WO1996029327A1 - Trypsin and thrombin inhibitors - Google Patents
Trypsin and thrombin inhibitors Download PDFInfo
- Publication number
- WO1996029327A1 WO1996029327A1 PCT/GB1996/000520 GB9600520W WO9629327A1 WO 1996029327 A1 WO1996029327 A1 WO 1996029327A1 GB 9600520 W GB9600520 W GB 9600520W WO 9629327 A1 WO9629327 A1 WO 9629327A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ethyl
- formula
- acid
- residue
- tetrahydro
- Prior art date
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- 229940122388 Thrombin inhibitor Drugs 0.000 title description 18
- 239000003868 thrombin inhibitor Substances 0.000 title description 18
- 108090000631 Trypsin Proteins 0.000 title description 4
- 102000004142 Trypsin Human genes 0.000 title description 4
- 239000002753 trypsin inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 95
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 80
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 50
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 35
- 239000001257 hydrogen Substances 0.000 claims abstract description 35
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 20
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 13
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 13
- 125000005843 halogen group Chemical group 0.000 claims abstract description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 12
- 229910006069 SO3H Inorganic materials 0.000 claims abstract description 11
- 239000001301 oxygen Substances 0.000 claims abstract description 11
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims abstract description 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000003118 aryl group Chemical group 0.000 claims abstract description 9
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 9
- 125000000539 amino acid group Chemical group 0.000 claims abstract description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 8
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims abstract description 8
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims abstract description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000011593 sulfur Substances 0.000 claims abstract description 6
- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 claims abstract description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 5
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims abstract description 5
- 239000004475 Arginine Substances 0.000 claims abstract description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 75
- -1 amino acyl amide Chemical class 0.000 claims description 59
- 239000000460 chlorine Substances 0.000 claims description 38
- 238000006243 chemical reaction Methods 0.000 claims description 37
- 239000002253 acid Substances 0.000 claims description 26
- 150000001413 amino acids Chemical class 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 150000002431 hydrogen Chemical class 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 9
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 claims description 4
- 125000002837 carbocyclic group Chemical group 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 4
- 125000005561 phenanthryl group Chemical group 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 claims description 3
- 241001595582 Octolasmis cor Species 0.000 claims description 3
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical group [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 3
- XOCUXOWLYLLJLV-UHFFFAOYSA-N [O].[S] Chemical compound [O].[S] XOCUXOWLYLLJLV-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
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- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 3
- MALIONKMKPITBV-UHFFFAOYSA-N 2-(3-chloro-4-hydroxyphenyl)-n-[2-(4-sulfamoylphenyl)ethyl]acetamide Chemical compound C1=CC(S(=O)(=O)N)=CC=C1CCNC(=O)CC1=CC=C(O)C(Cl)=C1 MALIONKMKPITBV-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- DBTDEFJAFBUGPP-UHFFFAOYSA-N Methanethial Chemical compound S=C DBTDEFJAFBUGPP-UHFFFAOYSA-N 0.000 claims description 2
- 125000005157 alkyl carboxy group Chemical group 0.000 claims description 2
- 125000006350 alkyl thio alkyl group Chemical group 0.000 claims description 2
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 2
- 125000004657 aryl sulfonyl amino group Chemical group 0.000 claims description 2
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- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
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- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000004954 trialkylamino group Chemical group 0.000 claims description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims 1
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims 1
- 125000001072 heteroaryl group Chemical group 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 171
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 156
- 239000002904 solvent Substances 0.000 description 154
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 151
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- 235000019341 magnesium sulphate Nutrition 0.000 description 73
- 238000003818 flash chromatography Methods 0.000 description 57
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- 230000008020 evaporation Effects 0.000 description 54
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 40
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- 238000004108 freeze drying Methods 0.000 description 32
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 30
- 238000005984 hydrogenation reaction Methods 0.000 description 30
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- RQKYHDHLEMEVDR-UHFFFAOYSA-N oxo-bis(phenylmethoxy)phosphanium Chemical compound C=1C=CC=CC=1CO[P+](=O)OCC1=CC=CC=C1 RQKYHDHLEMEVDR-UHFFFAOYSA-N 0.000 description 1
- YWWARDMVSMPOLR-UHFFFAOYSA-M oxolane;tetrabutylazanium;fluoride Chemical compound [F-].C1CCOC1.CCCC[N+](CCCC)(CCCC)CCCC YWWARDMVSMPOLR-UHFFFAOYSA-M 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910003445 palladium oxide Inorganic materials 0.000 description 1
- JQPTYAILLJKUCY-UHFFFAOYSA-N palladium(ii) oxide Chemical compound [O-2].[Pd+2] JQPTYAILLJKUCY-UHFFFAOYSA-N 0.000 description 1
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- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 1
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- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 1
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- 125000005936 piperidyl group Chemical group 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
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- 229910052697 platinum Inorganic materials 0.000 description 1
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- 229940068917 polyethylene glycols Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
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- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
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- 230000002035 prolonged effect Effects 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 239000011241 protective layer Substances 0.000 description 1
- 150000003216 pyrazines Chemical class 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
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- 238000011069 regeneration method Methods 0.000 description 1
- 230000007363 regulatory process Effects 0.000 description 1
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- 239000013557 residual solvent Substances 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
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- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 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
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
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- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical compound [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
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- 239000008117 stearic acid Substances 0.000 description 1
- 229960005202 streptokinase Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- FWMUJAIKEJWSSY-UHFFFAOYSA-N sulfur dichloride Chemical compound ClSCl FWMUJAIKEJWSSY-UHFFFAOYSA-N 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000004291 sulphur dioxide Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- YBNJZIDYXCGAPX-UHFFFAOYSA-N tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CCO)CC1 YBNJZIDYXCGAPX-UHFFFAOYSA-N 0.000 description 1
- CUOVFWBJOMFTTD-UHFFFAOYSA-N tert-butyl 4-(6-diethoxyphosphorylhexyl)piperidine-1-carboxylate Chemical compound CCOP(=O)(OCC)CCCCCCC1CCN(C(=O)OC(C)(C)C)CC1 CUOVFWBJOMFTTD-UHFFFAOYSA-N 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 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
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 description 1
- 238000005866 tritylation reaction Methods 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
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- 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
- C07D207/08—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 hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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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
- 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
- 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
- C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
-
- 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
- C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
-
- 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
- C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
- C07D215/36—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
- C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
-
- 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
- C07D401/12—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 chain containing hetero atoms as chain links
-
- 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
- C07D401/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur 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
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- 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
- C07D417/02—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 two hetero rings
- C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/59—Hydrogenated pyridine rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
- C07F9/650952—Six-membered rings having the nitrogen atoms in the positions 1 and 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
Definitions
- the present invention relates to new compounds which have activity as inhibitors of trypsin and thrombin.
- Ar is a substituted or unsubstituted aryl or heterocyclic residue
- Aa is an amino acid residue usually of L configuration
- X is hydrogen or a C r C 5 alkyl group
- Y is a) a SO 3 H, POCOR 14 ) ⁇ OH, SH
- NR 15 R 16 or halogen group or is b) a residue -(C-H ⁇ -Q wherein Q is H, COR 14 , CO 2 R 14 ,
- R 15 R 16 SO 3 H, OR 14 , OCOR, 14 , PO(OR 14 ) 2 , NR 15 R 16 , SR 14 or Hal
- R 14 , R 15 and R 16 are hydrogen, C r C 5 alkyl, C 5 -C 8 cycloalkyl or C 7 -C ⁇ aralkyl or R 15 and R 16 together with the nitrogen atom to which they are bound form a 5 or 6 membered azacycloalkyl or oxazacycloalkyl
- q is 0 or an integer from 1 to 8 and the residue C-H ⁇ may be optionally substituted by OH or interrupted by oxygen, sulfur, oxycarbonyl
- Ar may be a substituted or unsubstituted phenyl residue, a substituted or unsubstituted naphthyl or partially hydrogenated naphthyl residue or a substituted or unsubstituted anthryl, phenanthryl or heterocyclic residue which may be partially hydrogenated.
- Ar is a substituted phenyl residue it may be substituted with one or more groups such as alkyl, alkoxy, hydroxy, alkyl thio, thio, halo, amino, substituted amino, nitro, cyano, aralkyl and the like. Particularly preferred are compounds of formula I wherein Ar is a residue of formula II
- R 1 and R 2 are C1-C 5 alkyl or are linked to form a C 3 -C 7 carbocyclic ring and R 3 , R 4 and R 5 are the same or different and are hydrogen, C r C 5 alkyl, OR 6 , SR 6 , halo, NR 7 R 8 , NO 2 ,
- R 6 is C r C 5 alkyl, C 3 -C 8 cycloalkyl, C 7 -C ⁇ aralkyl and
- R 7 , R 8 , and R 9 are hydrogen, C r C 5 alkyl, C 3 -C 8 cycloalkyl, or C ⁇ -C ⁇ aralkyl, or R 7 and R 8 together with the nitrogen atom to which they are bound form a 5 or 6 membered azacycloalkyl or oxazacycloalkyl, and especially where R 3 is H or NH 2 and R 4 and R 5 are H or OCH 3 .
- Ar is a naphthyl or partially hydrogenated naphthyl residue it may be substituted for example by one or more residues R 3 which may be the same or different and where R 3 has its previous significance.
- Ar is an anthryl, phenanthryl or heterocyclic residue such as anthryl, phenanthryl, pyridyl, benzfuranyl, benzo(b)thienyl, quinolyl, isoquinolyl or the like which may be partially hydrogenated it may be substituted for example by one or more residues R 3 which may be the same or different and where R 3 has its previous significance.
- Ar is a quinolyl or partially hydrogenated quinolyl residue and especially where the residue Ar is a residue of formula IH, wherein R 10 is hydrogen, halo e.g. bromo, chloro or fluoro, R 20 is hydrogen or (CH ⁇ -D where p is 0 or an integer from 1 to 4 and D is -C5 alkyl optionally interrupted by one or more oxygen atoms, -C 5 alkenyl, Cj-Cs alkoxy, a silane group, CHO, tetrazolyl, carboxyl, alkylcarboxyl.fluoro, cyano or CHNOH, R 11 and R 12 are hydrogen, a -C5 alkyl which may be interrupted by one or more oxygen atoms, -C5 alkenyl, alkoxyal yl, hydroxyalkyl, alkylthioalkyl, alkylamino dialkylamino or trialkylamino, or together form either
- R 10 is hydrogen or halo
- R 20 is C1-C5 alkyl optionally interrupted by one or more oxygen atoms
- R 11 and R 12 are hydrogen or methyl
- R 13 is hydrogen.
- C1-C5 Alkyl is, for example, a branched or unbranched alkyl such as ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or especially, methyl.
- C3-C Cycloalkyl is, for example, cyclopentyl or cyclohexyl. Halogen is, for example, fluoro, chloro or bromo.
- C 7 -C ⁇ Aralkyl is, for example, phenyl- C r C 4 - alkyl such as 2-phenylethyl or, in particular, benzyl.
- 5 or 6 membered azacycloalkyl is, for example, pyrrolidyl or piperidyl while 5 or 6 membered oxazacycloalkyl is especially morpholyl.
- Amino acid residue Aa may be a heteroaliphatic or heteroaro atic group having the formula XVI
- R 19 is H or CH 3
- A is O, S, NH, S0 2 , CH 2 S or CH 2
- R 21 is H or CH 3
- a is an integer from 1 to 4 or the formula XVII
- B is a heterocyclic ring or heterocyclic methyl group, wherein the heterocyclic ring is optionally fused to a second ring which is a hydrocarbon or heterocyclic ring, and wherein the single or double ring system is optionally substituted by methyl, aminomethyl, phenyl or OH.
- the carbon atom next to the N atom in formulae XVI and XVII may give rise to stereoisomers.
- the present invention includes the individual stereoisomers as well as mixtures.
- the compounds Preferably have the L configuration.
- the piperidine ring is substituted by an ethyl group or a fluorethyl group.
- Aa has the formula XVI and N He J has the formula IV.
- Aa has the formula XVII and has the formula IV.
- N ⁇ -arylsulfonyl-aminoacyl amides of formula I and the salts thereof of this invention arc inhibitors of high specific activity in mammals including humans against thrombin and therefore these compounds arc useful in the determination of thrombin in blood as diagnostic reagents, and/or for the medical treatment or prevention of thrombosis.
- the compounds of formula I may be made by various processes as outlined in Methods A to E of the Synthetic Schemes below. In these schemes below, A represents ArSO 2 , B
- Arylsulfonyl(l)-aminoacyl-base (by method A or B)
- Arylsulfonyl-aminoacylfl)-base (by method A or B) j, i) modification of amino acid j ii) deprotection (if needed)
- Arylsulfonyl-aminoacyl-base(l) (by method A or B) j i) modification of base i ii) deprotection (if needed)
- the reaction of compounds of formula IX with arylsulfonyl derivatives VHI is carried out for instance under conditions known for introducing arylsulfonyl groups onto amino substituted compounds.
- protected species are typically protected on the ⁇ -amino group, by benzyloxycarbonyl or t-butoxycarbonyl.
- compounds of formula I may be prepared by die condensation of an aminoacyl amide (IX) with a substantially equimolar amount of an arylsulfonyl halide VHI, preferably a chloride, to give a protected intermediate which yields the product I on deprotection.
- the condensation reaction is generally effected in a suitable inert solvent in the presence of an excess of a base, such as an organic base e.g. triethylamine, di-isopropylethylamine, pyridine, N-methyl or N -ethyl mo ⁇ holine or a solution of an inorganic base e.g.
- the preferred solvents for the condensation include dichlorometiiane or other chlorinated hydrocarbons, DMF, benzene-diethyl ether, dietfiyl ether-water and dioxan-water.
- the compounds of formula IX may be prepared by reaction of an amino acid with a nitrogen heterocycle of formula V ⁇
- the aminoacyl amide compounds of formula IX starting materials required for the condensation reaction can be prepared by protecting the ⁇ -amino group of the amino acid via acetylation, formylation, phthaloylation, trifluroacetylation, p-methoxybenzyloxycarbonylation, benzoylation, benzyloxycarbonylation, t-butoxycarbonylation, arylsulfonylation, or tritylation and then condensing the formed N ⁇ -substituted amino acid with a nitrogen heterocycle of formula VH to give a protected form of IX by a conventional process such as the acid chloride method, azide method, mixed anhydride method, activated ester method, or carbodiimide mediod, with or without additives such as hydroxysuccininide, hydroxybenztriazole, diethyl phosphite or the like, and d ercafter selectively removing the protective groups to give a compound of formula EX.
- NHet is a residue of formula IV or V and wherein X, Y, Q, Z, q, m, n, j and h have their previous significance are new compounds and form part of the invention. Preferred among such compounds are those in which amino acid residue Aa has the formula XVI or XVII.
- compounds of formula I may be prepared by reaction of arylsulfonyl amino acid compounds of formula VI, wherein Ar has its previous significance, with a nitrogen heterocycle of formula V ⁇
- the compounds of formulae VI and VII are optionally protected.
- the residue ArS0 2 in Compound I comprises a partially hydrogenated aromatic or heterocyclic system
- the compound VI may contain hydrogenatable double bonds.
- reaction of a compound of formula VI with a heterocycle of formula VH is carried out for instance under reaction conditions known for coupling amino acids to form peptides and according to methods described in the literature (Houben Weyl, Methoden Der Organischen Chemie, Vol.15, Pans 1 and 2).
- protected species are typically protected on ⁇ -amino groups by benzyloxycarbonyl or t-butoxycarbonyl.
- the compounds of formula I maybe prepared by the condensation of an N ⁇ -arylsulfonyl aminoacyl halide, preferably a chloride, a mixed anhydride, or a similar activated species derived in situ from N ⁇ -arylsulfonyl amino acid VI with at least an equimolar amount of cyclic nitrogen base derivative (VH).
- the condensation reaction can be carried out with or without an added solvent in the presence of a base.
- Solvents such as dimethylformamide (DMF) or dimethylacetamide (DMF) or halogenated solvents such as chloroform or dichloromethane may be used.
- the amount of the solvent to be used is not critical and may vary from about 5 to 100 times the weight of the N ⁇ -arylsulfonyl amino acid (VI). In the other cases the activating principle such as diethyl phosphite may be the solvent.
- the activated species is an N ⁇ -arylsulfonyl aminoacyl halide it may be prepared by reacting an N -arylsulfonyl amino acid VI with at least an equimolar amount of a halogenating agent such as thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or phosphorus tribromide.
- a halogenating agent such as thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or phosphorus tribromide.
- the halogenation may be carried out with or without an added solvent.
- the preferred solvents are chlorinated hydrocarbons such as chloroform and dichloromethane, and ethers such as tetrahydrofuran and dioxan.
- Preferred reaction temperatures are in the range of-10°C to room temperature.
- the reaction time is not critical,
- compounds of formula I may be prepared by reaction of N ⁇ -arylsulfonyl amino acid of formula VI with nitrogen heterocycles of formula V ⁇ in the presence of a condensing agent such as a carbodiimide, for instance dicyclohexyl-carbodiimide in the presence or absence of an activating species such as hydroxy benzotriazole or diethyl phosphite and in the presence of a base.
- the base used in die above reactions may be either an organic base such as Huenig Base, triethylamine, N-methylmorpholine, or pyridine or an inorganic base such as sodium hydroxide or potassium carbonate.
- the condensation reaction may be carried out at a temperature between -10° and the boiling point of the solvent. Preferred condensation reaction temperatures are in the range from -10°C to room temperature.
- the reaction time is not critical, but varies with the derivative (VII) employed. In general, a period of from 5 minutes to 10 hours is operable.
- the acidolysis is generally effected by contacting the protected form of I and an excess of an acid such as hydrogen fluoride, hydrogen chloride, hydrogen bromide or trifluoroacetic acid, without a solvent or in a solvent, such as an ether e.g. tetrahydrofuran or dioxan, an alcohol e.g. methanol or ethanol or acetic acid at a temperature of -10°C to 100°C, and preferably at room temperature for a period of 30 minutes to 24 hours.
- an acid such as hydrogen fluoride, hydrogen chloride, hydrogen bromide or trifluoroacetic acid
- the products are isolated by evaporation of the solvent and the excess acid, or by trituration with a suitable solvent followed by filtration and drying. Because of the use of excess acid, die products are in certain cases the acid addition salts of the compounds of formula I, which can easily be converted to a free amide by neutralisation.
- the protected compound of formula I contains the benzoxycarbonyl protection group the removal is readily accomplished by hydrogenolysis. At die same time any benzyl ester moiety is converted to die carboxyl group by the hydrogenolysis.
- Hydrogenation also serves to specifically convert certain aryl functions to die hydrogenated form in those compounds incorporating such an element of structure, for instance 3-metl ⁇ ylquinolinyl (MQ) to 3-(RS)-methyl- 1 ,2,3,4-tetrahydroquinolinyl.
- MQ 3-metl ⁇ ylquinolinyl
- RS 3-(RS)-methyl- 1 ,2,3,4-tetrahydroquinolinyl.
- the hydrogenolysis is effected in an inert reaction solvent, e.g. methanol, ethanol, tetrahydrofuran or dioxan optionally in the presence of an acid such as acetic acid and in the presence of a hydrogen-activating catalyst e.g. Raney nickel, palladium or platinum, in a hydrogen atmosphere at a temperature of 0°C to the boiling temperature of the solvent for a period of 2 hours to 120 hours.
- a hydrogen-activating catalyst e.g. Raney nickel, palladium or platinum
- the hydrogen pressure is not critical, and atmospheric pressure is sufficient.
- the products of formula I are isolated by filtration of d e catalyst followed by evaporation of the solvent.
- Suitable solvent such as ethyl acetate, diethyl ether-tetrahydrofuran, diediyl ether-methanol and water-methanol, or may be chromatographed on silica gel, ion-exclusion gels or reverse-phase liquid chromatography supports.
- the carboxylic acid or alcohol can be prepared from the ester derivative by conventional hydrolysis or acidolysis methods.
- the conditions under which esterification, hydrolysis or acidolysis can be carried out will be apparent to those skilled in the an.
- Methods C, D and E in die Synthetic Schemes above refer to those cases where a compound of formula I is made by Metiiod A or B and it is dien modified in one of the three parts of the molecule (A, B and C). These modifications may be to change one substituent for another, or to add a substituent, or to change a compound ABC which does not fit the definition of formula I above into a compound ABC which does fit that definition.
- Method C examples include oxidation; alkylation; hydrolysis; carrying out a Wittig reaction on an aldehyde; converting an aldehyde to a hydroxyiminomed yl oxime; and converting an oxime to a tetrazolyl group via cyano.
- Examples of modifications falling under Method D include converting a chloro to amino; and cyclising an aliphatic group to a heterocyclic ring.
- N ⁇ -Arylsulfonyl aminoacyl amides (D of this invention in certain cases form acid addition salts widi any of a variety of inorganic and organic acids.
- Some of the N ⁇ -arylsulfonyl aminoacyl amides containing a free carboxyl group form salts with any of a variety of inorganic and organic bases.
- d e product can be obtained as acid addition salts by reacting one of die free bases with an acid, such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, citric, maleic, succinic, lactic, tartaric, gluconic, benzoic, med anesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic acid or the like.
- an acid such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, citric, maleic, succinic, lactic, tartaric, gluconic, benzoic, med anesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic acid or the like.
- the product can be obtained as salts by reacting the free carboxylic acid widi a base, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, procaine, dibenzylamine, N,N'-dibenzylethylenediamine, N-ethylpiperidine or the like.
- a base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, procaine, dibenzylamine, N,N'-dibenzylethylenediamine, N-ethylpiperidine or the like.
- Compounds of formula VI wherein Ar has its previous significance may be prepared by reacting an amino acid which may be optionally protected wid an aryl sulfonic acid derivative of formula VHI as defined above in the presence of a base.
- the reaction is carried out under conditions well known to those skilled in die art, generally in an inert solvent and in die presence of an excess of an organic or inorganic base as hereinbefore described and at a temperature of 0°C to the boiling point of the solvent.
- Suitable halogenating agents include phosphorus halides such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus pentabromide and phosphorus oxychloride; phosgene, benzotrichloride, thionyl chloride, chlorosulfonic acid, sulfur dichloride, sulfur and chlorine, chlorine and fluorosulfonic acid.
- phosphorus halides such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus pentabromide and phosphorus oxychloride
- phosgene benzotrichloride, thionyl chloride, chlorosulfonic acid, sulfur dichloride, sulfur and chlorine, chlorine and fluorosulfonic acid.
- Suitable solvents for the reaction include dimethylformamide (DMF), dimetiiylacetamide (DMA), l,3-dimethyl-2-imidazolidinone (DMID), and pyridine.
- reaction is conveniendy carried out between -10°C and die boiling point of the solvent It is advantageous to disperse or dissolve die sulfonic acid or its salt in die solvent whilst applying ultrasound.
- reaction product is poured into ice water and then extracted widi a solvent such as ether, benzene, ethyl acetate, chloroform or die like.
- Arylsulfonyl chlorides may also be prepared by chlorosulfonylation of aromatic hydrocarbons.
- the arylsulfonyl halide can be purified by recrystallisation from a suitable solvent such as hexane, benzene or the like.
- the sulfonyl halide of formula VHI may be prepared in a single pot reaction from the conesponding arylamine of formula X
- Widi ArHal 1 of formula XI as the starting material die halogen Hal 1 is replaced by lithium using an organo lithium reagent. Subsequent treatment with sulfur dioxide followed by halogenation for instance using and N-halo imide yields the desired arylsulfonyl halide VIH.
- sulfonyl halides of formula VHI may be prepared from die corresponding parent aromatic compound of formula XII
- Ar is a residue of formula II wherein R 1 - R 5 have their previous significance may be prepared by aralkylation of aniline or substituted anilines using Friedel Crafts conditions as described for instance in European Patent 69065 (Ciba-Geigy).
- Suitable derivatives ArHal 1 of formula XI for conversion to the corresponding sulfonyl chloride ar those of formula XIa wherein R 11 , R 12 and R 13 have d eir previous significance and Hal 1 is chlorine, bromine or iodine.
- Compounds of formula XIa may be prepared by d e sequence of reactions shown in Scheme 1.
- Sulfonyl halides of formula VIH may also be prepared by die following schemes 3 and 4.
- Suitable reagents for sulfonation include sulfuric acid, oleum, sulfur trioxide and complexes of sulfur trioxide, for instance the pyridine complex, acid sulfates such as potassium hydrogen sulfate, and chlorosulfonic acid.
- the sulfonation may be carried out with or without d e presence of a catalyst.
- Catalysts may include metal salts, such as mercury salts or acids such as hydrogen fluoride or Lewis acids such as boron trifluoride.
- the reaction may be carried out in the presence or absence of a solvent inert under the reaction conditions and at a temperature between 0°C and die boiling point of die solvent
- die sulfonic acid of formula VIH When die sulfonic acid of formula VIH is produced by de-amination of an amino sulfonic acid of formula XIV the de-amination may be achieved by diazotisation followed by reduction widi hypophosphorous acid. Salts of the sulfonic acids may be made by neutralisation of the free acid widi the appropriate base.
- Amino sulfonic acids of formula XIV where Ar has its previous significance may be prepared by aralkylation of amino sulfonic acids using Friedel Crafts conditions using the mediod described for instance in European Patent 69065, or by aralkylation of amino phenyl sulfonic acids in the absence of a catalyst and in solution in water or a mixture of water and a water-miscible solvent
- aromatic sulfonic acids of formula VI ⁇ where Ar is a residue of formula HI with the sulfonic acid residue in the 8-position may be obtained.
- X 1 and Y 1 are bodi H.
- substituted piperidines may be obtained by reduction of die corresponding substituted pyridines.
- the starting substituted pyridines are either known or may be prepared by known methods.
- carboxy substituted pyridines may be reduced to give hydroxy alkyl piperidines.
- X is hydrogen or C 1 -C 5 alkyl
- Y is (C q H 2 -)-Q or (C w H 2w + ! . y . z )F y OH z
- Q is COR 14 , CO 2 R 14 , CONR 15 R 16 SO 3 H, OR 14 , OCOR 14 , PO(OR 14 ) 2 , NR 15 R 16 , SR 14 or halogen wherein R 14 , R 15 and R 16 are independentiy hydrogen C r C 5 alkyl, C 5 -C 8 cycloalkyl or C 7 -C ⁇ aralkyl groups, or R 15 and R 16 togedier with the nitrogen atom to which they are bound form a 5 or 6 membered azacycloalkyl or oxazacycloalkyl, q is 0 or an integer from 1 to 8, w is an integer from 1 to 8, y is an integer from 1 to 17 and z is 0 or 1 and d e residue C q H ⁇ may be optionally substituted by
- Compounds of formula Vila may be prepared by reduction of corresponding aromatic compounds or by ring closure methods described in die references below.
- functionally substituted piperidines and piperazines of formula I carrying a group ( j H_i q )-Q may be prepared by reduction of the corresponding pyridines and pyrazines.
- Such procedures are described in chemistry of Heterocyclic Compound Ed: A. Weissberger - Pyridine and its derivatives; Comprehensive Heterocyclic Chemistry, Katritzky and Rees Vol 2; and Heterocyclic Compounds Vol 6 Elderfield.
- a functional group Q may be converted into a different functional group Q by standard interconversion methods. For instance where the functional group Q is a carboxylic acid it may be converted to an ester or an amide by treatment widi an alcohol or an amine. Conversely where the functional group is a carboxylic ester or carboxylic amide it may be hydrolysed to the acid using for instance acid or basic conditions.
- the functional group Q is an alcohol or an amine it may be acylated using a (functional) carboxylic acid and a condensing agent or by use of an activated species such as an acid halide or anhydride.
- the reaction may be carried out in a solvent and in die presence or absence of a catalyst
- catalyst are acids such as hydrogen chloride, or toluenesulfonic acid.
- the nitrogen(s) of the ring may be protected whilst a side chain functional group is reacted.
- protecting groups for the nitrogens are t-butoxycarbonyl and benzyloxycarbonyl.
- Compounds of formula 1 wherein Q is a COOH group may also be prepared from a corresponding alcohol by oxidation of a CH OH group to a COOH group, for instance by using an oxidising agent such as pyridinium dichromate or d e like.
- the compounds of formula I provide interesting compounds which contain potent and orally bioavailable inhibitors of serine proteases, especially thrombin and trypsin.
- the compounds of die present invention are useful in compositions, combinations and mediods for the treatment and prophylaxis of various diseases attributed to thrombin-mediated and tiirombin-associated functions and processes. These include myocardial infarction, stroke, pulmonary embolism, deep vein thrombosis, disseminated intravascular coagulation, peripheral arterial occlusion, restenosis following arterial injury or invasive cardiological procedures including percutaneous transluminal coronary angioplasty, atrial fibrillation, acute or chronic atherosclerosis, edema and inflammation, various cell regulatory processes (e.g. secretion, shape changes, proliferation), cancer and metastasis, and neurodegenerative diseases.
- diseases attributed to thrombin-mediated and tiirombin-associated functions and processes include myocardial infarction, stroke, pulmonary embolism, deep vein thrombosis, disseminated intravascular coagulation, peripheral arterial occlusion, restenosis following arterial injury or invasive cardiological procedures including
- the thrombin inhibitors of the present invention may be formulated into pharmaceutically useful compositions, such as by mixing with a pharmaceutically acceptable carrier or diluent These compositions may be used for treating or preventing dirombotic diseases in a patient
- the thrombin inhibitors may be employed in compositions for treating thrombotic disease, and for decreasing the dosage of a thrombolytic agent required to establish reperfusion or prevent reocclusion in a patient
- d e thrombin inhibitors of this invention may be used in compositions for decreasing reperfusion time or the incidence of acute reocclusion in a patient treated widi a dirombolytic agent.
- These compositions may comprise a pharmaceutically effective amount of a thrombin inhibitor of die present invention and a pharmaceutically effective amount of a thrombolytic agent.
- the thrombin inhibitor and die thrombolytic agent work in a complementary fashion to dissolve blood clots, resulting in decreased reperfusion times and incidence of acute reocclusion in patients treated with diem.
- the thrombolytic agent dissolves the clot, while the tiirombin inhibitor prevents newly exposed, clot-entrapped or clot-bound tiirombin from regenerating the clot.
- the use of the thrombin inhibitor in the compositions of this invention advantageously allows d e administration of a dirombolytic reagent in dosages previously considered too low to result in dirombolytic effects if given alone.
- thrombolytic agents which may be employed in the combinations and compositions of die present invention are those known in the art Such agents include tissue plasminogen activator purified from natural sources, recombinant tissue plasminogen activator, streptokinase, urokinase, prourokinase, anisolated streptokinase plasminogen activator complex (ASPAC), animal salivary gland plasminogen activators, hybrids of the above and known, biologically active derivatives.
- the thrombin inhibitor and die dirombolytic agent may be in die same or in separate dosage forms which are administered separately, but concuirendy or sequentially.
- die tiirombin inhibitor may be given to the patient at a time from 5 hours before to 5 hours after administration of the dirombolyic agent
- the thrombin inhibitor is administered to die patient at a time from 2 hours before to 2 hours after administration of the thrombolytic agent.
- the compounds of die invention may also be used in combinations and compositions with otiier antidirombotic drugs such as aspirin, fibrinogen receptor blockers, platelet aggregation inhibitors and die like.
- otiier antidirombotic drugs such as aspirin, fibrinogen receptor blockers, platelet aggregation inhibitors and die like.
- compositions of die invention may be administered to a patient in various ways e.g. enterally such as orally or rectally, parenterally or topically.
- the compositions will be formulated using adjuvants and diluents suitable for the desired method of administration.
- the compositions may be administered intravenously or intra-arterially as bolus or by continued infusion, intramuscularly - including paravertebrally and periarticularly - subcutaneously, intracutaneously, intra-articularly, intrasynovially, intrathecally, intra-lesionally, periostally or by oral, nasal, or topical routes.
- they may be given direcdy into the central nervous system.
- they may be applied transdermally by either passive or active methods, including by iontophoresis.
- compositions are preferably administered intravenously either in a bolus form or as an infusion.
- die thrombin inhibitor may be either suspended or dissolved in a sterile vehicle, optionally together widi otiier components, and sterilized before filling into a suitable vial or ampule and sealing.
- adjuvants such as a local anesthetic, preservatives, stabilizers, solution promoters and/or buffers may also be dissolved in the vehicle.
- the composition may men be frozen and lyophilized to enhance stability.
- a surfactant or wetting agent and or otiier adjuvant as mentioned above may be included in die composition to facilitate uniform distribution of its components.
- Tablets and capsules e.g. gelatin capsules for oral administration may comprise die active ingredient together with a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salts and/or polyethylene glycol; for tablets also c) binders, e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired, d) disintegrants, e.g.
- diluents e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine
- lubricants e.g. silica, talcum, ste
- starches starch derivatives such as sodium starch glycolate, croscarmellose, agar, alginic acid or its sodium salt, or effervescent mixtures; e) wetting agents such as sodium lauryl sulphate; and or f) absorbents, colourants, flavours and sweeteners.
- Suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents.
- Oral liquid preparations may be in he form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstruction with water or anotiier suitable vehicle before use.
- Such liquid preparations may contain conventional additives.
- suspending agents such as sorbitol, syrup, mediyl cellulose, gelatin, hydroxyediylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents, such as lecithin, sorbitan monooleate, polyethylene glycols, or acacia; non-aqueous vehicles, such as almond oil, fractionated coconut oil, and oily esters; and preservatives, such as methyl or propyl p-hydroxybenzoate or sorbic acid
- compositions formulated for topical administration may, for example, be in aqueous jelly, oily suspension or emulsified ointment form.
- compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75%, preferably about 1 to 50%, of the active ingredient.
- Transdermal systems may be made by applying an adhesive layer to a base layer, e.g. a peel-off protective layer, applying a reservoir to the base layer, the reservoir containing die active ingredient and optionally a polymeric material for forming a porous or permeable membrane and/or a penetration enhancer, and tiien applying an impermeable outer layer on top.
- a base layer e.g. a peel-off protective layer
- a reservoir to the base layer, the reservoir containing die active ingredient and optionally a polymeric material for forming a porous or permeable membrane and/or a penetration enhancer, and tiien applying an impermeable outer layer on top.
- the dosage of active compound administered is dependent on d e species of warm-blooded animal (mammal), the body weight, age and individual condition, and on die form of administration.
- a preferred pharmaceutically effective dose of the thrombin inhibitor of this invention is from O.Olmg/kg body weight of the patient to be treated to 50mg/kg body weight, preferably from 0.1 to l.Omg kg.
- the amount used depend on die mediod of administration. Normally lower amounts are needed for parenteral administration than for enteral administration. The dose for infusions however may be higher than the range given, preferably from 0.01 to l.Omg kg hr.
- a pharmaceutically effective dose of die dirombolytic agent may be between 10% and 80% of the conventional dosage range, i.e. die dosage used when tiiat agent is employed in a monotiierapy.
- the compounds of the invention may also be used in die form of conjugates with materials such as polyediylene glycol. This would modify the pharmacokinetic properties of the compounds and result in lower doses being needed, or less frequent doses.
- the thrombin inhibitors of the invention may also be used in compositions and mediods for coating the surfaces of invasive or extra-corporeal devices, resulting in a lower risk of clot formation or platelet activation in patients receiving or using such devices.
- Surfaces that may be coated with die compositions of this invention include, for example, prostheses, artificial valves, vascular grafts, stents tubing, membranes and cadieters.
- Methods for coating diese devices are known to those of skill in the art. These include chemical cross-linking or physical adsorption of die thrombin inhibitor-containing compositions on to the surfaces of the devices.
- compositions containing the tiirombin inhibitors of this invention may also be used in the treatment of tumor metastases, as indicated by die inhibition of metastatic growth.
- metastatic tumors which may be treated by die tiirombin inhibitors of this invention include carcinoma of the brain, carcinoma of the liver, carcinoma of the lung, osteocarcinoma and neoplastic plasma cell carcinoma.
- compositions containing the thrombin inhibitors of the invention may also be used to inhibit thrombin-induced endoetiielial cell activation, including the repression of synthesis of mediators, including platelet-activating factor (PAF), eicosanoids, endodielial-derived relaxing factor (EDRF) and endothelin, by endothelial cells.
- PAF platelet-activating factor
- EDRF endodielial-derived relaxing factor
- endothelial cells endothelial cells.
- the compositions have important applications in the treatment of diseases characterized by thrombin-induced inflammation and edema, which is diough to be mediated by PAF. Such diseases include adult respiratory distress syndrome, septic shock, septicemia, reperfusion damage, and for treating or preventing septicemia and other diseases.
- the thrombin inhibitors of the invention or compositions comprising them may also be used as anticoagulants for extracorporeal blood, for instance in such processes as dialysis procedures, blood filtration, or blood bypass during surgery at doses from 0.01 to l.Omg/kg as well as in blood products which are stored extracorporeally for eventual administration to a patient and blood collected from a patient to be used for various assays.
- blood products include whole blood, plasma, or any blood fraction in which inhibition of coagulation is desired.
- the amount or concentration of thrombin inhibitor in these types of compositions is based on die volume of blood to be treated or, more preferably, its thrombin content, and may be from 0.01mg/60ml of extracorporeal blood to 5mg 60ml of extracorporeal blood.
- the thrombin inhibitors of this invention may also be used to inhibit clot-bound tiirombin, which is believed to contribute to thrombus growth and clot accretion, and to prevent thrombus extension. This is particularly important because commonly used anti-thrombin agents, such as heparin and low molecular weight heparin, are ineffective against clot-bound thrombin.
- inhibitors of this invention may be used for treating neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, inflammatory diseases and cerebral ischaemia.
- N-(4-chloro-phenyl)-2,2- dimethyl-malonamic acid m.p. 169-170'C.
- N-(4-Chloro-phenyl)-2,2-dimethyl-malonamic acid 150g is added in one charge to a stirred solution of phosphorus pentoxide (50g) in methane sulphonic acid (11) at 70 * C under nitrogen.
- Aluminium trichloride (6.52g) is dissolved in dry ether (50ml) under nitrogen, cooled to -20 * C and lithium aluminium hydride (M in THF, 49ml) is added dropwise. The mixture is allowed to warm to 20 * C and stirred for 30 minutes.
- 6-Bromo-3,3-dimethyl- 3,4-dihydro-1 H-quinolin-2-one (12.42g) dissolved in dry THF (100ml) under nitrogen is added dropwise to the UAIH4/AICI3 at -20'C (CaCl2 tube). The stirred mixture is allowed to warm to 20 * C and stirred for a further 20 hours.
- 6-Bromo-3,3-dimethyl-1 ,2,3,4-tetrahydro-quinoline (5.6g) dissolved in dry DMF (50ml), under nitrogen, is added to the DMF/sulfur trioxide complex via a septum.
- the reaction mixture is heated at 60 * C under nitrogen for 2.5 hours, the DMF removed by distillation and the resultant solid washed with cold ethyl acetate.
- the dried product, 6-bromo-3,3-dimethyl-1 ,2,3,4-tetrahydro-quinoline-8- sulfonic acid (m.p. 198-9'C (decomp.)) is sufficiently pure for the next step.
- Method 2 6-Chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-sulfonic acid (20g) is dissolved in a mixture of methanol (200ml) and triethylamine (50.4ml) and hydrogenated in the presence of 10% palladium on charcoal (4.0g) for 72 hours at 20'C.
- the catalyst is removed by filtration and the solvent removed by rotary evaporation to give crude 3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-sulphonic acid as brown crystals which are stored in vacuo.
- Triphenylphosphine (38g) is dissolved in dichloromethane (200ml) and cooled to 0 * C and a solution of sulfuryl chloride (15ml) in dichloromethane (15ml) is added during 15 minutes keeping the temperature of the stirred mixture below 5 * C.
- the mixture is allowed to warm to room temperature and a solution of crude 3,3-dimethyl- 1 ,2,3,4-tetrahydro-quinoline-8-sulfonic acid (34g) in dichloromethane (250ml) is added during 30 minutes with stirring.
- the mixture is stirred for 2 hours at 20'C and then extracted with water (500ml).
- the water extract is back-washed with dichloromethane (200ml), the combined organic layers are dried (MgSO4) and the solvent removed by rotary evaporation.
- the residue is stirred with dry ether (400ml) for 1 hour at 20'C and the solid triphenylphosphine oxide removed by filtration and washed with ether (3x30ml).
- the combined ether solutions are dried by rotary evaporation and the residue stirred with dry ether (60ml) as above to remove more triphenylphosphine oxide. Evaporation of the resultant ether solution gives 3,3-dimethyl-1 ,2,3,4- tetrahydro-quinoline-8-sulfonyl chloride as a yellow oil which is suitable for immediate use.
- aqueous extracts are acidified with aqueous hydrochloric acid (5M) and the resultant orange oil extracted with ether (2x40ml).
- the combined extracts are dried (MgSO4) and the solvent evaporated to give .N.-(4- bromo-phenyl)-2,2-dimethyl-malonamic acid as a pale orange solid.
- the filtrate is reduced in volume and the recovered crude material purified by chromatography on a 29 column of silicagel eluting with ethyl acetate:hexane (1 :9 by volume) to give a second crop of the dione.
- Lithium aluminium hydride (M in THF, 2.0ml) is treated with a cooled (0-5"C) solution of aluminium chloride (2.7g) in dry THF (20ml). The mixture is sti ed at 20 * C for 5 minutes. The mixture is treated with a solution of 8-bromo-3,3-dimethyl-1H- quinoline-2,4-dione (2.7g) in dry ether (40ml) dropwise at such a rate as to maintain a gentle reflux. The mixture is stirred at 20'C for 30 minutes. The mixture is poured into ether (30ml) and water (20ml) and aqueous sodium hydroxide (M, 20ml) are added.
- the ether and any residual methyl iodide are removed by evaporation.
- the residual oil is purified by chromatography on a column of silicagel which is eluted with ethyl acetate :hexane (15:985, by vol.) to give 8-bromo- 1 ,3,3-trimethyl-1 ,2,3,4-tetrahydro-quinoline as a colourless oil.
- N-Chlorosuccinimide (134 mg) is added and the resultant green suspension is allowed to warm to room temperature and stirred for 1.5 hours. The mixture is washed with water (20ml) and the aqueous washings are extracted with dichloromethane (10ml). The combined organic extracts are washed with brine (20ml) and dried (MgSO4). Evaporation of the solvent gives an oil which is purified by chromatography on a column of silicagel eluted with ethyl acetate :hexane (1 :19, by vol.) to give 1,3,3-trimethyl-1 ,2,3,4- tetrahydro-quinoline-8-sulfonyl chloride as a yellow oil.
- aqueous phase is extracted with ether (25ml) and the combined organic extracts are washed with portions (2x25ml) of water, brine and dried ( gSO4). Evaporation of the solvent gives a viscous orange oil.
- N-(2(R)-Methyl-3-[2-nitrophenyl]-propionyl)-2(S)-bornane-2,10-sultam (7.9g) is dissolved in THFrwater (4:1 , by vol., 150ml) at ice temperature (0-5 * C) and treated with hydrogen peroxide (30% w/v, 18.5ml) followed by lithium hydroxide hydrate (3.64g). The mixture is stirred at 0-5'C for 1.3 hours and then at 20 * C for 3.5 hours. Aqueous hydrochloric acid (M, 150ml) is added and the mixture is poured into dichloromethane (100ml).
- the aqueous phase is extracted with dichloromethane (2x50ml).
- the combined organic phases are extracted into 10% aqueous sodium bicarbonate (2x25ml).
- the combined aqueous extracts are acidified to pH 1 -2 with aqueous hydrochloric acid (M) and extracted with ether (4x25 ml), the combined extracts are dried (MgSO4) and the solvent evaporated to give 2(R)-methyl-3-(2- nitrophe ⁇ yl)-propionic acid as a pale yellow oil which is used directly in the next step.
- Aluminium chloride (1.198g) is added over 5-10 minutes to dry ether (10ml) at - 10 * C under nitrogen. Lithium aluminium hydride (M in THF, 8.35ml) is added to this solution and the resultant mixture stirred for 10 minutes at 20'C. 6-Bromo-3(R)- methyl-3,4-dihydro-1H-quinolin-2-one (457mg) in ether (30ml) is added over 10 minutes and the mixture is stirred at 20 * C for 2 hours. The mixture is cooled to -5 * C and water (5ml) followed by aqueous sodium hydroxide (M, 10ml) are added.
- 3,3-Dimethyl-2,4-dioxo-1 ,2,3,4-tetrahydro-6-carboxylic acid ethyl ester (3.52g) is dissolved in trifluoroacetic acid (100ml) and trimethylsilane (5.6ml) is added. The mixture is heated under nitrogen at 60°C for 6 hours, cooled and poured cautiously into a mixture of saturated aqueous potassium carbonate (20ml) and ice (20ml).
- 3(RS)-Methyl-6-methoxy-1 ,2,3,4-tetrahydro-quinoline 310mg
- pyridine/sulfur trioxide complex 556mg
- the mixture is heated to 95 * C for 1 hour, diluted with ethyl acetate (30ml) and washed with dilute aqueous ammonia (3x10ml).
- aqueous extracts are evaporated to dryness and the resulting solid purified by flash chromatography on a column of silicagel using dichloromethane:methanol (5:1 , by vol.) as eluant to give 3(RS)-methyl-6-methoxy- 1 ,2,3,4-tetrahydro-quinoline-8-sulfonic acid as a white solid.
- 3(RS)-Methyl-6-methoxy-1 ,2,3,4-tetrahydro-quinoline-8-sulfonic acid (357mg) is dissolved in a mixture of pyridine (0.22ml) and DMID (2ml), cooled to O'C and treated with phosphoryl chloride (0.25ml) added slowly in portions. The mixture is allowed to warm to 20 * C and is stirred for 40 minutes. The mixture is diluted with ethyl acetate:ether (1 :1 , by vol., 20ml) and washed with water (2x10ml).
- N-(4-Ethoxycarbonylmethyl-phenyl)-2,2-dimethyl-malonamic acid (10g) and phosphorous pentoxide (5.4g) are dissolved in methane sulfonic acid (75ml) and heated to 70'C with stirring for 3 hours.
- the reaction mixture is cooled to 20"C and iced water (400ml) is added slowly with stirring.
- the aqueous phase is extracted with ethyl acetate (3x300ml) and the combined extracts are dried (MgSO4) and evaporated to a black tar which dissolved in ethyl acetate (200ml) and the solution extracted with saturated aqueous sodium bicarbonate (2x200ml).
- the combined aqueous extracts are adjusted with aqueous hydrochloric acid (2M) to pH3 and extracted with ethyl acetate (3x200ml).
- the combined ethyl acetate fractions are dried (MgSO4) and the residue recrystallised (3x) from ethyl acetate/hexane to give 3,3-dimethyl-2,4-dioxo- 1.2,3,4-tetrahydro-quinolin-6-yl)-acetic acid ethyl ester as white crystals.
- Aluminium chloride (2.81 g) is dissolved in dry ether (15ml) and lithium aluminium hydride (M in THF, 26.3ml) is added slowly at room temperature under nitrogen to maintain a gentle reflux. The mixture is stirred for 30 minutes.
- 3,3-Dimethyl-2,4- dioxo-1 ,2,3,4-tetrahydro-quinolin-6-yl)-acetic acid ethyl ester (2.9g) is dissolved in dry THF (30ml) and added slowly to maintain a gentle reflux.
- the filtrate is evaporated and the residue is purified by crystallising from ethyl acetate and column chromatography on silicagel using hexane/ethyl acetate (3:1 , by vol.) as eluant to yield futher 6-[2-(tert.-butyl-diphenyl-silanyloxy)-ethyl]-3,3-dimethyl-1 ,2.3,4-tetrahydro- quinoline as a white solid.
- Method 1 a) 2-Aminobenzonitrile (130.3g) in dichloromethane (1.11) is added with stirring to a solution of potassium carbonate (152.4g) in water (550ml). A solution of 2-bromo-2- methyl priopionyl bromide (279.1 g) in dichloromethane (300ml) is added dropwise over 1 hour keeping the temperature of the mixture below 25°C and the resulting emulsion is stirred vigorously for 3 hours. The organic phase is separated and the aqueous phase is washed with dichloromethane (220ml).
- 6-Fluoro-3.3-dimethyl-1 ,2,3,4-tetrahydro- quinoline-8-sulfonic acid is purified by flash chromatography on a column of silicagel using dichloromethane:methanol (4:1 , by vol.) as eluant.
- 3(RS)-Ethyl-1 ,2,3,4-tetrahydro-quinoline (5g) is dissolved in dry dichloromethane (135ml) and BTMA.ICI2 (10.8g) is added. Calcium carbonate (4g) and methanol (50ml) are added and the resultant slurry is stirred at 20°C for 16 hours, diluted with dichloromethane (100ml) and washed with portions (2x100ml) of 5% (w/v) aqueous sodium bisulphite. The organic phase is dried (MgSO4) and evaporated to dryness to give 3(RS)-ethyl-6-iodo-1 ,2,3,4-tetrahydro-quinoline as a colouriess oil which solidifies on storage.
- N.O-Dimethylhydroxylamine hydrochloride (2.88g) is added and the mixture is stirred for a further two hours.
- the solution is diluted with dichloromethane (200ml), washed with aqueous hydrochloric acid (2M, 200ml), dried (MgSO4) and solvent removed by rotary evaporation.
- the residue is purified by flash chromatography on a column of silicagel using ethyl acetate :hexane (4:1 , by vol.) as eluant to give 3(RS)-(methoxymethylcarbamoyl)-3,4-dihydro-2H-quinoline-1 -carboxylic acid benzyl ester.
- the stirred mixture is cooled to O°C and sodium hydride suspension (60% w/v, 0.8g) is added.
- the mixture is stirred ar 20°C for 2 hours, diluted with ether (100ml) and washed with portions (2x100ml) of water.
- the organic phase is dried (MgSO4), the solvent removed by rotary evaporation and the residue obtained is purified by flash chromatography on a column of silicagel using ethyl acetate :hexane (1 :5, by vol.) as eluant to give 3(RS)-ethoxy-3,4-dihydro-2H-quinoline-1- carboxylic acid benzyl ester as a colourless oil.
- Piperidin-4-ylmethanol (7g) is suspended in acetic acid (15ml) and the mixture is cooled in ice. Hydrogen chloride gas is passed through the mixture until all the material has dissolved. The reaction mixture is heated at reflux for 30 minutes. The solvent is removed by evaporation and the oil obtained is dried (NaOH pellets) in vacuo. The resulting solid is recrystallised from ethanol to yield acetic acid piperidin- 4-ylmethyl ester hydrochloride as a white solid, m.p. 164-165 * C. (Found: C, 48.85; H. 8.01 ; N. 7.26; Cl, 17.89. C 8 H 16 NO CI.0.2H 2 O requires C, 48.71 ; H. 8.38; N. 7.1 ; Cl, 17.97%).
- Piperidin-4-yl-ethanol (50g) is dissolved in acetic acid (11) and cooled in ice. Hydrogen chloride gas is passed through the solution for 2 hours, the reaction mixture is sealed and kept at 20'C for 16 hours and finally heated at reflux for 30 minutes. After cooling, the solvent is removed by evaporation and the residue held in vacuo (NaOH pellets) to give an oil which is stirred with ether (11) to give crystals, m.p. 80-90'C. Recrystallisation from ethyl acetate affords acetic acid 2-piperidin-4-yl-ethyl ester hydrochloride. m.p. 115-7'C. (Found: C, 51.90; H. 8.99; N. 6.64; Cl, 17.19. C 9 H 18 N ⁇ 2CI requires C. 52.04; H. 8.74; N. 6.74; Cl, 17.07%).
- Method 1 a) 4-(2-Hydroxy-ethyl)-piperidine-1 -carboxylic acid tert.-butyl ester (5.15g) is dissolved in fluorotrichloromethane (15ml) and cooled to -78 * C in an atmosphere of dry nitrogen. A solution of DAST (3.55ml) in fluorotrichloromethane (15ml) is added and the mixture is stirred with exclusion of moisture for 10 minutes at -78 * C and then allowed to warm to room temperature.
- Piperidin-4-yl-ethanol (1.5g) is dissolved in dichloromethane (30ml) and cooled with stirring to 0-5 * C.
- Trifluoromethane sulphonic acid (2.86g) is added dropwise at ⁇ 5 * C and iso-butylene is passed through the solution for 1 hour at ⁇ 5 * C.
- the mixture is stirred for 1 hour at 20 * C and aqueous potassium carbonate (50%, 20ml) added dropwise over 10 minutes with stirring followed by ether (20ml).
- 6-Pyridin-4-yl-hexan-1-ol (4.65g) is dissolved in ethanol (120ml), cone, aqueous hydrochloric acid (2.5ml) is added and the mixture is hydrogenated in the presence of Adam's catalyst (1g) at 20'C for 16 hours.
- the catalyst is removed by filtration through a pad of Celite and solvents removed by rotary evaporation to give 6- piperidin-4-yl-hexan-1-ol hydrochloride as a light orange solid which is stored in vacuo (NaOH pellets).
- 6-Piperidin-4-yl-hexan-1-ol hydrochloride (5.5g) is heated to 120 * C (oil-bath) to melt the substance.
- Phosphorus tribromide (1.43g) is added dropwise over several minutes with stirring and the mixture is then cooled to give crude 4-(6-bromo-hexyl)- piperidine hydrobromide salt as a viscous oil which is stored in vacuo (NaOH pellets). The residue is dissolved in 50% aqueous dioxan (100ml) and adjusted to pH 7 by the addition of solid sodium bicarbonate.
- Piperidin-2(S)-ylmethanol (6.45g) in dichloromethane (140ml) is cooled to 0-5°C and concentrated sulphuric acid (5.5g) is added dropwise with vigorous stirring.
- Isobutylene is bubbled through the mixture for 1 hour with the temperature maintained at 0-5°C.
- Concentrated sulphuric acid (1.37g) is added dropwise.
- the mixture is closed securely and allowed to warm to room temperature with vigorous stirring for five hours.
- the mixture is cooled to 0-5°C and aqueous potassium carbonate (50% w/v, 85ml) is added slowly, followed by diethyl ether (85ml).
- the organic layer is separated and the aqueous phase is washed with diethyl ether (2x75ml).
- the combined organic layers are washed with brine (2x50 ml), dried (MgSO4), filtered and evaporated to give an oil which is distilled.
- the fraction boiling at 66-7° at 3.5 mm is
- N-(2-Pyridin-4-yl-ethyl)-succinamic acid methyl ester (7.5g) is dissolved in ethanol (100ml) and aqueous hydrochloric acid (4M, 1 equiv.) is added. The mixture is hydrogenated in the presence of Adam's catalyst (1.2g) for 16 hours at 20°C and the catalyst removed by filtration through a pad of Celite. Evaporation of the filtrate gives N-(2-piperidin-4-yl-ethyl)-succinamic acid methyl ester hydrochloride as a colourless oil which is kept in vacuo (NaOH pellets).
- the gum is kept in vacuo (NaOH pellets) for 20 minutes to give a crisp white foam of 5-guanidino- 2(S)-[3-(1 -methyl-1 -phenyl-ethyl)-benzenesu!fonylamino]-pentanoyl chloride hydrochloride salt.
- Example 2b The product of Example 2b is hydrogenated (1 bar, 10% palladium on charcoal, 20°C, 26 hours) in methanol :acetic acid; water (30:3:1 , by vol.) at 68mM concentration.
- the product is isolated by preparative HPLC (using Zorbax C8 support) using acetonitrilerwate ⁇ trifluoroacetic acid (200:800:1 by vol.) and converted to the acetate salt by filtration through Dowex 1 (acetate form) resin, to yield 3(RS)- methyl-1 ,2,3,4-tetrahydro-quinoline-8-sulfonic acid ⁇ 4-guanidino-1 (S)-[4-(2-hydroxy- ethyl)-piperazine-1-carbonyl]-butyl ⁇ -amide acetate, m.p.
- fractions 14-29 afford, after evaporation of the solvent, 3-methylquinoline-8-sulfonic acid ⁇ 4-(3-nitro-guanidino)-1 (S)-[4-(2- hydroxy-ethyl)-piperidine-1-carbonyl]-butyl ⁇ -amide as product with chromatographic purity >99.5% (HPLC). Impure side-fractions are stock-piled for recovery of further product by rechromatography.
- Solid potassium carbonate (5g) is added and the mixture stirred, allowing to come to room temperature over 30 minutes.
- the tetrahydrofuran is removed by evaporation and the aqueous residue is extracted with ethyl acetate (2x25 ml).
- the combined extracts are washed with aqueous potassium carbonate solution (10% by wt., 15ml) and saturated aqueous sodium chloride solution (15ml), dried (MgSO4), filtered and evaporated to give a foam.
- Example 1b-c Analogously as described for Example 1b-c but using (1 ,2.3.4-tetrahydro-isoquinolin- 3(RS)-yl)-methanol and 5-guanidino-2(S)-naphthalenesulphonylamino-pentanoic acid is prepared naphthalene-2-sulfonic acid [4-guanidino-1 (S)-(3(RS)-hydroxymethyl-3,4- dihydro-1 H-isoquinoline-2-carbonyl)-butyl]-amide hydrochloride salt isolated after purification by gel filtration chromatography as described for Example 1 c and lyophilisation of the eluate.
- the acetate salt is obtained after passage of an aqueous solution of the hydrochloride salt through a short column of Dowex-1 (acetate form) resin and lyophilisation of the eluate. (Found: C. 55.65; H. 5.9; N, 11.5; S. 5.4. C26H31 N5O4S.CH3COOH.2H2O requires C. 55.5; H, 6.5; N. 11.6; S, 5.3%).
- reaction mixture is stoppered and stirred for 3 hours, after which time solvent is removed by evaporation and the residue is co- evaporated with ethanol (3 times) to give a residual orange oil.
- the oil is dissolved in aqueous ethanol (1 :1 , by vol., 35ml) and the solution is applied to a column (25ml) of Dowex 50 (H + form) resin. The column is washed with 50% aqueous ethanol (140ml) to remove impurities and eluted with cone. ammoniarwater:ethanol (1 :4:5, by vol.).
- the flask containing the mixture is stoppered and kept at 20°C for 2 hours.
- the mixture is concentrated under vacuum and the residue is triturated with ether to give an off-white solid which is co- evaporated (twice) with ether.
- the solid is dissolved in a mixture of water (10ml) and dioxan (5ml) and the solution is adjusted to pH>10 by addition of ammonia (sp. gr. .880) and extracted with ethyl acetate (3x20ml).
- Example 1b-c and 3b Analogously as described for Example 1b-c and 3b but using 5-guanidi ⁇ o-2(S)- naphthalenesulfonylamino-pentanoic acid and 2(R)-tert.-butoxymethyl-piperidine is prepared naphthalene-2-sulfonic acid [4-guanidino-1 (S)-(2(R)-hydroxymethyl- pyrrolidine-1 -carbonyl)-butyl]-amide isolated as the hydrochloride salt after purification by gel filtration chromatography as described for Example 1c and lyophilisation of the eluate. (Found: C, 49.91 ; H. 6.19; N, 13.75; S. 6.47; Cl. 7.29. C 2 1 H29N5O4S.HCI.H2O requires C. 50.24; H. 6.43; N. 13.9; S. 6.38; Cl. 7.06%).
- Example 18 Analogously as described for Example 9 but using 4-(2-tert.-butoxy-ethyl)-piperidine in place of 2(S)-tert.-butoxymethyl-piperidine and using the acidolysis and work-up conditions described for Example 18 is prepared N- ⁇ 4-guanidino-1(S)-[4-(2-hydroxy- ethyl)-piperidine-1 -carbonyl]-butyl ⁇ -3-(1 -methyl-1 -phenyl-ethyl)-benzenesulfonamide, m.p. 90 - I00°C. The 13C-NMR spectrum is consistent with the claimed structure.
- Method 1 a Analogously as described for Example 3a-c but using 3-(1 -methyl-1 -phenyl-ethyl)- benzenesulfonyl chloride and 1-(2-benzyloxy-ethyl)-piperazine in place of 3- methylquinoline-8-sulfonyl chloide and acetic acid 2-piperidin-4-yl-ethyl ester hydrochloride is prepared N- ⁇ 4-(3-nitro-guanidino)-1(S)-[4-(2-benzyloxy-ethyl)- piperazine-1 -carbonyl]-butyl ⁇ -3-(1 -methyl-1 -phenyl-ethyl)-be ⁇ zenesulfonamide.
- the mixture is concentrated by evaporation to give a residue which on trituration with ether gives a solid which is collected by filtration, washed with ether and dried.
- the solid is dissolved in water (5ml) and the solution is adjusted to pH>10 by addition of cone, ammonia (sp. gr. .880) to give a gelatinous precipitate which is dissolved by addition of dioxan.
- the solution obtained is evaporated to dryness and the residue triturated with ether, collected by filtration, washed with ether and dried.
- the white solid obtained is purified by chromatography on a column of silicagel using isopropano acetic acid: water (6:1 :1 , by vol.) as eluant to give N- ⁇ 4-guanidino-1 (S)-[4- (2-hydroxy-ethyl)-piperazine-1-carbonyl]-butyl ⁇ -3-(1 -methyl-1 -phenyl-ethyl)- be ⁇ zenesulfonamide carbonate salt, isolated as the carbonate salt.
- m.p. 178-184°C. (Found: C, 47.8; H. 6.9; N. 12.3; S, 4.85. C27H40N6O4S.H2CO3.H2O requires C, 48.2; H. 7.2; N. 12.5; S. 4.8%).
- Example 9 Analogously as described for Example 3a-c and 3e but using tetrahydrofuran as solvent and triethylamine as the base in procedure 3a and using 2(RS)- benzyloxycarbonylaminomethyl-piperidine and 3-(1 -methyl-1 -phenyl-ethyl)- benzenesulfonyl chloride in place of acetic acid 2-piperidin-4-yl-ethyl ester hydrochloride and 3-methylquinoline-8-sulfonyl chloride and work-up as described for Example 9 is prepared N-[1(S)-(2(RS)-aminomethyl-piperidine-1-carbo ⁇ yl)-4- guanidino-butyl]-3-(1 -methyl-1 -phe ⁇ yl-ethyl)-benzenesulfonamide as a white solid, m.p.
- Example 3a-c and 3e Analogously as described for Example 3a-c and 3e but using 4-(2-chloro-ethyl)- piperidine hydrochloride and 3-(1 -methyl-1 -phenyl-ethyl)-benzenesulfonyl chloride in place of acetic acid 2-piperidin-4-yl-ethyl ester hydrochloride and 3-methylquinoline-8- sulfonyl chloride and the hydrogenation solvent described for Example 37 is prepared N- ⁇ 1(S)-[4-(2-chloro-ethyl)-piperidine-1-carbonyl]-4-guanidi ⁇ o-butyl ⁇ -3-(1-methyl-1- phenyl-ethyl)-benzenesulfonamide as the hydrochloride salt.
- Chlorocarbonyl-acetic acid benzyl ester (2.8g) and 3(RS)-methyl-1 ,2,3,4-tetrahydro- quinoline-8-sulfonic acid ⁇ 4-guanidino-1 (S)-[4-(2-hydroxy-ethyl)-piperidine-1-carbonyl]- butylj-amide hydrochloride are dissolved in dry pyridine (30ml) in a dry flask and the mixture is stirred with exclusion of moisture for 72 hours at 20°C.
- Solvent is removed by rotary evaporation and the residue is purified by flash chromatography on silicagel using chloroform:methanol:acetic acid (6:1 :1 , by vol.) as solvent to give the semi-solid benzyl ester of malonic acid (2- ⁇ 1-[5-guanidino-2(S)-(3(RS)-methyl-1 ,2,3,4-tetrahydro- quinoline-8-sulfonylamino)-pentanoyl]-piperidin-4-yl ⁇ -ethyl) ester hydrochloride salt (2g) which is dissolved in a mixture of methanol (40ml) and acetic acid (2ml) and hydrogenated (1 bar) for 16 hours at 20°C in the presence of 10% palladium on charcoal (570mg).
- the catalyst is removed by filtration through a pad of Celite and the solvents removed to give a residue which is purified by preparative HPLC using ch!oroform:methanol:trifluoroacetic acid (390:610:1 , by vol.) as solvent to afford malonic acid mono-(2- ⁇ 1 -[5-guanidino-2(S)-(3(RS)-methyl-1 ,2,3,4-tetrahydro-quinoline- 8-sulfonylamino)-pentanoyl]-piperidin-4-yl ⁇ -ethyl) ester as the trifluoracetate salt.
- ch!oroform:methanol:trifluoroacetic acid 390:610:1 , by vol.
- Glutaric anhydride (2.3g) and 3(RS)-methyl-1 ,2,3,4-tetrahydro-quinoline-8-sulfonic acid ⁇ 4-guanidino-1(S)-[4-(2-hydroxy-ethyl)-piperidine-1-carbonyl]-butyl ⁇ -amide hydrochloride salt (2.0g) are dissolved in dry pyridine (40ml) at -20°C and stirred for 16 hours at room temperature.
- Hydrogen bromide gas is bubbled for 1 hour through a solution of 3(RS)-methyl- 1 ,2.3,4-tetrahydro-quinoli ⁇ e-8-sulfonic acid (4-guanidino-1 (S)-[4-(2-t.-butoxy-ethyl)- piperidine-1-carbonyl]-butyl ⁇ -amide acetate (Example 4d, 100mg) in propionic acid (5ml) cooled to 0-5°C and the mixture is stirred at room temperature for 3.5 hours. The mixture is concentrated by evaporation to give a residue which is trituated with ether, collected by filtration, washed with ether and dried.
- 3(RS)-methyl- 1 ,2.3,4-tetrahydro-quinoli ⁇ e-8-sulfonic acid (4-guanidino-1 (S)-[4-(2-t.-butoxy-ethyl)- piperidine-1-carbonyl]-butyl ⁇ -amide
- Example 3a-c and 3e Analogously as described for Example 3a-c and 3e but using propionic acid 2- piper idin-4-yl-ethyl ester hydrochloride and quinoline-8-sulfonyl chloride in place of acetic acid 2-piperidin-4-yl-ethyl ester hydrochloride and 3-methylquinoline-8-sulfonyl chloride and using the hydrogenation solvent described for Example 37 is prepared propionic acid 2- ⁇ 1-[5-guanidino-2(S)-(1 ,2,3,4-tetrahydro-quinoline-8-sulfonylamino)- pentanoyl]-piperidin-4-yl ⁇ -ethyl ester as the hydrochloride salt.
- Example 3a-c and 3e Analogously as described for Example 3a-c and 3e but using propionic acid 2- piperidin-4-yl-ethyl ester hydrochloride and 3-(1 -methyl-1 -phenyl-ethyl)- benzenesulfonyl chloride in place of acetic acid 2-piper idin-4-yl-ethyl ester hydrochloride and 3-methylquinoIine-8-sulfonyl chloride and using the hydrogenation solvent described for Example 37 is prepared propionic acid 2-(1- ⁇ 5-guanidino-2(S)-[3- (1 -methyl-1 -phenyl-ethyl)-benzenesulfonylamino]-pentanoyl ⁇ -piperidin-4-yl)-ethyl ester as the hydrochloride salt.
- Example 3a-c and 3e Analogously as described for Example 3a-c and 3e but using acetic acid 2-piperazin- 1-yl-ethyl ester hydrochloride and 3-(1 -methyl-1 -phenyl-ethyl)-benzenesulfonyl chloride in place of acetic acid 2-piper idin-4-yl-ethyl ester hydrochloride and 3- methylquinoli ⁇ e-8-sulfonyl chloride and using the hydrogenation solvent described for Example 37 is prepared acetic acid 2-(4- ⁇ 5-guanidino-2(S)-[3-(1 -methyl-1 -phenyl- ethyl)-benzenesulfonylamino]-pentanoyl ⁇ -piperazin-1-yl)-ethyl ester as the di- hydrochloride salt.
- Example 3a-c and 3e Analogously as described for Example 3a-c and 3e but using propionic acid 2- piperazin- -yl-ethyl ester hydrochloride and 3-(1 -methyl-1 -phenyl-ethyl)- benzenesulfonyl chloride in place of acetic acid 2-piperidin-4-yl-ethyl ester hydrochloride and 3-methylquinoline-8-sulfonyl chloride and using the hydrogenation solvent described for Example 37 is prepared propionic acid 2-(4- ⁇ 5-guanidino-2(S)-[3- (1 -methyl-1 -phenyl-ethyl)-benzenesulfonylamino]-pentanoyl ⁇ -piperazin-1-yl)-ethyl ester as the hydrochloride salt.
- Example 3a-c and 3e Analogously as described for Example 3a-c and 3e but using quinoline-8-sulfonyl chloride in place of 3-methylquinoline-8-sulfonyl chloride and using the hydrogenation solvent described for Example 37 is prepared acetic acid 2- ⁇ 1-[5-guanidino-2(S)- (1 ,2,3,4-tetrahydro-quinoline-8-sulfonylamino)-pentanoyl]-piperidin-4-yl ⁇ -ethyl ester hydrochloride. (Found: C, 51.57; H, 7.18; N, 13.64; S, 4.79. c 24 H 38 N 6°5 s - CH 3 COOH - 1 - 5H * 0 requires C, 51.21 ; H, 7.44; N. 13.78; S, 5.26%).
- the residue is purified by flash chromatography on a column of silicagel using chloroform :methanol (1 :1 , by vol.) as eluant and by preparative HPLC on Zorbax C8 resin using acetonitrilerwater:trifluoroacetic acid (370:630:1 , by vol.) as eluant.
- the catalyst is removed by filtration and the solvents by rotary evaporation to give a residue which is purified by flash chromatography on a column of silicagel using chloroform:methanol:acetic acid (60:5:10, by vol.) as eluant to give acetic acid 2- ⁇ 1-[5-guanidino-2(S)-(6-chloro-3,3-dimethyl-1 ,2,3,4-tetrahydro-qui ⁇ oline- 8-sulfonylamino)-pentanoyl]-piperidin-4-yl ⁇ -ethyl ester acetate salt which is saponified as described for Example 3d to give 6-chloro-3,3-dimethyl-1 ,2,3,4-tetrahydro- quinoline-8-sulfonic acid ⁇ 4-guanidino-1 (S)-[4-(2-hydroxy-ethyl)-piperidine-1-carbonyl]- butylj-amide isolated as the
- the catalyst is removed by filtration and the filtrate evaporated to dryness to give material which is purified by flash chromatography on a column of silicagel using chloroform:methanol:acetic acid (6:1 :1 , by vol.) as eluant to give, after passage of an aqueous solution of the recovered material through a column of Dowex-1 (chloride form) resin and lyophilisation of the eluate, 6-chloro-3,3-dimethyl-1 ,2,3.4-tetrahydro-quinoline-8- sulfonic acid ⁇ 1 (S)-[4-(2-fluoro-ethyl)-piperidine-1 -carbonyl]-4-guanidino-butyl ⁇ -amide hydrochloride salt as a white solid.
- aqueous hydrochloric acid M
- ethyl acetate 2x75ml
- the combined organic extracts are washed with brine, dried (MgSO4) and evaporated to yield 3-(3- benzyloxycarbonylamino-propylsulfanyl)-2(R)-.tert.-butoxycarbonylamino-propionic acid as a viscous pale yellow oil.
- NMM (1.0ml) is added and the mixture stirred at -15'C for 15 minutes. This mixture is slowly added to the first mixture at -15 * C and the whole is stirred at -15"C for 15 minutes and then at 20 * C for 3 hours. The reaction mixture is evaporated and the residue redissolved in ethyl acetate (175ml).
- Acetic acid 2- ⁇ 1-[3-(3-benzyloxycarbony.amino-propylsulfanyl)-2(R)-tert.- butoxycarbonylamino-propionyl]-piperidin-4-yl ⁇ -ethyl ester (1.9g) is dissolved in acetic acid (10ml) with stirring. Hydrogen chloride in acetic acid (M, 3ml) is added dropwise.
- NMM (0.93ml) is added. The mixture is stirred for 10 minutes at O'C. 3-(1 -Methyl-1 -phenyl-ethyl)-benzene-sulfonyl chloride (1.Og) is added to the mixture at O'C over 2 minutes and the mixture stirred at 4 * C for 16 hours.
- Acetic acid 2-(1 - ⁇ 3-(3-amino-propylsulfanyl)-2(R)-[3-(1 -methyl-1 -phenyl-ethyl)- benzenesulfonylamino]-propionyl ⁇ -piperidin-4-yl)-ethyl ester hydrochloride salt (562mg) is dissolved in dry methanol (5ml) and sodium methoxide (649mg) is added. The mixture is kept at 0°C for 2.5 hours and acetic acid (0.69ml) is added.
- the crude hydrobromide salt (2.0g) is dissolved in saturated aqueous sodium bicarbonate solution (50ml) and the solution is extracted with portions (2x70ml) of chloroform. The combined chloroform extracts are washed with portions (2x70ml) of acetic acid (M), dried (MgSO4) and tne solvent evaporated.
- Acetic acid 2-(1 - ⁇ 3-(3-amino-propylsulfanyl)-2(R)-[3(RS)-methyl-1 ,2,3,4-tetrahydro- quinoline-8-sulfonylamino]-propionyl ⁇ -piperidin-4-yl)-ethyl ester acetate salt (188mg) is dissolved in aqueous methanol (50%, 5ml) and potassium carbonate (156mg) is added. The mixture is stirred at 20°C for 75 minutes and solvents are removed by rotary evaporation.
- Catalyst is removed by filtration and sovents by rotary evaporation.
- the residue is purified by flash chromatography on a column of silicagel using chloroform:methanolrwater:acetic acid (80:20:2:1 , by vol.) as eluant to afford acetic acid 2-(1 - ⁇ 3-(3-amino-propylsulfanyl)-2(R)-[6-chloro-3,3-dimethyl-1 ,2,3,4-tetrahydro- quinoline-8-sulfonylamino]-propionyl ⁇ -piperidin-4-yl)-ethyl ester as its acetate salt.
- C 2 6H 1 N405S2CI.CH3COOH.3H2O requires C, 47.82; H, 7.31 ; N, 7.97; S, 9.12%).
- the product is an hygroscopic, off-white foamy solid after freeze drying and must be kept in vacuo (NaOH pellets). (Found: C, 52.41 ; H, 7.33: N, 8.71. C26H42 405S2.CH3COOH.I .5H2O requires C, 52.40; H, 7.70; N. 8.73%).
- Acetic acid 2- ⁇ 1-[3-(3-benzyloxycarbonylamino-propylsulfanyl)-2(R)-tert.- butoxycarbonylamino-propionyl]-piperidin-4-yl ⁇ -ethyl ester (257mg) is dissolved in aetone (4ml) and hydrogen peroxide (0.13ml, 27.5% by vol.) and ammonium molybdate tetrahydrate (608mg) is added. The mixture is stirred at 20°C for 35 minutes, filtered through a plug of cotton wool to remove solids and the filtrate evaporated to dryness.
- Aziridine-1 ,2(S)-dicarboxylic acid 1 -benzyl ester 2-methyl ester (1.53g) is dissolved in chloroform (5ml) and place under an atmosphere of nitrogen. (3-Hydroxy-propyl)- carbamic acid tert.-butyl ester (2.84g) dissolved in chloroform (5ml) is added. Boron trifluoride etherate (0.125ml) is added by syringe and the reaction is stirred under nitrogen at room temperature for 16 hours.
- the catalyst is removed by filtration and the solvent evaporated to yield acetic acid 2- ⁇ 1-[3-(3-tert.-butoxycarbonylamino-propoxy)-2(S)-(3(RS)-methyl-1 ,2,3,4- tetrahydro-quinoline-8-sulfonylamino)-propionyl]-piperidin-4-yl ⁇ -ethyl ester as a yellow oil.
- Acetic acid 2- ⁇ 1-[3-(3-tert.-butoxycarbonylamino-propoxy)-2(S)-(3(RS)-methyl- 1 ,2,3,4-tetrahydro-quinoline-8-sulfonylamino)-propionyl]-piperidin-4-yl ⁇ -ethyl ester (0.46g) is dissolved in hydrogen chloride in acetic acid (M, 5ml) and stirred at room temperature for 1.5 hours. The solvent is removed by evaporation, and co- evaporated several times with ethanol, and the resulting yellow residual oil held under vacuum.
- Example 88a Analogously as described for Example 90 but using (RS)-homocysteine and (2-bromo- ethyl)-carbamic acid benzyl ester in place of (R)-cysteine and (3-bromo-propyl)- carbamic acid benzyl ester (Example 88a) is prepared acetic acid 2- ⁇ 1-[4-(2-amino- ethylsulfanyl)-2(RS)-(3(RS)-methyl-1.2.3,4-tetrahydro-quinoline-8-sulfonylamino)- butyryl]-piperidi ⁇ -4-yl ⁇ -ethyl ester.
- the resulting white foam is pre-absorbed onto a column of silicagel and eluted with chloroform:methanol:acetic acid (12:1 :1 , by vol.) to give 3-(3-benzyloxycarbonylamino-propylamino)-2(S)-tert.-butoxycarbonylamino- propionic acid, obtained as a white solid after lypohilisation from aqueous solution.
- Acetic acid 2- ⁇ 1-[3-(3-be ⁇ zyloxycarbonylamino-propylamino)-2(S)-tert.- butoxycarbonylamino-propionyl]-piperidin-4-yl ⁇ -ethyl ester (1.22g) is dissolved in hydrogen chloride in acetic acid (M, 15ml) and the mixture is stirred at room temperature for 1 hour.
- Solvents are removed by rotary evaporation and the residue is purified by chromatography on a column of silicagel which is eluted with ethyl acetate to give acetic acid 2- ⁇ 1 -[3-(3- benzyloxycarbonylamino-propylamino)-2(S)-(3,3-dimethyl-1 ,2,3,4-tetrahydro-quinoline- 8-sulfonylamino)-propionyl]-piperidin-4-yl ⁇ -ethyl ester as a white foam after evaporation from ethanol :diethyl ether (1 :1 , by vol.).
- the solution is diluted with ethyl acetate (25ml) and extracted at O'C with portions (25ml) of aqueous hydrochloric acid (0.1 M, 3x), brine (2x), saturated aqueous sodium bicarbonate (3x) and brine, dried (MgSO4) and evaporated to dryness to give a residue which is purified by flash chromatography on a column of silicagel using ethyl acetate :hexane (1 :1 , by vol.) as eluant to give acetic acid 2- ⁇ 1-[3-benzothiazol-2-yl- 2(S)-(6-chloro-3,3-dimethyl-1 ,2.3,4-tetrahydro-quinoline-8-sulfonylamino)-propionyl]- piperidin-4-yl ⁇ -ethyl ester as a colourless foam.
- aqueous hydrochloric acid 0.1 M, 3x
- the solution is extracted with ether (3x1 Oml), acidified to pH2 (M aqueous hydrochloric acid) and the solution is extracted with ethyl acetate (3x1 Oml).
- the combined organic extracts are dried (MgSO4) and evaporated to give cream crystals.
- the product is isolated by flash column chromatography on a column of silicagel using dichloromethane :methanol (96:4, by vol.) as eluant.
- reaction solution is concentrated in vacuo and the residue dissolved in water (30ml).
- the solution is washed with ethyl acetate (30ml).
- the separated aqueous layer is acidified to pH3 by the careful addition of aqueous hydrochloric acid (M) and the product extracted with ethyl acetate (3x30ml).
- the combined organic extracts are washed with brine, filtered, dried (MgSO4) and concentrated in vacuo to yield pure 2(S)-tert.-butoxycarbonylamino-3-(4-chloromethyl- thiazol-2-yl)-propionic acid as a colourless solid.
- the dichloromethane phase is dried (MgSO4) and concentrated in vacuo to give the crude product which is purified by flash chromatography on a column of silicagel to give pure acetic acid 2- ⁇ 1 -[2(S)-tert.-butyloxycarbonyl-amino-3- (4-chloromethyl-thiazol-2-yl)-propionyl]-piperidin-4-yl ⁇ -ethyl ester as a white foam.
- Triethylamine (2.15ml) is added to 4-[4-(2-acetoxy-ethyl)-piperidin-1-yl]-3(S)-amino- 4-oxo-butyric acid benzyl ester (2.9g) dissolved in dichloromethane (50ml), 6-chloro- 3.3-dimethyl-1 ,2,3,4-tetrahydro-quinoline-8-sulfonyl chloride (2.35g) is added and the mixture is stirred for 16 hours at 20'C. The solution is evaporated, the residue is dissolved in ethyl acetate (50ml) and the solution is extracted with portions (20ml) of water (2x) and brine.
- Triethylamine (1.76ml) is added to a solution of 4-[4-(2-acetoxy-ethyl)-piperidin-1- yl]-3(S)-(6-chloro-3,3-dimethyl-1 ,2.3,4-tetrahydro-quinoline-8-sulfonylamino)-4-oxo- butyric acid benzyl ester (1.9g) in methanol (25ml) and 10% palladium on charcoal (400mg) is added. The mixture is hydrogenated (1 atm.) for 4 hours at 20 * C.
- Triethylamine 140 ⁇ l is added to a solution of 4-[4-(2-acetoxy-ethyl)-piperidin-1-yl]- 3(S)-(6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-sulfonylamino)-4-oxo-butyric acid (544mg) dissolved in THF (8ml). The solution is cooled to -10'C and isobutylchloroformate (0.13ml) is added. After 10 minutes a solution of 1 ,2- phenylenediamine (120mg) in THF (2ml) is added.
- the organic phase is dried (MgSO4), evaporated and purified by flash chromatography on a column of silicagel using methanol.dichloromethane (1 :19, by vol.) as eluant to give the crude product as a white foam.
- Example 109c Analogously as described for Example 111 b-e but using chloroacetone in place of 1 ,3-dichloroacetone and saponifying as described for Example 109c is prepared 3,3- dimethyl-1 ,2,3,4-tetrahydro-quinoline-8-sulfonic acid [2-[4-(2-hydroxy-ethyl)-piperidin- 1-yl]-1(S)-(4-methyl-thiazol-2-ylmethyl)-2-oxo-ethyl]-amide. (Found: C, 57.34; H, 7.07; N, 10.57; S. 12.54. C25H36N4O4S2 requires C, 57.67; H. 6.97; N, 10.76; S. 12.32%).
- Acetic acid 2- ⁇ 1-[3-benzooxazol-2-yl-2(S)-(3(RS)-methyl-1 ,2,3,4-tetrahydro-quinoline- 8-sulfonylamino)-propionyl]-piperidin-4-yl ⁇ -ethyl ester is treated as described in Example 109c to give 3(RS)-methyl-1 ,2,3,4-tetrahydro-qui ⁇ oline-8-sulfonic acid ⁇ 2- benzooxazol-2-yl-1 (S)-[4-(2-hydroxy-ethyl)-piperidine-1-carbonyl]-ethyl ⁇ -amide.
- C27H34N4O5S requires C, 61.58; H, 6.51 ; N, 10.64; S, 6.09%).
- Acetic acid 1 -[3-benzothiazol-2-yl-2(S)-(3,3-dimethyl-1 ,2,3,4-tetrahydro-quinoline-8- sulfonylamino)-propionyl]-pyrrolidin-2(R)-ylmethyl ester is treated as described in Example 109c to give 3,3-dimethyl-1 ,2,3,4-tetrahydro-quinoline-8-sulfonic acid [1(S)- benzothia_ol-2-yl-methyl-2-(2(R)-hydroxymethyl-pyrrolidin-1-yl)-2-oxo-ethyl]-amide.
- C26H32N4O4S2.O.5H2O requires C. 58.08; H. 6.19; N. 10.42; S, 11.93%).
- Acetic acid 2-(2- ⁇ 4-[3-benzothiazol-2-yl-2(S)-(3,3-dimethyl-1 ,2,3,4-tetrahydro- quinoline-8-sulfonylamino)-propionyl]-piperazin-1-yl ⁇ -ethoxy)-ethyl ester is treated as described in Example 109c to give 3,3-dimethyl-1 ,2,3,4-tetrahydro-quinoline-8-sulfonic acid (2-benzothiazol-2-yl-1 (S)- ⁇ 4-[2-(2-hydroxy-ethoxy)-ethyl]-piperazine-1 -carbonyl ⁇ - ethyl)-amide isolated as its hydrochloride salt as a stable iyophilisate.
- the 1 H- and 13C-NMR spectra are consistent with the claimed structure.
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Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
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AU48872/96A AU4887296A (en) | 1995-03-18 | 1996-03-08 | Trypsin and thrombin inhibitors |
EP96904963A EP0815103A1 (en) | 1995-03-18 | 1996-03-08 | Trypsin and thrombin inhibitors |
JP8528155A JPH11502219A (en) | 1995-03-18 | 1996-03-08 | Trypsin and thrombin inhibitors |
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GB9505538.0 | 1995-03-18 | ||
GBGB9505538.0A GB9505538D0 (en) | 1995-03-18 | 1995-03-18 | New compounds |
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WO1996029327A1 true WO1996029327A1 (en) | 1996-09-26 |
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PCT/GB1996/000520 WO1996029327A1 (en) | 1995-03-18 | 1996-03-08 | Trypsin and thrombin inhibitors |
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EP (1) | EP0815103A1 (en) |
JP (1) | JPH11502219A (en) |
AR (1) | AR001801A1 (en) |
AU (1) | AU4887296A (en) |
GB (1) | GB9505538D0 (en) |
IL (1) | IL117437A0 (en) |
WO (1) | WO1996029327A1 (en) |
ZA (1) | ZA962112B (en) |
Cited By (9)
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EP0823430A1 (en) * | 1996-08-07 | 1998-02-11 | Mitsubishi Chemical Corporation | Method for preparing n2-arylsulfonyl-l-argininamides |
FR2761065A1 (en) * | 1997-03-20 | 1998-09-25 | Synthelabo | N- (ARGINYL) BENZENESULFONAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE |
WO2002100860A2 (en) * | 2001-06-08 | 2002-12-19 | Aventis Pharma S.A. | Heterocyclic compounds, method for preparing same and use thereof as medicines, in particular as anti-bacterial agents |
US7365071B2 (en) | 2002-09-05 | 2008-04-29 | Branislav Musicki | Heterocyclic compounds, preparation process and intermediates, and use as medicaments, in particular as β-lactamase inhibitors and antibacterials |
US7612087B2 (en) | 2002-01-28 | 2009-11-03 | Novexel | Heterocyclic compounds as inhibitors of beta-lactamases |
EP2326650A2 (en) * | 2008-08-06 | 2011-06-01 | BioMarin Pharmaceutical Inc. | Dihydropyridophthalazinone inhibitors of poly(adp-ribose)polymerase (parp) |
US8541403B2 (en) | 2010-02-03 | 2013-09-24 | Biomarin Pharmaceutical Inc. | Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP) for use in treatment of diseases associated with a PTEN deficiency |
US8735392B2 (en) | 2010-10-21 | 2014-05-27 | Biomarin Pharmaceutical Inc. | Crystalline (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one tosylate salt |
US8765945B2 (en) | 2010-02-08 | 2014-07-01 | Biomarin Pharmaceutical Inc. | Processes of synthesizing dihydropyridophthalazinone derivatives |
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US5925760A (en) * | 1996-08-07 | 1999-07-20 | Mitsubishi Chemical Corporation | Method for preparing N2 -arylsulfonyl-L-argininamides |
EP0823430A1 (en) * | 1996-08-07 | 1998-02-11 | Mitsubishi Chemical Corporation | Method for preparing n2-arylsulfonyl-l-argininamides |
FR2761065A1 (en) * | 1997-03-20 | 1998-09-25 | Synthelabo | N- (ARGINYL) BENZENESULFONAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE |
WO1998042700A1 (en) * | 1997-03-20 | 1998-10-01 | Sanofi-Synthelabo | N-(arginyl)benzenesulphonamide derivatives and use thereof as antithrombotic agents |
US8148540B2 (en) | 2001-06-08 | 2012-04-03 | Astrazeneca | Heterocyclic compounds, their preparation and their use as medicaments, in particular as anti-bacterial agents |
WO2002100860A2 (en) * | 2001-06-08 | 2002-12-19 | Aventis Pharma S.A. | Heterocyclic compounds, method for preparing same and use thereof as medicines, in particular as anti-bacterial agents |
WO2002100860A3 (en) * | 2001-06-08 | 2003-11-20 | Aventis Pharma Sa | Heterocyclic compounds, method for preparing same and use thereof as medicines, in particular as anti-bacterial agents |
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Also Published As
Publication number | Publication date |
---|---|
GB9505538D0 (en) | 1995-05-03 |
EP0815103A1 (en) | 1998-01-07 |
ZA962112B (en) | 1996-09-18 |
AU4887296A (en) | 1996-10-08 |
IL117437A0 (en) | 1996-10-16 |
AR001801A1 (en) | 1997-12-10 |
JPH11502219A (en) | 1999-02-23 |
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