RU2176645C2 - Ингибиторы тромбина, фармацевтическая композиция на их основе, способ лечения, способ их получения (варианты) и защищенное производное - Google Patents

Ингибиторы тромбина, фармацевтическая композиция на их основе, способ лечения, способ их получения (варианты) и защищенное производное Download PDF

Info

Publication number: RU2176645C2
Authority: RU; Russia
Prior art keywords: pab; alkyl; aze; compound; group
Prior art date: 1995-07-06

Application number

RU98102188/04A

Other languages

English (en)

Russian (ru)

Other versions

RU98102188A (ru

Inventor

Давид Густафссон

Ян-Эрик Нюстрем

Original Assignee

Астра Актиеболаг

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.)

1995-07-06

Filing date

1996-07-02

Publication date

2001-12-10

1995-07-06 Priority claimed from SE9502487A external-priority patent/SE9502487D0/xx

1995-07-07 Priority claimed from SE9502505A external-priority patent/SE9502505D0/xx

1995-07-07 Priority claimed from SE9502504A external-priority patent/SE9502504D0/xx

1995-11-07 Priority claimed from SE9503923A external-priority patent/SE9503923D0/xx

1995-12-05 Priority claimed from SE9504349A external-priority patent/SE9504349D0/xx

1995-12-22 Priority claimed from GBGB9526411.5A external-priority patent/GB9526411D0/en

1996-07-02 Application filed by Астра Актиеболаг filed Critical Астра Актиеболаг

1999-12-20 Publication of RU98102188A publication Critical patent/RU98102188A/ru

2001-12-10 Application granted granted Critical

2001-12-10 Publication of RU2176645C2 publication Critical patent/RU2176645C2/ru

Links

238000000034 method Methods 0.000 title claims abstract description 167
238000011282 treatment Methods 0.000 title claims abstract description 20
239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 5
229940122388 Thrombin inhibitor Drugs 0.000 title claims description 16
239000003868 thrombin inhibitor Substances 0.000 title claims description 16
230000015572 biosynthetic process Effects 0.000 title abstract description 11
238000003786 synthesis reaction Methods 0.000 title abstract description 10
150000001875 compounds Chemical class 0.000 claims abstract description 309
239000012634 fragment Substances 0.000 claims abstract description 52
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 42
-1 C1-4-alkoxy-group Chemical group 0.000 claims abstract description 36
108090000190 Thrombin Proteins 0.000 claims abstract description 29
229960004072 thrombin Drugs 0.000 claims abstract description 28
125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 27
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 22
125000001624 naphthyl group Chemical group 0.000 claims abstract description 19
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 19
150000003839 salts Chemical class 0.000 claims abstract description 18
125000005843 halogen group Chemical group 0.000 claims abstract description 14
208000007536 Thrombosis Diseases 0.000 claims abstract description 13
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims abstract description 12
125000001041 indolyl group Chemical group 0.000 claims abstract description 12
230000005764 inhibitory process Effects 0.000 claims abstract description 11
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 11
125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims abstract description 9
239000003146 anticoagulant agent Substances 0.000 claims abstract description 8
230000000694 effects Effects 0.000 claims abstract description 7
125000003055 glycidyl group Chemical group C(C1CO1)* 0.000 claims abstract description 3
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims abstract description 3
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125000000217 alkyl group Chemical group 0.000 claims description 69
239000000203 mixture Substances 0.000 claims description 56
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 44
229910052799 carbon Inorganic materials 0.000 claims description 21
125000003545 alkoxy group Chemical group 0.000 claims description 20
125000001309 chloro group Chemical group Cl* 0.000 claims description 16
125000002947 alkylene group Chemical group 0.000 claims description 13
125000001424 substituent group Chemical group 0.000 claims description 13
210000004369 blood Anatomy 0.000 claims description 9
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238000004519 manufacturing process Methods 0.000 claims description 9
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
229910052736 halogen Inorganic materials 0.000 claims description 8
150000002367 halogens Chemical class 0.000 claims description 8
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150000001721 carbon Chemical group 0.000 claims description 6
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125000004432 carbon atom Chemical group C* 0.000 claims description 5
125000000753 cycloalkyl group Chemical group 0.000 claims description 5
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
229910052757 nitrogen Inorganic materials 0.000 claims description 5
125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 4
125000001246 bromo group Chemical group Br* 0.000 claims description 4
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125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 4
UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 4
206010020608 Hypercoagulation Diseases 0.000 claims description 3
230000003027 hypercoagulation Effects 0.000 claims description 3
239000002671 adjuvant Substances 0.000 claims description 2
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239000003085 diluting agent Substances 0.000 claims description 2
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OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
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125000004429 atom Chemical group 0.000 claims 1
239000003112 inhibitor Substances 0.000 abstract description 13
125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 7
125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 2
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238000005481 NMR spectroscopy Methods 0.000 description 217
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 103
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XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 68
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239000002253 acid Substances 0.000 description 40
238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 38
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
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239000000460 chlorine Substances 0.000 description 27
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RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
239000000243 solution Substances 0.000 description 19
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
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VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
230000035602 clotting Effects 0.000 description 6
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JWJVSDZKYYXDDN-LURJTMIESA-N (2s)-1-[(2-methylpropan-2-yl)oxycarbonyl]azetidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CC[C@H]1C(O)=O JWJVSDZKYYXDDN-LURJTMIESA-N 0.000 description 4
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CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 4
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0 *C(C1)CC1C(N*)=O Chemical compound *C(C1)CC1C(N*)=O 0.000 description 3
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PGOHTUIFYSHAQG-LJSDBVFPSA-N (2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]hexanoic acid Chemical class CSCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O PGOHTUIFYSHAQG-LJSDBVFPSA-N 0.000 description 2
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QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
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238000002399 angioplasty Methods 0.000 description 2
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HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 2
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URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
239000001509 sodium citrate Substances 0.000 description 1
NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
235000010262 sodium metabisulphite Nutrition 0.000 description 1
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
238000010561 standard procedure Methods 0.000 description 1
239000007858 starting material Substances 0.000 description 1
239000000758 substrate Substances 0.000 description 1
229960002317 succinimide Drugs 0.000 description 1
238000001356 surgical procedure Methods 0.000 description 1
230000009885 systemic effect Effects 0.000 description 1
238000003419 tautomerization reaction Methods 0.000 description 1
125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 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
WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
230000001225 therapeutic effect Effects 0.000 description 1
HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 1
UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical class NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 1
229960000103 thrombolytic agent Drugs 0.000 description 1
229960005001 ticlopidine Drugs 0.000 description 1
PHWBOXQYWZNQIN-UHFFFAOYSA-N ticlopidine Chemical compound ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 PHWBOXQYWZNQIN-UHFFFAOYSA-N 0.000 description 1
210000001519 tissue Anatomy 0.000 description 1
229960000187 tissue plasminogen activator Drugs 0.000 description 1
210000003437 trachea Anatomy 0.000 description 1
125000004665 trialkylsilyl group Chemical group 0.000 description 1
ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 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
YFMZQCCTZUJXEB-UHFFFAOYSA-N tris(methylsulfanyl)methane Chemical compound CSC(SC)SC YFMZQCCTZUJXEB-UHFFFAOYSA-N 0.000 description 1
239000012588 trypsin Substances 0.000 description 1
229960005356 urokinase Drugs 0.000 description 1
238000007631 vascular surgery Methods 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen 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
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
General Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Medicinal Chemistry (AREA)
Chemical Kinetics & Catalysis (AREA)
Public Health (AREA)
Hematology (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Diabetes (AREA)
Pharmacology & Pharmacy (AREA)
Bioinformatics & Cheminformatics (AREA)
Animal Behavior & Ethology (AREA)
Engineering & Computer Science (AREA)
General Chemical & Material Sciences (AREA)
Veterinary Medicine (AREA)
Biochemistry (AREA)
Biophysics (AREA)
Genetics & Genomics (AREA)
Molecular Biology (AREA)
Proteomics, Peptides & Aminoacids (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Peptides Or Proteins (AREA)
Plural Heterocyclic Compounds (AREA)

RU98102188/04A 1995-07-06 1996-07-02 Ингибиторы тромбина, фармацевтическая композиция на их основе, способ лечения, способ их получения (варианты) и защищенное производное RU2176645C2 (ru)

Applications Claiming Priority (12)

Application Number	Priority Date	Filing Date	Title
SE9502487A SE9502487D0 (sv)	1995-07-06	1995-07-06	New amino acid derivatives
SE9502487-3		1995-07-06
SE9502505A SE9502505D0 (sv)	1995-07-07	1995-07-07	New amino acid derivatives
SE9502504-5		1995-07-07
SE9502505-2		1995-07-07
SE9502504A SE9502504D0 (sv)	1995-07-07	1995-07-07	New amino acid derivatives
SE9503923A SE9503923D0 (sv)	1995-11-07	1995-11-07	New amino acid derivatives
SE9503923-6		1995-11-07
SE9504349A SE9504349D0 (sv)	1995-12-05	1995-12-05	New amino acid derivatives
SE9504349-3		1995-12-05
GB9526411.5		1995-12-22
GBGB9526411.5A GB9526411D0 (en)	1995-12-22	1995-12-22	Compounds

Related Child Applications (1)

Application Number	Title	Priority Date	Filing Date
RU2000128495/15A Division RU2262508C2 (ru)	1995-11-07	1996-07-02	Новые ингибиторы тромбина, их получение и применение

Publications (2)

Publication Number	Publication Date
RU98102188A RU98102188A (ru)	1999-12-20
RU2176645C2 true RU2176645C2 (ru)	2001-12-10

Family

ID=27547251

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
RU98102188/04A RU2176645C2 (ru)	1995-07-06	1996-07-02	Ингибиторы тромбина, фармацевтическая композиция на их основе, способ лечения, способ их получения (варианты) и защищенное производное

Country Status (30)

Country	Link
US (4)	US6051568A (2)
EP (1)	EP0836615B1 (2)
JP (1)	JP4107682B2 (2)
KR (1)	KR100435008B1 (2)
CN (1)	CN1147504C (2)
AR (1)	AR003440A1 (2)
AT (1)	ATE238342T1 (2)
AU (1)	AU709710B2 (2)
BR (1)	BR9609447A (2)
CA (1)	CA2226256C (2)
CZ (1)	CZ298487B6 (2)
DE (1)	DE69627659T2 (2)
DK (1)	DK0836615T3 (2)
EE (1)	EE04500B1 (2)
ES (1)	ES2197240T3 (2)
HU (1)	HUP9802315A3 (2)
IL (1)	IL122813A0 (2)
IS (1)	IS2081B (2)
MX (1)	MX9800146A (2)
MY (1)	MY116539A (2)
NO (1)	NO324092B1 (2)
NZ (2)	NZ311854A (2)
PL (1)	PL185606B1 (2)
PT (1)	PT836615E (2)
RU (1)	RU2176645C2 (2)
SA (1)	SA96170106A (2)
SI (1)	SI0836615T1 (2)
SK (1)	SK284695B6 (2)
TR (1)	TR199800009T1 (2)
WO (1)	WO1997002284A1 (2)

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SE9602263D0 (sv)	1996-06-07	1996-06-07	Astra Ab	New amino acid derivatives
US6200967B1 (en)	1996-06-25	2001-03-13	Eli Lilly And Company	Anticoagulant agents
JP2000514788A (ja) *	1996-06-25	2000-11-07	イーライ・リリー・アンド・カンパニー	抗凝固剤
SE9602646D0 (sv)	1996-07-04	1996-07-04	Astra Ab	Pharmaceutically-useful compounds
AR013084A1 (es)	1997-06-19	2000-12-13	Astrazeneca Ab	Derivados de amidino utiles como inhibidores de la trombina, composicion farmaceutica, utilizacion de dichos compuestos para la preparacion demedicamentos y proceso para la preparacion de los compuestos mencionados
SE9704543D0 (sv) *	1997-12-05	1997-12-05	Astra Ab	New compounds
AU750561B2 (en)	1998-04-24	2002-07-25	3-Dimensional Pharmaceuticals, Inc.	Amino acid amidinohydrazones, alkoxyguanidines and aminoguanidines as protease inhibitors
SE9802938D0 (sv)	1998-09-01	1998-09-01	Astra Ab	Improved stability for injection solutions
AU1185400A (en) *	1998-11-20	2000-06-13	Banyu Pharmaceutical Co., Ltd.	1-acylazetidine derivatives
SE9804313D0 (sv)	1998-12-14	1998-12-14	Astra Ab	New compounds
KR20000047461A (ko) *	1998-12-29	2000-07-25	성재갑	트롬빈 억제제
KR100639274B1 (ko) *	1999-01-13	2006-10-27	아스트라제네카 아베	신규 아미디노벤질아민 유도체 및 트롬빈 억제제로서의 용도
AR023510A1 (es)	1999-04-21	2002-09-04	Astrazeneca Ab	Un equipo de partes, formulacion farmaceutica y uso de un inhibidor de trombina.
SE0001803D0 (sv) *	2000-05-16	2000-05-16	Astrazeneca Ab	New compounds i
DK1311480T3 (da) *	2000-08-16	2008-12-01	Astrazeneca Ab	Nye amidinoderivater og deres anvendelse som thrambininhibitor
US6433186B1 (en) *	2000-08-16	2002-08-13	Astrazeneca Ab	Amidino derivatives and their use as thormbin inhibitors
US7129233B2 (en)	2000-12-01	2006-10-31	Astrazeneca Ab	Mandelic acid derivatives and their use as thrombin inhibitors
SE0102921D0 (sv)	2001-08-30	2001-08-30	Astrazeneca Ab	Pharmaceutically useful compounds
AR035216A1 (es) *	2000-12-01	2004-05-05	Astrazeneca Ab	Derivados de acido mandelico ,derivados farmaceuticamente aceptables, uso de estos derivados para la fabricacion de medicamentos, metodos de tratamiento ,procesos para la preparacion de estos derivados, y compuestos intermediarios
RU2300521C2 (ru) *	2000-12-01	2007-06-10	Астразенека Аб	Новые производные миндальной кислоты и их применение в качестве ингибиторов тромбина
US6528503B2 (en) *	2000-12-18	2003-03-04	Merck & Co., Inc.	Thrombin inhibitors
CA2436176A1 (en) *	2001-02-09	2002-08-22	Merck & Co., Inc.	Thrombin inhibitors
SE0101762D0 (sv) *	2001-05-18	2001-05-18	Astrazeneca Ab	New use
AR034517A1 (es) *	2001-06-21	2004-02-25	Astrazeneca Ab	Formulacion farmaceutica
UA78195C2 (uk) *	2001-08-30	2007-03-15	Astrazeneca Ab	Похідні мигдалевої кислоти та їх застосування як інгібіторів тромбіну, фармацевтична композиція на їх основі
SE0201658D0 (sv) *	2002-05-31	2002-05-31	Astrazeneca Ab	Immediate release pharmaceutical formulation
SE0201659D0 (sv) *	2002-05-31	2002-05-31	Astrazeneca Ab	Modified release pharmaceutical formulation
SE0201661D0 (sv)	2002-05-31	2002-05-31	Astrazeneca Ab	New salts
US7781424B2 (en) *	2003-05-27	2010-08-24	Astrazeneca Ab	Modified release pharmaceutical formulation
US7524354B2 (en) *	2005-07-07	2009-04-28	Research Foundation Of State University Of New York	Controlled synthesis of highly monodispersed gold nanoparticles
TW200827336A (en) *	2006-12-06	2008-07-01	Astrazeneca Ab	New crystalline forms
US20090061000A1 (en) *	2007-08-31	2009-03-05	Astrazeneca Ab	Pharmaceutical formulation use 030

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SA96170106A (ar) *	1995-07-06	2005-12-03	أسترا أكتيبولاج	مشتقات حامض أميني جديدة
SE9602263D0 (sv) *	1996-06-07	1996-06-07	Astra Ab	New amino acid derivatives

1996
- 1996-06-22 SA SA96170106A patent/SA96170106A/ar unknown
- 1996-06-24 AR ARP960103292A patent/AR003440A1/es active IP Right Grant
- 1996-07-02 US US08/687,466 patent/US6051568A/en not_active Expired - Fee Related
- 1996-07-02 ES ES96922355T patent/ES2197240T3/es not_active Expired - Lifetime
- 1996-07-02 DE DE69627659T patent/DE69627659T2/de not_active Expired - Fee Related
- 1996-07-02 DK DK96922355T patent/DK0836615T3/da active
- 1996-07-02 CA CA002226256A patent/CA2226256C/en not_active Expired - Fee Related
- 1996-07-02 SK SK1804-97A patent/SK284695B6/sk not_active IP Right Cessation
- 1996-07-02 PL PL96324483A patent/PL185606B1/pl not_active IP Right Cessation
- 1996-07-02 NZ NZ311854A patent/NZ311854A/en not_active IP Right Cessation
- 1996-07-02 EE EE9700354A patent/EE04500B1/xx not_active IP Right Cessation
- 1996-07-02 MX MX9800146A patent/MX9800146A/es active IP Right Grant
- 1996-07-02 CZ CZ0421297A patent/CZ298487B6/cs not_active IP Right Cessation
- 1996-07-02 PT PT96922355T patent/PT836615E/pt unknown
- 1996-07-02 KR KR10-1998-0700054A patent/KR100435008B1/ko not_active Expired - Fee Related
- 1996-07-02 JP JP50507197A patent/JP4107682B2/ja not_active Expired - Fee Related
- 1996-07-02 WO PCT/SE1996/000878 patent/WO1997002284A1/en not_active Ceased
- 1996-07-02 NZ NZ509474A patent/NZ509474A/en not_active IP Right Cessation
- 1996-07-02 RU RU98102188/04A patent/RU2176645C2/ru not_active IP Right Cessation
- 1996-07-02 IL IL12281396A patent/IL122813A0/xx unknown
- 1996-07-02 SI SI9630615T patent/SI0836615T1/xx unknown
- 1996-07-02 EP EP96922355A patent/EP0836615B1/en not_active Expired - Lifetime
- 1996-07-02 HU HU9802315A patent/HUP9802315A3/hu unknown
- 1996-07-02 TR TR1998/00009T patent/TR199800009T1/xx unknown
- 1996-07-02 AT AT96922355T patent/ATE238342T1/de not_active IP Right Cessation
- 1996-07-02 BR BR9609447A patent/BR9609447A/pt not_active Application Discontinuation
- 1996-07-02 CN CNB961967811A patent/CN1147504C/zh not_active Expired - Fee Related
- 1996-07-02 AU AU63253/96A patent/AU709710B2/en not_active Ceased
- 1996-07-05 MY MYPI96002787A patent/MY116539A/en unknown
1997
- 1997-12-22 IS IS4639A patent/IS2081B/is unknown
1998
- 1998-01-02 NO NO19980015A patent/NO324092B1/no not_active IP Right Cessation
2000
- 2000-03-29 US US09/537,344 patent/US6337343B1/en not_active Expired - Fee Related
2001
- 2001-11-29 US US09/995,564 patent/US6617320B2/en not_active Expired - Fee Related
2003
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Also Published As

Publication number	Publication date
AR003440A1 (es)	1998-08-05
SI0836615T1 (en)	2003-10-31
US20020042396A1 (en)	2002-04-11
EP0836615B1 (en)	2003-04-23
DE69627659D1 (de)	2003-05-28
CA2226256C (en)	2008-12-30
MX9800146A (es)	1998-03-31
EP0836615A1 (en)	1998-04-22
NZ311854A (en)	2000-06-23
PT836615E (pt)	2003-09-30
HK1008995A1 (en)	1999-05-21
US20040087647A1 (en)	2004-05-06
TR199800009T1 (xx)	1998-05-21
US6617320B2 (en)	2003-09-09
SK284695B6 (sk)	2005-09-08
SK180497A3 (en)	1998-11-04
IS4639A (is)	1997-12-22
DE69627659T2 (de)	2004-03-04
CZ298487B6 (cs)	2007-10-17
CN1195354A (zh)	1998-10-07
DK0836615T3 (da)	2003-08-11
US6051568A (en)	2000-04-18
KR100435008B1 (ko)	2004-07-16
MY116539A (en)	2004-02-28
CZ421297A3 (cs)	1998-06-17
PL185606B1 (pl)	2003-06-30
JP4107682B2 (ja)	2008-06-25
JPH11508591A (ja)	1999-07-27
BR9609447A (pt)	1999-03-02
HUP9802315A3 (en)	1999-03-01
EE9700354A (et)	1998-06-15
WO1997002284A1 (en)	1997-01-23
US6921758B2 (en)	2005-07-26
ES2197240T3 (es)	2004-01-01
NO324092B1 (no)	2007-08-13
US6337343B1 (en)	2002-01-08
AU709710B2 (en)	1999-09-02
AU6325396A (en)	1997-02-05
EE04500B1 (et)	2005-06-15
NZ509474A (en)	2005-08-26
PL324483A1 (en)	1998-05-25
IS2081B (is)	2006-02-15
ATE238342T1 (de)	2003-05-15
CA2226256A1 (en)	1997-01-23
HUP9802315A2 (hu)	1999-01-28
IL122813A0 (en)	1998-08-16
KR19990028755A (ko)	1999-04-15
CN1147504C (zh)	2004-04-28
NO980015L (no)	1998-02-25
NO980015D0 (no)	1998-01-02
SA96170106A (ar)	2005-12-03

Legal Events

Date	Code	Title	Description
2011-06-10	MM4A	The patent is invalid due to non-payment of fees	Effective date: 20100703

Publication	Publication Date	Title
RU2176645C2 (ru)	2001-12-10	Ингибиторы тромбина, фармацевтическая композиция на их основе, способ лечения, способ их получения (варианты) и защищенное производное
JP4237824B2 (ja)	2009-03-11	新規なアミノ酸誘導体およびトロンビン阻害剤としてのその使用
RU2176644C2 (ru)	2001-12-10	Пролекарства ингибиторов тромбина
RU2262508C2 (ru)	2005-10-20	Новые ингибиторы тромбина, их получение и применение
HK1008995B (en)	2003-09-05	New thrombin inhibitors, their preparation and use
TW585853B (en)	2004-05-01	Novel tripeptide compounds as inhibitors of trypsin-like serine proteases, process for preparation and pharmaceutical composition thereof
KR100483869B1 (ko)	2005-09-09	신규한 아미노산 유도체 및 트롬빈 억제제로서의 그의 용도
UA61057C2 (en)	2003-11-17	Thrombin inhibitors, a method for preparation , a pharmaceutical composition based thereon and a method for treatment