Thienopyrimidinediones and their use in the modulation of autoimmune disease
1 Assignment
0 Petitions
Accused Products
Abstract
The invention relates to a compound of formula (1); wherein: R1 and R2 each independently represent a C1-6alkyl, C3-6 alkenyl, C3-6 cycloalkyl C1-3 alkyl or C3-6 cycloalkyl; each of which may be optionally substituted by 1 to 3 halogen atoms; R3 is isoxyzolidin-2-ylcarbonyl or tetrahydroisoxazin-2-ylcarbonyl wherein each ring is optionally substituted by one hydroxy group; Q is CO— or C(R4)(R5)—(wherein R4 is a hydrogen atom or C1-4alkyl and R5 is a hydrogen atom or hydroxy group); Ar is a 5- to 10-membered aromatic ring system wherein up to 4 ring atoms may be heteroatoms independently selected from nitrogen, oxygen and sulphur, the ring system being optionally substituted by one or more substituents as defined in the specification. It also relates to methods of preparing, pharmaceutical compositions containing and methods of using the compound of the formula (1), particularly in the modulation of autoimmune disease.
-
Citations
16 Claims
-
1. A compound of formula (1):
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 14, 15, 16)
-
2. A compound according to claim 1 wherein R2 is methyl or ethyl.
-
3. A compound according to claim 1 wherein R1 is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylpropyl, cyclopropylmethyl, trifluoromethyl 2,2,2-trifluoroethyl, 2-chloroethyl, 2-chloropropyl or 3,3,3-trifluoropropyl.
-
4. A compound according to claim 1 wherein Q is —
- CO—
or —
CH2—
.
- CO—
-
5. A compound according to claim 1 wherein Ar contains at least 1 ring nitrogen.
-
6. A compound according to claim 1 wherein Ar contains at least 2 ring nitrogens.
-
7. A compound according to claim 1 wherein Ar is selected from imidazolyl, pyrazolyl, pyrrolyl, isoxazolyl, phenyl, quinolyl, indolyl, benzimidazolyl, indazolyl, benztriazolyl, 2,3-dihydrothiazolyl, 2,3-dihydrobenzoxazolyl, pyrrolo [2,3-b]pyridyl, imidazo[1,2-a]pyridyl, imidazo[4,5-b]pyridyl, 2,3-dihydrothiazolo[5,4-b]pyridyl, 2,3-dihydropyrazinyl, 2,3-dihydrobenzothiazolyl and 2,3-dihydrobenzimidazolyl each ring system being optionally substituted according to claim 1.
-
8. A compound according to claim 1 wherein Ar is substituted by 1, 2 or 3 substituents independently selected from C1-4alkyl (optionally substituted by 1 or 2 hydroxy groups), C1-4alkoxy, halogen, trihaloalkyl, C1-4alkylthio, C2-4alkanoyl, oxo, thioxo, cyano and —
- (CH2)pN(R8)R9 (wherein p is 1 or
2), hydroxy, C1-4alkylsulphonyl, carbamoyl, C1-4alkylcarbamoyl, di-(C1-4alkyl)carbamoyl, carboxy, and a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from nitrogen, oxygen and sulphur.
- (CH2)pN(R8)R9 (wherein p is 1 or
-
9. A compound according to claim 1 which is:
-
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(4-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(R) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-11-(2-methylpropyl)-6-(4-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[4,5-dichloro-2-methyl- 1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(4-quinolinylcarbonyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-indol-3-yl)methyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]thieno[2,3,d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl- 1H-indol-3-yl)carbonyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(1-methylethyl)-6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propyl-6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[4,5-dichloro-2-oxo-3(2H)-thiazolylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[(3,5-dimethyl- 1H-pyrazol-4-yl)methyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-1-isobutyl-3-methyl-6-[1,3,5-trimethyl- 1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(R) 6-[(4,5-dichloro-2-methyl- 1H-imidazol-1-yl)methyl]-5-[4-hydroxy-isoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-benzimidazol-1-yl)methyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[(2-ethyl-1H-benzimidazol-1-yl)methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2-propyl-1H-benzimidazol-1-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-(methylthio)-1H-benzimidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4 (1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benzimidazol-1-ylmethyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)- 1H-benzimidazol-1-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-amino-1H-benzimidazol-1-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2,4,5-trichloro-1H-imidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-thioxo-3(2H)-benzothiazolylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[4-chloro-2-oxo-3(2H)-thiazolylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[2-oxo-1,3-benzoxazol-3(2H)-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[(2-oxo[1,3]thiazolo[5,4-b]pyridin-1-(2H)-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(1H-1,2,3-benzotriazol-1-ylmethyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(1H-pyrrolo[2,3-b]pyridin-1-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2-methyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 1-[1,2,3,4-tetrahydro-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-ylmethyl)-1H-indole-5-carbonitrile;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[2-oxo-1,3-benzothiazol-3(2H)-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(R) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-methyl-1H-indol-3-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(R) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-methyl-1H-indol-3-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-3H-imidazo[4,5-b]pyridin-3-ylmethyl]-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-prop yl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-1H-benzimidazol-1-ylmethyl]-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-5-carboxamide;
(S) 6-[3,5-diethyl- 1H-pyrazol-4-ylmethyl]-5-{4-hydroxyisoxazolidin-2-yl]arbonyl}-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[3-(1,1-dimethylethyl)-5-methyl-1H-pyrazol-4-ylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-methyl-4-quinolinylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[6-fluoro-4-quinolinylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[8-fluoro-4-quinolinylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-(5-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-propyl-6-(quinolin-4-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(1-methylethyl)-6-(4-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2-methyl-1H-pyrrolo[2,3,b]pyridin-3-yl)methyl]thieno[2,3,d]pyrimidine-2,4(1H,3H)-dione;
(R) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2-methyl-1H-pyrrolo[2,3,b]pyridin-3-yl)methyl]thieno[2,3,d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2,3-dihydro-6-methyl-3-oxo-pyrazin-2-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benzimidazol-1-ylmethyl]-3-methyl-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propyl-6-[2-amino- 1H-benzimidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benzimidazol-1-yl methyl]-3-methyl-1-(isopropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-amino-1H-benzimidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-methyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[4,5-dichloro-2-(hydroxymethyl)- 1H-imidazol-1-yl methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[3,5-dimethyl- 1H-pyrazol-1-yl methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[4-hydroxyisoxazolidin-2-yl carbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-yl carbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S) 6-[3,5-dmethyl-1H-pyrazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isopropyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[3,5-dmethylisoxazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[4,5-dichloro-2-methyl- 1H-imidazol-1-ylmethyl]-1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-propyl- 1H-benzimidazol-1-yl methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-oxo-3 (2H)-benzothiazolylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-methyl- 1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[5-cyano- 1H-indol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-6-[1-isopropyl-3,5-dimethyl-1H-pyrazol-4-ylmethyl]-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-methyl-6-[5-methyl-3-phenyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-methyl-6-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-6-[3-isopropyl-5-methyl-1H-pyrazol-4-ylmethyl]-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[3,5-dimethyl-1-phenyl- 1H-pyrazol-4-ylmethyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-(1H-1,2,3-benzotriazol-1-ylmethyl)-5-[(4S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4H)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isopropyl)-6-[(2-oxothiazolo[5,4-b]pyridin-[(2H)-yl)methyl]-thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione 6-[2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[(S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione 6-[5,6-difluoro-2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-6-(imidazo[1,2-a]pyridin-3-ylmethyl)-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
3-methyl-6-[2-methylindol-3-ylmethyl]-1-(isobutyl)-5-(tetrahydroisoxazin-2-ylcarbonyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[2-bromo-4,5-dichloro-1H-imidazol-1-ylmethyl]-5-[(4S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(methylthio)-1H-imidazo[4,5-b]pyridin-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[(4S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(methylthio)-3H-imidazo[4,5-b]pyridin-3-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[3,5-dimethyl- 1H-pyrazol-4-ylmethyl]-3-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(trifluoromethyl)phenylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(methylthio)-1H-imidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
or(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2,3-dihydro-6-methyl-3-oxo-pyrazin-2-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
or a pharmaceutically-acceptable salt thereof.
-
-
10. A process for the preparation of a compound of the formula (1) as defined in claim 1, or a compound of the formula (1) as defined in claim 1 wherein at least 1 functional group is protected, using one of the following processes
a) reacting a compound of the formula (10): -
with isoxazolidine or tetrahydroisoxazine (each being optionally substituted by a hydroxy group);
b) when Q is methylene, reacting a compound of the formula (11);
with a compound of the formula Ar;
c) when Q is methylene, reducing a compound of the formula (12);
d) reacting a compound of the formula (11) or (13) to form Ar by primary ring
synthesis;
e) reacting a compound of the formula (14) with R1-L2;
wherein L and L2 are leaving groups and R1, R2, R3, Q and Ar are as hereinabove defined and optionally after a), b), c) or d), converting the compound of the formula (1) into a further compound of formula (1) and/or forming a pharmaceutically-acceptable salt or solvate thereof.
-
-
11. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable adjuvant, diluent or carrier.
-
14. A method of inhibiting the proliferation of T cells, which comprises administering to a patient a therapeutically effective amount of a compound according to claim 1.
-
15. A method of effecting immunosuppression, which comprises administering to a patient a therapeutically effective amount of a compound according to claim 1.
-
16. A method of treating or reducing the risk of a reversible obstructive airways disease in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound according to claim 1.
-
2. A compound according to claim 1 wherein R2 is methyl or ethyl.
-
12-13. -13. (Canceled)
Specification
- Resources
-
Current AssigneeAstrazeneca AB (Astrazeneca PLC)
-
Original AssigneeAstrazeneca AB (Astrazeneca PLC)
-
InventorsGuile, Simon David, Cooper, Martin Edward, Reynolds, Rachel Heulwen, Rasul, Rukhsana Tasneem, Ingall, Anthony Howard
-
Granted Patent
-
Time in Patent OfficeDays
-
Field of Search
-
US Class Current514/260.1
-
CPC Class CodesA61P 1/00 Drugs for disorders of the ...A61P 11/00 Drugs for disorders of the ...A61P 11/06 AntiasthmaticsA61P 13/12 of the kidneysA61P 17/00 Drugs for dermatological di...A61P 17/08 AntiseborrheicsA61P 19/02 for joint disorders, e.g. a...A61P 21/00 Drugs for disorders of the ...A61P 21/04 for myasthenia gravisA61P 25/00 Drugs for disorders of the ...A61P 27/16 OtologicalsA61P 29/00 Non-central analgesic, anti...A61P 3/10 for hyperglycaemia, e.g. an...A61P 31/18 for HIVA61P 35/00 Antineoplastic agentsA61P 37/00 Drugs for immunological or ...A61P 37/02 ImmunomodulatorsA61P 37/06 Immunosuppressants, e.g. dr...A61P 37/08 Antiallergic agents antiast...A61P 43/00 Drugs for specific purposes...A61P 9/10 : for treating ischaemic or a...C07D 495/04 : Ortho-condensed systems