Chemical compounds

• US 6,071,921 A
• Filed: 12/02/1998
• Issued: 06/06/2000
• Est. Priority Date: 12/18/1995
• Status: Expired due to Term

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Zeneca Incorporated (Astrazeneca PLC), Zeneca Pharma S.A.
• Inventors: Hennequin, Laurent Francois Andre, Thomas, Andrew Peter, Lohmann, Jean-Jacques Marcel
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): Kifle, Bruck
• Application Number:
  US09/203,764
• Time in Patent Office: 552 Days
• Field of Search: 544/283, 544/284, 544/287, 544/288, 544/293, 514/259
• US Class Current: 514/266.22
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 239/88 Oxygen atoms
• 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 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 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

Abstract

The invention relates to quinazoline derivatives of the formula: ##STR1## [wherein: Y¹ represents --O--, --S--, --CH₂ --, --SO--, --SO₂ --, --NR⁵ CO--, --CONR⁶ --, --SO₂ NR⁷ --, --NR⁸ SO₂ -- or --NR⁹ -- (wherein R⁵, R⁶, R⁷, R⁸ and R⁹ each independently represents hydrogen, alkyl or alkoxyalkyl);

R¹ represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, alkyl, alkoxy, alkylthio, amino or alkylamino.

R² represents hydrogen, hydroxy, halogeno, alkyl, alkoxy, trifluoromethyl, cyano, amino or nitro;

m is an integer from 1 to 5;

R³ represents hydroxy, halogeno, alky, alkoxy, alkanoyloxy, trifluoromethyl, cyano, amino or nitro;

R⁴ represents a group which is or which contains an optionally substituted pyridone, phenyl or aromatic heterocyclic group] and salts thereof; processes for their preparation and pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof as active ingredient.

The compounds of formula I and the pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.

Claims

1. A quinazoline derivative of the formula I:

##STR27## wherein;

Y¹ represents --O--, --S--, --CH₂ --, --SO--, --SO₂ --, --NR⁵ CO--, --CONR⁶ --, --SO₂ NR⁷ --, --NR⁸ SO₂ -- or --NR⁹ --,

wherein R⁵, R⁶, R⁷, R⁸ and R⁹ each independently represents hydrogen, C_1-3 alkyl or C_1-3 alkoxyC_2-3 alkyl;

R¹ represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 alkylthio, or NR¹⁰ R¹¹,

wherein R¹⁰ and R¹¹, which may be the same or different, each represents hydrogen or C_1-3 alkyl;

R² represents hydrogen, hydroxy, halogeno, C_1-3 alkyl, C_1-3 alkoxy, trifluoromethyl, cyano, amino or nitro;

m is an integer from 1 to 5;

R³ represents hydroxy, halogeno, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 alkanoyloxy, trifluoromethyl, cyano, amino or nitro;

R⁴ is selected from one of the following eight groups;

1) X¹, wherein X¹ represents a pyridone group, a phenyl group or a 5 or 6-membered aromatic heterocyclic group with 1 to 3 heteroatoms selected from O, N and S, which pyridone, phenyl or heterocyclic group may carry up to 5 substituents selected from halogeno, amino, C_1-4 alkyl, C_1-4 alkoxy, C_1-4 hydroxyalkyl, C_1-4 aminoalkyl, C_1-4 alkylamino, C_1-4 hydroxyalkoxy, carboxy, cyano, --CONR¹² R¹³ and --NR¹⁴ COR¹⁵,

wherein R¹², R¹³, R¹⁴ and R¹⁵, which may be the same or different, each represents hydrogen, C_1-4 alkyl or C_1-3 alkoxyC_2-3 alkyl;

2) C_1-5 alkylX¹, wherein X¹ is as defined hereinbefore;

3) C_2-5 alkenylX¹, wherein X¹ is as defined hereinbefore;

4) C_2-5 alkynylX¹, wherein X¹ is as defined hereinbefore;

5) C_1-5 alkylY² X¹, wherein Y² represents --O--, --S--, --SO--, --SO₂ --, --OCO--, --NR¹⁶ CO--, --CONR¹⁷ --, --SO₂ NR¹⁸ --, --NR¹⁹ SO₂ -- or --NR²⁰ --,

wherein R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ each independently represents hydrogen, C_1-3 alkyl or C_1-3 alkoxyC_2-3 alkyl, and X¹ is as defined hereinbefore;

6) C_2-5 alkenylY³ X¹, wherein Y³ represents --O--, --S--, --SO--, --SO₂ --, --OCO--, --NR²¹ CO--, --CONR²² --, --SO₂ NR²³ --, --NR²⁴ SO₂ -- or --NR²⁵ --,

wherein R²¹, R²², R²³, R²⁴, and R²⁵ each independently represents hydrogen, C_1-3 alkyl or C_1-3 alkoxyC_2-3 alkyl) and X¹ is as defined hereinbefore;

7) C_2-5 alkynylY⁴ X¹, wherein Y⁴ represents --O--, --S--, --SO--, --SO₂ --, --OCO--, --NR²⁶ CO--, --CONR²⁷ --, --SO₂ NR²⁸ --, --NR²⁹ SO₂ -- or --NR³⁰ --,

wherein R²⁶, R²⁷, R²⁸, R²⁹ and R³⁰ each independently represents hydrogen, C_1-3 alkyl or C_1-3 alkoxyC_2-3 alkyl, and X¹ is as defined hereinbefore; and

8) C_1-3 alkylY⁵ C_1-3 alkylX¹, wherein Y⁵ represents --O--, --S--, --SO--, --SO₂ --, --NR³¹ CO--, --CONR³² --, --SO₂ NR³³ --, --NR³⁴ SO₂ -- or --NR³⁵ --,

wherein R³¹, R³², R³³, R³⁴ and R³⁵ each independently represents hydrogen, C_1-3 alkyl or C_1-3 alkoxyC_2-3 alkyl, and X¹ is as defined hereinbefore; and

Z represents --O--, --S-- or --CH₂ --;

and salts thereof.

2. A quinazoline derivative as claimed in claim 1 wherein R¹ represents hydrogen, hydroxy, methyl, ethyl, methoxy or ethoxy.

3. A quinazoline derivative as claimed in claim 1 or claim 2 wherein R² is hydrogen.

4. A quinazoline derivative as claimed in claim 1 wherein the phenyl group bearing (R³)_m is of the formula:

##STR28## wherein;

R^a represents hydrogen, methyl, fluoro or chloro;

R^b represents hydrogen, methyl, methoxy, bromo, fluoro or chloro;

R^c represents hydrogen or hydroxy; and

R^d represents hydrogen, fluoro or chloro.

5. A quinazoline derivative as claimed in claim 1 wherein Y¹ represents --O--, --S--, --CH₂ --, --NR⁵ CO--, --NR⁸ SO₂ -- or --NH--, wherein R⁵ and R⁸ each independently represent hydrogen, C_1-2 alkyl or C_1-2 alkoxyethyl.

6. A quinazoline derivative as claimed in claim 1 wherein the moiety X¹ in the group R⁴ represents a pyridone group or a 5 or 6-membered aromatic heterocyclic group with 1 to 3 heteroatoms selected from O, N and S, which pyridone or heterocyclic group may carry up to 5 substituents.

7. A quinazoline derivative as claimed in claim 6 wherein the moiety X¹ represents a pyridone, pyridyl, imidazolyl, thiazolyl, thienyl, triazolyl or pyridazinyl group which may carry up to 5 substituents.

8. A quinazoline derivative as claimed in any one of claims 1, 6 and 7 wherein R⁴ represents the group X¹ --Y⁶ --(CH₂)_n -- in which Y⁶ is a direct bond --O--, --S-- or --NH--, and n is an integer from 1 to 3.

9. A quinazoline derivative as claimed in claim 1 in the form of a pharmaceutically acceptable salt.

10. A pharmaceutical composition which comprises as active ingredient a quinazoline derivative of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient or carrier.

11. A method for producing an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof as defined in claim 1.

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

7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylphenoxy)-6-methoxyquinazoline;

4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-((4-pyridyl)methoxy)quinazoline;

and salts thereof.

13. A quinazoline derivative of the formula Ia:

##STR29## wherein;

Y¹ represents --O--, --NH--, --S-- or --CH₂ --;

n is an integer from 0 to 5;

X¹ represents a phenyl group or a 5- or 6-membered aromatic heterocyclic group with 1 to 3 heteroatoms selected from O, N and S, which phenyl or heterocyclic group may carry up to 5 substituents selected from halogeno, C_1-4 alkyl, C_1-4 alkoxy, C_1-4 hydroxyalkyl, C_1-4 hydroxyalkoxy, carboxy, cyano, --CONR⁴¹ R⁴² and --NR⁴³ COR⁴⁴,

wherein R⁴¹, R⁴², R⁴³ and R⁴⁴, which may be the same or different, each represents hydrogen or C_1-4 alkyl;

R¹ represents hydrogen, hydroxy, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 alkylthio, or NR⁴⁵ R⁴⁶,

wherein R⁴⁵ and R⁴⁶, which may be the same or different, each represents hydrogen or C_1-3 alkyl;

R² represents hydrogen, hydroxy, halogeno, C_1-3 alkyl, C_1-3 alkoxy, trifluoromethyl, cyano, amino or nitro;

m is an integer from 1 to 5;

R³ represents hydroxy, halogeno, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 alkanoyloxy, trifluoromethyl, cyano, amino or nitro;

Z represents --O--; and

Y⁶ represents a direct bond;

and salts thereof.