UA123330C2 - Гетероароматичні модулятори ретинол-зв'язаного орфанного рецептора гамма - Google Patents
Гетероароматичні модулятори ретинол-зв'язаного орфанного рецептора гамма Download PDFInfo
- Publication number
- UA123330C2 UA123330C2 UAA201901406A UAA201901406A UA123330C2 UA 123330 C2 UA123330 C2 UA 123330C2 UA A201901406 A UAA201901406 A UA A201901406A UA A201901406 A UAA201901406 A UA A201901406A UA 123330 C2 UA123330 C2 UA 123330C2
- Authority
- UA
- Ukraine
- Prior art keywords
- methyl
- oxadiazol
- carboxylate
- methylpiperazine
- alkyl
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims abstract description 432
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims abstract description 96
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 84
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 84
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 56
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 50
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 39
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 20
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims abstract description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 441
- -1 chloro, methyl Chemical group 0.000 claims description 234
- 125000000217 alkyl group Chemical group 0.000 claims description 224
- 238000000034 method Methods 0.000 claims description 194
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 139
- 150000002367 halogens Chemical class 0.000 claims description 78
- WEVYAHXRMPXWCK-UHFFFAOYSA-N methyl cyanide Natural products CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 71
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 claims description 54
- 125000001424 substituent group Chemical group 0.000 claims description 53
- ZPJZSEHCMJYUPI-UHFFFAOYSA-N methyl piperazine-1-carboxylate Chemical compound COC(=O)N1CCNCC1 ZPJZSEHCMJYUPI-UHFFFAOYSA-N 0.000 claims description 48
- 150000003839 salts Chemical class 0.000 claims description 36
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 27
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 25
- 238000011282 treatment Methods 0.000 claims description 25
- 150000004677 hydrates Chemical class 0.000 claims description 20
- 239000012453 solvate Substances 0.000 claims description 20
- FFGQNQREEKKFSL-UHFFFAOYSA-N methyl 2-methylpiperazine-1-carboxylate Chemical compound COC(=O)N1CCNCC1C FFGQNQREEKKFSL-UHFFFAOYSA-N 0.000 claims description 16
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 15
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- 230000001363 autoimmune Effects 0.000 claims description 14
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- 208000027866 inflammatory disease Diseases 0.000 claims description 13
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 12
- 125000003944 tolyl group Chemical group 0.000 claims description 12
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 10
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- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 6
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 5
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 5
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 5
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- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 208
- 239000000543 intermediate Substances 0.000 abstract description 38
- 125000005843 halogen group Chemical group 0.000 abstract description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract description 9
- 238000002560 therapeutic procedure Methods 0.000 abstract description 3
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- 230000002829 reductive effect Effects 0.000 description 114
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- 239000000203 mixture Substances 0.000 description 80
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
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- 239000011575 calcium Substances 0.000 description 60
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- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 44
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 38
- 238000010438 heat treatment Methods 0.000 description 34
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 33
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- 125000004432 carbon atom Chemical group C* 0.000 description 27
- 238000002953 preparative HPLC Methods 0.000 description 26
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 23
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- 241000282414 Homo sapiens Species 0.000 description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 20
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- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 20
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 19
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- 125000001309 chloro group Chemical group Cl* 0.000 description 18
- 239000000010 aprotic solvent Substances 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 150000001299 aldehydes Chemical class 0.000 description 15
- 239000004480 active ingredient Substances 0.000 description 14
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 14
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 14
- 241000905957 Channa melasoma Species 0.000 description 13
- 239000012634 fragment Substances 0.000 description 13
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 12
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 12
- 229910052938 sodium sulfate Inorganic materials 0.000 description 12
- 235000011152 sodium sulphate Nutrition 0.000 description 12
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- 238000009472 formulation Methods 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 235000019445 benzyl alcohol Nutrition 0.000 description 10
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- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Substances [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
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- 229910052717 sulfur Inorganic materials 0.000 description 9
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- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 8
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- 125000003118 aryl group Chemical group 0.000 description 8
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- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- BRWIZMBXBAOCCF-UHFFFAOYSA-N hydrazinecarbothioamide Chemical compound NNC(N)=S BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 description 8
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
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- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- 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
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- A61P17/00—Drugs for dermatological disorders
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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
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- 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
- A61P37/08—Antiallergic agents
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Dermatology (AREA)
- Rheumatology (AREA)
- Epidemiology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Pain & Pain Management (AREA)
- Pulmonology (AREA)
- Transplantation (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Hydrogenated Pyridines (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP16020268 | 2016-07-13 | ||
| PCT/EP2017/067390 WO2018011201A1 (en) | 2016-07-13 | 2017-07-11 | Heteroaromatic modulators of the retinoid-related orphan receptor gamma |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| UA123330C2 true UA123330C2 (uk) | 2021-03-17 |
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| UAA201901406A UA123330C2 (uk) | 2016-07-13 | 2017-07-11 | Гетероароматичні модулятори ретинол-зв'язаного орфанного рецептора гамма |
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|---|---|
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| EP (1) | EP3484880B1 (https=) |
| JP (1) | JP7016344B2 (https=) |
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| CN (1) | CN109476653B (https=) |
| AU (1) | AU2017294969B2 (https=) |
| BR (1) | BR112019000486A2 (https=) |
| CA (1) | CA3030370A1 (https=) |
| DK (1) | DK3484880T3 (https=) |
| ES (1) | ES2834009T3 (https=) |
| IL (1) | IL264141B (https=) |
| MX (1) | MX383770B (https=) |
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| UA (1) | UA123330C2 (https=) |
| WO (1) | WO2018011201A1 (https=) |
| ZA (1) | ZA201808436B (https=) |
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| CN109476653B (zh) * | 2016-07-13 | 2022-04-22 | 利奥制药有限公司 | 类视黄醇相关孤儿受体γ的杂芳族调节剂 |
| CN111825654A (zh) * | 2019-04-19 | 2020-10-27 | 北京酷瓴生物技术有限公司 | 苯甲烯哌啶衍生物及其制备方法、中间体和用途 |
| CN112898292A (zh) * | 2019-12-03 | 2021-06-04 | 微境生物医药科技(上海)有限公司 | 新型极光激酶抑制剂及其用途 |
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| CS244821B2 (en) * | 1983-06-16 | 1986-08-14 | Boehringer Ingelheim Ltd | Production method of new substituted phenylalkyl(piperazinyl or homopiperazinyle)-prpylureas or thioureas |
| WO2004073612A2 (en) | 2003-02-13 | 2004-09-02 | Merck & Co. Inc. | Estrogen receptor modulators |
| FR2879381B1 (fr) | 2004-12-15 | 2008-12-26 | Thales Sa | Systeme de distribution quantique de cle de cryptage a variables continues |
| AU2006231929B2 (en) * | 2005-04-04 | 2012-09-06 | Ab Science | Substituted oxazole derivatives and their use as tyrosine kinase inhibitors |
| EP2511275A1 (en) | 2011-04-12 | 2012-10-17 | Bioprojet | Novel piperidinyl monocarboxylic acids as S1P1 receptor agonists |
| WO2014086894A1 (en) * | 2012-12-06 | 2014-06-12 | Glaxo Group Limited | Modulators of the retinoid-related orphan receptor gamma (ror-gamma) for use in the treatment of autoimmune and inflammatory diseases |
| CN105705492B (zh) * | 2013-11-05 | 2019-11-05 | 豪夫迈·罗氏有限公司 | 作为rorc调节剂用于治疗自身免疫性疾病的5,6,7,8-四氢-5,8-亚甲基噌啉衍生物 |
| WO2015180613A1 (en) | 2014-05-28 | 2015-12-03 | Glaxosmithkline Intellectual Property Development Limited | Novel compounds |
| AU2015267909B2 (en) | 2014-05-28 | 2018-03-22 | Glaxosmithkline Intellectual Property Development Limited | Novel compounds |
| JP6522665B2 (ja) | 2014-05-28 | 2019-05-29 | グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ | 新規化合物 |
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| IL264141A (en) | 2019-02-28 |
| WO2018011201A1 (en) | 2018-01-18 |
| US20190284177A1 (en) | 2019-09-19 |
| CN109476653A (zh) | 2019-03-15 |
| CA3030370A1 (en) | 2018-01-18 |
| SA519400868B1 (ar) | 2022-06-13 |
| SG11201811107WA (en) | 2019-01-30 |
| JP7016344B2 (ja) | 2022-02-04 |
| CN109476653B (zh) | 2022-04-22 |
| MY196990A (en) | 2023-05-17 |
| MX383770B (es) | 2025-03-14 |
| RU2771280C2 (ru) | 2022-04-29 |
| NZ749301A (en) | 2021-03-26 |
| PL3484880T3 (pl) | 2021-04-06 |
| IL264141B (en) | 2021-09-30 |
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