Chemical compounds

• US 20030207878A1
• Filed: 01/30/2003
• Published: 11/06/2003
• Est. Priority Date: 08/09/2000
• Status: Abandoned Application

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Hennequin, Lawrent Francois Andre
• Application Number:
  US10/343,236
• Publication Number:
  US 20030207878A1
• Time in Patent Office: Days
• US Class Current: 514/228.2
• CPC Class Codes: A61K 31/502 ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
• CPC Class Codes: A61K 31/5025 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• 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 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 495/04 Ortho-condensed systems

Abstract

The invention relates to compounds of the formula (I): wherein: ring C is 9 or 10-membered bicyclic heteroaromatic group containing at least one nitrogen atom in the ring attached to Z and optionally containing a further 1-3 heteroatoms, selected independently from O, S, and N, with the proviso that ring C is not a quinazoline, quinoline or cinnoline group; 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 substituents R¹ may be attached at any free carbon atom of the indole, azaindole or indazole group; m is an integer from 0 to 2; R^b represents hydrogen or another value as defined herein; R¹ represents hydrogen, hydroxy, halogeno, C_1-4alkyl, or any other value as defined herein; R² represents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C_1-3alkyl, C_1-3alkoxy, C_1-3alkylsulphanyl, —NR³R⁴ (wherein R³ and R⁴, which may be the same or different, each represents hydrogen or C_1-3alkyl), or R⁵X¹— (wherein R⁵ and X¹ are as defined herein) and salts thereof, processes for the preparation of such compounds, pharmaceutical compositions

Claims

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

2. The use of a compound according to claim 1 wherein the optionally substituted indole moiety of formula II:

3. A compound of the formula Ib:

4. A compound according to claim 3 wherein ring C is selected from one of the following seven moieties:

5. A compound according to claim 3 or claim 4 wherein ring C is a thienopyrimidine ring or a phthalazine ring.

6. A compound according to any one of claims 3 to 5 wherein Zb is —

O—

or —

NH—

.

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

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

9. A compound according to any one of claims 3 to 8 wherein R² represents hydroxy, halogeno, nitro, trifluoromethyl, C_1-3alkyl, cyano, amino or R⁵—

X¹—

[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-(E-methylcarbamoyloxy)ethyl, 3-(N-methylcarbamoyloxy)propyl, 2-(carbamoyloxy)ethyl, 3-(carbamoyloxy)propyl, or 2-(N-methyl-N-(butoxycarbonyl)amino)ethyl;

3) C_2-3alkylR³R⁶ (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 R¹⁸ is as defined in claim 1);

6) C_1-3alkylR²⁹ (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—

)_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)) 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_2-3alkylX⁹C_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,N-di(C_1-4alkyl)aminosulphonyl;

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

19) C_2-3alkynylX⁹C_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_2-5alkyl group in R⁵X¹—

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

12. A process for the preparation of a compound of formula Ib or a salt thereof which comprises:

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

(wherein ring C, 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 and n are as defined in claim 1, G₁, G₂, G₃, G₄ and G₅ are all —

CH— and

Zb is as defined in claim 3);

(b) a compound of formula Ib 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 ring C, R^b, R¹, R² and n are as defined in claim 1, G, G₂, G₃, G₄ and G₅ are all —

CH—

, Zb is as defined in claim 3, X¹ is as herein defined in this section and s is 0 or

     1) 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 Ib or a salt thereof wherein at least one R¹ 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 ring C, R^b, R¹, R², R⁵ and n are all as defined in claim 1, G₁, G₂, G₃, G₄ and G₅ are all —

CH—

, Zb is as defined in claim 3, L¹ and s are as defined herein and X¹ is as herein defined in this section);

(d) a compound of formula Ib 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) X¹C_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 R⁶⁶ which may be the same or different are each hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl);

3) X¹¹C_1-5alkylX⁵R²² (wherein X 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 I;

(wherein ring C, X¹, R^b, R¹, R² and n are as defined in claim 1, G₁, G₂, G₃, G₄ and G₅ are all —

CH—

, Zb is as defined in claim 3 and L¹, and s are as defined herein) with a compound of the formula X;

R⁶²—

H 

 

(X)

(wherein R¹² is as defined herein);

(e) a compound of the formula Ib 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 the formula Ib 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 Ib is required, reaction of the compound obtained with an acid or base whereby to obtain the desired salt.

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

14. 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 as defined in claim 1 or a pharmaceutically acceptable salt thereof.

10. A compound selected from:

1-(4-fluoroindol-5-yloxy)-4-(4-pyridylmethyl)phthalazine,

1-(indol-6-yloxy)-4-(4-pyridylmethyl)phthalazine,

1-(2-methylindol-6-yloxy)-4-(4-pyridylmethyl)phthalazine,

4-(4-fluoro-2-methylindol-5-yloxy)thieno[3,2-d]pyrimidine and

1-(4-fluoro-2-methylindol-5-yloxy)-4-(4-pyridylmethyl)phthalazine, or a salt thereof.

11. A compound according to any one of claims 3 to 10 in the form of a pharmaceutically acceptable salt.