Quinazoline derivatives

• US 5,580,870 A
• Filed: 12/10/1993
• Issued: 12/03/1996
• Est. Priority Date: 12/10/1992
• Status: Expired due to Term

• Current Assignee: Astrazeneca UK Limited (Astrazeneca PLC)
• Original Assignee: Zeneca Incorporated (Astrazeneca PLC)
• Inventors: Brown, Dearg S., Barker, Andrew J.
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): Grumbling, Matthew V.
• Application Number:
  US08/164,725
• Time in Patent Office: 1,089 Days
• Field of Search: 514/234.5, 514/249, 514/259, 514/267, 544/119, 544/250, 544/284, 544/293
• US Class Current: 514/234.5
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 239/94 Nitrogen atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 491/04 Ortho-condensed systems

Abstract

The invention concerns quinazoline derivatives of the formula I ##STR1## wherein m is 1, 2 or 3 and each R¹ includes hydroxy, amino, ureido, hydroxyamino, trifluoromethoxy, (1-4C)alkyl, (1-4C)alkoxy and (1-3C)alkylenedioxy; and Q is a 9- or 10-membered bicyclic heterocyclic moiety containing one or two nitrogen heteroatoms and optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur, or Q is a 9- or 10-membered bicyclic aryl moiety which heterocyclic or aryl moiety may optionally bear one or two substituents selected from halogeno, hydroxy, oxo, amino, nitro, carbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino and (2-4C)alkanoylamino; or a pharmaceutically-acceptable salt thereof; processes for their preparation; pharmaceutical compositions containing them; and the use of the receptor tyrosine kinase inhibitory properties of the compounds in the treatment of cancer.

Claims

1. A quinazoline derivative of the formula I ##STR6## wherein m is 1, 2 or 3 and each R¹ is independently hydroxy, amino, ureido, hydroxyamino, trifluoromethoxy, (1-4C)alkyl, (1-4C)alkoxy, (1-3C)alkylenedioxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-(1-4C)alkylpiperazin-1-yl, (1-4C)alkylthio, halogeno-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (2-4C)alkanoyloxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(1-4C)alkyl, piperidino-(1-4C)alkyl, morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl, 4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl, hydroxy-(2-4C)alkoxy-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkoxy-(1-4C)alkyl, hydroxy-(2-4C)alkylamino-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkylamino-(1-4C)alkyl, halogeno-(2-4C)alkoxy, hydroxy-(2-4C)alkoxy, (2-4C)alkanoyloxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, amino-(2-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl]amino-(2-4C)alkoxy, (2-4C)alkanoyloxy, hydroxy-(2-4C)alkanoyloxy, (1-4C)alkoxy-(2-4C)alkanoyloxy, phenyl-(1-4C)alkoxy, halogeno-(2-4C)alkylamino, hydroxy-(2-4C)alkylamino, (2-4C)alkanoyloxy-(2-4C)alkylamino, (1-4C)alkoxy-(2-4C)alkylamino, amino-(2-4C)alkylamino, (1-4C)alkylamino-(2-4C)alkylamino, di-[(1-4C)alkyl]amino-(2-4C)alkylamino, (2-4C)alkanoylamino, (1-4C)alkoxycarbonylamino, benzamido, 3-phenylureido, halogeno-(2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino or (1-4C)alkoxy-(2-4C)alkanoylamino, and wherein said benzamido substituent or any phenyl group in a R¹ substituent may optionally bear one or two halogeno, (1-4C)alkyl or (1-4C)alkoxy substituents;

and Q is a 9- or 10-membered bicyclic heterocyclic moiety, or a hydrogenated derivative thereof, containing one or two nitrogen heteroatoms and optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur, which heterocyclic moiety, or a hydrogenated derivative thereof, may optionally bear one or two substituents selected from halogeno, hydroxy, oxo, amino, nitro, carbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino and (2-4C)alkanoylamino;

or a pharmaceutically-acceptable salt thereof.

4. A quinazoline derivative of the formula I as claimed in claim 1 or claim 2 wherein m is 1, 2 or 3 and each R¹ is independently hydroxy, amino, fluoro, chloro, nitro, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylenedioxy, ethylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin-1-yl, methylthio, ethylthio, acetamido, propionamido or 2-chloroacetamido;

and Q is indolyl, 1H-benzimidazolyl, 1H-indazolyl, benzoxazolyl, benzothiazolyl, 1H-benzotriazolyl, benzo[c]furazanyl, benzo[c][2,1,3]thiadiazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl or, quinoxalinyl, which may optionally bear one or two substituents selected from fluoro, chloro, hydroxy, amino, carboxy, methyl, ethyl, methoxy, ethoxy, methylamino, dimethylamino, acetamido, methoxycarbonyl and ethoxycarbonyl;

or a pharmaceutically-acceptable salt thereof.

5. A quinazoline derivative of the formula I as claimed in claim 1 or claim 2 wherein (R¹)_m is 6-hydroxy, 7-hydroxy, 6,7-dihydroxy, 6-amino, 7-amino, 6-fluoro, 7-fluoro, 6-chloro, 7-chloro, 6-nitro, 6-methoxy, 7-methoxy, 6,7-dimethoxy, 6,7-diethoxy, 6-hydroxy-7-methoxy, 6,7-methylenedioxy, 6,7-ethylenedioxy, 6-methylamino, 7-methylamino, 6-ethylamino, 6-dimethylamino, 7-dimethylamino, 6-diethylamino, 6-pyrrolidin-1-yl, 7-pyrrolidin-1-yl, 6-piperidino, 7-piperidino, 6-morpholino, 7-morpholino, 6-piperazin-1-yl, 7-piperazin-1-yl, 6-(4-methylpiperazin-1-yl), 7-(4-methylpiperazin-1-yl), 6-methylthio, 7-methylthio, 6-amino-7-methoxy, 6-amino-7-methylamino, 6-acetamido, 7-acetamido, 6-(2-chloroacetamido) or 7-(2-chloroacetamido);

and Q is 4-, 5- or 6-indolyl, 1H-benzimidazol-4-yl, 1H-benzimidazol-5-yl, 1H-benzimidazol-6-yl, 1H-indazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, 5- or 6-benzoxazolyl, 5- or 6-benzothiazolyl, 1H-benzotriazol-4-yl, 1H-benzotriazol-5-yl, 1H-benzotriazol-6-yl, benzo[c][2,1,3]thiadiazol-4-yl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 4-, 5-, 6-, 7- or 8-cinnolinyl, 5-, 6-, 7- or 8-quinazolinyl or 2-, 5- or 6-quinoxalinyl, which may optionally bear one or two substituents selected from fluoro, chloro, methyl, ethyl and methoxy;

or a pharmaceutically-acceptable salt thereof.

6. A quinazoline derivative of the formula I as claimed in claim 1 wherein (R¹)_m is 6-amino, 6,7-dimethoxy, 6-piperidino or 6-acetamido;

and Q is 5-indolyl, 1H-indazol-5-yl, 6-benzothiazolyl, 1H-benzotriazol-5-yl, benzo[c][2,1,3]thiadiazol-4-yl, 5-quinolyl, 6-quinolyl, 8-quinolyl, 5-isoquinolyl or 5-quinoxalinyl;

or a pharmaceutically-acceptable salt thereof.

7. A quinazoline derivative of the formula I as claimed in claim 1 selected from:

6,7-dimethoxy-4-(5-quinolylamino)quinazoline,

6,7-dimethoxy-4-(6-quinolylamino)quinazoline,

6,7-dimethoxy-4-(5-isoquinolylamino)quinazoline,

6,7-dimethoxy-4-(5-indolylamino)quinazoline,

6,7-dimethoxy-4-[(1H-indazol-5-yl)amino]quinazoline,

4-(6-benzothiazolylamino)-6,7-dimethoxyquinazoline and

4-[(benzo[c][2,1,3]thiadiazol-4-yl)amino]-6,7-dimethoxyquinazoline;

or a pharmaceutically-acceptable acid-addition salt thereof.

8. A pharmaceutical composition which comprises a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1-7 in association with a pharmaceutically-acceptable diluent or carrier.

9. A method for producing an anti-cancer effect in a warm-blooded animal having a cancer which is sensitive to inhibition of the EGF-type of receptor tyrosine kinase enzymes which comprises administering to said animal an effective amount of a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 4-7.

10. A method for producing an anti-proliferative effect in a warm-blooded animal having a cancer which is sensitive to inhibition of the EGF-type of receptor tyrosine kinase enzymes which comprises administering to said animal an effective amount of a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 4-7.

11. A method for aiding the regression or palliation in a warm-blooded animal of a cancer which is sensitive to inhibition of the EGF-type of receptor tyrosine kinase enzymes which comprises administering to said animal an effective amount of a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 4-7.

12. A method for producing in a warm-blooded animal an inhibitory effect against the EGF-type of receptor tyrosine kinase enzymes which comprises administering to said animal an effective amount of a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 4-7.

2. A quinazoline derivative of the formula I ##STR7## wherein m is 1, 2 or 3 and each R¹ is independently hydrogen, halogeno, nitro, hydroxy, amino, ureido, hydroxyamino, trifluoromethoxy, (1-4C)alkyl, (1-4C)alkoxy, (1-3C)alkylenedioxy, (1-4C)alkylamino, di-[1-4C)alkyl]amino, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-(1-4C)alkylpiperazin-1-yl, (1-4C)alkylthio, halogeno-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (2-4C)alkanoyloxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl, amino-1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di [(1-4C)alkyl ]amino-(1-4C)alkyl, piperidino-(1-4C)alkyl, morpholino-(1-4C)alkyl, piperazin-1-yl (1-4C)alkyl, 4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl, hydroxy-(2-4C)alkoxy-(1-4C)alkyl, (1-4C)alkoxy(2-4C)alkoxy-(1-4C)alkyl, hydroxy-(2-4C)alkylamino-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkylamino-(1-4C)alkyl, halogeno-(2-4C)alkoxy, hydroxy-(2-4C)alkoxy, (2-4C)alkanoyloxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, amino-(2-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl]amino-(2-4C)alkoxy, (2-4C)alkanoyloxy, hydroxy-(2-4C)alkanoyloxy, (1-4C)alkoxy-(2-4C)alkanoyloxy, phenyl-(1-4C)alkoxy, halogeno-(2-4C)alkylamino, hydroxy-(2-4C)alkylamino, (2-4C)alkanoyloxy-(2-4C)alkylamino, (1-4C)alkoxy-(2-4C)alkylamino, amino-(2-4C)alkylamino, (1-4C)alkylamino-(2-4C)alkylamino, di-[(1-4C)alkyl]amino-(2-4C)alkylamino, (2-4C)alkanoylamino, (1-4C)alkoxycarbonylamino, benzamido, 3-phenylureido, halogeno-(2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino or (1-4C)alkoxy-(2-4C)alkanoylamino, and wherein said benzamido substituent or any phenyl group in a R¹ substituent may optionally bear one or two halogeno, (1-4C)alkyl or (1-4C)alkoxy substituents;

and Q is a 9- or 10-membered bicyclic heterocyclic moiety, or a hydrogenated derivative thereof, containing one or two nitrogen heteroatoms and optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur, which heterocyclic moiety, or a hydrogenated derivative thereof, may optionally bear one or two substituents selected from carboxy, (1-4C)alkoxycarbonyl, halogeno, hydroxy, oxo, amino, nitro, carbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino and (2-4C)alkanoylamino;

or a pharmaceutically-acceptable salt thereof;

except that 4-(4-quinazolinylamino)quinazoline is excluded.

3. A quinazoline derivative of the formula I ##STR8## wherein M is 1, 2 or 3 and each R¹ is independently hydrogen, halogeno, nitro, hydroxy, amino, ureido, hydroxyamino, trifluoromethoxy, (1-4C)alkyl, (1-4C)alkoxy, (1-3C)alkylenedioxy, (1-4C)alkylamino, di-[1-4C)alkyl]amino, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-(1-4C)alkylpiperazin-1-yl, (1-4C)alkylthio, halogeno-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (2-4C)alkanoyloxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl, amino-1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di[(1-4C)alkyl]amino-(1-4C)alkyl, piperidino-(1-4C)alkyl, morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl, 4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl, hydroxy-(2-4C)alkoxy-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkoxy-(1-4C)alkyl, hydroxy-(2-4C)alkylamino-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkylamino-(1-4C)alkyl, halogeno-(2-4C)alkoxy, hydroxy-(2-4C)alkoxy, (2-4C)alkanoyloxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, amino-(2-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl]amino-(2-4C)alkoxy, (2-4C)alkanoyloxy, hydroxy-(2-4C)alkanoyloxy, (1-4C)alkoxy-(2-4C)alkanoyloxy, phenyl-(1-4C)alkoxy, halogeno-(2-4C)alkylamino, hydroxy-(2-4C)alkylamino, (2-4C)alkanoyloxy-(2-4C)alkylamino, (1-4C)alkoxy-(2-4C)alkylamino, amino-(2 -4C)alkylamino, (1-4C)alkylamino-(2 -4C)alkylamino, di-[(1-4C)alkyl]amino-(2-4C)alkylamino, (2-4C)alkanoylamino, (1-4C)alkoxycarbonylamino, benzamido, 3-phenylureido, halogeno-(2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino, (1-4C)alkoxy-(2-4C)alkanoylamino, 2-oxopyrrolidin-1-yl or 2-oxopiperidin-1-yl, and wherein said benzamido substituent or any phenyl group in a R¹ substituent may optionally bear one or two halogeno, (1-4C)alkyl or (1-4C)alkoxy substituents;

and Q is a 9- or 10-membered bicyclic heterocyclic moiety, or a hydrogenated derivative thereof, containing one or two nitrogen heteroatoms and optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur, which heterocyclic moiety, or a hydrogenated derivative thereof, may optionally bear one or two substituents selected from cyano, carboxy, (1-4C)alkoxycarbonyl, halogeno, hydroxy, oxo, amino, nitro, carbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino and (2-4C)alkanoylamino;

or a pharmaceutically-acceptable salt thereof;

except that 4-(4-quinazolinylamino)quinazoline is excluded.