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WO1999051232A1 - Antagonistes de l'hormone liberant la gonadotropine (gnrh) - Google Patents

Antagonistes de l'hormone liberant la gonadotropine (gnrh) Download PDF

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Publication number
WO1999051232A1
WO1999051232A1 PCT/US1999/006726 US9906726W WO9951232A1 WO 1999051232 A1 WO1999051232 A1 WO 1999051232A1 US 9906726 W US9906726 W US 9906726W WO 9951232 A1 WO9951232 A1 WO 9951232A1
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WO
WIPO (PCT)
Prior art keywords
substituted
alkyl
aryl
compound
aralkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1999/006726
Other languages
English (en)
Inventor
Thomas F. Walsh
Feroze Ujjainwalla
Mark T. Goulet
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9815854.6A external-priority patent/GB9815854D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Priority to JP2000542003A priority Critical patent/JP2002510629A/ja
Priority to AU31183/99A priority patent/AU3118399A/en
Priority to CA002326143A priority patent/CA2326143A1/fr
Priority to EP99912924A priority patent/EP1067930A4/fr
Publication of WO1999051232A1 publication Critical patent/WO1999051232A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
    • A61P5/04—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin for decreasing, blocking or antagonising the activity of the hypothalamic hormones
    • 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
    • A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
    • 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
  • 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.
  • 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
  • A is C1-C6 alkyl, substituted Cl-C6 alkyl, C3-C7 cycloalkyl, substituted C3-C7 cycloalkyl, C3-C6 alkenyl, substituted C3-C6 alkenyl, C3-C6 alkynyl, substituted C3-C6 alkynyl, C1-C6 alkoxy, or C0-C5 alkyl-S(O) n -C()-C5 alkyl, C0-C5 alkyl- O-C0-C5 alkyl, C0-C5 alkyl-NRi8-C()-C5 alkyl where Ri8 and the C0-C5 alkyl can be joined to form a ring, ⁇ N-(CH 2 ) p -
  • 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.
  • oxirane oxetane, tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, tetrahydropyridine, tetrahydropyrimidine, tetrahydrothiophene, tetrahydrothiopyran, morpholine, hydantoin, valerolactam, pyrrolidinone, and the like
  • 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.
  • some of the crystalline forms for compounds of the present invention may exist as polymorphs and
  • the isomer 4a 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 3b is formed almost exclusively.
  • Z is a substituted aryl group, then both isomers 3c and 4c may be formed and the product mixture is separated using chromatographie or crystallization techniques to afford the individual isomers.
  • Scheme B illustrates the preparation of substituted 3-iodo- 2-aminopyridines (1) which are utilized in the Larock 7-azaindole synthesis described in Scheme A.
  • the 3-iodo-2-aminopyridines (1) may be prepared in several ways described in the literature of organic synthesis.
  • a preferred method involves the or ⁇ .o-iodination of substituted 2-aminopyridine derivatives of general formula 9 with an electrophilic iodination reagent such as iodine, iodine monochloride, N-iodosuccinimide or the like.
  • An alcohol of general formula 21 may be converted to a primary amine of general formula 23 using a variety of methods known in the literature of organic chemistry.
  • the bottom of Scheme F illustrates a process where the alcohol 21 is first converted to an azide of general formula 22, followed by reduction to afford the amine derivative 23.
  • the synthesis of an azide of general formula 22 from alcohols like 21 is best accomplished by performing a Mitsunobu reaction in the presence of an appropriate azide source such as diphenylphosphoryl azide or zinc azide pyridine complex.
  • the tryptamine 23 can be modified using the Fukuyama modification of the Mitsunobu reaction (Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373- 74).
  • Test compounds are examined over a range of concentrations from 0.01 to 10,000 nM. The incubation is terminated by vacuum filtration onto 96-well Packard GF/C Unifilter plates (pretreated with 0.1% polyethyleneimine) and then washed with 2 L of cold phosphate buffered saline (pH 7.5). The Unifilter plates are dried prior to addition of scintillation fluid and counting in a Packard TopCount detector
  • GnRH receptor functionally coupled to phospholipase C were established and seeded at a concentration of 60,000 cells/mL/well in inositol-free F12 medium containing 10% dialyzed fetal bovine serum, 1% Pen/Strep, 2 M glutamine, 500 ⁇ g/mL G418 and 1 ⁇ Ci ( 3 H)inositol in 24-well tray. Forty-eight hours after seeding, cells were washed with 3 x 1 mL of PBS containing 10 mM LiCl and treated with various concentrations of GnRH antagonist for 2 hrs at 37°C before the addition of 0.5 nM GnRH.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • Step 1A Methyl (S)-2-[3-(2-benzyloxy-l-methylethyl)-2-triethylsilyl- lH-pyrrolor2.3-6]pyridin-5-yl]-2-methylpropanoate
  • Step lJ (S)-l-(7-Azabicyclo[2.2.1]hept-7-yl)-2- ⁇ 2-(3,5-dimethyl- phenyl)-3-[l-methyl-2-(4-pyridin-4-yl-butylamino)ethyl]-lH- l-(tert-butoxycarbonyl)pyrrolo[2,3-6]pyridin-5-yl ⁇ -2- methylpropan-1-one
  • a solution of 4-(pyridin-4-yl)butanal (89.0 mg, 0.597 mmol) in chloroform (0.8 mL) was added via syringe to a stirred suspension of (S)-l-(7-azabicyclo[2.2.1]hept-7-yl)-2-[3-(2-amino-l-methylethyl)-2-(3,5- dimethylphenyl)-lH-l-( ⁇ er ⁇ -butoxycarbonyl)pyrrolo[2,3-6]pyri

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Immunology (AREA)
  • Reproductive Health (AREA)
  • Transplantation (AREA)
  • Gynecology & Obstetrics (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention porte sur des composés de la formule (I) et sur leurs sels pharmaceutiquement acceptables qui sont utilisés comme antagonistes de GnRH et, en conséquence, dans le traitement d'états relatifs à l'hormone sexuelle et à d'autres hormones chez l'homme et chez la femme.
PCT/US1999/006726 1998-04-02 1999-03-29 Antagonistes de l'hormone liberant la gonadotropine (gnrh) Ceased WO1999051232A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2000542003A JP2002510629A (ja) 1998-04-02 1999-03-29 性腺刺激ホルモン放出ホルモン拮抗薬
AU31183/99A AU3118399A (en) 1998-04-02 1999-03-29 Antagonists of gonadotropin releasing hormone
CA002326143A CA2326143A1 (fr) 1998-04-02 1999-03-29 Antagonistes de l'hormone liberant la gonadotropine (gnrh)
EP99912924A EP1067930A4 (fr) 1998-04-02 1999-03-29 Antagonistes de l'hormone liberant la gonadotropine (gnrh)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US8040598P 1998-04-02 1998-04-02
US60/080,405 1998-04-02
GBGB9815854.6A GB9815854D0 (en) 1998-07-21 1998-07-21 Antagonists of gonadotropin releasing hormone
GB9815854.6 1998-07-21

Publications (1)

Publication Number Publication Date
WO1999051232A1 true WO1999051232A1 (fr) 1999-10-14

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PCT/US1999/006726 Ceased WO1999051232A1 (fr) 1998-04-02 1999-03-29 Antagonistes de l'hormone liberant la gonadotropine (gnrh)

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EP (1) EP1067930A4 (fr)
JP (1) JP2002510629A (fr)
AU (1) AU3118399A (fr)
CA (1) CA2326143A1 (fr)
WO (1) WO1999051232A1 (fr)

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000069859A1 (fr) * 1999-05-14 2000-11-23 Neurocrine Biosciences, Inc. Imidazo- et pyrrolo[1,2-a]pyrimid-4-ones utilises comme antagonistes du recepteur de l'hormone de liberation de la gonadotrophine
WO2001029044A1 (fr) * 1999-10-15 2001-04-26 Neurocrine Biosciences, Inc. Antagonistes du recepteur de l'hormone liberant de la gonadotropine et methodes d'utilisation
US6346534B1 (en) 1998-09-23 2002-02-12 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US6534189B1 (en) 1994-07-15 2003-03-18 Exxonmobil Oil Corporation Uniaxially shrinkable biaxially oriented polypropylene film and method for use as tobacco pack overwrap
US6537998B1 (en) 1999-10-15 2003-03-25 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US6608197B2 (en) 2000-01-25 2003-08-19 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US6770643B2 (en) 1999-12-24 2004-08-03 Aventis Pharma Limited Azaindoles
US6809098B2 (en) 2001-02-20 2004-10-26 Astrazeneca Ab Compounds
US6897207B2 (en) 2001-06-21 2005-05-24 Aventis Pharmaceuticals Inc. Azaindoles
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
US7256188B2 (en) 2001-05-14 2007-08-14 Astrazeneca Ab 3-aminoalkyl-2-aryl-indole derivatives and their use as GnRH antagonists
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
US7384955B2 (en) 2003-03-31 2008-06-10 Astrazeneca Ab Azaindole derivatives, preparations thereof, uses thereof and compositions containing them
US7449489B2 (en) 2002-08-21 2008-11-11 Astrazeneca Ab Indolylalkylamino-methylidenecarbamate derivatives useful as GnRH antagonists
US7504509B2 (en) 2003-12-19 2009-03-17 Plexxikon, Inc. Compounds and methods for development of Ret modulators
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
US8865735B2 (en) 2011-02-21 2014-10-21 Hoffman-La Roche Inc. Solid forms of a pharmaceutically active substance
US9096593B2 (en) 2009-11-06 2015-08-04 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9150570B2 (en) 2012-05-31 2015-10-06 Plexxikon Inc. Synthesis of heterocyclic compounds
US9169250B2 (en) 2006-11-22 2015-10-27 Plexxikon Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
US9447089B2 (en) 2009-04-03 2016-09-20 Plexxikon Inc. Compositions and uses thereof
US9469640B2 (en) 2007-07-17 2016-10-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9624213B2 (en) 2011-02-07 2017-04-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor

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WO1997014682A1 (fr) * 1995-10-19 1997-04-24 Takeda Chemical Industries, Ltd. Derives de la quinoleine en tant qu'antagonistes du gn-rh
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US5849764A (en) * 1995-12-14 1998-12-15 Merck & Co., Inc. Antagonists of gonadotropin releasing hormone

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CA2240108A1 (fr) * 1995-12-14 1997-06-19 Peter Lin Antagonistes de l'hormone de liberation de la gonadotropine
JP2002510630A (ja) * 1998-04-02 2002-04-09 メルク エンド カムパニー インコーポレーテッド 性腺刺激ホルモン放出ホルモン拮抗薬

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WO1997014682A1 (fr) * 1995-10-19 1997-04-24 Takeda Chemical Industries, Ltd. Derives de la quinoleine en tant qu'antagonistes du gn-rh
US5849764A (en) * 1995-12-14 1998-12-15 Merck & Co., Inc. Antagonists of gonadotropin releasing hormone

Non-Patent Citations (2)

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Title
CHO et al., "Discovery of a Novel, Potent and Orally Active Nonpeptide Antagonist of the Human Luteinizing Hormone-Releasing Hormone (LHRH) Receptor", J. MED. CHEM., 1998, Vol. 41, No. 22, pages 4190-4195, XP002918858 *
See also references of EP1067930A4 *

Cited By (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6534189B1 (en) 1994-07-15 2003-03-18 Exxonmobil Oil Corporation Uniaxially shrinkable biaxially oriented polypropylene film and method for use as tobacco pack overwrap
US6346534B1 (en) 1998-09-23 2002-02-12 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
WO2000069859A1 (fr) * 1999-05-14 2000-11-23 Neurocrine Biosciences, Inc. Imidazo- et pyrrolo[1,2-a]pyrimid-4-ones utilises comme antagonistes du recepteur de l'hormone de liberation de la gonadotrophine
WO2001029044A1 (fr) * 1999-10-15 2001-04-26 Neurocrine Biosciences, Inc. Antagonistes du recepteur de l'hormone liberant de la gonadotropine et methodes d'utilisation
US6537998B1 (en) 1999-10-15 2003-03-25 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
JP2003512379A (ja) * 1999-10-15 2003-04-02 ニューロクライン バイオサイエンシーズ， インコーポレイテッド 性腺刺激ホルモン放出ホルモンレセプターアンタゴニストおよびそれに関連する方法
AU769855B2 (en) * 1999-10-15 2004-02-05 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US7227020B2 (en) 1999-12-24 2007-06-05 Aventis Pharma Limited Azaindoles
US6770643B2 (en) 1999-12-24 2004-08-03 Aventis Pharma Limited Azaindoles
US6608197B2 (en) 2000-01-25 2003-08-19 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US6872728B2 (en) 2000-01-25 2005-03-29 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US7462625B2 (en) 2000-01-25 2008-12-09 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US7179815B2 (en) 2000-01-25 2007-02-20 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
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
US6897207B2 (en) 2001-06-21 2005-05-24 Aventis Pharmaceuticals Inc. Azaindoles
US7943616B2 (en) 2001-06-21 2011-05-17 Aventis Pharmaceuticals Inc. Azaindoles for inhibiting aurora2 and other kinases
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
US7268158B2 (en) 2002-08-21 2007-09-11 Astrazeneca Ab 6H-THIENO [2,3-b]pyrrole derivatives as antagonists of gonadotropin releasing hormone (GnRH)
US7547722B2 (en) 2002-08-21 2009-06-16 Astrazeneca Ab Chemical compounds
US7317010B2 (en) 2002-08-21 2008-01-08 Astrazeneca Ab Thieno-pyrrole compounds as antagonists of gonadotropin releasing hormone
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
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CA2326143A1 (fr) 1999-10-14
AU3118399A (en) 1999-10-25
JP2002510629A (ja) 2002-04-09
EP1067930A1 (fr) 2001-01-17
EP1067930A4 (fr) 2002-09-18

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