Phosphodiesterase 10 inhibitors

• US 20070287707A1
• Filed: 02/27/2007
• Published: 12/13/2007
• Est. Priority Date: 02/28/2006
• Status: Abandoned Application

• Current Assignee: Amgen Inc., Memory Pharmaceuticals Corp. (Roche Holding AG)
• Original Assignee: Memory Pharmaceuticals Corp. (Roche Holding AG)
• Inventors: Hess, Hans-Jurgen, Conticello, Richard, Hopper, Allen, Arrington, Mark, Hitchcock, Stephen
• Application Number:
  US11/712,264
• Publication Number:
  US 20070287707A1
• Time in Patent Office: Days
• US Class Current: 514/235.200
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 237/28 Cinnolines
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention if directed to certain cinnoline compounds that are PDE10 inhibitors, pharmaceutical compounds containing the same and processes for preparing the same. The invention is also directed to methods of treating diseases mediated by PDE10 enzyme such as obesity, non-insulin dependent diabetes, schizophrenia or bipolar disorder, obsessive-compulsive disorder, and the like.

Claims

1. A compound of Formula (I):

wherein;

Y and Z are nitrogen and X is —

CR═

(where R is hydrogen, alkyl, halo, or cyano);

or X and Y are nitrogen and Z is —

CH═

;

or X and Z are nitrogen and Y is ═

CH—

;

one of R¹, R², and R³ is cycloalkyloxy, cycloalkylalkyloxy, hydroxyalkyl, hydroxyalkyloxy, alkoxyalkyl, alkoxyalkyloxy, -(alkylene)NR¹³R¹⁴ or —

O-(alkylene)NR¹⁵R¹⁶ [(where R¹³, R¹⁴, R¹⁵, and R¹⁶ are independently hydrogen or alkyl) and wherein one or two carbon atoms in the alkyl chain in hydroxyalkyl, hydroxyalkyloxy, alkoxyalkyl, alkoxyalkyloxy, -(alkylene)NR¹³R¹⁴ or —

O-(alkylene)NR¹⁵R¹⁶ are optionally replaced by one to two oxygen or nitrogen atom(s)] and the other two of R¹, R², and R³ are independently selected from hydrogen, alkyl, alkoxy, cycloalkyl, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, alkylcarbonyl, cycloalkyl, cycloalkyloxy, cycloalkylalkyloxy, hydroxyalkyl, hydroxyalkyloxy, alkoxyalkyl, alkoxyalkyloxy, -(alkylene)NR¹⁷R¹⁸ or —

O-(alkylene)NR¹⁹R²⁰ [(where R¹⁷, R¹⁸, R¹⁹, and R²⁰ are independently hydrogen or alkyl and wherein one or two carbon atoms in the alkyl chain in hydroxyalkyl, alkoxyalkyl, -(alkylene)NR¹⁷R¹⁸ or —

O-(alkylene)NR¹⁹R²⁰ are optionally replaced by one to two oxygen or nitrogen atom(s)]; and

R^3a is aryl, heteroaryl, or heterocyclyl ring substituted with;

R⁴ where R⁴ is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, or —

X¹R⁷ (where X¹ is —

O—

, —

CO—

, —

C(O)O—

, —

OC(O)—

, —

NR⁸CO—

, —

CONR⁹—

, —

NR¹⁰—

, —

S—

, —

SO—

, —

SO₂—

, —

NR¹¹SO₂—

, or —

SO₂NR¹—

where R⁸-R¹² are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R⁷ is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl); and

R⁵ and R⁶ where R⁵ and R⁶ are independently hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, nitro, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, acyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, disubstituted amino, aryl, heteroaryl or heterocyclyl;

and wherein the aromatic or alicyclic ring in R⁴, R⁵, R⁶, and R⁷ is optionally substituted with one to three substitutents independently selected from R^a, R^b, and R^c which are alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, nitro, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, disubstituted amino, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; and

additionally substituted with one or two substitutents independently selected from R^d and R^e where R^d and R^e are hydrogen or fluoro;

or

an individual stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, provided that;

(i) when X and Z are nitrogen, R¹ is hydrogen, R² is alkoxy, alkoxyalkyloxy (wherein one or two carbon atoms in alkoxyalkyloxy are optionally replaced by one to two oxygen atoms), hydroxyalkoxy, or —

O-(alkylene)-NR¹³R¹⁴ where R¹³ and R¹⁴ are independently hydrogen or alkyl, and R³ is hydrogen, alkoxy, alkoxyalkyloxy, or hydroxyalkyloxy, then R^3a is not

2,3-dihydroindolyl, 2-oxoindolyl, indolyl, 7-aza-2-oxo-indol-3-yl, 4-aza-2-oxo-indol-3-yl, 5,7-diazaoxindol-3-yl, or piperidinyl, each of which is substituted with R⁴, R⁵ or R⁶ as defined above;

6-chloro-7-aza-2-oxo-indol-3-yl;

2-alkyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one-5-yl;

4-carboxypiperidin-1-yl;

or

piperazin-1-yl substituted with R⁴, R⁵ or R⁶ at the 4-position of the piperazin-1-yl ring where R⁴, R⁵ or R⁶ are as defined above or where R⁴, R⁵ or R⁶ are hydrogen, alkoxycarbonyl, or —

CONHR where R is phenyl substituted with alkoxy, cyano, alkyl, 5-hydroxyindol-1-yl, or cyclopropyl;

(ii) when X and Z are nitrogen, R¹ is hydrogen, R² is cycloalkylpropoxy, R³ is alkoxy, then and R^3a is not piperazin-1-yl substituted with R⁴, R⁵ or R⁶ where two of R⁴, R⁵ or R⁶ are hydrogen and the other of R⁴, R⁵ or R⁶ is at the 4-position of the piperazin-1-yl ring and is hydrogen or —

CONHR where R is phenyl substituted with alkoxy; and

(iii) when X and Z are nitrogen, R¹ is hydrogen, R² is 2-(dimethylamino)ethoxy, and R³ is methoxy, then R^3a is not 1,6-dimethyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl-piperidin-1-yl;

or a salt of (i)-(iii).

2. The compound of claim 1 wherein X and Y are nitrogen and Z is ═

CH—

.

3. The compound of claim 1 wherein Y and Z are nitrogen and X is —

CH═

.

4. The compound of claim 1 wherein X and Z are nitrogen and Y is ═

CH.

5. The compound of claim 2 wherein R¹ is hydrogen, one of R² and R³ is alkoxy and the other is cycloalkoxy.

6. The compound of claim 2 wherein R¹ is hydrogen, one of R² and R³ is alkoxy and the other is hydroxyalkyloxy or alkoxyalkyloxy.

7. The compound of claim 2 wherein R¹ is hydrogen, one of R² and R³ is alkoxy and the other is —

O-(alkylene)-NR¹⁵R¹⁶.

8. The compound of claim 2 wherein R¹ is hydrogen, one of R² and R³ is alkoxy and the other is alkoxyalkoxy, and R^3a is a ring of formula:

where R⁴ phenyl, heteroaryl, or six membered saturated heterocyclyl optionally substituted with R^a, R^b and R^c and the rings are substituted, including the hydrogen atom on the —

NH—

group within the ring, with R⁵ and R⁶.

9. The compound of claim 2 wherein R¹ is hydrogen, one of R² and R³ is alkyl and the other is hydroxyalkoxy or alkoxyalkoxy, and R^3a is a ring of formula:

where R⁴ is phenyl, heteroaryl, or six membered saturated heterocyclyl optionally substituted with R^a, R^b and R^c and the rings are substituted, including the hydrogen atom on the —

NH—

group within the ring, with R⁵ and R⁶.

10. The compound of claim 2 wherein R¹ is hydrogen, one of R² and R³ is alkoxy and the other is —

O-(alkylene)-NR¹⁵R¹⁶, and R^3a is a ring of formula;

where R⁴ is phenyl, heteroaryl, or six membered saturated heterocyclyl optionally substituted with R^a, R^b and R^c and the rings are substituted, including the hydrogen atom on the —

NH—

group within the ring, with R⁵ and R⁶.

11. The compound of claim 2 wherein R¹ is hydrogen, one of R² and R³ is alkoxy and the other is alkoxyalkoxy, and R^3a is a ring of formula:

12. The compound of claim 2 wherein R¹ is hydrogen, one of R² and R³ is alkyl and the other is hydroxyalkoxy or alkoxyalkyloxy, and R^3a is a ring of formula:

13. The compound of claim 2 wherein R¹ is hydrogen, one of R² and R³ is alkoxy and the other is alkoxyalkoxy, and R^3a is a ring of formula:

14. The compound of claim 2 wherein R¹ is hydrogen, one of R² and R³ is alkyl and the other is hydroxyalkoxy or alkoxyalkyloxy, and R^3a is a ring of formula:

15. The compound of claim 2 wherein R¹ is hydrogen, one of R² and R³ is alkyl and the other is hydroxyalkoxy or alkoxyalkyloxy, and R^3a is a ring of formula:

where R⁵ is monosubstituted or disubstituted amino and R⁴ is hydrogen, alkyl, or halo.

16. The compound of claim 2 wherein R¹ is hydrogen, one of R² and R³ is alkoxy and the other is hydroxyalkoxy or alkoxyalkyloxy, and R^3a is a ring of formula:

where R⁵ is hydrogen or alkyl and R⁴ is aryl, heteroaryl, aralkyl, heteroaralkyl, or heterocyclyl optionally substituted with one to three substitutents independently selected from R^a, R^b, and R^c which are alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, acyl, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfonyl, monosubstituted amino, disubstituted amino, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.

17. The compound of claim 2 wherein R¹ is hydrogen, one of R² and R³ is alkyl and the other is hydroxyalkoxy or alkoxyalkyloxy, and R^3a is a ring of formula:

where R⁵ is hydrogen or alkyl and R⁴ is aryl, heteroaryl, aralkyl, heteroaralkyl, or heterocyclyl optionally substituted with one to three substitutents independently selected from R^a, R^b, and R^c which are alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, acyl, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfonyl, monosubstituted amino, disubstituted amino, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.

18. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable expicient.

19. A method of treating a disorder treatable by inhibition of PDE10 enzyme in a patient which method comprises administering to the patient a pharmaceutical composition comprising a a compound of claim 1 and a pharmaceutically acceptable expicient.

20. The method of claim 18 wherein the disease is schizophrenia, bipolar disorder, or obsessive-compulsive disorder.