KR20060052790A - 고나도트로핀-방출 호르몬 수용체 길항제로서의피리미딘-2,4-디온 유도체 - Google Patents
고나도트로핀-방출 호르몬 수용체 길항제로서의피리미딘-2,4-디온 유도체 Download PDFInfo
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- KR20060052790A KR20060052790A KR1020067000435A KR20067000435A KR20060052790A KR 20060052790 A KR20060052790 A KR 20060052790A KR 1020067000435 A KR1020067000435 A KR 1020067000435A KR 20067000435 A KR20067000435 A KR 20067000435A KR 20060052790 A KR20060052790 A KR 20060052790A
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- Prior art keywords
- methyl
- compound
- fluoro
- dione
- mmol
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- RIMFTIRVOAFUCC-DEOSSOPVSA-N tert-butyl n-[(1r)-2-[3-[(2,6-difluorophenyl)methyl]-5-(2-fluoro-3-hydroxyphenyl)-4-methyl-2,6-dioxopyrimidin-1-yl]-1-phenylethyl]carbamate Chemical compound O=C1N(C[C@H](NC(=O)OC(C)(C)C)C=2C=CC=CC=2)C(=O)N(CC=2C(=CC=CC=2F)F)C(C)=C1C1=CC=CC(O)=C1F RIMFTIRVOAFUCC-DEOSSOPVSA-N 0.000 description 1
- OIHVGMJEFOZEGR-VWLOTQADSA-N tert-butyl n-[(1r)-2-[3-[(2,6-difluorophenyl)methyl]-5-(2-fluoro-3-methoxyphenyl)-4-methyl-2,6-dioxopyrimidin-1-yl]-1-phenylethyl]carbamate Chemical compound COC1=CC=CC(C=2C(N(C[C@H](NC(=O)OC(C)(C)C)C=3C=CC=CC=3)C(=O)N(CC=3C(=CC=CC=3F)F)C=2C)=O)=C1F OIHVGMJEFOZEGR-VWLOTQADSA-N 0.000 description 1
- LCDCTOYTSRVTFS-VWLOTQADSA-N tert-butyl n-[(1r)-2-[5-(2-chloro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-2,6-dioxopyrimidin-1-yl]-1-phenylethyl]carbamate Chemical compound COC1=CC=CC(C=2C(N(C[C@H](NC(=O)OC(C)(C)C)C=3C=CC=CC=3)C(=O)N(CC=3C(=CC=CC=3F)C(F)(F)F)C=2)=O)=C1Cl LCDCTOYTSRVTFS-VWLOTQADSA-N 0.000 description 1
- VUYBNDDQJVLNEJ-SANMLTNESA-N tert-butyl n-[(1r)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-4-methyl-2,6-dioxopyrimidin-1-yl]-1-phenylethyl]-n-methylcarbamate Chemical compound COC1=CC=CC(C=2C(N(C[C@H](N(C)C(=O)OC(C)(C)C)C=3C=CC=CC=3)C(=O)N(CC=3C(=CC=CC=3F)C(F)(F)F)C=2C)=O)=C1F VUYBNDDQJVLNEJ-SANMLTNESA-N 0.000 description 1
- FRYAICDFIOVZRY-NRFANRHFSA-N tert-butyl n-[(1r)-2-[5-bromo-3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-4-methyl-2,6-dioxopyrimidin-1-yl]-1-phenylethyl]-n-methylcarbamate Chemical compound C([C@H](N(C)C(=O)OC(C)(C)C)C=1C=CC=CC=1)N(C1=O)C(=O)C(Br)=C(C)N1CC1=C(F)C=CC=C1C(F)(F)F FRYAICDFIOVZRY-NRFANRHFSA-N 0.000 description 1
- CTRYPLXHKHHCGW-UHFFFAOYSA-N tert-butyl-[4-methyl-1-(4-methylphenyl)sulfonyloxypentan-2-yl]carbamic acid Chemical compound CC1=CC=C(C=C1)S(=O)(=O)OCC(CC(C)C)N(C(=O)O)C(C)(C)C CTRYPLXHKHHCGW-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical class C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 150000003852 triazoles Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- 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
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- 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
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- 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
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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- 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
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- 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
- A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
-
- 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
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Reproductive Health (AREA)
- Immunology (AREA)
- Dermatology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Anesthesiology (AREA)
- Urology & Nephrology (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Biomedical Technology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US48543603P | 2003-07-07 | 2003-07-07 | |
| US60/485,436 | 2003-07-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20060052790A true KR20060052790A (ko) | 2006-05-19 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| KR1020067000435A Withdrawn KR20060052790A (ko) | 2003-07-07 | 2004-07-06 | 고나도트로핀-방출 호르몬 수용체 길항제로서의피리미딘-2,4-디온 유도체 |
Country Status (14)
| Country | Link |
|---|---|
| US (2) | US7071200B2 (https=) |
| EP (1) | EP1660091B1 (https=) |
| JP (2) | JP4658044B2 (https=) |
| KR (1) | KR20060052790A (https=) |
| CN (2) | CN100376246C (https=) |
| AT (1) | ATE428427T1 (https=) |
| AU (1) | AU2004257636B2 (https=) |
| BR (1) | BRPI0412327A (https=) |
| CA (1) | CA2531507C (https=) |
| DE (1) | DE602004020638D1 (https=) |
| EA (1) | EA200600188A1 (https=) |
| IL (1) | IL172834A0 (https=) |
| MX (1) | MXPA06000300A (https=) |
| WO (1) | WO2005007164A1 (https=) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100837785B1 (ko) * | 2007-01-17 | 2008-06-13 | 한국화학연구원 | 1,2,4-티아다이아졸리딘-3,5-다이온 화합물을 포함하는염증관련 질환의 치료 및 예방을 위한 약제학적 조성물 |
| WO2011062437A3 (ko) * | 2009-11-20 | 2011-11-03 | 에스케이케미칼주식회사 | 고나도트로핀 방출 호르몬 수용체 길항제, 이의 제조방법 및 이를 함유하는 약제학적 조성물 |
Families Citing this family (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001055119A2 (en) * | 2000-01-25 | 2001-08-02 | Neurocrine Biosciences, Inc. | Gonadotropin-releasing hormone receptor antagonists and methods relating thereto |
| AU2004257639B2 (en) * | 2003-07-07 | 2011-01-06 | Neurocrine Biosciences, Inc. | Pyrimidine-2, 4-dione derivatives as gonadotropin-releasing hormone receptor antagonists |
| ES2387495T3 (es) * | 2003-07-07 | 2012-09-25 | Neurocrine Biosciences, Inc. | Arilpirimidinas útiles en el tratamiento de trastornos relacionados con las hormonas sexuales, tales como endometriosis, cáncer de próstata y similares |
| UA85871C2 (uk) * | 2004-03-15 | 2009-03-10 | Такеда Фармасьютікал Компані Лімітед | Інгібітори дипептидилпептидази |
| JP2008537548A (ja) | 2005-03-24 | 2008-09-18 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | プロキネチシン１受容体 |
| KR20080006564A (ko) | 2005-03-24 | 2008-01-16 | 얀센 파마슈티카 엔.브이. | 프로키네티신 1 수용체 길항제 |
| EP2155194B1 (en) | 2007-04-06 | 2015-01-21 | Neurocrine Biosciences, Inc. | Gonadotropin-releasing hormone receptor antagonists and methods relating thereto |
| CL2008000986A1 (es) | 2007-04-06 | 2008-10-17 | Neurocrine Biosciences Inc | COMPUESTO DERIVADO DE HETEROCICLOS DE NITROGENO, AGONISTAS DEL RECEPTOR GnRH; COMPOSICION FARMACEUTICA QUE COMPRENDE A DICHO COMPUESTO; Y USO PARA TRATAR UNA AFECCION RELACIONADA CON LAS HORMONAS SEXUALES, ENDOMETRIOSIS, DISMENORREA, ENFERMEDAD DE OV |
| US8765948B2 (en) | 2007-11-07 | 2014-07-01 | Neurocrine Biosciences, Inc. | Processes for the preparation of uracil derivatives |
| TW201130854A (en) | 2009-12-22 | 2011-09-16 | Bayer Schering Pharma Ag | Pyridinone derivatives and pharmaceutical compositions thereof |
| WO2012175514A1 (en) | 2011-06-21 | 2012-12-27 | Bayer Intellectual Property Gmbh | Pyridinone derivatives and pharmaceutical compositions thereof |
| CN107935863A (zh) * | 2017-11-30 | 2018-04-20 | 厦门海乐景生化有限公司 | Elagolix的关键原料化合物C的合成方法 |
| EP3724167A1 (en) * | 2017-12-11 | 2020-10-21 | Synthon B.V. | Process for preparing elagolix |
| BR112021000973A2 (pt) | 2018-07-23 | 2021-04-20 | Abbvie Inc. | composições e processos de sódio de elagolix |
| US20220242831A1 (en) * | 2019-05-24 | 2022-08-04 | Dr. Reddy's Laboratories Limited | Improved process for the preparation of elagolix and its intermediates |
| ES2802815B2 (es) | 2019-07-12 | 2022-03-14 | Moehs Iberica Sl | Sal clorhidrato de 3-[2(r)-amino-2-feniletil]-5-(2-fluoro-3-metoxifenil)-1-[2-fluoro-6-(trifluorometil)bencil]-6-metil-1h-pirimidin-2,4(1h,3h)-diona (i) en forma solida, procedimiento para su preparacion y uso de la misma en la sintesis de elagolix |
| CN112300081A (zh) * | 2019-07-31 | 2021-02-02 | 上海度德医药科技有限公司 | 噁拉戈利的中间体及其制备方法和应用 |
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Family Cites Families (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU5844896A (en) | 1995-06-01 | 1996-12-18 | Takeda Chemical Industries Ltd. | Tricyclic diazepines useful as gnrh receptor antagonists |
| US5859014A (en) * | 1995-06-09 | 1999-01-12 | Syntex (U.S.A.) Inc. | Pyrimidinedione, pyrimidinetrione, triazinedione and tetrahydroquinazolinedione derivatives as α1 -adrenergic receptor antagonists |
| CN1063446C (zh) | 1995-10-19 | 2001-03-21 | 武田药品工业株式会社 | 作为促性腺激素释放激素拮抗剂的噻吩并吡啶衍生物 |
| CN1200114A (zh) | 1995-10-19 | 1998-11-25 | 武田药品工业株式会社 | 作为gnrh拮抗剂的喹啉衍生物 |
| WO1997021435A1 (en) | 1995-12-14 | 1997-06-19 | Merck & Co., Inc. | Antagonists of gonadotropin releasing hormone |
| JP3092946B2 (ja) | 1995-12-14 | 2000-09-25 | メルク エンド カンパニー インコーポレーテッド | ゴナドトロピン放出ホルモン拮抗剤 |
| SK77598A3 (en) | 1995-12-14 | 1999-01-11 | Merck & Co Inc | Nonpeptide derivatives, pharmaceutical composition containing them and their use |
| CN1208412A (zh) | 1995-12-14 | 1999-02-17 | 麦克公司 | 促性腺激素释放激素拮抗剂 |
| AU729752B2 (en) | 1997-06-05 | 2001-02-08 | Merck & Co., Inc. | Antagonists of gonadotropin releasing hormone |
| EP0986385A4 (en) | 1997-06-05 | 2001-05-16 | Merck & Co Inc | GONADORELIN ANTAGONISTS |
| AU7806998A (en) | 1997-06-05 | 1998-12-21 | Merck & Co., Inc. | Antagonists of gonadotropin releasing hormone |
| WO1998055479A1 (en) | 1997-06-05 | 1998-12-10 | Merck & Co., Inc. | Antagonists of gonadotropin releasing hormone |
| US6313301B1 (en) | 1997-08-13 | 2001-11-06 | Takeda Chemical Industries, Ltd. | Thienopyridine derivatives, their intermediates and production thereof |
| CA2372044A1 (en) | 1999-05-14 | 2000-11-23 | Neurocrine Biosciences, Inc. | Imidazo- and pyrrolo[1,2-a]pyrimid-4-ones as gonadotropin-releasing hormone receptor antagonists |
| US20020065309A1 (en) | 1999-08-04 | 2002-05-30 | Ge Peng | Novel Bicyclic and tricyclic pyrrolidine derivatives as GnRH antagonists |
| MXPA02003614A (es) | 1999-10-15 | 2002-10-23 | Neurocrine Biosciences Inc | Antagonistas del receptor de la hormona liberadora de ganadotropina y metodos relacionados con los mismos.. |
| WO2001055119A2 (en) | 2000-01-25 | 2001-08-02 | Neurocrine Biosciences, Inc. | Gonadotropin-releasing hormone receptor antagonists and methods relating thereto |
| SE0100566D0 (sv) | 2001-02-20 | 2001-02-20 | Astrazeneca Ab | Compounds |
| AU2002324586B2 (en) | 2001-08-02 | 2008-04-24 | Neurocrine Biosciences, Inc. | 1,3,5-triazine-2,4,6-triones, preparation and use as gonadotropin-releasing hormone receptor antagonists |
| WO2003011870A1 (en) | 2001-08-02 | 2003-02-13 | Neurocrine Biosciences, Inc. | Gonadotropin-releasing hormone receptor antagonists |
| US6939883B2 (en) | 2001-08-02 | 2005-09-06 | Neurocrine Biosciences, Inc. | Gonadotropin-releasing hormone receptor antagonists and methods relating thereto |
| JP2005500352A (ja) | 2001-08-02 | 2005-01-06 | 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 | ゴナドトロピン放出ホルモンレセプター（ＧｎＲＨ）アンタゴニストとしての１，２，４−トリアジン−３，５−ジオン |
| EP1411941A2 (en) | 2001-08-02 | 2004-04-28 | Neurocrine Biosciences, Inc. | Pyridinone and pyridazinone derivatives as gonadotropin-releasing hormone receptor antagonists |
| ES2387495T3 (es) | 2003-07-07 | 2012-09-25 | Neurocrine Biosciences, Inc. | Arilpirimidinas útiles en el tratamiento de trastornos relacionados con las hormonas sexuales, tales como endometriosis, cáncer de próstata y similares |
| AU2004257639B2 (en) | 2003-07-07 | 2011-01-06 | Neurocrine Biosciences, Inc. | Pyrimidine-2, 4-dione derivatives as gonadotropin-releasing hormone receptor antagonists |
-
2004
- 2004-07-06 DE DE602004020638T patent/DE602004020638D1/de not_active Expired - Fee Related
- 2004-07-06 JP JP2006518838A patent/JP4658044B2/ja not_active Expired - Lifetime
- 2004-07-06 US US10/885,511 patent/US7071200B2/en not_active Expired - Lifetime
- 2004-07-06 WO PCT/US2004/021569 patent/WO2005007164A1/en not_active Ceased
- 2004-07-06 EA EA200600188A patent/EA200600188A1/ru unknown
- 2004-07-06 AU AU2004257636A patent/AU2004257636B2/en not_active Ceased
- 2004-07-06 MX MXPA06000300A patent/MXPA06000300A/es active IP Right Grant
- 2004-07-06 CN CNB2004800196064A patent/CN100376246C/zh not_active Expired - Fee Related
- 2004-07-06 CA CA2531507A patent/CA2531507C/en not_active Expired - Fee Related
- 2004-07-06 CN CNA2008100027460A patent/CN101229165A/zh active Pending
- 2004-07-06 EP EP04777596A patent/EP1660091B1/en not_active Expired - Lifetime
- 2004-07-06 AT AT04777596T patent/ATE428427T1/de not_active IP Right Cessation
- 2004-07-06 KR KR1020067000435A patent/KR20060052790A/ko not_active Withdrawn
- 2004-07-06 BR BRPI0412327-1A patent/BRPI0412327A/pt not_active IP Right Cessation
-
2005
- 2005-12-26 IL IL172834A patent/IL172834A0/en unknown
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2006
- 2006-06-02 US US11/446,583 patent/US7329669B2/en not_active Expired - Lifetime
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2010
- 2010-11-29 JP JP2010265832A patent/JP2011088903A/ja not_active Withdrawn
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100837785B1 (ko) * | 2007-01-17 | 2008-06-13 | 한국화학연구원 | 1,2,4-티아다이아졸리딘-3,5-다이온 화합물을 포함하는염증관련 질환의 치료 및 예방을 위한 약제학적 조성물 |
| WO2011062437A3 (ko) * | 2009-11-20 | 2011-11-03 | 에스케이케미칼주식회사 | 고나도트로핀 방출 호르몬 수용체 길항제, 이의 제조방법 및 이를 함유하는 약제학적 조성물 |
| US9034850B2 (en) | 2009-11-20 | 2015-05-19 | Sk Chemicals Co., Ltd. | Gonadotropin releasing hormone receptor antagonist, preparation method thereof and pharmaceutical composition comprising the same |
Also Published As
| Publication number | Publication date |
|---|---|
| JP4658044B2 (ja) | 2011-03-23 |
| CN1826119A (zh) | 2006-08-30 |
| WO2005007164A1 (en) | 2005-01-27 |
| ATE428427T1 (de) | 2009-05-15 |
| BRPI0412327A (pt) | 2006-09-05 |
| US20070015778A1 (en) | 2007-01-18 |
| EA200600188A1 (ru) | 2006-08-25 |
| AU2004257636A1 (en) | 2005-01-27 |
| CA2531507A1 (en) | 2005-01-27 |
| EP1660091B1 (en) | 2009-04-15 |
| CN100376246C (zh) | 2008-03-26 |
| JP2007521308A (ja) | 2007-08-02 |
| AU2004257636B2 (en) | 2011-01-06 |
| IL172834A0 (en) | 2006-06-11 |
| CN101229165A (zh) | 2008-07-30 |
| MXPA06000300A (es) | 2006-03-28 |
| EP1660091A1 (en) | 2006-05-31 |
| US7071200B2 (en) | 2006-07-04 |
| CA2531507C (en) | 2013-10-01 |
| US20050043338A1 (en) | 2005-02-24 |
| JP2011088903A (ja) | 2011-05-06 |
| US7329669B2 (en) | 2008-02-12 |
| DE602004020638D1 (de) | 2009-05-28 |
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