Cinnoline derivatives and use as medicine

• US 7,087,602 B2
• Filed: 12/05/2002
• Issued: 08/08/2006
• Est. Priority Date: 03/15/1996
• Status: Expired due to Fees

• Current Assignee: Astrazeneca UK Limited (Astrazeneca PLC)
• Original Assignee: Astrazeneca UK Limited (Astrazeneca PLC)
• Inventors: Hennequin, Laurent Francois Andre, Thomas, Andrew Peter
• Primary Examiner(s): PRYOR, ALTON NATHANIEL
• Application Number:
  US10/310,074
• Publication Number:
  US 20030199513A1
• Time in Patent Office: 1,342 Days
• Field of Search: 514/234.5, 514/248, 514/228.2, 544/11, 544/119, 544/62, 544/235
• US Class Current: 514/234.5
• CPC Class Codes: A61K 31/502 ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 237/28 Cinnolines
• 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 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 the use of cinnoline derivatives of formula (I)

wherein Z represents —O—, —NH—, —S— or —CH₂—; m is an integer from 1 to 5; R¹ represents hydrogen, hydroxy, halogeno, nitro, cyano, trifluoromethyl, C_1-3alkyl, C_1-3alkoxy, C_1-3alkylthio or NR⁶R⁷ (wherein R⁶ and R⁷, which may be the same or different, each represents hydrogen or C_1-3alkyl); R² represents hydrogen, hydroxy, fluoro, chloro, methoxy, amino or nitro; R³ represents hydroxy, halogeno, C_1-3alkyl, C_1-3alkoxy, C_1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro; R⁴ represents hydrogen, hydroxy, halogeno, cyano, nitro, amino, trifluoromethyl, C_1-3alkyl or a group R⁵—X¹ (wherein X¹ represents —O—, —CH₂—, —S—, —SO—, —SO₂—, —NR⁸CO—, —CONR⁹⁻, —SO₂NR¹⁰—, —NR¹¹SO₂— or —NR¹²— (wherein R⁸, R⁹, R¹⁰, R¹¹ and R¹² each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxy C_2-3alkyl) and R⁵is an optionally substituted alkyl, carbocylic or heterocylic group which may be saturated or unsaturated and may be directly linked to the cinnoline ring or be linked via a carbon chain which may have heteroatom linking groups within it and salts thereof, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human being, 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.

Claims

1. 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 a vascular endothelial growth factor inhibiting effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof:

2. The method as claimed in claim 1 wherein R² is hydrogen.

3. The method as claimed in claim 1 wherein Z is —

NH—

.

4. The method as claimed in claim 1 wherein R¹ is methoxy.

5. The method as claimed in claim 1 wherein the phenyl group bearing (R³)_m is a 2-fluoro-5-hydroxy-4-methylphenyl, 4-chloro-2-fluoro-5-hydroxyphenyl, 4-chloro-3-hydroxyphenyl, 4-bromo-3-hydroxyphenyl, 3-hydroxy-4-methylphenyl, or a 4-bromo-2-fluoro-5-hydroxyphenyl group.

6. The method as claimed in claim 1 wherein R⁵ is selected from one of the following four groups:

1) C_2-4alkylX^3aR^14a (wherein X^3a represents —

O— and

R^14a represents C_1-3alkyl);

2) C_2-3alkylX^4aC_2-3alkylX^5aR^15a (wherein X^4a and X^5a are each —

O— and

R^15a represents hydrogen or C_1-3alkyl);

3) C_1-4alkylR^25a (wherein R^25a is selected from pyrrolidinyl, piperazinyl, piperidyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and 1,3-dithian-2-yl, such that R^25a is linked to C_1-4alkyl through a carbon atom) or C_2-4alkylR^26a (wherein R^26a is selected from morpholino, pyrrolidin-1-yl, piperazin-1-yl and piperidino); and

4) (CH₂)_naR^20a (wherein na is an integer from 1 to 3 and R^20a is a 5 or 6 membered aromatic heterocyclic group with 1 to 2 heteroatoms selected from O, N and S, which aromatic heterocyclic group may be substituted as hereinbefore defined,

wherein the 5 or 6 membered aromatic heterocyclic group is selected from pyridyl, imidazolyl, thiazolyl, thienyl, pyridazinyl and triazolyl.

7. The method as claimed in claim 1 wherein R⁵ is selected from one of the following four groups:

1) C_2-3alkylX^3aR^14a (wherein X^3a represents —

O— and

R^14a represents C_1-2alkyl);

2) C_2-3alkylX^4aC_2-3alkylX^5aR^15a (wherein X^4a and X^5a are each —

O— and

R^15a represents hydrogen or C_1-2alkyl);

3) C_1-2alkylR^25a (wherein R^25a is selected from pyrrolidinyl, piperazinyl, piperidyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and 1,3-dithian-2-yl, such that R^25a is linked to C_1-2alkyl through a carbon atom) or C_2-3alkylR^26a (wherein R^26a is selected from morpholino, piperidino, piperazin-1-yl and pyrrolidin-1-yl); and

4) (CH₂)_naR^20a (wherein na is an integer from 1 to 3 and R^20a is selected from pyridyl, imidazolyl, thiazolyl, thienyl and pyridazinyl, and R^20a may be substituted with one substituent selected from halogeno, C_1-2alkyl, C_1-2alkoxy, C_1-2hydroxyalkyl, C_1-2hydroxyalkoxy, carboxy, cyano, CONR^21aR^22a and NR^23aCOR^24a (wherein R^21a, R^22a, R^23a and R^24a, which may be the same or different, each represents hydrogen or C_1-2alkyl).

8. The method as claimed in claim 1 wherein R⁴ is a group R⁵—

X¹, wherein;

X¹ is —

O—

; and

R⁵ is 2-methoxyethyl, 3-methoxypropyl, 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, 2-(1,3-dioxolan-2-yl)methyl, 3-(1,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl, 2-methylthiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl or 3-(4-pyridyl)propyl.

10. The method as claimed in claim 1 wherein the compound of formula I is selected from:

4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-methoxyethoxy)cinnoline,

4-(4-bromo-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-methoxyethoxy)cinnoline,

4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(2-methoxyethoxy)cinnoline,

4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(3-morphohnopropoxy)cinnoline,

4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-[(2-methylthiazol-4-yl)methoxy]cinnoline,

4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(3-pyrrolidinopropoxy)cinnoline,

or a pharmaceutically acceptable salt thereof.

9. 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 a vascular endothelial growth factor inhibiting effective amount of a compound of formula Ib, or a pharmaceutically acceptable salt thereof: