CN105283452B - 四唑酮衍生物 - Google Patents
四唑酮衍生物 Download PDFInfo
- Publication number
- CN105283452B CN105283452B CN201480032918.2A CN201480032918A CN105283452B CN 105283452 B CN105283452 B CN 105283452B CN 201480032918 A CN201480032918 A CN 201480032918A CN 105283452 B CN105283452 B CN 105283452B
- Authority
- CN
- China
- Prior art keywords
- phenyl
- dihydro
- tetrazol
- carbonyl
- oxo
- 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 - Fee Related
Links
- -1 Tetrazolium ketone Chemical class 0.000 title claims description 341
- 150000001875 compounds Chemical class 0.000 claims abstract description 234
- 239000003814 drug Substances 0.000 claims abstract description 16
- 229940079593 drug Drugs 0.000 claims abstract description 14
- 239000002585 base Substances 0.000 claims description 168
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 161
- RICSERNEQQBWKE-UHFFFAOYSA-N 4-(3-fluorophenyl)-5-oxotetrazole-1-carboxylic acid Chemical compound OC(=O)n1nnn(-c2cccc(F)c2)c1=O RICSERNEQQBWKE-UHFFFAOYSA-N 0.000 claims description 130
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 109
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 48
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 34
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
- 238000006243 chemical reaction Methods 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 125000000623 heterocyclic group Chemical group 0.000 claims description 20
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical class C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 18
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 17
- 206010064930 age-related macular degeneration Diseases 0.000 claims description 16
- 150000001408 amides Chemical class 0.000 claims description 15
- NEVDMOBXCWMCIL-UHFFFAOYSA-N 5-oxo-4-[3-(trifluoromethoxy)phenyl]tetrazole-1-carboxylic acid Chemical compound OC(=O)n1nnn(-c2cccc(OC(F)(F)F)c2)c1=O NEVDMOBXCWMCIL-UHFFFAOYSA-N 0.000 claims description 14
- 206010063837 Reperfusion injury Diseases 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- 208000028867 ischemia Diseases 0.000 claims description 13
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 claims description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 12
- BLRHMMGNCXNXJL-UHFFFAOYSA-N 1-methylindole Chemical compound C1=CC=C2N(C)C=CC2=C1 BLRHMMGNCXNXJL-UHFFFAOYSA-N 0.000 claims description 11
- JUIGFUOFSFZXNM-UHFFFAOYSA-N 4-cyclopropyl-n-methyl-5-oxo-n-pyridin-3-yltetrazole-1-carboxamide Chemical compound C=1C=CN=CC=1N(C)C(=O)N(C1=O)N=NN1C1CC1 JUIGFUOFSFZXNM-UHFFFAOYSA-N 0.000 claims description 11
- 206010061218 Inflammation Diseases 0.000 claims description 11
- 230000004054 inflammatory process Effects 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 206010016654 Fibrosis Diseases 0.000 claims description 10
- 206010029164 Nephrotic syndrome Diseases 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 208000009928 nephrosis Diseases 0.000 claims description 10
- 231100001027 nephrosis Toxicity 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 10
- 208000010412 Glaucoma Diseases 0.000 claims description 9
- 206010023421 Kidney fibrosis Diseases 0.000 claims description 9
- 206010046851 Uveitis Diseases 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 9
- 150000003851 azoles Chemical class 0.000 claims description 9
- FQXXSQDCDRQNQE-UHFFFAOYSA-N markiertes Thebain Natural products COC1=CC=C2C(N(CC3)C)CC4=CC=C(OC)C5=C4C23C1O5 FQXXSQDCDRQNQE-UHFFFAOYSA-N 0.000 claims description 9
- 208000010125 myocardial infarction Diseases 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 229930003945 thebaine Natural products 0.000 claims description 9
- 208000007788 Acute Liver Failure Diseases 0.000 claims description 8
- 206010000804 Acute hepatic failure Diseases 0.000 claims description 8
- 201000001320 Atherosclerosis Diseases 0.000 claims description 8
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 8
- 208000008069 Geographic Atrophy Diseases 0.000 claims description 8
- 206010019280 Heart failures Diseases 0.000 claims description 8
- 208000002260 Keloid Diseases 0.000 claims description 8
- 208000018737 Parkinson disease Diseases 0.000 claims description 8
- 201000009594 Systemic Scleroderma Diseases 0.000 claims description 8
- 206010042953 Systemic sclerosis Diseases 0.000 claims description 8
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 8
- TZIHFWKZFHZASV-UHFFFAOYSA-N anhydrous methyl formate Natural products COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 8
- 206010012601 diabetes mellitus Diseases 0.000 claims description 8
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 8
- 235000019253 formic acid Nutrition 0.000 claims description 8
- 230000001969 hypertrophic effect Effects 0.000 claims description 8
- 210000001117 keloid Anatomy 0.000 claims description 8
- 208000002780 macular degeneration Diseases 0.000 claims description 8
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 8
- 231100000241 scar Toxicity 0.000 claims description 8
- 230000009885 systemic effect Effects 0.000 claims description 8
- 208000024827 Alzheimer disease Diseases 0.000 claims description 7
- 208000031229 Cardiomyopathies Diseases 0.000 claims description 7
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 7
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 7
- 206010028980 Neoplasm Diseases 0.000 claims description 7
- 208000002193 Pain Diseases 0.000 claims description 7
- 206010037660 Pyrexia Diseases 0.000 claims description 7
- 206010038933 Retinopathy of prematurity Diseases 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 7
- 125000002757 morpholinyl group Chemical group 0.000 claims description 7
- 208000031225 myocardial ischemia Diseases 0.000 claims description 7
- 108010048734 sclerotin Proteins 0.000 claims description 7
- 208000011580 syndromic disease Diseases 0.000 claims description 7
- 206010023330 Keloid scar Diseases 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 230000003685 thermal hair damage Effects 0.000 claims description 6
- RERCGOXDTWFKKC-UHFFFAOYSA-N 4-(3-fluorophenyl)-n-methyl-5-oxo-n-(2-phenylethyl)tetrazole-1-carboxamide Chemical compound N1=NN(C=2C=C(F)C=CC=2)C(=O)N1C(=O)N(C)CCC1=CC=CC=C1 RERCGOXDTWFKKC-UHFFFAOYSA-N 0.000 claims description 5
- 208000032109 Transient ischaemic attack Diseases 0.000 claims description 5
- 206010052779 Transplant rejections Diseases 0.000 claims description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
- 230000008859 change Effects 0.000 claims description 5
- 230000007882 cirrhosis Effects 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- QJEPGNLCNSVDOD-UHFFFAOYSA-N n-benzyl-n-ethyl-4-(3-fluorophenyl)-5-oxotetrazole-1-carboxamide Chemical compound N1=NN(C=2C=C(F)C=CC=2)C(=O)N1C(=O)N(CC)CC1=CC=CC=C1 QJEPGNLCNSVDOD-UHFFFAOYSA-N 0.000 claims description 5
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 5
- 201000010875 transient cerebral ischemia Diseases 0.000 claims description 5
- 229940017219 methyl propionate Drugs 0.000 claims description 4
- RNXCGEXDIPDEMI-UHFFFAOYSA-N n-methyl-5-oxo-4-propyl-n-pyridin-3-yltetrazole-1-carboxamide Chemical compound O=C1N(CCC)N=NN1C(=O)N(C)C1=CC=CN=C1 RNXCGEXDIPDEMI-UHFFFAOYSA-N 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 150000003053 piperidines Chemical group 0.000 claims description 4
- 150000003235 pyrrolidines Chemical class 0.000 claims description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
- YEPBNCQVUMFKAI-UHFFFAOYSA-N 4-(3-fluorophenyl)-n-methyl-5-oxo-n-(3-phenylpropyl)tetrazole-1-carboxamide Chemical compound N1=NN(C=2C=C(F)C=CC=2)C(=O)N1C(=O)N(C)CCCC1=CC=CC=C1 YEPBNCQVUMFKAI-UHFFFAOYSA-N 0.000 claims description 3
- UTIJCCHKQRPZEJ-UHFFFAOYSA-N 4-(3-fluorophenyl)-n-methyl-5-oxo-n-pyridin-3-yltetrazole-1-carboxamide Chemical compound C=1C=CN=CC=1N(C)C(=O)N(C1=O)N=NN1C1=CC=CC(F)=C1 UTIJCCHKQRPZEJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 3
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 3
- 208000006011 Stroke Diseases 0.000 claims description 3
- 208000027418 Wounds and injury Diseases 0.000 claims description 3
- 125000004175 fluorobenzyl group Chemical group 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 208000017169 kidney disease Diseases 0.000 claims description 3
- ZOIZFAFRHIOWEA-UHFFFAOYSA-N n,n-diethyl-4-[4-(3-fluorophenyl)-5-oxotetrazole-1-carbonyl]piperazine-1-carboxamide Chemical compound C1CN(C(=O)N(CC)CC)CCN1C(=O)N1C(=O)N(C=2C=C(F)C=CC=2)N=N1 ZOIZFAFRHIOWEA-UHFFFAOYSA-N 0.000 claims description 3
- CLUNRAHSJKQDHA-UHFFFAOYSA-N n-(2-cyanoethyl)-4-(3-fluorophenyl)-n-methyl-5-oxotetrazole-1-carboxamide Chemical compound O=C1N(C(=O)N(CCC#N)C)N=NN1C1=CC=CC(F)=C1 CLUNRAHSJKQDHA-UHFFFAOYSA-N 0.000 claims description 3
- JMFNPHVYTRFDGR-UHFFFAOYSA-N n-(2-cyanoethyl)-n-cyclopropyl-4-(3-fluorophenyl)-5-oxotetrazole-1-carboxamide Chemical compound FC1=CC=CC(N2C(N(C(=O)N(CCC#N)C3CC3)N=N2)=O)=C1 JMFNPHVYTRFDGR-UHFFFAOYSA-N 0.000 claims description 3
- JEKPLVDYMVZQOK-UHFFFAOYSA-N n-[1-[4-(3-fluorophenyl)-5-oxotetrazole-1-carbonyl]piperidin-4-yl]acetamide Chemical compound C1CC(NC(=O)C)CCN1C(=O)N1C(=O)N(C=2C=C(F)C=CC=2)N=N1 JEKPLVDYMVZQOK-UHFFFAOYSA-N 0.000 claims description 3
- WUZMBOBZOASAIN-UHFFFAOYSA-N n-[1-[4-(3-fluorophenyl)-5-oxotetrazole-1-carbonyl]pyrrolidin-3-yl]acetamide Chemical compound C1C(NC(=O)C)CCN1C(=O)N1C(=O)N(C=2C=C(F)C=CC=2)N=N1 WUZMBOBZOASAIN-UHFFFAOYSA-N 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000005936 piperidyl group Chemical group 0.000 claims description 3
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 claims description 3
- NDOVLWQBFFJETK-UHFFFAOYSA-N 1,4-thiazinane 1,1-dioxide Chemical compound O=S1(=O)CCNCC1 NDOVLWQBFFJETK-UHFFFAOYSA-N 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims description 2
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 2
- XKVUYEYANWFIJX-UHFFFAOYSA-N 5-methyl-1h-pyrazole Chemical compound CC1=CC=NN1 XKVUYEYANWFIJX-UHFFFAOYSA-N 0.000 claims description 2
- AULWPXHFRBLPAE-UHFFFAOYSA-N 6-chloropyridine Chemical compound ClC1=C=CC=C[N]1 AULWPXHFRBLPAE-UHFFFAOYSA-N 0.000 claims description 2
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 claims description 2
- IIXRENZGQHGUCT-UHFFFAOYSA-N N-benzyl-4-cyclopropyl-5-oxo-N-propan-2-yltetrazole-1-carboxamide Chemical compound CC(C)N(Cc1ccccc1)C(=O)n1nnn(C2CC2)c1=O IIXRENZGQHGUCT-UHFFFAOYSA-N 0.000 claims description 2
- ZUSWDTWYONAOPH-UHFFFAOYSA-N [2-(trifluoromethyl)phenyl]hydrazine;hydrochloride Chemical group [Cl-].[NH3+]NC1=CC=CC=C1C(F)(F)F ZUSWDTWYONAOPH-UHFFFAOYSA-N 0.000 claims description 2
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 2
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 2
- 125000005805 dimethoxy phenyl group Chemical group 0.000 claims description 2
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- RQCNHUCCQJMSRG-UHFFFAOYSA-N tert-butyl piperidine-1-carboxylate Chemical group CC(C)(C)OC(=O)N1CCCCC1 RQCNHUCCQJMSRG-UHFFFAOYSA-N 0.000 claims description 2
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 2
- WUZMBOBZOASAIN-LLVKDONJSA-N n-[(3r)-1-[4-(3-fluorophenyl)-5-oxotetrazole-1-carbonyl]pyrrolidin-3-yl]acetamide Chemical compound C1[C@H](NC(=O)C)CCN1C(=O)N1C(=O)N(C=2C=C(F)C=CC=2)N=N1 WUZMBOBZOASAIN-LLVKDONJSA-N 0.000 claims 2
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 claims 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 1
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims 1
- IXKMQKONAVRFRA-UHFFFAOYSA-N n,n-dimethyl-2-[4-[5-oxo-4-[3-(trifluoromethoxy)phenyl]tetrazole-1-carbonyl]piperazin-1-yl]acetamide Chemical compound C1CN(CC(=O)N(C)C)CCN1C(=O)N1C(=O)N(C=2C=C(OC(F)(F)F)C=CC=2)N=N1 IXKMQKONAVRFRA-UHFFFAOYSA-N 0.000 claims 1
- WUZMBOBZOASAIN-NSHDSACASA-N n-[(3s)-1-[4-(3-fluorophenyl)-5-oxotetrazole-1-carbonyl]pyrrolidin-3-yl]acetamide Chemical compound C1[C@@H](NC(=O)C)CCN1C(=O)N1C(=O)N(C=2C=C(F)C=CC=2)N=N1 WUZMBOBZOASAIN-NSHDSACASA-N 0.000 claims 1
- 210000001957 retinal vein Anatomy 0.000 claims 1
- XPDWGBQVDMORPB-UHFFFAOYSA-N trifluoromethane acid Natural products FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 claims 1
- GQHWSLKNULCZGI-UHFFFAOYSA-N trifluoromethoxybenzene Chemical compound FC(F)(F)OC1=CC=CC=C1 GQHWSLKNULCZGI-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 description 145
- 238000003786 synthesis reaction Methods 0.000 description 137
- 238000002360 preparation method Methods 0.000 description 133
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 46
- 239000000203 mixture Substances 0.000 description 30
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 27
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 22
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 239000007787 solid Substances 0.000 description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 108010073376 CB2 Cannabinoid Receptor Proteins 0.000 description 9
- 102000009135 CB2 Cannabinoid Receptor Human genes 0.000 description 9
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 9
- 230000001684 chronic effect Effects 0.000 description 9
- 238000005259 measurement Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 208000004644 retinal vein occlusion Diseases 0.000 description 9
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 230000006378 damage Effects 0.000 description 7
- 238000010828 elution Methods 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 7
- 230000008020 evaporation Effects 0.000 description 7
- 208000012947 ischemia reperfusion injury Diseases 0.000 description 7
- 238000002953 preparative HPLC Methods 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- UQRJCIVXFYCUDV-UHFFFAOYSA-N 4-(3-fluorophenyl)-1H-tetrazol-5-one Chemical compound Fc1cccc(c1)-n1nn[nH]c1=O UQRJCIVXFYCUDV-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 230000000302 ischemic effect Effects 0.000 description 6
- 201000006417 multiple sclerosis Diseases 0.000 description 6
- 230000010410 reperfusion Effects 0.000 description 6
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 5
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 5
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000004761 fibrosis Effects 0.000 description 5
- 210000000056 organ Anatomy 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- MSLVTZDNJRIWSU-UHFFFAOYSA-N 1-(3-chlorophenyl)-2h-tetrazol-5-one Chemical compound ClC1=CC=CC(N2C(N=NN2)=O)=C1 MSLVTZDNJRIWSU-UHFFFAOYSA-N 0.000 description 4
- IECMOFZIMWVOAS-UHFFFAOYSA-N 4,4-dimethylpiperidine Chemical compound CC1(C)CCNCC1 IECMOFZIMWVOAS-UHFFFAOYSA-N 0.000 description 4
- 108010073366 CB1 Cannabinoid Receptor Proteins 0.000 description 4
- 102000009132 CB1 Cannabinoid Receptor Human genes 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 208000017442 Retinal disease Diseases 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 239000000470 constituent Substances 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- HDCCJUCOIKLZNM-ZCFIWIBFSA-N n-[(3r)-pyrrolidin-3-yl]acetamide Chemical compound CC(=O)N[C@@H]1CCNC1 HDCCJUCOIKLZNM-ZCFIWIBFSA-N 0.000 description 4
- HDCCJUCOIKLZNM-LURJTMIESA-N n-[(3s)-pyrrolidin-3-yl]acetamide Chemical compound CC(=O)N[C@H]1CCNC1 HDCCJUCOIKLZNM-LURJTMIESA-N 0.000 description 4
- VGEMYWDUTPQWBN-UHFFFAOYSA-N n-ethyl-2-methoxyethanamine Chemical compound CCNCCOC VGEMYWDUTPQWBN-UHFFFAOYSA-N 0.000 description 4
- NHMWGGURJSUYGU-UHFFFAOYSA-N n-ethyl-n-pyrrolidin-3-ylacetamide Chemical compound CCN(C(C)=O)C1CCNC1 NHMWGGURJSUYGU-UHFFFAOYSA-N 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 229940095574 propionic acid Drugs 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 230000001052 transient effect Effects 0.000 description 4
- VZNCSZQPNIEEMN-UHFFFAOYSA-N 1-fluoro-2-isocyanatobenzene Chemical compound FC1=CC=CC=C1N=C=O VZNCSZQPNIEEMN-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical compound NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 description 3
- 150000001200 N-acyl ethanolamides Chemical class 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 206010038923 Retinopathy Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 3
- 239000002269 analeptic agent Substances 0.000 description 3
- 230000017531 blood circulation Effects 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 210000000170 cell membrane Anatomy 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
- 239000013078 crystal Substances 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000002621 endocannabinoid Substances 0.000 description 3
- 239000007888 film coating Substances 0.000 description 3
- 238000009501 film coating Methods 0.000 description 3
- 230000002962 histologic effect Effects 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- RIKWVZGZRYDACA-UHFFFAOYSA-N 1-fluoro-3-isocyanatobenzene Chemical compound FC1=CC=CC(N=C=O)=C1 RIKWVZGZRYDACA-UHFFFAOYSA-N 0.000 description 2
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- XBQNZPDIRJPFAI-UHFFFAOYSA-N 3,3-dimethylpyrrolidine Chemical compound CC1(C)CCNC1 XBQNZPDIRJPFAI-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- 208000032544 Cicatrix Diseases 0.000 description 2
- 206010066786 Diabetic keratopathy Diseases 0.000 description 2
- 206010051920 Glomerulonephropathy Diseases 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- QNZWBDPQZFVVSF-UHFFFAOYSA-N N-butyl-2-[4-[5-oxo-4-[3-(trifluoromethoxy)phenyl]tetrazole-1-carbonyl]piperazin-1-yl]acetamide Chemical compound CCCCNC(=O)CN1CCN(CC1)C(=O)n1nnn(-c2cccc(OC(F)(F)F)c2)c1=O QNZWBDPQZFVVSF-UHFFFAOYSA-N 0.000 description 2
- RQWZXPVOODBDHF-UHFFFAOYSA-N N-ethyl-2-[4-[5-oxo-4-[3-(trifluoromethoxy)phenyl]tetrazole-1-carbonyl]piperazin-1-yl]acetamide Chemical compound CCNC(=O)CN1CCN(CC1)C(=O)n1nnn(-c2cccc(OC(F)(F)F)c2)c1=O RQWZXPVOODBDHF-UHFFFAOYSA-N 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
- 206010069385 Ocular ischaemic syndrome Diseases 0.000 description 2
- 229920003110 Primojel Polymers 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 241000219061 Rheum Species 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 231100000836 acute liver failure Toxicity 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 229930003827 cannabinoid Natural products 0.000 description 2
- 239000003557 cannabinoid Substances 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 230000027950 fever generation Effects 0.000 description 2
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 208000007565 gingivitis Diseases 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- UIWVKFKFKOLMOU-GWCFXTLKSA-N methyl (2s,3s)-2-[[4-(3-fluorophenyl)-5-oxotetrazole-1-carbonyl]-methylamino]-3-methylpentanoate Chemical class O=C1N(C(=O)N(C)[C@@H]([C@@H](C)CC)C(=O)OC)N=NN1C1=CC=CC(F)=C1 UIWVKFKFKOLMOU-GWCFXTLKSA-N 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 210000004165 myocardium Anatomy 0.000 description 2
- YBSVIYBDGVOMQH-UHFFFAOYSA-N n-[1-[4-(3-fluorophenyl)-5-oxotetrazole-1-carbonyl]pyrrolidin-3-yl]-n-methylacetamide Chemical compound C1C(N(C)C(C)=O)CCN1C(=O)N1C(=O)N(C=2C=C(F)C=CC=2)N=N1 YBSVIYBDGVOMQH-UHFFFAOYSA-N 0.000 description 2
- SASNBVQSOZSTPD-UHFFFAOYSA-N n-methylphenethylamine Chemical compound CNCCC1=CC=CC=C1 SASNBVQSOZSTPD-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 230000010355 oscillation Effects 0.000 description 2
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 230000002028 premature Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 230000037387 scars Effects 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- MUWAEBAXEVXDRT-YFKPBYRVSA-N (2s)-2-methoxypyrrolidine Chemical class CO[C@H]1CCCN1 MUWAEBAXEVXDRT-YFKPBYRVSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-UHFFFAOYSA-N 0.000 description 1
- NVNPLEPBDPJYRZ-UHFFFAOYSA-N 1-(bromomethyl)-4-fluorobenzene Chemical compound FC1=CC=C(CBr)C=C1 NVNPLEPBDPJYRZ-UHFFFAOYSA-N 0.000 description 1
- HHIRBXHEYVDUAM-UHFFFAOYSA-N 1-chloro-3-isocyanatobenzene Chemical compound ClC1=CC=CC(N=C=O)=C1 HHIRBXHEYVDUAM-UHFFFAOYSA-N 0.000 description 1
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 1
- GUTNODKBPXZJOD-UHFFFAOYSA-N 1-cyclopropyl-2h-tetrazol-5-one Chemical compound O=C1NN=NN1C1CC1 GUTNODKBPXZJOD-UHFFFAOYSA-N 0.000 description 1
- DSVGFKBFFICWLZ-UHFFFAOYSA-N 1-fluoro-4-isocyanatobenzene Chemical compound FC1=CC=C(N=C=O)C=C1 DSVGFKBFFICWLZ-UHFFFAOYSA-N 0.000 description 1
- NPOVTGVGOBJZPY-UHFFFAOYSA-N 1-isocyanato-3-methoxybenzene Chemical compound COC1=CC=CC(N=C=O)=C1 NPOVTGVGOBJZPY-UHFFFAOYSA-N 0.000 description 1
- CPPGZWWUPFWALU-UHFFFAOYSA-N 1-isocyanato-3-methylbenzene Chemical compound CC1=CC=CC(N=C=O)=C1 CPPGZWWUPFWALU-UHFFFAOYSA-N 0.000 description 1
- FMDGXCSMDZMDHZ-UHFFFAOYSA-N 1-isocyanato-4-methoxybenzene Chemical compound COC1=CC=C(N=C=O)C=C1 FMDGXCSMDZMDHZ-UHFFFAOYSA-N 0.000 description 1
- VLEDIUXXQKUSRF-UHFFFAOYSA-N 1-methyl-3-pyrrolidin-2-ylpyrazole Chemical class CN1C=CC(C2NCCC2)=N1 VLEDIUXXQKUSRF-UHFFFAOYSA-N 0.000 description 1
- HJMDKIXQKXDUMY-UHFFFAOYSA-N 1-methyl-5-pyrrolidin-2-ylpyrazole Chemical class CN1N=CC=C1C1NCCC1 HJMDKIXQKXDUMY-UHFFFAOYSA-N 0.000 description 1
- PHODFIDDEBEGCS-UHFFFAOYSA-N 2,2-dimethylpyrrolidine Chemical compound CC1(C)CCCN1 PHODFIDDEBEGCS-UHFFFAOYSA-N 0.000 description 1
- SDGKUVSVPIIUCF-UHFFFAOYSA-N 2,6-dimethylpiperidine Chemical compound CC1CCCC(C)N1 SDGKUVSVPIIUCF-UHFFFAOYSA-N 0.000 description 1
- HNJWKRMESUMDQE-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-n-methylethanamine Chemical compound CNCCC1=CC=C(OC)C(OC)=C1 HNJWKRMESUMDQE-UHFFFAOYSA-N 0.000 description 1
- ZDCXMSDSTZZWAX-UHFFFAOYSA-N 2-(4-fluorophenyl)pyrrolidine Chemical class C1=CC(F)=CC=C1C1NCCC1 ZDCXMSDSTZZWAX-UHFFFAOYSA-N 0.000 description 1
- RVKSDKZRQYLEAT-UHFFFAOYSA-N 2-chloro-3-(trifluoromethoxy)benzoyl chloride Chemical compound FC(F)(F)Oc1cccc(C(Cl)=O)c1Cl RVKSDKZRQYLEAT-UHFFFAOYSA-N 0.000 description 1
- PKEMXTIVOBWBNO-UHFFFAOYSA-N 2-chloro-3-(trifluoromethyl)benzoyl chloride Chemical compound FC(F)(F)C1=CC=CC(C(Cl)=O)=C1Cl PKEMXTIVOBWBNO-UHFFFAOYSA-N 0.000 description 1
- OCLDSIAHVMNJMC-UHFFFAOYSA-N 2-chloro-4-(trifluoromethyl)benzoyl chloride Chemical compound FC(F)(F)C1=CC=C(C(Cl)=O)C(Cl)=C1 OCLDSIAHVMNJMC-UHFFFAOYSA-N 0.000 description 1
- FNRMMDCDHWCQTH-UHFFFAOYSA-N 2-chloropyridine;3-chloropyridine;4-chloropyridine Chemical compound ClC1=CC=NC=C1.ClC1=CC=CN=C1.ClC1=CC=CC=N1 FNRMMDCDHWCQTH-UHFFFAOYSA-N 0.000 description 1
- IBZKBSXREAQDTO-UHFFFAOYSA-N 2-methoxy-n-(2-methoxyethyl)ethanamine Chemical compound COCCNCCOC IBZKBSXREAQDTO-UHFFFAOYSA-N 0.000 description 1
- ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 description 1
- DNYWGUIJLFDIPD-UHFFFAOYSA-N 2-methoxypiperidine Chemical class COC1CCCCN1 DNYWGUIJLFDIPD-UHFFFAOYSA-N 0.000 description 1
- OXXXNXISRXFPBK-UHFFFAOYSA-N 2-oxa-8-azaspiro[4.5]decane Chemical compound C1OCCC21CCNCC2 OXXXNXISRXFPBK-UHFFFAOYSA-N 0.000 description 1
- KVTUSMPNLUCCQO-UHFFFAOYSA-N 3,3-difluoropyrrolidine Chemical compound FC1(F)CCNC1 KVTUSMPNLUCCQO-UHFFFAOYSA-N 0.000 description 1
- CDODDZJCEADUQQ-UHFFFAOYSA-N 3,3-dimethylpiperidine Chemical compound CC1(C)CCCNC1 CDODDZJCEADUQQ-UHFFFAOYSA-N 0.000 description 1
- OZHWHTICSNFGBZ-UHFFFAOYSA-N 3-(cyclopropylamino)propanenitrile Chemical compound N#CCCNC1CC1 OZHWHTICSNFGBZ-UHFFFAOYSA-N 0.000 description 1
- UNIJBMUBHBAUET-UHFFFAOYSA-N 3-(methylamino)propanenitrile Chemical compound CNCCC#N UNIJBMUBHBAUET-UHFFFAOYSA-N 0.000 description 1
- PBOOZQFGWNZNQE-UHFFFAOYSA-N 3-bromobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC(Br)=C1 PBOOZQFGWNZNQE-UHFFFAOYSA-N 0.000 description 1
- SFYQTXFSGQMRSM-UHFFFAOYSA-N 3-chloro-2-(trifluoromethyl)benzoyl chloride Chemical compound FC(F)(F)C1=C(Cl)C=CC=C1C(Cl)=O SFYQTXFSGQMRSM-UHFFFAOYSA-N 0.000 description 1
- WHIHIKVIWVIIER-UHFFFAOYSA-N 3-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC(Cl)=C1 WHIHIKVIWVIIER-UHFFFAOYSA-N 0.000 description 1
- ISULZYQDGYXDFW-UHFFFAOYSA-N 3-methylbutanoyl chloride Chemical compound CC(C)CC(Cl)=O ISULZYQDGYXDFW-UHFFFAOYSA-N 0.000 description 1
- PRRFFTYUBPGHLE-UHFFFAOYSA-N 3-phenylpyrrolidine Chemical compound C1NCCC1C1=CC=CC=C1 PRRFFTYUBPGHLE-UHFFFAOYSA-N 0.000 description 1
- RKIDDEGICSMIJA-UHFFFAOYSA-N 4-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1 RKIDDEGICSMIJA-UHFFFAOYSA-N 0.000 description 1
- TVGVHXVLMROUII-UHFFFAOYSA-N 4-isocyanato-1-methylindole Chemical compound C1=CC=C2N(C)C=CC2=C1N=C=O TVGVHXVLMROUII-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- ZEYSHALLPAKUHG-UHFFFAOYSA-N 4-methoxypiperidine Chemical class COC1CCNCC1 ZEYSHALLPAKUHG-UHFFFAOYSA-N 0.000 description 1
- MGYGFNQQGAQEON-UHFFFAOYSA-N 4-tolyl isocyanate Chemical compound CC1=CC=C(N=C=O)C=C1 MGYGFNQQGAQEON-UHFFFAOYSA-N 0.000 description 1
- RDQRMCJCROUHOF-UHFFFAOYSA-N 5-isocyanato-1-methylindole Chemical compound O=C=NC1=CC=C2N(C)C=CC2=C1 RDQRMCJCROUHOF-UHFFFAOYSA-N 0.000 description 1
- FMEBIWNKYZUWFV-UHFFFAOYSA-N 6-chloropyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)N=C1 FMEBIWNKYZUWFV-UHFFFAOYSA-N 0.000 description 1
- IGFFEMNFESMQQW-UHFFFAOYSA-N 6-fluoro-1,2,3,4-tetrahydroisoquinoline Chemical class C1NCCC2=CC(F)=CC=C21 IGFFEMNFESMQQW-UHFFFAOYSA-N 0.000 description 1
- NNPKUXMSIKSIDR-UHFFFAOYSA-N 6-isocyanato-1-methylindole Chemical compound C1=C(N=C=O)C=C2N(C)C=CC2=C1 NNPKUXMSIKSIDR-UHFFFAOYSA-N 0.000 description 1
- ZZOKVYOCRSMTSS-UHFFFAOYSA-N 9h-fluoren-9-ylmethyl carbamate Chemical compound C1=CC=C2C(COC(=O)N)C3=CC=CC=C3C2=C1 ZZOKVYOCRSMTSS-UHFFFAOYSA-N 0.000 description 1
- 101100230376 Acetivibrio thermocellus (strain ATCC 27405 / DSM 1237 / JCM 9322 / NBRC 103400 / NCIMB 10682 / NRRL B-4536 / VPI 7372) celI gene Proteins 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 101800000734 Angiotensin-1 Proteins 0.000 description 1
- 102400000344 Angiotensin-1 Human genes 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 102000007527 Autoreceptors Human genes 0.000 description 1
- 108010071131 Autoreceptors Proteins 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 101800004538 Bradykinin Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 108090000932 Calcitonin Gene-Related Peptide Proteins 0.000 description 1
- 102100025588 Calcitonin gene-related peptide 1 Human genes 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 102100033868 Cannabinoid receptor 1 Human genes 0.000 description 1
- 102100036214 Cannabinoid receptor 2 Human genes 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 206010063209 Chronic allograft nephropathy Diseases 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 101150106726 Cnr2 gene Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 201000001200 Crouzon syndrome-acanthosis nigricans syndrome Diseases 0.000 description 1
- 244000285774 Cyperus esculentus Species 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
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 1
- 101000710899 Homo sapiens Cannabinoid receptor 1 Proteins 0.000 description 1
- 101000875075 Homo sapiens Cannabinoid receptor 2 Proteins 0.000 description 1
- 101001116937 Homo sapiens Protocadherin alpha-4 Proteins 0.000 description 1
- 101001116931 Homo sapiens Protocadherin alpha-6 Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 102100035792 Kininogen-1 Human genes 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 244000134336 Malus baccata Species 0.000 description 1
- 235000005079 Malus baccata Nutrition 0.000 description 1
- 208000029578 Muscle disease Diseases 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- GQCKTIWYYYUEQD-UHFFFAOYSA-N N-methyl-N-pyridin-3-ylcarbamoyl chloride Chemical compound CN(C(Cl)=O)c1cccnc1 GQCKTIWYYYUEQD-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000006057 Non-nutritive feed additive Substances 0.000 description 1
- 244000131316 Panax pseudoginseng Species 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 229920002873 Polyethylenimine Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229920003081 Povidone K 30 Polymers 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 239000012317 TBTU Substances 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
- 235000009754 Vitis X bourquina Nutrition 0.000 description 1
- 235000012333 Vitis X labruscana Nutrition 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000000278 alkyl amino alkyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 1
- XLJMAIOERFSOGZ-UHFFFAOYSA-N anhydrous cyanic acid Natural products OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 1
- 230000003510 anti-fibrotic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
- KDPAWGWELVVRCH-UHFFFAOYSA-M bromoacetate Chemical compound [O-]C(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-M 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000003556 cannabinoid 2 receptor agonist Substances 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- LMLOMPMKDILPOS-UHFFFAOYSA-N carbonochloridic acid;trichloromethyl carbonochloridate Chemical compound OC(Cl)=O.ClC(=O)OC(Cl)(Cl)Cl LMLOMPMKDILPOS-UHFFFAOYSA-N 0.000 description 1
- 230000003293 cardioprotective effect Effects 0.000 description 1
- 230000002612 cardiopulmonary effect Effects 0.000 description 1
- 210000001638 cerebellum Anatomy 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 208000037902 enteropathy Diseases 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 229940031098 ethanolamine Drugs 0.000 description 1
- IOLQWGVDEFWYNP-UHFFFAOYSA-N ethyl 2-bromo-2-methylpropanoate Chemical compound CCOC(=O)C(C)(C)Br IOLQWGVDEFWYNP-UHFFFAOYSA-N 0.000 description 1
- UBUCGEQKZOBBLK-UHFFFAOYSA-N ethyl formate;piperazine Chemical compound CCOC=O.C1CNCCN1 UBUCGEQKZOBBLK-UHFFFAOYSA-N 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 208000028774 intestinal disease Diseases 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000006662 intracellular pathway Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 208000037906 ischaemic injury Diseases 0.000 description 1
- 230000002530 ischemic preconditioning effect Effects 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
- 238000001471 micro-filtration Methods 0.000 description 1
- 210000000274 microglia Anatomy 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 201000000585 muscular atrophy Diseases 0.000 description 1
- 210000000651 myofibroblast Anatomy 0.000 description 1
- IWJSZNIFIDAYDY-UHFFFAOYSA-N n,n-diethylpiperazine-1-carboxamide Chemical compound CCN(CC)C(=O)N1CCNCC1 IWJSZNIFIDAYDY-UHFFFAOYSA-N 0.000 description 1
- HFWOEYXMOCJUBF-UHFFFAOYSA-N n-benzyl-n-ethylcarbamoyl chloride Chemical compound CCN(C(Cl)=O)CC1=CC=CC=C1 HFWOEYXMOCJUBF-UHFFFAOYSA-N 0.000 description 1
- KOEKUQRWTOSZOR-UHFFFAOYSA-N n-methyl-n-pyrrolidin-3-ylacetamide Chemical compound CC(=O)N(C)C1CCNC1 KOEKUQRWTOSZOR-UHFFFAOYSA-N 0.000 description 1
- HNBDRPTVWVGKBR-UHFFFAOYSA-N n-pentanoic acid methyl ester Natural products CCCCC(=O)OC HNBDRPTVWVGKBR-UHFFFAOYSA-N 0.000 description 1
- YLWUSMHZABTZGP-UHFFFAOYSA-N n-piperidin-4-ylacetamide Chemical compound CC(=O)NC1CCNCC1 YLWUSMHZABTZGP-UHFFFAOYSA-N 0.000 description 1
- HDCCJUCOIKLZNM-UHFFFAOYSA-N n-pyrrolidin-3-ylacetamide Chemical compound CC(=O)NC1CCNC1 HDCCJUCOIKLZNM-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100001160 nonlethal Toxicity 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003605 opacifier Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000008816 organ damage Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 229940116315 oxalic acid Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229920001721 polyimide Polymers 0.000 description 1
- 239000009719 polyimide resin Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- RDRCCJPEJDWSRJ-UHFFFAOYSA-N pyridine;1h-pyrrole Chemical compound C=1C=CNC=1.C1=CC=NC=C1 RDRCCJPEJDWSRJ-UHFFFAOYSA-N 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 238000003653 radioligand binding assay Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CKXZPVPIDOJLLM-UHFFFAOYSA-N tert-butyl n-piperidin-4-ylcarbamate Chemical class CC(C)(C)OC(=O)NC1CCNCC1 CKXZPVPIDOJLLM-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- 230000000287 tissue oxygenation Effects 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- PHLBKPHSAVXXEF-UHFFFAOYSA-N trazodone Chemical class ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 PHLBKPHSAVXXEF-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 238000007631 vascular surgery Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Diabetes (AREA)
- Immunology (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Ophthalmology & Optometry (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Psychology (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Transplantation (AREA)
- Hospice & Palliative Care (AREA)
- Pulmonology (AREA)
- Psychiatry (AREA)
- Vascular Medicine (AREA)
- Dermatology (AREA)
- Gastroenterology & Hepatology (AREA)
Abstract
本发明涉及式(I)的化合物,其中R1和R2是如在说明书中和在权利要求书中限定的。式(I)的化合物可以用作药物。
Description
本发明涉及可用于哺乳动物中的治疗和/或预防的有机化合物,并且尤其涉及作为大麻素受体2的优先激动剂的化合物。
本发明尤其涉及式(I)的化合物,
其中
R1是正丙基、异丁基、环丙基、3-氟苯基、6-氯吡啶-3-基、3-氯苯基、 4-氯苯基、3-三氟甲氧基苯基、2-(三氟甲基)苯基、3-(三氟甲基)苯基、4-(三氟甲基)苯基、2,6-二氟苯基、2,5-二氟苯基、3,4-二氟苯基、3,5-二氟苯基、 3-甲基苯基、4-甲基苯基、3-甲氧基苯基、4-甲氧基苯基、2,3-二氯苯基、 1-甲基吲哚基或3-溴苯基;
R2是-C(O)NR3R4或R5;
R3和R4中的一个是氢、烷基、环烷基或烷氧基烷基,而另一个是 -(CH2)n-R6;
或R3和R4与它们所连接的氮原子一起形成杂环基或取代的杂环基,其中杂环基是哌啶基、吗啉基、吡咯烷基、3,4-二氢-1H-异喹啉基、氮杂环丁基、哌嗪基、1,1-二氧代硫代吗啉基或2-氧杂-8-氮杂-螺[4.5]癸基,并且其中取代的杂环基是被一个选自卤素、烷基、氰基、烷氧基烷基、氨基羰基、二烷基氨基羰基、二烷基氨基羰基烷基、烷基氨基羰基烷基、苯基、卤代苯基、苯基烷基、卤代苯基烷基、甲基吡唑基、甲基异唑基、烷氧基烷基、烷基羰基氨基、烷基羰基、烷氧基羰基、烷基-[1,2,4]二唑基、吡咯烷基羰基烷基、吡嗪基、(烷基)(烷基羰基)氨基、烷基异唑基和吗啉基羰基烷基的取代基取代的或被两个独立地选自烷基、卤素、烷氧基羰基和烷氧基羰基氨基的取代基取代的杂环基;
R5是卤代苯基烷基、烷氧基羰基哌啶基、烷氧基羰基烷基、(烷基磺酰基)(烷基)[1,2,4]三唑基烷基或吗啉基羰基烷基;
R6是烷氧基、二烷氧基苯基、氰基、苯基、吡啶基或烷氧基羰基烷基;并且
n是0、1、2或3;
或其药用盐或酯;
前提是排除以下各项:
1-环丙基-4-(吡咯烷-1-羰基)-1,4-二氢-四唑-5-酮;
1-环丙基-4-(2-甲基-吡咯烷-1-羰基)-1,4-二氢-四唑-5-酮;
1-环丙基-4-(2,5-二甲基-吡咯烷-1-羰基)-1,4-二氢-四唑-5-酮;
1-环丙基-4-(2,6-二甲基-哌啶-1-羰基)-1,4-二氢-四唑-5-酮;
4-环丙基-5-氧代-4,5-二氢-四唑-1-甲酸苄基-异丙基-酰胺;
[4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-基]-乙酸乙酯;
2-[4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-基]-丙酸乙酯;
3-[4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-基]-丙酸甲酯;
1-(2,3-二氯-苯基)-4-(2-甲基-哌啶-1-羰基)-1,4-二氢-四唑-5-酮;
1-(2,6-二氟苯基)-4-(3,4-二氢-1H-异喹啉-2-羰基)四唑-5-酮;
4-(2,6-二氟苯基)-5-氧代-N-苯基-正丙基-四唑-1-甲酰胺;
4-(2,6-二氟苯基)-N-乙基-5-氧代-N-苯基-四唑-1-甲酰胺;
4-(2,6-二氟苯基)-N-甲基-5-氧代-N-苯基-四唑-1-甲酰胺;
4-(2,6-二氟苯基)-N-异丙基-5-氧代-N-苯基-四唑-1-甲酰胺;
N-环己基-4-(2,6-二氟苯基)-5-氧代-N-苯基-四唑-1-甲酰胺;
4-(2,6-二氟苯基)-N-甲基-5-氧代-N-(2-吡啶基)四唑-1-甲酰胺;
N,4-二环丙基-5-氧代-N-苯基-四唑-1-甲酰胺;
N-丁基-4-环丙基-5-氧代-N-苯基-四唑-1-甲酰胺;
4-环丙基-N-异丁基-5-氧代-N-苯基-四唑-1-甲酰胺;
4-环丙基-N-异丙基-5-氧代-N-苯基-四唑-1-甲酰胺;
4-环丙基-5-氧代-N-苯基-正丙基-四唑-1-甲酰胺;
4-环丙基-N-甲基-5-氧代-N-苯基-四唑-1-甲酰胺;
4-环丙基-N-乙基-5-氧代-N-苯基-四唑-1-甲酰胺;
4-环丙基-5-氧代-N-苯基-N-仲丁基-四唑-1-甲酰胺;
N-(1-苄基-2-甲基-丙基)-4-环丙基-5-氧代-N-苯基-四唑-1-甲酰胺;
1-(2-甲基哌啶-1-羰基)-4-(对-甲苯基)四唑-5-酮;
1-(2-甲基哌啶-1-羰基)-4-(间-甲苯基)四唑-5-酮;
N-异丙基-5-氧代-N-苯基-4-丙基-四唑-1-甲酰胺;
1-(4-氯苯基)-4-[(2-氟苯基)甲基]四唑-5-酮;
1-(4-氯苯基)-4-[(3-氟苯基)甲基]四唑-5-酮;
1-(4-氯苯基)-4-[(3-氯苯基)甲基]四唑-5-酮;
1-[(4-溴苯基)甲基]-4-(4-氯苯基)四唑-5-酮;和
3-[5-氧代-4-(对-甲苯基)四唑-1-基]丙酸甲酯。
式(I)化合物特别可用于治疗或预防例如疼痛(pain),动脉粥样硬化(atherosclerosis),老年性黄斑退化症(age-related macular degeneration),糖尿病性视网膜病变(diabetic retinopathy),青光眼(glaucoma),视网膜静脉闭塞(retinal veinocclusion),早产儿视网膜病(retinopathy of prematurity),眼缺血综合征(ocularischemic syndrome),地图样萎缩(geographic atrophy),糖尿病(diabetes mellitus),炎症(inflammation),炎性肠病(inflammatory bowel disease),缺血-再灌注损伤(ischemia-reperfusion injury),急性肝衰竭 (acute liver failure),肝纤维化(liverfibrosis),肺纤维化(lung fibrosis),肾纤维化(kidney fibrosis),系统性纤维化(systemic fibrosis),急性同种异体移植排斥(acute allografi rejection),慢性同种异体移植肾病(chronic allograft nephropathy),糖尿病肾病(diabetic nephropathy),肾小球肾病 (glomerulonephropathy),心肌病(cardiomyopathy),心力衰竭(heartfailure),心肌缺血(myocardial ischemia),心肌梗死(myocardial infarction),系统性硬化(systemic sclerosis),热损伤(thermal injury),烧伤(burning),肥大性疤痕(hypertrophic scars),瘢痕疙瘩(keloids),龈炎发热(gingivitis pyrexia),肝硬化(liver cirrhosis)或肿瘤(tumors),骨质调节(regulation of bone mass),肌萎缩侧索硬化(amyotrophic lateral sclerosis),多发性硬化(multiple sclerosis),阿尔茨海默病(Alzheimer′s disease),帕金森病(Parkinson′s disease),卒中 (stroke),一过性缺血发作(transient ischemic attack)或葡萄膜炎(uveitis)。
式(I)的化合物尤其可用于治疗或预防糖尿病性视网膜病变、视网膜静脉闭塞或葡萄膜炎。
大麻素受体是一类细胞膜受体,属于G蛋白-偶联受体超家族。目前存在两种已知亚型,称为大麻素受体1(CB1)和大麻素受体2(CB2)。CB1 受体主要表达在中枢神经(即杏仁核小脑,海马体)系统中并且在外周中以较少量表达。由CNR2基因编码的CB2主要在免疫系统的细胞,如巨噬细胞和T-细胞上(Ashton,J.C.等Curr Neuropharmacol 2007,5(2),73-80; Miller,A.M.等Br J Pharmacol 2008,153(2),299-308;Centonze,D.,等 Curr PharmDes 2008,14(23),2370-42),和在胃肠系统中(Wright,K.L. 等Br J Pharmacol 2008,153(2),263-70)外周表达。CB2受体还广泛分布于脑中,其中它主要发现于小胶质细胞而非神经元上(Cabral,G.A.等Br J Pharmacol 2008,153(2):240-51)。
对于CB2受体激动剂的兴趣在过去十年间稳步提升(目前有30-40件专利申请/年),原因在于早期化合物中的几种已经在许多人类疾病的临床前模型中显示了具有有益效果的事实,所述疾病包括慢性疼痛(Beltramo, M.Mini Rev Med Chem 2009,9(1),11-25),动脉粥样硬化(Mach,F.等,J Neuroendocrinol 2008,20Suppl 1,53-7),骨质调节(Bab,I.等,Br J Pharmacol 2008,153(2),182-8),神经炎症(Cabral,G.A.等,J LeukocBiol 2005,78(6), 1192-7),缺血/再灌注损伤(Pacher,P.等,Br J Pharmacol 2008,153(2), 252-62),系统性纤维化(Akhmetshina,A.等,Arthritis Rheum 2009,60(4), 1129-36;Garcia-Gonzalez,E.等,Rheumatology(Oxford)2009,48(9), 1050-6),肝纤维化(Julien,B.等,Gastroenterology 2005,128(3),742-55; Munoz-Luque,J.等,JPharmacol Exp Ther 2008,324(2),475-83)。
缺血/再灌注(I/R)损伤是在诸如卒中,心肌梗塞,心肺转流术和其他血管手术,以及器官移植的病症中出现的组织损害的主要原因,并且是使各种病因学的循环休克过程复杂化的终器损害的主要机制。所有这些病症特征均在于正常血液供给的中断,导致不充分的组织氧合。再氧合例如再灌注是复原正常组织氧合的最终治疗。但是缺乏来自血液的氧和营养产生其中循环的复原导致进一步组织损害的病症。再灌注损伤的损害原因部分在于损害的组织的炎性反应。由新回流的血液运送到该区域的白细胞响应组织损害释放大量炎性因子如白细胞介素以及自由基。复原的血流再引入细胞内的氧,其损害细胞蛋白、DNA和质膜。
远端缺血预处理(remote ischemic preconditioning)(RIPC)代表一种利用身体内源保护能力对抗由缺血和再灌注导致的损伤的策略。其描述其中一个器官或组织的暂时性非致死缺血和再灌注给予对在远端器官或组织中“致死”缺血再灌注损伤的随后事件的抗性的有趣现象。尽管提出了几种假设,但器官或组织的暂时性缺血和再灌注通过其给予保护的实际机理目前是未知的。
体液假设提出远端器官或组织中产生的内源物质(如腺苷,缓激肽,阿片样物质,CGRP,内源性大麻素(endocannabinoids),血管紧张素I或一些其他还未确认的体液因子)进入血流并在靶组织中活化其各自受体并从而恢复缺血预处理中涉及的心脏保护的各种细胞内途径。
最近的数据显示内源性大麻素和它们的受体,特别是CB2可能涉及于预处理中并有助于通过炎症反应的减量调节防止再灌注损伤(Pacher,P.等, Br J Pharmacol 2008,153(2),252-62)。具体地,最近使用CB2工具激动剂的研究显示了该概念用于减少心脏(Defer,N.等,Faseb J 2009,23(7), 2120-30),脑(Zhang,M.等,J Cereb Blood FlowMetab 2007,27(7),1387-96),肝(Batkai,S.等,Faseb J 2007,21(8),1788-800)和肾(Feizi,A.等,Exp Toxicol Pathol 2008,60(4-5),405-10)中I/R损伤的功效。
此外,过去数年间,越来越多的文献表明CB2还可以在亚慢性和慢性情况中有意义。CB1和CB2的特定增量调节已经显示在与纤维化有关的慢性疾病的动物模型中(Garcia-Gonzalez,E.等,Rheumatology(Oxford) 2009,48(9),1050-6;Yang,Y.Y.等,Liver Int2009,29(5),678-85)与肌成纤维细胞即作为负责纤维化进程的细胞中的CB2相关表达关联。
CB2受体通过选择性CB2激动剂的活化实际上已经显示在弥散系统性硬化中产生抗纤维化效果(Garcia-Gonzalez,E.等,Rheumatology(Oxford) 2009,48(9),1050-6)并且CB2受体已经显现为实验真皮纤维化中 (Akhmetshina,A.等,Arthritis Rheum 2009,60(4),1129-36)和在肝病理生理学,包括与慢性肝病相关的纤维发生中(Lotersztajn,S.等,Gastroenterol Clin Biol 2007,31(3),255-8;Mallat,A.等,Expert Opin Ther Targets2007, 11(3),403-9;Lotersztajn,S.等,Br J Pharmacol 2008,153(2),286-9)的关键靶。
本发明的化合物结合于并调节CB2受体且具有较低CB1受体活性。
在本说明书中,术语“烷基”,单独或组合地表示具有1至8个碳原子的直链或支链烷基,特别是具有1至6个碳原子的直链或支链烷基,更特别是具有1至4个碳原子的直链或支链烷基。直链和支链C1-C8烷基的实例为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、异构的戊基、异构的己基、异构的庚基和异构的辛基,特别是甲基、乙基、丙基、丁基和戊基。烷基的特别的实例是甲基、乙基、丙基、异丙基、丁基和戊基。
术语“环烷基”,单独或组合地表示具有3至8个碳原子的环烷基环,并且特别是具有3至6个碳原子的环烷基环。环烷基的实例是环丙基、环丁基、环戊基和环己基、环庚基和环辛基。环烷基的特别的实例是环丙基。
术语“烷氧基”,单独或组合地表示式烷基-O-的基团,其中术语″烷基″具有之前给出的含义,如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基和叔丁氧基。特别的“烷氧基”是甲氧基、乙氧基和叔丁氧基。
术语“卤素”或“卤代”,单独或组合地表示氟、氯、溴或碘,并特别是氟、氯或溴,更特别是氟和氯。术语“卤代”,与另一基团组合地表示所述基团被至少一个卤素的取代,特别是被一至五个卤素,特别是一至四个卤素,即一、二、三或四个卤素的取代。特别的“卤素”是氟、氯和溴。
术语“卤代烷基”,单独或组合地表示被至少一个卤素取代,特别是被一至五个卤素,特别是一至三个卤素取代的烷基。特别的“卤代烷基”是三氟甲基。
术语“羟基(hydroxyl)”和“羟基(hydroxy)”,单独或组合地表示-OH基团。
术语“羰基”,单独或组合地表示-C(O)-基团。
术语“氧代”,单独地或组合地表示-O-基团。
术语“氨基”,单独或组合地表示伯氨基(-NH2),仲氨基(-NH-),或叔氨基(-N-)。特别的氨基是-NH-。
术语“磺酰基”,单独地或组合地表示-S(O)2-基团。
术语“药用盐”是指保持游离碱或游离酸的生物有效性和性质的那些盐,并且它们不是生物学上或其他方面不适宜的。所述盐用无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸,特别是盐酸,以及有机酸如乙酸、丙酸、羟基乙酸、丙酮酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸、 N-乙酰基半胱氨酸形成。此外,这些盐可以通过无机碱或有机碱向游离酸的加入而制备。得自无机碱的盐包括,但是不限于,钠、钾、锂、铵、钙、镁盐。得自有机碱的盐包括,但是不限于以下物质的盐:伯、仲和叔胺,取代的胺,包括天然存在的取代的胺、环状胺和碱性离子交换树脂,如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、赖氨酸、精氨酸、N- 乙基哌啶、哌啶、聚胺树脂。式(I)的化合物也可以以两性离子的形式存在。特别优选的式(I)的化合物的药用盐是盐酸、氢溴酸、硫酸、磷酸和甲磺酸的盐。
″药用酯″表示通式(I)的化合物可以在官能团处衍生化以提供衍生物,其能够体内转化回母体化合物。这种化合物的实例包括生理上可接受的和易代谢的酯衍生物,如甲氧基甲酯,甲硫基甲酯和新戊酰基氧基甲酯。此外,类似于易代谢的酯的、能够在体内产生通式(I)母体化合物的、通式(I) 化合物的生理上可接受的任何等同物均在本发明的范围内。
如果原料之一或式(I)化合物含有一个或多个在一个或多个反应步骤的反应条件下不稳定或具有反应性的官能团,则可以应用本领域周知的方法在关键步骤之前引入合适的保护基(如例如T.W.Greene和P.G.M.Wuts 在“Protective Groups in OrganicChemistry”,第3版,1999,Wiley,New York 中所述)。这样的保护基可以在合成的稍后阶段使用文献中所述的标准方法除去。保护基的实例是叔丁氧羰基(Boc),氨基甲酸9-芴基甲酯(Fmoc),氨基甲酸2-三甲基甲硅烷基乙酯(Teoc),苄氧羰基(Cbz)和对甲氧基苄氧基羰基(Moz)。
式(I)化合物可以含有几个不对称中心,并且其存在形式可以是光学纯对映异构体,对映异构体的混合物,如例如外消旋物,非对映异构体的混合物,非对映异构体外消旋物或非对映异构体外消旋物的混合物。
术语“不对称碳原子”表示具有四个不同取代基的碳原子。根据 Cahn-Ingold-Prelog Convention,不对称碳原子可以为“R”或“S”构型。
本发明尤其涉及:
式(I)的化合物,其中当R1是2,6-二氟苯基时,则R2是-C(O)NR3R4并且R3和R4与它们所连接的氮原子一起形成吗啉基;
式(I)的化合物,其中当R1是正丙基或环丙基时,则R2是-C(O)NR3R4, R3是甲基并且R4是吡啶基;
式(I)的化合物,其中R1是3-氟苯基、3-氯苯基或4-氯苯基;
式(I)的化合物,其中R3和R4中的一个是烷基,而另一个是-(CH2)n-R6;
式(I)的化合物,其中R3和R4中的一个是甲基或乙基,而另一个是 -(CH2)n-R6;
式(I)的化合物,其中R3和R4与它们所连接的氮原子一起形成杂环基或取代的杂环基,其中杂环基是哌啶基、吡咯烷基或吗啉基,并且其中取代的杂环基是被一个选自烷基和烷基羰基氨基的取代基取代的或被两个独立地选自烷基的取代基取代的杂环基;
式(I)的化合物,其中R3和R4与它们所连接的氮原子一起形成吗啉基、二甲基哌啶基或甲基羰基氨基吡咯烷基;
式(I)的化合物,其中R5是叔丁氧基羰基哌啶基、氟苯基甲基、乙氧基羰基甲基、乙氧基羰基(二甲基)甲基、(甲基磺酰基)(甲基)[1,2,4]三唑基或吗啉基羰基甲基;
式(I)的化合物,其中R6是烷氧基、二烷氧基苯基、苯基或吡啶基;
式(I)的化合物,其中R6是甲氧基、二甲氧基苯基、苯基或吡啶基;
式(I)的化合物,其中n是1、2或3;
本发明还涉及选自以下的式(I)的化合物:
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(2-氰基-乙基)-甲基-酰胺;
1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌啶-3-甲酸酰胺;
1-(3-氟-苯基)-4-(吗啉-4-羰基)-1,4-二氢-四唑-5-酮;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸甲基-苯乙基-酰胺;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸乙基-吡啶-4-基甲基-酰胺;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸乙基-(2-甲氧基-乙基)-酰胺;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸甲基-(3-苯基-丙基)-酰胺;
1-(2-苄基-吡咯烷-1-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮;
1-(3-氟-苯基)-4-[2-(4-氟-苯基)-吡咯烷-1-羰基]-1,4-二氢-四唑-5-酮;
1-(6-氟-3,4-二氢-1H-异喹啉-2-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5- 酮;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸苄基-乙基-酰胺;
(2S,3S)-2-{[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-甲基-氨基}-3-甲基-戊酸甲酯;
1-(4-氟-苄基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮;
4-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-基]-哌啶-1-甲酸叔丁酯;
2-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-基]-2-甲基-丙酸乙酯;
1-(3-氟-苯基)-4-(5-甲磺酰基-4-甲基-4H-[1,2,4]三唑-3-基甲基)-1,4-二氢-四唑-5-酮;
1-(3-氟-苯基)-4-[2-(2-甲基-2H-吡唑-3-基)-吡咯烷-1-羰基]-1,4-二氢-四唑-5-酮;
1-(3-氟-苯基)-4-[2-(1-甲基-1H-吡唑-3-基)-吡咯烷-1-羰基]-1,4-二氢-四唑-5-酮;
1-(3-氟-苯基)-4-[2-(3-甲基-异唑-5-基)-吡咯烷-1-羰基]-1,4-二氢-四唑-5-酮;
1-(3-氟-苯基)-4-((S)-2-甲氧基甲基-吡咯烷-1-羰基)-1,4-二氢-四唑-5- 酮;
(S)-1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-2-甲酸酰胺;
N-{1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}-乙酰胺;
1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-氮杂环丁烷-3-甲酸甲酯;
1-(3-氟-苯基)-4-[2-(3-甲基-[1,2,4]二唑-5-基)-吡咯烷-1-羰基]-1,4-二氢-四唑-5-酮;
N-{1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌啶-4-基}-乙酰胺;
1-(3-氟-苯基)-4-[4-(2-氧代-2-吡咯烷-1-基-乙基)-哌嗪-1-羰基]-1,4-二氢-四唑-5-酮;
1-(4,4-二甲基-哌啶-1-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮;
1-(1,1-二氧代-1λ6-硫代吗啉-4-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5- 酮;
1-(3-氟-苯基)-4-(2,3,5,6-四氢-[1,2′]二吡嗪基-4-羰基)-1,4-二氢-四唑-5-酮;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(2-氰基-乙基)-环丙基-酰胺;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸甲基-吡啶-2-基-酰胺;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸甲基-吡啶-3-基-酰胺;
1-(3-氟-苯基)-4-(2-甲氧基甲基-哌啶-1-羰基)-1,4-二氢-四唑-5-酮;
4-环丙基-5-氧代-4,5-二氢-四唑-1-甲酸甲基-吡啶-3-基-酰胺;
5-氧代-4-丙基-4,5-二氢-四唑-1-甲酸甲基-吡啶-3-基-酰胺;
4-异丁基-5-氧代-4,5-二氢-四唑-1-甲酸甲基-吡啶-3-基-酰胺;
1-(4-乙酰基-哌嗪-1-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮;
1-(3-氟-苯基)-4-(4-丙酰基-哌嗪-1-羰基)-1,4-二氢-四唑-5-酮;
4-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌嗪-1-甲酸二乙基酰胺;
1-(3-氟-苯基)-4-(3-苯基-吡咯烷-1-羰基)-1,4-二氢-四唑-5-酮;
N-{(S)-1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}- 乙酰胺;
N-{(R)-1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}- 乙酰胺;
N-乙基-N-{1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}-乙酰胺;
1-(3,3-二氟-吡咯烷-1-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮;
1-(2,2-二甲基-吡咯烷-1-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮;
1-(3,3-二甲基-吡咯烷-1-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮;
1-(3-氟-苯基)-4-(2-甲基-吡咯烷-1-羰基)-1,4-二氢-四唑-5-酮;
N-{1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}-N-甲基-乙酰胺;
4-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌嗪-1-甲酸乙酯;
(S)-1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-2-甲腈;
(R)-1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-2-甲腈;
4-(6-氯-吡啶-3-基)-5-氧代-4,5-二氢-四唑-1-甲酸苄基-乙基-酰胺;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(2-甲氧基-乙基)-甲基-酰胺;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸异丙基-(2-甲氧基-乙基)-酰胺;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(2-甲氧基-乙基)-丙基-酰胺;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸双-(2-甲氧基-乙基)-酰胺;
1-(2,6-二甲基-吗啉-4-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮;
1-((2S,6R)-2,6-二甲基-吗啉-4-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5- 酮;
1-(3-氟-苯基)-4-(4-甲氧基甲基-哌啶-1-羰基)-1,4-二氢-四唑-5-酮;
1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌啶-4-甲腈;
4-叔丁氧基羰基氨基-1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]- 哌啶-4-甲酸甲酯;
1-(3,3-二甲基-哌啶-1-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮;
1-(3-氟-苯基)-4-(2-氧杂-8-氮杂-螺[4.5]癸烷-8-羰基)-1,4-二氢-四唑-5-酮;
N-{(R)-1-[4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}- 乙酰胺;
N-{(R)-1-[5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}-乙酰胺;
N-{(R)-1-[4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}- 乙酰胺;
N-{(S)-1-[4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}- 乙酰胺;
N-{(S)-1-[5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}-乙酰胺;
N-{(S)-1-[4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}- 乙酰胺;
N-{1-[4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}-N-乙基-乙酰胺;
N-乙基-N-{1-[5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-羰基]- 吡咯烷-3-基}-乙酰胺;
N-{1-[4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}-N-乙基-乙酰胺;
1-(3-氯-苯基)-4-[2-(3-甲基-异唑-5-基)-吡咯烷-1-羰基]-1,4-二氢-四唑-5-酮;
1-[2-(3-甲基-异唑-5-基)-吡咯烷-1-羰基]-4-(3-三氟甲氧基-苯基)-1,4-二氢-四唑-5-酮;
1-(4-氯-苯基)-4-[2-(3-甲基-异唑-5-基)-吡咯烷-1-羰基]-1,4-二氢-四唑-5-酮;
1-(3-氯-苯基)-4-(4,4-二甲基-哌啶-1-羰基)-1,4-二氢-四唑-5-酮;
1-(4,4-二甲基-哌啶-1-羰基)-4-(3-三氟甲氧基-苯基)-1,4-二氢-四唑-5- 酮;
1-(4-氯-苯基)-4-(4,4-二甲基-哌啶-1-羰基)-1,4-二氢-四唑-5-酮;
4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸乙基-(2-甲氧基-乙基)-酰胺;
5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-甲酸乙基-(2-甲氧基- 乙基)-酰胺;
4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸乙基-(2-甲氧基-乙基)-酰胺;
4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸异丙基-(2-甲氧基-乙基)-酰胺;
5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-甲酸异丙基-(2-甲氧基 -乙基)-酰胺;
4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸异丙基-(2-甲氧基-乙基)-酰胺;
4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(3-甲氧基-丙基)-甲基-酰胺;
5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-甲酸(3-甲氧基-丙基)- 甲基-酰胺;
4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(3-甲氧基-丙基)-甲基-酰胺;
1-(3-氯-苯基)-4-[4-(2-吗啉-4-基-2-氧代-乙基)-哌嗪-1-羰基]-1,4-二氢-四唑-5-酮;
1-[4-(2-吗啉-4-基-2-氧代-乙基)-哌嗪-1-羰基]-4-(3-三氟甲氧基-苯基)-1,4-二氢-四唑-5-酮;
1-(4-氯-苯基)-4-[4-(2-吗啉-4-基-2-氧代-乙基)-哌嗪-1-羰基]-1,4-二氢-四唑-5-酮;
2-{4-[4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌嗪-1-基}-N,N-二甲基-乙酰胺;
N,N-二甲基-2-{4-[5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-羰基]-哌嗪-1-基}-乙酰胺;
2-{4-[4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌嗪-1-基}-N,N-二甲基-乙酰胺;
1-(3-氯-苯基)-4-[4-(2-氧代-2-吡咯烷-1-基-乙基)-哌嗪-1-羰基]-1,4-二氢-四唑-5-酮;
1-[4-(2-氧代-2-吡咯烷-1-基-乙基)-哌嗪-1-羰基]-4-(3-三氟甲氧基-苯基)-1,4-二氢-四唑-5-酮;
1-(4-氯-苯基)-4-[4-(2-氧代-2-吡咯烷-1-基-乙基)-哌嗪-1-羰基]-1,4-二氢-四唑-5-酮;
4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(2-乙氧基-乙基)-乙基-酰胺;
5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-甲酸(2-乙氧基-乙基)- 乙基-酰胺;
4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(2-乙氧基-乙基)-乙基-酰胺;
1-(3-氯-苯基)-4-(吗啉-4-羰基)-1,4-二氢-四唑-5-酮
1-(吗啉-4-羰基)-4-(3-三氟甲氧基-苯基)-1,4-二氢-四唑-5-酮
1-(4-氯-苯基)-4-(吗啉-4-羰基)-1,4-二氢-四唑-5-酮;
2-{4-[4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌嗪-1-基}-N-乙基-乙酰胺;
N-乙基-2-{4-[5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-羰基]-哌嗪-1-基}-乙酰胺;
2-{4-[4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌嗪-1-基}-N-乙基-乙酰胺;
N-丁基-2-{4-[4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌嗪-1-基}-乙酰胺;
N-丁基-2-{4-[5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-羰基]-哌嗪-1-基}-乙酰胺;
N-丁基-2-{4-[4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌嗪-1-基}-乙酰胺;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(2-甲氧基-乙基)-酰胺;
4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(2-乙氧基-乙基)-甲基-酰胺;
5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-甲酸(2-乙氧基-乙基)- 甲基-酰胺;
4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(2-乙氧基-乙基)-甲基-酰胺;
[4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-基]-乙酸乙酯;
1-(3-氯-苯基)-4-(2-吗啉-4-基-2-氧代-乙基)-1,4-二氢-四唑-5-酮;
1-(3-氯-苯基)-4-[4-(1-甲基-2-氧代-2-吡咯烷-1-基-乙基)-哌嗪-1-羰基]-1,4-二氢-四唑-5-酮;
1-[4-(1-甲基-2-氧代-2-吡咯烷-1-基-乙基)-哌嗪-1-羰基]-4-(3-三氟甲氧基-苯基)-1,4-二氢-四唑-5-酮;
1-(4-氯-苯基)-4-[4-(1-甲基-2-氧代-2-吡咯烷-1-基-乙基)-哌嗪-1-羰基]-1,4-二氢-四唑-5-酮;
1-(吗啉-4-羰基)-4-[2-(三氟甲基)苯基]四唑-5-酮;
1-(吗啉-4-羰基)-4-[3-(三氟甲基)苯基]四唑-5-酮;
1-(吗啉-4-羰基)-4-[4-(三氟甲基)苯基]四唑-5-酮;
1-(2,6-二氟苯基)-4-(吗啉-4-羰基)四唑-5-酮;
1-(2,4-二氟苯基)-4-(吗啉-4-羰基)四唑-5-酮;
1-(2,5-二氟苯基)-4-(吗啉-4-羰基)四唑-5-酮;
1-(3,4-二氟苯基)-4-(吗啉-4-羰基)四唑-5-酮;
1-(3,5-二氟苯基)-4-(吗啉-4-羰基)四唑-5-酮;
1-(3-甲基苯基)-4-(吗啉-4-羰基)四唑-5-酮;
1-(4-甲基苯基)-4-(吗啉-4-羰基)四唑-5-酮;
1-(3-甲氧基苯基)-4-(吗啉-4-羰基)四唑-5-酮;
1-(4-甲氧基苯基)-4-(吗啉-4-羰基)四唑-5-酮;
1-(2,3-二氯苯基)-4-(吗啉-4-羰基)四唑-5-酮;
1-(1-甲基吲哚-4-基)-4-(吗啉-4-羰基)四唑-5-酮;
1-(1-甲基吲哚-5-基)-4-(吗啉-4-羰基)四唑-5-酮;
1-(1-甲基吲哚-6-基)-4-(吗啉-4-羰基)四唑-5-酮;
1-(3-溴苯基)-4-(吗啉-4-羰基)四唑-5-酮;
1-(3-氯苯基)-4-[(2R,6S)-2,6-二甲基吗啉-4-羰基]四唑-5-酮;
1-(3-氯苯基)-4-(2,6-二甲基吗啉-4-羰基)四唑-5-酮;和
1-(3-氯苯基)-4-(3,3-二甲基吡咯烷-1-羰基)四唑-5-酮。
本发明还涉及选自以下的式(I)的化合物:
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸甲基-苯乙基-酰胺;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸乙基-吡啶-4-基甲基-酰胺;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸苄基-乙基-酰胺;
1-(4,4-二甲基-哌啶-1-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮;
N-{(R)-1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}- 乙酰胺;
1-(3-氯-苯基)-4-(4,4-二甲基-哌啶-1-羰基)-1,4-二氢-四唑-5-酮;
1-(4-氯-苯基)-4-(4,4-二甲基-哌啶-1-羰基)-1,4-二氢-四唑-5-酮;
4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(3-甲氧基-丙基)-甲基-酰胺;和
1-(3-氯-苯基)-4-(吗啉-4-羰基)-1,4-二氢-四唑-5-酮。
本发明的式(I)的化合物的制备可以以连续的或汇聚的(convergent)合成途径进行。在以下方案中,示出了本发明的化合物的合成。进行所得的产品的反应和纯化所需要的技能对本领域技术人员来说是公知的。除非存在相反指示,在以下的过程描述中所用的取代基和符号具有本文此前给出的含义。更详细地,可以通过以下给出的方法、通过在实施例中给出的方法或通过类似的方法制造式(I)的化合物。用于各个反应步骤的合适的反应条件对于本领域技术人员来说是公知的。而且,对于在文献中描述的影响所述反应的条件,参见例如:综合有机转化:对官能团制备的指南 (Comprehensive OrganicTransformations:A Guide to Functional Group Preparations),第2版,RichardC.Larock.John Wiley&Sons,New York,NY. 1999)。我们发现,在存在溶剂或不存在溶剂的情况下进行反应都是便利的。对于所用的溶剂的性质没有特别的限制,条件是它对反应或者涉及的试剂没有不利的影响并且它可以在至少一定程度上溶解试剂。所述的反应可以在宽温度范围内进行,并且精确的反应温度对本发明来说不是关键性的。在-78℃至回流之间的温度范围内进行所述反应是便利的。反应所需的时间也可以宽泛地变化,取决于许多因素,显著地取决于反应温度和试剂的性质。然而,从0.5h至若干天的时间段将通常足以制得所述的中间体和化合物。反应顺序不限于在方案中展示的反应顺序,而是取决于原材料和它们各自的反应性,反应步骤的顺序可以自由改变。原材料可商购的,或者可以通过与以下给出的方法类似的方法、通过在说明书中引用的参考文献中或实施例中描述的方法、或者通过本领域公知的方法制备。
方案1
a)四唑酮II是可商购的或可以根据本领域中已知的方法合成。方便地,将异氰酸酯衍生物与叠氮基三甲基硅烷反应(类似于:J.Org.Chem. 1980,45,5130-5136)或将酰基氯衍生物与叠氮基三甲基硅烷反应(类似于: J.Org.Chem.1995,60,7641-7645)以获得四唑酮衍生物II。
b)在R2是R5的情况下,方便地将四唑酮II与亲电体在碱性(例如 Cs2CO3)条件下反应从而产生四唑酮衍生物I。这些衍生物是最终的化合物或方便地进一步反应以获得最终的四唑酮I。在R2是-C(O)NR3R4的情况下,方便地将四唑酮II与C1-等效物(例如光气或双光气)任选地在碱存在下反应,并且随后与合适的胺衍生物或任选地与合适的氨基甲酰氯在碱存在下反应以获得四唑酮衍生物I。这些衍生物是最终的化合物或方便地进一步反应以获得最终的四唑酮I。
本发明还涉及用于制备式(I)的化合物的方法,所述方法包括式(A)的化合物
(a)在R5-X和碱存在下的反应;或
(b)在光气、双光气或三光气存在下的反应,继之以在HNR3R4和碱存在下的反应;
其中X是吸电子基团并且其中R1、R3、R4和R5是如上所定义的。
X例如是氯化物或溴化物。
在步骤(a)中,所述碱例如是DMAP或K2CO3。
在步骤(b)中,所述碱例如是Cs2CO3或K2CO3。
本发明还涉及根据以上方法制备的式(I)的化合物。
本发明还尤其涉及:
式(I)化合物用于治疗或预防疼痛、动脉粥样硬化(atherosclerosis)、老年性黄斑退化症(age-related macular degeneration)、糖尿病性视网膜病变 (diabeticretinopathy)、青光眼(glaucoma)、视网膜静脉闭塞(retinal vein occlusion)、早产儿视网膜病(retinopathy of prematurity)、眼缺血综合征 (ocular ischemic syndrome)、地图样萎缩(geographic atrophy)、糖尿病 (diabetes mellitus)、炎症(inflammation)、炎性肠病(inflammatory bowel disease)、缺血-再灌注损伤(ischemia-reperfusioninjury)、急性肝衰竭(acute liver failure)、肝纤维化(liver fibrosis)、肺纤维化(lung fibrosis)、肾纤维化 (kidney fibrosis)、系统性纤维化(systemic fibrosis)、急性同种异体移植排斥 (acute allografi rejection)、慢性同种异体移植肾病(chronicallografi nephropathy)、糖尿病肾病(diabetic nephropathy)、肾小球肾病(glomerulonephropathy)、心肌病(cardiomyopathy)、心力衰竭(heart failure)、心肌缺血(myocardial ischemia)、心肌梗死(myocardial infarction)、系统性硬化(systemicsclerosis)、热损伤(thermal injury)、烧伤(burning)、肥大性疤痕 (hypertrophicscars)、瘢痕疙瘩(keloids)、龈炎发热(gingivitis pyrexia)、肝硬化(liver cirrhosis)或肿瘤、骨质调节(regulation of bone mass)、肌萎缩侧索硬化(amyotrophic lateralsclerosis)、多发性硬化(multiple sclerosis)、阿尔茨海默病(Alzheimer′s disease)、帕金森病(Parkinson′s disease)、卒中(stroke)、一过性缺血发作(transient ischemicattack)或葡萄膜炎(uveitis)的用途;
根据式(I)的化合物在制备药物中的用途,所述药物用于治疗或预防疼痛、动脉粥样硬化、老年性黄斑退化症、糖尿病性视网膜病变、青光眼、视网膜静脉闭塞、早产儿视网膜病、眼缺血综合征、地图样萎缩、糖尿病、炎症、炎性肠病、缺血-再灌注损伤、急性肝衰竭、肝纤维化、肺纤维化、肾纤维化、系统性纤维化、急性同种异体移植排斥、慢性同种异体移植肾病、糖尿病肾病、肾小球肾病、心肌病、心力衰竭、心肌缺血、心肌梗死、系统性硬化、热损伤、烧伤、肥大性疤痕、瘢痕疙瘩、龈炎发热、肝硬化或肿瘤、骨质调节、肌萎缩侧索硬化、多发性硬化、阿尔茨海默病、帕金森病、卒中、一过性缺血发作或葡萄膜炎;
式(I)化合物,其用于治疗或预防疼痛、动脉粥样硬化、老年性黄斑退化症、糖尿病性视网膜病变、青光眼、视网膜静脉闭塞、早产儿视网膜病、眼缺血综合征、地图样萎缩、糖尿病、炎症、炎性肠病、缺血-再灌注损伤、急性肝衰竭、肝纤维化、肺纤维化、肾纤维化、系统性纤维化、急性同种异体移植排斥、慢性同种异体移植肾病、糖尿病肾病、肾小球肾病、心肌病、心力衰竭、心肌缺血、心肌梗死、系统性硬化、热损伤、烧伤、肥大性疤痕、瘢痕疙瘩、龈炎发热、肝硬化或肿瘤、骨质调节、肌萎缩侧索硬化、多发性硬化、阿尔茨海默病、帕金森病、卒中、一过性缺血发作或葡萄膜炎;和
一种用于治疗或预防疼痛、动脉粥样硬化、老年性黄斑退化症、糖尿病性视网膜病变、青光眼、视网膜静脉闭塞、早产儿视网膜病、眼缺血综合征、地图样萎缩、糖尿病、炎症、炎性肠病、缺血-再灌注损伤、急性肝衰竭、肝纤维化、肺纤维化、肾纤维化、系统性纤维化、急性同种异体移植排斥、慢性同种异体移植肾病、糖尿病肾病、肾小球肾病、心肌病、心力衰竭、心肌缺血、心肌梗死、系统性硬化、热损伤、烧伤、肥大性疤痕、瘢痕疙瘩、龈炎发热、肝硬化或肿瘤、骨质调节、肌萎缩侧索硬化、多发性硬化、阿尔茨海默病、帕金森病、卒中、一过性缺血发作或葡萄膜炎的方法,所述方法包括将有效量的式(I)化合物向需要它的患者给药。
本发明特别涉及式(I)化合物,其用于治疗或预防缺血、再灌注损伤、肝纤维化或肾纤维化,特别是缺血或再灌注损伤。
本发明还特别涉及式(I)化合物,其用于治疗或预防老年性黄斑退化症、糖尿病性视网膜病变、青光眼、视网膜静脉闭塞、早产儿视网膜病、眼缺血综合征、地图样萎缩或葡萄膜炎。
本发明还特别涉及式(I)化合物,其用于治疗或预防肌萎缩侧索硬化或多发性硬化。
本发明还涉及根据本发明的方法制备的式(I)的化合物。
本发明的另一实施方案提供药物组合物或药物,其包含本发明的化合物和治疗惰性载体,稀释剂或赋形剂,以及使用本发明的化合物制备这种组合物和药物的方法。在一个实例中,可以将式(I)化合物按如下配制:通过在环境温度在合适的pH,并在期望的纯度程度,与生理学上可接受的载体即在所采用的剂量和浓度对受者无毒的载体混合成盖仑给药形式。制剂的pH主要取决于具体的用途和化合物的浓度,但是优选在约3至约8 范围内的任意处。在一个实例中,将式(I)化合物在乙酸盐缓冲液中在pH 5 配制。在另一个实施方案中,式(I)化合物是无菌的。可以将化合物例如作为固体或非晶组合物,作为冻干的制剂或作为水溶液储存。
以与良好医疗实践相一致的方式将组合物配制,定剂量,和给药。在此考虑的因素包括所治疗的具体病症,所治疗的具体哺乳动物,个体患者的临床状况,病症的原因,药剂的输送位置,给药方法,给药的时间安排,和执业医师已知的其他因素。
本发明的化合物可以通过任何合适的方式给药,包括口服、局部(包括含服和舌下)、直肠、阴道、经皮、肠胃外、皮下、腹膜内、肺内、皮内、鞘内和硬膜外和鼻内,并且,如果需要局部治疗,则病灶内给药。肠胃外输液包括肌肉内、静脉内、动脉内、腹膜内或皮下给药。
本发明的化合物可以以任何方便的给药形式给药,例如,片剂、散剂、胶囊、溶液剂、分散剂、混悬剂、糖浆剂、喷雾剂、栓剂、凝胶、乳剂、贴剂等。这样的组合物可以含有药物制剂中的常规组分,例如,稀释剂、载体、pH调节剂、甜味剂、填充剂和其他活性剂。
典型的制剂通过混合本发明的化合物和载体或赋形剂制备。合适的载体和赋形剂是本领域技术人员周知的并详述于,例如,Ansel,Howard C.,等,Ansel’s PharmaceuticalDosage Forms and Drug Delivery Systems. Philadelphia:Lippincott,Williams&Wilkins,2004;Gennaro,Alfonso R.,等Remington:The Science and Practice ofPharmacy.Philadelphia: Lippincott,Williams&Wilkins,2000;和Rowe,RaymondC.Handbook of Pharmaceutical Excipients.Chicago,Pharmaceutical Press,2005中。制剂还可以包括一种或多种缓冲剂、稳定剂、表面活性剂、润湿剂、润滑剂、乳化剂、助悬剂、防腐剂、抗氧化剂、遮光剂(opaquing agent)、助流剂、加工助剂、着色剂、甜味剂、加香剂、增味剂、稀释剂和其他已知添加剂,以提供药物(即,本发明的化合物或其药物组合物)的优良存在形式或协助制备药物产品(即,药品)。
现将通过以下没有限制性质的实施例说明本发明。
实施例
实施例1
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺
a)1-(3-氟-苯基)-1,4-二氢-四唑-5-酮
将1-氟-3-异氰酸根合苯(2g,14.6mmol)和TMS-N3(2.52g,2.9ml, 21.9mmol)的混合物加热至100℃达18h。在真空下除去过量的TMS-N3并将残余物置于1mL含水MeOH中。将沉淀滤出,用水洗涤并在高真空下干燥从而产生2.42g(92%)的标题化合物,为白色晶体。MS(m/e):222.1 (MH++CH3CN)。
b)4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)- 乙基]-甲基-酰胺
将1-(3-氟苯基)-1H-四唑-5(4H)-酮(30mg,167μmol)和DMAP(50.9 mg,416μmol)在DCM(8mL)中的混合物在0℃用三氯甲基氯甲酸酯 (carbonochloridate)(39.5mg,24.7μl,200μmol)处理并振荡30min。加入 2-(3,4-二甲氧基苯基)-N-甲基乙胺(51.9mg,266μmol)并在室温振荡过夜。除去挥发物并加入DMF和甲酸,并将混合物通过制备型HPLC在反相上利用由乙腈、水和甲酸形成的梯度洗脱而纯化。蒸发含产物的级分从而产生18mg(27%)的标题化合物。MS(m/e):402.3(MH+)。
实施例2
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(2-氰基-乙基)-甲基-酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和3-(甲基氨基)丙腈。MS(m/e):291.2 (MH+)。
实施例3
1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌啶-3-甲酸酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和哌啶-3-甲酰胺。MS(m/e):334.2 (MH+)。
实施例4
1-(3-氟-苯基)-4-(吗啉-4-羰基)-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和吗啉。MS(m/e):294.2(MH+)。
实施例5
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸甲基-苯乙基-酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和N-甲基-2-苯基乙胺。MS(m/e):342.2 (MH+)。
实施例6
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸乙基-吡啶-4-基甲基-酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和N-(吡啶-4-基甲基)乙胺。MS(m/e): 342.2(MH+)。
实施例7
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸乙基-(2-甲氧基-乙基)-酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和N-乙基-2-甲氧基乙胺。MS(m/e): 310.2(MH+)。
实施例8
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸甲基-(3-苯基-丙基)-酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和N-甲基-3-苯基丙-1-胺。MS(m/e): 356.3(MH+)。
实施例9
1-(2-苄基-吡咯烷-1-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和2-苄基吡咯烷。MS(m/e):368.3 (MH+)。
实施例10
1-(3-氟-苯基)-4-[2-(4-氟-苯基)-吡咯烷-1-羰基]-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和2-(4-氟苯基)吡咯烷。MS(m/e):372.2 (MH+)。
实施例11
1-(6-氟-3,4-二氢-1H-异喹啉-2-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和6-氟-1,2,3,4-四氢异喹啉。MS(m/e): 358.2(MH+)。
实施例12
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸苄基-乙基-酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和N-苄基乙胺。MS(m/e):342.2(MH+)。
实施例13
(2S,3S)-2-{[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-甲基-氨基}-3-甲基-戊酸甲酯
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和(2S,3S)-3-甲基-2-(甲基氨基)戊酸甲酯盐酸盐。MS(m/e):366.3(MH+)。
实施例14
1-(4-氟-苄基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮
将1-(3-氟苯基)-1H-四唑-5(4H)-酮(30mg,167μmol)和Cs2CO3(57.0 mg,175μmol)在DMF(2mL)中的混合物在室温用1-(溴甲基)-4-氟苯(32.4 mg,21.1μl,172μmol)处理。用水稀释混合物并过滤悬浮液。将沉淀用水洗涤并在高真空下干燥从而产生38mg(78%)的标题化合物,为白色粉末。 MS(m/e):288(MH+)。
实施例15
4-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-基]-哌啶-1-甲酸叔丁酯
将1-(3-氟苯基)-1H-四唑-5(4H)-酮(55mg,305μmol),DMAP(39.2mg, 321μmol)和4-溴哌啶-1-甲酸叔丁酯(80.7mg,305μmol)在DMF(1mL)中的混合物在室温振荡24h。加入Cs2CO3(99.5mg,305μmol)并将混合物在85℃振荡16h。在冷却至室温后,对混合物进行在反相上、利用由乙腈、水和NEt3形成的梯度洗脱的制备型HPLC分离。蒸发含产物的级分从而产生13.9mg(12%)的标题化合物,为无定形固体。MS(m/e):364 (MH+)。
实施例16
2-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-基]-2-甲基-丙酸乙酯
将1-(3-氟苯基)-1H-四唑-5(4H)-酮(80mg,444μmol)和Cs2CO3(289 mg,888μmol)在DMF(2mL)中的混合物在室温振荡15min并且随后用 2-溴-2-甲基丙酸乙酯(95.3mg,72.5μl,489μmol)处理并在室温反应。将沉淀滤出并对滤液进行通过利用由乙腈、水和NEt3形成的梯度洗脱的制备型HPLC的纯化。蒸发含产物的级分从而产生28mg(21%)的标题化合物,为无色液体。MS(m/e):295.2(MH+)。
实施例17
1-(3-氟-苯基)-4-(5-甲磺酰基-4-甲基-4H-[1,2,4]三唑-3-基甲基)-1,4-二氢-四唑-5-酮
将1-(3-氟苯基)-1H-四唑-5(4H)-酮(15.2mg,84.4μmol)和K2CO3(23.3 mg,169μmol)在DMF(1000μL)中的混合物用3-(碘甲基)-4-甲基-5-(甲基磺酰基)-4H-1,2,4-三唑(25.4mg,84.4μmol)处理并在室温搅拌过夜。将混合物过滤并进行通过利用由乙腈、水和NEt3形成的梯度洗脱的制备型 HPLC的纯化。蒸发含产物的级分从而产生18mg(62%)的标题化合物,为无色液体。MS(m/e):354.3(MH+)。
实施例18
1-(3-氟-苯基)-4-[2-(2-甲基-2H-吡唑-3-基)-吡咯烷-1-羰基]-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和1-甲基-5-(吡咯烷-2-基)-1H-吡唑。 MS(m/e):358.3(MH+)。
实施例19
1-(3-氟-苯基)-4-[2-(1-甲基-1H-吡唑-3-基)-吡咯烷-1-羰基]-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和1-甲基-3-(吡咯烷-2-基)-1H-吡唑。 MS(m/e):358.2(MH+)。
实施例20
1-(3-氟-苯基)-4-[2-(3-甲基-异唑-5-基)-吡咯烷-1-羰基]-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和3-甲基-5-(吡咯烷-2-基)异唑。 MS(m/e):359.2(MH+)。
实施例21
1-(3-氟-苯基)-4-((S)-2-甲氧基甲基-吡咯烷-1-羰基)-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和(S)-2-(甲氧基甲基)吡咯烷。MS(m/e): 322.1(MH+)。
实施例22
(S)-1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-2-甲酸酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和(S)-吡咯烷-2-甲酰胺。
实施例23
N-{1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}-乙酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和N-(吡咯烷-3-基)乙酰胺。MS(m/e): 335.2(MH+)。
实施例24
1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-氮杂环丁烷-3-甲酸甲酯
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和氮杂环丁烷-3-甲酸甲酯。MS(m/e): 322.1(MH+)。
实施例25
1-(3-氟-苯基)-4-[2-(3-甲基-[1,2,4]二唑-5-基)-吡咯烷-1-羰基]-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和3-甲基-5-(吡咯烷-2-基)-1,2,4-二唑。MS(m/e):360.2(MH+)。
实施例26
N-{1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌啶-4-基}-乙酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和N-(哌啶-4-基)乙酰胺。MS(m/e): 349.3(MH+)。
实施例27
1-(3-氟-苯基)-4-[4-(2-氧代-2-吡咯烷-1-基-乙基)-哌嗪-1-羰基]-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和2-(哌嗪-1-基)-1-(吡咯烷-1-基)乙酮。 MS(m/e):404.3(MH+)。
实施例28
1-(4,4-二甲基-哌啶-1-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和4,4-二甲基哌啶。MS(m/e):320.2 (MH+)。
实施例29
1-(1,1-二氧代-1λ6-硫代吗啉-4-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和硫代吗啉1,1-二氧化物。MS(m/e): 359.0(MH++NH4)。
实施例30
1-(3-氟-苯基)-4-(2,3,5,6-四氢-[1,2′]二吡嗪基-4-羰基)-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和2-(哌嗪-1-基)吡嗪。MS(m/e):371.2 (MH+)。
实施例31
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(2-氰基-乙基)-环丙基-酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和3-(环丙基氨基)丙腈。MS(m/e):317.1 (MH+)。
实施例32
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸甲基-吡啶-2-基-酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和N-甲基吡啶-2-胺。MS(m/e):315.1 (MH+)。
实施例33
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸甲基-吡啶-3-基-酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和N-甲基吡啶-3-胺。MS(m/e):315.1 (MH+)。
实施例34
1-(3-氟-苯基)-4-(2-甲氧基甲基-哌啶-1-羰基)-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和2-(甲氧基甲基)哌啶。MS(m/e):336.2 (MH+)。
实施例35
4-环丙基-5-氧代-4,5-二氢-四唑-1-甲酸甲基-吡啶-3-基-酰胺
a)1-环丙基-1,4-二氢-四唑-5-酮
将环丙烷碳酰氯(100mg,957μmol)和叠氮基三甲基硅烷(661mg,760 μl,5.74mmol)的混合物在0℃反应1h。随后,将混合物温热至室温并加热至60℃达1h并加热至90℃过夜。除去所有挥发物产生粗制标题化合物,其在不进行进一步纯化的情况下用于随后的步骤。
b)4-环丙基-5-氧代-4,5-二氢-四唑-1-甲酸甲基-吡啶-3-基-酰胺
将1-环丙基-1H-四唑-5(4H)-酮(27.1mg,215μmol),K2CO3(35.6mg, 258μmol)和DMAP(31.5mg,258μmol)在乙腈(1mL)中的混合物在室温振荡15min。将混合物用甲基(吡啶-3-基)氨基甲酰氯(36.7mg,215μmol)处理并在60℃振荡过夜。将混合物蒸发并将残余物置于DMF和甲酸中并经由在反相上、利用由乙腈、水和NEt3形成的梯度洗脱的制备型HPLC 进行纯化。蒸发含产物的级分从而产生16mg(29%)的标题化合物,为褐色固体。MS(m/e):261.1(MH+)。
实施例36
5-氧代-4-丙基-4,5-二氢-四唑-1-甲酸甲基-吡啶-3-基-酰胺
a)1-丙基-1,4-二氢-四唑-5-酮
类似于对于1-环丙基-1,4-二氢-四唑-5-酮(实施例35)的合成所述的程序,标题化合物制备自丁酰氯和叠氮基三甲基硅烷,为淡黄色油状物并在不进行进一步纯化的情况下用于随后的步骤。
b)5-氧代-4-丙基-4,5-二氢-四唑-1-甲酸甲基-吡啶-3-基-酰胺
类似于对于4-环丙基-5-氧代-4,5-二氢-四唑-1-甲酸甲基-吡啶-3-基-酰胺(实施例35)的合成所述的程序,标题化合物制备自1-丙基-1,4-二氢-四唑 -5-醇和甲基(吡啶-3-基)氨基甲酰氯,为褐色固体。MS(m/e):263.2(MH+)。
实施例37
4-异丁基-5-氧代-4,5-二氢-四唑-1-甲酸甲基-吡啶-3-基-酰胺
a)1-异丁基-1,4-二氢-四唑-5-酮
类似于对于1-环丙基-1,4-二氢-四唑-5-酮(实施例35)的合成所述的程序,标题化合物制备自3-甲基丁酰氯和叠氮基三甲基硅烷,为淡黄色油状物并在不进行进一步纯化的情况下用于随后的步骤。
b)4-异丁基-5-氧代-4,5-二氢-四唑-1-甲酸甲基-吡啶-3-基-酰胺
类似于对于4-环丙基-5-氧代-4,5-二氢-四唑-1-甲酸甲基-吡啶-3-基-酰胺(实施例35)的合成所述的程序,标题化合物制备自1-异丁基-1,4-二氢- 四唑-5-酮和甲基(吡啶-3-基)氨基甲酰氯,为褐色固体。MS(m/e):277.2 (MH+)。
实施例38
1-(4-乙酰基-哌嗪-1-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和1-(哌嗪-1-基)乙酮。MS(m/e):335.1 (MH+)。
实施例39
1-(3-氟-苯基)-4-(4-丙酰基-哌嗪-1-羰基)-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和1-(哌嗪-1-基)丙-1-酮。MS(m/e): 349.2(MH+)。
实施例40
4-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌嗪-1-甲酸二乙基酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和N,N-二乙基哌嗪-1-甲酰胺。MS(m/e): 392.3(MH+)。
实施例41
1-(3-氟-苯基)-4-(3-苯基-吡咯烷-1-羰基)-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和3-苯基吡咯烷。MS(m/e):354.2 (MH+)。
实施例42
N-{(S)-1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}- 乙酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和(S)-N-(吡咯烷-3-基)乙酰胺。MS(m/e): 335.2(MH+)。
实施例43
N-{(R)-1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}- 乙酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和(R)-N-(吡咯烷-3-基)乙酰胺。 MS(m/e):335.2(MH+)。
实施例44
N-乙基-N-{1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}-乙酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和N-乙基-N-(吡咯烷-3-基)乙酰胺。 MS(m/e):363.2(MH+)。
实施例45
1-(3,3-二氟-吡咯烷-1-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和3,3-二氟吡咯烷。MS(m/e):314 (MH+)。
实施例46
1-(2,2-二甲基-吡咯烷-1-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和2,2-二甲基吡咯烷。MS(m/e):306.2 (MH+)。
实施例47
1-(3,3-二甲基-吡咯烷-1-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和3,3-二甲基吡咯烷。MS(m/e):306.2 (MH+)。
实施例48
1-(3-氟-苯基)-4-(2-甲基-吡咯烷-1-羰基)-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和2-甲基吡咯烷。MS(m/e):292.2 (MH+)。
实施例49
N-{1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}-N-甲基-乙酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和N-甲基-N-(吡咯烷-3-基)乙酰胺。 MS(m/e):349.2(MH+)。
实施例50
4-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌嗪-1-甲酸乙酯
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和哌嗪-1-甲酸乙酯。MS(m/e):365.1 (MH+)。
实施例51
(S)-1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-2-甲腈
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和(R)-吡咯烷-2-甲腈。MS(m/e):303.2 (MH+)。
实施例52
(R)-1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-2-甲腈
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和(S)-吡咯烷-2-甲腈。MS(m/e):303.2 (MH+)。
实施例53
4-(6-氯-吡啶-3-基)-5-氧代-4,5-二氢-四唑-1-甲酸苄基-乙基-酰胺
a)1-(6-氯-吡啶-3-基)-1,4-二氢-四唑-5-酮
类似于对于1-环丙基-1,4-二氢-四唑-5-酮(实施例35)的合成所述的程序,标题化合物制备自6-氯烟酰氯和叠氮基三甲基硅烷,为灰白色晶体并在不进行进一步纯化的情况下用于随后的步骤。
b)4-(6-氯-吡啶-3-基)-5-氧代-4,5-二氢-四唑-1-甲酸苄基-乙基-酰胺
类似于对于4-环丙基-5-氧代-4,5-二氢-四唑-1-甲酸甲基-吡啶-3-基-酰胺(实施例35)的合成所述的程序,标题化合物制备自1-(6-氯-吡啶-3- 基)-1,4-二氢-四唑-5-酮和苄基(乙基)氨基甲酰氯,为无色粘性油状物。 MS(m/e):400.3(MH+)。
实施例54
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(2-甲氧基-乙基)-甲基-酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和2-甲氧基-N-甲基乙胺。MS(m/e): 296.2(MH+)。
实施例55
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸异丙基-(2-甲氧基-乙基)-酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和N-(2-甲氧基乙基)丙-2-胺。MS(m/e): 324.2(MH+)。
实施例56
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(2-甲氧基-乙基)-丙基-酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和N-(2-甲氧基乙基)丙-1-胺。MS(m/e): 324.2(MH+)。
实施例57
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸双-(2-甲氧基-乙基)-酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和双(2-甲氧基乙基)胺。MS(m/e):340.2 (MH+)。
实施例58
1-(2,6-二甲基-吗啉-4-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和2,6-二甲基吗啉。MS(m/e):322.2 (MH+)。
实施例59
1-((2S,6R)-2,6-二甲基-吗啉-4-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和(2R,6S)-2,6-二甲基吗啉。MS(m/e): 322.3(MH+)。
实施例60
1-(3-氟-苯基)-4-(4-甲氧基甲基-哌啶-1-羰基)-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和4-(甲氧基甲基)哌啶。MS(m/e):336.2 (MH+)。
实施例61
1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌啶-4-甲腈
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和哌啶-4-甲腈。MS(m/e):317.3(MH+)。
实施例62
4-叔丁氧基羰基氨基-1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]- 哌啶-4-甲酸甲酯
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和4-(叔丁氧基羰基氨基)哌啶-4-甲酸甲酯。MS(m/e):465.4(MH+)。
实施例63
1-(3,3-二甲基-哌啶-1-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和3,3-二甲基哌啶。MS(m/e):320.2 (MH+)。
实施例64
1-(3-氟-苯基)-4-(2-氧杂-8-氮杂-螺[4.5]癸烷-8-羰基)-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氟-苯基)-1,4-二氢-四唑-5-酮和2-氧杂-8-氮杂螺[4.5]癸烷。MS(m/e): 348.2(MH+)。
实施例65
N-{(R)-1-[4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}- 乙酰胺
a)1-(3-氯-苯基)-1,4-二氢-四唑-5-酮
类似于对于1-环丙基-1,4-二氢-四唑-5-酮(实施例35)的合成所述的程序,标题化合物制备自3-氯苯甲酰氯和叠氮基三甲基硅烷,为白色固体。
b)N-{(R)-1-[4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3- 基}-乙酰胺
类似于对于4-环丙基-5-氧代-4,5-二氢-四唑-1-甲酸甲基-吡啶-3-基-酰胺(实施例35)的合成所述的程序,标题化合物制备自1-(3-氯-苯基)-1,4-二氢-四唑-5-酮和(R)-N-(吡咯烷-3-基)乙酰胺。MS(m/e):351.4(MH+)。
实施例66
N-{(R)-1-[5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}-乙酰胺
a)1-(3-三氟甲氧基-苯基)-1,4-二氢-四唑-5-酮
类似于对于1-环丙基-1,4-二氢-四唑-5-酮(实施例35)的合成所述的程序,标题化合物制备自3-(三氟甲氧基)苯甲酰氯和叠氮基三甲基硅烷,为白色固体。
b)N-{(R)-1-[5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}-乙酰胺
类似于对于4-环丙基-5-氧代-4,5-二氢-四唑-1-甲酸甲基-吡啶-3-基-酰胺(实施例35)的合成所述的程序,标题化合物制备自1-(3-三氟甲氧基-苯基)-1,4-二氢-四唑-5-酮和(R)-N-(吡咯烷-3-基)乙酰胺。MS(m/e):401.4 (MH+)。
实施例67
N-{(R)-1-[4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}- 乙酰胺
a)1-(4-氯-苯基)-1,4-二氢-四唑-5-酮
类似于对于1-环丙基-1,4-二氢-四唑-5-酮(实施例35)的合成所述的程序,标题化合物制备自4-氯苯甲酰氯和叠氮基三甲基硅烷,为白色固体。
b)N-{(R)-1-[4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3- 基}-乙酰胺
类似于对于4-环丙基-5-氧代-4,5-二氢-四唑-1-甲酸甲基-吡啶-3-基-酰胺(实施例35)的合成所述的程序,标题化合物制备自1-(4-氯-苯基)-1,4-二氢-四唑-5-酮和(R)-N-(吡咯烷-3-基)乙酰胺。MS(m/e):351.4(MH+)。
实施例68
N-{(S)-1-[4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}- 乙酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氯-苯基)-1,4-二氢-四唑-5-酮和(S)-N-(吡咯烷-3-基)乙酰胺。MS(m/e): 351.4(MH+)。
实施例69
N-{(S)-1-[5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}-乙酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-(三氟甲氧基)苯基)-1H-四唑-5(4H)-酮和(S)-N-(吡咯烷-3-基)乙酰胺。MS(m/e):401.4(MH+)。
实施例70
N-{(S)-1-[4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}- 乙酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(4-氯-苯基)-1,4-二氢-四唑-5-酮和(S)-N-(吡咯烷-3-基)乙酰胺。MS(m/e): 351.4(MH+)。
实施例71
N-{1-[4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}-N-乙基-乙酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氯-苯基)-1,4-二氢-四唑-5-酮和N-乙基-N-(吡咯烷-3-基)乙酰胺。 MS(m/e):379.4(MH+)。
实施例72
N-乙基-N-{1-[5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-羰基]- 吡咯烷-3-基}-乙酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-(三氟甲氧基)苯基)-1H-四唑-5(4H)-酮和N-乙基-N-(吡咯烷-3-基)乙酰胺。MS(m/e):429.4(MH+)。
实施例73
N-{1-[4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}-N-乙基-乙酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(4-氯-苯基)-1,4-二氢-四唑-5-酮和N-乙基-N-(吡咯烷-3-基)乙酰胺。 MS(m/e):379.4(MH+)。
实施例74
1-(3-氯-苯基)-4-[2-(3-甲基-异唑-5-基)-吡咯烷-1-羰基]-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氯-苯基)-1,4-二氢-四唑-5-酮和3-甲基-5-(吡咯烷-2-基)异唑。 MS(m/e):375.4(MH+)。
实施例75
1-[2-(3-甲基-异唑-5-基)-吡咯烷-1-羰基]-4-(3-三氟甲氧基-苯基)-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-(三氟甲氧基)苯基)-1H-四唑-5(4H)-酮和3-甲基-5-(吡咯烷-2-基)异唑。MS(m/e):425.4(MH+)。
实施例76
1-(4-氯-苯基)-4-[2-(3-甲基-异唑-5-基)-吡咯烷-1-羰基]-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(4-氯-苯基)-1,4-二氢-四唑-5-酮和3-甲基-5-(吡咯烷-2-基)异唑。 MS(m/e):375.4(MH+)。
实施例77
1-(3-氯-苯基)-4-(4,4-二甲基-哌啶-1-羰基)-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氯-苯基)-1,4-二氢-四唑-5-酮和4,4-二甲基哌啶。MS(m/e):336.4 (MH+)。
实施例78
1-(4,4-二甲基-哌啶-1-羰基)-4-(3-三氟甲氧基-苯基)-1,4-二氢-四唑-5- 酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-(三氟甲氧基)苯基)-1H-四唑-5(4H)-酮和4,4-二甲基哌啶。MS(m/e): 386。(MH+)。
实施例79
1-(4-氯-苯基)-4-(4,4-二甲基-哌啶-1-羰基)-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(4-氯-苯基)-1,4-二氢-四唑-5-酮和4,4-二甲基哌啶。MS(m/e):336.4 (MH+)。
实施例80
4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸乙基-(2-甲氧基-乙基)-酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氯-苯基)-1,4-二氢-四唑-5-酮和N-乙基-2-甲氧基乙胺。MS(m/e): 326.4(MH+)。
实施例81
5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-甲酸乙基-(2-甲氧基- 乙基)-酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-(三氟甲氧基)苯基)-1H-四唑-5(4H)-酮和N-乙基-2-甲氧基乙胺。 MS(m/e):376.3(MH+)。
实施例82
4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸乙基-(2-甲氧基-乙基)-酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(4-氯-苯基)-1,4-二氢-四唑-5-酮和N-乙基-2-甲氧基乙胺。MS(m/e): 326.4(MH+)。
实施例83
4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸异丙基-(2-甲氧基-乙基)-酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氯-苯基)-1,4-二氢-四唑-5-酮和N-(2-甲氧基乙基)丙-2-胺。MS(m/e): 340.5(MH+)。
实施例84
5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-甲酸异丙基-(2-甲氧基 -乙基)-酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-(三氟甲氧基)苯基)-1H-四唑-5(4H)-酮和N-(2-甲氧基乙基)丙-2-胺。 MS(m/e):390.4(MH+)。
实施例85
4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸异丙基-(2-甲氧基-乙基)-酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(4-氯-苯基)-1,4-二氢-四唑-5-酮和N-(2-甲氧基乙基)丙-2-胺。MS(m/e): 340.4(MH+)。
实施例86
4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(3-甲氧基-丙基)-甲基-酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氯-苯基)-1,4-二氢-四唑-5-酮和3-甲氧基-N-甲基丙-1-胺。MS(m/e): 326.4(MH+)。
实施例87
5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-甲酸(3-甲氧基-丙基)- 甲基-酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-(三氟甲氧基)苯基)-1H-四唑-5(4H)-酮和3-甲氧基-N-甲基丙-1-胺。 MS(m/e):376.5(MH+)。
实施例88
4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(3-甲氧基-丙基)-甲基-酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(4-氯-苯基)-1,4-二氢-四唑-5-酮和3-甲氧基-N-甲基丙-1-胺。MS(m/e): 326.4(MH+)。
实施例89
1-(3-氯-苯基)-4-[4-(2-吗啉-4-基-2-氧代-乙基)-哌嗪-1-羰基]-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氯-苯基)-1,4-二氢-四唑-5-酮和1-吗啉代-2-(哌嗪-1-基)乙酮。 MS(m/e):436.4(MH+)。
实施例90
1-[4-(2-吗啉-4-基-2-氧代-乙基)-哌嗪-1-羰基]-4-(3-三氟甲氧基-苯基)-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-(三氟甲氧基)苯基)-1H-四唑-5(4H)-酮和1-吗啉代-2-(哌嗪-1-基)乙酮。MS(m/e):486.4(MH+)。
实施例91
1-(4-氯-苯基)-4-[4-(2-吗啉-4-基-2-氧代-乙基)-哌嗪-1-羰基]-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(4-氯-苯基)-1,4-二氢-四唑-5-酮和1-吗啉代-2-(哌嗪-1-基)乙酮。 MS(m/e):436.4(MH+)。
实施例92
2-{4-[4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌嗪-1-基}-N,N-二甲基-乙酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氯-苯基)-1,4-二氢-四唑-5-酮和N,N-二甲基-2-(哌嗪-1-基)乙酰胺。 MS(m/e):394.5(MH+)。
实施例93
N,N-二甲基-2-{4-[5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-羰基]-哌嗪-1-基}-乙酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-(三氟甲氧基)苯基)-1H-四唑-5(4H)-酮和N,N-二甲基-2-(哌嗪-1-基) 乙酰胺。MS(m/e):444.4(MH+)。
实施例94
2-{4-[4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌嗪-1-基}-N,N-二甲基-乙酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(4-氯-苯基)-1,4-二氢-四唑-5-酮和N,N-二甲基-2-(哌嗪-1-基)乙酰胺。 MS(m/e):394.5(MH+)。
实施例95
1-(3-氯-苯基)-4-[4-(2-氧代-2-吡咯烷-1-基-乙基)-哌嗪-1-羰基]-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氯-苯基)-1,4-二氢-四唑-5-酮和2-(哌嗪-1-基)-1-(吡咯烷-1-基)乙酮。 MS(m/e):420.5(MH+)。
实施例96
1-[4-(2-氧代-2-吡咯烷-1-基-乙基)-哌嗪-1-羰基]-4-(3-三氟甲氧基-苯基)-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-(三氟甲氧基)苯基)-1H-四唑-5(4H)-酮和2-(哌嗪-1-基)-1-(吡咯烷-1- 基)乙酮。MS(m/e):470.4(MH+)。
实施例97
1-(4-氯-苯基)-4-[4-(2-氧代-2-吡咯烷-1-基-乙基)-哌嗪-1-羰基]-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(4-氯-苯基)-1,4-二氢-四唑-5-酮和2-(哌嗪-1-基)-1-(吡咯烷-1-基)乙酮。 MS(m/e):420.5(MH+)。
实施例98
4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(2-乙氧基-乙基)-乙基-酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氯-苯基)-1,4-二氢-四唑-5-酮和2-乙氧基-N-乙基乙胺。MS(m/e): 340.4(MH+)。
实施例99
5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-甲酸(2-乙氧基-乙基)- 乙基-酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-(三氟甲氧基)苯基)-1H-四唑-5(4H)-酮和2-乙氧基-N-乙基乙胺。 MS(m/e):390.2(MH+)。
实施例100
4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(2-乙氧基-乙基)-乙基-酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(4-氯-苯基)-1,4-二氢-四唑-5-酮和2-乙氧基-N-乙基乙胺。MS(m/e): 340.2(MH+)。
实施例101
1-(3-氯-苯基)-4-(吗啉-4-羰基)-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氯-苯基)-1,4-二氢-四唑-5-酮和吗啉。MS(m/e):309.9(MH+)。
实施例102
1-(吗啉-4-羰基)-4-(3-三氟甲氧基-苯基)-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-(三氟甲氧基)苯基)-1H-四唑-5(4H)-酮和吗啉。MS(m/e):360.3 (MH+)。
实施例103
1-(4-氯-苯基)-4-(吗啉-4-羰基)-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(4-氯-苯基)-1,4-二氢-四唑-5-酮和吗啉。MS(m/e):310.1(MH+)。
实施例104
2-{4-[4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌嗪-1-基}-N-乙基-乙酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氯-苯基)-1,4-二氢-四唑-5-酮和N-乙基-2-(哌嗪-1-基)乙酰胺。 MS(m/e):394.2(MH+)。
实施例105
N-乙基-2-{4-[5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-羰基]-哌嗪-1-基}-乙酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-(三氟甲氧基)苯基)-1H-四唑-5(4H)-酮和N-乙基-2-(哌嗪-1-基)乙酰胺。MS(m/e):444.4(MH+)。
实施例106
2-{4-[4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌嗪-1-基}-N-乙基-乙酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(4-氯-苯基)-1,4-二氢-四唑-5-酮和N-乙基-2-(哌嗪-1-基)乙酰胺。 MS(m/e):394.2(MH+)。
实施例107
N-丁基-2-{4-[4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌嗪-1-基}-乙酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氯-苯基)-1,4-二氢-四唑-5-酮和N-丁基-2-(哌嗪-1-基)乙酰胺。 MS(m/e):422.3(MH+)。
实施例108
N-丁基-2-{4-[5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-羰基]-哌嗪-1-基}-乙酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-(三氟甲氧基)苯基)-1H-四唑-5(4H)-酮和N-丁基-2-(哌嗪-1-基)乙酰胺。MS(m/e):472.3(MH+)。
实施例109
N-丁基-2-{4-[4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌嗪-1-基}-乙酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(4-氯-苯基)-1,4-二氢-四唑-5-酮和N-丁基-2-(哌嗪-1-基)乙酰胺。 MS(m/e):422.3(MH+)。
实施例110
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(2-甲氧基-乙基)-酰胺
将1-(3-氟苯基)-1H-四唑-5(4H)-酮(222.2mg,1.23mmol)和DMAP(301 mg,2.47mmol)在DCM(12.3mL)中的混合物在0℃用双光气(254mg, 155μl,1.28mmol)处理并且随后用2-甲氧基乙胺(139mg,159μl,1.85 mmol)处理。将混合物在室温搅拌过夜并蒸发。将残余物置于DMF(5mL) 和300uL HCOOH中并通过利用由乙腈、水和HCOOH形成的梯度洗脱的制备型HPLC进行纯化。蒸发含产物的级分从而产生145mg(40%)的标题化合物,为白色固体。MS(m/e):282.1(MH+)。
实施例111
4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(2-乙氧基-乙基)-甲基-酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氯-苯基)-1,4-二氢-四唑-5-酮和2-乙氧基-N-甲基乙胺盐酸盐。 MS(m/e):326.1(MH+)。
实施例112
5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-甲酸(2-乙氧基-乙基)- 甲基-酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-(三氟甲氧基)苯基)-1H-四唑-5(4H)-酮和2-乙氧基-N-甲基乙胺盐酸盐。MS(m/e):376.2(MH+)。
实施例113
4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(2-乙氧基-乙基)-甲基-酰胺
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(4-氯-苯基)-1,4-二氢-四唑-5-酮和2-乙氧基-N-甲基乙胺盐酸盐。 MS(m/e):326.1(MH+)。
实施例114
[4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-基]-乙酸乙酯
类似于对于2-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-基]-2-甲基-丙酸乙酯(实施例16)的合成所述的程序,标题化合物制备自1-(3-氯-苯基)-1,4- 二氢-四唑-5-酮和2-溴乙酸乙酯并被分离为白色固体。MS(m/e):283.1 (MH+)。
实施例115
1-(3-氯-苯基)-4-(2-吗啉-4-基-2-氧代-乙基)-1,4-二氢-四唑-5-酮
将2-(4-(3-氯苯基)-5-氧代-4,5-二氢-1H-四唑-1-基)乙酸乙酯(57.4mg, 203μmol)和LiOH(一水合物)(15mg,357μmol)在水(2mL)、MeOH(2mL) 和THF(0.5mL)中的混合物在室温搅拌2h。对混合物进行蒸发并且水和 HCl(1M水溶液)是42mg(81%)的所述酸,为白色晶体。
将在DMF(1.5mL)中的31.2mg(123μmol)的所述酸和TBTU(43.3 mg,135μmol)用吗啉(21.3mg,21.3μl,245μmol)处理并在室温振荡1.5h。加入HCOOH并将混合物通过利用由乙腈、水和HCOOH形成的梯度洗脱的制备型HPLC进行纯化。蒸发含产物的级分从而产生28mg(72%)的标题化合物,为白色固体。MS(m/e):324.1(MH+)。
实施例116
1-(3-氯-苯基)-4-[4-(1-甲基-2-氧代-2-吡咯烷-1-基-乙基)-哌嗪-1-羰基]-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-氯-苯基)-1,4-二氢-四唑-5-酮和2-(哌嗪-1-基)-1-(吡咯烷-1-基)丙-1- 酮。MS(m/e):434.4(MH+)。
实施例117
1-[4-(1-甲基-2-氧代-2-吡咯烷-1-基-乙基)-哌嗪-1-羰基]-4-(3-三氟甲氧基-苯基)-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(3-(三氟甲氧基)苯基)-1H-四唑-5(4H)-酮和2-(哌嗪-1-基)-1-(吡咯烷-1- 基)丙-1-酮。MS(m/e):484.4(MH+)。
实施例118
1-(4-氯-苯基)-4-[4-(1-甲基-2-氧代-2-吡咯烷-1-基-乙基)-哌嗪-1-羰基]-1,4-二氢-四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺(实施例1)的合成所述的程序,标题化合物制备自1-(4-氯-苯基)-1,4-二氢-四唑-5-酮和2-(哌嗪-1-基)-1-(吡咯烷-1-基)丙-1- 酮。MS(m/e):434.4(MH+)。
实施例119
1-(吗啉-4-羰基)-4-[2-(三氟甲基)苯基]四唑-5-酮
a)1-(2-三氟甲基-苯基)-1,4-二氢-四唑-5-酮
类似于对于1-环丙基-1,4-二氢-四唑-5-酮(实施例35)的合成所述的程序,标题化合物制备自2-(三氟甲基)苯甲酰氯和叠氮基三甲基硅烷,为自色固体并被用于随后的步骤中。
b)1-(吗啉-4-羰基)-4-[2-(三氟甲基)苯基]四唑-5-酮
类似于对于4-环丙基-5-氧代-4,5-二氢-四唑-1-甲酸甲基-吡啶-3-基-酰胺(实施例35)的合成所述的程序,标题化合物制备自1-(2-三氟甲基-苯基)-1,4-二氢-四唑-5-酮和吗啉-4-碳酰氯。MS(m/e):344.2(MH+)。
实施例120
1-(吗啉-4-羰基)-4-[3-(三氟甲基)苯基]四唑-5-酮
类似于对于1-(吗啉-4-羰基)-4-[2-(三氟甲基)苯基]四唑-5-酮(实施例 119)的合成所述的程序,标题化合物制备自3-(三氟甲基)苯甲酰氯、叠氮基三甲基硅烷和吗啉-4-碳酰氯。MS(m/e):344.3(MH+)。
实施例121
1-(吗啉-4-羰基)-4-[4-(三氟甲基)苯基]四唑-5-酮
类似于对于1-(吗啉-4-羰基)-4-[2-(三氟甲基)苯基]四唑-5-酮(实施例 119)的合成所述的程序,标题化合物制备自4-(三氟甲基)苯甲酰氯、叠氮基三甲基硅烷和吗啉-4-碳酰氯。MS(m/e):344.2(MH+)。
实施例122
1-(2,6-二氟苯基)-4-(吗啉-4-羰基)四唑-5-酮
a)1-(2,6-二氟-苯基)-1,4-二氢-四唑-5-酮
类似于对于1-(3-氟-苯基)-1,4-二氢-四唑-5-酮(实施例1)的合成所述的程序,标题化合物制备自1,3-二氟-2-异氰酸根合苯和叠氮基三甲基硅烷。 MS(m/e):240.1(MH+)。
b)1-(2,6-二氟苯基)-4-(吗啉-4-羰基)四唑-5-酮
类似于对于1-(吗啉-4-羰基)-4-[2-(三氟甲基)苯基]四唑-5-酮(实施例 119)的合成所述的程序,标题化合物制备自1-(2,6-二氟-苯基)-1,4-二氢-四唑-5-酮和吗啉-4-碳酰氯。MS(m/e):312.3(MH+)。
实施例123
1-(2,4-二氟苯基)-4-(吗啉-4-羰基)四唑-5-酮
a)1-(2,4-二氟-苯基)-1,4-二氢-四唑-5-酮
类似于对于1-(3-氟-苯基)-1,4-二氢-四唑-5-酮(实施例1)的合成所述的程序,标题化合物制备自2,4-二氟-2-异氰酸根合苯和叠氮基三甲基硅烷。 MS(m/e):240.1(MH+)。
b)1-(2,4-二氟苯基)-4-(吗啉-4-羰基)四唑-5-酮
类似于对于1-(吗啉-4-羰基)-4-[2-(三氟甲基)苯基]四唑-5-酮(实施例119)的合成所述的程序,标题化合物制备自1-(2,4-二氟-苯基)-1,4-二氢-四唑-5-酮和吗啉-4-碳酰氯。MS(m/e):312.3(MH+)。
实施例124
1-(2,5-二氟苯基)-4-(吗啉-4-羰基)四唑-5-酮
类似于对于1-(2,6-二氟苯基)-4-(吗啉-4-羰基)四唑-5-酮(实施例122)的合成所述的程序,标题化合物制备自1,4-二氟-2-异氰酸根合苯、叠氮基三甲基硅烷和吗啉-4-碳酰氯。MS(m/e):312.2(MH+)。
实施例125
1-(3,4-二氟苯基)-4-(吗啉-4-羰基)四唑-5-酮
类似于对于1-(2,6-二氟苯基)-4-(吗啉-4-羰基)四唑-5-酮(实施例122)的合成所述的程序,标题化合物制备自1,2-二氟-4-异氰酸根合-苯、叠氮基三甲基硅烷和吗啉-4-碳酰氯。MS(m/e):312.2(MH+)。
实施例126
1-(3,5-二氟苯基)-4-(吗啉-4-羰基)四唑-5-酮
类似于对于1-(2,6-二氟苯基)-4-(吗啉-4-羰基)四唑-5-酮(实施例122)的合成所述的程序,标题化合物制备自1,3-二氟-5-异氰酸根合苯、叠氮基三甲基硅烷和吗啉-4-碳酰氯。MS(m/e):312.1(MH+)。
实施例127
1-(3-甲基苯基)-4-(吗啉-4-羰基)四唑-5-酮
类似于对于1-(2,6-二氟苯基)-4-(吗啉-4-羰基)四唑-5-酮(实施例122)的合成所述的程序,标题化合物制备自1-异氰酸根合-3-甲基苯、叠氮基三甲基硅烷和吗啉-4-碳酰氯。MS(m/e):290.2(MH+)。
实施例128
1-(4-甲基苯基)-4-(吗啉-4-羰基)四唑-5-酮
类似于对于1-(2,6-二氟苯基)-4-(吗啉-4-羰基)四唑-5-酮(实施例122)的合成所述的程序,标题化合物制备自1-异氰酸根合-4-甲基苯、叠氮基三甲基硅烷和吗啉-4-碳酰氯。MS(m/e):290.1(MH+)。
实施例129
1-(3-甲氧基苯基)-4-(吗啉-4-羰基)四唑-5-酮
类似于对于1-(2,6-二氟苯基)-4-(吗啉-4-羰基)四唑-5-酮(实施例122)的合成所述的程序,标题化合物制备自1-异氰酸根合-3-甲氧基苯、叠氮基三甲基硅烷和吗啉-4-碳酰氯。MS(m/e):306.2(MH+)。
实施例130
1-(4-甲氧基苯基)-4-(吗啉-4-羰基)四唑-5-酮
类似于对于1-(2,6-二氟苯基)-4-(吗啉-4-羰基)四唑-5-酮(实施例122)的合成所述的程序,标题化合物制备自1-异氰酸根合-4-甲氧基苯、叠氮基三甲基硅烷和吗啉-4-碳酰氯。MS(m/e):306.2(MH+)。
实施例131
1-(2,3-二氯苯基)-4-(吗啉-4-羰基)四唑-5-酮
类似于对于1-(2,6-二氟苯基)-4-(吗啉-4-羰基)四唑-5-酮(实施例122)的合成所述的程序,标题化合物制备自1,2-二氯-3-异氰酸根合苯、叠氮基三甲基硅烷和吗啉-4-碳酰氯。MS(m/e):344.1(MH+)。
实施例132
1-(1-甲基吲哚-4-基)-4-(吗啉-4-羰基)四唑-5-酮
类似于对于1-(2,6-二氟苯基)-4-(吗啉-4-羰基)四唑-5-酮(实施例122)的合成所述的程序,标题化合物制备自4-异氰酸根合-1-甲基-1H-吲哚、叠氮基三甲基硅烷和吗啉-4-碳酰氯。MS(m/e):329.2(MH+)。
实施例133
1-(1-甲基吲哚-5-基)-4-(吗啉-4-羰基)四唑-5-酮
类似于对于1-(2,6-二氟苯基)-4-(吗啉-4-羰基)四唑-5-酮(实施例122)的合成所述的程序,标题化合物制备自5-异氰酸根合-1-甲基-1H-吲哚、叠氮基三甲基硅烷和吗啉-4-碳酰氯。MS(m/e):329.2(MH+)。
实施例134
1-(1-甲基吲哚-6-基)-4-(吗啉-4-羰基)四唑-5-酮
类似于对于1-(2,6-二氟苯基)-4-(吗啉-4-羰基)四唑-5-酮(实施例122)的合成所述的程序,标题化合物制备自6-异氰酸根合-1-甲基-1H-吲哚、叠氮基三甲基硅烷和吗啉-4-碳酰氯。MS(m/e):329.3(MH+)。
实施例135
1-(3-溴苯基)-4-(吗啉-4-羰基)四唑-5-酮
类似于对于1-(吗啉-4-羰基)-4-[2-(三氟甲基)苯基]四唑-5-酮(实施例 119)的合成所述的程序,标题化合物制备自3-溴苯甲酰氯、叠氮基三甲基硅烷和吗啉-4-碳酰氯。MS(m/e):354.2(MH+)。
实施例136
1-(3-氯苯基)-4-[(2R,6S)-2,6-二甲基吗啉-4-羰基]四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(2-甲氧基-乙基)-酰胺(实施例110)的合成所述的程序,标题化合物制备自1-(3-氯苯基)-1H-四唑-5(4H)-酮和(2R,6S)-2,6-二甲基吗啉(顺-2,6-)。MS(m/e):338.3 (MH+)。
实施例137
1-(3-氯苯基)-4-(2,6-二甲基吗啉-4-羰基)四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(2-甲氧基-乙基)-酰胺(实施例110)的合成所述的程序,标题化合物制备自1-(3-氯苯基)-1H-四唑-5(4H)-酮和2,6-二甲基吗啉。MS(m/e):338.3(MH+)。
实施例138
1-(3-氯苯基)-4-(3,3-二甲基吡咯烷-1-羰基)四唑-5-酮
类似于对于4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(2-甲氧基-乙基)-酰胺(实施例110)的合成所述的程序,标题化合物制备自1-(3-氯苯基)-1H-四唑-5(4H)-酮和3,3-二甲基吡咯烷。MS(m/e):322.2(MH+)。
实施例139
药理学试验
进行以下试验以确定式(I)化合物的活性:
放射性配体结合测定
本发明化合物对大麻素CB1受体的亲和性使用建议量的表达人CNR1 或CNR2受体的人胚胎肾(HEK)细胞的膜制品(PerkinElmer)各自分别结合1.5或2.6nM[3H]-CP-55,940(Perkin Elmer)作为放射性配体确定。结合在总体积为0.2ml的结合缓冲液(对于CB1受体50mM Tris,5mM MgC12,2.5 mM EDTA,和0.5%(wt/vol)无脂肪酸BSA,pH 7.4,和对于CB2受体50mM Tris,5mM MgCl2,2.5mM EGTA,和0.1%(wt/vol)无脂肪酸BSA,pH 7.4) 中进行,在30℃振荡1h。通过经涂布有0.5%聚乙烯亚胺的微过滤板 (UniFilter GF/B过滤板;Packard)快速过滤将反应终止。对于Ki使用非线性回归分析(Activity Base,ID BusinessSolution,Limited)来分析结合的放射性,对于[3H]CP55,940的Kd值从饱和试验确定。式(I)化合物显示对于 CB2受体的优异的亲和性,亲和性低于10μM,更特别是1nM至3μM并且最特别是1nM至100nM。
cAMP测定
将表达人CB1或CB2受体的CHO细胞在实验之前17-24小时以50.000细胞/孔接种在具有透明平底的黑色96孔平板(Corning Costar# 3904)中、在DMEM(InvitrogenNo.31331)中,补充1x HT,具有10%胎牛血清,并在湿润的培养箱中在5%CO2和37℃下温育。将培养基用具有 1mM IBMX的Krebs Ringer Bicarbonate缓冲液交换,并且在30℃温育30 分钟。加入化合物至最终测定体积为100μl,并且在30℃温育30分钟。使用cAMP-Nano-TRF检测试剂盒(Roche Diagnostics),通过加入50μl裂解试剂(Tris,NaCl,1.5%TritonX100,2.5%NP40,10%NaN3)和50μl检测溶液(20μM mAb Alexa700-cAMP 1∶1,和48μM钌-2-AHA-cAMP)终止测定,并且室温振荡2h。通过装备有ND:YAG激光器作为激发源的TRF读出器(Evotec Technologies GmbH)测量时间分辨能量转移。将平板测量两次,在355nm激发和分别在730(带宽30nm)或645nm(带宽75nm)以100 ns的延迟和100ns的栅极(gate)发射,总暴露时间是10s。FRET信号的计算如下:FRET=T730-Alexa730-P(T645-B645),P= Ru730-B730/Ru645-B645,其中T730是在730nM测量的测试孔,T645是在645nm测量的测试孔,B730和B645是分别在730nm和645nm的缓冲液对照。cAMP含量从跨度为从10μM至0.13nM cAMP的标准曲线的函数来测定。
使用Activity Base分析(ID Business Solution,Limited)测定EC50值。从该测定产生的宽范围的大麻素激动剂的EC50值与科学文献中公开的值吻合。
本发明的化合物是CB2受体激动剂,其EC50低于1μM,并且在相应测定中相对于CB1的选择性为至少10倍。本发明的特别的化合物是CB2 受体激动剂,其EC50低于0.05μM,并且在相应测定中相对于CB1的选择性为至少500倍。
例如,以下化合物在上述功能cAMP测定中显示以下的人EC50值 (uM):
实施例A
可以以常规方式制备含有下列成分的薄膜包衣片剂:
<u>成分</u> | <u>每片</u> | |
核: | ||
式(I)的化合物 | 10.0mg | 200.0mg |
微晶纤维素 | 23.5mg | 43.5mg |
含水乳糖 | 60.0mg | 70.0mg |
聚维酮(Povidone)K30 | 12.5mg | 15.0mg |
淀粉羟乙酸钠 | 12.5mg | 17.0mg |
硬脂酸镁 | 1.5mg | 4.5mg |
(核重) | 120.0mg | 350.0mg |
薄膜包衣: | ||
羟丙基甲基纤维素 | 3.5mg | 7.0mg |
聚乙二醇6000 | 0.8mg | 1.6mg |
滑石 | 1.3mg | 2.6mg |
氧化铁(黄) | 0.8mg | 1.6mg |
二氧化钛 | 0.8mg | 1.6mg |
筛分活性成分,并将活性成分与微晶纤维素混和,并将混合物用聚乙烯吡咯烷酮的水溶液制粒。然后将颗粒与淀粉羟乙酸钠和硬脂酸镁混和并且压制,分别获得120或350mg的核。将所述核用上述薄膜包衣的水溶液 /悬浮液包衣。
实施例B
可以以常规方式制备含有下列成分的胶囊:
<u>成分</u> | <u>每片</u> |
式(I)的化合物 | 25.0mg |
乳糖 | 150.0mg |
玉米淀粉 | 20.0mg |
滑石 | 5.0mg |
筛分组分并混合和填充到2号胶囊中。
实施例C
注射液可以具有下列组成:
式(I)的化合物 | 3.0mg |
聚乙二醇400 | 150.0mg |
乙酸 | 适量至获得pH 5.0 |
注射液用水 | 加至1.0ml |
将活性成分溶解在聚乙二醇400和注射用水(一部分)的混合物中。通过加入乙酸将pH调到5.0。加入余量的水将体积调到1.0ml。将溶液过滤,使用适当过量装入小瓶中并灭菌。
Claims (16)
1.式(I)的化合物
其中
R1是正丙基、异丁基、环丙基、3-氟苯基、6-氯吡啶-3-基、3-氯苯基、4-氯苯基、3-三氟甲氧基苯基、2-(三氟甲基)苯基、3-(三氟甲基)苯基、4-(三氟甲基)苯基、2,6-二氟苯基、2,5-二氟苯基、3,4-二氟苯基、3,5-二氟苯基、3-甲基苯基、4-甲基苯基、3-甲氧基苯基、4-甲氧基苯基、2,3-二氯苯基、1-甲基吲哚基或3-溴苯基;
R2是-C(O)NR3R4或R5;
R3和R4中的一个是氢、C1-8烷基、C3-8环烷基或C1-8烷氧基C1-8烷基,而另一个是-(CH2)n-R6;
或R3和R4与它们所连接的氮原子一起形成杂环基或取代的杂环基,其中杂环基是哌啶基、吗啉基、吡咯烷基、3,4-二氢-1H-异喹啉基、氮杂环丁基、哌嗪基、1,1-二氧代硫代吗啉基或2-氧杂-8-氮杂-螺[4.5]癸基,并且其中取代的杂环基是被一个选自卤素、C1-8烷基、氰基、C1-8烷氧基C1-8烷基、氨基羰基、二(C1-8烷基)氨基羰基、二(C1-8烷基)氨基羰基C1-8烷基、C1-8烷基氨基羰基C1-8烷基、苯基、卤代苯基、苯基C1-8烷基、卤代苯基C1-8烷基、甲基吡唑基、甲基异唑基、C1-8烷氧基C1-8烷基、C1-8烷基羰基氨基、C1-8烷基羰基、C1-8烷氧基羰基、C1-8烷基-[1,2,4]二唑基、吡咯烷基羰基C1-8烷基、吡嗪基、(C1-8烷基)(C1-8烷基羰基)氨基、C1-8烷基异唑基和吗啉基羰基C1-8烷基的取代基取代的或被两个独立地选自C1-8烷基、卤素、C1-8烷氧基羰基和C1-8烷氧基羰基氨基的取代基取代的杂环基;
R5是卤代苯基C1-8烷基、C1-8烷氧基羰基哌啶基、C1-8烷氧基羰基C1-8烷基、(C1-8烷基磺酰基)(C1-8烷基)[1,2,4]三唑基C1-8烷基或吗啉基羰基C1-8烷基;
R6是C1-8烷氧基、二(C1-8烷氧基)苯基、氰基、苯基、吡啶基或C1-8烷氧基羰基C1-8烷基;并且
n是0、1、2或3;
或其药用盐;
前提是排除以下各项:
1-环丙基-4-(吡咯烷-1-羰基)-1,4-二氢-四唑-5-酮;
1-环丙基-4-(2-甲基-吡咯烷-1-羰基)-1,4-二氢-四唑-5-酮;
1-环丙基-4-(2,5-二甲基-吡咯烷-1-羰基)-1,4-二氢-四唑-5-酮;
1-环丙基-4-(2,6-二甲基-哌啶-1-羰基)-1,4-二氢-四唑-5-酮;
4-环丙基-5-氧代-4,5-二氢-四唑-1-甲酸苄基-异丙基-酰胺;
[4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-基]-乙酸乙酯;
2-[4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-基]-丙酸乙酯;
3-[4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-基]-丙酸甲酯;
1-(2,3-二氯-苯基)-4-(2-甲基-哌啶-1-羰基)-1,4-二氢-四唑-5-酮;
1-(2,6-二氟苯基)-4-(3,4-二氢-1H-异喹啉-2-羰基)四唑-5-酮;
4-(2,6-二氟苯基)-5-氧代-N-苯基-正丙基-四唑-1-甲酰胺;
4-(2,6-二氟苯基)-N-乙基-5-氧代-N-苯基-四唑-1-甲酰胺;
4-(2,6-二氟苯基)-N-甲基-5-氧代-N-苯基-四唑-1-甲酰胺;
4-(2,6-二氟苯基)-N-异丙基-5-氧代-N-苯基-四唑-1-甲酰胺;
N-环己基-4-(2,6-二氟苯基)-5-氧代-N-苯基-四唑-1-甲酰胺;
4-(2,6-二氟苯基)-N-甲基-5-氧代-N-(2-吡啶基)四唑-1-甲酰胺;
N,4-二环丙基-5-氧代-N-苯基-四唑-1-甲酰胺;
N-丁基-4-环丙基-5-氧代-N-苯基-四唑-1-甲酰胺;
4-环丙基-N-异丁基-5-氧代-N-苯基-四唑-1-甲酰胺;
4-环丙基-N-异丙基-5-氧代-N-苯基-四唑-1-甲酰胺;
4-环丙基-5-氧代-N-苯基-正丙基-四唑-1-甲酰胺;
4-环丙基-N-甲基-5-氧代-N-苯基-四唑-1-甲酰胺;
4-环丙基-N-乙基-5-氧代-N-苯基-四唑-1-甲酰胺;
4-环丙基-5-氧代-N-苯基-N-仲丁基-四唑-1-甲酰胺;
N-(1-苄基-2-甲基-丙基)-4-环丙基-5-氧代-N-苯基-四唑-1-甲酰胺;
1-(2-甲基哌啶-1-羰基)-4-(对-甲苯基)四唑-5-酮;
1-(2-甲基哌啶-1-羰基)-4-(间-甲苯基)四唑-5-酮;
N-异丙基-5-氧代-N-苯基-4-丙基-四唑-1-甲酰胺;
1-(4-氯苯基)-4-[(2-氟苯基)甲基]四唑-5-酮;
1-(4-氯苯基)-4-[(3-氟苯基)甲基]四唑-5-酮;
1-(4-氯苯基)-4-[(3-氯苯基)甲基]四唑-5-酮;
1-[(4-溴苯基)甲基]-4-(4-氯苯基)四唑-5-酮;和
3-[5-氧代-4-(对-甲苯基)四唑-1-基]丙酸甲酯。
2.根据权利要求1的化合物,其中R1是3-氟苯基、3-氯苯基或4-氯苯基。
3.根据权利要求1或2的化合物,其中R3和R4中的一个是C1-8烷基,而另一个是-(CH2)n-R6。
4.根据权利要求1或2的化合物,其中R3和R4中的一个是甲基或乙基,而另一个是-(CH2)n-R6。
5.根据权利要求1或2的化合物,其中R3和R4与它们所连接的氮原子一起形成杂环基或取代的杂环基,其中杂环基是哌啶基、吡咯烷基或吗啉基,并且其中取代的杂环基是被一个选自C1-8烷基和C1-8烷基羰基氨基的取代基取代的或被两个独立地选自C1-8烷基的取代基取代的杂环基。
6.根据权利要求1或2的化合物,其中R3和R4与它们所连接的氮原子一起形成吗啉基、二甲基哌啶基或甲基羰基氨基吡咯烷基。
7.根据权利要求1或2的化合物,其中R5是叔丁氧基羰基哌啶基、氟苯基甲基、乙氧基羰基甲基、乙氧基羰基(二甲基)甲基、(甲基磺酰基)(甲基)[1,2,4]三唑基甲基或吗啉基羰基甲基。
8.根据权利要求1或2的化合物,其中R6是C1-8烷氧基、二(C1-8烷氧基)苯基、苯基或吡啶基。
9.根据权利要求1或2的化合物,其中R6是甲氧基、二甲氧基苯基、苯基或吡啶基。
10.根据权利要求1或2的化合物,其中n是1、2或3。
11.化合物,其选自:
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(2-氰基-乙基)-甲基-酰胺;
1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌啶-3-甲酸酰胺;
1-(3-氟-苯基)-4-(吗啉-4-羰基)-1,4-二氢-四唑-5-酮;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸甲基-苯乙基-酰胺;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸乙基-吡啶-4-基甲基-酰胺;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸乙基-(2-甲氧基-乙基)-酰胺;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸甲基-(3-苯基-丙基)-酰胺;
1-(2-苄基-吡咯烷-1-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮;
1-(3-氟-苯基)-4-[2-(4-氟-苯基)-吡咯烷-1-羰基]-1,4-二氢-四唑-5-酮;
1-(6-氟-3,4-二氢-1H-异喹啉-2-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸苄基-乙基-酰胺;
(2S,3S)-2-{[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-甲基-氨基}-3-甲基-戊酸甲酯;
1-(4-氟-苄基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮;
4-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-基]-哌啶-1-甲酸叔丁酯;
2-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-基]-2-甲基-丙酸乙酯;
1-(3-氟-苯基)-4-(5-甲磺酰基-4-甲基-4H-[1,2,4]三唑-3-基甲基)-1,4-二氢-四唑-5-酮;
1-(3-氟-苯基)-4-[2-(2-甲基-2H-吡唑-3-基)-吡咯烷-1-羰基]-1,4-二氢-四唑-5-酮;
1-(3-氟-苯基)-4-[2-(1-甲基-1H-吡唑-3-基)-吡咯烷-1-羰基]-1,4-二氢-四唑-5-酮;
1-(3-氟-苯基)-4-[2-(3-甲基-异唑-5-基)-吡咯烷-1-羰基]-1,4-二氢-四唑-5-酮;
1-(3-氟-苯基)-4-((S)-2-甲氧基甲基-吡咯烷-1-羰基)-1,4-二氢-四唑-5-酮;
(S)-1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-2-甲酸酰胺;
N-{1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}-乙酰胺;
1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-氮杂环丁烷-3-甲酸甲酯;
1-(3-氟-苯基)-4-[2-(3-甲基-[1,2,4]二唑-5-基)-吡咯烷-1-羰基]-1,4-二氢-四唑-5-酮;
N-{1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌啶-4-基}-乙酰胺;
1-(3-氟-苯基)-4-[4-(2-氧代-2-吡咯烷-1-基-乙基)-哌嗪-1-羰基]-1,4-二氢-四唑-5-酮;
1-(4,4-二甲基-哌啶-1-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮;
1-(1,1-二氧代-1λ6-硫代吗啉-4-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮;
1-(3-氟-苯基)-4-(2,3,5,6-四氢-[1,2′]二吡嗪基-4-羰基)-1,4-二氢-四唑-5-酮;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(2-氰基-乙基)-环丙基-酰胺;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸甲基-吡啶-2-基-酰胺;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸甲基-吡啶-3-基-酰胺;
1-(3-氟-苯基)-4-(2-甲氧基甲基-哌啶-1-羰基)-1,4-二氢-四唑-5-酮;
4-环丙基-5-氧代-4,5-二氢-四唑-1-甲酸甲基-吡啶-3-基-酰胺;
5-氧代-4-丙基-4,5-二氢-四唑-1-甲酸甲基-吡啶-3-基-酰胺;
4-异丁基-5-氧代-4,5-二氢-四唑-1-甲酸甲基-吡啶-3-基-酰胺;
1-(4-乙酰基-哌嗪-1-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮;
1-(3-氟-苯基)-4-(4-丙酰基-哌嗪-1-羰基)-1,4-二氢-四唑-5-酮;
4-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌嗪-1-甲酸二乙基酰胺;
1-(3-氟-苯基)-4-(3-苯基-吡咯烷-1-羰基)-1,4-二氢-四唑-5-酮;
N-{(S)-1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}-乙酰胺;
N-{(R)-1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}-乙酰胺;
N-乙基-N-{1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}-乙酰胺;
1-(3,3-二氟-吡咯烷-1-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮;
1-(2,2-二甲基-吡咯烷-1-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮;
1-(3,3-二甲基-吡咯烷-1-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮;
1-(3-氟-苯基)-4-(2-甲基-吡咯烷-1-羰基)-1,4-二氢-四唑-5-酮;
N-{1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}-N-甲基-乙酰胺;
4-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌嗪-1-甲酸乙酯;
(S)-1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-2-甲腈;
(R)-1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-2-甲腈;
4-(6-氯-吡啶-3-基)-5-氧代-4,5-二氢-四唑-1-甲酸苄基-乙基-酰胺;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(2-甲氧基-乙基)-甲基-酰胺;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸异丙基-(2-甲氧基-乙基)-酰胺;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(2-甲氧基-乙基)-丙基-酰胺;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸双-(2-甲氧基-乙基)-酰胺;
1-(2,6-二甲基-吗啉-4-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮;
1-((2S,6R)-2,6-二甲基-吗啉-4-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮;
1-(3-氟-苯基)-4-(4-甲氧基甲基-哌啶-1-羰基)-1,4-二氢-四唑-5-酮;
1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌啶-4-甲腈;
4-叔丁氧基羰基氨基-1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌啶-4-甲酸甲酯;
1-(3,3-二甲基-哌啶-1-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮;
1-(3-氟-苯基)-4-(2-氧杂-8-氮杂-螺[4.5]癸烷-8-羰基)-1,4-二氢-四唑-5-酮;
N-{(R)-1-[4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}-乙酰胺;
N-{(R)-1-[5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}-乙酰胺;
N-{(R)-1-[4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}-乙酰胺;
N-{(S)-1-[4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}-乙酰胺;
N-{(S)-1-[5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}-乙酰胺;
N-{(S)-1-[4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}-乙酰胺;
N-{1-[4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}-N-乙基-乙酰胺;
N-乙基-N-{1-[5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}-乙酰胺;
N-{1-[4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}-N-乙基-乙酰胺;
1-(3-氯-苯基)-4-[2-(3-甲基-异唑-5-基)-吡咯烷-1-羰基]-1,4-二氢-四唑-5-酮;
1-[2-(3-甲基-异唑-5-基)-吡咯烷-1-羰基]-4-(3-三氟甲氧基-苯基)-1,4-二氢-四唑-5-酮;
1-(4-氯-苯基)-4-[2-(3-甲基-异唑-5-基)-吡咯烷-1-羰基]-1,4-二氢-四唑-5-酮;
1-(3-氯-苯基)-4-(4,4-二甲基-哌啶-1-羰基)-1,4-二氢-四唑-5-酮;
1-(4,4-二甲基-哌啶-1-羰基)-4-(3-三氟甲氧基-苯基)-1,4-二氢-四唑-5-酮;
1-(4-氯-苯基)-4-(4,4-二甲基-哌啶-1-羰基)-1,4-二氢-四唑-5-酮;
4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸乙基-(2-甲氧基-乙基)-酰胺;
5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-甲酸乙基-(2-甲氧基-乙基)-酰胺;
4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸乙基-(2-甲氧基-乙基)-酰胺;
4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸异丙基-(2-甲氧基-乙基)-酰胺;
5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-甲酸异丙基-(2-甲氧基-乙基)-酰胺;
4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸异丙基-(2-甲氧基-乙基)-酰胺;
4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(3-甲氧基-丙基)-甲基-酰胺;
5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-甲酸(3-甲氧基-丙基)-甲基-酰胺;
4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(3-甲氧基-丙基)-甲基-酰胺;
1-(3-氯-苯基)-4-[4-(2-吗啉-4-基-2-氧代-乙基)-哌嗪-1-羰基]-1,4-二氢-四唑-5-酮;
1-[4-(2-吗啉-4-基-2-氧代-乙基)-哌嗪-1-羰基]-4-(3-三氟甲氧基-苯基)-1,4-二氢-四唑-5-酮;
1-(4-氯-苯基)-4-[4-(2-吗啉-4-基-2-氧代-乙基)-哌嗪-1-羰基]-1,4-二氢-四唑-5-酮;
2-{4-[4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌嗪-1-基}-N,N-二甲基-乙酰胺;
N,N-二甲基-2-{4-[5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-羰基]-哌嗪-1-基}-乙酰胺;
2-{4-[4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌嗪-1-基}-N,N-二甲基-乙酰胺;
1-(3-氯-苯基)-4-[4-(2-氧代-2-吡咯烷-1-基-乙基)-哌嗪-1-羰基]-1,4-二氢-四唑-5-酮;
1-[4-(2-氧代-2-吡咯烷-1-基-乙基)-哌嗪-1-羰基]-4-(3-三氟甲氧基-苯基)-1,4-二氢-四唑-5-酮;
1-(4-氯-苯基)-4-[4-(2-氧代-2-吡咯烷-1-基-乙基)-哌嗪-1-羰基]-1,4-二氢-四唑-5-酮;
4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(2-乙氧基-乙基)-乙基-酰胺;
5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-甲酸(2-乙氧基-乙基)-乙基-酰胺;
4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(2-乙氧基-乙基)-乙基-酰胺;
1-(3-氯-苯基)-4-(吗啉-4-羰基)-1,4-二氢-四唑-5-酮;
1-(吗啉-4-羰基)-4-(3-三氟甲氧基-苯基)-1,4-二氢-四唑-5-酮;
1-(4-氯-苯基)-4-(吗啉-4-羰基)-1,4-二氢-四唑-5-酮;
2-{4-[4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌嗪-1-基}-N-乙基-乙酰胺;
N-乙基-2-{4-[5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-羰基]-哌嗪-1-基}-乙酰胺;
2-{4-[4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌嗪-1-基}-N-乙基-乙酰胺;
N-丁基-2-{4-[4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌嗪-1-基}-乙酰胺;
N-丁基-2-{4-[5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-羰基]-哌嗪-1-基}-乙酰胺;
N-丁基-2-{4-[4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-哌嗪-1-基}-乙酰胺;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(2-甲氧基-乙基)-酰胺;
4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(2-乙氧基-乙基)-甲基-酰胺;
5-氧代-4-(3-三氟甲氧基-苯基)-4,5-二氢-四唑-1-甲酸(2-乙氧基-乙基)-甲基-酰胺;
4-(4-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(2-乙氧基-乙基)-甲基-酰胺;
[4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-基]-乙酸乙酯;
1-(3-氯-苯基)-4-(2-吗啉-4-基-2-氧代-乙基)-1,4-二氢-四唑-5-酮;
1-(3-氯-苯基)-4-[4-(1-甲基-2-氧代-2-吡咯烷-1-基-乙基)-哌嗪-1-羰基]-1,4-二氢-四唑-5-酮;
1-[4-(1-甲基-2-氧代-2-吡咯烷-1-基-乙基)-哌嗪-1-羰基]-4-(3-三氟甲氧基-苯基)-1,4-二氢-四唑-5-酮;
1-(4-氯-苯基)-4-[4-(1-甲基-2-氧代-2-吡咯烷-1-基-乙基)-哌嗪-1-羰基]-1,4-二氢-四唑-5-酮;
1-(吗啉-4-羰基)-4-[2-(三氟甲基)苯基]四唑-5-酮;
1-(吗啉-4-羰基)-4-[3-(三氟甲基)苯基]四唑-5-酮;
1-(吗啉-4-羰基)-4-[4-(三氟甲基)苯基]四唑-5-酮;
1-(2,6-二氟苯基)-4-(吗啉-4-羰基)四唑-5-酮;
1-(2,4-二氟苯基)-4-(吗啉-4-羰基)四唑-5-酮;
1-(2,5-二氟苯基)-4-(吗啉-4-羰基)四唑-5-酮;
1-(3,4-二氟苯基)-4-(吗啉-4-羰基)四唑-5-酮;
1-(3,5-二氟苯基)-4-(吗啉-4-羰基)四唑-5-酮;
1-(3-甲基苯基)-4-(吗啉-4-羰基)四唑-5-酮;
1-(4-甲基苯基)-4-(吗啉-4-羰基)四唑-5-酮;
1-(3-甲氧基苯基)-4-(吗啉-4-羰基)四唑-5-酮;
1-(4-甲氧基苯基)-4-(吗啉-4-羰基)四唑-5-酮;
1-(2,3-二氯苯基)-4-(吗啉-4-羰基)四唑-5-酮;
1-(1-甲基吲哚-4-基)-4-(吗啉-4-羰基)四唑-5-酮;
1-(1-甲基吲哚-5-基)-4-(吗啉-4-羰基)四唑-5-酮;
1-(1-甲基吲哚-6-基)-4-(吗啉-4-羰基)四唑-5-酮;
1-(3-溴苯基)-4-(吗啉-4-羰基)四唑-5-酮;
1-(3-氯苯基)-4-[(2R,6S)-2,6-二甲基吗啉-4-羰基]四唑-5-酮;
1-(3-氯苯基)-4-(2,6-二甲基吗啉-4-羰基)四唑-5-酮;和
1-(3-氯苯基)-4-(3,3-二甲基吡咯烷-1-羰基)四唑-5-酮。
12.化合物,其选自:
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸[2-(3,4-二甲氧基-苯基)-乙基]-甲基-酰胺;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸甲基-苯乙基-酰胺;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸乙基-吡啶-4-基甲基-酰胺;
4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸苄基-乙基-酰胺;
1-(4,4-二甲基-哌啶-1-羰基)-4-(3-氟-苯基)-1,4-二氢-四唑-5-酮;
N-{(R)-1-[4-(3-氟-苯基)-5-氧代-4,5-二氢-四唑-1-羰基]-吡咯烷-3-基}-乙酰胺;
1-(3-氯-苯基)-4-(4,4-二甲基-哌啶-1-羰基)-1,4-二氢-四唑-5-酮;
1-(4-氯-苯基)-4-(4,4-二甲基-哌啶-1-羰基)-1,4-二氢-四唑-5-酮;
4-(3-氯-苯基)-5-氧代-4,5-二氢-四唑-1-甲酸(3-甲氧基-丙基)-甲基-酰胺;和
1-(3-氯-苯基)-4-(吗啉-4-羰基)-1,4-二氢-四唑-5-酮。
13.用于制备根据权利要求1的化合物的方法,所述方法包括:式(A)的化合物
(a)在R5-X和碱存在下的反应;或
(b)在光气、双光气或三光气存在下的反应,继之以在HNR3R4和碱存在下的反应;
其中X是吸电子基团并且其中R1、R3、R4和R5是如权利要求1所定义的。
14.药物组合物,所述药物组合物包含根据权利要求1至12中任一项的化合物和治疗惰性载体。
15.根据权利要求1至12中任一项的化合物用于制备药物的用途,所述药物用于治疗或预防疼痛、动脉粥样硬化、老年性黄斑退化症、糖尿病性视网膜病变、青光眼、视网膜静脉闭塞、早产儿视网膜病、眼缺血综合征、地图样萎缩、糖尿病、炎症、炎性肠病、缺血-再灌注损伤、急性肝衰竭、肝纤维化、肺纤维化、肾纤维化、系统性纤维化、急性同种异体移植排斥、慢性同种异体移植肾病、糖尿病肾病、肾小球肾病、心肌病、心力衰竭、系统性硬化、热损伤、烧伤、肥大性疤痕、瘢痕疙瘩、龈炎发热、肝硬化或肿瘤、骨质调节、肌萎缩侧索硬化、多发性硬化、阿尔茨海默病、帕金森病、卒中、一过性缺血发作或葡萄膜炎。
16.根据权利要求1至12中任一项的化合物用于制备药物的用途,所述药物用于治疗或预防心肌缺血或心肌梗死。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP13171479.2 | 2013-06-11 | ||
EP13171479 | 2013-06-11 | ||
PCT/EP2014/061527 WO2014198592A1 (en) | 2013-06-11 | 2014-06-04 | Novel tetrazolone derivatives |
Publications (2)
Publication Number | Publication Date |
---|---|
CN105283452A CN105283452A (zh) | 2016-01-27 |
CN105283452B true CN105283452B (zh) | 2019-01-04 |
Family
ID=48576904
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201480032918.2A Expired - Fee Related CN105283452B (zh) | 2013-06-11 | 2014-06-04 | 四唑酮衍生物 |
Country Status (12)
Country | Link |
---|---|
US (1) | US20160083357A1 (zh) |
EP (1) | EP3008055B1 (zh) |
JP (1) | JP6426721B2 (zh) |
KR (1) | KR20160018543A (zh) |
CN (1) | CN105283452B (zh) |
BR (1) | BR112015030824A2 (zh) |
CA (1) | CA2912735A1 (zh) |
ES (1) | ES2641210T3 (zh) |
HK (1) | HK1213566A1 (zh) |
MX (1) | MX363458B (zh) |
RU (1) | RU2664644C2 (zh) |
WO (1) | WO2014198592A1 (zh) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2714094T3 (es) | 2013-09-06 | 2019-05-27 | Hoffmann La Roche | Derivados de triazolo[4,5-d]pirimidina como antagonistas del receptor cb2 |
EP3250565B1 (en) * | 2015-01-26 | 2019-07-03 | Rigel Pharmaceuticals, Inc. | Tetrazolones as carboxylic acid bioisosteres |
US20170266157A1 (en) * | 2016-03-21 | 2017-09-21 | David Weinstein | Methods for wound healing and scar prevention |
US20210261512A1 (en) * | 2018-05-04 | 2021-08-26 | Inflazome Limited | Novel compounds |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009117444A1 (en) * | 2008-03-17 | 2009-09-24 | Northeastern University | Inhibitors of fatty acid amide hydrolase and monoacylglycerol lipase for modulation of cannabinoid receptors |
WO2011109324A1 (en) * | 2010-03-05 | 2011-09-09 | Boehringer Ingelheim International Gmbh | Tetrazole compounds which selectively modulate the cb2 receptor |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US124313A (en) * | 1872-03-05 | Improvement in plow-clevises | ||
US4826529A (en) * | 1983-12-09 | 1989-05-02 | Uniroyal Chemical Company, Inc. | Substituted tetrazolinones and herbicidal compositions thereof |
EP0708097A1 (en) * | 1994-10-18 | 1996-04-24 | Nihon Bayer Agrochem K.K. | Herbicidally active tetrazolinones |
US20070185100A1 (en) * | 2004-02-18 | 2007-08-09 | Astrazeneca Ab | Poly-heterocyclic compounds and their use as metabotropic glutamate receptor antagonists |
AR052342A1 (es) * | 2004-12-21 | 2007-03-14 | Janssen Pharmaceutica Nv | Derivados sustituidos de triazolona,tetrazolona e imidazolona con actividad selectiva antagonista de alfa2c-adenoreceptores |
EP3159331A1 (en) * | 2010-05-05 | 2017-04-26 | Infinity Pharmaceuticals, Inc. | Tetrazolones as inhibitors of fatty acid synthase |
-
2014
- 2014-06-04 RU RU2015151742A patent/RU2664644C2/ru not_active IP Right Cessation
- 2014-06-04 KR KR1020157034964A patent/KR20160018543A/ko not_active Application Discontinuation
- 2014-06-04 EP EP14730804.3A patent/EP3008055B1/en not_active Not-in-force
- 2014-06-04 BR BR112015030824A patent/BR112015030824A2/pt not_active Application Discontinuation
- 2014-06-04 CN CN201480032918.2A patent/CN105283452B/zh not_active Expired - Fee Related
- 2014-06-04 CA CA2912735A patent/CA2912735A1/en not_active Abandoned
- 2014-06-04 ES ES14730804.3T patent/ES2641210T3/es active Active
- 2014-06-04 JP JP2016518919A patent/JP6426721B2/ja not_active Expired - Fee Related
- 2014-06-04 WO PCT/EP2014/061527 patent/WO2014198592A1/en active Application Filing
- 2014-06-04 MX MX2015016766A patent/MX363458B/es unknown
-
2015
- 2015-12-04 US US14/959,933 patent/US20160083357A1/en not_active Abandoned
-
2016
- 2016-02-12 HK HK16101538.9A patent/HK1213566A1/zh not_active IP Right Cessation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009117444A1 (en) * | 2008-03-17 | 2009-09-24 | Northeastern University | Inhibitors of fatty acid amide hydrolase and monoacylglycerol lipase for modulation of cannabinoid receptors |
WO2011109324A1 (en) * | 2010-03-05 | 2011-09-09 | Boehringer Ingelheim International Gmbh | Tetrazole compounds which selectively modulate the cb2 receptor |
Non-Patent Citations (1)
Title |
---|
Tetrazole-biarylpyrazole derivatives as cannabinoid CB1 receptor antagonists;Suk Youn Kang et al.;《Bioorganic & Medicinal Chemistry Letters》;20080229;第18卷;第2385-2389页 |
Also Published As
Publication number | Publication date |
---|---|
ES2641210T3 (es) | 2017-11-08 |
HK1213566A1 (zh) | 2016-07-08 |
WO2014198592A1 (en) | 2014-12-18 |
EP3008055A1 (en) | 2016-04-20 |
BR112015030824A2 (pt) | 2017-07-25 |
US20160083357A1 (en) | 2016-03-24 |
KR20160018543A (ko) | 2016-02-17 |
CN105283452A (zh) | 2016-01-27 |
JP6426721B2 (ja) | 2018-11-21 |
MX2015016766A (es) | 2016-04-13 |
EP3008055B1 (en) | 2017-07-19 |
JP2016521736A (ja) | 2016-07-25 |
RU2664644C2 (ru) | 2018-08-21 |
CA2912735A1 (en) | 2014-12-18 |
MX363458B (es) | 2019-03-25 |
RU2015151742A (ru) | 2017-07-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN104854092B (zh) | 可用作cb2激动剂的吡啶-2-酰胺类 | |
US20210130342A1 (en) | Pyridazinones as parp7 inhibitors | |
CN105555788B (zh) | 三唑并[4,5-d]嘧啶衍生物 | |
US9694012B2 (en) | Pyrazol derivatives | |
CN104837830B (zh) | 作为cb2受体激动剂的吡嗪衍生物 | |
US7622471B2 (en) | Pyrazole derivatives having a pyridazine and pyridine functionality | |
CN104039791B (zh) | 作为大麻素受体2激动剂的[1,2,3]三唑并[4,5-d]嘧啶衍生物 | |
ZA200407665B (en) | New compounds. | |
EP2057141A1 (en) | Pyrimidone compounds as gsk-3 inhibitors | |
CN105209466B (zh) | 作为cb2受体激动剂的嘌呤衍生物 | |
CN105164133B (zh) | 作为CB2受体激动剂的吡咯并[2,3‑d]嘧啶衍生物 | |
TW201427952A (zh) | 新穎吡啶衍生物 | |
CN105283452B (zh) | 四唑酮衍生物 | |
JP2012505173A (ja) | ピロリジンn−ベンジル誘導体 | |
EP3386951B1 (en) | Phenyl derivatives as cannabinoid receptor 2 agonists | |
CN103080086B (zh) | 抑制前列腺素d合成酶的哌啶化合物 | |
CA2846122A1 (en) | Radiolabeled compounds and their use as radiotracers for quantitative imaging of phosphodiesterase (pde10a) in mammals | |
JP2012517981A (ja) | Nk3受容体アンタゴニストとしてのピロリジン誘導体 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1213566 Country of ref document: HK |
|
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20190104 Termination date: 20200604 |