CN1761671A - 用作PDE7抑制剂的4-氨基噻吩并[2,3-d]嘧啶-6-甲腈衍生物 - Google Patents
用作PDE7抑制剂的4-氨基噻吩并[2,3-d]嘧啶-6-甲腈衍生物 Download PDFInfo
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- CN1761671A CN1761671A CNA2004800073628A CN200480007362A CN1761671A CN 1761671 A CN1761671 A CN 1761671A CN A2004800073628 A CNA2004800073628 A CN A2004800073628A CN 200480007362 A CN200480007362 A CN 200480007362A CN 1761671 A CN1761671 A CN 1761671A
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- pyrimidine
- methyl
- formonitrile hcn
- thieno
- amino
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- MLXWQNSUOXNSER-UHFFFAOYSA-N 4-aminothieno[2,3-d]pyrimidine-6-carbonitrile Chemical class NC1=NC=NC2=C1C=C(C#N)S2 MLXWQNSUOXNSER-UHFFFAOYSA-N 0.000 title abstract 2
- 229940123304 Phosphodiesterase 7 inhibitor Drugs 0.000 title description 8
- 239000002606 phosphodiesterase VII inhibitor Substances 0.000 title description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 47
- 238000000034 method Methods 0.000 claims abstract description 22
- 238000011282 treatment Methods 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 101100407335 Dictyostelium discoideum pde7 gene Proteins 0.000 claims abstract 4
- ZIEWSZYVEDTXGH-UHFFFAOYSA-N pyrimidine-4-carbonitrile Chemical compound N#CC1=CC=NC=N1 ZIEWSZYVEDTXGH-UHFFFAOYSA-N 0.000 claims description 288
- -1 hydroxycarbonyl group Chemical group 0.000 claims description 91
- 150000001875 compounds Chemical class 0.000 claims description 82
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 75
- 229910052799 carbon Inorganic materials 0.000 claims description 46
- 125000000217 alkyl group Chemical group 0.000 claims description 43
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 43
- 125000005843 halogen group Chemical group 0.000 claims description 32
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 27
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 25
- 125000002252 acyl group Chemical group 0.000 claims description 25
- 125000003545 alkoxy group Chemical group 0.000 claims description 25
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 21
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
- 229940095102 methyl benzoate Drugs 0.000 claims description 18
- 125000003342 alkenyl group Chemical group 0.000 claims description 16
- 125000000304 alkynyl group Chemical group 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000004414 alkyl thio group Chemical group 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 14
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 239000001301 oxygen Substances 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- 125000001118 alkylidene group Chemical group 0.000 claims description 9
- 150000001412 amines Chemical class 0.000 claims description 9
- 125000004104 aryloxy group Chemical group 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- 125000002947 alkylene group Chemical group 0.000 claims description 8
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 8
- 239000005864 Sulphur Substances 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 6
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 5
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- 208000028018 Lymphocytic leukaemia Diseases 0.000 claims description 5
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 201000004681 Psoriasis Diseases 0.000 claims description 5
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 5
- 125000004442 acylamino group Chemical group 0.000 claims description 5
- 208000006673 asthma Diseases 0.000 claims description 5
- 201000008937 atopic dermatitis Diseases 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 208000003747 lymphoid leukemia Diseases 0.000 claims description 5
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- 210000000056 organ Anatomy 0.000 claims description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 5
- 238000002054 transplantation Methods 0.000 claims description 5
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 5
- GSFNQBFZFXUTBN-UHFFFAOYSA-N 2-chlorothiophene Chemical compound ClC1=CC=CS1 GSFNQBFZFXUTBN-UHFFFAOYSA-N 0.000 claims description 4
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 claims description 4
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 claims description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- XMYYFMNNKDVTDK-UHFFFAOYSA-N 2-(1,3-benzodioxol-5-yl)-5-methyl-4-(4-methylpiperazin-1-yl)thieno[2,3-d]pyrimidine-6-carbonitrile Chemical compound C1CN(C)CCN1C1=NC(C=2C=C3OCOC3=CC=2)=NC2=C1C(C)=C(C#N)S2 XMYYFMNNKDVTDK-UHFFFAOYSA-N 0.000 claims description 3
- SMMQAGYVPPXWAV-UHFFFAOYSA-N 2-(3,5-dimethoxyphenyl)-4-[2-hydroxyethyl(methyl)amino]-5-methylthieno[2,3-d]pyrimidine-6-carbonitrile Chemical compound COC1=CC(OC)=CC(C=2N=C3SC(=C(C)C3=C(N(C)CCO)N=2)C#N)=C1 SMMQAGYVPPXWAV-UHFFFAOYSA-N 0.000 claims description 3
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 3
- BYGTYRGPMZUBLQ-UHFFFAOYSA-N 2-benzyl-5-methyl-4-(4-methylpiperazin-1-yl)thieno[2,3-d]pyrimidine-6-carbonitrile Chemical compound C1CN(C)CCN1C1=NC(CC=2C=CC=CC=2)=NC2=C1C(C)=C(C#N)S2 BYGTYRGPMZUBLQ-UHFFFAOYSA-N 0.000 claims description 3
- GGJGQGPSISDQPB-UHFFFAOYSA-N 4-(butan-2-ylamino)-5-methyl-2-[(3,4,5-trimethoxyphenyl)methyl]thieno[2,3-d]pyrimidine-6-carbonitrile Chemical compound N=1C=2SC(C#N)=C(C)C=2C(NC(C)CC)=NC=1CC1=CC(OC)=C(OC)C(OC)=C1 GGJGQGPSISDQPB-UHFFFAOYSA-N 0.000 claims description 3
- WFDKDEUISGLVFD-UHFFFAOYSA-N 4-(cyclobutylamino)-5-methyl-2-(2-phenylethyl)thieno[2,3-d]pyrimidine-6-carbonitrile Chemical compound N=1C(NC2CCC2)=C2C(C)=C(C#N)SC2=NC=1CCC1=CC=CC=C1 WFDKDEUISGLVFD-UHFFFAOYSA-N 0.000 claims description 3
- JDWYOBAQZIGHMU-UHFFFAOYSA-N 4-(cyclobutylamino)-5-methyl-2-[(3,4,5-trimethoxyphenyl)methyl]thieno[2,3-d]pyrimidine-6-carbonitrile Chemical compound COC1=C(OC)C(OC)=CC(CC=2N=C3SC(=C(C)C3=C(NC3CCC3)N=2)C#N)=C1 JDWYOBAQZIGHMU-UHFFFAOYSA-N 0.000 claims description 3
- ALTIHAONTRVFRF-UHFFFAOYSA-N 4-(cyclopropylamino)-5-methyl-2-[(3,4,5-trimethoxyphenyl)methyl]thieno[2,3-d]pyrimidine-6-carbonitrile Chemical compound COC1=C(OC)C(OC)=CC(CC=2N=C3SC(=C(C)C3=C(NC3CC3)N=2)C#N)=C1 ALTIHAONTRVFRF-UHFFFAOYSA-N 0.000 claims description 3
- PVGAVJVFCMUFEL-UHFFFAOYSA-N 4-(diethylamino)-5-methyl-2-(2-phenylethyl)thieno[2,3-d]pyrimidine-6-carbonitrile Chemical compound N=1C=2SC(C#N)=C(C)C=2C(N(CC)CC)=NC=1CCC1=CC=CC=C1 PVGAVJVFCMUFEL-UHFFFAOYSA-N 0.000 claims description 3
- QPEOXUMEOIGONP-UHFFFAOYSA-N 4-(diethylamino)-5-methyl-2-(3-phenylpropyl)thieno[2,3-d]pyrimidine-6-carbonitrile Chemical compound N=1C=2SC(C#N)=C(C)C=2C(N(CC)CC)=NC=1CCCC1=CC=CC=C1 QPEOXUMEOIGONP-UHFFFAOYSA-N 0.000 claims description 3
- VVXVVKKCKGVKHV-UHFFFAOYSA-N 4-(diethylamino)-5-methyl-2-(4-nitrophenyl)thieno[2,3-d]pyrimidine-6-carbonitrile Chemical compound N=1C=2SC(C#N)=C(C)C=2C(N(CC)CC)=NC=1C1=CC=C([N+]([O-])=O)C=C1 VVXVVKKCKGVKHV-UHFFFAOYSA-N 0.000 claims description 3
- YQDLVYQTNPKBIZ-UHFFFAOYSA-N 4-(diethylamino)-5-methyl-2-[(3,4,5-trimethoxyphenyl)methyl]thieno[2,3-d]pyrimidine-6-carbonitrile Chemical compound N=1C=2SC(C#N)=C(C)C=2C(N(CC)CC)=NC=1CC1=CC(OC)=C(OC)C(OC)=C1 YQDLVYQTNPKBIZ-UHFFFAOYSA-N 0.000 claims description 3
- AWXXKHKQDQFYMW-UHFFFAOYSA-N 4-(diethylamino)-5-methyl-2-[4-(trifluoromethyl)phenyl]thieno[2,3-d]pyrimidine-6-carbonitrile Chemical compound N=1C=2SC(C#N)=C(C)C=2C(N(CC)CC)=NC=1C1=CC=C(C(F)(F)F)C=C1 AWXXKHKQDQFYMW-UHFFFAOYSA-N 0.000 claims description 3
- QBDNAWNFHXEOLA-UHFFFAOYSA-N 4-(diethylamino)-5-methyl-2-phenylthieno[2,3-d]pyrimidine-6-carbonitrile Chemical compound N=1C=2SC(C#N)=C(C)C=2C(N(CC)CC)=NC=1C1=CC=CC=C1 QBDNAWNFHXEOLA-UHFFFAOYSA-N 0.000 claims description 3
- IXMHTMVEBNDOTD-UHFFFAOYSA-N 4-(diethylamino)-5-methyl-2-pyridin-4-ylthieno[2,3-d]pyrimidine-6-carbonitrile Chemical compound N=1C=2SC(C#N)=C(C)C=2C(N(CC)CC)=NC=1C1=CC=NC=C1 IXMHTMVEBNDOTD-UHFFFAOYSA-N 0.000 claims description 3
- ZRCSNSUJCXLBQL-UHFFFAOYSA-N 4-(dimethylamino)-5-methyl-2-[(3,4,5-trimethoxyphenyl)methyl]thieno[2,3-d]pyrimidine-6-carbonitrile Chemical compound COC1=C(OC)C(OC)=CC(CC=2N=C3SC(=C(C)C3=C(N(C)C)N=2)C#N)=C1 ZRCSNSUJCXLBQL-UHFFFAOYSA-N 0.000 claims description 3
- UEDLTCHMWYMVPZ-UHFFFAOYSA-N 4-(ethylamino)-5-methyl-2-[(3,4,5-trimethoxyphenyl)methyl]thieno[2,3-d]pyrimidine-6-carbonitrile Chemical compound N=1C=2SC(C#N)=C(C)C=2C(NCC)=NC=1CC1=CC(OC)=C(OC)C(OC)=C1 UEDLTCHMWYMVPZ-UHFFFAOYSA-N 0.000 claims description 3
- QMHDGVJYDHFMGR-UHFFFAOYSA-N 4-(tert-butylamino)-5-methyl-2-[(3,4,5-trimethoxyphenyl)methyl]thieno[2,3-d]pyrimidine-6-carbonitrile Chemical compound COC1=C(OC)C(OC)=CC(CC=2N=C3SC(=C(C)C3=C(NC(C)(C)C)N=2)C#N)=C1 QMHDGVJYDHFMGR-UHFFFAOYSA-N 0.000 claims description 3
- WUFSOXBAZDBOOL-UHFFFAOYSA-N 4-[ethyl(methyl)amino]-5-methyl-2-[(3,4,5-trimethoxyphenyl)methyl]thieno[2,3-d]pyrimidine-6-carbonitrile Chemical compound N=1C=2SC(C#N)=C(C)C=2C(N(C)CC)=NC=1CC1=CC(OC)=C(OC)C(OC)=C1 WUFSOXBAZDBOOL-UHFFFAOYSA-N 0.000 claims description 3
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- LULFVFCYVIPVTI-UHFFFAOYSA-N 5-methyl-4-(4-methylpiperazin-1-yl)-2-(4-nitrophenyl)thieno[2,3-d]pyrimidine-6-carbonitrile Chemical compound C1CN(C)CCN1C1=NC(C=2C=CC(=CC=2)[N+]([O-])=O)=NC2=C1C(C)=C(C#N)S2 LULFVFCYVIPVTI-UHFFFAOYSA-N 0.000 claims description 3
- NYJOYVZSRCHFLE-UHFFFAOYSA-N 5-methyl-4-(4-methylpiperazin-1-yl)-2-[(3,4,5-trimethoxyphenyl)methyl]thieno[2,3-d]pyrimidine-6-carbonitrile Chemical compound COC1=C(OC)C(OC)=CC(CC=2N=C3SC(=C(C)C3=C(N3CCN(C)CC3)N=2)C#N)=C1 NYJOYVZSRCHFLE-UHFFFAOYSA-N 0.000 claims description 3
- YXTLFUJDTXUANL-UHFFFAOYSA-N 5-methyl-4-(4-methylpiperazin-1-yl)-2-[4-(trifluoromethyl)phenyl]thieno[2,3-d]pyrimidine-6-carbonitrile Chemical compound C1CN(C)CCN1C1=NC(C=2C=CC(=CC=2)C(F)(F)F)=NC2=C1C(C)=C(C#N)S2 YXTLFUJDTXUANL-UHFFFAOYSA-N 0.000 claims description 3
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
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Abstract
本发明公开了具有通式(I)化学结构的新型4-氨基噻吩并[2,3-d]嘧啶-6-甲腈衍生物和其药物学上可接受的盐、它们的制备方法、包含它们的药用组合物以及它们在治疗、预防或抑制通过抑制PDE7而缓解的病症、疾病和紊乱中的用途。
Description
本发明涉及新型4-氨基噻吩并[2,3-d]嘧啶-6-甲腈衍生物、它们的制备方法以及包含它们的药用组合物。这些化合物为磷酸二酯酶7(PDE7)的有效选择性抑制剂,因此可用于治疗、预防或抑制通过抑制PDE7而缓解的病症、疾病和紊乱。
环核苷酸磷酸二酯酶(PDE)包括具有水解环核苷酸如cAMP(环腺苷3′-5′-一磷酸)和/或cGMP(环鸟苷3′5′-一磷酸)能力的超家族蛋白。环核苷酸为使众多细胞外刺激(例如激素、神经递质)信号整合为适当的细胞反应必不可少的细胞内第二信使。抑制PDE导致细胞内环核苷酸水平升高、调控许多细胞信号传导路径,在某些情况下产生有益的治疗作用(Trends in Medicinal Chemistry.Drug News Perspect Dec2000 13(10))。
磷酸二酯酶超家族蛋白具有至少40%序列同源性和共同的催化域。在磷酸二酯酶中,同源性在65%以上称为磷酸二酯酶家族,同时蛋白表现出其它共同的结构特征。迄今为止,已经介绍了11个家族,每个家族包括一个或多个基因和若干蛋白同工型。例如,PDE1家族包括至少3种基因:PDE1A、PDE1B和PDE1C。PDE1A产生2种不同组织分布的同工型:PDE1A1和PDE1A2(Dousa.1999.KidneyInternational 55:29-62)。
PDE7家族成员以高亲和力(Km~0.2μM)特异性水解cAMP。和其它cAMP特异性磷酸二酯酶(如PDE3和PDE4)不同的是PDE7蛋白不被cGMP抑制。1993年鉴定了PDE7家族的第一位成员PDE7A2(Michaeli等,J Biol Chem.1993 Jun 15;268(17):12925-32)。迄今为止,已经介绍了2种基因和多达5种同工型(Han等,J Biol Chem.1997Jun 27;272(26):16152-7;Hetman等,Proc Natl Acad Sci USA.2000Jan 4;97(1):472-6;Sasaki等,Biochem Biophys Res Commun.2000 May19;271(3):575-83;US-6146876)。
PDE7同工型表达于许多不同人体组织,包括气管上皮细胞、大脑、心脏、肝脏、胰腺、甲状腺、骨胳肌和淋巴组织(Miró等,Synapse.2001 Jun;40(3):201-14.;Fuhrmann,Am J Respir Cell Mol Biol.1999Feb;20(2):292-302;Gardner,Biochem Biophys Res Commun.2000 May27;272(1):186-92;Han,J Biol Chem.1997 Jun 27;272(26):16152-7;Bloom & Beavo.Proc Natl Acad Sci USA.1996 Nov 26;93(24):14188-92.;Hoffmann,Cell Biochem Biophys.1998;28(2-3):103-13.)。
在PDE7A同工型中,PDE7A1蛋白在B和T淋巴细胞中表达。特别是在CD4+T细胞中,在T细胞受体依赖性刺激后,PDE7A1是细胞激活所需要的(Lee,Cell Signal.2002 Mar;14(3):277-84;Nakata,Clin Exp Immunol.2002 Jun;128(3):460-6;Lee,Cell Signal.2002Mar;14(3):277-84;Glavas,Proc Natl Acad Sci USA.2001 May 22;98(11):6319-24。Li,Science.1999 Feb 5;283(5403):848-51;Kanda,Biochem Pharmacol.2001 Aug 15;62(4):495-507)。即使PDE3和PDE4的同工型也T淋巴细胞中表达,也只有PDE4和PDE7与这些细胞的功能性应答有关(Giembycz,Br J Pharmacol.1996 Aug;118(8):1945-58)。
实验研究还证实,用PDE4抑制剂使白血病细胞中的cAMP水平增加,可诱导凋亡或者程序性细胞死亡,产生治疗慢性淋巴性白血病的有益的治疗作用(Lerner,Leuk Lymphoma.2000 Mar;37(1-2):39-51;Kim & Lemer.Blood.1998 Oct 1;92(7):2484-94.)。
鉴于PDE7蛋白的组织分布和功能作用,已经公开了不同化学结构的PDE7抑制剂用于治疗或预防通过抑制PDE7蛋白而缓解的病症、疾病和紊乱,例如哮喘、特应性皮炎、慢性阻塞性肺病、节段性回肠炎、I型和II型糖尿病、淋巴性白血病和其它类型癌症、多发性硬化、器官移植后同种异体移植排斥、牛皮癣、类风湿性关节炎和溃疡性结肠炎。尤其是由于PDE7与T细胞功能有关,因此PDE7抑制剂可以用于治疗T细胞介导的免疫性疾病和呼吸道疾病。参见,例如,Bioorganic and Medicinal Chemistry Letters,11(2001)1081-1083;J.Med.Chem.,2000,43,683-689;Drug Data Report 2002,24(1):76/WO 01/74786A1;Drug Data Report 2002,24(7):639/WO02/28847A1;Drug Data Report 2002,24(8):703/WO 02/40449A1;Drug Data Report 2002,24(3):262/WO 01/98274A2。
迄今为止,还没有具有PDE7抑制能力的化合物投放市场,但某些化合物已经进行了生物学测试。
尽管可得的其它PDE(如PDE4和PDE5)的有效选择性抑制剂很多(其中一些正进行临床评估),但仍然需要有效的PDE7抑制剂,尤其是低浓度、优选低毫微摩尔浓度时有效的PDE7抑制剂。
目前我们已经发现了一系列新型4-氨基噻吩并[2,3-d]嘧啶-6-甲腈衍生物为PDE7酶的有效抑制剂,因此可用于治疗或预防通过抑制PDE7酶而缓解的病症、疾病和紊乱,例如哮喘、特应性皮炎、慢性阻塞性肺病、节段性回肠炎、I型和II型糖尿病、淋巴性白血病和其它类型癌症、多发性硬化、器官移植后同种异体移植排斥、牛皮癣、类风湿性关节炎和溃疡性结肠炎。尤其是由于PDE7与T细胞功能有关,因此PDE7抑制剂可用于治疗T细胞介导的免疫性疾病。
本发明化合物还可与已知有效治疗这些疾病的其它药物联合应用。例如,它们可以与选自下列的一种或多种化合物联合应用:PDE4抑制剂、A2A腺苷受体拮抗剂、NSAID、COX-2抑制剂、TNF-α抑制剂和类固醇。
因此,本发明提供新型结构式(I)化合物或其药物学上可接受的盐,
其中
·R1和R2
·(a)独立代表:
(i)氢原子;
(ii)选自烷基、链烯基或链炔基的基团,它们任选被一个或多个(例如1-4个)选自以下的取代基取代:卤素原子和羟基、烷氧基、芳氧基、烷硫基、羧基、氧代、氨基、单-或双-烷基氨基;
(iii)下式的基团
-(CH2)n-R6
其中n为0-4的整数,R6代表环烷基或环烯基;
或
(b)R1和R2与它们连接的氮原子一起形成包含1-4个选自氮、氧和硫的杂原子的3-至8-元环,该环任选被一个或多个(例如1-4个)选自以下的取代基取代:卤素原子和烷基、羟基、烷氧基、酰基、羟基羰基、烷氧基羰基、亚烷二氧基、氨基、单-或双-烷基氨基、单-或双-烷基氨基酰基、硝基、氰基或三氟甲基;
·R3为下式的基团
-(CH2)n-G
其中n为0-4的整数,G代表包含0-4个杂原子的单环或双环芳基或杂芳基,该基团任选被一个或多个(例如1-4个)选自以下的取代基取代:
(i)卤素原子;
(ii)烷基和亚烷基,它们任选被一个或多个(例如1-4个)选自卤素原子的取代基取代;和
(iii)苯基、羟基、羟基烷基、烷氧基、亚烷二氧基、芳氧基、烷硫基、氨基、单-或双-烷基氨基、酰基氨基、硝基、酰基、羟基羰基、烷氧基羰基、氰基、二氟甲氧基或三氟甲氧基;
·R4代表氢原子或者烷基或芳基;
前提条件是化合物不是5-甲基-2-苯基-4-吗啉-4-基噻吩并[2,3-d]嘧啶-6-甲腈。
WO98/06722、WO00/59912、WO02/49650已经公开了不在本发明范畴内但结构类似的某些氨基噻吩并[2,3-d]嘧啶衍生物。
本发明的其它方面为:a)制备所述化合物的方法,b)包含有效量所述化合物的药用组合物,c)所述化合物在制备用于治疗通过抑制磷酸二酯酶7(PDE7)而缓解的疾病的药物上的用途;和d)通过抑制磷酸二酯酶7(PDE7)而缓解疾病的治疗方法,所述方法包括对需其治疗的患者给予本发明化合物。
本文使用的术语烷基包括任选取代的具有1-20个碳原子、优选1-12个碳原子的直链或支链基团。更优选烷基为1-8个碳原子、优选1-6个且更优选1-4个碳原子的“低级烷基”。
实例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、异戊基、1-乙基丙基、1,1-二甲基丙基、1,2-二甲基丙基、正己基、1-乙基丁基、2-乙基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,2-二甲基丁基、2,3-二甲基丁基、2-甲基戊基、3-甲基戊基和异己基。
当提及烷基可任选取代时,是指上述定义的直链或支链烷基,它们可未被取代或在任何位被一个或多个(例如1-3个)取代基取代。当存在两个以上的取代基时,各个取代基可以相同或不同。
所述取代基通常为卤素原子(优选氟原子)、羟基或未被取代的烷氧基。
本文使用的术语链烯基包括任选取代的具有2-20个碳原子、优选2-12个碳原子的直链或支链单或多不饱和基团。术语链烯基包括“顺式”和“反式”方向的基团,或者“E”和“Z”方向的基团。更优选链烯基为具有2-8个碳原子、优选2-6个且更优选2-4个碳原子的“低级链烯基”。尤其优选单或双不饱和链烯基。
实例包括乙烯基、烯丙基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基和4-戊烯基。
当提及链烯基可以任选取代时,是指上文定义的直链或支链链烯基,其可未被取代或在任何位被一个或多个(例如1-3个)取代基取代。当存在两个以上的取代基时,各个取代基可以相同或不同。
所述取代基通常为卤素原子(优选氟原子)、羟基或未被取代的烷氧基。
本文使用的术语链炔基包括任选取代的具有2-20个碳原子、或者优选2-12个碳原子的直链或支链单或多不饱和基团。更优选链炔基为具有2-8个碳原子、优选2-6个且更优选2-4个碳原子的“低级链炔基”。尤其优选单或双不饱和链炔基。
实例包括1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基和3-丁炔基。
当提及链炔基可以任选取代时,是指上文定义的直链或支链链炔基,其可未被取代或在任何位被一个或多个(例如1-3个)取代基取代。当存在两个以上的取代基时,各个取代基可以相同或不同。
所述取代基通常为卤素原子(优选氟原子)、羟基或未被取代的烷氧基。
本文使用的术语亚烷基通常包括具有1-6个(例如1-4个)碳原子的二价烷基。C1-C4亚烷基的实例包括亚甲基、亚乙基、亚丙基、亚丁基、亚戊基和亚己基。亚烷基通常未被取代。
当亚烷基为另一基团的取代基时,其为一个取代基而不是两个取代基构成的基团。
本文使用的亚烷二氧基为连接两个氧原子的上文定义的亚烷基。
本文使用的术语烷氧基(或烷基氧基)包括任选取代的直链或支链包含氧基的基团,每个基团具有1-10个碳原子的烷基部分。更优选烷氧基为具有1-8个碳原子、优选1-6个且更优选1-4个碳原子的“低级烷氧基”。烷氧基通常未被取代或被1-3个选自卤素原子和羟基的取代基取代。优选未被取代的烷氧基。
优选的烷氧基包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、三氟甲氧基、二氟甲氧基、羟基甲氧基、2-羟基乙氧基或2-羟基丙氧基。
本文使用的术语烷硫基包括任选取代的1-10个碳原子的直链或支链烷基连接二价硫原子的基团。更优选烷硫基为具有1-8个碳原子、优选1-6个且更优选1-4个碳原子的“低级烷硫基”。烷硫基通常未被取代或被1-3个选自卤素原子和羟基的取代基取代。优选未被取代的烷硫基。
优选的任选取代的烷硫基包括甲硫基、乙硫基、正丙硫基、异丙硫基、正丁硫基、仲丁硫基、叔丁硫基、三氟甲硫基、二氟甲硫基、羟基甲硫基、2-羟基乙硫基和2-羟基丙硫基。
本文使用的术语单烷基氨基包括任选取代的1-10个碳原子的直链或支链烷基连接二价-NH-的基团。更优选单烷基氨基为具有1-8个碳原子、优选1-6个且更优选1-4个碳原子的“低级单烷基氨基”。单烷基氨基通常未被取代或被1-3个选自卤素原子和羟基的取代基取代。优选未被取代的单烷基氨基。
优选的任选取代的单烷基氨基包括甲氨基、乙氨基、正丙基氨基、异丙基氨基、正丁基氨基、仲丁基氨基、叔丁基氨基、三氟甲基氨基、二氟甲基氨基、羟基甲基氨基、2-羟基乙基氨基和2-羟基丙基氨基。
本文使用的术语二烷基氨基包括三价氮原子与两个任选取代的1-10个碳原子的直链或支链烷基连接的基团。更优选二烷基氨基为每个烷基具有1-8个碳原子、优选1-6个且更优选1-4个碳原子的“低级二烷基氨基”。二烷基氨基通常未被取代或在一个或各个烷基上被1-3个选自卤素原子和羟基的取代基取代。优选未被取代的二烷基氨基。
优选的任选取代的二烷基氨基包括二甲基氨基、二乙基氨基、甲基(乙基)氨基、二(正丙基)氨基、正丙基(甲基)氨基、正丙基(乙基)氨基、二(异丙基)氨基、异丙基(甲基)氨基、异丙基(乙基)氨基、二(正丁基)氨基、正丁基(甲基)氨基、正丁基(乙基)氨基、正丁基(异丙基)氨基、二(仲丁基)氨基、仲丁基(甲基)氨基、仲丁基(乙基)氨基、仲丁基(正丙基)氨基、仲丁基(异丙基)氨基、二(叔丁基)氨基、叔丁基(甲基)氨基、叔丁基(乙基)氨基、叔丁基(正丙基)氨基、叔丁基(异丙基)氨基、三氟甲基(甲基)氨基、三氟甲基(乙基)氨基、三氟甲基(正丙基)氨基、三氟甲基(异丙基)氨基、三氟甲基(正丁基)氨基、三氟甲基(仲丁基)氨基、二氟甲基(甲基)氨基、二氟甲基(乙基)氨基、二氟甲基(正丙基)氨基、二氟甲基(异丙基)氨基、二氟甲基(正丁基)氨基、二氟甲基(仲丁基)氨基、二氟甲基(叔丁基)氨基、二氟甲基(三氟甲基)氨基、羟基甲基(甲基)氨基、乙基(羟基甲基)氨基、羟基甲基(正丙基)氨基、羟基甲基(异丙基)氨基、正丁基(羟基甲基)氨基、仲丁基(羟基甲基)氨基、叔丁基(羟基甲基)氨基、二氟甲基(羟基甲基)氨基、羟基甲基(三氟甲基)氨基、羟基乙基(甲基)氨基、乙基(羟基乙基)氨基、羟基乙基(正丙基)氨基、羟基乙基(异丙基)氨基、正丁基(羟基乙基)氨基、仲丁基(羟基乙基)氨基、叔丁基(羟基乙基)氨基、二氟甲基(羟基乙基)氨基、羟基乙基(三氟甲基)氨基、羟基丙基(甲基)氨基、乙基(羟基丙基)氨基、羟基丙基(正丙基)氨基、羟基丙基(异丙基)氨基、正丁基(羟基丙基)氨基、仲丁基(羟基丙基)氨基、叔丁基(羟基丙基)氨基、二氟甲基(羟基丙基)氨基、羟基丙基(三氟甲基)氨基。
本文使用的术语羟基烷基包括具有1-10个碳原子、其中任何一个碳原子可被一个或多个羟基取代的直链或支链烷基。
这类基团的实例包括羟基甲基、羟基乙基、羟基丙基、羟基丁基和羟基己基。
本文使用的术语烷氧基羰基包括任选取代的、与氧基羰基连接的烷基部分具有1-10个碳原子的直链或支链基团。更优选烷氧基羰基为具有1-8个碳原子、优选1-6个且更优选1-4个碳原子的“低级烷氧基羰基”。烷氧基羰基通常未被取代或被1-3个选自卤素原子和羟基的取代基取代。优选未被取代的烷氧基羰基。
优选的任选取代的烷氧基羰基包括甲氧基羰基、乙氧基羰基、正丙氧基羰基、异丙氧基羰基、正丁氧基羰基、仲丁氧基羰基、叔丁氧基羰基、三氟甲氧基羰基、二氟甲氧基羰基、羟基甲氧基羰基、2-羟基乙氧基羰基和2-羟基丙氧基羰基。
本文使用的术语酰基包括任选取代的、1-20个碳原子或者优选1-12个碳原子的直链或支链连接羰基的基团。更优选酰基为具有2-8个碳原子、优选2-6个且更优选2-4个碳原子的“低级酰基”。因此,其通常为式-COR的基团。酰基通常未被取代。
优选的任选取代的酰基包括乙酰基、丙酰基、丁酰基、异丁酰基、异戊酰基、新戊酰基、戊酰基、月桂酰基、肉豆蔻酰基、硬脂酰基和棕榈酰基,
本文使用的烷氧基酰基为上文定义的烷氧基与上文定义的酰基连接。酰基氨基为上文定义的酰基与氨基连接。单-或双-烷基氨基酰基为上文定义的单-或双-烷基氨基与上文定义的酰基连接。
本文使用的术语芳基通常包括C5-C14单环或多环芳基,例如苯基、萘基、蒽基或菲基。如果多环基团的至少一个环为芳基,那么该多环基团为芳基。
芳基可以未被取代或被一个或多个(例如1-4个)取代基取代。当芳基携带2个以上的取代基时,这些取代基可以相同或不同。这些取代基通常选自卤素原子、苯基、羟基、羟基烷基、烷氧基、亚烷二氧基、芳氧基、烷硫基、氨基、单-或双-烷基氨基、酰基氨基、硝基、酰基、羟基羰基、烷氧基羰基、氰基、二氟甲氧基和三氟甲氧基以及烷基和亚烷基,这些基团本身未被取代或被一个或多个卤素原子取代。其中苯基为取代基时,这样的苯基取代基通常只有一个。优选芳基上的取代基为未被取代的C1-C4烷氧基、未被取代的C1-C4烷基、硝基、卤素、三氟甲基、未被取代的C1-C3亚烷二氧基和烷基部分具有1-4个碳原子的未被取代的烷氧基羰基。
本文使用的术语芳氧基包括上文定义的芳基连接氧原子的基团。
本文使用的术语杂芳基包括单环或多环5-至14-元环系,其包含至少一个杂芳环并且包含至少一个选自O、S和N的杂原子。杂芳基可以为单环或多稠合环,其中至少一个环包含杂原子。如果多环基团中至少一个环为杂芳基,那么该多环基团为杂芳基。
实例包括吡啶基、吡嗪基、嘧啶基、哒嗪基、呋喃基、噁二唑基、噁唑基、咪唑基、噻唑基、噻二唑基、噻吩基、吡咯基、吡啶基(pyridinyl)、苯并噻唑基、吲哚基、吲唑基、嘌呤基、喹啉基、异喹啉基、2,3-二氮杂萘基、萘啶基、喹喔啉基、喹唑啉基、喹嗪基、肉啉基、三唑基、吲嗪基、二氢吲哚基、异二氢吲哚基、异吲哚基、吲哚基、吲唑基、嘌呤基、咪唑烷基、蝶啶基和吡唑基。
优选噁二唑基、噁唑基、吡啶基、吡咯基、咪唑基、噻唑基、噻二唑基、噻吩基、呋喃基、吡嗪基和嘧啶基。
杂芳基可以未被取代或被一个或多个(例如1-4个)取代基取代。当杂芳基携带2个以上的取代基时,这些取代基可以相同或不同。这些取代基通常选自卤素原子、苯基、羟基、羟基烷基、烷氧基、亚烷二氧基、芳氧基、烷硫基、氨基、单-或双-烷基氨基、酰基氨基、硝基、酰基、羟基羰基、烷氧基羰基、氰基、二氟甲氧基和三氟甲氧基以及烷基和亚烷基,这些基团本身未被取代或被一个或多个卤素原子取代。其中苯基为取代基时,通常只有一个这样的苯基取代基。优选杂芳基上的取代基为未被取代的C1-C4烷氧基、未被取代的C1-C4烷基、硝基、卤素、三氟甲基、未被取代的C1-C3亚烷二氧基和烷基部分具有1-4个碳原子的未被取代的烷氧基羰基。优选未被取代的杂芳基。
本文使用的术语环烷基包括饱和碳环基团,除非另有说明,否则环烷基通常具有3-7个碳原子。
实例包括环丙基、环丁基、环戊基、环己基和环庚基。优选环丙基、环戊基或环己基。环烷基可以未被取代或被取代,通常未被取代。当环烷基携带2个以上的取代基时,这些取代基可以相同或不同。
本文使用的术语环烯基包括部分不饱和碳环基团,除非另有说明,否则环烯基通常具有3-7个碳原子。
实例包括环丁烯基、环戊烯基、环己烯基和环庚烯基。优选环戊烯基或环己烯基。环烯基可以未被取代或被取代,通常未被取代。当环烯基携带2个以上的取代基时,这些取代基可以相同或不同。
本文使用的本发明通式结构中的某些原子、基团、部分、链或环为“任选取代(的)”。是指这些原子、基团、部分、链或环可不被取代或在任何位被一个或多个(例如1-4个)取代基取代,因此与未被取代的原子、基团、部分、链或环连接的氢原子被化学上可接受的原子、基团、部分、链或环取代。当存在2个以上的取代基时,各取代基可以相同或不同。
一般来说,当环状基团通过亚烷基桥接时,桥接亚烷基于环非相邻原子与环连接。
本文使用的术语卤素原子包括氯、氟、溴或碘原子,通常为氟、氯或溴原子,最优选氯或氟。术语卤基用作前缀时的含义相同。
包含一个或多个手性中心的化合物可以以对映异构体或非对映异构体纯形式使用,或者以异构体混合物的形式使用。
本文使用的术语药物学上可接受的盐包括与药物学上可接受的酸或碱形成的盐。药物学上可接受的酸包括无机酸和有机酸,无机酸例如盐酸、硫酸、磷酸、焦磷酸、氢溴酸、氢碘酸和硝酸;有机酸例如柠檬酸、富马酸、马来酸、苹果酸、杏仁酸、抗坏血酸、草酸、琥珀酸、酒石酸、苯甲酸、乙酸、甲磺酸、乙磺酸、苯磺酸或对甲苯磺酸。药物学上可接受的碱包括碱金属(例如钠或钾)和碱土金属(例如钙或镁)氢氧化物及有机碱(例如烷基胺、芳烷基胺和杂环胺)。
本发明特定的具体化合物包括:
1)4-(4-乙基哌嗪-1-基)-5-甲基-2-苯基噻吩并[2,3-d]嘧啶-6-甲腈
2)4-(4-乙基哌嗪-1-基)-2-(4-甲氧基苯基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
3)4-(二乙基氨基)-5-甲基-2-苯基噻吩并[2,3-d]嘧啶-6-甲腈
4)5-甲基-2-苯基-4-哌啶-1-基噻吩并[2,3-d]嘧啶-6-甲腈
5)5-甲基-2-(4-硝基苯基)-4-哌啶-1-基噻吩并[2,3-d]嘧啶-6-甲腈
6)2-(4-甲氧基苯基)-5-甲基-4-哌啶-1-基噻吩并[2,3-d]嘧啶-6-甲腈
7)5-甲基-4-(4-甲基哌嗪-1-基)-2-(4-硝基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
8)5-甲基-2-苯基-4-哌嗪-1-基噻吩并[2,3-d]嘧啶-6-甲腈
9)2-(4-甲氧基苯基)-5-甲基-4-(4-甲基哌嗪-1-基)噻吩并[2,3-d]嘧啶-6-甲腈
10)4-(二乙基氨基)-2-(4-甲氧基苯基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
11)2-(4-甲氧基苯基)-5-甲基-4-吡咯烷-1-基噻吩并[2,3-d]嘧啶-6-甲腈
12)2-(4-甲氧基苯基)-5-甲基-4-哌嗪-1-基噻吩并[2,3-d]嘧啶-6-甲腈
13)5-甲基-2-(4-硝基苯基)-4-哌嗪-1-基噻吩并[2,3-d]嘧啶-6-甲腈
14)4-(二丁基氨基)-2-(4-甲氧基苯基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
15)2-(4-氯苯基)-5-甲基-4-(4-甲基哌嗪-1-基)噻吩并[2,3-d]嘧啶-6-甲腈
16)2-(3,4-二甲氧基苯基)-5-甲基-4-(4-甲基哌嗪-1-基)噻吩并[2,3-d]嘧啶-6-甲腈
17)4-[乙基(甲基)氨基]-2-(4-甲氧基苯基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
18)4-(二乙基氨基)-5-甲基-2-(4-硝基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
19)2-(4-氯苯基)-4-(二乙基氨基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
20)4-(二乙基氨基)-2-(3,4-二甲氧基苯基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
21)4-(二甲基氨基)-2-(4-甲氧基苯基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
22)2-(4-甲氧基苯基)-5-甲基-4-吗啉-4-基噻吩并[2,3-d]嘧啶-6-甲腈
23)2-(4-氯苯基)-5-甲基-4-吗啉-4-基噻吩并[2,3-d]嘧啶-6-甲腈
24)2-(4-甲氧基苯基)-5-甲基-4-[甲基(丙-2-炔基)氨基]噻吩并[2,3-d]嘧啶-6-甲腈
25)4-[(2-羟基乙基)(甲基)氨基]-2-(4-甲氧基苯基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
26)2-(3,4-二甲氧基苯基)-4-[乙基(甲基)氨基]-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
27)5-甲基-2-(4-甲基苯基)-4-(4-甲基哌嗪-1-基)噻吩并[2,3-d]嘧啶-6-甲腈
28)4-(二乙基氨基)-5-甲基-2-[4-(三氟甲基)苯基]噻吩并[2,3-d]嘧啶-6-甲腈
29)4-[烯丙基(甲基)氨基]-2-(4-甲氧基苯基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
30)2-(3,4-二甲氧基苯基)-4-[(2-羟基乙基)(甲基)氨基]-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
31)2-(3,4-二甲氧基苯基)-5-甲基-4-吗啉-4-基噻吩并[2,3-d]嘧啶-6-甲腈
32)5-甲基-2-(4-甲基苯基)-4-吗啉-4-基噻吩并[2,3-d]嘧啶-6-甲腈
33)5-甲基-4-(4-甲基哌嗪-1-基)-2-[4-(三氟甲基)苯基]噻吩并[2,3-d]嘧啶-6-甲腈
34)2-(1,3-苯并二氧杂环戊烯-5-基)-5-甲基-4-(4-甲基哌嗪-1-基)噻吩并[2,3-d]嘧啶-6-甲腈
35)4-(二乙基氨基)-5-甲基-2-(4-甲基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
36)2-(1,3-苯并二氧杂环戊烯-5-基)-4-(二乙基氨基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
37)2-(1,3-苯并二氧杂环戊烯-5-基)-5-甲基-4-吗啉-4-基噻吩并[2,3-d]嘧啶-6-甲腈
38)4-[乙基(甲基)氨基]-5-甲基-2-吡啶-4-基噻吩并[2,3-d]嘧啶-6-甲腈
39)4-[乙基(甲基)氨基]-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
40)2-苄基-5-甲基-4-(4-甲基哌嗪-1-基)噻吩并[2,3-d]嘧啶-6-甲腈
41)5-甲基-4-吗啉-4-基-2-吡啶-4-基噻吩并[2,3-d]嘧啶-6-甲腈
42)4-[(2-羟基乙基)(甲基)氨基]-5-甲基-2-吡啶-4-基噻吩并[2,3-d]嘧啶-6-甲腈
43)2-(1,3-苯并二氧杂环戊烯-5-基)-4-[(2-羟基乙基)(甲基)氨基]-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
44)4-[(2-羟基乙基)(甲基)氨基]-5-甲基-2-(4-甲基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
45)4-(二乙基氨基)-5-甲基-2-吡啶-4-基噻吩并[2,3-d]嘧啶-6-甲腈
46)2-(3,4-二甲氧基苯基)-4-(二甲基氨基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
47)2-(3,4-二甲氧基苯基)-5-甲基-4-(丙基氨基)噻吩并[2,3-d]嘧啶-6-甲腈
48)4-(二乙基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
49)2-苄基-4-(二乙基氨基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
50)5-甲基-4-(4-甲基哌嗪-1-基)-2-苯基噻吩并[2,3-d]嘧啶-6-甲腈
51)5-甲基-4-吗啉-4-基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
52)4-[(2-羟基乙基)-甲基氨基]-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
53)2-(3,5-二甲氧基苯基)-5-甲基-4-(4-甲基哌嗪-1-基)噻吩并[2,3-d]嘧啶-6-甲腈
54)4-二乙基氨基-2-(3,5-二甲氧基苯基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
55)2-(3,5-二甲氧基苯基)-4-(乙基甲基氨基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
56)4-(6-氰基-4-二乙基氨基-5-甲基噻吩并[2,3-d]嘧啶-2-基)-苯甲酸甲酯
57)4-[6-氰基-4-(乙基甲基氨基)-5-甲基噻吩并[2,3-d]嘧啶-2-基]-苯甲酸甲酯
58)2-苄基-5-甲基-4-吗啉-4-基噻吩并[2,3-d]嘧啶-6-甲腈
59)2-苄基-4-[(2-羟基乙基)甲基氨基]-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
60)5-甲基-4-(4-甲基哌嗪-1-基)-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
61)4-(6-氰基-5-甲基-4-吗啉-4-基噻吩并[2,3-d]嘧啶-2-基)苯甲酸甲酯
62)4-[6-氰基-5-甲基-4-(4-甲基哌嗪-1-基)噻吩并[2,3-d]嘧啶-2-基]苯甲酸甲酯
63)4-[6-氰基-4-(二甲基氨基)-5-甲基噻吩并[2,3-d]嘧啶-2-基]苯甲酸甲酯
64)4-{6-氰基-4-[(2-羟基乙基)(甲基)氨基]-5-甲基噻吩并[2,3-d]嘧啶-2-基}苯甲酸甲酯
65)5-甲基-4-(甲基氨基)-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
66)4-(二甲基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
67)4-(乙基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
68)5-甲基-4-(丙基氨基)-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
69)4-(丁基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
70)4-(异丙基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
71)4-(仲丁基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
72)4-(异丁基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
73)4-[(1-乙基丙基)氨基]-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
74)4-(叔丁基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
75)4-(环丙基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
76)4-(环丁基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
77)4-(环戊基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
78)4-[烯丙基(甲基)氨基]-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
79)5-甲基-4-[甲基(丙-2-炔基)氨基]-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
80)4-[(2-羟基乙基)氨基]-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
81)4-[(2-甲氧基乙基)氨基]-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
82)4-{[2-(二甲基氨基)乙基]氨基}-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
83)5-甲基-4-(3-甲基哌嗪-1-基)-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
84)4-(3,5-二甲基哌嗪-1-基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
85)4-(4-乙酰基哌嗪-1-基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
86)4-[(2-氨基乙基)(甲基)氨基]-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
87)N-[6-氰基-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-4-基]-β-丙氨酸
88)5-甲基-4-(1H-吡唑-1-基)-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
89)4-(1H-咪唑-1-基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
90)5-甲基-4-(2H-1,2,3-三唑-2-基)-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
91)5-甲基-4-(1H-1,2,4-三唑-1-基)-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
92)2-(3,4-二甲氧基苄基)-5-甲基-4-吗啉-4-基噻吩并[2,3-d]嘧啶-6-甲腈
93)2-(3,4-二甲氧基苄基)-5-甲基-4-(4-甲基哌嗪-1-基)噻吩并[2,3-d]嘧啶-6-甲腈
94)2-(3,4-二甲氧基苄基)-5-甲基-4-(甲基氨基)噻吩并[2,3-d]嘧啶-6-甲腈
95)2-(3,4-二甲氧基苄基)-4-(乙基氨基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
96)2-(3,4-二甲氧基苄基)-5-甲基-4-(丙基氨基)噻吩并[2,3-d]嘧啶-6-甲腈
97)4-(环丙基氨基)-2-(3,4-二甲氧基苄基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
98)4-(环丁基氨基)-2-(3,4-二甲氧基苄基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
99)2-(3,4-二甲氧基苄基)-4-(二甲基氨基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
100)2-(3,4-二甲氧基苄基)-4-[乙基(甲基)氨基]-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
101)4-(二乙基氨基)-2-(3,4-二甲氧基苄基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
102)4-[烯丙基(甲基)氨基]-2-(3,4-二甲氧基苄基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
103)2-(3,4-二甲氧基苄基)-5-甲基-4-[甲基(丙-2-炔基)氨基]噻吩并[2,3-d]嘧啶-6-甲腈
104)2-(3,4-二甲氧基苄基)-4-[(2-羟基乙基)氨基]-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
105)2-(3,4-二甲氧基苄基)-4-[(2-羟基乙基)(甲基)氨基]-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
106)2-(3,4-二甲氧基苄基)-4-[(2-甲氧基乙基)氨基]-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
107)4-[[2-(二甲基氨基)乙基](甲基)氨基]-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
108)5-甲基-4-吗啉-4-基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
109)5-甲基-4-(4-甲基哌嗪-1-基)-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
110)5-甲基-4-(甲基氨基)-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
111)4-(乙基氨基)-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
112)5-甲基-4-(丙基氨基)-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
113)4-(异丙基氨基)-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
114)4-(仲丁基氨基)-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
115)4-[(1-乙基丙基)氨基]-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
116)4-(叔丁基氨基)-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
117)4-(环丙基氨基)-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
118)4-(环丁基氨基)-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
119)4-(二甲基氨基)-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
120)4-[乙基(甲基)氨基]-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
121)4-(二乙基氨基)-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
122)4-[烯丙基(甲基)氨基]-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
123)5-甲基-4-[甲基(丙-2-炔基)氨基]-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
124)4-[(2-羟基乙基)氨基]-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
125)4-[(2-甲氧基乙基)氨基]-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
126)4-[(2-羟基乙基)(甲基)氨基]-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
127)5-甲基-4-(4-甲基哌嗪-1-基)-2-(2-苯基乙基)噻吩并[2,3-d]嘧啶-6-甲腈
128)4-(环丁基氨基)-5-甲基-2-(2-苯基乙基)噻吩并[2,3-d]嘧啶-6-甲腈
129)4-(二乙基氨基)-5-甲基-2-(2-苯基乙基)噻吩并[2,3-d]嘧啶-6-甲腈
130)5-甲基-4-(4-甲基哌嗪-1-基)-2-(3-苯基丙基)噻吩并[2,3-d]嘧啶-6-甲腈
131)4-(二乙基氨基)-5-甲基-2-(3-苯基丙基)噻吩并[2,3-d]嘧啶-6-甲腈
132)2-(3,5-二甲氧基-苯基)-4-[(2-羟基-乙基)-甲基-氨基]-5-甲基-噻吩并[2,3-d]嘧啶-6-甲腈
133)2-(3,5-二甲氧基-苯基)-5-甲基-4-吗啉-4-基噻吩并[2,3-d]嘧啶-6-甲腈
134)2-(3,5-二甲氧基苯基)-4-(乙基氨基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
135)4-(异丁基氨基)-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
和它们的药物学上可接受的盐。
根据本发明的一个实施方案,在结构式(I)化合物中,R1和R2:
(a)独立代表氢或选自以下的基团:具有1-4个碳原子的烷基、链烯基或链炔基,它们任选被一个羟基或具有3-6个碳原子的环烷基取代;
或
(b)R1和R2与它们连接的氮原子一起形成包含1-2个选自氮、氧和硫的杂原子的4-至6-元环,该环任选被1-2个C1-C4烷基取代,所述烷基自身未被取代或被一个羟基取代。
优选R1和R2:
(a)独立代表选自以下的基团:具有1-4个碳原子的烷基、链烯基或链炔基,它们任选被一个羟基或具有3-6个碳原子的环烷基取代;或
(b)R1和R2与它们连接的氮原子一起形成包含1-2个选自氮、氧和硫的杂原子的4-至6-元环,该环任选被1-2个C1-C4烷基取代,所述烷基自身未被取代或被一个羟基取代。
最优选R1:a)代表氢原子或具有1-4个碳原子的烷基,或b)和R2与它们连接的氮原子一起形成包含1-2个选自氮和氧的杂原子的4-至6-元环,该环任选被一个或多个选自卤素原子和烷基或酰基的取代基取代;
还优选R2:a)代表选自以下的基团:烷基、链烯基、链炔基、环烷基、羟基烷基或二烷基氨基,或b)和R1与它们连接的氮原子一起形成包含1-2个选自氮和氧的杂原子的4-至6-元环,该环任选被一个或多个选自卤素原子和烷基或酰基的取代基取代;
在本发明再一个实施方案中,R3代表下式的基团
-(CH2)n-G
其中n为0-4的整数,G代表包含0-1个杂原子的单环芳基或杂芳基,所述芳基或杂芳基任选被一个或多个(例如1-4个)选自以下的取代基取代:
(i)卤素原子;
(ii)未被取代的C1-C8烷基、未被取代的C1-C8烷氧基、未被取代的C1-C3亚烷二氧基、硝基、三氟甲基和具有C1-C8烷基部分的未被取代的烷氧基羰基。
更优选R3代表选自苯基、吡啶基或苄基的基团,这些基团任选被一个或多个(例如1-4个)选自以下的取代基取代:
(i)卤素原子;
(ii)未被取代的C1-C8烷基、未被取代的C1-C8烷氧基、未被取代的C1-C3亚烷二氧基、硝基、三氟甲基和未被取代的C1-C8烷氧基羰基。
在本发明又一个实施方案中,R4为氢、未被取代的C1-C8烷基或未被取代的C5-C14芳基。通常,R4代表未被取代的C1-C4烷基。优选R4代表-CH3。
其中
·R1和R2:
(a)独立代表氢或选自以下的基团:具有1-4个碳原子的烷基、链烯基或链炔基,它们任选被一个羟基取代;
或
(b)R1和R2与它们连接的氮原子一起形成包含1-2个选自氮、氧和硫的杂原子的4-至6-元环,该环任选被1-2个C1-C4烷基取代,所述烷基本身未被取代或被一个羟基取代;
·R3代表选自苯基、吡啶基或苄基的基团,所述基团任选被一个或多个(例如1-4个)选自以下的取代基取代:
(i)卤素原子;
(ii)未被取代的C1-C8烷基、未被取代的C1-C8烷氧基、未被取代的C1-C3亚烷二氧基、硝基、三氟甲基和未被取代的C1-C8烷氧基羰基;和
·R4代表未被取代的C1-4烷基。
在本发明另一个实施方案中,R3代表苯基或苄基,其被1-3个C1-6烷氧基取代。
在另一个更优选的本发明实施方案中,R1代表氢原子,R2代表
(i)选自烷基、链烯基或链炔基的基团,它们任选被一个或多个选自以下的取代基取代:卤素原子和羟基、烷氧基、芳氧基、烷硫基、羟基羰基、烷氧基羰基、单-或双-烷基氨基酰基、氧代、氨基、单-或双-烷基氨基;或
(ii)下式的基团
-(CH2)n-R6
其中n为0-4的整数,R6代表环烷基或环烯基;
R3代表被1-3个C1-6烷氧基取代的苯基或苄基。
另一方面,本发明包含制备流程3所示的结构式(I)化合物的合成方法,该方法包括以下步骤:(a)于回流下用氯化剂使式(VI)噻吩并嘧啶酮反应,(b)冷却后除去过量的氯化剂,(c)任选分离式(VII)的氯代噻吩并嘧啶和(d)使式(VII)的氯代噻吩并嘧啶与胺(VII)在密闭气氛中于40℃-120℃反应。
本发明化合物可以通过下列一种方法制备:
流程1
根据GB 1 454 529所述的方法,将氰基乙酸乙酯(III)、元素硫和催化量的哌啶加入3-氨基α,β-不饱和腈(II)溶于乙醇的溶液。加热混合物至50-60℃直到反应启动,证据为混合物的温度升高至90-100℃。开始降温后,回流混合物24小时。过滤收集冷却形成的固体4-取代的2-氨基-5-氰基-噻吩-3-羧酸烷基酯(IV),用乙醇重结晶。
流程2
将干燥的氯化氢气流通过4-取代的2-氨基-5-氰基-噻吩-3-羧酸烷基酯(IV)和相应的腈(V)在二氧杂环己烷中的混合物2小时。于室温搅拌反应物12小时,减压除去溶剂,残余物经二乙醚研磨。过滤获得的沉淀物后干燥,相应的噻吩并嘧啶酮(VI)用于下一步反应,不再进一步提纯。
流程3
将相应的噻吩并嘧啶酮(VI)溶于磷酰氯的溶液回流3-12h。冷却后,减压除去POCl3,将残余物溶于二氯甲烷,有机层经饱和NaHCO3水溶液、水、盐水依次洗涤。有机层经MgSO4干燥,过滤后蒸发,获得相应的粗产物4-氯噻吩并[2,3-d]嘧啶(VII),其用于下一步反应不再进一步提纯。
将胺(VIII)加入在可密封瓶中的4-氯噻吩并[2,3-d]嘧啶(VII)溶于乙醇或混合物乙腈和碱(例如,碱性碳酸盐或二异丙基乙胺)的溶液。用聚丙烯瓶盖密封反应瓶,在常规烘箱中于40-120℃加热过夜,优选60-85℃。冷却后,减压除去溶剂,残余物经快速色谱法提纯,获得终产物噻吩并[2,3-d]嘧啶-4-基胺(I)。
药理学活性
PDE7测定方法
将所有化合物以10mM的贮藏浓度重悬浮于DMSO。于1mM-1nM范围的浓度测试化合物以便计算IC50值。在96孔板中稀释。
对于各个反应,将10微升稀释的化合物加入“低结合”测定板。向每孔加入80微升反应混合物(包含50mM Tris pH 7.5、8.3mMMgCl2、1.7mM EGTA和15nM 3′,5′[3H]-cAMP(约150000dpm))。向反应混合物加入10微升含PDE7的溶液启动反应。然后于室温搅拌下温育反应板1小时。温育后,用50微升(0.89mg)PDE SPA珠(Amersham Pharmacia Biotech RPNQ0150)终止反应,将所得的混合物放置20分钟,然后用微量滴定板计数器计数。
使用上述测定测得实施例中所有化合物的IC50值低于10微摩尔,而且实施例2-7、9-11、13-17、20-22、24-27、31、33-39、41-49、51-57、60-62、64-85、87-93、95-109、111-126、128-129、131-135的化合物的IC50值低于1微摩尔。
PDE7抑制结果表明结构式(I)化合物是磷酸二酯酶7(PDE7)的有效抑制剂,因此可用于治疗或预防通过抑制PDE7而缓解的病症、疾病和紊乱,例如哮喘、特应性皮炎、慢性阻塞性肺病、节段性回肠炎、I型和II型糖尿病、淋巴性白血病和其它类型癌症、多发性硬化、器官移植后同种异体移植排斥、牛皮癣、类风湿性关节炎和溃疡性结肠炎。
某些本发明化合物不仅是有效的PDE7抑制剂,而且选择性抑制其它cAMP特异性磷酸二酯酶例如PDE3或PDE4。化合物中R3基团选自被1-3个C1-6烷氧基取代的苯基或苄基的化合物选择性尤其良好。
本发明化合物还可与已知有效治疗这些疾病的其它药物联合使用。例如,它们可与一种或多种选自以下的化合物联合应用:PDE4抑制剂、A2A腺苷受体拮抗剂、NSAID、COX-2抑制剂、TNF-α抑制剂和类固醇。
因此,本发明再一个实施方案是结构式(I)化合物在制备治疗或预防通过抑制PDE7而缓解的病症、疾病和紊乱的药物上的用途,以及治疗患有通过抑制PDE7而缓解的病症或疾病的患者的方法,该方法包括对所述患者给予有效量的结构式(I)化合物。
本发明还提供药用组合物,所述组合物包括用作有效成分的至少一种结构式(I)化合物或其药物学上可接受的盐和药物学上可接受的赋形剂(例如载体或稀释剂)。根据制剂的性质和应用前是否进一步稀释,有效成分可占组合物的0.001%-99%(重量),优选0.01%-90%(重量)。优选组合物为适于口服、局部应用、鼻、直肠、经皮或注射给予的形式。
与活性化合物或所述化合物的盐混合形成本发明组合物的药物学上可接受的赋形剂是众所周知的,而实际使用的赋形剂根据给予组合物的方法而定。
口服给予的组合物可以为包含本发明化合物的片剂、缓释片剂、舌下片、胶囊剂、吸入气雾剂、吸入溶液剂、干粉吸入剂,或液态制剂例如合剂、酏剂、糖浆剂或混悬剂;这样的制剂可用本领域公知的方法制备。
可用于制备所述组合物的稀释剂包括与有效成分匹配的液体和固体稀释剂,如果需要的话,包括着色剂或调味剂。片剂或胶囊剂通常包含2-500mg有效成分或其等量盐。
适于口服的液态组合物可为溶液剂或混悬剂。溶液剂可为活性化合物的可溶性盐或其它衍生物与例如蔗糖组合形成糖浆剂的水溶液。混悬剂可包含本发明不溶性活性化合物或其药物学上可接受的盐和水以及悬浮剂和调味剂。
肠胃外注射的组合物可由可溶性盐制备,其可以冻干或不冻干并可溶解于无致热原的水性溶媒或其它适当的肠胃外注射液体。
局部应用的组合物可以为包含本发明化合物的软膏剂、乳膏剂或洗剂;这样的制剂可用本领域公知的方法制备。
常规有效剂量为每天10-600mg有效成分。日剂量可以1次或多次给药,优选每天1-4次。
本发明通过下面的实施例进一步说明。给出的实施例仅起说明作用,不对本发明构成限制。
用Varian Unity 300仪于200或300MHz记录1H NMR光谱,于75MHz记录13C NMR光谱。化学位移表示为δ值(ppm)。作为CI(CH4)用HPLC-MS Agilent 1100-MSD-20获得低分辨质谱(MS)。用PerkinElmer DSC-7仪器记录熔点。记录红外光谱用Perkin-Elmer IR-FTSpectrum 2000分光光度计,KBr片或CHCl3膜,谱带以cm-1表示。用Heraeus CHN-O快速仪进行元素分析。
制备实施例:
制备1
2-氨基-5-氰基-4-甲基噻吩-3-羧酸乙酯
向3-氨基巴豆腈(0.01mol)溶于30ml乙醇的溶液加入元素硫(0.01mol)、氰基乙酸乙酯(0.01mol)和催化量的哌啶。最初加热混合物至50-60℃直到开始反应,这时混合物温度升至90-100℃。当反应温度开始下降时,回流混合物24小时。过滤收集冷却形成的固体,用乙醇重结晶,获得褐色固体标题化合物(65%产率)。
m.p.200-202℃;1H-NMR(CDCl3,300MHz)δ6.60(bs,2H),4.32(q,J=7.1Hz,2H),2.49(s,3H),1.38(t,J=7.1Hz,3H)。
制备2
5-甲基-4-氧代-2-苯基-3,4-二氢噻吩并[2,3-d]嘧啶-6-甲腈。
将干燥氯化氢气流通入2-氨基-5-氰基-4-甲基噻吩-3-羧酸乙酯(0.003mol)和苄腈(0.0045mol)在20ml二氧杂环己烷中的混合物2小时。然后,于室温搅拌反应物12小时,减压除去溶剂,残余物经二乙醚研磨。获得沉淀,过滤后干燥,获得褐色固体标题化合物(92%产率)。
1H-MR(DMSO-d6,300MHz)δ13.02(bs,1H),8.21(d,J=6.6Hz,2H),7.66-7.61(m,3H),2.73(s,3H);IR(KBr)3415,2219,1663,1539,700cm-1;
MS(API-ES-,m/z)266.0(M-1)。
制备3
5-甲基-2-(4-硝基苯基)-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-甲腈。
按照制备2介绍的实验方法,用2-氨基-5-氰基-4-甲基噻吩-3-羧酸乙酯和4-硝基苄腈,获得褐色固体标题化合物(47%)。
1H-NMR(DMSO-d6,300MHz)δ13.26(bs,1H),8.29(d,J=8.6Hz,2H),8.08(d,J=8.6Hz,2H),2.69(s,3H);MS(API-ES-,m/z)311.0(M-1)。
制备4
2-(4-甲氧基苯基)-5-甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-甲腈。
按照制备2介绍的实验方法,用2-氨基-5-氰基-4-甲基噻吩-3-羧酸乙酯和4-甲氧基苄腈,获得褐色固体标题化合物(99%)。
1H-NMR(CDCl3,300MHz)δ10.21(bs,1H),7.84(d,J=8.4Hz,2H),6.91(d,J=8.4Hz,2H),3.88(s,3H),2.56(t,3H)。
制备5
5-甲基-2-(4-甲基苯基)-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-甲腈。
按照制备2介绍的实验方法,用2-氨基-5-氰基-4-甲基噻吩-3-羧酸乙酯和4-甲基苄腈,获得褐色固体标题化合物(72%)。
1H-NMR(CDCl3,200MHz)δ10.30(bs,1H),7.97(d,J=7.7Hz,2H),7.29(d,J=7.7Hz,2H),2.78(s,3H),2.45(s,3H)。
制备6
5-甲基-4-氧代-2-[4-(三氟甲基)苯基]-3,4-二氢噻吩并[2,3-d]嘧啶-6-甲腈。
按照制备2介绍的实验方法,用2-氨基-5-氰基-4-甲基噻吩-3-羧酸乙酯和4-三氟甲基苄腈,获得褐色固体标题化合物(81%)。
1H-NMR(CDCl3,300MHz)δ13.00(bs,1H),8.12(d,J=8.0Hz,2H),7.65(d,J=8.0Hz,2H),2.56(t,3H)。
制备7
2-(4-氯苯基)-5-甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-甲腈。
按照制备2介绍的实验方法,用2-氨基-5-氰基-4-甲基噻吩-3-羧酸乙酯和4-氯苄腈,获得褐色固体标题化合物(84%)。
1H-NMR(CDCl3,200MHz)δ13.16(bs,1H),7.73(d,J=8.7Hz,2H),7.41(d,J=8.7Hz,2H),2.78(s,3H)。
制备8
2-(3,4-二甲氧基苯基)-5-甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-甲腈。
按照制备2介绍的实验方法,用2-氨基-5-氰基-4-甲基噻吩-3-羧酸乙酯和3,4-二甲氧基苄腈,获得褐色固体标题化合物(99%)。
1H-NMR(DMSO-d6,300MHz)δ12.62(bs,1H),8.09(d,J=8.4Hz,1H),8.04(s,1H),6.94(d,J=8.4Hz,1H),2.56(s,3H)。
制备9
2-(1,3-苯并二氧杂环戊烯-5-基)-5-甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-甲腈。
按照制备2介绍的实验方法,用2-氨基-5-氰基-4-甲基噻吩-3-羧酸乙酯和1,3-苯并二氧杂环戊烯-5-甲腈,获得褐色固体标题化合物(22%)。
1H-NMR(CDCl3,300MHz)δ13.0(bs,1H),7.79(d,J=7.5Hz,1H),7.7(s,1H),7.08(d,J=7.5Hz,1H),6.15(s,2H),2.65(s,3H)。
制备10
5-甲基-4-氧代-2-吡啶-4-基-3,4-二氢噻吩并[2,3-d]嘧啶-6-甲腈。
按照制备2介绍的实验方法,用2-氨基-5-氰基-4-甲基噻吩-3-羧酸乙酯和异烟酸腈,获得褐色固体标题化合物(63%)。
1H-NMR(DMSO-d6,300MHz)δ13.14(bs,1H),8.77(bs,2H),8.05(bs,2H),2.67(s,3H)。
制备11
2-苄基-5-甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-甲腈。
按照制备2介绍的实验方法,用2-氨基-5-氰基-4-甲基噻吩-3-羧酸乙酯和苯乙腈,获得褐色固体标题化合物(65%)。
1H-NMR(CDCl3,300MHz)δ10.80(bs,1H),7.34-7.28(s,5H),4.06(s,2H),2.71(s,3H)。
制备12
5-甲基-4-氧代-2-(4-苯甲酸甲酯)-3,4-二氢噻吩并[2,3-d]嘧啶-6-甲腈。
按照制备2介绍的实验方法,用2-氨基-5-氰基-4-甲基噻吩-3-羧酸乙酯和4-氰基苯甲酸甲酯,获得褐色固体标题化合物(85%)。
m.p.>250℃;1H-NMR(DMSO-d6,300MHz)δ12.90(bs,1H),8.51(d,J=8.35Hz,2H),8.10(d,J=8.35Hz,2H),3.94(s,3H),2.81(s,3H)。
制备13
5-甲基-4-氧代-2-(3,4,5-三甲氧基苯基)-3,4-二氢噻吩并[2,3-d]嘧啶-6-甲腈。
按照制备2介绍的实验方法,用2-氨基-5-氰基-4-甲基噻吩-3-羧酸乙酯和3,4,5-三甲氧基苄腈,获得褐色固体标题化合物(63%)。
m.p.>250℃;1H-NMR(DMSO-d6,300MHz)δ12.96(bs,1H),7.73(s,2H),3.90(s,6H),3.87(s,3H),2.81(s,3H)。
制备14
2-(3,4-二甲氧基-苄基)-5-甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-甲腈
按照制备2介绍的实验方法,用2-氨基-5-氰基-4-甲基噻吩-3-羧酸乙酯和3,4-二甲氧基苯乙腈,获得褐色固体标题化合物(47%)。
m.p.:>250℃;1H-NMR(DMSO-d6,300MHz):δ(ppm)12.40(bs,1H),6.95-6.89(m,2H),6.77-6.73(m,1H),4.5(s,2H),3.83(s,3H),3.79(s,3H),2.66(s,3H)。
制备15
5-甲基-4-氧代-2-(3,4,5-三甲氧基苄基)-3,4-二氢噻吩并[2,3-d]嘧啶-6-甲腈
按照制备2介绍的实验方法,用2-氨基-5-氰基-4-甲基噻吩-3-羧酸乙酯和3,4,5-三甲氧基苯乙腈,获得褐色固体标题化合物(69%)。
m.p.:>250℃;1H-NMR(CDCl3,300MHz):δ(ppm)10.80(s,1H),6.27(s,2H),4.23(s,2H),3.83(s,6H),3.82(s,3H),2.85(s,3H)。
制备16
5-甲基-4-氧代-2-(苯基乙基)-3,4-二氢噻吩并[2,3-d]嘧啶-6-甲腈
按照制备2介绍的实验方法,用2-氨基-5-氰基-4-甲基噻吩-3-羧酸乙酯和3-苯基丙腈,获得褐色固体标题化合物(69%)。
m.p.:>250℃;1H-NMR(CDCl3,300MHz):δ(ppm)7.37-7.22(m,5H),3.16-2.93(m,4H),22.62(s,3H)。
制备17
5-甲基-4-氧代-2-(苯基丙基)-3,4-二氢噻吩并[2,3-d]嘧啶-6-甲腈
按照制备2介绍的实验方法,用2-氨基-5-氰基-4-甲基噻吩-3-羧酸乙酯和4-苯基丁腈,获得褐色固体标题化合物(94%)。
m.p.:>250℃;1H-NMR(CDCl3,300MHz):δ(ppm)11.6(s,1H),7.28-7.14(m,5H),3.06(t,J=7.2Hz,2H),2.85(s,3H),2.72(t,J=7.2Hz,2H),2.27-2.15(m,2H)。
实施例
根据流程3介绍的合成方法,将相应的噻吩并嘧啶酮(VI)(0.18mmol)溶于磷酰氯(7ml)的溶液回流3-12h。冷却后,减压除去POCl3,将残余物溶于二氯甲烷(20ml),有机层经饱和NaHCO3水溶液、水和盐水依次洗涤。然后经MgSO4干燥,过滤后蒸发,获得相应的粗产物4-氯噻吩并[2,3-d]嘧啶(VII),其不再进一步提纯直接用于下一步反应。
将相应的胺(VIII)(1,3eq.)加入在可密封瓶中的0.27mmol 4-氯噻吩并[2,3-d]嘧啶(VII)溶于25ml乙醇的溶液。用聚丙烯瓶盖密封反应瓶,在常规烘箱中于75℃加热过夜。冷却后,减压除去溶剂,残余物经快速色谱法提纯,获得终产物噻吩并[2,3-d]嘧啶-4-基胺(I)。
实施例1
4-(4-乙基哌嗪-1-基)-5-甲基-2-苯基噻吩并[2,3-d]嘧啶-6-甲腈
m.p.178-179℃;1H-NMR(CDCl3,300MHz)δ8.49-8.45(m,2H),7.50-7.47(m,3H),3.66(t,4H,J=4.4Hz),2.73(s,3H),2.65(t,4H,J=4.4Hz),2.49(q,2H,J=7.1Hz),1.14(t,3H,J=7.1Hz);IR(KBr)2969,2212,1533,1491,1446,1261cm-1;MS(API-ES+,m/z)364(M+1)+。
C20H21N5S(363.480)的分析计算值:C,66.09;H,5.82;N,19.27。
实测值:C,65.36;H,6.86;N,19.05。产率=52%。
实施例2
4-(4-乙基哌嗪-1-基)-2-(4-甲氧基苯基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
m.p.:173-175℃;1H-NMR(CDCl3,200MHz)δ8.43(d,2H,J=8.7Hz),6.99(d,2H,J=8.7Hz),3.89(s,3H),3.65(t,4H,J=4.6Hz),2.72(s,3H),2.65(t,4H,J=4.6Hz),2.50(q,2H,J=7.1Hz),1.15(t,3H,J=7.1Hz);IR(KBr)2812,2211,1533,1252,1165cm-1;MS(API-ES+,m/z)394(M+1)+。C21H23N5OS(393.506)的分析计算值:C,64.10;H,5.89;N,17.80。实测值:C,63.80;H,5.94;N,17.37。产率=24%。
实施例3
4-(二乙基氨基)-5-甲基-2-苯基噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz)δ8.43-8.46(m,2H);7.45-7.47(m,3H),3.60(q,J=7.1Hz,4H),2.70(s,3H),1.23(t,J=7.1Hz,6H);MS(API-ES+,m/z)323(M+1)+。C18H18N4S(322.428),产率=52%。
实施例4
5-甲基-2-苯基-4-哌啶-1-基噻吩并[2,3-d]嘧啶-6-甲腈
m.p.142-144℃;1H-NMR(CDCl3,300MHz)δ8.45-8.48(m,2H),7.45-7.47(m,3H),3.52-4.55(m,4H),2.71(s,3H),1.74-1.77(m,6H)。C19H18N4S(334.439),产率=36%。
实施例5
5-甲基-2-(4-硝基苯基)-4-哌啶-1-基噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz)δ8.62(d,J=8.6Hz,2H),8.29(d,J=8.6Hz,2H),3.57(bs,4H),2.72(s,3H),1.76(bs,6H)。C19H17N5O2S(379.437),产率=20%。
实施例6
2-(4-甲氧基苯基)-5-甲基-4-哌啶-1-基噻吩并[2,3-d]嘧啶-6-甲腈
m.P.202-204℃;1H-NMR(CDCl3,300MHz)δ8.42(d,J=8.6Hz,2H),6.97(d,J=8.6Hz,2H),3.87(bs,3H),3.51(bs,4H),2.70(s,3H),1.75(bs,6H)。C20H20N4OS(364.465)的分析计算值:C,65.91;H,5.53;N,15.37。实测值:C,66.74 H,6.46;N,15.27。产率=15%。
实施例7
5-甲基-4-(4-甲基哌嗪-1-基)-2-(4-硝基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz)δ8.63(d,J=8.72Hz,2H),8.31(d,J=8.72Hz,2H),3.68-3.65(m,4H),2.73(s,3H),2.63-2.60(m,4H),2.36(s,3H);IR CHCl3(νmax)3392,2969,2939,2925,2212,1594,1532,1519,1464,1418,1341,1292,1180,1132,1106,1045,994,870,844,794,762,736,709cm-1;MS(API-ES+,m/z)395.1(M+1)+。C19H18N6O2S(394.451)的分析计算值:C,57.85;H,4.60;N,21.31。实测值:C,49.04;H,5.17;N,14.08。产率=57%。
实施例8
5-甲基-2-苯基-4-哌嗪-1-基噻吩并[2,3-d]嘧啶-6-甲腈
M.P.251-253℃;1H-NMR(CDCl3,200MHz)δ8.46-8.44(m,2H),7.50-7.48(m,3H),3.72-3.66(m,4H),3.20-3.16(m,4H),2.73(s,3H);IR CHCl3(νmax)3432,2926,2211,1635,1532,1490,1438,1403,1377,1362,1330,1298,1258,1229,1183,1171,1143,1120,1055,1025,862,772,706,665cm-1。C18H17N5S(335.427)的分析计算值:C,64.45;H,5.11;N,20.88。实测值:C,58.03;H,4.87;N,17.74。产率=58%。
实施例9
2-(4-甲氧基苯基)-5-甲基-4-(4-甲基哌嗪-1-基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.>250℃;1H-NMR(CDCl3,200MHz)δ8.40(d,J=8.84Hz,2H),6.97(d,J=8.84Hz,2H),3.87(s,3H),3.66-3.62(m,4H),2.71(s,3H),2.66-2.62(m,4H),2.37(s,3H);IR CHCl3(νmax)3316,2963,2818,2729,2488,2218,1653,1635,1604,1582,1522,1495,1468,1427,1417,1400,1381,1334,1303,1285,1247,1196,1171,1146,1105,1088,1068,1047,1022,1000,975,846,792,777,746cm-1。C20H21N5OS(379.480)的分析计算值:C,63.20;H,5.58;N,18.46。实测值:C,64.27;H,5.71;N,18.20。产率=46%。
实施例10
4-(二乙基氨基)-2-(4-甲氧基苯基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
M.P.154-156℃;1H-NMR(CDCl3,200MHz)δ8.41(d,J=9.0Hz,2H),6.97(d,J=9.0Hz,2H),3.87(s,3H),3.59(q,J=6.8Hz,4H),2.69(s,3H),1.23(t,J=6.8Hz,6H);IR(KBr)3413,2212,1605,1538,1245,1021,848cm-1。C19H20N4OS(352.454)的分析计算值:C,64.75;H,5.72;N,15.90。实测值:C,64.67;H,5.86;N,16.22。产率=44%。
实施例11
2-(4-甲氧基苯基)-5-甲基-4-吡咯烷-1-基噻吩并[2,3-d]嘧啶-6-甲腈
M.P.176-178℃;1H-NMR(CDCl3,300MHz)δ8.40(d,2H,J=8.7Hz),6.97(d,2H,J=8.7Hz),3.87(s,3H),3.82-2.97(m,4H),2.69(s,3H),1.99-1.96(m,4H);IR(KBr)2972,2206,1607,1500,1395,1248,1025cm-1。C19H18N4OS(350.439)的分析计算值:C,65.12;H,5.18;N,15.99。实测值:C,65.30;H,5.38;N,19.32。产率=43%。
实施例12
2-(4-甲氧基苯基)-5-甲基-4-哌嗪-1-基噻吩并[2,3-d]嘧啶-6-甲腈
M.P.210-212℃;1H-NMR(CDCl3,200MHz)δ8.36(2H,d,J=9.0Hz,H-苯基),7.07(d,J=9.0Hz,2H),3.83(s,3H),3.64-3.58(m,4H),3.02-2.96(m,4H),2.67(s,3H);IR(KBr)3432,2210,1605,1533,1492,1436,1336,1253,1166,1026,980,848,794cm-1。C19H19N5OS(365.453)的分析计算值:C,62.44;H,5.24;N,19.16。实测值:C,60.72;H,5.44;N,19.44。产率=36%。
实施例13
5-甲基-2-(4-硝基苯基)-4-哌嗪-1-基噻吩并[2,3-d]嘧啶-6-甲腈
M.P.250℃;1H-NMR(CDCl3,300MHz)δ8.43(d,J=8.8Hz,2H),8.33(d,J=8.8Hz,2H),3.50-3.45(m,4H),3.36-3.31(m,4H),2.67(s,3H);IR(KBr)3447,3090,2219,1667,1551,1521,1482,1428,1379,1337,1295,1211,1107,1042,1004,870,845,709,647,538cm-1。C18H16N6O2S(380.425)的分析计算值:C,56.83;H,4.24;N,22.09。实测值:C,56.79;H,4.76;N,22.79。产率=62%。
实施例14
4-(二丁基氨基)-2-(4-甲氧基苯基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
M.P.96-98℃;1H-NMR(CDCl3,300MHz)δ8.42(d,2H,J=8.9Hz),6.99(d,2H,J=8.9Hz),3.88(s,3H),3.55(t,4H,J=7.2Hz),2.69(s,3H),1.63(q,4H,J=7.2Hz),1.25(hex,4H,J=7.2Hz),0.88(t,6H,J=7.2Hz);IR(KBr)2957,2210,1606,1531,1334,1251cm-1。C23H28N4OS(408.561)的分析计算值:C,67.61;H,6.91;N,13.71。实测值:C,67.87;H,6.89;N,13.53。产率=38%。
实施例15
2-(4-氯苯基)-5-甲基-4-(4-甲基哌嗪-1-基)噻吩并[2,3-d]嘧啶-6-甲腈
M.p.209-210℃;1H-NMR(CDCl3,200MHz)δ8.41(d,2H,J=8.5Hz),7.45(d,2H,J=8.5Hz),3.66(t,4H,J=4.6Hz),2.74(s,3H),2.63(t,4H,J=4.6Hz),2.36(s,3H);IR(KBr)2937,2212,1532,1446,1264,1089cm-1;MS(API-ES+,m/z)384(M+1)+。C19H18ClN5S(383.899)的分析计算值:C,59.44;H,4.73;N,18.24。实测值:C,59.12;H,4.79;N,18.53。产率=30%。
实施例16
2-(3,4-二甲氧基苯基)-5-甲基-4-(4-甲基哌嗪-1-基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.208-209℃;1H-NMR(CDCl3,200MHz)δ8.12(dd,1H,J=8.4,1.8Hz),8.05(d,1H,J=1.8Hz),6.98(d,1H,J=8.4Hz),4.03(s,3H),3.98(s,3H),3.64(t,4H,J=4.6Hz),2.74(s,3H),2.64(t,4H,J=4.6Hz),2.39(s,3H);IR(KBr)2933,2210,1517,1456,1251,1025cm-1;MS(API-ES+,m/z)384(M-CN+1)+。C12H23N5O2S(409.506)的分析计算值:C,61.59;H,5.66;N,17.10。实测值:C,55.24;H,5.64;N,16.71。产率=16%。
实施例17
4-[乙基(甲基)氨基]-2-(4-甲氧基苯基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
M.P.122-123℃;1H-NMR(CDCl3,300MHz)δ8.42(d,2H,J=8.9Hz),6.98(d,2H,J=8.9Hz),3.89(s,3H),3.64(q,2H,J=7.1Hz),3.14(s,3H),2.70(s,3H),1.32(t,3H,J=7.1Hz);IR(KBr)2933,2209,1606,1582,1395,1250cm-1;MS(API-ES+,m/z)339(M+1)+。C18H18N4OS(338.428)的分析计算值:C,63.88;H,5.36;N,16.56。实测值:C,63.83;H,5.37;N,16.55。产率=58%。
实施例18
4-(二乙基氨基)-5-甲基-2-(4-硝基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,200MHz)δ8.61(d,J=9.0Hz,2H),8.30(d,J=9.0Hz,2H),3.64(q,J=6.9Hz,4H),2.71(s,3H),1.26(t,J=6.9Hz,6H);IR(KBr)3429,2925,2360,2208,1730,1596,1535,1276,714cm-1。C18H17N5O2S(367.426)。产率=44%。
实施例19
2-(4-氯苯基)-4-(二乙基氨基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,200MHz)δ8.38(d,J=8.7Hz,2H),7.42(d,J=8.7Hz,2H),3.58(q,J=6.9Hz,4H),2.69(s,3H),1.23(t,J=6.9Hz,6H);IR(KBr)3394,2969,2921,2860,2360,2211,1531,849,736cm-1。C18H17ClN4S(356.873)的分析计算值:C,60.58;H,4.80;N,15.70。实测值:C,59.41;H,5.66;N,12.68。产率=45%。
实施例20
4-(二乙基氨基)-2-(3,4-二甲氧基苯基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
M.P.159-161℃;1H-NMR(CDCl3,200MHz)δ8.02-8.11(m,2H);6.94(d,J=8.4Hz,1H),3.99(s,3H),3.94(s,3H),3.58(q,J=6.9Hz,4H),2.68(s,3H),1.23(t,J=6.9Hz,6H);IR(KBr)3448,2987,2213,1516,1018,796cm-1。C20H22N4O2S(382.480)的分析计算值:C,62.80;H,5.80;N,14.65。实测值:C,61.23;H,5.76;N,14.04。产率=22%。
实施例21
4-(二甲基氨基)-2-(4-甲氧基苯基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
M.p.123-125℃;1H-NMR(CDCl3,300MHz)δ8.42(d,J=8.7Hz,2H),6.96(d,J=8.7Hz,2H),3.86(s,3H),3.26(s,6H),2.70(s,3H);IR(KBr)3419,2926,2853,2206,1606,1512,839cm-1。C17H16N4OS(324.401)。产率=23%。
实施例22
2-(4-甲氧基苯基)-5-甲基-4-吗啉-4-基噻吩并[2,3-d]嘧啶-6-甲腈
M.p.204-206℃;1H-NMR(CDCl3,200MHz)δ8.41(d,J=8.8Hz,2H),6.97(d,J=8.8Hz,2H),3.92-3.88(m,4H),3.87(s,3H),3.60-3.56(m,4H),2.72(s,3H);IR(KBr)3438,2964,2837,2210,1605,1583,1533,1489,1464,1426,1400,1380,1363,1326,1301,1252,1235,1189,1162,1118,1067,1030,985,926,869,847,796,748,698,672,635,614,563,484cm-1。C19H18N4O2S(366.438)的分析计算值:C,62.28;H,4.95;N,15.29。实测值:C,58.38;H,4.76;N,14.32。产率=55%。
实施例23
2-(4-氯苯基)-5-甲基-4-吗啉-4-基噻吩并[2,3-d]嘧啶-6-甲腈
M.p.205-207℃;1H-NMR(CDCl3,300MHz)δ8.40(d,J=8.50Hz,2H),7.43(d,J=8.50Hz,2H),3.91-3.88(m,4H),3.61-3.60(m,4H),2.72(s,3H)。C18H15ClN4OS(370.857)的分析计算值:C,58.30;H,4.08;N,15.11。实测值:C,42.51;H,6.56;N,11.03。产率=69%。
实施例24
2-(4-甲氧基苯基)-5-甲基-4-[甲基(丙-2-炔基)氨基]噻吩并[2,3-d]嘧啶-6-甲腈
M.p.160-171℃;1H-NMR(CDCl3,300MHz)δ8.42(d,J=9.10Hz,2H),6.96(d,J=9.10Hz,2H),4.26(d,J=2.35Hz),3.85(s,3H),3.18(s,3H),2.72(s,3H),2.02(s,1H)。C19H16N4OS(348.423)的分析计算值:C,65.50;H,4.63;N,16.08。实测值:C,63.56;H,4.84;N,11.03。产率=39%。
实施例25
4-[(2-羟基乙基)(甲基)氨基]-2-(4-甲氧基苯基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
M.P.144-146℃;1H-NMR(CDCl3,300MHz)δ8.25(d,J=8.74Hz,2H),6.90(d,J=8.74Hz,2H),3.93(t,J=4.6Hz,2H),3.82(t,J=4.6Hz,2H),3.80(s,3H),3.15(s,3H),2.62(s,3H)。C18H18N4O2S(354.427)的分析计算值:C,61.00;H,5.12;N,15.81。实测值:C,60.74;H,5.31;N,14.78。产率=43%。
实施例26
2-(3,4-二甲氧基苯基)-4-[乙基(甲基)氨基]-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
M.P.133-135℃;1H-NMR(CDCl3,200MHz)δ8.11(dd,1H,J=8.4,2.0Hz),8.05(d,1H,J=2.0Hz),6.96(d,1H,J=8.4Hz),4.01(s,3H),3.96(s,3H),3.65(q,2H,J=7.0Hz),3.15(s,3H),2.71(s,3H),1.33(t,3H,J=7.0Hz);IR(KBr)2210,1601,1538,1418,1339,1271,1024cm-1。C19H20N4O2S(368.454)的分析计算值:C,61.94;H,5.47;N,15.21。实测值:C,60.34;H,5.42;N,14.09。产率=50%。
实施例27
5-甲基-2-(4-甲基苯基)-4-(4-甲基哌嗪-1-基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.207-209℃;1H-NMR(CDCl3,200MHz)δ8.36(d,2H,J=8.2Hz),7.29(d,2H,J=8.2Hz),3.65(t,4H,J=4.6Hz),2.74(s,3H),2.63(t,4H,J=4.6Hz),2.44(s,3H),2.38(s,3H);IR(KBr)2797,2211,1533,1492,1363,1172cm-1。C20H21N5S(363.480)的分析计算值:C,66.09;H,5.82;N,19.27。实测值:C,64.11;H,5.77;N,18.45。产率=34%。
实施例28
4-(二乙基氨基)-5-甲基-2-[4-(三氟甲基)苯基]噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,200MHz)δ8.55(d,J=8.2Hz,2H),7.71(d,J=8.2Hz,2H),3.63(q,J=6.9Hz,4H),2.71(s,3H),1.25(t,J=6.9Hz,6H);IR(KBr)3419,2976,2926,2209,1535,1517,1325,1116,854,695cm-1。C19H17F3N4S(390.426)。产率=33%。
实施例29
4-[烯丙基(甲基)氨基]-2-(4-甲氧基苯基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
M.P.126-128℃;1H-NMR(CDCl3,200MHz)δ8.40(d,J=8.4Hz,2H),6.96(d,J=8.4Hz,2H),5.92-6.00(m,1H),5.27-5.37(m,2H),4.17(d,J=5.4Hz,2H),3.87(s,3H),3.09(s,3H),2.70(s,3H);IR(KBr)3433,2962,2916,2360,2206,1533,1251,1168,847,790cm-1。C19H18N4OS(350.439)的分析计算值:C,65.12;H,5.18;N,15.99。实测值:C,65.70;H,6.13;N,13.52。产率=23%。
实施例30
2-(3,4-二甲氧基苯基)-4-[(2-羟基乙基)(甲基)氨基]-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz)δ7.87-7.78(m,2H),7.09(d,J=8.45Hz,1H),4.88(m,2H),4.03(m,2H),3.84(s,6H),2.65(s,3H),2.48(s,3H);MS(API-ES+,m/z)385.1(M+1)+。C19H20N4O3S(384.453)。产率=9%。
实施例31
2-(3,4-二甲氧基苯基)-5-甲基-4-吗啉-4-基噻吩并[2,3-d]嘧啶-6-甲腈
M.P.194-196℃;1H-NMR(CDCl3,300MHz)δ8.11-8.02(m,3H),6.95(d,J=8.46Hz,1H),4.00(s,3H),3.95(s,3H),3.92-3.88(m,4H),3.60-3.56(m,4H),2.72(s,3H);IR(KBr)3448,2963,2838,2361,2209,1600,1535,1492,1463,1407,1378,1339,1267,1252,1230,1183,1136,1113,1064,1024,990,915,876,861,827,790,768,740,676cm-1。C20H20N4O3S(396.464)的分析计算值:C,60.59;H,5.08;N,14.13。实测值:C,60.04;H,5.09;N,13.94。产率=47%。
实施例32
5-甲基-2-(4-甲基苯基)-4-吗啉-4-基噻吩并[2,3-d]嘧啶-6-甲腈
M.P.206-207℃;1H-NMR(CDCl3,300MHz)δ8.34(d,J=8.14Hz,2H),7.27(d,J=8.14Hz,2H),3.91-3.88(m,4H),3.61-3.58(m,4H),2.72(s,3H),2.41(s,3H);IR(KBr)3447,3023,2982,2928,2863,2210,1605,1524,1489,1441,1377,1329,1267,1170,1112,987,868,791,735cm-1。C19H18N4OS(350.439)的分析计算值:C,65.12;H,5.18;N,15.99。实测值:C,59.65;H,4.85;N,14.64。产率=92%。
实施例33
5-甲基-4-(4-甲基哌嗪-1-基)-2-[4-(三氟甲基)苯基]噻吩并[2,3-d]嘧啶-6-甲腈
M.P.187-189℃;1H-NMR(CDCl3,200MHz)δ8.58(d,J=8.2Hz,2H),7.73(d,J=8.2Hz,2H),3.67(t,J=4.6Hz,4H),2.74(s,3H),2.63(t,J=4.6Hz,4H),2.38(s,3H)。C20H18F3N5S(417.452)的分析计算值:C,57.54;H,4.35;N,16.78。实测值:C,57.75;H,4.76;N,15.98。产率=29%。
实施例34
2-(1,3-苯并二氧杂环戊烯-5-基)-5-甲基-4-(4-甲基哌嗪-1-基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.196-197℃;1H-NMR(CDCl3,200MHz)δ8.07(d,J=8.4Hz,1H),7.92(s,1H),6.89(d,J=8.2Hz,1H),6.04(s,2H),3.61(t,J=4.6Hz,4H),2.71(s,3H),2.61(t,J=4.6Hz,4H),2.37(s,3H)。C20H19N5O2S(393.463)的分析计算值:C,61.05;H,4.87;N,17.80。实测值:C,59.92;H,4.91;N,17.26。产率=43%。
实施例35
4-(二乙基氨基)-5-甲基-2-(4-甲基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz)δ8.33(d,J=8.0Hz,2H),7.24(d,J=8.0Hz,2H),3.58(q,J=6.9Hz,4H),2.69(s,3H),2.41(s,3H),1.22(t,J=6.9Hz,6H);IR(KBr)3440,2970,2928,2209,1534,734cm-1。C19H20N4S(336.455)。产率=32%。
实施例36
2-(1,3-苯并二氧杂环戊烯-5-基)-4-(二乙基氨基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
M.P.199-201℃;1H-NMR(CDCl3,300MHz)δ8.06(d,J=8.2Hz,1H),7.92(s,1H)6.88(d,J=8.2Hz,1H),6.02(s,2H),3.58(q,J=6.9Hz,4H),2.67(s,3H),1.22(t,J=6.9Hz,6H);IR(KBr)3440,2972,2901,2205,1531,1445,1035,928,737cm-1。C19H18N4O2S(366.438)的分析计算值:C,62.28;H,4.95;N,15.29。实测值:C,63.84;H,5.67;N,14.28。产率=17%。
实施例37
2-(1,3-苯并二氧杂环戊烯-5-基)-5-甲基-4-吗啉-4-基噻吩并[2,3-d]嘧啶-6-甲腈
M.P.197-198℃;1H-NMR(CDCl3,300MHz)δ8.07(dd,J=8.24y 1.65Hz,1H),7.92(d,J=1.65Hz,1H),6.89(d,J=8.24Hz,1H),6.03(s,2H),3.90-3.87(m,4H),3.59-3.50(m,4H),2.71(s,3H);IR(KBr)3445,2960,2901,2858,2207,1376,1358,1324,1257,1231,1178,1149,1111,1066,917,878,862,827,811,789,738,713cm-1。C19H16N4O3S(380.422)的分析计算值:C,59.99;H,4.24;N,14.73。实测值:C,58.82;H,4.20;N,14.25。产率=57%。
实施例38
4-[乙基(甲基)氨基]-5-甲基-2-吡啶-4-基噻吩并[2,3-d]嘧啶-6-甲腈
M.p.162-164℃;1H-NMR(CDCl3,200MHz)δ8.75(d,J=6.2Hz,2H),8.28(d,J=6.2Hz,2H),3.70(q,J=7.0Hz,2H),3.9(s,3H),2.73(s,3H),1.35(t,J=7.0Hz,3H);IR(KBr)2970,2212,1599,1539,1381,1181,1024cm-1。C16H15N5S(309.390)的分析计算值:C,62.11;H,4.89;N,22.64。实测值:C,61.46;H,4.83;N,21.87。产率=55%。
实施例39
4-[乙基(甲基)氨基]-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.163-164℃;1H-NMR(CDCl3,200MHz)δ7.78(s,2H),3.99(s,6H),3.93(s,3H),3.67(q,J=7.2Hz,2H),3.16(s,3H),2.72(s,3H),1.35(t,J=7.2Hz,3H);IR(KBr)2937,2210,1537,1391,1127cm-1。C20H22N4O3S(398.480)的分析计算值:C,60.28;H,5.56;N,14.06。实测值:C,59.98;H,5.43;N,13.95。产率=55%。
实施例40
2-苄基-5-甲基-4-(4-甲基哌嗪-1-基)噻吩并[2,3-d]嘧啶-6-甲腈
油状物;1H-NMR(CDCl3,200MHz)δ7.42-7.24(m,5H),4.17(s,2H),3.53(t,J=4.6Hz,4H),2.67(s,3H),2.53(t,J=4.6Hz,4H),2.34(s,3H);IR(KBr)2934,2212,1532,1261,1140cm-1。C20H21N5S(363.480)的分析计算值:C,66.09;H,5.82;N,19.27。实测值:C,64.48;H,5.90;N,19.51。产率=81%。
实施例41
5-甲基-4-吗啉-4-基-2-吡啶-4-基噻吩并[2,3-d]嘧啶-6-甲腈
M.P.>250℃;1H-NMR(CDCl3,200MHz)δ8.75(d,J=5.51Hz;2H),8.27(d,J=5.51Hz,2H),3.92-3.88(m,4H),3.66-3.62(m,4H),2.74(s,3H);IR(KBr)3434,2950,2922,2852,2210,1448,1427,1401,1379,1367,1324,1301,1242,1181,1110,1053,1011,984,916,869,846,789cm-1。C17H15N5OS(337.400)的分析计算值:C,60.52;H,4.48;N,20.76。实测值:C,58.97;H,4.50;N,20.05。产率=53%。
实施例42
4-[(2-羟基乙基)(甲基)氨基]-5-甲基-2-吡啶-4-基噻吩并[2,3-d]嘧啶-6-甲腈
M.P.194-195℃;1H-NMR(CDCl3,200MHz)δ8.73(d,J=6.15Hz,2H),8.30(d,J=6.15Hz,2H),3.64-3.57(m,2H),3.53-3.48(m,2H),3.38(s,3H),2.76(s,3H);IR(KBr)3279,2215,1601,1566,1534,1518,1492,1439,1400,1371,1331,1270,1155,1123,1069,1038,1000,845,795,748,702,672cm-1。C16H15N5OS(325.389)的分析计算值:C,59.06;H,4.65;N,21.52。实测值:C,48.32;H,4.02;N,21.90。产率=40%。
实施例43
2-(1,3-苯并二氧杂环戊烯-5-基)-4-[(2-羟基乙基)(甲基)氨基]-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
M.P.195-197℃;1H-NMR(CDCl3,300MHz)δ7.99(dd,J=8.24y 1.65Hz,1H),7.86(d,J=1.65Hz,1H),6.89(d,J=8.24Hz,1H),6.02(s,2H),4.01-3.97(m,2H),3.91-3.87(m,2H),3.22(s,3H),2.71(s,3H);IR(KBr)3548,3426,2901,2206,1735,1625,1539,1501,1444,1404,1377,1363,1343,1324,1249,1192,1109,1076,1059,1032,1009,953,933,914,878,833,812,792,738,713cm-1。
C18H16N4O3S(368.411)的分析计算值:C,58.68;H,4.38;N,15.21。实测值:C,57.66;H,4.56;N,15.01。产率=39%。
实施例44
4-[(2-羟基乙基)(甲基)氨基]-5-甲基-2-(4-甲基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz)δ8.35(d,J=8.24Hz,2H),7.49(d,J=8.24Hz,2H),4.00-3.97(m,2H),3.91-3.88(m,2H),3.22(s,3H),2.70(s,3H),2.40(s,3H);IR(KBr)3457,3413,2960,2921,2211,1670,1610,1535,1495,1436,1408,1391,1375,1331,1302,1173,1125,1050,1028,1005,835,788,736,692cm-1。C18H18N4OS(338.428)的分析计算值:C,63.88;H,5.36;N,16.56。实测值:C,62.71;H,5.68;N,16.26。产率=42%。
实施例45
4-(二乙基氨基)-5-甲基-2-吡啶-4-基噻吩并[2,3-d]嘧啶-6-甲腈
M.P.169-171℃;1H-NMR(CDCl3,300MHz)δ8.75(d,J=6.0Hz,2H);8.26(d,J=6.0Hz,2H),3.63(q,J=7.1Hz,4H),2.70(s,3H),1.25(t,J=7.1Hz,6H);IR(KBr)3423,2924,2212,1597,1535,842,785cm-1。C17H17N5S(323.417)的分析计算值:C,63.13;H,5.30;N,21.65。实测值:C,63.97;H,5.40;N,21.47。产率=8%。
实施例46
2-(3,4-二甲氧基苯基)-4-(二甲基氨基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
M.P.198-200℃;1H-NMR(CDCl3,200MHz)δ8.10(d,J=8.4Hz,1H),8.03(s,1H),6.93(d,J=8.4Hz,1H),4.00(s,3H),3.94(s,3H),3.17(s,6H),2.71(s,3H);IR(KBr)3440,2110,1667,1602,1456,1024,790cm-1。C18H18N4O2S(354.427)。产率=12%。
实施例47
2-(3,4-二甲氧基苯基)-5-甲基-4-(丙基氨基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.179-181℃;1H-NMR(CDCl3,200MHz)δ8.09(d,J=8.4Hz,1H),8.04(s,1H),6.94(d,J=8.4Hz,1H),5.53(bs,1H),4.00(s,3H),3.95(s3H),3.62-3.74(m,2H),2.77(s,3H),1.72-1.85(m,2H),1.06(t,J=7.4Hz,3H);IR(KBr)3440,2926,2204,1671,1556,1269,785cm-1。C19H20N4O2S(368.454)的分析计算值:C,61.94;H,5.47;N,15.21。实测值:C,60.97;H,6.00;N,15.11。产率=6%。
实施例48
4-(二乙基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,200MHz)δ7.76(s,2H),3.97(s,6H),3.91(s,3H),3.59(q,J=7.1Hz,4H),2.70(s,3H),1.25(t,J=7.1Hz,6H);IR(KBr)3438,2962,2936,2210,1737,1531,1127,858,713cm-1。C21H24N4O3S(412.506)的分析计算值:C,61.14;H,5.86;N,13.58。实测值:C,61.00;H,6.44;N,13.92。产率=33%。
实施例49
2-苄基-4-(二乙基氨基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,200MHz)δ7.17-7.38(m,5H),4.13(s,2H),3.51(q,J=6.9Hz,4H),2.62(s,3H),1.12(t,J=6.9Hz,6H),IR(KBr)3369,1727,1534,1494,794cm-1。C19H20N4S(336.455)。产率=12%。
实施例50
5-甲基-4-(4-甲基-哌嗪-1-基)-2-苯基-噻吩并[2,3-d]嘧啶-6-甲腈
M.P.223-225℃;1H-NMR(CDCl3,300MHz)δ8.48-8.40(m,3H),7.49-7.46(m,3H),3.69-3.63(m,4H),2.72(s,3H),2.66-2.62(m,4H),2.38(s,3H);IR(KBr)3416,2969,2921,2212,1532,1445,1402,1377,1360,1326,1298,1172,1141,1063,1027,998,861,772,705,691,680,661cm-1。C19H19N5S(349.454)的分析计算值:C,65.30;H,5.48;N,20.04。实测值:C,62.32;H,5.27;N,20.75。产率=42%。
实施例51
5-甲基-4-吗啉-4-基-2-(3,4,5-三甲氧基-苯基)-噻吩并[2,3-d]嘧啶-6-甲腈
M.P.>250℃;1H-NMR(CDCl3,300MHz)δ7.76(s,2H),3.97(s,6H),3.92(s,3H),3.91-3.88(m,4H),3.59-3.56(m,4H),2.73(s,3H);IR(KBr)3391,2922,2846,2359,2209,1592,1291,1225,1156,986,792,733cm-1。C21H22N4O4S(426.490)的分析计算值:C,59.14;H,5.20;N,13.14。实测值:C,56.47;H,5.96;N,13.72。产率=55%
实施例52
4-[(2-羟基-乙基)-甲基-氨基]-5-甲基-2-(3,4,5-三甲氧基-苯基)-噻吩并[2,3-d]嘧啶-6-甲腈
M.P.164-166℃;1H-NMR(CDCl3,300MHz)δ7.68(s,2H),3.99(t,J=4.64Hz,2H),3.96(s,6H),3.90(s,3H),3.88(t,J=4.64Hz,2H),2.72(s,3H);IR(KBr)3513,2935,2210,2203,1692,1591,1538,1501,1463,1391,1224,1004,925,789,717cm-1。C20H22N4O4S(414.479)的分析计算值:C,57.96;H,5.35;N,13.52。实测值:C,58.96;H,5.96;N,13.72。产率=19%。
实施例53
2-(3,5-二甲氧基-苯基)-5-甲基-4-(4-甲基-哌嗪-1-基)-噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz)δ7.64(s,2H),6.59(d,1H),3.87(s,6H),3.61(bs,4H),2.71(s,3H),2.59(bs,4H),2.34(s,3H);IR(KBr)3440,2938,2210,1740,1591,1534,1150,792cm-1。C21H23N5O2S(409.506)的分析计算值:C,61.59;H,5.66;N,17.10。实测值:C,61.05;H,5.78;N,17.78。产率=42%。
实施例54
4-二乙基氨基-2-(3,5-二甲氧基-苯基)-5-甲基-噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz)δ7.64(s,J=2.3Hz,2H),6.58(t,J=2.3Hz,1H),3.87(s,6H),3.59(c,J=6.9Hz,4H),2.69(s,3H),1.23(t,J=6.9Hz,6H);IR(KBr)3399,2976,2934,2211,1522,1442,1199,1067,738cm-1。C20H22N4O2S(382.480)的分析计算值:C,62.80;H,5.80;N,14.65。实测值:C,62.36;H,5.87;N,14.82。产率=44%。
实施例55
2-(3,5-二甲氧基-苯基)-4-(乙基-甲基-氨基)-5-甲基-噻吩并[2,3-d]嘧啶-6-甲腈
M.P.145-148℃;1H-NMR(CDCl3,300MHz)δ7.65(d,J=2.34Hz 2H),6.59(t,J=2.34Hz,1H),3.88(s,6H),3.64(dd,J=7.04Hz,4.07Hz,2H),3.14(s,3H),2.70(s,3H),1.31(t,J=7.04Hz,3H);IRNaCl(νmax)2210,1521,1497,1442,1391,1202,1064cm-1。C19H20N4O2S(368.454)的分析计算值:C,61.94;H,5.47;N,15.21。实测值:C,61.04;H,5.64;N,15.85。产率=50%。
实施例56
4-(6-氰基-4-二乙基氨基-5-甲基-噻吩并[2,3-d]嘧啶-2-基)-苯甲酸甲酯
1H-NMR(CDCl3,300MHz)δ8.49(d,J=8.2Hz,2H),8.11(d,J=8.2Hz,2H),3.94(s,3H),3.63(c,J=7.2Hz,4H),2.71(s,3H),1.25(t,J=7.2Hz,6H)。IR(KBr)3393,3295,2213,1714,1531,1274,1017,717cm-1。C20H20N4O2S(380.465)的分析计算值:C,63.14;H,5.30;N,14.73。实测值:C,60.89;H,5.47;N,14.39。产率=24%。
实施例57
4-[6-氰基-4-(乙基-甲基-氨基)-5-甲基-噻吩并[2,3-d]嘧啶-2-基]-苯甲酸甲酯
M.P.125-128℃;1H-NMR(CDCl3,300MHz)δ8.51(d,J=8.35Hz,2H),8.10(d,J=8.35Hz,2H),3.94(s,3H),3.67(dd,J=14.22Hz,7.18Hz,2H),3.16(s,3H),1.35(t,J=14.22Hz,3H);IR(KBr)2211,1721,1643,1536,1496,1277,1103,1015,719cm-1。C19H18N4O2S(366.438)的分析计算值:C,62.28;H,4.95;N,15.29。实测值:C,59.28;H,5.13;N,15.22。产率=57%。
实施例58
2-苄基-5-甲基-4-吗啉-4-基-噻吩并[2,3-d]嘧啶-6-甲腈
M.P.88-90℃;1H-NMR(CDCl3,300MHz)δ7.38-7.35(m,2H),7.30-7.25(m,2H),7.22-7.17(m,1H),4.16(s,2H),3.80-3.76(m,4H),3.51-3.47(m,4H)2.65(s,3H);IR(KBr)3385,3061,3028,2963,2498,1532,1298,1093,997,861,798,696cm-1。C19H18N4OS(350.439)的分析计算值:C,65.12;H,5.18;N,15.99。实测值:C,63.16;H,5.47;N,15.39。产率=59%。
实施例59
2-苄基-4-[(2-羟基-乙基)-甲基-氨基]-5-甲基-噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMRδ7.42-7.30(m,4H),7.27-7.23(m,1H),4.15(s,2H),3.89(t,J=4.64Hz,2H),3.76(t,J=4.64Hz,2H),3.19(s,3H),2.69(s,3H);IR(KBr)3401,3085,3028,2924,1503,1257,1074,1029,800,784,695cm-1。C18H18N4OS(338.428)的分析计算值:C,63.88;H,5.36;N,16.56。实测值:C,63.32;H,5.05;N,16.55。产率=43%。
实施例60
5-甲基-4-(4-甲基-哌嗪-1-基)-2-(3,4,5-三甲氧基-苯基)-噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz)δ7.77(s,2H),3.98(s,6H),3.92(s,3H),3.65-3.62(m,4H),2.73(s,3H),2.68-2.63(m,4H),2.39(s,3H);IR(KBr)3384,2925,2851,2360,1733,1590,1507,1259,1124,998,779cm-1。C22H25N5O3S(439.532)。产率=75%。
实施例61
4-(6-氰基-5-甲基-4-吗啉-4-基噻吩并[2,3-d]嘧啶-2-基)苯甲酸甲酯
1H-NMR(CDCl3,200MHz):δ(ppm)8.52(d,J=8.3Hz,2H),8.13(d,J=8.3Hz,2H),3.94(s,3H),3.93-3.88(m,4H),3.65-3.60(m,4H),2.74(s,3H)。产率=75%。
实施例62
4-[6-氰基-5-甲基-4-(4-甲基哌嗪-1-基)噻吩并[2,3-d]嘧啶-2-基]苯甲酸甲酯
1H-NMR(CDCl3,300MHz):δ(ppm)8.46(d,J=7.1Hz,2H),8.24(d,J=7.1Hz,2H),3.95(s,3H),3.62(bs,4H),2.78(s,3H),2.60(bs,4H),2.42(s,3H)。IR(KBr):νmáx(cm-1)3395,2925,2209,1719,1536,1324,11183,719。产率=45%。
实施例63
4-[6-氰基-4-(二甲基氨基)-5-甲基噻吩并[2,3-d]嘧啶-2-基]苯甲酸甲酯
1H-NMR(CDCl3,300MHz):δ(ppm)8.55(d,J=8.5Hz,2H),8.14(d,J=8.5Hz,2H),3.96(s,3H),3.23(s,6H),2.75(s,3H)。IR(KBr):νmáx(cm-1)2360,2341,2211,1719,1540,1519,1497,1276。产率=82%。
实施例64
4-{6-氰基-4-[(2-羟基乙基)(甲基)氨基]-5-甲基噻吩并[2,3-d]嘧啶-2-基}苯甲酸甲酯
1H-NMR(CDCl3,300MHz):δ(ppm)8.43(d,J=8.4Hz,2H),8.10(d,J=8.4Hz,2H),4.02-3.98(m,2H),3.93(s,3H),3.94-3.84(m,2H),3.25(s,3H),2.72(s,3H)。产率=40%。
实施例65
5-甲基-4-(甲基氨基)-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz):δ(ppm)7.79(s,2H),5.52(bs,1H),3.97(s,6H),3.91(s,3H),3.28(d,J=4.8Hz,3H),2.77(s,3H)。IR(KBr):νmáx(cm-1)3439,2923,2852,1728,1576,1128,788。产率=13%。
实施例66
4-(二甲基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz):δ(ppm)7.79(s,2H),3.99(s,6H),3.93(s,3H),3.20(s,6H),2.74(s,3H)。IR(KBr):νmáx(cm-1)2951,2928,2206,1542,1503,1464,1384,1340,1220,1127,997。产率=81%。
实施例67
4-(乙基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz):δ(ppm)7.77(s,2H),5.40(bs,1H),3.97(s,6H),3.91(s,3H),3.79-3.75(m,2H),2.77(s,3H),1.39(t,J=7.1Hz,3H)。IR(KBr):νmáx(cm-1)3443,2955,2207,1575,1400,1344,1127,788。产率=52%。
实施例68
5-甲基-4-(丙基氨基)-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz):δ(ppm)7.79(s,2H),5.63(m,1H),3.99(s,6H),3.93(s,3H),3.72(m,2H),2.79(s,3H),1.82(m,2H),1.08(t,J=7.4Hz,3H)。IR(KBr):νmáx(cm-1)3594,3526,2957,2211,1508,11224,1126。HPLC-MS(API-ES+,m/z)399.1(M+1)+。产率=77%。
实施例69
4-(丁基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:192-194℃;1H-NMR(CDCl3,300MHz):δ(ppm)7.79(s,2H),5.60(bs,1H),3.99(s,6H),3.93(s,3H),3.76(m,2H),2.78(s,3H),1.77(m,2H),1.52(m,2H),1.02(t,J=7.2Hz,3H)。IR(KBr):νmáx(cm-1)3428,2955,2872,2212,1222,1174,1129,1088,731,722。HPLC-MS(API-ES+,m/z)413.0(M+1)+。产率=75%。
实施例70
4-(异丙基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.191-193℃。1H-NMR(CDCl3,300MHz):δ(ppm)7.76(s,2H),5.36(bs,1H),4.58-4.43(m,1H),3.97(s,6H),3.91(s,3H),2.76(s,3H),1.32(d,J=5.9Hz,6H)。IR(KBr):νmáx(cm-1)3444,2969,2933,2212,1551,1399,1128。HPLC-MS(API-ES+,m/z)399.1(M+1)+。产率=75%。
实施例71
4-(仲丁基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:91-93℃。1H-NMR(CDCl3,300MHz):δ(ppm)7.76(s,2H),5.35(d,J=6.9Hz,1H),4.47-4.41(m,1H),3.97(s,6H),3.91(s,3H),2.76(s,3H),1.80-1.73(m,2H),1.36(d,J=6.4Hz,3H),1.03(t,J=7.4Hz,3H)。IR(KBr):νmáx(cm-1)3464,2962,2832,2205,1553,1398,1343,1133,1006,789,732。HPLC-MS(API-ES+,m/z)413.1(M+1)+。产率=41%。
实施例72
4-(异丁基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:182-184℃;1H-NMR(CDCl3,300MHz):δ(ppm)7.76(s,2H),5.67(t,J=5.4Hz,1H),3.97(s,6H),3.90(s,3H),3.55(t,J=6.2Hz,2H),2.76(s,3H),2.12(m,1H),1.03(d,J=6.9Hz,6H)。IR(KBr):νmáx(cm-1)3447,3431,2952,2210,1551,1507,1084,789,731。HPLC-MS(API-ES+,m/z)413.3(M+1)+。产率=95%。
实施例73
4-[(1-乙基丙基)氨基]-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:226-228℃;1H-NMR(CDCl3,300MHz):δ(ppm)7.76(s,2H),5.33(d,J=7.6Hz,1H),4.36-4.33(m,1H),3.97(s,6H),3.96(s,3H),2.76(s,3H),1.78-1.53(m,4H),1.01(t,J=7.4Hz,6H)。IR(KBr):νmáx(cm-1)3465,2965,2205,1553,1507,1398,1132,1005,789,617。HPLC-MS(API-ES+,m/z)427.1(M+1)+。产率=67%。
实施例74
4-(叔丁基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:195-197℃;1H-NMR(CDCl3,300MHz):δ(ppm)7.77(s,2H),5.51(bs,1H),3.97(s,6H),3.92(s,3H),2.75(s,3H),1.64(s,9H)。IR(KBr):νmáx(cm-1)3468,2952,2209,1553,1508,1401,1129,1009,789,731。HPLC-MS(API-ES+,m/z)413.2(M+1)+。产率=75%。
实施例75
4-(环丙基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz):δ(ppm)7.86(s,2H),5.75(s,1H),3.97(s,6H),3.39(s,3H),3.06(m,1H),2.73(s,3H),0.99(dd,J=6.6Hz,2H),0.72(dd,J=6.6Hz,2H)。IR(KBr):νmáx(cm-1)2209,1556,1505,1445,1400,1342,1233,1176,1131,865,789,732。产率=55%。
实施例76
4-(环丁基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz):δ(ppm)7.78(s,2H),5.63(d,J=5.5Hz,1H),4.75(m,1H),3.99(s,6H),3.92(s,3H),2.78(s,3H),2.58(m,2H),2.04(m,2H),1.94(m,2H)。IR(KBr):νmáx(cm-1)2350,2202,1565,1505,1447,1399,1341,1125,859,787。产率=55%。
实施例77
4-(环戊基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:218-220℃;1H-NMR(CDCl3,300MHz):δ(ppm)7.78(s,2H),5.50(d,J=6.0Hz,1H),4.67-4.60(m,1H),3.96(s,6H),3.90(s,3H),2.74(s,3H),2.40.22(m,2H),1.77-1.49(m,6H)。IR(KBr):νmáx(cm-1)3477,2962,2936,2866,2070,1553,1372,1125,790,732。HPLC-MS(API-ES+,m/z)425.1(M+1)+。产率=63%。
实施例78
4-[烯丙基(甲基)氨基]-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:162-164℃;1H-NMR(CDCl3,200MHz):δ(ppm)7.75(s,2H),6.10-5.92(m,1H),5.38-5.33(m,2H),4.19-4.16(m,2H),3.96(s,6H),3.90(s,3H),3.11(s,3H),2.71(s,3H)。IR(KBr):νmáx(cm-1)3365,2361,1728,1536,1133,1007,784。产率=38%。
实施例79
5-甲基-4-[甲基(丙-2-炔基)氨基]-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,200MHz):δ(ppm)7.83(s,2H),4.28(bs,2H),3.97(s,6H),3.91(s,3H),3.21(s,3H),2.75(s,3H),2.33(bs,1H)。IR(KBr):νmáx(cm-1)3293,3246,2993,2939,2826,2359,2212,1537,1462,733。产率=42%。
实施例80
4-[(2-羟基乙基)氨基]-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,200MHz):δ(ppm)7.71(s,2H),6.10(bs,1H),3.97(s,6H),3.96-3.91(m,4H),3.91(s,3H),2.78(s,3H)。IR(KBr):νmáx(cm-1)3494,3453,2212,1651,1582,1556,1511,1222,1180,735。HPLC-MS(API-ES+,m/z)401.1(M+1)+。产率=43%。
实施例81
4-[(2-甲氧基乙基)氨基]-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,200MHz):δ(ppm)7.74(s,2H),6.02(ta,1H),3.96(s,6H),3.94-3.88(m,2H),3.90(s,3H),3.68(t,J=5.0Hz,2H),3.43(s,3H),2.75(s,3H)。IR(KBr):νmáx(cm-1)3500,3406,2924,2205,1715,1569,1555,1511,1447,1224,730。HPLC-MS(API-ES+,m/z)415.1(M+1)+。产率=42%。
实施例82
4-{[2-(二甲基氨基)乙基]氨基}-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,200MHz):δ(ppm)7.73(s,2H),6.72(bs,1H),3.98(s,6H),3.94(s,3H),3.72(m,2H),2.75(s,3H),2.65(bs,2H),2.34(s,6H)。IR(KBr):νmáx(cm-1)3429,2943,2825,2773,2360,2341,2209,1570,1508,1448,1223,1127,732。HPLC-MS(API-ES+,m/z)426.1(M+1)+。产率=36%。
实施例83
5-甲基-4-(3-甲基哌嗪-1-基)-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:213-215℃;1H-NMR(CDCl3,200MHz):δ(ppm)7.75(s,2H),3.96(s,6H),3.90(s,3H),3.88(da,1H),3.25(td,J=11.0y 3.5Hz,1H),3.09(m,3H),2.82(dd,J=12.6y 10.6Hz,1H),2.70(s,3H),1.11(d,J=6.2Hz,3H)。IR(KBr):νmáx(cm-1)2209,1533,1498,1394,1344,1223,1126,1005,733。HPLC-MS(API-ES+,m/z)440.2(M+1)+。产率=44%。
实施例84
4-(3,5-二甲基哌嗪-1-基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:186-188℃;1H-NMR(CDCl3,200MHz):δ(ppm)7.75(s,2H),4.04(s,6H),3.96(s,3H),3.89(s,1H),3.87(s,1H),3.12(bs,2H),2.82(t,J=11Hz,2H),2.69(s,3H),1.12(d,J=6.2Hz,6H)。IR(KBr):νmáx(cm-1)3321,2961,2933,2831,2212,1591,1395,1126,1005,861,786,717。HPLC-MS(API-ES+,m/z)454.2(M+1)+。产率=17%。
实施例85
4-(4-乙酰基哌嗪-1-基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:211-213℃;1H-NMR(CDCl3,200MHz):δ(ppm)7.75(s,2H),3.97(s,6H),3.92(s,3H),3.69(bs,2H),3.59(bs,2H),3.55(bs,2H),3.54(bs,2H),2.74(s,3H),2.16(s,3H)。IR(KBr):νmáx(cm-1)3433,2914,2211,1639,1535,1432,1258,1132,998,792。产率=53%。
实施例86
4-[(2-氨基乙基)(甲基)氨基]-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:>290℃;1H-NMR(CDCl3,300MHz):δ(ppm)7.78(s,2H),6.68(ta,2H),3.99(s,6H),3.92(s,3H),3.77(ca,2H),2.97(ta,2H),2.77(s,3H),2.50(s,3H)。IR(KBr):νmáx(cm-1)3427,1575,1506,1446,1396,1221,1126,1001,788,668。HPLC-MS(API-ES+,m/z)414.3(M+1)+。产率=45%。
实施例87
N-[6-氰基-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-4-基]-β-丙氨酸
M.P.:222-225℃;1H-NMR(CDCl3,200MHz):δ(ppm)7.79(bs,2H),5.51(bs,4H),3.95(bs,6H),3.86(bs,3H),2.79(bs,3H),2.17(bs,1H)。IR(KBr):νmáx(cm-1)3440,2947,2211,1713,1551,1400,1126,789,733。HPLC-MS(API-ES+,m/z)429.2(M+1)+。产率=25%。
实施例88
5-甲基-4-(1H-吡唑-1-基)-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:209-214℃;1H-NMR(CDCl3,200MHz):δ(ppm)8.52(bs,1H),7.88(bs,1H),7.80(s,2H),6.62(bs,1H),3.99(s,6H),3.93(s,3H),2.66(s,3H)。IR(KBr):νmáx(cm-1)3433,2934,2836,2216,1520,1492,1235,1225,1185,635。HPLC-MS(API-ES+,m/z)408(M+1)+。产率=66%。
实施例89
4-(1H-咪唑-1-基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:238-240℃;1H-NMR(CDCl3,200MHz):δ(ppm)8.04(bs,1H),7.80(s,2H),7.44(bs,1H),7.34(bs,1H),3.98(s,6H),3.94(s,3H),2.39(s,3H)。IR(KBr):νmáx(cm-1)3425,3123,2933,2218,1556,1408,1128,1004,711。HPLC-MS(API-ES+,m/z)408.1(M+1)+。产率=33%。
实施例90
5-甲基-4-(2H-1,2,3-三唑-2-基)-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:208-210℃;1H-NMR(CDCl3,200MHz):δ(ppm)8.05(s,2H),7.82(s,2H),3.97(s,6H),3.92(s,3H),2.31(s,3H)。IR(KBr):νmáx(cm-1)3439,2939,2216,1558,1520,1398,1126,1000,839,713。HPLC-MS(API-ES+,m/z)409.1(M+1)+。产率=32%。
实施例91
5-甲基-4-(1H-1,2,4-三唑-1-基)-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:236-240℃;1H-NMR(CDCl3,300MHz):δ(ppm)9.11(s,1H),8.25(s,1H),7.78(s,2H),3.98(s,6H),3.94(s,3H),2.63(s,3H)。IR(KBr):νmáx(cm-1)3435,2939,2214,1560,1507,1491,1178,1126。HPLC-MS(API-ES+,m/z)409.2(M+1)+。产率=60%。
实施例92
2-(3,4-二甲氧基苄基)-5-甲基-4-吗啉-4-基噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:67-70℃;1H-NMR(CDCl3,300MHz):δ(ppm)6.95(s,1H),6.91(d,J=8.0Hz,1H),6.77(d,J=8.0Hz,1H),4.09(s,2H),3.85(s,3H),3.82(s,3H),3.81(t,J=4.0Hz,4H),3,49(t,J=4.0Hz,4H)。IR(KBr):νmáx(cm-1)2960,2855,2212,1534,1495,1442,730。HPLC-MS(API-ES+,m/z)411.1(M+1)+。产率=46%。
实施例93
2-(3,4-二甲氧基苄基)-5-甲基-4-(4-甲基哌嗪-1-基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz):δ(ppm)7.24-6.94(m,2H),6.90-6.79(m,1H),4.08(s,2H),3.83(d,J=4.8Hz,6H),3.54-3.49(m,4H),2.64(s,3H),2.54-2.49(m,4H),2.32(s,3H)。IR(KBr):νmáx(cm-1)3435,2935,2839,2791,2211,1534,1261,1140,1028,729。产率=58%。
实施例94
2-(3,4-二甲氧基苄基)-5-甲基-4-(甲基氨基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:161-163℃;1H-NMR(CDCl3,300MHz):δ(ppm)7.00(s,1H),6.94(d,J=8.2Hz,1H),6.77(d,J=8.2Hz,1H),5.45(bs,1H),4.04(s,2H),3.85(s,3H),3.82(s,3H),3.14(d,J=4.9Hz,3H),2.70(s,3H)。IR(KBr):νmáx(cm-1)3416,1926,2212,1676,1578,1512,1230,1026,753。产率=60%。
实施例95
2-(3,4-二甲氧基苄基)-4-(乙基氨基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:125-126℃;1H-NMR(CDCl3,300MHz):δ(ppm)7.23(s,1H),6.95(d,J=8.2Hz,1H),6.77(d,J=8.2Hz,1H),5.44(ta,1H),4.01(s,2H),3.85(s,3H),3.82(s,3H),3.66-3.61(m,2H),2.70(s,3H),1.27(t,J=7.3Hz,3H)。IR(KBr):νmáx(cm-1)3436,2931,2214,1577,1506,1445,1398,1270,1025,808,765。产率=48%。
实施例96
2-(3,4-二甲氧基苄基)-5-甲基-4-(丙基氨基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz):δ(ppm)6.99(s,1H),6.96(d,J=7.9Hz,1H),6.76(s,J=7.9Hz,1H),5.54(bs,1H),4.04(s,2H),3.87(s,3H),3.85(s,3H),3.60(c,J=6.9Hz,2H),2.73(s,3H),1.68(m,2H),1.00(t,J=7.1Hz,3H)。IR(KBr):νmáx(cm-1)3433,2961,2210,1572,1549,1508,1448,1260,1234,1154,1028,731,559。HPLC-MS(API-ES+,m/z)383.1(M+1)+。产率=85%。
实施例97
4-(环丙基氨基)-2-(3,4-二甲氧基苄基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz):δ(ppm)7.00(s,1H),6.97(d,J=8.0Hz,1H),6.77(d,J=8.0Hz,1H),5.63(bs,1H),4.05(s,2H),3.84(s,3H),3.82(s,3H),2.96(m,1H),2.64(s,3H),0.89(m,2H),0.56(m,2H)。IR(KBr):νmáx(cm-1)3433,2961,2210,1572,1549,1508,1448,1260,1234,1154,1028,731,559。HPLC-MS(API-ES+,m/z)388.1(M+1)+。产率=83%。
实施例98
4-(环丁基氨基)-2-(3,4-二甲氧基苄基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz):δ(ppm)6.95(s,1H),6.91(d,J=8.0Hz,1H),6.76(d,J=8.0Hz,1H),5.55(d,J=6.22Hz,1H),4.67(m,1H),4.00(s,2H),3.85(s,3H),3.82(s,3H),2.70(s,3H),2.44(m,2H),1.85(m,4H)。IR(KBr):νmáx(cm-1)3428,2939,2211,1568,1547,1260,1234,731。HPLC-MS(API-ES+,m/z)395.1(M+1)+。产率=80%。
实施例99
2-(3,4-二甲氧基苄基)-4-(二甲基氨基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz):δ(ppm)6.99(s,1H),6.97(d,J=8.2Hz,1H),6.77(d,J=8.2Hz,1H),4.05(s,2H),3.85(s,3H),3.82(s,3H),3.08(s,6H),2.64(s,3H)。IR(KBr):νmáx(cm-1)2998,2955,2933,2834,2211,1513,1261,1234,1155,1027。HPLC-MS(API-ES+,m/z)369.1(M+1)+。产率=84%。
实施例100
2-(3,4-二甲氧基苄基)-4-[乙基(甲基)氨基]-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz):δ(ppm)6.97(d,J=1.8Hz,1H),6.92(dd,J=7.9Hz y 1.8Hz,1H),6.76(d,J=7.9Hz,1H),4.04(s,2H),3.84(s,3H),3.52(c,J=7.1Hz,2H),3.04(s,3H),2.62(s,3H),1.20(t,J=7.1Hz,3H)。IR(KBr):νmáx(cm-1)3430,2963,2934,2834,2252,2211,1261,1235,767。HPLC-MS(API-ES+,m/z)383.1(M+1)+。产率=83%。
实施例101
4-(二乙基氨基)-2-(3,4-二甲氧基苄基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:107-109℃;1H-NMR(CDCl3,300MHz):δ(ppm)6.95-6.89(m,2H),6.78-6.74(m,1H),4.06(s,2H),3.85(s,3H),3.83(s,3H),3.49(c,J=7.1Hz,4H),2.62(s,3H),1.14(t,J=7.1Hz,6H)。IR(KBr):νmáx(cm-1)3418,2926,2212,1516,1267,1137,1030。HPLC-MS(API-ES+,m/z)397.1(M+1)+。产率=37%。
实施例102
4-[烯丙基(甲基)氨基]-2-(3,4-二甲氧基苄基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:98-100℃;1H-NMR(CDCl3,300MHz):δ(ppm)6.97-6.91(m,2H),6.79-6.76(m,1H),5.87-5.82(m,1H),5.28(d,J=5.8Hz,1H),5.24(s,1H),4.08-4.05(m,3H),3.87-3.82(m,7H),3.00(s,3H),2.64(s,3H)。IR(KBr):νmáx(cm-1)3433,2969,2934,2217,1538,1507,1259,1024,798。产率=55%。
实施例103
2-(3,4-二甲氧基苄基)-5-甲基-4-[甲基(丙-2-炔基)氨基]噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz):δ(ppm)6.98-6.93(m,2H),6.77(d,J=7.9Hz,1H),4.20(s,2H),4.09(s,2H),3.86(s,3H),3.83(s,3H),3.14(s,3H),2.69(s,3H),2.30(bs,1H)。IR(KBr):νmáx(cm-1)3412,3280,2931,2832,2212,1536,1463,1261,1028,911,797,730。HPLC-MS(API-ES+,m/z)393.1(M+1)+。产率=39%。
实施例104
2-(3,4-二甲氧基苄基)-4-[(2-羟基乙基)氨基]-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:149-151℃;1H-NMR(CDCl3,300MHz):δ(ppm)6.93-6.88(m,2H),6.77(d,J=7.9Hz,1H),6.00(bs,1H),4.00(s,2H),3.85-3.76(m,10H),3.09(t,J=8.9Hz,1H),2.73(s,3H)。IR(KBr):νmáx(cm-1)3457,3205,2996,2934,2832,2208,1673,1574,1448,1262,796,761,647。HPLC-MS(API-ES+,m/z)385.1(M+1)+。产率=64%。
实施例105
2-(3,4-二甲氧基苄基)-4-[(2-羟基乙基)(甲基)氨基]-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:62-63℃;1H-NMR(CDCl3,300MHz):δ(ppm)6.94-6.85(m,2H),6.80-6.74(m,1H),4.04(m,2H),3.99-3.82(m,8H),3.76-3.73(m,2H),3.16(s,3H),2.66(m,3H)。IR(KBr):νmáx(cm-1)3426,2932,2211,1661,1542,1514,1463,1261,1026,797。产率=64%。
实施例106
2-(3,4-二甲氧基苄基)-4-[(2-甲氧基乙基)氨基]-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:94-97℃;1H-NMR(CDCl3,300MHz):δ(ppm)6.95(s,1H),6.86(d,J=8.2Hz,1H),6.76(d,J=8.2Hz,1H),5.96(bs,1H),4.02(s,2H),3.85(s,3H),3.83(s,3H),3.79(t,J=5.1Hz,2H),3.56(t,J=5.1Hz,2H),3.38(s,3H),2.70(s,3H)。IR(KBr):νmáx(cm-1)3454,2931,2833,2211,1573,1549,1260,1234,1190,1154,1138,1123。HPLC-MS(API-ES+,m/z)399.1(M+1)+。产率=57%。
实施例107
4-[[2-(二甲基氨基)乙基](甲基)氨基]-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:125-127℃;1H-NMR(CDCl3,300MHz):δ(ppm)7.75(s,2H),3.97(s,6H),3.91(s,3H),3.7(t,J=6.6Hz,2H),3.20(s,3H),2.70(s,3H),2.61(t,J=6.6Hz,2H),2.24(s,6H)。IR(KBr):νmáx(cm-1)3445,2939,2205,1557,1499,1392,1341,1123,780。HPLC-MS(API-ES+,m/z)442.1(M+1)+。产率=34%。
实施例108
5-甲基-4-吗啉-4-基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz):δ(ppm)6.62(s,2H),4.08(s,2H),3.83(s,6H),3.82-3.80(m,4H),3.79(s,3H),3.53-3.48(m,4H),2.67(s,3H)。IR(KBr):νmáx(cm-1)3435,2961,2932,2854,2212,1680,1591,1380,1365,731。HPLC-MS(API-ES+,m/z)441.1(M+1)+。产率=75%。
实施例109
5-甲基-4-(4-甲基哌嗪-1-基)-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz):δ(ppm)6.63(s,2H),4.06(s,2H),3.82(s,6H),3.78(s,3H),5.52(bs,4H),2.65(s,3H),2.52(bs,4H),2.31(s,3H)。IR(KBr):νmáx(cm-1)3369,2938,1534,1494,140,1132,1001,783。产率=90%。
实施例110
5-甲基-4-(甲基氨基)-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:194-195℃;1H-NMR(CDCl3,300MHz):δ(ppm)6.67(s,2H),5.52(bs,1H),4.02(s,2H),3.82(s,6H),3.78(s,3H),3.15(d,J=4.7Hz,3H),2.71(s,3H)。IR(KBr):νmáx(cm-1)3437,2945,2213,15741506,1321,1121,635。产率=25%。
实施例111
4-(乙基氨基)-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:164-165℃;1H-NMR(CDCl3,300MHz):δ(ppm)6.65(s,2H),5.47(bs,1H),4.00(s,2H),3.82(s,6H),3.78(s,3H),3.67-3.63(m,2H),2.71(s,3H),1.27(t,J=7.1Hz,3H)。IR(KBr):νmáx(cm-1)3437,2945,2213,1574,1506,1321,1121,635。产率=27%。
实施例112
5-甲基-4-(丙基氨基)-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz):δ(ppm)6.65(s,2H),5.58(m,1H),4.00(s,2H),3.82(s,6H),3.79(s,3H),3.57(c,J=7.1Hz,2H),2.71(s,3H),1.68(m,2H),0.97(t,J=7.1Hz,3H)。IR(KBr):νmáx(cm-1)3426,3000,2961,2937,2874,2211,1505,1239,1126,1004。HPLC-MS(API-ES+,m/z)413.0(M+1)+。产率=81%。
实施例113
4-(异丙基氨基)-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:143-147℃;1H-NMR(CDCl3,300MHz):δ(ppm)6.63(s,3H),5.27(bs,1H),4.48(m,1H),3.99(s,2H),3.85(s,6H),3.82(s,3H),2.69(s,3H),1.28(d,J=6.3Hz,6H)。IR(KBr):νmáx(cm-1)3440,2970,2837,2210,1568,1548,1504,1450,1239,1006,973,732。HPLC-MS(API-ES+,m/z)413.0(M+1)+。产率=80%。
实施例114
4-(仲丁基氨基)-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:134-137℃;1H-NMR(CDCl3,300MHz):δ(ppm)6.63(s,2H),5.27(bs,1H),3.99(s,2H),3.82(s,6H),3.78(s,3H),2.69(s,3H),1.59(m,2H),1.24(d,J=6.4Hz,3H),0.94(t,J=7.3Hz,3H)。IR(KBr):νmáx(cm-1)3460,2965,2936,2836,2360,2341,2210,1127,1006,732。HPLC-MS(API-ES+,m/z)427.1(M+1)+。产率=82%。
实施例115
4-[(1-乙基丙基)氨基]-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:127-129℃;1H-NMR(CDCl3,300MHz):δ(ppm)6.61(s,2H),5.24(d,J=8.0Hz,1H),4.30(m,1H),3.98(s,2H),3.85(s,6H),3.82(s,3H),2.70(s,3H),2.63(m,2H),1.52(m,2H),0.90(t,J=7.4Hz,6H)。IR(KBr):νmáx(cm-1)3434,2963,2935,2660,2341,2210,1568,1127,1007,805,668。HPLC-MS(API-ES+,m/z)441.1(M+1)+。产率=84%。
实施例116
4-(叔丁基氨基)-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:146-148℃;1H-NMR(CDCl3,300MHz):δ(ppm)6.59(s,2H),5.44(bs,1H),4.01(s,2H),3.81(s,6H),3.79(s,3H),2.68(s,3H),1.48(s,9H)。IR(KBr):νmáx(cm-1)3468,2962,2937,2837,2209,1421,1127,1007。HPLC-MS(API-ES+,m/z)427.1(M+1)+。产率=59%。
实施例117
4-(环丙基氨基)-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz):δ(ppm)6.70(s,2H),5.68(bs,1H),4.06(s,2H),3.84(s,6H),3.80(s,3H),2.67(s,3H),0.92(bs,2H),0.60(bs,2H)。IR(KBr):νmáx(cm-1)3419,2210,1590,1566,1548,1504,1451,1238,1126。HPLC-MS(API-ES+,m/z)411.1(M+1)+。产率=68%。
实施例118
4-(环丁基氨基)-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz):δ(ppm)6.64(s,2H),5.58(d,J=6.2Hz,1H),4.69(m,1H),4.00(s,2H),3.84(s,6H),3.79(s,3H),2.72(s,3H),2.44(m,2H),1.89(m,4H)。IR(KBr):νmáx(cm-1)3433,2939,2250,2211,1574,1322,1241,1125,1006,908,729,647。HPLC-MS(API-ES+,m/z)425.0(M+1)+。产率=82%。
实施例119
4-(二甲基氨基)-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz):δ(ppm)6.69(s,2H),4.05(s,2H),3.84(s,6H),3.80(s,3H),3.11(s,6H),2.67(s,3H)。IR(KBr):νmáx(cm-1)3433,2939,2250,2211,1574,1322,1241,1125,1006,908,729,647。HPLC-MS(API-ES+,m/z)399.1(M+1)+。产率=80%。
实施例120
4-[乙基(甲基)氨基]-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz):δ(ppm)6.66(s,2H),4.04(s,2H),3.84(s,6H),3.82(s,3H),3.55(c,J=7.1Hz,2H),3.02(s,3H),2.56(s,3H),1.27(t,J=7.1Hz,3H)。IR(KBr):νmáx(cm-1)3435,2935,2837,2211,1591,1538,1499,1032,1006,733。HPLC-MS(API-ES+,m/z)413.2(M+1)+。产率=81%。
实施例121
4-(二乙基氨基)-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz):δ(ppm)6.63(s,2H),4.05(s,2H),3.82(s,6H),3.78(s,3H),3.50(c,J=7.1Hz,4H),2.63(s,3H),1.14(t,J=7.1Hz,6H)。IR(KBr):νmáx(cm-1)3372,2936,1588,1534,1132,784。产率=87%。
实施例122
4-[烯丙基(甲基)氨基]-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz):δ(ppm)6.65(s,2H),5.91-5.80(m,1H),5.29-5.23(m,2H),4.07(d,J=6.2Hz,2H),4.03(s,2H),3.83(s,6H),379(s,3H),3.02(s,3H),2.65(s,3H)。IR(KBr):νmáx(cm-1)2936,2212,1591,1538,1239,1127,803。产率=84%。
实施例123
5-甲基-4-[甲基(丙-2-炔基)氨基]-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz):δ(ppm)6.66(s,2H),4.20(d,J=2.0Hz,2H),4.07(s,2H),3.84(s,6H),3.79(s,3H),3.15(s,3H),2.70(s,3H),2.28(bs,1H)。IR(KBr):νmáx(cm-1)3276,2959,2937,2837,2213,1591,1537,1497,1239,1183,736。HPLC-MS(API-ES+,m/z)423.1(M+1)+。产率=63%。
实施例124
4-[(2-羟基乙基)氨基]-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz):δ(ppm)6.60(s,2H),6.07(ta,1H),3.98(s,2H),3.84-3.72(m,4H),3.81(s,6H),3.77(s,3H),2.70(s,3H)。IR(KBr):νmáx(cm-1)3435,3225,2943,2237,2215,1594,1471,1353,1330,1238,1151,1129。HPLC-MS(API-ES+,m/z)415.1(M+1)+。产率=97%。
实施例125
4-[(2-甲氧基乙基)氨基]-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz):δ(ppm)6.62(s,2H),5.98(bs,1H),4.00(s,2H),3.82(s,6H),6.62(s,2H),5.98(bs,1H),4.00(s,2H),3.82(s,6H),3.81-3.79(m,2H),3.78(s,3H),3.56(t,J=5.0Hz,2H),3.38(s,3H),2.70(s,3H)。IR(KBr):νmáx(cm-1)3435,3225,2943,2237,2215,1594,1471,1353,1330,1238,1151,1129。HPLC-MS(API-ES+,m/z)429.1(M+1)+。产率=77%。
实施例126
4-[(2-羟基乙基)(甲基)氨基]-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz):δ(ppm)6.62(s,2H),4.54(bs,1H),4.02(s,2H),3.88-3.72(m,4H),3.83(s,6H),3.79(s,3H),3.16(s,3H),2.66(s,3H)。IR(KBr):νmáx(cm-1)3418,2935,2839,2212,1680,1463,1240,1187,1126,1028,1004,737。HPLC-MS(API-ES+,m/z)429.1(M+1)+。产率=39%。
实施例127
5-甲基-4-(4-甲基哌嗪-1-基)-2-(2-苯基乙基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz):δ(ppm)7.23(m,5H),3.55(t,J=4.6Hz,4H),3.18(bs,4H),2.69(s,3H),2.55(t,J=4.6Hz,4H),2.36(s,3H)。IR(KBr):νmáx(cm-1)3430,3026,2971,2931,2360,2212,1603,1534,1278,1239,1178,1003,699。HPLC-MS(API-ES+,m/z)378.1(M+1)+。产率=65%。
实施例128
4-(环丁基氨基)-5-甲基-2-(2-苯基乙基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:153-155℃;1H-NMR(CDCl3,300MHz):δ(ppm)7.20(m,5H),5.56(d,J=6.1Hz,1H),4.69(m,1H),3.09(bs,4H),2.72(s,3H),2.49(m,2H),1.90(m,4H)。IR(KBr):νmáx(cm-1)3422,2980,2942,2360,2211,1575,1558,1546,1231,1201,1150,697。HPLC-MS(API-ES+,m/z)349.1(M+1)+。产率=85%。
实施例129
4-(二乙基氨基)-5-甲基-2-(2-苯基乙基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz):δ(ppm)7.23(m,5H),3.59(c,J=6.95,4H),3.14(bs,4H),2.65(s,3H),1.90(t,J=6.95Hz,6H)。IR(KBr):νmáx(cm-1)3422,2980,2942,2360,2211,1575,1558,1546,1231,1201,1150,697。产率=75%。
实施例130
5-甲基-4-(4-甲基哌嗪-1-基)-2-(3-苯基丙基)噻吩并[2,3-d]嘧啶-6-甲腈
M.P.:101-103℃;1H-NMR(CDCl3,300MHz):δ(ppm)7.26-7.14(m,5H),3.54-3.51(m,4H),2.89(t,J=7.4Hz,2H),2.71-2.67(m,5H),2.56-2.53(m,4H),2.33(s,3H),2.18-2.09(dt,J=7.4Hz,2H)。IR(KBr):νmáx(cm-1)3436,2933,2841,2749,2205,1535,1363,1139,995,700。HPLC-MS(API-ES+,m/z)392.2(M+1)+。产率=98%。
实施例131
4-(二乙基氨基)-5-甲基-2-(3-苯基丙基)噻吩并[2,3-d]嘧啶-6-甲腈
1H-NMR(CDCl3,300MHz):δ(ppm)7.18-7.07(m,5H),3.45(c,J=6.9Hz,4H),2.82(t,J=7.4Hz,2H),2.66-2.59(m,5H),2.15-2.03(m,2H),1.10(t,J=6.9Hz,6H)。IR(KBr):νmáx(cm-1)3419,2969,2931,2211,1534,1497,1149,746,700。HPLC-MS(API-ES+,m/z)365.1(M+1)+。产率=98%。
实施例132
2-(3,5-二甲氧基-苯基)-4-[(2-羟基-乙基)-甲基-氨基]-5-甲基-噻吩并[2,3-d]嘧啶-6-甲腈
IR(KBr):νmax(cm-1)3400,2925,2208,1605,1540,1392,1154,787。
1H-NMR(CDCl3,300MHz):δ(ppm)7.55(d,J=2.3Hz,2H),6.57(t,J=2.3Hz,1H),3.98(t,J=4.3Hz,2H),3.90-3.88(m,2H),3.87(s,6H),3.22(s,3H),2.71(s,3H)。
实施例133
2-(3,5-二甲氧基-苯基)-5-甲基-4-吗啉-4-基噻吩并[2,3-d]嘧啶-6-甲腈
IR(KBr):νmáx(cm-1)3381,2923,2211,1695,1533,992,729。1H-NMR(CDCl3,300MHz):δ(ppm)7.64(d,J=2.5Hz,2H),6.60(t,J=2.5Hz,1H),3.92-3.86(m,4H),3.88-3.86(m,4H),3.88(s,6H),3.61-3,56(m,4H),2.73(s,3H)。
实施例134
2-(3,5-二甲氧基苯基)-4-(乙基氨基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
M.p.207-208℃
IR(KBr):νmax(cm-1)3481,2934,2209,1554,1209,736。
1H-NMR(CDCl3,300MHz):δ(ppm)7.64(s,2H),6.57(s,1H),5.50(bs,1H),3.87(s,6H),3.74(c,J=7.0Hz,2H),2.75(s,3H),1.36(t,J=7.0H,3H)。
MS(IQ,m/z)355.30(M+1)+。
实施例135
4-(异丁基氨基)-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
m.p.129-131℃
IR(KBr):νmax(cm-1)3432,2949,2834,2211,1592,1506,1449,1422,1402,1130,1011。
1H-NMR(CDCl3,300MHz):δ(ppm)6.63(s,2H),5.28(bt,1H),4.00(s,2H),3.82(s,6H),3.79(s,3H),3.45(t,J=6.1Hz,2H),2.72(s,3H),2.03-1.91(m,1H),1.93(d,J=6.6Hz,6H)。
HPLC-MS(API-ES+,m/z)427.2(M+1)+。
组合物实施例:
组合物实施例1
制备片剂
配方:
本发明化合物 5.0mg
乳糖 113.6mg
微晶纤维素 28.4mg
轻硅酐 1.5mg
硬脂酸镁 1.5mg
用搅拌机将15g本发明化合物、340.8g乳糖和85.2g微晶纤维素混合。用滚轴碾压机将混合物压缩塑型得到片状压缩物。用锤式碾磨机将片状压缩物压成粉末,并经20目筛筛选粉末物。向筛过的颗粒物质中加入4.5g轻硅酐和4.5g硬脂酸镁并混合。用配有直径7.5mm的冲模/冲头系制片机将混合产物制成每片重量为150mg的片剂3,000片。
组合物实施例2
制备包衣片剂
配方:
本发明化合物 5.0mg
乳糖 95.2mg
玉米淀粉 40.8mg
聚乙烯吡咯烷酮K25 7.5mg
硬脂酸镁 1.5mg
羟丙基纤维素 2.3mg
聚乙二醇6000 0.4mg
二氧化钛 1.1mg
精制滑石粉 0.7mg
用流化床制粒机,将15g本发明化合物、285.6g乳糖和122.4g玉米淀粉混合。单独将22.5g聚乙烯吡咯烷酮溶于127.5g水制成粘合溶液。用流化床制粒机将粘合溶液喷雾到上述混合物上从而获得颗粒物。向获得的颗粒物加入4.5g硬脂酸镁并混合。用配有直径6.5mm的冲模/冲头的双面凹系制片机将获得的混合物制成每片重量为150mg的片剂3,000片。
另外,将6.9g羟丙基甲基纤维素2910、1.2g聚乙二醇6000、3.3g二氧化钛和2.1g精制滑石粉悬浮于72.6g水中制成包衣溶液。用HighCoated将包衣溶液涂覆于制备的3,000粒片剂上,获得每片重量为154.5mg的膜包衣片剂。
组合物实施例3
制备胶囊剂
配方:
本发明化合物 5.0mg
乳糖一水合物 200mg
胶态二氧化硅 2mg
玉米淀粉 20mg
硬脂酸镁 4mg
将25g活性化合物、1Kg乳糖一水合物、10g胶态二氧化硅、100g玉米淀粉和20g硬脂酸镁混合。混合物经60目筛筛选,然后填充于5,000粒明胶胶囊中制成胶囊剂。
组合物实施例4
制备乳膏剂
配方:
本发明化合物 1%
十六烷醇 3%
十八烷醇 4%
甘油一硬脂酸酯 4%
山梨聚糖一硬脂酸酯 0.8%
山梨聚糖一硬脂酸酯POE 0.8%
液体凡士林 5%
对羟基苯甲酸甲酯 0.18%
对羟基苯甲酸丙酯 0.02%
丙三醇 15%
纯水csp. 100%
用上列成分通过常规方法制备水包油乳膏剂。
Claims (20)
1一种结构式(I)化合物或其药物学上可接受的盐:
其中
·R1和R2
(a)独立代表:
(i)氢原子;
(ii)选自烷基、链烯基或链炔基的基团,它们任选被一个或多个选自以下的取代基取代:卤素原子和羟基、烷氧基、芳氧基、烷硫基、羟基羰基、烷氧基羰基、单-或双-烷基氨基酰基、氧代、氨基、单-或双-烷基氨基;
(iii)下式的基团
-(CH2)n-R6
其中n为0-4的整数,R6代表环烷基或环烯基;
或
(b)R1和R2与它们连接的氮原子一起形成包含1-4个选自氮、氧和硫的杂原子的3-至8-元环,该环为饱和或不饱和且任选被一个或多个选自以下的取代基取代:卤素原子和烷基、羟基、烷氧基、酰基、羟基羰基、烷氧基羰基、亚烷二氧基、氨基、单-或双-烷基氨基、单-或双-烷基氨基酰基、硝基、氰基或三氟甲基;
·R3为下式的基团
-(CH2)n-G
其中n为0-4的整数,G代表包含0-4个杂原子的单环或双环芳基或杂芳基,该基团任选被一个或多个选自以下的取代基取代:
(i)卤素原子;
(ii)烷基和亚烷基,它们任选被一个或多个选自卤素原子的取代基取代;和
(iii)苯基、羟基、羟基烷基、烷氧基、亚烷二氧基、芳氧基、烷硫基、氨基、单-或双-烷基氨基、酰基氨基、硝基、酰基、羟基羰基、烷氧基羰基、氰基、二氟甲氧基或三氟甲氧基;
·R4代表氢原子或者烷基或芳基;
前提条件是所述化合物不是5-甲基-2-苯基-4-吗啉-4-基噻吩并[2,3-d]嘧啶-6-甲腈。
2权利要求1的化合物,其中R1和R2:
a)独立代表氢或选自以下的基团:烷基、链烯基或链炔基,所述基团具有1-4个碳原子并且任选被一个羟基或3-6个碳原子的环烷基取代;
或
b)R1和R2与它们连接的氮原子一起形成包含1-2个选自氮、氧和硫的杂原子的4-至6-元环,该环任选被1-2个C1-C4烷基取代,所述取代基自身未被取代或被一个羟基取代。
3任一前述权利要求的化合物,其中R1:
a)代表氢原子或1-4个碳原子的烷基;
或
b)和R2与它们连接的氮原子一起形成包含1-2个选自氮和氧的杂原子的4-至6-元环,该环任选被一个或多个选自卤素原子以及烷基或酰基的取代基取代。
4任一前述权利要求的化合物,其中R2:
a)代表选自以下的基团:烷基、链烯基、链炔基、环烷基、羟基烷基或二-烷基氨基;
或
b)和R1与它们连接的氮原子一起形成包含1-2个选自氮和氧的杂原子的4-至6-元环,该环任选被一个或多个选自卤素原子以及烷基或酰基的取代基取代。
5任一前述权利要求的化合物,其中R3代表下式的基团
-(CH2)n-G
其中n为0-4的整数,G代表包含0-1个杂原子的单环芳基或杂芳基,所述芳基或杂芳基任选被一个或多个选自以下的取代基取代:
(i)卤素原子;
(ii)未被取代的C1-C8烷基、未被取代的C1-C8烷氧基、未被取代的C1-C3亚烷二氧基、硝基、三氟甲基和具有C1-C8烷基部分的未被取代的烷氧基羰基。
6任一前述权利要求的化合物,其中R4为氢、未被取代的C1-C8烷基或未被取代的C5-C14芳基。
7权利要求6的化合物,其中R4代表未被取代的C1-4烷基。
8任一前述权利要求的化合物,其中R3代表选自苯基、吡啶基或苄基的基团,所述基团任选被一个或多个选自以下的取代基取代:
(i)卤素原子;
(ii)未被取代的C1-C8烷基、未被取代的C1-C8烷氧基、未被取代的C1-C3亚烷二氧基、硝基、三氟甲基和具有C1-C8烷基部分的未被取代的烷氧基羰基。
9权利要求8的化合物,其中R3代表被1-3个C1-6烷氧基取代的苯基或苄基。
10权利要求9的化合物,其中R1代表氢原子且R2代表
(iii)选自烷基、链烯基或链炔基的基团,它们任选被一个或多个选自以下的取代基取代:卤素原子和羟基、烷氧基、芳氧基、烷硫基、羟基羰基、烷氧基羰基、单-或双-烷基氨基酰基、氧代、氨基、单-或双-烷基氨基;
或
(iv)下式的基团
-(CH2)n-R6
其中n为0-4的整数,R6代表环烷基或环烯基。
11权利要求1的化合物,其为下列一种化合物:
1)4-(4-乙基哌嗪-1-基)-5-甲基-2-苯基噻吩并[2,3-d]嘧啶-6-甲腈
2)4-(4-乙基哌嗪-1-基)-2-(4-甲氧基苯基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
3)4-(二乙基氨基)-5-甲基-2-苯基噻吩并[2,3-d]嘧啶-6-甲腈
4)5-甲基-2-苯基-4-哌啶-1-基噻吩并[2,3-d]嘧啶-6-甲腈
5)5-甲基-2-(4-硝基苯基)-4-哌啶-1-基噻吩并[2,3-d]嘧啶-6-甲腈
6)2-(4-甲氧基苯基)-5-甲基-4-哌啶-1-基噻吩并[2,3-d]嘧啶-6-甲腈
7)5-甲基-4-(4-甲基哌嗪-1-基)-2-(4-硝基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
8)5-甲基-2-苯基-4-哌嗪-1-基噻吩并[2,3-d]嘧啶-6-甲腈
9)2-(4-甲氧基苯基)-5-甲基-4-(4-甲基哌嗪-1-基)噻吩并[2,3-d]嘧啶-6-甲腈
10)4-(二乙基氨基)-2-(4-甲氧基苯基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
11)2-(4-甲氧基苯基)-5-甲基-4-吡咯烷-1-基噻吩并[2,3-d]嘧啶-6-甲腈
12)2-(4-甲氧基苯基)-5-甲基-4-哌嗪-1-基噻吩并[2,3-d]嘧啶-6-甲腈
13)5-甲基-2-(4-硝基苯基)-4-哌嗪-1-基噻吩并[2,3-d]嘧啶-6-甲腈
14)4-(二丁基氨基)-2-(4-甲氧基苯基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
15)2-(4-氯苯基)-5-甲基-4-(4-甲基哌嗪-1-基)噻吩并[2,3-d]嘧啶-6-甲腈
16)2-(3,4-二甲氧基苯基)-5-甲基-4-(4-甲基哌嗪-1-基)噻吩并[2,3-d]嘧啶-6-甲腈
17)4-[乙基(甲基)氨基]-2-(4-甲氧基苯基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
18)4-(二乙基氨基)-5-甲基-2-(4-硝基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
19)2-(4-氯苯基)-4-(二乙基氨基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
20)4-(二乙基氨基)-2-(3,4-二甲氧基苯基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
21)4-(二甲基氨基)-2-(4-甲氧基苯基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
22)2-(4-甲氧基苯基)-5-甲基-4-吗啉-4-基噻吩并[2,3-d]嘧啶-6-甲腈
23)2-(4-氯苯基)-5-甲基-4-吗啉-4-基噻吩并[2,3-d]嘧啶-6-甲腈
24)2-(4-甲氧基苯基)-5-甲基-4-[甲基(丙-2-炔基)氨基]噻吩并[2,3-d]嘧啶-6-甲腈
25)4-[(2-羟基乙基)(甲基)氨基]-2-(4-甲氧基苯基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
26)2-(3,4-二甲氧基苯基)-4-[乙基(甲基)氨基]-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
27)5-甲基-2-(4-甲基苯基)-4-(4-甲基哌嗪-1-基)噻吩并[2,3-d]嘧啶-6-甲腈
28)4-(二乙基氨基)-5-甲基-2-[4-(三氟甲基)苯基]噻吩并[2,3-d]嘧啶-6-甲腈
29)4-[烯丙基(甲基)氨基]-2-(4-甲氧基苯基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
30)2-(3,4-二甲氧基苯基)-4-[(2-羟基乙基)(甲基)氨基]-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
31)2-(3,4-二甲氧基苯基)-5-甲基-4-吗啉-4-基噻吩并[2,3-d]嘧啶-6-甲腈
32)5-甲基-2-(4-甲基苯基)-4-吗啉-4-基噻吩并[2,3-d]嘧啶-6-甲腈
33)5-甲基-4-(4-甲基哌嗪-1-基)-2-[4-(三氟甲基)苯基]噻吩并[2,3-d]嘧啶-6-甲腈
34)2-(1,3-苯并二氧杂环戊烯-5-基)-5-甲基-4-(4-甲基哌嗪-1-基)噻吩并[2,3-d]嘧啶-6-甲腈
35)4-(二乙基氨基)-5-甲基-2-(4-甲基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
36)2-(1,3-苯并二氧杂环戊烯-5-基)-4-(二乙基氨基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
37)2-(1,3-苯并二氧杂环戊烯-5-基)-5-甲基-4-吗啉-4-基噻吩并[2,3-d]嘧啶-6-甲腈
38)4-[乙基(甲基)氨基]-5-甲基-2-吡啶-4-基噻吩并[2,3-d]嘧啶-6-甲腈
39)4-[乙基(甲基)氨基]-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
40)2-苄基-5-甲基-4-(4-甲基哌嗪-1-基)噻吩并[2,3-d]嘧啶-6-甲腈
41)5-甲基-4-吗啉-4-基-2-吡啶-4-基噻吩并[2,3-d]嘧啶-6-甲腈
42)4-[(2-羟基乙基)(甲基)氨基]-5-甲基-2-吡啶-4-基噻吩并[2,3-d]嘧啶-6-甲腈
43)2-(1,3-苯并二氧杂环戊烯-5-基)-4-[(2-羟基乙基)(甲基)氨基]-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
44)4-[(2-羟基乙基)(甲基)氨基]-5-甲基-2-(4-甲基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
45)4-(二乙基氨基)-5-甲基-2-吡啶-4-基噻吩并[2,3-d]嘧啶-6-甲腈
46)2-(3,4-二甲氧基苯基)-4-(二甲基氨基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
47)2-(3,4-二甲氧基苯基)-5-甲基-4-(丙基氨基)噻吩并[2,3-d]嘧啶-6-甲腈
48)4-(二乙基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
49)2-苄基-4-(二乙基氨基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
50)5-甲基-4-(4-甲基哌嗪-1-基)-2-苯基噻吩并[2,3-d]嘧啶-6-甲腈
51)5-甲基-4-吗啉-4-基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
52)4-[(2-羟基乙基)甲基氨基]-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
53)2-(3,5-二甲氧基苯基)-5-甲基-4-(4-甲基哌嗪-1-基)-噻吩并[2,3-d]嘧啶-6-甲腈
54)4-二乙基氨基-2-(3,5-二甲氧基苯基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
55)2-(3,5-二甲氧基苯基)-4-(乙基甲基氨基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
56)4-(6-氰基-4-二乙基氨基-5-甲基噻吩并[2,3-d]嘧啶-2-基)-苯甲酸甲酯
57)4-[6-氰基-4-(乙基甲基氨基)-5-甲基噻吩并[2,3-d]嘧啶-2-基]-苯甲酸甲酯
58)2-苄基-5-甲基-4-吗啉-4-基-噻吩并[2,3-d]嘧啶-6-甲腈
59)2-苄基-4-[(2-羟基乙基)甲基氨基]-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
60)5-甲基-4-(4-甲基哌嗪-1-基)-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
61)4-(6-氰基-5-甲基-4-吗啉-4-基噻吩并[2,3-d]嘧啶-2-基)苯甲酸甲酯
62)4-[6-氰基-5-甲基-4-(4-甲基哌嗪-1-基)噻吩并[2,3-d]嘧啶-2-基]苯甲酸甲酯
63)4-[6-氰基-4-(二甲基氨基)-5-甲基噻吩并[2,3-d]嘧啶-2-基]苯甲酸甲酯
64)4-{6-氰基-4-[(2-羟基乙基)(甲基)氨基]-5-甲基噻吩并[2,3-d]嘧啶-2-基}苯甲酸甲酯
65)5-甲基-4-(甲基氨基)-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
66)4-(二甲基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
67)4-(乙基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
68)5-甲基-4-(丙基氨基)-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
69)4-(丁基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
70)4-(异丙基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
71)4-(仲丁基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
72)4-(异丁基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
73)4-[(1-乙基丙基)氨基]-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
74)4-(叔丁基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
75)4-(环丙基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
76)4-(环丁基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
77)4-(环戊基氨基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
78)4-[烯丙基(甲基)氨基]-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
79)5-甲基-4-[甲基(丙-2-炔基)氨基]-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
80)4-[(2-羟基乙基)氨基]-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
81)4-[(2-甲氧基乙基)氨基]-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
82)4-{[2-(二甲基氨基)乙基]氨基}-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
83)5-甲基-4-(3-甲基哌嗪-1-基)-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
84)4-(3,5-二甲基哌嗪-1-基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
85)4-(4-乙酰基哌嗪-1-基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
86)4-[(2-氨基乙基)(甲基)氨基]-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
87)N-[6-氰基-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-4-基]-β-丙氨酸
88)5-甲基-4-(1H-吡唑-1-基)-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
89)4-(1H-咪唑-1-基)-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
90)5-甲基-4-(2H-1,2,3-三唑-2-基)-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
91)5-甲基-4-(1H-1,2,4-三唑-1-基)-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
92)2-(3,4-二甲氧基苄基)-5-甲基-4-吗啉-4-基噻吩并[2,3-d]嘧啶-6-甲腈
93)2-(3,4-二甲氧基苄基)-5-甲基-4-(4-甲基哌嗪-1-基)噻吩并[2,3-d]嘧啶-6-甲腈
94)2-(3,4-二甲氧基苄基)-5-甲基-4-(甲基氨基)噻吩并[2,3-d]嘧啶-6-甲腈
95)2-(3,4-二甲氧基苄基)-4-(乙基氨基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
96)2-(3,4-二甲氧基苄基)-5-甲基-4-(丙基氨基)噻吩并[2,3-d]嘧啶-6-甲腈
97)4-(环丙基氨基)-2-(3,4-二甲氧基苄基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
98)4-(环丁基氨基)-2-(3,4-二甲氧基苄基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
99)2-(3,4-二甲氧基苄基)-4-(二甲基氨基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
100)2-(3,4-二甲氧基苄基)-4-[乙基(甲基)氨基]-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
101)4-(二乙基氨基)-2-(3,4-二甲氧基苄基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
102)4-[烯丙基(甲基)氨基]-2-(3,4-二甲氧基苄基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
103)2-(3,4-二甲氧基苄基)-5-甲基-4-[甲基(丙-2-炔基)氨基]噻吩并[2,3-d]嘧啶-6-甲腈
104)2-(3,4-二甲氧基苄基)-4-[(2-羟基乙基)氨基]-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
105)2-(3,4-二甲氧基苄基)-4-[(2-羟基乙基)(甲基)氨基]-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
106)2-(3,4-二甲氧基苄基)-4-[(2-甲氧基乙基)氨基]-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
107)4-[[2-(二甲基氨基)乙基](甲基)氨基]-5-甲基-2-(3,4,5-三甲氧基苯基)噻吩并[2,3-d]嘧啶-6-甲腈
108)5-甲基-4-吗啉-4-基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
109)5-甲基-4-(4-甲基哌嗪-1-基)-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
110)5-甲基-4-(甲基氨基)-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
111)4-(乙基氨基)-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
112)5-甲基-4-(丙基氨基)-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
113)4-(异丙基氨基)-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
114)4-(仲丁基氨基)-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
115)4-[(1-乙基丙基)氨基]-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
116)4-(叔丁基氨基)-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
117)4-(环丙基氨基)-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
118)4-(环丁基氨基)-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
119)4-(二甲基氨基)-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
120)4-[乙基(甲基)氨基]-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
121)4-(二乙基氨基)-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
122)4-[烯丙基(甲基)氨基]-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
123)5-甲基-4-[甲基(丙-2-炔基)氨基]-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
124)4-[(2-羟基乙基)氨基]-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
125)4-[(2-甲氧基乙基)氨基]-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
126)4-[(2-羟基乙基)(甲基)氨基]-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
127)5-甲基-4-(4-甲基哌嗪-1-基)-2-(2-苯基乙基)噻吩并[2,3-d]嘧啶-6-甲腈
128)4-(环丁基氨基)-5-甲基-2-(2-苯基乙基)噻吩并[2,3-d]嘧啶-6-甲腈
129)4-(二乙基氨基)-5-甲基-2-(2-苯基乙基)噻吩并[2,3-d]嘧啶-6-甲腈
130)5-甲基-4-(4-甲基哌嗪-1-基)-2-(3-苯基丙基)噻吩并[2,3-d]嘧啶-6-甲腈
131)4-(二乙基氨基)-5-甲基-2-(3-苯基丙基)噻吩并[2,3-d]嘧啶-6-甲腈
132)2-(3,5-二甲氧基-苯基)-4-[(2-羟基-乙基)-甲基-氨基]-5-甲基-噻吩并[2,3-d]嘧啶-6-甲腈
133)2-(3,5-二甲氧基-苯基)-5-甲基-4-吗啉-4-基噻吩并[2,3-d]嘧啶-6-甲腈
134)2-(3,5-二甲氧基苯基)-4-(乙基氨基)-5-甲基噻吩并[2,3-d]嘧啶-6-甲腈
135)4-(异丁基氨基)-5-甲基-2-(3,4,5-三甲氧基苄基)噻吩并[2,3-d]嘧啶-6-甲腈
和它们的药物学上可接受的盐。
13用于治疗通过抑制PDE7而缓解的病症或疾病的权利要求1-11任一项的化合物。
14一种药用组合物,其包含权利要求1-11任一项的化合物和药物学上可接受的稀释剂或载体。
15权利要求1-11任一项的化合物在制备药物上的用途,所述药物用于治疗通过抑制PDE7而缓解的病症或疾病。
16权利要求15的用途,其中所述药物用于治疗或预防T细胞介导的免疫性疾病和呼吸道疾病。
17权利要求15的用途,其中所述药物用于治疗或预防以下病症:哮喘、特应性皮炎、慢性阻塞性肺病、节段性回肠炎、I型和II型糖尿病、淋巴性白血病和其它类型癌症、多发性硬化、器官移植后同种异体移植排斥、牛皮癣、类风湿性关节炎和溃疡性结肠炎。
18一种治疗患有通过抑制PDE7而缓解的病症或疾病的患者的方法,该方法包括对所述患者给予有效量的权利要求1-11任一项的化合物。
19权利要求18的方法,其中所述病症或疾病是:哮喘、特应性皮炎、慢性阻塞性肺病、节段性回肠炎、I型和II型糖尿病、淋巴性白血病和其它类型癌症、多发性硬化、器官移植后同种异体移植排斥、牛皮癣、类风湿性关节炎和溃疡性结肠炎。
20一种联合药物产品,其包含:
a)权利要求1-11任一项的化合物;和
b)另一种化合物,该化合物选自(a)PDE4抑制剂,(b)A2A腺苷受体拮抗剂,(c)NSAID,(d)COX-2抑制剂,(e)TNF-α抑制剂和(f)类固醇,
上述药物同时、独立或序贯给药。
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CN101939006B (zh) * | 2007-09-12 | 2015-09-16 | 吉宁特有限公司 | 磷酸肌醇3-激酶抑制剂化合物与化疗剂的联合以及使用方法 |
CN113372358A (zh) * | 2012-09-28 | 2021-09-10 | 武田药品工业株式会社 | 噻吩并嘧啶衍生物的制备方法 |
US11731983B2 (en) | 2012-09-28 | 2023-08-22 | Takeda Pharmaceutical Company Limited | Production method of thienopyrimidine derivative |
US11795178B2 (en) | 2012-09-28 | 2023-10-24 | Takeda Pharmaceutical Company Limited | Compositions of thienopyrimidine derivatives |
CN113372358B (zh) * | 2012-09-28 | 2024-05-14 | 武田药品工业株式会社 | 噻吩并嘧啶衍生物的制备方法 |
CN108135906A (zh) * | 2015-07-24 | 2018-06-08 | 路易斯维尔大学研究基金会有限公司 | 治病化合物、组合物、方法、及化合物制备方法 |
US11312690B2 (en) | 2015-07-24 | 2022-04-26 | University Of Lousville Research Foundation, Inc. | Compounds, compositions, methods for treating diseases, and methods for preparing compounds |
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ES2217956B1 (es) | 2006-04-01 |
WO2004065391A1 (en) | 2004-08-05 |
US20060229306A1 (en) | 2006-10-12 |
ES2217956A1 (es) | 2004-11-01 |
ES2289475T3 (es) | 2008-02-01 |
EP1590352A1 (en) | 2005-11-02 |
EP1590352B1 (en) | 2007-06-27 |
CN100582112C (zh) | 2010-01-20 |
DE602004007239D1 (de) | 2007-08-09 |
ATE365742T1 (de) | 2007-07-15 |
DE602004007239T2 (de) | 2008-02-28 |
US7662814B2 (en) | 2010-02-16 |
JP2006515604A (ja) | 2006-06-01 |
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