CN100372851C - 具有crf活性的稠合的嘧啶衍生物 - Google Patents
具有crf活性的稠合的嘧啶衍生物 Download PDFInfo
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- CN100372851C CN100372851C CNB2004800122889A CN200480012288A CN100372851C CN 100372851 C CN100372851 C CN 100372851C CN B2004800122889 A CNB2004800122889 A CN B2004800122889A CN 200480012288 A CN200480012288 A CN 200480012288A CN 100372851 C CN100372851 C CN 100372851C
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- alkyl
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- ethyl
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- 102100021752 Corticoliberin Human genes 0.000 title description 17
- 150000003230 pyrimidines Chemical class 0.000 title description 7
- 230000000694 effects Effects 0.000 title description 6
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 107
- 150000003839 salts Chemical class 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 25
- 239000003814 drug Substances 0.000 claims abstract description 15
- 230000008569 process Effects 0.000 claims abstract description 11
- -1 hydroxy, cyanoAmino group Chemical group 0.000 claims description 126
- 125000000217 alkyl group Chemical group 0.000 claims description 80
- 229910052736 halogen Inorganic materials 0.000 claims description 65
- 150000002367 halogens Chemical class 0.000 claims description 65
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 52
- 125000001424 substituent group Chemical group 0.000 claims description 49
- 239000001257 hydrogen Substances 0.000 claims description 47
- 229910052739 hydrogen Inorganic materials 0.000 claims description 47
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 44
- 125000001188 haloalkyl group Chemical group 0.000 claims description 44
- 125000001072 heteroaryl group Chemical group 0.000 claims description 44
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 33
- 125000004472 dialkylaminosulfonyl group Chemical group 0.000 claims description 31
- 125000002947 alkylene group Chemical group 0.000 claims description 30
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 30
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 30
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 29
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 28
- 229910003827 NRaRb Inorganic materials 0.000 claims description 28
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 28
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 27
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 27
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 26
- 201000010099 disease Diseases 0.000 claims description 24
- 125000003118 aryl group Chemical group 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 21
- 238000006467 substitution reaction Methods 0.000 claims description 21
- 108010056643 Corticotropin-Releasing Hormone Receptors Proteins 0.000 claims description 19
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 125000004104 aryloxy group Chemical group 0.000 claims description 16
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 15
- 238000011282 treatment Methods 0.000 claims description 14
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 12
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- 125000004423 acyloxy group Chemical class 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- 150000003951 lactams Chemical class 0.000 claims description 10
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 9
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 8
- UNCQVRBWJWWJBF-UHFFFAOYSA-N 2-chloropyrimidine Chemical compound ClC1=NC=CC=N1 UNCQVRBWJWWJBF-UHFFFAOYSA-N 0.000 claims description 8
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims description 8
- 125000001769 aryl amino group Chemical group 0.000 claims description 8
- 125000002619 bicyclic group Chemical group 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 208000035475 disorder Diseases 0.000 claims description 7
- 230000001404 mediated effect Effects 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 230000002265 prevention Effects 0.000 claims description 7
- 150000003141 primary amines Chemical class 0.000 claims description 7
- 150000004982 aromatic amines Chemical class 0.000 claims description 6
- 229960000789 guanidine hydrochloride Drugs 0.000 claims description 6
- 150000003512 tertiary amines Chemical class 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 5
- 239000003638 chemical reducing agent Substances 0.000 claims description 5
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 208000030814 Eating disease Diseases 0.000 claims description 4
- 208000019454 Feeding and Eating disease Diseases 0.000 claims description 4
- 208000011688 Generalised anxiety disease Diseases 0.000 claims description 4
- 208000019022 Mood disease Diseases 0.000 claims description 4
- 239000012320 chlorinating reagent Substances 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 235000014632 disordered eating Nutrition 0.000 claims description 4
- 230000007160 gastrointestinal dysfunction Effects 0.000 claims description 4
- 208000029364 generalized anxiety disease Diseases 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 4
- 208000019899 phobic disease Diseases 0.000 claims description 4
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 3
- 239000002168 alkylating agent Substances 0.000 claims description 3
- 229940100198 alkylating agent Drugs 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- GXYFRZTUNKMBEH-UHFFFAOYSA-N n-ethyl-7-heptan-4-yl-4-methyl-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound CCCC(CCC)N1CCC(C(=N2)C)=C1N=C2N(CC)C1=C(C)C=C(C)C=C1C GXYFRZTUNKMBEH-UHFFFAOYSA-N 0.000 claims description 3
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 3
- DGVXMULITZBNCX-UHFFFAOYSA-N 3-[2-(n-ethyl-2,4,6-trimethylanilino)-4-methyl-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]propanenitrile Chemical compound N=1C=2N(CCC#N)CCC=2C(C)=NC=1N(CC)C1=C(C)C=C(C)C=C1C DGVXMULITZBNCX-UHFFFAOYSA-N 0.000 claims description 2
- VCMXGVACFDYIJB-UHFFFAOYSA-N 4-(n-(7-heptan-4-yl-4-methyl-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-yl)-2,4,6-trimethylanilino)butyl acetate Chemical compound CCCC(CCC)N1CCC(C(=N2)C)=C1N=C2N(CCCCOC(C)=O)C1=C(C)C=C(C)C=C1C VCMXGVACFDYIJB-UHFFFAOYSA-N 0.000 claims description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 2
- KLPRZIRQUAJXBR-UHFFFAOYSA-N 7-(1,2-diphenylethyl)-n-ethyl-4-methyl-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound CC=1C=C(C)C=C(C)C=1N(CC)C(N=C(C)C=1CC2)=NC=1N2C(C=1C=CC=CC=1)CC1=CC=CC=C1 KLPRZIRQUAJXBR-UHFFFAOYSA-N 0.000 claims description 2
- YUEWNQBYENMSDX-UHFFFAOYSA-N 7-(1,3-benzodioxol-5-ylmethyl)-n-ethyl-4-methyl-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound N=1C=2N(CC=3C=C4OCOC4=CC=3)CCC=2C(C)=NC=1N(CC)C1=C(C)C=C(C)C=C1C YUEWNQBYENMSDX-UHFFFAOYSA-N 0.000 claims description 2
- HRHJSTROYZXOTP-UHFFFAOYSA-N 7-(1-benzylpiperidin-4-yl)-n-ethyl-4-methyl-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound CC=1C=C(C)C=C(C)C=1N(CC)C(N=C(C)C=1CC2)=NC=1N2C(CC1)CCN1CC1=CC=CC=C1 HRHJSTROYZXOTP-UHFFFAOYSA-N 0.000 claims description 2
- ALXQBKHSXYDOPM-UHFFFAOYSA-N 7-(1-benzylpyrrolidin-3-yl)-n-ethyl-4-methyl-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound CC=1C=C(C)C=C(C)C=1N(CC)C(N=C(C)C=1CC2)=NC=1N2C(C1)CCN1CC1=CC=CC=C1 ALXQBKHSXYDOPM-UHFFFAOYSA-N 0.000 claims description 2
- LKIAJXFGACKKDC-UHFFFAOYSA-N 7-(2,3-dihydro-1h-inden-1-yl)-n-ethyl-4-methyl-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound N=1C=2N(C3C4=CC=CC=C4CC3)CCC=2C(C)=NC=1N(CC)C1=C(C)C=C(C)C=C1C LKIAJXFGACKKDC-UHFFFAOYSA-N 0.000 claims description 2
- GFWBGROODXJQQV-UHFFFAOYSA-N 7-(2,4-dimethylphenyl)-n-ethyl-4-methyl-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound CC=1C=C(C)C=C(C)C=1N(CC)C(N=C(C)C=1CC2)=NC=1N2C1=CC=C(C)C=C1C GFWBGROODXJQQV-UHFFFAOYSA-N 0.000 claims description 2
- IFSZMNWILYVDDK-UHFFFAOYSA-N 7-(cyclohexylmethyl)-n-ethyl-4-methyl-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound CC=1C=C(C)C=C(C)C=1N(CC)C(N=C(C)C=1CC2)=NC=1N2CC1CCCCC1 IFSZMNWILYVDDK-UHFFFAOYSA-N 0.000 claims description 2
- YRTLIEUCGZTJFR-UHFFFAOYSA-N 7-(cyclopropylmethyl)-n-ethyl-4-methyl-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound CC=1C=C(C)C=C(C)C=1N(CC)C(N=C(C)C=1CC2)=NC=1N2CC1CC1 YRTLIEUCGZTJFR-UHFFFAOYSA-N 0.000 claims description 2
- VYXHNFMVTXJVDI-UHFFFAOYSA-N 7-[(3,4-dimethoxyphenyl)methyl]-n-ethyl-4-methyl-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound CC=1C=C(C)C=C(C)C=1N(CC)C(N=C(C)C=1CC2)=NC=1N2CC1=CC=C(OC)C(OC)=C1 VYXHNFMVTXJVDI-UHFFFAOYSA-N 0.000 claims description 2
- BOXVHGYKFVDQNV-UHFFFAOYSA-N 7-[2-(1,3-dioxolan-2-yl)ethyl]-n-ethyl-4-methyl-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound CC=1C=C(C)C=C(C)C=1N(CC)C(N=C(C)C=1CC2)=NC=1N2CCC1OCCO1 BOXVHGYKFVDQNV-UHFFFAOYSA-N 0.000 claims description 2
- ZJAHDAQDTWUXFF-UHFFFAOYSA-N 7-[2-(1-benzylpiperidin-4-yl)ethyl]-n-ethyl-4-methyl-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound CC=1C=C(C)C=C(C)C=1N(CC)C(N=C(C)C=1CC2)=NC=1N2CCC(CC1)CCN1CC1=CC=CC=C1 ZJAHDAQDTWUXFF-UHFFFAOYSA-N 0.000 claims description 2
- FVDDNQWWIFUBGE-UHFFFAOYSA-N 7-[2-(cyclohexen-1-yl)ethyl]-n-ethyl-4-methyl-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound CC=1C=C(C)C=C(C)C=1N(CC)C(N=C(C)C=1CC2)=NC=1N2CCC1=CCCCC1 FVDDNQWWIFUBGE-UHFFFAOYSA-N 0.000 claims description 2
- HQNCMQNGMWPETO-UHFFFAOYSA-N 7-benzyl-n-ethyl-4-methyl-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound CC=1C=C(C)C=C(C)C=1N(CC)C(N=C(C)C=1CC2)=NC=1N2CC1=CC=CC=C1 HQNCMQNGMWPETO-UHFFFAOYSA-N 0.000 claims description 2
- WZLBBLOPJTUAQR-UHFFFAOYSA-N 7-cyclopropyl-n-ethyl-4-methyl-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound CC=1C=C(C)C=C(C)C=1N(CC)C(N=C(C)C=1CC2)=NC=1N2C1CC1 WZLBBLOPJTUAQR-UHFFFAOYSA-N 0.000 claims description 2
- GVOAGWRDDCDHTL-UHFFFAOYSA-N 7-heptan-4-yl-4-methyl-n-propan-2-yl-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound CCCC(CCC)N1CCC(C(=N2)C)=C1N=C2N(C(C)C)C1=C(C)C=C(C)C=C1C GVOAGWRDDCDHTL-UHFFFAOYSA-N 0.000 claims description 2
- LTVGVAMFDKXYLS-UHFFFAOYSA-N 7-heptan-4-yl-n,4-dimethyl-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound CCCC(CCC)N1CCC(C(=N2)C)=C1N=C2N(C)C1=C(C)C=C(C)C=C1C LTVGVAMFDKXYLS-UHFFFAOYSA-N 0.000 claims description 2
- KILUBFJQXBWRQK-UHFFFAOYSA-N n-(cyclopropylmethyl)-7-heptan-4-yl-4-methyl-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound CCCC(CCC)N1CCC(C(=N2)C)=C1N=C2N(C=1C(=CC(C)=CC=1C)C)CC1CC1 KILUBFJQXBWRQK-UHFFFAOYSA-N 0.000 claims description 2
- ZWXKRYWXGCELKI-UHFFFAOYSA-N n-benzyl-7-heptan-4-yl-4-methyl-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound CCCC(CCC)N1CCC(C(=N2)C)=C1N=C2N(C=1C(=CC(C)=CC=1C)C)CC1=CC=CC=C1 ZWXKRYWXGCELKI-UHFFFAOYSA-N 0.000 claims description 2
- HIZAMRQCPDZONE-UHFFFAOYSA-N n-butyl-7-heptan-4-yl-4-methyl-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound N=1C=2N(C(CCC)CCC)CCC=2C(C)=NC=1N(CCCC)C1=C(C)C=C(C)C=C1C HIZAMRQCPDZONE-UHFFFAOYSA-N 0.000 claims description 2
- BHERNDXJKLEKNV-UHFFFAOYSA-N n-cyclopentyl-7-heptan-4-yl-4-methyl-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound CCCC(CCC)N1CCC(C(=N2)C)=C1N=C2N(C=1C(=CC(C)=CC=1C)C)C1CCCC1 BHERNDXJKLEKNV-UHFFFAOYSA-N 0.000 claims description 2
- MIBXSQCHOQKDON-UHFFFAOYSA-N n-ethyl-4-methyl-7-(1,2,3,4-tetrahydronaphthalen-1-yl)-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound N=1C=2N(C3C4=CC=CC=C4CCC3)CCC=2C(C)=NC=1N(CC)C1=C(C)C=C(C)C=C1C MIBXSQCHOQKDON-UHFFFAOYSA-N 0.000 claims description 2
- DBFKEFDLSDWZCV-UHFFFAOYSA-N n-ethyl-4-methyl-7-(1-phenylpropyl)-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound C=1C=CC=CC=1C(CC)N1CCC(C(=N2)C)=C1N=C2N(CC)C1=C(C)C=C(C)C=C1C DBFKEFDLSDWZCV-UHFFFAOYSA-N 0.000 claims description 2
- GODZQMLQTUKHAU-UHFFFAOYSA-N n-ethyl-4-methyl-7-(2-phenoxyethyl)-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound CC=1C=C(C)C=C(C)C=1N(CC)C(N=C(C)C=1CC2)=NC=1N2CCOC1=CC=CC=C1 GODZQMLQTUKHAU-UHFFFAOYSA-N 0.000 claims description 2
- YWPJZDNPYKQENZ-UHFFFAOYSA-N n-ethyl-4-methyl-7-(2-phenylethyl)-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound CC=1C=C(C)C=C(C)C=1N(CC)C(N=C(C)C=1CC2)=NC=1N2CCC1=CC=CC=C1 YWPJZDNPYKQENZ-UHFFFAOYSA-N 0.000 claims description 2
- SLCMYKXPRACULV-UHFFFAOYSA-N n-ethyl-4-methyl-7-(2-piperidin-1-ylethyl)-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound CC=1C=C(C)C=C(C)C=1N(CC)C(N=C(C)C=1CC2)=NC=1N2CCN1CCCCC1 SLCMYKXPRACULV-UHFFFAOYSA-N 0.000 claims description 2
- AIMREPCARMPYIF-UHFFFAOYSA-N n-ethyl-4-methyl-7-(2-pyridin-2-ylethyl)-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound CC=1C=C(C)C=C(C)C=1N(CC)C(N=C(C)C=1CC2)=NC=1N2CCC1=CC=CC=N1 AIMREPCARMPYIF-UHFFFAOYSA-N 0.000 claims description 2
- UJNRXJWKFQPRMF-UHFFFAOYSA-N n-ethyl-4-methyl-7-(3-morpholin-4-ylpropyl)-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound CC=1C=C(C)C=C(C)C=1N(CC)C(N=C(C)C=1CC2)=NC=1N2CCCN1CCOCC1 UJNRXJWKFQPRMF-UHFFFAOYSA-N 0.000 claims description 2
- RDTAGOQVNFFUMG-UHFFFAOYSA-N n-ethyl-4-methyl-7-(3-propoxypropyl)-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound CCCOCCCN1CCC(C(=N2)C)=C1N=C2N(CC)C1=C(C)C=C(C)C=C1C RDTAGOQVNFFUMG-UHFFFAOYSA-N 0.000 claims description 2
- MTVASUIOIWPTCW-UHFFFAOYSA-N n-ethyl-4-methyl-7-(4-phenylbutan-2-yl)-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound CC=1C=C(C)C=C(C)C=1N(CC)C(N=C(C)C=1CC2)=NC=1N2C(C)CCC1=CC=CC=C1 MTVASUIOIWPTCW-UHFFFAOYSA-N 0.000 claims description 2
- ZEQMYVVAAVDJMM-UHFFFAOYSA-N n-ethyl-4-methyl-7-(naphthalen-1-ylmethyl)-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound N=1C=2N(CC=3C4=CC=CC=C4C=CC=3)CCC=2C(C)=NC=1N(CC)C1=C(C)C=C(C)C=C1C ZEQMYVVAAVDJMM-UHFFFAOYSA-N 0.000 claims description 2
- BZSBOLMMSKHYRV-UHFFFAOYSA-N n-ethyl-4-methyl-7-(oxolan-2-ylmethyl)-n-(2,4,6-trimethylphenyl)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-amine Chemical compound CC=1C=C(C)C=C(C)C=1N(CC)C(N=C(C)C=1CC2)=NC=1N2CC1CCCO1 BZSBOLMMSKHYRV-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
本发明涉及通常是CRF-1受体拮抗剂且由式I代表的化合物,其中X1是(CH2)n,n是0至2,且R1、R2、R3和R4如说明书中所定义,或单独的异构体、异构体的外消旋或非-外消旋混合物或其药学上可接受的盐。本发明还涉及制备所述化合物的方法、含有所述化合物的药物组合物和将它们用作治疗剂的方法。
Description
本发明涉及用作治疗剂和用于制备作为治疗剂的药物的具有CRF活性的稠合的嘧啶衍生物、相关的药物组合物,及其制备方法。
更准确而言,本发明涉及CRF受体拮抗剂,更具体地涉及式I的CRF受体拮抗剂化合物,
其中,
X1是(CH2)n,其中n=0至2;
R1是(i)C1-10烷基或C2-10链烯基,任选被选自下组的取代基取代:羟基、氰基、氨基、C1-3烷基氨基、C1-3二烷基氨基、(C1-3烷基)芳基氨基和苯基,所述苯基任选地被1-3个独立地选自下组的取代基取代:C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基磺酰基、氨基磺酰基、单烷基氨基磺酰基、二烷基氨基磺酰基、卤素、卤代烷基、氰基、硝基和-NRaRb,其中Ra和Rb各自独立地选自氢、C1-6烷基和C1-6烷基羰基,
(ii)C3-7环烷基,其任选地被C1-3烷基或羟基取代,
(iii)C3-7环烷基-C1-3烷基或C3-7环烯基-C1-3烷基,
(iv)C4-12双环或三环烷基,
(v)C3-7杂环烷基或C3-7杂环烷基-C1-3烷基,其任选地被C1-3烷基、苯基或苯基-C1-6烷基取代,或者杂环烷基部分中的CH2可以被C=O替换,
(vi)苯并稠合的C5-7环烷基,
(vii)苯基或杂芳基,所述苯基和杂芳基任选地被1-3个独立地选自下组的取代基取代:C1-6烷基、C1-6烷氧基、亚甲二氧基、C1-6烷硫基、C1-6烷基磺酰基、氨基磺酰基、单烷基氨基磺酰基、二烷基氨基磺酰基、卤素、卤代烷基、氰基、硝基和-NRaRb,其中Ra和Rb各自独立地选自氢、C1-6烷基和C1-6烷基羰基,
(viii)萘基,
(ix)杂芳基-C1-6烷基,所述杂芳基-C1-6烷基任选地被1-3个选自下组的取代基取代:C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基磺酰基、氨基磺酰基、单烷基氨基磺酰基、二烷基氨基磺酰基、卤素、卤代烷基、氰基、硝基和-NRaRb,其中Ra和Rb各自独立地选自氢、C1-6烷基和C1-6烷基羰基,
(x)1,2-二苯基乙基,
(xii)C1-3烷氧基-C1-6烷基,或,
(xiii)芳氧基-C1-6烷基,所述芳氧基任选地被1-3个选自下组的取代基取代:C1-3烷基、C1-3烷氧基和卤素;
R2是C1-6烷基或C1-3卤代烷基;
R3是(i)氢,
(ii)C1-6烷基,其任选地被羟基、C1-3烷氧基或C1-3酰氧基取代,
(iii)C3-6链烯基,
(iv)C3-7环烷基,
(v)C3-7环烷基-C1-3烷基,
(vi)C3-7环烯基,
(vii)C3-7环烯基-C1-3烷基,
(viii)苄基,其任选地被1-3个独立地选自下组的取代基取代:C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基磺酰基、氨基磺酰基、单烷基氨基磺酰基、二烷基氨基磺酰基、卤素、卤代烷基、氰基、硝基和-NRaRb,其中Ra和Rb各自独立地选自氢、C1-6烷基和C1-6烷基羰基;且,
R4是芳基,任选地被1-3个独立地选自下组的取代基取代:C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基磺酰基、氨基磺酰基、单烷基氨基磺酰基、二烷基氨基磺酰基、卤素、卤代烷基、氰基、硝基和-NRaRb,其中Ra和Rb各自独立地选自氢、C1-6烷基和C1-6烷基羰基,和,单独的异构体、异构体的外消旋或非外消旋混合物、溶剂合物、水合物或其药学上可接受的盐。
现已惊讶地发现,通式I化合物是CRF受体拮抗剂。式I化合物的特征是具有有价值的治疗性质。它们可以用于治疗或预防CRF受体介导的疾病。
促肾上腺皮质激素释放因子(CRF)或激素(CRH)是由脑中特定的下丘脑核合成的几种神经激素之一,它在脑中激活阿黑皮素原(POMC)基因的转录,导致从垂体前叶细胞释放促肾上腺皮质激素(ACTH)和β-内啡肽(vale等,Science213,1394-1397(1981))。CRF的基本功能是使生物体对各种应激物如物理创伤、免疫系统刺激和社会交互作用产生适当的反应。通过作用于其中广泛分布着CRF神经元的脑中的高中心、特别是皮质区,CRF还具有CNS作用。CRF据信是免疫、中枢神经、内分泌和心血管系统之间通信的关键中间物(Sapolsky等,Science238,522-524(1987))。本领域中已经描述了CRF在整合免疫系统对生理学、心理学和免疫学应激物的反应方面所起的作用,例如J.E.Blalock,Physiological Reviews69,1(1989)和J.E.Morley,Life Sci 41,527(1987)。
CRF是控制下丘脑-垂体-肾上腺轴的主要激素。CRF通过至少2种不同的G-蛋白偶联的受体亚型(它们的解剖学分布和对肽配体的反应有差别)发挥其药理学活性。已经观察到这2种亚型的不同的剪接修饰体(J.Saunders和J.P.Williams,“肾上腺皮质激素释放因子的研究新进展”,Ann.Rep.Med.Chem.200136:21-30)。第一种CRF受体拮抗剂是肽(见例如Rivier等.,美国专利No.4,605,642;Rivier等.,Science1984224:889)。虽然这些肽证实了CRF受体拮抗剂可以减弱对CRF的药理学反应,但肽CRF受体拮抗剂仍然具有肽治疗剂的常见缺点,包括缺乏稳定性,且口服活性有限。最近,已经报道了小分子CRF受体拮抗剂(Saunders和Williams,同上;D.E.Grigoriadis等.,“CRF受体:结构、功能和治疗干预潜力”,Curr.Med.Chem.-Central Nervous System Agents 20011:63-97;D.A.Gutman等,“作为新的心理治疗剂的肾上腺皮质激素释放因子拮抗剂”,Drugs of the Future 200025(9):923-31)。
CRF拮抗剂可以有效地治疗广范围的应激相关性疾病,心境障碍如抑郁、重度抑郁症、单发性抑郁、复发性抑郁、儿童虐待诱导的抑郁、产后抑郁、情绪不良、两极型障碍和躁郁性气质;慢性疲劳综合症;饮食障碍如肥胖、食欲缺乏和狂食症;泛化性焦虑障碍;惊慌性障碍;恐怖症;强迫性障碍;创伤后应激障碍(post-traumatic stress disorder);痛知觉如肌纤维痛(fibromyalgia);头痛;应激诱导的胃肠功能障碍如肠易激综合征(IBS)、结肠过敏症或痉挛性结肠;出血性应激反应;溃疡;应激诱导的精神病发作;炎性障碍如类风湿性关节炎和骨关节炎;哮喘;银屑病;变态反应;早产;高血压;充血性心力衰竭;睡眠障碍;神经变性疾病如阿尔茨海默病、老年痴呆、帕金森病和亨廷顿氏舞蹈病;头或脊髓创伤;缺血性神经元损伤;兴奋毒性(excitotoxic)神经元损伤;癫痫;中风;心理社会矮小病;化学品依赖性和成瘾;药物和酒精戒断症状;应激诱导的免疫功能障碍;免疫抑制和应激诱导的感染;心血管或心相关疾病;生育力问题;和/或人免疫缺陷病毒感染。相应地,临床数据表明CRF受体拮抗剂可以代表新型的抗抑郁药和/或抗焦虑药,其可以用于治疗表现出CRF分泌过多的神经精神障碍。
已经报道5,8-二氢-6H-吡啶并[2,3-d]嘧啶-7-酮具有多种药理学活性。WO200259083(J.L.Adams等)公开了作为p38激酶的5,8-二氢-6H-吡啶并[2,3-d]嘧啶-7-酮化合物。WO2001055148(R.J.Booth等)和WO9833798(D.H.Boschelli等)报道了具有细胞周期蛋白-依赖性激酶抑制活性的相关化合物。WO9801428(C.Dominguez等)公开了作为Xa因子和凝血酶抑制剂的脒基吲哚类、脒基吡咯类(amidinoazoles)物质和类似物。
虽然通过施用CRF受体拮抗剂在实现CRF调节方面已经取得了显著进步,该领域仍然需要有效的和选择性的小分子CRF受体拮抗剂。也需要含有这样的CRF受体拮抗剂的药物组合物,以及涉及使用其治疗例如应激相关疾病的方法。本发明满足了这些需要,并提供了其它的相关优点。
本发明涉及用于治疗或预防CRF受体介导的疾病的式I化合物及其药学上可接受的盐。
本发明还涉及按照本文中关于式I化合物所述的一般方法制备通式I化合物的方法。本发明还涉及通过所述方法得到的化合物。
而且,本发明还涉及含有一种或多种本发明化合物和药学上可接受的赋形剂的药物,其用于治疗和预防CRF受体介导的疾病如恐怖症、应激相关性疾病、心境障碍、饮食障碍、泛化性焦虑障碍、应激诱导的胃肠功能障碍、神经变性疾病和神经精神障碍。
本发明还涉及根据本发明的化合物在制备用于治疗和预防如上所述的CRF受体介导的疾病的药物中的应用。
本发明还涉及含有一种或多种本发明的CRF受体拮抗剂和药学上可接受的载体和/或稀释剂的药物组合物。
以下本说明书中使用的一般术语的定义无论该目标术语是单独出现还是组合出现均适用。
如本文所使用的短语“一种”物质是指一种或多种该物质;例如,一种化合物是指一种或多种化合物或至少一种化合物。就此,术语“一种”、“一种或多种”和“至少一种”在本文中可互换使用。
短语“如上文所定义的”是指在发明概述中提供的第一次定义。
如本文所使用的术语“任选的”或“任选地”是指随后所述的事件或情形可能(但是不需要)发生,且该描述包括该事件或情形发生的情况和其不发生的情况。例如,“任选地取代”是指该部分可以是氢或取代基。
如本文所使用的术语“烷基”是指无支链的或有支链的、饱和的、含有1-10个碳原子的单价烃残基。术语“低级烷基”是指直链的或支链的含有1-6个碳原子的烃残基。如本文所使用的“C1-10烷基”是指烷基,其中烷基是由1-10个碳组成。烷基的实例包括但不限于低级烷基,包括甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基或戊基、异戊基、新戊基、己基、庚基和辛基,也包括在本申请中特别实施的烷基。
如本文所使用的术语“亚烷基”是指二价的线性或支链的饱和烃基,其具有1-6个碳(包括1和6),除非另有说明。亚烷基的实例包括但不限于亚甲基、亚乙基、亚丙基、2-甲基-亚丙基、亚丁基和2-乙基亚丁基,也包括在本申请中特别实施的亚烷基。
如本文所使用的术语“链烯基”是指未取代的具有2-10个碳原子的烃链基团,其具有1个或2个烯双键[优选1个烯双键]。如本文所使用的“C2-10链烯基”是指由2-10个碳组成的链烯基。实例是乙烯基、1-丙烯基、2-丙烯基(烯丙基)或2-丁烯基(巴豆基),也包括在本申请中特别实施的链烯基。
如本文所使用的术语“双环烷基”或“三环烷基”分别是指2个或3个稠合的未取代的具有4-12个碳原子的烃环。实例包括但不限于降冰片烷和金刚烷。
如本文所使用的术语“环烷基”是指饱和的含有3-8个碳原子的碳环,即环丙基、环丁基、环戊基、环己基、环庚基或环辛基以及在本申请中特别实施的环烷基。如本文所使用的术语“C3-7环烷基”是指由3-7个碳环中的碳组成的环烷基。
如本文所使用的术语“苯并稠合的-C5-7环烷基”是指饱和的含有5-7个碳原子的碳环,其中环烷基的2个相邻碳通过双键连接,且所述2个相邻碳被-(CH=CH)2-取代,苯并稠合的环烷基连接到环烷基上。这样的苯并稠合的-C5-7环烷基的实例也包括在本申请中特别实施的那些。
如本文所使用的术语“环烷基烷基”是指基团R′R″-,其中R′是如本文所定义的环烷基,且R″是如本文所定义的烷基。环烷基烷基的实例包括但不限于环丙基甲基、环己基甲基、环戊基乙基,也包括在本申请中特别实施的环烷基烷基,且环烷基烷基基团的连接点是在亚烷基上。C3-7环烷基-C1-3烷基是指基团R′R″,其中R′是C3-7环烷基,且R″是如本文所定义的C1-3亚烷基。
如本文所使用的术语“酰基”是指式C(=O)R的基团,其中R是氢或如本文所定义的低级烷基。该术语或如本文所使用的“烷基羰基”是指式C(=O)R的基团,其中R是如本文所定义的烷基。如本文所使用的术语“芳基羰基”是指式C(=O)R的基团,其中R是芳基;如本文所使用的术语“苯甲酰基”是指“芳基羰基”,其中R是苯基。烷基羰基的实例也包括在本申请中特别实施的那些。
如本文所使用的术语“酰氧基”是指基团-OC(O)R,其中R是如本文所定义的低级烷基。酰氧基的实例包括但不限于乙酰氧基、丙酰氧基以及在本申请中特别实施的酰氧基。
如本文所使用的术语“氨基”、“烷基氨基”和“二烷基氨基”分别指-NH2、-NHR和-NR2,且R是如上定义的烷基。二烷基中的结合到同一个氮上的2个烷基可以相同或不同。氨基、烷基氨基和二烷基氨基的实例也包括在本申请中特别实施的那些。
如本文所使用的术语“(烷基)芳基氨基”是指基团R′R″,其中R′是-NH(芳基),且R″是如本文所定义的亚烷基,应理解(烷基)芳基氨基的连接点是在亚烷基上。(烷基)芳基氨基的实例也包括在本申请中特别实施的那些。
术语“烷氧基”是指-O-烷基,其中烷基如上定义,例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基、己氧基,包括它们的异构体,以及在本申请中特别实施的烷氧基。如本文所使用的“低级烷氧基”是指具有如前定义的“低级烷基”的烷氧基。如本文所使用的“C1-10烷氧基”是指-O-烷基,其中烷基是C1-10。
如本文所使用的术语“烷氧基烷基”是指基团R′R″-,其中R′是如本文所定义的烷氧基,R″是如本文所定义的亚烷基,应理解烷氧基烷基的连接点在亚烷基上。实例是甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、丙氧基丙基、甲氧基丁基、乙氧基丁基、丙氧基丁基、丁氧基丁基、叔丁氧基丁基、甲氧基戊基、乙氧基戊基、丙氧基戊基,包括它们的异构体以及在本申请中特别实施的烷氧基烷基。
如本文所使用的术语“烷氧基羰基烷基”和“芳氧基羰基烷基”是指基团R′R″,其中R′是烷氧基羰基或芳氧基羰基,R″是如本文所定义的亚烷基,且芳基(烷氧基)羰基烷基基团的连接点在亚烷基上。烷氧基羰基烷基的实例也包括在本申请中特别实施的那些。
术语“烷硫基”或“硫代烷基”是指-S-烷基,其中烷基如上所定义,例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基、己氧基,包括它们的异构体。烷硫基的实例也包括在本申请中特别实施的那些。如本文所使用的“低级烷硫基”或“低级硫代烷基”是指具有如前定义的“低级烷基”的烷硫基。如本文所使用的“C1-10烷硫基”是指-S-烷基,其中烷基是C1-10。
如本文所使用的术语“烷基磺酰基”和“芳基磺酰基”是指式-S(=O)2R基团,其中R分别是烷基或芳基,且烷基和芳基如本文所定义。烷氧基磺酰基的实例也包括在本申请中特别实施的那些。
如本文所使用的术语“氨基磺酰基”是指基团-S(O)2NH2。如本文所使用的术语“烷基氨基磺酰基”和“二烷基氨基磺酰基”是指基团-S(O)2NR′R″,其中R′和R″是氢和低级烷基,或R′和R″分别独立地是低级烷基。烷基氨基磺酰基的实例包括但不限于甲基氨基磺酰基、异丙基氨基磺酰基,也包括在本申请中特别实施的烷基氨基磺酰基。二烷基氨基磺酰基的实例包括但不限于二甲基氨基磺酰基、异丙基-甲基氨基磺酰基,也包括在本申请中特别实施的二烷基氨基磺酰基。
如本文所使用的术语“芳基”是指由一个单独的环或一个或多个(其中至少一个环是芳香性的)稠合环组成的单价芳香族碳环基团,其可以任选地被1个或多个、优选地1个或2个选自下组的取代基取代:羟基、硫代、氰基、烷基、烷氧基、低级卤代烷氧基、烷硫基、卤素、卤代烷基、羟基烷基、硝基、烷氧基羰基、氨基、烷基氨基、二烷基氨基、氨基烷基、烷基氨基烷基和二烷基氨基烷基、烷基磺酰基、芳基亚磺酰基、烷基氨基磺酰基、芳基氨基磺酰基、烷基磺酰基氨基、芳基磺酰基氨基、氨甲酰基、烷基氨甲酰基和二烷基氨甲酰基、芳基氨甲酰基、烷基羰基氨基、芳基羰基氨基,除非另有说明。或者,芳环的2个相邻原子可以被亚甲二氧基或亚乙二氧基取代。芳基的实例包括但不限于苯基、萘基、联苯基、二氢化茚基、蒽醌基(anthraqionolyl),也包括在本申请中特别实施的芳基。
如本文所使用的术语“芳氧基”是指O-芳基,其中芳基如上所定义。芳氧基可以是未取代的,或被1个或2个合适的取代基取代。术语“苯氧基”是指其中芳基是苯环的芳氧基。
如本文所使用的术语“芳氧基烷基”是指基团R′R″-,其中R′是如本文所定义的芳氧基,R″是如本文所定义的亚烷基,应理解芳氧基烷基的连接点在亚烷基上。芳氧基-C1-3烷基是指基团R′R″,其中R′是芳氧基,R″是如本文所定义的C1-3亚烷基。
如本文所使用的术语“环烯基”是指不饱和的含有4-8个碳原子的碳环,即环丁烯基、环戊烯基、环己烯基、环庚烯基或环辛烯基,以及在本申请中特别实施的环烯基。如本文所使用的“C4-7环烯基”是指碳环中由4-7个碳组成的环烯基。
如本文所使用的术语“环烯基烷基”是指基团R′R″-,其中R′是如本文所定义的环烯基,R″是如本文所定义的亚烷基,应理解环烯基烷基的连接点在亚烷基上。环烷基烷基的实例包括但不限于环丙基甲基、环己基甲基、环戊基乙基,也包括在本申请中特别实施的环烯基烷基。C3-7环烷基-C1-3烷基是指基团R′R″,其中R′是C3-7环烷基,R″是如本文所定义的C1-3亚烷基。
如本文所使用的术语“卤素”或“卤代″是指氟、氯、溴或碘。
如本文所使用的术语“卤代烷基”是指如上定义的无支链或有支链的烷基,其中1、2、3或多个氢原子被卤素取代。实例是1-氟甲基、1-氯甲基、1-溴甲基、1-碘甲基、三氟甲基、三氯甲基、三溴甲基、三碘甲基、1-氟乙基、1-氯乙基、1-溴乙基、1-碘乙基、2-氟乙基、2-氯乙基、2-溴乙基、2-碘乙基、2,2-二氯乙基、3-溴丙基或2,2,2-三氟乙基,也包括在本申请中特别实施的卤代烷基。
如本文所使用的术语“杂芳基”或“杂芳的”是指5-12个环原子的单环或双环基团,其具有至少一个含有4-8个原子/环的芳香环,包括一个或多个N、O或S杂原子,剩余的环原子是碳,应理解杂芳基的连接点是在芳香环上。如本领域的技术人员熟知,杂芳环较它们的全碳对应物具有较低的芳香性。因此,为了本发明的目的,杂芳基只需要具有一定程度的芳香性。杂芳基的实例包括具有5-6个环原子和1-3个杂原子的单环芳香杂环,包括但不限于吡啶基、嘧啶基、吡嗪基、吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三唑啉基、噻二唑啉基和噁二唑啉基以及在本申请中特别实施的杂芳基,其可以任选地被1个或多个、优选地1个或2个选自下组的取代基取代:羟基、氰基、烷基、烷氧基、硫代、低级卤代烷氧基、烷硫基、卤代、卤代烷基、烷基亚磺酰基、烷基磺酰基、卤素、氨基、烷基氨基、二烷基氨基、氨基烷基、烷基氨基烷基和二烷基氨基烷基、硝基、烷氧基羰基和氨甲酰基、烷基氨甲酰基和二烷基氨甲酰基以及在本申请中特别实施的取代基。双环部分的实例包括但不限于喹啉基、异喹啉基、苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、吲哚和苯并异噻唑以及在本申请中特别实施的双环部分。双环部分可以任选地在任一环上被取代。
术语“杂芳基烷基”或“杂芳烷基”是指式R′R″的基团,其中R′是如本文所定义的任选地被取代的杂芳基,且R″是如本文所定义的亚烷基,应理解杂芳基的连接点在亚烷基上。杂芳基烷基的实例包括但不限于2-咪唑基甲基、3-吡咯基乙基,还包括在本申请中特别实施的杂芳基烷基。
如本文所使用的术语“杂环烷基”是指含有3-7个碳原子和1、2或3个选自N、O和S的杂原子的饱和碳环。这种基团的实例包括但不限于特别实施的那些。
如本文所使用的术语“杂环烯基”是指含有3-7个碳原子和1、2或3个选自N、O和S的杂原子的不饱和碳环。这种基团的实例包括但不限于特别实施的那些。
如本文所使用的术语“羟基亚烷基”是指基团R′R″,其中R′是羟基,R″是如本文所定义的亚烷基,且羟基亚烷基的连接点在亚烷基上。羟基亚烷基的实例包括在本申请中特别实施的那些。
如本文所使用的术语“亚甲二氧基”是指二价取代基-OCH2O-,其中两个氧原子结合在芳基或杂芳环的相邻碳原子上。
如本文所使用的术语“氯代亚烷基”是指基团R′R″,其中R′是氯基团,R″是如本文所定义的亚烷基,氯代亚烷基的连接点在亚烷基上。氯代亚烷基的实例为在本申请中特别实施的那些。
本发明还包括式I化合物,其中
X1是(CH2)n;
n是0至2;
R1是(i)C1-10烷基,其任选地被选自下组的取代基取代:氨基、C1-3烷基氨基、C1-3二烷基氨基、(C1-3烷基)芳基氨基和苯基,所述苯基任选地被1-3个独立地选自下组的取代基取代:C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基磺酰基、氨基磺酰基、单烷基氨基磺酰基、二烷基氨基磺酰基、卤素、卤代烷基、氰基、硝基和-NRaRb,其中Ra和Rb各自独立地选自氢、C1-6烷基和C1-6烷基羰基,
(ii)C3-7环烷基,其任选地被C1-3烷基取代,
(iii)C3-7环烷基-C1-3烷基,
(iv)苯并稠合的-C5-7环烷基,
(v)苯基或杂芳基,所述苯基和杂芳基任选地被1-3个独立地选自下组的取代基取代:C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基磺酰基、氨基磺酰基、单烷基氨基磺酰基、二烷基氨基磺酰基、卤素、卤代烷基、氰基、硝基和-NRaRb,其中Ra和Rb各自独立地选自氢、C1-6烷基和C1-6烷基羰基,
(vi)杂芳基-C1-6烷基,所述杂芳基-C1-6烷基任选地被1-3个选自下组的取代基取代:C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基磺酰基、氨基磺酰基、单烷基氨基磺酰基、二烷基氨基磺酰基、卤素、卤代烷基、氰基、硝基和-NRaRb,其中Ra和Rb各自独立地选自氢、C1-6烷基和C1-6烷基羰基,
(vii)1,2-二苯基乙基,
(viii)C1-3烷氧基-C1-6烷基,或,
(ix)芳氧基-C1-6烷基,所述芳氧基任选地被1-3个选自下组的取代基取代:C1-3烷基、C1-3烷氧基和卤素;
R2是C1-6烷基或C1-3卤代烷基;
R3是(i)氢,
(ii)C1-6烷基,其任选地被羟基、C1-3烷氧基或C1-3酰氧基取代,
(iii)C3-6链烯基,
(iv)C3-7环烷基,
(v)C3-7环烷基-C1-3烷基;
(vi)C3-7环烯基,
(vii)C3-7环烯基-C1-3烷基,
(viii)苄基,其任选地被1-3个独立地选自下组的取代基取代:C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基磺酰基、氨基磺酰基、单烷基氨基磺酰基、二烷基氨基磺酰基、卤素、卤代烷基、氰基、硝基和-NRaRb,其中Ra和Rb各自独立地选自氢、C1-6烷基和C1-6烷基羰基;且,
R4是芳基,任选地被1-3个独立地选自下组的取代基取代:C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基磺酰基、氨基磺酰基、单烷基氨基磺酰基、二烷基氨基磺酰基、卤素、卤代烷基、氰基、硝基和-NRaRb,其中Ra和Rb各自独立地选自氢、C1-6烷基和C1-6烷基羰基;和单独的异构体、异构体的外消旋或非外消旋混合物、溶剂合物、水合物或其药学上可接受的盐。
在本发明的一个实施方案中,提供了式I的化合物,
其中X1是(CH2)n,且R1、R2、R3、R4和n如上文所定义。
在本发明的另一个实施方案中,提供了式I的化合物,其中X1是(CH2)n;n是0;R1是(i)C1-10有支链的或无支链的烷基,(ii)任选地被取代的杂芳基-C1-6烷基,所述杂芳基任选地被选自C1-3烷基、C1-3烷氧基和卤素的取代基取代,(iii)任选地被取代的苯基或杂芳基,所述苯基或杂芳基任选地被选自C1-3烷基、C1-3烷氧基和卤素的取代基取代,或(iv)被苯基取代的C1-3烷基,所述苯基任选地被选自C1-3烷基、C1-3烷氧基和卤素的取代基取代;R2是C1-6烷基或C1-3卤代烷基;R3是(i)氢,(ii)C1-6烷基,(iii)C3-7环烷基-C1-3烷基,或(iv)苄基,其任选地被C1-3烷基、C1-3烷氧基或卤素取代;R4是任选地被取代的苯基。
在本发明的另一个实施方案中,提供了式I的化合物,其中X1是(CH2)n;n是0;R1是(i)C1-10有支链的或无支链的烷基,(ii)被苯基取代的C1-10烷基,所述苯基任选地被取代,或(iii)杂芳基-C1-6烷基,其中所述杂芳基是2-噻吩基、2-呋喃基或3-二氢吲哚基,每个所述杂芳基任选地被取代;R2是C1-6烷基或C1-3卤代烷基;R3是(i)氢,(ii)C1-6烷基,(iii)C3-7环烷基-C1-3烷基,或(iv)苄基,其任选地被C1-3烷基、C1-3烷氧基或卤素取代;R4是任选地取代的苯基。
在本发明的另一个实施方案中,提供了式I的化合物,其中X1是(CH2)n;n是0;R1是(i)C1-10有支链的或无支链的烷基,(ii)被苯基取代的C1-10烷基,所述苯基任选地被取代,或(iii)杂芳基-C1-6烷基,其中所述杂芳基是2-噻吩基、2-呋喃基或3-二氢吲哚基,每个所述杂芳基任选地被取代;R2是C1-6烷基或C1-3卤代烷基;R3是(i)氢,(ii)C1-6烷基,(iii)C3-7环烷基-C1-3烷基,或(iv)苄基,其任选地被C1-3烷基、C1-3烷氧基或卤素取代;R4是2,4-二取代的或2,4,6-三取代的苯基。
在本发明的另一个实施方案中,提供了式I的化合物,其中X1是(CH2)n,n是0,R2是CH3,R3是CH2CH3,且R4是2,4-二取代的或2,4,6-三取代的-苯基。该实施方案的优选化合物可以选自下组:
乙基-[7-(1-乙基-丙基)-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
(7-环丙基-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基)-乙基-(2,4,6-三甲基-苯基)-胺,
(7-环己基甲基-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基)-乙基-(2,4,6-三甲基-苯基)-胺,
乙基-[4-甲基-7-(1,2,3,4-四氢-萘-1-基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
乙基-{4-甲基-7-[2-(1-甲基-吡咯烷-2-基)-乙基]-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基}-(2,4,6-三甲基-苯基)-胺,
乙基-(7-二氢化茚-1-基-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基)-(2,4,6-三甲基-苯基)-胺,
乙基-(4-甲基-7-萘-1-基甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基)-(2,4,6-三甲基-苯基)-胺,
乙基-[4-甲基-7-(四氢-呋喃-2-基甲基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
乙基-(4-甲基-7-噻吩-2-基甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基)-(2,4,6-三甲基-苯基)-胺,
(7-苯并[1,3]二氧杂环戊烯-5-基甲基-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基)-乙基-(2,4,6-三甲基-苯基)-胺,
乙基-[4-甲基-7-(3-吗啉-4-基-丙基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
乙基-[4-甲基-7-(2-吡啶-2-基-乙基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
乙基-(4-甲基-7-吡啶-3-基甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基)-(2,4,6-三甲基-苯基)-胺,
[7-(1-苄基-哌啶-4-基)-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-乙基-(2,4,6-三甲基-苯基)-胺,
乙基-[4-甲基-7-(2-哌啶-1-基-乙基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
[7-(1,2-二苯基-乙基)-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-乙基-(2,4,6-三甲基-苯基)-胺,
乙基-(7-异丙基-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基)-(2,4,6-三甲基-苯基)-胺,
乙基-[7-(2-甲氧基-1-甲基-乙基)-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
乙基-[4-甲基-7-(1-甲基-3-苯基-丙基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
(7-苄基-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基)-乙基-(2,4,6-三甲基-苯基)-胺,
乙基-[7-(3-氟-苄基)-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
[7-(3,4-二甲氧基-苄基)-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-乙基-(2,4,6-三甲基-苯基)-胺,
乙基-(4-甲基-7-苯乙基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基)-(2,4,6-三甲基-苯基)-胺,
(7-烯丙基-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基)-乙基-(2,4,6-三甲基-苯基)-胺,
乙基-(4-甲基-7-丙基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基)-(2,4,6-三甲基-苯基)-胺,
乙基-(4-甲基-7-戊基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基)-(2,4,6-三甲基-苯基)-胺,
乙基-[7-(3-咪唑-1-基-丙基)-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
[7-(2-环己-1-烯基-乙基)-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-乙基-(2,4,6-三甲基-苯基)-胺,
3-{2-[乙基-(2,4,6-三甲基-苯基)-氨基]-4-甲基-5,6-二氢-吡咯并[2,3-d]嘧啶-7-基}-丙腈,
(7-环丙基甲基-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基)-乙基-(2,4,6-三甲基-苯基)-胺,
乙基-[4-甲基-7-(1-苯基-丙基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
乙基-{7-[1-(4-氟-苯基)-乙基]-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基}-(2,4,6-三甲基-苯基)-胺,
乙基-[4-甲基-7-(2-苯氧基-乙基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
[7-(1-苄基-吡咯烷-3-基)-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-乙基-(2,4,6-三甲基-苯基)-胺,
乙基-{7-[2-(3-氟-苯基)-乙基]-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基}-(2,4,6-三甲基-苯基)-胺,
乙基-[4-甲基-7-(3-丙氧基-丙基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
[7-(2-[1,3]二氧戊环-2-基-乙基)-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-乙基-(2,4,6-三甲基-苯基)-胺,
乙基-[4-甲基-7-(5-甲基-吡嗪-2-基甲基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
{7-[2-(1-苄基-哌啶-4-基)-乙基]-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基}-乙基-(2,4,6-三甲基-苯基)-胺,和
[7-(2,4-二甲基-苯基)-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-乙基-(2,4,6-三甲基-苯基)-胺,
以及它们与三氟乙酸的酸加成盐。
在本发明的另一个实施方案中,提供了式I的化合物,其中X1是(CH2)n,n是0,R1是CH(正丙基)2,R2是CH3,R3是CH2CH3,且R4是2,4-二取代的或2,4,6-三取代的苯基。该实施方案的优选化合物可以选自下组:
甲基-[4-甲基-7-(1-丙基-丁基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
乙基-[4-甲基-7-(1-丙基-丁基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
异丙基-[4-甲基-7-(1-丙基-丁基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
丁基-[4-甲基-7-(1-丙基-丁基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
环戊基-[4-甲基-7-(1-丙基-丁基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
乙酸4-[[4-甲基-7-(1-丙基-丁基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-氨基]-丁基酯,
苄基-[4-甲基-7-(1-丙基-丁基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
环丙基甲基-[4-甲基-7-(1-丙基-丁基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,和
烯丙基-[4-甲基-7-(1-丙基-丁基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺
以及它们与三氟乙酸的酸加成盐。
在本发明的另一个实施方案中,提供了式I的化合物,其中X1是(CH2)n;n是1;R1是(i)C1-10有支链的或无支链的烷基,(ii)任选地被取代的杂芳基-C1-6烷基,所述杂芳基任选地被选自C1-3烷基、C1-3烷氧基和卤素的取代基取代,(iii)任选地被取代的苯基或杂芳基,所述苯基或杂芳基任选地被选自C1-3烷基、C1-3烷氧基和卤素的取代基取代,或(iv)被苯基取代的C1-3烷基,所述苯基任选地被选自C1-3烷基、C1-3烷氧基和卤素的取代基取代;R2是C1-6烷基或C1-3卤代烷基;R3是(i)氢,(ii)C1-6烷基,(iii)C3-7环烷基-C1-3烷基,或(iv)苄基,其任选地被C1-3烷基、C1-3烷氧基或卤素取代;R4是任选地被取代的苯基。
在本发明的另一个实施方案中,提供了式I的化合物,其中X1是(CH2)n;n是1;R1是(i)C1-10有支链的或无支链的烷基,(ii)任选地被取代的杂芳基-C1-6烷基,所述杂芳基任选地被选自C1-3烷基、C1-3烷氧基和卤素的取代基取代,(iii)任选地被取代的苯基或杂芳基,所述苯基或杂芳基任选地被选自C1-3烷基、C1-3烷氧基和卤素的取代基取代,或(iv)被苯基取代的C1-3烷基,所述苯基任选地被选自C1-3烷基、C1-3烷氧基和卤素的取代基取代;R2是C1-6烷基或C1-3卤代烷基;R3是(i)氢,(ii)C1-6烷基,(iii)C3-7环烷基-C1-3烷基,或(iv)苄基,其任选地被C1-3烷基、C1-3烷氧基或卤素取代;R4是2,4-二取代的或2,4,6-三取代的苯基。
在本发明的另一个实施方案中,提供了式I的化合物,其中R2是CH3,且R4是2-溴-4-异丙基苯基。
该实施方案的优选化合物可以选自:
(2-溴-4-异丙基-苯基)-[8-(1-乙基-丙基)-4-甲基-5,6,7,8-四氢-吡啶并[2,3-d]嘧啶-2-基]-胺,
(2-溴-4-异丙基-苯基)-乙基-[8-(1-乙基-丙基)-4-甲基-5,6,7,8-四氢-吡啶并[2,3-d]嘧啶-2-基]-胺,
(2-溴-4-异丙基-苯基)-[4-甲基-8-(1-丙基-丁基)-5,6,7,8-四氢-吡啶并[2,3-d]嘧啶-2-基]-胺,和
(2-溴-4-异丙基-苯基)-乙基-[4-甲基-8-(1-丙基-丁基)-5,6,7,8-四氢-吡啶并[2,3-d]嘧啶-2-基]-胺,
以及它们与氯化氢的酸加成盐。
在本发明的另一个实施方案中,提供了式I的化合物,其中X1是(CH2)n;n是2;R1是(i)C1-10有支链的或无支链的烷基,(ii)任选地被取代的杂芳基-C1-6烷基,所述杂芳基任选地被选自下组的取代基取代:C1-3烷基、C1-3烷氧基和卤素,(iii)任选地被取代的苯基或杂芳基,所述苯基或杂芳基任选地被选自C1-3烷基、C1-3烷氧基和卤素的取代基取代,或(iv)被苯基取代的C1-3烷基,所述苯基任选地被选自下组的取代基取代:C1-3烷基、C1-3烷氧基和卤素;R2是C1-6烷基或C1-3卤代烷基;R3是(i)氢,(ii)C1-6烷基,(iii)C3-7环烷基-C1-3烷基,或(iv)苄基,其任选地被C1-3烷基、C1-3烷氧基或卤素取代;R4是任选地被取代的苯基。
在本发明的另一个实施方案中,提供了式I的化合物,其中X1是(CH2)n;n是2;R1是(i)C1-10有支链的或无支链的烷基,(ii)任选地被取代的杂芳基-C1-6烷基,所述杂芳基任选地被选自C1-3烷基、C1-3烷氧基和卤素的取代基取代,(iii)任选地被取代的苯基或杂芳基,所述苯基或杂芳基任选地被选自下组的取代基取代:C1-3烷基、C1-3烷氧基和卤素,或(iv)被苯基取代的C1-3烷基,所述苯基任选地被选自下组的取代基取代:C1-3烷基、C1-3烷氧基和卤素;R2是C1-6烷基或C1-3卤代烷基;R3是(i)氢,(ii)C1-6烷基,(iii)C3-7环烷基-C1-3烷基,或(iv)苄基,其任选地被C1-3烷基、C1-3烷氧基或卤素取代;R4是2,4-二取代的或2,4,6-三取代的苯基。
在本发明的另一个实施方案中,提供了(根据权利要求15的化合物)式I的化合物,其中X1是(CH2)n,n是2,R2是CH3,R3是CH2CH3,R4是2,4,6-三取代的苯基。该实施方案的优选化合物可以选自下组:
(9-环己基甲基-4-甲基-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-基)-乙基-(2,4,6-三甲基-苯基)-胺,
乙基-(9-呋喃-2-基甲基-4-甲基-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-基)-(2,4,6-三甲基-苯基)-胺,
乙基-(9-二氢化茚-1-基-4-甲基-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-基)-(2,4,6-三甲基-苯基)-胺,
乙基-(4-甲基-9-噻吩-2-基甲基-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-基)-(2,4,6-三甲基-苯基)-胺,
乙基-(4-甲基-9-吡啶-3-基甲基-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-基)-(2,4,6-三甲基-苯基)-胺,
[9-(1,2-二苯基-乙基)-4-甲基-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-基]-乙基-(2,4,6-三甲基-苯基)-胺,
乙基-[9-(2-甲氧基-1-甲基-乙基)-4-甲基-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-基]-(2,4,6-三甲基-苯基)-胺,
乙基-[4-甲基-9-(1-甲基-3-苯基-丙基)-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-基]-(2,4,6-三甲基-苯基)-胺,
乙基-[9-(1-乙基-丙基)-4-甲基-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-基]-(2,4,6-三甲基-苯基)-胺,
(9-苄基-4-甲基-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-基)-乙基-(2,4,6-三甲基-苯基)-胺,
[9-(2,4-二氯-苄基)-4-甲基-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-基]-乙基-(2,4,6-三甲基-苯基)-胺,
乙基-[9-(3-氟-苄基)-4-甲基-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-基]-(2,4,6-三甲基-苯基)-胺,
乙基-[4-甲基-9-(2-苯基-丙基)-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-基]-(2,4,6-三甲基-苯基)-胺,
乙基-(4-甲基-9-苯乙基-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-基)-(2,4,6-三甲基-苯基)-胺,
(9-烯丙基-4-甲基-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-基)-乙基-(2,4,6-三甲基-苯基)-胺,
乙基-(4-甲基-9-戊基-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-基)-(2,4,6-三甲基-苯基)-胺,
乙基-[4-甲基-9-(1-丙基-丁基)-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-基]-(2,4,6-三甲基-苯基)-胺,
(9-环丙基甲基-4-甲基-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-基)-乙基-(2,4,6-三甲基-苯基)-胺,
乙基-[4-甲基-9-(1-苯基-丙基)-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-基]-(2,4,6-三甲基-苯基)-胺,
乙基-{9-[1-(4-氟-苯基)-乙基]-4-甲基-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-基}-(2,4,6-三甲基-苯基)-胺,
[9-(2,4-二氯-6-甲基-苄基)-4-甲基-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-基]-乙基-(2,4,6-三甲基-苯基)-胺,
乙基-[4-甲基-9-(2-苯氧基-乙基)-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-基]-(2,4,6-三甲基-苯基)-胺,
乙基-[4-甲基-9-(3-丙氧基-丙基)-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-基]-(2,4,6-三甲基-苯基)-胺,
[9-(2,4-二甲基-苯基)-4-甲基-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-基]-乙基-(2,4,6-三甲基-苯基)-胺,
[9-(2,4-二甲基-苄基)-4-甲基-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-基]-乙基-(2,4,6-三甲基-苯基)-胺,和
(4-甲基-9-噻吩-2-基甲基-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-基)-(2,4,6-三甲基-苯基)-胺,以及
它们与三氟乙酸的酸加成盐。
在本发明的另一个实施方案中,提供了以下通式I的化合物、单独的异构体、异构体的外消旋或非外消旋混合物、溶剂合物、水合物或其药学上可接受的盐在制备用于治疗或预防CRF受体介导的疾病的药物中的用途,
其中
X1是C=O;
R1是(i)C1-10烷基或C2-10链烯基,其任选地被选自下组的取代基取代:羟基、氰基、氨基、C1-3烷基氨基、C1-3二烷基氨基、(C1-3烷基)芳基氨基和苯基,所述苯基任选地被1-3个独立地选自下组的取代基取代:C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基磺酰基、氨基磺酰基、单烷基氨基磺酰基、二烷基氨基磺酰基、卤素、卤代烷基、氰基、硝基和-NRaRb,其中Ra和Rb各自独立地选自氢、C1-6烷基和C1-6烷基羰基,
(ii)C3-7环烷基,其任选地被C1-3烷基或羟基取代,
(iii)C3-7环烷基-C1-3烷基或C3-7环烯基-C1-3烷基(实施例49),
(iv)C4-12双环或三环烷基,
(v)C3-7杂环烷基或C3-7杂环烷基-C1-3烷基,其任选地被C1-3烷基、苯基或苯基-C1-6烷基取代,或者杂环基团中的CH2可以被C=O替换,
(vi)苯并稠合的-C5-7环烷基,
(vii)苯基或杂芳基,所述苯基和杂芳基任选地被1-3个独立地选自下组的取代基取代:C1-6烷基、C1-6烷氧基、亚甲二氧基、C1-6烷硫基、C1-6烷基磺酰基、氨基磺酰基、单烷基氨基磺酰基、二烷基氨基磺酰基、卤素、卤代烷基、氰基、硝基和-NRaRb,其中Ra和Rb各自独立地选自氢、C1-6烷基和C1-6烷基羰基,
(viii)萘基,
(ix)杂芳基-C1-6烷基,所述杂芳基-C1-6烷基任选地被1-3个选自下组的取代基取代:C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基磺酰基、氨基磺酰基、单烷基氨基磺酰基、二烷基氨基磺酰基、卤素、卤代烷基、氰基、硝基和-NRaRb,其中Ra和Rb各自独立地选自氢、C1-6烷基和C1-6烷基羰基;
(x)1,2-二苯基乙基,
(xii)C1-3烷氧基-C1-6烷基,或,
(xiii)芳氧基-C1-6烷基,所述芳氧基任选地被1-3个选自下组的取代基取代:C1-3烷基、C1-3烷氧基和卤素;
R2是C1-6烷基或C1-3卤代烷基;
R3是(i)氢,
(ii)C1-6烷基,其任选地被羟基、C1-3烷氧基或C1-3酰氧基取代,
(iii)C3-6链烯基,
(iv)C3-7环烷基,
(v)C3-7环烷基-C1-3烷基;
(vi)C3-7环烯基,
(vii)C3-7环烯基-C1-3烷基,
(viii)苄基,其任选地被1-3个独立地选自下组的取代基取代:C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基磺酰基、氨基磺酰基、单烷基氨基磺酰基、二烷基氨基磺酰基、卤素、卤代烷基、氰基、硝基和-NRaRb,其中Ra和Rb各自独立地选自氢、C1-6烷基和C1-6烷基羰基;且,
R4是芳基,任选地被1-3个独立地选自下组的取代基取代:C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基磺酰基、氨基磺酰基、单烷基氨基磺酰基、二烷基氨基磺酰基、卤素、卤代烷基、氰基、硝基和-NRaRb,其中Ra和Rb各自独立地选自氢、C1-6烷基和C1-6烷基羰基。
该实施方案的优选化合物可以选自下组:
2-(2-溴-4-异丙基-苯基氨基)-8-(1-乙基-丙基)-4-甲基-5,8-二氢-6H-吡啶并[2,3-d]嘧啶-7-酮,
2-(2-溴-4-异丙基-苯基氨基)-4-甲基-8-(1-丙基-丁基)-5,8-二氢-6H-吡啶并[2,3-d]嘧啶-7-酮,
2-[(2-溴-4-异丙基-苯基)-乙基-氨基]-4-甲基-8-(1-丙基-丁基)-5,8-二氢-6H-吡啶并[2,3-d]嘧啶-7-酮,以及
它们与盐酸的盐。
根据包括下述步骤的方法,可以制备本发明的式I化合物,其中R3是氢,X1、R1、R2、R4和n如上文所定义:
(i)使其中R4如上所定义的芳基胺盐酸盐XXII与氨腈接触,得到盐酸芳基胍鎓XXIII;
(ii)在碱存在下,使所述盐酸胍XXIII与α-取代的β-酮酯XXIV接触,在后者中,R2是C1-6烷基,R6是C1-6烷基,R7是烷氧基羰基烷基,或R6和R7一起是(CH2)o,且o是2-4,以得到嘧啶XXV,其中R5是烷氧基羰基烷基或(CH2)o-OH;
(iii)使所述嘧啶与氯化剂接触,所述氯化剂的反应性足以将XXV转化成对应的氯代嘧啶XXVI,并将R5上的羟基亚烷基侧链转化成对应的氯代亚烷基取代基;
(iv)使所述氯代嘧啶XXVI与伯胺接触,当R5是羟基亚烷基时,在替代嘧啶和R5侧链上的氯原子的条件下,生成稠合的杂环XXVII,其中R5是(CH2)o,或者当R5是烷氧基羰基烷基时,替代嘧啶上的氯,同时环化成内酰胺。
在本发明的另一个实施方案中,提供了制备式I化合物的方法,其中X1、R1、R2、R4和n如上文所定义,R3是(i)C1-6烷基,其任选地被羟基、C1-3烷氧基或C1-3酰氧基取代,(ii)C3-6链烯基,(iii)C3-7环烷基,(iv)C3-7环烷基-C1-3烷基,(v)C3-7环烯基,(vi)C3-7环烯基-C1-3烷基,(vii)苄基,其任选地被1-3个独立地选自下组的取代基取代:C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基磺酰基、氨基磺酰基、单烷基氨基磺酰基、二烷基氨基磺酰基、卤素、卤代烷基、氰基、硝基和-NRaRb,其中Ra和Rb各自独立地选自氢、C1-6烷基和C1-6烷基羰基;其中如上所述进行步骤(i)至(iv),并使其中R3是氢的嘧啶XXVII进一步与碱和烷化剂接触,以得到式XXVIII的叔胺。
在本发明的另一个实施方案中,提供了制备式I化合物的方法,其中X1是(CH2)n,R1、R2、R3、R4和n如上文所定义,其中使X1是C=O的式XXVIII的内酰胺与还原剂接触,以得到其中X1是CH2的式I的胺。
本发明还包括通过本发明的方法得到的化合物。
化合物和制备
通过下面显示和描述的解释性合成反应方案所述的多种方法,可以制备本发明的化合物。用于制备这些化合物的原料和试剂通常可以从商业供应商例如Aldrich Chemical Co.得到,或按照例如下述文献所述的步骤,通过本领域技术人员已知的方法制备:“Fieser和有机合成Fieser试剂”,Wiley & Sons:纽约,1-21卷;R.C.LaRock,“有机转化概述”,第2版,Wiley-VCH,纽约1999;“综合有机合成”B.Trost和I.Fleming(Eds.)vol.1-9Pergamon,Oxford,1991;“综合杂环化学”,A.R.Katritzky和C.W.Rees(Eds)Pergamon,Oxford 1984,1-9卷;“综合杂环化学II”,A.R.Katritzky和C.W.Rees(Eds)Pergamon,Oxford1996,1-11卷;以及“有机反应”,Wiley & Sons:纽约,1991,1-40卷。以下合成反应方案仅仅是可用以合成本发明化合物的众多方法的示例,可以对这些合成反应方案进行各种改进,且已经参考本发明所含公开内容的本领域的技术人员能够明白。
如果需要,可以使用常规技术,包括但不限于过滤、蒸馏、结晶、色谱等,分离和纯化合成反应方案的原料和中间体。可以使用常规手段、包括物理常数和光谱数据来表征这些物质。
除非另有相反说明,本文所述的反应优选地在惰性气氛中、在大气压下进行,反应温度范围为约-78℃至约150℃、更优选约0℃至约125℃、最优选且方便地在约室温(或环境温度),例如约20℃。
下述方案中的一些化合物用宽泛的取代基进行描述;但是,本领域的技术人员能够立即明白,R基团的性质可以变化,以得到本发明涵盖的各种化合物。而且,反应条件是示例性的,替代条件众所周知。以下实施例中的反应次序不意味着限制权利要求所述的本发明范围。
通常,在本申请中使用的命名是基于AUTONOMTM4.0版,这是Beilstein Institute计算机化系统,用于生成IUPAC系统命名。如果描述的结构和给该结构的命名不一致,应当以描述的结构为准。另外,如果没有例如用粗体或虚线指示结构或部分结构的立体化学,该结构或部分结构应当理解为包括其所有的立体异构体。
方案1
(a)HCl(1.0当量),氨腈(1.2当量),EtOH,回流43小时(100%);(b)NaOMe(1.0当量),2-乙酰基丁内酯(1.0当量)、EtOH-MeOH,回流19小时(38%);(c)SOCl2(1.05当量),甲苯,室温,69小时,然后POCl3(24当量,纯的),回流15小时(92%);(d)4-氨基庚烷(5.0当量),NMP,120℃,50小时(41%);(e)NaH(1.5当量),碘代乙烷(1.5当量),DMF,室温,8小时,然后40℃,12小时(通过制备型RP-HPLC纯化,为TFA盐)。
通过依次处理含有随后形成稠合二氢吡咯环所需元件的取代的嘧啶环,制备[4-甲基-7-(1-丙基-丁基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺(VIII)。基本合成提供了制备嘧啶环的非常通用的方法。基本合成需要2个3-原子片段的缩合。1个片段是β-二羰基化合物。羰基可以由酮、醛、羧酸衍生物或腈组成。第2个3-原子片段是脒,其可以被脲、硫代脲或胍替代。在制备取代的嘧啶时,能够进行该反应的等价物的范围提供了具有非常大的灵活性。(D.J.Brown,“综合杂环化学中的嘧啶和其苯并衍生物”,A.J.Boulton和A.McKillop(ed)第3卷第2部分第2.13章,Pergamon Press,Oxford1984,57-157页;D.J.Brown,“杂环化合物化学中的嘧啶,增刊II”,A.Weissberger和E.C.Taylor(ed),Wiley Interscience,纽约1985,21-62页)。
在本发明的情况下,通过在环化步骤中使用芳基胍,可以直接制备2-芳基氨基-取代的嘧啶。芳基胍可以容易地从芳基胺制备(I.A.CliffeFunctional Groups Containingan Iminocarbonyl Group and Any ElementOther thanAHalogen or Chalogen in Comprehensive Functional GroupTransformations,第6卷,T.L.Gilchrist(ed)Pergamon Press,Oxford,1995,640-42页)。在步骤(i)中,通过与氨腈缩合,将适当取代的芳基胺转化成对应的胍盐酸盐。
步骤(b)示例了基本嘧啶合成,其中通过环化胍和2-乙酰基丁内酯制备2-芳基氨基嘧啶,除了最终环化形成稠合吡咯烷的羟乙基和6-羟基之外,其将所需的2-芳基氨基和4-甲基取代基引至嘧啶环上。本领域技术人员能容易地明白,2-乙酰基丁内酯形式上仅仅是2-取代的乙酰醋酸衍生物,嘧啶合成可以使用多种侧链来完成,所述侧链能够改变稠合到嘧啶上的杂环上的取代。
通过用磷酰基卤化物、五卤化磷、三卤化磷或其混合物处理嘧啶酮,可以将羟基嘧啶转化成卤代嘧啶。叔胺碱有时用作卤化反应的催化剂。卤化反应可以在有各种无干扰的官能团存在下进行(Brown“综合杂环化学”,同上,139-140页)。在步骤(b)中,通过依次用下述试剂处理二醇VI,进行2次氯化反应:(a)在室温下用亚硫酰氯将羟乙基侧链转化成对应的氯乙基侧链,和(b)在回流下用三氯氧化磷将杂芳基羟基取代基转化成杂芳基氯部分。
通过置换嘧啶上的离去基团,可以容易地将胺取代基引入嘧啶中(Brown“综合杂环化学”,同上,129-133页)。在离去基团中,可以采用卤素、巯基、烷硫基、烷基磺酰基、烷基亚磺酰基和烷氧基。卤素和烷基磺酰基是最有效的离去基团。反应性通常是4或6卤代>2-卤代>>5-卤代。在步骤(d)中,用伯胺处理二氯中间体,所述伯胺能置换脂基氯和杂芳基氯、从而导致吡咯烷环闭合。
任选地,在步骤(e)中,通过形成胺盐和用所需的烷基卤进行烷基化,可以将仲胺转化成叔胺(J.March,“高等有机化学”,John Wiley & Sons,纽约1992,411-413)。产物可以是游离碱或酸加成盐。
通过选择步骤(a)中适当的芳基胺和步骤(e)中适当的伯胺,如方案1所述制备下述化合物。
如方案2所示,制备了4-甲基-5,6,7,8-四氢-吡啶并[2,3-d]嘧啶和4-甲基-5,8-二氢-6H-吡啶并[2,3-d]嘧啶-7-酮。在步骤(b)中,用2-乙酰基戊二酸二乙酯进行基本合成,以在嘧啶XI的5-位上引入三碳羧酸侧链。在步骤(c)中用三氯氧化磷将6-羟基转化成6-氯类似物后,与伯胺缩合,以得到嘧啶酮XIII。
在步骤(e)中,用BH3-THF还原内酰胺,以得到对应的叔胺XIV。除了BH3-THF之外,还可以使用氢化锂铝、二异丁基氢化铝或其它氢化物还原剂将酰胺还原成胺。一般较少使用硼氢化钠。使用氢化物还原剂的还原通常在非质子溶剂如二乙醚、THF和二甲氧基乙烷中进行。催化氢也可以用于还原酰胺,但是通常需要高温和高压(J.March,同上,1212-13页)。在步骤(f)中,胺任选地通过如前所述的烷基化被取代。
方案2
(a)HCl(1.0当量),氨腈(1.5当量),EtOH,回流16小时(89%);(b)NaOEt(1.2当量),2-乙酰基戊二酸二乙酯(1.1当量),EtOH,回流24小时(21%);(c)POCl3(6.0当量,纯的),回流2.5小时(54%);(d)3-氨基戊烷(5.0当量)、NMP,130℃,130小时(43%);(e)硼烷-THF(3.0当量),THF,0℃至室温,20小时(96%);(f)NaH(1.3当量),碘代乙烷(1.3当量),DMF,室温,14小时(67%)。
通过选择步骤(a)中适当的芳基胺和步骤(f)中适当的伯胺,如方案2所述制备下述化合物。
如方案3所述,制备了乙基-(4-甲基-9-噻吩-2-基甲基-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-基)-(2,4,6-三甲基-苯基)-胺的三氟乙酸盐。在步骤(b)中,使用3-乙酰基-氧杂庚环-2-酮进行基本合成,以在嘧啶的5-位上引入四碳侧链。如方案1所述,依次将侧链和环羟基转化成二氯化物。环化步骤(d)和任选的N-烷基化步骤(e)如方案1所述进行。
方案3
(a)LDA(1.1当量),丙酮腈(1.1当量),-78℃,10分钟(48%);(b)NaOMe(1.15当量),IV(1.15当量),EtOH-MeOH,回流21小时(46%);(c)POCl3(23当量,纯的),回流17小时(84%);(d)2-噻吩甲基胺(1.25当量),Et3N(2.5当量),NMP,130℃,65小时(90%);(e)NaH(1.8当量),碘代乙烷(1.8当量),DMF,室温8小时,然后40℃,9小时(通过制备型RP-HPLC纯化,为TFA盐)。
剂量和施用
本发明的化合物可以配制于多种经口施用的剂型和载体中。经口施用可以是片剂、包衣片剂、糖衣丸、硬和软明胶胶囊、溶液、乳剂、糖浆或混悬液的形式。当通过其它给药途径施用时,其中包括连续的(静脉滴注)局部肠胃外、肌肉内、静脉内、皮下、透皮(其可以包括渗透增强剂)、口含、鼻、吸入剂和栓剂施用,本发明的化合物是有效的。优选的施用方式通常是经口,使用方便的每日给药方案,其可以根据病患程度和患者对活性成分的反应进行调整。
可以将本发明的一种或多种化合物、它们的药学上可用的盐以及一种或多种常规赋形剂、载体或稀释剂一起制成药物组合物和单位剂型形式。该药物组合物和单位剂型可以包含常规比例的常规成分,有或没有其它活性化合物或成分,该单位剂型可以含有与待使用的目标日剂量范围相当的任意合适有效量的活性成分。
药物组合物可以作为固体使用,如片剂或填充胶囊、半固体、粉末、持续释放制剂,或液体如溶液、混悬液、乳剂、酏剂或经口使用的填充胶囊;或直肠或阴道施用的栓剂形式;或用于肠胃外使用的无菌注射液形式。典型的制剂可含有约5%至约95%的一种或多种活性化合物(w/w)。术语“制剂”或“剂型”意在包括活性化合物的固体和液体制剂,本领域的技术人员能够明白,根据目标器官或组织和所需剂量以及药物动力学参数,活性成分可以存在于不同的制剂中。
如本文所使用的术语“赋形剂”是指可用于制备药物组合物的化合物,其通常是安全、无毒的,且在生物学上或其它方面均不是不可接受的,包括兽用和人药用可接受的赋形剂。如本文所使用的术语“赋形剂”包括一种或多种这样的赋形剂。
短语化合物的“药学上可接受的盐”是指药学上可接受的且具有所需的母体化合物的药理学活性的盐。这些盐包括:(1)酸加成盐,与无机酸形成,如盐酸、氢溴酸、硫酸、硝酸、磷酸等;或与有机酸形成,如醋酸、丙酸、己酸、环戊烷丙酸、羟基乙酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙烷-二磺酸、2-羟基乙烷磺酸、苯磺酸、4-氯苯磺酸、2-萘磺酸、4-甲苯磺酸、樟脑磺酸、4-甲基双环[2.2.2]-辛-2-烯-1-甲酸、葡庚糖酸、3-苯基丙酸、三甲基醋酸、叔丁基醋酸、月桂基硫酸、葡糖酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂酸、粘康酸等;或(2)当母体化合物中的酸性质子被替换为金属离子时形成的盐,所述金属离子例如碱金属离子、碱土金属离子或铝离子;或与有机碱配位形成的盐,所述有机碱如乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、N-甲基葡糖胺等。
优选的药学上可接受的盐是与醋酸、盐酸、硫酸、甲磺酸、马来酸、磷酸、酒石酸、柠檬酸、钠、钾、钙、锌和镁形成的盐。应当明白,所有提及的药学上可接受的盐都包括相同酸加成盐的如本文所定义的溶剂加成形式(溶剂合物)或晶体形式(多晶形物)。
固体形式制剂包括粉末、片剂、丸剂、胶囊、扁囊剂、栓剂和可分散颗粒。固体载体可以是一种或多种还可以作为稀释剂、矫味剂、增溶剂、润滑剂、助悬剂、粘合剂、防腐剂、片剂崩解剂或包封材料的物质。在粉末中,载体通常是细碎的固体,它是与细碎的活性组分的混合物。在片剂中,通常将活性组分与具有必要粘合力的载体以合适的比例混合,并压制成所需的形状和大小。合适的载体包括但不限于碳酸镁、硬脂酸镁、滑石、糖、乳糖、果胶、糊精、淀粉、明胶、黄蓍胶、甲基纤维素、羧甲基纤维素钠、低熔点蜡、可可油等。除了活性组分外,固体形式制剂还可以含有着色剂、矫味剂、稳定剂、缓冲剂、人工和天然的甜味剂、分散剂、增稠剂、增溶剂等。
液体制剂也适用于经口使用,包括液体制剂,包括乳剂、糖浆、酏剂、水溶液、水悬液。这包括准备在使用前不久转变成液体形式制剂的固体制剂。乳剂可以在溶液如丙二醇水溶液中制备,或者可以含有乳化剂如卵磷脂、山梨糖醇酐单油酸酯或阿拉伯胶。通过将活性组分溶解到水中并加入合适的着色剂、矫味剂、稳定剂和增稠剂,可以制备水溶液。通过将细碎的活性组分溶解于含有粘性物质如天然或合成胶、树脂、甲基纤维素、羧甲基纤维素钠和其它众所周知的助悬剂的水中,可以制备水悬液。
本发明的化合物可以配制用于肠胃外施用(例如通过注射,例如快速浓注或连续灌输),且可以以单位剂量形式呈放在安瓿、预冲注射器、小体积输液中或在加有防腐剂的多剂量容器中。该组合物可以采取下述形式:在油性或水性介质中的悬液、溶液或乳液,例如在水性聚乙二醇中的溶液。油性或非水性载体、稀释剂、溶剂或介质的实例包括丙二醇、聚乙二醇、植物油(例如橄榄油)和可注射有机酯(例如油酸乙酯),且可以含有配制剂如防腐剂、润湿剂、乳化剂或助悬剂、稳定剂和/或分散剂。或者,活性成分可以是通过无菌分离无菌固体或冻干溶液得到的粉末形式,其可以在使用前用合适的介质、例如无菌、无热原的水配制。
本发明的化合物可以配制用于局部施用于表皮的软膏、霜剂或洗剂或透皮贴剂。软膏和霜剂可以例如用水性或油性基质、添加合适的增稠剂和/或胶凝剂配制。洗剂可以用水性或油性基质配制,且通常还含有一种或多种乳化剂、稳定剂、分散剂、助悬剂、增稠剂或着色剂。适用于局部施用于口腔的制剂包括:锭剂,其在矫味基质、通常是蔗糖和阿拉伯胶或黄蓍胶中含有活性剂;软锭剂,其在惰性基质如明胶和甘油或蔗糖和阿拉伯胶中含有活性成分;和漱口剂,其在合适的液体载体中含有活性成分。
本发明的化合物可以配制成栓剂施用。首先熔解低熔点蜡如脂肪酸甘油酯的混合物或可可油,然后例如通过搅拌均匀地分散活性组分。然后将熔化的均匀混合物倒入方便的固定大小的模具中,冷却,固化。
本发明的化合物可以配制用于阴道施用。适合的有除了活性成分外还含有本领域已知载体的阴道栓剂、止血塞(tampon)、霜剂、凝胶、糊剂、泡沫剂或喷雾剂。
本发明的化合物可以配制用于经鼻施用。通过常规方式、例如使用滴管、吸管或喷雾器,将溶液或悬液直接应用于鼻腔。该制剂可以以单次或多次剂量形式提供。在滴管或吸管的后一种情况下,这可以通过患者施用合适的预定体积的溶液或悬液来实现。在喷雾器的情况下,这可以例如借助于计量雾化喷雾泵来实现。
本发明的化合物可以配制用于气雾剂施用、特别是施用于呼吸道,包括鼻内施用。该化合物通常具有小粒径,例如5微米或更小的量级。通过本领域已知的方法、例如通过微粉化,可以得到这样的粒径。活性成分在加压的包装中提供,所述包装含有合适的抛射剂,如含氯氟烃(CFC),例如二氯二氟甲烷、三氯氟甲烷或二氯四氟乙烷,或二氧化碳或其它合适的气体。气雾剂还可以方便地含有表面活性剂如卵磷脂。药物的剂量可以通过计量阀控制。或者,活性成分可以以干粉的形式提供,例如化合物在合适的粉末基质如乳糖、淀粉、淀粉衍生物如羟丙基甲基纤维素和聚乙烯基吡咯烷(PVP)中的粉末混合物。粉末载体会在鼻腔中形成凝胶。粉末组合物可以以单位剂量形式存在,例如在例如明胶或泡罩包装的胶囊或药筒中,借助于吸入器可以从其中施用粉末。
当需要时,制剂可以具有肠溶衣,适用于持续或控释施用活性成分。例如,本发明的化合物可以配制于透皮或皮下药物递送装置中。当必须持续释放化合物时且当患者对治疗方案的依从性是至关重要时,这些递送系统是有利的。透皮递送系统中的化合物经常附着在皮肤粘附性固体支持物上。目标化合物还可以与渗透增强剂组合,例如Azone(1-十二烷基氮杂-环庚烷-2-酮)。通过手术或注射,将持续释放递送系统皮下插入皮下层中。皮下植入物将化合物包封在脂溶膜中,例如硅橡胶,或可生物降解的聚合物中,例如聚乳酸。
合适的制剂连同药物载体、稀释剂和赋形剂一起记载在“Remington:药学科学和实践1995”中,E.W.Martin编,Mack Publishing Company,第19版,Easton,Pennsylvania。熟练的制剂人员可以在说明书教导范围内改进该制剂,以提供众多的用于特定给药途径的制剂,而不会使本发明的组合物不稳定或者影响它们的治疗活性。
通过略微修饰(成盐、酯化等),可以容易地修饰本发明的化合物,使它们更易溶于水或其它介质。这是本领域的普通技术。改进特定化合物的给药途径和剂量方案,以控制该化合物的药物动力学以最大化在患者中产生的有益效果,这也属于本领域的普通技术。
如本文所使用的术语“治疗有效量”是指减轻个体中的疾病症状所需的量。在每种具体情况中,根据个体需要来调整剂量。剂量可以根据许多因素在宽范围内变化,如待治疗疾病的严重性、患者的年龄和总体健康情况、用以治疗该患者的其它药物、给药途径和方式和参与临床医生的偏好和经验。对于经口施用,在单次治疗和/或组合治疗中,约0.01至约100mg/kg体重/天的日剂量应该是合适的。优选的日剂量是约0.1至约500mg/kg体重、更优选0.1至约100mg/kg体重、最优选1.0至约10mg/kg体重/天。因此,施用于70kg的人时,剂量范围可为约7mg至0.7g/天。日剂量可以作为单次剂量或以分剂量施用,通常1-5剂/天。通常,从低于化合物的最佳剂量的较小剂量开始治疗。此后,以较小的增量增加剂量,直到达到该个别患者的最佳效果。在治疗本文所述疾病时,普通技术人员不经额外实验,依赖个人知识、经验和本申请的公开,即能够确定本发明化合物对特定疾病和患者的治疗有效量。
术语“疾病状态”是指任何疾病、病症、症状或适应症。疾病状态的“治疗”包括:(i)预防疾病状态,即使疾病状态的临床症状在对象中不发展,所述对象可能暴露于或倾向于患有该疾病状态,但是尚未经历或表现该疾病状态的症状;(ii)抑制疾病状态,即阻止疾病状态或其临床症状的发展,或(iii)缓解疾病状态,即造成疾病状态或其临床症状的暂时或永久消退。
药物制剂优选地呈单位剂型。在这样的形式中,制剂被细分成含有合适量的活性组分的单位剂量。单位剂型可以是经包装的制剂,该包装含有分散量的制剂,例如经包装的片剂、胶囊和小瓶或安瓿中的粉末。另外,单位剂型可以是胶囊、片剂、扁囊剂或锭剂本身,或者可以是合适量的这些包装形式中的任一种。
为了使本领域技术人员更清楚地理解和实现本发明,给出了实施例8中的药物组合物。其不应当理解为限制本发明的范围,而仅仅是对本发明的解释和示例。
实施例1
[4-甲基-7-(1-丙基-丁基)-6,7-二氢-5-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-
苯基)-胺(37)
步骤1:N-(2,4,6-三甲基-苯基)-胍盐酸盐(IV)
在0℃,将2,4,6-三甲基-苯基胺(13.5g,100mmol)的二乙醚(50mL)溶液加入剧烈搅拌的氯化氢的二乙醚(1.0M,100mL,100mmol)溶液,随后在室温搅拌30分钟。减压除去溶剂,得到米色固体状的2,4,6-三甲基-苯基胺盐酸盐(17.2g,100%),将其悬浮于乙醇(100mL)中并用氨腈(5.0g,120mmol)处理。将得到的溶液加热至回流达43小时,然后减压浓缩。将如此得到的粘稠残余物用二乙醚(2x100mL)研磨,得到盐酸胍IV,为吸湿的浅褐色泡沫(22g,100%;ESIMS m/z(M+H)=178)。
步骤2:5-(2-羟基-乙基)-2-(2,4,6-三甲基-苯基氨基)-嘧啶-4-醇(v)
用在甲醇(18mL)中的甲醇钠(4.3g,80mmol)处理N-(2,4,6-三甲基-苯基)-胍盐酸盐(17g,80mmol)的乙醇(100mL)溶液,随后用3-乙酰基-二氢-呋喃-2-酮(2-乙酰基丁内酯,10.3g,80mmol)处理。将反应混合物加热至回流达19小时,然后减压浓缩。将这样得到的残余物悬浮于水(200mL)中,并通过小心地加入浓盐酸,将得到的混合物调至pH5,用氯化钠饱和,用氯仿萃取(3x500mL)。合并的萃取液经硫酸钠干燥、过滤和减压浓缩。使这样得到的粗制橙色浆经硅胶层析,用二氯甲烷中的0至10%甲醇梯度洗脱,得到白色粉末状的嘧啶醇V(7.5g,38%;ESIMS m/z(M+H)=288)。
步骤3:[4-氯-5-(2-氯-乙基)-嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺(VI)
向剧烈搅拌的5-(2-羟基-乙基)-2-(2,4,6-三甲基-苯基氨基)-嘧啶-4-醇(V;4.6g,16mmol)的甲苯(100mL)悬液中经30分钟加入亚硫酰氯(2.0g,17mmol)的甲苯(60mL)溶液。将反应混合物在室温搅拌69小时,然后减压浓缩。将这样得到的棕褐色固体溶于三氯氧化磷(49g,320mmol),并加热至回流达19小时。冷却至室温后,将反应混合物倒于冰上(500g),用碳酸氢钠中和,并用乙酸乙酯萃取(3x500mL)。合并的萃取液经硫酸钠干燥、过滤和减压浓缩。使粗制棕色固体经硅胶层析,用己烷中的10至30%乙酸乙酯梯度洗脱,得到浅黄色固体状的氯代嘧啶VI(3.8g,92%;ESIMSm/z(M+H)324)。
步骤4:[4-甲基-7-(1-丙基-丁基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺(VII)
用1-丙基-丁基胺(1.6g,14mmol)处理[4-氯-5-(2-氯-乙基)-嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺(1.3g,4.1mmol)的N-甲基吡咯烷酮(15mL)溶液,在密封试管中加热至120℃达18小时。再加入1-乙基-丁基胺(0.76g,6.6mmol),恢复在120℃加热达32小时。减压浓缩反应混合物,使得到的橙色固体在乙酸乙酯(100mL)和水(100mL)之间分配。用乙酸乙酯(2x75mL)进一步萃取水层,用15%氢氧化钠水溶液(2x50mL)和盐水(30mL)洗涤合并的萃取液,经硫酸镁干燥、过滤并减压浓缩。粗制棕色油经硅胶层析,用二氯甲烷中的1-15%甲醇梯度洗脱,得到米色固体VII(0.64g,41%;ESIMS m/z(M+H)=367)。
步骤5:乙基-[4-甲基-7-(1-丙基-丁基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺;与三氟乙酸的化合物(VIII)
在氮气下,用氢化钠在N,N-二甲基甲酰胺中的细悬液(0.16M,1.0mL,0.16mmol)处理[4-甲基-7-(1-丙基-丁基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺(0.040g,0.11mmol)。在室温摇动45分钟后,加入碘代乙烷(0.025g,0.16mmol),将得到的混合物在室温摇动8小时,随后在40℃摇动12小时。然后用三氟乙酸(1滴)处理反应混合物,并减压浓缩。通过制备型反相HPLC纯化残余物,用0.1%三氟乙酸/水/乙腈洗脱,得到37(ESIMS m/z(M+H)=395)。
实施例2
2-(2-溴-4-异丙基-苯基氨基)-8-(1-乙基-丙基)-4-甲基-5,8-二氢-6H-吡啶并
[2,3-d]嘧啶-7-酮(113)
步骤1:N-(2-溴-4-异丙基-苯基)-胍盐酸盐(X)
向在冰水浴中冷却的2-溴-4-异丙基-苯基胺(IX;17g,79mmol)的乙醇(200mL)溶液中经10分钟加入气体氯化氢,随后在室温搅拌30分钟。然后减压浓缩反应混合物,得到白色固体状的2-溴-4-异丙基-苯基胺盐酸盐(19.9g,100%),将其溶于温乙醇(100mL)中,并加入到氨腈(4.0g,95mmol)中。将得到的溶液加热至回流达16小时,4小时后再加入氨腈(1.0g,24mmol)。然后减压浓缩反应混合物,将这样得到的残余物用二乙醚(4x50mL)研磨,得到棕褐色半固体状的盐酸胍(X;21g,89%;ESIMSm/z(M+H)=256)。
步骤2:3-[2-(2-溴-4-异丙基-苯基氨基)-4-羟基-6-甲基-嘧啶-5-基]-丙酸乙酯(XI)。
向N-(2-溴-4-异丙基-苯基)-胍盐酸盐(X;21g,72mmol)和2-乙酰基-戊二酸二乙酯(2-乙酰基戊二酸二乙酯,18g,79mmol)的乙醇(100mL)溶液中,加入新制备的乙醇钠(87mmol)的乙醇(50mL)溶液。将反应混合物加热至回流达24小时,然后减压浓缩。将这样得到的残余物悬浮于水(200mL)中,通过小心地加入浓盐酸,将得到的混合物调至pH5,用氯化钠饱和,并用乙酸乙酯萃取(3x100mL)。用盐水(150mL)洗涤合并的萃取液,经硫酸镁干燥、过滤并减压浓缩。这样得到的粗制棕色油经硅胶层析,用二氯甲烷中的0.5至6%甲醇梯度洗脱,得到膏状固体羟基嘧啶(XI;7.2g,21%;ESIMSm/z(M+H)=422)。
步骤3:3-[2-(2-溴-4-异丙基-苯基氨基)-4-氯-6-甲基-嘧啶-5-基]-丙酸乙酯(XII)
将3-[2-(2-溴-4-异丙基-苯基氨基)-4-羟基-6-甲基-嘧啶-5-基]丙酸乙酯(XI;6.6g,16mmol)的三氯氧化磷(14g,94mmol)溶液加热至回流达2.5小时。冷却至室温后,将反应混合物倒于冰上(150g),并用乙酸乙酯萃取(2x150mL)。依次用盐水(150mL)、饱和的碳酸氢钠水溶液(100mL)和盐水(100mL)洗涤合并的萃取液,然后经硫酸镁干燥、过滤并减压浓缩。粗制深色油经硅胶层析,用己烷中的0至20%乙酸乙酯梯度洗脱,以得到浅黄油状的氯代嘧啶(XII;3.8g,54%;ESIMS m/z(M+H)=440)。
步骤4:2-(2-溴-4-异丙基-苯基氨基)-8-(1-乙基-丙基)-4-甲基-5,8-二氢-6H-吡啶并[2,3-d]嘧啶-7-酮(113)
用1-乙基-丙基胺(0.22g,2.5mmol)处理3-[2-(2-溴-4-异丙基-苯基氨基)-4-氯-6-甲基-嘧啶-5-基]-丙酸乙基酯(XII;0.22g,0.50mmol)的N-甲基吡咯烷酮(2.5mL)溶液,在密封的试管中加热至130℃达130小时。将冷却的反应混合物倒入水中(50mL),并用二乙醚萃取(3x50mL)。用盐水(50mL)洗涤合并的萃取液,经硫酸镁干燥、过滤并减压浓缩。棕色固体经硅胶层析,用己烷中的20%醋酸乙酯洗脱,得到白色固体113(0.11g,43%;mp124-126℃;ESIMS m/z(M+H)445)。
实施例3
(2-溴-4-异丙基-苯基)-[8-(1-乙基-丙基)-4-甲基-5,6,7,8-四氢-吡啶并[2,3-d]嘧
啶-2-基]-胺(114)
在氮气下,将2-(2-溴-4-异丙基-苯基氨基)-8-(1-乙基-丙基)-4-甲基-5,8-二氢-6H-吡啶并[2,3-d]嘧啶-7-酮(XIII;0.070g,0.16mmol)的四氢呋喃(1mL)溶液冷却至0℃,并用硼烷-四氢呋喃复合物的四氢呋喃溶液(1.0M,0.48mL,0.48mmol)处理。将反应混合物在室温保持20小时,然后加入33%乙酸的乙酸乙酯(1mL)溶液。使得到的混合物在室温静置过夜,加入到3%氢氧化钠水溶液(50mL)中,并用乙酸乙酯萃取(3x35mL)。用15%氢氧化钠水溶液(15mL)和盐水(15mL)洗涤合并的萃取液,经硫酸镁干燥、过滤并减压浓缩,得到澄清的无色膜114(0.066g,96%;ESIMS m/z(M+H)=431)。
实施例4
(2-溴-4-异丙基-苯基)-乙基-[8-(1-乙基-丙基)-4-甲基-5,6,7,8-四氢-吡啶并
[2,3-d]嘧啶-2-基]-胺(116)
向氮气下剧烈搅拌的氢化钠(0.004g,0.17mmol)的N,N-二甲基甲酰胺(0.5mL)悬液中,加入(2-溴-4-异丙基-苯基)-[8-(1-乙基-丙基)-4-甲基-5,6,7,8-四氢-吡啶并[2,3-d]嘧啶-2-基]-胺(XIV;0.056g,0.13mmol)的N,N-二甲基甲酰胺(0.5mL)溶液。在室温30分钟后,加入碘代乙烷(0.026g,0.17mmol),将得到的混合物在室温搅拌14小时。然后将反应混合物倒入水(20mL)中,并用乙酸乙酯(3x20mL)萃取。用盐水(10mL)洗涤合并的萃取液,经硫酸镁干燥、过滤并减压浓缩。这样得到的黄色油经硅胶层析,用己烷中的20至50%乙酸乙酯梯度洗脱,得到浅黄色油116(0.040g,67%)。ESIMS m/z459(M+H)。
实施例5
乙基-(4-甲基-9-噻吩-2-基甲基-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-
基)-(2,4,6-三甲基-苯基)-胺;与三氟乙酸的化合物(123).
步骤1:3-乙酰基-氧杂庚环-2-酮(XVII)。
在氮气下,向-78℃的二异丙基胺(2.2g,22mmol)的四氢呋喃(100mL)溶液中,加入丁基锂的己烷(1.6M,14mL,22mmol)溶液。在-78℃搅拌得到的溶液45分钟,然后用四氢呋喃(50mL)中的氧杂庚环-2-酮(XVI,2.3g,20mmol)处理15分钟。在-78℃搅拌得到的溶液1小时,然后用丙酮腈(1.5g,22mmol)处理。在-78℃搅拌得到的溶液10分钟,然后用水(0.4mL)处理。然后将混合物倒入二乙醚(400mL)和水(400mL)中。用二乙醚(450mL)进一步萃取水层。用盐水(50mL)洗涤合并的萃取物,经硫酸镁干燥、过滤并减压浓缩。得到的黄色油经硅胶层析,用己烷中的5至30%乙酸乙酯梯度洗脱,得到无色固体酮酯(XVII;1.5g,48%;mp53-59℃)。
步骤2:5-(4-羟基-丁基)-6-甲基-2-(2,4,6-三甲基-苯基氨基)-嘧啶-4-醇
用甲醇(2.2mL)中的甲醇钠(0.52g,9.5mmol)处理N-(2,4,6-三甲基-苯基)-胍盐酸盐(IV;2.0g,9.4mmol)的乙醇(10mL)溶液,随后用乙醇(2mL)中的3-乙酰基-氧杂庚环-2-酮(1.3g,8.2mmol)处理。将反应混合物加热至回流达21小时,然后减压浓缩。将这样得到的残余物悬浮于水(200mL)中,通过小心地加入浓盐酸,将得到的混合物调至pH4,用氯仿萃取(2x50mL)。合并的萃取液经硫酸钠干燥、过滤并减压浓缩。这样得到的浅棕色固体经硅胶层析,用二氯甲烷中的1-7%甲醇梯度洗脱,得到白色固体状的嘧啶醇(XVIII;1.2g,46%;ESIMS m/z(M+H)=316)。
步骤3:[4-氯-5-(4-氯-丁基)-6-甲基-嘧啶-2-基]-乙基-(2,4,6-三甲基-苯基)-胺(XIX)。
将5-(4-羟基-丁基)-6-甲基-2-(2,4,6-三甲基-苯基氨基)-嘧啶-4-醇(1.0g,3.2mmol)溶于三氯氧化磷(12g,75mmol),加热至回流达17小时。冷却至室温后,减压浓缩反应混合物。将这样得到的残余物在碳酸氢钠水溶液(40mL)和氯仿(50mL)之间分配,用氯仿(25mL)进一步萃取水层。用浓碳酸氢钠水溶液(25mL)和盐水(15mL)洗涤合并的萃取液,经碳酸钠干燥、过滤并减压浓缩,得到棕褐色固体氯代嘧啶(XIX;0.98g,84%;ESIMS(M+H)m/z352)。该产物不经纯化用于下一步骤。
步骤4:(4-甲基-9-噻吩-2-基甲基-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-基)-(2,4,6-三甲基-苯基)-胺(XX)
用C-噻吩-2-基-甲基胺(2-噻吩甲基胺,0.014g,0.125mmol)于N-甲基吡咯烷酮(0.125mL)和三乙基胺(0.025g,0.25mmol)中的溶液处理[4-氯-5-(4-氯-丁基)-6-甲基-嘧啶-2-基]-乙基-(2,4,6-三甲基-苯基)-胺(XIX;0.035g,0.10mmol)的N-甲基吡咯烷酮(0.4mL)溶液,并在密闭试管中加热至130℃达65小时。减压浓缩反应混合物,用甲醇(0.4mL)中的甲醇钠(0.011g,0.20mmol)处理这样得到的残余物。减压浓缩得到的混合物,得到深色固体四氢嘧啶并氮杂???XX和氯化钠。该产物不经纯化用于下一步骤。或者,通过制备型反相HPLC纯化这样得到的残余物,用0.1%三氟乙酸/水/乙腈洗脱,得到四氢嘧啶并氮杂???(XX;ESIMS m/z(M+H)=393)。步骤5:乙基-(4-甲基-9-噻吩-2-基甲基-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-基)-(2,4,6-三甲基-苯基)-胺;与三氟乙酸的化合物(123)
在氮气下,用氢化钠的N,N-二甲基甲酰胺(0.18M,1.0mL,0.18mmol)细悬液处理(4-甲基-9-噻吩-2-基甲基-6,7,8,9-四氢-5H-嘧啶并[4,5-b]氮杂???-2-基)-(2,4,6-三甲基-苯基)-胺(XX;0.039g,0.10mmol)。在室温摇动1.25小时后,加入在N,N-二甲基甲酰胺(0.15mL)中的碘代乙烷(0.028g,0.18mmol),将得到的混合物在室温摇动8小时,随后在40℃摇动9小时。然后用三氟乙酸(1滴)处理反应混合物,减压浓缩。通过制备型反相HPLC纯化这样得到的残余物,用0.1%三氟乙酸/水/乙腈洗脱,得到123(ESIMSm/z(M+H)=421)。
实施例6
CRF受体结合实验
使人IMR-32成神经细胞瘤细胞在含有10%热灭活FBS、1mM丙酮酸钠和0.1mM非必需氨基酸的MEM培养基中生长至80%融合。根据Dieterich和DeSouza(1996)的方法制备细胞膜。将细胞(约5E+9)重新悬浮于10体积的洗涤缓冲液(5mM Tris HCl,10mM MgCl2,2mM EGTA,pH7.4,室温)中,用Polytron均化,然后在4℃以45,000G离心20分钟。用洗涤缓冲液洗涤膜沉淀2次(45,000G,20分钟,4℃),然后重新悬浮(50mM Tris HCl,10mM MgCl2,2mM EGTA,pH7.4,室温)。使用Pierce试剂、以BSA作为标准,测定蛋白浓度。将1-1.5mL等分试样储存在-80℃,直至进行结合实验。
以250μl的终体积进行竞争性结合实验,其中含有实验缓冲液(50mMTris-HCl,10mM MgCl2,2mM EGTA,0.2%BSA,0.1mM杆菌肽和100kIU/mL抑酶肽,pH7.2,室温)、0.05nM[125I]Tyro-绵羊CRF(Du PontNew England Nuclear)、50μg膜蛋白和不同浓度的实验化合物。用1μMhCRF测定非特异性结合。在25℃孵育2小时后,使用PackardHarvester(Filtermate196)经96-孔GF/C滤板过滤,终止结合反应。该96-孔滤板经0.3%聚乙烯亚胺预处理,并经洗涤缓冲液(50mM Tris-HCl,10mM MgCl2,2mM EGTA,0.2%BSA,pH7.2,4℃)预洗涤。通过用洗涤缓冲液快速洗涤4次(0.8ml/孔),去除未结合的放射活性。使用PackardTopCount定量放射活性。使用非线性迭代曲线拟合,分析数据,得到IC50和Hill斜率值。从pIC50值(IC50的负对数)得出pKi值。
化合物 | pIC<sub>50</sub> | pK<sub>i</sub> |
2 | 5.68 | 6.71 |
115 | <4.3 | <4 |
实施例7
胞内cAMP刺激实验
使人Y-79视网膜母细胞瘤细胞在含有15%FBS的RPMI1640培养基中生长。使用NEN腺苷环化酶FlashPlate试剂盒(SMP004),检测cAMP积累。从培养基分离出细胞,用PBS洗涤2次(150Xg,8分钟),重新悬浮于刺激缓冲液(由试剂盒提供)中(2E+6细胞/ml),然后加入到96-孔FlashPlate中(50,000细胞/孔)。在加入hCRF(30nM)之前,将不同浓度的实验化合物与细胞孵育20分钟。总实验体积是100μl。在加入hCRF20分钟后,通过加入检测缓冲液和[125I]cAMP,终止实验。在室温2小时后,吸出混合物,用Packard TopCount检测结合的放射活性。通过用交互式曲线拟合方法进行非线性回归分析,测定实验化合物在抑制hCRF-刺激的cAMP积累方面的潜能(IC50值)。
实施例8
如本实施例所述,制备了经几种途径施用的主题化合物的药物组合物。
经口施用的组合物(A)
成分 | %重量/重量 |
活性成分乳糖硬脂酸镁 | 20.0%79.5%0.5% |
混合各成分,并分装至胶囊中,每粒含有约100mg;一粒胶囊接近总日剂量。
经口施用的组合物(B)
成分 | %重量/重量 |
活性成分硬脂酸镁交联羧甲基纤维素钠乳糖PVP(聚乙烯吡咯烷) | 20.0%0.5%2.0%76.5%1.0% |
合并各成分,并使用溶剂如甲醇制粒。然后干燥制剂,并用合适的压片机制成片剂(含有约20mg活性化合物)。
经口施用的组合物(C)
成分 | %重量/重量 |
活性成分富马酸氯化钠对羟基苯甲酸甲酯对羟基苯甲酸丙酯粒状糖山梨醇(70%溶液)VeegumK(VanderbiltCo.)矫味剂着色剂蒸馏水 | 1.0g0.5g2.0g0.15g0.05g25.5g12.85g1.0g0.035ml0.5mg适量至100ml |
混合各成分,形成经口施用的混悬液。
肠胃外制剂(D)
成分 | %重量/重量 |
活性成分氯化钠注射用水 | 0.25g适量至等渗100ml |
将活性成分溶解于一部分注射用水中。然后在搅拌下加入足量的氯化钠,使溶液等渗。用剩下的注射用水补足溶液,经0.2微米膜过滤器过滤,在无菌条件下包装。
栓剂(E)
成分 | %重量/重量 |
活性成分聚乙二醇1000聚乙二醇4000 | 1.0%74.5%24.5% |
在蒸气浴上,将各成分一起熔解并混合,倒入含2.5g总重的模具中。
局部制剂(F)
成分 | 克 |
活性化合物Span60Tween60矿物油矿脂对羟基苯甲酸甲酯对羟基苯甲酸丙酯BHA(丁基化羟基苯甲醚)水 | 0.2-2225100.150.050.01适量至100 |
合并除水以外的所有成分,搅拌下加热至约60℃。然后在剧烈搅拌下加入足量的约60℃的水,以乳化各成分,然后加入水适量至100g。
鼻喷雾剂(G)
将含有约0.025-0.5%活性化合物的几种水性混悬液制成鼻喷雾剂。该制剂任选地含有无活性的成分,例如微晶纤维素、羧甲基纤维素钠、右旋糖等。可以加入盐酸来调节pH。鼻喷雾剂可以经鼻喷雾计量泵递送,通常每次按压递送约50-100微升制剂。典型的给药方案是2-4次喷雾/4-12小时。
在前面的描述和下面的权利要求中所公开的以它们的具体形式或按照实现所公开功能或者用于达到所述结果的方法或工艺的手段所表示的特征,在适当时可以分别地或以这些特征的任意组合,用于以不同的形式实现本发明。
为了清楚和理解的目的,已经借助于说明和实施例较详细地描述了前面的发明。对本领域的技术人员而言,显然可以在所附权利要求的范围内进行改变和修改。因此,应当理解,上面的描述是用于解释而非限制。因此,本发明的范围不应当根据上面的描述来确定,而应当参考下面所附的权利要求书、同时包括这些权利要求的等同方案的全部范围来确定。
在本申请中引用的所有专利、专利申请和出版物,均在此全体引入作为参考,其程度与分别指明各专利、专利申请和出版物相同。
Claims (18)
1.式I的化合物,
其中,
X1是(CH2)n,其中n=0;
R1是(i)C1-10烷基或C2-10链烯基,其任选地被选自下组的取代基取代:羟基、氰基、氨基、C1-3烷基氨基、C1-3二烷基氨基、(C1-3烷基)芳基氨基和苯基,所述苯基任选地被1-3个独立地选自下组的取代基取代:C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基磺酰基、氨基磺酰基、单烷基氨基磺酰基、二烷基氨基磺酰基、卤素、卤代烷基、氰基、硝基和-NRaRb,其中Ra和Rb各自独立地选自氢、C1-6烷基和C1-6烷基羰基,
(ii)C3-7环烷基,其任选地被C1-3烷基或羟基取代,
(iii)C3-7环烷基-C1-3烷基或C3-7环烯基-C1-3烷基,
(iv)C4-12双环或三环烷基,
(v)C3-7杂环烷基或C3-7杂环烷基-C1-3烷基,其任选地被C1-3烷基、苯基或苯基-C1-6烷基取代,或者杂环烷基部分的CH2可以被C=O替换,
(vi)苯并稠合的-C5-7环烷基,
(vii)苯基或杂芳基,所述苯基和杂芳基任选地被1-3个独立地选自下组的取代基取代:C1-6烷基、C1-6烷氧基、亚甲二氧基、C1-6烷硫基、C1-6烷基磺酰基、氨基磺酰基、单烷基氨基磺酰基、二烷基氨基磺酰基、卤素、卤代烷基、氰基、硝基和-NRaRb,其中Ra和Rb各自独立地选自氢、C1-6烷基和C1-6烷基羰基,
(viii)萘基,
(ix)杂芳基-C1-6烷基,所述杂芳基-C1-6烷基任选地被1-3个选自下组的取代基取代:C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基磺酰基、氨基磺酰基、单烷基氨基磺酰基、二烷基氨基磺酰基、卤素、卤代烷基、氰基、硝基和-NRaRb,其中Ra和Rb各自独立地选自氢、C1-6烷基和C1-6烷基羰基,
(x)1,2-二苯基乙基,
(xii)C1-3烷氧基-C1-6烷基,或
(xiii)芳氧基-C1-6烷基,所述芳氧基任选地被1-3个选自下组的取代基取代:C1-3烷基、C1-3烷氧基和卤素;
R2是C1-6烷基或C1-3卤代烷基;
R3是(i)氢,
(ii)C1-6烷基,其任选地被羟基、C1-3烷氧基或C1-3酰氧基取代,
(iii)C3-6链烯基,
(iv)C3-7环烷基,
(v)C3-7环烷基-C1-3烷基;
(vi)C3-7环烯基,
(vii)C3-7环烯基-C1-3烷基,
(viii)苄基,其任选地被1-3个独立地选自下组的取代基取代:C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基磺酰基、氨基磺酰基、单烷基氨基磺酰基、二烷基氨基磺酰基、卤素、卤代烷基、氰基、硝基和-NRaRb,其中Ra和Rb各自独立地选自氢、C1-6烷基和C1-6烷基羰基;且,
R4是芳基,任选地被1-3个独立地选自下组的基团取代:C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基磺酰基、氨基磺酰基、单烷基氨基磺酰基、二烷基氨基磺酰基、卤素、卤代烷基、氰基、硝基和-NRaRb,其中Ra和Rb各自独立地选自氢、C1-6烷基和C1-6烷基羰基,或其药学上可接受的盐。
2.根据权利要求1的化合物,其中
X1是(CH2)n,其中n是0;
R1是(i)C1-10烷基,其任选地被选自下组的取代基取代:氨基、C1-3烷基氨基、C1-3二烷基氨基、(C1-3烷基)芳基氨基和苯基,所述苯基任选地被1-3个独立地选自下组的取代基取代:C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基磺酰基、氨基磺酰基、单烷基氨基磺酰基、二烷基氨基磺酰基、卤素、卤代烷基、氰基、硝基和-NRaRb,其中Ra和Rb各自独立地选自氢、C1-6烷基和C1-6烷基羰基,
(ii)C3-7环烷基,其任选地被C1-3烷基取代,
(iii)C3-7环烷基-C1-3烷基,
(iv)苯并稠合的-C5-7环烷基,
(v)苯基或杂芳基,所述苯基和杂芳基任选地被1-3个独立地选自下组的取代基取代:C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基磺酰基、氨基磺酰基、单烷基氨基磺酰基、二烷基氨基磺酰基、卤素、卤代烷基、氰基、硝基和-NRaRb,其中Ra和Rb各自独立地选自氢、C1-6烷基和C1-6烷基羰基,
(vi)杂芳基-C1-6烷基,所述杂芳基-C1-6烷基任选地被1-3个选自下组的取代基取代:C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基磺酰基、氨基磺酰基、单烷基氨基磺酰基、二烷基氨基磺酰基、卤素、卤代烷基、氰基、硝基和-NRaRb,其中Ra和Rb各自独立地选自氢、C1-6烷基和C1-6烷基羰基,
(vii)1,2-二苯基乙基,
(viii)C1-3烷氧基-C1-6烷基,或
(ix)芳氧基-C1-6烷基,所述芳氧基任选地被1-3个选自下组的取代基取代:C1-3烷基、C1-3烷氧基和卤素;
R2是C1-6烷基或C1-3卤代烷基;
R3是(i)氢,
(ii)C1-6烷基,其任选地被羟基、C1-3烷氧基或C1-3酰氧基取代,
(iii)C3-6链烯基,
(iv)C3-7环烷基,
(v)C3-7环烷基-C1-3烷基;
(vi)C3-7环烯基,
(vii)C3-7环烯基-C1-3烷基,
(viii)苄基,其任选地被1-3个独立地选自下组的基团取代:C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基磺酰基、氨基磺酰基、单烷基氨基磺酰基、二烷基氨基磺酰基、卤素、卤代烷基、氰基、硝基和-NRaRb,其中Ra和Rb各自独立地选自氢、C1-6烷基和C1-6烷基羰基;且
R4是芳基,任选地被1-3个独立地选自下组的基团取代:C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基磺酰基、氨基磺酰基、单烷基氨基磺酰基、二烷基氨基磺酰基、卤素、卤代烷基、氰基、硝基和-NRaRb,其中Ra和Rb各自独立地选自氢、C1-6烷基和C1-6烷基羰基;或其药学上可接受的盐。
3.根据权利要求2的化合物,其中
n是0;
R1是(i)C1-10支链或无支链烷基,或
(ii)任选地被取代的杂芳基-C1-6烷基,所述杂芳基任选地被选自C1-3烷基、C1-3烷氧基和卤素的取代基取代,
(iii)任选地被取代的苯基或杂芳基,所述苯基或杂芳基任选地被选自C1-3烷基、C1-3烷氧基和卤素的取代基取代,
(iv)被苯基取代的C1-3烷基,所述苯基任选地被选自C1-3烷基、C1-3烷氧基和卤素的取代基取代;
R3是(i)氢,
(ii)C1-6烷基,
(iii)C3-7环烷基-C1-3烷基,或
(iv)苄基,其任选地被C1-3烷基、C1-3烷氧基或卤素取代;
R4是任选地被取代的苯基。
4.根据权利要求3的化合物,其中R1是
(i)C1-10支链或无支链烷基,
(ii)被苯基取代的C1-10烷基,所述苯基任选地被取代,或
(iii)杂芳基-C1-6烷基,其中所述杂芳基是2-噻吩基、2-呋喃基或3-二氢吲哚基,每个所述杂芳基任选地被取代。
5.根据权利要求4的化合物,其中R4是2,4-二取代的或2,4,6-三取代的苯基。
6.根据权利要求5的化合物,其中X1是(CH2)n,n是0,R2是CH3,R3是CH2CH3,且R4是2,4-二取代的或2,4,6-三取代的苯基。
7.根据权利要求6的化合物,其中该化合物选自
乙基-[7-(1-乙基-丙基)-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
(7-环丙基-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基)-乙基-(2,4,6-三甲基-苯基)-胺,
(7-环己基甲基-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基)-乙基-(2,4,6-三甲基-苯基)-胺,
乙基-[4-甲基-7-(1,2,3,4-四氢-萘-1-基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
乙基-{4-甲基-7-[2-(1-甲基-吡咯烷-2-基)-乙基]-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基}-(2,4,6-三甲基-苯基)-胺,
乙基-(7-二氢化茚-1-基-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基)-(2,4,6-三甲基-苯基)-胺,
乙基-(4-甲基-7-萘-1-基甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基)-(2,4,6-三甲基-苯基)-胺,
乙基-[4-甲基-7-(四氢-呋喃-2-基甲基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
乙基-(4-甲基-7-噻吩-2-基甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基)-(2,4,6-三甲基-苯基)-胺,
(7-苯并[1,3]二氧杂环戊烯-5-基甲基-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基)-乙基-(2,4,6-三甲基-苯基)-胺,
乙基-[4-甲基-7-(3-吗啉-4-基-丙基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
乙基-[4-甲基-7-(2-吡啶-2-基-乙基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
乙基-(4-甲基-7-吡啶-3-基甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基)-(2,4,6-三甲基-苯基)-胺,
[7-(1-苄基-哌啶-4-基)-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-乙基-(2,4,6-三甲基-苯基)-胺,
乙基-[4-甲基-7-(2-哌啶-1-基-乙基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
[7-(1,2-二苯基-乙基)-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-乙基-(2,4,6-三甲基-苯基)-胺,
乙基-(7-异丙基-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基)-(2,4,6-三甲基-苯基)-胺,
乙基-[7-(2-甲氧基-1-甲基-乙基)-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
乙基-[4-甲基-7-(1-甲基-3-苯基-丙基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
(7-苄基-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基)-乙基-(2,4,6-三甲基-苯基)-胺,
乙基-[7-(3-氟-苄基)-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
[7-(3,4-二甲氧基-苄基)-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-乙基-(2,4,6-三甲基-苯基)-胺,
乙基-(4-甲基-7-苯乙基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基)-(2,4,6-三甲基-苯基)-胺,
(7-烯丙基-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基)-乙基-(2,4,6-三甲基-苯基)-胺,
乙基-(4-甲基-7-丙基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基)-(2,4,6-三甲基-苯基)-胺,
乙基-(4-甲基-7-戊基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基)-(2,4,6-三甲基-苯基)-胺,
乙基-[7-(3-咪唑-1-基-丙基)-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
[7-(2-环己-1-烯基-乙基)-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-乙基-(2,4,6-三甲基-苯基)-胺,
3-{2-[乙基-(2,4,6-三甲基-苯基)-氨基]-4-甲基-5,6-二氢-吡咯并[2,3-d]嘧啶-7-基}-丙腈,
(7-环丙基甲基-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基)-乙基-(2,4,6-三甲基-苯基)-胺,
乙基-[4-甲基-7-(1-苯基-丙基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
乙基-{7-[1-(4-氟-苯基)-乙基]-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基}-(2,4,6-三甲基-苯基)-胺,
乙基-[4-甲基-7-(2-苯氧基-乙基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
[7-(1-苄基-吡咯烷-3-基)-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-乙基-(2,4,6-三甲基-苯基)-胺,
乙基-{7-[2-(3-氟-苯基)-乙基]-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基}-(2,4,6-三甲基-苯基)-胺,
乙基-[4-甲基-7-(3-丙氧基-丙基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
[7-(2-[1,3]二氧戊环-2-基-乙基)-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-乙基-(2,4,6-三甲基-苯基)-胺,
乙基-[4-甲基-7-(5-甲基-吡嗪-2-基甲基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
{7-[2-(1-苄基-哌啶-4-基)-乙基]-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基}-乙基-(2,4,6-三甲基-苯基)-胺,
[7-(2,4-二甲基-苯基)-4-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-乙基-(2,4,6-三甲基-苯基)-胺,
以及它们与三氟乙酸的酸加成盐。
8.根据权利要求5的化合物,其中X1是(CH2)n,n是0,R1是CH(正丙基)2,R2是CH3,R3是CH2CH3,且R4是2,4-二取代的或2,4,6-三取代的苯基。
9.根据权利要求8的化合物,其中该化合物选自
甲基-[4-甲基-7-(1-丙基-丁基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
乙基-[4-甲基-7-(1-丙基-丁基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
异丙基-[4-甲基-7-(1-丙基-丁基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
丁基-[4-甲基-7-(1-丙基-丁基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
环戊基-[4-甲基-7-(1-丙基-丁基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
乙酸4-[[4-甲基-7-(1-丙基-丁基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-氨基]-丁基酯,
苄基-[4-甲基-7-(1-丙基-丁基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,
环丙基甲基-[4-甲基-7-(1-丙基-丁基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺,和
烯丙基-[4-甲基-7-(1-丙基-丁基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2-基]-(2,4,6-三甲基-苯基)-胺
以及它们与三氟乙酸的酸加成盐。
10.制备权利要求1所述的式I化合物或其药学上可接受的盐的方法,其包括下述步骤:
(i)使其中R4如上所定义的芳基胺盐酸盐XXII与氨腈接触,得到盐酸芳基胍XXIII;
(ii)在碱存在下,使所述盐酸胍XXIII与α-取代的β-酮酯XXIV接触,在后者中,R2是C1-6烷基,R6是C1-6烷基,R7是烷氧基羰基烷基,或R6和R7一起是(CH2)o,且o是2-4,以得到嘧啶XXV,其中R5是烷氧基羰基烷基或(CH2)o-OH;
(iii)使所述嘧啶与氯化剂接触,所述氯化剂的反应性足以将XXV转化成对应的氯代嘧啶XXVI,并将R5上的羟基亚烷基侧链转化成对应的氯代亚烷基取代基;
(iv)使所述氯代嘧啶XXVI与伯胺接触,当R5是羟基亚烷基时,在替代嘧啶和R5侧链上的氯原子的条件下,生成稠合的杂环XXVII,其中R5是(CH2)o,或者当R5是烷氧基羰基烷基时,替代嘧啶上的氯,同时环化成内酰胺,
11.根据权利要求10的方法,还包括使嘧啶XXVII与碱和烷化剂接触,以得到叔胺XXVIII,
其中,
R3是(i)C1-6烷基,其任选地被羟基、C1-3烷氧基或C1-3酰氧基取代,
(ii)C3-6链烯基,
(iii)C3-7环烷基,
(iv)C3-7环烷基-C1-3烷基;
(v)C3-7环烯基,
(vi)C3-7环烯基-C1-3烷基,
(vii)苄基,其任选地被1-3个独立地选自下组的基团取代:C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基磺酰基、氨基磺酰基、单烷基氨基磺酰基、二烷基氨基磺酰基、卤素、卤代烷基、氰基、硝基和-NRaRb,其中Ra和Rb各自独立地选自氢、C1-6烷基和C1-6烷基羰基。
12.根据权利要求10的方法,还包括使其中X1是C=O的式XXVIII的内酰胺与还原剂接触,以得到其中X1是CH2的胺。
13.制备权利要求1-9中任意一项所述的化合物的方法,
其包括下述步骤:
使氯代嘧啶XXVI与伯胺接触,当R5是羟基亚烷基时,在替代嘧啶和R5侧链上的氯原子的条件下,生成稠合的杂环XXVII,其中R5是(CH2)o,
或者当R5是烷氧基羰基烷基时,替代嘧啶上的氯,同时环化成内酰胺,并且,如果需要的话,使嘧啶XXVII与碱和烷化剂接触,以得到叔胺XXVIII,
其中,
R3是(i)C1-6烷基,其任选地被羟基、C1-3烷氧基或C1-3酰氧基取代,
(ii)C3-6链烯基,
(iii)C3-7环烷基,
(iv)C3-7环烷基-C1-3烷基;
(v)C3-7环烯基,
(vi)C3-7环烯基-C1-3烷基,
(vii)苄基,其任选地被1-3个独立地选自下组的基团取代:C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基磺酰基、氨基磺酰基、单烷基氨基磺酰基、二烷基氨基磺酰基、卤素、卤代烷基、氰基、硝基和-NRaRb,其中Ra和Rb各自独立地选自氢、C1-6烷基和C1-6烷基羰基。
14.根据权利要求13的方法,还包括使其中X1是C=O的式XXVIII的内酰胺与还原剂接触,以得到其中X1是CH2的胺。
15.用于治疗或预防CRF受体介导的疾病的药物,其含有一种或多种根据权利要求1-9中任一项的化合物和药学上可接受的赋形剂。
16.根据权利要求15的药物,用于治疗或预防恐怖症、应激相关疾病、心境障碍、饮食障碍、泛化性焦虑障碍、应激诱导的胃肠功能障碍、神经变性疾病和神经精神障碍。
17.根据权利要求1-9中任一项的化合物在制备用于治疗或预防CRF受体介导的疾病的药物中的用途。
18.权利要求17所述的用途,其中该疾病状态选自恐怖症、应激相关疾病、心境障碍、饮食障碍、泛化性焦虑障碍、应激诱导的胃肠功能障碍、神经变性疾病和神经精神障碍。
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