MUSCARINIC AGONISTS

• US 20070155795A1
• Filed: 02/16/2007
• Published: 07/05/2007
• Est. Priority Date: 04/28/2000
• Status: Abandoned Application

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Andersson, Carl-Magnus, Skjaerbaek, Niels, Spalding, Tracy, Uldam, Allan, Friberg, Bo Lennart
• Application Number:
  US11/676,178
• Publication Number:
  US 20070155795A1
• Time in Patent Office: Days
• US Class Current: 514/337
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 473/00 Heterocyclic compounds containing purine ring systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

Compounds and methods are provided for the treatment of disease conditions in which modification of cholinergic, especially muscarinic m1, m4, or both m1 and m4, receptor activity has a beneficial effect. In the method, an effective amount of a compound is administered to a patient in need of such treatment.

Claims

1-76. -76. (canceled)

77. A compound of formula (I):

wherein;

Z₁ is CR₁, Z₂ is CR₂, Z₃ is CR₃, and Z₄ is CR₄;

W₁ is S, W₂ is N or CR₆, and W₃ is CG;

G is of formula (II);

Y is O, S, CHOH, —

NHC(O)—

, —

C(O)NH—

, —

C(O)—

, —

OC(O)—

, —

(O)CO—

, —

NR₇—

, —

CH═

N—

, or absent;

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

Z is CR₈R₉ or absent;

each t is 1, 2, or 3;

each R₁, R₂, R₃, and R₄, independently, is H, amino, hydroxyl, halo, or straight- or branched-chain C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 heteroalkyl, C_1-6 haloalkyl, —

CN, —

CF₃, —

OR₁₁, —

COR₁₁, —

NO₂, —

SR₁₁, —

NHC(O)R₁₁, —

C(O)NR₁₂R₁₃, —

NR₁₂R₁₃, NR₁₁C(O)NR₁₂R₁₃, —

SO₂NR₁₂R₁₃, —

OC(O)R₁₁, —

O(CH₂)_qNR₁₂R₁₃, or —

(CH₂)_qNR₁₂R₁₃, where q is an integer from 2 to 6, or R₁ and R₂ together form —

NH—

N═

N—

or R₃ and R₄ together form —

NH—

N═

N—

;

each R₅, R₆, and R₇, independently, is H, C_1-6 alkyl;

formyl;

C_3-6 cycloalkyl;

C_5-6 aryl, optionally substituted with halo or C_1-6 alkyl;

or C_5-6 heteroaryl, optionally substituted with halo or C_1-6 alkyl;

each R₈ and R₉, independently, is H or straight- or branched-chain C_1-8 alkyl;

R₁₀ is straight- or branched-chain C_1-8 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_1-8 alkylidene, C_1-8 alkoxy, or C_1-8 heteroalkyl;

R₁₀′

is H, straight- or branched-chain C_1-8 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_1-8 alkylidene, C_1-8 alkoxy, C_1-8 heteroalkyl, C_1-8 aminoalkyl, C_1-8 haloalkyl, C_1-8 alkoxycarbonyl, C_1-8 hydroxyalkoxy, C_1-8 hydroxyalkyl, or C_1-8 alkylthio;

each R₁₁, independently, is H, straight- or branched-chain C_1-8 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_2-8 heteroalkyl, C_2-8 aminoalkyl, C_2-8 haloalkyl, C_1-8 alkoxycarbonyl, C_2-8 hydroxyalkyl, —

C(O)—

C_5-6 aryl substituted with C_1-3 alkyl or halo, C_5-6 aryl, C_5-6 heteroaryl, C_5-6 cycloalkyl, C_5-6 heterocycloalkyl, —

C(O)NR₁₂R₁₃, —

CR₅R₁₂R₁₃, —

(CH₂)_tNR₁₂R₁₃, t is an integer from 2 to 8; and

each R₁₂ and R₁₃, independently, is H, C_1-6 alkyl;

C_3-6 cycloalkyl;

C_5-6 aryl, optionally substituted with halo or C_1-6 alkyl;

or C_5-6 heteroaryl, optionally substituted with halo or C_1-6 alkyl;

or a pharmaceutically acceptable salt, ester or prodrug thereof.

78. The compound of claim 77, wherein each t is 2.

79. The compound of claim 78, wherein R₁₀ is n-butyl.

80. The compound of claim 78, wherein each R₁, R₂, R₃, and R₄, independently, is H, hydroxyl, halo, C_1-6 heteroalkyl, CF₃, —

NO₂, or straight- or branched-chain C_1-6 alkyl, or R₁ and R₂ together form —

NH—

N═

N—

or R₃ and R₄ together form —

NH—

N═

N—

.

81. The compound of claim 78, wherein Y is absent or O, p is 0, 1, 2 or 3, and R₈ and R₉ are H.

82. The compound of claim 81, wherein Z is absent, Y is absent and p is 3.

83. The compound of claim 82, wherein R₁₀ is n-butyl.

84. The compound of claim 77, wherein the compound is:

1-benzo[b]thiophen-2-yl-4-(4-butylpiperidin-1-yl)-butan-1-one;

4-(4-butylpiperidin-1-yl)-1-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-butan-1-one;

1-(3-bromo-benzo[b]thiophen-2-yl)-4-(4-butylpiperidin-1-yl)-butan-1-one

1-(3-benzo[b]thiophen-2-yl-propyl)-4-butylpiperidine;

4-butyl-1-[3-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-propyl]-piperidine;

1-(3-benzo [b]thiophen-2-yl-propyl)-4-methylpiperidine

1-(3-benzo[b]thiophen-2-yl-propyl)-4-benzylpiperidine;

or

3-[3-(4-butyl-piperidin-1-yl)-propyl]-benzo[d]isothiazole.

85. A pharmaceutical composition comprising an effective amount of a compound of formula (I):

wherein;

Z₁ is CR₁, Z₂ is CR₂,Z₃ is CR₃, and Z₄is CR₄;

W₁ is S, W₂ is N or CR₆, and W₃ is CG;

G is of formula (II);

Y is O, S, CHOH, —

NHC(O)—

, —

C(O)NH—

, —

C(O)—

, —

OC(O)—

, —

(O)CO—

, —

NR₇—

, —

CH═

N—

, or absent;

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

Z is CR₈R₉ or absent;

each t is 1, 2, or 3;

each R₁, R₂, R₃, and R₄, independently, is H, amino, hydroxyl, halo, or straight- or branched-chain C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 heteroalkyl, C_1-6 haloalkyl, —

CN, —

CF₃, —

OR₁₁, —

COR₁₁, —

NO₂, —

SR₁₁, —

NHC(O)R₁₁, —

C(O)NR₁₂R₁₃, —

NR₁₂R₁₃, NR₁₁C(O)NR₁₂R₁₃, —

SO₂NR₁₂R₁₃, —

OC(O)R₁₁, —

O(CH₂)_qNR₁₂R₁₃, or —

(CH₂)_qNR₁₂R₁₃, where q is an integer from 2 to 6, or R₁ and R₂ together form —

NH—

N═

N—

or R₃ and R₄ together form —

NH—

N═

N—

;

each R₅, R₆, and R₇, independently, is H, C_1-6 alkyl;

formyl;

C_3-6 cycloalkyl;

C_5-6 aryl, optionally substituted with halo or C_1-6 alkyl;

or C_5-6 heteroaryl, optionally substituted with halo or C_1-6 alkyl;

each R₈ and R₉, independently, is H or straight- or branched-chain C_1-8 alkyl;

R₁₀ is straight- or branched-chain C_1-8 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_1-8 alkylidene, C_1-8 alkoxy, or C_1-8 heteroalkyl;

R₁₀′

is H, straight- or branched-chain C_1-8 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_1-8 alkylidene, C_1-8 alkoxy, C_1-8 heteroalkyl, C_1-8 aminoalkyl, C_1-8 haloalkyl, C_1-8 alkoxycarbonyl, C_1-8 hydroxyalkoxy, C_1-8 hydroxyalkyl, or C_1-8 alkylthio;

each R₁₁, independently, is H, straight- or branched-chain C_1-8 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_2-8 heteroalkyl, C_2-8 aminoalkyl, C_2-8 haloalkyl, C_1-8 alkoxycarbonyl, C_2-8 hydroxyalkyl, —

C(O)—

C_5-6 aryl substituted with C_1-3 alkyl or halo, C_5-6 aryl, C_5-6 heteroaryl, C_5-6 cycloalkyl, C_5-6 heterocycloalkyl, —

C(O)NR₁₂R₁₃, —

CR₅R₁₂R₁₃, —

(CH₂)_tNR₁₂R₁₃, t is an integer from 2 to 8; and

each R₁₂ and R_1-3, independently, is H, C_1-6 alkyl;

C_3-6 cycloalkyl;

C_5-6 aryl, optionally substituted with halo or C_1-6 alkyl;

or C_5-6 heteroaryl, optionally substituted with halo or C_1-6 alkyl;

or a pharmaceutically acceptable salt, ester or prodrug thereof.

86. A pharmaceutical composition of claim 85, wherein each t is 2.

87. A pharmaceutical composition of claim 86, wherein R₁₀ is n-butyl.

88. A pharmaceutical composition of claim 86, wherein each R₁, R₂, R₃, and R₄, independently, is H, hydroxyl, halo, C_1-6heteroalkyl, CF₃, —

NO₂, or straight- or branched-chain C_1-6 alkyl, or R₁ and R₂ together form —

NH—

N═

N—

or R₃ and R₄ together form —

NH—

N═

N—

.

89. A pharmaceutical composition of claim 86, wherein Y is absent or O, p is 0, 1, 2 or 3, and R₈ and R₉ are H.

90. A pharmaceutical composition of claim 89, wherein Z is absent, Y is absent and p is 3.

91. A pharmaceutical composition of claim 90, wherein R₁₀ is n-butyl.

92. A pharmaceutical composition of claim 86, wherein the compound is:

1-benzo[b]thiophen-2-yl-4-(4-butylpiperidin-1-yl)-butan-1-one;

4-(4-butylpiperidin-1-yl)-1-(5-fluoro-3-methyl-benzo [b]thiophen-2-yl)-butan-1-one;

1-(3-bromo-benzo [b]thiophen-2-yl)-4-(4-butylpiperidin-1-yl)-butan-1-one

1-(3-benzo [b]thiophen-2-yl-propyl)-4-butylpiperidine;

4-butyl-1-[3-(5-fluoro-3-methyl-benzo [b]thiophen-2-yl)-propyl]-piperidine;

1-(3-benzo [b]thiophen-2-yl-propyl)-4-methylpiperidine;

1-(3-benzo[b]thiophen-2-yl-propyl)-4-benzylpiperidine;

or

3-[3-(4-butyl-piperidin-1-yl)-propyl]-benzo[d]isothiazole.