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US 6,646,124 B2Granted
Substituted 4-oxo-napthyridine-3-carboxamides: GABA brain receptor ligands
AssigneeNeurogen Corporation
InventorsPamela A. Albaugh, Robert W. DeSimone, Gang Liu
Life of this patent
Estimating the term…
Abstract
The present invention encompasses structures of the Formula or the pharmaceutically acceptable non-toxic salts thereof wherein: X is hydrogen, halogen, (un)substituted alkyl, (un)substituted alkoxy or amino; and Y is (un)substituted alkyl, aryl, or heteroaryl, which compounds are highly selective agonists, antagonists or inverse agonists for GABAa brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABAa brain receptors. These compounds are useful in the diagnosis and treatment of anxiety, Down Syndrome, sleep, cognitive and seizure disorders, and overdose with benzodiazepine drugs and for enhancement of alertness.
Claims8
A compound of the formula:
- or a Pharmaceutically acceptable salt thereof wherein:
- X is
- (i) hydrogen, halogen, mono- or dialkylamino, alkoxy,
- (ii) a group of the formula:
- where G is lower alkylene having 1-6 carbon atoms, or a cyclic group of the formula
- where n is 0, 1, or 2, and m is an integer of from 1 to 5, with the proviso that the sum of n+m is not less than 1 or greater than 5;
- and
- R1 is hydrogen, lower alkyl, or (C3-C7)cycloalkyl, where the alkyl or cycloalkyl is optionally substituted with halogen, lower alkoxy, or mono- or di (C1-C6) alkylamino;
- (iii) a group of the formula:
- where C is as defined for ii;
- and
- R2 and R3 independently represent hydrogen, lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7 carbon atoms, —SO2R8 where R8 is (C1-C6)alkyl, (C3-C7)cycloalkyl, or optionally substituted phenyl, or
- R2 and R3 together with the nitrogen atom to which they are attached form a heterocyclic moiety such as imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl, or piperidinyl;
- (iv) a group of the formula:
- where
- R2 is as defined for iii;
- R4 is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms, and may be optionally substituted with one or more (C1-C6)alkoxy or mono-or di(C1-C6)alkylamino groups;
- and
- G is as defined for ii;
- (v) a group of the formula:
- where
- R2 and G are as defined for iv and ii, respectively, and
- R5 and R6 independently represent hydrogen, lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7 carbon atoms, —SO2R8 where R8 is (C1-C6)alkyl, (C3-C7)cycloalkyl, or optionally substituted phenyl, or
- R5 and R6 together with the nitrogen atom to which they are attached form a heterocyclic moiety;
- (vi) a group of the formula:
- where G is as defined for ii;
- or
- (vii) a group of the formula:
- where each G is as defined above for ii;
- and
- Y is
- (viii) pyrimidinyl (C1-C6alkyl) or pyridyl (C1-C5) alkyl;
- or
- (ix) a group of the formula:
- where is R18 hydrogen, amino, mono-, or di(C1-C6)alkylamino, or C1-C6 alkyl optionally substituted with R19 where R19 represents:
- where V and V′ are independently CH or nitrogen;
- A″ is C1-C6 alkylene;
- and
- R20 is phenyl, pyridyl, or pyrimidinyl, each of which is optionally mono-, di-, or tri-substituted independently with halogen, hydroxy, C1-C6alkoxy, amino, and mono- and di(C1-C6) alkylamino.
36 more elements
A compound of the Formula:
- or a pharmaceutically acceptable salt thereof wherein:
- X is a group of the formula:
- and
- Y is
- (i) lower alkyl having 1-8 carbon atoms or cycloalkyl having 3-7 carbon atoms, any of which may be optionally substituted with one or more halogen, (C1-C6)alkoxy, alkoxyalkoxy where each alkoxy is (C1-C6)alkoxy, (C1-C6)alkylthio, (C3-C7)cycloalkylthio, aryl, heteroaryl, or mono- or di(C1-C6) alkylamino groups;
- (ii) a group of the formula:
- where K is lower alkylene having 1-6 carbon atoms optionally substituted with (C1-C6)alkyl or alkylene, or a cyclic group of the formula
- where K′ independently represents hydrogen or (C1-C6)alkyl or alkylene, n is 0, 1, or 2, and m is an integer of from 1 to 5, with the proviso that the sum of n+m is not less than 1 or greater than 5;
- and
- R9 is hydrogen, lower alkyl, or (C3-C7)cycloalkyl, where the alkyl or cycloalkyl is optionally substituted with halogen, lower alkoxy, or mono- or dialkylamino;
- (iii)a group of the formula:
- where K is defined as in ii;
- (iv) a group of the formula:
- where K is as defined for ii, and
- R13 is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms, where the alkyl and cycloalkyl groups are optionally substituted with one or more (C1-C6)alkoxy or mono- or di(C1-C6) alkylamino groups;
- and
- (v) a group of the formula:
- where
- K is as defined for ii, and
- R7 is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms;
- and
- (vi) a group of the formula:
- where
- K is as defined for ii;
- and
- R14 and R15 independently represent hydrogen, lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7 carbon atoms, —SO2R8 where R8 is (C1-C6)alkyl, (C3-C7)cycloalkyl, or optionally substituted phenyl, or
- R14 and R15 together with the nitrogen atom to which they are attached form a heterocyclic moiety;
- (vii) a group of the formula:
- where K and R15 are as defined above in ii and vi, respectively;
- (viii) a group of the formula:
- where
- K is as defined for ii;
- R10 and R10′ are the same or different and are selected from hydrogen, halogen, hydroxy, lower alkoxy having 1-6 carbon atoms, or cycloalkoxy having 3-7 carbon atoms;
- R11, R11′, and R12 are the same or different and are selected from hydrogen, halogen, hydroxy, and —OR4,—CR7(R9)NR5R6, —CR7, (R16)OR4,
- where
- R4 is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms, and may be optionally substituted with one or more (C1-C6)alkoxy or mono- or di(C1-C6)alkylamino groups;
- R5 and R6 independently represent hydrogen, lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7 carbon atoms, or —SO2R8;
- or
- R5 and R6 together with the nitrogen atom to which they are attached form a heterocyclic moiety;
- and
- R9 is hydrogen, lower alkyl, or (C3-C7)cycloalkyl, where the alkyl or cycloalkyl is optionally substituted with halogen, lower alkoxy, or mono- or dialkylamino;
- R16 is hydrogen, lower alkyl having 1-6 carbon atoms,
- or cycloalkyl having 3-7 carbon atoms;
- or
- R11 and R12 taken together with the atoms to which they are attached form a (hetero)cyclic ring;
- (ix) a group of the formula:
- where K is as defined above for ii;
- and W is heteroaryl;
- (x) a group of the formula:
- where
- K is as defined for ii;
- R10 and R11 are as defined for viii, and
- R17 is hydrogen, lower alkyl, or (C3-C7)cycloalkyl, where the alkyl or cycloalkyl is optionally substituted with halogen, lower alkoxy, or mono- or di(C1-C6)alkylamino;
- (xi) a group of the formula:
- where K, R10, R12, and R17 are as defined above;
- (xii) a group of the formula:
- where each K is as defined as for ii and R10 is defined above;
- (xii-1) a group of the formula:
- where K, R10, R11, R14, and R15 are as defined above;
- and
- (xiii) a group of the formula:
- where K, R10, R12, R14, and R15 are as defined above;
- (xiv) pyrimidinyl (C1-C6alkyl) or pyridyl (C1-C5)alkyl;
- or
- (xv) a group of the formula:
- where R18 is hydrogen, amino, mono-, or di(C1-C6)alkylamino, or C1-C6 alkyl optionally substituted with R19 where R19 represents:
- where V and V′ are independently CH or nitrogen;
- A″ is C1-C6 alkylene;
- and
- R20 is phenyl, pyridyl, or pyrimidinyl, each of which is optionally mono-, di-, or tri-substituted independently with halogen, hydroxy, C1-C6alkoxy, amino, and mono- and di (C1-C6) alkylamino.
67 more elements
A compound of the formula:
- or a Pharmaceutically acceptable salt thereof, wherein
- R1 is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms, where each alkyl may be optionally substituted with —OR4 or —NR5R6;
- R4 is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms, and may be optionally substituted with one or more (C1-C6)alkoxy or mono- or di (C1-C6) alkylamino groups;
- R5 and R6 independently represent hydrogen, lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7 carbon atoms, or —SO2R8, where R8 is (C1-C6)alkyl, (C3-C7)cycloalkyl or optionally substituted phenyl;
- or
- R5 and R6 together with the nitrogen atom to which they are attached form a heterocyclic moiety;
- Y is
- (i) lower alkyl having 1-8 carbon atoms or cycloalkyl having 3-7 carbon atoms, any of which may be optionally substituted with one or more halogen, (C1-C6)alkoxy, alkoxyalkoxy where each alkoxy is (C1-C6)alkoxy, (C1-C6)alkylthio, (C3-C7)cycloalkylthio, aryl, heteroaryl, or mono- or di(C1-C6) alkylamino groups;
- (ii) a group of the formula:
- where K is lower alkylene having 1-6 carbon atoms optionally substituted with (C1-C6)alkyl or alkylene, or a cyclic group of the formula
- where K′ independently represents hydrogen or (C1-C6)alkyl or alkylene, n is 0, 1, or 2, and m is an integer of from 1 to 5, with the proviso that the sum of n+m is not less than 1 or greater than 5;
- and
- R9 is hydrogen, lower alkyl, or (C3-C7)cycloalkyl, where the alkyl or cycloalkyl is optionally substituted with halogen, lower alkoxy, or mono- or dialkylamino;
- (iii) a group of the formula:
- where K is defined as in ii;
- (iv) a group of the formula:
- where K is as defined for ii, and
- R13 is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms, where the alkyl and cycloalkyl groups are optionally substituted with one or more (C1-C6)alkoxy or mono- or di(C1-C6) alkylamino groups;
- and
- (v) a group of the formula:
- where
- K is as defined for ii, and
- R7 is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms;
- and
- (vi) a group of the formula:
- where
- K is as defined for ii;
- and
- R14 and R15 independently represent hydrogen, lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7 carbon atoms, —SO2R8 where R8 carries the definition set forth above, or
- R14 and R15 together with the nitrogen atom to which they are attached form a heterocyclic moiety;
- (vii) a group of the formula:
- where K and R15 are as defined above in ii and vi, respectively;
- (viii) a group of the formula:
- where
- K is as defined for ii;
- R10 and R10′ are the same or different and are selected from hydrogen, halogen, hydroxy, lower alkoxy having 1-6 carbon atoms, or cycloalkoxy having 3-7 carbon atoms;
- R11, R11′, and R12 are the same or different and are selected from hydrogen, halogen, hydroxy, and —OR4, —CR7(R9)NR5R6, —CR7(R16)OR4,
- where
- R4, R5, and R6 carry the definitions set forth above;
- and
- R9 is hydrogen, lower alkyl, or (C3-C7)cycloalkyl, where the alkyl or cycloalkyl is optionally substituted with halogen, lower alkoxy, or mono- or dialkylamino;
- R16 is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms;
- or
- R11 and R12 taken together with the atoms to which they are attached form a (hetero)cyclic ring;
- (ix) a group of the formula:
- where K is as defined above for ii;
- and W is heteroaryl;
- (x) a group of the formula:
- where
- K is as defined for ii;
- R10 and R11 are as defined for viii, and
- R17 is hydrogen, lower alkyl, or (C3-C7)cycloalkyl, where the alkyl or cycloalkyl is optionally substituted with halogen, lower alkoxy, or mono- or di(C1-C6)alkylamino;
- (xi) a group of the formula:
- where K, R10, R12, and R17 are as defined above;
- (xii) a group of the formula:
- where each K is as defined as for ii and R10 is defined above;
- (xii-1) a group of the formula:
- where K, R10, R11, R14, and R15 are as defined above;
- and
- (xiii) a group of the formula:
- where K, R10, R12, R14, and R15 are as defined above;
- (xiv) pyrimidinyl (C1-C6alkyl) or pyridyl (C1-C5)alkyl;
- or
- (xv) a group of the formula:
- where R18 is hydrogen, amino, mono-, or di(C1-C6)alkylamino, or C1-C6 alkyl optionally substituted with R19 where R19 represents:
- where V and V′ are independently CH or nitrogen;
- A″ is C1-C6 alkylene;
- and
- R20 is phenyl, pyridyl, or pyrimidinyl, each of which is optionally mono-, di-, or tri-substituted independently with halogen, hydroxy, C1-C6alkoxy, amino, and mono- and di (C1-C6) alkylamino.
66 more elements
A compound of the formula:
- or a pharmaceutically acceptable salt thereof, wherein
- G is lower alkylene having 1-6 carbon atoms;
- R5 and R6 independently represent hydrogen, lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7 carbon atoms, or —SO2R8, where R8 is (C1-C6)alkyl, (C3-C7)cycloalkyl, or optionally substituted phenyl;
- or
- R5 and R6 together with the nitrogen atom to which they are attached form a heterocyclic moiety;
- Y is
- (i) lower alkyl having 1-8 carbon atoms or cycloalkyl having 3-7 carbon atoms, any of which may be optionally substituted with one or more halogen, (C1-C6)alkoxy, alkoxyalkoxy where each alkoxy is (C1-C6)alkoxy, (C1-C6)alkylthio, (C3-C7)cycloalkylthio, aryl, heteroaryl, or mono- or di(C1-C6) alkylamino groups;
- (ii) a group of the formula:
- where K is lower alkylene having 1-6 carbon atoms optionally substituted with (C1-C6)alkyl or alkylene, or a cyclic group of the formula
- where K′ independently represents hydrogen or (C1-C6)alkyl or alkylene, n is 0, 1, or 2, and m is an integer of from 1 to 5, with the proviso that the sum of n+m is not less than 1 or greater than 5;
- and
- R9 is hydrogen, lower alkyl, or (C3-C7)cycloalkyl, where the alkyl or cycloalkyl is optionally substituted with halogen, lower alkoxy, or mono- or dialkylamino;
- (iii)a group of the formula:
- where K is defined as in ii;
- (iv) a group of the formula:
- where K is as defined for ii, and
- R13 is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms, where the alkyl and cycloalkyl groups are optionally substituted with one or more (C1-C6)alkoxy or mono- or di(C1-C6) alkylamino groups;
- and
- (v) a group of the formula:
- where
- K is as defined for ii, and
- R7 is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms;
- and
- (vi) a group of the formula:
- where
- K is as defined for ii;
- and
- R14 and R15 independently represent hydrogen, lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7 carbon atoms, —SO2R8 where R8 carries the definition set forth above, or
- R14 and R15 together with the nitrogen atom to which they are attached form a heterocyclic moiety;
- (vii) a group of the formula:
- where K and R15 are as defined above in ii and vi, respectively;
- (viii) a group of the formula:
- where
- K is as defined for ii;
- R10 and R10′ are the same or different and are selected from hydrogen, halogen, hydroxy, lower alkoxy having 1-6 carbon atoms, or cycloalkoxy having 3-7 carbon atoms;
- R11, R11′, and R12 are the same or different and are selected from hydrogen, halogen, hydroxy, and —OR4, —CR7(R9)NR5R6, —CR7(R16)OR4,
- where
- R4 is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms, and may be optionally substituted with one or more (C1-C6)alkoxy or mono- or di(C1-C6)alkylamino groups;
- R5 and R6 carry the definitions set forth above;
- and
- R9 is hydrogen, lower alkyl, or (C3-C7)cycloalkyl, where the alkyl or cycloalkyl is optionally substituted with halogen, lower alkoxy, or mono- or dialkylamino;
- R16 is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms;
- or
- R11 and R12 taken together with the atoms to which they are attached form a (hetero)cyclic ring;
- (ix) a group of the formula:
- where K is as defined above for ii;
- and W is heteroaryl;
- (x) a group of the formula:
- where
- K is as defined for ii;
- R10 and R11 are as defined for viii, and
- R17 is hydrogen, lower alkyl, or (C3-C7)cycloalkyl, where the alkyl or cycloalkyl is optionally substituted with halogen, lower alkoxy, or mono- or di(C1-C6)alkylamino;
- (xi) a group of the formula:
- where K, R10, R12, and R17 are as defined above;
- (xii) a group of the formula:
- where each K is as defined as for ii and R10 is defined above;
- (xii-1) a group of the formula:
- where K, R10, R11, R14, and R15 are as defined above;
- and
- (xiii) a group of the formula:
- where K, R10, R12, R14, and R15 are as defined above;
- (xiv) pyrimidinyl (C1-C6alkyl) or pyridyl (C1-C5)alkyl;
- or
- (xv) a group of the formula:
- where R18 is hydrogen, amino, mono-, or di(C1-C6)alkylamino, or C1-C6 alkyl optionally substituted with R19 where R19 represents:
- where V and V′ are independently CH or nitrogen;
- A″ is C1-C6 alkylene;
- and
- R20 is phenyl, pyridyl, or pyrimidinyl, each of which is optionally mono-, di-, or tri-substituted independently with halogen, hydroxy, C1-C6alkoxy, amino, and mono- and di (C1-C6) alkylamino.
66 more elements
A compound of the formula:
- or a pharmaceutically acceptable salt thereof, wherein
- G is lower alkylene having 1-6 carbon atoms;
- Y is
- (i) lower alkyl having 1-8 carbon atoms or cycloalkyl having 3-7 carbon atoms, any of which may be optionally substituted with one or more halogen, (C1-C6)alkoxy, alkoxyalkoxy where each alkoxy is (C1-C6)alkoxy, (C1-C6)alkylthio, (C3-C7)cycloalkylthio, aryl, heteroaryl, or mono- or di(C1-C6) alkylamino groups;
- (ii) a group of the formula:
- where K is lower alkylene having 1-6 carbon atoms optionally substituted with (C1-C6)alkyl or alkylene, or a cyclic group of the formula
- where K′ independently represents hydrogen or (C1-C6)alkyl or alkylene, n is 0, 1, or 2, and m is an integer of from 1 to 5, with the proviso that the sum of n+m is not less than 1 or greater than 5;
- and
- R9 is hydrogen, lower alkyl, or (C3-C7)cycloalkyl, where the alkyl or cycloalkyl is optionally substituted with halogen, lower alkoxy, or mono- or dialkylamino;
- (iii) a group of the formula:
- where K is defined as in ii;
- (iv) a group of the formula:
- where K is as defined for ii, and
- R13 is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms, where the alkyl and cycloalkyl groups are optionally substituted with one or more (C1-C6)alkoxy or mono- or di(C1-C6) alkylamino groups;
- and
- (v) a group of the formula:
- where
- K is as defined for ii, and
- R7 is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms;
- and
- (vi) a group of the formula:
- where
- K is as defined for ii;
- and
- R14 and R15 independently represent hydrogen, lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7 carbon atoms, —SO2R8, where R8 is (C1-C6)alkyl, (C3-C7)cycloalkyl, or optionally substituted phenyl;
- or
- R14 and R15 together with the nitrogen atom to which they are attached form a heterocyclic moiety;
- (vii) a group of the formula:
- where K and R15 are as defined above in ii and vi, respectively;
- (viii) a group of the formula:
- where
- K is as defined for ii;
- R10 and R10′ are the same or different and are selected from hydrogen, halogen, hydroxy, lower alkoxy having 1-6 carbon atoms, or cycloalkoxy having 3-7 carbon atoms;
- R11, R11′, and R12 are the same or different and are selected from hydrogen, halogen, hydroxy, and —OR4, —CR7(R9)NR5R6, —CR7(R16)OR4,
- where
- R4 is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms, and may be optionally substituted with one or more (C1-C6)alkoxy or mono- or di(C1-C6)alkylamino groups;
- R5 and R6 independently represent hydrogen, lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7 carbon atoms, or —SO2R8;
- or
- R5 and R6 together with the nitrogen atom to which they are attached form a heterocyclic moiety;
- R5 and R6 carry the definitions set forth above;
- and
- R9 is hydrogen, lower alkyl, or (C3-C7)cycloalkyl, where the alkyl or cycloalkyl is optionally substituted with halogen, lower alkoxy, or mono- or dialkylamino;
- R16 is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms;
- or
- R11 and R12 taken together with the atoms to which they are attached form a (hetero)cyclic ring;
- (ix) a group of the formula:
- where K is as defined above for ii;
- and W is heteroaryl;
- (x) a group of the formula:
- where
- K is as defined for ii;
- R10 and R11 are as defined for viii, and
- R17 is hydrogen, lower alkyl, or (C3-C7)cycloalkyl, where the alkyl or cycloalkyl is optionally substituted with halogen, lower alkoxy, or mono- or di(C1-C6)alkylamino;
- (xi) a group of the formula:
- where K, R10, R12, and R17 are as defined above;
- (xii) a group of the formula:
- where each K is as defined as for ii and R10 is defined above;
- (xii-1) a group of the formula:
- where K, R10, R11, R14, and R15 are as defined above;
- and
- (xiii) a group of the formula:
- where K, R10, R12, R14, and R15 are as defined above;
- (xiv) pyrimidinyl (C1-C6alkyl) or pyridyl (C1-C5)alkyl;
- or
- (xv) a group of the formula:
- where R18 is hydrogen, amino, mono-, or di(C1-C6)alkylamino, or C1-C6 alkyl optionally substituted with R19 where R19 represents:
- where V and V′ are independently CH or nitrogen;
- A″ is C1-C6 alkylene;
- and
- R20 is phenyl, pyridyl, or pyrimidinyl, each of which is optionally mono-, di-, or tri-substituted independently with halogen, hydroxy, C1-C6alkoxy, amino, and mono- and di(C1-C6) alkylamino.
67 more elements
Dependencies are inferred from the claim text.