CN1809539A - 有助于治疗由crth2介导的疾病的嘧啶衍生物 - Google Patents
有助于治疗由crth2介导的疾病的嘧啶衍生物 Download PDFInfo
- Publication number
- CN1809539A CN1809539A CNA2004800173378A CN200480017337A CN1809539A CN 1809539 A CN1809539 A CN 1809539A CN A2004800173378 A CNA2004800173378 A CN A2004800173378A CN 200480017337 A CN200480017337 A CN 200480017337A CN 1809539 A CN1809539 A CN 1809539A
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- China
- Prior art keywords
- amino
- benzyl
- acetic acid
- pyrimidinyl
- dimethylamino
- Prior art date
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- 102000009389 Prostaglandin D receptors Human genes 0.000 title claims abstract description 24
- 108050000258 Prostaglandin D receptors Proteins 0.000 title claims abstract description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 23
- 150000003230 pyrimidines Chemical class 0.000 title claims abstract description 20
- 201000010099 disease Diseases 0.000 title claims abstract description 18
- 238000011282 treatment Methods 0.000 title claims abstract description 15
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 title description 9
- 230000001404 mediated effect Effects 0.000 title description 2
- 230000000694 effects Effects 0.000 claims abstract description 31
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 239000004480 active ingredient Substances 0.000 claims abstract description 12
- 208000032671 Allergic granulomatous angiitis Diseases 0.000 claims abstract description 6
- 208000006344 Churg-Strauss Syndrome Diseases 0.000 claims abstract description 6
- 206010010744 Conjunctivitis allergic Diseases 0.000 claims abstract description 6
- 206010012438 Dermatitis atopic Diseases 0.000 claims abstract description 6
- 208000018428 Eosinophilic granulomatosis with polyangiitis Diseases 0.000 claims abstract description 6
- 206010039085 Rhinitis allergic Diseases 0.000 claims abstract description 6
- 208000002205 allergic conjunctivitis Diseases 0.000 claims abstract description 6
- 201000010105 allergic rhinitis Diseases 0.000 claims abstract description 6
- 208000006673 asthma Diseases 0.000 claims abstract description 6
- 208000024998 atopic conjunctivitis Diseases 0.000 claims abstract description 6
- 201000008937 atopic dermatitis Diseases 0.000 claims abstract description 6
- 201000009890 sinusitis Diseases 0.000 claims abstract description 6
- 206010052568 Urticaria chronic Diseases 0.000 claims abstract description 5
- 208000024376 chronic urticaria Diseases 0.000 claims abstract description 5
- 241000124008 Mammalia Species 0.000 claims abstract description 4
- 206010024378 leukocytosis Diseases 0.000 claims abstract description 4
- 238000011321 prophylaxis Methods 0.000 claims abstract 2
- -1 nitro, guanidino, pyrrolyl Chemical group 0.000 claims description 201
- 150000001875 compounds Chemical class 0.000 claims description 191
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 85
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 49
- 238000000034 method Methods 0.000 claims description 35
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 34
- 235000011054 acetic acid Nutrition 0.000 claims description 30
- 229960000583 acetic acid Drugs 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 29
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 21
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 15
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 14
- 150000002431 hydrogen Chemical class 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 150000002148 esters Chemical class 0.000 claims description 12
- 125000003282 alkyl amino group Chemical group 0.000 claims description 10
- 239000000651 prodrug Substances 0.000 claims description 10
- 229940002612 prodrug Drugs 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 125000006312 cyclopentyl amino group Chemical group [H]N(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 7
- 125000002541 furyl group Chemical group 0.000 claims description 7
- 125000001041 indolyl group Chemical group 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 7
- 125000004414 alkyl thio group Chemical group 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 150000003254 radicals Chemical class 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000004750 (C1-C6) alkylaminosulfonyl group Chemical group 0.000 claims description 4
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 4
- XEOSTBFUCNZKGS-UHFFFAOYSA-N 2-[4,6-bis(dimethylamino)-2-[[4-[[4-(trifluoromethyl)benzoyl]amino]phenyl]methyl]pyrimidin-5-yl]acetic acid Chemical compound CN(C)C1=C(CC(O)=O)C(N(C)C)=NC(CC=2C=CC(NC(=O)C=3C=CC(=CC=3)C(F)(F)F)=CC=2)=N1 XEOSTBFUCNZKGS-UHFFFAOYSA-N 0.000 claims description 4
- KXPAVCJDTRYMRP-UHFFFAOYSA-N 2-[4,6-dichloro-2-[[4-(naphthalene-2-carbonylamino)phenyl]methyl]pyrimidin-5-yl]acetic acid Chemical compound N1=C(Cl)C(CC(=O)O)=C(Cl)N=C1CC(C=C1)=CC=C1NC(=O)C1=CC=C(C=CC=C2)C2=C1 KXPAVCJDTRYMRP-UHFFFAOYSA-N 0.000 claims description 4
- XSGQONMWVRQSTD-UHFFFAOYSA-N 2-[4-(dimethylamino)-2-[[4-(naphthalene-2-carbonylamino)phenyl]methyl]pyrimidin-5-yl]acetic acid Chemical compound C1=C(CC(O)=O)C(N(C)C)=NC(CC=2C=CC(NC(=O)C=3C=C4C=CC=CC4=CC=3)=CC=2)=N1 XSGQONMWVRQSTD-UHFFFAOYSA-N 0.000 claims description 4
- SETQVYMZHIVBRU-UHFFFAOYSA-N 2-[4-(dimethylamino)-2-[[4-(phenylmethoxycarbonylamino)phenyl]methyl]pyrimidin-5-yl]acetic acid Chemical compound C1=C(CC(O)=O)C(N(C)C)=NC(CC=2C=CC(NC(=O)OCC=3C=CC=CC=3)=CC=2)=N1 SETQVYMZHIVBRU-UHFFFAOYSA-N 0.000 claims description 4
- QLEXLARZQWPJAH-UHFFFAOYSA-N 2-[4-(dimethylamino)-2-[[4-[(4-fluorophenyl)methoxycarbonylamino]phenyl]methyl]pyrimidin-5-yl]acetic acid Chemical compound C1=C(CC(O)=O)C(N(C)C)=NC(CC=2C=CC(NC(=O)OCC=3C=CC(F)=CC=3)=CC=2)=N1 QLEXLARZQWPJAH-UHFFFAOYSA-N 0.000 claims description 4
- OGZNYVIPIIDZLY-UHFFFAOYSA-N 2-[4-(dimethylamino)-6-morpholin-4-yl-2-[[4-(naphthalene-2-carbonylamino)phenyl]methyl]pyrimidin-5-yl]acetic acid Chemical compound OC(=O)CC=1C(N(C)C)=NC(CC=2C=CC(NC(=O)C=3C=C4C=CC=CC4=CC=3)=CC=2)=NC=1N1CCOCC1 OGZNYVIPIIDZLY-UHFFFAOYSA-N 0.000 claims description 4
- CUNNBJJEJUDKNN-UHFFFAOYSA-N 2-[4-chloro-6-(dimethylamino)-2-[[4-(naphthalene-2-carbonylamino)phenyl]methyl]pyrimidin-5-yl]acetic acid Chemical compound ClC1=C(CC(O)=O)C(N(C)C)=NC(CC=2C=CC(NC(=O)C=3C=C4C=CC=CC4=CC=3)=CC=2)=N1 CUNNBJJEJUDKNN-UHFFFAOYSA-N 0.000 claims description 4
- NNTXSGFBNMXPTD-UHFFFAOYSA-N 2-[4-methyl-2-[[4-(naphthalene-2-carbonylamino)phenyl]methyl]-6-pyrrolidin-1-ylpyrimidin-5-yl]acetic acid Chemical compound OC(=O)CC=1C(C)=NC(CC=2C=CC(NC(=O)C=3C=C4C=CC=CC4=CC=3)=CC=2)=NC=1N1CCCC1 NNTXSGFBNMXPTD-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 229940124003 CRTH2 antagonist Drugs 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 4
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- OCXZEAWOZHRQKP-UHFFFAOYSA-N 2-[4-chloro-2-[[4-(naphthalene-2-carbonylamino)phenyl]methyl]-6-pyrrolidin-1-ylpyrimidin-5-yl]acetic acid Chemical compound OC(=O)CC1=C(Cl)N=C(CC=2C=CC(NC(=O)C=3C=C4C=CC=CC4=CC=3)=CC=2)N=C1N1CCCC1 OCXZEAWOZHRQKP-UHFFFAOYSA-N 0.000 claims description 3
- 125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 claims description 3
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 2
- BRAVLCWGFGRYAJ-UHFFFAOYSA-N 2-[2-[(4-benzamidophenyl)methyl]-4-[[2-(cyclopentylamino)-2-oxoethyl]-methylamino]pyrimidin-5-yl]acetic acid Chemical compound N=1C(CC=2C=CC(NC(=O)C=3C=CC=CC=3)=CC=2)=NC=C(CC(O)=O)C=1N(C)CC(=O)NC1CCCC1 BRAVLCWGFGRYAJ-UHFFFAOYSA-N 0.000 claims description 2
- YBKWXSXHGJHDKJ-UHFFFAOYSA-N 2-[2-[(4-benzamidophenyl)methyl]-4-chloro-6-[[2-(cyclopentylamino)-2-oxoethyl]-methylamino]pyrimidin-5-yl]acetic acid Chemical compound N=1C(CC=2C=CC(NC(=O)C=3C=CC=CC=3)=CC=2)=NC(Cl)=C(CC(O)=O)C=1N(C)CC(=O)NC1CCCC1 YBKWXSXHGJHDKJ-UHFFFAOYSA-N 0.000 claims description 2
- VNJYZANVNXLMBK-UHFFFAOYSA-N 2-[2-[1-[4-[(3,4-dichlorobenzoyl)amino]phenyl]ethyl]-4-(dimethylamino)pyrimidin-5-yl]acetic acid Chemical compound N=1C=C(CC(O)=O)C(N(C)C)=NC=1C(C)C(C=C1)=CC=C1NC(=O)C1=CC=C(Cl)C(Cl)=C1 VNJYZANVNXLMBK-UHFFFAOYSA-N 0.000 claims description 2
- WFSKXLWLRRRIJO-UHFFFAOYSA-N 2-[2-[1-[4-[(4-chlorobenzoyl)amino]phenyl]ethyl]-4-(dimethylamino)pyrimidin-5-yl]acetic acid Chemical compound N=1C=C(CC(O)=O)C(N(C)C)=NC=1C(C)C(C=C1)=CC=C1NC(=O)C1=CC=C(Cl)C=C1 WFSKXLWLRRRIJO-UHFFFAOYSA-N 0.000 claims description 2
- HSJTTYZHQSKFMU-UHFFFAOYSA-N 2-[2-[[4-(1-benzofuran-2-carbonylamino)phenyl]methyl]-4-chloro-6-[[2-(cyclopentylamino)-2-oxoethyl]-methylamino]pyrimidin-5-yl]acetic acid Chemical compound N=1C(CC=2C=CC(NC(=O)C=3OC4=CC=CC=C4C=3)=CC=2)=NC(Cl)=C(CC(O)=O)C=1N(C)CC(=O)NC1CCCC1 HSJTTYZHQSKFMU-UHFFFAOYSA-N 0.000 claims description 2
- OQGHYGCQIHVPKX-UHFFFAOYSA-N 2-[2-[[4-(3,3-dimethylbutanoylamino)phenyl]methyl]-4-pyrrolidin-1-ylpyrimidin-5-yl]acetic acid Chemical compound C1=CC(NC(=O)CC(C)(C)C)=CC=C1CC1=NC=C(CC(O)=O)C(N2CCCC2)=N1 OQGHYGCQIHVPKX-UHFFFAOYSA-N 0.000 claims description 2
- QWKZLHMASPOSDC-UHFFFAOYSA-N 2-[2-[[4-(benzylcarbamoylamino)phenyl]methyl]-4-(dimethylamino)pyrimidin-5-yl]acetic acid Chemical compound C1=C(CC(O)=O)C(N(C)C)=NC(CC=2C=CC(NC(=O)NCC=3C=CC=CC=3)=CC=2)=N1 QWKZLHMASPOSDC-UHFFFAOYSA-N 0.000 claims description 2
- BLYDFBFHXASRNY-UHFFFAOYSA-N 2-[2-[[4-(benzylcarbamoylamino)phenyl]methyl]-4-chloro-6-[[2-(cyclopentylamino)-2-oxoethyl]-methylamino]pyrimidin-5-yl]acetic acid Chemical compound N=1C(CC=2C=CC(NC(=O)NCC=3C=CC=CC=3)=CC=2)=NC(Cl)=C(CC(O)=O)C=1N(C)CC(=O)NC1CCCC1 BLYDFBFHXASRNY-UHFFFAOYSA-N 0.000 claims description 2
- VIACNMLRKMDHEV-UHFFFAOYSA-N 2-[2-[[4-(naphthalene-2-carbonylamino)phenyl]methyl]-4-pyrrolidin-1-ylpyrimidin-5-yl]acetic acid Chemical compound OC(=O)CC1=CN=C(CC=2C=CC(NC(=O)C=3C=C4C=CC=CC4=CC=3)=CC=2)N=C1N1CCCC1 VIACNMLRKMDHEV-UHFFFAOYSA-N 0.000 claims description 2
- BLGFEKQGRRINTG-UHFFFAOYSA-N 2-[2-[[4-[(3,4-dichlorobenzoyl)amino]phenyl]methyl]-4,6-bis(dimethylamino)pyrimidin-5-yl]acetic acid Chemical compound CN(C)C1=C(CC(O)=O)C(N(C)C)=NC(CC=2C=CC(NC(=O)C=3C=C(Cl)C(Cl)=CC=3)=CC=2)=N1 BLGFEKQGRRINTG-UHFFFAOYSA-N 0.000 claims description 2
- ANWJXEFKLMMCHP-UHFFFAOYSA-N 2-[2-[[4-[(3,4-dichlorobenzoyl)amino]phenyl]methyl]-4-(dimethylamino)-6-methylpyrimidin-5-yl]acetic acid Chemical compound CC1=C(CC(O)=O)C(N(C)C)=NC(CC=2C=CC(NC(=O)C=3C=C(Cl)C(Cl)=CC=3)=CC=2)=N1 ANWJXEFKLMMCHP-UHFFFAOYSA-N 0.000 claims description 2
- IVOAQFSTFIFFRD-UHFFFAOYSA-N 2-[2-[[4-[(3,4-dichlorobenzoyl)amino]phenyl]methyl]-4-(dimethylamino)-6-morpholin-4-ylpyrimidin-5-yl]acetic acid Chemical compound N=1C(N2CCOCC2)=C(CC(O)=O)C(N(C)C)=NC=1CC(C=C1)=CC=C1NC(=O)C1=CC=C(Cl)C(Cl)=C1 IVOAQFSTFIFFRD-UHFFFAOYSA-N 0.000 claims description 2
- WULJEVKZTZYJFW-UHFFFAOYSA-N 2-[2-[[4-[(3,4-dichlorobenzoyl)amino]phenyl]methyl]-4-(dimethylamino)pyrimidin-5-yl]acetic acid Chemical compound C1=C(CC(O)=O)C(N(C)C)=NC(CC=2C=CC(NC(=O)C=3C=C(Cl)C(Cl)=CC=3)=CC=2)=N1 WULJEVKZTZYJFW-UHFFFAOYSA-N 0.000 claims description 2
- OXZAIUCHPIZYDI-UHFFFAOYSA-N 2-[2-[[4-[(3,4-dichlorobenzoyl)amino]phenyl]methyl]-4-methyl-6-pyrrolidin-1-ylpyrimidin-5-yl]acetic acid Chemical compound N=1C(N2CCCC2)=C(CC(O)=O)C(C)=NC=1CC(C=C1)=CC=C1NC(=O)C1=CC=C(Cl)C(Cl)=C1 OXZAIUCHPIZYDI-UHFFFAOYSA-N 0.000 claims description 2
- LOCILIUQLADHQZ-UHFFFAOYSA-N 2-[2-[[4-[(3-chlorobenzoyl)amino]phenyl]methyl]-4-(dimethylamino)pyrimidin-5-yl]acetic acid Chemical compound C1=C(CC(O)=O)C(N(C)C)=NC(CC=2C=CC(NC(=O)C=3C=C(Cl)C=CC=3)=CC=2)=N1 LOCILIUQLADHQZ-UHFFFAOYSA-N 0.000 claims description 2
- QBCSHZVZVUKCQO-UHFFFAOYSA-N 2-[2-[[4-[(4-acetamidobenzoyl)amino]phenyl]methyl]-4-chloro-6-pyrrolidin-1-ylpyrimidin-5-yl]acetic acid Chemical compound C1=CC(NC(=O)C)=CC=C1C(=O)NC(C=C1)=CC=C1CC1=NC(Cl)=C(CC(O)=O)C(N2CCCC2)=N1 QBCSHZVZVUKCQO-UHFFFAOYSA-N 0.000 claims description 2
- WDYCRZAIFVIUEV-UHFFFAOYSA-N 2-[2-[[4-[(4-bromobenzoyl)amino]phenyl]methyl]-4-(dimethylamino)pyrimidin-5-yl]acetic acid Chemical compound C1=C(CC(O)=O)C(N(C)C)=NC(CC=2C=CC(NC(=O)C=3C=CC(Br)=CC=3)=CC=2)=N1 WDYCRZAIFVIUEV-UHFFFAOYSA-N 0.000 claims description 2
- AARBEQQNTOZBTL-UHFFFAOYSA-N 2-[2-[[4-[(4-bromobenzoyl)amino]phenyl]methyl]-4-chloro-6-(dimethylamino)pyrimidin-5-yl]acetic acid Chemical compound ClC1=C(CC(O)=O)C(N(C)C)=NC(CC=2C=CC(NC(=O)C=3C=CC(Br)=CC=3)=CC=2)=N1 AARBEQQNTOZBTL-UHFFFAOYSA-N 0.000 claims description 2
- ZBWYVWIGXMTAMQ-UHFFFAOYSA-N 2-[2-[[4-[(4-chlorobenzoyl)amino]phenyl]methyl]-4-(dimethylamino)-6-pyrrolidin-1-ylpyrimidin-5-yl]acetic acid Chemical compound N=1C(N2CCCC2)=C(CC(O)=O)C(N(C)C)=NC=1CC(C=C1)=CC=C1NC(=O)C1=CC=C(Cl)C=C1 ZBWYVWIGXMTAMQ-UHFFFAOYSA-N 0.000 claims description 2
- LACBHKONDFDLLO-UHFFFAOYSA-N 2-[2-[[4-[(4-chlorobenzoyl)amino]phenyl]methyl]-4-(dimethylamino)pyrimidin-5-yl]acetic acid Chemical compound C1=C(CC(O)=O)C(N(C)C)=NC(CC=2C=CC(NC(=O)C=3C=CC(Cl)=CC=3)=CC=2)=N1 LACBHKONDFDLLO-UHFFFAOYSA-N 0.000 claims description 2
- YTMBTJPYTXLXLT-UHFFFAOYSA-N 2-[2-[[4-[(4-chlorobenzoyl)amino]phenyl]methyl]-4-pyrrolidin-1-ylpyrimidin-5-yl]acetic acid Chemical compound N1=C(N2CCCC2)C(CC(=O)O)=CN=C1CC(C=C1)=CC=C1NC(=O)C1=CC=C(Cl)C=C1 YTMBTJPYTXLXLT-UHFFFAOYSA-N 0.000 claims description 2
- PTVJXKKBDDFIEH-UHFFFAOYSA-N 2-[2-[[4-[(4-fluorobenzoyl)amino]phenyl]methyl]-4-pyrrolidin-1-ylpyrimidin-5-yl]acetic acid Chemical compound N1=C(N2CCCC2)C(CC(=O)O)=CN=C1CC(C=C1)=CC=C1NC(=O)C1=CC=C(F)C=C1 PTVJXKKBDDFIEH-UHFFFAOYSA-N 0.000 claims description 2
- YAUYYYFLGPQZJN-UHFFFAOYSA-N 2-[2-[[4-[(4-tert-butylcyclohexanecarbonyl)amino]phenyl]methyl]-4-chloro-6-(dimethylamino)pyrimidin-5-yl]acetic acid Chemical compound ClC1=C(CC(O)=O)C(N(C)C)=NC(CC=2C=CC(NC(=O)C3CCC(CC3)C(C)(C)C)=CC=2)=N1 YAUYYYFLGPQZJN-UHFFFAOYSA-N 0.000 claims description 2
- VIADXYASLLIBBI-NTEUORMPSA-N 2-[2-[[4-[[(e)-3-(4-chlorophenyl)prop-2-enoyl]amino]phenyl]methyl]-4,6-bis(dimethylamino)pyrimidin-5-yl]acetic acid Chemical compound CN(C)C1=C(CC(O)=O)C(N(C)C)=NC(CC=2C=CC(NC(=O)\C=C\C=3C=CC(Cl)=CC=3)=CC=2)=N1 VIADXYASLLIBBI-NTEUORMPSA-N 0.000 claims description 2
- ONUBVPYJYUPJMQ-NTEUORMPSA-N 2-[2-[[4-[[(e)-3-(4-chlorophenyl)prop-2-enoyl]amino]phenyl]methyl]-4-(dimethylamino)-6-pyrrolidin-1-ylpyrimidin-5-yl]acetic acid Chemical compound N=1C(N2CCCC2)=C(CC(O)=O)C(N(C)C)=NC=1CC(C=C1)=CC=C1NC(=O)\C=C\C1=CC=C(Cl)C=C1 ONUBVPYJYUPJMQ-NTEUORMPSA-N 0.000 claims description 2
- HRFIBVDUAZPDBR-UHFFFAOYSA-N 2-[4,6-bis(dimethylamino)-2-[[4-(naphthalene-2-carbonylamino)phenyl]methyl]pyrimidin-5-yl]acetic acid Chemical compound CN(C)C1=C(CC(O)=O)C(N(C)C)=NC(CC=2C=CC(NC(=O)C=3C=C4C=CC=CC4=CC=3)=CC=2)=N1 HRFIBVDUAZPDBR-UHFFFAOYSA-N 0.000 claims description 2
- UEZPEEKSXSVHHW-NTCAYCPXSA-N 2-[4,6-bis(dimethylamino)-2-[[4-[[(e)-3-phenylprop-2-enoyl]amino]phenyl]methyl]pyrimidin-5-yl]acetic acid Chemical compound CN(C)C1=C(CC(O)=O)C(N(C)C)=NC(CC=2C=CC(NC(=O)\C=C\C=3C=CC=CC=3)=CC=2)=N1 UEZPEEKSXSVHHW-NTCAYCPXSA-N 0.000 claims description 2
- IEQWOVCCLCITJC-UHFFFAOYSA-N 2-[4-(dimethylamino)-2-[1-[4-(naphthalene-2-carbonylamino)phenyl]ethyl]pyrimidin-5-yl]acetic acid Chemical compound C=1C=C(NC(=O)C=2C=C3C=CC=CC3=CC=2)C=CC=1C(C)C1=NC=C(CC(O)=O)C(N(C)C)=N1 IEQWOVCCLCITJC-UHFFFAOYSA-N 0.000 claims description 2
- JBCJIXHGOBOQOI-UHFFFAOYSA-N 2-[4-(dimethylamino)-2-[1-[4-(quinoline-2-carbonylamino)phenyl]ethyl]pyrimidin-5-yl]acetic acid Chemical compound C=1C=C(NC(=O)C=2N=C3C=CC=CC3=CC=2)C=CC=1C(C)C1=NC=C(CC(O)=O)C(N(C)C)=N1 JBCJIXHGOBOQOI-UHFFFAOYSA-N 0.000 claims description 2
- IYJAOVLMZKODOB-NTEUORMPSA-N 2-[4-(dimethylamino)-2-[1-[4-[[(e)-3-phenylprop-2-enoyl]amino]phenyl]ethyl]pyrimidin-5-yl]acetic acid Chemical compound N=1C=C(CC(O)=O)C(N(C)C)=NC=1C(C)C(C=C1)=CC=C1NC(=O)\C=C\C1=CC=CC=C1 IYJAOVLMZKODOB-NTEUORMPSA-N 0.000 claims description 2
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- WXBFZIGGWGVNCY-UHFFFAOYSA-N 2-[4-(dimethylamino)-2-[[4-(naphthalene-2-carbonylamino)phenyl]methyl]-6-propan-2-ylpyrimidin-5-yl]acetic acid Chemical compound CN(C)C1=C(CC(O)=O)C(C(C)C)=NC(CC=2C=CC(NC(=O)C=3C=C4C=CC=CC4=CC=3)=CC=2)=N1 WXBFZIGGWGVNCY-UHFFFAOYSA-N 0.000 claims description 2
- VZQIUAMJIMFSOW-UHFFFAOYSA-N 2-[4-(dimethylamino)-2-[[4-(naphthalene-2-carbonylamino)phenyl]methyl]-6-pyrrolidin-1-ylpyrimidin-5-yl]acetic acid Chemical compound OC(=O)CC=1C(N(C)C)=NC(CC=2C=CC(NC(=O)C=3C=C4C=CC=CC4=CC=3)=CC=2)=NC=1N1CCCC1 VZQIUAMJIMFSOW-UHFFFAOYSA-N 0.000 claims description 2
- WZQHWHBFSVGSTJ-UHFFFAOYSA-N 2-[4-(dimethylamino)-2-[[4-(quinoline-2-carbonylamino)phenyl]methyl]pyrimidin-5-yl]acetic acid Chemical compound C1=C(CC(O)=O)C(N(C)C)=NC(CC=2C=CC(NC(=O)C=3N=C4C=CC=CC4=CC=3)=CC=2)=N1 WZQHWHBFSVGSTJ-UHFFFAOYSA-N 0.000 claims description 2
- ZSKOFFLYTKCEIM-UHFFFAOYSA-N 2-[4-(dimethylamino)-2-[[4-[(3-methoxybenzoyl)amino]phenyl]methyl]pyrimidin-5-yl]acetic acid Chemical compound COC1=CC=CC(C(=O)NC=2C=CC(CC=3N=C(C(CC(O)=O)=CN=3)N(C)C)=CC=2)=C1 ZSKOFFLYTKCEIM-UHFFFAOYSA-N 0.000 claims description 2
- PBUBGDUPQPHGCQ-UHFFFAOYSA-N 2-[4-(dimethylamino)-2-[[4-[(3-phenoxybenzoyl)amino]phenyl]methyl]-6-pyrrolidin-1-ylpyrimidin-5-yl]acetic acid Chemical compound N=1C(N2CCCC2)=C(CC(O)=O)C(N(C)C)=NC=1CC(C=C1)=CC=C1NC(=O)C(C=1)=CC=CC=1OC1=CC=CC=C1 PBUBGDUPQPHGCQ-UHFFFAOYSA-N 0.000 claims description 2
- MGGOTZPTECHQAR-UHFFFAOYSA-N 2-[4-(dimethylamino)-2-[[4-[(3-phenylbenzoyl)amino]phenyl]methyl]-6-pyrrolidin-1-ylpyrimidin-5-yl]acetic acid Chemical compound N=1C(N2CCCC2)=C(CC(O)=O)C(N(C)C)=NC=1CC(C=C1)=CC=C1NC(=O)C(C=1)=CC=CC=1C1=CC=CC=C1 MGGOTZPTECHQAR-UHFFFAOYSA-N 0.000 claims description 2
- JAOFGXGCUKKDCF-UHFFFAOYSA-N 2-[4-(dimethylamino)-2-[[4-[(4-fluorobenzoyl)amino]phenyl]methyl]pyrimidin-5-yl]acetic acid Chemical compound C1=C(CC(O)=O)C(N(C)C)=NC(CC=2C=CC(NC(=O)C=3C=CC(F)=CC=3)=CC=2)=N1 JAOFGXGCUKKDCF-UHFFFAOYSA-N 0.000 claims description 2
- SHPWFAJUVZRUIY-UHFFFAOYSA-N 2-[4-(dimethylamino)-2-[[4-[(4-methoxybenzoyl)amino]phenyl]methyl]pyrimidin-5-yl]acetic acid Chemical compound C1=CC(OC)=CC=C1C(=O)NC(C=C1)=CC=C1CC1=NC=C(CC(O)=O)C(N(C)C)=N1 SHPWFAJUVZRUIY-UHFFFAOYSA-N 0.000 claims description 2
- RQZCDOIOWMSAAL-UHFFFAOYSA-N 2-[4-(dimethylamino)-2-[[4-[(4-phenoxybenzoyl)amino]phenyl]methyl]-6-pyrrolidin-1-ylpyrimidin-5-yl]acetic acid Chemical compound N=1C(N2CCCC2)=C(CC(O)=O)C(N(C)C)=NC=1CC(C=C1)=CC=C1NC(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 RQZCDOIOWMSAAL-UHFFFAOYSA-N 0.000 claims description 2
- QAAHQJRWEYVWSL-UHFFFAOYSA-N 2-[4-(dimethylamino)-2-[[4-[(4-phenylbenzoyl)amino]phenyl]methyl]-6-pyrrolidin-1-ylpyrimidin-5-yl]acetic acid Chemical compound N=1C(N2CCCC2)=C(CC(O)=O)C(N(C)C)=NC=1CC(C=C1)=CC=C1NC(=O)C(C=C1)=CC=C1C1=CC=CC=C1 QAAHQJRWEYVWSL-UHFFFAOYSA-N 0.000 claims description 2
- HJXKYTZHIYYTPN-JLHYYAGUSA-N 2-[4-(dimethylamino)-2-[[4-[[(e)-3-(2-methoxyphenyl)prop-2-enoyl]amino]phenyl]methyl]-6-morpholin-4-ylpyrimidin-5-yl]acetic acid Chemical compound COC1=CC=CC=C1\C=C\C(=O)NC(C=C1)=CC=C1CC1=NC(N(C)C)=C(CC(O)=O)C(N2CCOCC2)=N1 HJXKYTZHIYYTPN-JLHYYAGUSA-N 0.000 claims description 2
- KZCGWNVWJRIYQZ-MDWZMJQESA-N 2-[4-(dimethylamino)-2-[[4-[[(e)-3-(4-methoxyphenyl)prop-2-enoyl]amino]phenyl]methyl]-6-morpholin-4-ylpyrimidin-5-yl]acetic acid Chemical compound C1=CC(OC)=CC=C1\C=C\C(=O)NC(C=C1)=CC=C1CC1=NC(N(C)C)=C(CC(O)=O)C(N2CCOCC2)=N1 KZCGWNVWJRIYQZ-MDWZMJQESA-N 0.000 claims description 2
- DLPWHXJHKLBDDS-KPKJPENVSA-N 2-[4-(dimethylamino)-2-[[4-[[(e)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl]amino]phenyl]methyl]pyrimidin-5-yl]acetic acid Chemical compound C1=C(CC(O)=O)C(N(C)C)=NC(CC=2C=CC(NC(=O)\C=C\C=3C=CC(=CC=3)C(F)(F)F)=CC=2)=N1 DLPWHXJHKLBDDS-KPKJPENVSA-N 0.000 claims description 2
- JXZKZHYRSWFZLW-NTCAYCPXSA-N 2-[4-(dimethylamino)-2-[[4-[[(e)-3-phenylprop-2-enoyl]amino]phenyl]methyl]-6-pyrrolidin-1-ylpyrimidin-5-yl]acetic acid Chemical compound N=1C(N2CCCC2)=C(CC(O)=O)C(N(C)C)=NC=1CC(C=C1)=CC=C1NC(=O)\C=C\C1=CC=CC=C1 JXZKZHYRSWFZLW-NTCAYCPXSA-N 0.000 claims description 2
- GSHAEHFCCIKSRP-UHFFFAOYSA-N 2-[4-(dimethylamino)-2-[[4-[[4-(trifluoromethoxy)benzoyl]amino]phenyl]methyl]pyrimidin-5-yl]acetic acid Chemical compound C1=C(CC(O)=O)C(N(C)C)=NC(CC=2C=CC(NC(=O)C=3C=CC(OC(F)(F)F)=CC=3)=CC=2)=N1 GSHAEHFCCIKSRP-UHFFFAOYSA-N 0.000 claims description 2
- DJSYVPDFYKAFFR-UHFFFAOYSA-N 2-[4-(dimethylamino)-2-[[4-[[4-(trifluoromethyl)benzoyl]amino]phenyl]methyl]pyrimidin-5-yl]acetic acid Chemical compound C1=C(CC(O)=O)C(N(C)C)=NC(CC=2C=CC(NC(=O)C=3C=CC(=CC=3)C(F)(F)F)=CC=2)=N1 DJSYVPDFYKAFFR-UHFFFAOYSA-N 0.000 claims description 2
- QCPVMOCGIQWSRP-UHFFFAOYSA-N 2-[4-(dimethylamino)-6-(methoxymethyl)-2-[[4-(naphthalene-2-carbonylamino)phenyl]methyl]pyrimidin-5-yl]acetic acid Chemical compound CN(C)C1=C(CC(O)=O)C(COC)=NC(CC=2C=CC(NC(=O)C=3C=C4C=CC=CC4=CC=3)=CC=2)=N1 QCPVMOCGIQWSRP-UHFFFAOYSA-N 0.000 claims description 2
- SBKQRLWONFKCFV-UHFFFAOYSA-N 2-[4-(dimethylamino)-6-ethyl-2-[[4-(naphthalene-2-carbonylamino)phenyl]methyl]pyrimidin-5-yl]acetic acid Chemical compound CN(C)C1=C(CC(O)=O)C(CC)=NC(CC=2C=CC(NC(=O)C=3C=C4C=CC=CC4=CC=3)=CC=2)=N1 SBKQRLWONFKCFV-UHFFFAOYSA-N 0.000 claims description 2
- PVUSLECUHKYKFI-UHFFFAOYSA-N 2-[4-(dimethylamino)-6-ethyl-2-[[4-[[4-(trifluoromethyl)benzoyl]amino]phenyl]methyl]pyrimidin-5-yl]acetic acid Chemical compound CN(C)C1=C(CC(O)=O)C(CC)=NC(CC=2C=CC(NC(=O)C=3C=CC(=CC=3)C(F)(F)F)=CC=2)=N1 PVUSLECUHKYKFI-UHFFFAOYSA-N 0.000 claims description 2
- OMDIJQIRAXUPFB-UHFFFAOYSA-N 2-[4-(dimethylamino)-6-methyl-2-[[4-(naphthalene-2-carbonylamino)phenyl]methyl]pyrimidin-5-yl]acetic acid Chemical compound CC1=C(CC(O)=O)C(N(C)C)=NC(CC=2C=CC(NC(=O)C=3C=C4C=CC=CC4=CC=3)=CC=2)=N1 OMDIJQIRAXUPFB-UHFFFAOYSA-N 0.000 claims description 2
- IWDZLCBGILKSMO-SDNWHVSQSA-N 2-[4-(dimethylamino)-6-methyl-2-[[4-[[(e)-3-phenylprop-2-enoyl]amino]phenyl]methyl]pyrimidin-5-yl]acetic acid Chemical compound CC1=C(CC(O)=O)C(N(C)C)=NC(CC=2C=CC(NC(=O)\C=C\C=3C=CC=CC=3)=CC=2)=N1 IWDZLCBGILKSMO-SDNWHVSQSA-N 0.000 claims description 2
- DINJPARSGWZJLN-JLHYYAGUSA-N 2-[4-(dimethylamino)-6-morpholin-4-yl-2-[[4-[[(e)-3-phenylprop-2-enoyl]amino]phenyl]methyl]pyrimidin-5-yl]acetic acid Chemical compound N=1C(N2CCOCC2)=C(CC(O)=O)C(N(C)C)=NC=1CC(C=C1)=CC=C1NC(=O)\C=C\C1=CC=CC=C1 DINJPARSGWZJLN-JLHYYAGUSA-N 0.000 claims description 2
- GEJHDNYRGZSUTQ-UHFFFAOYSA-N 2-[4-(dimethylamino)-6-morpholin-4-yl-2-[[4-[[4-(trifluoromethyl)benzoyl]amino]phenyl]methyl]pyrimidin-5-yl]acetic acid Chemical compound N=1C(N2CCOCC2)=C(CC(O)=O)C(N(C)C)=NC=1CC(C=C1)=CC=C1NC(=O)C1=CC=C(C(F)(F)F)C=C1 GEJHDNYRGZSUTQ-UHFFFAOYSA-N 0.000 claims description 2
- MRMSMOWNKYPGHI-UHFFFAOYSA-N 2-[4-(dimethylamino)-6-propan-2-yl-2-[[4-[[4-(trifluoromethyl)benzoyl]amino]phenyl]methyl]pyrimidin-5-yl]acetic acid Chemical compound CN(C)C1=C(CC(O)=O)C(C(C)C)=NC(CC=2C=CC(NC(=O)C=3C=CC(=CC=3)C(F)(F)F)=CC=2)=N1 MRMSMOWNKYPGHI-UHFFFAOYSA-N 0.000 claims description 2
- BKHLPFXCOHVKNA-UHFFFAOYSA-N 2-[4-(dimethylamino)-6-pyrrolidin-1-yl-2-[[4-[[4-(trifluoromethyl)benzoyl]amino]phenyl]methyl]pyrimidin-5-yl]acetic acid Chemical compound N=1C(N2CCCC2)=C(CC(O)=O)C(N(C)C)=NC=1CC(C=C1)=CC=C1NC(=O)C1=CC=C(C(F)(F)F)C=C1 BKHLPFXCOHVKNA-UHFFFAOYSA-N 0.000 claims description 2
- FZZZSCVAJSHOTP-UHFFFAOYSA-N 2-[4-[[2-(cyclopentylamino)-2-oxoethyl]-methylamino]-2-[[4-(naphthalene-2-carbonylamino)phenyl]methyl]pyrimidin-5-yl]acetic acid Chemical compound N=1C(CC=2C=CC(NC(=O)C=3C=C4C=CC=CC4=CC=3)=CC=2)=NC=C(CC(O)=O)C=1N(C)CC(=O)NC1CCCC1 FZZZSCVAJSHOTP-UHFFFAOYSA-N 0.000 claims description 2
- MGOYNGXEMSANKG-UHFFFAOYSA-N 2-[4-[methyl-(2-oxo-2-pyrrolidin-1-ylethyl)amino]-2-[[4-(naphthalene-2-carbonylamino)phenyl]methyl]pyrimidin-5-yl]acetic acid Chemical compound N=1C(CC=2C=CC(NC(=O)C=3C=C4C=CC=CC4=CC=3)=CC=2)=NC=C(CC(O)=O)C=1N(C)CC(=O)N1CCCC1 MGOYNGXEMSANKG-UHFFFAOYSA-N 0.000 claims description 2
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- UAPLHVKACQBFRY-UHFFFAOYSA-N 2-[4-chloro-2-[[4-[(2,5-dichlorobenzoyl)amino]phenyl]methyl]-6-(dimethylamino)pyrimidin-5-yl]acetic acid Chemical compound ClC1=C(CC(O)=O)C(N(C)C)=NC(CC=2C=CC(NC(=O)C=3C(=CC=C(Cl)C=3)Cl)=CC=2)=N1 UAPLHVKACQBFRY-UHFFFAOYSA-N 0.000 claims description 2
- ZNTGLJGJOQBPOJ-UHFFFAOYSA-N 2-[4-chloro-2-[[4-[(2-cyclohexylacetyl)amino]phenyl]methyl]-6-[[2-(cyclopentylamino)-2-oxoethyl]-methylamino]pyrimidin-5-yl]acetic acid Chemical compound N=1C(CC=2C=CC(NC(=O)CC3CCCCC3)=CC=2)=NC(Cl)=C(CC(O)=O)C=1N(C)CC(=O)NC1CCCC1 ZNTGLJGJOQBPOJ-UHFFFAOYSA-N 0.000 claims description 2
- JCPPYXISAHHCPF-UHFFFAOYSA-N 2-[4-chloro-2-[[4-[(3,4-dichlorobenzoyl)amino]phenyl]methyl]-6-(dimethylamino)pyrimidin-5-yl]acetic acid Chemical compound ClC1=C(CC(O)=O)C(N(C)C)=NC(CC=2C=CC(NC(=O)C=3C=C(Cl)C(Cl)=CC=3)=CC=2)=N1 JCPPYXISAHHCPF-UHFFFAOYSA-N 0.000 claims description 2
- YGFDDDQXTSQSQN-UHFFFAOYSA-N 2-[4-chloro-2-[[4-[(3,4-dichlorobenzoyl)amino]phenyl]methyl]-6-pyrrolidin-1-ylpyrimidin-5-yl]acetic acid Chemical compound N1=C(N2CCCC2)C(CC(=O)O)=C(Cl)N=C1CC(C=C1)=CC=C1NC(=O)C1=CC=C(Cl)C(Cl)=C1 YGFDDDQXTSQSQN-UHFFFAOYSA-N 0.000 claims description 2
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- DOHVYOHYPAGMAF-UHFFFAOYSA-N 2-[4-chloro-2-[[4-[(3,4-dimethoxybenzoyl)amino]phenyl]methyl]-6-(dimethylamino)pyrimidin-5-yl]acetic acid Chemical compound C1=C(OC)C(OC)=CC=C1C(=O)NC(C=C1)=CC=C1CC1=NC(Cl)=C(CC(O)=O)C(N(C)C)=N1 DOHVYOHYPAGMAF-UHFFFAOYSA-N 0.000 claims description 2
- SFKVETIQAWQTMS-UHFFFAOYSA-N 2-[4-chloro-2-[[4-[(3,5-dichlorobenzoyl)amino]phenyl]methyl]-6-(dimethylamino)pyrimidin-5-yl]acetic acid Chemical compound ClC1=C(CC(O)=O)C(N(C)C)=NC(CC=2C=CC(NC(=O)C=3C=C(Cl)C=C(Cl)C=3)=CC=2)=N1 SFKVETIQAWQTMS-UHFFFAOYSA-N 0.000 claims description 2
- QKSKYWATPYQNRY-UHFFFAOYSA-N 2-[4-chloro-2-[[4-[(3-chloro-4-methoxybenzoyl)amino]phenyl]methyl]-6-pyrrolidin-1-ylpyrimidin-5-yl]acetic acid Chemical compound C1=C(Cl)C(OC)=CC=C1C(=O)NC(C=C1)=CC=C1CC1=NC(Cl)=C(CC(O)=O)C(N2CCCC2)=N1 QKSKYWATPYQNRY-UHFFFAOYSA-N 0.000 claims description 2
- GXRGQPPSNFDVRG-UHFFFAOYSA-N 2-[4-chloro-2-[[4-[(3-chlorobenzoyl)amino]phenyl]methyl]-6-(dimethylamino)pyrimidin-5-yl]acetic acid Chemical compound ClC1=C(CC(O)=O)C(N(C)C)=NC(CC=2C=CC(NC(=O)C=3C=C(Cl)C=CC=3)=CC=2)=N1 GXRGQPPSNFDVRG-UHFFFAOYSA-N 0.000 claims description 2
- DJZFUDKILTZUGL-UHFFFAOYSA-N 2-[4-chloro-2-[[4-[(4-chlorobenzoyl)amino]phenyl]methyl]-6-(dimethylamino)pyrimidin-5-yl]acetic acid Chemical compound ClC1=C(CC(O)=O)C(N(C)C)=NC(CC=2C=CC(NC(=O)C=3C=CC(Cl)=CC=3)=CC=2)=N1 DJZFUDKILTZUGL-UHFFFAOYSA-N 0.000 claims description 2
- WXARHGJSLJJRPG-UHFFFAOYSA-N 2-[4-chloro-2-[[4-[(4-chlorobenzoyl)amino]phenyl]methyl]-6-pyrrolidin-1-ylpyrimidin-5-yl]acetic acid Chemical compound N1=C(N2CCCC2)C(CC(=O)O)=C(Cl)N=C1CC(C=C1)=CC=C1NC(=O)C1=CC=C(Cl)C=C1 WXARHGJSLJJRPG-UHFFFAOYSA-N 0.000 claims description 2
- HVTPKJKYFNCJTQ-UHFFFAOYSA-N 2-[4-chloro-2-[[4-[(4-cyanobenzoyl)amino]phenyl]methyl]-6-[[2-(cyclopentylamino)-2-oxoethyl]-methylamino]pyrimidin-5-yl]acetic acid Chemical compound N=1C(CC=2C=CC(NC(=O)C=3C=CC(=CC=3)C#N)=CC=2)=NC(Cl)=C(CC(O)=O)C=1N(C)CC(=O)NC1CCCC1 HVTPKJKYFNCJTQ-UHFFFAOYSA-N 0.000 claims description 2
- SLPMFCFFPOSDJT-UHFFFAOYSA-N 2-[4-chloro-2-[[4-[(4-methoxy-3,5-dimethylbenzoyl)amino]phenyl]methyl]-6-pyrrolidin-1-ylpyrimidin-5-yl]acetic acid Chemical compound C1=C(C)C(OC)=C(C)C=C1C(=O)NC(C=C1)=CC=C1CC1=NC(Cl)=C(CC(O)=O)C(N2CCCC2)=N1 SLPMFCFFPOSDJT-UHFFFAOYSA-N 0.000 claims description 2
- RJIDXIAMEKHXNS-UHFFFAOYSA-N 2-[4-chloro-2-[[4-[(4-methylsulfanylbenzoyl)amino]phenyl]methyl]-6-pyrrolidin-1-ylpyrimidin-5-yl]acetic acid Chemical compound C1=CC(SC)=CC=C1C(=O)NC(C=C1)=CC=C1CC1=NC(Cl)=C(CC(O)=O)C(N2CCCC2)=N1 RJIDXIAMEKHXNS-UHFFFAOYSA-N 0.000 claims description 2
- GYUDXTUDABEZFS-UHFFFAOYSA-N 2-[4-chloro-2-[[4-[(4-nitrobenzoyl)amino]phenyl]methyl]-6-pyrrolidin-1-ylpyrimidin-5-yl]acetic acid Chemical compound N1=C(N2CCCC2)C(CC(=O)O)=C(Cl)N=C1CC(C=C1)=CC=C1NC(=O)C1=CC=C([N+]([O-])=O)C=C1 GYUDXTUDABEZFS-UHFFFAOYSA-N 0.000 claims description 2
- RGPFGWBVFSTDOG-UHFFFAOYSA-N 2-[4-chloro-2-[[4-[(4-phenoxybenzoyl)amino]phenyl]methyl]-6-pyrrolidin-1-ylpyrimidin-5-yl]acetic acid Chemical compound N1=C(N2CCCC2)C(CC(=O)O)=C(Cl)N=C1CC(C=C1)=CC=C1NC(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 RGPFGWBVFSTDOG-UHFFFAOYSA-N 0.000 claims description 2
- NCBINUVTUKRPQC-UHFFFAOYSA-N 2-[4-chloro-2-[[4-[(4-propan-2-yloxybenzoyl)amino]phenyl]methyl]-6-pyrrolidin-1-ylpyrimidin-5-yl]acetic acid Chemical compound C1=CC(OC(C)C)=CC=C1C(=O)NC(C=C1)=CC=C1CC1=NC(Cl)=C(CC(O)=O)C(N2CCCC2)=N1 NCBINUVTUKRPQC-UHFFFAOYSA-N 0.000 claims description 2
- BWGGXLQPWBJNOG-FQEVSTJZSA-N 2-[4-chloro-2-[[4-[[(2s)-3,4-dihydro-2h-chromene-2-carbonyl]amino]phenyl]methyl]-6-(dimethylamino)pyrimidin-5-yl]acetic acid Chemical compound ClC1=C(CC(O)=O)C(N(C)C)=NC(CC=2C=CC(NC(=O)[C@H]3OC4=CC=CC=C4CC3)=CC=2)=N1 BWGGXLQPWBJNOG-FQEVSTJZSA-N 0.000 claims description 2
- RADBTWDKEJPKEO-KPKJPENVSA-N 2-[4-chloro-2-[[4-[[(e)-3-(4-chlorophenyl)prop-2-enoyl]amino]phenyl]methyl]-6-pyrrolidin-1-ylpyrimidin-5-yl]acetic acid Chemical compound N1=C(N2CCCC2)C(CC(=O)O)=C(Cl)N=C1CC(C=C1)=CC=C1NC(=O)\C=C\C1=CC=C(Cl)C=C1 RADBTWDKEJPKEO-KPKJPENVSA-N 0.000 claims description 2
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- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
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- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Substances BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 1
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- 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
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
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- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
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- 239000003638 chemical reducing agent Substances 0.000 description 1
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- 238000010367 cloning Methods 0.000 description 1
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- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 1
- 125000006637 cyclobutyl carbonyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000006640 cycloheptyl carbonyl group Chemical group 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006639 cyclohexyl carbonyl group Chemical group 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
- 125000006638 cyclopentyl carbonyl group Chemical group 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- 125000006255 cyclopropyl carbonyl group Chemical group [H]C1([H])C([H])([H])C1([H])C(*)=O 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 description 1
- XREKLQOUFWBSFH-UHFFFAOYSA-N dimethyl 2-acetylbutanedioate Chemical compound COC(=O)CC(C(C)=O)C(=O)OC XREKLQOUFWBSFH-UHFFFAOYSA-N 0.000 description 1
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- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000006260 ethylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])C([H])([H])[H] 0.000 description 1
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- 238000009472 formulation Methods 0.000 description 1
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- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
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- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000004997 halocarbonyl group Chemical group 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000007970 homogeneous dispersion Substances 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
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- 239000004615 ingredient Substances 0.000 description 1
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- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
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- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
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- 239000000594 mannitol Substances 0.000 description 1
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- 238000004949 mass spectrometry Methods 0.000 description 1
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- ZZMPNWDHIAEIHA-UHFFFAOYSA-N methyl 2-[4-(dimethylamino)-2-[[4-(phenoxycarbonylamino)phenyl]methyl]pyrimidin-5-yl]acetate Chemical compound N1=C(N(C)C)C(CC(=O)OC)=CN=C1CC(C=C1)=CC=C1NC(=O)OC1=CC=CC=C1 ZZMPNWDHIAEIHA-UHFFFAOYSA-N 0.000 description 1
- XWBTZCPAKTVXGJ-UHFFFAOYSA-N methyl 2-[4-chloro-6-(dimethylamino)-2-[[4-(methylamino)phenyl]methyl]pyrimidin-5-yl]acetate Chemical compound C1=CC(NC)=CC=C1CC1=NC(Cl)=C(CC(=O)OC)C(N(C)C)=N1 XWBTZCPAKTVXGJ-UHFFFAOYSA-N 0.000 description 1
- YLOSZJHYPWGYEC-UHFFFAOYSA-N methyl 2-[4-chloro-6-methyl-2-[(4-nitrophenyl)methyl]pyrimidin-5-yl]acetate Chemical compound N1=C(Cl)C(CC(=O)OC)=C(C)N=C1CC1=CC=C([N+]([O-])=O)C=C1 YLOSZJHYPWGYEC-UHFFFAOYSA-N 0.000 description 1
- ITCYNWZKTHQHHA-UHFFFAOYSA-N methyl 2-[4-hydroxy-2-[(4-nitrophenyl)methyl]-6-oxo-1h-pyrimidin-5-yl]acetate Chemical compound N1=C(O)C(CC(=O)OC)=C(O)N=C1CC1=CC=C([N+]([O-])=O)C=C1 ITCYNWZKTHQHHA-UHFFFAOYSA-N 0.000 description 1
- UDSUZQCSWWADQM-UHFFFAOYSA-N methyl 2-[4-methyl-2-[(4-nitrophenyl)methyl]-6-pyrrolidin-1-ylpyrimidin-5-yl]acetate Chemical compound N1=C(N2CCCC2)C(CC(=O)OC)=C(C)N=C1CC1=CC=C([N+]([O-])=O)C=C1 UDSUZQCSWWADQM-UHFFFAOYSA-N 0.000 description 1
- NVCHUNVJIWZRRR-UHFFFAOYSA-N methyl 2-[6-methyl-2-[(4-nitrophenyl)methyl]-4-oxo-1h-pyrimidin-5-yl]acetate Chemical compound N1=C(O)C(CC(=O)OC)=C(C)N=C1CC1=CC=C([N+]([O-])=O)C=C1 NVCHUNVJIWZRRR-UHFFFAOYSA-N 0.000 description 1
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- WNSNYYLIQITQFJ-UHFFFAOYSA-N n-[4-[[4-chloro-6-(dimethylamino)-5-(2h-tetrazol-5-ylmethyl)pyrimidin-2-yl]methyl]phenyl]naphthalene-2-carboxamide Chemical compound CN(C)C1=NC(CC=2C=CC(NC(=O)C=3C=C4C=CC=CC4=CC=3)=CC=2)=NC(Cl)=C1CC1=NN=NN1 WNSNYYLIQITQFJ-UHFFFAOYSA-N 0.000 description 1
- 125000001298 n-hexoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 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 1
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- 125000005184 naphthylamino group Chemical group C1(=CC=CC2=CC=CC=C12)N* 0.000 description 1
- 125000005185 naphthylcarbonyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
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- 235000005985 organic acids Nutrition 0.000 description 1
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- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
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- 239000008194 pharmaceutical composition Substances 0.000 description 1
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- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- BSCCSDNZEIHXOK-UHFFFAOYSA-N phenyl carbamate Chemical compound NC(=O)OC1=CC=CC=C1 BSCCSDNZEIHXOK-UHFFFAOYSA-N 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
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- 229920001155 polypropylene Polymers 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 230000037452 priming Effects 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
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- 239000000047 product Substances 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- IWRRRCZSVINKHU-UHFFFAOYSA-N pyrazol-3-ylidenemethanone Chemical class O=C=C1C=CN=N1 IWRRRCZSVINKHU-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
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- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 1
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- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
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- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
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- 239000000454 talc Substances 0.000 description 1
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- 235000012222 talc Nutrition 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
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 239000006211 transdermal dosage form Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- TVWZLLYAJDSSCJ-UHFFFAOYSA-N triethyl ethane-1,1,2-tricarboxylate Chemical compound CCOC(=O)CC(C(=O)OCC)C(=O)OCC TVWZLLYAJDSSCJ-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
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- 229940082509 xanthan gum Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
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- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- A—HUMAN NECESSITIES
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Abstract
本发明涉及一种用作药物制品活性成分的式(I)嘧啶衍生物及其盐。本发明的嘧啶衍生物具有极佳的CRTH2(G-蛋白-偶联的化学引诱物受体,在Th2细胞表达)拮抗剂的活性并且可用于预防和治疗与CRTH2活性相关的疾病,尤其是治疗过敏性疾病,如哮喘、过敏性鼻炎、特应性皮炎以及过敏性结膜炎;嗜酸性细胞相关的疾病,如Churg-Strauss综合征和窦炎;嗜碱性细胞相关的疾病,如嗜碱细胞性白血症、慢性荨麻疹以及人和其它哺乳动物的嗜碱性白细胞增多;具有T淋巴细胞和过多白血球浸润特征的感染性疾病,如牛皮癣、湿疹、炎性肠疾病、溃疡性结肠炎、克罗恩氏病(Crohn′s disease)、COPD(慢性阻塞性肺病)以及关节炎。
Description
发明详述
技术领域
本发明涉及一种用作药物制品活性成分的嘧啶衍生物。本发明的嘧啶衍生物具有CRTH2(G-蛋白-偶联的化学引诱物受体,在Th2细胞表达)拮抗剂的活性并且可用于预防和治疗与CRTH2活性相关的疾病,尤其是治疗过敏性疾病,如哮喘、过敏性鼻炎、特应性皮炎以及过敏性结膜炎;嗜酸性细胞相关的疾病,如Churg-Strauss综合征和窦炎;嗜碱性细胞相关的疾病,如嗜碱细胞性白血症,慢性荨麻疹以及人和其它哺乳动物的嗜碱性白细胞增多;具有T淋巴细胞和过多白血球浸润特征的感染性疾病,如牛皮癣、湿疹、炎性肠疾病、溃疡性结肠炎、克罗恩氏病(Crohn′s disease)、COPD(慢性阻塞性肺病)以及关节炎。
背景技术
CRTH2是一个G-蛋白-偶联的化学引诱物受体,在Th2细胞(Nagata et al.J.Immunol.,162,1278-1286,1999)、嗜酸性细胞以及嗜碱性细胞(Hirai et al.,J.Exp.Med.,193,255-261,2001)上表达。
Th2-极化已被发现在变应性疾病中,如哮喘、过敏性鼻炎、特应性皮炎以及变应性结膜炎(Romagnani S.Immunology Today,18,263-266,1997;Hammad H.et al.,Blood,98,1135-1141,2001)。Th2细胞通过产生Th2细胞因子,如IL-4、IL-5和IL-13来调节过敏性疾病(Oriss et al.,J.Immunol.,162,1999-2007,1999;Viola et al.,Blood,91,2223-2230,1998;Webb et al.,J.Immunol.,165,108-113,2000;Dumont F.J.,Exp.Opin.Ther.Pat.,12,341-367,2002)。这些Th2细胞因子直接或间接诱导迁移、激活、初敏和延长在变应性疾病中的效应器细胞,如嗜碱性粒细胞和嗜酸性粒细胞的存活(Sanz et al.,J.Immunol.,160,5637-5645,1998;Pope et al.,J.Allergy Clin.Immunol.,108,594-601,2001;Teran L.M.,Clin.Exp.Exp.Allergy,29,287-290,1999)。
PGD2是由在变应性疾病中的肥大细胞以及其它重要效应器细胞产生的一种CRTH2配体(Nagata et al.,FEBS Lett.459,195-199,1999;Hirai et al.,J.Exp.Med.,193,255-261,2001)。PGD2经由CRTH2诱导Th2细胞、嗜酸性细胞及嗜碱性细胞在人细胞中迁移和激活(Hirai etal.,J.Exp.Med.,193,255-261,2001;Gervais et al.,J.Allergy Clin.Immunol.,108,982-988,2001;Sugimoto et al.,J.Pharmacol.Exp.Ther.,305,(1),347-52,2003)。
因此,抑制CRTH2和PGD2结合的拮抗剂应该有益于治疗变应性疾病,如哮喘、过敏性鼻炎、特应性皮炎以及过敏性结膜炎。
此外,多条实验证据已证明了嗜酸性细胞在窦炎(Hamilos et al.,Am.J.Respir.Cell and Mol.Biol.,15,443-450,1996;Fan et al.,J.Allergy Clin.Immunol.,106,551-558,2000)以及Churg-Strauss综合征(Coffin et al.,J.Allergy Clin.Immunol.,101,116-123,1998;Kurosawa etal.,Allergy,55,785-787,2000)中的作用。在这些患者的组织里,可观察到肥大细胞与嗜酸性细胞共同定位(Khan et al.,J.Allergy Clin.Immunol.,106,1096-1101,2000)。有建议称从肥大细胞中产生的PGD2诱导嗜酸性细胞的募集。因此,CRTH2拮抗剂还有助于治疗其它与嗜酸性细胞相关的疾病,如Churg-Strauss综合征及窦炎。由于CRTH2在嗜碱性细胞上的高表达,CRTH2拮抗剂还可有效治疗一些与嗜碱性细胞相关的疾病,如嗜碱性肺炎、慢性荨麻疹及嗜碱性白细胞增多。
Ordukhanyan,A.A等人公开了由以下通式代表的作为制备抗肿瘤剂的中间体的嘧啶衍生物的合成:
其中,
R=烷基
R′=H或烷基
(Khimiko-Farmatsevticheskii Zhurnal(1979),13(9),36-40)。专利GB2262096公开了由以下通式代表的嘧啶衍生物,
其中,
A1、Ra、Rb、Rc和Rd如申请中所定义,作为血管紧张素II拮抗剂。
然而,没有一个参考文献及其它参考文献公开了具有CRTH2拮抗剂活性的嘧啶衍生物。
期望开发出一个具有有效CRTH2拮抗剂活性并且能用于预防和治疗与CRTH2活性相关疾病的化合物。
发明概述
本发明旨在提供一种式(I)的嘧啶衍生物,以及它们的互变异构和立体异构形式,或其盐、酯或前药,其中
R1代表氢,
或
其中,
n代表0-6的整数;
-Q1-代表-NH-、-N(C1-6烷基)-或-O-;
Y代表氢、任选被C1-6烷基取代的C3-8环烷基、被苯稠合的C3-8环烷基、芳基或杂芳基,其中所述芳基及杂芳基任选在可取代位置上被一或多个取代基取代,所述取代基选自氰基、卤素、硝基、胍基、吡咯基、氨磺酰基、C1-6烷氨基磺酰基、二(C1-6烷基)氨基磺酰基、苯氧基、苯基、氨基、C1-6烷氨基、二(C1-6)-烷氨基、C1-6烷氧羰基、C1-6烷酰基、C1-6烷酰氨基、氨基甲酰基、C1-6烷基氨基甲酰基、二(C1-6烷基)-氨基甲酰基、C1-6烷基磺酰基、任选被单-、双-或三-卤素取代的C1-6烷基、任选被单-、双-或三-卤素取代的C1-6烷氧基以及任选被单-、双-或三-卤素取代的C1-6烷硫基,或被1,3-二氧戊环稠合的芳基;
R2代表氢或C1-6烷基;
R3代表卤素、任选被单-、双-或三-卤素取代的C1-6烷氧基,
其中:
R3a和R3b独立代表C3-8环烷基或C1-6烷基,其中的C1-6烷基任选被羧基、C3-8环烷基、氨基甲酰基、C1-6烷基-氨基甲酰基、芳基-取代的C1-6烷基氨基甲酰基、C1-6烷基氨基甲酰基、二(C1-6烷基)氨基甲酰基、C3-8环烷基氨基甲酰基、C3-8杂环基羰基、(C1-6)烷基氨基、二(C1-6)烷基氨基或C1-6烷氧基取代;
q代表1-3的整数;
R3c代表氢、羟基、羧基或任选被羟基、羧基或(苯基-取代的C1-6烷基)氨基甲酰基取代的C1-6烷基;
Xa代表-O-、-S-或-N(R3d)-,
其中
R3d代表C1-6烷基;
R4代表氢、卤素、C1-6烷氧基、二(C1-6烷基)氨基或任选被C1-6烷氧基、或单-、双-或三-卤素取代的C1-6烷基;
R5代表氢或C1-6烷基;并且
R6代表羧基、氨甲酰(carboxamide)、腈(nitrile)或四唑基。
在一个实施方案中,式(I)的化合物为那些化合物,其中,
R1代表
其中
n为0-2的整数;
-Q1-代表-NH-、-N-(C1-6烷基)-或-O-;
Y代表C1-6烷基、任选被C1-6烷基取代的C3-8环烷基、选自茚基和四氢化萘基的被苯稠合的C3-8环烷基、选自苯基和萘基的芳基或选自吲哚基、喹啉基、苯并呋喃基、呋喃基、苯并二氢吡喃基和吡啶基的杂芳基,其中所述芳基和杂芳基任选在可取代的位置被一或多个取代基取代,所述取代基选自氰基、卤素、硝基、吡咯基、氨磺酰基、C1-6烷氨基磺酰基、二(C1-6烷基)氨基磺酰基、苯氧基、苯基、C1-6烷基氨基、二(C1-6)烷基氨基、C1-6烷氧羰基、C1-6烷酰基氨基、氨基甲酰基、C1-6烷基氨基甲酰基、双-(C1-6烷基)氨基甲酰基、C1-6烷基磺酰基、任选被单-、双-或三-卤素取代的C1-6烷基、任选被单-、双-或三-卤素取代的C1-6烷氧基、任选被单-、双-或三-卤素取代的C1-6烷硫基;并且
R2代表氢。
在另一个实施方案中,式(I)化合物为那些化合物,
其中,
R3代表任选被一、二或三卤素取代的C1-6烷氧基,
其中
R3a和R3b独立代表C1-6烷基,任选被羧基、羟基、C3-8环烷基、氨基甲酰基、C1-6烷基氨基甲酰基、二(C1-6烷基)-氨基甲酰基、C3-8环烷基氨基甲酰基、C3-8杂环基羰基、(C1-6)-烷基氨基、二(C1-6)烷基氨基或C1-6烷氧基取代;
R3c代表氢、羟基、羧基或任选被羟基、羧基或(苯基-取代的C1-6烷基)氨基甲酰基取代的C1-6烷基;并且,
Xa代表-O-、-S-或-N(R3d)-,
其中
R3d代表C1-6烷基。
在另一个实施方案中,式(I-i)化合物为那些化合物,其中:
R1代表
其中
n代表0-2整数;
-Q1-代表-NH-、-N(C1-6烷基)-、或-O-;
Y代表苯基、萘基、吲哚基、喹啉基、苯并呋喃基、呋喃基或吡啶基,其中所述的苯基、萘基、吲哚基、喹啉基、苯并呋喃基、呋喃基和吡啶基任选在可取代的位置上被一或两个取代基取代,所述取代基选自氰基、卤素、硝基、苯氧基、苯基、任选被单-、双-或三-卤素取代的C1-6烷基、任选被单-、双-或三-卤素取代的C1-6烷氧基、任选被单-、双-或三-卤素取代的C1-6烷硫基;
R2代表氢或C1-6烷基;
R3代表,
其中
R3a及R3b独立代表C3-8环烷基,或任选被C3-8环烷基、氨基甲酰基、C1-6烷基氨基甲酰基、苯基取代的C1-6烷基氨基甲酰基、C1-6烷基氨基甲酰基、二(C1-6烷基)-氨基甲酰基、C3-8环烷基氨基甲酰基、C3-8杂环基羰基、(C1-6)烷基氨基、二(C1-6)烷基氨基或C1-6烷氧基取代的C1-6烷基;
R3c代表氢、羟基、羧基或任选被羟基、羧基或(苯基-取代的C1-6烷基)氨基甲酰基取代的C1-6烷基;
R4代表氢、氯、溴、C1-6烷氧基、二(C1-6烷基)氨基或C1-6烷基;
R5代表氢或甲基;
R6代表羧基或四唑基。
本发明的优选化合物如下:
1){4-氯-6-(二甲基氨基)-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
2){4-氯-6-{甲基[2-氧代-2-(1-吡咯烷基)乙基]氨基}-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
3){4-氯-6-[[2-(异丙氨基)-2-氧代乙基](甲基)氨基]-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
4){4-氯-6-[[2-(环己氨基)-2-氧代乙基](甲基)氨基]-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
5){2-[4-(苯甲酰氨基)苄基]-4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-5-嘧啶基}乙酸;
6){4-氯-2-{4-[(环己基乙酰基)氨基]苄基}-6-[[2-(环戊氨基)-2-氧代乙基](甲基)-氨基]-5-嘧啶基}乙酸;
7)(4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-2-{4-[(3-苯基丙酰基)氨基]苄基}-5-嘧啶基)乙酸;
8)[4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-2-(4-{[(4-甲基苯基)乙酰基]-氨基}苄基)-5-嘧啶基]乙酸;
9)(4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-2-{4-[(2-喹啉基羰基)氨基]苄基}-5-嘧啶基)乙酸;
10)[4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-2-(4-{[(2E)-3-苯基-2-丙烯酰基]氨基}苄基)-5-嘧啶基]乙酸;
11){4-氯-2-{4-[(4-氯苯甲酰基)氨基]苄基}-6-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-5-嘧啶基}乙酸;
12){4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-2-{4-[(3,4-二氯苯甲酰基)氨基]苄基}-5-嘧啶基}乙酸;
13){4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-2-{4-[(4-甲氧基苯甲酰基)氨基]苄基}-5-嘧啶基}乙酸;
14){4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-2-{4-[(4-甲基苯甲酰基)氨基]苄基}-5-嘧啶基}乙酸;
15){4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-2-[4-(1-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
16){2-{4-[(1-苯并呋喃-2-基羰基)氨基]苄基}-4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-5-嘧啶基}乙酸;
17){4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-2-{4-[(1H-吲哚-2-基羰基)-氨基]苄基}-5-嘧啶基}乙酸;
18){4-氯-2-{4-[(4-氰基苯甲酰基)氨基]苄基}-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-5-嘧啶基}乙酸;
19){4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-2-{4-[(2,3-二氢-1H-茚-2-基乙酰基)氨基]苄基}-5-嘧啶基}乙酸;
20)[4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-2-(4-{[(3-苯氧基苯基)乙酰基]氨基}苄基)-5-嘧啶基]乙酸;
21)[4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-2-(4-{[(4-苯氧基苯基)乙酰基]-氨基}苄基)-5-嘧啶基]乙酸;
22)(4-氯-6-(二甲基氨基)-2-{4-[(2-喹啉基羰基)氨基]苄基}-5-嘧啶基)乙酸;
23)[4-氯-6-(二甲基氨基)-2-(4-{[(2E)-3-苯基-2-丙烯酰基]氨基}苄基)-5-嘧啶基]乙酸;
24)[4-氯-2-{4-[(3,4-二氯苯甲酰基)氨基]苄基}-6-(二甲基氨基)-5-嘧啶基]乙酸;
25)[4-氯-2-{4-[(4-氯苯甲酰基)氨基]苄基}-6-(二甲基氨基)-5-嘧啶基]乙酸;
26)(4-氯-6-(二甲基氨基)-2-{4-[(4-甲氧基苯甲酰基)氨基]苄基}-5-嘧啶基)乙酸;
27)[4-氯-6-(二甲基氨基)-2-(4-{[4-(二甲基氨基)苯甲酰基]氨基}苄基)-5-嘧啶基]-乙酸;
28)[4-氯-2-{4-[(3,4-二甲氧基苯甲酰基)氨基]苄基}-6-(二甲基氨基)-5-嘧啶基]乙酸;
29)[4-氯-6-(二甲基氨基)-2-(4-{[4-(三氟甲基)苯甲酰基]氨基}苄基)-5-嘧啶基]乙酸;
30)[4-氯-2-(4-{[(2E)-3-(4-氯苯基)-2-丙烯酰基]氨基}苄基)-6-(二甲基氨基)-5-嘧啶基]乙酸;
31)[2-{4-[(4-溴苯甲酰基)氨基]苄基}-4-氯-6-(二甲基氨基)-5-嘧啶基]乙酸;
32)[4-氯-2-{4-[(2,5-二氯苯甲酰基)氨基]苄基}-6-(二甲基氨基)-5-嘧啶基]乙酸;
33)[4-氯-2-{4-[(3,4-二氟苯甲酰基)氨基]苄基}-6-(二甲基氨基)-5-嘧啶基]乙酸;
34)[4-氯-2-{4-[(3,5-二氯苯甲酰基)氨基]苄基}-6-(二甲基氨基)-5-嘧啶基]乙酸;
35)[4-氯-2-{4-[(3-氯苯甲酰基)氨基]苄基}-6-(二甲基氨基)-5-嘧啶基]乙酸;
36)(4-氯-6-(二甲基氨基)-2-{4-[(3-甲氧基苯甲酰基)氨基]苄基}-5-嘧啶基)乙酸;
37){4-氯-6-(二甲基氨基)-2-[3-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
38)[2-(4-{[(4-叔-丁基环己基)羰基]氨基}苄基)-4-氯-6-(二甲基氨基)-5-嘧啶基]乙酸;
39)[4-氯-2-{4-[(4-硝基苯甲酰基)氨基]苄基}-6-(1-吡咯烷基)-5-嘧啶基]乙酸;
40)[2-(4-{[4-(乙酰氨基)苯甲酰基]氨基}苄基)-4-氯-6-(1-吡咯烷基)-5-嘧啶基]乙酸;
41)[4-氯-2-{4-[(4-苯氧基苯甲酰基)氨基]苄基}-6-(1-吡咯烷基)-5-嘧啶基]乙酸;
42)[4-氯-2-{4-[(4-异丙氧基苯甲酰基)氨基]苄基}-6-(1-吡咯烷基)-5-嘧啶基]乙酸;
43)[4-氯-6-(1-吡咯烷基)-2-(4-{[4-(1H-吡咯-1-基)苯甲酰基]氨基}苄基)-5-嘧啶基]乙酸;
44)[4-氯-2-{4-[(4-甲氧基-3-;硝基苯甲酰基)氨基]苄基}-6-(1-吡咯烷基)-5-嘧啶基]乙酸;
45)[4-氯-2-{4-[(4-甲氧基-3,5-二甲基苯甲酰基)氨基]苄基}-6-(1-吡咯烷基)-5-嘧啶基]乙酸;
46)[4-氯-2-(4-{[(2E)-3-苯基-2-丙烯酰基]氨基}苄基)-6-(1-吡咯烷基)-5-嘧啶基]乙酸;
47)[4-氯-2-{4-[(3,4-二氯苯甲酰基)氨基]苄基}-6-(1-吡咯烷基)-5-嘧啶基]乙酸;
48){4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
49)(4-氯-2-{4-[(4-氯苯甲酰基)氨基]苄基}-6-吡咯烷-1-基嘧啶-5-基)乙酸;
50)[4-氯-6-吡咯烷-1-基-2-(4-{[4-(三氟甲基)苯甲酰基]氨基}苄基)嘧啶-5-基]乙酸;
51)[4-氯-2-(4-{[(2E)-3-(4-氯苯基)丙-2-烯酰基]氨基}苄基)-6-吡咯烷-1-基嘧啶-5-基]乙酸;
52){4-氯-6-[(2-羟基乙基)(甲基)氨基]-2-[4-(2-萘甲酰氨基)苄基]嘧啶-5-基}乙酸;
53)[4-氯-2-(4-{[(2S)-3,4-二氢-2H-苯并吡喃-2-基羰基]氨基}苄基)-6-(二甲基氨基)-嘧啶-5-基]乙酸;
54){4-氯-6-(二甲基氨基)-2-[4-({(2E)-3-[4-(三氟甲基)苯基]丙-2-烯酰基}氨基)苄基]嘧啶-5-基}乙酸;
55){4-(二甲基氨基)-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
56){4-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
57){4-{甲基[2-氧代-2-(1-吡咯烷基)乙基]氨基}-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
58){2-[4-(苯甲酰氨基)苄基]-4-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-5-嘧啶基}乙酸;
59)[4-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-2-(4-{[(2E)-3-苯基-2-丙烯酰基]氨基}苄基)-5-嘧啶基]乙酸;
60)[2-{4-[(4-氯苯甲酰基)氨基]苄基}-4-(二甲基氨基)-5-嘧啶基]乙酸;
61)(4-(二甲基氨基)-2-{4-[(4-甲氧基苯甲酰基)氨基]苄基}-5-嘧啶基)乙酸;
62)[2-{4-[(3,4-二氯苯甲酰基)氨基]苄基}-4-(二甲基氨基)-5-嘧啶基]乙酸;
63)(4-(二甲基氨基)-2-{4-[(2-喹啉基羰基)氨基]苄基}-5-嘧啶基)乙酸;
64)[4-(二甲基氨基)-2-(4-{[(2E)-3-苯基-2-丙烯酰基]氨基}苄基)-5-嘧啶基]乙酸;
65)[2-(4-{[(2E)-3-(4-氯苯基)-2-丙烯酰基]氨基}苄基)-4-(二甲基氨基)-5-嘧啶基]乙酸;
66)[4-(二甲基氨基)-2-(4-{[4-(三氟甲基)苯甲酰基]氨基}苄基)-5-嘧啶基]乙酸;
67)(4-(二甲基氨基)-2-{4-[(3-甲氧基苯甲酰基)氨基]苄基}-5-嘧啶基)乙酸;
68)[2-{4-[(3-氯苯甲酰基)氨基]苄基}-4-(二甲基氨基)-5-嘧啶基]乙酸;
69)[2-{4-[(4-溴苯甲酰基)氨基]苄基}-4-(二甲基氨基)-5-嘧啶基]乙酸;
70){4-(二甲基氨基)-2-[4-({(2E)-3-[4-(三氟甲基)苯基]丙-2-烯酰基}氨基)苄基]嘧啶-5-基}乙酸;
71)(4-(二甲基氨基)-2-{1-[4-(2-萘甲酰氨基)苯基]乙基}嘧啶-5-基)乙酸;
72)[4-(二甲基氨基)-2-(4-{[4-(三氟甲氧基)苯甲酰基]氨基}苄基)嘧啶-5-基]乙酸;
73)(4-(二甲基氨基)-2-{4-[(4-氟苯甲酰基)氨基]苄基}嘧啶-5-基)乙酸;
74)[2-(1-{4-[(3,4-二氯苯甲酰基)氨基]苯基}乙基)-4-(二甲基氨基)嘧啶-5-基]乙酸;
75){4-(二甲基氨基)-2-[1-(4-{[4-(三氟甲基)苯甲酰基]氨基}苯基)乙基]嘧啶-5-基}乙酸;
76){4-(二甲基氨基)-2-[1-(4-{[(2E)-3-苯丙-2-烯酰基]氨基}苯基)乙基]嘧啶-5-基}乙酸;
77)[4-(二甲基氨基)-2-[1-{4-[(喹啉-2-基羰基)氨基]苯基}乙基]嘧啶-5-基]乙酸;
78)[2-(1-{4-[(4-氯苯甲酰基)氨基]苯基}乙基)-4-(二甲基氨基)嘧啶-5-基]乙酸;
79)[4-(二甲基氨基)-2-(1-{4-[(4-氟苯甲酰基)氨基]苯基}乙基)嘧啶-5-基]乙酸;
80)(4-吡咯烷-1-基-2-{4-[(喹啉-2-基羰基)氨基]苄基}嘧啶-5-基)乙酸;
81)(2-{4-[(4-氯苯甲酰基)氨基]苄基}-4-吡咯烷-1-基嘧啶-5-基)乙酸;
82)(2-{4-[(4-氟苯甲酰基)氨基]苄基}-4-吡咯烷-1-基嘧啶-5-基)乙酸;
83)[4-吡咯烷-1-基-2-(4-{[4-(三氟甲基)苯甲酰基]氨基}苄基)嘧啶-5-基]乙酸;
84){2-[4-(2-萘甲酰氨基)苄基]-4-吡咯烷-1-基嘧啶-5-基}乙酸;
85)(2-{4-[(3-甲基丁酰基)氨基]苄基}-4-吡咯烷-1-基嘧啶-5-基)乙酸钠;
86)(2-{4-[(3,3-二甲基丁酰基)氨基]苄基}-4-吡咯烷-1-基嘧啶-5-基)乙酸;
87)[4-氯-2-[4-(2-萘甲酰氨基)苄基]-6-(1-吡咯烷基)-5-嘧啶基]乙酸;
88)N-{5-(羧甲基)-6-氯-2-[4-(2-萘甲酰氨基)苄基]-4-嘧啶基}-N-甲基甘氨酸;
89){4-氯-6-[环己基(甲基)氨基]-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
90){4-氯-6-[异丙基(甲基)氨基]-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
91){4-氯-6-[(2-甲氧基乙基)(甲基)氨基]-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
92){4-氯-6-(4-吗啉基)-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
93)[4-氯-2-[4-(2-萘甲酰氨基)苄基]-6-(1-哌啶基)-5-嘧啶基]乙酸;
94)(4-氯-6-(二甲基氨基)-2-{4-[(1H-吲哚-6-基羰基)氨基]苄基}-5-嘧啶基)乙酸;
95){4-氯-6-甲氧基-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
96){4-氯-6-(2,5-二氢-1H-吡咯-1-基)-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
97){4-氯-6-(二乙氨基)-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
98){4-氯-6-[乙基(甲基)氨基]-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
99){4-氯-6-(3-羟基-1-吡咯烷基)-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
100)1-{5-(羧甲基)-6-氯-2-[4-(2-萘甲酰氨基)苄基]-4-嘧啶基}-L-脯氨酸;
101)[4-氯-2-(4-{[4-(甲硫基)苯甲酰基]氨基}苄基)-6-(1-吡咯烷基)-5-嘧啶基]乙酸;
102)[4-氯-2-{4-[(3-氯-4-甲氧基苯甲酰基)氨基]苄基}-6-(1-吡咯烷基)-5-嘧啶基]乙酸;
103){2-{4-[(苯胺基羰基)氨基]苄基}-4-氯-6-[[2-(环戊基氨基)-2-氧代乙基](甲基)氨基]-5-嘧啶基}乙酸;
104){2-(4-{[(苯甲氨基)羰基]氨基}苄基)-4-氯-6-[[2-(环戊基氨基)-2-氧代乙基](甲基)氨基]-5-嘧啶基}乙酸;
105){4-氯-6-[[2-(环戊基氨基)-2-氧代乙基](甲基)氨基]-2-[4-({[(2-苯乙基)氨基]羰基}氨基)苄基]-5-嘧啶基}乙酸;
106)[4-氯-6-[[2-(环戊基氨基)-2-氧代乙基](甲基)氨基]-2-(4-{[(2-萘氨基)羰基]氨基}苄基)-5-嘧啶基]乙酸;
107)[2-(4-{[(苄基氨基)羰基]氨基}苄基)-4-(二甲基氨基)嘧啶-5-基]乙酸;
108)[2-[4-({[苄基(甲基)氨基]羰基}氨基)苄基]-4-(二甲基氨基)嘧啶-5-基]乙酸;
109){4-(二甲基氨基)-6-(4-吗啉基)-2-[4-(2-萘甲酰基氨基)苄基]-5-嘧啶基}乙酸;
110)[4,6-双(二甲基氨基)-2-(4-{[4-(三氟甲基)苯甲酰基]氨基}苄基)嘧啶-5-基]乙酸;
111){4,6-双(二甲基氨基)-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
112)[4-(二甲基氨基)-2-[4-(2-萘甲酰氨基)苄基]-6-(1-吡咯烷基)-5-嘧啶基]乙酸;
113)[4-(二甲基氨基)-2-[4-(2-萘甲酰氨基)苄基]-6-(1-哌啶基)-5-嘧啶基]乙酸;
114)[2-{4-[(3,4-二氯苯甲酰基)氨基]苄基}-4,6-双(二甲基氨基)嘧啶-5-基]乙酸;
115)[4,6-双(二甲基氨基)-2-(4-{[(2E)-3-苯丙-2-烯酰基]氨基}苄基)嘧啶-5-基]乙酸;
116)[2-(4-{[(2E)-3-(4-氯苯基)丙-2-烯酰基]氨基}苄基)-4,6-双(二甲基氨基)嘧啶-5-基]乙酸;
117)[2-(4-{[(2E)-3-(4-氯苯基)丙-2-烯酰基]氨基}苄基)-4-(二甲基氨基)-6-吡咯烷-1-基嘧啶-5-基]乙酸;
118)[4-(二甲基氨基)-2-(4-{[(2E)-3-苯丙-2-烯酰基]氨基}苄基)-6-吡咯烷-1-基嘧啶-5-基]乙酸;
119)[4-(二甲基氨基)-6-吡咯烷-1-基2-(4-{[4-(三氟甲基)苯甲酰基]氨基}苄基)嘧啶-5-基]乙酸;
120)[2-{4-[(联苯-3-基羰基)氨基]苄基}-4-(二甲基氨基)-6-吡咯烷-1-基嘧啶-5-基]乙酸;
121)[2-{4-[(联苯-4-基羰基)氨基]苄基}-4-(二甲基氨基)-6-吡咯烷-1-基嘧啶-5-基]乙酸;
122)[2-{4-[(3,4-二氯苯甲酰基)氨基]苄基}-4-(二甲基氨基)-6-吗啉-4-基嘧啶-5-基]乙酸;
123)[4-(二甲基氨基)-6-吗啉-4-基-2-(4-{[4-(三氟甲基)苯甲酰基]氨基}苄基)嘧啶-5-基]乙酸;
124)[4-(二甲基氨基)-6-吗啉-4-基-2-(4-{[(2E)-3-苯丙-2-烯酰基]氨基}苄基)嘧啶-5-基]乙酸;
125)(4-(二甲基氨基)-2-{4-[(3-苯氧基苯甲酰基)氨基]苄基}-6-吡咯烷-1-基嘧啶-5-基)乙酸;
126)(4-(二甲基氨基)-2-{4-[(4-苯氧基苯甲酰基)氨基]苄基}-6-吡咯烷-1-基嘧啶-5-基)乙酸;
127)[4-(二甲基氨基)-2-(4-{[(2E)-3-(4-甲氧基苯基)丙-2-烯酰基]氨基}苄基)-6-吗啉-4-基嘧啶-5-基]乙酸;
128)[4-(二甲基氨基)-2-(4-{[(2E)-3-(2-甲氧基苯基)丙-2-烯酰基]氨基}苄基)-6-吗啉-4-基嘧啶-5-基]乙酸;
129)[2-{4-[(4-氯苯甲酰基)氨基]苄基}-4-(二甲基氨基)-6-吡咯烷-1-基嘧啶-5-基]乙酸;
130)[4-甲基-2-[4-(2-萘甲酰氨基)苄基]-6-(1-吡咯烷基)-5-嘧啶基]乙酸;
131)[2-{4-[(3,4-二氯苯甲酰基)氨基]苄基}-4-甲基-6-(1-吡咯烷基)-5-嘧啶基]乙酸;
132){4-(二甲基氨基)-6-甲基-2-[4-(2-萘甲酰氨基)苄基]嘧啶-5-基}乙酸;
133)[2-{4-[(3,4-二氯苯甲酰基)氨基]苄基}-4-(二甲基氨基)-6-甲基嘧啶-5-基]乙酸;
134)[4-(二甲基氨基)-6-甲基-2-(4-{[(2E)-3-苯丙-2-烯酰基]氨基}苄基)嘧啶-5-基]乙酸;
135){4-(二甲基氨基)-6-(甲氧基甲基)-2-[4-(2-萘甲酰氨基)苄基]嘧啶-5-基}乙酸;
136)[4-(二甲基氨基)-6-(甲氧基甲基)-2-(4-{[4-(三氟甲基)苯甲酰基]氨基}苄基)-嘧啶-5-基]乙酸;
137){4-(二甲基氨基)-6-乙基-2-[4-(2-萘甲酰氨基)苄基]嘧啶-5-基}乙酸;
138)[4-(二甲基氨基)-6-乙基-2-(4-{[4-(三氟甲基)苯甲酰基]氨基}苄基)嘧啶-5-基]乙酸;
139){4-(二甲基氨基)-6-异丙基-2-[4-(2-萘甲酰氨基)苄基]嘧啶-5-基}乙酸;
140)[4-(二甲基氨基)-6-异丙基-2-(4-{[4-(三氟甲基)苯甲酰基]氨基}苄基)嘧啶-5-基]乙酸;
141)[2-(4-{[(苄氧基)羰基]氨基}苄基)-4-(二甲基氨基)嘧啶-5-基]乙酸;
142){4-(二甲基氨基)-2-[4-({[(4-氟苄基)氧基]羰基}氨基)苄基]-嘧啶-5-基}乙酸;
143)[2-(4-{[(苄氧基)羰基]氨基}苄基)-4-氯-6-(二甲基氨基)嘧啶-5-基]乙酸;
144){4-(二甲基氨基)-2-[4-({[(4-硝基苄基)氧基]羰基}氨基)苄基}-嘧啶-5-基}乙酸;
145){4,6-二氯-2-[4-(2-萘甲酰氨基)苄基]嘧啶-5-基}乙酸;
146)N-(4-{[5-(2-氨基-2-氧代乙基)-4-氯-6-(二甲基氨基)嘧啶-2-基]甲基}苯基)-2-萘甲酰胺;以及
147)N-(4-{[4-氯-6-(二甲基氨基)-5-(1H-四唑-5-基甲基)嘧啶-2-基]甲基}苯基)-2-萘甲酰胺。
以及它们的互变异构和立体异构形式及其盐。
式(I)的嘧啶衍生物显示出优良的CRTH2拮抗剂活性。因此,它们尤其适于预防和治疗与CRTH2活性相关联的疾病。
更特别地,式(I)的嘧啶衍生物有效治疗或避免变应性病症,如哮喘、过敏性鼻炎、特应性皮炎和过敏性结膜炎。
式(I)化合物还有效治疗或预防如Churg-Strauss综合征、窦炎、嗜碱细胞性白血症、慢性荨麻疹以及嗜碱性白细胞增多等疾病,因为此类疾病亦与CRTH2活性有关。
进一步地,本发明提供一种医药品,它包括上述的化合物以及任选药学上可接受的赋形剂。
烷基本身以及在烷氧基、烷酰基、烷氨基甲酰基、烷硫基、烷氨基、烷氨基羰基、烷氨基磺酰基、烷磺酰氨基、烷氧羰基、烷氧羰基-氨基以及烷酰基氨基中的“烷”和“烷基”代表一个直的或支的烷根,通常具有1-6个,优选1-4个并且特别优选1-3个碳原子,代表说明性和优选的甲基、乙基、正-丙基、异丙基、叔-丁基、正-戊基和正-己基。
烷氧基说明性及优选性地代表甲氧基、乙氧基、正-丙氧基、异丙氧基、叔-丁氧基、正-戊氧基和正-己氧基。
烷酰基说明性及优选性地代表乙酰基和丙酰基。
烷基氨基代表具有一或两个(独立选择)烷基取代基的烷基氨基,说明性和优选代表甲氨基、乙氨基、正-丙氨基、异丙氨基、叔-丁氨基、正-戊氨基、正-己基-氨基、N,N-二甲基氨基、N,N-二乙基氨基、N-乙基-N-甲基氨基、N-甲基-N-正-丙基氨基、N-异丙基-N-正-丙基-氨基、N-叔-丁基-N-甲氨基、N-乙基-N-正-戊基氨基和N-正己基-N-甲基氨基。
烷氨基羰基或烷氨基甲酰基代表一个具有一或两(独立选取)个烷基取代基的烷氨基羰基根,说明性地和优选代表甲基氨基羰基、乙基氨基羰基、正-丙基氨基羰基、异丙基氨基-羰基、叔-丁基氨基羰基、正-戊基氨基羰基、正-己基氨基羰基、N,N-二甲基-氨基羰基、N,N-二乙基氨基羰基、N-乙基-N-甲基氨基羰基、N-甲基-N-正丙基氨基羰基、N-异丙基-N-正丙基氨基羰基、N-叔-丁基-N-甲基氨基羰基、N-乙基-N-正戊基氨基-羰基以及N-正己基-N-甲基氨基羰基。
烷氨基磺酰基代表一个具有一或两个(独立选取)烷基取代基的烷氨基磺酰基,说明性和优选代表甲氨基磺酰基、乙氨基磺酰基、正-丙氨基磺酰基、异丙氨基磺酰基、叔-丁氨基-磺酰基、正-戊基氨基磺酰基、正-己基-氨基磺酰基、N,N-二甲基氨基磺酰基、N,N-二乙基氨基磺酰基、N-乙基-N-甲基氨基磺酰基、N-甲基-N-正-丙基氨基磺酰基、N-异丙基-N-正-丙基氨基磺酰基、N-叔-丁基-N-甲基氨基磺酰基、N-乙基-N-正戊基-氨基磺酰基和N-正-己基-N-甲基氨基磺酰基。
烷基磺酰氨基说明性地并优选代表甲基磺酰氨基、乙基-磺酰氨基、正-丙基磺酰氨基、异丙基磺酰氨基、叔-丁基-磺酰氨基、正-戊基磺酰氨基及正-己基磺酰氨基。
烷氧基羰基说明性地及优选地代表甲氧羰基、乙氧羰基、正-丙氧羰基、异丙氧羰基、叔-丁氧羰基、正-戊氧羰基及正-己氧羰基。烷氧羰基氨基说明性地并优选代表甲氧基羰基氨基、乙氧基羰基氨基、正-丙氧基羰基氨基、异丙氧基羰基氨基、叔-丁氧基羰基氨基、正-戊氧基羰基氨基及正-己氧基羰基氨基。
烷酰氨基说明性及优选性地代表乙酰氨基和乙基羰基氨基。
环烷基本身及在环烷氨基和在环烷羰基中的环烷基代表一个具有一般为3-8个并优选为5-7个碳原子的环烷基团,说明及优选代表环丙基、环丁基、环戊基、环己基和环庚基。
环烷基氨基代表一个具有一或多个(独立选取的)环烷基取代基的环烷基氨基,说明性及优选性地代表环丙基氨基、环-丁基氨基、环戊基氨基、环己基氨基和环庚基氨基。
环烷基羰基说明性和优选性地代表环丙基羰基、环丁基-羰基、环戊基羰基、环己基羰基和环庚基羰基。
芳基本身及在芳基氨基以及在芳基羰基中的芳基代表一个具有一般为6-14个碳原子的单-三环的芳基碳环基,说明及优选代表苯基、萘基和菲基。
芳基氨基代表一个具有一或二个(独立选取的)芳基取代基的芳基氨基,说明及优选代表苯氨基、联苯氨基和萘氨基。
芳基羰基说明性及优选性地代表苯基羰基和萘基羰基。
杂芳基本身及在杂芳氨基和杂芳羰基中的杂芳基代表一个具有通常为5-10并优选为5或6环原子以及最多为5个,优选为4个选自S,O和N组成的基团中的杂原子的单或双环基,说明及优选代表噻吩基、呋喃基、吡咯基、噻唑基、噁唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、吲哚基、吲唑基、苯并呋喃基、苯并噻吩基、喹啉基、异喹啉基。
杂芳基氨基代表一个杂芳基氨基,具有一或二个(独立选取的)杂芳基取代基,说明及优选代表噻吩氨基、呋喃氨基、吡咯基氨基、噻唑基氨基、噁唑基氨基、咪唑基氨基、吡啶基氨基、嘧啶基氨基、哒嗪基氨基、吲哚基氨基、吲唑基氨基、苯并呋喃基氨基、苯并苯硫基氨基、喹啉基氨基、异喹啉基氨基。
杂芳基羰基说明性及优选性地代表噻吩基羰基、呋喃基羰基、吡咯基羰基、噻唑基羰基、噁唑基羰基、咪唑基羰基、吡啶基羰基、嘧啶基羰基、哒嗪基羰基、吲哚基羰基、吲唑基羰基、苯并呋喃基-羰基、苯并苯硫基-羰基、喹啉基羰基、异喹啉基羰基。
杂环基本身及在杂环羰基中的杂环基代表一个单或多环,优选单或双环,非芳香的杂环基,具有通常4-10并优选5-8个环原子以及最多3个优选最多2个选自N、O、S、SO和SO2的杂原子和/或杂基团。杂环残基可被饱和或部分饱和。优选给出5-8员单环饱和的杂环基,具有最多2个选自由O、N和S组成的基团的杂原子,如说明和优选的四氢呋喃-2-基、吡咯烷-2-基、吡咯烷-3-基、吡咯啉基、哌啶基、吗啉基、全氢化氮杂基。
杂环羰基说明性和优选性地代表四氢呋喃-2-羰基、吡咯烷-2-羰基、吡咯烷-3-羰基、吡咯啉羰基、哌啶基羰基、吗啉羰基、全氢化氮杂羰基(perhydroazepinecarbonyl)。
本发明的实施方案
本发明的式(I)化合物可以但并不限于由合并几种已知方法制备。在一些实施方案中,作为起始原料或中间体使用的化合物的一个或多个取代基,如氨基、羰基和羟基,被本领域内一般技术人员已知的保护基有效保护。保护基的实例在“Protective Groups in OrganicSynthesis(3rd Edition)″by Greene and Wuts,John Wiley and Sons,NewYork 1999”中有描述。
本发明的式(I)化合物可以,但不限于,经由下列方法[A]、[B]、[C]、[D]、[E]、[F]、[G]、[H]、[I]或[J]制备。
[方法A]
式(I-a)的化合物(其中R3、R4及R5与上述定义一致并且R1a为
其中n和Y为如上所定义)可以,例如,通过下列过程以两步制备。
在步骤A-1中,式(IV)化合物(其中R1a、R3、R4和R5与上述定义一致并且Z1为C1-6烷基、苄基、4-甲氧基苄基或3,4-二甲氧基苄基)可通过式(II)(其中R3、R4、R5和Z1与上述定义一致)与式(III)化合物(其中R1a与上述定义一致并且L1代表一个离去基团包括,例如,卤素如氯、溴和碘原子,唑类(azole)如咪唑和三唑以及羟基)的反应制备。
该反应可以在溶剂中进行,所述溶剂包括,例如,卤代烃类如二氯甲烷、氯仿和1,2-二氯乙烷;醚类如乙醚、异丙醚、二氧六环和四氢呋喃(THF)以及1,2-二甲氧基乙烷;芳香烃如苯、甲苯和二甲苯;腈类如乙腈;酰胺类如N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMAC)和N-甲基吡咯烷酮(NMP);脲如1,3-二甲基-2-咪唑啉酮(DMI);亚砜类如二甲亚砜(DMSO)等。任选地,两种或多种上述所列的溶剂可以混合使用。
反应温度可任意设定,取决于被反应的化合物。反应温度通常,但并不限于,约在0℃-180℃,并且优选为约20℃-100℃。反应可以进行,通常为,30分钟至24小时并优选1-12小时。
该反应在碱存在下有利进行,包括,例如,碳酸钠、碳酸钾、吡啶、三乙胺和N,N-二异丙基乙基胺、二甲苯胺、二乙基苯胺及其它碱。
在式(III)化合物中(其中R1a为
或
其中的n和Y与上述定义一致)当L1代表羟基的情况下,式(IV)化合物(其中R3、R4、R5和Z1均与上述定义一致并且R1a为
其中的n和Y与上述定义一致)可通过式(II)化合物(其中R3、R4、R5和Z1与上述定义一致)与式(III)化合物使用一种偶合试剂包括,例如,碳二亚胺类如N,N-二环己基碳二亚胺和1-(3-二甲基氨丙基)-3-乙碳二亚胺、苯并三唑-1-基-氧基-三-吡咯烷-膦六氟磷酸酯(PyBOP)、二苯基磷酰叠氮化物的反应制备。N-羟基丁二酰亚胺、1-羟基苯并三唑单水合物(HOBt)等均可作为反应的加速剂。
该反应可以在一种溶剂中溶剂中进行,所述溶剂包括,例如,卤代烃如二氯甲烷、氯仿及1,2-二氯乙烷;醚类如乙醚、异丙醚、二氧六环和四氢呋喃(THF)以及1,2-二甲氧基乙烷;芳香烃如苯、甲苯和二甲苯;腈类如乙腈;酰胺类如N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMAC)和N-甲基吡咯烷酮(NMP);脲如1,3-二甲基-2-咪唑啉酮(DMI);亚砜类如二甲亚砜(DMSO);以及其它的溶剂。任选地,两种或多种上述所列的溶剂可以混合使用。
反应温度可任意设定,取决于被反应的化合物。反应温度通常,但并不限于,约在0℃-180℃,并且优选为约20℃-100℃。反应可以进行,通常为,30分钟至24小时并优选1-12小时。
在步骤A-2中,式(I-a)化合物(其中R1a、R3、R4和R5与上述定义一致)可通过去除式(IV)化合物(其中R1a、R3、R4、R5及Z1与上述定义一致)的保护基团Z1制备。
保护基团Z1的去除,可通过使用一种碱,包括,例如,氢氧化钠、氢氧化锂及氢氧化钾,或者一种酸包括,例如,HCl、HBr、三氟醋酸和BBr3进行。当Z为苄基、4-甲氧基苄基或3,4-二甲氧基苄基时,还可以通过使用催化剂包括,例如,钯碳和氢氧化钯氢化进行脱保护。当Z1为4-甲氧基苄基或3,4-二甲氧基苄基时还可通过使用一种试剂如四硝酸铈铵(CAN)或2,3-二氯-5,6-二氰基-1,4-苯醌(DDQ)进行脱保护。
该反应可以在溶剂中进行,包括,例如,卤代烃如二氯甲烷、氯仿及1,2-二氯乙烷;醚类如乙醚、异丙醚、1,4-二氧六环和四氢呋喃(THF)以及1,2-二甲氧基乙烷;芳香烃如苯、甲苯和二甲苯;N,N-二甲基甲酰胺(DMF)、二甲基乙酰胺(DMAC);1,3-二甲基-3,4,5,6-四氢-2(1H)-嘧啶酮(DMPU);1,3-二甲基-2-咪唑啉酮(DMI);N-甲基吡咯烷酮(NMP);亚砜类如二甲亚砜(DMSO);醇类如甲醇、乙醇、1-丙醇、异丙醇和叔-丁醇、水以及其它。任选地,两种或多种上述所列的溶剂可以混合使用。
反应温度可任意设定,取决于被反应的化合物。反应温度通常,但并不限于,约在0℃-180℃,并且优选为约20℃-100℃。反应可以进行,通常为,30分钟至24小时并优选1-12小时。
式(III)化合物可商业获取或者可通过常规方法合成。
[方法B]
式(I-b)化合物(其中R3、R4和R5如上述定义一致并且Z2为
或,
其中,n及Y如上述定义)可以,例如通过下列过程以两步制备。
在步骤B-1中,式(VI)化合物(其中R3、R4、R5、Z1及Z2如上述定义一致)可通过式(II)化合物(其中R3、R4、R5及Z1与上述定义一致)与式(V)化合物(其中Z2与上述定义一致)使用一种还原试剂如三乙酰氧基硼氢化钠反应制备。
该反应可以在路易斯酸或质子酸,如乙酸或氢氯酸,或者脱氢剂如分子筛存在下有利进行。
该反应可在溶剂中进行,包括,例如,卤代烃如1,2-二氯乙烷;醚类如乙醚、异丙醚、1,4-二氧六环和四氢呋喃(THF)以及1,2-二甲氧基乙烷;芳香烃如苯、甲苯和二甲苯以及其它。任选地,两种或多种上述所列的溶剂可以混合使用。
反应温度可任意设定,取决于被反应的化合物。反应温度通常,但并不限于,约在0℃-180℃,并且优选为约20℃-100℃。反应可以进行,通常为,30分钟至24小时并优选1-12小时。
在步骤B-2中,式(I-b)化合物(其中R3、R4、R5及Z2与上述定义一致)可通过与步骤A-2中制备式(I-a)化合物的类似方式去除式(IV)化合物(其中R3、R3、R4、Rs、Z及Z2与上述定义一致)的保护基团Z1来制备。
[方法C]
式(I-c)化合物(其中n、R3、R4、R5及Y与上述定义一致)可,例如,通过下列过程以两步制备。
在步骤C-1中,式(VIII)化合物(其中n、R3、R4、R5、Y及Z1与上述定义一致)可通过式(II)化合物(其中R3、R4、R5及Z1与上述定义一致)与式(VII)化合物(其中n和Y与上述定义一致)反应制得。该反应可以在溶剂包括,例如,卤代烃如二氯甲烷、氯仿及1,2-二氯乙烷;醚类如乙醚、异丙醚、1,4-二氧六环和四氢呋喃(THF)以及1,2-二甲氧基乙烷;芳香烃如苯、甲苯和二甲苯;腈类如乙腈;酰胺类如N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMAC)和N-甲基吡咯烷酮(NMP);脲如1,3-二甲基-2-咪唑啉酮(DMI);亚砜类如二甲亚砜(DMSO)以及其它溶剂中进行。任选地,两种或多种上述所列的溶剂可以混合使用。
反应温度可任意设定,取决于被反应的化合物。反应温度通常,但并不限于,约在0℃-180℃,并且优选为约20℃-100℃。反应可以进行,通常为,30分钟至24小时并优选1-12小时。
在步骤C-2中,式(I-c)化合物(其中n、R3、R4、R5及Y与上述定义一致)可通过与步骤A-2中制备式(I-a)化合物的类似方式去除式(VIII)化合物(其中n,R3、R4、R5、Y及Z1与上述定义一致)的保护基团Z来制备。
式(VII)化合物可商业获取或可通过常规方法合成。
[方法D]
式(I-d)化合物(其中n,R3、R4、R5及Y与上述定义一致)可,例如,通过下列过程以两步制备。
在步骤D-1中,式(X)化合物(其中n,R3、R4、R5、Y及Z1与上述定义一致)可通过式(II)化合物(其中R3、R4、R5及Z1与上述定义一致)与式(IX)化合物(其中n和Y与上述定义一致,并且L2代表一个离去基团包括,例如,卤原子如氯和溴)反应制得。
该反应可以在溶剂包括,例如,卤代烃如二氯甲烷、氯仿及1,2-二氯乙烷;醚类如乙醚、异丙醚、1,4-二氧六环和四氢呋喃(THF)以及1,2-二甲氧基乙烷;芳香烃如苯、甲苯和二甲苯;腈类如乙腈;酰胺类如N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMAC)和N-甲基吡咯烷酮(NMP);脲如1,3-二甲基-2-咪唑啉酮(DMI);亚砜类如二甲亚砜(DMSO)以及其它溶剂中进行。任选地,两种或多种上述所列的溶剂可以混合使用。
反应温度可任意设定,取决于被反应的化合物。反应温度通常,但并不限于,约在0℃-180℃,并且优选为约20℃-100℃。反应可以进行,通常为,30分钟至24小时并优选1-12小时。
在步骤D-2中,式(I-d)化合物(其中n、R3、R4、R5、及Y与上述定义一致)可通过与步骤A-2中制备式(I-a)化合物的类似方式去除式(VIII)化合物(其中n,R3、R4、R5、Y及Z1与上述定义一致)的保护基团Z1来制备。式(IX)化合物为商业获取或者可通过常规方式合成。
[方法E]
式(I-e)化合物(其中n,R3、R4、R5及Y与上述定义一致并且Q1代表-NH-、-N-C1-6烷基或-O-)可,例如,通过下列过程以两步制备。
在步骤E-1中,式(XII)化合物(其中n、Q1、R3、R4、R5、Y和Z1与上述定义一致)可经由式(II)化合物(其中R3、R4、R5及Z1与上述定义一致)与式(XI)化合物(其中n、Q1和Y与上述定义一致)并且包括,例如,芳基甲酰衍生物如苯甲酰氯;卤碳酰衍生物如光气、双光气及三光气;羰基重氮衍生物如1,1-羰基二咪唑(CDI)以及1,1’-羰基二(1,2,4-三唑)(CDT)等试剂反应制得。
该反应可以在溶剂,包括,例如,卤代烃如二氯甲烷、氯仿及1,2-二氯乙烷;醚类如乙醚、异丙醚、1,4-二氧六环和四氢呋喃(THF)以及1,2-二甲氧基乙烷;芳香烃如苯、甲苯和二甲苯;腈类如乙腈;酰胺类如N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMAC)和N-甲基吡咯烷酮(NMP);脲如1,3-二甲基-2-咪唑啉酮(DMI);以及其它溶剂中进行。任选地,两种或多种上述所列的溶剂可以混合使用。
反应温度可任意设定,取决于被反应的化合物。反应温度通常,但并不限于,约在0℃-180℃,并且优选为约20℃-100℃。反应可以进行,通常为,30分钟至24小时并优选1-12小时。
该反应可在,包括例如,有机胺如吡啶、三乙胺和N,N-二异丙基乙胺、二甲基苯胺、二乙基苯胺、4-二甲基氨基吡啶及其它碱存在下有利进行。
在步骤E-2-中,式(I-e)化合物(其中n、Q1、R3、R4、R5及Y与上述定义一致)可通过与步骤A-2中制备式(I-a)化合物的类似方式去除式(XII)化合物(其中n,Q1、R3、R4、Rs、Y及Z1与上述定义一致)的保护基团Z1来制备。
式(XI)化合物为商业获取或者可通过常规方式合成。
[方法F]
式(I-f)化合物(其中R1及R5与上述定义一致并且R3a除了卤素外具有与R3一样如上定义意义),可通过下列过程制备。
在步骤F-1中,式(XIII)化合物(其中R1、R5和Z1与上述定义一致)可经由式(II-a)化合物(其中R5及Z1与上述定义一致)以在步骤A-1,B-1,C-1,D-1及E-1中所描述的类似方法制备。
在步骤F-2中,式(XV)化合物(其中R1,R3a,R5和Z1与前面定义一致)可通过式(XIII)化合物(其中R1、R5及Z1与前面定义一致)与式(XIV)化合物(其中R3a与前面定义一致)的反应制备。
该反应可在无溶剂或在溶剂中进行,所述溶剂包括,例如,醚类如乙醚、异丙醚、二氧六环和四氢呋喃(THF)和1,2-二甲氧基乙烷;芳烃类如苯、甲苯和二甲苯;腈类如乙腈;亚胺类如N,N-二甲基甲酰胺(DMF),N,N-二甲基乙酰胺(DMAC)和N-甲基-吡咯烷酮(NMP);脲类如1,3-二甲基-2-咪唑啉酮(DMI);亚砜类如二甲亚砜(DMSO);以及其它溶剂。优选地,选自上面所列溶剂中的两种或多种溶液可以混合使用。
反应温度可以任选设定,取决于所反应的化合物。反应温度通常,但并不限于,约为0℃-180℃并且优选为约20℃-100℃。该反应可以进行,通常为30分钟至24小时并优选1-12小时。
该反应可在一种碱的存在下有利进行,例如,有机胺如吡啶,三乙胺、N,N-二异丙基乙胺、二甲基苯胺、二乙基苯胺及其它。
在步骤F-3中,式(1-f)化合物(其中R1、R3a和R5如前面定义一致)可通过以步骤A-2中式(I)化合物制备的类似方法去除式(XV)化合物(其中R1、R3a、R5和Z1如前面定义一致)的保护基Z1来制备。
式(XIV)化合物可商业获取或者可以通过常规方法合成。
[方法G]
式(I-g)化合物(其中R1、R3a和R5与上述定义一致并且R4a具有如上所定义的R4同样的意义除了卤素),可以通过下列过程制备。
在步骤G-1中,式(XVII)化合物(其中R1、R3a、R4a、R5和Z1与上述定义一致)可通过式(XV)化合物(其中R1、R3a、R5和Z1与上述定义一致)与式(XVI)化合物(其中R4a与上述定义一致)以在步骤F-2中所描述的制备式(XV)化合物的类似方法制备。
在步骤G-2中,式(I-g)化合物(其中R1、R3a、R4a和R5与前述定义一致)可通过在步骤A-2中制备式(I)化合物的类似方法去除式(XVII)化合物(其中R1、R3a、R4a、R5和Z1如前述定义一致)制备。
式(XVI)化合物可商业获取或可以通过常规方法合成。
[方法H]
式(I-h)化合物(其中R1、R3a和R5与上述定义一致),可通过下列过程制备。
在步骤H-1中,式(XVIII)化合物(其中R1、R3a、R5和Z1如上述定义一致)可通过采用催化剂,包括,例如,钯碳和铂碳,在碱如醋酸钾的存在下进行氢化还原式(XV)化合物(其中R1、R3a、R5和Z1如上述定义一致)制备。
该反应可在溶剂中,包括,例如,醚类如乙醚、异丙醚、二氧六环和四氢呋喃(THF)和1,2-二甲氧基乙烷;芳烃类如苯、甲苯和二甲苯;醇类如甲醇、乙醇、1-丙醇、异丙醇和叔-丁醇、水和其它溶剂中进行。
反应温度可任选设定,取决于被反应的化合物。反应温度通常,但并不限于,约为0℃-180℃并且优选为约20℃-100℃。该反应可以进行,通常为30分钟至24小时并优选1-12小时。
在步骤H-2中,式(I-h)化合物(其中R1、R3a和R5与上述定义一致)可通过以步骤A-2中制备式(I)化合物的类似方法去除式(XVIII)化合物(其中R1、R3a、R5和Z1如前面定义一致)的保护基Z1来制备。
[方法I]
式(I-i)化合物(其中R3、R4和R5如前面定义一致,R1a代表
或
其中的n和Y如上述定义一致并且Z3代表氢或C1-5烷基)可通过下列程序制备。
在步骤I-1中,式(XX)化合物(其中R3、R4、R5、Z1和Z3如上述定义一致)可通过式(II)化合物(其中R3、R4、R5和Z1如上述定义一致)与式(XIX)化合物(其中Z3与上述定义一致)以在步骤B-1中制备式(VI)化合物的类似方法制备。
在步骤I-2中,式(XXII)化合物(其中R3、R4、R5、Z1和Z3如上述定义一致并且R1a代表
其中的n和Y如上述定义一致)可通过式(XX)化合物(其中R3、R4、R5、Z1和Z3如上述定义一致)与式(XXI)化合物(其中R1a和L1与上述定义一致)以在步骤A-1中制备式(IV)化合物的类似方法制备。
在步骤I-3中,式(I-i)化合物(其中R1a、R3、R4、R5和Z3如上述定义一致)可通过步骤A-2中制备式(I)化合物的相同方法去除式(XXII)化合物(其中R1a、R3、R4、R5、Z1和Z3与前面定义一致)的保护基Z1来制备。
式(XIX)和(XXI)化合物可商业获取或可通过常规方法合成。制备式(II-a)、(II-b)、(II-c)及(II-d)的起始化合物
式(II-b)化合物(其中R3a、R4a、R5和Z1如前所定义)可以,例如通过下列过程制备。
在步骤i-1中,式(XXIV)化合物(其中R3a、R5和Z1如上述定义一致)可通过式(XXIII)化合物(其中R5和Z1如上述定义一致)与式(XIV)化合物(其中R3a与上述定义一致)以在步骤F-2中所描述的制备式(XV)化合物的类似方法制备。
在步骤i-2中,式(XXV)化合物(其中R3a、R4a、R5和Z1与上述定义一致)可通过式(XXIV)化合物(其中R3a、R5和Z1与上述定义一致)与式(XVI)化合物(其中R4a与上述定义一致)以在步骤G-1中所描述的制备式(XVII)化合物的类似方法制备。
在步骤i-3中,式(II-b)化合物(其中R3a、R4a、R5和Z1如上述定义一致)可通过采用试剂包括,例如,金属如锌和铁在酸,包括,例如,氢氯酸和乙酸,或氯化亚锡的存在下还原式(XXV)化合物(其中R3a、R4a、R5和Z1与上述定义一致)的硝基制备,或者通过采用催化剂,包括,例如,钯碳和铂碳进行氢化制得。
该反应可以在溶剂中,包括,例如,醚类如乙醚、异丙醚、二氧六环和四氢呋喃(THF)和1,2-二甲氧基乙烷;芳烃类如苯、甲苯和二甲苯;醇类如甲醇、乙醇、1-丙醇、异丙醇和叔-丁醇、水和其它溶剂中进行。
反应温度可任意设定,取决于被反应的化合物。反应温度通常,但并不限于,约为0℃-180℃并且优选为约20℃-100℃。该反应可以进行,通常为30分钟至24小时并优选1-12小时。
在步骤i-4中,式(II-a)化合物(其中R5和Z与前面定义一致)可通过以步骤i-3中所描述的制备式(II-b)的类似方法还原式(XXIH)化合物(其中R5和Z,与前面定义一致)中的硝基制备。
在步骤i-5中,式(II-c)化合物(其中R3a、R5和Z1与前面定义一致)可通过以步骤i-3中所描述的制备式(II-b)的类似方法还原式(XXIV)化合物(其中R3a、R5和Z1与前面定义一致)中的硝基制备。
在步骤i-6中,式(II-d)化合物(其中R3a、R5和Z1与上述定义一致)可通过采用催化剂,包括,例如,钯碳和铂碳,在碱,如醋酸钾的存在下氢化还原式(XXIV)化合物(其中R3a、R5和Z1与上述定义一致)中的硝基和氯基制备。
该反应可以在溶剂中,包括,例如,醚类如乙醚、异丙醚、二氧六环和四氢呋喃(THF)和1,2-二甲氧基乙烷;芳烃类如苯、甲苯和二甲苯;醇类如甲醇、乙醇、1-丙醇、异丙醇和叔-丁醇、水和其它溶剂中进行。
反应温度可任意设定,取决于被反应的化合物。反应温度通常,但并不限于,约为0℃-180℃并且优选为约20℃-100℃。该反应可以进行,通常为30分钟至24小时并优选1-12小时。
制备式(XXIII)化合物
式(XXIII)化合物(其中R5和Z1如上述定义一致)可以,例如,通过下列过程制备。
在步骤ii-1中,式(XXVIII)化合物(其中R5和Z1与上述定义一致)可通过式(XXVI)化合物(其中R5与上述定义一致)与式(XXVII)化合物(其中Z1与上述定义一致并且Z3为C1-6烷基)的反应制备。该反应可在碱,如甲氧基钠存在下有利进行。
该反应可在溶剂,包括,例如,醇类如甲醇、乙醇、1-丙醇、异丙醇和叔-丁醇存在下有利进行。
反应温度可任选设定,取决于被反应的化合物。反应温度通常,但并不限于,约为0℃-180℃并且优选为约20℃-100℃。该反应可以进行,通常为30分钟至24小时并优选1-12小时。
在步骤ii-2中,式(XXIII)化合物(其中R5和Z1与上述定义一致)可以,例如,通过式(XXVIII)化合物(其中R5和Z1,与上述定义一致)与适合的卤化试剂,包括,例如,POCl3、PCl5等进行反应制备。
该反应可以在没有溶剂或在溶剂,包括,例如,卤代烃如二氯甲烷、氯仿和1,2-二氯乙烷;芳烃如苯、甲苯和二甲苯等中进行。任选地,选自上述所列中的两种或多种溶剂可以混合使用。
该反应可在碱,包括,例如,吡啶、三乙胺和N,N-二异丙基乙胺、N,N-二甲基苯胺、二乙基苯胺等存在下有利进行。
反应温度可任选设定,取决于被反应的化合物。反应温度通常,但并不限于,约为0℃-180℃并且优选为约20℃-100℃。该反应可以进行,通常为30分钟至24小时并优选1-12小时。
式(XXVI)和(XXVII)化合物可商业获取或可通过常规方法合成。
式(II-e)化合物的制备
式(II-e)化合物(其中R3a、R5和Z1与上述定义一致并且R4b为C1-6烷基,任选被单-、双-或三-卤素取代)可,例如,通过下列过程制备。
在步骤iii-1中,式(XXX)化合物(其中R4b、R5和Z1与上述定义一致)可通过式(XXVI)化合物(其中R5与上述定义一致)与式(XXIX)化合物(其中R4b、Z1和Z3与上述定义一致)以步骤ii-1中所描述的制备式(XXVIII)化合物的类似方法反应制备。
在步骤iii-2中,式(XXXI)化合物(其中R4b、R5和Z1与上述定义一致)可通过式(XXX)化合物(其中R4b、R5和Z1与上述定义一致)与合适的卤代试剂通过和在步骤ii-2中所描述的制备式(XXIII)化合物的类似方法反应制备。
在步骤iii-3中,式(XXXII)化合物(其中R3a、R4b、R5和Z1与上述定义一致)可通过式(XXXI)化合物(其中R4b、R和Z与上述定义一致)与式(XIV)化合物(其中R3a与上述定义一致)以在步骤F-2中所描述的制备式(XV)化合物的类似方法进行反应制备。
在步骤iii-4中,式(II-e)化合物(其中R3a、R4b、R5和Z1与上述定义一致)可通过以在步骤i-3中所描述的制备式(II-b)化合物的方法还原式(XXXII)(其中R3a、R4b、R5和Z1与上述所描述的一致)中的硝基制备。
式(XXIX)化合物为商业获取或可通过常规方法合成。
[方法J]
式(I-j-2)、(I-j-3)和(I-j-4)化合物可通过下列过程制备。
在步骤J-1中,式(Ij-2)化合物(其中R1、R2、R3、R4和R5与上述定义一致)可通过式(Ij-1)化合物(其中R’、R2、R3、R4和R5与上述定义一致)与氨水反应制备。
可以采用试剂,包括,例如,芳香甲酯衍生物如苯基氯甲酯;卤代试剂如SOCl2和POCl3;羰基二唑衍生物如1,1-羰基二咪唑(CDI)以及1,1’-羰基二(1,2,4-三唑)(CDT)等,以活化式(Ij-1)化合物的羧基基团而进行该反应。
可以在,包括,例如,卤代烃如二氯甲烷、氯仿和1,2-二氯乙烷;醚类如乙醚、异丙醚、二氧六环和四氢呋喃(THF)及1,2-二甲氧基乙烷;芳烃如苯、甲苯和二甲苯;腈类如乙腈;亚胺类如N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMAC)和N-甲基吡咯烷酮(NMP);脲类如1,3-二甲基-2-咪唑啉酮(DMI)以及其它溶剂中进行该反应。优选地,选自上列两种或多种溶剂可以混合使用。
反应温度可任选设定,取决于被反应的化合物。反应温度通常,但并不限于,约为0℃-180℃并且优选为约20℃-100℃。该反应可以进行,通常为30分钟至24小时并优选1-12小时。
在步骤J-2中,式(Ij-3)化合物(其中R’、R2、R3、R4和R与上述定义一致)可通过式(I-j-2)化合物(其中R’、R2、R3、R4和R5与上述定义一致)采且一种试剂,包括,例如,三氟醋酐进行反应制备。
该反应可在无溶剂下或在溶剂中包括,例如,卤代烃如二氯甲烷、氯仿和1,2-二氯乙烷;醚类如乙醚、异丙醚、二氧六环、四氢呋喃(THF)以及1,2-二甲氧基乙烷;芳烃如苯、甲苯和二甲苯等溶剂中进行。
任选地,选自上列的两种或多种溶剂可以混合使用。
反应温度可任选设定,取决于被反应的化合物。反应温度通常,但并不限于,约为0℃-180℃并且优选为约20℃-100℃。该反应可以进行,通常为30分钟至24小时并优选1-12小时。
在步骤J-3中,式(Ij-4)化合物(其中R’、R2、R3、R4和R5与上述定义一致)可通过式(Ij-3)化合物(其中R’、R2、R3、R4和R5与上述定义一致)与一种试剂包括,例如,叠氮化钠进行反应制备。
该反应可在催化剂,包括,例如,二溴化锌以及其它等存在下有利进行。
该反应可在溶剂中,包括,例如,卤代烃如二氯甲烷、氯仿和1,2-二氯乙烷;醚类如乙醚、异丙醚、二氧六环、四氢呋喃(THF)以及1,2-二甲氧基乙烷;芳烃如苯、甲苯和二甲苯;醇类如甲醇、乙醇、1-丙醇、异丙醇和叔-丁醇、水等溶剂中进行。任选地,选自上列的两种或多种溶剂可以混合使用。
反应温度可任选设定,取决于被反应的化合物。反应温度通常,但并不限于,约为0℃-180℃并且优选为约20℃-100℃。该反应可以进行,通常为30分钟至24小时并优选1-12小时。
式(I-j-1)化合物可通过上述所描述的方法[A]、[B]、[C]、[D]、[E]、[F]、[G]、[H]或[I]合成。
式(I)所示的典型的盐包括本发明化合物与无机或有机酸,或者有机或无机碱反应所形成的盐。这些盐分别为已知的酸加成和碱加成盐。
形成酸加成盐的酸包括无机酸如,并不局限于,硫酸、磷酸、氢氯酸、氢溴酸、氢碘酸等,以及有机酸如,并不局限于,对-甲苯磺酸、甲磺酸、乙二酸、对-溴苯磺酸、碳酸、丁二酸、柠檬酸、苯甲酸、乙酸等。
碱加成盐包括那些从无机碱,如,并不局限于,氢氧化铵、碱金属氢氧化物、碱土金属氢氧化物、碳酸盐、碳酸氢盐等所衍生的盐。无机碱的实例包括,氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、碳酸氢钠、碳酸氢钾、氢氧化钙、碳酸钙等。
本发明的化合物或其盐,取决于它的取代基,可被修饰以形成较低烷基酯或已知的其它酯;并且/或水合物或其它溶剂化物。那些酯、水合物以及溶剂化物均包括在本发明的范围内。
本发明的化合物还可用于形成包括酯类的前药。这些可以作为包含羧基化合物前药的酯类的实例可在由E.B.Roche,Pergamon Press,New York(1987)所著的“在药物设计中的生物反转载体:理论及应用”(Bioreversible Carriers in Drug Design:Theory and Application″,edited by E.B.Roche,Pergamon Press,New York(1987))中第14-21页中的找到。代表性的羧基保护基团为C1-C8烷基(如,甲基、乙基或第三丁基等);卤烷基;烯基;环烷基烷基和取代的衍生物,如环己基甲基、环戊基甲基及类似物;芳烷基,例如,苯乙基或苄基及其取代衍生物,如烷氧基苯甲基等;5-吲哚基等;二烷基氨烷基(如二甲基氨基乙基等);烷酰基氧基烷基基团,如乙酰氧基甲基、丁酰氧基甲基、戊酰氧基甲基、异丁酰氧基甲基、异戊酰氧基甲基、1-(丙酰氧基)-1-乙基、1-(新戊酰氧基)-1-乙基、1-甲基-1-(丙酰氧基)-1-乙基、新戊酰氧基甲基、丙酰氧基甲基等;环烷酰基氧基烷基基团,如环丙基羰基氧基甲基、环丁基羰基氧基甲基、环戊基羰基氧基甲基、环己基羰基氧基甲基等;芳酰基氧基烷基,如苯甲酰氧基甲基、苯甲酰基氧基乙基等;芳烷基羰基氧基烷基,如苯甲基羰基氧基甲基、2-苯甲基羰基氧基乙基等;烷氧基羰基烷基,如甲氧基羰基甲基、环己基氧基羰基甲基、1-甲氧基羰基-1-乙基等;烷氧基羰基氧基烷基,如甲氧羰基氧基甲基、叔-丁氧羰基氧基甲基、1-乙氧基羰基氧基-1-乙基、1-环己基氧基羰基氧基-1-乙基等;烷氧基羰基-氨基烷基,如叔-丁氧基羰基氨基甲基等;烷基氨基羰基氨烷基,如甲氨基羰基氨甲基等;烷酰基氨基烷基,如乙酰基氨基甲基等;杂环羰基氧基烷基,如4-甲基哌嗪基羰基氧基甲基等;二烷基氨基羰基烷基,如二甲基氨基羰基甲基、二乙基氨基羰基甲基等;(5-(低级烷基)-2-氧代-1,3-二氧杂环戊烯-4-基)烷基,如(5-叔-丁基-2-氧代-1,3-二氧杂环戊烯-4-基)甲基等;以及(5-苯基-2-氧代-1,3-二氧杂环戊烯-4-基)烷基,如(5-苯基-2-氧代-1,3-二氧杂环戊烯-4-基)甲基等。
本发明的化合物可以以口服剂型给药,如,非局限于,普通和肠衣片、胶囊、丸剂、散剂、粒剂、酏剂、酊剂、溶液剂、混悬剂、糖浆剂、固体和液体气雾剂及乳剂。它们还可以以非肠道剂型给药,如,非局限于,静脉内、腹膜内、皮下、肌内等对于药学领域内一般技术人员所熟知的剂型。本发明的化合物可以通过局部使用适合的鼻内载体以鼻内剂型给药,或者使用领域内一般技术人员熟知的透皮传输系统通过透皮途径给药
本发明化合物的剂量方案由本领域普通技术人员选择,考虑到多种因素,包括但不限于,年龄、体重、性别以及接受者的医疗条件、被治疗病症的严重性、给药途径、接受者的代谢水平和排泄功能、所采用的剂型、所采用的特定的化合物及其盐。
本发明的化合物优选在给药前用一种或多种药学上可接受的赋形剂配制。赋形剂为惰性的物质例如但不限于,载体、稀释剂、调味剂、甜味剂、润滑剂、加溶剂、混悬剂、粘合剂、片剂崩解剂以及封包材料。
然而本发明的另一个实施方案为包含本发明化合物以及一个或多个药学上可接受的、与制剂中的其它成分兼容并且对受试者无害的赋形剂。本发明的药物剂型通过将有效量的本发明化合物与一或多个药学上可接受的赋形剂合并而制备。在制备本发明组合物时,活性成分可以与稀释剂混合或包入载体中,其可以以胶囊、药囊、纸或其它容器形态。该载体可以作为稀释剂,其可以为固体、半固体、或作为媒介的液体物质、或可为片剂、丸剂、散剂、锭剂、酏剂、混悬剂、乳剂、溶液剂、粮桨剂、气雾剂、软膏形式,其中含有例如,最多达10%重量的活性化合物、软和硬明胶胶囊、栓剂、无菌注射溶液以及无菌分装粉末。
对于口服给药,该活性成分可以与一种口服的、无毒的、药学上可接受的载体,例如但不限于,乳糖、淀粉、蔗糖、葡萄糖、碳酸钠、甘露糖醇、山梨醇、碳酸钙、磷酸钙、硫酸钙、甲基纤维素等;任选与崩解剂,例如但不限于,玉米、淀粉、甲基纤维素、琼脂膨润土、黄原胶、海藻酸等;以及,任选地,与粘合剂,例如但不限于,明胶、天然糖、β-乳糖、玉米甜味剂、天然及合成的树胶、阿拉伯胶、黄芪胶、藻酸钠、羧甲基纤维素、聚乙烯乙二醇、蜡等;以及,任选地,润滑剂,例如但不限于,硬脂酸镁、硬脂酸钠、硬脂酸、油酸钠、苯甲酸钠、乙酸钠、氯化钠、滑石粉等。
在粉末剂中,所述载体可以为与均匀分布的活性成分混合的均匀分布的固体。活性成分可以以适合的比率与具有粘合性质的载体混合并且被压缩为所需产品片剂的形状与大小。
粉末剂及片剂优选含有从约1-99%重量百分比的活性成分,该活性成分为本发明的新型组合物。适合的固体载体为羧甲基纤维素镁、低熔点石蜡以及椰子油。
无菌液体制剂包括混悬剂、乳剂、糖浆剂及酏剂。该活性成分可被溶解或混悬在药学可接受载体中,如无菌水、无菌有机溶剂或者无菌水和无菌有机溶剂二者的混合物。
该活性成分还可溶解在一种适宜的有机溶剂中,例如,含水丙二醇中。其它组合物可通过将均匀分布的活性成分分散在淀粉或羧甲基纤维素钠水溶液或者在一种适宜的油中。
该剂型可以为单位剂量形式,其为包含单位剂量的物理分散单位,适于在人或其它哺乳动物中给药。单位剂型可为胶囊或片剂,或者为一定数量的胶囊或片剂。“单位剂量”指预先确定的本发明活性组合物的量,经计算以产生所需的治疗效果,与一或多个赋形剂结合在一起。在单位剂量中活性成分的量可以根据所涉及的特定治疗从约0.1毫克至1000毫克或以上变化或调整。
本发明化合物典型的口服剂量,当用于所指示的效应时,将会从约1mg/kg/天至约10mg/kg/天变化。本发明的化合物可以以单日剂量给药,或者日总剂量可以以分剂量,每日两次、三次或更多次给药。对于经由透皮剂型给药时,当然,为连续给药。
实施例
将以实施例的形式对本发明进行描述,但他们应该决不被解释为对本发明边界及范围的限制。
在下列实施例中,所有的定量数据,如果无另外声明,都涉及重量百分比。
质谱为使用电喷雾(ES)离子化技术(微质量平台LC)。熔点未校正过。液相色谱-质谱(LC-MS)数据记录在微质量平台LC上,该平台配有Shimadzu Phenomenex ODS柱(4.6mmX30mm),用乙腈-水(9∶1至1∶9)以1ml/min流速洗脱。TLC是在预制硅胶板(Merck硅胶60F-254)上进行。硅胶(WAKO-gel C-200(75-150pm))为所有柱色谱分离所使用。所有的化学品为试剂纯并且是购自Sigma-Aldrich、Wako纯化学工业有限公司、Great Britain、东京kasei kogyo有限公司、Nacalai tesque公司、Watanabe化学工业有限公司、Maybridge plc、Lancaster合成有限公司、Merck KgaA、德国Kanto化学有限公司。
1H NMR谱采用Bruker DRX-300(300MHz for′H)光谱仪或Brucker 500 UltraShieled(500MHz for 1H)记录。化学位移以每百万(ppm)单位报告,在Oppm以四甲基硅烷(TMS)作为内标。偶合常数(J)以赫兹给出并且缩写s、d、t、q、m及br分别指单峰、双重峰、三重峰、四重峰、多重峰及宽峰。质量测定由MAT95(Finnigan MAT)执行。
所有的起始原料为商业获取或者可使用参考文献中的制备方法制备。
本发明化合物的作用通过下列分析和药理试验检验。
实施例1
[制备人CRTH2-转染L1.2细胞系]
人CRTH2 cDNA是用基因特异性引物从人嗜酸性细胞的cDNA中扩增的,含有克隆进入pEAK载体(Edge Bio Systems)的限制性位点。人CRTH2 cDNA被克隆至哺乳动物表达载体pEAK中。该表达质粒(40μg)通过使用电穿孔仪(Gene Pulser II,BioRad)在250V/1,000μF以1×107细胞/500μl的细胞密度被转染至L1.2细胞内。转染一天后,将嘌呤霉素(1ug/ml,Sigma)加入细胞培养板中。转染两周后,挑出生长的细胞进行进一步的生长。
[测量在人CRTH2-转染的L1.2细胞系中Ca2+的转移](分析1)
Ca2+荷载缓冲液通过将5μl的氟-3AM(2mM在DMSO中,终1uM,分子探针)与10μl多聚醇F-127(分子探针)混合并将所得混合物稀释在10ml Ca2+分析缓冲液(20mM HEPES pH 7.6,0.1% BSA,1mM丙磺舒,Hanks溶液)。在实施例1中制备的CRTH2转染的细胞用PBS洗涤,以1×107细胞/毫升重悬于Ca2+荷载缓冲液中,并且于室温下孵育60分钟。孵育后,洗涤细胞并重悬于Ca2+分析缓冲液中,然后以2×105细胞/孔分配在透明底的96-孔板中(#3631,Costar)。细胞与多种浓度的被测化合物在室温下孵育5分钟。在FDSS6000,一种Ca2+-测量仪器(Hamamatsu Photonics,Hamamatsu,Japan)上测量发射的480nm的荧光。该转染子表明PGD2-诱导的Ca2+转移以剂量依赖方式。
[人CRTH2受体结合分析](分析2)
CRTH2转染子用PBS洗涤一次并且重悬于结合缓冲液(50mMTris-HCl,pH7.4,40mM MgCl2,0.1% BSA,0.1% NaN3)中。100μl的细胞悬浮液(2×105细胞)、[3H]-标记的PGD2以及多种浓度的被测化合物随后在96-孔U-底的聚丙烯板中混合并且于室温下孵育60分钟以使结合发生。孵育后,细胞悬液被转移至一过滤板上(#MAFB,Millipore)并且以结合缓冲液洗涤3次。将闪烁物加入过滤板中,并且留在过滤器上的放射活性以闪烁计数器TopCount(Packard)测量。非-特异性结合通过孵育在1μm未标记的PGD2存在下的细胞悬液以及[3H]-标记的PGD2来测量。嘌呤霉素抗性的L1.2转染子与[3H]-标记的PGD2高亲和性(KD=6.3nM)结合。
[人嗜酸性细胞的迁移分析](分析3)
通过将血放置在Mono-Poly Resolbing Medium(ICN Biomedicals,Co.Ltd)上并且在室温下以400×g离心30分钟从健康供体的肝素化静脉血中分离出人多形核细胞。离心后,通过采用抗-CD16-缀合的磁珠(Miltenyi Biotech GmbH)的CD16-阴性选择将嗜酸性粒细胞从较低层的多形核细胞中分离出。
人嗜酸性粒细胞用PBS洗涤并且以6×106细胞/ml重悬于趋化性缓冲液(20mM HEPES pH 7.6,0.1% BSA,Hanks溶液)中。50微升细胞悬液(3×105细胞/孔)随后被悬浮在96-孔趋化室(直径=5μm,#106-5,Neuro Prob)中的靠上的室中并且将30μl的配基溶液(PGD2,1nM,最终浓度)加入到较低的室中。细胞与多种浓度的待测化合物在37℃预先孵育10分钟。随后使趋化在潮湿的培养箱中在37℃、5%CO2下发生2小时。通过FACScan(Becton-Dickinson)计算细胞迁移至低室中的数量。
[人CD4+T细胞的迁移分析](分析4)
通过将血放置在Mono-Poly Resolbing Medium(ICN Biomedicals,Co.Ltd)上并且在室温下以400×g离心30分钟从健康供体的肝素化静脉血中分离出人单形核细胞。离心后,通过使用CD4+T细胞分离试剂盒(Miltenyi Biotec GmbH)将CD4+T淋巴细胞从单核细胞中分离出来。
用PBS洗涤人CD4+T淋巴细胞并以6×106细胞/毫升重悬于趋化缓冲液((20mM HEPES pH 7.6,0.1% BSA,Hanks溶液)中。50微升的细胞悬液(3×105细胞/孔)随后被分在96-孔趋化室(直径=3μm,#106-3,Neuro Prob)中的靠上的室中并且将30μl的配基溶液(PGD2,10nM,最终浓度)加入到较低的室中。细胞与多种浓度的待测化合物在37℃预先孵育10分钟。随后使趋化在潮湿的培养箱中在37℃、5%CO2下发生4小时。通过FACScan(Becton-Dickinson)计算细胞迁移至低室中的数量。
在下列实施例与实施例表格中显示了分析1中的分析结果。与化合物相对应的数据是通过固相合成得到,因此纯度水平为约40%-90%。由于实际原因,化合物被分组为如下4类活性:
IC50=A(<或=)10nM<B(<或=)100nM<C(<或=)500nM<D
本发明的化合物在上述所描述的分析2、3和4中表现出优秀的选择性及有效活性。
在熔点中所使用的Z在下列章节中指分解。除非另有说明,所有的无机酸和碱均为水溶液。洗脱浓度以%v/v表示。
制备化合物
[4,6-二氯-2-(4-硝基苄基)嘧啶-5-基]乙酸甲酯
将4-硝基苯基乙腈(81.07g,500mmol)悬浮在EtOH(300mL)中并加入二氧六环(300mL)。当所有固体溶解后,鼓入干燥的氯化氢气体1小时,然后在室温下搅拌15小时。随后加入乙醚并通过抽滤收集分离的固体,用乙醚洗涤。该中间体溶解在氨气饱和的乙醇中然后所得溶液在室温下搅拌14小时。真空除去过量溶剂,得2-(4-硝基苄基)乙亚胺酰胺(ethanimidamide)氢氯酸盐(73.65g,68%收率),为白色粉末。
1,1,2-乙烷三羧酸三乙酯(3.51mL,15.30mmol)与2-(4-硝基苯基)乙亚胺酰胺氢氯酸盐(46.95g,217.72mmol)在无水MeOH(300mL)中的混合物在室温下加入甲醇钠(3.8.82g,718.49mmol)并且所得混悬液回流16小时。冷却至r.t.后,反应混合物冷冻至0℃,用6N HCl酸化,抽滤收集所分离的固体并且用冷水洗涤。在高真空下于45℃干燥6小时后得[4,6-二羟基-2-(4-硝基苄基)嘧啶-5-基]乙酸甲酯(56.48g,81%收率),为灰白色粉末。
在室温、氩气流下将N,N-二甲基苯胺(8.17mL,64.44mmol)加入在POCl3(24mL)中的[4,6-二羟基-2-(4-硝基苄基)嘧啶-5-基]乙酸甲酯(4.12g,12.89mmol)混悬液中,所得黑色混悬液回流加热16小时。冷却至室温后,蒸除过量的POCl3并将所得黑色混悬物溶解在EtOAc中。该有机层然后依次用NaHCO3、水和饱和食盐水洗涤,用无水MgSO4干燥,过滤并真空浓缩。所得粗品溶解于二氯甲烷中并经过一短硅胶柱以得到纯的[4,6-二氯-2-(4-硝基苄基)嘧啶-5-基]乙酸甲酯(2.98g,65%收率)的类白色粉末。
[4-氯-6-(二甲基氨基)-2-(4-硝基苄基)嘧啶-5-基]乙酸甲酯
于室温、在氩气流下向在无水DMF(5mL)中的[4,6-二氯-2-(4-硝基苄基)嘧啶-5-基]乙酸甲酯(0.5g,1.40mmol)中的溶液中加入N,N-二异丙基乙基胺(0.054mL,3.09mmol)和二甲基胺氢氯酸盐(0.126g,1.54mmol)。所得溶液在85℃下搅拌16小时并在该时间将反应混合物浓缩至干并且残留物在硅胶上层析,以在正-己烷中的50%EtOAc洗脱,得[4-氯-6-(二甲基氨基)-2-(4-硝基苄基)嘧啶-5-基]乙酸甲酯(0.505g,99%收率),为棕色油状物。
[2-(4-氨基苄基)-4-氯-6-(二甲基氨基)嘧啶-5-基]乙酸甲酯
在室温下用10%Pd/C(0.100g)处理在无水THF(20mL)中的[4-氯-6-(二甲基氨基)-2-(4-硝基苄基)嘧啶-5-基]乙酸甲酯(1.00g,2.74mmol)溶液,并且所得黑色混悬液在氢气流下搅拌。13小时后,反应混合物在Celite上过滤。将滤液蒸发得粗品,为一澄清油状物,该油状物经过一短柱子以在正-己烷中的40%EtOAc洗脱,得[2-(4-氨基苄基)-4-氯-6-(二甲基氨基)嘧啶-5-基]乙酸甲酯(0.876g,95%收率),为一浅橙色油状物并于室温下慢慢固化。
实施例1-1
{4-氯-6-(二甲基氨基)-2-[4-(2-萘甲酰氨基)苄基]嘧啶-5-基}乙酸
在室温下在无水DMF(1mL)中的[2-(4-氨基苄基)-4-氯-6-(二甲基氨基)嘧啶-5-基]乙酸甲酯(0.090g,0.30mmol)和PyBOP(0.187g,0.36mmol)的混合物中加入2-萘甲酸(0.062g,0.36mmol)。所得反应混合物在室温下搅拌3小时并在该时间点加入水,所得水层用EtOAc萃取。合并的有机萃取物依次用0.5N HCl、饱和NaHCO3和饱和食盐水洗涤,用无水MgSO4干燥,过滤并真空浓缩,得{4-氯-6-(二甲基氨基)-2-[4-(2-萘甲酰氨基)苄基]嘧啶-5-基}乙酸甲酯,为一无色油状物。
将所得的{4-氯-6-(二甲基氨基)-2-[4-(2-萘甲酰氨基)苄基]嘧啶-5-基}乙酸甲酯溶解在THF(1mL)中并用1N NaOH(0.5mL)处理。所得两相混合物在室温下搅拌14小时并在该时间点将其倾入水中。分离的水相用EtOAc洗涤然后用1N HCl酸化后用EtOAc萃取。合并的有机萃取物用饱和食盐水洗涤,用无水MgSO4干燥,过滤并真空浓缩。所得粗品溶解在小体积的THF中并加入正-己烷。抽滤收集分离的固体,用正-己烷洗涤,并在真空下干燥得{4-氯-6-(二甲基氨基)-2-[4-(2-萘甲酰氨基)苄基]嘧啶-5-基}乙酸(0.038g,40%产率),为一白色粉末。
1H NMR(300MHz,DMSO-d6)δ:3.05(s,6H),3.67(s,2H),3.93(s,2H),7.32(d,J=8Hz,2H),7.59-7.68(m,2H),7.75(d,J=8Hz,2H),8.00-8.10(m,4H),8.57(s,1H),10.40(s,1H),12.77(bs,1H).
分子量:474.95
质谱:475
熔点:188Z℃
活性等级:A
表1所显示的化合物为实施例1-2至1-68中,以类似于实施例1-1中的方法合成的化合物。
表1
[2-(4-氨基苄基)-4-(二甲基氨基)嘧啶-5-基]乙酸甲酯
[4-氯-6-(二甲基氨基)-2-(4-硝基苄基)嘧啶-5-基]乙酸甲酯(3.00g,8.22mmol)与醋酸钾(2.42g,24.7mmol)在甲醇(30mL)中的混悬液用10% Pd/C(1.00g)处理。所得黑色混悬液在氢气流下搅拌15小时然后在Celite上过滤。残留物用甲醇洗涤并且滤液在分配于乙酸乙酯和水之前浓缩至干。分离的有机层随后用饱和NaHCO3和饱和食盐水洗涤,无水MgSO4干燥,过滤并真空浓缩。所得粗品色谱纯化(硅胶,1% MeOH在CHCl3中)即得到[2-(4-氨基苄基)-4-(二甲基氨基)嘧啶-5-基]乙酸甲酯(2.40g,97%收率),为棕色油状物。
实施例2-1
{4-(二甲基氨基)-2-[4-(2-萘甲酰氨基)苄基]嘧啶-5-基}乙酸
含有[2-(4-氨基苄基)-4-(二甲基氨基)嘧啶-5-基]乙酸甲酯(0.090g,0.30mmol)及PyBOP(0.187g,0.36mmol)的无水DMF(1mL)溶液,于室温下用2-萘甲酸(0.062g,0.36mmol)处理。所得反应混合物在用水稀释前搅拌3小时。所得猝灭过的反应混合物用EtOAc萃取并且合成的有机萃取物依次用0.5N HCl、饱和NaHCO3及饱和食盐水洗涤,用无水MgSO4干燥,过滤并浓缩至干,得粗品{4-(二甲基氨基)-2-[4-(2-萘甲酰氨基)苄基]嘧啶-5-基}乙酸甲酯。
将所得的{4-(二甲基氨基)-2-[4-(2-萘甲酰氨基)苄基]嘧啶-5-基}乙酸甲酯溶解在THF(6mL)中并用1N NaOH(3mL)处理。两相反应混合物在室温下搅拌14小时然后加入乙醚。虹吸出有机层并且残留的水层用6N HCl中和。抽滤收集分离的固体,用异丙基醚研制,过滤得到{4-(二甲基氨基)-2-[4-(2-萘甲酰氨基)苄基]嘧啶-5-基}乙酸(0.047g,36%产率)。
1H NMR(500MHz,DMSO-d6)δ:3.04(s,6H),3.65(s,2H),3.93(s,2H),7.32(d,J=9Hz,2H),7.60-7.66(m,2H),7.73(d,J=9Hz,2H),7.97(s,1H),8.00-8.09(m,4H),10.35(s,1H),12.54(s,1H).
分子量:440.51
质谱:441
熔点:210℃。
活性等级:A
表2列出了在实施例2-2至2-36中以实施例2-1中所描述的类似方法合成的化合物。
表2
[2-(4-氨基苄基)-4,6-二氯嘧啶-5-基]乙酸甲酯
在无水THF(50mL)中的[4,6-二氯-2-(4-硝基苄基)嘧啶-5-基]乙酸甲酯(2.00g,5.62mmol)溶液用Pd/C(10% Pd,0.200g)处理并且所得黑色混悬液于室温下在氢气流下搅拌。16小时后,所得反应混合物在Celite上过滤并且残留物用大量甲醇洗涤。滤液真空浓缩得粗品,为一黑黄色油状物,该油状物层析(硅胶,40% EtOAc在正-己烷中)得[2-(4-氨基苄基)-4,6-二氯嘧啶-5-基]乙酸甲酯(1.32g,72%产率),为一白色粉末。
{4,6-二氯-2-[4-(2-萘甲酰基氨基)苄基]嘧啶-5-基}乙酸甲酯
在无水THF(3mL)中的[2-(4-氨基苄基)-4,6-二氯嘧啶-5-基]乙酸甲酯(0.073g,0.23mmol)、2-萘酸(0.048g,0.028mmol)和WSCI(0.049g,0.026mmol)的混合物在室温下氩气流下搅拌10小时。投入EtOAc(80mL)并且有机相依次用饱和NaHCO3、水和饱和食盐水洗涤,无水硫酸镁干燥,过滤并真空浓缩。所得粗品为浅橙色油状物与二异丙醚研磨,抽滤收集所分离的固体得{4,6-二氯-2-[4-(2-萘甲酰基氨基)苄基]嘧啶-5-基}乙酸甲酯(0.090g,78%产率),为一白色粉末。
实施例3-1
{4-氯-2-[4-(2-萘甲酰基氨基)苄基]-6-吡咯烷-1-基嘧啶-5-基}乙酸
在无水DMF(2mL)中的{4,6-二氯-2-[4-(2-萘甲酰氨基)苄基]嘧啶-5-基}乙酸甲酯(0.100g,0.21mmol)、吡咯烷(0.019mL,0.23mmol)和N,N-二异丙基乙基胺(0.109mL,0.62mmol)混合物在80℃下搅拌5小时。冷却至室温后,蒸除溶剂并将所得残留物溶解在EtOAc中。该有机溶液依次用1N HCl、水和饱和食盐水洗涤,无水硫酸镁干燥,过滤并真空浓缩。用制备TLC纯化后得{4-氯-2-[4-(2-萘甲酰基氨基)苄基]-6-吡咯烷-1-基嘧啶-5-基}乙酸甲酯(0.100g,95%产率),得白色粉末。
在THF(3mL)中的{4-氯-2-[4-(2-萘甲酰基氨基)苄基]-6-吡咯烷-1-基嘧啶-5-基}乙酸甲酯(0.085g,0.17mmol)溶液用1N NaOH(1.5mL)处理并且两相混合物在室温下搅拌45小时。然后加入乙醚并且虹吸除去有机层。残余的水层冷却至0℃并用6N HCl酸化。抽滤收集所分离的固体并用水洗涤。在高真空下于45℃下干燥5小时,得{4-氯-2-[4-(2-萘甲酰氨)苄基]-6-吡咯-1-基嘧啶-5-基}乙酸(0.050g,56%产率),为一类白色固体。
1H NMR(300MHz,DMSO-d6)δ:1.86(bs,4H),3.59(bs,4H),3.78(s,2H),3.88(s,2H),7.32(d,J=9Hz,2H),7.63(m,2H),7.96-8.13(m,4H),8.57(s,1H),10.39(s,1H),12.72(s,1H).
分子量:500.99
质谱:501
熔点:196Z℃
活性等级:A
表3-1显示出在实施例3-2至3-16中以类似于实施例3-1中所描述的方法所合成的化合物。
表3
实施例4-1
{2-{4-[苯胺基羰基]氨基}苄基}-4-氯-6-[[2-(环戊基氨基)-2-氧代乙基](甲基)氨基]嘧啶-5-基]乙酸
在DMF(2mL)中的{2-(4-氨基苯甲基)-4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]嘧啶-5-基}乙酸甲酯(0.050g,0.11mmol)溶液用异氰酸苯酯(0.022mL,0.20mmol)处理。在室温下搅拌18小时后,加入乙酸乙酯并且有机相用8%NaHCO3及饱和食盐水洗涤,无水硫酸钠干燥,过滤并真空浓缩。所得粗品用二氯甲烷和二异丙醚研磨,得{2-{4-[苯胺基羰基]氨基}苄基}-4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]嘧啶-5-基]乙酸甲酯(0.055g,87%产率),为一白色粉末。
将1N NaOH(1.5mL)加入在THF(3mL)中的{2-{4-[(苯胺基羰基)氨基]苄基}-4-氯-6-[[2-(环戊基-氨基)-2-氧代乙基](甲基)氨基]嘧啶-5-基}乙酸甲酯(0.047g,0.083mmol)溶液中,并且两相混合物在室温下搅拌18小时。加入乙醚并虹吸除去有机层。残余的水层用6N HCl酸化,抽滤收集所分离的固体并用水和二异丙醚洗涤。在高真空下干燥5小时,得{2-{4-[(苯胺基羰基)氨基]苄基}-4-氯-6-[[2-(环戊基氨基)-2-氧代乙基](甲基)氨基]嘧啶-5-基}乙酸甲酯(0.026g,56%产率),为一白色粉末。
1H NMR(300MHz,DMSO-d6)δ:1.26-1.82(m,8H),3.08(s,3H),3.69(s,2H),3.81(s,2H),3.98(s,2H),4.00-4.18(m,1H),6.95(t,J=7Hz,1H),7.20(d,J=9Hz,2H),7.27(t,J=8Hz,2H),7.35(d,J=9Hz,2H),7.43(d,J=8Hz,2H),7.94(d,J=7Hz,1H),8.61(d,J=5Hz,2H),12.76(bs,1H).
分子量:551.05
质谱:551
熔点:>153Z℃
活性等级:B
表4中显示了在实施例4-2至4-4中以实施例4-1中所描述的类似方法合成的化合物。
表4
实施例5-1
{4-氯-2-{4-[(环己基甲基)氨基]苄基}-6-[[2-(环戊基氨基)-2-氧代乙基](甲基)氨基]嘧啶-5-基}乙酸
{2-(4-氨基苄基)-4-氯-6-[[2-(环戊基氨基)-2-氧代乙基](甲基)氨基]嘧啶-5-基}乙酸甲酯(0.150g,0.336mmol)、环己烷甲醛(cyclohexanecarbaldehyde)(0.042g,0.370mmol)、乙酸(0.019mL,0.336mmol)和三乙酰氧基硼氢化钠(0.107g,0.505mmol)在1,2-二氯乙烷(3mL)中的混合物于室温下搅拌过夜。
然后加入水并且该混合物用1N NaOH中和,随后用二氯甲烷萃取。合并的有机萃取物依次用水和饱和食盐水洗涤,用无水硫酸镁干燥,过滤并真空浓缩。所得粗品以制备TLC层析,得{4-氯-2-{4-[(环己基甲基)氨基]苄基}-6-[[2-(环戊基氨基)-2-氧代乙基](甲基)氨基]嘧啶-5-基}乙酸甲酯(0.092g,51%产率),为一无定形固体。
将{4-氯-2-{4-(环己基甲基)氨基}苄基}-6-[[2-(环戊基氨基)-2-氧代乙基](甲基)氨基]嘧啶-5-基}乙酸甲酯(0.083g,0.15mmol)的THF(5mL)溶液用1N NaOH(2.5mL)处理,将所得混合物在室温下搅拌13小时。随后用6N HCl中和,猝灭的反应混合物蒸发至干,将残余的残留物用EtOH溶解。过滤除去不溶有无机盐,滤液真空浓缩。所得粗品用制备TLC纯化,用在CH2Cl2中的15%EtOH洗脱,得{4-氯-2-{4-(环己基甲基)氨基}苄基}-6-[[2-(环戊基氨基)-2-氧代乙基](甲基)氨基]嘧啶-5-基}乙酸(0.023g,28%产率),为一澄清油状物。
1H NMR(300MHz,CDCl3)δ:0.85-1.32(m,4H),1.48-1.95(m,15H),2.80-3.05(m,7H),3.73(s,2H),3.89(s,2H),4.01(s,2H),6.51(d,J=9Hz,2H),6.69(d,J=7Hz,1H),7.13(d,J=7Hz,2H)
分子量:528.10
质谱:528
活性等级:D
在表5中显示了在实施例5-2至5-5中以类似于实施例5-1中所描述的类似方法合成的化合物。
表5
实施例6-1
{4-氯-2-{4-[(4-氯苯甲酰基)(甲基)氨基]苄基}-6-(二甲基氨基)嘧啶-5-基}乙酸
于0℃、氩气流下将甲酸(0.24mL,6.31mmol)滴加到醋酐(0.48mL,5.13mmol)中,随后将混合物在60℃加热2小时。冷却至室温后,加入THF(1mL),随后加入在THF(1ml)中的[2-(4-氨基苄基)-4-氯-6-(二甲基氨基)嘧啶-5-基]乙酸甲酯(0.660g,1.97mmol)溶液,然后搅拌3小时并浓缩至干。残余的残留物溶解在THF中并冷却至0℃,随后滴加硼烷二甲基硫复合物直至急剧的冒泡停止。将混合物温和回流14小时然后冷却至0℃。加入甲醇,该混合物在室温下搅拌1小时然后通过加入浓HCl至pH~5,再持续搅拌30分钟。真空蒸除溶剂,残余的残留物用水和1N NaOH碱化,水层用乙醚萃取。合并的有机层用无水硫酸钠干燥,过滤并浓缩至干得粗品,该粗品在硅胶上层析,用在二氯甲烷中的5%丙酮洗脱,得{4-氯-6-(二甲基氨基)-2-[4-(甲基氨基)苄基]嘧啶-5-基}乙酸甲酯(0.260g,38%产率),为一灰黄色油状物。
{4-氯-6-(二甲基氨基)-2-[4-(甲基氨基)苄基]嘧啶-5-基}乙酸甲酯(0.080g,0.23mmol)、1-羟基苯并三唑(0.043g,0.32mmol)、三乙胺(0.11mL,0.80mmol)及4-氯苯甲酸(0.043g,0.28mmol)的溶液在室温下用WSCI(0.066g,0.34mmol)处理并且反应混合物在室温下搅拌16小时。然后加入乙酸乙酯,有机层依次用0.5N HCl、饱和NaHCO3及饱和食盐水洗涤,无水硫酸钠干燥,过滤并浓缩至干,得粗品[4-氯-2-{4-[(4-氯苯甲酰基)(甲基)氨基]苄基}-6-(二甲基氨基)嘧啶-5-基]乙酸甲酯。
将该粗品[4-氯-2-{4-[(4-氯苯甲酰基)(甲基)氨基]苄基}-6-(二甲基氨基)嘧啶-5-基]乙酸甲酯溶解在THF(3mL)中并用1N NaOH(2mL)处理并在室温下搅拌24小时。加入乙醚并虹吸除去有机相。残余的水层用6N HCl酸化至pH~5,抽滤收集所分离的固体并用水和二异丙醚洗涤。于室温下高真空干燥4小时后得[4-氯-2-{4-[(4-氯苯甲酰基)(甲基)氨基]-苄基}-6-(二甲基氨基)嘧啶-5-基]乙酸(0.029g,27%产率),为一灰黄色粉末。
1H NMR(300MHz,DMSO-d6)δ:2.50(s,3H),2.98(s,6H),3.65(s,2H),3.88(s,2H),7.10(d,J=9Hz,2H),7.20(d,J=9Hz,2H),7.20-7.27(bs,4H),12.77(bs,1H).
分子量:473.36
质谱:473
熔点:>68Z℃
活性等级:C
以实施例6-1中所描述的类似方法,合成示于表6的实施例6-2至6-3中的化合物。
表6
p
实施例7-1
{4-(二甲基氨基)-6-吗啉-4-基-2-[4-(2-萘甲酰氨基)苄基]嘧啶-5-基}乙酸
于室温下向无水DMF(1mL)中的[2-(4-氨基苯甲基)-4-氯-6-(二甲基氨基)嘧啶-5-基]乙酸甲酯(0.090g,0.30mmol)和PyBOP(0.187g,0.36mmol)的混合物中加入2-萘甲酸(0.062g,0.36mmol)。所得反应混合物在室温下搅拌3小时并在该时间点加入水,所得水相用乙酸乙酯萃取。合并的有机萃取物依次用0.5N HCl、饱和NaHCO3及饱和食盐水洗涤,无水硫酸镁干燥,过滤并真空浓缩,得{4-氯-6-(二甲基氨基)-2-[4-(2-萘甲酰氨基)苄基]嘧啶-5-基}乙酸甲酯,为一无色油状物。
将在DMPU(2mL)中的4-氯-6-(二甲基氨基)-2-[4-(2-萘甲酰氨基)苄基]嘧啶-5-基}乙酸甲酯(0.094g,0.19mmol)及吗啉(0.048mL,0.55mmol)的混合物于封管中在150℃下加热15小时。冷却至室温后,将该反应混合物倾入水中并用乙酸乙酯萃取。合并的有机萃取物依次用1N HCl、饱和NaHCO3及饱和食盐水洗涤,用无水硫酸镁干燥,过滤并真空浓缩。所得粗品在硅胶上层析,用在二氯甲烷中的5%乙酸乙酯洗脱,得{4-(二甲基氨基)-6-吗啉-4-基-2-[4-(2-萘甲酰氨基)苄基]嘧啶-5-基}乙酸甲酯(0.096g,95%产率),为一油状物。
在MeOH(2mL)中的{4-(二甲基氨基)-6-吗啉-4-基-2-[4-(2-萘甲酰氨基)苄基]嘧啶-5-基}乙酸甲酯(0.096g,0.18mmol)溶液于室温下用1N NaOH(1mL)处理,所得混合物在60℃下加热5小时。冷却至室温后,减压蒸除易挥发物,残余的水层用乙醚洗涤并用1N HCl酸化。抽滤收集所分离的固体,用水洗涤并真空干燥,得{4-(二甲基氨基)-6-吗啉-4-基-2-[4-(2-萘甲酰氨基)苄基]嘧啶-5-基}乙酸(0.059g,64%产率),为一白色固体。
1H NMR(300MHz,DMSO-d6)δ:2.90(s,6H),3.17(m,4H),3.43(s,2H),3.65(m,4H),3.86(s,2H),7.34(d,J=9Hz,2H),7.59-7.68(m,2H),7.72(d,J=9Hz,2H),7.99-8.10(m,4H),8.56(s,1H),10.37(s,1H),12.20(bs,1H)
分子量:525.61
质谱:526
熔点:218Z℃
活性等级:B
实施例7-2
[4,6-双(二甲基氨基)-2-(4-{[4-(三氟甲基)苯甲酰基]氨基}苄基)嘧啶-5-基]乙酸
在DMPU(50mL)中的[4-氯-6-(二甲基氨基)-2-(4-硝基苄基)嘧啶-5-基]乙酸甲酯(7.75g,21.25mmol)、二甲基氯化铵(5.20g,63.74mmol)和N,N-二异丙基乙基胺(10.98g,84.98mmol)的混合物在封管中在150℃下加热15小时。冷却至室温后,将黑色混合物倾入水中并用乙酸乙酯萃取。合并的萃取物依次用水和饱和食盐水洗涤,用无水硫酸钠干燥,过滤并浓缩得粗品的黑色油状物。该粗品在硅胶上色谱纯化,用含有0.1%三乙胺的在正-己烷中的25%乙酸乙酯洗脱,得[4,6-双(二甲基氨基)-2-(4-硝基苯甲基)嘧啶-5-基]乙酸甲酯(5.44g,69%),为一红色油状物。
在甲醇(150mL)中的[4,6-双(二甲基氨基)-2-(4-硝基苯甲基)嘧啶-5-基]乙酸甲酯(5.00g,13.39mmol)溶液用钯炭(10%Pd,0.50g)处理,并且所得黑色混悬物在氢气流过滤层下、于室温下搅拌10小时。反应混合物经由一个Celite垫过滤,将滤液浓缩,得[2-(4-氨基苄基)-4,6-双(二甲基氨基)嘧啶-5-基]乙酸甲酯(4.53g,98%)。
在二氯甲烷(120mL)中的[2-(4-氨基苯甲基)-4,6-双(二甲基氨基)嘧啶-5-基]乙酸甲酯(4.00g,11.65mmol)溶液用4-三氟甲基苯甲酰氯(2.92g,13.98mmol)和三乙胺(3.54g,34.94mmol)处理。在室温搅拌1小时后,反应混合物在水和氯仿中分配并且水层用氯仿萃取。合并的有机萃取物用水和食盐水洗涤、硫酸钠干燥、过滤并真空浓缩得粗品,为一黄色固体,可从甲醇中重结晶得[4,6-双(二甲基氨基)-2-(4-{[4-(三氟甲基)苯甲酰基]氨基}-苯甲基)嘧啶-5-基]乙酸甲酯(4.34g,73%),为一白色固体。
[4,6-双(二甲基氨基)-2-(4-{[4-(三氟甲基)苯甲酰基]氨基}-苯甲基)嘧啶-5-基]乙酸甲酯(4.34g,8.42mmol)的20%四氢呋喃/甲醇(100mL)溶液用1N氢氧化钠溶液(25mL)处理。所得混合物在回流温度加热5小时然后在减压下旋转蒸发除去挥发物。所得水溶液用乙醚洗涤然后用1N氢氯酸在0℃下中和。通过抽滤收集分离沉淀并且用冷水洗涤。在甲醇中重结晶后得无色针状的[4,6-双(二甲基氨基)-2-(4-{[4-(三氟甲基)苯甲酰基]氨基}苯甲基)嘧啶-5-基]乙酸(3.86g,81%)。
1H NMR(500MHz,DMSO-d6):δ3.29(s,12H),3.44(s,2H),3.83(s,2H),7.33(d,J=8.2Hz,2H),7.66(d,J=8.2Hz,2H),7.90(d,J=8.2Hz,2H),8.13(d,J=8.2Hz,2H),10.28(s,1H),12.02(s,1H).
分子量:501.51
质谱:502(M+H)+
熔点:200Z℃。
活性等级:A
以实施例7-1或实施例7-2所描述的类似方法,合成表7中显示的在实施例7-3至7-30中的化合物。
表7
[4-氯-6-甲基-2-(4-硝基苄基)嘧啶-5-基]乙酸甲酯
2-(4-硝基苄基)乙亚胺酰胺氢氯酸盐(0.22g,1.0mmol)、乙酰-丁二酸二甲基酯(0.19g,1.0mmol)以及甲氧化钠(0.07g,1.3mmol)在MeOH(10mL)中的混合物回流15小时。冷却至室温后,抽滤收集分离的固体并且加入预先制备好的在甲醇(7.5mL)中的亚硫酰氯(0.65mL,8.9mmol)溶液。所得反应混合物回流16小时然后冷却至室温。加入丙酮并抽滤收集所析出的固体,用丙酮洗涤并真空干燥4小时得[4-羟基-6-甲基-2-(4-硝基苄基)-嘧啶-5-基]乙酸甲酯(0.12g,38%产率),为一白色固体。
在POCl3(2.33mL,25mmol)中的[4-羟基-6-甲基-2-(4-硝基苄基)嘧啶-5-基]乙酸甲酯(1.59g,5.0mmol)和N,N-二甲基苯胺(0.56mL,4.4mmol)溶液回流14小时。冷却至室温后,将反应混合物倾入冰-冻的饱和K2CO3中。所得水层用乙酸乙酯萃取并且合并的有机萃取物用饱和食盐水洗涤,无水硫酸镁干燥,过滤并真空浓缩。所得粗品经由硅胶层析,用20%乙酸乙酯/正己烷洗脱得[4-氯-6-甲基-2-(4-硝基苄基)嘧啶-5-基]乙酸甲酯(0.54g,32%产率)的白色粉末。
实施例8-1
{4-甲基-2-[4-(2-萘甲酰氨基)苄基]-6-吡咯烷-1-基嘧啶-5-基}乙酸
在DMF(10mL)中的[4-氯-6-甲基-2-(4-硝基苄基)嘧啶-5-基]乙酸甲酯(0.45g,1.3mmol)和吡咯烷(0.13mL,1.6mmol)溶液在室温下用三乙胺(0.22mL,1.6mmol)处理然后所得混合物在85℃搅拌13小时。冷却至室温后,将反应混合物倾入水中并用乙酸乙酯萃取。合并的有机萃取物用饱和NaHCO3和饱和食盐水洗涤,无水硫酸镁干燥,过滤并真空浓缩。所得粗品经由硅胶层析,用50%乙酸乙酯/二氯甲烷洗脱,得[4-甲基-2-(4-硝基苄基)-6-吡咯烷-1-基嘧啶-5-基]乙酸甲酯(0.40g,80%产率)的白色粉末。
在无水THF(2mL)中的[4-甲基-2-(4-硝基苄基)-6-吡咯烷-1-基嘧啶-5-基]乙酸甲酯(0.074g,0.20mmol)溶液中加入Pd/C(10% Pd,0.050g)并且所得黑色混悬液在氢气流下搅拌。1小时后,反应混合物在Celite上过滤并且滤液真空浓缩得[2-(4-氨基苄基)-4-甲基-6-吡咯烷-1-基嘧啶-5-基]乙酸甲酯。
在THF(1mL)中的[2-(4-氨基苄基)-4-甲基-6-吡咯烷-1-基嘧啶-5-基]乙酸甲酯(0.034g,0.10mmol)溶液在室温下用PyBOP(0.052g,0.10mmol)、2-萘甲酸(0.019g,0.11mmol)以及N,N-二异丙基乙胺(0.017mL,0.10mmol)处理。
在室温下搅拌17小时后,将该反应混合物倾入水中并用乙酸乙酯萃取。合并的有机萃取物用无水硫酸镁干燥,过滤并真空浓缩。残余的残留物在硅胶上层析,用60%乙酸乙酯/二氯甲烷洗脱,得{4-甲基-2-[4-(2-萘甲酰氨基)苄基]-6-吡咯烷-1-基嘧啶-5-基}乙酸甲酯(0.018g,36%产率),为一黄色油状物。
在THF(1mL)中的{4-甲基-2-[4-(2-萘甲酰氨基)苄基]-6-吡咯烷-1-基嘧啶-5-基}乙酸甲酯(0.018g,0.04mmol)溶液于室温下用1NNaOH(0.5mL)处理并且所得两相混合物在60℃下搅拌13小时。冷却至室温后,加入乙醚并将有机层虹吸除去。残余的水层用6N HCl酸化并抽滤收集分离的固体,用水洗涤并在高真空下干燥4小时,得{4-甲基-2-[4-(2-萘甲酰基-氨基)苄基]-6-吡咯烷-1-基嘧啶-5-基}乙酸(0.006g,37%产率)的白色固体。
1H NMR(300MHz,DMSO-d6)δ:1.86(bs,4H),2.29(s,3H),3.60(bs,4H),3.71(s,2H),3.94(s,2H),7.35(d,J=8Hz,2H),7.60-7.67(m,2H),7.75(d,J=8Hz,2H),8.00-8.10(m,4H),8.56(s,1H),10.40(s,1H),12.73(bs,1H)
分子量:480.57
质谱:481
熔点:184Z℃
活性等级:A
表8中显示了在实施例8-2至8-11中以实施例8-1所描述的类似方法合成的化合物。
表8
实施例9-1
[2-(4-{[(苄氧基)羰基]氨基}苄基)-4-(二甲基氨基)嘧啶-5-基]乙酸
向吡啶(1.21mL)和二氯甲烷(20mL)中的[2-(4-氨基苄基)-4-(二甲基氨基)嘧啶-5-基]乙酸甲酯(1.50g,4.99mmol)混合物中加入氯甲酸苄酯(1.07mL,7.49mmol)。在室温下搅拌14小时后,减压浓缩反应混合物。剩余残留物在硅胶上层析(NH硅胶,正己烷/乙酸乙酯2∶1),得[2-(4-{[(苯甲氧基)羰基]氨基}-苄基)-4-(二甲基氨基)嘧啶-5-基]乙酸甲酯(1.99g,92%)。
向四氢呋喃(8mL)和甲醇(15mL)中的[2-(4-{[(苯甲氧基)羰基]氨基}苄基)-4-(二甲基氨基)嘧啶-5-基]乙酸甲酯(1.51g,3.48mmol)的混合物中加入1N NaOH水溶液(5mL)。反应混合物在室温下搅拌20小时后减压浓缩。残留物用1N氢氯酸中和并减压浓缩。所得残留物用氯仿/甲醇(10∶1)溶解并且将不溶物滤出。滤液减压浓缩。残留固体用乙腈/乙醇(10∶1)重结晶,得[2-(4-{[(苯甲氧基)羰基]氨基}苄基)-4-(二甲基氨基)嘧啶-5-基]乙酸(1.14g,78%),为一白色固体。
1H NMR(500MHz,DMSO-d6):δ=3.02(s,6H),3.62(s,2H),3.86(s,2H),5.13(s,2H),7.21(d,J=8.5Hz,2H),7.31-7.42(m,7H),7.94(s,1H),9.64(s,1H),12.5(s,1H).
分子量:420.47
质谱:421(M+H)+
熔点:101-104℃
活性等级:B
实施例9-2
{4-(二甲基氨基)-2-[4-({[(4-氟苯甲基)氧基]羰基}氨基)苄基]嘧啶-5-基}乙酸
于0℃下向在吡啶(0.43mL)和二氯甲烷(5mL)中的[2-(4-氨基苄基)-4-(二甲基氨基)嘧啶-5-基]乙酸甲酯(400mg,1.33mmol)的混合物中加入氯甲酸苯酯(0.25mL,2.00mmol)。反应混合物在室温下搅拌15小时并在该时间减压浓缩。粗品氨基甲酸苯酯(即(4-(二甲基氨基)-2-{4-[(苯氧基羰基)氨基]苄基}嘧啶-5-基)乙酸甲酯)直接用于下步反应而无需进一步纯化。
将在N,N-二异丙基乙胺(0.17mL,0.95mmol)和四氢呋喃(2mL)中的(4-(二甲基氨基)-2-{4-[(苯氧基羰基)氨基]苄基}嘧啶-5-基)乙酸甲酯(100mg,0.24mmol)和4-氟苯甲醇(60mg,0.48mmol)的混合物回流24小时。冷却至室温后,反应混合物减压浓缩并且所得残留物经由制备TLC(氯仿/甲醇30∶1)纯化,得{4-(二甲基氨基)-2-[4-({[(4-氟苯甲基)氧基]羰基}氨基)苄基]嘧啶-5-基}乙酸甲酯(45mg,42%)。
向在甲氢呋喃(0.5mL)和甲醇(0.5mL)的{4-(二甲基氨基)-2-[4-({[(4-氟苯甲基)氧基]羰基}氨基)苄基]嘧啶-5-基}乙酸甲酯(45mg,0.10mmol)中加入1N NaOH水溶液(0.2mL)。所得反应混合物在室温下搅拌20小时并减压浓缩。残留物用1N氢氯酸中和并减压浓缩。所得残留物用氯仿/甲醇(10∶1)溶解并且过滤除去不溶物。滤液减压浓缩,得{4-(二甲基氨基)-2-[4-({[(4-氟-苯甲基)氧基]羰基}氨基)苄基]嘧啶-5-基}乙酸(35mg,80%)的灰黄色固体。
1H NMR(500MHz,DMSO-d6):δ=3.06(s,6H),3.66(s,2H),3.88(s,2H),5.11(s,2H),7.22(d,J=8.5Hz,4H),7.36(d,J=8.5Hz,2H),7.47(dd,J=8.5,8.5Hz,2H),7.96(s,1H),9.68(s,1H),12.6(s,1H).
分子量:438.46
质谱:439(M+H)+
熔点:95-97℃
活性等级:A
表9中显示了在实施例9-3至9-8中以实施例9-1或实施例9-2所描述的类似方法合成的化合物。
表9
实施例10
{4,6-二氯-2-[4-(2-萘甲酰氨基)苄基]嘧啶-5-基}乙酸
{4,6-二氯-2-[4-(2-萘甲酰氨基)苄基]嘧啶-5-基}乙酸甲酯的THF(1.5mL)溶液于室温下用1N NaOH(1mL)处理。在室温下搅拌16小时后,将反应混合物倾入水中并用乙酸乙酯洗涤。水层用1N HCl酸化并用乙酸乙酯反萃取。合并的有机萃取物用饱和食盐水洗涤,无水硫酸镁干燥,过滤并真空浓缩。残余的残留物在硅胶上纯化,用含有0.5%醋酸的10%THF二氯甲烷溶液洗脱,得{4,6-二氯-2-[4-(2-萘甲酰基-氨基)苄基]嘧啶-5-基}乙酸(0.007g,15%产率),为一白色固体。
1H NMR(300MHz,DMSO-d6)δ:3.87(s,2H),4.19(s,2H),7.31(d,J=9Hz,2H),7.59-7.68(m,2H),7.78(d,J=9Hz,2H),7.97-8.10(m,4H),8.57(s,1H),10.42(s,1H),13.03(bs,1H).
分子量:466.33
质谱:466
熔点:230Z℃
活性等级:A
实施例11
N-(4-{[5-(2-氨基-2-氧代乙基)-4-氯-6-(二甲基氨基)嘧啶-2-基]甲基}苯基)-2-萘甲酰胺
将1,1’-羰基二咪唑(diimidazole)(0.353mg,2.18mmol)加入{4-氯-6-(二甲基氨基)-2-[4-(2-萘甲酰氨基)苄基]嘧啶-5-基}乙酸(0.940g,1.98mmol)的THF(18mL)溶液中。反应混合物在室温下搅拌2小时后加入氨水溶液(28% NH3,0.94mL)。于室温下搅拌16小时后,将反应混合物在乙酸乙酯和水中分配,所分离的有机层用饱和食盐水洗涤,无水硫酸镁干燥,过滤并真空浓缩,残存的残留物经过一短的硅胶柱。经由PS-碳酸盐树脂去除酸性杂质后得N-(4-{[5-(2-氨基-2-氧代乙基)-4-氯-6-(二甲基氨基)嘧啶-2-基]甲基}苯基)-2-萘甲酰胺的白色固体(0.670g,71%)。
1H-NMR(500MHz,DMSO-d6):δ3.05(s,6H),3.54(s,2H),3.92(s,2H),7.07(s,1H),7.31(d,J=8.5Hz,2H),7.57(s,1H),7.62-7.65(m,2H),7.74(d,J=8.5Hz,2H),8.00-8.06(m,3H),8.07-8.09(m,1H),8.57(s,1H),10.37(s,1H)
分子量:473.96
质谱:474
熔点:189-190℃
活性等级:B
实施例12
N-(4-{[4-氯-5-(氰基甲基)-6-(二甲基氨基)嘧啶-2-基]甲基}苯基)-2-萘甲酰胺
在rt下向N-(4-{[5-(2-氨基-2-氧代乙基)-4-氯-6-(二甲基氨基)嘧啶-2-基]甲基}苯基)-2-萘甲酰胺(0.360g,0.76mmol)的吡啶(15mL)溶液中滴加三氟乙酸酐(0.161mL,1.14mmol),所得反应混合物在室温下搅拌15小时。真空除去挥发性溶剂并且所余残留物在乙酸乙酯和饱和氯化铵水溶液中分配。分离的有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤并真空浓缩。所得粗品用硅胶色谱纯化,用20%EtOH/CHCl3洗脱,得N-(4-{[4-氯-5-(氰甲基)-6-(二甲基-氨基)嘧啶-2-基]甲基}苯基)-2-萘甲酰胺的无定形固体(0.345g,100%)。
1H-NMR(500MHz,DMSO-d6):δ3.13(s,6H),3.68(s,2H),4.04(s,2H),7.41(d,J=8.5Hz,2H),7.56-7.63(m,4H),7.90-7.97(m,5H),8.37(s,1H)
分子量:455.95
质谱:456
熔点:无定形固体
活性等级:C
实施例13
N-(4-{[4-氯-6-(二甲基氨基)-5-(1H-四唑-5-基甲基)嘧啶-2-基}甲基)-苯基]-2-萘甲酰胺
将含有N-(4-{[4-氯-5-(氰基甲基)-6-(二甲基氨基)嘧啶-2-基]甲基}苯基)-2-萘甲酰胺(0.279g,0.61mmol)、叠氮化钠(0.159g,2.44mmol)、二溴化锌(0.345g,1.55mmol)、2-丙醇(2.7mL)、水(4mL)和1,4-二氧六环(5mL)的溶液加热回流24小时。冷却至室温后,加入EtOAc(4mL)并且继续搅拌2小时。将所得混合物倾入水中并抽滤收集所得沉淀,用水和甲醇洗涤,真空干燥得N-(4-{[4-氯-6-(二甲基氨基)-5-(1H-四唑-5-基甲基)嘧啶-2-基]甲基}-苯基)-2-萘甲酰胺的浅灰色固体(0.095g,31%)。
1H-NMR(500MHz,DMSO-d6):δ2.95(s,6H),3.93(s,2H),4.14(s,2H),7.32(d,J=8.5Hz,2H),7.16-7.64(m,3H),7.74(d,J=8.5Hz,2H),8.00-8.03(m,3H),8.07-8.09(m,2H),8.56(s,1H)
分子量:498.97
质谱:499
熔点:280z℃
活性等级:A
Claims (13)
1.一种式(I)嘧啶衍生物,其互变异构或立体异构形式,或其盐、酯或前药:
其中,
R1代表氢,
或
其中,
n 代表0-6的整数;
-Q1- 代表-NH-、-N(C1-6烷基)-或-O-;
Y 代表氢、C1-6烷基、任选被C1-6烷基取代的C3-8环烷基、被苯稠合的C3-8环烷基、芳基或杂芳基,其中所述芳基及杂芳基任选在可取代位置上被一或多个取代基取代,所述取代基选自氰基、卤素、硝基、胍基、吡咯基、氨磺酰基、C1-6烷氨基磺酰基、二(C1-6烷基)氨基磺酰基、苯氧基、苯基、氨基、C1-6烷氨基、二(C1-6)-烷氨基、C1-6烷氧基羰基、C1-6烷酰基、C1-6烷酰氨基、氨基甲酰基、C1-6烷基氨基甲酰基、二(C1-6烷基)-氨基甲酰基、C1-6烷基磺酰基、任选被单-、双-或三-卤素取代的C1-6烷基、任选被单-、双-或三-卤素取代的C1-6烷氧基以及任选被单-、双-或三-卤素取代的C1-6烷硫基,
或被1,3-二氧戊环稠合的芳基;
R2 代表氢或C1-6烷基;
R3 代表卤素、任选被单-、双-或三-卤素取代的C1-6烷氧基,
其中:
R3a和R3b独立代表C3-8环烷基或C1-6烷基,其中的C1-6烷基任选被羟基、羧基、C3-8环烷基、氨基甲酰基、C1-6烷基氨基甲酰基、芳基-取代的C1-6烷基氨基甲酰基、C1-6烷基氨基甲酰基、二(C1-6烷基)氨基甲酰基、C3-8环烷基氨基甲酰基、C3-8杂环基羰基、(C1-6)烷基氨基、二(C1-6)烷基氨基或C1-6烷氧基取代;
q 代表1-3的整数;
R3c 代表氢、羟基、羧基或任选被羟基、羧基或(苯基-取代的C1-6烷基)氨基甲酰基取代的C1-6烷基;
Xa 代表-O-、-S-或-N(R3d)-,
其中
R3d 代表C1-6烷基;
R4 代表氢、卤素、C1-6烷氧基、二(C1-6烷基)氨基或任选被C1-6烷氧基、或单-、双-或三-卤素取代的C1-6烷基;
R5 代表氢或C1-6烷基;并且
R6 代表羧基、氨甲酰、腈或四唑基。
2.权利要求1中要求保护的式(I)嘧啶衍生物,其互变异构或立体异构形式,或其盐、酯或前药,
其中,
R1代表
其中
n 代表0-2的整数;
-Q1- 代表-NH-、-N-(C1-6烷基)-或-O-;
Y 代表C1-6烷基、任选被C1-6烷基取代的C3-8环烷基、选自茚基和四氢化萘基的被苯稠合的C3-8环烷基、选自苯基和萘基的芳基或选自吲哚基、喹啉基、苯并呋喃基、呋喃基、苯并二氢吡喃基和吡啶基的杂芳基,其中所述芳基和杂芳基任选在可取代的位置被一或多个取代基取代,所述取代基选自氰基、卤素、硝基、吡咯基、氨磺酰基、C1-6烷氨基磺酰基、二(C1-6烷基)氨基磺酰基、苯氧基、苯基、C1-6烷基氨基、二(C1-6)烷基氨基、C1-6烷氧羰基、C1-6烷酰基氨基、氨基甲酰基、C1-6烷基氨基甲酰基、双-(C1-6烷基)氨基甲酰基、C1-6烷基磺酰基、任选被单-、双-或三-卤素取代的C1-6烷基、任选被单-、双-或三-卤素取代的C1-6烷氧基、任选被单-、双-或三-卤素取代的C1-6烷硫基;并且
R2 代表氢。
3.权利要求1中要求保护的式(I)嘧啶衍生物,其互变异构或立体异构形式,或其盐、酯或前药,
其中,
R3代表任选被单-、双-或三卤素-取代的C1-6烷氧基、
其中,
R3a和R3b独立代表C1-6烷基,任选被羟基、羧基、C3-8环烷基、氨基甲酰基、C1-6烷基氨基甲酰基、二(C1-6烷基)-氨基甲酰基、C3-8环烷基氨基甲酰基、C3-8杂环基羰基、(C1-6)烷基氨基、二(C1-6)烷基氨基或C1-6烷氧基取代;
R3c 代表氢、羟基、羧基或任选被羟基、羧基或(苯基-取代的C1-6烷基)氨基甲酰基取代的C1-6烷基;并且,
Xa 代表-O-、-S-或-N(R3d)-,
其中
R3d 代表C1-6烷基。
4.式(I-i)嘧啶衍生物,其互变异构或立体异构形式,或其盐、酯或前药;
其中,
R1代表
其中
n 代表0-2整数;
-Q1- 代表-NH-、-N(C1-6烷基)-、或-O-;
Y 代表苯基、萘基、吲哚基、喹啉基、苯并呋喃基、呋喃基或吡啶基,其中所述的苯基、萘基、吲哚基、喹啉基、苯并呋喃基、呋喃基和吡啶基任选在可取代的位置上被一或两个取代基取代,所述取代基选自氰基、卤素、硝基、苯氧基、苯基、任选被单-、双-或三-卤素取代的C1-6烷基、任选被单-、双-或三-卤素取代的C1-6烷氧基、任选被单-、双-或三-卤素取代的C1-6烷硫基;
R2 代表氢或C1-6烷基;
R3 代表,
其中
R3a及R3b 独立代表C3-8环烷基,或任选被C3-8环烷基、氨基甲酰基、C1-6烷基氨基甲酰基、苯基取代的C1-6烷基氨基甲酰基、C1-6烷基氨基甲酰基、二(C1-6烷基)-氨基甲酰基、C3-8环烷基氨基甲酰基、C3-8杂环基羰基、(C1-6)烷基氨基、二(C1-6)烷基氨基或C1-6烷氧基取代的C1-6烷基;
R3c 代表氢、羟基、羧基或任选被羟基、羧基或(苯基-取代的C1-6烷基)氨基甲酰基取代的C1-6烷基;
R4 代表氢、氯、溴、C1-6烷氧基、二(C1-6烷基)氨基或任选被C1-6烷氧基取代的C1-6烷基;
R5 代表氢或甲基;且
R6 代表羧基或四唑基。
5.权利要求1中要求保护的式(I)嘧啶衍生物,其互变异构或立体异构形式,或其盐、酯或前药,其中所述的式(I)嘧啶衍生物选自:
1){4-氯-6-(二甲基氨基)-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
2){4-氯-6-{甲基[2-氧代-2-(1-吡咯烷基)乙基]氨基}-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
3){4-氯-6-[[2-(异丙氨基)-2-氧代乙基](甲基)氨基]-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
4){4-氯-6-[[2-(环己氨基)-2-氧代乙基](甲基)氨基]-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
5){2-[4-(苯甲酰氨基)苄基]-4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-5-嘧啶基}乙酸;
6){4-氯-2-{4-[(环己基乙酰基)氨基]苄基}-6-[[2-(环戊氨基)-2-氧代乙基](甲基)-氨基]-5-嘧啶基}乙酸;
7)(4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-2-{4-[(3-苯基丙酰基)氨基]苄基}-5-嘧啶基)乙酸;
8)[4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-2-(4-{[(4-甲基苯基)乙酰基]-氨基}苄基)-5-嘧啶基]乙酸;
9)(4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-2-{4-[(2-喹啉基羰基)氨基]苄基}-5-嘧啶基)乙酸;
10)[4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-2-(4-{[(2E)-3-苯基-2-丙烯酰基]氨基}苄基)-5-嘧啶基]乙酸;
11){4-氯-2-{4-[(4-氯苯甲酰基)氨基]苄基}-6-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-5-嘧啶基}乙酸;
12){4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-2-{4-[(3,4-二氯苯甲酰基)氨基]苄基}-5-嘧啶基}乙酸;
13){4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-2-{4-[(4-甲氧基苯甲酰基)氨基]苄基}-5-嘧啶基}乙酸;
14){4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-2-{4-[(4-甲基苯甲酰基)氨基]苄基}-5-嘧啶基}乙酸;
15){4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-2-[4-(1-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
16){2-{4-[(1-苯并呋喃-2-基羰基)氨基]苄基}-4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-5-嘧啶基}乙酸;
17){4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-2-{4-[(1H-吲哚-2-基羰基)-氨基]苄基}-5-嘧啶基}乙酸;
18){4-氯-2-{4-[(4-氰基苯甲酰基)氨基]苄基}-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-5-嘧啶基}乙酸;
19){4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-2-{4-[(2,3-二氢-1H-茚-2-基乙酰基)氨基]苄基}-5-嘧啶基}乙酸;
20)[4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-2-(4-{[(3-苯氧基苯基)乙酰基]氨基}苄基)-5-嘧啶基]乙酸;
21)[4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-2-(4-{[(4-苯氧基苯基)乙酰基]-氨基}苄基)-5-嘧啶基]乙酸;
22)(4-氯-6-(二甲基氨基)-2-{4-[(2-喹啉基羰基)氨基]苄基}-5-嘧啶基)乙酸;
23)[4-氯-6-(二甲基氨基)-2-(4-{[(2E)-3-苯基-2-丙烯酰基]氨基}苄基)-5-嘧啶基]乙酸;
24)[4-氯-2-{4-[(3,4-二氯苯甲酰基)氨基]苄基}-6-(二甲基氨基)-5-嘧啶基]乙酸;
25)[4-氯-2-{4-[(4-氯苯甲酰基)氨基]苄基}-6-(二甲基氨基)-5-嘧啶基]乙酸;
26)(4-氯-6-(二甲基氨基)-2-{4-[(4-甲氧基苯甲酰基)氨基]苄基}-5-嘧啶基)乙酸;
27)[4-氯-6-(二甲基氨基)-2-(4-{[4-(二甲基氨基)苯甲酰基]氨基}苄基)-5-嘧啶基]-乙酸;
28)[4-氯-2-{4-[(3,4-二甲氧基苯甲酰基)氨基]苄基}-6-(二甲基氨基)-5-嘧啶基]乙酸;
29)[4-氯-6-(二甲基氨基)-2-(4-{[4-(三氟甲基)苯甲酰基]氨基}苄基)-5-嘧啶基]乙酸;
30)[4-氯-2-(4-{[(2E)-3-(4-氯苯基)-2-丙烯酰基]氨基}苄基)-6-(二甲基氨基)-5-嘧啶基]乙酸;
31)[2-{4-[(4-溴苯甲酰基)氨基]苄基}-4-氯-6-(二甲基氨基)-5-嘧啶基]乙酸;
32)[4-氯-2-{4-[(2,5-二氯苯甲酰基)氨基]苄基}-6-(二甲基氨基)-5-嘧啶基]乙酸;
33)[4-氯-2-{4-[(3,4-二氟苯甲酰基)氨基]苄基}-6-(二甲基氨基)-5-嘧啶基]乙酸;
34)[4-氯-2-{4-[(3,5-二氯苯甲酰基)氨基]苄基}-6-(二甲基氨基)-5-嘧啶基]乙酸;
35)[4-氯-2-{4-[(3-氯苯甲酰基)氨基]苄基}-6-(二甲基氨基)-5-嘧啶基]乙酸;
36)(4-氯-6-(二甲基氨基)-2-{4-[(3-甲氧基苯甲酰基)氨基]苄基}-5-嘧啶基)乙酸;
37){4-氯-6-(二甲基氨基)-2-[3-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
38)[2-(4-{[(4-叔-丁基环己基)羰基]氨基}苄基)-4-氯-6-(二甲基氨基)-5-嘧啶基]乙酸;
39)[4-氯-2-{4-[(4-硝基苯甲酰基)氨基]苄基}-6-(1-吡咯烷基)-5-嘧啶基]乙酸;
40)[2-(4-{[4-(乙酰氨基)苯甲酰基]氨基}苄基)-4-氯-6-(1-吡咯烷基)-5-嘧啶基]乙酸;
41)[4-氯-2-{4-[(4-苯氧基苯甲酰基)氨基]苄基}-6-(1-吡咯烷基)-5-嘧啶基]乙酸;
42)[4-氯-2-{4-[(4-异丙氧基苯甲酰基)氨基]苄基}-6-(1-吡咯烷基)-5-嘧啶基]乙酸;
43)[4-氯-6-(1-吡咯烷基)-2-(4-{[4-(1H-吡咯-1-基)苯甲酰基]氨基}苄基)-5-嘧啶基]乙酸;
44)[4-氯-2-{4-[(4-甲氧基-3-硝基苯甲酰基)氨基]苄基}-6-(1-吡咯烷基)-5-嘧啶基]乙酸;
45)[4-氯-2-{4-[(4-甲氧基-3,5-二甲基苯甲酰基)氨基]苄基}-6-(1-吡咯烷基)-5-嘧啶基]乙酸;
46)[4-氯-2-(4-{[(2E)-3-苯基-2-丙烯酰基]氨基}苄基)-6-(1-吡咯烷基)-5-嘧啶基]乙酸;
47)[4-氯-2-{4-[(3,4-二氯苯甲酰基)氨基]苄基}-6-(1-吡咯烷基)-5-嘧啶基]乙酸;
48){4-氯-6-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
49)(4-氯-2-{4-[(4-氯苯甲酰基)氨基]苄基}-6-吡咯烷-1-基嘧啶-5-基)乙酸;
50)[4-氯-6-吡咯烷-1-基-2-(4-{[4-(三氟甲基)苯甲酰基]氨基}苄基)嘧啶-5-基]乙酸;
51)[4-氯-2-(4-{[(2E)-3-(4-氯苯基)丙-2-烯酰基]氨基}苄基)-6-吡咯烷-1-基嘧啶-5-基]乙酸;
52){4-氯-6-[(2-羟基乙基)(甲基)氨基]-2-[4-(2-萘甲酰氨基)苄基]嘧啶-5-基}乙酸;
53)[4-氯-2-(4-{[(2S)-3,4-二氢-2H-苯并吡喃-2-基羰基]氨基}苄基)-6-(二甲基氨基)-嘧啶-5-基]乙酸;
54){4-氯-6-(二甲基氨基)-2-[4-({(2E)-3-[4-(三氟甲基)苯基]丙-2-烯酰基}氨基)苄基]嘧啶-5-基}乙酸;
55){4-(二甲基氨基)-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
56){4-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
57){4-{甲基[2-氧代-2-(1-吡咯烷基)乙基]氨基}-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
58){2-[4-(苯甲酰氨基)苄基]-4-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-5-嘧啶基}乙酸;
59)[4-[[2-(环戊氨基)-2-氧代乙基](甲基)氨基]-2-(4-{[(2E)-3-苯基-2-丙烯酰基]氨基}苄基)-5-嘧啶基]乙酸;
60)[2-{4-[(4-氯苯甲酰基)氨基]苄基}-4-(二甲基氨基)-5-嘧啶基]乙酸;
61)(4-(二甲基氨基)-2-{4-[(4-甲氧基苯甲酰基)氨基]苄基}-5-嘧啶基)乙酸;
62)[2-{4-[(3,4-二氯苯甲酰基)氨基]苄基}-4-(二甲基氨基)-5-嘧啶基]乙酸;
63)(4-(二甲基氨基)-2-{4-[(2-喹啉基羰基)氨基]苄基}-5-嘧啶基)乙酸;
64)[4-(二甲基氨基)-2-(4-{[(2E)-3-苯基-2-丙烯酰基]氨基}苄基)-5-嘧啶基]乙酸;
65)[2-(4-{[(2E)-3-(4-氯苯基)-2-丙烯酰基]氨基}苄基)-4-(二甲基氨基)-5-嘧啶基]乙酸;
66)[4-(二甲基氨基)-2-(4-{[4-(三氟甲基)苯甲酰基]氨基}苄基)-5-嘧啶基]乙酸;
67)(4-(二甲基氨基)-2-{4-[(3-甲氧基苯甲酰基)氨基]苄基}-5-嘧啶基)乙酸;
68)[2-{4-[(3-氯苯甲酰基)氨基]苄基}-4-(二甲基氨基)-5-嘧啶基]乙酸;
69)[2-{4-[(4-溴苯甲酰基)氨基]苄基}-4-(二甲基氨基)-5-嘧啶基]乙酸;
70){4-(二甲基氨基)-2-[4-({(2E)-3-[4-(三氟甲基)苯基]丙-2-烯酰基}氨基)苄基]嘧啶-5-基}乙酸;
71)(4-(二甲基氨基)-2-{1-[4-(2-萘甲酰氨基)苯基]乙基}嘧啶-5-基)乙酸;
72)[4-(二甲基氨基)-2-(4-{[4-(三氟甲氧基)苯甲酰基]氨基}苄基)嘧啶-5-基]乙酸;
73)(4-(二甲基氨基)-2-{4-[(4-氟苯甲酰基)氨基]苄基}嘧啶-5-基)乙酸;
74)[2-(1-{4-[(3,4-二氯苯甲酰基)氨基]苯基}乙基)-4-(二甲基氨基)嘧啶-5-基]乙酸;
75){4-(二甲基氨基)-2-[1-(4-{[4-(三氟甲基)苯甲酰基]氨基}苯基)乙基]嘧啶-5-基}乙酸;
76){4-(二甲基氨基)-2-[1-(4-{[(2E)-3-苯丙-2-烯酰基]氨基}苯基)乙基]嘧啶-5-基}乙酸;
77)[4-(二甲基氨基)-2-[1-{4-[(喹啉-2-基羰基)氨基]苯基}乙基]嘧啶-5-基]乙酸;
78)[2-(1-{4-[(4-氯苯甲酰基)氨基]苯基}乙基)-4-(二甲基氨基)嘧啶-5-基]乙酸;
79)[4-(二甲基氨基)-2-(1-{4-[(4-氟苯甲酰基)氨基]苯基}乙基)嘧啶-5-基]乙酸;
80)(4-吡咯烷-1-基-2-{4-[(喹啉-2-基羰基)氨基]苄基}嘧啶-5-基)乙酸;
81)(2-{4-[(4-氯苯甲酰基)氨基]苄基}-4-吡咯烷-1-基嘧啶-5-基)乙酸;
82)(2-{4-[(4-氟苯甲酰基)氨基]苄基}-4-吡咯烷-1-基嘧啶-5-基)乙酸;
83)[4-吡咯烷-1-基-2-(4-{[4-(三氟甲基)苯甲酰基]氨基}苄基)嘧啶-5-基]乙酸;
84){2-[4-(2-萘甲酰氨基)苄基]-4-吡咯烷-1-基嘧啶-5-基}乙酸;
85)(2-{4-[(3-甲基丁酰基)氨基]苄基}-4-吡咯烷-1-基嘧啶-5-基)乙酸钠;
86)(2-{4-[(3,3-二甲基丁酰基)氨基]苄基}-4-吡咯烷-1-基嘧啶-5-基)乙酸;
87)[4-氯-2-[4-(2-萘甲酰氨基)苄基]-6-(1-吡咯烷基)-5-嘧啶基]乙酸;
88)N-{5-(羧甲基)-6-氯-2-[4-(2-萘甲酰氨基)苄基]-4-嘧啶基}-N-甲基甘氨酸;
89){4-氯-6-[环己基(甲基)氨基]-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
90){4-氯-6-[异丙基(甲基)氨基]-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
91){4-氯-6-[(2-甲氧基乙基)(甲基)氨基]-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
92){4-氯-6-(4-吗啉基)-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
93)[4-氯-2-[4-(2-萘甲酰氨基)苄基]-6-(1-哌啶基)-5-嘧啶基]乙酸;
94)(4-氯-6-(二甲基氨基)-2-{4-[(1H-吲哚-6-基羰基)氨基]苄基}-5-嘧啶基)乙酸;
95){4-氯-6-甲氧基-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
96){4-氯-6-(2,5-二氢-1H-吡咯-1-基)-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
97){4-氯-6-(二乙氨基)-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
98){4-氯-6-[乙基(甲基)氨基]-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
99){4-氯-6-(3-羟基-1-吡咯烷基)-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
100)1-{5-(羧甲基)-6-氯-2-[4-(2-萘甲酰氨基)苄基]-4-嘧啶基}-L-脯氨酸;
101)[4-氯-2-(4-{[4-(甲硫基)苯甲酰基]氨基}苄基)-6-(1-吡咯烷基)-5-嘧啶基]乙酸;
102)[4-氯-2-{4-[(3-氯-4-甲氧基苯甲酰基)氨基]苄基}-6-(1-吡咯烷基)-5-嘧啶基]乙酸;
103){2-{4-[(苯胺基羰基)氨基]苄基}-4-氯-6-[[2-(环戊基氨基)-2-氧代乙基](甲基)氨基]-5-嘧啶基}乙酸;
104){2-(4-{[(苯甲氨基)羰基]氨基}苄基)-4-氯-6-[[2-(环戊基氨基)-2-氧代乙基](甲基)氨基]-5-嘧啶基}乙酸;
105){4-氯-6-[[2-(环戊基氨基)-2-氧代乙基](甲基)氨基]-2-[4-({[(2-苯乙基)氨基]羰基}氨基)苄基]-5-嘧啶基}乙酸;
106)[4-氯-6-[[2-(环戊基氨基)-2-氧代乙基](甲基)氨基]-2-(4-{[(2-萘氨基)羰基]氨基}苄基)-5-嘧啶基]乙酸;
107)[2-(4-{[(苄基氨基)羰基]氨基}苄基)-4-(二甲基氨基)嘧啶-5-基]乙酸;
108)[2-[4-({[苄基(甲基)氨基]羰基}氨基)苄基]-4-(二甲基氨基)嘧啶-5-基]乙酸;
109){4-(二甲基氨基)-6-(4-吗啉基)-2-[4-(2-萘甲酰基氨基)苄基]-5-嘧啶基}乙酸;
110)[4,6-双(二甲基氨基)-2-(4-{[4-(三氟甲基)苯甲酰基]氨基}苄基)嘧啶-5-基]乙酸;
111){4,6-双(二甲基氨基)-2-[4-(2-萘甲酰氨基)苄基]-5-嘧啶基}乙酸;
112)[4-(二甲基氨基)-2-[4-(2-萘甲酰氨基)苄基]-6-(1-吡咯烷基)-5-嘧啶基]乙酸;
113)[4-(二甲基氨基)-2-[4-(2-萘甲酰氨基)苄基]-6-(1-哌啶基)-5-嘧啶基]乙酸;
114)[2-{4-[(3,4-二氯苯甲酰基)氨基]苄基}-4,6-双(二甲基氨基)嘧啶-5-基]乙酸;
115)[4,6-双(二甲基氨基)-2-(4-{[(2E)-3-苯丙-2-烯酰基]氨基}苄基)嘧啶-5-基]乙酸;
116)[2-(4-{[(2E)-3-(4-氯苯基)丙-2-烯酰基]氨基}苄基)-4,6-双(二甲基氨基)嘧啶-5-基]乙酸;
117)[2-(4-{[(2E)-3-(4-氯苯基)丙-2-烯酰基]氨基}苄基)-4-(二甲基氨基)-6-吡咯烷-1-基嘧啶-5-基]乙酸;
118)[4-(二甲基氨基)-2-(4-{[(2E)-3-苯丙-2-烯酰基]氨基}苄基)-6-吡咯烷-1-基嘧啶-5-基]乙酸;
119)[4-(二甲基氨基)-6-吡咯烷-1-基2-(4-{[4-(三氟甲基)苯甲酰基]氨基}苄基)嘧啶-5-基]乙酸;
120)[2-{4-[(联苯-3-基羰基)氨基]苄基}-4-(二甲基氨基)-6-吡咯烷-1-基嘧啶-5-基]乙酸;
121)[2-{4-[(联苯-4-基羰基)氨基]苄基}-4-(二甲基氨基)-6-吡咯烷-1-基嘧啶-5-基]乙酸;
122)[2-{4-[(3,4-二氯苯甲酰基)氨基]苄基}-4-(二甲基氨基)-6-吗啉-4-基嘧啶-5-基]乙酸;
123)[4-(二甲基氨基)-6-吗啉-4-基-2-(4-{[4-(三氟甲基)苯甲酰基]氨基}苄基)嘧啶-5-基]乙酸;
124)[4-(二甲基氨基)-6-吗啉-4-基-2-(4-{[(2E)-3-苯丙-2-烯酰基]氨基}苄基)嘧啶-5-基]乙酸;
125)(4-(二甲基氨基)-2-{4-[(3-苯氧基苯甲酰基)氨基]苄基}-6-吡咯烷-1-基嘧啶-5-基)乙酸;
126)(4-(二甲基氨基)-2-{4-[(4-苯氧基苯甲酰基)氨基]苄基}-6-吡咯烷-1-基嘧啶-5-基)乙酸;
127)[4-(二甲基氨基)-2-(4-{[(2E)-3-(4-甲氧基苯基)丙-2-烯酰基]氨基}苄基)-6-吗啉-4-基嘧啶-5-基]乙酸;
128)[4-(二甲基氨基)-2-(4-{[(2E)-3-(2-甲氧基苯基)丙-2-烯酰基]氨基}苄基)-6-吗啉-4-基嘧啶-5-基]乙酸;
129)[2-{4-[(4-氯苯甲酰基)氨基]苄基}-4-(二甲基氨基)-6-吡咯烷-1-基嘧啶-5-基]乙酸;
130)[4-甲基-2-[4-(2-萘甲酰氨基)苄基]-6-(1-吡咯烷基)-5-嘧啶基]乙酸;
131)[2-{4-[(3,4-二氯苯甲酰基)氨基]苄基}-4-甲基-6-(1-吡咯烷基)-5-嘧啶基]乙酸;
132){4-(二甲基氨基)-6-甲基-2-[4-(2-萘甲酰氨基)苄基]嘧啶-5-基}乙酸;
133)[2-{4-[(3,4-二氯苯甲酰基)氨基]苄基}-4-(二甲基氨基)-6-甲基嘧啶-5-基]乙酸;
134)[4-(二甲基氨基)-6-甲基-2-(4-{[(2E)-3-苯丙-2-烯酰基]氨基}苄基)嘧啶-5-基]乙酸;
135){4-(二甲基氨基)-6-(甲氧基甲基)-2-[4-(2-萘甲酰氨基)苄基]嘧啶-5-基}乙酸;
136)[4-(二甲基氨基)-6-(甲氧基甲基)-2-(4-{[4-(三氟甲基)苯甲酰基]氨基}苄基)-嘧啶-5-基]乙酸;
137){4-(二甲基氨基)-6-乙基-2-[4-(2-萘甲酰氨基)苄基]嘧啶-5-基}乙酸;
138)[4-(二甲基氨基)-6-乙基-2-(4-{[4-(三氟甲基)苯甲酰基]氨基}苄基)嘧啶-5-基]乙酸;
139){4-(二甲基氨基)-6-异丙基-2-[4-(2-萘甲酰氨基)苄基]嘧啶-5-基}乙酸;
140)[4-(二甲基氨基)-6-异丙基-2-(4-{[4-(三氟甲基)苯甲酰基]氨基}苄基)嘧啶-5-基]乙酸;
141)[2-(4-{[(苄氧基)羰基]氨基}苄基)-4-(二甲基氨基)嘧啶-5-基]乙酸;
142){4-(二甲基氨基)-2-[4-({[(4-氟苄基)氧基]羰基}氨基)苄基]-嘧啶-5-基}乙酸;
143)[2-(4-{[(苄氧基)羰基]氨基}苄基)-4-氯-6-(二甲基氨基)嘧啶-5-基]乙酸;
144){4-(二甲基氨基)-2-[4-({[(4-硝基苄基)氧基]羰基}氨基)苄基]-嘧啶-5-基}乙酸;
145){4,6-二氯-2-[4-(2-萘甲酰氨基)苄基]嘧啶-5-基}乙酸;
146)N-(4-{[5-(2-氨基-2-氧代乙基)-4-氯-6-(二甲基氨基)嘧啶-2-基]甲基}苯基)-2-萘甲酰胺;以及
147)N-(4-{[4-氯-6-(二甲基氨基)-5-(1H-四唑-5-基甲基)嘧啶-2-基]甲基}苯基)-2-萘甲酰胺。
6.一种药剂,包含作为活性成分的权利要求1中要求保护的嘧啶衍生物,其互变异构体或立体异构形式,或者其生理学上可接受的盐、酯或前药。
7.权利要求6中要求保护的药剂,进一步包含一种或多种药学上可接受的赋形剂。
8.权利要求6中要求保护的药剂,其中所述的式(I)嘧啶衍生物,其互变异构或立体异构形式,或其生理学上可接受的盐、酯或前药为CRTH2拮抗剂。
9.权利要求6中要求保护的药剂,用于治疗和/或预防与CRTH2活性相关的紊乱或疾病。
10.权利要求9中要求保护的药剂,其中所述的紊乱或疾病选自哮喘、过敏性鼻炎、特应性皮炎及过敏性结膜炎。
11.权利要求9中要求保护的药剂,其中所述的紊乱或疾病选自Churg-Strauss综合征、窦炎、嗜碱细胞性白血病、慢性荨麻疹及嗜碱细胞性白细胞增多。
12.权利要求1的化合物在生产治疗和/或预防与CRTH2活性相关的紊乱或疾病的药剂上的用途。
13.控制人和哺乳动物的与CRTH2活性相关的紊乱或疾病的方法,所述方法为给予CRTH2拮抗有效量的权利要求1的化合物。
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EP03009384A EP1471057B1 (en) | 2003-04-25 | 2003-04-25 | Pyrimidinylacetic acid derivatives useful for the treatment of diseases mediated by CRTH2 |
EP03009384.3 | 2003-04-25 | ||
PCT/EP2004/003910 WO2004096777A1 (en) | 2003-04-25 | 2004-04-14 | Pyrimidine derivatives useful for the treatment of diseases mediated by crth2 |
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CN2010101716294A Division CN101914065A (zh) | 2003-04-25 | 2004-04-14 | 有助于治疗由crth2介导的疾病的嘧啶衍生物 |
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CN1809539B CN1809539B (zh) | 2012-05-09 |
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CN2010101716294A Pending CN101914065A (zh) | 2003-04-25 | 2004-04-14 | 有助于治疗由crth2介导的疾病的嘧啶衍生物 |
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US (2) | US7812160B2 (zh) |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101772489B (zh) * | 2007-06-21 | 2013-02-20 | 艾克提麦斯医药品有限公司 | 一种crth2拮抗剂的胺盐 |
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