EP0115933A2
Expired / Lapsed
EP
⏱️ 0.0 years remaining
Amide derivatives of azabicycloalkanes
Assignee: Beecham Group PLC
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Filing: 1984-01-24
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Granted: —
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Expires: 2004-01-24
Abstract
Abstract Compounds of formula (I), pharmaceutically acceptable salts, quaternary derivatives and N-oxides thereof, and pharmaceutically acceptable solvates of any of the foregoing: wherein p is 1 to 3; B is C 1-7 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-2 alkyl, or a group (CH 2 ) t R 11 where t is 1 or 2 and R 11 is thienyl or furyl optionally substituted by one or two substituents selected from C 1-6 alkyl, C 1-6 alkoxy, trifluoromethyl or halogen, or is phenyl optionally substituted by one or two substituents selected from C 1-4 alkoxy, trifluoromethyl, halogen, nitro, carboxy, esterified carboxy, and C 1-4 alkyl optionally substituted by hydroxy, C 1-4 alkoxy, carboxy, esterified carboxy or in vivo hydrolysable acyloxy; and i) A is a group of formula (II): in which either a) one of X and Y is CO and the other is NH; and R, is selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, and amino optionally substituted by one or two groups selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-4 alkyl, phenyl and phenyl C 1-4 alkyl groups or optionally N,N-disubstituted by C 4-5 polymethylene; or X is CO and Y is NR 6 where R 1 and R 6 together are C 1-2 alkylene; and either R 2 , R 3 and R 4 are each independently selected from the hydrogen, halogen, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 thio. C 1-7 acyl, C 1-7 carboxylic acylamino, C 1-6 alkyl- amino, N-(C 1-6 alkyl-sulphonyl)-N-C 1 4 alkylamino, alkylsulphonyl, C 1-6 alkylsulphinyl, hydroxy, nitro, or aminocarbonyl, aminosclphonyl, aminosulphonyl- N-(aminosulphonyl)-N-C 1-4 alkylamino optionally N-substituted by ore or two groups selected from C 1-6 alkyl, C 3 - 8 C 8-8 cycloalkyl C 1-4 alkyl, phenyl and phenyl C 1-4 optionally N,N-disubstituted by C 4 . 5 polymethylene; or one of R 2 , R 3 and R 4 is selected from the foregoing class and the remaining two of R 2 , R 3 and R 4 when on adjacent atoms are together C 1-2 alkylenedioxy; or one of X and Y is CO and the other is NH; R 1 and R 2 together are C 1-2 alkylenedioxy or C 1-2 oxyalkylenethio, or C 2-3 alkyleneoxy in which the oxygen atom is attached to the ring at the 2- position; as depicted in formula (II); and R 3 and R 4 are each independently selected from the class of values recited hereinbefore for R 2 , R 3 and R 4 in paragraph i) a) fereinbefore or when on adjacent atoms are together C 1-2 alkylenedioxy; or iii A is a group of formula (III): in which one of X and Y is CO and the other is NH; and R 22 , R 23 and R 24 are each independently selected from the class of values of the variables R 2 , R 3 and R 4 as defined hereinbefore in paragraph i) a) in relation to formula (II), except C 1-2 alkylenedioxy, having useful pharmacological properties, pharmaceutical compositions containing them, a process and intermediates for their preparation, and the use of the compounds.
Inventors
- 👤 Francis Edward Blaney
- 👤 Michael Stewart Hadley
- 👤 Francis David King
- 👤 Eric Alfred Watts
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-11-09 21:44
CPC Classifications
C; C07; C07D; C07D453/00; C07D453/06; A; A61; A61P; A61P1/00; A61P1/08; A61P25/00; A61P25/18; A61P3/00; A61P3/02; A61P43/00; C07D209/00; C07D209/56; C07D209/80; C07D209/94
Claims Analysis
Total Claims: 23
Claim 1
Independent Claim
557 words
A compound of formula (I), or a pharmaceutically acceptable salt, quaternary derivative or N-oxide thereof, or a pharmaceutically acceptable solvate of any of the foregoing: wherein p is 1 to 3; B is C l - 7 alkyl, C 3 - 8 cycloalkyl, C 3 - 8 cycloalkyl-C l - 2 alkyl, or a group (CH 2 ) t R ll where t is 1 or 2 and R 11 is thienyl or furyl optionally substituted by one or two substituents selected from C 1-6 alkyl, C 1-6 alkoxy, trifluoromethyl or halogen, or is phenyl optionally substituted by one or two substituents selected from C l - 4 alkoxy, trifluoromethyl, halogen, nitro, carboxy, esterified carboxy, and C l - 4 alkyl optionally substituted by hydroxy, C l - 4 alkoxy, carboxy, esterified carboxy or in vivo hydrolysable acyloxy; and i) A is a group of formula (II): in which either a) one of X and Y is CO and the other is NH; and R 1 is selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, and amino optionally substituted by one or two groups selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 3 - 8 cycloalkyl C l - 4 alkyl, phenyl and phenyl C 1-4 alkyl groups or optionally N,N-disubstituted by C 4-5 polymethylene; or X is CO and Y is NR 6 where R 1 and R 6 together are C 1-2 alkylene; and either R 2 , R 3 and R 4 are each independently selected from the class of hydrogen, halogen, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-7 acyl, C 1-7 carboxylic acylamino, C l - 6 alkylsulphonylamino, N-(C 1-6 alkyl-sulphonyl)-N-C 1-4 alkylamino, C 1-6 alkylsulphonyl, C 1-6 alkylsulphinyl, hydroxy, nitro, or amino, aminocarbonyl, aminosulphonyl, aminosulphonylamino or N-(aminosulphonyl)-N-C 1-4 alkylamino optionally N-substituted by one or two groups selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 3 - 8 cycloalkyl C l - 4 alkyl, phenyl and phenyl C l - 4 alkyl or optionally N,N-disubstituted by C 4 - 5 polymethylene; or one of R 2 , R 3 and R 4 is selected from the foregoing class and the remaining two of R 2 , R 3 and R 4 when on adjacent atoms are together C l - 2 alkylenedioxy; or b) one of X and Y is CO and the other is NH; R l and R 2 together are C l - 2 alkylenedioxy or C l - 2 oxyalkylenethio, or C 2 - 3 alkyleneoxy in which the oxygen atom is attached to the ring at the 2- position; as depicted in formula (II); and R 3 and R 4 are each independently selected from the class of values recited hereinbefore for R 2 , R 3 and R 4 in paragraph i) a) hereinbefore or when on adjacent atoms are together C 1-2 alkylenedioxy; or ii) A is a group of formula (III): in which one of X and Y is CO and the other is NH; and R 2 2, R 23 and R 24 are each independently selected from the class of values of the variables R 2 , R 3 and R 4 as defined hereinbefore in paragraph i) a) in relation to formula (II), except C l - 2 alkylenedioxy.
Claim 2
Dependent Claim
557 words
A compound of formula (I), or a pharmaceutically acceptable salt, quaternary derivative or N-oxide thereof, or a pharmaceutically acceptable solvate of any of the foregoing: wherein p is 1 to 3; B is C l - 7 alkyl, C 3 - 8 cycloalkyl, C 3 - 8 cycloalkyl-C l - 2 alkyl, or a group (CH 2 ) t R ll where t is 1 or 2 and R 11 is thienyl or furyl optionally substituted by one or two substituents selected from C 1-6 alkyl, C 1-6 alkoxy, trifluoromethyl or halogen, or is phenyl optionally substituted by one or two substituents selected from C l - 4 alkoxy, trifluoromethyl, halogen, nitro, carboxy, esterified carboxy, and C l - 4 alkyl optionally substituted by hydroxy, C l - 4 alkoxy, carboxy, esterified carboxy or in vivo hydrolysable acyloxy; and i) A is a group of formula (II): in which either a) one of X and Y is CO and the other is NH; and R 1 is selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, and amino optionally substituted by one or two groups selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 3 - 8 cycloalkyl C l - 4 alkyl, phenyl and phenyl C 1-4 alkyl groups or optionally N,N-disubstituted by C 4-5 polymethylene; or X is CO and Y is NR 6 where R 1 and R 6 together are C 1-2 alkylene; and either R 2 , R 3 and R 4 are each independently selected from the class of hydrogen, halogen, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-7 acyl, C 1-7 carboxylic acylamino, C l - 6 alkylsulphonylamino, N-(C 1-6 alkyl-sulphonyl)-N-C 1-4 alkylamino, C 1-6 alkylsulphonyl, C 1-6 alkylsulphinyl, hydroxy, nitro, or amino, aminocarbonyl, aminosulphonyl, aminosulphonylamino or N-(aminosulphonyl)-N-C 1-4 alkylamino optionally N-substituted by one or two groups selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 3 - 8 cycloalkyl C l - 4 alkyl, phenyl and phenyl C l - 4 alkyl or optionally N,N-disubstituted by C 4 - 5 polymethylene; or one of R 2 , R 3 and R 4 is selected from the foregoing class and the remaining two of R 2 , R 3 and R 4 when on adjacent atoms are together C l - 2 alkylenedioxy; or b) one of X and Y is CO and the other is NH; R l and R 2 together are C l - 2 alkylenedioxy or C l - 2 oxyalkylenethio, or C 2 - 3 alkyleneoxy in which the oxygen atom is attached to the ring at the 2- position; as depicted in formula (II); and R 3 and R 4 are each independently selected from the class of values recited hereinbefore for R 2 , R 3 and R 4 in paragraph i) a) hereinbefore or when on adjacent atoms are together C 1-2 alkylenedioxy; or ii) A is a group of formula (III): in which one of X and Y is CO and the other is NH; and R 2 2, R 23 and R 24 are each independently selected from the class of values of the variables R 2 , R 3 and R 4 as defined hereinbefore in paragraph i) a) in relation to formula (II), except C l - 2 alkylenedioxy.
Claim 3
Dependent Claim
198 words
A compound according to claim 1 of formula (IV): wherein either R 1 1 is C 1-6 alkoxy or amino optionally N-substituted by one or two groups selected from C 1-6 alkyl or C 3-8 cycloalkyl or optionally N,N-disubstituted by C 4-5 polymethylene; and one of R 1 2 , R 1 3 and R 1 4 is hydrogen and the other two are independently selected from the class of hydrogen, amino optionally substituted by one or two C 1-6 alkyl groups or N,N-disubstituted by C 4-5 polymethylene, carboxylic C l - 7 acylamino, chloro, bromo, trifluoromethyl, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkyl, C 1-6 alkylsulphonyl, C l - 6 alkylsulphinyl or aminosulphonyl optionally N-substituted by one or two C 1-6 alkyl group or N,N-disubstituted by C 4 - 5 polymethylene; or R 1 1 and R 1 2 together are methylenedioxy or ethylenedioxy and R 1 3 and R 1 4 are the same or different and are selected from the class of substituent hereinbefore defined for R 1 2 , R 1 3 and R 1 4 ; p 1 is 1 or 2; and B is as defined in claim 1.
Claim 4
Dependent Claim
70 words
A compound according to claim 1 of formula (V): wherein R 1 1 , p 1 and B are as defined in claim 2 and one of R 2 2 , R 2 3 and R 2 4 is hydrogen, and the other two are independently selected from hydrogen, amino, carboxylic C 1-7 acylamino, chloro, bromo, trifluoromethyl, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio and C l - 6 alkyl.
Claim 5
Dependent Claim
89 words
A compound according to claim 1 of formula (VI): wherein p 1 and B are as defined in claim 2 R 3 3 is hydrogen or amino. R3 4 is C 1-6 alkylsulphonyl, C I - 6 alkylsulphinyl, or aminosulphonyl optionally N-substituted by one or two Cl- 6 alkyl groups or C 4 - 5 polymethylene; and either R 2 1 is R 1 1 as hereinbefore defined and R 2 2 is hydrogen; or R 2 1 and R 3 2 together are C 2 - 3 alkylenedioxy.
Claim 6
Dependent Claim
70 words
A compound according to claim 1 which is the axial isomer of (±)-4-amino-5-chloro-2-methoxy-N-(5-[2-methyl-2-azabicyclo[2,2,2]octyl]benzamide, the equatorial isomer of (±)-4-amino-5-chloro-2-methoxy-N-(5-[2-methyl-2-azabicyclo[2,2,2]octyl] benzamide, the axial isomer of (i)-4 - amino-5-chloro-2-methoxy-N-(5-[2-benzyl-2-azabicyclo[2,2,2]octyl]benzamide, the equatorial isomer of (±)-4-amino-5-chloro-2-methoxy-N-(5-[2-benzyl-2-azabicyclo[2,2,2]octyl] benzamide, the equatorial isomer of (±)-4-amino-5-chloro-2-methoxy-N-[5-(2-methyl-2-azabicyclo[2.2.1]heptyl)] benzamide, the axial isomer of (±)-4-amino-2-methoxy-5-methylsulphonyl-N-[5-(2-benzyl-2-azabicyclo[2.2.2] octyl)]benzamide, the equatorial isomer of (±)-4-amino-2-methoxy-5-methylsulphonyl-N-[5-(2-benzyl-2-azabicyclo[2.2.2] octyl)]benzamide, or a pharmaceutically acceptable salt, quaternary derivative or N-oxide thereof or a pharmaceutically acceptable solvate of any of the foregoing.
Claim 7
Dependent Claim
22 words
A compound according to claim 1 which is the equatorial isomer of (±)4-amino-5-chloro-2-methoxy-N-[5-(2-methyl-2-azabicyclo[2.2.1]heptyl]benzamide hydrochloride or the equatorial isomer of (±)4-amino-2-methoxy-5-methylsulphonyl-N-[5-(2-benzyl-2-azabicyclo[2.2.2] octyl]benzamide hemihydrate.
Claim 8
Dependent Claim
25 words
A compound according to claim 1 which is the axial isomer of (±)-4-amino-5-chloro-2-methoxy-N-(5-[2-methyl-2-azabicyclo[2,2,2]octyl]benzamide, or the equatorial isomer of (±)-4-amino-5-chloro-2-methoxy-N-(5-[2-methyl-2-azabicyclo[2,2,2]octyl] benzamide, or the hydrochloride salt thereof.
Claim 9
Dependent Claim
38 words
A pharmaceutical composition comprising a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, quaternary derivative or N-oxide thereof, or a pharmaceutically acceptable solvate of any of the foregoing, and a pharmaceutically acceptable carrier.
Claim 10
Dependent Claim
49 words
A compound of formula (VIII): wherein B and p are as defined in claim 1; and Q 3 is NH 2 or COQ 4 where Q 4 is a group displaceable by a nucleophile; or a compound of formula (X): wherein the variables are as defined in claim 1.
Claim 11
Dependent Claim
47 words
A compound according to claim 1 of formula (I) or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable solvate of either of the foregoing for the treatment or prophylaxis of emesis, or disorders related to impaired gastro-intestinal motility or of the central nervous system.
Claim 12
Dependent Claim
37 words
A quaternary derivative or N-oxide of a compound according to claim 1 of formula (I) or a pharmaceutically acceptable solvate of either of the foregoing for the treatment or prophylaxis of disorders related to impaired gastro-intestinal motility.
Claim 13
Dependent Claim
130 words
A process for the preparation of a compound according to claim 1, which process comprises: a) when the group A in the compound according to claim 1 is of formula (II) as defined in claim 1, reacting a compound of formula (VII): wherein i) X is CO and Q 1 is a group displaceable by a nucleophile, or X is NH and Q 1 is H; R 16 is R 1 as defined in formula (II) in claim 1 when one of X and Y in formula (II) in claim 1 is CO and the other is NH; and R 2 , R 3 and R 4 are as defined in formula (II) when one of X and Y in formula (II) is CO and the other is NH; or
Claim 14
Dependent Claim
112 words
(ii) X is CO and Q 1 is a group displaceable by a nucleophile; and R16 is a group (CH 2 ) v CR 17 R 18 Q 2 where v is 0 or 1, R 17 and R 18 are each H or together are O and Q 2 is a group displaceable by a nucleophile, or together with Q 1 is O; and R 2 , R 3 and R 4 are as defined in formula (II) in claim 1 when X is CO and Y is NR 6 is as hereinbefore defined with a compound of formula (VIII): wherein B and p are as defined in claim 1; and
Claim 15
Dependent Claim
30 words
i) when Q 1 in the compound of formula (VII) is a group displaceable by a nucleophile or together with Q 2 is O, Q 3 is NH 2 ;
Claim 16
Dependent Claim
30 words
i) when Q 1 in the compound of formula (VII) is a group displaceable by a nucleophile or together with Q 2 is O, Q 3 is NH 2 ;
Claim 17
Dependent Claim
28 words
ii) when Q 1 in the compound of formula (VII) is H, Q 3 is COQ 4 where Q 4 is a group displaceable by a nucleophile; and
Claim 18
Dependent Claim
28 words
ii) when Q 1 in the compound of formula (VII) is H, Q 3 is COQ 4 where Q 4 is a group displaceable by a nucleophile; and
Claim 19
Dependent Claim
50 words
when the desired compound of formula (I) is one wherein R l and R 6 together are C 1-2 alkylene, and R 17 and R 18 in the compound of formula (VII) are together O, reducing the compound resulting from the reaction of the compounds of formulae (VII) and (VIII);
Claim 20
Dependent Claim
50 words
when the desired compound of formula (I) is one wherein R l and R 6 together are C 1-2 alkylene, and R 17 and R 18 in the compound of formula (VII) are together O, reducing the compound resulting from the reaction of the compounds of formulae (VII) and (VIII);
Claim 21
Dependent Claim
127 words
b) when the group A in the compound according to claim 1 is of formula (III) as defined in claim 1, reacting a compound of formula (IX): wherein X is CO and Q 1 is a group displaceable by a nucleophile, or X is NH and Q 1 is H; and R 22 , R 23 and R 24 are as defined in relation to formula (III) in claim 1 with a compound of formula (VIII) wherein i) when 0 1 in the compound of formula (IX) is a group displaceable by a nucleophile, Q3 is NH 2 : ii) when Q 1 in the compound of formula (IX) is H, Q 3 is COQ 4 where Q 4 is a group displaceable by a nucleophile; or
Claim 22
Dependent Claim
15 words
c) for any compound according to claim 1, N-alk ylating a compound of formula (X):
Claim 23
Dependent Claim
93 words
wherein the variables are as defined in claim 1; and for any of the foregoing process variants optionally thereafter as appropriate in the resulting compound of formula (I) interconverting any Rl, R2, R 3 , R 4 , R 22 , R 23 , R 24 or B group to another R 1 , R 2 , R 3 , R 4 , R 22 , R 23 , R 24 or B group respectively; and optionally forming a pharmaceutically acceptable salt, quaternary derivative or N-oxide of the resulting compound of formula (I).
References Cited (Backward Citations)
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