US 7521445 B2 - Heterocyclic Substituted Carbonyl Derivatives And Their Use As Dopamine D3 Receptor Ligands - The Lens

Heterocyclic Substituted Carbonyl Derivatives And Their Use As Dopamine D3 Receptor Ligands

Published: Apr 21, 2009
Earliest Priority: Feb 16 2001
Family: 13
Cited Works: 0
Cited by: 0
Cites: 1
Additional Info: Full text

Abstract

The invention relates to heterocyclic substituted carbonyl derivatives that display selective binding to dopamine D3 receptors. In another aspect, the invention relates to a method for treating central nervous system disorders associated with the dopamine D3 receptor activity in a patient in need of such treatment comprising administering to the subject a therapeutically effective amount of said compounds for alleviation of such disorder. The central nervous system disorders that may be treated with these compounds include Psychotic Disorders, Substance Dependence, Substance Abuse, Dyskinetic Disorders (e.g. Parkinson's Disease, Parkinsonism, Neuroleptic-Induced Tardive Dyskinesia, Gilles de la Tourette Syndrome and Huntington's Disease), Dementia, Anxiety Disorders, Sleep Disorders, Circadian Rhythm Disorders and Mood Disorders. The subject invention is also directed towards processes for the preparation of the compounds described herein as well as methods for making and using the compounds as imaging agents for dopamine D3 receptors.

Claims

A compound of the formula (I): wherein
A is CH;

n is 1;

g is 1 or 2;

each R₃is independently hydrogen, C₁-C₆alkyl, or
wherein w is 1, 2, or 3;
R is selected from the group consisting of (a), h), i), k), n)-q), r), t) and (w):
wherein
each R₄, R₁₁, R₁₂and R₁₈is independently hydrogen, C₁-C₆alkyl, halogen, trifluoromethyl, —CO₂C₁-C₆alkyl or —CH₂OC₁-C₆alkyl;

each R₇₁, R₇₂, R₇₄and R₈₀is independently hydrogen, C₁-C₆alkyl, C₁-C₆alkoxy, halogen, trifluoromethyl, —CO₂C₁-C₆alkyl or —CH₂OC₁-C₆alkyl;

R₇₃is hydrogen, alkyl, pyridyl, benzyl, —CH₂CF₃, —CO₂C₁-C₆alkyl, phenyl optionally substituted with halogen, trifluoromethyl, trifluoromethoxy or R₇₃is
wherein w is 1, 2 or 3;
each R₇₅is hydrogen, halogen, C₁-C₆alkyl or C₁-C₆alkoxy;

each R₇₇is hydrogen, halogen, C₁-C₆alkyl or C₁-C₆alkoxy;

p and s are 0, 1, or 2;

R₁₇is hydrogen, C₁-C₆alkyl, Ar, —COAr, —CONHAr or —SO₂—Ar wherein Ar is a phenyl group which is optionally mono- or di-substituted with substituents independently selected from C₁-C₆alkyl, halogen, trifluoromethyl, C₁-C₆alkoxy, nitro, CN and COC₁-C₆alkyl; and
represents a group selected from (b)-(f): wherein
each R₁₉and R₂₀is independently hydrogen, hydroxy or C₁-C₆alkyl;

R₂₁, R₂₂, and R₂₃are each independently hydrogen or C₁-C₃linear alkyl; and

d is 3 or 4;
R₁is a) hydrogen;
b) C₁-C₆alkyl optionally mono- or di-substituted with hydroxy; or
wherein
each R₂₄is independently hydrogen or C₁-C₆alkyl;

each R₂₅, and R₂₆is independently hydrogen or C₁-C₆alkyl;

t is 0 or 1; and

q is 0 or 1;
R₂is a group selected from (a)-(jj): wherein
each R₂₇and R₂₈is independently selected from:
(1) hydrogen;

(2) C₁-C₆alkyl;

(3) C₁-C₆alkoxy;

(4) —CO₂—R₄₃wherein R₄₃is hydrogen or C₁-C₆alkyl;

(5) hydroxy;

(6) —(CH₂)_a—OR₄₄wherein a is 1, 2 or 3 and R₄₄is hydrogen or C₁-C₆alkyl;

(7) —(CO)—NR₄₅R₄₆wherein R₄₅and R₄₆are each independently hydrogen, C₁-C₂alkyl, or R₄₅and R₄₆taken together with the nitrogen to which they are attached form

z is 0 or 1;

e is 2, 3, 4, 5, 6 or 7;

h is 0, 1, 2 or 3;

u is 0, 1, 2, 3 or 4;

o is 0 or 1;

l is 0 or 1;

j is 0, 1, 2 or 3;

v is 0, 1, 2, 3 or 4;

w is 1, 2 or 3;

f is 1, 2, 3 or 4;

t is 0 or 1;

b is 0, 1 or 2;

q is 0 or 1;

aa is 0 or 2;

X is O, S or NR₉₀wherein R₉₀is hydrogen, C₁-C₆alkyl, or
wherein R₁₄₃is hydrogen or alkyl;
each M and V is a group independently selected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆alkoxy, trifluoromethyl, hydroxy, phenyl, phenoxy, —SO₂NH₂or

—NR₄₈R₄₉wherein R₄₈and R₄₉are each independently hydrogen or C₁-C₂alkyl;

each R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, R₃₆, R₃₇, R₃₈, R₃₉, R₄₀, R₆₈, and R₆₉is independently hydrogen or C₁-C₆alkyl;

each R₂₉, R₃₀is independently hydrogen, phenyl or C₁-C₆alkyl;

each R₈₃, R₈₄, R₈₆, R₈₇, R₈₈, R₈₉, R₉₂, R₉₃, R₉₈, R₉₉, R₉₄, R₉₅, R₁₀₀, R₁₀₁, R₁₀₃, R₁₀₄, R₁₀₅, R₁₀₆, R₁₀₈, R₁₀₉, R₁₁₀, R₁₁₁, R₁₁₃, R₁₁₄, R₁₁₅, R₁₁₆, R₁₁₇, R₁₁₈, R₁₁₉, R₁₂₀, R₁₂₂, R₁₂₃, R₁₂₄, R₁₂₅, R₁₂₇, R₁₂₈, R₁₃₀, R₁₃₁, R₁₃₃, R₁₃₄, R₁₃₅, R₁₃₆, R₁₃₇, R₁₃₈, R₁₃₉and R₁₄₀is independently hydrogen or C₁-C₆alkyl;

each R₆₃, R₆₄and R₆₅is independently hydrogen, halogen, C₁-C₆alkyl or C₁-C₆alkoxy;

each R₆₆is independently hydrogen, hydroxy, C₁-C₆alkyl or C₁-C₆alkoxy;

Q is CH₂, CHOH or C═O;

X₅is O or S;

each R₆₇is independently hydrogen or C₁-C₆alkyl;

R₇₀is hydrogen, C₁-C₆alkyl, halogen, nitro or a phenyl group optionally mono-substituted with C₁-C₆alkyl, halogen or trifluoromethyl;

R₈₁is hydrogen, C₁-C₆alkyl, or —CO₂C₁-C₆alkyl;

R₉₁is hydrogen, halogen, C₁-C₆alkyl or C₁-C₆alkoxy;

R₉₆is hydrogen, C₁-C₆alkyl or
wherein R₁₄₅and R₁₄₆are each independently hydrogen or C₁-C₆alkyl and b is 0, 1 or 2;
R₉₇is hydrogen or C₁-C₆alkyl;

each R₁₀₂is independently hydrogen, halogen, C₁-C₆alkyl or C₁-C₆alkoxy;

R₁₀₇is hydrogen or C₁-C₆alkyl;

each R₁₂₁is independently hydrogen, halogen, C₁-C₆alkyl or C₁-C₆alkoxy;

R₁₂₇is hydrogen or C₁-C₆alkyl;

R₁₂₆is C₁-C₆alkyl or benzyl;

R₁₂₉is hydrogen or C₁-C₆alkyl;

R₁₃₂is hydrogen, C₁-C₆alkyl, halogen or C₁-C₆alkoxy;

X₃is O or —NR₁₂₇wherein R₁₂₇is hydrogen or C₁-C₆alkyl;

X₄is O, S or —NR₁₄₃wherein R₁₄₃is hydrogen or C₁-C₆alkyl;

R₁₄₁is hydrogen, C₁-C₆alkyl or amino;

R₁₄₂is benzyl or phenyl each of which may be optionally substituted with C₁-C₆alkyl, halogen or C₁-C₆alkoxy;

R₁₄₄is hydrogen or C₁-C₆alkyl;

R₈₅is hydrogen, C₁-C₆alkoxy, C₁-C₆alkyl, —CO₂C₁-C₆alkyl, C(O)C₁-C₆alkyl or a group selected from the following:
wherein
j is 0, 1, 2 or 3;

w is 1, 2 or 3;

m is 0, 1 or 2;

e is 2, 3, 4, 5, 6 or 7;

each R₁₄₇, R₁₄₈, R₁₅₀, R₁₅₁, R₁₅₂, R₁₅₃, R₁₅₆, R₁₅₇, R₁₅₉, R₁₆₀R₁₆₂and R₁₆₃is independently hydrogen or C₁-C₆alkyl;

R₁₄₉is hydrogen, halogen, C₁-C₆alkyl, phenoxy, trifluoromethyl or trifluoromethoxy;

R₁₅₅is hydrogen, halogen or C₁-C₆alkyl;

R₁₅₈is hydrogen or C₁-C₆alkyl;

R₁₆₁is hydrogen or C₁-C₆alkyl;

R₁₆₄is hydrogen, halogen, C₁-C₆alkyl or trifluoromethyl;

R₁₆₅is hydrogen, C₁-C₆alkyl or halogen;

X₇is O or S or —NR₁₆₇wherein R₁₆₇is hydrogen or C₁-C₆alkyl;

R₁₆₆is hydrogen or C₁-C₆alkyl;

or R₁and R₂are joined together to form a pyrrolidinyl or piperidinyl ring, and in which the ring is optionally mono- or di-substituted, the substituents independently selected from:

(1) C₁-C₆alkyl;

(2) —CO₂—(C₁-C₆alkyl);

(3) —NR₅₀R₅₁wherein R₅₀and R₅₁are each independently hydrogen, C₁-C₆alkyl, or a phenyl group which is optionally mono- or disubstituted with substituents independently selected from C₁-C₆alkyl, halogen or trifluoromethyl;

(4) —C(O)phenyl wherein the phenyl group is optionally mono- or disubstituted with substituents independently selected from C₁-C₆alkyl, halogen or trifluoromethyl;

(5) —(CH₂)_mOR₅₂wherein R₅₂is hydrogen or C₁-C₂alkyl or a phenyl group which is optionally mono- or disubstituted with substituents independently selected from C₁-C₆alkyl, halogen or trifluoromethyl, and m is 0, 1 or 2;

(6) —NR₅₄—COR₅₃wherein R₅₄is hydrogen or C₁-C₆alkyl and R₅₃is hydrogen or C₁-C₂alkyl;

(7) =O;

(8) —CN;
wherein
b is 0, 1 or 2;

w is 1, 2 or 3;

t is 0 or 1;

i is 0, 1 or 2;

v is 0, 1, 2, 3 or 4;

k is 0 or 1;

c are 0, 1 or 2;

R₁₆₇is hydrogen or C₁-C₆alkyl;

each R₅₅, R₅₆, R₅₈, R₅₉, R₁₆₉and R₁₇₀is independently hydrogen or C₁-C₆alkyl;

each R₅₇is independently hydrogen, halogen or C₁-C₆alkyl;

each R₆₀is independently hydrogen, halogen or C₁-C₆alkyl;

R₆₁and R₆₂are each independently hydrogen or C₁-C₆alkyl;

R₁₆₈is hydrogen, thienyl or furanyl;

R₁₇₁is hydrogen, C₁-C₆alkyl, halogen, trifluoromethyl or trifluoromethoxy;
or R₁and R₂are joined together to form a group of formula X; or R₁and R₂are joined together to form the group of formula (Y) or R₁and R₂are joined together to form any of the following groups: wherein
g is 1 or 2;

p is 0, 1 or 2;

R₁₇₂is hydrogen, C₁-C₆alkyl or C₁-C₆alkoxy;

R₁₇₃is hydrogen, C₁-C₆alkyl or phenyl optionally mono- or disubstituted with C₁-C₆alkyl or halogen; and

R₈₂is a substituent selected from the following groups:

(a) C₁-C₆alkyl optionally substituted with hydroxy;

(b) C₁-C₆alkenyl;

(c) C₁-C₆alkoxy;

(d) —(CH₂)OC₁-C₆alkyl;
wherein X₈is —(CR₁₇₅R₁₇₆)_h- or —(CR₁₇₇=CR₁₈₈)—
wherein each R₁₇₄is independently hydrogen, C₁-C₆alkyl, halogen, trifluoromethyl, C₁-C₆alkoxy or benzyloxy;

h is 0, 1, 2 or 3; each R₁₇₅, R₁₇₆, R₁₇₇and R₁₇₈is independently hydrogen or C₁-C₆alkyl; and

j is 0, 1, 2 or 3;
wherein X₉is —(CR₁₈₀R₁₈₁)_j- or —(CR₁₈₄R₁₈₅CR₁₈₆═CR₁₈₇)— or —(CR₁₈₂═CR₁₈₃)—
wherein

aa is 0 or 2;

R₁₇₉is hydrogen, C₁-C₆alkyl, halogen, trifluoromethyl, C₁-C₆alkoxy, benzyloxy or phenyl;

each R₁₈₀, R₁₈₁, R₁₈₂, R₁₈₃, R₁₈₄, R₁₈₅, R₁₈₆and R₁₈₇is independently hydrogen or C₁-C₆alkyl;

j is 0, 1, 2, or 3;
wherein w is 1, 2 or 3;
each R₁₈₈and R₁₈₉is independently hydrogen or C₁-C₆alkyl;
wherein
i is 0, 1 or 2;

each R₁₉₀is independently hydrogen, alkyl or halogen;

b is 0, 1, or 2;

each R₁₉₁and R₁₉₂is independently hydrogen or C₁-C₆alkyl;
wherein
a is 1, 2 or 3;

each R₁₉₃and R₁₉₄is independently hydrogen or C₁-C₆alkyl;

R₁₉₅is hydrogen, halogen or C₁-C₆alkyl;
wherein
e is 2, 3, 4, 5 or 6;

b is 0, 1 or 2;

each R₁₉₆and R₁₉₇is independently hydrogen or C₁-C₆alkyl;

each R₁₉₈and R₁₉₉is independently hydrogen or C₁-C₆alkyl;
wherein
each R₂₀₀and R₂₀₁is independently hydrogen or C₁-C₆alkyl;

w is 1, 2 or 3;
wherein
each R₂₀₂, R₂₀₃, R₂₀₄and R₂₀₅is independently hydrogen or C₁-C₆alkyl; and

w is 1, 2 or 3;
(n)
—(CR₂₀₆R₂₀₇)_w—OC₁-C₆alkyl

wherein

C₁-C₆alkyl is optionally substituted with hydroxy;

each R₂₀₆and R₂₀₇is independently hydrogen or C₁-C₆alkyl; and

w is 1, 2 or 3;
(o)
—(CR₂₀₈R₂₀₉)_w—NR₂₁₀R₂₁₁

wherein

each R₂₀₈, R₂₀₉, R₂₁₀and R₂₁₁is independently hydrogen or C₁-C₆alkyl;

w is 1, 2 or 3;
The compound of claim 1 which is 2-(4-thieno[2,3-d]isoxazol-3-yl-piperidin-1-ylmethyl)-(2R,3R)-cyclopropanecarboxylic acid (trans4-methyl-cyclohexyl)-amide.
The compound of claim 1 which is 2-(4-thieno[2,3-d]isoxazol-3-yl-piperidin-1-ylmethyl)-(2R,3R)-cyclopropanecarboxylic acid (3-imidazol-1-yl-propyl)-amide.
The compound of claim 1 which is 2R-[4-(5-Trifluoromethyl-benzo[d]isoxazol-3-yl)-piperidin-1-ylmethyl]-cyclopropane-1R-carboxylic acid trans-(4-methyl-cyclohexyl)-amide.
The compound of claim 1 which is (3S-Imidazol-1-ylmethyl-piperidin-1-yl)-{2R-[4-(7-methoxy-benzo[d]isoxazol-3-yl)-piperidin-1-ylmethyl]-1R-cyclopropyl}-methanone.
The compound of claim 1 which is 2R-[4-(1-Methyl-7-trifluoromethyl-1H-indazol-3-yl)-piperidin-1-ylmethyl]-1R-cycloproanecarboxylic acid (3-imidazol-1-yl-propyl)-amide.
The compound of claim 1 which is (3S-Imidazol-1-ylmethyl-pipendin-1-yl)-{2R-[4-(7-trifluoromethyl-benzo[d]isoxazol-3-yl)-piperidin-1-ylmethyl]-1R-cyclopropyl}-methanone.
The compound of claim 1 which is 2R-[4-(7-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperidin-1-ylmethyl]-1R-cyclopropanecarboxylic acid (trans-4-methyl-cyclohexyl)-amide.
The compound of claim 1 which is (3S-lmidazol-1-ylmethyl-piperidin-1-yl)-{2R-[4-(1-methyl-6-trifluoromethyl-1H-indazol-3-yl)-piperidin-1-ylmethyl]-1R-cyclopropyl}-methanone.
The compound of claim 1 which is 2R-[4-(6-Trifluoromethyl-benzo[d]isoxazol-3-yl)-piperidin-1-ylmethyl]-1R-cycloproanecarboxylic acid (3-imidazol-1-yl-propyl)-amide.
The compound of claim 1 which is (3S-Imidazol-1-ylmethyl-piperidin-1-yl)-{2R-[4-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperidin-1-ylmethyl]-1R-cyclopropyl}-methanone.
The compound of claim 1 which is 2R-[4-(6-Fluoro-7-methoxy-benzo[d]isoxazol-3-yl)-piperidin-1-ylmethyl]-1R-cyclopranecarboxylic acid (trans-4-methyl-cyclohexyl)-amide.
The compound of claim 1 which is 2R-[4-(1-Methyl-1H-thienol[3,2-c]pyrazol-3-yl)-piperidin-1-ylmethyl]-1R-cycloproanecarboxylic acid (3-imidazol-1-yl-propyl)-amide.
The compound of claim 1 which is 2R-{4-[1-(2,2,2-Trifluoro-ethyl)-1H-thieno [3,2-c]pyrazol-3-yl)-piperidin-1-ylmethyl]-1R-cycloproanecarboxylic acid (3-imidazol-1-yl-propyl)-amide.
The compound of claim 1 which is 2R-(4-Benzo[b]thiophen-2-yl-piperidin-1-ylmethyl)-1R-cyclopranecarboxylic acid (trans-4-methyl-cyclohexyl )-amide.
A pharmaceutical composition comprising an effective amount of a compound of claim 1 with a pharmaceutically-acceptable carrier or diluent.
A pharmaceutical composition comprising an effective amount of a compound of claim 1 with a pharmaceutically-acceptable carrier or diluent in conjunction with one or more dopamine D₁, D₂, D₄, D₅or 5HT receptor antagonists.
A process for preparing a compound of formula I of claim 1 which comprises:
(a) reacting a compound of formula (II):
wherein R₃, g, R, A and n are as defined in formula I of claim 1; with a compound of formula (III) wherein “LG” is a suitable leaving group selected from chlorine, bromine, iodine and mesyl; and is as defined in formula I of claim 1;
to provide a compound of formula (IV)

b) hydrolyzing a compound of formula (IV) to provide a compound of formula (V)
and (c) reacting a compound of formula (V) with a compound of formula (VI) wherein R₁and R₂are as defined in formula (I) of claim 1; to provide the compound of formula (I).
A process for preparing compounds of formula I of claim 1 which comprises:
(a) reacting a compound of formula (VII)

wherein “LG” is a suitable leaving group selected from chlorine, bromine, iodine and mesyl;

and
R₁and R₂are as defined in formula I of claim 1; with a compound of formula (II)
wherein R₃, g,R, A and n are as defined in formula I of claim 1; to provide th compound of formula (I).