1, 4-DISUBSTITUTED 3-CYANO-PYRIDONE DERIVATIVES AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2-RECEPTORS
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Abstract
The present invention relates to novel compounds, in particular novel pyridinone derivatives according to Formula (I)
wherein all radicals are defined in the application and claims. The compounds according to the invention are positive allosteric modulators of metabotropic receptors-subtype 2 (“mGluR2”) which are useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved. In particular, such diseases are central nervous system disorders selected from the group of anxiety, schizophrenia, migraine, depression, and epilepsy. The invention is also directed to pharmaceutical compositions and processes to prepare such compounds and compositions, as well as to the use of such compounds for the prevention and treatment of such diseases in which mGluR2 is involved.
148 Citations
66 Claims
-
1-33. -33. (canceled)
-
34. A compound comprising Formula (I),
wherein V1 is selected from the group of a covalent bond and a bivalent saturated or unsaturated, straight or branched hydrocarbon radical having from 1 to 6 carbon atoms; -
M1 is selected from the group of hydrogen;
cycloC3-7alkyl;
aryl;
alkylcarbonyl;
alkyloxy;
aryloxy;
arylalkyloxy;
arylcarbonyl;
hexahydrothiopyranyl; and
Het1;L is selected from the group of a covalent bond;
—
O—
;
—
OCH2—
;
—
OCH2CH2—
;
—
OCH2CH2O—
;
—
OCH2CH2OCH2—
;
—
S—
;
—
NR7—
;
—
NR7CH2—
;
—
NR7cycloC3-7;
—
NR7CH2CH2—
;
—
OCH2CH2N(R7)CH2—
;
—
CH2—
;
—
CH2CH2—
;
—
CH2CH2CH2;
—
C≡
C—
;
—
C═
O—
; and
—
C(R8)═
C(R9)—
;
wherein each of R7, independently of each other, is selected from the group of hydrogen and C1-3alkyl; and
wherein R8 and R9, independently of each other, are selected from the group of hydrogen, halo and C1-3alkyl;R2 and R3 are each independently of each other hydrogen, halo or alkyl; A is Het2 or phenyl, wherein each radical is optionally substituted with n radicals R4, wherein n is an integer equal to zero, 1, 2 or 3; R4 is selected from the group of halo;
cyano;
hydroxy;
oxo;
formyl;
ethanoyl;
carboxyl;
nitro;
thio;
alkyl;
alkyloxy;
alkyloxyalkyl;
alkyloxycarbonyl;
alkyloxycarbonylalkyl;
alkylcarbonyl;
alkylcarbonyloxy;
alkylcarbonylalkyloxy;
polyhaloC1-3alkyl;
polyhaloC1-3alkyloxy;
polyhaloC1-3alkylthio;
alkylthio;
alkylsulfonyl;
Het3;
Het3-alkyl;
Het3-oxy;
Het3-oxyalkyl;
Het3-alkyloxy;
Het3-oxyalkyloxy;
Het3-carbonyl;
Het3-carbonylalkyl;
Het3-thio;
Het3-thioalkyl;
Het3-sulfonyl;
aryl;
arylalkyl;
aryloxy;
aryloxyalkyl;
arylalkyloxy;
arylalkenyl;
arylcarbonylalkyl;
arylthioalkyl;
arylsulfonyl;
—
NRaRb;
alkyl-NRaRb;
O-alkyl-NRaRb;
—
C(═
O)—
NRaRb;
—
C(═
O)-alkyl-NRaRb; and
O-alkyl-C(═
O)—
NRaRb;
wherein Ra and Rb are selected from the group of hydrogen, alkyl, alkylcarbonyl, arylalkyl, alkyloxyalkyl, Het3, Het3alkyl, alkylsulfonyl, alkyl-NRcRd, and C(═
O)alkyl-NRcRd, wherein Rc and Rd are selected from the group of hydrogen, alkyl and alkylcarbonyl;or two radicals R4 may be combined to form a bivalent radical —
X1—
C1-6—
X2—
wherein C1-6 is a saturated or unsaturated, straight or branched hydrocarbon radical having 1 to 6 carbon atoms and X1 and X2 are each independently C, O or NH;
wherein the bivalent radical is optionally substituted with one or more radicals selected from the group of halo, polyhaloC1-3alkyl, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio, formyl and ethanoyl;Het1 is selected from the group of tetrahydropyranyl; and
pyridinyl;
wherein each radical is optionally substituted with 1, 2 or 3 substituents, each independently from each other, selected from the group of halo, C1-3alkyl, polyhaloC1-3alkyl, polyhaloC1-3alkyloxy, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio, formyl, ethanoyl, and C1-3alkyloxy;Het2 is selected from the group of piperazinyl;
piperidinyl;
thienyl;
furanyl;
1H-indazolyl;
1H-benzimidazolyl;
1,2,3,4-tetrahydro-isoquinolinyl;
2,5-diaza-bicyclo[2.2.1]heptyl;
pyrrolidinyl;
azetidinyl;
2,7-diaza-spiro[3.5]nonyl;
pyridinyl;
pyrazolyl;
indolinyl;
1H-indolyl;
1H-indazolyl;
benzomorpholinyl;
thiazolyl;
1,2,3,4-tetrahydroquinolinyl;
3,9-diazaspiro[5.5]undecyl;
1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolinyl;
1,2,3,4,4a,10a-hexahydro-benzo[5,6][1,4]dioxino[2,3-c]pyridinyl;
2,3,4,9tetrahydro-1H-indeno[2,1-c]pyridinyl;
2,3,4,9-tetrahydro-1H-β
-carbolinyl;
1,2,3,4-tetrahydro-benzo[4,5]furo[2,3-c]pyridinyl;
1,2,3,4-tetrahydrobenzo[4,5]thieno[2,3-c]pyridinyl;
[1,4]diazepyl;
isoxazolyl;
indanyl; and
indolyl;Het3 is selected from the group of pyridinyl;
pyrimidinyl;
pyridazilyl;
pyrazinyl;
piperidinyl;
pyrrolyl;
pyrrolidinyl;
piperazinyl;
triazolyl;
tetrazolyl;
indolyl;
thienyl;
furanyl;
tetrahydropyranyl;
tetrahydro-thiopyran-1,1-dioxide;
thiazolyl;
thiadiazolyl;
isothiazolyl;
oxazolyl;
morpholinyl;
oxadiazolyl;
isoxazolyl;
imidazolyl;
pyrazolyl;
benzoimidazolyl;
benzoxazolyl;
benzothienyl;
benzothiazolyl;
benzofuranyl;
benzomorpholinyl;
1,2,3,4-tetrahydro-isoquinolinyl;
thionaphtyl;
indolyl;
indolinyl;
quinolyl;
isoquinolyl;
quinoxalyl;
phthalazyl;
benzo[1,3]dioxyl; and
quinazolyl;
wherein each radical is optionally substituted with 1, 2 or 3 substituents, each independently from each other, selected from the group of halo, C1-6alkyl, polyhaloC1-3alkyl, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio, formyl, ethanoyl, phenyl, pyrrolidinyl, piperidinyl, pyridinyl, morpholinyl, mono- and di(alkyl)amino, and C1-3alkyloxy;Aryl is naphthyl, phenyl, or biphenyl;
wherein each radical is optionally substituted with 1, 2 or 3 substituents, each independently from each other selected from the group of halo, C1-3alkyl, polyhaloC1-3alkyl, polyhaloC1-3alkyloxy, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio, formyl, ethanoyl, ethyloxycarbonyl, and C1-3alkyloxy;alkyl is a saturated, straight or branched hydrocarbon radical having from 1 to 6 carbon atoms;
or is a saturated, cyclic hydrocarbon radical having from 3 to 7 carbon atoms;
or is saturated hydrocarbon radical from 4 to 12 carbon atoms, comprising at least one saturated, straight or branched hydrocarbon radical having from 1 to 6 carbon atoms and at least one saturated, cyclic hydrocarbon radical having from 3 to 7 carbon atoms;
wherein each carbon atom may optionally be substituted with one or more radicals selected from the group of halo, polyhaloC1-3alkyl, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio, formyl, ethanoyl, carbamoyl;
phenyl; and
a bivalent radical —
OCH2CH2O—
; andalkenyl is alkyl, additionally containing one or more double bonds. - View Dependent Claims (35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 64, 66)
M1 is selected from the group of hydrogen;
cycloC3-7alkyl;
phenyl;
biphenyl;
phenyloxy;
benzyloxy;
furanyl, and pyridinyl;
wherein M1 is optionally substituted with one or more radicals selected from the group of halo;
C1-3alkyl;
polyhaloC1-3alkyl;
polyhaloC1-3alkyloxy; and
C1-3alkyloxy;L is selected from the group of covalent bond;
—
O—
;
—
OCH2—
;
—
OCH2CH2—
;
—
OCH2CH2O—
;
—
OCH2CH2OCH2—
;
—
NR7—
;
—
NR7CH2—
;
—
NR7cycloC3-7;
—
OCH2CH2N(R7)CH2—
;
—
CH2CH2—
;
—
C≡
C—
;
—
C═
O— and
—
CH═
CH—
;
wherein each of R7, independently of each other, is selected from the group of hydrogen and C1-3alkyl;R2 and R3 are each independently of each other hydrogen, halo or alkyl; A is selected from the group of phenyl, piperazinyl, and piperidinyl, wherein each radical is optionally substituted with n radicals R4, wherein n is an integer equal to zero or 1; R4 is selected from the group of halo;
cyano;
hydroxy;
ethanoyl;
alkyl;
alkyloxy;
alkyloxyalkyl;
alkyloxycarbonyl;
alkyloxycarbonylalkyl;
alkylcarbonyl;
alkylcarbonyloxy;
alkylcarbonylalkyloxy;
poly-;
polyhalo C1-3 alkyloxy;
alkylthio;
alkylsulfonyl;
Het3;
Het3-alkyl;
Het3-oxy;
Het3-oxyalkyl;
Het3-alkyloxy;
Het3-oxyalkyloxy;
Het3-carbonyl;
Het3-thio alkyl;
aryl;
arylalkyl;
aryloxy;
aryloxyalkyl;
arylalkyloxy;
arylalkenyl;
arylcarbonylalkyl;
arylsulfonyl;
—
NRaRb;
alkyl-NRaRb;
O-alkyl-NRaRb;
—
C(═
O)—
NRaRb;
—
C(═
O)-alkyl-NRaRb; and
O-alkyl-C(═
O)—
NRaRb;
wherein Ra and Rb are selected from the group of hydrogen, alkyl, alkyl-carbonyl, arylalkyl, alkyloxyalkyl, Het3, Het3 alkyl, alkylsulfonyl, alkyl-NRcRd and C(═
O)alkyl-NRcRd, wherein Rc and Rd are selected from the group of hydrogen, alkyl and alkylcarbonyl;
or two radicals R4 may be combined to form a bivalent radical selected from the group of —
CH2CH2—
O—
;
—
O—
CH2—
O—
; and
—
O—
CH2CH2—
O—
;Het1 is selected from the group of tetrahydropyranyl; and
pyridinyl;
wherein each radical Het1 is optionally substituted with 1, 2 or 3 polyhaloC1-3alkyl substituents;Het2 is selected from the group of piperazinyl;
piperidinyl;
thienyl;
furanyl;
1H-indazolyl;
1H-benzimidazolyl;
1,2,3,4-tetrahydro-isoquinolinyl;
2,5-diaza-bicyclo[2.2.1]heptyl;
pyrrolidinyl;
azetidinyl;
2,7-diaza-spiro[3.5]nonyl;
pyridinyl;
pyrazolyl;
indolinyl;
1H-indolyl;
1H-indazolyl;
benzomorpholinyl;
thiazolyl;
1,2,3,4-tetrahydroquino-linyl;
3,9-diazaspiro[5.5]undecyl;
1,2,3,4,4a,5,6,10b-octahydro-benzo-[fjquinolinyl;
1,2,3,4,4a,10a-hexahydro-benzo[5,6][1,4]dioxino[2,3-c]-pyridinyl;
2,3,4,9-tetrahydro-1H-indeno[2,1-c]pyridinyl;
2,3,4,9-tetrahydro-1H-β
-carbolinyl;
1,2,3,4-tetrahydro-benzo[4,5]furo[2,3-c]pyridinyl;
1,2,3,4-tetrahydro-benzo[4,5]thieno[2,3-c]pyridinyl;
[1,4]diazepyl;
isoxazolyl;
indanyl; and
indolyl;Het3 is selected from the group of pyridinyl;
pyrimidinyl;
pyridazilyl;
pyrazinyl;
piperidinyl;
pyrrolidinyl;
piperazinyl;
triazolyl;
tetrahydropyranyl;
tetrahydro-thiopyran-1,1-dioxide;
thiazolyl;
oxazolyl;
morpholinyl;
oxadiazolyl;
imidazolyl;
benzoxazolyl;
benzothienyl;
benzofuranyl;
1,2,3,4-tetrahydro-isoquinolinyl;
indolyl;
indolinyl;
phthalazyl; and
benzo[1,3]dioxyl;
wherein each radical is optionally substituted with 1, 2 or 3 substituents, each independently from each other, selected from the group of halo, C1-6alkyl, cyano, hydroxy, oxo, ethanoyl, phenyl, pyrrolidinyl, piperidinyl, pyridinyl, morpholinyl, mono- and di(alkyl)amino, and C1-3alkyloxy;aryl is phenyl or biphenyl;
wherein each radical is optionally substituted with 1, 2 or 3 substituents, each independently from each other selected from the group of halo, C1-3 alkyl, polyhaloC1-3 alkyloxy, cyano, nitro, ethyloxycarbonyl, and C1-3alkyloxy; and
alkyl is a saturated, straight or branched hydrocarbon radical having from 1 to 6 carbon atoms;
or is a saturated, cyclic hydrocarbon radical having from 3 to 7 carbon atoms;
or is saturated hydrocarbon radical from 4 to 12 carbon atoms, comprising at least one saturated, straight or branched hydrocarbon radical having from 1 to 6 carbon atoms and at least one saturated, cyclic hydrocarbon radical having from 3 to 7 carbon atoms;
wherein each carbon atom may optionally be substituted with one or more radicals selected from the group of cyano, hydroxy, carboxyl, carbamoyl, phenyl, and a bivalent radical —
OCH2CH2O—
.
-
-
46. The compound of claim 34, wherein Formula I comprises 4-(4-(N-acetylmethyl)phenyl)-3-cyano-1-(3-methylbutyl)pyridine-2(1H)-one (compound 1-179);
- 4-(3,4-dimethoxyphenyl-3-cyano-1-(3-methylbutyl)pyridine-2(1H)-one (compound 1-110);
3-cyano-4-(3-fluoro-4-methoxyphenyl)-1-(3-methylbutyl)pyridine-2(1H)—
one (compound 1-114);
3-cyano-4-(4-hydroxypropylphenyl)-1-(3-methylbutyl)pyridine-2(1H)-one (compound 1-095);
3-cyano-4-(4-methoxymethylphenyl)-1-(3-methylbutyl)pyridine-2(1H)-one (compound 1-103);
3-cyano-4-(2-fluoro-4-methoxyphenyl)-1-(3-methylbutyl)pyridine-2(1H)—
one (compound 1-113);
3-cyano-4-(4-(N-morpholyl)phenyl)-1-(3-methylbutyl)pyridine-2(1H)-one (compound 1-223);
3-cyano-1-(3-methylbutyl)-4-(phenylethynyl)pyridine-2(1H)-one (compound 1-267);
3-cyano-1-butyl-4-[4-(2-methyl-pyridin-4-yloxy)-phenyl]-pyridine-2(1H)—
one (compound 1-064);
or 3-cyano-1-cyclopropylmethyl-4-(4-phenyl-piperidin-1-yl)-pyridine-2(1H)—
one (compound 4-047).
- 4-(3,4-dimethoxyphenyl-3-cyano-1-(3-methylbutyl)pyridine-2(1H)-one (compound 1-110);
-
47. The compound of claim 34, wherein the compound exists as optical isomers, wherein said compound is either the racemic mixture or the individual optical isomer.
-
48. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 34 and a pharmaceutically acceptable carrier and/or excipient.
-
49. The compound of claim 34, further comprising a medicament.
-
64. The method of claim 50, wherein an orthosteric agonist of mGluR2 is used in combination with a compound of claim 34.
-
66. A method for imaging an mGluR2 receptor, the method comprising administering to the subject a compound of claim 34.
- 50. A method for treating, preventing, ameliorating, or reducing the risk of a condition in a mammal, wherein the treatment, prevention, amelioration, or reduction of risk is affected or facilitated by the neuromodulatory effect of an mGluR2 positive allosteric modulator.
Specification