PDE1 inhibitory compounds and methods

Patent metadata

Field	Value
Publication number	US-9763948-B2
Application number	US-201113701244-A
Country	US
Kind code	B2
Filing date	May 31, 2011
Priority date	May 31, 2010
Publication date	Sep 19, 2017
Grant date	Sep 19, 2017

Abstract

Optionally substituted (1- or 3-oxy)-4,5,7,8-tetrahydro-(optionally 4-oxo, 4-thioxo or 4-imino)-2H-imidazo[1,2-a]pyrrolo[3,4-e]pyrimidine or (1- or 3-oxy)-4,5,7,8,9-pentahydro-(optionally 4-oxo, 4-thioxo or 4-imino)-2H-pyrimido[1,2-a]pyrrolo[3,4-e]pyrimidine compounds, processes for their production, their use as pharmaceuticals and pharmaceutical compositions comprising the same.

First claim

What is claimed is:

1. A Compound of Formula II-A or II-B

wherein
(i) Q is C(═O),
(ii) L is —O—;
(iii) R 1 is H or C 1-4 alkyl;
R 2 is H and R 3 and R 4 together form a di-, tri- or tetramethylene bridge;

(iv) R 5 is
c) attached to the nitrogen on the pyrrolo portion of Formula II-A or II-B and is a moiety of Formula A

wherein X, Y and Z are, independently, N or C, and R 8 , R 9 , R 11 and R 12 are independently H or halogen, and R 10 is
halogen,
C 1-6 alkyl,
C 1-6 alkoxy,
C 3-7 cycloalkyl,
heteroC 3-7 cycloalkyl,
C 1-6 haloalkyl,
aryl,
heteroaryl,
arylcarbonyl,
C 1-6 alkylsulfonyl,
heteroarylcarbonyl, or
C 1-6 alkoxycarbonyl;

wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl is independently, optionally substituted with one or more C 1-6 alkyl, halogen, haloC 1-6 alkyl, hydroxy, C 1-6 -carboxy, —SH or an additional aryl, heteroaryl or C 3-8 cycloalkyl,
provided that when X, Y, or Z is nitrogen, R 8 , R 9 , or R 10 , respectively, is not present;

(v) R 6 is
C 1-6 alkyl,
C 3-7 cycloalkyl,
aryl,
heteroaryl, or
arylC 1-6 alkyl,
wherein the aryl or heteroaryl is optionally substituted with one or more group selected from halo, hydroxy, C 1-6 alkyl, C 1-6 alkoxy and C 3-8 cycloalkyl;

(vi) R 7 is H, C 1-6 alkyl,
(vii) n=0;

in free or salt form.

2. A compound selected from any one of the following:
F) a Compound of Formula VIII-A or VIII-B:

wherein
(i) Q is C(═O);
(ii) L is —O—;
(iii) R 1 is H or C 1-4 alkyl;
(iv) R 2 is H and R 3 and R 4 together form a di- or tri- or tetramethylene bridge;
(v) R 5 is attached to the nitrogen on the pyrrolo portion of Formula VIII-A or VIII-B and is a moiety of Formula A

wherein X, Y and Z are, C; and R 8 , R 9 , R 11 and R 12 are H; and R 10 is, heteroC 3-7 cycloalkyl,
heteroaryl,
wherein the heteroaryl, or heterocycloalkyl is independently,
optionally substituted with one or more C 1-6 alkyl (e.g.,

(vi) R 6 is
C 1-6 alkyl,
C 3-7 cycloalkyl,
aryl,
heteroaryl, or
arylC 1-6 alkyl,
wherein the aryl or heteroaryl is optionally substituted with one or more group selected from halo, hydroxy, C 1-6 alkyl, C 1-6 alkoxy and C 3-8 cycloalkyl;

(vii) R 7 is H;
(viii) n=0 or 1; and
(ix) when n=1, A is —C(R 13 R 14 )—, wherein R 13 and R 14 , are, independently, H or C 1-6 alkyl, aryl, heteroaryl, (optionally hetero)arylC 1-6 alkoxy, (optionally hetero)arylC 1-6 alkyl or R 14 can form a bridge with R 2 or R 4 ;

in free or salt form;
G) a Compound of Formula IX-A or IX-B:

wherein
(i) Q is C(═O);
(ii) L is —O—;
(iii) R 1 is H or C 1-6 alkyl;
(iv) R 2 is H and R 3 and R 4 together form a di-, tri- or tetramethylene bridge;
(v) R 5 is attached to the nitrogen on the pyrrolo portion of Formula IX-A or IX-B and is a moiety of Formula A

wherein X, Y and Z are C; and R 8 , R 9 , R 11 and R 12 are H; and R 10 is selected from the following: pyrrolidinyl, piperidinyl, pyridyl, thiadiazolyl, diazolyl, triazolyl, tetrazolyl, wherein R 10 is optionally substituted with one or more C 1-6 alkyl, halogen,
(vi) R 6 is
C 1-6 alkyl,
C 3-7 cycloalkyl,
aryl,
heteroaryl, or
arylC 1-6 alkyl,
wherein the aryl or heteroaryl is optionally substituted with one or more group selected from halo, hydroxy, C 1-6 alkyl, C 1-6 alkoxy and C 3-8 cycloalkyl;

(vii) R 7 is H; and
(viii) n=0

in free or salt form;
H) a Compound of Formula X-A or X-B:

wherein
(i) Q is C(═O);
(ii) L is —O—;
(iii) R 1 is H or C 1-4 alkyl;
(iv) R 2 is H and R 3 and R 4 together form a di-, tri- or tetramethylene bridge;
(v) R 5 is attached to the nitrogen on the pyrrolo portion of Formula X-A or X-B and is a moiety of Formula A

wherein X, Y and Z are C; and R 8 , R 9 , R 11 and R 12 are H; and R 10 is pyrid-2-yl, 1,2,4-triazolyl, 6-fluoropyrid-2-yl or 1-methylpyrrolidin-2-yl;

(vi) R 6 is
C 1-6 alkyl,
C 3-7 cycloalkyl,
aryl,
heteroaryl, or
arylC 1-6 alkyl,
wherein the aryl or heteroaryl is optionally substituted with one or more group selected from halo, hydroxy, C 1-6 alkyl, C 1-6 alkoxy and C 3-8 cycloalkyl;

(vii) R 7 is H;
(viii) n=0

in free or salt form;
I) a Compound of Formula XI-A or XI-B

wherein
(i) Q is C(═O);
(ii) L is —O—;
(iii) R 1 is H or C 1-6 alkyl;
(iv) R 2 is H and R 3 and R 4 together form a di-, tri- or tetramethylene bridge;
(v) R 5 is attached to the nitrogen on the pyrrolo portion of Formula XI-A or XI-B and is a moiety of Formula A

wherein X, Y and Z are C; and R 8 , R 9 , R 11 and R 12 are H; and R 10 is C 1-6 alkoxy;

(vi) R 6 is
(vii) R 7 is H;
(viii) n=0,

in free or salt form.

3. The compound according to claim 1 , wherein said compound is:

in free or salt form.

4. A pharmaceutical composition comprising a compound according to claim 1 , in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier.

5. The pharmaceutical composition according to claim 4 , wherein the salt and the diluents or carrier are ophthalmically acceptable.

Assignees

• Li Peng
• Zhao Jun
• Intra Cellular Therapies Inc

Inventors

• Li Peng
• Zhao Jun

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P5/34

  Gestagens · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P5/32

  Antioestrogens · CPC title