WO2001070227A1 - Antagonists of gonadotropin releasing hormone - Google Patents

Antagonists of gonadotropin releasing hormone Download PDF

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Publication number
WO2001070227A1
WO2001070227A1 PCT/US2001/007878 US0107878W WO0170227A1 WO 2001070227 A1 WO2001070227 A1 WO 2001070227A1 US 0107878 W US0107878 W US 0107878W WO 0170227 A1 WO0170227 A1 WO 0170227A1
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aryl
alkyl
aralkyl
crι
alkoxy
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PCT/US2001/007878
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French (fr)
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Robert J. Devita
Mark T. Goulet
Mamta Parikh
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Merck & Co., Inc.
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Priority to AU47381/01A priority Critical patent/AU4738101A/en
Publication of WO2001070227A1 publication Critical patent/WO2001070227A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones

Definitions

  • the gonadotropin-releasing hormone also referred to as luteinizing hormone-releasing hormone (LHRH)
  • LHRH luteinizing hormone-releasing hormone
  • LH released from the pituitary gland is primarily responsible for the regulation of gonadal steroid production in both sexes, whereas FSH regulates spermatogenesis in males and follicular development in females.
  • GnRH agonists and antagonists have proven effective in the treatment of certain conditions which require inhibition of LH FSH release.
  • GnRH-based therapies have proven effective in the treatment of endometriosis, uterine fibroids, polycystic ovarian disease, precocious puberty and several gonadal steroid-dependent neoplasia, most notably cancers of the prostate, breast and ovary.
  • GnRH agonists and antagonists have also been utilized in various assisted fertilization techniques and have been investigated as a potential contraceptive in both men and women.
  • GnRH antagonists may also be useful in combination with bisphosphonates (bisphosphonic acids) and other agents, such as growth hormone secretagogues, for the treatment and the prevention of disturbances of calcium, phosphate and bone metabolism, in particular, for the prevention of bone loss during therapy with the GnRH antagonist, and in combination with estrogens, progesterones, antiestrogens, antiprogestins and/or androgens for the prevention or treatment of bone loss or hypogonadal symptoms such as hot flashes during therapy with the GnRH antagonist.
  • bisphosphonates bisphosphonic acids
  • other agents such as growth hormone secretagogues
  • GnRH antagonists may be co-administered with a 5a- reductase 2 inhibitor, such as finasteride or epristeride; a 5a-reductase 1 inhibitor such as 4,7b-dimethyl-4-aza-5a-cholestan-3-one, 3-oxo-4-aza-4,7b-dimethyl-16b-(4- chlorophenoxy)-5a-androstane, and 3-oxo-4-aza-4,7b-dimethyl-16b-(phenoxy)-5a- androstane as disclosed in WO 93/23420 and WO 95/11254; dual inhibitors of 5a- reductase 1 and 5a-reductase 2 such as 3-oxo-4-aza-17b-(2,5-trifluoromethylphenyl- carbamoyl)-5a-androstane as disclosed in WO 95/07927; antiandrogens such as flutamide, casodex and cyproterone
  • GnRH antagonists may be useful in combination with growth hormone, growth hormone releasing hormone or growth hormone secretagogues, to delay puberty in growth hormone deficient children, which will allow them to continue to gain height before fusion of the epiphyses and cessation of growth at puberty.
  • GnRH antagonists may be useful in combination or co-administered with a compound having luteinizing hormone releasing activity such as a peptide or natural hormone or analog thereof.
  • a compound having luteinizing hormone releasing activity such as a peptide or natural hormone or analog thereof.
  • peptide compounds include leuprorelin, gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterlin and recirelin.
  • GnRH antagonists may be useful as described in U.S. Patent No. 5,824,286 which discloses the administration of peptide GnRH antagonists such as Antide and azaline B to premenopausal women to enhance the readability of mammographic film relative to a mammogram effected in the absence of the administration.
  • GnRH antagonists are GnRH-like decapeptides which are generally administered intravenously or subcutaneously presumably because of negligible oral activity. These have amino acid substitutions usually at positions one, two, three, six and ten.
  • Non-peptide GnRH antagonists offer the possible advantage of oral administration.
  • Non-peptide GnRH antagonists have been described in European Application 0 219 292 and in De, B. et al., J. Med. Chem., 32, 2036-2038 (1989), in WO 95/28405, WO 95/29900 and EP 0679642 all to Takeda Chemical Industries, Ltd.
  • JP-A-63- 295561 discloses a class of 3-phenyl-2(lH)-quinolone derivatives, substituted at the 4-position by an unsubstituted straight or branched alkoxy group and at the 7-position by an unsubstituted straight or branched alkoxy group. These compounds are alleged to exhibit a strong inhibitory action on bone resorption and a stimulatory effect on ossification, and thus to be useful as therapeutic agents for the prevention and treatment of osteoporosis.
  • J. Heterocycl. Chem., 1989, 26, 281 discloses a range of 3-(2- methoxyphenyl)-2(lH)-quinolones possessing a halogen substituent in the 6- or 7- position and an optional carboxylic acid substituent at the 4-position.
  • a family of 3- phenyl-2(lH)-quinolone derivatives, substituted at the 4-position by an amino or benzylamino group and at the 7-position by a methyl or methoxy group, is described in Monatsh. Chem., 1982, 113, 751 and Nestn. Slov. Kern. Pros., 1986, 33, 271.
  • WO 93/10783 and WO 93/11115 disclose a class of 2-(lH)-quinolone derivatives, substituted at the 3-position by an optionally substituted aryl substituent and are selective non-competitive antagonists of ⁇ MD A receptors and/or are antagonists of AMPA receptors, and are therefore of utility in the treatment of conditions, such as neurodegenerative disorders, convulsions or schizophrenia.
  • FR 2711992-A1 discloses quinolone derivatives which are allegedly useful as antagonists of platelet activating factor.
  • WO 97/44321, WO 97/44339, WO 97/44037 and WO 97/44041 disclose non-peptidyl, arylquinolone derivatives as GnRH antagonists.
  • the present invention relates to compounds which are non-peptide antagonists of GnRH which can be used to treat a variety of sex-hormone related conditions in men and women, to methods for their preparation, and to methods and pharmaceutical compositions containing said compounds for use in mammals.
  • the compounds of the present invention are useful to treat a variety of sex-hormone related conditions in both men and women. These conditions include endometriosis, uterine fibroids, polycystic ovarian disease, hirsutism, precocious puberty, gonadal steroid-dependent neoplasias such as cancers of the prostate, breast and ovary, gonadotrophe pituitary adenomas, sleep apnea, irritable bowel syndrome, premenstrual syndrome and benign prostatic hypertophy.
  • the compounds of the invention are also useful as an adjunct to treatment of growth hormone deficiency and short stature, and for the treatment of systemic lupus erythematosis.
  • the compounds of the invention may be useful in in vitro fertilization and as contraceptives.
  • the compounds may also be useful in combination with androgens, estrogens, progesterones, antiestrogens and antiprogestogens for the treatment of endometriosis, fibroids and in contraception. They may also be useful in combination with testosterone or other androgens or antiprogestogens in men as a contraceptive.
  • the compounds may also be used in combination with an angiotensin-converting enzyme inhibitor such as Enalapril or Captopril, an angiotensin 13-receptor antagonist such as Losartan or a renin inhibitor for the treatment of uterine fibroids.
  • an angiotensin-converting enzyme inhibitor such as Enalapril or Captopril
  • an angiotensin 13-receptor antagonist such as Losartan or a renin inhibitor
  • the compounds of the invention may also be used in combination with bisphosphonates (bisphosphonic acids) and other agents, for the treatment and the prevention of disturbances of calcium, phosphate and bone metabolism, in particular, for the prevention of bone loss during therapy with the GnRH antagonist, and in combination with estrogens, progesterones and/or androgens for the prevention or treatment of bone loss or hypogonadal symptoms such as hot flashes during therapy with the GnRH antagonist.
  • a compound of the present invention may be co-administered with a 5a-reductase 2 inhibitor, such as finasteride or epristeride; a 5a-reductase 1 inhibitor such as 4,7b-dimethyl-4-aza-5a-cholestan-3-one, 3-oxo-4- aza-4,7b-dimethyl-16b-(4-chlorophenoxy)-5a-androstane, and 3-oxo-4-aza-4,7b- dimethyI-16b-(phenoxy)-5a-androstane as disclosed in WO 93/23420 and WO 95/11254; dual inhibitors of 5a-reductase 1 and 5a-reductase 2 such as 3-oxo- 4-aza-17b-(2,5-trifluoromethylphenyl-carbamoyl)-5a-androstane as disclosed in WO 95/07927; antiandrogens such as flutamide, casodex and
  • a compound of the present invention may be used in combination with growth hormone, growth hormone releasing hormone or growth hormone secretagogues, to delay puberty in growth hormone deficient children, which will allow them to continue to gain height before fusion of the epiphyses and cessation of growth at puberty.
  • a compound of the present invention may be used in combination or co-administered with a compound having luteinizing hormone releasing activity such as a peptide or natural hormone or analog thereof.
  • a compound having luteinizing hormone releasing activity such as a peptide or natural hormone or analog thereof.
  • peptide compounds include leuprorelin, gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterlin and recirelin.
  • a compound of the present invention may be used as described in U.S. Patent No. 5,824,286 which discloses the administration of peptide GnRH antagonists such as Antide and azaline B to premenopausal women to enhance the readability of mammographic film relative to a mammogram effected in the absence of the administration.
  • peptide GnRH antagonists such as Antide and azaline B
  • the present invention relates to compounds of the general formula
  • A is a bond, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkoxy, said alkyl, alkenyl, alkoxy and alkynyl groups optionally substituted with C1-C6 alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C1-C6 alkoxy, fluoro, C(O)ORi5 5 and aryl C1-C3 alkoxy;
  • B is a bond or C ⁇ -C6 alkyl, said alkyl group optionally substituted with C1-C6 alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C1-C alkoxy, fluoro, C ⁇ ORi ⁇ and aryl C1-C3 alkoxy;
  • X is O, S, SO, SO2, NR12, C R.13R14), or can be absent; E is a bond, O, S, SO or SO2;
  • the nitrogen atoms contained in the heteroaromatic rings may exist either as drawn or, when chemically allowed, in their oxidized (N— >O) state;
  • Rl is H, C1-C6 alkyl, C3-C6 cycloalkyl, aryl or C1-C6 aralkyl, said alkyl and cycloalkyl groups optionally substituted with C -C6 alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C1-C6 alkoxy, fluoro, C ⁇ ORi ⁇ and aryl C1-C3 alkoxy; said aryl groups optionally substituted with H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, C1-C6 aralkyl, l5O(CRi3Ri4) p -, -Rl6C(O)O(CR ⁇ 3 Ri4)
  • R2, 3 and R4 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, -C ⁇ aralkyl, Ri5 ⁇ (CRi3Rl4)p-, Rl6C(O)O(CR ⁇ 3 Ri4) p -, Ri5OC(O) (CR ⁇ 3 Rl4)p-, -(CRi 3 Rl4)pS(O) n Rl2, (CR ⁇ 3 Rl4)pC(O)NR ⁇ 7 Rl8, -(CR ⁇ 3 Rl4)pNRl7C(O)Ri6, -(CR ⁇ 3 Rl4)pN(Ri7Rl8) or halogen; said alkyl, alkenyl, alkoxy and alkynyl groups optionally substituted with C1-C6 alkyl, C3-C7 cyclo
  • R2 and R3 taken together form a carbocyclic ring, saturated or unsaturated, of 3-7 carbon atoms or a heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;
  • R5, R6, R7 and R ⁇ independently are H, halogen, NO2, -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, Ci-Cg aralkyl, heteroaryl, Ci-C ⁇ heteroaralkyl, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, Ri5 ⁇ (CRi3Ri4)p-, -(CR ⁇ 3 Rl4)pCN, -(CR ⁇ 3 Rl4)pSO n Rl2.
  • Rg and Rg ⁇ are independently H, Ci-C ⁇ alkyl, aryl or C ⁇ -C6 aralkyl, said alkyl group optionally substituted with Ci-C ⁇ alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C ⁇ -C6 alkoxy, fluoro, C(O)ORi5 5 and aryl C1-C3 alkoxy; said aryl groups optionally substituted with H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, C1-C6 aralkyl, Ri5O(CRi3Ri4)p-, -Rl6C(O)O(CRi 3 Rl4)p-, Rl5OC(O)(CRi3
  • RlO is H, C ⁇ -C6 alkyl, aryl or Ci-Cg aralkyl, said alkyl group optionally substituted with Ci-C ⁇ alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C -Cg alkoxy, fluoro, C(O)ORi5 5 and aryl C1-C3 alkoxy; said aryl groups optionally substituted with H, C1-C6 alkyl, C2-C15 alkenyl, C2-C6 alkynyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, C1-C6 aralkyl, Ri5O(CRi3Ri4)p-, -Rl6C(O)O(CRi 3 Rl4)p-, Rl5OC(O)(CRi3Rl4)p-
  • R9 and R9a can be taken together to form a carbocyclic ring, saturated or unsaturated, of 3-7 variously substituted carbon atoms, or; R9 and Rio are taken together to form a heterocyclic ring, saturated or unsaturated, of
  • Rl2 is H, C1-C6 alkyl, aryl or -C6 aralkyl; said alkyl group optionally substituted with C -C6 alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C1-C6 alkoxy, fluoro, C(O)ORi5 ; and aryl C1-C3 alkoxy; said aryl and aralkyl groups optionally substituted with H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, C1-C6 aralkyl, Ri5 ⁇ (CRi3Ri4) p -, Ri6C(O)O
  • Rl5 is H, C1-C6 alkyl, aryl, C1-C6 aralkyl, heteroaryl, substituted heteroaryl,
  • Ci-C ⁇ heteroaralkyl or a heterocyclic ring containing 1-4 heteroatoms selected from O, N, and S; said alkyl group optionally substituted with C1-C6 alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, Ci-C ⁇ alkoxy, fluoro, C(O)ORi5 j and aryl C1-C3 alkoxy; said aryl, aralkyl, heteroaryl and heteroaralkyl groups optionally substituted with H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, C1-C6 aralkyl, Ri5 ⁇ (CR ⁇ 3 Rl4)p-, Rl6C(O)O(CR ⁇ 3 Rl4)
  • Rl6 is H, C ⁇ -C6 alkyl, aryl, C1-C6 aralkyl, heteroaryl, C1-C6 heteroaralkyl, or a heterocyclic ring containing 1-4 heteroatoms selected from O, N, and S; said alkyl group optionally substituted with C1-C6 alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C1-C6 alkoxy, fluoro, C(O)ORi5 5 and aryl C1-C3 alkoxy; said
  • Rl9 is H, C1-C6 alkyl or -CN; said alkyl group optionally substituted with Ci-C ⁇ alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C1-C6 alkoxy, fluoro, C(O)ORi5 5 and aryl C1-C3 alkoxy; is 0, 1, or 2; p is 0, 1, 2, 3 or 4;
  • the invention relates to compounds of the general formula
  • A is a bond or C1-C6 alkyl
  • B is a bond or C1-C6 alkyl
  • X is O
  • Y is
  • R3 is H, Cl or CH3
  • R 6 is (CRi 3 Rl4)pC(O)N(Ri 7 Ri 8 );
  • R7 is halogen
  • R9 and Rio are taken together to form a heterocyclic ring, saturated or unsaturated, of
  • any variable e.g., aryl, heterocycle, Ri, etc.
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • alkyl is intended to include both branched- and straight- chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, e.g., methyl (Me), ethyl (Et), propyl, butyl, pentyl, hexyl, heptyl, octyl, nonanyl, decyl, undecyl, dodecyl, and the isomers thereof such as isopropyl (i-Pr), isobutyl (i-Bu), sec-butyl (s-Bu), tert-butyl (t-Bu), isopentane, isohexane, etc.
  • aryl includes phenyl and naphthyl.
  • aryl is phenyl.
  • halogen or halo is intended to include fluorine, chlorine, bromine and iodine.
  • heterocycle or “heterocyclic ring” is defined by all non- aromatic, heterocyclic rings of 3-7 atoms containing 1-3 heteroatoms selected from N, O, and S, such as oxirane, oxetane, tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, tetrahydropyridine, tetrahydropyrimidine, tetrahydrothiophene, tetrahydrothiopyran, morpholine, hydantoin, valerolactam, pyrrolidinone, and the like.
  • heteroaryl is intended to include the compounds shown below:
  • the nitrogen atoms contained in the heteroaromatic rings may exist either as drawn or, when chemically allowed, in their oxidized (N— >O) state.
  • optical isomeric forms that is mixtures of enantiomers, e.g., racemates, or diastereomers as well as individual enantiomers or diastereomers of the instant compound are included.
  • These individual enantiomers are commonly designated according to the optical rotation they effect by the symbols (+) and (-), (L) and (D), (1) and (d) or combinations thereof.
  • These isomers may also be designated according to their absolute spatial configuration by (S) and (R), which stands for sinister and rectus, respectively.
  • the individual optical isomers may be prepared using conventional resolution procedures, e.g., treatment with an appropriate optically active acid, separating the diastereomers and then recovering the desired isomer.
  • the individual optical isomers may be prepared by asymmetric synthesis.
  • a given chemical formula or name shall encompass pharmaceutically acceptable addition salts thereof and solvates thereof, such as hydrates.
  • the compounds of the present invention while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable addition salts for purposes of stability, convenience of crystallization, increased solubility and other desirable properties.
  • the compounds of the present invention may be administered in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt is intended to include all acceptable salts.
  • acid salts are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic, methane sulfonic and the like which can be used as a dosage form for modifying the solubility or hydrolysis characteristics or can be used in sustained release or prodrug formulations.
  • salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N -dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N- benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide.
  • bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N -dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N- benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)amin
  • esters can be employed, e.g. methyl, ethyl, butyl, acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
  • the compounds of the present invention may have chiral centers other than those centers whose stereochemistry is depicted in formula I, and therefore may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers, with all such isomeric forms being included in the present invention as well as mixtures thereof.
  • crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention.
  • some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this invention.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • amine (1) and an arylacetic acid (3) treatment of amine (1) and an arylacetic acid (3) with the coupling reagent l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), 1,3-dicyclo- hexylcarbodiimide (DCC) or the like with or without 1-hydroxybenzotriazole (HOBt) and a tertiary amine base such as N-methylmorpholine (NMM), triethylamine or the like in an inert organic solvent such as methylene chloride, chloroform, dimethylformamide, or mixtures thereof at or near room temperature for a period of 3-24 hours provides the corresponding amide derivative (4).
  • EDC 1,3-dicyclo- hexylcarbodiimide
  • HOBt 1-hydroxybenzotriazole
  • NMM N-methylmorpholine
  • NMM N-methylmorpholine
  • triethylamine or the like inert
  • Cyclization of amide (4) is effected by treatment with a strong base such as sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide or the like in an inert organic solvent such as tetrahydrofuran at a temperature of -20°-25° C for a period of 2-4 hours to give quinolone (5).
  • a strong base such as sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide or the like in an inert organic solvent such as tetrahydrofuran
  • reaction Scheme B treatment of the 4-hydroxy- quinolone (5) with an alkylamine containing a halogen or sulfonate leaving group (6) and a suitable base such as potassium carbonate, sodium carbonate, sodium bicarbonate, DBU or the like along with the catalyst sodium iodide in an inert organic solvent such as N,N-dimethylformamide, tetrahydrofuran, acetonitrile or the like at or around 80°C for a period of 4-24 hours provides the ether derivative (7).
  • a suitable base such as potassium carbonate, sodium carbonate, sodium bicarbonate, DBU or the like
  • an inert organic solvent such as N,N-dimethylformamide, tetrahydrofuran, acetonitrile or the like
  • a suitably protected amino alcohol (8) may be coupled to (5) by treatment under Mitsunobu reaction conditions with triphenylphosphine and an activating agent such as diethyl azodicarboxylate, disopropyl azodicarboxylate or the like in an inert solvent such as tetrahydrofuran, toluene, chlorobenzene or the like at ambient temperature for a period of 4-64 hours to give (7).
  • triphenylphosphine and an activating agent such as diethyl azodicarboxylate, disopropyl azodicarboxylate or the like in an inert solvent such as tetrahydrofuran, toluene, chlorobenzene or the like at ambient temperature for a period of 4-64 hours to give (7).
  • the 4-hydroxyquinolone structure (5) may be modified by conversion to a sulfonate leaving group such as the trifluoromethanesulfonate (9) upon treatment with trifluoromethane-sulfonic anhydride in an inert organic solvent such as methylene chloride and an amine base such as diazabicycloundecene, 2,6-lutidine, pyridine or the like at or below room temperature for a period of 30 minutes to 2 hours.
  • a sulfonate leaving group such as the trifluoromethanesulfonate (9) upon treatment with trifluoromethane-sulfonic anhydride in an inert organic solvent such as methylene chloride and an amine base such as diazabicycloundecene, 2,6-lutidine, pyridine or the like at or below room temperature for a period of 30 minutes to 2 hours.
  • nitro groups appended to these structures can be reduced to the corresponding amines (13) by treatment with hydrazine and a reduction catalyst such as iron (HI) chloride and carbon in an inert organic solvent such as methanol, ethanol or the like at a temperature of 65°-100°C for a period of 5-20 hours.
  • a reduction catalyst such as iron (HI) chloride and carbon
  • an inert organic solvent such as methanol, ethanol or the like
  • amines such as (13) can be converted to the corresponding urea derivatives (14) by treatment with an appropriate acylating agent such as phosgene, triphosgene, carbonyldiimidazole or the like, with or without an amine base such as pyridine in an inert organic solvent such as methylene chloride, chloroform, dichloroethane or the like together with the desired primary or secondary amine at 0°-25°C for a period of 1-48 hours.
  • an appropriate acylating agent such as phosgene, triphosgene, carbonyldiimidazole or the like
  • an amine base such as pyridine
  • an inert organic solvent such as methylene chloride, chloroform, dichloroethane or the like
  • amines such as (15) can be converted to the corresponding amide (18) or sulfonamide derivatives (19) by treatment with an appropriate acylating agent such as an acetyl chloride, acid anhydride, sulfonylchloride, sulfonic anhydride or the like, with or without an amine base such as pyridine, in an inert organic solvent such as methylene chloride, chloroform, dichloroethane, benzene, toluene, chlorobenzene or the like at 0°-100°C for a period of 1-10 hours.
  • an appropriate acylating agent such as an acetyl chloride, acid anhydride, sulfonylchloride, sulfonic anhydride or the like, with or without an amine base such as pyridine
  • an inert organic solvent such as methylene chloride, chloroform, dichloroethane, benzene, toluene, chlorobenz
  • iodides such as (20) can be converted to the corresponding amide (22) by treatment with an appropriate amine (21) and a palladium catalyst such as dichlorobis(triphenylphosphine)palladium(II) in the presence of an amine base such as triethylamine in an inert organic solvent such as N,N-dimethylformamide, or the like, under an atmosphere of carbon monoxide at 90 °C for a period of 5-25 hours.
  • amine base such as triethylamine
  • an inert organic solvent such as N,N-dimethylformamide, or the like
  • iodide (20) can be coupled with alkyl-, vinyl-, aryl- and heteroaryl-stannanes (23) using an appropriate palladium catalyst such as dichlorobis(triphenylphosphine) palladium(II) in an inert organic solvent such as N,N-dimethylformamide, toluene, or the like, at a temperature of 80°- 110°C with or without the presence of carbon monoxide to provide ketones (24) and carbon-linked derivatives (25), respectively.
  • palladium catalyst such as dichlorobis(triphenylphosphine) palladium(II) in an inert organic solvent such as N,N-dimethylformamide, toluene, or the like
  • ester (26) can be converted to the corresponding carboxylic acid (27) by base-catalyzed hydrolysis.
  • Treatment of (26) with an inorganic base such as lithium hydroxide, sodium hydroxide, or the like in a mixture of water and an inert organic solvent such as ethanol, methanol, or the like at a temperature such as 40°-100°C for a period of 30 minutes to 6 hours followed by neutralization with acid provides acid (27).
  • the compounds of the present invention are useful in the treatment of various sex hormone related conditions in men and women. This utility is manifested in their ability to act as antagonists of the neuropeptide hormone GnRH as demonstrated by activity in the following in vitro assays.
  • Human GnRH receptor binding assay Human GnRH receptor binding assay
  • the compounds to be assayed were dissolved and diluted in DMSO.
  • the final concentration of DMSO in the incubation medium was 0.5%.
  • the Wistar male rats (150-200 grams) were obtained from Charles River Laboratories (Wilmington, MA). Rats were maintained at a constant temperature (25°C) on a 12-hr light, 12-hr dark cycle. Rat chow and water were available ad libitum. The animals were sacrificed by decapitation and pituitary glands were aseptically removed and placed in Hank's Balanced Salt Solution (HBSS) in a 50-mL polypropylene centrifuge tube. The collection tube was centrifuged for 5 min at 250 x g, and HBSS was removed by aspiration. Pituitary glands were transferred to a disposable petri plate and minced with a scalpel.
  • HBSS Hank's Balanced Salt Solution
  • the minced tissue was then transferred to a 50-mL disposable centrifuge tube by suspending the tissue fragments in three successive 10-mL aliquots of HBSS containing 0.2% collagenase and 0.2% hyaluronidase.
  • the cell dispersion was carried out in a water bath at 37°C with gentle stirring for 30 min.
  • the cells were aspirated 20 to 30 times with a pipet and the undigested pituitary fragments were allowed to settle for 3 to 5 min.
  • the suspended cells were removed by aspiration, and then subjected to a 1200 x g centrifugation for 5 min. The cells were then resuspended in Culture medium.
  • the undigested pituitary fragments were treated with 30 mL aliquots of the digestion enzymes as above for a total of 3 digestions with the collagenase/ hyaluronidase mixture.
  • the resulting cell suspensions were pooled, counted and diluted to a concentration of 3 x 10-5 cells/ml, and 1.0 ml of this suspension was placed in each well of a 24-well tray (Costar, Cambridge, MA). Cells were maintained in a humidified 5% CO2-95% air atmosphere at 37°C for 3 to 4 days.
  • the culture medium consisted of DMEM containing 0.37% NaHCO3, 10% horse serum, 2.5% fetal bovine serum, 1% non-essential amino acids, 1% glutamine, and 0.1% gentamycin.
  • DMEM containing 0.37% NaHCO3, 10% horse serum, 2.5% fetal bovine serum, 1% non-essential amino acids(lOOX), 1% glutamine(lOOX), 1% Penicillin/Streptomycin (10,000 Units of Penicillin and 10,000 micrograms of Streptomycin per ml), and 25 mM HEPES, pH 7.4.
  • LH release was initiated by adding 1 ml of fresh medium containing test compounds in the presence of 2 nM GnRH to each well in duplicate. Incubation was carried out at 37°C for 3 hr. After incubation, medium was removed and centrifuged at 2,000 x g for 15 min to remove any cellular material. The supernatant fluid was removed and assayed for LH content with a double antibody RIA procedure using materials obtained from Dr. A. F. Parlow (Harbor-UCLA Medical Center, Torrance, CA).
  • the compounds of formula I are useful in a number of areas affected by GnRH. They may be useful in sex hormone related conditions, sex-hormone dependent cancers, benign prostatic hypertrophy or myoma of the uterus. Sex- hormone dependent cancers which may benefit from the administration of the compounds of this invention include prostatic cancer, uterine cancer, breast cancer and pituitary gonadotrophe adenomas. Other sex-hormone dependent conditions which may benefit from the administration of the compounds of this invention include endometriosis, polycystic ovarian disease, uterine fibroids and precocious puberty.
  • the compounds may also be used in combination with an angiotensin-converting enzyme inhibitor such as Enalapril or Captopril, an angiotensin H-receptor antagonist such as Losartan or a renin inhibitor for the treatment of uterine fibroids.
  • an angiotensin-converting enzyme inhibitor such as Enalapril or Captopril
  • an angiotensin H-receptor antagonist such as Losartan or a renin inhibitor for the treatment of uterine fibroids.
  • the compounds of the invention may also be useful for controlling pregnancy, as a contraceptive in both men and women, for in vitro fertilization, in the treatment of premenstrual syndrome, in the treatment of lupus erythematosis, in the treatment of hirsutism, in the treatment of irritable bowel syndrome and for the treatment of sleep disorders such as sleep apnea.
  • a further use of the compounds of this invention is as an adjunct to growth hormone therapy in growth hormone deficient children.
  • the compounds may be administered with growth hormone or a compound which increases the endogenous production or release of growth hormone.
  • Certain compounds have been developed which stimulate the release of endogenous growth hormone.
  • Peptides which are known to stimulate the release of endogenous growth hormone include growth hormone releasing hormone, the growth hormone releasing peptides GHRP-6 and GHRP-1 (described in U.S. Patent No. 4,411,890, PCT Patent Pub. No. WO 89/07110, and PCT Patent Pub. No. WO 89/07111) and GHRP-2 (described in PCT Patent Pub. No. WO 93/04081), as well as hexarelin (J.
  • Representative preferred growth hormone secretagoues employed in the present combination include the following:
  • the compounds of the invention may also be used in combination with bisphosphonates (bisphosphonic acids) and other agents, such as growth hormone secretagogues, e.g. MK-0677, for the treatment and the prevention of disturbances of calcium, phosphate and bone metabolism, in particular, for the prevention of bone loss during therapy with the GnRH antagonist, and in combination with estrogens, progesterones and or androgens for the prevention or treatment of bone loss or hypogonadal symptoms such as hot flashes during therapy with the GnRH antagonist.
  • Bisphosphonates (bisphosphonic acids) are known to inhibit bone resorption and are useful for the treatment of bone lithiasis as disclosed in U.S. Patent 4,621,077 to Rosini, et al.
  • the literature discloses a variety of bisphosphonic acids which are useful in the treatment and prevention of diseases involving bone resorption. Representative examples may be found in the following: U.S. Patent No. 3,251,907; U.S. Patent No. 3,422,137; U.S. Patent No. 3,584,125; U.S. Patent No. 3,940,436; U.S. Patent No. 3,944,599; U.S. Patent No. 3,962,432; U.S. Patent No. 4,054,598; U.S. Patent No. 4,267,108; U.S. Patent No. 4,327,039; U.S. Patent No. 4,407,761; U.S. Patent No. 4,578,376; U.S. Patent No.
  • Preferred bisphosphonates are selected from the group of the following compounds: alendronic acid, etidrononic acid, clodronic acid, pamidronic acid, tiludronic acid, risedronic acid, 6-amino-l-hydroxy-hexylidene-bisphosphonic acid, and l-hydroxy-3(methylpentylamino)-propylidene-bisphosphonic acid;or any pharmaceutically acceptable salt thereof.
  • a particularly preferred bisphosphonate is alendronic acid (alendronate), or a pharmaceutically acceptable salt thereof.
  • An especially preferred bisphosphonate is alendronate sodium, including alendronate sodium trihydrate. Alendronate sodium has received regulatory approval for marketing in the United States under the trademark FOS AMAX®.
  • a compound of the present invention may be co-administered with a 5a-reductase 2 inhibitor, such as finasteride or epristeride; a 5a-reductase 1 inhibitor such as 4,7b-dimethyl-4-aza-5a-cholestan-3-one, 3-oxo- 4-aza-4,7b-dimethyl- 16b-(4-chlorophenoxy)-5 a-androstane, and 3-oxo-4-aza-4,7b- dimethyl-16b-(phenoxy)-5a-androstane as disclosed in WO 93/23420 and WO 95/11254; dual inhibitors of 5a-reductase 1 and 5a-reductase 2 such as 3-oxo-4- aza-17b-(2,5-trifluoromethylphenyl-carbamoyl)-5a-androstane as disclosed in WO 95/07927; antiandrogens such as flutamide, casodex and c
  • a compound of the present invention may be used in combination with growth hormone, growth hormone releasing hormone or growth hormone secretagogues, to delay puberty in growth hormone deficient children, which will allow them to continue to gain height before fusion of the epiphyses and cessation of growth at puberty.
  • a compound of the present invention may be used in combination or co-administered with a compound having luteinizing hormone releasing activity such as a peptide or natural hormone or analog thereof.
  • peptide compounds include leuprorelin, gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterlin and recirelin.
  • the active agents may be administered separately or in conjunction.
  • the administration of one element may be prior to, concurrent to, or subsequent to the administration of the other agent.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in U.S. Patents 4,256,108; 4,166,452 and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene- oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n- propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • preservatives for example ethyl, or n- propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n- propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n- propyl, p-hydroxybenzoate
  • flavoring agents such as sucrose, saccharin or aspartame.
  • sweetening agents such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy beans, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Compounds of Formula I may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • compositions, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula I are employed.
  • topical application shall include mouth washes and gargles.
  • the compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • Compounds of the present invention may also be delivered as a suppository employing bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed.
  • a physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter, arrest or reverse the progress of the condition.
  • Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
  • doses of the compound of structural formula I useful in the method of the present invention range from 0.01 to 1000 mg per adult human per day. Most preferably, dosages range from 0.1 to 500 mg/day.
  • the compositions are preferably provided in the form of tablets containing 0.01 to 1000 milligrams of the active ingredient, particularly 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0002 mg/kg to about 50 mg/kg of body weight per day. The range is more particularly from about 0.001 mg/kg to 1 mg/kg of body weight per day.
  • the active agent of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in dividend doses of two, three or four times daily.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • Step 1A 4-chloro-5-nitro-2-(2-thiophen-2-yl-acetylamino)-benzoic acid methyl ester
  • Step 1C 2-[2-(7-chloro-6-nitro-2-oxo-3-thiophen-2-yl-l,2-dihydro-quinolin-4- yloxy)-ethyll -2-tetrahydrofuran
  • Step IE l-[7-chloro-2-oxo-4-(tetrahydrofuran-2-yl-ethoxy)-3-thiophen-2-yl- l,2-dihydroquinolin-6-yl1-3-pyridin-4-yl-urea
  • Step A 2-acetylamino-4-chloro-5-nitrobenzoic acid methyl ester
  • Step B 2-amino-4-chloro-5-nitrobenzoic acid methyl ester
  • Step 2B 7-chloro-3-(5-chlorothiophen-2-yl)-4-hydroxy-6-iodo-lH-quinolin-2- one
  • Step 2D (S)-4-[2-(oxetan-2-yl)-ethoxy]-7-chloro-3-(5-chlorothiophen-2-yl)-2- oxo-1 ,2-dihydroquinoline-6-carboxylic acid
  • Step 2E (S)-7-chloro-3-(5-chlorothiophen-2-yl)-2-oxo-4-(2-oxetan-2-yl- ethoxy)-l,2-dihydroquinoline-6-carboxylic acid pyrimidin-4-ylamide
  • To a solution of (S)-4-[2-(oxetan-2-yl)-ethoxy]-7-chloro-3-(5- chlorothiophen-2-yl)-2-oxo-l,2-dihydroquinoline-6-carboxylic acid in dry methylene chloride is added l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) followed by a catalytic amount of 4-dimethylaminopyridine and an excess of 4-aminopyrimidine and the mixture stirred at room temperature. After completion of reaction, the mixture is diluted with methylene chloride and washed with brine

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Abstract

There are disclosed compounds of formula (I) or pharmaceutically acceptable salts thereof which are useful as antagonists of GnRH and as such may be useful for the treatment of a variety of sex-hormone related conditions in both men and women.

Description

TITLE OF THE INNENTION
ANTAGONISTS OF GONADOTROP RELEASING HORMONE
BACKGROUND OF THE INNENTION
The gonadotropin-releasing hormone (GnRH), also referred to as luteinizing hormone-releasing hormone (LHRH), is a decapeptide that plays a key role in human reproduction. The hormone is released from the hypothalamus and acts on the pituitary gland to stimulate the biosynthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH released from the pituitary gland is primarily responsible for the regulation of gonadal steroid production in both sexes, whereas FSH regulates spermatogenesis in males and follicular development in females. GnRH agonists and antagonists have proven effective in the treatment of certain conditions which require inhibition of LH FSH release. In particular, GnRH-based therapies have proven effective in the treatment of endometriosis, uterine fibroids, polycystic ovarian disease, precocious puberty and several gonadal steroid-dependent neoplasia, most notably cancers of the prostate, breast and ovary. GnRH agonists and antagonists have also been utilized in various assisted fertilization techniques and have been investigated as a potential contraceptive in both men and women. They have also shown possible utility in the treatment of pituitary gonadotrophe adenomas, sleep disorders such as sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hyperplasia, hirsutism, as an adjunct to growth hormone therapy in growth hormone deficient children, and in murine models of lupus. GnRH antagonists may also be useful in combination with bisphosphonates (bisphosphonic acids) and other agents, such as growth hormone secretagogues, for the treatment and the prevention of disturbances of calcium, phosphate and bone metabolism, in particular, for the prevention of bone loss during therapy with the GnRH antagonist, and in combination with estrogens, progesterones, antiestrogens, antiprogestins and/or androgens for the prevention or treatment of bone loss or hypogonadal symptoms such as hot flashes during therapy with the GnRH antagonist.
Additionally, GnRH antagonists may be co-administered with a 5a- reductase 2 inhibitor, such as finasteride or epristeride; a 5a-reductase 1 inhibitor such as 4,7b-dimethyl-4-aza-5a-cholestan-3-one, 3-oxo-4-aza-4,7b-dimethyl-16b-(4- chlorophenoxy)-5a-androstane, and 3-oxo-4-aza-4,7b-dimethyl-16b-(phenoxy)-5a- androstane as disclosed in WO 93/23420 and WO 95/11254; dual inhibitors of 5a- reductase 1 and 5a-reductase 2 such as 3-oxo-4-aza-17b-(2,5-trifluoromethylphenyl- carbamoyl)-5a-androstane as disclosed in WO 95/07927; antiandrogens such as flutamide, casodex and cyproterone acetate, and alpha- 1 blockers such as prazosin, terazosin, doxazosin, tamsulosin, and alfuzosin.
Further, GnRH antagonists may be useful in combination with growth hormone, growth hormone releasing hormone or growth hormone secretagogues, to delay puberty in growth hormone deficient children, which will allow them to continue to gain height before fusion of the epiphyses and cessation of growth at puberty.
Further, GnRH antagonists may be useful in combination or co-administered with a compound having luteinizing hormone releasing activity such as a peptide or natural hormone or analog thereof. Such peptide compounds include leuprorelin, gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterlin and recirelin.
Additionally, GnRH antagonists may be useful as described in U.S. Patent No. 5,824,286 which discloses the administration of peptide GnRH antagonists such as Antide and azaline B to premenopausal women to enhance the readability of mammographic film relative to a mammogram effected in the absence of the administration.
Current GnRH antagonists are GnRH-like decapeptides which are generally administered intravenously or subcutaneously presumably because of negligible oral activity. These have amino acid substitutions usually at positions one, two, three, six and ten.
Non-peptide GnRH antagonists offer the possible advantage of oral administration. Non-peptide GnRH antagonists have been described in European Application 0 219 292 and in De, B. et al., J. Med. Chem., 32, 2036-2038 (1989), in WO 95/28405, WO 95/29900 and EP 0679642 all to Takeda Chemical Industries, Ltd.
Arylquinolone analogs have been described in the art and include those described in the following patents, patent applications and journal articles. JP-A-63- 295561 discloses a class of 3-phenyl-2(lH)-quinolone derivatives, substituted at the 4-position by an unsubstituted straight or branched alkoxy group and at the 7-position by an unsubstituted straight or branched alkoxy group. These compounds are alleged to exhibit a strong inhibitory action on bone resorption and a stimulatory effect on ossification, and thus to be useful as therapeutic agents for the prevention and treatment of osteoporosis.
J. Heterocycl. Chem., 1989, 26, 281 discloses a range of 3-(2- methoxyphenyl)-2(lH)-quinolones possessing a halogen substituent in the 6- or 7- position and an optional carboxylic acid substituent at the 4-position. A family of 3- phenyl-2(lH)-quinolone derivatives, substituted at the 4-position by an amino or benzylamino group and at the 7-position by a methyl or methoxy group, is described in Monatsh. Chem., 1982, 113, 751 and Nestn. Slov. Kern. Pros., 1986, 33, 271.
WO 93/10783 and WO 93/11115 disclose a class of 2-(lH)-quinolone derivatives, substituted at the 3-position by an optionally substituted aryl substituent and are selective non-competitive antagonists of ΝMD A receptors and/or are antagonists of AMPA receptors, and are therefore of utility in the treatment of conditions, such as neurodegenerative disorders, convulsions or schizophrenia.
FR 2711992-A1 discloses quinolone derivatives which are allegedly useful as antagonists of platelet activating factor.
WO 97/44321, WO 97/44339, WO 97/44037 and WO 97/44041 disclose non-peptidyl, arylquinolone derivatives as GnRH antagonists.
SUMMARY OF THE INVENTION
The present invention relates to compounds which are non-peptide antagonists of GnRH which can be used to treat a variety of sex-hormone related conditions in men and women, to methods for their preparation, and to methods and pharmaceutical compositions containing said compounds for use in mammals.
Because of their activity as antagonists of the hormone GnRH, the compounds of the present invention are useful to treat a variety of sex-hormone related conditions in both men and women. These conditions include endometriosis, uterine fibroids, polycystic ovarian disease, hirsutism, precocious puberty, gonadal steroid-dependent neoplasias such as cancers of the prostate, breast and ovary, gonadotrophe pituitary adenomas, sleep apnea, irritable bowel syndrome, premenstrual syndrome and benign prostatic hypertophy. They are also useful as an adjunct to treatment of growth hormone deficiency and short stature, and for the treatment of systemic lupus erythematosis. Further, the compounds of the invention may be useful in in vitro fertilization and as contraceptives. The compounds may also be useful in combination with androgens, estrogens, progesterones, antiestrogens and antiprogestogens for the treatment of endometriosis, fibroids and in contraception. They may also be useful in combination with testosterone or other androgens or antiprogestogens in men as a contraceptive. The compounds may also be used in combination with an angiotensin-converting enzyme inhibitor such as Enalapril or Captopril, an angiotensin 13-receptor antagonist such as Losartan or a renin inhibitor for the treatment of uterine fibroids. Additionally, the compounds of the invention may also be used in combination with bisphosphonates (bisphosphonic acids) and other agents, for the treatment and the prevention of disturbances of calcium, phosphate and bone metabolism, in particular, for the prevention of bone loss during therapy with the GnRH antagonist, and in combination with estrogens, progesterones and/or androgens for the prevention or treatment of bone loss or hypogonadal symptoms such as hot flashes during therapy with the GnRH antagonist.
Additionally, a compound of the present invention may be co-administered with a 5a-reductase 2 inhibitor, such as finasteride or epristeride; a 5a-reductase 1 inhibitor such as 4,7b-dimethyl-4-aza-5a-cholestan-3-one, 3-oxo-4- aza-4,7b-dimethyl-16b-(4-chlorophenoxy)-5a-androstane, and 3-oxo-4-aza-4,7b- dimethyI-16b-(phenoxy)-5a-androstane as disclosed in WO 93/23420 and WO 95/11254; dual inhibitors of 5a-reductase 1 and 5a-reductase 2 such as 3-oxo- 4-aza-17b-(2,5-trifluoromethylphenyl-carbamoyl)-5a-androstane as disclosed in WO 95/07927; antiandrogens such as flutamide, casodex and cyproterone acetate, and alpha- 1 blockers such as prazosin, terazosin, doxazosin, tamsulosin, and alfuzosin.
Further, a compound of the present invention may be used in combination with growth hormone, growth hormone releasing hormone or growth hormone secretagogues, to delay puberty in growth hormone deficient children, which will allow them to continue to gain height before fusion of the epiphyses and cessation of growth at puberty.
Further, a compound of the present invention may be used in combination or co-administered with a compound having luteinizing hormone releasing activity such as a peptide or natural hormone or analog thereof. Such peptide compounds include leuprorelin, gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterlin and recirelin.
Additionally, a compound of the present invention may be used as described in U.S. Patent No. 5,824,286 which discloses the administration of peptide GnRH antagonists such as Antide and azaline B to premenopausal women to enhance the readability of mammographic film relative to a mammogram effected in the absence of the administration.
DETAILED DESCRIPTION OF THE INNENTION
The present invention relates to compounds of the general formula
Figure imgf000006_0001
wherein A is a bond, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkoxy, said alkyl, alkenyl, alkoxy and alkynyl groups optionally substituted with C1-C6 alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C1-C6 alkoxy, fluoro, C(O)ORi55and aryl C1-C3 alkoxy;
B is a bond or Cχ-C6 alkyl, said alkyl group optionally substituted with C1-C6 alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C1-C alkoxy, fluoro, C^ORi^and aryl C1-C3 alkoxy;
X is O, S, SO, SO2, NR12, C R.13R14), or can be absent; E is a bond, O, S, SO or SO2;
Y is
Figure imgf000007_0001
where Z is O, S, or NR12; the nitrogen atoms contained in the heteroaromatic rings may exist either as drawn or, when chemically allowed, in their oxidized (N— >O) state;
Rl is H, C1-C6 alkyl, C3-C6 cycloalkyl, aryl or C1-C6 aralkyl, said alkyl and cycloalkyl groups optionally substituted with C -C6 alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C1-C6 alkoxy, fluoro, C^ORi^and aryl C1-C3 alkoxy; said aryl groups optionally substituted with H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, C1-C6 aralkyl, l5O(CRi3Ri4)p-, -Rl6C(O)O(CRι3Ri4)p-, Ri5θC(O)(CRi3Rl4)p-, -(CRi3Rl4)pS(O)nRl2. (CRl3Rl4)pC(O)NRι7Rl8, -(CRi3Ri4)pNRι7C(O)Ri6, -(CRi3Rl4)pN(Rl7Rl8) or halogen;
R2, 3 and R4 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, -Cβ aralkyl, Ri5θ(CRi3Rl4)p-, Rl6C(O)O(CRι3Ri4)p-, Ri5OC(O) (CRι3Rl4)p-, -(CRi3Rl4)pS(O)nRl2, (CRι3Rl4)pC(O)NRι7Rl8, -(CRι3Rl4)pNRl7C(O)Ri6, -(CRι3Rl4)pN(Ri7Rl8) or halogen; said alkyl, alkenyl, alkoxy and alkynyl groups optionally substituted with C1-C6 alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, Ci-Cβ alkoxy, fluoro, C^OR^a d aryl C1-C3 alkoxy; said aryl groups optionally substituted with H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, C1-C6 aralkyl, Ri5θ(CRi3Ri4) -, -Rl6C(O)O(CRι3Rl4)p-, Rl5θC(O)(CRi3Rl4)p-, -(CRi3Rl4)pS(O)nRl2, (CRl3Rl4)pC(O)NRι7Rl8, -(CRi Rl4)pNRl7C(O)Ri6, -(CRi3Rl4)pN(Rl7Rl8) or halogen; or
R2 and R3 taken together form a carbocyclic ring, saturated or unsaturated, of 3-7 carbon atoms or a heterocyclic ring containing 1-3 heteroatoms selected from N, O and S; R5, R6, R7 and Rξ independently are H, halogen, NO2, -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, Ci-Cg aralkyl, heteroaryl, Ci-Cβ heteroaralkyl, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, Ri5θ(CRi3Ri4)p-, -(CRι3Rl4)pCN, -(CRι3Rl4)pSOnRl2. -(CRi3Rl4)pSO2N (R17R18), -(CRl3Rl4)pN(Rl7Rl8). -(CRι3Rl4)pN(Rl7)C(O)Ri6, -(CRi3Rl4)pN(Rl7)C(O)N(Ri7Rl8); -(CRi3Rl4)pN(Rl7)SO2N (R17R18), -(CRi3Rl4)pN(Rl7)SO2Rl2, -(CRι3Rι4)pC(O)ORi5, -(CRι3Rl4)pOC(O)Ri6, -(CRi3Rl4)pC(O)N(Rι7Rl8), -(CRι3Rl4)p OC(O)N(Ri7Rl8), -(CRι3Rl4)pN(Rl7)C(O)ORι5, or -(CRι3Rl4)pN (Rl7)C(=NRi9)(NRι7Rl8); said alkyl, alkenyl, alkoxy and alkynyl groups optionally substituted with C1-C6 alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C1-C6 alkoxy, fluoro, C(O)ORi5,and aryl C1-C3 alkoxy; said aryl, aralkyl or heteroaryl groups optionally substituted with H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, Ci-Cβ aralkyl, R15O (CRi3Rl4)p-, Rl6C(O)O(CRi3Rl4)p-. Rl5OC(O)(CRi3Rl4)p-, -(CRi3Rl4)pS(O)nRl2, (CRι3Rl4)pC(O)NRι7Rl8, -(CRι3Rl4)p NRi7C(O)Ri6, -(CRi3Rl4)pN(Rl7 l8) or halogen; with the proviso that at least one of R5, R6, R7 and Rs contains a heteroaromatic group;
Rg and RgΑ are independently H, Ci-Cβ alkyl, aryl or Cχ-C6 aralkyl, said alkyl group optionally substituted with Ci-Cβ alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, Cχ-C6 alkoxy, fluoro, C(O)ORi55and aryl C1-C3 alkoxy; said aryl groups optionally substituted with H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, C1-C6 aralkyl, Ri5O(CRi3Ri4)p-, -Rl6C(O)O(CRi3Rl4)p-, Rl5OC(O)(CRi3Rl4)p-, -(CRi3Rl4)pS(O)nRi2, (CRι3Rl4)pC(O)NRi7Rl8, -(CRι3Rl4)pNRl7C(O)Ri6, -(CRi3Rl4)pN(Rl7Rl8) or halogen;
RlO is H, Cχ-C6 alkyl, aryl or Ci-Cg aralkyl, said alkyl group optionally substituted with Ci-Cβ alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C -Cg alkoxy, fluoro, C(O)ORi55and aryl C1-C3 alkoxy; said aryl groups optionally substituted with H, C1-C6 alkyl, C2-C15 alkenyl, C2-C6 alkynyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, C1-C6 aralkyl, Ri5O(CRi3Ri4)p-, -Rl6C(O)O(CRi3Rl4)p-, Rl5OC(O)(CRi3Rl4)p-, -(CRi3Rl4)pS(O)nRi2, (CRi3Rl4)pC(O)NRι7Rl8, -(CRi3Rl4)pNRl7C(O)Ri6, -(CRi3Rl4)pN(RπRl8) or halogen; or
R9 and R9a can be taken together to form a carbocyclic ring, saturated or unsaturated, of 3-7 variously substituted carbon atoms, or; R9 and Rio are taken together to form a heterocyclic ring, saturated or unsaturated, of
4-7 atoms containing 1-3 heteroatoms selected from O and S, or; Rl2 is H, C1-C6 alkyl, aryl or -C6 aralkyl; said alkyl group optionally substituted with C -C6 alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C1-C6 alkoxy, fluoro, C(O)ORi5;and aryl C1-C3 alkoxy; said aryl and aralkyl groups optionally substituted with H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, C1-C6 aralkyl, Ri5θ(CRi3Ri4)p-, Ri6C(O)O (CRι3Rl4)p-, Rl5θC(O)(CRι Rl4)p-5 -(CRi3Rl4)pS(O)nRι2, (CRi3Rl4)pC(O)NRi7Rl8, (CRl3Rl4)pNRl7C(O)Ri6) -(CRi3Ri4)pN(Ri7Ri8) or halogen; or Rl3 and R14 are independently H, Ci-Cβ alkyl, aryl or Ci-Cg aralkyl; said alkyl group optionally substituted with C -Cβ alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C1-C6 alkoxy, fluoro, C(O)ORi55and aryl C1-C3 alkoxy; said aryl and aralkyl group optionally substituted with H, Ci-Cβ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, C1-C6 aralkyl, Ri5θ(CRi3R 4)p-, Ri6C(O)O
(CRι3Rl4)p-, Rl5OC(O)(CRi3Rl4)p-, -(CRι3Rl4)pS(O)nRl2, (CRi3Rl4)pC(O)NRι7Rl8, (CRl3Rl4)pNRl7C(O)Ri6, -(CRi3Ri4)pN(Ri7Ri8) or halogen; Rl5 is H, C1-C6 alkyl, aryl, C1-C6 aralkyl, heteroaryl, substituted heteroaryl,
Ci-Cβ heteroaralkyl, or a heterocyclic ring containing 1-4 heteroatoms selected from O, N, and S; said alkyl group optionally substituted with C1-C6 alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, Ci-Cβ alkoxy, fluoro, C(O)ORi5jand aryl C1-C3 alkoxy; said aryl, aralkyl, heteroaryl and heteroaralkyl groups optionally substituted with H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, C1-C6 aralkyl, Ri5θ(CRι3Rl4)p-, Rl6C(O)O(CRι3Rl4)p-. Rl5OC(O) (CRi3Rl4)p-, -(CRi3Rl4)pS(O)„Ri2, (CRι3Rl4)pC(O)NRi7Rl8, (CRι Ri4)pNRi7C(O)Ri6, -(CRi3Rl4)pN(Rl7Rl8) or halogen; Rl6 is H, Cχ-C6 alkyl, aryl, C1-C6 aralkyl, heteroaryl, C1-C6 heteroaralkyl, or a heterocyclic ring containing 1-4 heteroatoms selected from O, N, and S; said alkyl group optionally substituted with C1-C6 alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C1-C6 alkoxy, fluoro, C(O)ORi55and aryl C1-C3 alkoxy; said aryl, aralkyl, heteroaryl and heteroaralkyl groups optionally substituted with H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, Ci-Cβ aralkyl, Rι5O(CRι3Rl4)p-, Rl6C(O)O(CRι3Rl4)p-, Rl5OC(O) (CRι3Rl4)p-, -(CRl3Rl4)pS(O)nRi2, (CRi3Rl4)pC(O)NRι7Rl8, (CRι3Rl4)pNRl7C(O)Ri6, -(CRι3Rl4)pN(Rl7Rl8) or halogen; Rl7 and Ri8 are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, Ci-Cβ aralkyl, heteroaryl, C1-C6 heteroaralkyl, or taken together form a carbocyclic ring(s) of 4-7 carbon atoms each or a heterocyclic ring containing 1-4 heteroatoms selected from O, N, and S; said alkyl and cycloalkyl groups optionally substituted with C1-C6 alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C1-C6 alkoxy, fluoro, C(O)ORi5;and aryl C1-C3 alkoxy; said aryl, aralkyl, heteroaryl and heteroaralkyl groups optionally substituted with H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, Ci-Cβ aralkyl, Ri5θ(CRi3Rl4) -, Rl6C(O)O(CRι Rl4)p-, Rl5OC(O) (CRι3Rl4)p-, -(CRι3Rl4)pS(O)nRi2, (CRι3Rl4)pC(O)NRι7Ri8, (CRi3Rl4)pNRl7C(O)Ri6, -(CRι3Rl4)pN(Rl7Rl8) or halogen;
Rl9 is H, C1-C6 alkyl or -CN; said alkyl group optionally substituted with Ci-Cβ alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C1-C6 alkoxy, fluoro, C(O)ORi55and aryl C1-C3 alkoxy; is 0, 1, or 2; p is 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable addition salt, hydrate, prodrug or active metabolite thereof, or where applicable, a geometric or optical isomer or racemic mixture thereof.
In a preferred embodiment, the invention relates to compounds of the general formula
Figure imgf000012_0001
wherein
A is a bond or C1-C6 alkyl; B is a bond or C1-C6 alkyl; X is O; Y is
Figure imgf000012_0002
R3 is H, Cl or CH3;
R6 is (CRi3Rl4)pC(O)N(Ri7Ri 8);
R7 is halogen;
R9 and Rio are taken together to form a heterocyclic ring, saturated or unsaturated, of
4-7 atoms containing 1-3 heteroatoms selected from O and S;
or a pharmaceutically acceptable addition salt, hydrate, prodrug or active metabolite thereof, or where applicable, a geometric or optical isomer or racemic mixture thereof.
Unless otherwise stated or indicated, the following definitions shall apply throughout the specification and claims.
When any variable (e.g., aryl, heterocycle, Ri, etc.) occurs more than one time in any constituent or in formula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The term "alkyl" is intended to include both branched- and straight- chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, e.g., methyl (Me), ethyl (Et), propyl, butyl, pentyl, hexyl, heptyl, octyl, nonanyl, decyl, undecyl, dodecyl, and the isomers thereof such as isopropyl (i-Pr), isobutyl (i-Bu), sec-butyl (s-Bu), tert-butyl (t-Bu), isopentane, isohexane, etc.
The term "aryl" includes phenyl and naphthyl. Preferably, aryl is phenyl.
The term "halogen" or "halo" is intended to include fluorine, chlorine, bromine and iodine.
The term "heterocycle" or "heterocyclic ring" is defined by all non- aromatic, heterocyclic rings of 3-7 atoms containing 1-3 heteroatoms selected from N, O, and S, such as oxirane, oxetane, tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, tetrahydropyridine, tetrahydropyrimidine, tetrahydrothiophene, tetrahydrothiopyran, morpholine, hydantoin, valerolactam, pyrrolidinone, and the like.
The term "heteroaryl" is intended to include the compounds shown below:
Figure imgf000014_0001
where Z is O, S, or Ri2; the nitrogen atoms contained in the heteroaromatic rings may exist either as drawn or, when chemically allowed, in their oxidized (N— >O) state.
In addition, it is well known to those skilled in the art that many of the foregoing heterocyclic groups can exist in more than one tautomeric form. It is intended that all such tautomers be included within the ambit of this invention.
The optical isomeric forms, that is mixtures of enantiomers, e.g., racemates, or diastereomers as well as individual enantiomers or diastereomers of the instant compound are included. These individual enantiomers are commonly designated according to the optical rotation they effect by the symbols (+) and (-), (L) and (D), (1) and (d) or combinations thereof. These isomers may also be designated according to their absolute spatial configuration by (S) and (R), which stands for sinister and rectus, respectively.
The individual optical isomers may be prepared using conventional resolution procedures, e.g., treatment with an appropriate optically active acid, separating the diastereomers and then recovering the desired isomer. In addition, the individual optical isomers may be prepared by asymmetric synthesis.
Additionally, a given chemical formula or name shall encompass pharmaceutically acceptable addition salts thereof and solvates thereof, such as hydrates.
The compounds of the present invention, while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable addition salts for purposes of stability, convenience of crystallization, increased solubility and other desirable properties.
The compounds of the present invention may be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" is intended to include all acceptable salts. Examples of acid salts are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic, methane sulfonic and the like which can be used as a dosage form for modifying the solubility or hydrolysis characteristics or can be used in sustained release or prodrug formulations. Depending on the particular functionality of the compound of the present invention, pharmaceutically acceptable salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N -dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N- benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide. These salts may be prepared by standard procedures, e.g. by reacting a free acid with a suitable organic or inorganic base, or alternatively by reacting a free base with a suitable organic or inorganic acid.
Also, in the case of an acid (-COOH) or alcohol group being present, pharmaceutically acceptable esters can be employed, e.g. methyl, ethyl, butyl, acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations. The compounds of the present invention may have chiral centers other than those centers whose stereochemistry is depicted in formula I, and therefore may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers, with all such isomeric forms being included in the present invention as well as mixtures thereof. Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this invention.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The compounds of the invention are prepared by the following reaction schemes. All substituents are as defined above unless indicated otherwise.
Scheme A
Figure imgf000016_0001
Figure imgf000016_0002
Reaction Scheme A
As shown in reaction Scheme A, treatment of amino ester (1) with an aryl acetyl chloride (2) in an inert organic solvent such as dichloroethane, chloroform, methylene chloride or the like at a temperature of 25°-80° C for a period of 30 minutes to 4 hours gives the corresponding amide (4). Alternatively, treatment of amine (1) and an arylacetic acid (3) with the coupling reagent l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), 1,3-dicyclo- hexylcarbodiimide (DCC) or the like with or without 1-hydroxybenzotriazole (HOBt) and a tertiary amine base such as N-methylmorpholine (NMM), triethylamine or the like in an inert organic solvent such as methylene chloride, chloroform, dimethylformamide, or mixtures thereof at or near room temperature for a period of 3-24 hours provides the corresponding amide derivative (4). Cyclization of amide (4) is effected by treatment with a strong base such as sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide or the like in an inert organic solvent such as tetrahydrofuran at a temperature of -20°-25° C for a period of 2-4 hours to give quinolone (5).
Scheme B
Figure imgf000018_0001
Reaction Scheme B
As shown in reaction Scheme B, treatment of the 4-hydroxy- quinolone (5) with an alkylamine containing a halogen or sulfonate leaving group (6) and a suitable base such as potassium carbonate, sodium carbonate, sodium bicarbonate, DBU or the like along with the catalyst sodium iodide in an inert organic solvent such as N,N-dimethylformamide, tetrahydrofuran, acetonitrile or the like at or around 80°C for a period of 4-24 hours provides the ether derivative (7). As an alternative, a suitably protected amino alcohol (8) may be coupled to (5) by treatment under Mitsunobu reaction conditions with triphenylphosphine and an activating agent such as diethyl azodicarboxylate, disopropyl azodicarboxylate or the like in an inert solvent such as tetrahydrofuran, toluene, chlorobenzene or the like at ambient temperature for a period of 4-64 hours to give (7). Scheme C
Figure imgf000019_0001
Reaction Scheme C
As shown in reaction Scheme C, the 4-hydroxyquinolone structure (5) may be modified by conversion to a sulfonate leaving group such as the trifluoromethanesulfonate (9) upon treatment with trifluoromethane-sulfonic anhydride in an inert organic solvent such as methylene chloride and an amine base such as diazabicycloundecene, 2,6-lutidine, pyridine or the like at or below room temperature for a period of 30 minutes to 2 hours. Reaction of (9) with an appropriate thiol (10) and an amine base such as diisopropylethylamine, triethylamine or the like in an inert organic solvent such as N,N-dimethylformamide at or below room temperature for a period of 4-24 hours gives the thioether analog
(ID- Scheme D
Figure imgf000020_0001
Reaction Scheme D
As shown in reaction Scheme D, nitro groups appended to these structures, such as in (12), can be reduced to the corresponding amines (13) by treatment with hydrazine and a reduction catalyst such as iron (HI) chloride and carbon in an inert organic solvent such as methanol, ethanol or the like at a temperature of 65°-100°C for a period of 5-20 hours. Alternatively, treatment of (12) with tin(II)chloride dihydrate in a polar solvent such as ethanol or methanol at a temperature of 70°-80°C for a period of 30 minutes to 4 hours gives the reduced, amino derivative (13).
Scheme E
Figure imgf000021_0001
14
Reaction Scheme E
As shown in reaction Scheme E, amines such as (13) can be converted to the corresponding urea derivatives (14) by treatment with an appropriate acylating agent such as phosgene, triphosgene, carbonyldiimidazole or the like, with or without an amine base such as pyridine in an inert organic solvent such as methylene chloride, chloroform, dichloroethane or the like together with the desired primary or secondary amine at 0°-25°C for a period of 1-48 hours.
Scheme F
Figure imgf000022_0001
Reaction Scheme F
As shown in reaction Scheme F, amines such as (15) can be converted to the corresponding amide (18) or sulfonamide derivatives (19) by treatment with an appropriate acylating agent such as an acetyl chloride, acid anhydride, sulfonylchloride, sulfonic anhydride or the like, with or without an amine base such as pyridine, in an inert organic solvent such as methylene chloride, chloroform, dichloroethane, benzene, toluene, chlorobenzene or the like at 0°-100°C for a period of 1-10 hours. Scheme G
Figure imgf000023_0001
22
Reaction Scheme G
As shown in Scheme G, iodides such as (20) can be converted to the corresponding amide (22) by treatment with an appropriate amine (21) and a palladium catalyst such as dichlorobis(triphenylphosphine)palladium(II) in the presence of an amine base such as triethylamine in an inert organic solvent such as N,N-dimethylformamide, or the like, under an atmosphere of carbon monoxide at 90 °C for a period of 5-25 hours. Scheme H
Figure imgf000024_0001
23 20 23
(Ph3P)2PdCI2 (cat.) CO(g) (Ph3P)2PdCI2 (cat.) triethylamine LiCI
Figure imgf000024_0002
Figure imgf000024_0003
ReactioReaction Scheme H
As shown in Reaction Scheme H, iodide (20) can be coupled with alkyl-, vinyl-, aryl- and heteroaryl-stannanes (23) using an appropriate palladium catalyst such as dichlorobis(triphenylphosphine) palladium(II) in an inert organic solvent such as N,N-dimethylformamide, toluene, or the like, at a temperature of 80°- 110°C with or without the presence of carbon monoxide to provide ketones (24) and carbon-linked derivatives (25), respectively. Scheme I
Figure imgf000025_0001
27
Reaction Scheme I
As shown in Scheme I, ester (26) can be converted to the corresponding carboxylic acid (27) by base-catalyzed hydrolysis. Treatment of (26) with an inorganic base such as lithium hydroxide, sodium hydroxide, or the like in a mixture of water and an inert organic solvent such as ethanol, methanol, or the like at a temperature such as 40°-100°C for a period of 30 minutes to 6 hours followed by neutralization with acid provides acid (27).
Scheme J
Figure imgf000026_0001
29
Reaction Scheme J
As shown in Scheme J, treatment of carboxylic acid (27) and an appropriate amine such as (28) with the coupling reagent l-(3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (EDC), 1,3-dicyclohexylcarbodiimide (DCC) or the like with or without 1-hydroxybenzotriazole (HOBt) and a tertiary amine base such as N-methylmorpholine (NMM), triethylamine or the like in an inert organic solvent such as methylene chloride, chloroform, dimethylformamide, or mixtures thereof at or near room temperature for a period of 3-24 hours provides the corresponding amide derivative (29).
The compounds of the present invention are useful in the treatment of various sex hormone related conditions in men and women. This utility is manifested in their ability to act as antagonists of the neuropeptide hormone GnRH as demonstrated by activity in the following in vitro assays. Human GnRH receptor binding assay
Crude membranes prepared from CHO cells expressing human GnRH receptors were the sources for GnRH receptor. [125l]Buserelin (a peptidyl GnRH analog) was used as the radiolabelled ligand. The binding activity was determined as an IC50 which is the antagonist concentration required to inhibit the specific binding of [125i]buserelin to GnRH receptors by 50%.
Rat pituitary GnRH receptor binding assay:
Crude plasma membranes prepared from rat pituitary tissues were incubated in a Tris.HCl buffer (50 mM, PH. 7.5) containing bovine serum albumin (.1%), [I-125]D-t-Bu-Ser6-Pro9-ethyl amide-GnRH, and the desired concentration of a test compound. The assay mixtures were incubated at 4°C for 90-120 minutes followed by rapid filtration and repeated washings through a glass fiber filter. The radioactivity of membrane bound radioligands was determined in a gamma-counter. From this data, the IC50 of the radioligand binding to GnRH receptors in the presence of test compound was estimated.
Inhibition of LH release assay
Active compounds from the GnRH receptor binding assay were further evaluated with an in vitro LH release assay to confirm their antagonist activity (blocking GnRH-induced LH release).
1. Sample Preparation
The compounds to be assayed were dissolved and diluted in DMSO. The final concentration of DMSO in the incubation medium was 0.5%.
2. Assay
The Wistar male rats (150-200 grams) were obtained from Charles River Laboratories (Wilmington, MA). Rats were maintained at a constant temperature (25°C) on a 12-hr light, 12-hr dark cycle. Rat chow and water were available ad libitum. The animals were sacrificed by decapitation and pituitary glands were aseptically removed and placed in Hank's Balanced Salt Solution (HBSS) in a 50-mL polypropylene centrifuge tube. The collection tube was centrifuged for 5 min at 250 x g, and HBSS was removed by aspiration. Pituitary glands were transferred to a disposable petri plate and minced with a scalpel. The minced tissue was then transferred to a 50-mL disposable centrifuge tube by suspending the tissue fragments in three successive 10-mL aliquots of HBSS containing 0.2% collagenase and 0.2% hyaluronidase. The cell dispersion was carried out in a water bath at 37°C with gentle stirring for 30 min. At the end of the incubation, the cells were aspirated 20 to 30 times with a pipet and the undigested pituitary fragments were allowed to settle for 3 to 5 min. The suspended cells were removed by aspiration, and then subjected to a 1200 x g centrifugation for 5 min. The cells were then resuspended in Culture medium. The undigested pituitary fragments were treated with 30 mL aliquots of the digestion enzymes as above for a total of 3 digestions with the collagenase/ hyaluronidase mixture. The resulting cell suspensions were pooled, counted and diluted to a concentration of 3 x 10-5 cells/ml, and 1.0 ml of this suspension was placed in each well of a 24-well tray (Costar, Cambridge, MA). Cells were maintained in a humidified 5% CO2-95% air atmosphere at 37°C for 3 to 4 days. The culture medium consisted of DMEM containing 0.37% NaHCO3, 10% horse serum, 2.5% fetal bovine serum, 1% non-essential amino acids, 1% glutamine, and 0.1% gentamycin. On the day of an experiment, cells were washed three times 1 1/2 hrs prior to and two more times immediately before the start of the experiment with DMEM containing 0.37% NaHCO3, 10% horse serum, 2.5% fetal bovine serum, 1% non-essential amino acids(lOOX), 1% glutamine(lOOX), 1% Penicillin/Streptomycin (10,000 Units of Penicillin and 10,000 micrograms of Streptomycin per ml), and 25 mM HEPES, pH 7.4. LH release was initiated by adding 1 ml of fresh medium containing test compounds in the presence of 2 nM GnRH to each well in duplicate. Incubation was carried out at 37°C for 3 hr. After incubation, medium was removed and centrifuged at 2,000 x g for 15 min to remove any cellular material. The supernatant fluid was removed and assayed for LH content with a double antibody RIA procedure using materials obtained from Dr. A. F. Parlow (Harbor-UCLA Medical Center, Torrance, CA).
The compounds of formula I are useful in a number of areas affected by GnRH. They may be useful in sex hormone related conditions, sex-hormone dependent cancers, benign prostatic hypertrophy or myoma of the uterus. Sex- hormone dependent cancers which may benefit from the administration of the compounds of this invention include prostatic cancer, uterine cancer, breast cancer and pituitary gonadotrophe adenomas. Other sex-hormone dependent conditions which may benefit from the administration of the compounds of this invention include endometriosis, polycystic ovarian disease, uterine fibroids and precocious puberty. The compounds may also be used in combination with an angiotensin-converting enzyme inhibitor such as Enalapril or Captopril, an angiotensin H-receptor antagonist such as Losartan or a renin inhibitor for the treatment of uterine fibroids.
The compounds of the invention may also be useful for controlling pregnancy, as a contraceptive in both men and women, for in vitro fertilization, in the treatment of premenstrual syndrome, in the treatment of lupus erythematosis, in the treatment of hirsutism, in the treatment of irritable bowel syndrome and for the treatment of sleep disorders such as sleep apnea.
A further use of the compounds of this invention is as an adjunct to growth hormone therapy in growth hormone deficient children. The compounds may be administered with growth hormone or a compound which increases the endogenous production or release of growth hormone. Certain compounds have been developed which stimulate the release of endogenous growth hormone. Peptides which are known to stimulate the release of endogenous growth hormone include growth hormone releasing hormone, the growth hormone releasing peptides GHRP-6 and GHRP-1 (described in U.S. Patent No. 4,411,890, PCT Patent Pub. No. WO 89/07110, and PCT Patent Pub. No. WO 89/07111) and GHRP-2 (described in PCT Patent Pub. No. WO 93/04081), as well as hexarelin (J. Endocrinol Invest.. 15(Suppl 4), 45 (1992)). Other compounds which stimulate the release of endogenous growth hormone are disclosed, for example, in the following: U.S. Patent No. 3,239,345; U.S. Patent No. 4,036,979; U.S. Patent No. 4,411,890; U.S. Patent No. 5,206,235; U.S. Patent No. 5,283,241; U.S. Patent No. 5,284,841; U.S. Patent No. 5,310,737; U.S. Patent No. 5,317,017; U.S. Patent No. 5,374,721; U.S. Patent No. 5,430,144; U.S. Patent No. 5,434,261; U.S. Patent No. 5,438,136; EPO Patent Pub. No. 0,144,230; EPO Patent Pub. No. 0,513,974; PCT Patent Pub. No. WO 94/07486; PCT Patent Pub. No. WO 94/08583; PCT Patent Pub. No. WO 94/11012; PCT Patent Pub. No. WO 94/13696; PCT Patent Pub. No. WO 94/19367; PCT Patent Pub. No. WO 95/03289; PCT Patent Pub. No. WO 95/03290; PCT Patent Pub. No. WO 95/09633; PCT Patent Pub. No. WO 95/11029; PCT Patent Pub. No. WO 95/12598; PCT Patent Pub. No. WO 95/13069; PCT Patent Pub. No. WO 95/14666; PCT Patent Pub. No. WO 95/16675; PCT Patent Pub. No. WO 95/16692; PCT Patent Pub. No. WO 95/17422; PCT Patent Pub. No. WO 95/17423; Science. 260. 1640-1643 (lune 11, 1993); Ann. Rep. Med. Chem., 28, 177-186 (1993); Bioorg. Med. Chem. Ltrs., 4(22), 2709-2714 (1994); and Proc. Natl. Acad. Sci. USA 92, 7001-7005 (July 1995).
Representative preferred growth hormone secretagoues employed in the present combination include the following:
1 ) N- [ 1 (R)- [( 1 ,2-Dihydro- 1 -methanesulf onylspiro [3H-indole-3 ,4 -piperidin] - 1 - yl)carbonyl]-2-(lH-indol-3-yl)ethyl]-2-amino-2-methyl-propanamide;
2) N-[l(R)-[(l,2-Dihydro-l-methanecarbonylspiro[3H-indole-3,4-ρiperidin]-l - yl)carbonyl]-2-(lH-indol-3-yl)ethyl]-2-amino-2-methyl-propanamide;
3) N-[l(R)-[(l,2-Dihydro-l-benzenesulfonylspiro[3H-indole-3,4-piperidin]-l - yl)carbonyl]-2-(lH-indol-3-yl)ethyl]-2-amino-2-methyl-propanamide;
4) N-[l(R)-[(3,4-Dihydro-spiro[2H-l-benzopyran-2,4 -piρeridin]-l -yl) carbonyl]-2- (lH-indol-3-yl)ethyl]-2-amino-2-methylpropanamide;
5) N-[l(R)-[(2-Acetyl-l,2,3,4-tetrahydrospiro[isoquinolin-4,4'-piperidin]-r- yl)carbonyl]-2-(indol-3-yl)ethyl]-2-amino-2-methyl-propanamide;
6) N-[ 1 (R)- [(1 ,2-Dihydro- 1-methanesulf onylspiro [3H-indole-3 ,4 -piperidin]- 1 - yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide;
7) N-[l(R)-[(l,2-Dihydro-l-methanesulfonylspiro[3H-indole-3,4'-piperidin]-l - yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide methanesulf onate;
8) N-[l(R)-[(l,2-Dihydro-l-methanesulfonylspiro[3H-indole-3,4'-piperidin]-l - yl)carbonyl]-2-(2',6 -difluorophenylmethyloxy)ethyl]-2-amino-2-methylpropanamide;
9) N-[l(R)-[(l,2-Dihydro-l-methanesulfonyl-5-fluorospiro[3H-indole-3,4- piperidin] - 1 -yl)carbonyl] -2-(phenylmethyloxy)ethyl] -2-amino-2-methylpropanamide ; 10) N-[l(S)-[(l,2-Dihydro-l-methanesulfonylspiro[3H-indole-3,4'-piperidin]-l'-yl) carbonyl]-2-(phenylmethylthio)ethyl]-2-amino-2-methylpropanamide;
11) N-[l(R)-[(l,2-Dihydro-l-methanesulfonylspiro[3H-indole-3,4 -piperidin]-l - yl)carbonyl] -3 -phenylpropyl] -2-amino-2-methyl-propanamide;
12) N-[l(R)-[(l,2-Dihydro-l-methanesulfonylspiro[3H-indole-3,4'-piperidin]-l - yl)carbonyl]-3-cyclohexylpropyl]-2-amino-2-methyl-propanamide;
13) N-[l(R)-[(l,2-Dihydro-l-methanesulfonylspiro[3H-indole-3,4'-piperidin]-l - yl)carbonyl]-4-phenylbutyl]-2-amino-2-methyl-propanamide;
14) N-[1(R)-[(1 ,2-Dihydro-l-methanesulfonylspiro[3H-indole-3,4 -piperidin]-l - yl)carbonyl] -2-(5 -fluoro- lH-indol-3 -yl)ethyl] -2-amino-2-methylpropanamide ;
15) N-[l(R)-[(l,2-Dihydro-l-methanesulfonyl-5-fluorospiro[3H-indole-3,4 - piperidin]-r-yl)carbonyl]-2-(5-fluoro-lH-indol-3-yl)ethyl]-2-amino-2- methylpropanamide;
16) N-[l(R)-[(l,2-Dihydro-l-(2-ethoxycarbonyl)methylsulfonylspiro-[3H-indole- 3,4-piperidin]-l -yl)carbonyl]-2-(lH-indol-3-yl)ethyl]-2-amino-2- methylpropanamide;
17) N-[l(R)-[(lJ2-Dihydro-l,l-dioxospiro[3H-benzothiophene-3,4'-piperidin]-l - yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide;
or pharmaceutically acceptable salts thereof.
The compounds of the invention may also be used in combination with bisphosphonates (bisphosphonic acids) and other agents, such as growth hormone secretagogues, e.g. MK-0677, for the treatment and the prevention of disturbances of calcium, phosphate and bone metabolism, in particular, for the prevention of bone loss during therapy with the GnRH antagonist, and in combination with estrogens, progesterones and or androgens for the prevention or treatment of bone loss or hypogonadal symptoms such as hot flashes during therapy with the GnRH antagonist. Bisphosphonates (bisphosphonic acids) are known to inhibit bone resorption and are useful for the treatment of bone lithiasis as disclosed in U.S. Patent 4,621,077 to Rosini, et al.
The literature discloses a variety of bisphosphonic acids which are useful in the treatment and prevention of diseases involving bone resorption. Representative examples may be found in the following: U.S. Patent No. 3,251,907; U.S. Patent No. 3,422,137; U.S. Patent No. 3,584,125; U.S. Patent No. 3,940,436; U.S. Patent No. 3,944,599; U.S. Patent No. 3,962,432; U.S. Patent No. 4,054,598; U.S. Patent No. 4,267,108; U.S. Patent No. 4,327,039; U.S. Patent No. 4,407,761; U.S. Patent No. 4,578,376; U.S. Patent No. 4,621,077; U.S. Patent No. 4,624,947; U.S. Patent No. 4,746,654; U.S. Patent No. 4,761,406; U.S. Patent No. 4,922,007; U.S. Patent No. 4,942,157; U.S. Patent No. 5,227,506; U.S. Patent No. 5,270,365; EPO Patent Pub. No. 0,252,504; and J. Org. Chem., 36, 3843 (1971).
The preparation of bisphosphonic acids and halo-bisphosphonic acids is well known in the art. Representative examples may be found in the above mentioned references which disclose the compounds as being useful for the treatment of disturbances of calcium or phosphate metabolism, in particular, as inhibitors of bone resorption.
Preferred bisphosphonates are selected from the group of the following compounds: alendronic acid, etidrononic acid, clodronic acid, pamidronic acid, tiludronic acid, risedronic acid, 6-amino-l-hydroxy-hexylidene-bisphosphonic acid, and l-hydroxy-3(methylpentylamino)-propylidene-bisphosphonic acid;or any pharmaceutically acceptable salt thereof. A particularly preferred bisphosphonate is alendronic acid (alendronate), or a pharmaceutically acceptable salt thereof. An especially preferred bisphosphonate is alendronate sodium, including alendronate sodium trihydrate. Alendronate sodium has received regulatory approval for marketing in the United States under the trademark FOS AMAX®.
Additionally, a compound of the present invention may be co-administered with a 5a-reductase 2 inhibitor, such as finasteride or epristeride; a 5a-reductase 1 inhibitor such as 4,7b-dimethyl-4-aza-5a-cholestan-3-one, 3-oxo- 4-aza-4,7b-dimethyl- 16b-(4-chlorophenoxy)-5 a-androstane, and 3-oxo-4-aza-4,7b- dimethyl-16b-(phenoxy)-5a-androstane as disclosed in WO 93/23420 and WO 95/11254; dual inhibitors of 5a-reductase 1 and 5a-reductase 2 such as 3-oxo-4- aza-17b-(2,5-trifluoromethylphenyl-carbamoyl)-5a-androstane as disclosed in WO 95/07927; antiandrogens such as flutamide, casodex and cyproterone acetate, and alpha-1 blockers such as prazosin, terazosin, doxazosin, tamsulosin, and alfuzosin.
Further, a compound of the present invention may be used in combination with growth hormone, growth hormone releasing hormone or growth hormone secretagogues, to delay puberty in growth hormone deficient children, which will allow them to continue to gain height before fusion of the epiphyses and cessation of growth at puberty. Further, a compound of the present invention may be used in combination or co-administered with a compound having luteinizing hormone releasing activity such as a peptide or natural hormone or analog thereof. Such peptide compounds include leuprorelin, gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterlin and recirelin.
For combination treatment with more than one active agent, where the active agents are in separate dosage formulations, the active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of the other agent.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in U.S. Patents 4,256,108; 4,166,452 and 4,265,874 to form osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene- oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n- propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy beans, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Compounds of Formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula I are employed. (For purposes of this application, topical application shall include mouth washes and gargles.) The compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. Compounds of the present invention may also be delivered as a suppository employing bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter, arrest or reverse the progress of the condition. Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug. Preferably, doses of the compound of structural formula I useful in the method of the present invention range from 0.01 to 1000 mg per adult human per day. Most preferably, dosages range from 0.1 to 500 mg/day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01 to 1000 milligrams of the active ingredient, particularly 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0002 mg/kg to about 50 mg/kg of body weight per day. The range is more particularly from about 0.001 mg/kg to 1 mg/kg of body weight per day.
Advantageously, the active agent of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in dividend doses of two, three or four times daily. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
The following examples illustrate the preparation of some of the compounds of the invention and are not to be construed as limiting the invention disclosed herein.
EXAMPLE 1
Figure imgf000037_0001
l-[7-chloro-2-oxo-4-(tetrahydrofuran-2-yl-ethoxy)-3-thiophen-2-yl-l,2- dihydroquinolin-6-yl1-3-pyridin-4-yl-urea
Step 1A 4-chloro-5-nitro-2-(2-thiophen-2-yl-acetylamino)-benzoic acid methyl ester
To a suspension of 2-amino-4-chloro-5-nitrobenzoic acid methyl ester (221 mg in 2.5 mL of dry 1,2-dichloroethane) was added a solution of thiophen-2- yl-acetyl chloride (169 mg in 3.0 mL dry 1,2-dichloroethane) and the mixture heated at reflux on an oil bath. After 18 hours, the reaction was cooled and the solvent removed in vacuo. Recrystallization of the crude product from methanol gave the title compound (230 mg). Step IB 7-chloro-4-hvdroxy-6-nitro-3 -thiophen-2-yl- lH-quinolin-2-one
To a solution of 4-chloro-5-nitro-2-(2-thiophen-2-yl-acetylamino)- benzoic acid methyl ester (130 mg in 4.0 mL dry tetrahydrofuran) at 0°C was added dropwise a solution of sodium bis(trimethylsilyl)amide (0.92 mL of a 1.0M solution in tetrahydrofuran) and the mixture warmed to room temperature. After 3 hours, the reaction was quenched by the addition of 6N hydrochloric acid. The slurry was stirred for 10 minutes then filtered and washed with ice cold acetonitrile. The residue was dried in vacuo to give the title compound (79 mg).
Step 1C 2-[2-(7-chloro-6-nitro-2-oxo-3-thiophen-2-yl-l,2-dihydro-quinolin-4- yloxy)-ethyll -2-tetrahydrofuran
To a solution of 7-chloro-4-hydroxy-6-nitro-3-thiophen-2-yl-lH- quinolin-2-one in tetrahydrofuran at 0°C is added 2-(tetrahydrofuran-2-yl) ethanol followed by triphenylphosphine and diethyl azodicarboxylate and the mixture warmed to room temperature. After completion of the reaction, the solvents are removed in vacuo and the residue purified by flash chromatography on silica gel to give the title compound.
Step ID 2-[2-(6-amino-7-chloro-2-oxo-3-thiophen-2-yl-l,2-dihydroquinolin-4- yloxy)-ethyl1 -2-tetrahydrofuran
To a solution of 2-[2-(7-chloro-6-nitro-2-oxo-3-thiophen-2-yl-l,2- dihydro-quinolin-4-yloxy)-ethyl]-2-tetrahydrofuran in ethanol is added tin(IJ)cloride dihydrate and the mixture heated to 70°C on an oil bath. After several hours, the reaction is cooled to room temperature and quenched by the addition of ice-water. The acidity of the resulting solution is adjusted to pΗ 8 by the addition of saturated aqueous sodium bicarbonate and the mixture extracted (2x) with ethyl acetate. The combined organics are washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification of the crude oil by flash chromatography on silica gel gives the title compound.
Step IE l-[7-chloro-2-oxo-4-(tetrahydrofuran-2-yl-ethoxy)-3-thiophen-2-yl- l,2-dihydroquinolin-6-yl1-3-pyridin-4-yl-urea
To a solution of 2-[2-(6-amino-7-chloro-2-oxo-3-thiophen-2-yl-l,2- dihydroquinolin-4-yloxy)-ethyl]-2-tetrahydrofuran in dry methylene chloride at 0°C is added phosgene followed by an excess of triethylamine and the mixture stirred for 1 hour at 0°C. At this time, 4-aminopyridine is added and the mixture allowed to warm to room temperature. Upon completion of reaction, the mixture is diluted with ethyl acetate and the mixture quenched by the addition of 10% citric acid. The organic portion is concentrated in vacuo and purified by flash chromatography on silica gel to provide the title compound.
Preparation of Synthetic Intermediates
2-amino-4-chloro-5-nitrobenzoic acid methyl ester
Step A: 2-acetylamino-4-chloro-5-nitrobenzoic acid methyl ester
To a solution of 3 mL cone, sulfuric acid and 0.40 mL of 90% nitric acid at 0°C was added 2-acetylamino-4-chlorobenzoic acid methyl ester (1.5 g) in three portions over a period of 20 minutes. This was stirred at 0°C for 30 minutes then allowed to warm to room temperature for an additional 1 hour. At this time the reaction was poured into 50 mL of an ice/water mixture and extracted with ethyl acetate (3x 50 mL). The combined organics were washed sequentially with water (2x 50 mL), 10% sodium bicarbonate (2x 50 mL) and brine (50 mL) then dried over magnesium sulfate and concentrated in vacuo. Recrystallization of the crude product from methanol gave the title compound (1.02 g).
Step B: 2-amino-4-chloro-5-nitrobenzoic acid methyl ester
To a solution of 2-acetylamino-4-chloro-5-nitrobenzoic acid methyl ester (1.02 g in 15 mL methanol) was added 1 mL of cone, sulfuric acid and the mixture heated to reflux on an oil bath. After 1 hour, the mixture was concentrated in vacuo and the resulting solid dissolved in 200 mL ethyl acetate. This was then washed with 10% sodium bicarbonate (2x 100 mL) and brine (100 mL) and the organics dried over magnesium sulfate. The concentrate was recrystallized from methanol to give the title compound (0.82 g). Thiophen-2-yl-acetyl chloride
To a solution of 2-thiophenyl acetic acid (150 mg in 2.5 mL dry methylene chloride) at 0°C was added 0.004 mL N,N-dimethylformamide followed by the dropwise addition of 0.097 mL of oxalyl chloride. After 15 minutes the mixture was warmed to room temperature and stirred for an additional 2.5 hours. Removal of the solvents in vacuo provided the title compound which was used without purification.
2-(Tetrahydrofuran-2-yl) ethanol
To a solution of (tetrahydrofuran-2-yl) acetic acid ethyl ester (2.0 mL in 100 mL dry diethyl ether) at 0°C was added 0.361g of lithium aluminum hydride and the mixture stirred at low temperature. After 45 minutes the reaction was quenched by the addition of 0.36mL water then 0.36mL 2N sodium hydroxide followed by 1.08mL water and the mixture stirred vigorously for 20 minutes. After this time the solids were removed by filtration and washed successively with ether and ethyl acetate. The combined organics were concentrated in vacuo to give the crude title compound (0.947g)
Following a procedure similar to that described above, the following compounds may be prepared:
Figure imgf000040_0001
Figure imgf000040_0002
Figure imgf000041_0002
EXAMPLE 2
Figure imgf000041_0001
(S)-7-chloro-3-(5-chlorothiophen-2-yl)-2-oxo-4-(2-oxetan-2-yl-ethoxy)-l,2- dihydroquinoline-6-carboxylic acid pyrimidin-4-ylamide Step 2A 4-chloro-2-[2-(5-chlorothiophen-2-yl)-acetylamino]-5-iodo-benzoic acid methyl ester
Prepared essentially as described in EXAMPLE 1, Step A from 5.0 g
2-amino-4-chloro-5-iodobenzoic acid methyl ester and 2.8 g (5-chlorothiophen-2- yl)acetyl chloride (also prepared essentially as described in EXAMPLE 1) to give the title compound (5.0 g).
Step 2B 7-chloro-3-(5-chlorothiophen-2-yl)-4-hydroxy-6-iodo-lH-quinolin-2- one
Prepared essentially as described in EXAMPLE 1, Step B from 7.5 g
(4-chloro-2-[2-(5-chlorothiophen-2-yl)-acetylamino]-5-iodo-benzoic acid methyl ester to give the title compound (5.9 g).
Step 2C (S)-2-{2-[7-chloro-3-(5-chlorothiophen-2-yl)-6-iodo-2-oxo-l,2- dihydroquinolin-4-yloxyl -ethyl } -2-oxetane
Prepared essentially as described in EXAMPLE 1, Step C from 7- chloro-3-(5-chlorothiophen-2-yl)-4-hydroxy-6-iodo-lH-quinolin-2-one and (S)-2-
(oxetan-2-yl)ethanol to give the title compound.
Step 2D (S)-4-[2-(oxetan-2-yl)-ethoxy]-7-chloro-3-(5-chlorothiophen-2-yl)-2- oxo-1 ,2-dihydroquinoline-6-carboxylic acid
To a solution of (S)-2-{2-[7-chloro-3-(5-chlorothiophen-2-yl)- 6-iodo-2-oxo-l,2-dihydroquinolin-4-yloxy]-ethyl}-2-oxetane is added [1,1 - bis(diphenylphosphino)ferrocene)dichloropalladium (II) followed by an excess of potassium acetate and the mixture heated to 60°C under an atmosphere of carbon monoxide. After approximately 6 hours, the mixture is cooled to room temperature and partitioned between ethyl acetate and 0.5N hydrochloric acid and extracted. The organic portion is then dried over sodium sulfate and the concentrate purified by flash chromatography on silica gel to give the title compound.
Step 2E (S)-7-chloro-3-(5-chlorothiophen-2-yl)-2-oxo-4-(2-oxetan-2-yl- ethoxy)-l,2-dihydroquinoline-6-carboxylic acid pyrimidin-4-ylamide To a solution of (S)-4-[2-(oxetan-2-yl)-ethoxy]-7-chloro-3-(5- chlorothiophen-2-yl)-2-oxo-l,2-dihydroquinoline-6-carboxylic acid in dry methylene chloride is added l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) followed by a catalytic amount of 4-dimethylaminopyridine and an excess of 4-aminopyrimidine and the mixture stirred at room temperature. After completion of reaction, the mixture is diluted with methylene chloride and washed with brine. The organic portion is concentrated in vacuo and the residue purified by flash chromatography on silica gel to give the title compound.
Following a procedure similar to that described above, the following compounds may be prepared:
Figure imgf000043_0001
Figure imgf000043_0002
Figure imgf000044_0001

Claims

WHAT IS CLAIMED IS:
A compound of the formula
Figure imgf000045_0001
wherein A is a bond, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkoxy, said alkyl, alkenyl, alkoxy and alkynyl groups optionally substituted with Ci-Cβ alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, Ci-Cβ alkoxy, fluoro, C(O)ORi5;and aryl C1-C3 alkoxy;
B is a bond or Ci-Cβ alkyl, said alkyl group optionally substituted with C1-C6 alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, Ci-Cβ alkoxy, fluoro, C(O)ORi5;and aryl C1-C3 alkoxy;
X is O, S, SO, SO2, NR12, C(Ri3Ri4), or can be absent; E is a bond, O, S, SO or SO2;
Y is
Figure imgf000046_0001
where Z is O, S, or NRi2; the nitrogen atoms contained in the heteroaromatic rings may exist either as drawn or, when chemically allowed, in their oxidized (N— >O) state;
Rl is H, C1-C6 alkyl, C3-C6 cycloalkyl, aryl or C1-C6 aralkyl, said alkyl and cycloalkyl groups optionally substituted with Ci-Cβ alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C1-C6 alkoxy, fluoro, C(O)ORi5;and aryl C1-C3 alkoxy; said aryl groups optionally substituted with H, Ci-Cβ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, C1-C6 aralkyl, Ri5O(CRi3Ri4)p-, -Rl6C(O)O(CRι3Rl4)p-) Rl5θC(O)(CRi3Rl4)p-, -(CRi3Rl4)pS(O)nRi2, (CRi3Rl4)pC(O)NRι7Rl8, -(CRi3Rl4)p Rl7C(O)Ri6, -(CRi3Rl4)pN(Ri7Rl8) or halogen;
R2, R3 and R4 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, C1-C6 aralkyl, Rι5O(CRι3Rl4)p-, Rl6C(O)O(CRι3Rl4)p-. Rl5OC(O) (CRι3Rl4)p-, -(CRl3Rl4)pS(O)nRl2, (CRι3Rl4)pC(O)NRι7Rl8, -(CRι3Rl4)pNRl7C(O)Ri6; -(CRι3Rl4)pN(Rl7Rl8) or halogen; said alkyl, alkenyl, alkoxy and alkynyl groups optionally substituted with C1-C6 alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C1-C6 alkoxy, fluoro, C(O)ORi5sand aryl C1-C3 alkoxy; said aryl groups optionally substituted with H, Ci-Cβ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, C1-C6 aralkyl, Ri5θ(CRi3Ri4) -, -Rl6C(O)O(CRι3Rl4)p-, Rl5θC(O)(CRi3Rl4)p-, -(CRi3Rl4)pS(O)nRl2, (CRl3Rl4)pC(O)NRi7Rl8, -(CRi3Rl4)p Rl7C(O)Ri6, -(CRi3Rl4)pN(Rl7Rl8) or halogen; or
R2 and R3 taken together form a carbocyclic ring, saturated or unsaturated, of 3-7 carbon atoms or a heterocyclic ring containing 1-3 heteroatoms selected from N, O and S; R5, R6, R7 and Rg independently are H, halogen, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, C1-C6 aralkyl, heteroaryl, C1-C6 heteroaralkyl, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, Ri5θ(CRi3Ri4) -, -(CRι3Rl4)pCN, -(CRι3Rl4)pSOnRl2, -(CRι3Rl4)pSO2N (R17R18), -(CRi3Rl4)pN(Rl7Rl8). -(CRi3Rl4)pN(Rl7)C(O)Rι6, -(CRi3Rl4)pN(Rl7)C(O)N(Ri7Rl8), -(CRl3Rl4)pN(Rl7)SO2N
(R17R18), -(CRi3Rl4)pN(Rl7)SO2Rl2, -(CRι3Rl4)pC(O)ORι5, -(CRi3Rl4)pOC(O)Ri6, -(CRi3Rl4)pC(O)N(Ri7Rl8). -(CRi3Rl4)p OC(O)N(Rι7Rl8), -(CRi3Rl4)pN(Rl7)C(O)ORi5, or -(CRι3Rl4)pN (Rl7)C(=NRi9)(NRi7Rl8); said alkyl, alkenyl, alkoxy and alkynyl groups optionally substituted with C1-C6 alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C1-C6 alkoxy, fluoro, C(O)ORi5;and aryl C1-C3 alkoxy; said aryl, aralkyl or heteroaryl groups optionally substituted with H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, C1-C6 aralkyl, R15O (CRι3Rl4)p-, Rl6C(O)O(CRi3Rl4)p-. Rl5OC(O)(CRi3Rl4)p-, -(CRι3Rl4)pS(O)nRi2, (CRι3Rl4)pC(O)NRι7Rl8, -(CRι3Rl4)p NRπC(O)Ri6, -(CRi3Rl4)pN(Rl7Rl8) or halogen; with the proviso that at least one of R5, R6, R7 and Rg contains a heteroaromatic group;
R9 and R9a are independently H, C1-C6 alkyl, aryl or Ci-Cβ aralkyl, said alkyl group optionally substituted with Cχ-C alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C1-C6 alkoxy, fluoro, C(O)ORi5;and aryl C1-C3 alkoxy; said aryl groups optionally substituted with H, Ci-Cβ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, Ci-Cβ aralkyl, Ri5θ(CRi3Ri4) -, -Rl6C(O)O(CRι3Rl4)p-, Rl5θC(O)(CRi3Rl4)p-, -(CRi3Rl4)pS(O)nRl2, (CRl3Rl4)pC(O)NRi7Rl8, -(CRi3Rl4)pNRπC(O)Ri6, -(CRi3Ri4)pN(Rι7Ri8) or halogen;
RlO is H, C1-C6 alkyl, aryl or C1-C6 aralkyl, said alkyl group optionally substituted with Ci-Cβ alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C -Cβ alkoxy, fluoro, C(O)ORi55and aryl C1-C3 alkoxy; said aryl groups optionally substituted with H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, C1-C6 aralkyl, Ri5O(CRi3Ri4)p-, -Rl6C(O)O(CRι3Ri4)p-, Rl5θC(O)(CRι3Rl4)p-, -(CRi3Rl4)pS(O)nRl2, (CRl3Rl4)pC(O)NRi7Rl8, -(CRι3Ri4)pNRi7C(O)Ri6, -(CRi3Rl4)pN(Ri7Ri8) or halogen; or
R9 and R9a can be taken together to form a carbocyclic ring, saturated or unsaturated, of 3-7 variously substituted carbon atoms, or; R9 and Rio are taken together to form a heterocyclic ring, saturated or unsaturated, of
4-7 atoms containing 1-3 heteroatoms selected from O and S, or; Rl2 is H, C1-C6 alkyl, aryl or C1-C6 aralkyl; said alkyl group optionally substituted with C1-C6 alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C\-C alkoxy, fluoro, C(O)ORi53and aryl C1-C3 alkoxy; said aryl and aralkyl groups optionally substituted with H, Ci-Cβ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, C1-C6 aralkyl, Ri5θ(CRi3Ri4)p-, Ri6C(O)O (CRi3Rl4)p-, Rl5θC(O)(CRι3Rl4)p-, -(CRl3Rl4)pS(O)nRι2, (CRi3Rl4)pC(O)NRι7Rl8, (CRl3Rl4)pNRi7C(O)Ri6, -(CRi3Ri4) N(Ri7Ri8) or halogen; or
Rl3 and R14 are independently H, C1-C6 alkyl, aryl or C1-C6 aralkyl; said alkyl group optionally substituted with Ci-Cβ alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C1-C6 alkoxy, fluoro, C(O)ORi55and aryl C1-C3 alkoxy; said aryl and aralkyl group optionally substituted with H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, C1-C6 aralkyl, Ri5θ(CRi3Ri4)p-, Ri6C(O)O (CRι3Rl4)p-, Rl5OC(O)(CRi3Rl4)p-, -(CRi3Rl4)pS(O)nRi2, (CRi3Rl4)pC(O)NRi7Rl8, (CRl3Rl4)pNRl7C(O)Ri6, -(CRi3Ri4)pN(RπRi8) or halogen;
Rl5 is H, C1-C6 alkyl, aryl, C1-C6 aralkyl, heteroaryl, substituted heteroaryl,
C1-C6 heteroaralkyl, or a heterocyclic ring containing 1-4 heteroatoms selected from O, N, and S; said alkyl group optionally substituted with C1-C6 alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C1-C6 alkoxy, fluoro, C(O)ORi5,and aryl C1-C3 alkoxy; said aryl, aralkyl, heteroaryl and heteroaralkyl groups optionally substituted with H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, Ci-Cβ aralkyl, Ri5θ(CRι3Rι4)p-, Ri6C(O)O(CRi3Rl4)p-, Rl5OC(O) (CRi3Rl4)p-, -(CRi3Rl4)pS(O)nRl2, (CRι3Rl4)pC(O)NRi7Ri8, (CRι3Rl4)pNRl7C(O)Ri6, -(CRι3Rl4)pN(Ri7Rl8) or halogen; Rl6 is H, C1-C6 alkyl, aryl, C1-C6 aralkyl, heteroaryl, C1-C6 heteroaralkyl, or a heterocyclic ring containing 1-4 heteroatoms selected from O, N, and S; said alkyl group optionally substituted with C1-C6 alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C1-C6 alkoxy, fluoro, C(O)ORi55and aryl C1-C3 alkoxy; said aryl, aralkyl, heteroaryl and heteroaralkyl groups optionally substituted with H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, Ci-Cβ aralkyl, Rι5O(CRi3Rl4)p-, Rl6C(O)O(CRι3Ri4)p-, Rl5OC(O) (CRι3Rl4)p-, -(CRi3Rl4)pS(O)nRi2, (CRι3Rl4)pC(O)NRι7Rl8, (CRι Rl4)pNRl7C(O)Ri6, -(CRι Rl4)pN(Rl7Rl8) or halogen; Rl7 and Ri8 are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, C1-C6 aralkyl, heteroaryl, C1-C6 heteroaralkyl, or taken together form a carbocyclic ring(s) of 4-7 carbon atoms each or a heterocyclic ring containing 1-4 heteroatoms selected from O, N, and S; said alkyl and cycloalkyl groups optionally substituted with C -C6 alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C1-C6 alkoxy, fluoro, C(O)ORi5;and aryl C1-C3 alkoxy; said aryl, aralkyl, heteroaryl and heteroaralkyl groups optionally substituted with H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, Ci-Cβ aralkyl, Ri5θ(CRi3Rl4)p-, Rl6C(O)O(CRi3Ri4)p-, Rl5OC(O) (CRi3Rl4)p-, -(CRl3Rl4)pS(O)nRl2, (CRi3Rl4)pC(O)NRi7Rl8, (CRι3Rl4)pNRl7C(O)Ri6, -(CRi3Rl4)pN(Rl7Rl8) or halogen;
Rl9 is H, C1-C6 alkyl or -CN; said alkyl group optionally substituted with C1-C6 alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C1-C6 alkoxy, fluoro, C(O)ORi5;and aryl C1-C3 alkoxy; is 0, 1, or 2; p is 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable addition salt, hydrate, prodrug or active metabolite thereof, or where applicable, a geometric or optical isomer or racemic mixture thereof.
2. The compound of Claim 1 of the formula
Figure imgf000051_0001
wherein
A is a bond or C1-C6 alkyl;
B is a bond or Ci-Cβ alkyl;
X is O;
Y is
Figure imgf000051_0002
R3 is H, Cl or CH3;
R6 is (CRi3Rl4)pC(O)N(RπRl8);
R7 is halogen;
R9 and Rio are taken together to form a heterocyclic ring, saturated or unsaturated, of
4-7 atoms containing 1-3 heteroatoms selected from O and S;
or a pharmaceutically acceptable addition salt, hydrate, prodrug or active metabolite thereof, or where applicable, a geometric or optical isomer or racemic mixture thereof. The compound of Claim 1 of the formula
Figure imgf000052_0001
wherein R is as shown in the table below:
Figure imgf000052_0002
Figure imgf000053_0002
The compound of Claim 1 of the formula
Figure imgf000053_0001
wherein R is as shown in the table below:
Figure imgf000053_0003
Figure imgf000054_0001
5. A pharmaceutical composition which comprises an effective amount of a compound as defined in Claim 1 and a pharmaceutically acceptable carrier therefor.
6. A method for antagonizing gonadotropin-releasing hormone in a subject in need thereof which comprises administering to said subject an effective amount of a compound as defined in Claim 1 to a subject suffering from a gonadotropin-releasing hormone derived disorder.
7. A method according to Claim 6 wherein the gonadotropin- releasing hormone derived disorder is a sex-hormone related condition.
8. A method according to Claim 6 wherein the gonadotropin- releasing hormone derived disorder is a sex hormone dependent cancer, benign prostatic hypertropy or myoma of the uterus.
9. A method according to Claim 8 wherein the sex hormone dependent cancer is selected from the group consisting of prostatic cancer, uterine cancer, breast cancer and pituitary gonadotrophe adenomas.
10. A method according to Claim 7 wherein the sex hormone related condition is selected from the group consisting of endometriosis, polycystic ovarian disease, uterine fibroids and precocious puberty.
11. A method for preventing pregnancy in a subject in need thereof which comprises administering an effective amount of a compound as defined in Claim 1.
12. A method for treating lupus erythematosis in a subject in need thereof which comprises administering to said subject an effective amount of a compound as defined in Claim 1.
13. A method for treating irritable bowel syndrome in a subject in need thereof which comprises administering to said subject an effective amount of a compound as defined in Claim 1.
14. A method for treating premenstrual syndrome in a subject in need thereof which comprises administering to said subject an effective amount of a compound as defined in Claim 1.
15. A method for treating hirsutism in a subject in need thereof which comprises administering to said subject an effective amount of a compound as defined in Claim 1.
16. A method for treating short stature or a growth hormone deficiency in a subject in need thereof which comprises administering to said subject an effective amount of a compound which stimulates the endogenous production or release of growth hormone and an effective amount of a compound as defined in Claim 1.
17. A method for treating sleep disorders in a subject in need thereof which comprises administering to said subject an effective amount of a compound as defined in Claim 1.
18. The method of Claim 17 wherein the sleep disorder is sleep apnea.
19. A mammographic method in which the image on the mammographic film has enhanced readability relative to a mammogram effected in the absence of the method, which comprises administering to a premenopausal woman an effective amount of a compound as defined in Claim 1.
20. A pharmaceutical composition which comprises an inert carrier and an effective amount of a compound which stimulates the endogenous production or release of growth hormone in combination with a compound as defined in Claim 1.
21. A pharmaceutical composition made by combining the compound of Claim 1 and a pharmaceutically acceptable carrier therefor.
22. A process for making a pharmaceutical composition comprising combining a compound of Claim 1 and a pharmaceutically acceptable carrier.
23. Pharmaceutical therapy comprising co-administration of a compound having luteinizing hormone releasing hormone activity with a compound of Claim 1.
24. The therapy of Claim 23 wherein the compound having luteinizing hormone releasing hormone activity is a peptide compound.
25. The therapy of Claim 24 wherein the peptide compound is a natural hormone or an analog thereof.
26. The therapy of Claim 24 wherein the peptide compound is a compound selected from the group consisting of leuprorelin, gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterelin and recirelin.
27. Pharmaceutical combination therapy comprising a compound having luteinizing hormone releasing hormone activity in combination with a compound of Claim 1.
28. The therapy of Claim 27 wherein the compound having luteinizing hormone releasing hormone activity is a peptide compound.
29. The therapy of Claim 28 wherein the peptide compound is a natural hormone or an analog thereof.
30. The therapy of Claim 28 wherein the peptide compound is a compound selected from the group consisting of leuprorelin, gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterelin and recirelin.
PCT/US2001/007878 2000-03-17 2001-03-13 Antagonists of gonadotropin releasing hormone WO2001070227A1 (en)

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WO2004018479A1 (en) * 2002-08-21 2004-03-04 Astrazeneca Ab Thieno-pyrrole compounds as antagonists of gonadotropin releasing hormone
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