JPH0255427B2 - - Google Patents
Info
- Publication number
- JPH0255427B2 JPH0255427B2 JP632181A JP632181A JPH0255427B2 JP H0255427 B2 JPH0255427 B2 JP H0255427B2 JP 632181 A JP632181 A JP 632181A JP 632181 A JP632181 A JP 632181A JP H0255427 B2 JPH0255427 B2 JP H0255427B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- hydrogen atom
- general formula
- oxamide
- lower alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 150000001875 compounds Chemical class 0.000 claims description 29
- 230000002519 immonomodulatory effect Effects 0.000 claims description 12
- YIKSCQDJHCMVMK-UHFFFAOYSA-N Oxamide Chemical class NC(=O)C(N)=O YIKSCQDJHCMVMK-UHFFFAOYSA-N 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- PYSJLPAOBIGQPK-UHFFFAOYSA-N 4-phenyl-1,3-thiazol-2-amine Chemical class S1C(N)=NC(C=2C=CC=CC=2)=C1 PYSJLPAOBIGQPK-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- 238000002619 cancer immunotherapy Methods 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims 1
- 238000012360 testing method Methods 0.000 description 18
- 239000003814 drug Substances 0.000 description 12
- 201000010099 disease Diseases 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 206010070834 Sensitisation Diseases 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 230000008313 sensitization Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 4
- 208000009386 Experimental Arthritis Diseases 0.000 description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 description 4
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 4
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 4
- 230000036737 immune function Effects 0.000 description 4
- -1 oxamide compound Chemical class 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 208000023275 Autoimmune disease Diseases 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 208000006313 Delayed Hypersensitivity Diseases 0.000 description 3
- LAZPBGZRMVRFKY-HNCPQSOCSA-N Levamisole hydrochloride Chemical compound Cl.C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 LAZPBGZRMVRFKY-HNCPQSOCSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 210000005069 ears Anatomy 0.000 description 3
- 229960003734 levamisole hydrochloride Drugs 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 230000005951 type IV hypersensitivity Effects 0.000 description 3
- 208000027930 type IV hypersensitivity disease Diseases 0.000 description 3
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 description 2
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000024932 T cell mediated immunity Effects 0.000 description 2
- 206010053613 Type IV hypersensitivity reaction Diseases 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 229960001614 levamisole Drugs 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- HJRJRUMKQCMYDL-UHFFFAOYSA-N 1-chloro-2,4,6-trinitrobenzene Chemical compound [O-][N+](=O)C1=CC([N+]([O-])=O)=C(Cl)C([N+]([O-])=O)=C1 HJRJRUMKQCMYDL-UHFFFAOYSA-N 0.000 description 1
- DMNJPLQUXVZFSJ-UHFFFAOYSA-N 2-chloro-1,3,5-trinitrobenzene Chemical compound [O-][N+](=O)C1=CC([N+]([O-])=O)=C(Cl)C([N+]([O-])=O)=C1.[O-][N+](=O)C1=CC([N+]([O-])=O)=C(Cl)C([N+]([O-])=O)=C1 DMNJPLQUXVZFSJ-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 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
- 206010061218 Inflammation Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000002456 anti-arthritic effect Effects 0.000 description 1
- 238000011224 anti-cancer immunotherapy Methods 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000002900 effect on cell Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- GLZFYIHBHBXCJE-UHFFFAOYSA-N n,n'-bis(4-phenyl-1,3-thiazol-2-yl)oxamide Chemical compound N=1C(C=2C=CC=CC=2)=CSC=1NC(=O)C(=O)NC(SC=1)=NC=1C1=CC=CC=C1 GLZFYIHBHBXCJE-UHFFFAOYSA-N 0.000 description 1
- FFYNJKRCECPPCP-UHFFFAOYSA-N n,n'-bis(5-methylsulfanyl-4-phenyl-1,3-thiazol-2-yl)oxamide Chemical compound N=1C(C=2C=CC=CC=2)=C(SC)SC=1NC(=O)C(=O)NC(SC=1SC)=NC=1C1=CC=CC=C1 FFYNJKRCECPPCP-UHFFFAOYSA-N 0.000 description 1
- OVBSBCCGGMLLFX-UHFFFAOYSA-N n,n'-bis[4-(2-bromophenyl)-1,3-thiazol-2-yl]oxamide Chemical compound BrC1=CC=CC=C1C1=CSC(NC(=O)C(=O)NC=2SC=C(N=2)C=2C(=CC=CC=2)Br)=N1 OVBSBCCGGMLLFX-UHFFFAOYSA-N 0.000 description 1
- LHRRVHAADIIGPG-UHFFFAOYSA-N n,n'-bis[4-(2-chlorophenyl)-1,3-thiazol-2-yl]oxamide Chemical compound ClC1=CC=CC=C1C1=CSC(NC(=O)C(=O)NC=2SC=C(N=2)C=2C(=CC=CC=2)Cl)=N1 LHRRVHAADIIGPG-UHFFFAOYSA-N 0.000 description 1
- CJCCLEGUDDPCDN-UHFFFAOYSA-N n,n'-bis[4-(2-methoxyphenyl)-1,3-thiazol-2-yl]oxamide Chemical compound COC1=CC=CC=C1C1=CSC(NC(=O)C(=O)NC=2SC=C(N=2)C=2C(=CC=CC=2)OC)=N1 CJCCLEGUDDPCDN-UHFFFAOYSA-N 0.000 description 1
- LBLQJNFOSNOINV-UHFFFAOYSA-N n,n'-bis[4-(2-methylphenyl)-1,3-thiazol-2-yl]oxamide Chemical compound CC1=CC=CC=C1C1=CSC(NC(=O)C(=O)NC=2SC=C(N=2)C=2C(=CC=CC=2)C)=N1 LBLQJNFOSNOINV-UHFFFAOYSA-N 0.000 description 1
- FSVMSLXDSRNWFU-UHFFFAOYSA-N n,n'-bis[4-(3-bromophenyl)-1,3-thiazol-2-yl]oxamide Chemical compound BrC1=CC=CC(C=2N=C(NC(=O)C(=O)NC=3SC=C(N=3)C=3C=C(Br)C=CC=3)SC=2)=C1 FSVMSLXDSRNWFU-UHFFFAOYSA-N 0.000 description 1
- OZAKSUJDZQJTQN-UHFFFAOYSA-N n,n'-bis[4-(3-chlorophenyl)-1,3-thiazol-2-yl]oxamide Chemical compound ClC1=CC=CC(C=2N=C(NC(=O)C(=O)NC=3SC=C(N=3)C=3C=C(Cl)C=CC=3)SC=2)=C1 OZAKSUJDZQJTQN-UHFFFAOYSA-N 0.000 description 1
- WRSWCCTVVZPRBB-UHFFFAOYSA-N n,n'-bis[4-(3-methoxyphenyl)-1,3-thiazol-2-yl]oxamide Chemical compound COC1=CC=CC(C=2N=C(NC(=O)C(=O)NC=3SC=C(N=3)C=3C=C(OC)C=CC=3)SC=2)=C1 WRSWCCTVVZPRBB-UHFFFAOYSA-N 0.000 description 1
- WAKJENHQQSQPJD-UHFFFAOYSA-N n,n'-bis[4-(3-methylphenyl)-1,3-thiazol-2-yl]oxamide Chemical compound CC1=CC=CC(C=2N=C(NC(=O)C(=O)NC=3SC=C(N=3)C=3C=C(C)C=CC=3)SC=2)=C1 WAKJENHQQSQPJD-UHFFFAOYSA-N 0.000 description 1
- JBCOMVIDMULCOG-UHFFFAOYSA-N n,n'-bis[4-(3-nitrophenyl)-1,3-thiazol-2-yl]oxamide Chemical compound [O-][N+](=O)C1=CC=CC(C=2N=C(NC(=O)C(=O)NC=3SC=C(N=3)C=3C=C(C=CC=3)[N+]([O-])=O)SC=2)=C1 JBCOMVIDMULCOG-UHFFFAOYSA-N 0.000 description 1
- MSYZHTZONRHIJI-UHFFFAOYSA-N n,n'-bis[4-(4-bromophenyl)-1,3-thiazol-2-yl]oxamide Chemical compound C1=CC(Br)=CC=C1C1=CSC(NC(=O)C(=O)NC=2SC=C(N=2)C=2C=CC(Br)=CC=2)=N1 MSYZHTZONRHIJI-UHFFFAOYSA-N 0.000 description 1
- LFHDBOSOFWWQMH-UHFFFAOYSA-N n,n'-bis[4-(4-chlorophenyl)-1,3-thiazol-2-yl]oxamide Chemical compound C1=CC(Cl)=CC=C1C1=CSC(NC(=O)C(=O)NC=2SC=C(N=2)C=2C=CC(Cl)=CC=2)=N1 LFHDBOSOFWWQMH-UHFFFAOYSA-N 0.000 description 1
- JQOYDGSTULSKJP-UHFFFAOYSA-N n,n'-bis[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]oxamide Chemical compound C1=CC(OC)=CC=C1C1=CSC(NC(=O)C(=O)NC=2SC=C(N=2)C=2C=CC(OC)=CC=2)=N1 JQOYDGSTULSKJP-UHFFFAOYSA-N 0.000 description 1
- ZNNJNFGSJIGHAJ-UHFFFAOYSA-N n,n'-bis[4-(4-methylphenyl)-1,3-thiazol-2-yl]oxamide Chemical compound C1=CC(C)=CC=C1C1=CSC(NC(=O)C(=O)NC=2SC=C(N=2)C=2C=CC(C)=CC=2)=N1 ZNNJNFGSJIGHAJ-UHFFFAOYSA-N 0.000 description 1
- YUYFLHFMOAMDJS-UHFFFAOYSA-N n,n'-bis[4-(4-nitrophenyl)-1,3-thiazol-2-yl]oxamide Chemical compound C1=CC([N+](=O)[O-])=CC=C1C1=CSC(NC(=O)C(=O)NC=2SC=C(N=2)C=2C=CC(=CC=2)[N+]([O-])=O)=N1 YUYFLHFMOAMDJS-UHFFFAOYSA-N 0.000 description 1
- LMOGNAGICZLCAM-UHFFFAOYSA-N n,n'-bis[4-(4-phenoxyphenyl)-1,3-thiazol-2-yl]oxamide Chemical compound N=1C(C=2C=CC(OC=3C=CC=CC=3)=CC=2)=CSC=1NC(=O)C(=O)NC(SC=1)=NC=1C(C=C1)=CC=C1OC1=CC=CC=C1 LMOGNAGICZLCAM-UHFFFAOYSA-N 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 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
- 230000000704 physical effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Thiazole And Isothizaole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
æ¬çºæã¯æ°èŠãªãªããµããèªå°äœããã®è£œæ³ãª
ãã³ã«ãããå«æããå»è¬çµæç©ã«é¢ããã
ããã«è©³ããèšãã°ãæ¬çºæã¯å
ç«èª¿ç¯äœçšã
æããåŸã€ãŠæ
¢æ§é¢ç¯ãªãŠãŒããã®ãããªå
ç«çŸ
æ£ã«å¯ŸããŠæ²»çå¹æãæãããŠã€ã«ã¹æ§çŸæ£ãŸã
ã¯æçå
ç«çæ³ã«ãæçšãªãªããµããèªå°äœãã
ã®è£œæ³ãªãã³ã«ãããå«æããå»è¬çµæç©ã«é¢ã
ãã
åŸæ¥ããªãŠãŒãããªã©ã®èªå·±å
ç«çŸæ£ã«å¯Ÿãã
ã¹ããã€ãç³»ããã³éã¹ããã€ãç³»ã®æççå€
ããèšåºçã«ãæ°å€ã䜿ãããŠãããããããªã
ãããããå€ãã®è¬å€ã¯ããã®è¬çå¹æãå¯äœ
çšãæ¯æ§ãªã©ã®ç¹ã§æªã å
åæºè¶³åºæ¥ããã®ã§ã¯
ãªããæ¬çºæè
ãã¯ãå
ç«å¿çã«é¢äžãã现èãž
ç¹ç°çå¹æãåãŒãã宿䞻ã®å
ç«å¿çãå€ããå
ãããæããååŠç©è³ªã«ã€ãéææ¢ç©¶ã®çµæãæ¬
çºæã«ãããåªããå
ç«èª¿ç¯äœçšãæãããã€ã
æ¯äœçšã®å°ãããå»è¬ãšããŠæ¥µããŠæãŸããæ°èŠ
ãªãªããµããååç©ãåŸãããšã«æåããã
æ¬çºæã«ããæäŸãããæ°èŠååç©ã¯ãäžè¬åŒ
ïŒåŒäžãR1ã¯æ°ŽçŽ ååãããã²ã³ååãäœçŽ
ã¢ã«ãã«åºãäœçŽã¢ã«ã³ãã·åºã眮æãŸãã¯é眮
æã®ããšããã·åºããããåºãåã¯ã·ã¢ãåºãè¡š
ãããR2ã¯æ°ŽçŽ ååãäœçŽã¢ã«ãã«åºåã¯äœçŽ
ã¢ã«ãã«ããªåºãè¡šããïŒ
ã§ç€ºããããããããã®ååç©ã¯ã¢ãã³åãšã€ã
ã³åã®äºå€ç°æ§äœã瀺ãããããã€ãŠãæ¬çºæã®
ååç©ã«ã¯ããããå
šãŠã®äºå€ç°æ§äœãå
å«ãã
ããã®ã§ããã
æ¬çºæã®ååç©ã®ä»£è¡šçãªãã®ãäŸç€ºãããšä»¥
äžã®åŠãã§ããã
ïŒNâ²âãã¹ïŒïŒâããšãã«ãã¢ãŸãŒã«âïŒ
âã€ã«ïŒãªããµããã
ïŒNâ²âãã¹ãïŒâïŒïœâã¯ããããšãã«ïŒã
ã¢ãŸãŒã«âïŒâã€ã«ããªããµããã
ïŒNâ²âãã¹ãïŒâïŒïœâã¯ããããšãã«ïŒã
ã¢ãŸãŒã«âïŒâã€ã«ããªããµããã
ïŒNâ²âãã¹ãïŒâïŒïœâã¯ããããšãã«ïŒã
ã¢ãŸãŒã«âïŒâã€ã«ããªããµããã
ïŒNâ²âãã¹ãïŒâïŒïœâããã¢ããšãã«ïŒã
ã¢ãŸãŒã«âïŒâã€ã«ããªããµããã
ïŒNâ²âãã¹ãïŒâïŒïœâããã¢ããšãã«ïŒã
ã¢ãŸãŒã«âïŒâã€ã«ããªããµããã
ïŒNâ²âãã¹ãïŒâïŒïœâããã¢ããšãã«ïŒã
ã¢ãŸãŒã«âïŒâã€ã«ããªããµããã
ïŒNâ²âãã¹ãïŒâïŒïœâã¡ãã«ããšãã«ïŒã
ã¢ãŸãŒã«âïŒâã€ã«ããªããµããã
ïŒNâ²âãã¹ãïŒâïŒïœâã¡ãã«ããšãã«ïŒã
ã¢ãŸãŒã«âïŒâã€ã«ããªããµããã
ïŒNâ²âãã¹ãïŒâïŒïœâã¡ãã«ããšãã«ïŒã
ã¢ãŸãŒã«âïŒâã€ã«ããªããµããã
ïŒNâ²âãã¹ãïŒâïŒïœâã¡ããã·ããšãã«ïŒ
ãã¢ãŸãŒã«âïŒâã€ã«ããªããµããã
ïŒNâ²âãã¹ãïŒâïŒïœâã¡ããã·ããšãã«ïŒ
ãã¢ãŸãŒã«âïŒâã€ã«ããªããµããã
ïŒNâ²âãã¹ãïŒâïŒïœâã¡ããã·ããšãã«ïŒ
ãã¢ãŸãŒã«âïŒâã€ã«ããªããµããã
ïŒNâ²âãã¹ãïŒâïŒïœâããšããã·ããšã
ã«ïŒãã¢ãŸãŒã«âïŒâã€ã«ããªããµããã
ïŒNâ²âãã¹ãïŒâïŒïœâïŒïŒâã¯ããããšã
ãã·ïŒããšãã«ïŒâïŒâã¡ãã«ãã¢ãŸãŒã«âïŒâ
ã€ã«ããªããµããã
ïŒNâ²âãã¹ãïŒâïŒïœâãããããšãã«ïŒã
ã¢ãŸãŒã«âïŒâã€ã«ããªããµããã
ïŒNâ²âãã¹ãïŒâïŒïœâãããããšãã«ïŒã
ã¢ãŸãŒã«âïŒâã€ã«ããªããµããã
ïŒNâ²âãã¹ãïŒâïŒïœâãããããšãã«ïŒã
ã¢ãŸãŒã«âïŒâã€ã«ããªããµããã
ïŒNâ²âãã¹ãïŒâïŒïœâã·ã¢ãããšãã«ïŒã
ã¢ãŸãŒã«âïŒâã€ã«ïŒãªããµããã
ïŒNâ²âãã¹ãïŒâïŒïœâã·ã¢ãããšãã«ïŒã
ã¢ãŸãŒã«âïŒâã€ã«ããªããµããã
ïŒNâ²âãã¹ãïŒâïŒïœâã·ã¢ãããšãã«ïŒã
ã¢ãŸãŒã«âïŒâã€ã«ïŒãªããµããã
ïŒNâ²âãã¹ïŒïŒâã¡ãã«ããªâïŒâããšã
ã«ãã¢ãŸãŒã«âïŒâã€ã«ïŒãªããµããã
äžè¬åŒïŒïŒïŒã§ç€ºãããæ¬çºæã®ååç©ã¯ãæ¬
çºæã®æ¹æ³ã«ããäžè¬åŒ
ïŒåŒäžãR1ããã³R2ã¯åè¿°ã®å®çŸ©ãæããïŒ
ã§ç€ºãããïŒâã¢ãããã¢ãŸãŒã«é¡ãšãªãã¶ãªã«
ã¯ããªããšãåå¿ãããããšã«ãã補é ããããš
ãã§ããã
ãã®åå¿ã¯äžè¬åŒïŒïŒã§ç€ºãããåºçºç©è³ª
ïŒããã¯é©åœãªé
žä»å å¡©ã®åœ¢æ
ã§çšããããšãã§
ããïŒã溶åªã«æº¶è§£ãããããŸãã¯æžæ¿ãããŠã
ããããã«ãªãã¶ãªã«ã¯ããªãã滎äžãããªã©ã®
æ¹æ³ã§æ·»å ããããšã«ããè¡ãããããšãã§ã
ããåå¿æåã®äœ¿çšéã¯éåžžãååŠéè«çã«èšç®
ãããéã§å
åã§ãããå³ã¡åè¿°ã®ïŒâã¢ããã
ã¢ãŸãŒã«é¡ããªãã¶ãªã«ã¯ããªãã®ïŒåã¢ã«éã§
çšããã®ãé©åœã§ããããã®åå¿ã®éã«çšãã溶
åªãšããŠã¯ãäŸãã°ããã³ãŒã³ããã«ãšã³ããã·
ã¬ã³ãã¢ã»ãã³ããšãã«ã¡ãã«ã±ãã³ããžãªããµ
ã³ãïŒïŒïŒâãžã¡ããã·ãšã¿ã³ãããã©ãããã
ã©ã³ãïŒïŒ®âãžã¡ãã«ãã«ã ã¢ãããªã©ãé©åœ
ã§ãããåå¿é²è¡ã®éã«çæããŠããå¡©åæ°ŽçŽ ã
é€å»ããç®çã§ãããªãžã³ãããªãšãã«ã¢ãã³ã®
ãããªææ©å¡©åºãŸãã¯çé
žãããªãŠã ãçé
žã«ãª
ãŠã ãçé
žæ°ŽçŽ ãããªãŠã ã®ãããªç¡æ©å¡©åºãçš
ããŠãããããã®åå¿ã¯é垞宀枩以äžã®æž©åºŠã§ã
é²è¡ããããåå¿ãå éããããã«æº¶åªã®æ²žç¹ãŸ
ã§ã®æž©åºŠã«å ç±ããããšãå¯èœã§ããã
äžè¬åŒïŒïŒã§ç€ºãããåºçºç©è³ªã§ããïŒâã¢
ããâïŒâããšãã«ãã¢ãŸãŒã«é¡ã®æ®ãã©ã®åå
ç©ã¯å
¬ç¥ååç©ã§ãããäŸãã°æç®ãJacques
V.MetzgerïŒed.âThe Chemistry of
Heterocyclic CompoundsïŒâVol34ïŒThiazole
And Its DerivativesïŒPart twoïŒ1979ïŒãã«è©³è¿°
ãããŠããã
æ¬çºæã®åèšäžè¬åŒïŒïŒã§è¡šããããååç©
ã¯ãè¬çç掻æ§ãæããŠãããç¹çãã¹ãããšã¯
ãããã®ååç©ãåªããå
ç«èª¿ç¯äœçšãæããã
ãšã§ãããããããã®æ¬çºæã®ååç©ã¯æ¯æ§ã匱
ãã®ã§å»è¬ãšããŠæ¥µããŠæçšãªãã®ã§ããã
æ¬çºæã®ååç©ã®è¬çç掻æ§ã¯æ¬¡ã®åŠãããŠç¢º
èªãããã
åç©ãçšããŠå
ç«èª¿ç¯äœçšãè©Šéšããçºã«å€æ°
ã®å®éšç³»ãåžžçšãããŠãããããã®äžã§æã代衚
çãªè©Šéšã§ããé
延åéæåå¿ã®å¢åŒ·è©Šéšã®çµæ
ã以äžã«ç€ºãã
å¡©åãã¯ãªã«ïŒïŒâã¯ããâïŒïŒïŒïŒïŒâããª
ããããã³ãŒã³ïŒãç®èã«å¡åžããããšã«ããã
ãŠã¹ã«èªå°ãããé
延åéæçã¯å
žåçãªçŽ°èæ§
å
ç«çŸè±¡ãšããŠç¥ãããŠãããå®éšç³»ãšããŠã¯äž
ççã«æ±çšãããŠããç³»ã®äžã€ã§ãã
ïŒAsherson.G.L.and PtakïŒW.ïŒContact and
delayed hypersensitivity in the mouse I.
Active sensitization and passive transfer.
ImmunologyïŒ15ïŒ405ã416ïŒ1968ïŒïŒã
ãã®å®éšç³»ãé
延åéæçå¢åŒ·è©Šéšã«çšããã
è©ŠéšäŸïŒ é
延åéæåå¿ã®å¢åŒ·è©Šéš
è©Šéšæ¹æ³ïŒICRç³»éæ§ããŠã¹äœé30ïœååŸã®ã
ã®ãïŒçŸ€ïŒå¹ãšããŠäœ¿çšããã
æäœã¯ããªãªãŒãæ²¹ãšã¢ã»ãã³ãïŒïŒïŒã«æº¶è§£
ãã液ã«ïŒïŒ
ãšãªãããã«å¡©åãã¯ãªã«ã溶解ã
ããã®ããåæ¯ããããŠã¹ã®è
¹éšã«å¡åžããŠè¡ãª
ã€ãã
æäœãšåæã«æ¬çºæã®ååç©ã0.2ïŒ
ã«ã«ãã
ã·ã¡ãã«ã»ã«ããŒã¹ççé£å¡©æ¶²ã«æº¶è§£ãŸãã¯æžæ¿
ãããã®ããããŠã¹äœéïŒKgããã50mgã®å²åã§
çµå£æäžããã察ç
§çŸ€ã¯0.2ïŒ
ã«ã«ããã·ã¡ãã«
ã»ã«ããŒã¹ççé£å¡©æ¶²ãåæ§ã«æäžããã
é
延åéæçã®æ¹èµ·ïŒãã€ã¬ã³ãžïŒã¯æäœãã
ïŒæ¥åŸã«ãïŒïŒ
ã®å¡©åãã¯ãªã«ã溶解ãããªãªãŒ
ãæ²¹ãæ
ã¿èŸŒãŸããããšã«ããéåã«å·»ãããã®
ã§ãããŠã¹ã®è³ãã¯ããã§å¡åžããŠè¡ãªã€ããã
ã€ã¬ã³ãžåãšãã€ã¬ã³ãžã®24æéåŸã®ããŠã¹ã®è³
ã®åãã枬å®ãåãã®å¢å çïŒïŒå¹ã®äž¡è³ã®å¹³å
å€ïŒãè¡šïŒã«ç€ºããã
ãªãæ¯èŒãšããŠã¬ãããŸãŒã«å¡©é
žå¡©ãçšããŠå
æ§ã«è©Šéšããçµæã瀺ããã
è©Šéšçµæã«ã€ããŠïŒŠã»ïœæ€å®ãè¡ãªãã察ç
§çŸ€
ã«å¯ŸããŠå±éºçïŒ0.05ã§ææãªãã®ã«ã¯ãå°ã
ïŒ0.01ã§ææãªãã®ã«ã¯ããå°ãä»ããã
çµæïŒæ¬çºæã®ååç©ãæäœãšåæã«æäžãã
ãšããã€ã¬ã³ãžã«ããæ¹èµ·ãããé
延åéæåå¿
ã¯å¢åŒ·ããããæ¬çºæã®ååç©ã¯æ¯èŒã«çšããã¬
ãããŸãŒã«ãšåçãªãããã以äžã®æŽ»æ§ãèªãã
ããã
ããªãã¡ãæ¬çºæã®ååç©ã¯ããŠã¹ã®çŽ°èæ§å
ç«å¿çã調ç¯ããäœçšïŒå
ç«èª¿ç¯èœïŒãæããŠã
ããšèããããã
The present invention relates to novel oxamide derivatives, processes for their preparation, and pharmaceutical compositions containing them. More specifically, the present invention provides oxamide derivatives which have an immunomodulatory effect and therefore have a therapeutic effect on immune diseases such as rheumatoid arthritis, and which are also useful for viral diseases or anti-cancer immunotherapy. The present invention relates to a manufacturing method and a pharmaceutical composition containing the same. Traditionally, for autoimmune diseases such as rheumatoid arthritis,
Numerous steroidal and non-steroidal anti-inflammatory drugs are also used clinically. However, many of these drugs are still not fully satisfactory in terms of their pharmacological effects, side effects, toxicity, etc. The present inventors have conducted extensive research into chemical substances that exert specific effects on cells involved in immune responses and have the ability to change the immune response of the host. and,
We have succeeded in obtaining a new oxamide compound that has low toxic effects and is highly desirable as a pharmaceutical. The novel compounds provided by the present invention have the general formula (In the formula, R 1 represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a substituted or unsubstituted phenoxy group, a nitro group, or a cyano group, and R 2 represents a hydrogen atom, a lower alkyl group, or a lower alkylthio group. These compounds exhibit amine-type and imine-type tautomers. Therefore, the compounds of the present invention include all these tautomers. Representative examples of the compounds of the present invention are as follows. N,N'-bis(4-phenylthiazole-2
-yl)oxamide. N,N'-bis[4-(p-chlorophenyl)thiazol-2-yl]oxamide. N,N'-bis[4-(m-chlorophenyl)thiazol-2-yl]oxamide. N,N'-bis[4-(o-chlorophenyl)thiazol-2-yl]oxamide. N,N'-bis[4-(p-bromophenyl)thiazol-2-yl]oxamide. N,N'-bis[4-(m-bromophenyl)thiazol-2-yl]oxamide. N,N'-bis[4-(o-bromophenyl)thiazol-2-yl]oxamide. N,N'-bis[4-(p-methylphenyl)thiazol-2-yl]oxamide. N,N'-bis[4-(m-methylphenyl)thiazol-2-yl]oxamide. N,N'-bis[4-(o-methylphenyl)thiazol-2-yl]oxamide. N,N'-bis[4-(p-methoxyphenyl)
Thiazol-2-yl]oxamide. N,N'-bis[4-(m-methoxyphenyl)
Thiazol-2-yl]oxamide. N,N'-bis[4-(o-methoxyphenyl)
Thiazol-2-yl]oxamide. N,N'-bis[4-(p-phenoxyphenyl)thiazol-2-yl]oxamide. N,N'-bis[4-(p-(4-chlorophenoxy)phenyl)-5-methylthiazole-2-
] Oxamide. N,N'-bis[4-(p-nitrophenyl)thiazol-2-yl]oxamide. N,N'-bis[4-(m-nitrophenyl)thiazol-2-yl]oxamide. N,N'-bis[4-(o-nitrophenyl)thiazol-2-yl]oxamide. N,N'-bis[4-(p-cyanophenyl)thiazol-2-yl)oxamide. N,N'-bis[4-(m-cyanophenyl)thiazol-2-yl]oxamide. N,N'-bis[4-(o-cyanophenyl)thiazol-2-yl)oxamide. N,N'-bis(5-methylthio-4-phenylthiazol-2-yl)oxamide. The compound of the present invention represented by the general formula (1) can be obtained by the method of the present invention by the general formula (In the formula, R 1 and R 2 have the above definitions.) It can be produced by reacting the 2-aminothiazole represented by the following with oxalyl chloride. This reaction is carried out by dissolving or suspending the starting material represented by the general formula () in a solvent or suspending it in a solvent, and adding oxalyl chloride dropwise to this solution. This can be done by adding by the following methods. The amounts of reaction components used are usually stoichiometrically calculated amounts. That is, it is appropriate to use the aforementioned 2-aminothiazoles in twice the molar amount of oxalyl chloride. Suitable solvents used in this reaction include, for example, benzene, toluene, xylene, acetone, ethylmethylketone, dioxane, 1,2-dimethoxyethane, tetrahydrofuran, and N,N-dimethylformamide. In order to remove hydrogen chloride generated during the reaction, an organic base such as pyridine or triethylamine or an inorganic base such as sodium carbonate, potassium carbonate, or sodium bicarbonate may be used. Although this reaction usually proceeds at temperatures below room temperature, it is also possible to heat the solvent to a temperature up to the boiling point of the solvent in order to accelerate the reaction. Most of the 2-amino-4-phenylthiazoles which are the starting materials represented by the general formula () are known compounds, for example, in the literature [Jacques
V. Metzger, ed. âThe Chemistry of
Heterocyclic Compounds,âVol34: Thiazole
And Its Derivatives, Part two (1979)]. The compound represented by the general formula () of the present invention has pharmacological activity. What is noteworthy is that these compounds have excellent immunomodulatory effects, and the compounds of the present invention have low toxicity, making them extremely useful as medicines. The pharmacological activity of the compounds of the present invention was confirmed as follows. Many experimental systems are routinely used to test immunomodulatory effects using animals, but the results of the most representative test, the delayed-type hypersensitivity reaction enhancement test, are shown below. Delayed hypersensitivity induced in mice by applying picryl chloride (2-chloro-1,3,5-trinitrobenzene) to the skin is known as a typical cell-mediated immune phenomenon, and as an experimental system. It is one of the systems widely used worldwide (Asherson. GLand Ptak, W.: Contact and
delayed hypersensitivity in the mouse I.
Active sensitization and passive transfer.
Immunology, 15 , 405-416 (1968)). This experimental system was used in a delayed hypersensitivity enhancement test. Test Example 1 Delayed hypersensitivity reaction enhancement test Test method: ICR male mice weighing approximately 30 g were used in groups of 8 mice. Sensitization was performed by dissolving 3% picryl chloride in a 4:1 solution of olive oil and acetone and applying it to the shaved abdomen of the mouse. Simultaneously with sensitization, the compound of the present invention dissolved or suspended in 0.2% carboxymethylcellulose physiological saline was orally administered at a rate of 50 mg per kg of mouse body weight. For the control group, 0.2% carboxymethylcellulose physiological saline was administered in the same manner. To induce delayed-type hypersensitivity (challenge), 7 days after sensitization, a felt wrapped in forceps soaked in olive oil containing 1% picry chloride was applied to the ears of the mouse. I did it. The thickness of the mouse ears was measured before the challenge and 24 hours after the challenge, and the rate of increase in thickness (average value of both ears of 8 mice) is shown in Table 1. For comparison, the results of a similar test using levamisole hydrochloride are also shown. An F-t test was performed on the test results, and those with a significant risk rate P < 0.05 compared to the control group were marked with a ã.
Significant values at P<0.01 are marked with â. Results: When the compound of the present invention was administered simultaneously with sensitization, the delayed hypersensitivity response induced by challenge was enhanced. The compound of the present invention was found to have an activity equal to or greater than that of levamisole used for comparison. That is, the compound of the present invention is considered to have an effect of regulating cellular immune response in mice (immunomodulating ability).
ãè¡šããtableã
ãè¡šã
次ã«ãçµæ žèã¢ãžãŠãã³ãã泚å°ããããšã«ã
ãçºçããã©ããã®ã¢ãžãŠãã³ãé¢ç¯çã¯ããæ
¢
æ§é¢ç¯ãªãŠããã®å®éšã¢ãã«ãšããŠé »çšãããŠã
ãã
æ¬çã®çºçæ©æ§ã¯ååæããã«ãããŠããªã
ãã现èæ§å
ç«ãéèŠãªåœ¹å²ãæŒããŠããããšã
ç¥ãããŠããããã®å
¬ç¥ã®ã¢ãžãŠãã³ãé¢ç¯çè©Š
éšãçšããŠãæ¬çºæã®ååç©ã®å
ç«èª¿ç¯äœçšã調
ã¹ãã
è©ŠéšäŸïŒ ã¢ãžãŠãã³ãé¢ç¯çè©ŠéšïŒè¡šïŒïŒ
è©Šéšæ¹æ³ïŒSDç³»éæ§ã©ããïŒé±ä»€ãçšããã
åçµæ žèïŒMycobacterium tuberculosisïŒä¹Ÿç¥
æ»èäœ0.4mgãæµåãã©ãã€ã³0.1mläžã«æžæ¿ãã
ãŠãå³åŸè¢è¶³è¹ ç®å
ã«æ³šå
¥ãããæ¬çºæã®ååç©
ã¯ã¢ãžãŠãã³ã泚å
¥ååŸèšïŒåç®äžæäžãããå
åç©ã¯0.2ïŒ
ã«ã«ããã·ã¡ãã«ã»ã«ããŒã¹ççé£
塩液ã«æº¶è§£ãŸãã¯æžæ¿ããŠãäœéïŒKgãããïŒmg
ã®å²åã§æäžãããã¢ãžãŠãã³ã泚å
¥æ¥ããè©Šéš
çµäºãŸã§å·ŠåŸè¢ã®æµ®è
«ã®å®¹ç©æž¬å®ãè¡ãªãè
«è¹ç
ãç®å®ãããå°ãæ¯èŒãšããŠã¬ãããŸãŒã«å¡©é
žå¡©
ãçšããŠè©Šéšãè¡ã€ããè©Šéšçµæã«ã€ããŠïŒŠã»ïœ
æ€å®ãè¡ãªã0.2ïŒ
ã«ã«ããã·ã¡ãã«ã»ã«ããŒã¹
ççé£å¡©æ¶²ã®ã¿ãæäžãã察ç
§çŸ€ã«å¯ŸããŠå±éºç
ïŒ0.05ã§ææã®ãã®ã«ã¯ãå°ãïŒ0.01ã§ææ
ã®ãã®ã«ã¯ããå°ãä»ããã
çµæïŒæ¬çºæã®ååç©ã«ããã¢ãžãŠãã³ãé¢ç¯
çã®ïŒæ¬¡ççã¯åŒ·ãæå¶ããããã®äœçšã¯å¯Ÿç
§çŸ€
ã«å¯Ÿãçµ±èšåŠçã«ææã§ãã€ãããŸãæ¬çºæã®å
åç©ã¯æ¯èŒã«çšããã¬ãããŸãŒã«ãšåçä¹è³ãã
以äžã®æŽ»æ§ãèªãããããããªãã¡ãæ¬çºæã®å
åç©ã¯å
ç«èª¿ç¯äœçšããŸããæé¢ç¯çäœçšãæã
ãŠãããšèããããã[Table] Next, adjuvant arthritis in rats, which is caused by injection of Mycobacterium tuberculosis adjuvant, is frequently used as an experimental model for human rheumatoid arthritis. Although the onset mechanism of this disease is not fully understood, it is known that cell-mediated immunity plays an important role. Using this known adjuvant arthritis test, the immunomodulatory effects of the compounds of the invention were investigated. Test Example 2 Adjuvant Arthritis Test (Table 2) Test method: Using 8-week-old SD male rats, 0.4 mg of dried dead Mycobacterium tuberculosis cells were suspended in 0.1 ml of liquid paraffin, and the right hind limb was suspended. It was injected into the footpad skin. The compound of the present invention was administered subcutaneously a total of 9 times before and after injection of the adjuvant. The compound was dissolved or suspended in 0.2% carboxymethyl cellulose saline at a dose of 5 mg/kg body weight.
was administered at the rate of The volume of edema in the left hind paw was measured from the day of adjuvant injection until the end of the test, and the swelling rate was calculated. For comparison, a test was conducted using levamisole hydrochloride. Regarding test results F.t.
A test was performed, and those with a significant risk ratio of P<0.05 were marked with a â mark, and those with a significant P<0.01 were marked with a ââ mark with respect to the control group to which only 0.2% carboxymethylcellulose physiological saline was administered. Results: The compound of the present invention strongly suppressed secondary inflammation in adjuvant arthritis, and the effect was statistically significant compared to the control group. Furthermore, the compound of the present invention was found to have an activity equivalent to or greater than that of levamisole used for comparison. That is, the compounds of the present invention are considered to have immunomodulatory and anti-arthritic effects.
ãè¡šããtableã
ãè¡šã
æ¬çºæã®ååç©ã¯è©ŠéšäŸïŒãšè©ŠéšäŸïŒã«ç€ºãã
ããã«åªããå
ç«èª¿ç¯äœçšãæããŠãããåŸã€ãŠ
å
ç«æ©èœã®äœäžãŸãã¯ç°åžžã䌎ãããšãç¥ãããŠ
ããçŸæ£ãäŸãã°æ
¢æ§é¢ç¯ãªãŠãããªã©ã®èªå·±å
ç«çŸæ£ã®æ²»çã«æå¹ã§ããã
次ã«æ¬çºæã®å»è¬ã®æå¹æåã®æ¯æ§è©Šéšã«ã€ã
ãŠãè©ŠéšäŸïŒã«ããã瀺ãã
è©ŠéšäŸïŒ çµå£æäžã«ããæ¥æ§æ¯æ§è©Šéš
è©Šéšæ¹æ³ïŒddYç³»éæ§ããŠã¹ãïŒçŸ€ïŒå¹ãçšã
ççé£å¡©æ°Žã«æº¶è§£ãŸãã¯æžæ¿ããè¬ç©ãçµå£æäž
ãããæäžåŸïŒæ¥éçµéã芳å¯ããæšå®LD50å€
ãæ±ããã
çµæïŒæ¬çºæã®å»è¬ã®æå¹æåã®æšå®LD50å€
ã¯1000mgïŒKg以äžã§ãã€ãããã®å€ã¯ã¬ãããŸãŒ
ã«ã»å¡©é
žå¡©ã®æšå®LD50200ã300mgïŒKgã«æ¯ã¹ã
ãšã¯ããã«å€§ãããæ¬çºæã®ååç©ã®æ¯æ§ã¯åŒ±ã
ãšèããããã
æ¬çºæã®ååç©ã¯ããããå»è¬ãšããŠå©çšãã
å Žåã¯éé¢å¡©åºã®ãŸãŸè£œå€åæãšããŠäœ¿çšããã
ãšãå¯èœã§ããããå®å®æ§ã補å€åã®å®¹æãã®ç¹
ãªã©ãèæ
®ããŠãããã«ãäŸãã°æ³šå°å€ã®ããã«
氎溶æ§ã§ããããšãèŠæ±ãããå Žåã«ã¯ãç¹ã«ã
äŸãã°å¡©é
žå¡©ãã¯ãšã³é
žå¡©ããªã³é
žå¡©ãªã©ãå»è¬
ãšããŠèš±å®¹ãããçš®é¡ã®å¡©ãšããŠãããã補å€å
æã«çšããããšã奜ãŸããã
æ¬çºæã®å»è¬ã¯éåžžã®å
ç«èª¿ç¯å€ãŸãã¯å¶çå€
ãšåæ§ã®å€åããã³æäžæ¹æ³ã«ãããããçšãã
ããšãã§ãããäŸãã°çµå£æäžå€ãšããŠã¯ãã«ã
ã»ã«å€ãé¡ç²å€ãäžžå€ã现ç²å€ãé å€ãã·ããã
å€ãªã©ãšããŠçšããããšãã§ããããŸãçŽè
žå
æ
äžå€ãšããŠã¯åå€ãé©åœã§ããã泚å°å€ãšããŠã¯
ç®äžãçèå
ããŸãã¯éèå
æäžå€ãªã©ãçšãã
ããšãã§ããã
æ¬çºæã®æ°èŠååç©ã®å
ç«èª¿ç¯äœçšãå©çšãã
éã®é©çšçŸæ£ãšããŠã¯ãå
ç«æ©èœã®ç°åžžã䌎ãã
ãšãç¥ãããŠããçŸæ£ãäŸãã°æ
¢æ§é¢ç¯ãªãŠã
ããå€çºæ§ççãªã©ã®èªå·±å
ç«çŸæ£ãåçš®ã®ææ
çãåçš®ã®çãªã©ããããæ¬çºæã®ååç©ãçšã
ãããšã«ãããããã®çŸæ£ã®æ£è
ã®å
ç«æ©èœã®æ£
åžžåãæåŸ
ããããšãã§ããã
æ¬çºæã®æ°èŠååç©ãå»è¬ãšããŠçšããéã®æ
äžæ³ããã³å€åã¯ãã®çŸæ£ã®çš®é¡ãæ£è
ã®ç¶æ
ãª
ã©ã«å¿ããŠé©å®éžæããããšãæãŸãããæäžé
ã¯çµå£æäžã®å Žåã«ã¯äœéïŒKgãããã®ïŒæ¥éã¯
0.5mgãªãã100mgã奜ãŸããã¯ïŒmgãªãã30mgã
é©åœã§ãããçŽè
žå
æäžã®å Žåã«ã¯ïŒmgãªãã
100mgãéèå
æäžã®å Žåã«ã¯ïŒmgãªãã10mgã
ç®äžæäžãŸãã¯çèå
æäžã®å Žåã«ã¯ïŒmgãªãã
30mgãããããé©åœã§ãããããããã®æäžéã«
ã€ããŠã¯ãã®çŸæ£ã®çš®é¡ãæ£è
ã®ç¶æ
ãªã©ã«å¿ã
ãŠããã«é©åœéãéžå®ããããšãæãŸããããŸã
ãã®çŸæ£ã®çš®é¡ãæ£è
ã®ç¶æ
ã«ãã€ãŠã¯å¿
èŠã«å¿
ããŠä»ã®è¬å€ã䜵çšããããšã«ãããæ¬çºæã®æ
å¹æåã®æ²»çå¹æãå¢å€§ãããããšãå¯èœã§ã
ããäŸããããã°çã®ååŠçæ³å€ãäŸãã°ã¢ã«ã
ã«åå€ã代è¬æ®æå€ãªã©ãæ£è
ã®å
ç«èœãäœäžã
ããå¯äœçšãæã€ãŠããã®ã§ããã®ãããªè¬å€ã
æäžããå Žåã«æ¬çºæã®æå¹æåã䜵çšããããš
ã«ããããããè¬å€ã®å¯äœçšã®çºçŸãé²æ¢ããŠçž
ä¹çã«æ²»çå¹æãé«ããããšãæåŸ
ã§ããã
以äžã«æ¬çºæã®å®æœäŸãèšèŒããã
å®æœäŸ ïŒ
ïŒâã¢ããâïŒâããšãã«ãã¢ãŸãŒã«17.6ïœã
ãã³ããªãšãã«ã¢ãã³10.0ïœãããã©ããããã©
ã³80mläžã«æº¶è§£ããïŒâã«å·åŽããããã®æº¶æ¶²ã«
ãªãã¶ãªã«ã¯ããªã6.4ïœãå«æããããã©ãã
ããã©ã³æº¶æ¶²ã滎äžããã滎äžçµäºåŸã宀枩ã§ïŒ
æéæ¹æããããšãæåºããçµæ¶ãå¥ãããã
ã«æ°Žãã¡ã¿ããŒã«ã§é 次æŽæµãããåŸãããçµæ¶
ãïŒïŒ®âãžã¡ãã«ãã«ã ã¢ããããåçµæ¶ãã
ïŒNâ²âãã¹ïŒïŒâããšãã«ãã¢ãŸãŒã«âïŒâ
ã€ã«ïŒãªããµãã7.5ïœãåŸãã
èç¹ïŒ292ã293â
å
çŽ åæå€ïŒC20H14N4O2S2ãšããŠ
   
çè«å€ïŒ
59.10 3.47 13.78 15.78
å®éšå€ïŒ
58.97 3.43 13.81 15.51
IRïŒÏ
KBr naxïŒcm-1ïŒïŒ3440ïŒ1690ïŒ1555ïŒ1480ïŒ
1435ïŒ1330ïŒ1280ïŒ1080ïŒ1070ïŒ1035ïŒ
870ïŒ860ïŒ745ïŒ705
äžèšå®æœäŸïŒã®æäœã«æºããŠãçžåœããåæå
åç©ããäžèšå®æœäŸã®ååç©ã補é ãããããã
ã®ç©æ§ã第ïŒè¡šã«ç€ºãã[Table] As shown in Test Examples 1 and 2, the compounds of the present invention have excellent immunomodulatory effects, and therefore are effective against diseases known to be accompanied by decreased or abnormal immune function, such as It is effective in treating autoimmune diseases such as rheumatoid arthritis. Next, Test Example 3 shows a toxicity test for the active ingredient of the medicine of the present invention. Test Example 3 Acute toxicity test by oral administration Test method: A drug dissolved or suspended in physiological saline was orally administered to ddY male mice (5 mice per group). The progress was observed for 7 days after administration, and the estimated LD 50 value was determined. Results: The estimated LD 50 value of the active ingredient of the medicament of the present invention was 1000 mg/Kg or more. This value is much larger than the estimated LD 50 of 200 to 300 mg/Kg for levamisole hydrochloride, and the toxicity of the compound of the present invention is considered to be weak. When using the compound of the present invention as a medicine, it is possible to use it as a free base as a raw material for pharmaceutical preparations, but in consideration of stability and ease of formulation, it can also be used as a pharmaceutical raw material, for example, by injection. In particular, when it is required to be water-soluble such as a drug,
It is preferable to use this in the pharmaceutical raw material as a pharmaceutically acceptable salt such as, for example, hydrochloride, citrate, or phosphate. The medicament of the present invention can be used in the same dosage form and administration method as conventional immunomodulators or anticancer agents. For example, as oral preparations, capsules, granules, pills, fine granules, tablets, syrups, etc. can be used. Suppositories are suitable for intrarectal administration, and subcutaneous, intramuscular, or intravenous injections can be used for injections. Diseases to which the immunomodulatory effects of the novel compounds of the present invention can be applied include diseases known to be accompanied by abnormalities in immune function, such as autoimmune diseases such as rheumatoid arthritis and polymyositis, and various infections. and various cancers, and the use of the compounds of the present invention can be expected to normalize the immune function of patients suffering from these diseases. When using the novel compound of the present invention as a medicine, it is desirable that the administration method and dosage form be appropriately selected depending on the type of disease, patient's condition, etc. In the case of oral administration, the daily dose per 1 kg of body weight is
0.5 mg to 100 mg, preferably 1 mg to 30 mg, and 1 mg to 30 mg for rectal administration.
100mg, 1mg to 10mg for intravenous administration,
1mg or more for subcutaneous or intramuscular administration
Although 30 mg is appropriate for each dose, it is desirable to select a more appropriate dose depending on the type of disease, patient condition, etc. Furthermore, depending on the type of disease and the condition of the patient, the therapeutic effect of the active ingredient of the present invention can be increased by using other drugs in combination as necessary. For example, cancer chemotherapy drugs such as alkylating agents and antimetabolites have side effects that reduce the patient's immune function, so when administering such drugs, the active ingredient of the present invention may be used in combination. By doing so, it is expected that the side effects of these drugs will be prevented and the therapeutic effects will be synergistically enhanced. Examples of the present invention will be described below. Example 1 17.6 g of 2-amino-4-phenylthiazole and 10.0 g of triethylamine are dissolved in 80 ml of tetrahydrofuran and cooled to 5°C. A tetrahydrofuran solution containing 6.4 g of oxalyl chloride was added dropwise to this solution. After dropping, at room temperature
After stirring for an hour, the precipitated crystals were separated and washed successively with water and methanol. The obtained crystals were recrystallized from N,N-dimethylformamide,
N,N'-bis(4-phenylthiazole-2-
7.5 g of oxamide was obtained. Melting point: 292-293â Elemental analysis value: C 20 H 14 N 4 O 2 S 2 Theoretical value % 59.10 3.47 13.78 15.78 Experimental value % 58.97 3.43 13.81 15.51 IR (Ï
KBr nax , cm -1 ): 3440, 1690, 1555, 1480,
1435, 1330, 1280, 1080, 1070, 1035,
870, 860, 745, 705 According to the procedure of Example 1 above, the compounds of the following examples were produced from the corresponding raw material compounds. Their physical properties are shown in Table 1.
ãè¡šããtableã
Claims (1)
ã¢ã«ãã«åºãäœçŽã¢ã«ã³ãã·åºã眮æãŸãã¯é眮
æã®ããšããã·åºããããåºåã¯ã·ã¢ãåºãè¡šã
ããR2ã¯æ°ŽçŽ ååãäœçŽã¢ã«ãã«åºãåã¯äœçŽ
ã¢ã«ãã«ããªåºãè¡šããïŒ ã§ç€ºããããªããµããèªå°äœã ïŒ äžè¬åŒïŒïŒïŒäžã®R1ãæ°ŽçŽ ååãå¡©çŽ ååã
ã¡ãã«åºãã¡ããã·åºãããšããã·åºããããåº
åã¯ã·ã¢ãåºã§ãR2ãæ°ŽçŽ ååãã¡ãã«åºåã¯
ã¡ãã«ããªåºã§ããç¹èš±è«æ±ã®ç¯å²ç¬¬ïŒé èšèŒã®
ååç©ã ïŒ äžè¬åŒ ïŒåŒäžãR1ã¯æ°ŽçŽ ååãããã²ã³ååãäœçŽ
ã¢ã«ãã«åºãäœçŽã¢ã«ã³ãã·åºã眮æãŸãã¯é眮
æã®ããšããã·åºããããåºåã¯ã·ã¢ãåºãè¡šã
ããR2ã¯æ°ŽçŽ ååãäœçŽã¢ã«ãã«åºãåã¯äœçŽ
ã¢ã«ãã«ããªåºãè¡šããïŒ ã§ç€ºããããªããµããèªå°äœã®è£œé æ³ã§ãã€ãŠã
äžè¬åŒ ïŒåŒäžãR1ããã³R2ã¯åè¿°ã®å®çŸ©ãæããïŒ ã§ç€ºããããïŒâã¢ããâïŒâããšãã«ãã¢ãŸãŒ
ã«é¡ãšãªãã¶ãªã«ã¯ããªããšãåå¿ãããããšã
ç¹åŸŽãšããåèšäžè¬åŒïŒïŒïŒã§è¡šãããããªããµ
ããèªå°äœã®è£œé æ³ã ïŒ äžè¬åŒ ïŒåŒäžãR1ã¯æ°ŽçŽ ååãããã²ã³ååãäœçŽ
ã¢ã«ãã«åºãäœçŽã¢ã«ã³ãã·åºã眮æãŸãã¯é眮
æã®ããšããã·åºããããåºåã¯ã·ã¢ãåºãè¡šã
ããR2ã¯æ°ŽçŽ ååãäœçŽã¢ã«ãã«åºåã¯äœçŽã¢
ã«ãã«ããªåºãè¡šããïŒ ã§ç€ºããããªããµããèªå°äœãæå¹æåãšããŠå«
æããããšãç¹åŸŽãšããå ç«èª¿ç¯çšå»è¬çµæç©ã ïŒ å»è¬ãšããŠèš±å®¹ãåŸãåžéå€ãŸãã¯æ äœãšçµ
åãããç¹èš±è«æ±ã®ç¯å²ç¬¬ïŒé èšèŒã®å ç«èª¿ç¯çš
å»è¬çµæç©ã ïŒ æ ¢æ§é¢ç¯ãªãŠãŒããã®æ²»çã«å©çšãããç¹èš±
è«æ±ã®ç¯å²ç¬¬ïŒé èšèŒã®å ç«èª¿ç¯çšå»è¬çµæç©ã ïŒ ã¬ã³ã®å ç«çæ³ã«å©çšãããç¹èš±è«æ±ã®ç¯å²
第ïŒé èšèŒã®å ç«èª¿ç¯çšå»è¬çµæç©ã[Claims] 1. General formula (In the formula, R 1 represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a substituted or unsubstituted phenoxy group, a nitro group, or a cyano group, and R 2 represents a hydrogen atom, a lower alkyl group, or a lower alkylthio group. An oxamide derivative represented by (representing a group). 2 R 1 in general formula (1) is a hydrogen atom, a chlorine atom,
2. The compound according to claim 1, wherein R2 is a hydrogen atom, a methyl group, or a methylthio group, and is a methyl group, a methoxy group, a phenoxy group, a nitro group, or a cyano group. 3 General formula (In the formula, R 1 represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a substituted or unsubstituted phenoxy group, a nitro group, or a cyano group, and R 2 represents a hydrogen atom, a lower alkyl group, or a lower alkylthio group. A method for producing an oxamide derivative represented by (representing a group),
general formula (wherein R 1 and R 2 have the above definitions) The above general formula (1) is characterized in that 2-amino-4-phenylthiazoles and oxalyl chloride are reacted. A method for producing the represented oxamide derivative. 4 General formula (In the formula, R 1 represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a substituted or unsubstituted phenoxy group, a nitro group, or a cyano group, and R 2 represents a hydrogen atom, a lower alkyl group, or a lower alkylthio group. An immunomodulatory pharmaceutical composition comprising an oxamide derivative represented by the following formula as an active ingredient. 5. The immunomodulatory pharmaceutical composition according to claim 4, which is combined with a pharmaceutically acceptable diluent or carrier. 6. The immunomodulatory pharmaceutical composition according to claim 4, which is used for the treatment of rheumatoid arthritis. 7. The immunomodulatory pharmaceutical composition according to claim 4, which is used in cancer immunotherapy.
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP632181A JPS57136578A (en) | 1981-01-21 | 1981-01-21 | Oxamide derivative, its preparation, and pharmaceutical composition containing the same |
| IT25957/81A IT1142649B (en) | 1981-01-08 | 1981-12-31 | N 4 Phenyl 2 thiazolyl carbamate derivs. |
| PCT/JP1982/000012 WO1982002383A1 (en) | 1981-01-13 | 1982-01-13 | Novel thiazole compounds,process for their preparation,and medicinal composition containing same |
| DE8282900258T DE3273781D1 (en) | 1981-01-13 | 1982-01-13 | Novel thiazole compounds, process for their preparation, and medicinal composition containing same |
| US06/420,257 US4501750A (en) | 1981-01-13 | 1982-01-13 | Thiazole compounds, a process for preparing same and a pharmaceutical composition containing the thiazole compounds |
| EP82900258A EP0069154B1 (en) | 1981-01-13 | 1982-01-13 | Novel thiazole compounds, process for their preparation, and medicinal composition containing same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP632181A JPS57136578A (en) | 1981-01-21 | 1981-01-21 | Oxamide derivative, its preparation, and pharmaceutical composition containing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS57136578A JPS57136578A (en) | 1982-08-23 |
| JPH0255427B2 true JPH0255427B2 (en) | 1990-11-27 |
Family
ID=11635093
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP632181A Granted JPS57136578A (en) | 1981-01-08 | 1981-01-21 | Oxamide derivative, its preparation, and pharmaceutical composition containing the same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS57136578A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0395755A (en) * | 1989-09-07 | 1991-04-22 | Mitsubishi Electric Corp | Loading mechanism for magnetic recording and reproducing device |
| JPH03113863A (en) * | 1989-09-27 | 1991-05-15 | Mitsubishi Electric Corp | Magnetic recording and reproducing device |
-
1981
- 1981-01-21 JP JP632181A patent/JPS57136578A/en active Granted
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0395755A (en) * | 1989-09-07 | 1991-04-22 | Mitsubishi Electric Corp | Loading mechanism for magnetic recording and reproducing device |
| JPH03113863A (en) * | 1989-09-27 | 1991-05-15 | Mitsubishi Electric Corp | Magnetic recording and reproducing device |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS57136578A (en) | 1982-08-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4225610A (en) | Immunoactivators derived from amino thiazoles | |
| US3949089A (en) | Substituted guanidine compounds as antifibrillatory agents | |
| JPH04503212A (en) | 4-Hydroxythiazole as a 5-lipoxygenase inhibitor | |
| EP0069784B1 (en) | Thiazolylurea derivatives, process for their preparation, and medicinal composition containing same | |
| EP0087629B1 (en) | Antiinflammatory and/or analgesic 2,3-diaryl-5-halo thiophenes | |
| US4590205A (en) | Antiinflammatory and/or analgesic 2,3-diaryl-5-halo thiophenes | |
| EP0069154B1 (en) | Novel thiazole compounds, process for their preparation, and medicinal composition containing same | |
| JPH0255427B2 (en) | ||
| JPS6324514B2 (en) | ||
| EP0068033B1 (en) | N-(4-phenyl-2-thiazolyl)carbamate derivatives, process for their preparation, and medicinal composition containing same | |
| GB2059963A (en) | 2-Amino-3-benzoyl- phenylacetamides and cyclic homologues | |
| JPH0260670B2 (en) | ||
| JPS6254306B2 (en) | ||
| US4524147A (en) | Uracil derivatives, process for preparing same, and pharmaceutical compositions comprising same | |
| BRPI0611096A2 (en) | (5z) -5- (6-quinoxalinylmethylidene) -2 - [(2,6-dichlorophenyl) mino] -1,3-thiazol-4 (5h) -one | |
| JPH0255426B2 (en) | ||
| JPH0255428B2 (en) | ||
| US3592905A (en) | Therapeutic methods | |
| JPH0324473B2 (en) | ||
| US4447437A (en) | Pharmaceutical composition and method for treatment of peptic ulcer | |
| US4532137A (en) | 2-Thiazolamine derivatives, process for preparing same, and pharmaceutical compositions comprising same | |
| JPH0260672B2 (en) | ||
| US4473577A (en) | 2-Thiazolamine derivatives, process for preparing same, and pharmaceutical compositions comprising same | |
| JPH0254354B2 (en) | ||
| CA1079732A (en) | Pyrimidine derivative |