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
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A compound of the formula (I):
wherein
A is CH;
n is 1;
g is 1 or 2;
each R3 is 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):
whereineach R4, R11, R12 and R18 is independently hydrogen, C1-C6alkyl, halogen, trifluoromethyl, —CO2C1-C6alkyl or —CH2OC1-C6alkyl;
each R71, R72, R74 and R80 is independently hydrogen, C1-C6alkyl, C1-C6alkoxy, halogen, trifluoromethyl, —CO2C1-C6alkyl or —CH2OC1-C6alkyl;
R73 is hydrogen, alkyl, pyridyl, benzyl, —CH2CF3, —CO2C1-C6alkyl, phenyl optionally substituted with halogen, trifluoromethyl, trifluoromethoxy or R73 is
wherein w is 1, 2 or 3;each R75 is hydrogen, halogen, C1-C6alkyl or C1-C6alkoxy;
each R77 is hydrogen, halogen, C1-C6alkyl or C1-C6alkoxy;
p and s are 0, 1, or 2;
R17 is 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): whereineach R19 and R20 is independently hydrogen, hydroxy or C1-C6alkyl;
R21, R22, and R23 are each independently hydrogen or C1-C3 linear alkyl; and
d is 3 or 4;
R1 is a) hydrogen;b) C1-C6alkyl optionally mono- or di-substituted with hydroxy; or
whereineach R24 is independently hydrogen or C1-C6alkyl;
each R25, and R26 is independently hydrogen or C1-C6alkyl;
t is 0 or 1; and
q is 0 or 1;
R2 is a group selected from (a)-(jj): whereineach R27 and R28 is independently selected from:
(1) hydrogen;
(2) C1-C6alkyl;
(3) C1-C6alkoxy;
(4) —CO2—R43 wherein R43 is hydrogen or C1-C6alkyl;
(5) hydroxy;
(6) —(CH2)a—OR44 wherein a is 1, 2 or 3 and R44 is hydrogen or C1-C6alkyl;
(7) —(CO)—NR45R46 wherein R45 and R46 are each independently hydrogen, C1-C2alkyl, or R45 and R46 taken 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 NR90 wherein R90 is hydrogen, C1-C6alkyl, or
wherein R143 is hydrogen or alkyl;each M and V is a group independently selected from hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy, trifluoromethyl, hydroxy, phenyl, phenoxy, —SO2NH2 or
—NR48R49 wherein R48 and R49 are each independently hydrogen or C1-C2alkyl;
each R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R68, and R69 is independently hydrogen or C1-C6alkyl;
each R29, R30 is 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, R139 and R140 is independently hydrogen or C1-C6alkyl;
each R63, R64 and R65 is independently hydrogen, halogen, C1-C6alkyl or C1-C6alkoxy;
each R66 is independently hydrogen, hydroxy, C1-C6alkyl or C1-C6alkoxy;
Q is CH2, CHOH or C═O;
X5is O or S;
each R67 is independently hydrogen or C1-C6alkyl;
R70 is hydrogen, C1-C6alkyl, halogen, nitro or a phenyl group optionally mono-substituted with C1-C6alkyl, halogen or trifluoromethyl;
R81 is hydrogen, C1-C6alkyl, or —CO2C1-C6alkyl;
R91 is hydrogen, halogen, C1-C6alkyl or C1-C6alkoxy;
R96 is hydrogen, C1-C6alkyl or
wherein R145 and R146 are each independently hydrogen or C1-C6alkyl and b is 0, 1 or 2;R97 is hydrogen or C1-C6alkyl;
each R102 is independently hydrogen, halogen, C1-C6alkyl or C1-C6alkoxy;
R107 is hydrogen or C1-C6alkyl;
each R121 is independently hydrogen, halogen, C1-C6alkyl or C1-C6alkoxy;
R127 is hydrogen or C1-C6alkyl;
R126 is C1-C6alkyl or benzyl;
R129 is hydrogen or C1-C6alkyl;
R132 is hydrogen, C1-C6alkyl, halogen or C1-C6alkoxy;
X3 is O or —NR127 wherein R127 is hydrogen or C1-C6alkyl;
X4 is O, S or —NR143 wherein R143 is hydrogen or C1-C6alkyl;
R141 is hydrogen, C1-C6alkyl or amino;
R142 is benzyl or phenyl each of which may be optionally substituted with C1-C6alkyl, halogen or C1-C6alkoxy;
R144 is hydrogen or C1-C6alkyl;
R85 is hydrogen, C1-C6alkoxy, C1-C6alkyl, —CO2C1-C6alkyl, C(O)C1-C6alkyl or a group selected from the following:
whereinj 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, R160 R162 and R163 is independently hydrogen or C1-C6alkyl;
R149 is hydrogen, halogen, C1-C6alkyl, phenoxy, trifluoromethyl or trifluoromethoxy;
R155 is hydrogen, halogen or C1-C6alkyl;
R158 is hydrogen or C1-C6alkyl;
R161 is hydrogen or C1-C6alkyl;
R164 is hydrogen, halogen, C1-C6alkyl or trifluoromethyl;
R165 is hydrogen, C1-C6alkyl or halogen;
X7 is O or S or —NR167 wherein R167 is hydrogen or C1-C6alkyl;
R166 is hydrogen or C1-C6alkyl;
or R1 and R2 are 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) —NR50R51 wherein R50 and R51 are 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)mOR52 wherein R52 is 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—COR53 wherein R54 is hydrogen or C1-C6alkyl and R53 is hydrogen or C1-C2alkyl;
(7) =O;
(8) —CN;
whereinb 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;
R167 is hydrogen or C1-C6alkyl;
each R55, R56, R58, R59, R169 and R170 is independently hydrogen or C1-C6alkyl;
each R57 is independently hydrogen, halogen or C1-C6alkyl;
each R60 is independently hydrogen, halogen or C1-C6alkyl;
R61 and R62 are each independently hydrogen or C1-C6alkyl;
R168 is hydrogen, thienyl or furanyl;
R171 is hydrogen, C1-C6alkyl, halogen, trifluoromethyl or trifluoromethoxy;
or R1 and R2 are joined together to form a group of formula X; or R1 and R2 are joined together to form the group of formula (Y) or R1 and R2 are joined together to form any of the following groups: whereing is 1 or 2;
p is 0, 1 or 2;
R172 is hydrogen, C1-C6alkyl or C1-C6alkoxy;
R173 is hydrogen, C1-C6alkyl or phenyl optionally mono- or disubstituted with C1-C6alkyl or halogen; and
R82 is 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 X8 is —(CR175R176)h- or —(CR177=CR188)—wherein each R174 is independently hydrogen, C1-C6alkyl, halogen, trifluoromethyl, C1-C6alkoxy or benzyloxy;
h is 0, 1, 2 or 3; each R175, R176, R177 and R178 is independently hydrogen or C1-C6alkyl; and
j is 0, 1, 2 or 3;
wherein X9 is —(CR180R181)j- or —(CR184R185CR186═CR187)— or —(CR182═CR183)—wherein
aa is 0 or 2;
R179 is hydrogen, C1-C6alkyl, halogen, trifluoromethyl, C1-C6alkoxy, benzyloxy or phenyl;
each R180, R181, R182, R183, R184, R185, R186 and R187 is independently hydrogen or C1-C6alkyl;
j is 0, 1, 2, or 3;
wherein w is 1, 2 or 3;each R188 and R189 is independently hydrogen or C1-C6alkyl;
whereini is 0, 1 or 2;
each R190 is independently hydrogen, alkyl or halogen;
b is 0, 1, or 2;
each R191 and R192 is independently hydrogen or C1-C6alkyl;
whereina is 1, 2 or 3;
each R193 and R194 is independently hydrogen or C1-C6alkyl;
R195 is hydrogen, halogen or C1-C6alkyl;
whereine is 2, 3, 4, 5 or 6;
b is 0, 1 or 2;
each R196 and R197 is independently hydrogen or C1-C6alkyl;
each R198 and R199 is independently hydrogen or C1-C6alkyl;
whereineach R200 and R201 is independently hydrogen or C1-C6alkyl;
w is 1, 2 or 3;
whereineach R202, R203, R204 and R205 is 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 R206 and R207 is independently hydrogen or C1-C6alkyl; and
w is 1, 2 or 3;
(o)—(CR208R209)w—NR210R211
wherein
each R208, R209, R210 and R211 is 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, D5 or 5HT receptor antagonists.
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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 R1 and R2 are 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
R1 and R2 are 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).
Owners (US)
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Aventis Pharmaceuticals Inc
(Nov 25 2005)
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Aventis Pharma Deutschland Gmbh
(May 01 2002)
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Aventis Pharma S.a
(Apr 18 2002)
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Applicants
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Aventis Pharma Inc
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Inventors
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Hendrix James
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Hemmerle Horst
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Urmann Matthias
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Shutske Gregory M
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Strupczewski Joseph T
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Bordeau Kenneth J
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Jurcak John G
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Nieduzak Thaddeus
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Jackson Sharon A
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Angell Paul
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Carey James P
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Lee George
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Fink David
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Sabuco Jean-francois
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Chiang Yulin
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Collar Nicola
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A61K31/496
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C07D209/08
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A61K31/5377
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514/233.8
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Document Preview
- Publication: Apr 21, 2009
-
Application:
Mar 5, 2007
US 71404707 A
-
Priority:
Mar 5, 2007
US 71404707 A
-
Priority:
Apr 6, 2004
US 81903704 A
-
Priority:
Feb 19, 2002
US 7822502 A
-
Priority:
Jul 19, 2001
GB 0117577 A
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Priority:
Feb 16, 2001
US 26967201 P