JPH0353316B2 - - Google Patents
Info
- Publication number
- JPH0353316B2 JPH0353316B2 JP60085679A JP8567985A JPH0353316B2 JP H0353316 B2 JPH0353316 B2 JP H0353316B2 JP 60085679 A JP60085679 A JP 60085679A JP 8567985 A JP8567985 A JP 8567985A JP H0353316 B2 JPH0353316 B2 JP H0353316B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- group
- thiazole
- water
- dihydroimidazo
- 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
- 150000003839 salts Chemical class 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- YXKTZRFQHQSXTF-UHFFFAOYSA-N 3-methyl-5,6-dihydroimidazo[2,1-b][1,3]thiazole-2-carboxamide Chemical class C1CN2C(C)=C(C(N)=O)SC2=N1 YXKTZRFQHQSXTF-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 57
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 32
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 230000000694 effects Effects 0.000 description 19
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- 238000010992 reflux Methods 0.000 description 17
- 238000001816 cooling Methods 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- -1 organic acid salts Chemical class 0.000 description 12
- 238000002844 melting Methods 0.000 description 11
- 230000008018 melting Effects 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 239000013078 crystal Substances 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- 210000004369 blood Anatomy 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 229940125904 compound 1 Drugs 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- QWEWLLNSJDTOKH-UHFFFAOYSA-N 1,3-thiazole-2-carboxamide Chemical class NC(=O)C1=NC=CS1 QWEWLLNSJDTOKH-UHFFFAOYSA-N 0.000 description 6
- 239000004342 Benzoyl peroxide Substances 0.000 description 6
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 description 6
- 235000019400 benzoyl peroxide Nutrition 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 229960001614 levamisole Drugs 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- PDQAZBWRQCGBEV-UHFFFAOYSA-N Ethylenethiourea Chemical compound S=C1NCCN1 PDQAZBWRQCGBEV-UHFFFAOYSA-N 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 210000004988 splenocyte Anatomy 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- PGDPAXPJJNAPGC-UHFFFAOYSA-N 1,3-thiazole-2-carboxamide hydrochloride Chemical compound Cl.NC(=O)c1nccs1 PGDPAXPJJNAPGC-UHFFFAOYSA-N 0.000 description 3
- TXRCQKVSGVJWAW-UHFFFAOYSA-N 4,4-dimethylimidazolidine-2-thione Chemical compound CC1(C)CNC(=S)N1 TXRCQKVSGVJWAW-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- 206010060891 General symptom Diseases 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 206010030113 Oedema Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 241001494479 Pecora Species 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 206010070834 Sensitisation Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 210000003743 erythrocyte Anatomy 0.000 description 3
- 230000002519 immonomodulatory effect Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 210000004698 lymphocyte Anatomy 0.000 description 3
- 230000008313 sensitization Effects 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 238000011725 BALB/c mouse Methods 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-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
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000035584 blastogenesis Effects 0.000 description 2
- 230000036755 cellular response Effects 0.000 description 2
- WASQWSOJHCZDFK-UHFFFAOYSA-N diketene Chemical compound C=C1CC(=O)O1 WASQWSOJHCZDFK-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- UFBBWLWUIISIPW-UHFFFAOYSA-N imidazo[2,1-b][1,3]thiazole Chemical class C1=CSC2=NC=CN21 UFBBWLWUIISIPW-UHFFFAOYSA-N 0.000 description 2
- 210000003141 lower extremity Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000003226 mitogen Substances 0.000 description 2
- YHCRDEFQMDWSAJ-UHFFFAOYSA-N n-[(3,4-dichlorophenyl)methyl]-3-oxobutanamide Chemical compound CC(=O)CC(=O)NCC1=CC=C(Cl)C(Cl)=C1 YHCRDEFQMDWSAJ-UHFFFAOYSA-N 0.000 description 2
- LWNOHVIQOGIHFD-UHFFFAOYSA-N n-[(4-chlorophenyl)methyl]-3-oxobutanamide Chemical compound CC(=O)CC(=O)NCC1=CC=C(Cl)C=C1 LWNOHVIQOGIHFD-UHFFFAOYSA-N 0.000 description 2
- PPASDJZMHMGQRG-UHFFFAOYSA-N n-[(4-chlorophenyl)methyl]-n-ethyl-3,6,6-trimethyl-5h-imidazo[2,1-b][1,3]thiazole-2-carboxamide;hydrochloride Chemical compound Cl.CC=1N2CC(C)(C)N=C2SC=1C(=O)N(CC)CC1=CC=C(Cl)C=C1 PPASDJZMHMGQRG-UHFFFAOYSA-N 0.000 description 2
- ZFRQWRWOFYQQIH-UHFFFAOYSA-N n-[(4-chlorophenyl)methyl]-n-methyl-3-oxobutanamide Chemical compound CC(=O)CC(=O)N(C)CC1=CC=C(Cl)C=C1 ZFRQWRWOFYQQIH-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 231100000272 reduced body weight Toxicity 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 229940104230 thymidine Drugs 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- LMBUJNXYGGNSAH-UHFFFAOYSA-N 1-(4-chlorophenyl)-n-methylmethanamine Chemical compound CNCC1=CC=C(Cl)C=C1 LMBUJNXYGGNSAH-UHFFFAOYSA-N 0.000 description 1
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- UMZCLZPXPCNKML-UHFFFAOYSA-N 2h-imidazo[4,5-d][1,3]thiazole Chemical group C1=NC2=NCSC2=N1 UMZCLZPXPCNKML-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- CHOLATABIDAABF-UHFFFAOYSA-N 3-oxo-n-[[3-(trifluoromethyl)phenyl]methyl]butanamide Chemical compound CC(=O)CC(=O)NCC1=CC=CC(C(F)(F)F)=C1 CHOLATABIDAABF-UHFFFAOYSA-N 0.000 description 1
- GYAHKUOFGNDLJV-UHFFFAOYSA-N 4,5-dimethylimidazolidine-2-thione Chemical compound CC1NC(=S)NC1C GYAHKUOFGNDLJV-UHFFFAOYSA-N 0.000 description 1
- NGZJXCFNBVJLQN-UHFFFAOYSA-N 4-methylimidazolidine-2-thione Chemical compound CC1CNC(=S)N1 NGZJXCFNBVJLQN-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 208000027932 Collagen disease Diseases 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
- 208000009386 Experimental Arthritis Diseases 0.000 description 1
- 206010018367 Glomerulonephritis chronic Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 206010023644 Lacrimation increased Diseases 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-L aspartate group Chemical class N[C@@H](CC(=O)[O-])C(=O)[O-] CKLJMWTZIZZHCS-REOHCLBHSA-L 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- KQNZLOUWXSAZGD-UHFFFAOYSA-N benzylperoxymethylbenzene Chemical compound C=1C=CC=CC=1COOCC1=CC=CC=C1 KQNZLOUWXSAZGD-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
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- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229940113088 dimethylacetamide Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
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- 230000000212 effect on lymphocytes Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
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- 239000004220 glutamic acid Substances 0.000 description 1
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- 150000002306 glutamic acid derivatives Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
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- 239000012442 inert solvent Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
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- 230000004317 lacrimation Effects 0.000 description 1
- 238000011694 lewis rat Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 150000004701 malic acid derivatives Chemical class 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- SDIISVNEGSYDSS-UHFFFAOYSA-N n-[(2,4-dichlorophenyl)methyl]-n,3-dimethyl-5,6-dihydroimidazo[2,1-b][1,3]thiazole-2-carboxamide Chemical compound CC=1N2CCN=C2SC=1C(=O)N(C)CC1=CC=C(Cl)C=C1Cl SDIISVNEGSYDSS-UHFFFAOYSA-N 0.000 description 1
- ABFNHJRUTREWLU-UHFFFAOYSA-N n-[(3,4-dichlorophenyl)methyl]-n,3-dimethyl-5,6-dihydroimidazo[2,1-b][1,3]thiazole-2-carboxamide;hydrochloride Chemical compound Cl.CC=1N2CCN=C2SC=1C(=O)N(C)CC1=CC=C(Cl)C(Cl)=C1 ABFNHJRUTREWLU-UHFFFAOYSA-N 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000003716 rejuvenation Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
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[Industrial Application Field] The present invention relates to novel 3-methyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivatives, more particularly to the following compounds which have excellent immunomodulatory uses: General formula (I) (In the formula, A is a lower alkylene group which may be branched, R 1 , R 2 , R 3 and R 4 are the same or different and represent a hydrogen atom or a lower alkyl group, R 5 is a hydrogen atom,
a lower alkyl group or a cycloalkyl group, n X's are the same or different, a hydrogen atom, a halogen atom,
trifluoromethyl group, lower alkyl group, lower alkoxy group, cyano group or nitro group, n is 0 to
The present invention relates to a 3-methyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivative or a salt thereof represented by the formula (indicating an integer of 5). [Prior Art] Conventionally, many compounds having an imidazothiazole skeleton have been synthesized, for example, the following formula: It has been reported that the imidazo[2,1-b]thiazole derivative (levamisole) represented by
issue). Also, the expression (In the formula, R 9 is C 1 to C 3 alkylsulfonyl or
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ãã©ã¯ãïŒChemical AbstractsïŒ19ïŒ43ïŒ1925ïŒã
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Coll.3ïŒ394é ã«èšèŒã®æ¹æ³ã«åŸã€ãŠã次ã®æ¹æ³
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å¹å°ã«ãŠCO2ã€ã³ããŠããŒã¿ãŒïŒ37âïŒäžïŒæ¥é
å¹é€ãããã·ãšã«ãã¢ãŒã«ïŒã¢ã€ïŒMischellïŒR.
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ïŒJ.Evp.Med.ïŒ126ïŒ423ïŒ1967ïŒã®å€æ³ãã
åºçŸãããã©ãŒã¯åœ¢æ现èæ°ãã€ãšã«ãã»ã¢ã³
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ããµã€ãšã³ã¹ïŒScienceïŒ140ïŒ405ïŒ1963ïŒã§æž¬å®
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Under these circumstances, the present inventors synthesized various imidazo[2,1-b]thiazole derivatives and examined their physiological activities. 3-methyl-5,6-dihydroimidazo[2,1-b]
The present invention was completed based on the discovery that thiazole-2-carboxamide derivatives have excellent immunomodulatory effects. That is, the present invention provides 3 represented by the formula (I)
-Methyl-5,6-dihydroimidazo[2,1-
b] Thiazole-2-carboxamide derivatives and salts thereof. In the present invention, the salts of the 3-methyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivative include pharmaceutically acceptable salts such as hydrochloride, sulfate, carbonate, Inorganic or organic acid salts such as nitrates, hydrobromides, phosphates, sulfonates, acetates, oxalates, tartrates, citrates, malates, glutamates, aspartates, etc. can be mentioned. Further, the compound of formula (I) and its salt of the present invention may have water of crystallization, and any of these hydrates are included within the scope of the present invention. The compound (I) of the present invention can be produced, for example, by reacting an amide represented by the formula () with an imidazolidine-2-thione represented by the formula (), according to the following reaction formula. (In the formula, A, R 1 , R 2 , R 3 , R 4 , R 5 , X and n have the above-mentioned meanings) This reaction is preferably carried out in a suitable inert solvent, such as benzene, toluene,
xylene, acetone, methyl ethyl ketone, dimethyl formamide, dimethyl acetamide, dimethyl forskide, acetonitrile, ether,
Tetrahydrofuran, dioxane, chloroform, water, etc. are used. The reaction temperature is -5°C to 100°C, preferably 20°C to
The temperature is 80°C, and the compound of the present invention can be obtained in high yield and purity by reaction for 1 to 6 hours. In order to obtain the free compound of general formula (I) from the hydrochloride thus obtained, bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, ammonia and other inorganic It may be treated with a base, an organic base such as pyridine, or triethylamine. In order to lead to other salts, the corresponding acids such as sulfuric acid, carbonic acid, nitric acid, hydrobromic acid, phosphoric acid, sulfonic acid, acetic acid, oxalic acid, tartaric acid, citric acid, malic acid, glutamic acid, aspartic acid, etc. The above hydrochloride or free compound may be treated with. The compound of the formula () used as a raw material in this method is, for example, prepared by converting diketene () into a compound of the formula () of amines () according to the following reaction formula, and then converting this into sulfuryl chloride [Chemical Abstracts) 19 , 43 (1925)]
Alternatively, it is produced by chlorination with N-chlorosuccinimide or the like. (In the formula, A, R 5 , X and n have the above-mentioned meanings.) In addition, another raw material compound () is, for example, Organic Synthesis (Org.Synth.),
It is produced by the following method according to the method described in Coll. 3, page 394. [Effect] Next, the pharmacological effects of the compound of the present invention () and its salt will be explained. Test Example 1 Effect on in vitro plaque-forming cell response using mouse splenocytes: 1 x 10 7 BALB/c mouse splenocytes were injected with sheep red blood cells (1 x 10 6 ) and test compound (0.2 or 1 ÎŒg/
RPMIâ1640 containing 10% fetal bovine serum (ml)
Cultured in a CO 2 incubator (37°C) for 5 days in a medium [Michelle, Earl. Eye (Mischell, R.
(J.Evp.Med.) 126:423 (1967)], the number of appearing plaque-forming cells was determined by the method of Jerne and Nordin [Science 140:405]. (1963). The results are shown in Table 1-1.
ãè¡šããtableã
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ïŒJ.Med.Chem.ïŒïŒ24ïŒ604ã609ïŒ1981ïŒã«èšèŒã
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ãã®çµæãè¡šïŒâïŒã«ç€ºãã[Table] Also, for comparison, the following compounds described in JP-A-52-106893 and Journal of Medicinal Chemistry (J.Med.Chem.), 24 , 604-609 (1981) The effects on in vitro plaque-forming cellular responses were determined.
The results are shown in Table 1-2.
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ããª3Hâãããžã³ã®å蟌ã¿å¢å ãã¿ãããã[Table] As is clear from Tables 1-1 and 1-2, the compounds of the present invention exhibit immune response activity at low concentrations of 0.2 to 1 ÎŒg/ml, whereas the comparative compounds exhibit almost no activity. Test Example 2 Effect on in vitro lymphocyte blastogenesis using mouse splenocytes: BALB/c mouse splenocytes (1Ã10 5 cells) or thymocytes (2Ã10 â5 cells) were treated with T cell mitogen. ConA (2.5ÎŒg/ml) and test compound (1ÎŒg/ml)
RPMI containing 5% fetal bovine serum (g/ml)
The cells were cultured in 1640 medium (0.2 ml) in a CO 2 incubator (37°C) for 48 hours. Then 0.5 ÎŒCi of 3Hâ
Thymidine was added and cultured for an additional 18 hours, and the radioactivity of 3 H-thymidine incorporated into the cells was measured.
The results are shown in Table 2. A clear increase in the uptake of 3 H-thymidine was observed with the addition of the compound of the present invention.
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è©ŠéšäŸïŒã®æ¹æ³ã«åŸã€ããçµæãè¡šïŒã«ç€ºãã[Table] Test Example 3: Effect on lymphocyte rejuvenation response when test compound was administered selectively: Six BALB/c female mice were used in each group.
The test compound was orally administered at 0.25 mg/Kg per day for 5 days.
On the 6th day, the spleen was removed and splenocytes (2 x 10 cells) were treated with mitogen (LPS: 10 ÎŒg/ml or ConA: 2.5 ÎŒg/ml).
g/ml), and the lymphocyte maturation reaction was examined. The culture conditions and the measurement of lymphocyte blastogenesis were conducted according to the method of Test Example 2. The results are shown in Table 3.
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è¡šïŒã«ç€ºãã[Table] For levamisole to show effect in this study
Although it required administration of 2.5 mg/Kg/day, the compound of the present invention showed a promoting activity equal to or greater than that of levamisole when administered at 1/10 the dose of 0.25 mg/Kg/day. Test Example 4 Effect on delayed allergic reaction: One group of 8 male ddY mice were sensitized by subcutaneously injecting 2 x 10 8 sheep red blood cells into the back. 4 days after sensitization,
5 x 10 7 sheep red blood cells were subcutaneously injected into the footpad of one side of the hind leg, and physiological saline was injected into the footpad of the opposite side. After 24 hours, the thickness of both footpads was measured with a micrometer to determine the edema rate. Ta. The test compound was orally administered once a day for 5 days from the day of sensitization (2 hours after sensitization). The results are shown in Table 4.
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«ãåªäœã«æå¶ããã[Table] The compound of the present invention significantly inhibited delayed allergic reactions when administered at 0.1 mg/Kg/day. Test Example 5 Effect on adjuvant arthritis: One group of 8 female Lewis rats were used. Abajuvant arthritis was induced by injecting 0.6 mg/0.1 ml of killed Mycobacterium tuberculosis suspended in liquid paraffin as an adjuvant into the footpad of one hind leg, and the test compound was orally administered once a day for 20 days. After 21 days, the volume of both limbs and footpads was measured, and the edema rate of each was determined. The results are shown in Table 5. The compound of the present invention is 1 to 5 mg/
Kg/day administration significantly suppressed edema in the non-adjuvant-injected feet and in the adjuvant-injected feet.
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The test compound was orally administered at 300 mg/kg once a day for 4 days to 4 male rats per group, and changes in general symptoms were observed, and the effects on body weight, liver weight, and serum cholesterol level were examined. Serum cholesterol was measured using a Beca cholesterol measurement kit and a Centrifikem autoanalyzer. Compound 1 is used as the compound of the present invention, and compound 1 is used as the comparative compound.
3,4-Cl 2 compound (relatively soft compound) and R 1 = R 3
= R4 =H, (X)n3= -CF3 compound (comparative compound 7 was used, and levamisole was used in some tests. Blood concentrations of the compounds were also compared. High performance liquid chromatography was used to measure blood concentrations. (1) Effects on general symptoms There were no changes in general symptoms in the Compound 1 and Comparative Compound 6 administration groups. However, with Comparative Compound 7, lacrimation, bleeding from the eyes, sedation, imbalance, and tremor were observed in the treated group. Half of the patients in the reversisol-treated group died. (2) Effect on body weight Table 6 shows the body weights before and after continuous administration of the test compound.
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åç©ïŒã¯ææã«èèééãå¢å ãããã[Table] Compound 1 had no effect on body weight, but comparative compound 6 significantly reduced body weight. Levamisole significantly reduced body weight even when administered at 100 mg/Kg/day. (3) Effect on liver weight The results obtained are shown in Table 7. Compound 1 had no significant effect on liver weight, whereas comparative compound 6 significantly increased liver weight.
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As is clear from the above test results, the compound (I) of the present invention has an excellent immunomodulatory effect, and therefore can be used as a prophylactic and therapeutic agent for immune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, collagen disease, chronic nephritis, etc. It can be used for the treatment and prevention of autoimmune diseases such as autoimmune hemolytic anemia, immediate and delayed allergic diseases, malignant tumors, severe infections, and the like. The compounds of the present invention can be administered orally or parenterally (eg, intramuscularly, subcutaneously, intravenously, anally, or cutaneously) as such or in various dosage unit forms. The dosage forms include solid preparations such as tablets, sugar-coated tablets, film tablets, hard or soft capsules, troches, pills, granules, and powders; semi-solid preparations such as suppositories, patches, and ointments; injections, It can be made into liquid preparations such as syrups, inhalants, emulsions, and suspensions. Although the compound of the present invention can be used alone as the above-mentioned preparation, it may also be combined with other medicinal ingredients such as non-steroidal analgesics, anti-inflammatory agents, etc. [Example] Next, reference examples and examples will be given and explained. Reference Example 1 4-Chloro-N-methyl-benzylamine (3.1 g, 0.02M) was dissolved in toluene, a contact amount of pyridine was added, and diketene (1.8 g,
0.022M) was added dropwise. The reaction solution was stirred at room temperature for 3 hours, poured into water, extracted with toluene, and purified to obtain oily N-methyl-N-(4-chlorobenzyl)-acetoacetamide. Example 1 () N-methyl-N-(4
-chlorobenzyl)acetoacetamide (4.0g,
0.017M), N-chlorosuccinimide (2,
3g, 0.017M) and a small amount of benzoyl peroxide were suspended in carbon tetrachloride and heated under reflux for 1 hour. After cooling, it was poured into water, extracted with carbon tetrachloride, purified, dried, and concentrated to obtain an oily crude composition. This material was added to a silica gel column (c-300,
Purification was performed using n-hexane-ethyl acetate) to obtain 3.5 g of oily N-methyl-N-(4-chlorobenzyl)-2-chloro-acetoacetamide ( n20D : 1.5336 ). This substance and 4,4-dimethylimidazolidine-2-thione (1.7 g,
0.013M) in methyl ethyl ketone,
After heating under reflux for an hour and cooling, the resulting precipitate was collected, washed with ascent, and recrystallized from isopropanol/isopropyl ether to yield 4.8 g of N-(4-chloropenzyl)-N,3,6,6-
Tetramethyl-5,6-dihydroimidazo[2,1-b]thiazole, -2-carboxamide hydrochloride (Compound 1) (melting point 187-190°C, white crystals) was obtained. () 3.9 g (0.01 M) of the obtained hydrochloride was dissolved in water, and 10% caustic soda water was added dropwise to the solution while stirring at room temperature. The resulting crystals were collected and purified by washing with a large amount of water. This material was dried under reduced pressure.
3.3 N-(4-chloropenzyl)-N,3,6,
6-Tetramethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide (melting point 139°C, pale yellow powder crystal) was obtained. Example 2 N-(4-chlorobenzyl)acetoacetamide (2.3 g, obtained in the same manner as Reference Example 1)
0.01M) and N-chlorosuccinimide (1.3g,
0.01M) and a small amount of benzoyl peroxide were suspended in carbon tetrachloride and heated under reflux for 1 hour. After pouring this into water and extracting with carbon tetrachloride,
After washing with water, drying, and concentrating, the obtained oily substance was subjected to the next reaction without being purified. The compound thus obtained and imidazolidine-2-thione (1.0 g, 0.01 M) were suspended in methyl ethyl ketone and heated under reflux for 3 hours. After cooling, the precipitate was collected, washed with acetone, and recrystallized with isopropyl alcohol/isopropyl ether.
-(4-chlorobenzyl)-3-methyl-5,6-
Dihydroimidazo[2,1-b]thiazole-2
-2.8 g of carboxamide hydrochloride (compound 2) was obtained. Melting point: 241-242â, white crystals. Example 3 N-(3-trifluoromethylbenzyl)acetoacetamide (2.6 g, 0.01 M) obtained in the same manner as in Reference Example 1, N-chlorosuccinimide (1.3 g, 0.01 M) and a small amount of benzyl peroxide were added. The mixture was suspended in carbon tetrachloride and heated under reflux for 1 hour. After cooling, the reaction solution was poured into water, extracted with carbon tetrachloride, washed with water, dried and concentrated, and the obtained oily substance was used in the next reaction without purification. The compound thus obtained and imidazolidine-2-thione (1.0 g, 0.01 M) were suspended in methylethylcetone and heated under reflux for 3 hours.
After cooling, the resulting precipitate was collected, washed with acetone, and recrystallized with ethanol to obtain 3-methyl-N.
-(3-trifluoromethylbenzyl)-5,6-
Dihydroimidazo[2,1-b]thiazole-2
-Carbosisamide hydrochloride (compound 3) (melting point 210~
216°C, 2.5 g of colorless prismatic crystals were obtained. Example 4 N-ethyl- obtained in the same manner as Reference Example 1
N-(4-chlorobenzyl)acetoacetamide (2.5 g, 0.01 M), N-chlorosuccinimide (1.3 g, 0.01 M) and a small amount of benzoyl peroxide were suspended in carbon tetrachloride and heated under reflux for 1 hour. Ivy. After cooling, the reaction solution was poured into water, extracted with carbon tetrachloride, washed with water, dried, and concentrated. The resulting oily substance was used in the next reaction without purification.
The compound thus obtained and 4,4-dimethylimidazolidine-2-thione (1.3g, 0.01M)
was dissolved in methyl ethyl ketone and heated under reflux for 3 hours. After cooling, the resulting precipitate was collected, washed with acetone, and recrystallized from isopropanol/isopropyl ether to obtain N-(4-chlorobenzyl)-N-ethyl-3,6,6-trimethyl-5,
6-dihydroimidazo[2,1-b]thiazole-2-carboxamide hydrochloride (compound 4) (melting point
2.7 g of white crystals (178-181°C) were obtained. Example 5 N-methyl- obtained in the same manner as Reference Example 1
N-(3,4-dichlorobenzyl)acetoacetamide (2.6 g, 0.01 M), N-chlorosuccinimide (1.3 g, 0.01 M), and a small amount of benzoyl peroxide were suspended in carbon tetrachloride and heated under reflux for 1 hour. I went there. After cooling, the reaction solution was poured into water.
After extraction with carbon tetrachloride, the oily substance obtained by washing with water, drying, and concentrating was used for the next reaction without purification. The compound thus obtained and imidazolidine-2-thione (1.0 g, 0.01 M) were suspended in methyl ethyl ketone and heated under reflux for 3 hours. After cooling, the resulting precipitate was collected, washed with acetone, and recrystallized with ethanol to obtain N-(3,
4-dichlorobenzyl)-N,3-dimethyl-5,
6-dihydroimidazo[2,1-b]thiazole-2-carboxamide hydrochloride (compound 5) (melting point
3.1 g of pale yellow microacicular crystals (196-198°C) were obtained. Example 6 N-(3,4
-dichlorobenzyl)-acetoacetamide (5.2
g, 0.02M) and N-chlorosuccinimide (2.7
g, 0.02M) and a small amount of benzoyl peroxide were suspended in carbon tetrachloride and heated under reflux for 1 hour. After cooling, it was poured into water, extracted with carbon tetrachloride, washed with water, and concentrated, and the obtained oily substance was subjected to the next reaction without being purified. The compound thus obtained and 4,5-dimethylimidazolidine-2-thione (2.6 g, 0.02M) were dissolved in methyl ethyl ketone and heated under reflux for 3 hours.
After cooling, the precipitate was collected and purified by washing with a large amount of acetone to obtain N-(3,4-dichlorobenzyl)-
3,5,6-trimethyl-5,6-dihyloimidazo[2,1-b]thiazole-2-carboxamide hydrochloride (compound 6) (melting point 148-152°C, white powder) was obtained. Example 7 N-(3-chlorobenzyl)N-methylacetoacetamide (4.8g, 0.02M) obtained in the same manner as in Reference Example 1, N-chlorosuccinimide (2.7g, 0.02M) and a small amount of benzoyl. Peroxide was suspended in carbon tetrachloride and heated under reflux for 1 hour. This was poured into water, extracted with carbon tetrachloride, washed with water, dried and concentrated, and the obtained oily substance was subjected to the next reaction without being purified. The compound thus obtained and 4-methylimidazolidine-2-thione (2.4 g, 0.02M) were dissolved in methyl ethyl ketone and heated under reflux for 3 hours. After cooling, the precipitate was collected and purified by washing with acetone and isopropyl ether to obtain N-(3-chlorobenzyl)-N,3,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2. - Carboxamide hydrochloride (compound 7) (melting point 41-47°C,
A brown glassy substance) was obtained. Example 8 () N-(2,
4-dichlorobenzyl)-N-methylacetoacetamide (5.2 g, 0.02 M), N-chlorosuccinimide (2.7 g, 0.02 M), and a small amount of benzoyl peroxide were suspended in carbon tetrachloride for 1 hour. The mixture was heated to reflux. After cooling, the reaction solution was poured into water, extracted with carbon tetrachloride, washed with water, dried,
It was concentrated, and the obtained oily substance was used in the next reaction without purification. The compound thus obtained and imidazolidine-2-thione (1.0 g,
0.01M) in methyl ethyl ketone,
The mixture was heated under reflux for an hour. After cooling, the resulting precipitate was collected, washed with acetone, and purified.
(2,4-dichlorobenzyl)-N,3-dimethyl-5,6-dihydroimidazo[2,1-b]
5.3 g of thiazole-2-carboxamide hydrochloride (compound 8) (melting point 251-254°C, colorless powder) was obtained. () Obtained N-(2,4-dichlorobenzyl)
3.6 g (0.01 M) of -N,3-dimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide hydrochloride was dissolved in water, and aqueous ammonia was added dropwise with stirring at room temperature. Collect the resulting precipitate and wash and purify it with a large amount of water.
3.0 g of N-(2,4-dichlorobenzyl)-N,
3-dimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide (melting point 55-56°C, pale yellow powder) was obtained. Examples 9-94 The compounds shown in Table 10 below were produced in the same manner as in Reference Example 1 and Examples 1-8 above.
ãè¡šããtableã
ãè¡šããtableã
ãè¡šããtableã
ãè¡šã
å®æœäŸ 95ã99
äžèšåèäŸåã³å®æœäŸãšåæ§ã«ããŠæ¬¡ã®è¡š11èš
èŒã®ååç©ã補é ããã[Table] Examples 95 to 99 The compounds shown in Table 11 below were produced in the same manner as in the above Reference Examples and Examples.
ãè¡šã
å®æœäŸ 100
ã¡ãã«ãšãã«ã±ãã³10mlã«ãβâããšããã«ã¢
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ãšãã«ãšãã«ïŒã¢ã»ãã¢ã»ã¿ããïŒæªç²Ÿè£œïŒ2.5
ïœåã³ïŒïŒïŒâãžã¡ãã«ã€ãããŸãªãžã³âïŒâã
ãªã³1.3ïœã溶解ããïŒæéå ç±éæµãããå·åŽ
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žåãããªãŠã 氎溶液20
mlåã³ãã«ãšã³20mlã®æ··å液äžã«ãæ¹æäžæ»Žäžã
ããæåºããçµæ¶ãæ¿Ÿåããæ°Ž20mlã§æŽæµãã也
ç¥ãããŠïŒ®âïŒïŒâããšãã«ãšãã«ïŒâïŒïŒïŒïŒïŒ
âããªã¡ãã«âïŒïŒïŒâãžãããã€ãããŸãïŒïŒ
ïŒâïœããã¢ãŸãŒã«âïŒâã«ã«ãããµããïŒåå
ç©98ïŒæ·¡è€è²ç²æ«ãèç¹102ã105âïŒ2.5ïœãåŸ
ãã
æŽã«ããã®æ·¡è€è²ç²æ«ïŒïŒïŒïœããã€ãœããã
ã«ã¢ã«ã³ãŒã«10mlã«æº¶è§£ãã次ãã§ã€ãœãããã«
ãšãŒãã«20mlãåŸã
ã«æ·»å ãããæåºããçµæ¶ã
æ¿Ÿåããã€ãœãããã«ãšãŒãã«10mlã§æŽæµãã也
ç¥ãããŠçœè²éç¶çµæ¶ïŒ120ã121âïŒã®ååç©98
ã1.1ïœåŸãã[Table] Example 100 2-chloro-N-(2-phenylethyl)acetoacetamide (unpurified) obtained in the same manner as in Reference Example 1 and Example 1 () using β-phenethylamine in 10 ml of methyl ethyl ketone (unpurified) 2.5
g and 1.3 g of 4,4-dimethylimidazolidine-2-thione were dissolved and heated under reflux for 3 hours. After cooling and concentrating to remove methyl ethyl ketone,
The residue was dissolved in 20 ml of water. Add this aqueous solution to 10% sodium hydroxide solution 20%
ml and toluene (20 ml) under stirring. The precipitated crystals were collected by filtration, washed with 20 ml of water, and dried to give N-(2-phenylethyl)-3,6,6
-trimethyl-5,6-dihydroimidazo[2,
1-b] 2.5 g of thiazole-2-carboxamide (compound 98, light brown powder, melting point 102-105°C) was obtained. Further, 2.5 g of this light brown powder was dissolved in 10 ml of isopropyl alcohol, and then 20 ml of isopropyl ether was gradually added. The precipitated crystals were collected by filtration, washed with 10 ml of isopropyl ether, and dried to give compound 98 as white needle-like crystals (120-121°C).
1.1g of was obtained.
Claims (1)
åºããR1ïŒR2ïŒR3åã³R4ã¯åäžåã¯ç°ãªã€ãŠæ°Ž
çŽ åååã¯äœçŽã¢ã«ãã«åºããR5ã¯æ°ŽçŽ ååã
äœçŽã¢ã«ãã«åºåã¯ã·ã¯ãã¢ã«ãã«åºããïœåã®
ã¯åäžåã¯ç°ã€ãŠãæ°ŽçŽ ååãããã²ã³ååã
ããªãã«ãªãã¡ãã«åºãäœçŽã¢ã«ãã«åºãäœçŽã¢
ã«ã³ãã·åºãã·ã¢ãåºåã¯ãããåºããïœã¯ïŒã
ïŒã®æŽæ°ã瀺ãïŒ ã§è¡šããããïŒâã¡ãã«âïŒïŒïŒâãžãããã€ã
ããŸãïŒïŒïŒâïœããã¢ãŸãŒã«âïŒâã«ã«ãããµ
ããèªå°äœåã¯ãã®å¡©ã[Claims] First-order general formula (I) (In the formula, A is a lower alkylene group that may be branched, R 1 , R 2 , R 3 and R 4 are the same or different and represent a hydrogen atom or a lower alkyl group, R 5 is a hydrogen atom,
a lower alkyl group or a cycloalkyl group, n X's are the same or different, a hydrogen atom, a halogen atom,
trifluoromethyl group, lower alkyl group, lower alkoxy group, cyano group or nitro group, n is 0 to
A 3-methyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivative or a salt thereof represented by:
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP60085679A JPS61251686A (en) | 1985-04-22 | 1985-04-22 | 3-methyl-5,6-dihydroimidazo(2,1-b)thiazol-2-carboxamide derivative and its salt |
CA000506963A CA1271480A (en) | 1985-04-22 | 1986-04-17 | 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivatives or salts thereof |
DE8686105485T DE3680815D1 (en) | 1985-04-22 | 1986-04-21 | 5,6-DIHYDROIMIDAZO (2,1-B) THIAZOL-2-CARBOXAMIDE DERIVATIVES AND THEIR SALTS. |
EP86105485A EP0200134B1 (en) | 1985-04-22 | 1986-04-21 | 5,6-Dihydroimidazo[2,1-b]thiazole-2-carboxamide derivatives or salts thereof |
US06/922,407 US4736038A (en) | 1985-04-22 | 1986-10-23 | 5,6-dihydroimidazo(2,1-b)thiazole-2-carboxamide derivatives or salts thereof |
US07/242,171 US4910315A (en) | 1985-04-22 | 1988-09-09 | 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivatives of salts thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP60085679A JPS61251686A (en) | 1985-04-22 | 1985-04-22 | 3-methyl-5,6-dihydroimidazo(2,1-b)thiazol-2-carboxamide derivative and its salt |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2309416A Division JPH03163086A (en) | 1990-11-15 | 1990-11-15 | Production of 3-methyl-5,6-dihydroimidazo(2,1-b)thiazole-2-carboxyamide derivative or salt thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS61251686A JPS61251686A (en) | 1986-11-08 |
JPH0353316B2 true JPH0353316B2 (en) | 1991-08-14 |
Family
ID=13865520
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP60085679A Granted JPS61251686A (en) | 1985-04-22 | 1985-04-22 | 3-methyl-5,6-dihydroimidazo(2,1-b)thiazol-2-carboxamide derivative and its salt |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS61251686A (en) |
-
1985
- 1985-04-22 JP JP60085679A patent/JPS61251686A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS61251686A (en) | 1986-11-08 |
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