IP Library › Granted Patent US 7,741,333

Granted Patent B2

US 7,741,333 · App. 11/766,232 · Granted Jun 22, 2010

Quinazoline derivatives, their preparation, their use, and medicaments comprising them

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Quick Facts

Patent No.: US 7,741,333
App. No.: 11/766,232
Granted: Jun 22, 2010
Kind: B2

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Abstract

The present invention relates to a quinazoline derivative having the general formula (A): in which R 1 , R 2 , X, Y and Z are indicated in the description and the claims, the use of the compounds of the general formula (A) for the treatment of various disorders, and the preparation of compounds of the general formula (A).

Claims (88)

1. A quinazoline compound according to formula (A):

where

R 1 and R 2 are identical or different and are each independently selected from hydrogen, hydroxy, halogen, nitro, cyano, —C 1 -C 6 -alkyl, —C 1 -C 4 -hydroxyalkyl, —C 2 -C 6 -alkenyl, —C 2 -C 6 -alkynyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 12 -heterocycloalkyl, —C 6 -C 12 -aryl, —C 5 -C 18 -heteroaryl, —C 1 -C 6 -alkoxy, —C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy, —C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —(CH 2 ) n —C 6 -C 12 -aryl, —(CH 2 ) n —C 5 -C 18 -heteroaryl, —(CH 2 ) n —C 3 -C 10 -cycloalkyl, —(CH 2 ) n —C 3 -C 12 -heterocycloalkyl, -phenylene-(CH 2 ) p —R 6 , —(CH 2 ) p PO 3 (R 6 ) 2 , —(CH 2 ) p —NR 5 R 6 , —(CH 2 ) p —NR 4 COR 5 , —(CH 2 ) p —NR 4 CSR 5 , —(CH 2 ) p —NR 4 S(O)R 5 , —(CH 2 ) p —NR 4 S(O) 2 R 5 , —(CH 2 ) p —NR 4 CONR 5 R 6 , —(CH 2 ) p —NR 4 COOR 5 , —(CH 2 ) p —NR 4 C(NH)NR 5 R 6 , —(CH 2 ) p —NR 4 CSNR 5 R 6 , —(CH 2 ) p —NR 4 S(O)NR 5 R 6 , —(CH 2 ) p —NR 4 S(O) 2 NR 5 R 6 , —(CH 2 ) p —COR 5 , —(CH 2 ) p —CSR 5 , —(CH 2 ) p —S(O)R 5 , —(CH 2 ) p —S(O)(NH)R 5 , —(CH 2 ) p —S(O) 2 R 5 , —(CH 2 ) p —S(O) 2 NR 5 R 6 , —(CH 2 ) p —SO 2 OR 5 , —(CH 2 ) p —CO 2 R 5 , —(CH 2 ) p —CONR 5 R 6 , —(CH 2 ) p —CSNR 5 R 6 , —OR 5 , —CHR 5 R 6 , —(CH 2 ) p —SR 5 and —CR 5 (OH)—R 6 ,

where —C 1 -C 6 -alkyl, —C 2 -C 6 -alkenyl, —C 2 -C 6 -alkynyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 12 -heterocycloalkyl, —C 6 -C 12 -aryl, —C 5 -C 18 -heteroaryl, and —C 1 -C 6 -alkoxy are each unsubstituted or are substituted one or more times independently of one another by hydroxy, halogen, nitro, cyano, —NR 5 R 6 , —C(O)NR 5 R 6 , —S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —NR 5 C(O)R 6 , —SR 5 , —R 5 , or —OR 5 ,

where the carbon framework of the —C 3 -C 10 -cycloalkyl and of the —C 1 -C 10 -alkyl optionally contain one or more times independently of one another nitrogen, oxygen, sulphur atoms, —NR 4 or C═O groups, or one or more double bonds, or

R 1 and R 2 are optionally together a bridge of 3-10 methylene units forming a ring structure with the N atom to which they are attached, where up to two methylene units are each optionally replaced by O, S or —NR 4 ;

X, Y, Z are identical or different and are each independently selected —CR 3 ═, CR 3 R 4 —, —C(O)—, —N═, —S—, —O—, —NR 3 —, —S(O) 2 —, —S(O)— and —S(O)(N═R 3 )—, and single or double bonds are present between X, Y and Z, but a maximum of one of X, Y and Z is identical with —O—, and at most one of X, Y and Z is identical with —N═ or —NR 3 —, or else a maximum of two of X, Y and Z are identical with —CR 3 ═ or —CR 3 R 4 —, and wherein —X—Y—Z— is not —NH—CH═CH— or —CH═CH—NH—;

R 3 and R 4 are each independently selected from hydrogen, —C 1 -C 10 -alkyl, —C 2 -C 6 -alkenyl, —C 2 -C 6 -alkynyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 12 -heterocycloalkyl, and —C 1 -C 10 -alkanoyl, where —C 1 -C 10 -alkyl, —C 2 -C 6 -alkenyl, —C 2 -C 6 -alkynyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 12 -heterocycloalkyl, and —C 1 -C 10 -alkanoyl are each unsubstituted or substituted one or more times independently of one another by hydroxy, halogen, nitro, cyano, phenyl, —NR 5 R 6 , alkyl, —SR 5 or —OR 5 ;

R 5 and R 6 are identical or different and are each independently selected from hydrogen, —C 1 -C 10 -alkyl, —C 2 -C 10 -alkenyl, —C 2 -C 10 -alkynyl, —C 1 -C 6 -alkoxy, —C 3 -C 10 -cycloalkyl, —C 3 -C 12 -heterocycloalkyl, —C 6 -C 12 -aryl, and —C 5 -C 18 -heteroaryl,

where —C 1 -C 10 -alkyl, —C 2 -C 10 -alkenyl, —C 2 -C 10 -alkynyl, —C 1 -C 6 -alkoxy, —C 3 -C 10 -cycloalkyl, —C 3 -C 12 -heterocycloalkyl, —C 6 -C 12 -aryl, and —C 5 -C 18 -heteroaryl are each unsubstituted or are substituted one or more times independently of one another by hydroxy, halogen, cyano, nitro, —OR 7 , —NR 7 R 8 , —C(O)NR 7 R 8 , —C(O)OR 7 or —C 1 -C 6 -alkyl, where —C 1 -C 6 -alkyl is unsubstituted or is substituted one or more times independently of one another by halogen, hydroxy, cyano, —NR 7 R 8 , —OR 7 or phenyl, or

R 5 and R 6 are optionally together a bridge of 3-10 methylene units forming a ring structure with the N atom to which they are attached, where up to two methylene units are each optionally replaced by O, S or NR 4 ;

R 7 , R 8 are identical or different and are each independently selected from hydrogen, —C 1 -C 4 -alkyl, —C 6 -C 12 -aryl, and —C 5 -C 18 -heteroaryl,

where alkyl, aryl, and heteroaryl are each unsubstituted or substituted one or more times independently of one another by halogen or alkoxy, or

R 7 and R 8 are optionally together a bridge of 3-10 methylene units forming a ring structure with the N atom to which they are attached, where up to two methylene units are each optionally replaced by O, S or —NR 4 ;

m′, m″ are each independently of one another 0, 1, 2, 3, or 4;

n is 1, 2, 3, 4, 5, or 6;

p is 0, 1, 2, 3, 4, 5, or 6; or

an N-oxide, stereoisomer, diastereomer, enantiomer, or salt thereof.

2. A quinazoline compound according to claim 1 , where:

R 1 and R 2 are identical or different and are each independently selected from hydrogen, —C 1 -C 6 -alkyl, —C 1 -C 4 -hydroxyalkyl, —C 2 -C 6 -alkenyl, —C 2 -C 6 -alkynyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 12 -heterocycloalkyl, —C 6 -C 12 -aryl, —C 5 -C 18 -heteroaryl, —C 1 -C 6 -alkoxy, —C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy, —C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —(CH 2 ) n —C 6 -C 12 -aryl, —(CH 2 ) n —C 5 -C 18 -heteroaryl, —(CH 2 ) n —C 3 -C 10 -cycloalkyl, —(CH 2 ) n —C 3 -C 12 -heterocycloalkyl, -phenylene-(CH 2 ) p —R 6 , —(CH 2 ) p —NR 5 R 6 , —(CH 2 ) p —NR 4 COR 5 , —(CH 2 ) p —NR 4 CSR 5 , —(CH 2 ) p —NR 4 S(O)R 5 , —(CH 2 ) p —NR 4 S(O) 2 R 5 , —(CH 2 ) p —NR 4 CONR 5 R 6 , —(CH 2 ) p —NR 4 COOR 5 , —(CH 2 ) p —NR 4 C(NH)NR 5 R 6 , —(CH 2 ) p —NR 4 CSNR 5 R 6 , —(CH 2 ) p —NR 4 S(O)NR 5 R 6 , —(CH 2 ) p —NR 4 S(O) 2 NR 5 R 6 , —(CH 2 ) p —COR 5 , —(CH 2 ) p —CSR 5 , —(CH 2 ) p —S(O)R 5 , —(CH 2 ) p —S(O)(NH)R 5 , —(CH 2 ) p —S(O) 2 R 5 , —(CH 2 ) p —S(O) 2 NR 5 R 6 , —(CH 2 ) p —SO 2 OR 5 , —(CH 2 ) p —CO 2 R 5 , —(CH 2 ) p —CONR 5 R 6 , —(CH 2 ) p —CSNR 5 R 6 , —OR 5 , —CHR 5 R 6 , —(CH 2 ) p —SR 5 and —CR 5 (OH)—R 6 ,

X, Y, Z are identical or different and are each independently selected from —CR 3 ═, —CR 3 R 4 —, —C(O)—, —N═, —S—, —O—, —NR 3 —, —S(O) 2 —, —S(O)— and —S(O)(N═R 3 )—, and single or double bonds are present between X, Y and Z, but a maximum of one of X, Y and Z is identical with —O—, and at most one of X, Y and Z is identical with —N═ or —NR 3 —, or else a maximum of two of X, Y and Z are identical with —CR 3 ═ or —CR 3 R 4 —, and wherein —X—Y—Z— is not —NH—CH═CH— or —CH═CH—NH—;

C 1 -C 10 -alkyl, —C 2 -C 6 -alkenyl, —C 2 -C 6 -alkynyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 12 -heterocycloalkyl, and —C 1 -C 10 -alkanoyl are each unsubstituted or substituted one or more times independently of one another by hydroxy, halogen, nitro, cyano, phenyl, —NR 5 R 6 , alkyl, —SR 5 or —OR 5 ,

R 5 and R 6 are identical or different and are each independently from hydrogen, —C 1 -C 10 -alkyl, —C 2 -C 10 -alkenyl, —C 2 -C 10 -alkynyl, —C 1 -C 6 -alkoxy, —C 3 -C 10 -cycloalkyl, —C 3 -C 12 -heterocycloalkyl, —C 6 -C 12 -aryl and —C 5 -C 18 -heteroaryl,

where —C 1 -C 10 -alkyl, —C 2 -C 10 -alkenyl, —C 2 -C 10 -alkynyl, —C 1 -C 6 -alkoxy, —C 3 -C 10 -cycloalkyl, —C 3 -C 12 -heterocycloalkyl, —C 6 -C 12 -aryl, and —C 5 -C 18 -heteroaryl are each unsubstituted or substituted one or more times independently of one another by hydroxy, halogen, cyano, nitro, —OR 7 , —NR 7 R 8 , —C(O)NR 7 R 8 , —C(O)OR 7 or —C 1 -C 6 -alkyl, where —C 1 -C 6 -alkyl is unsubstituted or is substituted one or more times independently of one another by halogen, hydroxy, cyano, —NR 7 R 8 , —OR 7 or phenyl; or

R 7 , R 8 are identical or different and are each independently selected hydrogen, —C 1 -C 4 -alkyl, —C 6 -C 12 -aryl and —C 5 -C 18 -heteroaryl, where alkyl, aryl, and heteroaryl are each unsubstituted or substituted one or more times independently of one another by halogen or alkoxy, or

R 7 and R 8 are optionally together a bridge of 3-10 methylene units forming a ring structure with the N atom to which they are attached, where up to two methylene units are optionally replaced by O, S or —NR 4 ;

m′, m″ are each independently of one another 0, 1, 2, 3, or 4;

n is 1, 2, 3, 4, 5, or 6;

p is 0, 1, 2, 3, 4, 5, or 6; or

an N-oxide, stereoisomer, diastereomer, enantiomer, or salt thereof.

3. A quinazoline compound according to claim 1 , wherein said compound is of formulae (A1-A5):

where:

where —C 1 -C 6 -alkyl, —C 2 -C 6 -alkenyl, —C 2 -C 6 -alkynyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 12 -heterocycloalkyl, —C 6 -C 12 -aryl, —C 5 -C 18 -heteroaryl, and —C 1 -C 6 -alkoxy are each unsubstituted or substituted one or more times independently of one another by hydroxy, halogen, nitro, cyano, —NR 5 R 6 , —C(O)NR 5 R 6 , —S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —NR 5 C(O)R 6 , —SR 5 , —R 5 or —OR 5 ,

R 3 and R 4 are each independently selected from hydrogen, —C 1 -C 10 -alkyl, —C 2 -C 6 -alkenyl, —C 2 -C 6 -alkynyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 12 -heterocycloalkyl or —C 1 -C 10 -alkanoyl, where —C 1 -C 10 -alkyl, —C 2 -C 6 -alkenyl, —C 2 -C 6 -alkynyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 12 -heterocycloalkyl, and —C 1 -C 10 -alkanoyl is unsubstituted or is substituted one or more times independently of one another by hydroxy, halogen, nitro, cyano, phenyl, —NR 5 R 6 , alkyl, —SR 5 or —OR 5 ,

where —C 1 -C 10 -alkyl, —C 2 -C 10 -alkenyl, —C 2 -C 10 -alkynyl, —C 1 -C 6 -alkoxy, —C 3 -C 10 -cycloalkyl, —C 3 -C 12 -heterocycloalkyl, —C 6 -C 12 -aryl, and —C 5 -C 18 -heteroaryl are unsubstituted or are substituted one or more times independently of one another by hydroxy, halogen, cyano, nitro, —OR 7 , —NR 7 R 8 , —C(O)NR 7 R 8 , —C(O)OR 7 or —C 1 -C 6 -alkyl, where —C 1 -C 6 -alkyl is unsubstituted or is substituted one or more times independently of one another by halogen, hydroxy, cyano, —NR 7 R 8 , —OR 7 or phenyl; or

R 7 , R 8 are identical or different and are each independently selected from hydrogen, —C 1 -C 4 -alkyl, —C 6 -C 12 -aryl and —C 5 -C 18 -heteroaryl, where alkyl, aryl, and heteroaryl are each unsubstituted or substituted one or more times independently of one another by halogen or alkoxy, or

m′, m″ are each independently of one another 0, 1, 2, 3, or 4;

n is 1, 2, 3, 4, 5, or 6;

p is 0, 1, 2, 3, 4, 5, or 6; or

an N-oxide, stereoisomer, diastereomer, enantiomer, or salt thereof.

4. A quinazoline compound according to claim 1 , wherein said compound is of formulae (A1-A5):

where:

R 1 and R 2 are identical or different and are each independently selected from hydrogen, —C 1 -C 6 -alkyl, —C 1 -C 4 -hydroxyalkyl, —C 2 -C 6 -alkenyl, —C 2 -C 6 -alkynyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 12 -heterocycloalkyl, —C 6 -C 12 -aryl, —C 5 -C 18 -heteroaryl, —C 1 -C 6 -alkoxy, —C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy, —C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, —(CH 2 ) n —C 6 -C 12 -aryl, —(CH 2 ) n —C 5 -C 18 -heteroaryl, —(CH 2 ) n —C 3 -C 10 -cycloalkyl, —(CH 2 ) n —C 3 -C 12 -heterocycloalkyl, -phenylene-(CH 2 ) p —R 6 , —(CH 2 ) p —NR 5 R 6 , —(CH 2 ) p —NR 5 COR 5 , —(CH 2 ) p —NR 4 CSR 5 , —(CH 2 ) p —NR 4 S(O)R 5 , —(CH 2 ) p —NR 4 S(O) 2 R 5 , —(CH 2 ) p —NR 4 CONR 5 R 6 , —(CH 2 ) p —NR 4 COOR 5 , —(CH 2 ) p —NR 4 C(NH)NR 5 R 6 , —(CH 2 ) p —NR 4 CSNR 5 R 6 , —(CH 2 ) p —NR 4 S(O)NR 5 R 6 , —(CH 2 ) p —NR 4 S(O) 2 NR 5 R 6 , —(CH 2 ) p —COR 5 , —(CH 2 ) p —CSR 5 , —(CH 2 ) p —S(O)R 5 , —(CH 2 ) p —S(O)(NH)R 5 , —(CH 2 ) p —S(O) 2 R 5 , —(CH 2 ) p —S(O) 2 NR 5 R 6 , —(CH 2 ) p —SO 2 OR 5 , —(CH 2 ) p —CO 2 R 5 , —(CH 2 ) p —CONR 5 R 6 , —(CH 2 ) p —CSNR 5 R 6 , —OR 5 , —CHR 5 R 6 , —(CH 2 ) p —SR 5 and —CR 5 (OH)—R 6 ,

R 4 is hydrogen, —C 1 -C 10 -alkyl, —C 2 -C 6 -alkenyl, —C 2 -C 6 -alkynyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 12 -heterocycloalkyl or —C 1 -C 10 -alkanoyl, where —C 1 -C 10 -alkyl, —C 2 -C 6 -alkenyl, —C 2 -C 6 -alkynyl, —C 3 -C 10 -cycloalkyl, —C 3 -C 12 -heterocycloalkyl, and —C 1 -C 10 -alkanoyl are each unsubstituted or substituted one or more times independently of one another by hydroxy, halogen, nitro, cyano, phenyl, —NR 5 R 6 , alkyl, —SR 5 or —OR 5 ;

where —C 1 -C 10 -alkyl, —C 2 -C 10 -alkenyl, —C 2 -C 10 -alkynyl, —C 1 -C 6 -alkoxy, —C 3 -C 10 -cycloalkyl, —C 3 -C 12 -heterocycloalkyl, —C 6 -C 12 -aryl, and —C 5 -C 18 -heteroaryl are each unsubstituted or substituted one or more times independently of one another by hydroxy, halogen, cyano, nitro, —OR 7 , —NR 7 R 8 , —C(O)NR 7 R 8 , —C(O)OR 7 or —C 1 -C 6 -alkyl, where —C 1 -C 6 -alkyl is unsubstituted or is substituted one or more times independently of one another by halogen, hydroxy, cyano, —NR 7 R 8 , —OR 7 or phenyl; or

m′, m″ are each independently of one another 0, 1, 2, 3, or 4;

n is 1, 2, 3, 4, 5, or 6;

p is 0, 1, 2, 3, 4, 5, or 6; or

an N-oxide, stereoisomer, diastereomer, enantiomer, or salt thereof.

5. A quinazoline compound according to claim 1 , wherein said compound is selected from:

(3-bromophenyl)-(3,3-dioxo-2,3-dihydro-1H-3λ 6 -thia-6,8-diazacyclopenta[a]naphthalen-9-yl)amine;

(3,3-dioxo-2,3-dihydro-1H-3λ 6 -thia-6,8-diazacyclopenta[a]naphthalen-9-yl)-(3-methoxyphenyl)amine; and

and pharmaceutically acceptable salts thereof.

6. A process for preparing a quinazoline compound according to claim 1 , said process comprising:

reacting an intermediate of formula V:

in which A is a leaving group, with a reagent of formula V′:

to give a compound of formula (A):

7. A pharmaceutical composition for enteral, parenteral and oral administration comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

8. A quinazoline compound according to claim 1 , wherein said compound is of one of the following formulas:

9. A quinazoline compound according to claim 1 , wherein said compound is of one of the following formulas:

10. A quinazoline compound according to claim 1 , wherein said compound is of one of the following formulas:

11. A quinazoline compound according to claim 1 , wherein said compound is of one of the following formulas:

12. A quinazoline compound according to claim 1 , wherein said compound is of one of the following formulas:

13. A quinazoline compound according to claim 1 , wherein said compound is of one of the following formulas:

14. A quinazoline compound according to claim 1 , wherein said compound is of one of the following formulas:

15. A quinazoline compound according to claim 1 , wherein said compound is of one of the following formulas:

16. A quinazoline compound according to claim 1 , wherein said compound is of one of the following formulas:

17. A quinazoline compound according to claim 1 , wherein said compound is of one of the following formulas:

18. A quinazoline compound according to claim 1 , wherein said compound is of one of the following formulas:

19. A quinazoline compound selected from the following compounds and pharmaceutically acceptable salts thereof: