ES2647585T3 - Derivados de aminoácido beta como antagonistas de integrina - Google Patents
Derivados de aminoácido beta como antagonistas de integrina Download PDFInfo
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- ES2647585T3 ES2647585T3 ES13742135.0T ES13742135T ES2647585T3 ES 2647585 T3 ES2647585 T3 ES 2647585T3 ES 13742135 T ES13742135 T ES 13742135T ES 2647585 T3 ES2647585 T3 ES 2647585T3
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- 102000006495 integrins Human genes 0.000 title description 84
- 108010044426 integrins Proteins 0.000 title description 84
- 239000005557 antagonist Substances 0.000 title description 13
- 150000001576 beta-amino acids Chemical class 0.000 title description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 241
- -1 CF2H Chemical group 0.000 claims abstract description 169
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 117
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 76
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 70
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 68
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 65
- 239000001257 hydrogen Substances 0.000 claims abstract description 64
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 59
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 56
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims abstract description 47
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 44
- 150000003839 salts Chemical class 0.000 claims abstract description 43
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims abstract description 38
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 38
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 32
- 125000001246 bromo group Chemical group Br* 0.000 claims abstract description 29
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 23
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 22
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 19
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 16
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 15
- 125000005843 halogen group Chemical group 0.000 claims abstract description 15
- 229910014033 C-OH Inorganic materials 0.000 claims abstract description 12
- 229910014570 C—OH Inorganic materials 0.000 claims abstract description 12
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims abstract 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 91
- 201000010099 disease Diseases 0.000 claims description 59
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- 230000004761 fibrosis Effects 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 201000011510 cancer Diseases 0.000 claims description 12
- 206010038933 Retinopathy of prematurity Diseases 0.000 claims description 10
- 208000028506 Familial Exudative Vitreoretinopathies Diseases 0.000 claims description 9
- 201000006902 exudative vitreoretinopathy Diseases 0.000 claims description 9
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 8
- 208000001132 Osteoporosis Diseases 0.000 claims description 8
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
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- 208000037147 Hypercalcaemia Diseases 0.000 claims description 3
- 208000002158 Proliferative Vitreoretinopathy Diseases 0.000 claims description 3
- 206010039710 Scleroderma Diseases 0.000 claims description 3
- 230000002440 hepatic effect Effects 0.000 claims description 3
- 230000000148 hypercalcaemia Effects 0.000 claims description 3
- 208000030915 hypercalcemia disease Diseases 0.000 claims description 3
- 230000001363 autoimmune Effects 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 abstract description 12
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 abstract 2
- 239000011541 reaction mixture Substances 0.000 description 233
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 169
- 239000000243 solution Substances 0.000 description 163
- 239000000203 mixture Substances 0.000 description 119
- 238000000034 method Methods 0.000 description 110
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 97
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 91
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 85
- 238000002360 preparation method Methods 0.000 description 85
- 229910001868 water Inorganic materials 0.000 description 84
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 76
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 66
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 63
- 235000019439 ethyl acetate Nutrition 0.000 description 62
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 60
- 238000006243 chemical reaction Methods 0.000 description 56
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 52
- 239000012043 crude product Substances 0.000 description 49
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- 239000002904 solvent Substances 0.000 description 48
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 46
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 46
- 125000003118 aryl group Chemical group 0.000 description 46
- 239000012044 organic layer Substances 0.000 description 45
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 44
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 41
- 235000002639 sodium chloride Nutrition 0.000 description 41
- 238000003756 stirring Methods 0.000 description 40
- 239000000725 suspension Substances 0.000 description 39
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 37
- 239000003607 modifier Substances 0.000 description 37
- 239000012299 nitrogen atmosphere Substances 0.000 description 35
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 34
- 229910052938 sodium sulfate Inorganic materials 0.000 description 34
- 235000011152 sodium sulphate Nutrition 0.000 description 34
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 33
- 239000000741 silica gel Substances 0.000 description 33
- 229910002027 silica gel Inorganic materials 0.000 description 33
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 31
- 230000015572 biosynthetic process Effects 0.000 description 31
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 28
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- 239000007832 Na2SO4 Substances 0.000 description 27
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 26
- 150000001721 carbon Chemical group 0.000 description 26
- 210000004027 cell Anatomy 0.000 description 26
- 238000004458 analytical method Methods 0.000 description 25
- 150000002148 esters Chemical class 0.000 description 25
- 238000003818 flash chromatography Methods 0.000 description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 23
- 238000003786 synthesis reaction Methods 0.000 description 23
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- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 22
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 22
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 22
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 20
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- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical group [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 19
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 19
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- 125000001072 heteroaryl group Chemical group 0.000 description 19
- 230000002401 inhibitory effect Effects 0.000 description 19
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 18
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 18
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 18
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 18
- QCIXLBJRJKTXCU-UHFFFAOYSA-N 1-(3,5-dibromophenyl)cyclopropane-1-carbonitrile Chemical compound BrC1=CC(Br)=CC(C2(CC2)C#N)=C1 QCIXLBJRJKTXCU-UHFFFAOYSA-N 0.000 description 17
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 17
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 17
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D239/26—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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| AU2014324426A1 (en) | 2013-09-30 | 2016-04-21 | The Regents Of The University Of California | Anti-alphavbeta1 integrin compounds and methods |
| CA2981371A1 (en) | 2015-03-10 | 2016-09-15 | The Regents Of The University Of California | Anti-alphavbeta1 integrin inhibitors and methods of use |
| US20180110762A1 (en) * | 2015-03-26 | 2018-04-26 | Merck Sharp & Dohme Corp | Compositions Methods for Treating Chronic Kidney Disease |
| KR20180107121A (ko) * | 2015-12-30 | 2018-10-01 | 세인트 루이스 유니버시티 | 팬 인테그린 길항제로서의 메타-아자사이클릭 아미노 벤조산 유도체 |
| CN109996541A (zh) * | 2016-09-07 | 2019-07-09 | 普利安特治疗公司 | N-酰基氨基酸化合物及其使用方法 |
| BR112019012515A2 (pt) | 2016-12-29 | 2019-11-19 | Saint Louis University | antagonistas de integrina |
| TW201835078A (zh) | 2017-02-28 | 2018-10-01 | 美商萊築理公司 | αvβ6整合蛋白之抑制劑 |
| AU2018227417B2 (en) | 2017-02-28 | 2021-12-23 | Morphic Therapeutic, Inc. | Inhibitors of (alpha-v)(beta-6) integrin |
| CN109879969B (zh) * | 2017-12-06 | 2024-04-09 | 天士力生物医药股份有限公司 | 一种hm-3融合蛋白及其应用 |
| HUE065887T2 (hu) * | 2018-03-07 | 2024-06-28 | Pliant Therapeutics Inc | Aminosav vegyületek és alkalmazási eljárások |
| EP4086254B1 (en) | 2018-08-29 | 2024-12-18 | Morphic Therapeutic, Inc. | Integrin inhibitors |
| CN114173803A (zh) * | 2019-04-08 | 2022-03-11 | 普利安特治疗公司 | 氨基酸化合物的剂型和方案 |
| CN110974938A (zh) * | 2019-12-02 | 2020-04-10 | 上海长海医院 | 整合素α1β1抑制剂在制备预防或治疗主动脉疾病药物中的应用 |
| CA3182964A1 (en) * | 2020-05-14 | 2021-11-18 | Ube Corporation | 1,4,5,6-tetrahydropyrimidin-2-amine derivative |
| WO2023085396A1 (ja) * | 2021-11-12 | 2023-05-19 | Ube株式会社 | アルポート症候群を治療または予防するための医薬組成物 |
| WO2024262620A1 (ja) * | 2023-06-22 | 2024-12-26 | 株式会社抗体医学研究所 | インテグリン阻害低分子化合物 |
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| US5602155A (en) | 1995-01-17 | 1997-02-11 | G. D. Searle & Co. | Platelet aggregation inhibitors |
| US5639765A (en) | 1995-01-17 | 1997-06-17 | G. D. Searle & Co. | Guanidinoalkyl glycine β-amino acids useful for inhibiting bone loss |
| US5681820A (en) | 1995-05-16 | 1997-10-28 | G. D. Searle & Co. | Guanidinoalkyl glycine β-amino acids useful for inhibiting tumor metastasis |
| PT850221E (pt) | 1995-08-30 | 2001-11-30 | Searle & Co | Derivados de meta-guanidina ureia tioureia ou acido aminobenzoico azaciclico como antagonistas de integrina |
| US6013651A (en) | 1995-08-30 | 2000-01-11 | G. D. Searle & Co. | Meta-azacyclic amino benzoic acid compounds and derivatives thereof |
| EP0894084B1 (en) | 1996-03-29 | 2002-06-26 | G.D. Searle & Co. | Cinnamic acid derivatives and their use as integrin antagonists |
| AU2337097A (en) | 1996-03-29 | 1997-10-22 | G.D. Searle & Co. | Meta-substituted phenylene derivatives and their use as alphavbeta3 integrin antagonists or inhibitors |
| PT891325E (pt) | 1996-03-29 | 2002-07-31 | Searle & Co | Derivados do acido fenilpropanoico para-substituido como antagonistas de integrina |
| ES2167758T3 (es) | 1996-07-12 | 2002-05-16 | Searle & Co | Sintesis asimetrica de beta-aminoacidos quirales. |
| US6372719B1 (en) | 1998-03-04 | 2002-04-16 | Jay Cunningham | ανβ3 integrin antagonists in combination with chemotherapeutic agents |
| ZA994406B (en) | 1998-03-04 | 2000-02-11 | Searle & Co | Meta-azacyclic amino benzoic acid and derivatives thereof. |
| ZA991105B (en) | 1998-03-04 | 2000-02-11 | Searle & Co | Synthesis of chiral beta-amino acids. |
| ZA991107B (en) | 1998-03-04 | 2000-02-14 | Searle & Co | Process for preparing 3-hydroxy-5-[(1,4,5,6-tetrahydro-5-hydroxy-2-pyrimidinyl)amino] benzoic acid. |
| PL343406A1 (en) | 1998-04-10 | 2001-08-13 | Searle & Co | Heterocyclic glycyl beta-alanine derivatives as vitronectin antagonists |
| JP2002533422A (ja) | 1998-12-23 | 2002-10-08 | ジー・ディー・サール・アンド・カンパニー | 新形成の治療における併用療法としてシクロオキシゲナーゼ−2阻害剤とインテグリン拮抗剤を使用する方法 |
| JP2004511434A (ja) | 2000-06-15 | 2004-04-15 | ファルマシア・コーポレーション | インテグリン受容体アンタゴニストとしてのヘテロアリールアルカン酸 |
| US20020072500A1 (en) * | 2000-09-27 | 2002-06-13 | Thomas Rogers | Hydroxy acid integrin antagonists |
| BR0317487A (pt) * | 2002-12-20 | 2005-11-29 | Pharmacia Corp | O r-isÈmero de compostos de aminoácido beta como derivados de antagonistas de receptores de integrina |
| DK1667668T3 (da) | 2003-10-01 | 2008-09-15 | Merck Patent Gmbh | Alfabeta3 og altabeta6-integrinantagonister som antifibrotiske midler |
| TWI433839B (zh) | 2006-08-11 | 2014-04-11 | Neomed Inst | 新穎的苯并咪唑衍生物290 |
| WO2010010184A1 (en) | 2008-07-25 | 2010-01-28 | Galapagos Nv | [1, 2, 4] triazolo [1, 5-a] pyridines as jak inhibitors |
| US8614221B2 (en) | 2009-03-11 | 2013-12-24 | Merck Sharp & Dohme Corp. | Inhibitors of Akt activity |
| AR077975A1 (es) | 2009-08-28 | 2011-10-05 | Irm Llc | Derivados de pirazol pirimidina y composiciones como inhibidores de cinasa de proteina |
| EP2609092B1 (en) | 2010-08-26 | 2015-04-01 | Boehringer Ingelheim International GmbH | Oxadiazole inhibitors of leukotriene production |
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