist by utilizing the assay described in Lafferty I. Thus, all such compounds are included within the scope of the term "alpha-andrenergic receptor antagonist" as used herein.

By the term "minoxidil" as used herein is meant the compound of the structure:

chemically minoxidil is designated as 2,4-pyrimidineadiamine, 6-(l-piperidinyl)-,3- oxide. Minoxidil is the active ingredient in Rogaine® which is sold as topical solution for stimulating hair growth by the Upjohn Company, Kalamazoo, Michigan. The term "aromatase inhibitor", as used herein, refers to a known class of compounds, steroidal and non-steroidal, which prevent the conversion of androgens to estrogens, such as described in Gormley et al. International Publication Number WO 92/18132. Aromatase inhibitors are disclosed in Gormley et al. as having utility in treating benign prostatic hyperplasia when used in combination with a 5- α -reductase inhibitor.

A preferred aromatase inhibitor for use in the compositions and methods of the invention 4-(5,6,7,8-tetrahydroimidazo-[l,5-α]pyridin-5-yl)benzonitrile (fadrazole). Fadrazole is disclosed in U.S. Patent No. 4,728,645. Additionally, all compounds disclosed in Gormley, et al. International Publication No. WO 92/18132 as having aromatase inhibiting activity are preferred aromatase inhibitors as used herein.

As used herein, when a 5-α-reductase inhibitor, as described herein and a further active ingredient or ingredients are utilized together, said 5-α-reductase inhibitor can be co-administered with said further active ingredient or ingredients. By the term "co-administering" and derivatives thereof as used herein is meant either simultaneous administration or any manner of separate sequential administration of a 5-α-reductase inhibiting compound, as described herein, and a further active ingredient or ingredients, such as other compounds known to treat the disease states of acne vulgaris, seborrhea, female hirsutism, male pattern baldness, benign prostate hypertrophy or prostatic adenocarcinoma or compounds known to have utility when used in combination with 5-α-reductase inhibitors. Preferably, if the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.

As used above and throughout the remainder of the application and claims the carbons of the benzo[f]quinoline nucleus are numbered as follows

The novel compounds of Formula I of the present invention can be prepared by methods outlined in Schemes I - V below and in the examples from the starting material described in each respective scheme.

SCHEME I

(a) (b) Scheme I shows synthesis of dihydrobenzo[f]quinolin-3-one compounds of

Formula (I) wherein the B ring is aromatic and in which R* is methyl. The formula

(a) starting materials are known and can be synthesized from available materials using known methods such as described in EPO Publn. No. 0531026A1. Formula

(b) compounds are prepared by treating formula (a) compounds in a suitable organic solvent, such as, toluene with an oxidant, such as 2,3-dichloro-5,6 -dicyano- 1,4-benzoquinone and heated preferably at reflux.

SCHEME II

(c) ( d)

Scheme II shows synthesis of tetrahydrobenzo[f]quinolin-3-one compounds of Formula (I) wherein the B ring is aromatic and R* is hydrogen. The formula (c) starting materials are known and can be synthesized from available materials using known methods such as described in EPO Publn. No. 0531026A1. Formula (d) compounds are prepared by treating formula (c) compounds in a suitable organic solvent, such as, toluene, with an oxidant, such as 2,3-dichloro-5,6-dicyano-l,4- benzoq uinone, and heated, preferably at reflux.

SCHEME in

(d) (e)

Scheme IE shows synthesis of tetrahydrobenzo[flquinolin-3-one compounds of Formula (I), wherein the B ring is aromatic and R* is methyl. The starting materials are formula (d) compounds from Scheme π. Formula (e) compounds are prepared by first treating formula (d) compounds in a suitable organic solvent, such as 1,2-dimethoxy ethane, with a base, such as sodium hydride, and heated, preferably at reflux. Thereafter, the mixture is treated with a methylating agent, preferably methyl iodide, and heated, preferably at reflux.

SCHEME IV

(a) (f)

Scheme IV shows synthesis of tetrahydrobenzo[f]quinolin-3-one compounds of Formula I, wherein there is a C1-C2 double bond and R is methyl. The starting materials are formula (a) compounds from Scheme I. Formula (f) compounds are prepared by first treating a formula (a) compound in a suitable organic solvent such as tetrahydrofuran, with a base such as potassium bis(trime thylislyl) amide, at reduced temperatures, preferably -78°C, followed by the addition of a selenation agent, preferably phenyl selenyl chloride and allowed to return to room temperature. Thereafter, treatment with and oxidizing reagent, such as hydrogen peroxide, yields formula (f) compounds. Scheme V

(e)

(a)

Scheme V shows synthesis of tetrahy drobenzo[f]quinolin-3-one compounds of Formula (I) wherein the B ring is aromatic and R is methyl. The starting materials are formula (a) compounds from Scheme I. Formula (e) compounds are prepared by treating formula (a) compounds in a suitable organic solvent, such as, toluene, with an oxidant, such as 2,3-dichloro-5,6-dicyano-l,4-benzoquinone, and heated.

Compounds of Formula II, in which R is methyl and R3 is hydrogen, are prepared as described in Bunting, et al. J. Org. Chem. 1986, 51, 2068-2071.

Pharmaceutically acceptable salts, hydrates and solvates of Formula (II) compounds are formed, where appropriate, by methods well known to those of skill in the art.

A preferred process the formula

in which the A ring has an optional double bond where indicated by, the broken line;

R! is hydrogen or -CH3; and

R2 is halogen or methoxy; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof comprises reacting a compound of the formula

in which R and R^ are as described above with 2,3-dichloro-5,6-dicyano-l,4-benzofuinone (DDQ)in a solvent, preferably toluene, preferably at a temperature above room temperature and thereafter optionally forming a pharmaceutically acceptable salt, hydrate or solvate thereof.

Because the pharmaceutically active compounds of the invention inhibit steroid 5-α-reductase activity, they have therapeutic utility in treating diseases and conditions wherein decreases in DHT activity produces the desired therapeutic effect. Such diseases and conditions include acne vulgaris, seborrhea, female hirsutism, male pattern baldness, prostate diseases such as benign prostatic hypertrophy, and prostatic adenocarcinoma.

In determining potency in inhibiting the human 5α-reductase enzyme, the following procedure was employed:

Preparation of membrane particulates used as source for recombinant steroid 5α-reductase isozvme 1.

Chinese hamster ovary (CHO) cells containing expressed, recombinant human steroid 5α -reductase isoenzyme 1 (Andersson, S., Berman, D.M., Jenkins, E.P., and Russell, D.W. (1991) Nature 354 159-161) were homogenized in 20 mM potassium phosphate, pH 6.5, buffer containing 0.33 M sucrose, 1 mM dithiothreitol, and 50 μM NADPH (buffer A) using a Dounce glass-to-glass hand homogenizer (Kontes Glass Co., Vineland, N.J.). Membrane particulates were isolated by centrifugation (100,000 x g at 4°C for 60 minutes) and resuspended in 20 mM potassium phosphate, pH 6.5, containing 20% glycerol, 1 mM dithiothreitol, and 50 μM NADPH (buffer B). The suspended paniculate solution was stored at -80°C.

Preparation of membrane particulates used as source for recombinant steroid 5-α- reductase isozvme 2.

Chinese hamster ovary (CHO) cells containing expressed, recombinant human steroid 5-α-reductase isozyme 2 were homogenized in 20 mM potassium phosphate, pH 6.5, buffer containing 0.33 M sucrose, lmM dithiothreitol, and 50 μM NADPH (buffer A) using a Douce hand homogenizer. Membrane particulates containing the recombinant human enzyme were isolated by centrifugation (100,000 x g at 4°C for 60 minutes) and resuspended in 20 mM potassium phosphate, pH 6.5 containing 20% glycerol, lmM dithiothreitol, and 50 μM NADPH (buffer B). The suspended particulate solution was stored at -80°C until used.

Assay for enzvmes activities and inhibitors potency. A constant amount of [ 14 C]testosterone (50 to 55 mCi/mmol) in ethanol and varying amounts of potential inhibitor in ethanol were deposited in test tubes and concentrated to dryness in vacuo. To each tube was added buffer, 10 μL (recombinant isoenzyme 1 or isoenzyme 2) or 20 μL (isoenzyme 2 from human prostate tissue) of 10 mM NADPH and an aliquot of a steroid 5α-reductase preparation to a final volume of 0.5 mL. Assays for human steroid 5α-reductase isoenzyme 1 were conducted with a sample of the recombinant protein expressed in CHO cells in 50 mM phosphate buffer, pH 7.5 while assays of isoenzyme 2 were conducted with a suspension of human prostatic particulates and/or recombinant protein expressed in CHO cells in 50 mM citrate buffer at pH 5.0.

After incubating the solution at 37°C for 20 or 30 minutes the reaction was quenched by the addition of 4 mL ethyl acetate and 0.25 μmol each of testosterone, 5α-dihydrotestosterone, androstanediol, and androstanedione as carriers. The organic layer was removed to a second test tube and evaporated to dryness in a Speed Vac. The residue was dissolved in 40 μL chloroform, spotted on an individual lane of a 20 x 20 cm prechannelled silica gel TLC plate (Si 250F-PA, Baker Chemical) and developed twice with acetone hloroform ( 1:9). The radiochemical content in the bands of the substrate and the products was determined with a BIOSCAN Imaging Scanner (Bioscan Inc., Washington, D.C.). The percent of recovered radiolabel converted to product was calculated, from which enzyme activity was determined. All incubations were conducted such that no more than 20% of the substrate (testosterone) was consumed.

The experimentally obtained data was computer fit to a linear function by plotting the reciprocal of the enzyme activity (1/velocity) against the variable inhibitor concentration; apparent inhibition constants (Ki app) were determined by the Dixon analysis (Dixon, M. (1953).

The value for the inhibition constant (Ki) was calculated from known procedures (Levy, M. (1989), Biochemistry. 22:2815-2824). All of the compounds within the scope of this invention are useful in inhibiting steroid 5-α-reductase in a mammal, including humans, in need thereof.

Compounds within the scope of this invention have been tested and have shown an activity of from 0.5 Ki(nM) to 100 Ki(nM) against isoz me 1 and an activity of >2000 Ki(nM) against isozyme 2. Particularly preferred among the compounds of the invention and the compounds used in the invented pharmaceutical compositions and invented methods are 8-chloro-4-methyl-3,4-dihydrobenzo[f]quinolin-3-one, 8-chloro-l,2,3,4-tetrahydrobenzo[f]quinolin-3-one, 8-methoxy-4-methyl- 1 ,2,3,4-tetrahydrobenzo[f]quinolin-3-one, 4-methyl-3,4-dihydrobenzo[f]quinolin-3-one,

8-chloro-4-methyl- 1 ,2,3,4-tetrahydrobenzo[f]quinolin-3-one and 8-chloro-4-methyl-3,4,5,6-tetrahydrobenzo[f]quinolin-3-one.

The pharmaceutically active compounds of the present invention are preferably incorporated into convenient dosage forms such as capsules, tablets, or injectable preparations. Solid or liquid pharmaceutical carriers are employed.

Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline, and water. Similarly, the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit. When a liquid carrier is used, the preparation will preferably be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension. The pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingreidents, as appropriate, to give the desired oral or parenteral products.

Doses of the presently invented pharmaceutically active compounds in a pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity preferably selected from the range of 0.01 - 1000 mg/kg of active compound, preferably 0J - 100 mg kg. When treating a human patient in need of steroid 5-α-reductase inhibition, the selected dose is administered preferably from 1-6 times daily, orally or parenterally. Preferred forms of parenteral administration include topically, rectally, transdermally, by injection and continuously by infusion. Oral dosage units for human administration preferably contain from 0J to 500 mg of active compound. Oral administration, which uses lower dosages is preferred. Parenteral administration, at high dosages, however, also can be used when safe and convenient for the patient.

The method of this invention of inhibiting steroid 5-α-reductase activity in mammals, including humans, comprises administering to a subject in need of such inhibition an effective steroid 5-α-reductase inhibiting amount of a pharmaceutically active compound of the present invention.

The invention also provides for the use of a compound of Formula (II) in the manufacture of a medicament for use in the inhibition of steroid 5-α-reductase. The invention also provides for a pharmaceutical composition for use in the treatment of benign prostate hypertrophy which comprises a compound of Formula II and a pharmaceutically acceptable carrier.

The invention also provides for a pharmaceutical composition for use in the treatment of prostatic adenocarcinoma which comprises a compound of Formula II and a pharmaceutically acceptable carrier. The invention also provides for a process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and a compound of Formula II which comprises bringing the compound of Formula II into association with the pharmaceutically acceptable carrier or diluent.

No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention.

In addition, the pharmaceutically active compounds of the present invention can be co-administered with further active ingredients, such as other compounds known to treat the disease states of acne vulgaris, seborrhea, female hirsutism, male pattern baldness, benign prostate hypertrophy or prostatic adenocarcinoma or compounds known to have utility when used in combination with 5-α-reductase inhibitors. Particularly preferred is the co-administration of a 5-α-reductase inhibitor, as disclosed herein, and minoxidil for use in the treatment of male pattern baldness. Particularly preferred is the co-administration of a 5α-reductase inhibitor, as disclosed herein, and a α-receptor antagonist for use in the treatment of benign prostatic hypertrophy. Preferred is the co-administration of a 5-α-reductase inhibitor, as disclosed herein, and an aromatase inhibitor for use in the treatment of benign prostatic hypertrophy. Preferred is the co-administration of a 5-α -reductase inhibitor, as disclosed herein, a α -receptor antagonist and an aromatase inhibitor for use in the treatment of benign prostatic hypertrophy.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way.

Example I - corresponding to Scheme I 8-chloro-4-methyl-3.4-dihydro-benzorflquinolin-3-one a) 8-chloro-4-methyl-3,4-dihydro-benzo[fjquinolin-3-one

2, 3-Dichloro-5, 6-dicyano-l,4-benzoquinone (DDQ) ( 550 mg, 2.4 mmol) was added to a solution of 8-chloro-4-methy 1-1, 2,3,4,5,6- hexahydrobenzo[f]quinolin-3-one (200 mg, 0.8 mmol) in toluene (10 ml) and was heated to reflux. After 48 hours the reaction was filtered, concentrated, and flash chromatographed (silica gel, 30% EtOAc/hexanes) to yield the title compound (85 mg, 43%). MS (DCI/NH3) m e 244[M+H]+

Example 2 - corresponding to Scheme II 8-chloro-l. 2. 3. 4-tetrahvdrobenzorflquinolin-3-one a) 8-chloro-l, 2, 3, 4-tetrahydrobenzo[f]quinolin-3-one

2, 3-Dichloro-5, 6-dicyano-l,4-benzoquinone (DDQ) ( 55 mg, 0.24 mmol) was added to a solution of 8-chloro-l, 2,3,4,5,6-hexahydrobenzo[fJquinolin-3-one (20 mg, 0.08 mmol) in toluene (5 ml) and was heated to reflux. After 48 h the reaction was filtered, concentrated, and flash chromatographed (silica gel, 30% EtOAc/hexanes) to yield the title compound (7 mg, 35%). MS (DCI/NH3) m/e 232 [M _-H]⁺

Example 3 - corresponding to Scheme m 8-chloro-4-methyl-l. 2. 3. 4-tetrahvdrobenzorflquinolin-3-one a) 8-chloro-4-methyl-l, 2, 3, 4-tetrahydrobenzo[f]quinolin-3-one

Sodium hydride (2 mg, 0.06 mmol) was added to a solution of 8-chloro-l, 2, 3, 4-tetrahydrobenzo[f]quinolin-3-one (7 mg, 0.03 mmol)in 1,2-dimethoxy ethane (4 ml) and was refluxed for 2 h. Methyl iodide (0.01 ml, 0J8 mmol) was added, and the reaction was refluxed an additional 2 h. The reaction was treated with H2O and was extracted with EtOAc. The combined organic extracts were dried (MgSO₄), filtered, concentrated, and flash chromatographed (silica gel, 30% EtOAc-hexanes) to yield the title compound (5mg, 68%). MS (DCI/NH3) m/e 246 [M _-H]⁺

Example 4 - corresponding to Scheme IV 8-chloro-4-methvl-3.4-5.6-tetrahvdrobenzorflquinolin-3-one a) 8-chloro-4-methyl-3,4,5,6-tetrahydrobenzo[f]quinolin-3-one

Potassium bis(trimethylsilyl)amide (0.5 M in toluene, 3.4 ml, 1.7 mmol) was added to a solution of 8-chloro-4-methyl-l,2,3,4,5,6-hexahydrobenzo[f]quinolin-3- one (210 mg, 0.85 mmol) in THF (10 ml) at -78 degrees. After 2 h phenyl selenenyl chloride (390 mg, 2.04 mmol) was added and the reaction was warmed to RT and stirred 2 additional hours. The reaction was treated with aqueous NH4CI and was extracted with EtOAc. The combined extracts were dried (MgSO4), filtered, then concentrated. The residue was dissolved in THF (10 ml) and was buffered with excess solid NaHCO3, then was cooled to 0 degrees and treated with 30% H2Q2 ( 0.29 ml, 2.5 mmol) and was stirred for lh. Then, the reaction was treated with H₂O and was extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered, concentrated, and flash chromatographed (silica gel, 30% EtOAc-hexanes) to yield the title compound (14 mg, 7 %). MS (DCI NH3) m/e 246 [M+H]⁺

EXAMPLE 5 - corresponding to Scheme V 8-methoxy-4-methyl-l,2,3,4-tetrahydrobenzo[f]quinolin-3-one a) 8-methoxy-4-methyl-l,2,3,4-tetrahydrobenzo[f]quinolin-3-one

2,3-Dichloro-5,6-dicyano-l,4-benzoquinone (DDQ)(110 mg, 0.5 mmol) was added to a solution of 8-me thoxy-4 -methyl- 1 ,2,3,4,5,6-hexahydro benzo[f]quinolin- 3-one (50 mg, 0.22 mmol) in toluene (10 ml) and was heated to 80°C. After 4 hours the reaction was flash chromatographed (silica gel, 30% EtOAc/hexanes) to yield the title compound (17 mg, 35%). MS (DCI/NH3) m/e 242 [M + H}+

Example 6 An oral dosage form for administering Formula II comounds is produced by screening, mixing, and filling into hard gelatin capsules the ingredients in the proportions shown in Table 1, below. Table I

Ingredients Amounts

8-chloro-4-methyl-3,4- 50 mg dihydrobenzo[f]quinolin-3-one magnesium stearate 5 mg lactose 75 mg

EXAMPLE 7

The sucrose, calcium sulfate dihydrate and Formula (II) compound shown in Table II below, are mixed and granulated in the proportions shown with a 10% gelatin solution. The wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet.

Table π

Ingredients Amounts

8-chloro-4-methyl-3,4- 100 mg dihydrobenzo[f]quinolin-3-one calcium sulfate dihydrate 150 mg sucrose 20 mg starch 10 mg talc 5 mg stearic acid 3 mg

EXAMPLE 8

8-chloro-4-methyl-3,4-dihydrobenzo[f]quinolin-3-one, 75 mg, is dispursed in 25 ml of normal saline to prepare an injectable preparation.

While the preferred embodiments of the invention are illustrated by the above, it is to be understood that the invention is not limited to the precise instructions herein disclosed and that the right to all modifications comming within the scope of the following claims is reserved.

Claims

What is claimed is:

1. A compound represented by the formula:

in which the A and B rings have optional double bonds where indicated by the broken lines, provided that the A ring or the B ring or both the A and B rings have a double bond where indicated by the broken lines; R! is hydrogen or -CH3; and R2 is halogen or methoxy; and and pharmaceutically acceptable salts, hydrates and solvates thereof.

2. A compound of claim 1 that is 8-chloro-4-methyl-3,4-dihydrobenzo[f]quinolin-3-one, 8-chloro-l,2,3,4-tetrahydrobenzo[f]quinolin-3-one, 8-methoxy-4-methyl-l,2,3,4-tetr_hydrobenzo[f]quinolin-3-one, 8-chloro-4-methyl- 1 ,2,3,4-tetrahydrobenzo[f]quinolin-3-one or 8-chloro-4-methyl-3,4,5,6-tetrahydrobenzo[f]quinolin-3-one, and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.

3. A compound according to claim 1 substantially as hereinbefore defined with reference to anyone of the examples.

4. A pharmaceutical composition comprising a compound of the formula:

in which: the A and B rings have optional double bonds where indicated by the broken lines, provided that the A ring or the B ring or both the A and B rings have a double bond where indicated by the broken lines; R! is hydrogen or -CH3; and R3 is hydrogen, methoxy or halogen; and pharmaceutically acceptable salts, hydrates and solvates and esters thereof; except compounds in which R* and R-' are both hydrogen and a pharmaceutically acceptable carrier.

5. A composition of claim 4 wherein the compound is: 8-chloro-4-methyl-3,4-dihydrobenzo[f]quinolin-3-one,

8-chloro- 1 ^,3,4-tetrahydrobenzo[f]quinolin-3-one, 8-methoxy-4-methyl- 1 ,2,3,4-tetrahy drobenzo[f]quinolin-3-one, 4-methyl-3,4-dihydrobenzo[f]quinolin-3-one, 8-chloro-4-methyl- 1 ,2,3,4-tetrahydrobenzo[f]quinolin-3-one or 8-chloro-4-methyl-3,4,5,6-tetrahydrobenzo[f]quinolin-3-one.

6. A compound according to any one of claims 1 or 2 for use in therapy.

7. A compound according to any one of claims 1 or 2 in the manufacture of a medicament for use as a steroid 5-α-reductase inhibitor.

8. A compound according to any one of claims 1 or 2 in the manufacture of a medicament for use in treatment to reduce prostate size.

9. A compound according to any one of claims 1 or 2 in the manufacture of a medicament for use in treatment of prostatic adenocarcinoma.

10. A composition according to anyone of claims 4 or 5 for use in therapy.

11. A composition according to any one of claims 4 or 5 in the manufacture of a medicament for use as a steroid 5-α-reductase inhibitor.

12. A composition according to any one of claims 4 or 5 in the manufacture of a medicament for use in treatment to reduce prostatic size.

13. A composition according to any one of claims 4 or 5 in the manufacture of a medicament for use in treatment of prostatic adenocarcinoma.

14. A process for the preparation of a compound of the formula

in which the A ring has an optional double bond where indicated by the broken line; R2 is halogen or methoxy; and and pharmaceutically acceptable salts, hydrates, solvates and esters thereof which comprises reacting a compound of the formula

in which Rl and R^ are as described above with

2,3-di chloro-5, _~dicyano-l,4-benzofuinone (DDQ)in a solvent, preferably toluene, preferably at a temperature above room temperature and thereafter optionally forming a pharmaceutically acceptable salt, hydrate or solvate thereof.

15. A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of the Formula (II) as described in claim 4 and pharmaceutically acceptable salts, hydrates, solvates and esters thereof which process comprises bringing the compound of the Formula (II) into association with the pharmaceutically acceptable carrier or diluent.

16. Use of a compound according to any one of claims 1 or 2 in the manufacture of a medicament for use in inhibiting steroid 5-α-reductase.

17. A method of inhibiting steroid 5-α-reductase in mammals which comprises the administration to a mammal in need of such inhibition, an effective amount of a compound according to any one of claims 1 or 2.

18. The use of a compound according to anyone of claims 1 or 2 and an alpha-receptor antagonist compound as an active therapeutic substance which use consist of separate sequential or simultaneous administration of a compound according to anyone of claims 1 or 2 and an alpha-receptor antagonist compound.

19. The use of a compound according to anyone of claims 1 or 2 and an alpha-receptor antagonist compound in the manufacture of medicament for use in the treatment of benign prostatic hypertrophy which use consist of separate sequential or simultaneous administration of a compound according to anyone of claims 1 or 2 and an alpha-receptor antagonist compound.

20. The use of a compound according to anyone of claims 1 or 2 and minoxidil as an active therapeutic substance which use consist of separate sequential or simultaneous administration of a compound according to anyone of claims 1 or 2 and minoxidil.

21. The use of a compound according to anyone of claims 1 or 2 and minoxidil in the manufacture of a medicament for use in the treatment of male pattern baldness which use consist of separate sequential or simultaneous administration of a compound according to anyone of claims 1 or 2 and minoxidil.

22. Use of a composition according to anyone of claims 4 or 5 in the manufacture of a medicament for use in inhibiting steroid 5-α-reductase.

23. A method of inhibiting steroid 5-α-reductase in mammals which comprises the administration to a mammal in need of such inhibition, an effective amount of a composition according to anyone of claims 4 or 5.

24. The use of a composition according to anyone of claims 4 or 5 and an alpha-receptor antagonist compound as an active therapeutic substance which use consist of separate sequential or simultaneous administration of a composition according to anyone of claims 4 or 5 and an alpha-receptor antagonist compound.

25. The use of a composition according to anyone of claims 4 or 5 and an alpha-receptor antagonist compound in the manufacture of medicament for use in the treatment of benign prostatic hypertrophy which use consist of separate sequential or simultaneous administration of a composition according to anyone of claims 4 or 5 and an alpha-receptor antagonist compound.

26. The use of a composition according to anyone of claims 4 or 5 and minoxidil as an active therapeutic substance which use consist of separate sequential or simultaneous administration of a composition according to anyone of claims 4 or 5 and minoxidil. i

27. The use of a composition according to anyone of claims 4 or 5 and minoxidil in the manufacture of a medicament for use in the treatment of male pattern baldness which use consist of separate sequential or simultaneous administration of a composition according to anyone of claims 4 or 5 and minoxidil.