Quinoline derivatives inhibiting the effect of growth factors such as VEGF

US 6,809,097 B1
Filed: 03/09/1999
Issued: 10/26/2004
Est. Priority Date: 09/25/1996
Status: Expired due to Fees

First Claim

Patent Images

1. A compound of the formula Id:

wherein;

G^1crepresents phenyl or 1H-indazol-6-yl;

Y^4crepresents C—

H;

R^fcrepresents hydrogen or fluoro;

R^2crepresents hydroxy, halogeno, C_1-3alkyl, C_1-3alkoxy, C_1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro;

nc is an integer from 1 to 3;

R^1crepresents hydrogen, hydroxy, methoxy, amino, nitro or halogeno;

R^3crepresents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C_1-3alkyl, C_1-3alkoxy, C_1-3alkylthio, or —

NR^6cR^7c(wherein R^6cand R^7c, which may be the same or different, each represents hydrogen or C_1-3alkyl), and additionally R^3cmay have any of the values of R^5c—

X^1c—

(wherein R^5cand X^1care as defined below);

R^4crepresents cyano, —

NR^8cR^9c(wherein R^8cand R^9c, which may be the same or different, each represents C_1-3alkyl), or a group R^5c—

X^1crepresents —

OCO—

, —

S—

, —

SO—

, —

SO₂—

, —

CONR^11c, —

SO₂NR^12c—

or —

NR^14c—

(wherein R^11c, R^12cand R^14ceach independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl), and R^5cis selected from one of the following eight groups;

1) C_1-5alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy and amino;

2) C_1-5alkylX^2cCOR^15c(wherein X^2crepresents —

O—

or —

NR^16c—

(wherein R^16crepresents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R^15crepresents —

NR^17cR^18c—

or —

OR^19c—

(wherein R^17c, R^18cand R^19cwhich may be the same or different each represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl));

3) C_1-5alkylX^3cR^20c(wherein X^3crepresents —

O—

, —

S—

, —

SO—

, —

SO₂—

, —

OCO—

, —

NR^21cCO—

, —

CONR^22c, —

SO₂NR^23c—

, —

NR^24cSO²—

or —

NR^25c—

(wherein R^21c, R^22c, R^23c, R^24cand R^25ceach independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R^20crepresents hydrogen, C_1-3alkyl, cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which C_1-3alkyl group may bear one or two substituents selected from oxo, hydroxy, halogeno and C_1-4alkoxy and which cyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-4alkyl, C_1-4hydroxyalkyl and C_1-4alkoxy);

4) C_1-5alkylX^4cC_1-5alkylX^5cR^26c(wherein X^4cand X^5cwhich may be the same or different are each —

O—

, —

S—

, —

SO—

, —

SO₂—

, —

NR^27cCO—

, —

CONR^28c—

, —

SO₂NR^29c—

, —

NR^30cSO₂—

or —

NR^31c—

(wherein R^27c, R^28c, R^29c, R^30cand R^31ceach independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R^26crepresents hydrogen or C_1-3alkyl);

5) C_1-5alkylR^32c(wherein R^32cis a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-4alkyl, C_1-4hydroxyalkyl and C_1-4alkoxy);

6) (CH2)_qcX^6cR^33c(wherein qc is an integer from 0 to 5, X^6crepresents a direct bond, —

O—

, —

S—

, —

SO—

, —

NR^34cCO, CONR^35c, —

SO₂N^36c—

, —

NR^37cSO₂—

or —

NR^38c—

(wherein R^34c, R^35c, R^36c, R^37cand R^38ceach independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R^33cis a phenyl group, a pyridone group or a 5 or 6 membered aromatic heterocyclic group with 1 to 3 heteroatoms selected from O, N and S, which phenyl, pyridone or aromatic heterocyclic group may carry up to 5 substituents selected from hydroxy, halogeno, C_1-4alkyl, C_1-4alkoxy, C_1-4hydroxyalkyl, C_1-4hydroxyalkoxy, carboxy, cyano, —

CONR^39cR^40cand —

NR^41cCOR^42c(wherein R^39c, R^40c, R^41cand R^42c, which may be the same or different, each represents hydrogen or C_1-4alkyl));

7) C_2-6alkenylR^32c(wherein R^32cis as defined above); and

8) C_2-6alkynylR^32c(wherein R^32cis as defined above);

or a salt thereof.

View all claims

5 Assignments

Timeline View

Assignment View

0 Petitions

Accused Products

Abstract

Compounds of the formula (I): embedded image

wherein: R²represents hydroxy, halogeno, C_1-3alkyl, C_1-3alkoxy, C_1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro; n is an integer from 0 to 5; Z represents —O—, —NH—, —S— or —CH₂—; G¹represents phenyl or a 5-10 membered heteroaromatic cyclic or bicyclic group; Y¹, Y², Y³and Y⁴each independently represents carbon or nitrogen; R¹represents fluoro or hydrogen; m is an integer from 1 to 3; R³represents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C_1-3alkyl, —NR⁴R⁵(wherein R⁴and R⁵, can each be hydrogen or C_1-3alkyl), or a group R⁶—X¹— wherein X¹represents —CH₂— or a heteroatom linker group and R⁶is an alkyl, alkenyl or alkynyl chain optionally substituted by for example hydroxy, amino, nitro, alkyl, cycloalkyl, alkoxyalkyl, or an optionally substituted group selected from pyridone, phenyl and a heterocyclic ring, which alkyl, alkenyl or alkynyl chain may have a heteroatom linker group, or R⁶is an optionally substituted group selected from pyridone, phenyl and a heterocyclic ring and salts thereof, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals such as humans, processes for the preparation of such derivatives, pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof as active ingredient and compounds of formula I. 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.

79 Citations

View as Search Results

24 Claims

1. A compound of the formula Id:
- wherein;
  
  G^1crepresents phenyl or 1H-indazol-6-yl;
  
  Y^4crepresents C—
  
  H;
  
  R^fcrepresents hydrogen or fluoro;
  
  R^2crepresents hydroxy, halogeno, C_1-3alkyl, C_1-3alkoxy, C_1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro;
  
  nc is an integer from 1 to 3;
  
  R^1crepresents hydrogen, hydroxy, methoxy, amino, nitro or halogeno;
  
  R^3crepresents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C_1-3alkyl, C_1-3alkoxy, C_1-3alkylthio, or —
  
  NR^6cR^7c(wherein R^6cand R^7c, which may be the same or different, each represents hydrogen or C_1-3alkyl), and additionally R^3cmay have any of the values of R^5c—
  
  X^1c—
  
  (wherein R^5cand X^1care as defined below);
  
  R^4crepresents cyano, —
  
  NR^8cR^9c(wherein R^8cand R^9c, which may be the same or different, each represents C_1-3alkyl), or a group R^5c—
  
  X^1crepresents —
  
  OCO—
  
  , —
  
  S—
  
  , —
  
  SO—
  
  , —
  
  SO₂—
  
  , —
  
  CONR^11c, —
  
  SO₂NR^12c—
  
  or —
  
  NR^14c—
  
  (wherein R^11c, R^12cand R^14ceach independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl), and R^5cis selected from one of the following eight groups;
  
  1) C_1-5alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy and amino;
  
  2) C_1-5alkylX^2cCOR^15c(wherein X^2crepresents —
  
  O—
  
  or —
  
  NR^16c—
  
  (wherein R^16crepresents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R^15crepresents —
  
  NR^17cR^18c—
  
  or —
  
  OR^19c—
  
  (wherein R^17c, R^18cand R^19cwhich may be the same or different each represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl));
  
  3) C_1-5alkylX^3cR^20c(wherein X^3crepresents —
  
  O—
  
  , —
  
  S—
  
  , —
  
  SO—
  
  , —
  
  SO₂—
  
  , —
  
  OCO—
  
  , —
  
  NR^21cCO—
  
  , —
  
  CONR^22c, —
  
  SO₂NR^23c—
  
  , —
  
  NR^24cSO²—
  
  or —
  
  NR^25c—
  
  (wherein R^21c, R^22c, R^23c, R^24cand R^25ceach independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R^20crepresents hydrogen, C_1-3alkyl, cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which C_1-3alkyl group may bear one or two substituents selected from oxo, hydroxy, halogeno and C_1-4alkoxy and which cyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-4alkyl, C_1-4hydroxyalkyl and C_1-4alkoxy);
  
  4) C_1-5alkylX^4cC_1-5alkylX^5cR^26c(wherein X^4cand X^5cwhich may be the same or different are each —
  
  O—
  
  , —
  
  S—
  
  , —
  
  SO—
  
  , —
  
  SO₂—
  
  , —
  
  NR^27cCO—
  
  , —
  
  CONR^28c—
  
  , —
  
  SO₂NR^29c—
  
  , —
  
  NR^30cSO₂—
  
  or —
  
  NR^31c—
  
  (wherein R^27c, R^28c, R^29c, R^30cand R^31ceach independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R^26crepresents hydrogen or C_1-3alkyl);
  
  5) C_1-5alkylR^32c(wherein R^32cis a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-4alkyl, C_1-4hydroxyalkyl and C_1-4alkoxy);
  
  6) (CH2)_qcX^6cR^33c(wherein qc is an integer from 0 to 5, X^6crepresents a direct bond, —
  
  O—
  
  , —
  
  S—
  
  , —
  
  SO—
  
  , —
  
  NR^34cCO, CONR^35c, —
  
  SO₂N^36c—
  
  , —
  
  NR^37cSO₂—
  
  or —
  
  NR^38c—
  
  (wherein R^34c, R^35c, R^36c, R^37cand R^38ceach independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R^33cis a phenyl group, a pyridone group or a 5 or 6 membered aromatic heterocyclic group with 1 to 3 heteroatoms selected from O, N and S, which phenyl, pyridone or aromatic heterocyclic group may carry up to 5 substituents selected from hydroxy, halogeno, C_1-4alkyl, C_1-4alkoxy, C_1-4hydroxyalkyl, C_1-4hydroxyalkoxy, carboxy, cyano, —
  
  CONR^39cR^40cand —
  
  NR^41cCOR^42c(wherein R^39c, R^40c, R^41cand R^42c, which may be the same or different, each represents hydrogen or C_1-4alkyl));
  
  7) C_2-6alkenylR^32c(wherein R^32cis as defined above); and
  
  8) C_2-6alkynylR^32c(wherein R^32cis as defined above);
  
  or a salt thereof.
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 10, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22)
- - 2. The compound as claimed in claim 1 wherein R^3crepresents hydrogen, hydroxy, cyano, nitro, trifluoromethyl, methyl, ethyl, methoxy, ethoxy or methoxycarbonyl.
  - 3. The compound as claimed in claim 1 wherein R^4crepresents R^5c—
    - X^1c—
      
      (wherein X^1crepresents —
      
      S—
      
      ) and R^5cis selected from one of the following eight groups;
4. The compound as claimed in claim 3 wherein R^5cis methyl, ethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl, 2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-(piperazin-1-yl)ethyl, 3-(piperazin-1-yl)propyl, 2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl, (1,3-dioxolan-2-yl)methyl, 2-(1,3dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl, 2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl, 3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl, 2-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl, 2-(imidazol-1-yl)ethyl, 2-(1,2,3-triazol-1-yl)ethyl, 2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl, 2-(1,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl, 3-(4-pyridyl)propyl, benzyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl, 2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl, 3-(3-pyridyl)propyl, 2-(N-(1-methylimidazol-4-ylsulphonyl)-N-methyl)amino)ethyl, 2-((N-methyl-N-4-pyridyl)amino)ethyl, 2-(4-oxidomorpholino)ethyl, 3-(4-oxidomorpholino)propyl, 3-(4-oxo-1,4-dihydro-1-pyridyl)propyl, 3-(1,2,4-triazol-1-yl)propyl, 3-(1,2,4-triazol-4-yl)propyl, 3-(4-pyridyloxy)propyl, 3-(4-pyridylamino)propyl, 2-(2-methylimidazol-1-yl)ethyl, 3-(2-methylimidazol-1-yl)propyl, 2-(5-methyl-1,2,4-triazol-1-yl)ethyl, 3-(5-methyl-1,2,4-triazol-1-yl)propyl, 3-(imidazol-1-yl)propyl,3-(1,2,3-triazol-1-yl)propyl, 3-(1,2,3-triazol-2-yl)propyl, 2-thiomorpholinoethyl, 3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl, 3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl, 2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl, 3-(methylsulphinyl)propyl or 3-(methylsulphonyl)propyl.
5. The compound as claimed in claim 3 wherein R^5cis methyl, ethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl, 2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl, 2-sulphamoyiethyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-(piperazin-1-yl)ethyl, 3-(piperazin-1-yl)propyl, 2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl, (1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl, 2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl, 3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl, 2-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl, 2-(imidazol-1-yl)ethyl, 2-(1,2,3-triazol-1-yl)ethyl, 2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl, 2-(1,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl, 3-(4-pyridyl)propyl, benzyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl or 2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl.
6. A compound as claimed in claim 1 selected from:
- 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinoline;
  
  4-(4-chloro-2-fluoroanilino)-7-(3-(dimethylamino)propoxy)-6-methoxyquinoline;
  
  4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-([1,2,4]-triazol-1-yl)ethoxy)quinoline;
  
  4-(4-chloro-2-fluoroanilino)-7-(3-hydroxypropoxy)-6-methoxyquinoline;
  
  4-(4-chloro-2-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinoline;
  
  7-benzyloxy-4-(3-hydroxy-4-methylanilino)-6-methoxyquinoline; and
  
  4-(4-chloro-2-fluoroanilino)-7-methoxy-6-(N-[3-morpholinopropyl]carbamoyl)quinoline; and
  
  salts thereof.
7. A compound as claimed in claim 1 selected from:
- 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-methoxy-6-methoxycarbonylquinoline;
  
  6-cyano-4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-methoxyethoxy)quinoline;
  
  4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-methoxyethoxy)quinoline;
  
  4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(3-(3-pyridyl)propoxy)quinoline;
  
  4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-methylthiazol-4-ylmethoxy)-quinoline;
  
  4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(2-methoxyethoxy)quinoline;
  
  4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinoline;
  
  4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinoline;
  
  4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(2-methoxyethoxy)quinoline;
  
  6-cyano-4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(3-morpholinopropoxy)quinoline;
  
  4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(3-morpholinopropoxy)quinoline;
  
  4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(3-morpholinopropoxy)quinoline;
  
  4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(4-pyridylmethoxy)quinoline;
  
  4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-morpholinoethoxy)quinoline;
  
  6-cyano-4-(2-fluoro-5-hydroxy-4-methylanilino)-7-methoxyquinoline; and
  
  4-(4-chloro-2-fluoroanilino)-7-(2-hydroxyethoxy)-6-methoxyquinoline; and
  
  salts thereof.
8. A compound as claimed in claim 1 selected from:
- 6-cyano-4-(3-hydroxy-4-methylanilino)-7-(2-methoxyethoxy)quinoline;
  
  7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxyquinoline;
  
  7-benzyloxy-4-(4-bromo-2-fluoro-5-hydroxyanilino)-6-methoxyquinoline;
  
  4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(1-methylimidazol-2-ylmethoxy)-quinoline;
  
  4-(4-chloro-2-fluoroanilino)-6-cyano-7-(2-methoxyethoxy)quinoline;
  
  4-(4-chloro-2-fluoroanilino)-6-cyano-7-(3-morpholinopropoxy)quinoline;
  
  4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-methoxyethoxy)quinoline; and
  
  4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-morpholinopropoxy)quinoline; and
  
  salts thereof.
10. The compound as claimed in claim 9 wherein R^4crepresents R^5c—
- X^1c—
  
  (wherein X^1crepresents —
  
  O—
  
  , —
  
  S—
  
  ,—
  
  NR^10cCO—
  
  or —
  
  NR^13cSO₂—
  
  (wherein R^10cand R^13ceach independently represents hydrogen or C_1-2alkyl) and R^5cis selected from one of the following seven groups;
  
  1) C_2-3alkylX^2cCOR^15c(wherein X^2cis as defined in claim 1 and R^15crepresents —
  
  NR^17cR^8c—
  
  or —
  
  OR^19c—
  
  (wherein R^17c, R^18cand R^19cwhich may be the same or different each represents hydrogen, C_1-2alkyl or C_1-2alkoxyethyl));
  
  2) C_2-3alkylX^3cR^20c(wherein X^3cis as defined in claim 1 and R^20cis a group selected from C_1-3alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl which group is linked to X^3cthrough a carbon atom and which C_1-3alkyl group may bear one or two substituents selected from oxo, hydroxy, halogeno and C_1-2alkoxy and which cyclopentyl, cyclohexyl, pyrrolidinyl or piperidinyl group may carry one substituent selected from oxo, hydroxy, halogeno, C_1-2alkyl, C_1-2hydroxyalkyl and C_1-2alkoxy);
  
  3) C_2-3alkylX^4cC_2-3alkylX^5cR^26c(wherein X^4cand X^5care as defined in claim 1) and R^26crepresents hydrogen or C_1-2alkyl);
  
  4) C_1-4alkylR^43c(wherein R^43cis a group selected from pyrrolidinyl, piperazinyl, piperidinyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and 1,3-dithian-2-yl, which group is linked to C_1-4alkyl through a carbon atom and which group may carry one or two substituents selected from oxo, hydroxy, halogeno, C_1-2alkyl, C_1-2hydroxyalkyl and C_1-2alkoxy) or C_2-4alkylR^44c(wherein R^44cis a group selected from morpholino, thiomorpholino, pyrrolidin-1-yl, piperazin-1-yl and piperidino which group may carry one or two substituents selected from oxo, hydroxy, halogeno, C_1-2alkyl, C_1-2hydroxyalkyl and C_1-2alkoxy); and
  
  5) (CH₂)_qcX^6cR^33c(wherein X^6cis as defined in claim 1;
  
  qc is an integer from 1 to 3 if X^6cis a direct bond and qc is 2 or 3 if X^6cis other than a direct bond; and
  
  R^33cis a phenyl group, a pyridone group or a 5 or 6 membered aromatic heterocyclic group with 1 to 2 heteroatoms selected from O, N and S, which phenyl group, pyridone group or aromatic heterocyclic group may be substituted as defined in claim 1);
  
  6) C_4-5alkenylR^45c(wherein R^45crepresents R^43cor R^44cas defined above); and
  
  7) C_4-5alkynylR^45c(wherein R^45crepresents R^43cor R^44cas defined above).
13. A compound as claimed in claim 10 wherein R^5cis 2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl,2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-(piperazin-1-yl)ethyl, 3-(piperazine-1-yl)propyl, 2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl, (1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl, 2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl, 3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl, 2-acetamidothiazol-4ylmethyl, 1-methylimidazol-2-ylmethyl, 2-(imidazol-1-yl)ethyl, 2-(1,2,3-triazol-1-yl)ethyl, 2-(1,2,-3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl, 2-(1,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl, 3-(4-pyridyl)propyl, benzyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl, 2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl, 3-(3-pyridyl)propyl, 2-((N-(1-methylimidazol-4-ylsulphonyl)-N-methyl)amino)ethyl, 2-((N-methyl-N-4-pyridyl)amino)ethyl, 2-(4-oxidomorpholino)ethyl, 3-(4-oxidomorpholino)propyl, 3-(4-oxo-1,4-dihydro-1-pyridyl)propyl, 3-(1,2,4-triazol-1-yl)propyl, 3-(1,2,4-triazol-4-yl)propyl, 3-(4-pyridyloxy)propyl, 3-(4-pyridylamino)propyl, 2-(2-methylimidazol-1-yl)ethyl, 3-(2-methylimidazol-1-yl)propyl, 2-(5-methyl-1,2,4-triazol-1-yl)ethyl, 3-(5-methyl-1,2,4-triazol-1-yl)propyl, 3-(imidazol-1-yl)propyl, 3-(1,2,3-triazol-1-yl)propyl, 3-(1,2,3-triazol-2-yl)propyl, 2-thiomorpholinoethyl, 3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl, 3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl, 2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl, 3-(methylsulphinyl)propyl or 3-(methylsulphonyl)propyl.
14. A compound as claimed in claim 10 wherein R^5cis 2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl, 2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-(piperazin-1-yl)ethyl, 3-(piperazine-1-yl)propyl, 2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl, (1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl, 2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl, 3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl, 2-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl, 2-(imidazol-1-yl)ethyl, 2-(1,2,3-triazol-1-yl)ethyl, 2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl, 2-(1,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl, 3-(4-pyridyl)propyl, benzyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl or 2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl.
15. The compound as claimed in claim 1 or claim 9 wherein R^1cis hydrogen.
16. The compound as claimed in claim 1 or claim 9 wherein R^fcis hydrogen.
17. The compound as claimed in claim 1 or claim 9 wherein G^1cis phenyl.
18. The compound as claimed in claim 1 or claim 9 wherein the phenyl group bearing (R^2c)_ncis the 2-fluoro-5-hydroxy-4-methylphenyl group, the 4-chloro-2-fluoro-5-hydroxyphenyl group, the 4-chloro-2-fluorophenyl group, the 3-hydroxy-4-methylphenyl group, the 3-hydroxyphenyl group or the 4-bromo-2-fluoro-5-hydroxyphenyl group.
19. The compound as claimed in claim 1 or claim 9 wherein R^4crepresents cyano or a group R^5c—
- X^1c—
  
  , wherein R^5cand X^1care as defined in claim 1 or claim 9.
20. A compound as claimed in any one of claims 1, 3 to 8, 9, 10, and 2-13 in the form of a pharmaceutically acceptable salt.
21. A pharmaceutical composition which comprises as active ingredient a compound of formula I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1, 3 to 8, 9, 10 and 2-14 in association with a pharmaceutically acceptable excipient or carrier.
22. 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 claimed in any one of claims 1, 3 to 8, 9, 10 and 2-14.

9. A compound of the formula Id:
- wherein;
  
  G^1crepresents phenyl or 1H-indazol-6-yl;
  
  Y^4crepresents C—
  
  H;
  
  R^fcrepresents hydrogen or fluoro;
  
  R^2crepresents hydroxy, halogeno, C_1-3alkyl, C_1-3alkoxy, C_1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro;
  
  nc is an integer from 0 to 5;
  
  R^1crepresents hydrogen, hydroxy, methoxy, amino, nitro or halogeno;
  
  R^3crepresents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C_1-3alkyl, C_1-3alkoxy, C_1-3alkylthio, or —
  
  NR^6cR^7c(wherein R^6cand R^7c, which may be the same or different, each represents hydrogen or C_1-3alkyl), and additionally R^3cmay have any of the values of R^5c—
  
  X^1c—
  
  (wherein R^5cand X^1care as defined below);
  
  R^4crepresents cyano, —
  
  NR^8cR^9c(wherein R^8cand R^9c, which may be the same or different, each represents C_1-3alkyl), or a group R^5c—
  
  X^1c—
  
  wherein X^1crepresents —
  
  O—
  
  , —
  
  CH₂—
  
  , —
  
  OCO—
  
  , —
  
  S—
  
  , —
  
  SO—
  
  , —
  
  SO₂—
  
  , —
  
  NR^10cCO—
  
  , —
  
  CONR^11c—
  
  , —
  
  SO₂NR^12c—
  
  , —
  
  NR^13cSO₂—
  
  or —
  
  NR^14c—
  
  (wherein R^10c, R^11c, R^12c, R^13cand R^14ceach independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl), and R^5cis selected from one of the following seven groups;
  
  1) C_1-5alkylX^2cCOR^15c(wherein X^2crepresents —
  
  O—
  
  or —
  
  NR^16c—
  
  (wherein R^16crepresents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R^15crepresents —
  
  NR^17cR^18c—
  
  or —
  
  OR^19c—
  
  (wherein R^17c, R^18cand R^19cwhich may be the same or different each represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl));
  
  2) C_1-5alkylX^3cR^20c(wherein X^3crepresents —
  
  O—
  
  , —
  
  S—
  
  , —
  
  SO—
  
  , —
  
  SO₂—
  
  , —
  
  OCO—
  
  , —
  
  NR^21cCO—
  
  , —
  
  CONR^22c—
  
  , —
  
  SO₂NR^23c—
  
  , —
  
  NR^24cSO₂—
  
  or —
  
  NR^25c—
  
  (wherein R^21c, R^22c, R^23c, R^24cand R^25ceach independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R^20crepresents hydrogen, C_1-3alkyl, cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which C_1-3alkyl group may bear one or two substituents selected from oxo, hydroxy, halogeno and C_1-4alkoxy and which cyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-4alkyl, C_1-4hydroxyalkyl and C_1-4alkoxy);
  
  3) C_1-5alkylX^4cC_1-5alkylX^5cR^26c(wherein X^4cand X^5cwhich may be the same or different are each —
  
  O—
  
  , —
  
  S—
  
  , —
  
  SO—
  
  , —
  
  SO₂—
  
  , —
  
  NR^27cCO—
  
  , —
  
  CONR^28c—
  
  , —
  
  SO₂NR^29c—
  
  , —
  
  NR^30cSO₂—
  
  or —
  
  NR^31c—
  
  (wherein R^27c, R^28c, R^29c, R^30cand R^31ceach independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R^26crepresents hydrogen or C_1-3alkyl);
  
  4) C_1-5alkylR^32c(wherein R^32cis a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-4alkyl, C_1-4hydroxyalkyl and C_1-4alkoxy);
  
  5) (CH₂)_qcX^6cR^33c(wherein qc is an integer from 0 to 5, X^6crepresents a direct bond, —
  
  O—
  
  , —
  
  S—
  
  , —
  
  SO—
  
  , —
  
  SO₂—
  
  , NR^34cCO—
  
  , CONR³⁵C—
  
  , —
  
  SO₂NR^36c—
  
  , —
  
  NR^37cSO₂—
  
  or NR^38c—
  
  (wherein R^34c, R^35c, R^36c, R^37cand R^38ceach independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R^33cis 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 aromatic heterocyclic group may carry up to 5 substituents selected from hydroxy, halogeno, C_1-4alkyl, C_1-4alkoxy, C_1-4hydroxyalkyl, C_1-4hydroxyalkoxy, carboxy, cyano, —
  
  CONR^39cR^40cand —
  
  NR^41cCOR^42c(wherein R^39c, R^40c, R^41cand R^42c, which may be the same or different, each represents hydrogen or C_1-4alkyl));
  
  6) C_2-6alkenylR^32c(wherein R^32cis as defined above); and
  
  7) C_2-6alkynylR^32c(wherein R^32cis as defined above);
  
  or a salt thereof.
- View Dependent Claims (11)
- - 11. The compound as claimed in claim 9 wherein R^3crepresents hydrogen, hydroxy, cyano, nitro, trifluoromethyl, methyl, ethyl, methoxy, ethoxy, 3-morpholinopropoxy or 3-morpholinopropylcarbamoyl.

12. A compound of the formula Id:
- wherein;
  
  G^1crepresents phenyl or 1H-indazol-6-yl;
  
  Y^4crepresents C—
  
  H;
  
  R^fcrepresents hydrogen or fluoro;
  
  R^2crepresents hydroxy, halogeno, C_1-3alkyl, C_1-3alkoxy, C_1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro;
  
  nc is an integer from 1 to 3;
  
  R^1crepresents hydrogen, hydroxy, methoxy, amino, nitro or halogeno;
  
  R^3crepresents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C_1-3alkyl, C_1-3alkoxy, C_1-3alkylthio, or —
  
  NR^6cR^7c(wherein R^6cand R^7c, which may be the same or different, each represents hydrogen or C_1-3alkyl), and additionally R^3cmay have any of the values of R^5c—
  
  X^1c—
  
  (wherein R^5cand X^1care as defined below);
  
  R^4crepresents cyano, —
  
  NR^8cR^9c(wherein R^8cand R^9c, which may be the same or different, each represents C_1-3alkyl), or a group R^5c—
  
  X^1c—
  
  wherein X^1crepresents —
  
  OCO—
  
  , —
  
  S—
  
  , —
  
  SO—
  
  , —
  
  SO₂—
  
  , —
  
  NR^10cCO—
  
  , —
  
  CONR^11c—
  
  , —
  
  SO₂NR^12c—
  
  or —
  
  NR^14c—
  
  (wherein R^11c, R^12cand R^14ceach independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl, and R^10crepresents C_1-3alkyl or C_1-3alkoxyC_2-3alkyl), and R^5cis selected from one of the following eight groups;
  
  1) C_1-5alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy and amino;
  
  2) C_1-5alkylX^2cCOR^15c(wherein X^2crepresents —
  
  O—
  
  or —
  
  NR^16c—
  
  (wherein R^16crepresents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R^15crepresents —
  
  NR^17cR^18c—
  
  or —
  
  OR^19c—
  
  (wherein R^17c, R^18cand R^19cwhich may be the same or different each represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl));
  
  3) C_1-5alkylX^3cR^20c(wherein X^3crepresents —
  
  O—
  
  , —
  
  S—
  
  , —
  
  SO—
  
  , —
  
  SO₂—
  
  , —
  
  OCO—
  
  , —
  
  NR^21cCO—
  
  , —
  
  CONR^22c—
  
  , —
  
  SO₂NR^23c—
  
  , —
  
  NR^24cSO₂—
  
  or NR^25c—
  
  (wherein R^21c, R^22c, R^23c, R^24cand R^25ceach independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R^20crepresents hydrogen, C_1-3alkyl, cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which C_1-3alkyl group may bear one or two substituents selected from oxo, hydroxy, halogeno and C_1-4alkoxy and which cyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_{1 4}alkyl, C_1-4hydroxyalkyl and C_1-4alkoxy);
  
  4) C_1-5alkylX^4cC_1-5alkylX^5cR^26c(wherein X^4cand X^5cwhich may be the same or different are each —
  
  O—
  
  , —
  
  S—
  
  , —
  
  SO—
  
  , —
  
  SO₂—
  
  , —
  
  NR ^27cCO—
  
  , —
  
  CONR^28c—
  
  , —
  
  SO₂NR^29c—
  
  , —
  
  NR^30cSO₂—
  
  or —
  
  NR^31c—
  
  (wherein R^27c, R^28c, R^29c, R^30cand R^31ceach independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R^26crepresents hydrogen or C_1-3alkyl);
  
  5) C_1-5alkylR^32c(wherein R^32cis a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-4alkyl, C_1-4hydroxyalkyl and C_1-4alkoxy);
  
  6) (CH₂)_qcX^6cR^33c(wherein qc is an integer from 0 to 5, X^6crepresents a direct bond, —
  
  O—
  
  , —
  
  S—
  
  , —
  
  SO—
  
  , —
  
  NR^34cCO—
  
  , —
  
  CONR^35c—
  
  , —
  
  SO₂NR^36c—
  
  , —
  
  NR^37cSO₂—
  
  or —
  
  NR^38c—
  
  (wherein R^34c, R^35c, R^36c, R^37cand R^38ceach independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R^33cis a phenyl group, a pyridone group or a 5 or 6 membered aromatic heterocyclic group with 1 to 3 heteroatoms selected from O, N and S, which phenyl, pyridone or aromatic heterocyclic group may carry up to 5 substituents selected from hydroxy, halogeno, C_1-4alkyl, C_1-4alkoxy, C_1-4hydroxyalkyl, C_1-4hydroxyalkoxy, carboxy, cyano, —
  
  CONR^39cR^40cand —
  
  NR^41cCOR^42c(wherein R^39c, R^40c, R^41cand R^42c, which may be the same or different, each represents hydrogen or C_1-4alkyl));
  
  7) C_2-6alkenylR^32c(wherein R^32cis as defined above); and
  
  8) C_2-6alkynylR^32c(wherein R^32cis as defined above);
  
  or a salt thereof.

23. A process for the preparation of a compound of formula Id or salt thereof wherein:
- G^1crepresents phenyl or 1H-indazol-6-yl;
  
  Y^4crepresents C—
  
  H;
  
  R^fcrepresents hydrogen or fluoro;
  
  R^2crepresents hydroxy, halogeno, C_1-3alkyl, C_1-3alkoxy, C_1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro;
  
  nc is an integer from 1 to 3;
  
  R^1crepresents hydrogen, hydroxy, methoxy, amino, nitro or halogeno;
  
  R^3crepresents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C_1-3alkyl, C_-3alkoxy, C_1-3alkylthio, or —
  
  NR^6cR^7c(wherein R^6cand R^7c, which may be the same or different, each represents hydrogen or C_1-3alkyl), and additionally R^3cmay have any of the values of R^5c—
  
  X^1c—
  
  (wherein R^5cand X^1care as defined below);
  
  R^4crepresents cyano, —
  
  NR^8cR^9c(wherein R^8cand R^9c, which may be the same or different, each represents C_1-3alkyl), or a group R^5c—
  
  X^1c—
  
  wherein X^1crepresents —
  
  OCO—
  
  , —
  
  S—
  
  , —
  
  SO—
  
  , —
  
  SO₂—
  
  , —
  
  CONR^11c—
  
  , —
  
  SO₂NR^12c—
  
  or —
  
  NR^14c—
  
  (wherein R^11c, R^12cand R^14ceach independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl), and R^5cis selected from one of the following eight groups;
  
  1) C_1-5alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy and amino;
  
  2) C_1-5alkylX^2cCOR^15c(wherein X^2crepresents —
  
  O—
  
  or —
  
  NR^16c—
  
  (wherein R^16crepresents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R^15crepresents —
  
  NR^17cR^18c—
  
  or —
  
  OR^19c—
  
  (wherein R^17c, R^18cand R^19cwhich may be the same or different each represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl));
  
  3) C_1-5alkylX^3cR^20c(wherein X^3crepresents —
  
  O—
  
  , —
  
  S—
  
  , —
  
  SO—
  
  , —
  
  SO₂—
  
  , —
  
  OCO—
  
  , —
  
  NR^21cCO—
  
  , —
  
  CONR^22c—
  
  , —
  
  SO₂NR^23c—
  
  , —
  
  NR^24cSO₂—
  
  or —
  
  NR^25c—
  
  (wherein R^21c, R^22c, R^23c, R^24cand R^25ceach independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R^20crepresents hydrogen, C_1-3alkyl, cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which C_1-3alkyl group may bear one or two substituents selected from oxo, hydroxy, halogeno and C_1-4alkoxy and which cyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-4alkyl, C_1-4hydroxyalkyl and C_1-4alkoxy);
  
  4) C_1-5alkylX^4cC_1-5alkylX^5cR^26c(wherein X^4cand X^5cwhich may be the same or different are each —
  
  O—
  
  , —
  
  S—
  
  , —
  
  SO—
  
  , —
  
  SO₂—
  
  , —
  
  NR^27cCO—
  
  , —
  
  CONR^28c—
  
  , —
  
  SO₂NR^29c—
  
  , —
  
  NR^30cSO₂—
  
  or —
  
  NR^31c—
  
  (wherein R^27c, R^28c, R^29c, R^30cand R^31ceach independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R^26crepresents hydrogen or C_1-3alkyl);
  
  5) C_1-5alkylR^32c(wherein R^32cis a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-4alkyl, C_1-4hydroxyalkyl and C_1-4alkoxy);
  
  6) (CH₂)_qcX^6cR^33c(wherein qc is an integer from 0 to 5, X^6crepresents a direct bond, —
  
  O—
  
  , —
  
  S—
  
  , —
  
  SO—
  
  , —
  
  NR^34cCO—
  
  , —
  
  CONR^35c—
  
  , —
  
  SO₂NR^36c—
  
  , —
  
  NR^37cSO₂—
  
  or —
  
  NR^38c—
  
  (wherein R^34c, R^35c, R^36c, R^37cand R^38ceach independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R^33cis a phenyl group, a pyridone group or a 5 or 6 membered aromatic heterocyclic group with 1 to 3 heteroatoms selected from O, N and S, which phenyl, pyridone or aromatic heterocyclic group may carry up to 5 substituents selected from hydroxy, halogeno, C_1-4alkyl, C_1-4alkoxy, C_1-4hydroxyalkyl, C_1-4hydroxyalkoxy, carboxy, cyano, —
  
  CONR^39cR^40cand —
  
  NR^41cCOR^42c(wherein R^39c, R^40c, R^41cand R^42c, which may be the same or different, each represents hydrogen or C_1-4alkyl));
  
  7) C_2-6alkenylR^32c(wherein R^32cis as defined herein); and
  
  8) C_2-6alkynylR^32c(wherein R^32cis as defined herein);
  
  which process comprises;
  
  (a) the reaction of a compound of the formula III;
  
  (wherein R^1c, R^3c, R^4c, Y^4c, and R^fcare as defined above and L¹is a displaceable moiety), with a compound of the formula IV;
  
  (wherein G^1c, R^2cand nc are as defined above) whereby to obtain compounds of the formula Id and salts thereof;
  
  (b) where the group G^1c, as defined above, represents a phenyl group carrying one or more hydroxy groups, a compound of the formula Id and salts thereof can be prepared by the deprotection of a compound of formula V;
  
  (wherein nc, R^1c, R^2c, R^3c, R^4c, Y⁴, and R^fcare as defined above, P represents a phenolic hydroxy protecting group and p1 is an integer from 1 to 5 equal to the number of protected hydroxy groups and such that nc-p1 is equal to the number of R^2csubstituents which are not protected hydroxy);
  
  (c) compounds of formula Id and salts thereof wherein a substituent R^4cis R^5cX^1c— and
  
  wherein X^1cis —
  
  S—
  
  or —
  
  NR^14ccan be prepared by the reaction of a compound of the formula VI;
  
  (wherein nc, X^1c, Y^4c, G^1c, R^1c, R^2c, R^3c, and R^fcare as defined above) with a compound of formula VII;

24. A process for the preparation of a compound of formula Id or salt thereof wherein:
- G^1crepresents phenyl or 1H-indazol-6-yl;
  
  Y^4crepresents C—
  
  H;
  
  R^fcrepresents hydrogen or fluoro;
  
  R^2crepresents hydroxy, halogeno, C_1-3alkyl, C_1-3alkoxy, C_1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro;
  
  nc is an integer from 0 to 5;
  
  R^1crepresents hydrogen, hydroxy, methoxy, amino, nitro or halogeno;
  
  R^3crepresents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C_1-3alkyl, C_1-3alkoxy, C_1-3alkylthio, or —
  
  NR^6cR^7c(wherein R^6cand R^7c, which may be the same or different, each represents hydrogen or C_1-3alkyl), and additionally R^3cmay have any of the values of R^5c—
  
  X^1c—
  
  (wherein R^5cand X^1care as defined below);
  
  R^4crepresents cyano, —
  
  NR^8cR^9c(wherein R^8cand R^9c, which may be the same or different, each represents C_1-3alkyl), or a group R^5c—
  
  X^1c—
  
  wherein X^1crepresents —
  
  O—
  
  , —
  
  CH₂—
  
  , —
  
  OCO—
  
  , —
  
  S—
  
  , —
  
  SO—
  
  , —
  
  SO₂—
  
  , —
  
  NR^10cCO—
  
  , —
  
  CONR^12c—
  
  , —
  
  SO₂NR^12c—
  
  , —
  
  NR^13cSO₂—
  
  or —
  
  NR_4c—
  
  (wherein R^10c, R^11c, R^12c, R^13c, and R^14ceach independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl), and R^5cis selected from one of the following eight groups;
  
  1) C_1-5alkylX^2cCOR^15c(wherein X^2crepresents —
  
  O—
  
  or —
  
  NR^16c—
  
  (wherein R^16crepresents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R^15crepresents —
  
  NR^17cR^18c—
  
  or —
  
  OR^19c—
  
  (wherein R^17c, R^18cand R^19cwhich may be the same or different each represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl));
  
  2) C_1-5alkylX^3cR^20c(wherein X^3crepresents —
  
  O—
  
  , —
  
  S—
  
  , —
  
  SO—
  
  , —
  
  SO₂—
  
  , —
  
  OCO—
  
  , —
  
  NR^12cCO—
  
  , —
  
  CONR^22c—
  
  , —
  
  SO₂NR^23c, —
  
  NR^24cSO₂—
  
  or NR^25c—
  
  (wherein R^21c, R^22c, R^23c, R^24cand R^25ceach independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R^20crepresents hydrogen, C_1-3alkyl, cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which C_1-3alkyl group may bear one or two substituents selected from oxo, hydroxy, halogeno and C_1-4alkoxy and which cyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-4alkyl, C_1-4hydroxyalkyl and C_1-4alkoxy);
  
  3) C_1-5alkylX^4cC_1-5alkylX^5cR^26c(wherein X^4cand X^5cwhich may be the same or different are each —
  
  O—
  
  , —
  
  S—
  
  , —
  
  SO—
  
  , —
  
  SO₂—
  
  , —
  
  NR^27cCO—
  
  , —
  
  CONR^21c—
  
  , —
  
  SO₂NR^29c—
  
  , —
  
  NR^30cSO₂—
  
  or —
  
  NR^31c—
  
  (wherein R^27c, R^28c, R^29c, R^30cand R^31ceach independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R^26crepresents hydrogen or C_1-3alkyl);
  
  4) C_1-5alkylR^32c(wherein R^32cis a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-4alkyl, C_1-4hydroxyalkyl and C_1-4alkoxy);
  
  5) (CH₂)_qcX^6cR^33c(wherein qc is an integer from 0 to 5, X^6crepresents a direct bond, —
  
  O—
  
  , —
  
  S—
  
  , —
  
  SO—
  
  , —
  
  SO₂—
  
  , —
  
  NR^34cCO—
  
  , —
  
  CONR^35c—
  
  , —
  
  SO₂NR^36c—
  
  , —
  
  NR^37cSO₂—
  
  or —
  
  NR^38c—
  
  (wherein R^34c, R^35c, R^36c, R^37cand R^38ceach independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R^33cis 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 aromatic heterocyclic group may carry up to 5 substituents selected from hydroxy, halogeno, C_1-4alkyl, C_1-4alkoxy, C_1-4hydroxyalkyl, C_1-4hydroxyalkoxy, carboxy, cyano, —
  
  CONR^39cR^40cand —
  
  NR^41cCOR^42c(wherein R^39c, R^40c, R^41cand R^42c, which may be the same or different, each represents hydrogen or C_1-4alkyl));
  
  6) C_2-6alkenylR^32c(wherein R^32cis as defined herein); and
  
  7) C_2-6alkynylR^32c(wherein R^32cis as defined herein);
  
  which process comprises;
  
  (a) the reaction of a compound of the formula III;
  
  (wherein R^1c, R^3c, R^4c, Y^4c, and R^fcare as defined above and L¹is a displaceable moiety), with a compound of the formula IV;
  
  (wherein G^1c, R^2cand nc are as defined above) whereby to obtain compounds of the formula Id and salts thereof;
  
  (b) where the group G^1c, as defined above, represents a phenyl group carrying one or more hydroxy groups, a compound of the formula Id and salts thereof can be prepared by the deprotection of a compound of formula V;
  
  (wherein nc, R^1c, R^2c, R^3c, R^4c, Y⁴, and R^fcare as defined above, P represents a phenolic hydroxy protecting group and p1 is an integer from 1 to 5 equal to the number of protected hydroxy groups and such that nc-p1 is equal to the number of R^2csubstituents which are not protected hydroxy);
  
  (c) compounds of formula Id and salts thereof wherein a substituent R^4cis R^5c—
  
  X^1c— and
  
  wherein X^1cis —
  
  O—
  
  , —
  
  S—
  
  or —
  
  NR^14c—
  
  can be prepared by the reaction of a compound of the formula VI;
  
  (wherein nc, X^1c, Y^4c, G^1c, R^1c, R^2c, R^3c, and R^fcare as defined above) with a compound of formula VII;

Specification

Resources

Litigation Campaign Assessment

Current Assignee
Astrazeneca UK Limited (Astrazeneca PLC)
Original Assignee
Zeneca Incorporated (Astrazeneca PLC), Zeneca Pharma S.A.
Inventors
Hennequin, Laurent Francois Andre, Thomas, Andrew Peter, Ple, Patrick
Primary Examiner(s)
Shah, Mukund J.
Assistant Examiner(s)
Liu, Hong

Application Number

US09/254,440
Time in Patent Office

2,058 Days
Field of Search

546/152, 546/153, 546/160, 546/167, 546/171, 546/176, 546/178, 546/180, 544/128, 514/235.2, 514/311, 514/312, 514/313, 514/314
US Class Current

514/235.2
CPC Class Codes

A61P 43/00   Drugs for specific purposes...

A61P 9/00   Drugs for disorders of the ...

A61P 9/14   Vasoprotectives; Antihaemor...

C07D 215/233   only one oxygen atom which ...

C07D 215/44   with aryl radicals attached...

C07D 215/48   Carbon atoms having three b...

C07D 231/12   with only hydrogen atoms, h...

C07D 233/56   with only hydrogen atoms or...

C07D 249/08   1,2,4-Triazoles; Hydrogenat...

C07D 401/12   linked by a chain containin...

C07D 417/12   linked by a chain containin...

C07D 471/04   Ortho-condensed systems

Quinoline derivatives inhibiting the effect of growth factors such as VEGF

First Claim

5 Assignments

0 Petitions

Accused Products

Abstract

79 Citations

24 Claims

Specification

Solutions

Use Cases

Quick Links

Quinoline derivatives inhibiting the effect of growth factors such as VEGF

First Claim

5 Assignments

Subscription Required

Subscription Required

0 Petitions

Subscription Required

Accused Products

Subscription Required

Abstract

79 Citations

24 Claims

Specification

Subscription Required

Solutions

Use Cases

Quick Links