Quinazoline compounds

• US 20050085465A1
• Filed: 01/28/2003
• Published: 04/21/2005
• Est. Priority Date: 02/01/2002
• Status: Active Grant

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Hennequin, Laurent Francois Andre
• Granted Patent: US 7,268,230 B2
• Time in Patent Office: Days
• US Class Current: 514/227.800
• 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 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 35/02 specific for leukemia
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• 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: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/04 : Ortho-condensed systems

Abstract

The invention relates to compounds of the formula (I): wherein ring C is as defined herein, for example indolyl, indazolyl or azaindolyl; Z is —O—, —NH— or —S—; n is 0-5; m is 0-3; R¹ and R² are defined herein including groups: (i) Q¹X¹ wherein Q¹ and X¹ are as defined herein; (ii) Q¹⁵W³ wherein Q¹⁵ and W³ are as defined herein, (iii) Q²¹W⁴C_1-5alkylX¹- wherein Q²¹, W⁴ and X¹ are as defined herein, (iv) Q²⁸C_1-5alkylX¹-, Q²⁸C_2-5alkenylX¹- or Q²⁸C_2-5alkynylX¹- wherein Q²⁹ and X¹ are as defined herein and (v) Q²⁹C_1-5alkylX¹-, Q²⁹C_2-5alkenylX¹- or Q²⁹C^2-5alkynylX¹- wherein Q²⁹ and X¹ are as defined herein; R² can also be 6,7-methylenedioxy or 6,7-ethylenedioxy; and salts thereof; their use in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in warm?blooded animals; processes for the preparation of such compounds; intermediates used in such processes; processes for making such intermediates; pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof and methods of treating disease states involving angiogenesis by administering a compound of formula I or a pharmaceutically acceptable salt thereof. The compounds of formula I 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 compound of the formula I:

2. A compound according to claim 1 of the formula Ia:

3. A compound according to claim 2 wherein ma is 2.

4. A compound according to claim 1 or claim 2 wherein R² is selected from one of the five groups:

(i) Q¹X¹ wherein Q¹ and X¹ are as defined in claim 1;

(ii) Q¹⁵W³ wherein Q¹⁵ and W³ are as defined in claim 1;

(iii) Q²¹W⁴C_1-5alkylX¹- wherein Q²¹, W⁴ and X¹ are as defined in claim 1;

(iv) Q²⁸C_1-5alkylX¹-, Q²⁸C_2-5alkenylX¹- or Q²⁸C_2-5alkynylX¹- wherein Q²⁸ and X¹ are as defined in claim 1;

and

(v) Q²⁹C_1-5alkylX¹-, Q²⁹C_2-5alkenylX¹- or Q²⁹C_2-5alkynylX¹- wherein Q²⁹ and X¹ are as defined in claim 1;

and/or R² represents methoxy, or R² represents 6,7-methylenedioxy or 6,7-ethylenedioxy.

5. A compound according to claim 1 of the formula II:

6. A compound according to claim 5 wherein R^1a is fluoro or methyl.

7. A compound according to claim 5 or claim 6 wherein Z^a is —

O—

.

8. A compound according to any one of claims 5, 6 and 7 wherein R^2a is methoxy and R^2b is selected from one of the five following groups:

(i) Q¹X¹ wherein Q¹ and X¹ are as defined in claim 1;

(ii) Q¹⁵W³ wherein Q¹⁵ and W³ are as defined in claim 1;

(iii) Q²¹W⁴C_1-5alkylX¹- wherein Q²¹, W⁴ and X¹ are as defined in claim 1;

(iv) Q²⁸C_1-5alkyl, Q²⁸C_2-5alkenylX¹- or Q²⁸C_2-5alkynylX¹- wherein Q²⁸ and X¹ are as defined in claim 1;

and

(v) Q²⁹C_1-5alkylX¹-, Q²⁹C_2-5alkenylX¹- or Q²⁹C_2-5alkynylX¹- wherein Q²⁹ and X¹ are as defined in claim 1.

9. A compound according to any one of claims 5, 6 and 7 wherein R^2b is methoxy and R^2a is selected from one of the five following groups:

(i) Q¹X¹ wherein Q¹ and X¹ are as defined in claim 1;

(ii) Q¹⁵W³ wherein Q¹⁵ and W³ are as defined in claim 1;

(iii) Q²¹W⁴C_1-5alkylX¹- wherein Q²¹, W⁴ and X¹ are as defined in claim 1;

(iv) Q²⁸C_1-5alkylX¹-, Q²⁸C_2-5alkenylX¹- or Q²⁸C_2-5alkynylX¹- wherein Q²⁸ and X¹ are as defined in claim 1;

and

(v) Q²⁹C_1-5alkylX¹-, Q^29C_2-5alkenylX¹- or Q²⁹C_2-5alkynylX¹- wherein Q²⁹ and X¹ are as defined in claim 1.

10. A compound according to any one of claims 2 to 8 wherein the ring C^a is indol-5-yl, indol-6-yl, 7-azaindol-5-yl, indazol-5-yl or indazol-6-yl.

11. A compound according to claim 5 of the formula IId:

12. A compound according to claim 11 wherein one of R^2a and R^2b is methoxy and the other is Q¹X¹ wherein X¹ is —

O— and

Q¹ is selected from one of the following four groups;

1) Q² (wherein Q² is a heterocyclic group selected from pyrrolidinyl, piperidinyl, piperazinyl,

which heterocyclic group bears one substituent selected from C_2-5alkenyl, C_2-5alkynyl, C_1-4alkanoyl, aminoC_1-6alkanoyl, C_1-4alkylaminoC_1-6alkanoyl, di(C_1-4alkyl)aminoC_1-6alkanoyl, C_1-6fluoroalkanoyl, carbamoyl, C_1-4alkylcarbamoyl, di(C_1-4alkyl)carbamoyl, carbamoylC_1-6alkyl, C_1-4alkylcarbamoylC_1-6alkyl, di(C_1-4alkyl)carbamoylC_1-6alkyl, C_1-4alkylsulphonyl and C_1-4fluoroalkylsulphonyl;

2) C_1-5alkylQ² (wherein Q² is as defined herein);

3) C_1-4alkylW²C_1-4alkylQ² (wherein W² is as defined in claim 11 and Q² is as defined herein);

4) C_1-4alkylQ¹³(C_1-4alkyl)_j(W²)_kQ¹⁴ (wherein W² is as defined in claim 11, j is 0 or 1, k is 0 or 1, and Q¹³ and Q¹⁴ are each independently selected from pyrrolidinyl, piperidinyl, piperazinyl,

which heterocyclic group may bear 1, 2 or 3 substituents selected from C_2-5alkenyl, C_2-5alkynyl, C_1-4alkanoyl, aminoC_1-6alkanoyl, C_1-4alkylaminoC_1-4alkanoyl, di(C_1-4alkyl)aminoC₁alkanoyl, C_1-6fluoroalkanoyl, carbamoyl, C_1-4alkylcarbamoyl, di(C_1-4alkyl)carbamoyl, carbamoylC_1-6alkyl, C_1-4alkylcarbamoylC_1-6alkyl, di(C_1-4alkyl)carbamoylC_1-6alkyl, C_1-4alkylsulphonyl, C_1-4fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano, C_1-4cyanoalkyl, C_1-4alkyl, C_1-4hydroxyalkyl, C_1-4alkoxy, C_1-4alkoxyC_1-4alkyl;

with the proviso that at least one of Q¹³ and Q¹⁴ bears at least one substituent selected from C_2-5alkenyl, C_2-5alkynyl, C_1-4alkanoyl, aminoC_1-6alkanoyl, C_1-4alkylaminoC_1-6alkanoyl, di(C_1-4alkyl)aminoC_1-6alkanoyl, C_1-6fluoroalkanoyl, carbamoyl, C_1-4alkylcarbamoyl, di(C_1-4alkyl)carbamoyl, carbamoylC_1-6alkyl, C_1-6alkylcarbamoylC_1-6alkyl, di(C_1-4alkyl)carbamoylC_1-4alkyl, C_1-4alkylsulphonyl and C_1-4fluoroalkylsulphonyl);

and additionally wherein any C_1-5alkyl, group in Q¹X¹—

which is linked to X¹ may bear one or more substituents selected from hydroxy, halogeno and amino.

13. A compound according to claim 5 of the formula IIh:

14. A compound according to claim 1 selected from:

4-(7-azaindol-5-yloxy)-7-methoxy-6-(3-(4-methylsulphonylpiperazin-1-yl)propoxy)quinazoline,

6-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(7-azaindol-5-yloxy)-7-methoxyquinazoline,

4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-{[(2S)-1-isobutyrylpyrrolidin-2-yl]methoxy}-6-methoxyquinazoline,

4-(7-azaindol-5-yloxy)-6-methoxy-7-[3-(4-carbamoylpiperazin-1-yl)propoxy]quinazoline,

6-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-[(4-fluoro-1H-indol-5-yl)oxy]-7-methoxyquinazoline,

6-[(1-acetylpiperidin-4-yl)methoxy]-4-[(4-fluoro-1H-indol-5-yl)oxy]-7-methoxyquinazoline,

7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-(7-azaindol-5-yloxy)-6-methoxyquinazoline,

4-(7-azaindol-5-yloxy)-7-[3-(4-carbamoylmethyl)piperazin-1-yl)propoxy]-6-methoxyquinazoline,

4-(7-azaindol-5-yloxy)-7-{2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy)-6-methoxyquinazoline,

4-(7-azaindol-5-yloxy)-6-methoxy-7-[3-(4-prop-2-yn-1-ylpiperazin-1-yl)propoxy]quinazoline,

7-[1-(N,N-dimethylaminoacetyl)piperidin-4-ylmethoxy]-4-[(4-fluoro-2-methyl-1H-indol)-5-yloxy]-6-methoxyquinazoline,

and salts thereof.

15. A compound according to claim 1 selected frond

6-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-7-methoxyquinazoline,

7-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(7-azaindol-5-yloxy)-6-methoxyquinazoline,

4-(7-azaindol-5-yloxy)-6-methoxy-7-(3-(4-methylsulphonylpiperazin-1-yl)propoxy)quinazoline,

4-(7-azaindol-5-yloxy)-6-methoxy-7-[2-(N-methyl-N-prop-2-yn-1-ylamino)ethoxy]quinazoline,

4-(4-fluoro-2-methylindol-5-yloxy)-7-methoxy-6-(3-(4-methylsulphonylpiperazin-1-yl)propoxy)quinazoline,

4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(4-methylsulphonylpiperazin-1-yl)propoxy)quinazoline,

6-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(4-fluoroindol-5-yloxy)-7-methoxyquinazoline,

7-[(1-acetylpiperidin-4-yl)methoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline,

7-[(2S)-1-acetylpyrrolidin-2-ylmethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline,

7-[(2R)-1-acetylpyrrolidin-2-ylmethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline,

4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[1-(2,2,2-trifluoroethyl)piperidin-4-ylmethoxy]quinazoline,

4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxy-7-{3-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]propoxy}quinazoline,

4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-{3-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]ethoxy}quinazoline,

7-{2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy}-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline,

7-{2-[2-(4-acetylpiperazin-1-yl)ethoxy]ethoxy}-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline,

4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-[(1-isobutyrylpiperidin-4-yl)methoxy]-6-methoxyquinazoline,

4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-{[(2R)-1-isobutyrylpyrrolidin-2-yl]methoxy}-6-methoxyquinazoline,

4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-{[1-(methylsulfonyl)piperidin-4-yl]methoxy}quinazoline,

4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-{[(2S)-1-(methylsulfonyl)pyrrolidin-2-yl]methoxy}quinazoline,

4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-{[(2R)-1-(methylsulfonyl)pyrrolidin-2-yl]methoxy)quinazoline,

7-[3-(4-allylpiperazin-1-yl)propoxy]-4-(7-azaindol-5-yloxy)-6-methoxyquinazoline,

4-[(4-fluoro-2-methylindol-5-yl)oxy]-6-methoxy-7-{3-[4-(2-propynyl)piperazin-1-yl]propoxy}quinazoline,

7-{3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy}-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline,

7-[3-(4acetylpiperazin-1-yl)propoxy]-4-(H-indol-5-yloxy)-6-methoxyquinazoline

7-[(2S)-1-carbamoylpyrrolidin-2-ylmethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline,

7-(3-[4-carbamoylpiperazin-1-yl]propoxy}-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline,

7-(3-[2,5-dioxo-4-(1-hydroxy-1-methylethyl)imidazolidin-1-yl]propoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yloxy]-6-methoxyquinazoline,

6-[(1-acetylpiperidin-4-yl)oxy]-4-[(4-fluoro-1H-indol-5-yl)oxy]-7-methoxyquinazoline,

4-[(4-fluoro-1H-indol-5-yl)oxy]-7-methoxy-6-{[1-(methylsulphonyl)piperidin-4-yl]oxy}quinazoline,

4-[(4-fluoro-2-methyl-1H-idol-5-yl)oxy]-6-methoxy-7-(2-[N-methyl-N-(2-propynyl)amino]ethoxy}quinazoline,

7-[3-(4-acetylpiperazin-1-yl)propoxy]-6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]quinazoline,

7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-[(4-fluoro-1H-indol-5-yl)oxy]-6-methoxyquinazoline,

7-[3-(4-carbamoylmethylpiperazin-1-yl)propoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline,

7-(3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy)-6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]quinazoline,

4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-{(2R)-2-hydroxy-3-[4-prop-2-yn-1-ylpiperazin-1-yl]propoxy}-6-methoxyquinazoline,

7-{(2R)-3-[(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)]-2-hydroxypropoxy}-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline,

7-{(2R)-3-[4-acetylpiperazin-1-yl]-2-hydroxypropoxy}-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline,

and salts thereof.

16. A compound according to claim 1 which is 7-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline and salts thereof.

17. A compound according to claim 1 which is 7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline and salts thereof.

18. A compound according to claim 1, claim 2 or claim 5 in the form of a pharmaceutically acceptable salt.

19. A process for the preparation of a compound according to claim 1 of the formula I or salt thereof which comprises:

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

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

(wherein ring C, R¹, Z and n are as defined in claim 1);

(b) a compound of formula I and salts thereof wherein at least one R² is R⁵X¹, Q¹X¹, Q¹⁵W or Q²¹WC_1-5alkylX¹, wherein R⁵, Q¹, Q¹⁵, W³, Q²¹ and W⁴ are 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, Z. W³, R¹, R² and n are as defined in claim 1 and X¹ is as defined in this section and s is an integer from 0 to

     2) with one of the compounds of the formulae VIa-d;

R⁵-L¹ 

 

(VIa)
Q¹-L¹ 

 

(VIb)
Q⁵-L¹ 

 

(VIc)
Q²¹-W⁴—

C₅alkyl-L¹ 

 

(VId)

(wherein R⁵, Q¹, Q¹⁵, Q²¹ and W⁴ are as defined in claim 1 and L¹ is as defined herein);

(c) a compound of the formula I and salts thereof wherein at least one R² is R⁵X¹, Q¹X¹, Q¹⁵W³ or Q²W⁴C_1-5alkylX¹, wherein R⁵, Q¹, Q¹⁵, W³, Q²¹ and W⁴ are 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 one of the compounds of the formulae VIIIa-d;

R⁵—

X¹—

H 

 

(VIIIa)
Q¹-X¹—

H 

 

(VIIIb)
Q¹⁵-W³—

H 

 

(VIIIc)
Q²¹-W⁴—

C_1-5alkyl-X¹—

H 

 

(VIIId)

(wherein s and L¹ are as defined herein, R¹, R², R⁵, Q¹, Q¹⁵, W³, Q²¹, W⁴, ring C, Z and n are all as defined in claim 1 and X¹ is as defined in this section);

(d) a compound of the formula I and salts thereof wherein at least one R² is R⁵X¹, Q¹X¹, Q²¹W⁴C_1-5alkylX¹, Q²⁸C_1-5alkylX¹ or Q²⁹C_1-5alkylX¹ wherein X¹ is as defined in claim 1, R is C_1-5alkylR¹¹³, wherein R¹¹³ is selected from one of the following nine groups;

1) X¹⁹C_1-3alkyl (wherein X¹⁹ represents —

O—

, —

S—

, —

SO₂, —

NR¹¹⁴C(O)_or —

NR¹¹⁵SO₂—

(wherein R¹¹⁴ and R¹¹⁵ which may be the same or different are each hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl);

2) NR¹¹⁶R¹¹⁷ (wherein R¹¹⁶ and R¹¹⁷ which may be the same or different are each hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl);

3) X²⁰C_1-5alkylX⁵R²² (wherein X²⁰ represents —

O—

, —

S—

, —

SO₂—

, —

NR¹¹⁸C(O), —

NR¹¹⁹SO₂—

or —

NR¹²⁰—

(wherein R¹¹⁸, R¹¹⁹, and R¹²⁰ 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) X²¹R²⁹ (wherein X²¹ represents —

O—

, —

S—

, —

SO₂—

, —

NR¹²¹C(O)—

, —

NR¹²²SO₂—

, or —

NR¹²³—

(wherein R¹²¹, R¹²², and R¹²³ 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) X²²C_1-3alkylR²⁹ (wherein X²² represents —

O—

, —

S—

, —

SO₂—

, —

NR¹²⁴C(O)—

, —

NR¹²⁵SO₂—

or —

NR¹²⁶—

(wherein R¹²⁴, R¹²⁵ and R¹²⁶ 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) X_C_1-4alkylR²⁸ (wherein X²² 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);

Q¹ is C_1-5alkylQ²⁷ wherein Q²⁷ is selected from;

10) W¹Q² (wherein W¹ and Q² are as defined in claim 1);

11) Q² (wherein Q² is as defined in claim 1);

12) W²C_1-4alkylQ² (wherein W² and Q² are as defined in claim 1); and

13) Q¹³(C_1-4alkyl)_j(W²)_kQ⁴ (wherein W², j, k, Q¹³ and Q¹⁴ are as defined in claim 1);

14) Q¹³(C_1-4alkanoyl)Q¹⁴ⁿ (wherein Q¹³ and Q¹⁴ⁿ are as defined in claim

     1), and Q²¹, W⁴, Q²⁹ and Q²⁹ are as defined in claim 1,

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

(wherein L¹ and s are as defined herein, X¹, R¹, R², ring C, Z and n are as defined in claim

     1) with one of the compounds of the formulae Xa-e;

R¹¹³—

H 

 

(Xa)
Q²⁷-H 

 

(Xb)
Q²¹-W⁴—

H 

 

(Xc)
Q²⁸-H 

 

(Xd)
Q²⁹-H 

 

(Xe)

(wherein R¹¹³ and Q²⁷ are as defined herein and Q²¹, W⁴, Q²⁸ and Q²⁹ are as defined in claim 1);

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

NR¹²⁷R¹²⁸, where one (and the other is hydrogen) or both of R¹²⁷ and R¹²⁸ 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;

or

(f) a compound of the 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—

;

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.

20. A pharmaceutical composition which comprises as active ingredient a compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, claim 2 or claim 5 in association with a pharmaceutically acceptable excipient or carrier.

21. Use of a compound according to claim 1, claim 2 or claim 5 or a pharmaceutically acceptable salt 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.

22. A method for producing an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound according to claim 1, claim 2 or claim 5, or a pharmaceutically acceptable salt thereof.

23. The compound 7-benzyloxy-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline or a salt thereof.

24. The compound 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline or a salt thereof.

25. A process for the preparation of 5-bromo-7-azaindole comprising:

step 1;

the reduction of 7-azaindole to give 7-azaindoline;

followed by

step 2;

the bromination of 7-azaindoline to give 5-bromo-7-azaindoline;

followed by

step 3;

the oxidation of 5-bromo-7-azaindoline to give 5-bromo-7-azaindole.

26. A process for the production of 5-methoxy-7-azaindole comprising mixing a solution of the following materials in relative quantities according to the amounts given herein:

5-bromo-7-azaindole (8.6 g, 44 mmol), copper (I) bromide (12.6 g, 88 mmol) and sodium methoxide (100 g, 1.85 mol) in a mixture of “

degassed”

DMF (260 mls) and methanol (175 mls);

stirring the resulting mixture at ambient temperature in a nitrogen atmosphere; and

then heating the mixture at reflux.