Carboline derivatives useful in the inhibition of angiogenesis
View Patent ↗In accordance with the present invention, compounds that inhibit the expression of VEGF post-transcriptionally have been identified, and methods for their use provided. In one aspect of the invention, compounds useful in the inhibition of VEGF production, in the inhibition of angiogenesis, and/or in the treatment of cancer, diabetic retinopathy or exudative macular degeneration are provided. In another aspect of the invention, methods are provided for the inhibition of VEGF production, the inhibition of angiogenesis, and/or the treatment of cancer, diabetic retinopathy or exudative macular degeneration using the compounds of the invention.
1. A compound of Formula (I′):
or a pharmaceutically acceptable salt, racemate or stereoisomer thereof, wherein,
X is hydrogen; C 1 to C 6 alkyl optionally substituted with one or more halogen hydroxyl; halogen; or C 1 to C 5 alkoxy optionally substituted with phenyl;
R 0 is halogen; cyano; nitro; sulfonyl substituted with C 1 to C 6 alkyl or morpholinyl; amino optionally substituted with C 1 to C 6 alkyl, —C(O)—R b , —C(O)O—R b , alkylsulfonyl, morpholinyl or tetrahydropyranyl; C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from hydroxyl, halogen or amino; —C(O)—R n ; or —OR a ;
R a is hydrogen; C 2 to C 8 alkenyl; —C(O)O—R b ; —C(O)—NH—R b ; C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from hydroxyl, halogen, C 1 to C 4 alkoxy, C 1 to C 4 alkoxy-C 1 to C 4 alkoxy, amino, alkylamino, dialkylamino, acetamide, —C(O)—R b , —C(O)O—R b , aryl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,3-dioxolan-2-one, oxiranyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3-triazole, 1,2,4-triazole, furan, imidazole, isoxazole, isothiazole, oxazole, pyrazole, thiazole, thiophene or tetrazole;
wherein amino is optionally substituted with C 1 to C 4 alkoxycarbonyl, imidazole, isothiazole, pyrazole, pyridine, pyrazine, pyrimidine, pyrrole, thiazole wherein pyridine and thiazole are each optionally substituted with C 1 to C 4 alkyl;
wherein alkylamino and dialkylamino are each optionally substituted on alkyl with hydroxyl, C 1 to C 4 alkoxy, imidazole, pyrazole, pyrrole or tetrazole; and,
wherein morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl and oxiranyl are each optionally substituted with —C(O)—R n , —C(O)O—R n or C 1 to C 4 alkyl, wherein C 1 to C 4 alkyl is optionally substituted with hydroxyl;
R b is hydroxyl; amino; alkylamino, optionally substituted on alkyl with hydroxyl, amino, alkylamino or C 1 to C 4 alkoxy C 1 to C 4 alkoxy; C 2 to C 8 alkenyl; C 2 to C 8 alkynyl; aryl optionally substituted with one or more substituents independently selected from halogen and C 1 to C 4 alkoxy; furan; or C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from C 1 to C 4 alkoxy, aryl, amino, morpholinyl, piperidinyl or piperazinyl;
R d is phenyl substituted by one or more substituents independently selected from halogen, nitro, C 1 to C 6 alkyl, —C(O)O—R e , and —OR e ;
R c is hydrogen; C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from halogen and alkoxy; or phenyl, wherein phenyl is optionally substituted with one or more substituents independently selected from halogen and alkoxy; and
R d is hydroxyl, C 1 to C 4 alkoxy, amino or C 1 to C 6 alkyl.
2. A compound, wherein said compound is selected from the group consisting of
or a pharmaceutically acceptable salt, racemate or stereoisomer thereof.
3. The compound of claim 1 , wherein
X is C 1 to C 6 alkyl optionally substituted with one or more halogen halogen; or C 1 to C 5 alkoxy optionally substituted with phenyl;
R o is halogen; cyano; nitro; sulfonyl substituted with C 1 to C 6 alkyl or morpholinyl; amino optionally substituted with C 1 to C 6 alkyl, —C(O)—R b , —C(O)O—R b , alkylsulfonyl and tetrahydropyranyl; C 1 to C 6 alkyl optionally substituted with one or more halogen substituents; —C(O)—R n ; or —OR a ;
R a is hydrogen; C 2 to C 8 alkenyl; —C(O)—R b ; C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from hydroxyl, halogen, C 1 to C 4 alkoxy, C 1 to C 4 alkoxy-C 1 to C 4 alkoxy, amino, alkylamino, dialkylamino, acetamide, —C(O)—R b , —C(O)O—R b , aryl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,3-dioxolan-2-one, oxiranyl, 1,2,3-triazole, 1,2,4-triazole, imidazole or pyrazole;
wherein amino is optionally substituted with C 1 to C 4 alkoxycarbonyl pyridine, thiazole, wherein pyridine and thiazole are each optionally substituted with C 1 to C 4 alkyl;
wherein alkylamino and dialkylamino are each optionally substituted on alkyl with hydroxyl, C 1 to C 4 alkoxy or imidazole; and
wherein morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl and oxiranyl are each optionally substituted with —C(O)—R n , —C(O)O—R n or C 1 to C 4 alkyl, wherein C 1 to C 4 alkyl is optionally substituted with hydroxyl;
R b is hydroxyl; C 1 to C 4 alkoxy; C 2 to C 8 alkenyl; phenyl optionally substituted with one or more halogen substituents; furan; or C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from C 1 to C 4 alkoxy, phenyl, amino or morpholinyl; and,
R d is phenyl substituted by one or more substituents independently selected from halogen, nitro, C 1 to C 6 alkyl and —OR e ; and,
wherein all other variables are as previously defined.
4. The compound of claim 3 , wherein
X is C 1 to C 6 alkyl; halogen; or C 1 to C 5 alkoxy optionally substituted with phenyl;
R 0 is halogen; cyano; nitro; sulfonyl substituted with C 1 to C 6 alkyl or morpholinyl; amino optionally substituted with —C(O)—R b , —C(O)O—R b , alkylsulfonyl and tetrahydropyranyl; C 1 to C 6 alkyl optionally substituted with one or more halogen substituents; —C(O)—R n ; or —OR a ;
R a is hydrogen; C 2 to C 8 alkenyl; —C(O)O—R b ; C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from hydroxyl, halogen, C 1 to C 4 alkoxy, C 1 to C 4 alkoxy-C 1 to C 4 alkoxy, amino, alkylamino, dialkylamino, acetamide, —C(O)O—R b , morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,3-dioxolan-2-one, oxiranyl, 1,2,3-triazole, 1,2,4-triazole, imidazole or pyrazole;
wherein amino is optionally substituted with C 1 to C 4 alkoxycarbonyl, pyridine, thiazole, wherein pyridine and thiazole are each optionally substituted with C 1 to C 4 alkyl;
wherein alkylamino and dialkylamino are each optionally substituted on alkyl with hydroxyl, C 1 to C 4 alkoxy or imidazole; and,
wherein morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl and oxiranyl are each optionally substituted with —C(O)—R n , —C(O)O—R n or C 1 to C 4 alkyl, wherein C 1 to C 4 alkyl is optionally substituted with hydroxyl; and,
R b is hydroxyl; C 1 to C 4 alkoxy; C 2 to C 8 alkenyl; phenyl optionally substituted with one or more halogen substituents; furan; or C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from C 1 to C 4 alkoxy or morpholinyl; and,
wherein all other variables are as previously defined.
5. The compound of any of claims 1 , 2 , 3 or 4 wherein said compound has a chiral carbon at the point of attachment of the Ro, substituted and said compound is an (S) isomer at said chiral carbon.
6. A pharmaceutical composition comprising a compound of any of claims 1 , 2 , 3 or 4 or a pharmaceutically acceptable salt, racemate or stereoisomer thereof and a pharmaceutically acceptable excipient.
7. A pharmaceutical composition comprising a compound of claim 5 or a pharmaceutically acceptable salt, recemate or stereoisomer thereof and a pharmaceutically acceptable excipient.