Quinazoline derivatives

• US 5,866,572 A
• Filed: 02/13/1997
• Issued: 02/02/1999
• Est. Priority Date: 02/14/1996
• Status: Expired due to Term

• Current Assignee: Astrazeneca UK Limited (Astrazeneca PLC)
• Original Assignee: Zeneca Incorporated (Astrazeneca PLC)
• Inventors: Johnstone, Craig, Barker, Andrew John
• Primary Examiner(s): Ramsuer, Robert W.
• Application Number:
  US08/796,483
• Time in Patent Office: 719 Days
• Field of Search: 544/116, 544/293, 514/234.5
• US Class Current: 514/234.5
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 239/94 Nitrogen atoms
• CPC Class Codes: C07D 249/08 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings

Abstract

The invention concerns quinazoline derivatives of the formula I ##STR1## wherein X¹ is a direct link or a group such as CO, C(R²)₂ and CH(OR²);

wherein Q¹ is phenyl, naphthyl or a 5- or 6-membered heteroaryl moiety and Q¹ optionally bears up to 3 substituents;

wherein m is 1 or 2 and each R¹ may be a group such as hydrogen, halogeno and trifluoromethyl; and

wherein Q² may be phenyl or a 9- or 10-membered bicyclic heterocyclic moiety and Q² optionally bears up to 3 substituents;

or a pharmaceutically-acceptable salt thereof;

processes for their preparation, pharmaceutical compositions containing them and the use of their receptor tyrosine kinase inhibitory properties in the treatment of proliferative disease such as cancer.

Claims

1. A quinazoline derivative of the formula I ##STR13## wherein X¹ is a direct link;

wherein Q¹ is a 5-membered heteroaryl moiety containing one heteroatom selected from oxygen and sulphur, which heterocyclic moiety is a single ring or is fused to a benzo ring, and Q¹ optionally bears up to 3 substituents selected from halogeno, hydroxy, amino, trifluoromethoxy, trifluoromethyl, cyano, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, (2-4C)alkenyloxy, (2-4C)alkynyloxy, (1-3C)alklenedioxy, (1-4C)alkylamino, di- (1-4C)alkyl!amino, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-(1-4C)alkylpiperazin-1-yl, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl, N,N-di- (1-4C)alkyl!carbamoyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di- (1-4C)alkyl!amino-(1-4C)alkyl, pyrrolidin-1-yl-(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, halogeno-(2-4C)alkoxy, hydroxy-(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, pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy, piperazin-1-yl-(2-4C)alkoxy, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy, (1-4C)alkylthio-(2-4C)alkoxy, (1-4C)alkylsulphinyl-(2-4C)alkoxy, (1-4C)alkylsulphonyl-(2-4C)alkoxy, halogeno-(2-4C)alkylamino, hydroxy-(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, pyrrolidin-1-yl-(2-4C)alkylamino, piperidino-(2-4C)alkylamino, morpholino-(2-4C)alkylamino, piperazin-1-yl-(2-4C)alkylamino, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkylamino, N-(1-4C)alkyl-halogeno-(2-4C)alkylamino, N-(1-4C)alkyl-hydroxy-(2-4C)alkylamino, N-(1-4C)alkyl-(1-4C)alkoxy-(2-4C)alkylamino, halogeno-(2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino, (1-4C)alkoxy-(2-4C)alkanoylamino, (3-4C)alkenoylamino, (3-4C)alkynoylamino, amino-(2-4C)alkanoylamino, (1-4C)alkylamino-(2-4C)alkanoylamino, di- (1-4C)alkyl!amino-(2-4C)alkanoylamino, pyrrolidin-1-yl-(2-4C)alkanoylamino, piperidino-(2-4C)alkanoylamino, morpholino-(2-4C)alkanoylamino, piperazin-1-yl-(2-4C)alkanoylamino and 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkanoylamino, and wherein any of the above-mentioned substituents comprising a CH₂ (methylene) group which is not attached to a halogeno, SO or SO₂ group or to a N, O or S atom optionally bears on said CH₂ group a substituent selected from hydroxy, amino, (1-4C)alkoxy, (1-4C)alkylamino and di- (1-4C)alkyl!amino;

wherein m is 1 or 2 and each R¹ is independently hydrogen, halogeno, trifluoromethyl, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-4C)alkoxycarbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di- (1-4C)alkyl!amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl or N,N-di- (1-4C)alkyl!carbamoyl;

and wherein Q² is phenyl optionally bearing up to 3 substituents selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di- (1-4C)alkyl!amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl and N,N-di-(1-4C)alkylcarbamoyl, or Q² is a group of the formula II ##STR14## wherein X² is a group of the formula CO, C(R₃)₂, CH(OR³), C(R³)₂ --C(R³)₂, C(R³)═

C(R³), C.tbd.C, CH(CN), O, S, SO, SO₂, N(R³), CON(R³), SO₂ N(R³), N(R³)CO, N(R³)SO₂, OC(R³)₂, SC(³)₂, C(R³)₂ O or C(R³)₂ S wherein each R³ is independently hydrogen or (1-4C)alkyl, Q³ is phenyl or naphthyl or a 5- or 6-membered heteroaryl moiety containing up to 3 heteroatoms selected from oxygen, nitrogen and sulphur, which heteroaryl moiety is a single ring or is fused to a benzo ring, and wherein said phenyl or naphthyl group or heteroaryl moiety optionally bears up to 3 substituents selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di- (1-4C)alkyl!amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl and N,N-di- (1-4C)alkyl!carbamoyl, n is 1, 2 or 3 and each R⁴ is independently hydrogen, halogeno, trifluoromethyl, cyano, hydroxy, amino, nitro, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di- (1-4C)alkyl!amino or (2-4C)alkanoylamino;

or a pharmaceutically-acceptable salt thereof.

2. A quinazoline derivative of the formula I as claimed in claim 1

wherein X¹ is a direct link;

wherein Q¹ is a 5-membered heteroaryl moiety containing one heteroatom selected from oxygen and sulphur, which heterocyclic moiety is a single ring or is fused to a benzo ring, and Q¹ optionally bears up to 3 substituents selected from halogeno, hydroxy, amino, trifluoromethoxy, trifluoromethyl, cyano, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, (2-4C)alkenyloxy, (2-4C)alkynyloxy, (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, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl, N,N-di- (1-4C)alkyl!carbamoyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di- (1-4C)alkyl!amino-(1-4C)alkyl, pyrrolidin-1-yl-(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, halogeno-(2-4C)alkoxy, hydroxy-(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, pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy, piperazin-1-yl-(2-4C)alkoxy, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy, (1-4C)alkylthio-(2-4C)alkoxy, (1-4C)alkylsulphinyl-(2-4C)alkoxy, (1-4C)alkylsulphonyl-(2-4C)alkoxy, halogeno-(2-4C)alkylamino, hydroxy-(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, pyrrolidin-1-yl-(2-4C)alkylamino, piperidino-(2-4C)alkylamino, morpholino-(2-4C)alkylamino, piperazin-1-yl-(2-4C)alkylamino, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkylamino, N-(1-4C)alkyl-halogeno-(2-4C)alkylamino, N-(1-4C)alkyl-hydroxy-(2-4C)alkylamino, N-(1-4C)alkyl-(1-4C)alkoxy-(2-4C)alkylamino, halogeno-(2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino, (1-4C)alkoxy-(2-4C)alkanoylamino, (3-4C)alkenoylamino, (3-4C)alkynoylamino, amino-(2-4C)alkanoylamino, (1-4C)alkylamino-(2-4C)alkanoylamino, di- (1-4C)alkyl!amino-(2-4C)alkanoylamino, pyrrolidin-1-yl-(2-4C)alkanoylamino, piperidino-(2-4C)alkanoylamino, morpholino-(2-4C)alkanoylamino, piperazin-1-yl-(2-4C)alkanoylamino and 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkanoylamino, and wherein any of the above-mentioned substituents comprising a CH₂ (methylene) group which is not attached to a halogeno, SO or SO₂ group or to a N, O or S atom optionally bears on said CH₂ group a substituent selected from hydroxy, amino, (1-4C)alkoxy, (1-4C)alkylamino and di- (1-4C)alkyl!amino;

wherein m is 1 or 2 and each R¹ is independently hydrogen, halogeno, trifluoromethyl, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-4C)alkoxycarbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di- (1-4C)alkyl!amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl or N, N-di- (1-4C)alkyl!carbamoyl;

and wherein Q² is phenyl which optionally bears up to 3 substituents selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di- (1-4C)alkyl!amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl and N,N-di-(1-4C)alkylcarbamoyl;

or a pharmaceutically-acceptable salt thereof.

3. A quinazoline derivative of the formula I as claimed in claim 1

wherein X¹ is a direct link;

Q¹ is 2-furyl, 3-furyl, 2-thienyl or 3-thienyl which optionally bears a substituent selected from methyl, aminomethyl, 2-aminoethyl, methylaminomethyl, 2-methylaminoethyl, dimethylaminomethyl, 2-dimethylaminoethyl, pyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl, piperidinomethyl, 2-piperidinoethyl, morpholinomethyl, 2-morpholinoethyl, piperazin-1-ylmethyl, 2-piperazin-1-ylethyl, 4-methylpiperazin-1-ylmethyl and 2-(4-methylpiperazin-1-yl)ethyl;

m is 1 and R¹ is hydrogen or methoxy;

and Q² is phenyl which optionally bears 1, 2 or 3 substituents selected from fluoro, chloro, bromo, trifluoromethyl, cyano, methyl and methoxy, or Q² is a group of the formula II ##STR15## wherein X² is a group of the formula CO or OCH₂, Q³ is phenyl or 2-pyridyl which optionally bears 1 or 2 substituents selected from fluoro, chloro, bromo, methyl and methoxy, n is 1 and R⁴ is hydrogen, fluoro, chloro, bromo or methyl;

or a pharmaceutically-acceptable acid-addition salt thereof.

4. A quinazoline derivative of the formula I as claimed in claim 1

wherein X¹ is a direct link;

Q¹ is 2-furyl, 3-furyl, 2-thienyl or 3-thienyl which optionally bears a substituent selected from aminomethyl, morpholinomethyl and 2-morpholinoethyl;

m is 1 and R¹ is hydrogen or methoxy;

and Q² is phenyl which optionally bears 1 or 2 substituents selected from fluoro, chloro, bromo and methyl;

or a pharmaceutically-acceptable acid-addition salt thereof.

6. A quinazoline derivative of the formula I as claimed in claim 1:

wherein X¹ is a direct link;

Q¹ is thienyl which bears a substituent selected from amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di- (1-4C)alkyl!amino-(1-4C)alkyl, pyrrolidin-1-yl-(1-4C)alkyl, piperidino-(1-4C)alkyl, morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl and 4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl;

m is 1 and R¹ is hydrogen;

and Q² is phenyl which optionally bears up to 3 substituents selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di- (1-4C)alkyl!amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl and N,N-di-(1-4C)alkylcarbamoyl;

or a pharmaceutically-acceptable salt thereof.

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

wherein X¹ is a direct link;

Q¹ is 2-thienyl which optionally bears a substituent selected from methyl, aminomethyl, 2-aminoethyl, methylaminomethyl, 2-methylaminoethyl, dimethylaminomethyl, 2-dimethylaminoethyl, pyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl, piperidinomethyl, 2-piperidinoethyl, morpholinomethyl, 2-morpholinoethyl, piperazin-1-ylmethyl, 2-piperazin-1-ylethyl, 4-methylpiperazin-1-ylmethyl and 2-(4-methylpiperazin-1-yl)ethyl;

m is 1 and R¹ is hydrogen or methoxy;

and Q² is phenyl which optionally bears 1, 2 or 3 substituents selected from fluoro, chloro, bromo, trifluoromethyl, cyano, methyl and methoxy;

or a pharmaceutically-acceptable acid-addition salt thereof.

8. A quinazoline derivative of the formula I as claimed in claim 1

wherein X¹ is a direct link;

Q¹ is 2-thienyl which optionally bears a substituent selected from aminomethyl, morpholinomethyl and 2-morpholinoethyl;

m is 1 and R¹ is hydrogen or methoxy;

and Q² is phenyl which optionally bears 1 or 2 substituents selected from fluoro, chloro, bromo and methyl;

or a pharmaceutically-acceptable acid-addition salt thereof.

9. The quinazoline derivative of the formula I as claimed in claim 1:

4-(3-chloro-4-fluoroanilino)-6- 5-(2-morpholinoethyl)thien-2-yl!quinazoline

or a pharmaceutically-acceptable acid-addition salt thereof.

10. 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 to 9 in association with a pharmaceutically-acceptable diluent or carrier.

11. A method for producing an anti-proliferative effect in a warm-blooded animal, such as man, in need of such treatment 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 1 to 9.

5. A quinazoline derivative selected from the group consisting of:

4-(3-chloro-4-fluoroanilino)-6-(3-furyl)quinazoline,

4-(3-chloro-4-fluoroanilino)-6-(2-thienyl)quinazoline,

4-(3-chloro-4-fluoroanilino)-6- 5-(2-morpholinoethyl)thien-2-yl!quinazoline, and

4-(3-chloro-4-fluoroanilino)-6-(5-morpholinomethylthien-3-yl)quinazoline;

or a pharmaceutically-acceptable acid-addition salt thereof.