WO1995005821A1 - Di- et tetra-hydrobenzo[f]quinolein-3-ones - Google Patents

Di- et tetra-hydrobenzo[f]quinolein-3-ones Download PDF

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Publication number
WO1995005821A1
WO1995005821A1 PCT/US1994/009382 US9409382W WO9505821A1 WO 1995005821 A1 WO1995005821 A1 WO 1995005821A1 US 9409382 W US9409382 W US 9409382W WO 9505821 A1 WO9505821 A1 WO 9505821A1
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compound
anyone
quinolin
methyl
chloro
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PCT/US1994/009382
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English (en)
Inventor
Dennis Alan Holt
Dennis Shinji Yamashita
Hwa-Kwo Yen
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Smithkline Beecham Corporation
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Priority to EP94926534A priority Critical patent/EP0724440A4/fr
Priority to JP7507676A priority patent/JPH09501695A/ja
Priority to AU76341/94A priority patent/AU7634194A/en
Publication of WO1995005821A1 publication Critical patent/WO1995005821A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/10—Aza-phenanthrenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • 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- ⁇ - reductase. Also invented are novel processes useful in preparing these compounds.
  • 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- ⁇ - 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- ⁇ -reduced analogue, in these tissues but not in others such as muscle and testes.
  • DHT dihydrotestosterone
  • Steroid 5- ⁇ -reductase is a nicotinamide adenine dinucleotide phosphate (NADPH) dependent enzyme that converts testosterone to DHT.
  • NADPH nicotinamide adenine dinucleotide phosphate
  • TIPS (December 1989) Vol. 10, pp. 491-495, by B.W. Metcalf, et al., describes the effect of inhibitors of steroid 5 ⁇ -reductase in benign prostatic hyperplasia, male pattern baldness and acne;
  • the present invention resides in the discovery that steroid 5- ⁇ -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
  • the invention also is a method for inhibiting 5- ⁇ -reductase activity in mammals, including humans, that comprises administering to a subject an effective amount of a pharmaceutically active compound of the invention.
  • novel processes useful in preparing the presently invented 5- ⁇ -reductase inhibiting compounds include 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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,
  • ⁇ -receptor antagonist 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.
  • amsulosin as used herein is meant a compound of the structure
  • amsulosin is designated as (-)-(R)-5-[2-[[2-(O- ethoxyphenoxy)ethyl] amino]propyl] -2-methoxybenzenesulfona___.de.
  • terazosin as used herein is meant a compound of the structure
  • 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.
  • doxazosin as used herein is meant a compound of the structure
  • 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.
  • 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.
  • indoramin as used herein is meant a compound of the structure
  • prazosin as used herein is meant a compound of the structure
  • 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.
  • alpha-adrenergic receptor antagonists are preferred alpha-adrenergic receptor antagonists as used herein.
  • alpha-andrenergic receptor antagonist 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.
  • minoxidil as used herein is meant the compound of the structure:
  • minoxidil 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- ⁇ -reductase inhibitor.
  • a preferred aromatase inhibitor for use in the compositions and methods of the invention 4-(5,6,7,8-tetrahydroimidazo-[l,5- ⁇ ]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.
  • a 5- ⁇ -reductase inhibitor as described herein and a further active ingredient or ingredients are utilized together, said 5- ⁇ -reductase inhibitor can be co-administered with said further active ingredient or ingredients.
  • co-administering and derivatives thereof as used herein is meant either simultaneous administration or any manner of separate sequential administration of a 5- ⁇ -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- ⁇ -reductase inhibitors.
  • the compounds are administered in a close time proximity to each other.
  • the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.
  • 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.
  • (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.
  • a suitable organic solvent such as, toluene
  • an oxidant such as 2,3-dichloro-5,6 -dicyano- 1,4-benzoquinone
  • 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 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 ⁇ .
  • 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 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 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
  • 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.
  • R! is hydrogen or -CH3
  • R2 is halogen or methoxy; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof comprises reacting a compound of the formula
  • 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.
  • DDQ 2,3-dichloro-5,6-dicyano-l,4-benzofuinone
  • the pharmaceutically active compounds of the invention inhibit steroid 5- ⁇ -reductase activity, they have therapeutic utility in treating diseases and conditions wherein decreases in DHT activity produces the desired therapeutic effect.
  • diseases and conditions include acne vulgaris, seborrhea, female hirsutism, male pattern baldness, prostate diseases such as benign prostatic hypertrophy, and prostatic adenocarcinoma.
  • Chinese hamster ovary (CHO) cells containing expressed, recombinant human steroid 5 ⁇ -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 ⁇ M 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 ⁇ M NADPH (buffer B). The suspended paniculate solution was stored at -80°C.
  • Chinese hamster ovary (CHO) cells containing expressed, recombinant human steroid 5- ⁇ -reductase isozyme 2 were homogenized in 20 mM potassium phosphate, pH 6.5, buffer containing 0.33 M sucrose, lmM dithiothreitol, and 50 ⁇ M 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 ⁇ M 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 ⁇ L (recombinant isoenzyme 1 or isoenzyme 2) or 20 ⁇ L (isoenzyme 2 from human prostate tissue) of 10 mM NADPH and an aliquot of a steroid 5 ⁇ -reductase preparation to a final volume of 0.5 mL.
  • Assays for human steroid 5 ⁇ -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.
  • 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 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.
  • 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.
  • the preparation 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.
  • 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- ⁇ -reductase activity in mammals, including humans, comprises administering to a subject in need of such inhibition an effective steroid 5- ⁇ -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- ⁇ -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.
  • 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- ⁇ -reductase inhibitors.
  • 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- ⁇ -reductase inhibitors.
  • Particularly preferred is the co-administration of a 5- ⁇ -reductase inhibitor, as disclosed herein, and minoxidil for use in the treatment of male pattern baldness.
  • Particularly preferred is the co-administration of a 5 ⁇ -reductase inhibitor, as disclosed herein, and a ⁇ -
  • 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
  • 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.

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Abstract

L'invention concerne des composés de di- et tétra-hydrobenzo[f]quinoléin-3-ones, des compositions pharmaceutiques contenant ces composés et des procédés d'utilisation desdits composés, afin d'inhiber la stéroïde 5-α-réductase. Elle concerne également des procédés de préparation desdits composés.
PCT/US1994/009382 1993-08-20 1994-08-19 Di- et tetra-hydrobenzo[f]quinolein-3-ones WO1995005821A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP94926534A EP0724440A4 (fr) 1993-08-20 1994-08-19 Di- et tetra-hydrobenzo f]quinolein-3-ones
JP7507676A JPH09501695A (ja) 1993-08-20 1994-08-19 ジ−およびテトラ−ヒドロベンゾ［ｆ］キノリン−３−オン
AU76341/94A AU7634194A (en) 1993-08-20 1994-08-19 Di- and tetra-hydrobenzo(F)quinolin-3-ones

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GB939317314A GB9317314D0 (en) 1993-08-20 1993-08-20 Compounds
GB9317314.4 1993-08-20

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JP (1) JPH09501695A (fr)
CN (1) CN1133007A (fr)
AU (1) AU7634194A (fr)
CA (1) CA2169750A1 (fr)
GB (1) GB9317314D0 (fr)
WO (1) WO1995005821A1 (fr)
ZA (1) ZA946308B (fr)

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GB0129567D0 (en) 2001-12-11 2002-01-30 Trikon Technologies Ltd Diffusion barrier

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JOURNAL OF MEDICINAL CHEMISTRY, Volume 34, Number 2, issued February 1991, C. MELLIN et al., "A 3-D Model for 5-HT Receptor Agonist Based on Stereoselective Methyl-Substituted and Conformationally Restricted Analogues of 8-Hydroxy-2-(Dipropylamini)Tetralin", pages 497-510. *
JOURNAL OF MEDICINAL CHEMISTRY, Volume 36, Number 3, issued March 1993, C.D. JONES et al., "Nonsteroidal Inhibitors of Human Type I Steroid 5-a-Reductase", pages 421-423. *
See also references of EP0724440A4 *
SYNTHESIS, issued June 1986, J.G. CANNON et al., "Stereospecific Route to Trans-1,2,3,4,4a,5,6,10b-Octahydrobenzo[f]q uinolines", pages 494-496. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998029086A1 (fr) * 1996-12-31 1998-07-09 Handelman, Joseph, H. Reduction du developpement du systeme pileux
US6037326A (en) * 1996-12-31 2000-03-14 Styczynski; Peter Reduction of hair growth

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CN1133007A (zh) 1996-10-09
CA2169750A1 (fr) 1995-03-02
AU7634194A (en) 1995-03-21
JPH09501695A (ja) 1997-02-18
EP0724440A4 (fr) 1996-11-20
EP0724440A1 (fr) 1996-08-07
GB9317314D0 (en) 1993-10-06
ZA946308B (en) 1995-04-03

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