WO1999021553A1 - Antagonistes de l'hormone de liberation de la gonadothrophine - Google Patents

Antagonistes de l'hormone de liberation de la gonadothrophine Download PDF

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WO1999021553A1
WO1999021553A1 PCT/US1998/022799 US9822799W WO9921553A1 WO 1999021553 A1 WO1999021553 A1 WO 1999021553A1 US 9822799 W US9822799 W US 9822799W WO 9921553 A1 WO9921553 A1 WO 9921553A1
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Prior art keywords
substituted
alkyl
aryl
compound
aralkyl
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PCT/US1998/022799
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English (en)
Inventor
Lin Chu
Mark T. Goulet
Thomas F. Walsh
Stephanie L. Witkin
Matthew J. Wyvratt
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Merck & Co., Inc.
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Priority claimed from GBGB9809789.2A external-priority patent/GB9809789D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to JP2000517711A priority Critical patent/JP2001520996A/ja
Priority to EP98954019A priority patent/EP1027046A4/fr
Priority to CA002308454A priority patent/CA2308454A1/fr
Priority to AU11243/99A priority patent/AU1124399A/en
Publication of WO1999021553A1 publication Critical patent/WO1999021553A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/06—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing isoquinuclidine ring systems

Definitions

  • the gonadotropin-releasing hormone also referred to as luteinizing hormone-releasing hormone (LHRH)
  • LHRH luteinizing hormone-releasing hormone
  • 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.
  • 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.
  • 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, 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.
  • a compound of the present invention may be co-administered with a 5 ⁇ -reductase-2-inhibitor, such as finasteride or epristeride; a 5 ⁇ -reductase-l-inhibitor such as 4,7 ⁇ -dimethyl-4-aza-5 ⁇ - cholestan-3-one, 3-oxo-4-aza-4,7 ⁇ -dimethyl-16 ⁇ -(4-chlorophenoxy)-5 ⁇ - androstane, and 3-oxo-4-aza-4,7 ⁇ -dimethyl-16 ⁇ -(phenoxy)-5 ⁇ -androstane as disclosed in WO 93/23420 and WO 95/11254; dual inhibitors of 5 - reductase 1 and 5 ⁇ -reductase 2 such as 3-oxo-4-aza-17 ⁇ -(2,5-trifiuoro- methylphenyl-carbamoyl)-5 ⁇ -androstane as disclosed in WO 95/07927; antiandrogens
  • 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.
  • Non-peptide 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 adminstration.
  • 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. Additional non-peptide GnRH antagonists have been described in WO 97/21704, WO 97/21707, WO 97/21703 and WO 97/21435.
  • Substituted indoles known in the art include those described in the following patents and patent applications.
  • US Patent No. 5,030,640 discloses alpha-heterocyclic ethanol aminoalkyl indoles which are potent ⁇ -agonists.
  • US Patent No. 4,544,663 discloses indolamine derivatives which are allegedly useful as male anti-fertility agents.
  • WO 90/05721 discloses alpha-amino-indole-3-acetic acids useful as anti-diabetic, anti-obesity and anti-atherosclerotic agents.
  • French patent 2,181,559 discloses indole derivatives with sedative, neuroleptic, analgesic, hypotensive, antiserotonin and adrenolytic activity.
  • Belgian patent 879381 discloses 3-aminoalkyl-lH-indole-5-thioamide and carboxamide derivatives as cardiovascular agents used to treat hypertension, Raynaud's disease and migraine.
  • 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 Il-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 Il-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 5 ⁇ -reductase-2-inhibitor, such as finasteride or epristeride; a 5 ⁇ -reductase-l-inhibitor such as 4,7 ⁇ -dimethyl-4-aza- 5 ⁇ -cholestan-3-one, 3-oxo-4-aza-4,7 ⁇ -dimethyl-16 ⁇ -(4-chlorophenoxy)-5 ⁇ - androstane, and 3-oxo-4-aza-4,7 ⁇ -dimethyl-16 ⁇ -(phenoxy)-5 ⁇ -androstane as disclosed in WO 93/23420 and WO 95/11254; dual inhibitors of 5 ⁇ - reductase 1 and 5 ⁇ -reductase 2 such as 3-oxo-4-aza-17 ⁇ -(2,5-trifluoro- methylphenyl-carbamoyl)-5 ⁇ -androstane as disclosed in WO 95/07927; antiandrogens such as
  • 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.
  • the present invention relates to compounds of the general formula
  • R ⁇ is hydrogen, Ci-C ⁇ alkyl, substituted Ci-C ⁇ alkyl, wherein the substituents are as defined below; aryl, substituted aryl, aralkyl or substituted aralkyl, wherein the substituents are as defined for R3, R4 and R5; Rl and R2 are independently hydrogen, C -CQ alkyl, substituted
  • C3-C6 alkenyl substituted C3-C6 alkenyl, C3-C6 alkynyl, substituted C3-C6 alkynyl, Co-C5-alkyl-S(O)n-C 0 -C5 alkyl, C 2 -C 6 alkyl(NRnRi2), C 2 -C 6 alkyl(ORn).
  • Ruand R12 independently or taken together are not aryl, substituted aryl, aralkyl, or substituted aralkyl ; or Rl and R2 taken together form an optionally substituted non- heteroaromatic ring of 3-8 atoms containing 0,1 or 2 additional heteroatoms selected from S, O or N;
  • R3, R4 and R5 are independently hydrogen, Ci-C ⁇ alkyl, substituted
  • R17 is hydrogen, Ci-C ⁇ alkyl, C1-C3 perfluoroalkyl, aryl or substituted aryl; or R3 and R4 taken together form a carbocyclic ring of 3-7 carbon atoms or a heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;
  • R6 is hydrogen, C1-C6 alkyl, substituted Ci-C ⁇ alkyl, aryl, substituted aryl, C1-C3 perfluoroalkyl, CN, NO2, halogen,
  • R7 is hydrogen, Cl-C ⁇ alkyl, or substituted Ci-C ⁇ alkyl,;
  • R8 is C(O)OR 2 0, C(O)NR 2 ⁇ R21, NR20R2I, C(O)R 2 0, NR 2 lC(O)R 2 0,
  • NR2lC(O)NR2 ⁇ R21 NR 2 ⁇ S(O)2R21, NR 2 lS(O)2NR2 ⁇ R21, OC(O)R20, OC(O)NR 2 ⁇ R21, OR20, SO n R 2 0, S(O) n NR2 ⁇ R21, a heteroaromatic or substituted heteroaromatic ring, a heterocyclic ring or bicyclic heterocyclic ring with from 1 to 4 heteroatoms selected from N, O or S which can be optionally substituted by R3, R4 and R5, C1-C6 alkyl or substituted C1-C6 alkyl; or
  • R9 and Rg a are independently hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl; aryl or substituted aryl, aralkyl or substituted aralkyl when m ⁇ O; or
  • R9 and R9 a taken together form a carbocyclic ring of 3-7 atoms or when m ⁇ O;
  • RlO and RlOa are independently hydrogen, C1-C6 alkyl, substituted Ci-C ⁇ alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl; or
  • RlO and R2 taken together form a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms;
  • Rll and R12 are independently hydrogen , Ci-C ⁇ alkyl, substituted
  • R20 and R21 are independently hydrogen , C1-C6 alkyl, substituted C1-C6 alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, a heteroaromatic or substituted heteroaromatic r ng, a carbocyclic ring of 3-7 atoms, a substituted carbocyclic ring containing 3-7 atoms, a heterocyclic ring or bicyclic heterocyclic ring with from 1 to 4 heteroatoms selected from N, O or S which can be optionally substituted by R3, R4 and R5, Cl-C6-alkyl substituted by a
  • aryl C1-C3 alkoxy, substituted aryl C1-C3 alkoxy, and the aryl substituents are as defined for R3, R4 and R5; or a pharmaceutically acceptable addition salt and/or hydrate thereof, or where applicable, a geometric or optical isomer or racemic mixture thereof.
  • R20 and R21 Preferred substituents when R20 and R21 are taken together include 7-aza-bicyclo [2.2.1] heptane and 2-aza-bicyclo[2.2.2]octane.
  • 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), isopentyl, isohexyl, etc.
  • aryl includes phenyl and naphthyl.
  • aryl is phenyl.
  • heteroaryl refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, in which a carbon or nitrogen atom is the point of attachment, The heteroaryl group is optionally substituted with up to three groups. Heteroaryl includes aromatic and partially aromatic groups which contain one or more heteroatoms.
  • 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 3-8 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.
  • 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 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 tetrameth l- ammonium 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)
  • esters can be employed, e.g. methyl, ethyl, butyl, acetate, maleate, pivaloyloxym ethyl, 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.
  • the iV-phthalimidotryptamine (2) could be further modified by treatment with a brominating agent such as pyridinium hydrobromide perbromide, pyrrolidone hydrotribromide, or the like in an inert organic solvent such as tetrahydrofuran, methylene chloride, chloroform, or mixtures thereof at 0-25°C for a period of 30 minutes to 4 hours to provide the 2-bromotryptamine (3).
  • Bromide (3) may be reacted with an arylboronic acid (prepared essentially as described in : Gronowitz, S.; Hornfeldt, A.-B.; Yang, Y.-H. Chem. Scr.
  • the 2-aryltryptamine may be condensed with a carboxylic acid of type (6) using 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, dimethyl- formamide, or mixtures thereof at or near room temperature for a period of 3-24 hours to provide the corresponding amide derivative (7).
  • EDC 1-hydroxybenzotriazole
  • NMM N-methylmorpholine
  • NMM N-methylmorpholine
  • triethylamine or the like in an inert organic solvent such as methylene chloride, chloroform, dimethyl- formamide
  • 2-aryltryptamine (5) can be treated with an active ester or acid chloride of type (8) in an inert organic solvent such as methylene chloride, chloroform, tetrahydrofuran, diethyl ether, or the like and a tertiary amine base such as triethylamine, diisopropylethylamine, pyridine or the like at a temperature of 0°-25°C for 30 minutes to 4 hours to give (7).
  • an inert organic solvent such as methylene chloride, chloroform, tetrahydrofuran, diethyl ether, or the like
  • a tertiary amine base such as triethylamine, diisopropylethylamine, pyridine or the like
  • the amide carbonyl of (7) can be reduced by treatment with borane, lithium aluminum hydride, or equivalent hydride sources in an inert organic solvent such as tetrahydrofuran, diethyl ether, 1,4-dioxane or the like at 25°-100°C, preferably 65°C, for a period of 1-8 hours to give the corresponding amine compound (9).
  • an inert organic solvent such as tetrahydrofuran, diethyl ether, 1,4-dioxane or the like at 25°-100°C, preferably 65°C, for a period of 1-8 hours to give the corresponding amine compound (9).
  • (5) can be modified by treatment with an aldehyde or ketone of type (10) in the presence of a weak acid such as trifluorfoacetic acid (TFA), acetic acid or the like, with or without a dessicant such as 3A molecular sieves or magnesium sulfate, and a hydride source such as sodium borohydride or sodium cyanoborohydride, in an inert organic solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, chloroform, or mixtures thereof at a temperature of 0°-25°C for a period of 1-12 hours to give the corresponding secondary or tertiary amine derivative (11).
  • a weak acid such as trifluorfoacetic acid (TFA), acetic acid or the like
  • a dessicant such as 3A molecular sieves or magnesium sulfate
  • a hydride source such as sodium borohydride or sodium
  • reaction Scheme E treatment of an arylhydrazine or arylhydrazine hydrochloride (12) with an arylcyclo- propylketone of type (13) in a polar organic solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, preferably n- butanol, at a temperature of 70°-120°C for a period of 8-24 hours gives 2-aryl tryptamine (5).
  • a polar organic solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, preferably n- butanol
  • an arylhydrazine or arylhydrazine hydrochloride (12) is treated with an arylbutyl ketone of type (14) containing a leaving group (chloride, bromide, iodide, O-methansulfonate, O-trifluoromethansulfonate, or the like) at the 4-position in a polar solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, or mixtures thereof at room temperature for a period of 30 minutes to 2 hours followed by heating to a temperature of 65°-100°C for 4-24 hours, 2-aryltryptamine (5) is produced.
  • Scheme F 2-aryltryptamine
  • iodoanilines of type (15) may be reacted with aryl acetylenes, an appropriate palladium (0) catalyst such as tetrakis(triphenylphosphine)palladium, a copper (I) halide such as cuprous bromide in an inert organic solvent such as triethylamine at a temperature of 50°-88°C for a period of 30 minutes to 5 hours to provide the diarylacetylene (16).
  • an appropriate palladium (0) catalyst such as tetrakis(triphenylphosphine)palladium
  • a copper (I) halide such as cuprous bromide in an inert organic solvent such as triethylamine at a temperature of 50°-88°C for a period of 30 minutes to 5 hours to provide the diarylacetylene (16).
  • Acetylene (16) may be further modified by treatment with a palladium (II) catalyst such as palladium (II) chloride or palladium (II) acetate in an inert organic solvent such as acetonitrile at a temperature of 50°- 82°C for a period of 30 minutes to 6 hours to give 2-arylindole (17).
  • a palladium (II) catalyst such as palladium (II) chloride or palladium (II) acetate in an inert organic solvent such as acetonitrile at a temperature of 50°- 82°C for a period of 30 minutes to 6 hours to give 2-arylindole (17).
  • the crude product (18) may be reacted with an amine of type (19) in an inert organic solvent such as diethylether, tetrahydrofuran, methylene chloride, chloroform or the like and an amine base such as triethylamine, diisopropylethylamine or pyridine at a temperature of 0°C-25°C for a period of 30 minutes to 4 hours to provide the amide derivative (20).
  • Amide (20) may be further modified by treatment with a reducing agent such as borane or lithium aluminum hydride in an inert organic solvent such as tetrahydrofuran at elevated temperatures, preferably reflux, for a period of 1-5 hours to give compound (21).
  • N-benzyl derivatives of type (22a) or N-benzyloxycarbonyl derivatives of type (22b) may be reduced to provide the secondary amine analogs (7) by treatment with hydrogen (1 atm) and an appropriate catalyst such as palladium on carbon, palladium hydroxide on carbon, or the like in an inert organic solvent such as tetrahydrofuran, ethyl acetate, methanol, ethanol, or mixtures thereof to which has been added a weak acid such as 30% aqueous acetic acid for a period of 10 minutes to 3 hours or until the aryl group has been removed to give the secondary amine.
  • an appropriate catalyst such as palladium on carbon, palladium hydroxide on carbon, or the like
  • an inert organic solvent such as tetrahydrofuran, ethyl acetate, methanol, ethanol, or mixtures thereof to which has been added a weak acid such as 30% aqueous acetic acid for a period of 10 minutes to 3
  • (25) may be modified by acylation under a variety of conditions.
  • treatment of (25) with an acid chloride, acid anhydride or active ester and an amine base such as triethylamine, diisopropyl- ethylamine, pyridine, or the like in an inert organic solvent such as methylene chloride, chloroform, tetrahydrofuran, or mixtures thereof at 0°C to room temperature for a period of 1 to 12 hours gives the corresponding amide or ester derivatives (26).
  • (25) may be coupled with a carboxylic acid by one of the many dehydrating agents commonly employed.
  • urea or carbamate derivatives of (25) can be prepared by treatment with a carbamoyl chloride of type (27a), or alternatively with an isocyanate reagent of type (27b), and an amine base such as pyridine, triethylamine, diisopropylethylamine, _V-methylmorpholine or the like in an inert organic solvent such as methylene chloride, chloroform, dimethylformamide, tetrahydrofuran or mixtures thereof at a temperature of 0°-65°C for a period of 1-72 hours to give (28).
  • an inert organic solvent such as methylene chloride, chloroform, dimethylformamide, tetrahydrofuran or mixtures thereof at a temperature of 0°-65°C for a period of 1-72 hours to give (28).
  • Compound (25) can also be modified by treatment with a bis(electrophilic) reagent such as phosgene, triphosgene, l,l'-carbonyldiimidazole, N,N'-disuccinimidyl carbonate, or the like with or without the addition of an amine base such as pyridine, triethylamine, diisopropylethylamine, _V-methylmorpholine in an inert solvent such as methylene chloride, chloroform, or the like at a temperature of -20°-0°C for a period of 20 minutes to 2 hours. After this time, the reaction mixture is treated with an appropriate mono- or disubstituted amine at -20° to 25°C for a period of 1-5 hours to give the urea or carbamate analog (28).
  • a bis(electrophilic) reagent such as phosgene, triphosgene, l,l'-carbonyldiimidazole
  • amine (25) can be modified by treatment with an appropriate sulfonyl chloride of type (29) or sulfamyl chloride of type (30) with an amine base such as pyridine, triethylamine, diisopropylethylamine, ⁇ T-methylmorpholine in an inert solvent such as methylene chloride, chloroform, dichloroethane or the like at a temperature of -20°-25°C for a period of 20 minutes to 2 hours to give the corresponding N-sulfonamide (31) or iV-sulfamylamide (32) derivatives, respectively.
  • an amine base such as pyridine, triethylamine, diisopropylethylamine, ⁇ T-methylmorpholine in an inert solvent such as methylene chloride, chloroform, dichloroethane or the like
  • the 2-aryltryptamine (33) can be modified by treatment with an epoxide such as (34) in an inert organic solvent such as methanol, ethanol, isopropanol, butanol, tert- butanol, or mixtures thereof at a temperature of 65°-110°C for a period of 8-20 hours to give the corresponding amino-alcohol derivative (35).
  • an epoxide such as (34) in an inert organic solvent such as methanol, ethanol, isopropanol, butanol, tert- butanol, or mixtures thereof at a temperature of 65°-110°C for a period of 8-20 hours to give the corresponding amino-alcohol derivative (35).
  • amide derivatives of an acid-containing indole derivative such as (36) can be prepared by treatment with an appropriate amine (Rl2Rll NH) and a suitable coupling agent such as benzotriazol-l-yloxy-tris(pyrrolidino) phosphonium hexafluorophosphate (PyBOP), benzotriazol-1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphate (BOP), 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,
  • a preferred method for the synthesis of the substituted tryptamines described in this invention utilizes a Larock indole synthesis as a key step as shown in Scheme O.
  • This indole synthesis involves the reaction of a suitably functionalized onfbo-iodoaniline (38) with substituted acetylenes such as 39 in the presence of a base like potassium carbonate, lithium chloride, and a palladium catalyst such as palladium acetate in combination with tri phenyl phosphine.
  • the reaction is conducted in an inert organic solvent such as dimethyl- formamide at elevated temperatures, for instance at 100°C, and the reaction is conducted for a period of 30 minutes to 24 hours.
  • a standard workup and isolation affords the substituted isomeric indole derivatives 40 and 41, and the isomer of general formula 40 is the preferred isomer.
  • the acetylene utilized in this reaction may be a terminal acetylene
  • the substituent abreviated PGi indicates an alcohol protecting group such as a benzyl ether, tert--butyl ether or the like.
  • the nature of the Z substituent determines the distribution of the indole isomers (40 and 41) produced in the reaction. For example, if the substituent Z on the acetylene is a hydrogen atom then the isomer 41a is the major product of the reaction.
  • the substituent Z is chosen to be a substituted silyl group such as trimethylsilyl, triethylsilyl (as shown), or the like, then isomer 40b is formed almost exclusively.
  • Scheme P illustrates the preparation of the substituted ortrbo-iodoaniline (38) utilized in the Larock indole synthesis described in Scheme O.
  • the o bo-idoanilines may be prepared in several ways described in the literature of organic synthesis.
  • One preferred method employs nitrobenzene or a substituted nitrobenzene derivative such as generalized compounds of formula 42 as the starting material.
  • Nitrobenzene derivatives such as 42 may be commercially available or they can be readily prepared using standard methods known in organic chemistry. Reduction of the nitro group in compounds of general formula 42 using methods such as catalytic hydrogenation produces an aniline derivative such as 43.
  • nitro compound 42 when nitro compound 42 is reacted under a hydrogen atmosphere at a pressure between atmospheric pressure and 100 psig in the presence of a catalyst such as 10% palladium on powdered carbon and the reaction is conducted in an inert solvent like ethanol at temperatures between room temperature and 100°C, then the substituted aniline derivative 43 is produced usually within a period of 15 minutes to 6 hours.
  • the generalized aniline 43 is then converted to the or/Jio-iodoanilines 38 by reaction with an iodinating reagent such as iodine, iodine monochloride, iV-iodosuccinimide or the like.
  • reaction of an aniline derivative like 43 with iodine monochloride in the presence of a base such as calcium carbonate and in suitable inert solvent like an alcohol (ie. methanol or ethanol) or an alcohol-water mixture at temperature between 0°C and 50°C affords the or b.o-iodoaniline derivative 38 after reaction times between 30 minutes to 2 hours.
  • a base such as calcium carbonate
  • suitable inert solvent like an alcohol (ie. methanol or ethanol) or an alcohol-water mixture at temperature between 0°C and 50°C
  • Acetylenic compounds of general structure 39 are prepared using one of several methods depending upon the choice of the desired substituents.
  • substituents Rg, Rga > RlO an d RlOa are selected to be hydrogen or lower alkyl groups
  • compounds of formula 39 may be prepared from known acetylenic alcohols such as 3-butyn-l-ol, 4-pentyn-
  • Compounds of formula 39a may in turn be converted to acetylenes (39b) of general formula 39 wherein Z is a trialkylsilyl group by deprotonation of the acetylene with a base such as n-butyllithium in an inert organic solvent like tetrahydrofuran followed by reaction with a trialkylsilyl chloride such as triethylchlorosilane.
  • the deprotonation and silylation reactions are generally conducted at low temperatures, for instance between -78°C and room temperature, and after standard workup and purification a silylacetylene of formula 39b is obtained.
  • acetylenes of general formula 39c wherein Z is an aryl or substituted aryl group, are also useful in the indole synthesis illustrated in Scheme O.
  • Arylacetylenes 39c may be prepared using a coupling reaction of cuprous acetylides derived from acetylenic alcohols of formula 39a with various aryl halides or aryl triflates (45). Such coupling reactions produce aryl acetylenes of general formula 46 as shown at the bottom of Scheme Q.
  • Acetylenic compounds of general formula 39a may also be prepared by a process which employs an ethynylation reaction sequence of aldehydes of general formula 50 as shown in Scheme R.
  • the aldehydes (50) used in the ethynylation sequence may be prepared using various methods known in organic synthesis starting with hydroxyesters of general formula 47, from protected hydroxyesters of formula 48, or from alcohols related to the mono-hydroxyl protected diols of formula 49, and the choice of the prefered starting material depends upon the nature of the substituents R9, Rg a , Rl0 > an & RlOa selected.
  • Scheme R illustrates this strategy beginning with the generalized hydroxy ester 47. Protection of the hydroxyl group of 47, for instance as the O-benzylether shown, affords a protected hydroxy ester of formula 48.
  • the ester group of compounds of formula 48 is then converted to an aldehyde of formula 50 either directly using a reagent like diisobutyl- aluminum hydride in a solvent like toluene, or in a two step procedure. In the latter case, reduction of the ester group with a reagent such as lithium aluminum hydride in tetrahydrofuran affords alcohols of formula 49 which are then subjected to reoxidation, for instance a
  • aldehydes (50) are reacted with carbon tetrabromide and triphenylphosphine in an inert organic solvent like dichloro- methane to produce a dibromo-olefin of formula 51.
  • the dibromo-olefins (51) are treated with two equivalents of a strong base such as n-butyllithium in tetrahydrofuran at low temperature, for instance at -78°C.
  • the strong base induces dehydrohalogenation and metal-halogen exchange to afford lithium acetylides which upon quenching and workup afford acetylenes of general formula 39a.
  • the intermediate lithium acetylides formed in the reaction may be treated with a trialkylsilyl chloride such as triethylchlorosilane to afford silylacetylenes of general formula 39b.
  • the conversion of 2-silyl-substituted indoles of general formula 40b to 2-aryl-substituted indoles of general formula 40c may be accomplished in two steps as shown in Scheme S.
  • the first step is a halodesilylation reaction which converts silyl-substituted indoles of formula 40b into 2-haloindoles of general formula 52.
  • Scheme S illustrates this process using iodine monochloride so that the product obtained is a 2-iodoindole of general formula 52.
  • Silver tetrafluoroborate is also employed in this example to increase the reactivity of the halogenating reagent.
  • the second step is a palladium-catalyzed cross coupling reaction of the 2-haloindole 52 with a suitable aryl or substituted aryl organometallic reagent 53.
  • Scheme S illustrates this process with an aryl or substituted arylboronic acid as the organometallic reagent, however other organometallic reagents known to participate in palladium-catalyzed cross-coupling reactions such as arylboronic esters or arylstannanes may also be employed.
  • a 2-iodoindole of general formula 52 is coupled with a generalized boronic acid (53) using a catalyst such as [l,l'-bis(diphenylphosphino)- ferrocene] diehl oropalladium(II) complex with dichloromethane, tetrakis(triphenylphosphine)-palladium(0) or the like.
  • the reaction is usually conducted at temperatures between room temperature and 100°C for instance at 80°C.
  • This palladium catalyzed cross-coupling reaction may be effected using various combinations of palladium catalysts and solvent compositions known in organic chemistry, and the selection of the conditions is made depending upon the type of organometallic reagent (53) used and the identity of the substituent groups in the two starting materials.
  • organometallic reagent is a boronic acid or boronate ester then a preferred solvent mixture consists of toluene, ethanol and an aqueous solution of a base like cesium or sodium carbonate.
  • the organometallic reagent 53 is an arylstannane, then no additional base is required, and a polar aprotic solvent such as tetrahydrofuran or dimethylformamide is employed.
  • the tryptamine 33 can be modified using the Fukuyama modification of the Mitsunobu reaction (Fukuyama, T.; Jow, C.-K; Cheung, M. Tetrahedron Lett. 1995, 36, 6373- 74).
  • the tryptamine 33 may be reacted with an arylsufonyl chloride such as 2-nitrobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride or 2,4-dinitrobenzenesulfonyl chloride and a hindered amine base such as 2,4,6-collidine, 2,6-lutidine or the like in an inert organic solvent such as methylene chloride to provide the corresponding sulfonamide 54.
  • arylsufonyl chloride such as 2-nitrobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride or 2,4-dinitrobenzenesulfonyl chloride and a hindered amine base such as 2,4,6-collidine, 2,6-lutidine or the like
  • an inert organic solvent such as methylene chloride
  • sulfonamide 54 can be prepared by treatment of 33 and an arylsulfon
  • the sulfonamides can be further modified by reaction with an alcohol of type 55 in the presence of triphenylphosphine and an activating agent such as diethylazodicarboxylate (DEAD), diisopropylazodicaboxylate or the like in an inert organic solvent such as benzene, toluene, tetrahydrofuran or mixtures thereof to give the dialkylsulfonamide adduct.
  • DEAD diethylazodicarboxylate
  • diisopropylazodicaboxylate or the like in an inert organic solvent such as benzene, toluene, tetrahydrofuran or mixtures thereof to give the dialkylsulfonamide adduct.
  • DEAD diethylazodicarboxylate
  • diisopropylazodicaboxylate diisopropylazodicaboxylate or the like
  • an inert organic solvent such as benzene, toluene
  • a mono-nitrobenzenesulfonyl derivative When a mono-nitrobenzenesulfonyl derivative is employed, the removal of the sulfonamide is accomplished with a more nucleophilic reagent such as thiophenol or mercaptoacetic acid in combination with lithium hydroxide in DMF.
  • a more nucleophilic reagent such as thiophenol or mercaptoacetic acid in combination with lithium hydroxide in DMF.
  • Reaction Scheme U illustrates a method that is complimentary to reaction Scheme T for completing the synthesis of the novel compounds of formula (I).
  • Scheme U also employs the Fukuyama modification of the Mitsunobu reaction similar to that illustrated in reaction Scheme T.
  • the alcohol partner employed is a 2-aryltryptophol of general formula 57.
  • the 2-aryltryptophol (57) is reacted with a substituted sulfonamide of general formula 58, triphenylphosphine and diethylazodicarboxylate in a suitable inert organic solvent such as benzene, tetrahydrofuran, 1,4-dioxane or the like.
  • the reaction is generally conducted at room temperature for a period of 2 to 24 hours, typically overnight or for about 12-16 hours.
  • the product is an N,iV-disubstituted sulfonamide which is then separately subjected to reaction with a base such as ⁇ z-propylamine which removes the sulfonamide substituent and furnishes a secondary amine related to formula 57.
  • a base such as ⁇ z-propylamine which removes the sulfonamide substituent and furnishes a secondary amine related to formula 57.
  • the sulfonamides of formula 58 employed are readily obtained from a primary amine and either
  • 2-aryltryptamine 33 can be modified by treatment with an appropriate alpha, beta-unsaturated carbonyl containing compound such as 59.
  • Compound 59 can be variously substituted with (R) and, depending on the nature of "Z", may be either a ketone, ester or amide.
  • the reaction of 33 and 59 proceeds in an inert organic solvent such as ethanol at a temperature of 25° to 70°C for a period of 1 to 24 hours to provide adduct 60.
  • 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
  • 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.
  • 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 ⁇ 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 Il-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 Il-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.
  • 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
  • other agents such as growth hormone secretagogues, e.g. MK-0677
  • 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.
  • bisphosphonic acids and halo- bisphosphonic acids are 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(methylpentyl- amino)-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 FOSAMAX®.
  • a compound of the present invention may be co-administered with a 5 ⁇ -reductase 2 inhibitor, such as finasteride or epristeride; a 5 ⁇ -reductase 1 inhibitor such as 4,7 ⁇ -dimethyl-4-aza-5 ⁇ - cholestan-3-one, 3-oxo-4-aza-4,7 ⁇ -dimethyl-16 ⁇ -(4-chlorophenoxy)-5 ⁇ - androstane, and 3-oxo-4-aza-4,7 ⁇ -dimethyl-16 ⁇ -(phenoxy)-5 ⁇ -androstane as disclosed in WO 93/23420 and WO 95/11254; dual inhibitors of 5 ⁇ - reductase 1 and 5 ⁇ -reductase 2 such as 3-oxo-4-aza-17 ⁇ -(2,5-trifluoro- methylphenyl-carbamoyl)-5 -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.
  • 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.
  • 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.
  • 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 the U.S. Patent 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 poly oxy ethylene 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 conden- sation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for
  • 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.
  • Suitable 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 a 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.
  • 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.
  • 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.
  • 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.
  • 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 IB (S)-2-[3-(2-amino-l-methylethyl)-2-(3,5-dimethylphenyl)-lH- indol-5-yll-2-methylpropionic acid ethyl ester
  • Step lC (S)-2-[3-(2-/re ⁇ -butoxycarbonylamino-l-methylethyl)-2-(3,5- dimethylphenyl)-lH-indol-5-yl]-2-methylpropionic acid ethyl ester
  • (S)-2-[3-(2-amino-l-methylethyl)-2-(3,5- dimethylphenyl)-lH-indol-5-yl]-2-methylpropionic acid ethyl ester (2.13 g in 30 mL tetrahydrofuran) at 0°C was added a solution of di-ter- butyl dicarbonate (1.9 g in 6 mL tetrahydrofuran) followed by reliessium carbonate (1.2 g in 5 mL water) and the resulting suspension stirred vigourously at 0°C.
  • Step ID [S)-2-[3-(2-ter ⁇ butoxycarbonylamino-l-methylethyl)-2-(3,5- dimethylphenyl)-lH-indol-5-yll-2-methylpropionic acid
  • (S)-2-[3-(2-trert butoxycarbonylamino- l-methylethyl)-2-(3,5-dimethylphenyl)-lH-indol-5-yl]-2-methylpropionic acid ethyl ester (2.5 g in 80 mL methanol) was added 26 mL of 2. ON potassium hydroxide and the mixture heated to 94°C on an oil bath.
  • Step 1G (S)-l-(7-azabicyclo[2.2.1]hept-7-yl)-2-[3-(2-butylamino-l- methylethyl)-2-(3,5-dimethylphenyl)-lH-indol-5-yl]-2- methylpropan-1-one
  • Step BB (R)-4-methyldihydrofuran-2-one
  • a solution of (R)-4-hydroxy-3-methyl-butyronitrile (2.73g in 39 mL ethanol) was added a solution of sodium hydroxide (1.64g in 13 mL water) and the mixture heated to reflux on an oil bath. After 7 hours, the mixture was cooled and made acidic by the addition of 2N hydrochloric acid. The organics were removed in vacuo and the mixture then extracted with 90 mL benzene. The organics were washed with brine and transferred to a reaction flask fitted with a Dean-Stark trap. p-Toluenesulfonic acid (100 mg) was added and the mixture heated to reflux on an oil bath. After 3 hours, the benzene and product (138 °C) were collected by distillation under reduced pressure (1.79g).
  • Step CC (R)-3-(3.5-dimethylbenzoyl)-4-methyldihydrofuran-2-one
  • Step 2A (S)-2- ⁇ 2-(3,5-dimethylphenyl)-3-[l-methyl-2-(4-oxo-piperidin- l-yl)-ethyll-lH-indol-5-yl ⁇ -2-methylpropionic acid ethyl ester
  • EXAMPLE 1B 0.50g in 2 mL ethanol
  • l-ethyl-l-methyl-piperidinium-4-one chloride 513 mg in 0.80 mL water
  • Step 2B (S)-2- ⁇ 2-(3,5-dimethylphenyl)-3-[l-methyl-2-(4-oxo-piperidin- l-yl)-ethyll-lH-indol-5-yl)-2-methylpropionic acid
  • Step 4A (S)-iV- ⁇ 2-[5-[2-(7-azabicyclo[2.2.1]hept-7-yl)-l,l-dimethyl2-oxo- ethyl]-2-(3,5-dimethylphenyl)-lH-indol-3-yl]-propyl ⁇ -2,4- dinitrobenzenesulfonamide
  • Step 4B (S)-N- ⁇ 2-[5-[2-(7-aza-bicyclo[2.2.1]hept-7-yl)-l,l-dimethyl-2- oxo-ethyl]-2-(3,5-dimethylphenyl)-lH-indol-3-yl]-propyl ⁇ -N ' -
  • Step 4.1A (S)-3- ⁇ 2-[5-[2-(2-aza-bicyclo[2.2.2]oct-2-yl)-l,l-dimethyl-2-oxo- ethyl]-2-(3,5-dimethyl-phenyl)-l H -indol-3-yl]-propylamino ⁇ - propionic acid £ert butyl ester

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Abstract

L'invention concerne des composés représentés par la formule (I) et des sels pharmaceutiquement acceptables de ceux-ci, qui sont utiles comme antagonistes de l'hormone de libération de la gonadotrophine (GnRH) et peuvent, en tant que tels, être utiles pour traiter divers états pathologiques liés aux hormones sexuelles ainsi que d'autres affections chez l'homme et la femme.
PCT/US1998/022799 1997-10-28 1998-10-27 Antagonistes de l'hormone de liberation de la gonadothrophine WO1999021553A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2000517711A JP2001520996A (ja) 1997-10-28 1998-10-27 性腺刺激ホルモン放出ホルモン拮抗薬
EP98954019A EP1027046A4 (fr) 1997-10-28 1998-10-27 Antagonistes de l'hormone de liberation de la gonadothrophine
CA002308454A CA2308454A1 (fr) 1997-10-28 1998-10-27 Antagonistes de l'hormone de liberation de la gonadothrophine
AU11243/99A AU1124399A (en) 1997-10-28 1998-10-27 Antagonists of gonadotropin releasing hormone

Applications Claiming Priority (4)

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US6330597P 1997-10-28 1997-10-28
US60/063,305 1997-10-28
GBGB9809789.2A GB9809789D0 (en) 1998-05-07 1998-05-07 Antagonists of gonadotropin releasing hormone
GB9809789.2 1998-05-07

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6476045B2 (en) 2000-07-13 2002-11-05 Merck Sharp & Dohme Ltd. Azaindole derivatives and their use as therapeutic agents
WO2002092565A2 (fr) * 2001-05-14 2002-11-21 Astrazeneca Ab Composes
US6809098B2 (en) 2001-02-20 2004-10-26 Astrazeneca Ab Compounds
US7132442B2 (en) 2002-08-21 2006-11-07 Astrazeneca Ab 6H-thieno[2, 3-b]pyrrole derivatives as antagonists of gonadotropin releasing hormone (GnRH)
US7253290B2 (en) 2002-08-21 2007-08-07 Astrazeneca Ab Pyrazole derivatives as GnRH inhibitors
US7306922B2 (en) 2000-09-15 2007-12-11 Astrazeneca Ab Human and rat PGC-3, PPAR-gamma coactivations and splice variants thereof
US7317010B2 (en) 2002-08-21 2008-01-08 Astrazeneca Ab Thieno-pyrrole compounds as antagonists of gonadotropin releasing hormone
US7375127B2 (en) 2004-07-14 2008-05-20 Ae Zentaris Gmbh Tetrahydrocarbazole derivatives having improved biological action and improved solubility as ligands of G-protein coupled receptors (GPCRs)
US7446118B2 (en) 2005-11-30 2008-11-04 Roche Palo Alto Llc 3-amino-1-arylpropyl indoles and aza-substituted indoles and uses thereof
US7449489B2 (en) 2002-08-21 2008-11-11 Astrazeneca Ab Indolylalkylamino-methylidenecarbamate derivatives useful as GnRH antagonists
US7514570B2 (en) 2002-08-21 2009-04-07 Astrazeneca Ab Derivatives of 3-hydroxy-4-(cyclyl-alkylaminoalkyl)-5-phenyl-1h-pyrazole as antagonists of the gonadotropin releasing hormone (GnRH) for use in the treatment of sex hormone related conditions, such as prostatic of uterine cancer
EP2095818A1 (fr) 2008-02-29 2009-09-02 AEterna Zentaris GmbH Utilisation d'antagonistes LHRH dans des doses n'impliquant pas de castration
US7598399B2 (en) 2005-11-30 2009-10-06 Roche Palo Alto Llc Methods for synthesis of 3-amino-1-arylpropyl indoles
US7638517B2 (en) 2005-11-30 2009-12-29 Roche Palo Alto Llc 3-Amino-1-arylpropyl azaindoles and uses thereof
US7863305B2 (en) 2004-06-01 2011-01-04 Roche Palo Alto Llc 3-amino-1-arylpropyl indoles as monoamine reuptake inhibitors
US8378107B2 (en) 2008-10-01 2013-02-19 Panmira Pharmaceuticals, Llc Heteroaryl antagonists of prostaglandin D2 receptors
WO2017096045A1 (fr) * 2015-12-02 2017-06-08 Kyras Therapeutics, Inc. Composés de liaison ras multivalents
US11471455B2 (en) 2018-10-05 2022-10-18 Annapurna Bio, Inc. Compounds and compositions for treating conditions associated with APJ receptor activity

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* Cited by examiner, † Cited by third party
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EP2968566A1 (fr) * 2013-03-15 2016-01-20 AbbVie Inc. Compositions utiles pour traiter les règles abondantes et les fibromes

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US5756507A (en) * 1995-12-14 1998-05-26 Merck & Co., Inc. Antagonists of gonadotropin releasing hormone

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US4252803A (en) * 1978-10-12 1981-02-24 Glaxo Group Limited Indole compounds and use thereof
WO1997021704A1 (fr) * 1995-12-14 1997-06-19 Merck & Co., Inc. Antagonistes de l'hormone de liberation de la gonadotropine
US5756507A (en) * 1995-12-14 1998-05-26 Merck & Co., Inc. Antagonists of gonadotropin releasing hormone

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Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6476045B2 (en) 2000-07-13 2002-11-05 Merck Sharp & Dohme Ltd. Azaindole derivatives and their use as therapeutic agents
US7306922B2 (en) 2000-09-15 2007-12-11 Astrazeneca Ab Human and rat PGC-3, PPAR-gamma coactivations and splice variants thereof
US6809098B2 (en) 2001-02-20 2004-10-26 Astrazeneca Ab Compounds
US7256188B2 (en) 2001-05-14 2007-08-14 Astrazeneca Ab 3-aminoalkyl-2-aryl-indole derivatives and their use as GnRH antagonists
WO2002092565A2 (fr) * 2001-05-14 2002-11-21 Astrazeneca Ab Composes
WO2002092565A3 (fr) * 2001-05-14 2002-12-27 Astrazeneca Ab Composes
US7449489B2 (en) 2002-08-21 2008-11-11 Astrazeneca Ab Indolylalkylamino-methylidenecarbamate derivatives useful as GnRH antagonists
US7253290B2 (en) 2002-08-21 2007-08-07 Astrazeneca Ab Pyrazole derivatives as GnRH inhibitors
US7317010B2 (en) 2002-08-21 2008-01-08 Astrazeneca Ab Thieno-pyrrole compounds as antagonists of gonadotropin releasing hormone
US7268158B2 (en) 2002-08-21 2007-09-11 Astrazeneca Ab 6H-THIENO [2,3-b]pyrrole derivatives as antagonists of gonadotropin releasing hormone (GnRH)
US7132442B2 (en) 2002-08-21 2006-11-07 Astrazeneca Ab 6H-thieno[2, 3-b]pyrrole derivatives as antagonists of gonadotropin releasing hormone (GnRH)
US7514570B2 (en) 2002-08-21 2009-04-07 Astrazeneca Ab Derivatives of 3-hydroxy-4-(cyclyl-alkylaminoalkyl)-5-phenyl-1h-pyrazole as antagonists of the gonadotropin releasing hormone (GnRH) for use in the treatment of sex hormone related conditions, such as prostatic of uterine cancer
US7547722B2 (en) 2002-08-21 2009-06-16 Astrazeneca Ab Chemical compounds
US7863305B2 (en) 2004-06-01 2011-01-04 Roche Palo Alto Llc 3-amino-1-arylpropyl indoles as monoamine reuptake inhibitors
US7375127B2 (en) 2004-07-14 2008-05-20 Ae Zentaris Gmbh Tetrahydrocarbazole derivatives having improved biological action and improved solubility as ligands of G-protein coupled receptors (GPCRs)
EP1995238A2 (fr) 2004-07-14 2008-11-26 AEterna Zentaris GmbH Nouveaux dérivés de tetrahydrocarbazole à effet biologique et solubilité améliorés comme ligands pour des récepteurs couplés aux proteines G (RCPGS)
US8067456B2 (en) 2004-07-14 2011-11-29 Aeterna Zentaris Gmbh Tetrahydrocarbazole derivatives having improved biological action and improved solubility as ligands of G-protein coupled receptors (GPCPs)
US7446118B2 (en) 2005-11-30 2008-11-04 Roche Palo Alto Llc 3-amino-1-arylpropyl indoles and aza-substituted indoles and uses thereof
US7638517B2 (en) 2005-11-30 2009-12-29 Roche Palo Alto Llc 3-Amino-1-arylpropyl azaindoles and uses thereof
US7803830B2 (en) 2005-11-30 2010-09-28 Roche Palo Alto Llc 3-amino-1-arylpropyl indoles and AZA-substituted indoles and uses thereof
US7598399B2 (en) 2005-11-30 2009-10-06 Roche Palo Alto Llc Methods for synthesis of 3-amino-1-arylpropyl indoles
EP2095818A1 (fr) 2008-02-29 2009-09-02 AEterna Zentaris GmbH Utilisation d'antagonistes LHRH dans des doses n'impliquant pas de castration
US8378107B2 (en) 2008-10-01 2013-02-19 Panmira Pharmaceuticals, Llc Heteroaryl antagonists of prostaglandin D2 receptors
WO2017096045A1 (fr) * 2015-12-02 2017-06-08 Kyras Therapeutics, Inc. Composés de liaison ras multivalents
US11471455B2 (en) 2018-10-05 2022-10-18 Annapurna Bio, Inc. Compounds and compositions for treating conditions associated with APJ receptor activity
US11944622B2 (en) 2018-10-05 2024-04-02 Annapurna Bio, Inc. Compounds and compositions for treating conditions associated with APJ receptor activity

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EP1027046A1 (fr) 2000-08-16
EP1027046A4 (fr) 2002-04-03
JP2001520996A (ja) 2001-11-06
CA2308454A1 (fr) 1999-05-06
AU1124399A (en) 1999-05-17

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