IL122855A - History of N-Phenyl (Alkyl) - 7H-Pyrolo [-3,2d] Pyrimidine - 4 Amine, their preparation and pharmaceutical preparations containing them - Google Patents
History of N-Phenyl (Alkyl) - 7H-Pyrolo [-3,2d] Pyrimidine - 4 Amine, their preparation and pharmaceutical preparations containing themInfo
- Publication number
- IL122855A IL122855A IL12285596A IL12285596A IL122855A IL 122855 A IL122855 A IL 122855A IL 12285596 A IL12285596 A IL 12285596A IL 12285596 A IL12285596 A IL 12285596A IL 122855 A IL122855 A IL 122855A
- Authority
- IL
- Israel
- Prior art keywords
- carbamoyl
- lower alkyl
- phenyl
- pyrrolo
- amino
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims description 49
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 309
- -1 cyano, amino Chemical group 0.000 claims abstract description 262
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims abstract description 215
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 183
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 166
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 123
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 118
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 112
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 106
- 239000001257 hydrogen Substances 0.000 claims abstract description 104
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 90
- 150000003839 salts Chemical class 0.000 claims abstract description 85
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 77
- 150000002367 halogens Chemical group 0.000 claims abstract description 77
- 125000005236 alkanoylamino group Chemical group 0.000 claims abstract description 64
- 125000004423 acyloxy group Chemical group 0.000 claims abstract description 62
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 60
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 60
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 59
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 49
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 48
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 46
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 32
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 32
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 29
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims abstract description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 24
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 23
- 125000003302 alkenyloxy group Chemical group 0.000 claims abstract description 23
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims abstract description 16
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 14
- JJTNLWSCFYERCK-UHFFFAOYSA-N 7h-pyrrolo[2,3-d]pyrimidine Chemical class N1=CN=C2NC=CC2=C1 JJTNLWSCFYERCK-UHFFFAOYSA-N 0.000 claims abstract description 10
- 150000004943 pyrrolo[2,3-d]pyrimidines Chemical class 0.000 claims abstract description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 8
- 125000001589 carboacyl group Chemical group 0.000 claims abstract 11
- 150000003254 radicals Chemical class 0.000 claims description 155
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 93
- 125000006239 protecting group Chemical group 0.000 claims description 54
- 238000000034 method Methods 0.000 claims description 45
- 125000001424 substituent group Chemical group 0.000 claims description 39
- 230000008569 process Effects 0.000 claims description 32
- 125000000524 functional group Chemical group 0.000 claims description 25
- 206010028980 Neoplasm Diseases 0.000 claims description 18
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 18
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 18
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 11
- 241001465754 Metazoa Species 0.000 claims description 8
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 8
- JLYIDLKBGFXUTE-UHFFFAOYSA-N ethyl 4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxylate Chemical compound N1=CN=C2NC(C(=O)OCC)=CC2=C1NC1=CC=CC(Cl)=C1 JLYIDLKBGFXUTE-UHFFFAOYSA-N 0.000 claims description 7
- YOAQRPAYMXTKQI-UHFFFAOYSA-N 4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid Chemical compound N1=CN=C2NC(C(=O)O)=CC2=C1NC1=CC=CC(Cl)=C1 YOAQRPAYMXTKQI-UHFFFAOYSA-N 0.000 claims description 5
- UZDFIMXOVIIKQO-UHFFFAOYSA-N 6-(4-aminophenyl)-n-(3-chlorophenyl)-7h-pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound C1=CC(N)=CC=C1C(NC1=NC=N2)=CC1=C2NC1=CC=CC(Cl)=C1 UZDFIMXOVIIKQO-UHFFFAOYSA-N 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000012024 dehydrating agents Substances 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 150000003512 tertiary amines Chemical class 0.000 claims description 5
- WTGCGBNMDUJBEX-UHFFFAOYSA-N 4-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C(NC1=NC=N2)=CC1=C2NC1=CC=CC(Cl)=C1 WTGCGBNMDUJBEX-UHFFFAOYSA-N 0.000 claims description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 4
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- FLBNYSVQCAAWOC-UHFFFAOYSA-N ethyl 4-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1C(NC1=NC=N2)=CC1=C2NC1=CC=CC(Cl)=C1 FLBNYSVQCAAWOC-UHFFFAOYSA-N 0.000 claims description 4
- 150000003233 pyrroles Chemical class 0.000 claims description 4
- JJJQHTCJNMSSJV-UHFFFAOYSA-N pyrrolo[2,3-d]pyrimidin-4-one Chemical class O=C1N=CN=C2N=CC=C12 JJJQHTCJNMSSJV-UHFFFAOYSA-N 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- UPDHEPFPHMXRKP-UHFFFAOYSA-N [4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]methanol Chemical compound N1=CN=C2NC(CO)=CC2=C1NC1=CC=CC(Cl)=C1 UPDHEPFPHMXRKP-UHFFFAOYSA-N 0.000 claims description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 3
- ONUUZBLFKUZPCU-UHFFFAOYSA-N n-(3-chlorophenyl)-6-pyridin-2-yl-7h-pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound ClC1=CC=CC(NC=2C=3C=C(NC=3N=CN=2)C=2N=CC=CC=2)=C1 ONUUZBLFKUZPCU-UHFFFAOYSA-N 0.000 claims description 3
- ZPPJQVOJGAAFFM-MRXNPFEDSA-N 2,2-dimethyl-n-[3-[4-[[(1r)-1-phenylethyl]amino]-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]propanamide Chemical compound N([C@H](C)C=1C=CC=CC=1)C(C=1C=2)=NC=NC=1NC=2C1=CC=CC(NC(=O)C(C)(C)C)=C1 ZPPJQVOJGAAFFM-MRXNPFEDSA-N 0.000 claims description 2
- QWTLRAWOLQZKFX-MRXNPFEDSA-N 2,2-dimethyl-n-[4-[4-[[(1r)-1-phenylethyl]amino]-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]propanamide Chemical compound N([C@H](C)C=1C=CC=CC=1)C(C=1C=2)=NC=NC=1NC=2C1=CC=C(NC(=O)C(C)(C)C)C=C1 QWTLRAWOLQZKFX-MRXNPFEDSA-N 0.000 claims description 2
- VEBRIZYASKCCKZ-UHFFFAOYSA-N 2-[3-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenoxy]acetamide Chemical compound NC(=O)COC1=CC=CC(C=2NC3=NC=NC(NC=4C=C(Cl)C=CC=4)=C3C=2)=C1 VEBRIZYASKCCKZ-UHFFFAOYSA-N 0.000 claims description 2
- GYFHQWOKLLBICP-UHFFFAOYSA-N 2-[4-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenoxy]acetic acid Chemical compound C1=CC(OCC(=O)O)=CC=C1C(NC1=NC=N2)=CC1=C2NC1=CC=CC(Cl)=C1 GYFHQWOKLLBICP-UHFFFAOYSA-N 0.000 claims description 2
- VIYAUNPLBAEUSN-UHFFFAOYSA-N 4-(3-chloroanilino)-5-methyl-7h-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid Chemical compound C=12C(C)=C(C(O)=O)NC2=NC=NC=1NC1=CC=CC(Cl)=C1 VIYAUNPLBAEUSN-UHFFFAOYSA-N 0.000 claims description 2
- LNWOKFXJMDSXCT-UHFFFAOYSA-N 4-(3-chloroanilino)-6-methyl-7h-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde Chemical compound C=12C(C=O)=C(C)NC2=NC=NC=1NC1=CC=CC(Cl)=C1 LNWOKFXJMDSXCT-UHFFFAOYSA-N 0.000 claims description 2
- BYYLPECJKOEHBV-UHFFFAOYSA-N 4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde Chemical compound ClC1=CC=CC(NC=2C=3C=C(C=O)NC=3N=CN=2)=C1 BYYLPECJKOEHBV-UHFFFAOYSA-N 0.000 claims description 2
- DKRKYQJAGJAZRT-UHFFFAOYSA-N 4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidine-6-carbonitrile Chemical compound ClC1=CC=CC(NC=2C=3C=C(NC=3N=CN=2)C#N)=C1 DKRKYQJAGJAZRT-UHFFFAOYSA-N 0.000 claims description 2
- HRRSTGSFDNCRBK-UHFFFAOYSA-N 4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxamide Chemical compound N1=CN=C2NC(C(=O)N)=CC2=C1NC1=CC=CC(Cl)=C1 HRRSTGSFDNCRBK-UHFFFAOYSA-N 0.000 claims description 2
- YFOPRDNSBLGPMI-UHFFFAOYSA-N 4-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenol Chemical compound C1=CC(O)=CC=C1C(NC1=NC=N2)=CC1=C2NC1=CC=CC(Cl)=C1 YFOPRDNSBLGPMI-UHFFFAOYSA-N 0.000 claims description 2
- KFNHYCUETQTMIC-UHFFFAOYSA-N 6-(3-aminophenyl)-n-(3-chlorophenyl)-7h-pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound NC1=CC=CC(C=2NC3=NC=NC(NC=4C=C(Cl)C=CC=4)=C3C=2)=C1 KFNHYCUETQTMIC-UHFFFAOYSA-N 0.000 claims description 2
- SRSAKUNDUJJZAN-CYBMUJFWSA-N 6-(4-aminophenyl)-n-[(1r)-1-phenylethyl]-7h-pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound N([C@H](C)C=1C=CC=CC=1)C(C=1C=2)=NC=NC=1NC=2C1=CC=C(N)C=C1 SRSAKUNDUJJZAN-CYBMUJFWSA-N 0.000 claims description 2
- SRSAKUNDUJJZAN-ZDUSSCGKSA-N 6-(4-aminophenyl)-n-[(1s)-1-phenylethyl]-7h-pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound N([C@@H](C)C=1C=CC=CC=1)C(C=1C=2)=NC=NC=1NC=2C1=CC=C(N)C=C1 SRSAKUNDUJJZAN-ZDUSSCGKSA-N 0.000 claims description 2
- ACZQUYSPTJDIRG-UHFFFAOYSA-N 6-(4-aminophenyl)-n-[(3-methylphenyl)methyl]-7h-pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound CC1=CC=CC(CNC=2C=3C=C(NC=3N=CN=2)C=2C=CC(N)=CC=2)=C1 ACZQUYSPTJDIRG-UHFFFAOYSA-N 0.000 claims description 2
- NQGFVQYELMDSEE-UHFFFAOYSA-N 6-(4-aminophenyl)-n-benzyl-7h-pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound C1=CC(N)=CC=C1C(NC1=NC=N2)=CC1=C2NCC1=CC=CC=C1 NQGFVQYELMDSEE-UHFFFAOYSA-N 0.000 claims description 2
- RSJMXGTWBRPXFK-UHFFFAOYSA-N 6-(aminomethyl)-n-(3-chlorophenyl)-7h-pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound N1=CN=C2NC(CN)=CC2=C1NC1=CC=CC(Cl)=C1 RSJMXGTWBRPXFK-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- 241000282412 Homo Species 0.000 claims description 2
- 150000001448 anilines Chemical class 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- JMCVZMUNIHKBQR-UHFFFAOYSA-N methyl 2-[3-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenoxy]acetate Chemical compound COC(=O)COC1=CC=CC(C=2NC3=NC=NC(NC=4C=C(Cl)C=CC=4)=C3C=2)=C1 JMCVZMUNIHKBQR-UHFFFAOYSA-N 0.000 claims description 2
- XIYBXBOOMUTAAW-UHFFFAOYSA-N methyl 2-[4-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenoxy]acetate Chemical compound C1=CC(OCC(=O)OC)=CC=C1C(NC1=NC=N2)=CC1=C2NC1=CC=CC(Cl)=C1 XIYBXBOOMUTAAW-UHFFFAOYSA-N 0.000 claims description 2
- KXVFXQNQBCHBKL-UHFFFAOYSA-N n-(3-chlorophenyl)-5-methyl-6-pyridin-2-yl-7h-pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound C=12C(C)=C(C=3N=CC=CC=3)NC2=NC=NC=1NC1=CC=CC(Cl)=C1 KXVFXQNQBCHBKL-UHFFFAOYSA-N 0.000 claims description 2
- DHSPAWKUZSBXHS-UHFFFAOYSA-N n-(3-chlorophenyl)-6-(4-nitrophenyl)-7h-pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound C1=CC([N+](=O)[O-])=CC=C1C(NC1=NC=N2)=CC1=C2NC1=CC=CC(Cl)=C1 DHSPAWKUZSBXHS-UHFFFAOYSA-N 0.000 claims description 2
- BWKIKAJTKWXBHR-UHFFFAOYSA-N n-(3-chlorophenyl)-6-[4-(dimethylamino)phenyl]-7h-pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound C1=CC(N(C)C)=CC=C1C(NC1=NC=N2)=CC1=C2NC1=CC=CC(Cl)=C1 BWKIKAJTKWXBHR-UHFFFAOYSA-N 0.000 claims description 2
- GDQXIFMWBNDZHY-UHFFFAOYSA-N n-[3-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-2-methylpropanamide Chemical compound CC(C)C(=O)NC1=CC=CC(C=2NC3=NC=NC(NC=4C=C(Cl)C=CC=4)=C3C=2)=C1 GDQXIFMWBNDZHY-UHFFFAOYSA-N 0.000 claims description 2
- NOZSFOBLVYJJRV-UHFFFAOYSA-N n-[4-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-2,2-dimethylpropanamide Chemical compound C1=CC(NC(=O)C(C)(C)C)=CC=C1C(NC1=NC=N2)=CC1=C2NC1=CC=CC(Cl)=C1 NOZSFOBLVYJJRV-UHFFFAOYSA-N 0.000 claims description 2
- DXZDXJBFPMSDLT-UHFFFAOYSA-N n-[4-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-3-methylbutanamide Chemical compound C1=CC(NC(=O)CC(C)C)=CC=C1C(NC1=NC=N2)=CC1=C2NC1=CC=CC(Cl)=C1 DXZDXJBFPMSDLT-UHFFFAOYSA-N 0.000 claims description 2
- UZLGAFFKTLBDIB-UHFFFAOYSA-N n-[4-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]acetamide Chemical compound C1=CC(NC(=O)C)=CC=C1C(NC1=NC=N2)=CC1=C2NC1=CC=CC(Cl)=C1 UZLGAFFKTLBDIB-UHFFFAOYSA-N 0.000 claims description 2
- VUHIWJQXEJGBGV-UHFFFAOYSA-N n-[4-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]propanamide Chemical compound C1=CC(NC(=O)CC)=CC=C1C(NC1=NC=N2)=CC1=C2NC1=CC=CC(Cl)=C1 VUHIWJQXEJGBGV-UHFFFAOYSA-N 0.000 claims description 2
- MBJIUVXHGKAMMX-CQSZACIVSA-N n-[4-[4-[[(1r)-1-phenylethyl]amino]-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]acetamide Chemical compound N([C@H](C)C=1C=CC=CC=1)C(C=1C=2)=NC=NC=1NC=2C1=CC=C(NC(C)=O)C=C1 MBJIUVXHGKAMMX-CQSZACIVSA-N 0.000 claims description 2
- PGTNANTWNTYJNR-UHFFFAOYSA-N n-benzyl-4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxamide Chemical compound ClC1=CC=CC(NC=2C=3C=C(NC=3N=CN=2)C(=O)NCC=2C=CC=CC=2)=C1 PGTNANTWNTYJNR-UHFFFAOYSA-N 0.000 claims description 2
- YPFMMHFXVQVPGO-UHFFFAOYSA-N n-butyl-4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxamide Chemical compound N1=CN=C2NC(C(=O)NCCCC)=CC2=C1NC1=CC=CC(Cl)=C1 YPFMMHFXVQVPGO-UHFFFAOYSA-N 0.000 claims description 2
- RFLAVHHYEHEFAA-UHFFFAOYSA-N propan-2-yl 4-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]benzoate Chemical compound C1=CC(C(=O)OC(C)C)=CC=C1C(NC1=NC=N2)=CC1=C2NC1=CC=CC(Cl)=C1 RFLAVHHYEHEFAA-UHFFFAOYSA-N 0.000 claims description 2
- IBRLTAAEOLMURX-UHFFFAOYSA-N propyl 4-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]benzoate Chemical compound C1=CC(C(=O)OCCC)=CC=C1C(NC1=NC=N2)=CC1=C2NC1=CC=CC(Cl)=C1 IBRLTAAEOLMURX-UHFFFAOYSA-N 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- XLFTWOBDSIGCSU-UHFFFAOYSA-N 2-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenol Chemical compound OC1=CC=CC=C1C(NC1=NC=N2)=CC1=C2NC1=CC=CC(Cl)=C1 XLFTWOBDSIGCSU-UHFFFAOYSA-N 0.000 claims 1
- QEMJSPGYFNYBPQ-UHFFFAOYSA-N 2-methylpropyl 4-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]benzoate Chemical compound C1=CC(C(=O)OCC(C)C)=CC=C1C(NC1=NC=N2)=CC1=C2NC1=CC=CC(Cl)=C1 QEMJSPGYFNYBPQ-UHFFFAOYSA-N 0.000 claims 1
- RZRXPHUZFBUQFN-UHFFFAOYSA-N 3-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]benzoic acid Chemical compound OC(=O)C1=CC=CC(C=2NC3=NC=NC(NC=4C=C(Cl)C=CC=4)=C3C=2)=C1 RZRXPHUZFBUQFN-UHFFFAOYSA-N 0.000 claims 1
- STYSVCBDICPKCL-UHFFFAOYSA-N 3-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenol Chemical compound OC1=CC=CC(C=2NC3=NC=NC(NC=4C=C(Cl)C=CC=4)=C3C=2)=C1 STYSVCBDICPKCL-UHFFFAOYSA-N 0.000 claims 1
- KFIICRGOUMCPQI-UHFFFAOYSA-N 4-(3-chloroanilino)-n,n-dimethyl-7h-pyrrolo[2,3-d]pyrimidine-6-carboxamide Chemical compound N1=CN=C2NC(C(=O)N(C)C)=CC2=C1NC1=CC=CC(Cl)=C1 KFIICRGOUMCPQI-UHFFFAOYSA-N 0.000 claims 1
- QYVBDLWIXVYDDY-UHFFFAOYSA-N 4-(3-chloroanilino)-n-(3-methylbutyl)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxamide Chemical compound N1=CN=C2NC(C(=O)NCCC(C)C)=CC2=C1NC1=CC=CC(Cl)=C1 QYVBDLWIXVYDDY-UHFFFAOYSA-N 0.000 claims 1
- HTUAWMQFTGNRIW-UHFFFAOYSA-N 4-(3-chloroanilino)-n-methyl-7h-pyrrolo[2,3-d]pyrimidine-6-carboxamide Chemical compound N1=CN=C2NC(C(=O)NC)=CC2=C1NC1=CC=CC(Cl)=C1 HTUAWMQFTGNRIW-UHFFFAOYSA-N 0.000 claims 1
- ZATTZEUEAMCUQY-UHFFFAOYSA-N 4-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]-n,n-diethylbenzamide Chemical compound C1=CC(C(=O)N(CC)CC)=CC=C1C(NC1=NC=N2)=CC1=C2NC1=CC=CC(Cl)=C1 ZATTZEUEAMCUQY-UHFFFAOYSA-N 0.000 claims 1
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- IWGZZXIHUTZVBV-UHFFFAOYSA-N n-(3-chlorophenyl)-9h-pyrimido[4,5-b]indol-4-amine;hydrochloride Chemical compound Cl.ClC1=CC=CC(NC=2C=3C4=CC=CC=C4NC=3N=CN=2)=C1 IWGZZXIHUTZVBV-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- GEKBGSALZDJBEL-UHFFFAOYSA-N n-benzyl-5,6-dimethyl-7h-pyrrolo[2,3-d]pyrimidin-4-amine;hydrochloride Chemical compound Cl.C=12C(C)=C(C)NC2=NC=NC=1NCC1=CC=CC=C1 GEKBGSALZDJBEL-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
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- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
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- 210000003491 skin Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
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- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229940080236 sodium cetyl sulfate Drugs 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
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- RZWQDAUIUBVCDD-UHFFFAOYSA-M sodium;benzenethiolate Chemical compound [Na+].[S-]C1=CC=CC=C1 RZWQDAUIUBVCDD-UHFFFAOYSA-M 0.000 description 1
- GGHPAKFFUZUEKL-UHFFFAOYSA-M sodium;hexadecyl sulfate Chemical compound [Na+].CCCCCCCCCCCCCCCCOS([O-])(=O)=O GGHPAKFFUZUEKL-UHFFFAOYSA-M 0.000 description 1
- NWZBFJYXRGSRGD-UHFFFAOYSA-M sodium;octadecyl sulfate Chemical compound [Na+].CCCCCCCCCCCCCCCCCCOS([O-])(=O)=O NWZBFJYXRGSRGD-UHFFFAOYSA-M 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
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- 229940057429 sorbitan isostearate Drugs 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
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- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- DPUOLQHDNGRHBS-MDZDMXLPSA-N trans-Brassidic acid Chemical compound CCCCCCCC\C=C\CCCCCCCCCCCC(O)=O DPUOLQHDNGRHBS-MDZDMXLPSA-N 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- 150000004072 triols Chemical class 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
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- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Saccharide Compounds (AREA)
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH197695 | 1995-07-06 | ||
CH249895 | 1995-09-01 | ||
CH319895 | 1995-11-10 | ||
CH25596 | 1996-02-01 | ||
CH122496 | 1996-05-13 | ||
PCT/EP1996/002728 WO1997002266A1 (en) | 1995-07-06 | 1996-06-24 | Pyrrolopyrimidines and processes for the preparation thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
IL122855A0 IL122855A0 (en) | 1998-08-16 |
IL122855A true IL122855A (en) | 2004-08-31 |
Family
ID=27508793
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IL12285596A IL122855A (en) | 1995-07-06 | 1996-06-24 | History of N-Phenyl (Alkyl) - 7H-Pyrolo [-3,2d] Pyrimidine - 4 Amine, their preparation and pharmaceutical preparations containing them |
Country Status (26)
Country | Link |
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US (1) | US6140332A (xx) |
EP (1) | EP0836605B1 (xx) |
JP (1) | JP4146514B2 (xx) |
KR (1) | KR100437582B1 (xx) |
CN (1) | CN1100778C (xx) |
AT (1) | ATE212993T1 (xx) |
BR (1) | BR9609617B1 (xx) |
CA (1) | CA2224435C (xx) |
CY (1) | CY2365B1 (xx) |
CZ (1) | CZ1598A3 (xx) |
DE (1) | DE69619114T2 (xx) |
DK (1) | DK0836605T3 (xx) |
EA (1) | EA001428B1 (xx) |
ES (1) | ES2172670T3 (xx) |
HK (1) | HK1008222A1 (xx) |
HU (1) | HUP9900330A3 (xx) |
IL (1) | IL122855A (xx) |
MX (1) | MX9800215A (xx) |
NO (1) | NO310359B1 (xx) |
NZ (1) | NZ312665A (xx) |
PL (1) | PL188959B1 (xx) |
PT (1) | PT836605E (xx) |
SI (1) | SI9620103A (xx) |
SK (1) | SK398A3 (xx) |
TR (1) | TR199800012T1 (xx) |
WO (1) | WO1997002266A1 (xx) |
Families Citing this family (462)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE159257T1 (de) * | 1994-05-03 | 1997-11-15 | Ciba Geigy Ag | Pyrrolopyrimidinderivate mit antiproliferativer wirkung |
TW321649B (xx) * | 1994-11-12 | 1997-12-01 | Zeneca Ltd | |
GB9424233D0 (en) * | 1994-11-30 | 1995-01-18 | Zeneca Ltd | Quinazoline derivatives |
GB9508535D0 (en) * | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivative |
GB9508537D0 (en) * | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivatives |
GB9508538D0 (en) * | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivatives |
GB9508565D0 (en) * | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quiazoline derivative |
US5932574A (en) * | 1995-04-27 | 1999-08-03 | Zeneca Limited | Quinazoline derivatives |
US6395733B1 (en) * | 1995-06-07 | 2002-05-28 | Pfizer Inc | Heterocyclic ring-fused pyrimidine derivatives |
US6228871B1 (en) | 1995-07-10 | 2001-05-08 | Merck & Co., Inc. | Angiogenesis inhibitors |
GB9624482D0 (en) | 1995-12-18 | 1997-01-15 | Zeneca Phaema S A | Chemical compounds |
JP4275733B2 (ja) * | 1996-01-23 | 2009-06-10 | ノバルティス アクチエンゲゼルシャフト | ピロロピリミジンおよびその製造法 |
BR9707495A (pt) | 1996-02-13 | 1999-07-27 | Zeneca Ltd | Derivado de quinazolina processo para a preparação do mesmo composição farmacêutica e processo para a produç o de um efeito antiangiogênico e/ou de redução de permeabilidade vascular em um animal de sangue quente |
GB9603097D0 (en) * | 1996-02-14 | 1996-04-10 | Zeneca Ltd | Quinazoline compounds |
KR100489174B1 (ko) | 1996-03-05 | 2005-09-30 | 제네카-파마 소시에떼아노님 | 4-아닐리노퀴나졸린유도체 |
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WO2024085242A2 (en) | 2022-10-21 | 2024-04-25 | Kawasaki Institute Of Industrial Promotion | Non-fouling or super stealth vesicle |
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US11945823B1 (en) | 2023-09-14 | 2024-04-02 | King Faisal University | Substituted pyrrolo[2,3-d]pyrimidines as CK2 inhibitors |
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US3037980A (en) * | 1955-08-18 | 1962-06-05 | Burroughs Wellcome Co | Pyrrolopyrimidine vasodilators and method of making them |
DE3036390A1 (de) * | 1980-09-26 | 1982-05-13 | Troponwerke GmbH & Co KG, 5000 Köln | Neue pyrrolo-pyrimidine, verfahren zu ihrer herstellung und ihre verwendung bei der herstellung von biologischen wirkstoffen |
US5674998A (en) * | 1989-09-15 | 1997-10-07 | Gensia Inc. | C-4' modified adenosine kinase inhibitors |
DE69222637T2 (de) * | 1991-05-10 | 1998-02-26 | Rhone Poulenc Rorer Int | Bis mono- und bicyclische aryl- und heteroarylderivate mit inhibierender wirkung auf die egf und/oder pdgf-rezeptor tyrosinkinase |
IL112248A0 (en) * | 1994-01-25 | 1995-03-30 | Warner Lambert Co | Tricyclic heteroaromatic compounds and pharmaceutical compositions containing them |
IL112249A (en) * | 1994-01-25 | 2001-11-25 | Warner Lambert Co | Pharmaceutical compositions containing di and tricyclic pyrimidine derivatives for inhibiting tyrosine kinases of the epidermal growth factor receptor family and some new such compounds |
US5679683A (en) * | 1994-01-25 | 1997-10-21 | Warner-Lambert Company | Tricyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family |
ATE159257T1 (de) * | 1994-05-03 | 1997-11-15 | Ciba Geigy Ag | Pyrrolopyrimidinderivate mit antiproliferativer wirkung |
DK0783505T3 (da) * | 1994-09-29 | 2001-07-02 | Novartis Ag | Pyrrolo[2,3-d]pyrimidiner og deres anvendelse |
DE69609602T2 (de) * | 1995-04-03 | 2001-04-12 | Novartis Ag | Pyrazolderivate und verfahren zu deren herstellung |
US6403599B1 (en) * | 1995-11-08 | 2002-06-11 | Pfizer Inc | Corticotropin releasing factor antagonists |
ES2203642T3 (es) * | 1995-06-07 | 2004-04-16 | Pfizer Inc. | Derivados de pirimidina heterociclicos con anillos condensados. |
GB9604361D0 (en) * | 1996-02-29 | 1996-05-01 | Pharmacia Spa | 4-Substituted pyrrolopyrimidine compounds as tyrosine kinase inhibitors |
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1996
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