Quinoline derivatives having vegf inhibiting activity

• US 20030199491A1
• Filed: 01/07/2003
• Published: 10/23/2003
• Est. Priority Date: 08/09/2000
• Status: Active Grant

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Hennequin, Laurent Francois Andre
• Granted Patent: US 7,371,765 B2
• Time in Patent Office: Days
• US Class Current: 514/210.21
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• 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: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings

Abstract

The invention relates to compounds of formula (I) wherein: either any one of G₁, G₂, G₃, G₄ and G₅ is nitrogen and the other four are —CH—, or G₁, G₂, G₃, G₄ and G₅ are all —CH—; Z is —O—, —NH—, —S—, —CH₂— or a direct bond; Z is linked to any one of G₁, G₂, G₃ and G₄; n is an integer from 0 to 5; m is an integer from 0 to 3; R^a represents hydrogen or fluoro; R^b, R¹ and R² are defined herein and salt thereof, process for the preparation so such compounds, pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof as active ingredient and the use of a compound of formula I in the manufacture of a medicament for the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blodded animals. 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 diseases states including cancer and rheumatoid arthritis.

Claims

1. The use of a compound of the formula I:

2. The use of a compound of the formula I according to claim 1 wherein Z is —

O—

;

—

NH—

or —

S—

.

3. A compound of the formula I as defined in claim 1 or claim 2 with the proviso that R² at the 7-position of the quinoline ring cannot have any value selected from hydrogen, methyl, methoxy and chloro;

or a salt thereof.

4. A compound according to claim 3 wherein the optionally substituted indole, azaindole or indazole moiety of formula II:

5. A compound according to claim 3 wherein G₁, G₂, G₃, G₄ and G₅ are all —

CH—

forming an indole moiety which may bear one or more substituents R¹ as defined in claim 1.

6. A compound according to any one of claims 3 to 5 wherein R^b is hydrogen.

7. A compound according to any one of claims 3 to 6 wherein R¹ represents methyl, ethyl, trifluoromethyl or halogeno.

8. A compound according to any one of claims 3 to 7 wherein R² represents hydroxy, halogeno, nitro, trifluoromethyl, C_1-3alkyl, cyano, amino or R⁵X¹—

[wherein X¹ is as defined in claim 1 and R⁵ is selected from one of the following twenty groups;

1) C_1-3alkyl which may be unsubstituted or which may be substituted with one or more groups selected from fluoro, chloro and bromo, or C_2-3alkyl which may be unsubstituted or substituted with one or more groups selected from hydroxy and amino;

2) 2-(3,3-dimethylureido)ethyl, 3-(3,3-dimethylureido)propyl, 2-(3-methylureido)ethyl, 3-(3-methylureido)propyl, 2-ureidoethyl, 3-ureidopropyl, 2-(N,N-dimethylcarbamoyloxy)ethyl, 3-(N,N-dimethylcarbamoyloxy)propyl, 2-(N-methylcarbamoyloxy)ethyl, 3-(N-methylcarbamoyloxy)propyl, 2-(carbamoyloxy)ethyl, 3-(carbamoyloxy)propyl, or 2-(N-methyl-N-(butoxycarbonyl)amino)ethyl;

3) C_2-3alkylX³R¹⁶ (wherein X³ is as defined in claim 1 and R¹⁶ is a group selected from C_1-3alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, imidazolidinyl and tetrahydropyranyl which group is linked to X³ through a carbon atom and which C_1-3alkyl group may bear 1 or 2 substituents selected from hydroxy, halogeno and C_1-2alkoxy and which cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, imidazolidinyl or tetrahydropyranyl group may bear one substituent selected from oxo, hydroxy, halogeno, cyano, C_1-2cyanoalkyl, C_1-2alkyl, C_1-2hydroxyalkyl, C_1-2alkoxy, C_1-2alkoxyC_1-3alkyl, C_1-2alkylsulphonylC_1-3alkyl, C_1-2alkoxycarbonyl, C_1-3alkylamino, di(C_1-3alkyl)amino, C_1-3alkylaminoC_1-3alkyl, di(C_1-3alkyl)aminoC_1-3alkyl, C_1-3alkylaminoC_1-3alkoxy, di(C_1-3alkyl)aminoC_1-3alkoxy and a group —

(—

O—

)_f(C_1-3alkyl)_gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl, morpholino and thiomorpholino));

4) C_2-3alkylX⁴C_2-3alkylX⁵R²² (wherein X⁴ and X⁵ are as defined in claim 1 and R²² represents hydrogen or C_1-2alkyl);

5) R²⁸ (wherein R²⁸ is as defined in claim 1);

6) C_1-3alkylR⁵⁹ (wherein R⁵⁹ is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, imidazolidinyl, 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_1-3alkyl through a carbon atom and which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-2cyanoalkyl, C_1-2alkyl, C_1-2hydroxyalkyl, C_1-2alkoxy, C_1-2alkanoyl, C_1-2alkoxyC_1-3alkyl, C_1-2alkylsulphonyl, C_1-2alkylsulphonylC_1-3alkyl, C_1-2alkoxycarbonyl, C_1-3alkylamino, di(C_1-3alkyl)amino, C_1-3alkylaminoC_1-3alkyl, di(C_1-3alkyl)aminoC_1-3alkyl, C_1-3alkylaminoC_1-3alkoxy, di(C_1-3alkyl)aminoC_1-3alkoxy and a group —

(—

O—

)_fC_1-3alkyl)_gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl, morpholino and thiomorpholino)) or C_2-3alkylR⁶⁰ (wherein R⁶⁰ is a group selected from morpholino, thiomorpholino, azetidin-1-yl, pyrrolidin-1-yl, piperazin-1-yl and piperidino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-2cyanoalkyl, C_1-2alkyl, C_1-2hydroxyalkyl, C_1-2alkoxy, C_1-2alkanoyl, C_1-2alkoxyC_1-3alkyl, C_1-2alkylsulphonyl, C_1-2alkylsulphonylC_1-3alkyl, C_1-2alkoxycarbonyl, C_1-3alkylamino, di(C_1-3alkyl)amino, C_1-3alkylaminoC_1-3alkyl, di(C_1-3alkyl)aminoC_1-3alkyl, C_1-3alkylaminoC_1-3alkoxy, di(C_1-3alkyl)aminoC_1-3alkoxy and a group —

(—

O—

)_f(C_1-3alkyl)_gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl, morpholino and thiomorpholino));

7) R²⁹ (wherein R²⁹ is as defined in claim 1);

8) C_1-4alkylR²⁹ (wherein R²⁹ is as defined in claim 1);

9) 1-R²⁹but-2-en-4-yl (wherein R²⁹ is as defined in claim 1);

10) 1-R²⁹but-2-yn-4-yl (wherein R²⁹ is as defined in claim 1);

11) C_1-3alkylX⁶R²⁹ (wherein X⁶ and R²⁹ are as defined in claim 1);

12) 1-(R²⁹X⁷)but-2-en-4-yl (wherein X⁷ and R²⁹ are as defined in claim 1);

13) 1-(R²⁹X⁸)but-2-yn-4-yl (wherein X⁸ and R²⁹ are as defined in claim 1);

14) C_2-3alkylX⁹C_1-3alkylR²⁹ (wherein X⁹ and R²⁹ are as defined in claim 1);

15) C_2-3alkyl⁹C_1-3alkylR²⁸ (wherein X⁹ and R²⁸ are as defined in claim 1);

16) C_2-5alkenyl which may be unsubstituted or which may be substituted with one or more fluorine atoms or with one or two groups selected from hydroxy, fluoro, amino, C_1-4alkylamino, N,N-di(C_1-4alkyl)amino, aminosulphonyl, N—

C_1-4alkylaminosulphonyl and N,N-di(C_1-4alkyl)aminosulphonyl;

17) C_2-5alkynyl which may be unsubstituted or which may be substituted with one or more fluorine atoms or with one or two groups selected from hydroxy, fluoro, amino, C_1-4alkylamino, N,N-di(C_1-4alkyl)amino, aminosulphonyl, N-C_1-4alkylaminosulphonyl and N,Ndi(C_1-4alkyl)aminosulphonyl;

18) C_2-3alkenylX⁹C_1-3alkylR²⁸ (wherein X⁹ and R²⁸ are as defined in claim 1);

19) C_2-3X⁹C_1-3alkylR²⁸ (wherein X⁹ and R²⁸ are as defined in claim 1); and

20) C_1-3alkylR⁵⁴(C_1-3alkyl)_q(X⁹)_rR⁵⁵ (wherein X⁹, q, r, R⁵⁴ and R⁵⁵ are as defined in claim 1);

and additionally wherein any C_1-5alkyl, C_2-5alkenyl or C_2-5alkynyl group in R⁵X¹—

may bear one or more substituents selected from hydroxy, halogeno and amino].

9. A compound according to any one of claims 3 to 7 wherein one of the R² substituents is R⁵X¹—

, wherein R⁵ and X¹ are as defined in claim 1, and the substituent R⁵X¹—

is at the 7-position of the quinoline ring.

10. A compound according to claim 8 wherein one of the R² substituents is R⁵X¹—

, wherein R⁵ and X¹ are as defined in claim 8, and the substituent R⁵X¹—

is at the 7-position of the quinoline ring.

11. A compound according to claim 9 or claim 10 wherein the R² substituent at the 6-position of the-quinoline ring is hydrogen, methoxy or cyano.

15. A compound according to any one of claims 3 to 14 in the form of a pharmaceutically acceptable salt.

16. A process for the preparation of a compound as claimed in claim 3 or a salt thereof which comprises:

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

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

(wherein R^b, R¹, G₁, G₂, G₃, G₄, G₅, Z and n are as defined in claim 1);

(b) a compound of formula I or a salt thereof wherein at least one R² is R⁵X¹ wherein R⁵ is as defined in claim 1 and X¹ is —

O—

, —

S—

, —

OC(O)—

or —

NR¹⁰—

(wherein R¹⁰ independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) may be prepared by the reaction of a compound of the formula V;

(wherein R^a, R^b, Z, G₁, G₂, G₃, G₄, G₅, R¹, R² and n are as defined in claim 1 and X¹ is as herein defined in this section and s is an integer from 0 to

     2) with a compound of formula VI;

R⁵—

L¹  

 

(VI)

(wherein R⁵ is as defined in claim 1 and L¹ is as defined herein);

(c) a compound of formula I or a salt thereof wherein at least one R² is R⁵X¹ wherein R⁵ is as defined in claim 1 and X¹ is —

O—

, —

S—

, —

OC(O)—

or —

NR¹⁰—

(wherein R¹⁰ represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) may be prepared by the reaction of a compound of the formula VII;

with a compound of the formula VIII;

R⁵—

X¹—

H  

 

(VIII)

(wherein R^a, R^b, R¹, R², R⁵, G₁, G₂, G₃, G₄, G₅, Z and n are all as in claim 1, L¹ and s are as defined herein and X¹ is as herein defined in this section);

(d) a compound of formula I or a salt thereof wherein at least one R² is R⁵X¹ wherein X¹ is as defined in claim 1 and R⁵ is C_1-5alkylR⁶², wherein R⁶² is selected from one of the following nine groups;

1) X¹⁰C_1-3alkyl (wherein X¹⁰ represents —

O—

, —

S—

, —

SO₂—

, —

NR⁶³C(O)—

or —

NR⁶⁴SO₂—

(wherein R⁶³ and R⁶⁴ which may be the same or different are each hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl);

2) NR⁶⁵R⁶⁶ (wherein R⁶⁵ and R⁶⁶which may be the same or different are each hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl);

3) X¹¹C_1-5alkylX⁵R²² (wherein X¹¹ represents —

O—

, —

S—

, —

SO₂—

, —

NR⁶⁷C(O)—

, —

NR⁶⁸SO₂—

or —

NR⁶⁹—

(wherein R⁶⁷, R⁶⁸, and R⁶⁹ which may be the same or different are each hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and X⁵ and R²² are as defined in claim 1);

4) R²⁸ (wherein R²⁸ is as defined in claim 1);

5) X¹²R²⁹ (wherein X¹² represents —

O—

, —

S—

, —

SO₂—

, —

NR⁷⁰C(O)—

, —

NR⁷¹SO₂—

, or —

NR⁷²—

(wherein R⁷⁰, R⁷¹, and R⁷² which may be the same or different are each hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R²⁹ is as defined in claim 1); and

6) X¹³C_1-3alkylR²⁹ (wherein X¹³ represents —

O—

, —

S—

, —

SO₂—

, —

NR⁷³C(O)—

, —

NR⁷⁴SO₂—

or —

NR⁷⁵—

(wherein R⁷³, R⁷⁴ and R⁷⁵ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R²⁹ is as defined in claim 1);

7) R²⁹ (wherein R²⁹ is as defined in claim 1);

8) X¹³C_1-4alkylR²⁸ (wherein X¹³ and R²⁸ are as defined in claim 1); and

9) R⁵⁴(C_1-4alkyl)_q(X⁹)_rR⁵⁵ (wherein q, r, X⁹, R⁵⁴ and R⁵⁵ are as defined in claim 1);

may be prepared by reacting a compound of the formula IX;

(wherein X^{1 l, Ra}, R^b, R¹, R², G₁, G₂, G₃, G₄, G₅, Z and n are as defined in claim 1 and L¹ and s are as defined herein) with a compound of the formula X;

R⁶²—

H  

 

(X)

(wherein R⁶² is as defined herein);

(e) a compound of formula I or a salt thereof wherein one or more of the substituents (R²)_m is represented by —

NR⁷⁶R⁷⁷, where one (and the other is hydrogen) or both of R⁷⁶ and R⁷⁷ are C_1-3alkyl, may be effected by the reaction of compounds of formula I wherein the substituent (R²)_m is an amino group and an alkylating agent;

(f) a compound of formula I or a salt thereof wherein X¹ is —

SO—

or —

SO₂—

may be prepared by oxidation from the corresponding compound in which X¹ is —

S—

or —

SO—

(when X¹ is —

SO₂—

is required in the final product);

and when a salt of a compound of formula I is required, reaction of the compound obtained with an acid or base whereby to obtain the desired salt.

17. A pharmaceutical composition which comprises a compound of the formula I as defined in claim 3 or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier.

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

12. A compound selected from:

6-cyano-7-(3-(1,1-dioxothiomorpholino)propoxy)-4-(indol-5-ylamino)quinoline,

6-cyano-4-(indol-5-ylamino)-7-(2-(1,2,3-triazol-1-yl)ethoxy)quinoline,

6-cyano-4-(2-methylindol-5-ylamino)-7-(2-(1,2,3-triazol-1-yl)ethoxy)quinoline,

6-cyano-4-(2-methylindol-5-yloxy)-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline,

6-cyano-7-(3-(1,1-dioxothiomorpholino)propoxy)-4-(indol-5-yloxy)quinoline,

6-cyano-4-(4-fluoro-2-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinoline,

6-cyano-4-(4-fluoro-2-methylindol-5-yloxy)-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline,

6-cyano-4-(2-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinoline,

6-cyano-4-(indol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinoline,

6-cyano-4-(2,3-dimethylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinoline,

6-cyano-4-(1,2-dimethylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinoline,

6-cyano-4-(2,3-dimethylindol-5-yloxy)-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline,

6-cyano-4-(1,2-dimethylindol-5-yloxy)-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline,

6-cyano-4-(4-fluoroindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinoline,

6-cyano-4-(6-fluoroindol-5-yloxy)-7-(3-(pyrrolidin-1yl)propoxy)quinoline,

6-cyano-4-(6-fluoroindol-5-yloxy)-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline,

6-cyano-4-(indol-5-yloxy)-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline,

6-cyano-4-(4-fluoro-2-methylindol-5-ylamino)-7-(3-(pyrrolidin-1-yl)propoxy)quinoline,

6-cyano-4-(2-methylindol-5-ylamino)-7-(3-(pyrrolidin-1-yl)propoxy)quinoline, and

6-cyano-4-(3-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinoline,

or a salt thereof.

13. A compound selected from:

6-cyano-4-(indol-5-ylamino)-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline or a salt thereof.

14. A compound selected from:

6-cyano-4-(2-methylindol-6-yloxy)-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline,

6-cyano-4-(2-methylindol-6-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinoline,

6-cyano-4-(2,3-dimethylindol-5-ylamino)-7-(2-( 1,2,3-triazol-1-yl)ethoxy)quinoline,

6-cyano-7-(3-(1,1-dioxothiomorpholino)propoxy-4-(2-methylindol-5-ylamino)quinoline,

6-cyano-4-(2,3-dimethylindol-5-ylamino)-7-(3-(1,1-dioxothiomorpholino)propoxy)quinoline,

6-cyano-4-(2,3-dimethylindol-5-yloxy)-7-(3-(1,1-dioxothiomorpholino)propoxy)quinoline,

6-cyano-7-(3-(1,1-dioxothiomorpholino)propoxy)-4-(2-methylindol-5-yloxy)quinoline,

6-cyano-4-(4-fluoro-2-methylindol-5-yloxy)-7(2-methoxyethoxy)quinoline,

6-cyano-4-(4-fluoro-2-methylindol-5-yloxy)-7-(2-(1,2,3-triazol-1-yl)ethoxy)quinoline,

6-cyano-4-(4-fluoro-2-methylindol-5-yloxy)-7-(3-(1,2,3-triazol-1-yl)propoxy)quinoline, and

6-cyano-4-(4-fluoro-2-methylindol-5-yloxy)-7-(3-(1,1-dioxothiomorpholino)propoxy)quinoline,

or a salt thereof.