CN1066451C - Thiazoline derivative - Google Patents
Thiazoline derivative Download PDFInfo
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- CN1066451C CN1066451C CN95197913A CN95197913A CN1066451C CN 1066451 C CN1066451 C CN 1066451C CN 95197913 A CN95197913 A CN 95197913A CN 95197913 A CN95197913 A CN 95197913A CN 1066451 C CN1066451 C CN 1066451C
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- Prior art keywords
- salt
- compound
- formula
- thiazoline
- alkyl
- Prior art date
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- 150000003549 thiazolines Chemical class 0.000 title claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 208000010110 spontaneous platelet aggregation Diseases 0.000 claims abstract description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 4
- 239000003814 drug Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 25
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- -1 isobutyl- Chemical group 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 5
- ILUCEYQSSPPTTB-UHFFFAOYSA-N 2,3,4a,5,6,7,8,8a-octahydro-[1,4]dioxino[2,3-c]pyridine Chemical class O1CCOC2CNCCC21 ILUCEYQSSPPTTB-UHFFFAOYSA-N 0.000 description 4
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 4
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 238000002386 leaching Methods 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229940000406 drug candidate Drugs 0.000 description 3
- 210000002381 plasma Anatomy 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 210000004623 platelet-rich plasma Anatomy 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- KCMZYCFSSYXEQR-UHFFFAOYSA-N CCCC[K] Chemical group CCCC[K] KCMZYCFSSYXEQR-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 229920002253 Tannate Polymers 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 159000000013 aluminium salts Chemical class 0.000 description 1
- 229910000329 aluminium sulfate Inorganic materials 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical class C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- 150000004648 butanoic acid derivatives Chemical class 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- MWPIIMNHWGOFBL-UHFFFAOYSA-N dichloromethane;toluene Chemical compound ClCCl.CC1=CC=CC=C1 MWPIIMNHWGOFBL-UHFFFAOYSA-N 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000023589 ischemic disease Diseases 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 150000005451 methyl sulfates Chemical class 0.000 description 1
- 229950000081 metilsulfate Drugs 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- FGQJDHJXUZUTIQ-UHFFFAOYSA-N quinoline;1,3-thiazole Chemical compound C1=CSC=N1.N1=CC=CC2=CC=CC=C21 FGQJDHJXUZUTIQ-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 229960004249 sodium acetate Drugs 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- CWXOAQXKPAENDI-UHFFFAOYSA-N sodium methylsulfinylmethylide Chemical compound [Na+].CS([CH2-])=O CWXOAQXKPAENDI-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-N sodium;5-ethyl-5-pentan-2-yl-1,3-diazinane-2,4,6-trione Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)NC1=O QGMRQYFBGABWDR-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Abstract
The present invention provides a thiazoline derivative represented by the right formula in the specification or pharmacologically allowable salts thereof. The compound has an excellent function of inhibiting platelet aggregation by non-oral administration and oral administration. In the formula, R1 represents alkyl with 1 to 4 carbon atoms, and R2 represents hydrogen atoms or alkyl with 1 to 4 carbon atoms.
Description
Technical field
The present invention relates to have the novel thiazole quinoline derivant of good inhibition platelet aggregation effect.
Background technology
The compounds of this invention has been included in the general formula 1 of claim record of No. 94/02472, WO application, but does not specifically put down in writing The compounds of this invention in the specification sheets of this application.Concrete disclosed compound has the effect of good inhibition platelet aggregation in the specification sheets of No. 94/02472, WO application when non-oral administration, but shortcoming such as pharmacologically active is low when oral administration is arranged.
The compound that has good inhibition platelet aggregation effect when the object of the present invention is to provide oral administration.
Of the present invention open
Processes such as the inventor are concentrated on studies, found that, certain thiazoline derivative has the good oral administration activity that concrete disclosed compound did not have in the specification sheets of WO94/02472 number application, thereby has realized aforementioned purpose of the present invention, has finished the present invention.
That is, the present invention is as shown in the formula the thiazoline derivative of expression or its pharmacy salt of allowing,
R in the formula
1The alkyl of expression carbonatoms 1～4, R
2The alkyl of expression hydrogen atom or carbonatoms 1～4.
Among the present invention, the alkyl of said carbonatoms 1～4 is meant methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl.The salt that the pharmacy of said formula I compound is allowed, so long as allow on the pharmacology, have no particular limits, for example can enumerate and the basic metal class alkaline-earth metal class, ammonia, alkyl amine, mineral acid, carboxylic acid, the salt that sulfonic acid etc. form.Concrete example is as enumerating sodium salt, sylvite, calcium salt, ammonium salt, aluminium salt, triethylamine salt, 1-amantadine salt, hydrochloride, hydrobromate, hydriodate, vitriol, nitrate, phosphoric acid salt, single metilsulfate, acetate, propionic salt, butyrates, succinate, tartrate, Citrate trianion, tannate, malate, hexanoate, valerate, fumarate, maleate, mesylate, toluenesulfonate etc., but be not limited only to above-mentioned each salt.
The compounds of this invention can be according to for example following method preparation.
That is, the compound or its salt that is shown below and 4 that the method for putting down in writing according to page 4 in No. 94/02472 application specification of WO obtains, 4-ethylenedioxy piperidines or its reactant salt can obtain the salt that formula I compound or its pharmacy are allowed,
In the following formula, R
3The expression low alkyl group, R
1With R
2Implication is identical with the front.
Preparation R
2During the salt of allowing for formula I compound or its pharmacy of hydrogen atom, can be by with R
2For the formula I compound of the alkyl of carbonatoms 1～4 or the ester group partial hydrolysis of the salt that its pharmacy is allowed obtain.Said hydrolyzed can adopt general alkaline purification, and methods such as ore deposit acid or organic acid processing are carried out.
In addition, R
2Be the formula I compound of the alkyl of carbonatoms 1～4, also can by as carry out transesterification reaction and the phase co-conversion with acid as catalyst.
When adopting alkali in the above-mentioned reaction, for example can adopt alkaline metal salt (as yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, dimsyl sodium, sodium hydride, sodium amide or tertiary butyl potassium) as alkali, amine (as triethylamine, diisopropyl ethyl amine, pyridine), sodium-acetate, Potassium ethanoate etc.; Mineral acid is hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, nitric acid, sulfuric acid for example; Organic acid is acetic acid, methylsulfonic acid, tosic acid for example.4, the salt of 4-ethylenedioxy piperidines can adopt the organic acid salt as acetate etc., the inorganic acid salt of hydrochloride etc.As reaction solvent, can adopt as water, alcohols (as methyl alcohol, ethanol, Virahol or the trimethyl carbinol), ethers (such as diox, tetrahydrofuran (THF)), dimethyl formamide, methyl-sulphoxide, pyridine, methylene dichloride, chloroform, acetone, acetic acid etc. are to the solvent of reactionlessness.Industrial practicality
The The compounds of this invention that obtains according to the method described above is not only when non-oral administration, even and if have a good inhibition platelet aggregation effect when oral administration.
Prevention and treatment of diseases medicines such as therefore, The compounds of this invention can be used as ischemic diseases such as thrombosis, cerebral infarction, myocardial infarction, arteriosclerosis and working.
For achieving the above object, The compounds of this invention can be added into extender commonly used, tackiness agent, disintegrating agent, pH adjustment agent, solubilizing agent etc., makes tablet, pill, capsule, granule, powder, liquor, latex, suspensoid, injection etc. by preparation technique commonly used.
The compounds of this invention can adopt 1～1000 milligram/day dosage for adult patient, divides administration for several times.Above-mentioned dosage can suitably increase and decrease according to kinds of Diseases, patient age, body weight, symptom.
Below enumerating the routine good effect to The compounds of this invention of test describes.Test example (the cavy oral administration suppresses platelet aggregation effect test)
Adopting the male Hartley at one night of fasting in the test is cavy, 4 ages in week, body weight 250～300 grams, 1 group 4.Investigational agent is suspended in 10%Tween 80 solution by 1 mg/kg dose oral administration.Control group only gives solvent.Behind the oral administration 30 minutes, (30 mg/kg, ip) abdomen is opened in anesthesia, takes a blood sample with plastic injector (3.8% Trisodium Citrate is 1: 9 with the blood volume ratio) from aorta abdominalis with Sodital.With blood with 120g centrifugation 10 minutes, (platelet rich plasma PRP), remains blood plasma and continues with 1100g centrifugation 10 minutes the gained supernatant liquor as platelet-rich plasma, obtain platelet poor plasma (platelet poor plasma, PPP).Platelet count among the PRP is diluted to 4～6 * 10 with PPP
5Individual/microlitre.
The mensuration of platelet aggregation is that cohesion causes material and adopts adenosine diphosphate (ADP) (Sigma company produces, and is designated hereinafter simply as ADP) according to the method for Born G.V.R (Born, G.V.R, Nature, 194 volumes, 927 pages (1962)).That is, will add among the 250 microlitre PRP as ADP (ultimate density 3 μ M)/suprarenin (ultimate density 10 μ M) 25 microlitres of cohesion initiator, with platelet aggregation ability determinator (Aggricoda PAM-8C; Mebanix company) measures 5 minutes, organize in contrast, be calculated as follows the cohesion inhibiting rate of the cohesion inhibiting rate of investigational agent administration group, calculate 50% inhibition concentration (IC50 value) with respect to the maximum cohesion rate of control group to give group of solvents.
In addition, with compound N-(2-propyloic)-2-(4-amidino groups the benzoylimino)-3-sec.-propyl-4-methyl-3H-thiazoline-5-methane amide hydrobromate of No. 94/02472 specification sheets record in contrast medicine test equally, the result is as shown in table 1.
Table 1
| Investigational agent | Inhibiting rate ± SD (%) |
| Compound 3 contrast medicines | 99.3±0.7 15.0±5.7 |
The best mode that carries out an invention
Below, the present invention will be described in more detail to enumerate embodiment.Reference example
N-(2-methoxycarbonyl ethyl)-2-(4-(methylthio group formamino) benzoylimino)-3,4-dimethyl-3H-thiazoline-5-methane amide Methylsulfate (compound 1)
N-(2-methoxycarbonyl ethyl)-2-(4-thiocarbamyl benzoylimino)-3; 4-dimethyl-3H-thiazoline-5-methane amide (104 gram), methyl-sulfate (86.1 milliliters), N, the miscellany stirring at room of dinethylformamide (400 milliliters) 4 hours.1.5 liters of acetone of ice-cooled adding down, the crystallization that leaching is separated out is promptly to obtain title compound 126.5 grams behind the washing with acetone.
164～167 ℃ of fusing points
Embodiment 1
N-(2-methoxycarbonyl ethyl)-2-{4-((4,4-ethylenedioxy piperidines-1-yl) formamino) benzoylimino }-3,4-dimethyl-3H-thiazoline-5-methane amide Methylsulfate (compound 2)
Compound 1 (10.0 gram), 4, the miscellany of 4-ethylenedioxy piperidines (3.93 gram), acetic acid (1.57 milliliters) and acetone (100 milliliters) stirred 90 minutes down for 80 ℃.Reaction mixture put cold after, the crystallization that leaching is separated out with the mixed solvent wash of methyl alcohol and toluene, obtains title compound 7.66 and restrains.
215～216 ℃ of fusing points (decomposition)
Embodiment 2
N-(2-propyloic)-2-{4-((4,4-ethylenedioxy piperidines-1-yl) formamino) benzoylimino }-3,4-dimethyl-3H-thiazoline-5-methane amide trihydrate (compound 3)
The miscellany stirring at room of compound 2 (7.0 gram), 5% aqueous sodium hydroxide solution (19.2 milliliters), 2-propyl alcohol (70 milliliters) 1 hour.Add 1% phosphate aqueous solution (60 milliliters) in the reaction mixture, the crystallization that leaching is separated out obtains title compound 5.3 grams.
233～234 ℃ of fusing points (decomposition)
Embodiment 3
N-(2-methoxycarbonyl ethyl)-2-{4-((4,4-ethylenedioxy piperidines-1-yl) formamino) benzoylimino }-3,4-dimethyl-3H-thiazoline-5-methane amide hydriodate (compound 4)
N-(2-methoxycarbonyl ethyl)-2-(4-(first sulphur imido acyl group) benzoylimino)-3; 4-dimethyl-3H-thiazoline-5-methane amide hydriodate (1.0 gram), 4, the miscellany reflux of 4-ethylenedioxy piperidines (0.5 gram), acetic acid (0.2 milliliter) and methyl alcohol (15 milliliters) stirred 1.5 hours.The reaction mixture concentrating under reduced pressure, residue obtains title compound 1.0 grams with methylene dichloride-toluene recrystallization.
212～214 ℃ of fusing points (decomposition)
Embodiment 4
N-(2-propyloic)-2-{4-((4,4-ethylenedioxy piperidines-1-yl) formamino) benzoylimino }-3,4-dimethyl-3H-thiazoline-5-methane amide dihydrate (compound 5)
The miscellany reflux of compound 4 (0.4 gram), 10% aqueous sodium hydroxide solution (1 milliliter), methyl alcohol (15 milliliters) stirred 40 minutes.The reaction mixture concentrating under reduced pressure, with adding the neutralization of 3% hydrochloric acid after the less water dissolving, the crystallization that leaching is separated out obtains title compound 0.3 gram.
166～169 ℃ of fusing points (decomposition)
Claims (3)
1, the salt of allowing as shown in the formula thiazoline derivative or its pharmacy of expression,
R in the formula
1The alkyl of expression carbonatoms 1～4, R
2The alkyl of expression hydrogen atom or carbonatoms 1～4.
2, the pharmaceutical composition that is used to suppress platelet aggregation formed of salt of allowing by thiazoline derivative or its pharmacy of claim 1 record and medical carrier.
3, the salt of allowing according to thiazoline derivative or its pharmacy of claim 1 record is used for suppressing the application of the medicine of platelet aggregation in preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN95197913A CN1066451C (en) | 1995-07-07 | 1995-07-07 | Thiazoline derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN95197913A CN1066451C (en) | 1995-07-07 | 1995-07-07 | Thiazoline derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1190396A CN1190396A (en) | 1998-08-12 |
| CN1066451C true CN1066451C (en) | 2001-05-30 |
Family
ID=5083437
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95197913A Expired - Fee Related CN1066451C (en) | 1995-07-07 | 1995-07-07 | Thiazoline derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1066451C (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994002472A1 (en) * | 1992-07-15 | 1994-02-03 | Taisho Pharmaceutical Co., Ltd. | Thiazoline derivative |
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1995
- 1995-07-07 CN CN95197913A patent/CN1066451C/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994002472A1 (en) * | 1992-07-15 | 1994-02-03 | Taisho Pharmaceutical Co., Ltd. | Thiazoline derivative |
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| Publication number | Publication date |
|---|---|
| CN1190396A (en) | 1998-08-12 |
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