Cinnoline derivatives and use as medicine

• US 6,514,971 B1
• Filed: 04/13/1999
• Issued: 02/04/2003
• Est. Priority Date: 03/15/1996
• Status: Expired due to Fees

• 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
• Primary Examiner(s): BERNHARDT, EMILY A
• Application Number:
  US09/142,839
• Time in Patent Office: 1,393 Days
• Field of Search: 544/235, 544/116, 544/119, 544/62, 514/248, 514/234.5, 514/228.2
• 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 a n integer from 1 to 5; R¹ represents hydrogen, hydroxy, halogeno, nitro, cyano, trifluoromethyl, Cp_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, auoro, chioro, 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 R⁵ is 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 anti angiogenic and/or vascular permeability reducing effect in a warmn-blooded animal such as a human being, processes for the preparation of such derivatives, pharmnaceutical compositions containing a compound of formula (I) or a pharmnaceutically 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 cinnoline derivative of the 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 is a group R⁵—

X¹, wherein;

X¹ represents —

O—

; and

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_1-5alkylR^25a (wherein R^25a is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to C_1-5alkyl through a carbon atom and which heterocyclic group may bear one or two substituents selected from halogeno, C_1-4alkyl, C_1-4hydroxyalkyl and C_1-4alkoxy) or C_2-5alkylR^26a (wherein R^26a is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms of which one is N and the other is selected independently from O, S and N, which heterocyclic group is linked to C_2-5alkyl through a nitrogen atom and which heterocyclic group may bear one or two substituents selected from halogeno, C_1-4alkyl, C_1-4hydroxyalkyl and C_1-4alkoxy);

wherein the 5 or 6 membered heterocyclic ring is selected from pyrrolidinyl, piperazinyl, piperidinyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl, 1,3-dithian-2-yl, morpholino and thiomorpholino; and

4) (CH₂)_naR^20a (wherein na is an integer from 0 to 4 and R^20a is 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 aromatic heterocyclic group may carry up to 5 substituents selected from halogeno, C_1-4alkyl, C_1-4alkoxy, C_1-4hydroxyalkyl, C_1-4hydroxyalkoxy, 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_1-4alkyl); and

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

with the proviso that;

where m is 1, R³ is meta-hydroxy;

the phenyl group bearing (R³)_m is not 3,4-dimethylphenyl; and

when the phenyl group bearing (R³)_m is 2,5-dichlorophenyl, 3,5-dichlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,6-dichlorophenyl, 2,6-dimethylphenyl, 2-bromo-4-chloropbenyl, 4-bromo-2-chlorophenyl, 2-bromo-4-methylphenyl, 2-chloro-4-methylphenyl, 2-chloro-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 3,5-dichloro-4-hydroxyphenyl, 2,5-dichloro-4-hydroxyphenyl or 5-chloro-2-methylphenyl, Z is —

NH—

;

and salts thereof.

2. A cinnoline derivative as claimed in claim 1 wherein R² is hydrogen.

3. A cinnoline derivative as claimed in claim 1 wherein Z is —

NH—

.

4. A cinnoline derivative as claimed in claim 1 wherein R¹ is methoxy.

5. A cinnoline derivative 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. A cinnoline derivative 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. A cinnoline derivative 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 pynidyl, 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. A cinnoline derivative 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. A cinnoline derivative as claimed in claim 1 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-morpholinopropoxy)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,

and salts thereof.

11. A cinnoline derivative as claimed in any one of the claims 1-10 in the form of a pharmaceutically acceptable salt.

12. A process for the preparation of a cinnoline derivative of formula I or salt thereof, as defined in claim 1, which comprises:

(a) the reaction of a compound of the formula III;

 

(wherein R¹, R² and R⁴ are as defined in claim 1 and L¹ is a displaceable moiety), with a compound of the formula IV;

 

(wherein Z, R³ and m are as defined in claim 1) whereby to obtain compounds of the formula I and salts thereof;

(b) for the preparation of compounds of formula I and salts thereof in which the group of formula IIa;

 

(wherein R³ and m are as defined in claim 1) represents a phenyl group carrying one or more hydroxy groups, the deprotection of a compound of formula V;

 

wherein R¹, R², R³, R⁴, Z and m are as defined in claim 1, 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 m-p¹ is equal to the number of R³ substituents which are not protected hydroxy;

(c) for the preparation of those compounds of formula I and salts thereof wherein the substituent R⁴ represents R⁵—

X¹ in which R⁵ is as defined in claim 1 and X¹ is —

O—

, the reaction of a compound of the formula VI;

 

wherein X¹ is as defined herein, and R¹, R², Z, R³ and m are as defined in claim 1 with a compound of formula VII;

13. A pharmaceutical composition which comprises as active ingredient a cinnoline derivative of formula I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-10 in association with a pharmaceutically acceptable excipient or carrier.

9. A compound of the formula Ib:

wherein

R^1b is hydrogen, C_1-3alkoxy, or halogeno;

R^2b is hydrogen;

X^1b is —

O—

;

R^4b is C_1-3alkyl, 2-(C_1-3alkoxy)ethyl, benzyl, 4-pyridyl(C_1-3alkyl), morpholino(C_1-3alkyl), pyrrolidino(C_1-3alkyl), 2-methylthiazol-4-yl(C_1-3alkyl), 1-methylimidazol-2-yl(C_1-3alkyl) and 2-((C_1-3alkoxy)(C_1-3alkoxy))ethyl;

Z^b is —

NH—

or —

O—

;

mb is 2 or 3; and

the phenyl group bearing (R^3b)_mb is selected from;

3-hydroxy-4-methylphenyl, 4-chloro-2-fluorophenyl, 4-bromo-2-fluorophenyl, 4-chloro-2-fluoro-5-hydroxyphenyl, 5-acetoxy-4-chloro-2-fluorophenyl, 2-fluoro-5-bydroxy-4-methylphenyl and 4-bromo-2-fluoro-5-hydroxyphenyl;

or a salt thereof.