CN101312966A - 苯并噻唑环丁胺衍生物及其作为组胺-3受体配体的应用 - Google Patents

Info

Publication number

CN101312966A

CN101312966A CNA2006800436476A CN200680043647A CN101312966A CN 101312966 A CN101312966 A CN 101312966A CN A2006800436476 A CNA2006800436476 A CN A2006800436476A CN 200680043647 A CN200680043647 A CN 200680043647A CN 101312966 A CN101312966 A CN 101312966A

Authority

CN

China

Prior art keywords

benzothiazole

instead

cyclobutyl

basic ring

piperidines

Prior art date

2005-09-22

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.)

Pending

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• -1 Benzothiazole cyclobutyl amine derivatives Chemical class 0.000 title claims description 225
• IOJUPLGTWVMSFF-UHFFFAOYSA-N cyclobenzothiazole Natural products C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 title claims description 49
• 239000003446 ligand Substances 0.000 title abstract description 12
• 150000001875 compounds Chemical class 0.000 claims abstract description 454
• 238000000034 method Methods 0.000 claims abstract description 58
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 306
• HQULYFAKUZDRPB-UHFFFAOYSA-N 6-bromo-2-[4-(trifluoromethoxy)phenoxy]-1,3-benzothiazole Chemical compound BrC1=CC2=C(N=C(S2)OC2=CC=C(C=C2)OC(F)(F)F)C=C1 HQULYFAKUZDRPB-UHFFFAOYSA-N 0.000 claims description 245
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 134
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 133
• OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 128
• 150000001408 amides Chemical class 0.000 claims description 66
• 125000000217 alkyl group Chemical group 0.000 claims description 65
• 229910052757 nitrogen Inorganic materials 0.000 claims description 51
• 229910052739 hydrogen Inorganic materials 0.000 claims description 50
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 50
• 239000001257 hydrogen Substances 0.000 claims description 49
• 150000001412 amines Chemical class 0.000 claims description 45
• 125000003545 alkoxy group Chemical group 0.000 claims description 41
• 150000003839 salts Chemical class 0.000 claims description 41
• 229910052731 fluorine Inorganic materials 0.000 claims description 39
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 38
• 239000011737 fluorine Substances 0.000 claims description 38
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 36
• 125000003709 fluoroalkyl group Chemical group 0.000 claims description 36
• 150000002431 hydrogen Chemical class 0.000 claims description 36
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 35
• 229910052799 carbon Inorganic materials 0.000 claims description 29
• 239000000126 substance Substances 0.000 claims description 28
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 26
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 26
• 238000011282 treatment Methods 0.000 claims description 26
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 24
• 150000002148 esters Chemical class 0.000 claims description 24
• 125000003118 aryl group Chemical group 0.000 claims description 23
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 23
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 22
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 22
• WJJMNDUMQPNECX-UHFFFAOYSA-N dipicolinic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=N1 WJJMNDUMQPNECX-UHFFFAOYSA-N 0.000 claims description 22
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 22
• GVWISOJSERXQBM-UHFFFAOYSA-N n-methylpropan-1-amine Chemical compound CCCNC GVWISOJSERXQBM-UHFFFAOYSA-N 0.000 claims description 21
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 20
• 150000001721 carbon Chemical group 0.000 claims description 19
• 229910052736 halogen Inorganic materials 0.000 claims description 19
• 150000002367 halogens Chemical class 0.000 claims description 19
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 19
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 19
• 125000002252 acyl group Chemical group 0.000 claims description 18
• 125000002521 alkyl halide group Chemical group 0.000 claims description 18
• 125000004414 alkyl thio group Chemical group 0.000 claims description 18
• 125000006574 non-aromatic ring group Chemical group 0.000 claims description 18
• 230000000694 effects Effects 0.000 claims description 17
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 16
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
• HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 16
• 125000003368 amide group Chemical group 0.000 claims description 15
• 229910052760 oxygen Inorganic materials 0.000 claims description 15
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 14
• YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 13
• 125000003342 alkenyl group Chemical group 0.000 claims description 13
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 13
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
• 125000001072 heteroaryl group Chemical group 0.000 claims description 13
• 125000004423 acyloxy group Chemical group 0.000 claims description 12
• 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 12
• 125000001118 alkylidene group Chemical group 0.000 claims description 12
• WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 claims description 12
• NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims description 12
• QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 12
• 125000000304 alkynyl group Chemical group 0.000 claims description 11
• 125000000623 heterocyclic group Chemical group 0.000 claims description 11
• CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims description 11
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
• 125000000676 alkoxyimino group Chemical group 0.000 claims description 9
• 229910052794 bromium Inorganic materials 0.000 claims description 9
• 230000001149 cognitive effect Effects 0.000 claims description 9
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
• 239000000651 prodrug Substances 0.000 claims description 9
• 229940002612 prodrug Drugs 0.000 claims description 9
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 9
• 125000004076 pyridyl group Chemical group 0.000 claims description 9
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 9
• 125000005493 quinolyl group Chemical group 0.000 claims description 9
• 125000001422 pyrrolinyl group Chemical group 0.000 claims description 8
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 7
• BRUZQRBVNRKLJG-UHFFFAOYSA-N 2-methylpropyl carbamate Chemical compound CC(C)COC(N)=O BRUZQRBVNRKLJG-UHFFFAOYSA-N 0.000 claims description 6
• 230000008859 change Effects 0.000 claims description 6
• 230000007547 defect Effects 0.000 claims description 6
• HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 6
• 239000003937 drug carrier Substances 0.000 claims description 6
• SKRPCQXQBBHPKO-UHFFFAOYSA-N fluorocyclobutane Chemical compound FC1CCC1 SKRPCQXQBBHPKO-UHFFFAOYSA-N 0.000 claims description 6
• 125000002883 imidazolyl group Chemical group 0.000 claims description 6
• 229940047889 isobutyramide Drugs 0.000 claims description 6
• 125000002757 morpholinyl group Chemical group 0.000 claims description 6
• 125000004193 piperazinyl group Chemical group 0.000 claims description 6
• 125000005936 piperidyl group Chemical group 0.000 claims description 6
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 6
• 125000002098 pyridazinyl group Chemical group 0.000 claims description 6
• 230000001105 regulatory effect Effects 0.000 claims description 6
• ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 claims description 5
• 241000124008 Mammalia Species 0.000 claims description 5
• 235000019504 cigarettes Nutrition 0.000 claims description 5
• WGYKZJWCGVVSQN-UHFFFAOYSA-N mono-n-propyl amine Natural products CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 5
• 150000002825 nitriles Chemical class 0.000 claims description 5
• 201000000980 schizophrenia Diseases 0.000 claims description 5
• CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical compound C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 claims description 4
• KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 claims description 4
• CXWGKAYMVASWDQ-UHFFFAOYSA-N 1,2-dithiane Chemical compound C1CCSSC1 CXWGKAYMVASWDQ-UHFFFAOYSA-N 0.000 claims description 4
• WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims description 4
• YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 claims description 4
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
• KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 4
• 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
• 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
• 125000000259 cinnolinyl group Chemical class N1=NC(=CC2=CC=CC=C12)* 0.000 claims description 4
• 230000006735 deficit Effects 0.000 claims description 4
• 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 claims description 4
• 125000005056 dihydrothiazolyl group Chemical group S1C(NC=C1)* 0.000 claims description 4
• 208000035475 disorder Diseases 0.000 claims description 4
• LOZWAPSEEHRYPG-UHFFFAOYSA-N dithiane Natural products C1CSCCS1 LOZWAPSEEHRYPG-UHFFFAOYSA-N 0.000 claims description 4
• 125000002541 furyl group Chemical group 0.000 claims description 4
• 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 4
• 125000005956 isoquinolyl group Chemical group 0.000 claims description 4
• 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 claims description 4
• WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 4
• 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims description 4
• 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 4
• 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 4
• 238000000163 radioactive labelling Methods 0.000 claims description 4
• 125000001113 thiadiazolyl group Chemical group 0.000 claims description 4
• 125000000335 thiazolyl group Chemical group 0.000 claims description 4
• 125000001544 thienyl group Chemical group 0.000 claims description 4
• BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 4
• 125000004306 triazinyl group Chemical group 0.000 claims description 4
• 125000001425 triazolyl group Chemical group 0.000 claims description 4
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• SDVSGZYYDRMSJJ-UHFFFAOYSA-N 2-cyclobutyl-1,3-benzothiazole Chemical compound C1CCC1C1=NC2=CC=CC=C2S1 SDVSGZYYDRMSJJ-UHFFFAOYSA-N 0.000 claims description 2
• 208000019888 Circadian rhythm sleep disease Diseases 0.000 claims description 2
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