US 8,772,316 B2Granted

Substituted 6,7-dialkoxy-3-isoquinolinol derivatives as inhibitors of phosphodiesterase 10 (PDE10A)

AssigneesAllergan, Inc., Exonhit Therapeutics SA

InventorsBertrand Leblond, John E. Donello, Cédric Chauvignac, Thierry Taverne, Eric Beausoleil, Anne-Sophie Casagrande, Laurent Désiré, Matthew P. Pando, Rong Yang

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Abstract

The invention relates to compounds of the formula wherein R′, R1, through R7 and Ar are as defined herein. These compounds are useful as inhibitors of phosphodiesterase 10 (PDE10A) which are useful in treating central nervous system diseases such as psychosis and also in treating, for example, obesity, type II diabetes, metabolic syndrome, glucose intolerance, pain and ophthalmic diseases.

Claims20

Dependent claims

A compound of Formula (I)

a pharmaceutically acceptable salt or a tautomer form thereof;
wherein:
R1 is a (C1-C4)alkyl group optionally substituted with a —(C1-C4)alkoxy or a RaNH group, Ra being selected from the group consisting of (C1-C4)alkyl-C(═O)— and (C1-C4)alkyl-S(═O)2—;
R2 is a hydrogen atom;
R3 and R4 independently represent a (C1-C3)alkyl group;
R5 is a hydrogen atom;
R6 and R7 independently represent a hydrogen atom, a halogen atom, or R6 and R7 together with the carbon atom to which they are shown attached form a —C(═O)— group;
R′ is —NH2 or —OR, wherein R is a hydrogen atom, a (C1-C3)alkyl group or a (C1-C3)alkyl-C(═O)— group
Ar is an aryl or heteroaryl group optionally substituted with one to four substituents independently selected from the group consisting of halogen, azido, hydroxy, (C1-C4)alkyl, (C1-C4)alkoxy, —O—(C1-C4)alkyl-(C1-C6)cycloalkyl, aryl, (C1-C4)alkyl-aryl-, (C1-C4)alkoxy-aryl-, amino-substituted aryl, N((C1-C4)alkyl)2-substituted aryl, aryloxy, heteroaryl, (C1-C4)alkyl-heteroaryl-, and RbRcN, or wherein two substituents at adjacent positions of the aryl or heteroaryl together with the atoms to which they are attached form a heterocyclic ring;
and
Rb and Rc, are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, halogeno(C1-C4)alkyl-, (C1-C4)alkoxy(C1-C4)alkyl-, aryl(C1-C4)alkyl- and acetylamino(C1-C4)alkyl-.

8 more elements

A compound selected from the group consisting of:

4-benzyl-6,7-dimethoxy-1-methylisoquinolin-3-ol hydrochloride 1,
4-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol hydrochloride 2,
4-(3,4-dimethoxybenzyl)-3,6,7-trimethoxy-1-methylisoquinoline hydrochloride 3,
6,7-dimethoxy-1-methyl-4-(3-phenoxybenzyl)isoquinolin-3-ol hydrochloride 4,
6,7-dimethoxy-1-methyl-4-(4-phenoxybenzyl)isoquinolin-3-ol hydrochloride 5,
4-(dibenzo[b,d]furan-2-ylmethyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol hydrochloride 6,
4-(dibenzo[b,d]furan-2-ylmethyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol hydrochloride 7,
4-((3′-amino-[1,1′-biphenyl]-3-yl)methyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 10,
6,7-dimethoxy-1-methyl-4-(pyridin-4-ylmethyl)isoquinolin-3-ol hydrochloride 11,
6,7-dimethoxy-1-methyl-4-((6-phenylpyridin-2-yl)methyl)isoquinolin-3-ol dihydrochloride
6,7-dimethoxy-4-((6-(4-methoxyphenyl)pyridin-2-yl)methyl)-1-methylisoquinolin-3-ol dihydrochloride 13,
4-([2,4′-bipyridin]-6-ylmethyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol trihydrochloride 14,
6,7-dimethoxy-1-methyl-4-((5-phenylpyridin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 15,
6,7-dimethoxy-4-((5-(4-methoxyphenyl)pyridin-3-yl)methyl)-1-methylisoquinolin-3-ol dihydrochloride 16,
6,7-dimethoxy-1-methyl-4-(naphthalen-2-ylmethyl)isoquinolin-3-ol hydrochloride 17,
1-ethyl-6,7-dimethoxy-4-(naphthalen-2-ylmethyl)isoquinolin-3-ol hydrochloride 19,
6,7-dimethoxy-4-(naphthalen-2-ylmethyl)-1-propylisoquinolin-3-ol hydrochloride 20,
4-(isoquinolin-6-ylmethyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol dihydrochloride 21,
4-(isoquinolin-5-ylmethyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol 22,
6,7-dimethoxy-1-methyl-4-(quinolin-2-ylmethyl)isoquinolin-3-ol dihydrochloride 23,
6,7-dimethoxy-1-methyl-4-(quinolin-6-ylmethyl)isoquinolin-3-ol dihydrochloride 24,
6,7-dimethoxy-1-methyl-4-(quinolin-4-ylmethyl)isoquinolin-3-ol dihydrochloride 25,
6,7-dimethoxy-1-methyl-4-(quinolin-3-ylmethyl)isoquinolin-3-ol dihydrochloride 26,
6,7-dimethoxy-4-((5-methoxyquinolin-3-yl)methyl)-1-methylisoquinolin-3-ol dihydrochloride 27,
4-((5-ethoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol dihydrochloride 28,
6,7-dimethoxy-4-((7-methoxyquinolin-3-yl)methyl)-1-methylisoquinolin-3-ol dihydrochloride 29,
4-((7-ethoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol dihydrochloride 30,
1-ethyl-6,7-dimethoxy-4-((7-methoxyquinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 31,
6,7-dimethoxy-4-((7-methoxyquinolin-3-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride 32,
6,7-dimethoxy-1-methyl-4-((6-methyl-2-(methylamino)quinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 33,
6,7-dimethoxy-4-((6-methyl-2-(methylamino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride 34,
4-((2-(ethylamino)-6-methylquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 35,
4-((2-(dimethylamino)-6-methylquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 36,
6,7-dimethoxy-4-((6-methoxy-2-(methylamino)quinolin-3-yl)methyl)-1-methyl-isoquinolin-3-ol dihydrochloride 37,
6,7-dimethoxy-4-((6-methoxy-2-(propylamino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride 38,
1-ethyl-6,7-dimethoxy-4-((6-methoxy-2-(methylamino)quinolin-3-yl)methyl)isoquinolin-3-ol 39,
1-ethyl-6,7-dimethoxy-4-((6-methoxy-2-(ethylamino)quinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 40,
1-ethyl-6,7-dimethoxy-4-((6-ethoxy-2-(ethylamino)quinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 41,
1-ethyl-6,7-dimethoxy-4-((6-methoxy-2-(propylamino)quinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 42,
1-ethyl-4-((2-(isopropylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 43,
4-((2-(benzylamino)-6-methoxyquinolin-3-yl)methyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 44,
1-ethyl-6,7-dimethoxy-4-((6-methoxy-2-(2,2,2-trifluoroethylamino)quinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 45,
4-((6-ethoxy-2-(ethylamino)quinolin-3-yl)methyl)-1-isopropyl-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 46,
4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-1-isopropyl-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 47,
6,7-dimethoxy-4-((6-methoxy-2-(methylamino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride 48,
4-((6-ethoxy-2-(ethylamino)quinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 49,
4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 50,
1-isopropyl-6,7-dimethoxy-4-((6-methoxy-2-(2,2,2-trifluoroethylamino)quinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 51,
6,7-dimethoxy-4-((6-methoxy-2-(propylamino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride 52,
4-((2-(isopropylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 53,
6,7-dimethoxy-4-((6-methoxy-2-((2,2,2-trifluoroethyl)amino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride 54,
N-(2-((3-((3-hydroxy-6,7-dimethoxy-1-propylisoquinolin-4-yl)methyl)-6-methoxyquinolin-2-yl)amino)ethyl)acetamide dihydrochloride 55,
1-(acetamidomethyl)-4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxyisoquinolin-3-yl acetate 56,
N-((4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-3-hydroxy-6,7-dimethoxyisoquinolin-1-yl)methyl)acetamide dihydrochloride 57,
N-((4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-3-hydroxy-6,7-dimethoxyisoquinolin-1-yl)methyl)methanesulfonamide dihydrochloride 58,
3-((3-hydroxy-6,7-dimethoxy-1-methylisoquinolin-4-yl)methyl)-2-(methylamino)quinoline-6,7-diol dihydrochloride 59,
6,7-dimethoxy-1-methyl-4-((6-(methylamino)-[1,3]dioxolo[4,5-g]quinolin-7-yl)methyl)isoquinolin-3-ol dihydrochloride 60,
1-ethyl-6,7-dimethoxy-4-((6-(methylamino)-[1,3]dioxolo[4,5-g]quinolin-7-yl)methyl)isoquinolin-3-ol dihydrochloride 61,
6,7-dimethoxy-4-((6-(methylamino)-[1,3]dioxolo[4,5-g]quinolin-7-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride 62,
4-((6-(dimethylamino)-[1,3]dioxolo[4,5-g]quinolin-7-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 63,
4-((6-(ethylamino)-[1,3]dioxolo[4,5-g]quinolin-7-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 64,
4-((2-ethyl-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 66,
4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-(methoxymethyl)isoquinolin-3-ol dihydrochloride 67,
4-((2-azido-6-methoxyquinolin-3-yl)methyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 68,
N-(2-((3-((1-ethyl-3-hydroxy-6,7-dimethoxyisoquinolin-4-yl)methyl)-6-methoxyquinolin-2-yl)amino)ethyl)acetamide dihydrochloride 69,
4-((2-(ethylamino)-7-fluoro-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 70,
4-((2-butyl-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 71,
6,7-dimethoxy-4-((6-methoxy-2-(trifluoromethyl)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol hydrochloride 72,
N-(2-((3-((3-hydroxy-6,7-dimethoxy-1-methylisoquinolin-4-yl)methyl)-6-methoxyquinolin-2-yl)amino)ethyl)acetamide dihydrochloride 73,
6,7-dimethoxy-1-propyl-4-(quinolin-3-ylmethyl)isoquinolin-3-ol dihydrochloride 74,
6,7-dimethoxy-4-((6-methoxy-2-((2-methoxyethyl)amino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride 76,
1-ethyl-6,7-dimethoxy-4-((6-methoxy-2-((2-methoxyethyl)amino)quinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 77,
1-ethyl-6,7-dimethoxy-4-(quinolin-3-ylmethyl)isoquinolin-3-ol dihydrochloride 78,
1-isopropyl-6,7-dimethoxy-4-(quinolin-3-ylmethyl)isoquinolin-3-ol dihydrochloride 79,
6,7-dimethoxy-4-((2-methylquinolin-6-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride 80,
1-ethyl-6,7-dimethoxy-4-((2-methylquinolin-6-yl)methyl)isoquinolin-3-ol dihydrochloride 81,
1-ethyl-4-((2-(ethylamino)-7-fluoro-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 82,
N-(2-((6-(cyclopropylmethoxy)-3-((3-hydroxy-6,7-dimethoxy-1-propylisoquinolin-4-yl)methyl)quinolin-2-yl)amino)ethyl)acetamide dihydrochloride 83,
6,7-dimethoxy-4-((6-methoxyquinolin-3-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride 84,
1-ethyl-6,7-dimethoxy-4-((6-methoxyquinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 85,
4-((6-ethoxy-2-(ethylamino)-7-fluoroquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 86,
N-(2-((6-(cyclopropylmethoxy)-3-((1-ethyl-3-hydroxy-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-2-yl)amino)ethyl)acetamide dihydrochloride 87, and
N-(2-((6-ethoxy-3-((3-hydroxy-6,7-dimethoxy-1-propylisoquinolin-4-yl)methyl)quinolin-2-yl)amino)ethyl)acetamide dihydrochloride 88;
any other pharmaceutically acceptable salt, or a tautomer form thereof.

81 more elements

A compound selected from the group consisting of:

6,7-dimethoxy-4-((6-methoxy-2-(methylamino)quinolin-3-yl)methyl)-1-methyl-isoquinolin-3-ol dihydrochloride 37,
6,7-dimethoxy-4-((6-methoxy-2-(propylamino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride 38,
1-ethyl-6,7-dimethoxy-4-((6-methoxy-2-(methylamino)quinolin-3-yl)methyl)isoquinolin-3-ol 39,
1-ethyl-6,7-dimethoxy-4-((6-methoxy-2-(ethylamino)quinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 40,
1-ethyl-6,7-dimethoxy-4-((6-ethoxy-2-(ethylamino)quinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 41,
1-ethyl-6,7-dimethoxy-4-((6-methoxy-2-(propylamino)quinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 42,
1-ethyl-4-((2-(isopropylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxyisoquinolin-3-01 dihydrochloride 43,
4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-1-isopropyl-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 47,
6,7-dimethoxy-4-((6-methoxy-2-(methylamino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride 48,
4-((6-ethoxy-2-(ethylamino)quinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 49,
4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 50,
6,7-dimethoxy-4-((6-methoxy-2-(propylamino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride 52, and
4-((2-(isopropylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 53;
any other pharmaceutically acceptable salt, or a tautomer form thereof.

11 more elements

Dependencies are inferred from the claim text.

Facts

Application: 13/399,351Filed 17 Feb 2012 · us provisional application
Priority: 18 Feb 2011
Published: US 2012/0214837 A123 Aug 2012
Granted: 8 Jul 2014
Term ends: Not estimatedThe source records don’t support an estimate.

Classification28 codes

C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…
A61P 3/00
Drugs for disorders of the metabolism
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics

Family

Application61/444,566Us provisional application · filed 18 Feb 2011
US 2012/0214837 A1Pre-grant publication · published 23 Aug 2012
US 8,772,316 B2This patent

From the US filing history. Foreign family members aren’t listed.

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