US2009062322A1PendingUtilityA1
Novel Tricyclic Spiropiperidines or Spiropyrrolidines
Est. expiryJul 8, 2022(expired)· nominal 20-yr term from priority
A61P 37/00A61P 43/00A61P 25/26A61P 29/00A61P 25/00Y02P20/55C07D 491/10A61P 19/02A61P 11/06A61P 11/00C07D 221/20
56
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
The invention provides compounds of formula (I) wherein m R 1 , n, R 2 , q, X, Y, Z, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , t, and R 9 are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
Claims
exact text as granted — not AI-modified1 . An intermediate compound of formula:
wherein R 1a is selected from fluorine, chlorine, methyl and trifluoromethyl; s is 1 or 2; q is 0 or 1; w is 0 or 1; and R 2a is fluorine.
2 . A process for preparing a compound of formula (IIA) according to claim 1 in which s is 1, which comprises reacting a compound of formula:
wherein L 1 represents a suitable leaving group or an alkoxy group, L 1 represents a suitable leaving group and R 1a is as defined in formula (IIA), with a compound of formula:
wherein R 20 represents a protecting group and q, w and R 2a are as defined in formula (IIA) to form a compound of formula:
followed by a cyclisation reaction and then removal of the protecting group R 20 .
3 . A method of treating a disease or condition in which modulation of chemokine receptor activity is beneficial comprising administering to a patient a therapeutically effective amount of a compound of Formula I:
wherein
m is 0, 1, 2, 3 or 4;
each R 1 independently represents halogen, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy or sulphonamido;
either X represents a bond, —CH 2 —, —O— or —C(O)— and Y represents a bond, —CH 2 —, —O— or —C(O)—, or X and Y together represent a group —CH═C(CH 3 )— or —C(CH 3 )═CH—, and Z represents a bond, —O—, —NH— or —CH 2 —, provided that only one of X, Y and Z can represent a bond at any one time and provided that X and Y do not both simultaneously represent —O— or —C(O)—;
n is 0, 1 or 2;
each R 2 independently represents halogen or C 1 -C 6 alkyl;
q is 0 or 1;
R 3 represents —NHC(O)R 10 , —C(O)NR 11 R 12 or —COOR 12a ;
R 4 , R 5 , R 6 , R 7 and R 8 each independently represent a hydrogen atom or a C 1 -C 6 alkyl group;
t is 0, 1 or 2;
each R 9 independently represents halogen, cyano, hydroxyl, carboxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted by at least one substituent selected from carboxyl and C 1 -C 6 alkoxycarbonyl;
R 10 represents a group C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, adamantyl, C 5 -C 6 cycloalkenyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, each of which may be optionally substituted by one or more substituents independently selected from nitro, hydroxyl, oxo, halogen, carboxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl, phenyl and —NHC(O)—R 13 , or
R 10 represents a group —NR 14 R 15 or —O—R 16 ;
R 11 and R 12 each independently represent (i) a hydrogen atom, (ii) a 3-to 6-membered saturated or unsaturated ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur and optionally further comprising a bridging group, the ring being optionally substituted with at least one substituent selected from halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl and C 1 -C 6 haloalkyl,
(iii) a C 1 -C 6 alkyl group optionally substituted by at least one substituent selected from halogen, amino, hydroxyl, C 1 -C 6 haloalkyl, carboxyl, C 1 -C 6 alkoxy,
C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylcarbonylamino and a 3- to 6-membered saturated or unsaturated ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur and optionally further comprising a bridging group, the ring being optionally substituted with at least one substituent selected from halogen, hydroxyl, oxo (═O), C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl and C 1 -C 6 haloalkyl, or (iv) C 1 -C 6 alkylsulphonyl, or
R 11 and R 12 together with the nitrogen atom to which they are attached form a 4-to 7-membered saturated heterocyclic ring that optionally further comprises a ring nitrogen, oxygen or sulphur atom and that is optionally fused to a benzene ring to form a 8- to 11-membered ring system, the heterocyclic ring or ring system being optionally substituted with at least one substituent selected from halogen, hydroxyl, amido, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylcarbonylamino, C 1 -C 6 alkylaminocarbonyl, di-C 1 -C 6 alkylaminocarbonyl, phenyl, halophenyl, phenylcarbonyl, phenylcarbonyloxy and hydroxydiphenylmethyl;
R 12a represents a hydrogen atom or a C 1 -C 6 alkyl group;
R 13 represents a C 1 -C 6 alkyl, amino or phenyl group;
R 14 and R 15 each independently represent a hydrogen atom, or a group C 1 -C 6 alkyl, C 1 -C 6 alkylsulphonyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, each group being optionally substituted as defined above for R 10 , or
R 14 and R 15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring that optionally further comprises a ring nitrogen, oxygen or sulphur atom, the heterocyclic ring being optionally substituted by at least one hydroxyl; and
R 16 represents a hydrogen atom, or a group C 1 -C 6 alkyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, each group being optionally substituted as defined above for R;
or a pharmaceutically acceptable salt thereof.
4 . A method of treating rheumatoid arthritis comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I:
wherein
m is 0, 1, 2, 3 or 4;
each R 1 independently represents halogen, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy or sulphonamido;
either X represents a bond, —CH 2 —, —O— or —C(O)— and Y represents a bond, —CH 2 —, —O— or —C(O)—, or X and Y together represent a group —CH═C(CH 3 )— or —C(CH 3 )═CH—, and Z represents a bond, —O—, —NH— or —CH 2 —, provided that only one of X, Y and Z can represent a bond at any one time and provided that X and Y do not both simultaneously represent —O— or —C(O)—;
n is 0, 1 or 2;
each R 2 independently represents halogen or C 1 -C 6 alkyl;
q is 0 or 1;
R 3 represents —NHC(O)R 10 , —C(O)NR 11 R 12 or —COOR 12a ;
R 4 , R 5 , R 6 , R 7 and R 8 each independently represent a hydrogen atom or a C 1 -C 6 alkyl group;
t is 0, 1 or 2;
each R 9 independently represents halogen, cyano, hydroxyl, carboxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted by at least one substituent selected from carboxyl and C 1 -C 6 alkoxycarbonyl;
R 10 represents a group C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, adamantyl, C 5 -C 6 cycloalkenyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, each of which may be optionally substituted by one or more substituents independently selected from nitro, hydroxyl, oxo, halogen, carboxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl, phenyl and —NHC(O)—R 13 , or
R 10 represents a group —NR 14 R 15 or —O—R 16 ;
R 11 and R 12 each independently represent (i) a hydrogen atom, (ii) a 3-to 6-membered saturated or unsaturated ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur and optionally further comprising a bridging group, the ring being optionally substituted with at least one substituent selected from halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl and C 1 -C 6 haloalkyl,
(iii) a C 1 -C 6 alkyl group optionally substituted by at least one substituent selected from halogen, amino, hydroxyl, C 1 -C 6 haloalkyl, carboxyl, C 1 -C 6 alkoxy,
C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylcarbonylamino and a 3- to 6-membered saturated or unsaturated ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur and optionally further comprising a bridging group, the ring being optionally substituted with at least one substituent selected from halogen, hydroxyl, oxo (═O), C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl and C 1 -C 6 haloalkyl, or (iv) C 1 -C 6 alkylsulphonyl, or
R 11 and R 12 together with the nitrogen atom to which they are attached form a 4-to 7-membered saturated heterocyclic ring that optionally further comprises a ring nitrogen, oxygen or sulphur atom and that is optionally fused to a benzene ring to form a 8- to 11-membered ring system, the heterocyclic ring or ring system being optionally substituted with at least one substituent selected from halogen, hydroxyl, amido, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylcarbonylamino, C 1 -C 6 alkylaminocarbonyl, di-C 1 -C 6 alkylaminocarbonyl, phenyl, halophenyl, phenylcarbonyl, phenylcarbonyloxy and hydroxydiphenylmethyl;
R 12a represents a hydrogen atom or a C 1 -C 6 alkyl group;
R 13 represents a C 1 -C 6 alkyl, amino or phenyl group;
R 14 and R 15 each independently represent a hydrogen atom, or a group C 1 -C 6 alkyl, C 1 -C 6 alkylsulphonyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, each group being optionally substituted as defined above for R 10 , or
R 14 and R 15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring that optionally further comprises a ring nitrogen, oxygen or sulphur atom, the heterocyclic ring being optionally substituted by at least one hydroxyl; and
R 16 represents a hydrogen atom, or a group C 1 -C 6 alkyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, each group being optionally substituted as defined above for R 10 ;
or a pharmaceutically acceptable salt thereof.
5 . A method of treating chronic obstructive pulmonary disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I:
wherein
m is 0, 1, 2, 3 or 4;
each R 1 independently represents halogen, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy or sulphonamido;
either X represents a bond, —CH 2 —, —O— or —C(O)— and Y represents a bond, —CH 2 —, —O— or —C(O)—, or X and Y together represent a group —CH═C(CH 3 )— or —C(CH 3 )═CH—, and Z represents a bond, —O—, —NH— or —CH 2 —, provided that only one of X, Y and Z can represent a bond at any one time and provided that X and Y do not both simultaneously represent —O— or —C(O)—;
n is 0, 1 or 2;
each R 2 independently represents halogen or C 1 -C 6 alkyl;
q is 0 or 1;
R 3 represents —NHC(O)R 10 , —C(O)NR 11 R 12 or —COOR 12a ;
R 4 , R 5 , R 6 , R 7 and R 8 each independently represent a hydrogen atom or a C 1 -C 6 alkyl group;
t is 0, 1 or 2;
each R 9 independently represents halogen, cyano, hydroxyl, carboxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted by at least one substituent selected from carboxyl and C 1 -C 6 alkoxycarbonyl;
R 10 represents a group C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, adamantyl, C 5 -C 6 cycloalkenyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, each of which may be optionally substituted by one or more substituents independently selected from nitro, hydroxyl, oxo, halogen, carboxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl, phenyl and —NHC(O)—R 13 , or
R 10 represents a group —NR 14 R 5 or —O—R 16 ;
R 11 and R 12 each independently represent (i) a hydrogen atom, (ii) a 3-to 6-membered saturated or unsaturated ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur and optionally further comprising a bridging group, the ring being optionally substituted with at least one substituent selected from halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl and C 1 -C 6 haloalkyl,
(iii) a C 1 -C 6 alkyl group optionally substituted by at least one substituent selected from halogen, amino, hydroxyl, C 1 -C 6 haloalkyl, carboxyl, C 1 -C 6 alkoxy,
C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylcarbonylamino and a 3- to 6-membered saturated or unsaturated ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur and optionally further comprising a bridging group, the ring being optionally substituted with at least one substituent selected from halogen, hydroxyl, oxo (═O), C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl and C 1 -C 6 haloalkyl, or (iv) C 1 -C 6 alkylsulphonyl, or
R 11 and R 12 together with the nitrogen atom to which they are attached form a 4-to 7-membered saturated heterocyclic ring that optionally further comprises a ring nitrogen, oxygen or sulphur atom and that is optionally fused to a benzene ring to form a 8- to 11-membered ring system, the heterocyclic ring or ring system being optionally substituted with at least one substituent selected from halogen, hydroxyl, amido, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylcarbonylamino, C 1 -C 6 alkylaminocarbonyl, di-C 1 -C 6 alkylaminocarbonyl, phenyl, halophenyl, phenylcarbonyl, phenylcarbonyloxy and hydroxydiphenylmethyl;
R 12a represents a hydrogen atom or a C 1 -C 6 alkyl group;
R 13 represents a C 1 -C 6 alkyl, amino or phenyl group;
R 14 and R 15 each independently represent a hydrogen atom, or a group C 1 -C 6 alkyl, C 1 -C 6 alkylsulphonyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, each group being optionally substituted as defined above for R 10 , or
R 14 and R 15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring that optionally further comprises a ring nitrogen, oxygen or sulphur atom, the heterocyclic ring being optionally substituted by at least one hydroxyl; and
R 16 represents a hydrogen atom, or a group C 1 -C 6 alkyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, each group being optionally substituted as defined above for R 10 ;
or a pharmaceutically acceptable salt thereof.
6 . A method of treating asthma comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I:
wherein
m is 0, 1, 2, 3 or 4;
each R 1 independently represents halogen, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy or sulphonamido;
either X represents a bond, —CH 2 —, —O— or —C(O)— and Y represents a bond, —CH 2 —, —O— or —C(O)—, or X and Y together represent a group —CH═C(CH 3 )— or —C(CH 3 )═CH—, and Z represents a bond, —O—, —NH— or —CH 2 —, provided that only one of X, Y and Z can represent a bond at any one time and provided that X and Y do not both simultaneously represent —O— or —C(O)—;
n is 0, 1 or 2;
each R 2 independently represents halogen or C 1 -C 6 alkyl;
q is 0 or 1;
R 3 represents —NHC(O)R 10 , —C(O)NR 11 R 12 or —COOR 12a ;
R 4 , R 5 , R 6 , R 7 and R 8 each independently represent a hydrogen atom or a C 1 -C 6 alkyl group;
t is 0, 1 or 2;
each R 9 independently represents halogen, cyano, hydroxyl, carboxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted by at least one substituent selected from carboxyl and C 1 -C 6 alkoxycarbonyl;
R 10 represents a group C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, adamantyl, C 5 -C 6 cycloalkenyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, each of which may be optionally substituted by one or more substituents independently selected from nitro, hydroxyl, oxo, halogen, carboxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl, phenyl and —NHC(O)—R 13 , or
R 10 represents a group —NR 14 R 15 or —O—R 16 ;
R 11 and R 12 each independently represent (i) a hydrogen atom, (ii) a 3-to 6-membered saturated or unsaturated ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur and optionally further comprising a bridging group, the ring being optionally substituted with at least one substituent selected from halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl and C 1 -C 6 haloalkyl,
(iii) a C 1 -C 6 alkyl group optionally substituted by at least one substituent selected from halogen, amino, hydroxyl, C 1 -C 6 haloalkyl, carboxyl, C 1 -C 6 alkoxy,
C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylcarbonylamino and a 3- to 6-membered saturated or unsaturated ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur and optionally further comprising a bridging group, the ring being optionally substituted with at least one substituent selected from halogen, hydroxyl, oxo (═O), C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl and C 1 -C 6 haloalkyl, or (iv) C 1 -C 6 alkylsulphonyl, or
R 11 and R 12 together with the nitrogen atom to which they are attached form a 4-to 7-membered saturated heterocyclic ring that optionally further comprises a ring nitrogen, oxygen or sulphur atom and that is optionally fused to a benzene ring to form a 8- to 11-membered ring system, the heterocyclic ring or ring system being optionally substituted with at least one substituent selected from halogen, hydroxyl, amido, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylcarbonylamino, C 1 -C 6 alkylaminocarbonyl, di-C 1 -C 6 alkylaminocarbonyl, phenyl, halophenyl, phenylcarbonyl, phenylcarbonyloxy and hydroxydiphenylmethyl;
R 12a represents a hydrogen atom or a C 1 -C 6 alkyl group;
R 13 represents a C 1 -C 6 alkyl, amino or phenyl group;
R 14 and R 15 each independently represent a hydrogen atom, or a group C 1 -C 6 alkyl, C 1 -C 6 alkylsulphonyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, each group being optionally substituted as defined above for R 10 , or
R 14 and R 15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring that optionally further comprises a ring nitrogen, oxygen or sulphur atom, the heterocyclic ring being optionally substituted by at least one hydroxyl; and
R 16 represents a hydrogen atom, or a group C 1 -C 6 alkyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, each group being optionally substituted as defined above for R 10 ;
or a pharmaceutically acceptable salt thereof.
7 . A method of treating multiple sclerosis comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I:
wherein
m is 0, 1, 2, 3 or 4;
each R 1 independently represents halogen, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy or sulphonamido;
either X represents a bond, —CH 2 —, —O— or —C(O)— and Y represents a bond, —CH 2 —, —O— or —C(O)—, or X and Y together represent a group —CH═C(CH 3 )— or —C(CH 3 )═CH—, and Z represents a bond, —O—, —NH— or —CH 2 —, provided that only one of X, Y and Z can represent a bond at any one time and provided that X and Y do not both simultaneously represent —O— or —C(O)—;
n is 0, 1 or 2;
each R 2 independently represents halogen or C 1 -C 6 alkyl;
q is 0 or 1;
R 3 represents —NHC(O)R 10 , —C(O)NR 11 R 12 or —COOR 12a ;
R 4 , R 5 , R 6 , R 7 and R 8 each independently represent a hydrogen atom or a C 1 -C 6 alkyl group;
t is 0, 1 or 2;
each R 9 independently represents halogen, cyano, hydroxyl, carboxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted by at least one substituent selected from carboxyl and C 1 -C 6 alkoxycarbonyl;
R 10 represents a group C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, adamantyl, C 5 -C 6 cycloalkenyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, each of which may be optionally substituted by one or more substituents independently selected from nitro, hydroxyl, oxo, halogen, carboxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl, phenyl and —NHC(O)—R 13 , or
R 10 represents a group —NR 14 R 5 or —O—R 16 ;
R 11 and R 12 each independently represent (i) a hydrogen atom, (ii) a 3-to 6-membered saturated or unsaturated ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur and optionally further comprising a bridging group, the ring being optionally substituted with at least one substituent selected from halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl and C 1 -C 6 haloalkyl,
(iii) a C 1 -C 6 alkyl group optionally substituted by at least one substituent selected from halogen, amino, hydroxyl, C 1 -C 6 haloalkyl, carboxyl, C 1 -C 6 alkoxy,
C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylcarbonylamino and a 3- to 6-membered saturated or unsaturated ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur and optionally further comprising a bridging group, the ring being optionally substituted with at least one substituent selected from halogen, hydroxyl, oxo (═O), C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl and C 1 -C 6 haloalkyl, or (iv) C 1 -C 6 alkylsulphonyl, or
R 11 and R 12 together with the nitrogen atom to which they are attached form a 4-to 7-membered saturated heterocyclic ring that optionally further comprises a ring nitrogen, oxygen or sulphur atom and that is optionally fused to a benzene ring to form a 8- to 11-membered ring system, the heterocyclic ring or ring system being optionally substituted with at least one substituent selected from halogen, hydroxyl, amido, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylcarbonylamino, C 1 -C 6 alkylaminocarbonyl, di-C 1 -C 6 alkylaminocarbonyl, phenyl, halophenyl, phenylcarbonyl, phenylcarbonyloxy and hydroxydiphenylmethyl;
R 12a represents a hydrogen atom or a C 1 -C 6 alkyl group;
R 13 represents a C 1 -C 6 alkyl, amino or phenyl group;
R 14 and R 15 each independently represent a hydrogen atom, or a group C 1 -C 6 alkyl, C 1 -C 6 alkylsulphonyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, each group being optionally substituted as defined above for R 10 , or
R 14 and R 15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring that optionally further comprises a ring nitrogen, oxygen or sulphur atom, the heterocyclic ring being optionally substituted by at least one hydroxyl; and
R 16 represents a hydrogen atom, or a group C 1 -C 6 alkyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, each group being optionally substituted as defined above for R 10 ;
or a pharmaceutically acceptable salt thereof.
8 . A method of treating an inflammatory disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to Formula I:
wherein
m is 0, 1, 2, 3 or 4;
each R 1 independently represents halogen, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy or sulphonamido;
either X represents a bond, —CH 2 —, —O— or —C(O)— and Y represents a bond, —CH 2 —, —O— or —C(O)—, or X and Y together represent a group —CH═C(CH 3 )— or —C(CH 3 )═CH—, and Z represents a bond, —O—, —NH— or —CH 2 —, provided that only one of X, Y and Z can represent a bond at any one time and provided that X and Y do not both simultaneously represent —O— or —C(O)—;
n is 0, 1 or 2;
each R 2 independently represents halogen or C 1 -C 6 alkyl;
q is 0 or 1;
R 3 represents —NHC(O)R 10 , —C(O)NR 11 R 12 or —COOR 12a ;
R 4 , R 5 , R 6 , R 7 and R 8 each independently represent a hydrogen atom or a C 1 -C 6 alkyl group;
t is 0, 1 or 2;
each R 9 independently represents halogen, cyano, hydroxyl, carboxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted by at least one substituent selected from carboxyl and C 1 -C 6 alkoxycarbonyl;
R 10 represents a group C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, adamantyl, C 5 -C 6 cycloalkenyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, each of which may be optionally substituted by one or more substituents independently selected from nitro, hydroxyl, oxo, halogen, carboxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl, phenyl and —NHC(O)—R 13 , or
R 10 represents a group —NR 14 R 15 or —O—R 16 ;
R 11 and R 12 each independently represent (i) a hydrogen atom, (ii) a 3-to 6-membered saturated or unsaturated ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur and optionally further comprising a bridging group, the ring being optionally substituted with at least one substituent selected from halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl and C 1 -C 6 haloalkyl,
(iii) a C 1 -C 6 alkyl group optionally substituted by at least one substituent selected from halogen, amino, hydroxyl, C 1 -C 6 haloalkyl, carboxyl, C 1 -C 6 alkoxy,
C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylcarbonylamino and a 3- to 6-membered saturated or unsaturated ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur and optionally further comprising a bridging group, the ring being optionally substituted with at least one substituent selected from halogen, hydroxyl, oxo (═O), C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl and C 1 -C 6 haloalkyl, or (iv) C 1 -C 6 alkylsulphonyl, or
R 11 and R 12 together with the nitrogen atom to which they are attached form a 4-to 7-membered saturated heterocyclic ring that optionally further comprises a ring nitrogen, oxygen or sulphur atom and that is optionally fused to a benzene ring to form a 8- to 11-membered ring system, the heterocyclic ring or ring system being optionally substituted with at least one substituent selected from halogen, hydroxyl, amido, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylcarbonylamino, C 1 -C 6 alkylaminocarbonyl, di-C 1 -C 6 alkylaminocarbonyl, phenyl, halophenyl, phenylcarbonyl, phenylcarbonyloxy and hydroxydiphenylmethyl;
R 12a represents a hydrogen atom or a C 1 -C 6 alkyl group;
R 13 represents a C 1 -C 6 alkyl, amino or phenyl group;
R 14 and R 15 each independently represent a hydrogen atom, or a group C 1 -C 6 alkyl, C 1 -C 6 alkylsulphonyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, each group being optionally substituted as defined above for R 10 , or
R 14 and R 15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring that optionally further comprises a ring nitrogen, oxygen or sulphur atom, the heterocyclic ring being optionally substituted by at least one hydroxyl; and
R 16 represents a hydrogen atom, or a group C 1 -C 6 alkyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, each group being optionally substituted as defined above for R 10 ;
or a pharmaceutically acceptable salt thereof.
9 . A method of treating an airway disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to Formula I:
wherein
m is 0, 1, 2, 3 or 4;
each R 1 independently represents halogen, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy or sulphonamido;
either X represents a bond, —CH 2 —, —O— or —C(O)— and Y represents a bond, —CH 2 —, —O— or —C(O)—, or X and Y together represent a group —CH═C(CH 3 )— or —C(CH 3 )═CH—, and Z represents a bond, —O—, —NH— or —CH 2 —, provided that only one of X, Y and Z can represent a bond at any one time and provided that X and Y do not both simultaneously represent —O— or —C(O)—;
n is 0, 1 or 2;
each R 2 independently represents halogen or C 1 -C 6 alkyl;
q is 0 or 1;
R 3 represents —NHC(O)R 10 , —C(O)NR 11 R 12 or —COOR 12a ;
R 4 , R 5 , R 6 , R 7 and R 8 each independently represent a hydrogen atom or a C 1 -C 6 alkyl group;
t is 0, 1 or 2;
each R 9 independently represents halogen, cyano, hydroxyl, carboxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted by at least one substituent selected from carboxyl and C 1 -C 6 alkoxycarbonyl;
R 10 represents a group C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, adamantyl, C 5 -C 6 cycloalkenyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, each of which may be optionally substituted by one or more substituents independently selected from nitro, hydroxyl, oxo, halogen, carboxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl, phenyl and —NHC(O)—R 13 , or
R 10 represents a group —NR 14 R 15 or —O—R 16 ;
R 11 and R 12 each independently represent (i) a hydrogen atom, (ii) a 3-to 6-membered saturated or unsaturated ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur and optionally further comprising a bridging group, the ring being optionally substituted with at least one substituent selected from halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl and C 1 -C 6 haloalkyl,
(iii) a C 1 -C 6 alkyl group optionally substituted by at least one substituent selected from halogen, amino, hydroxyl, C 1 -C 6 haloalkyl, carboxyl, C 1 -C 6 alkoxy,
C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylcarbonylamino and a 3- to 6-membered saturated or unsaturated ring optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur and optionally further comprising a bridging group, the ring being optionally substituted with at least one substituent selected from halogen, hydroxyl, oxo (═O), C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl and C 1 -C 6 haloalkyl, or (iv) C 1 -C 6 alkylsulphonyl, or
R 11 and R 12 together with the nitrogen atom to which they are attached form a 4-to 7-membered saturated heterocyclic ring that optionally further comprises a ring nitrogen, oxygen or sulphur atom and that is optionally fused to a benzene ring to form a 8- to 11-membered ring system, the heterocyclic ring or ring system being optionally substituted with at least one substituent selected from halogen, hydroxyl, amido, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylcarbonylamino, C 1 -C 6 alkylaminocarbonyl, di-C 1 -C 6 alkylaminocarbonyl, phenyl, halophenyl, phenylcarbonyl, phenylcarbonyloxy and hydroxydiphenylmethyl;
R 12a represents a hydrogen atom or a C 1 -C 6 alkyl group;
R 13 represents a C 1 -C 6 alkyl, amino or phenyl group;
R 14 and R 15 each independently represent a hydrogen atom, or a group C 1 -C 6 alkyl, C 1 -C 6 alkylsulphonyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, each group being optionally substituted as defined above for R 10 , or
R 14 and R 15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring that optionally further comprises a ring nitrogen, oxygen or sulphur atom, the heterocyclic ring being optionally substituted by at least one hydroxyl; and
R 16 represents a hydrogen atom, or a group C 1 -C 6 alkyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, each group being optionally substituted as defined above for R 10 ;
or a pharmaceutically acceptable salt thereof.Join the waitlist — get patent alerts
Track US2009062322A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.