U.S. patent application number 12/039204 was filed with the patent office on 2008-06-26 for chemical compounds.
This patent application is currently assigned to ASTRAZENECA AB, a SWEDEN corporation. Invention is credited to Anthony Howard Ingall, Rachel Heulwen Reynolds.
Application Number | 20080153855 12/039204 |
Document ID | / |
Family ID | 9918788 |
Filed Date | 2008-06-26 |
United States Patent
Application |
20080153855 |
Kind Code |
A1 |
Reynolds; Rachel Heulwen ;
et al. |
June 26, 2008 |
Chemical Compounds
Abstract
The invention relates to a compound of formula (1) ##STR00001##
in which Q is --CO-- or --C(R.sup.4)(R.sup.5)--, where R.sup.4 is a
hydrogen atom or C.sub.1-4alkyl and R.sup.5 is a hydrogen atom or
hydroxy group; and Ar is a 5- to 10-membered aromatic ring system
where 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.
Inventors: |
Reynolds; Rachel Heulwen;
(Loughborough, GB) ; Ingall; Anthony Howard;
(Loughborough, GB) |
Correspondence
Address: |
FISH & RICHARDSON P.C.
P.O BOX 1022
MINNEAPOLIS
MN
55440-1022
US
|
Assignee: |
ASTRAZENECA AB, a SWEDEN
corporation
|
Family ID: |
9918788 |
Appl. No.: |
12/039204 |
Filed: |
February 28, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10483161 |
Jan 8, 2004 |
7361660 |
|
|
PCT/GB02/03250 |
Jul 16, 2002 |
|
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12039204 |
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Current U.S.
Class: |
514/260.1 |
Current CPC
Class: |
A61P 37/02 20180101;
C07D 495/04 20130101; A61P 11/00 20180101; A61P 43/00 20180101;
A61P 11/08 20180101; A61P 29/00 20180101; A61P 37/06 20180101 |
Class at
Publication: |
514/260.1 |
International
Class: |
A61K 31/519 20060101
A61K031/519; A61P 37/06 20060101 A61P037/06; A61P 11/00 20060101
A61P011/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 19, 2001 |
GB |
0117583.5 |
Claims
1. A method of inhibiting the proliferation of T cells, comprising
administering to a patient a therapeutically effective amount of a
compound of formula (1) ##STR00030## wherein R.sup.1 and R.sup.2
each independently represent a C.sub.1-6alkyl, C.sub.3-6alkenyl,
C.sub.3-6cycloalkylC.sub.1-3alkyl or C.sub.3-6cycloalkyl; each of
which is optionally substituted by 1 to 3 halogen atoms; R.sup.3 is
a group --CON(R.sup.10)YR.sup.11 or --SO.sub.2N(R.sup.10)YR.sup.11;
in which Y is O, S or NR.sub.12, R.sup.12 being hydrogen or
C.sub.1-6allyl; and R.sup.10 and R.sup.11 are independently
C.sub.1-6allyl optionally substituted by halo, hydroxy, amino,
C.sub.1-6alkylamino or di-(C.sub.1-6alkyl)amino; Q is --CO-- or
--C(R.sup.4)(R.sup.5)--; in which R.sup.4 is a hydrogen atom or
C.sub.1-4alkyl and R.sup.5 is a hydrogen atom or a hydroxy group;
Ar is a 5- to 10-membered aromatic ring system, in which up to 4
ring atoms are optionally heteroatoms independently selected from
the group consisting of nitrogen, oxygen and sulphur, and the ring
system is optionally substituted by one or more substituents
independently selected from the group consisting of C.sub.1-4alkyl
optionally substituted by 1, 2 or 3 hydroxy groups,
C.sub.1-4alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl,
C.sub.1-4alkoxyC.sub.1-4alkyl, C.sub.1-4alkylthio,
C.sub.1-4alkoxycarbonyl, C.sub.2-4alkanoyl, oxo, thioxo, nitro,
cyano, --N(R.sup.6)R.sup.7, --(CH.sub.2)pN(R.sup.8)R.sup.9,
hydroxy, C.sub.1-4alkylsulphonyl, C.sub.1-4alkylsulphinyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di-(C.sub.1-4alkyl)carbamoyl,
carboxy, and a 5 or 6 membered aromatic ring containing up to 4
heteroatoms independently selected from the group consisting of
nitrogen, oxygen and sulphur; p is 1 to 4; R.sup.6 and R.sup.7 each
independently represent a hydrogen atom, C.sub.1-4alkanoyl or
C.sub.1-4alkyl, or together with the nitrogen atom to which they
are attached form a 5- to 7-membered saturated heterocyclic ring;
R.sup.8 and R.sup.9 each independently represent a hydrogen atom,
C.sub.1-4alkanoyl or C.sub.1-4 alkyl, or together with the nitrogen
atom to which they are attached form a 5- to 7-membered saturated
heterocyclic ring; or a pharmaceutically acceptable salt
thereof.
2. The method of claim 1, wherein R.sup.2 is methyl or ethyl.
3. The method of claim 1, wherein R.sup.1 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. The method of claim 1, wherein Q is --CO-- or --CH.sub.2--.
5. The method of claim 1, wherein R.sup.10 is C.sub.1-4alkyl
optionally substituted by hydroxy.
6. The method of claim 1, wherein R.sup.11 is C.sub.1-4alkyl
optionally substituted by hydroxy.
7. The method of claim 1, wherein Y is O.
8. The method of claim 1, wherein R.sup.3 is --CON(Me)OMe,
--CON(Et)OMe, --CON(OEt)Me, --CON(Et)OEt,
--CON(CH.sub.2CH.sub.2OH)OEt, --CON(CH.sub.2CH.sub.2OH)Me,
--CON(OCH.sub.2CH.sub.2OH)Me, or --CON(OCH.sub.2CH.sub.2OH)Et.
9. The method of claim 1, wherein Ar contains at least 1 ring
nitrogen.
10. The method of claim 1, wherein Ar contains at least 2 ring
nitrogen.
11. The method of claim 1, wherein Ar is selected from the group
consisting of 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.
12. The method of claim 1, wherein Ar is substituted by 1, 2 or 3
substituents independently selected from the group consisting of
C.sub.1-4alkyl optionally substituted by 1 or 2 hydroxy groups,
C.sub.1-4alkoxy, halogen, trihaloalkyl, C.sub.1-4alkylthio,
C.sub.1-4alkoxycarbonyl, C.sub.2-4alkanoyl, oxo, thioxo, cyano,
--NHR.sup.7, --(CH.sub.2)pN(R.sup.8)R.sup.9 wherein p is 1 or 2,
hydroxy, C.sub.1-4alkylsulphonyl, carbamoyl,
C.sub.1-4alkylcarbamoyl, di-(C.sub.1-4alkyl)carbamoyl, carboxy, and
a 5 or 6 membered aromatic ring containing up to 4 heteroatoms
independently selected from the group consisting of nitrogen,
oxygen and sulphur.
13. A method of effecting immunosuppression, comprising
administering to a patient a therapeutically effective amount of a
compound of formula (1) ##STR00031## wherein R.sup.1 and R.sup.2
each independently represent a C.sub.1-6alkyl, C.sub.3-6alkenyl,
C.sub.3-6cycloalkylC.sub.1-3alkyl Our C.sub.3-6cycloalkyl; each of
which is optionally substituted by 1 to 3 is halogen atoms; R.sup.3
is a group --CON(R.sup.10)YR.sup.11 or
--SO.sub.2N(R.sup.10)YR.sup.11; in which Y is O S or NR.sub.12,
R.sup.12 being hydrogen or C.sub.1-6alkyl; and R.sup.10 and
R.sup.11 are independently C.sub.1-6alkyl optionally substituted by
halo, hydroxy, amino, C.sub.1-6alkylamino or
di-(C.sub.1-6alkyl)amino; Q is --CO-- or --C(R.sup.4)(R.sup.5)--;
in which R.sup.4 is a hydrogen atom or C.sub.1-4alkyl and R.sup.5
is a hydrogen atom or a hydroxy group; Ar is a 5- to 10-membered
aromatic ring system, in which up to 4 ring atoms are optionally
heteroatoms independently selected from the group consisting of
nitrogen, oxygen and sulphur, and the ring system is optionally
substituted by one or more substituents independently selected from
the group consisting of C.sub.1-4alkyl optionally substituted by 1,
2 or 3 hydroxy groups, C.sub.1-4alkoxy, halogen, haloalkyl,
dihaloalkyl, trihaloalkyl, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylthio, C.sub.1-4alkoxycarbonyl, C.sub.2-4alkanoyl,
oxo, thioxo, nitro, cyano, --N(R.sup.6)R.sup.7,
--(CH.sub.2)pN(R.sup.8)R.sup.9, hydroxy, C.sub.1-4alkylsulphonyl,
C.sub.1-4alkylsulphinyl, carbamoyl, C.sub.1-4alkylcarbamoyl,
di-(C.sub.1-4alkyl)carbamoyl, carboxy, and a 5 or 6 membered
aromatic ring containing up to 4 heteroatoms independently selected
from the group consisting of nitrogen, oxygen and sulphur; p is 1
to 4; R.sup.6 and R.sup.7 each independently represent a hydrogen
atom, C.sub.1-4alkanoyl or C.sub.1-4alkyl, or together with the
nitrogen atom to which they are attached form a 5- to 7-membered
saturated heterocyclic ring; R.sup.8 and R.sup.9 each independently
represent a hydrogen atom, C.sub.1-4alkanoyl or C.sub.1-4 alkyl, or
together with the nitrogen atom to which they are attached form a
5- to 7-membered saturated heterocyclic ring; or a pharmaceutically
acceptable salt thereof.
14. The method of claim 13, wherein R.sup.2 is methyl or ethyl.
15. The method of claim 13, wherein R.sup.1 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.
16. The method of claim 13, wherein Q is --CO-- or
--CH.sub.2--.
17. The method of claim 13, wherein R.sup.10 is C.sub.1-4alkyl
optionally substituted by hydroxy.
18. The method of claim 13, wherein R.sup.11 is C.sub.1-4alkyl
optionally substituted by hydroxy.
19. The method of claim 13, wherein Y is O.
20. The method of claim 13, wherein R.sup.3 is --CON(Me)OMe,
--CON(Et)OMe, --CON(OEt)Me, --CON(Et)OEt,
--CON(CH.sub.2CH.sub.2OH)OEt, --CON(CH.sub.2CH.sub.2OH)Me,
--CON(OCH.sub.2CH.sub.2OH)Me, or --CON(OCH.sub.2CH.sub.2OH)Et.
21. The method of claim 13, wherein Ar contains at least 1 ring
nitrogen.
22. The method of claim 13, wherein Ar contains at least 2 ring
nitrogen.
23. The method of claim 13, wherein Ar is selected from the group
consisting of 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 13.
24. The method of claim 13, wherein Ar is substituted by 1, 2 or 3
substituents independently selected from the group consisting of
C.sub.1-4alkyl optionally substituted by 1 or 2 hydroxy groups,
C.sub.1-4alkoxy, halogen, trihaloalkyl, C.sub.1-4alkylthio,
C.sub.1-4alkoxycarbonyl, C.sub.2-4alkanoyl, oxo, thioxo, cyano,
--NHR.sup.7, --(CH.sub.2)pN(R.sup.8)R.sup.9 wherein p is 1 or 2,
hydroxy, C.sub.1-4alkylsulphonyl, carbamoyl,
C.sub.1-4alkylcarbamoyl, di-(C.sub.1-4alkyl)carbamoyl, carboxy, and
a 5 or 6 membered aromatic ring containing up to 4 heteroatoms
independently selected from the group consisting of nitrogen,
oxygen and sulphur.
25. A method of treating or reducing the risk of a reversible
obstructive airways disease in a patient suffering from, or at risk
of, the disease, comprising administering to the patient a
therapeutically effective amount of a compound of formula (1)
##STR00032## wherein R.sup.1 and R.sup.2 each independently
represent a C.sub.1-6alkyl, C.sub.3-6alkenyl,
C.sub.3-6cycloalkylC.sub.1-3alkyl or C.sub.3-6cycloalkyl; each of
which is optionally substituted by 1 to 3 halogen atoms; R.sup.3 is
a group --CON(R.sup.10)YR.sup.11 or --SO.sub.2N(R.sup.10)YR.sup.11;
in which Y is O, S or NR.sub.12, R.sup.12 being hydrogen or
C.sub.1-6alkyl; and R.sup.10 and R.sup.11 are independently
C.sub.1-6alkyl optionally substituted by halo, hydroxy, amino,
C.sub.1-6alkylamino or di-(C.sub.1-6alkyl)amino; Q is --CO-- or
--C(R.sup.4)(R.sup.5)--; in which R.sup.4 is a hydrogen atom or
C.sub.1-4alkyl and R.sup.5 is a hydrogen atom or a hydroxy group;
Ar is a 5- to 10-membered aromatic ring system, in which up to 4
ring atoms are optionally heteroatoms independently selected from
the group consisting of nitrogen, oxygen and sulphur, and the ring
system is optionally substituted by one or more substituents
independently selected from the group consisting of C.sub.1-4alkyl
optionally substituted by 1, 2 or 3 hydroxy groups,
C.sub.1-4alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl,
C.sub.1-4alkoxyC.sub.1-4alkyl, C.sub.1-4alkylthio,
C.sub.1-4alkoxycarbonyl, C.sub.2-4alkanoyl, oxo, thioxo, nitro,
cyano, --N(R.sup.6)R.sup.7, --(CH.sub.2)pN(R.sup.8)R.sup.9,
hydroxy, C.sub.1-4alkylsulphonyl, C.sub.1-4alkylsulphinyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di-(C.sub.1-4alkyl)carbamoyl,
carboxy, and a 5 or 6 membered aromatic ring containing up to 4
heteroatoms independently selected from the group consisting of
nitrogen, oxygen and sulphur; p is 1 to 4; R.sup.6 and R.sup.7 each
independently represent a hydrogen atom, C.sub.1-4alkanoyl or
C.sub.1-4alkyl, or together with the nitrogen atom to which they
are attached form a 5- to 7-membered saturated heterocyclic ring;
R.sup.8 and R.sup.9 each independently represent a hydrogen atom,
C.sub.1-4alkanoyl or C.sub.1-4 alkyl, or together with the nitrogen
atom to which they are attached form a 5- to 7-membered saturated
heterocyclic ring; or a pharmaceutically acceptable salt
thereof.
26. The method of claim 25, wherein the obstructive airways disease
is chronic obstructive pulmonary disease (COPD).
27. The method of claim 25, where in the obstructive airways
disease is asthma.
28. The method of claim 25, wherein R.sup.2 is methyl or ethyl.
29. The method of claim 25, wherein R.sup.1 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.
30. The method of claim 25, wherein Q is --CO-- or
--CH.sub.2--.
31. The method of claim 25, wherein R.sup.10 is C.sub.1-4alkyl
optionally substituted by hydroxy.
32. The method of claim 25, wherein R.sup.11 is C.sub.1-4alkyl
optionally substituted by hydroxy.
33. The method of claim 25, wherein Y is O.
34. The method of claim 25, wherein R.sup.3 is --CON(Me)OMe,
--CON(Et)OMe, --CON(OEt)Me, --CON(Et)OEt,
--CON(CH.sub.2CH.sub.2OH)OEt, --CON(CH.sub.2CH.sub.2OH)Me,
--CON(OCH.sub.2CH.sub.2OH)Me, or --CON(OCH.sub.2CH.sub.2OH)Et.
35. The method of claim 25, wherein Ar contains at least 1 ring
nitrogen.
36. The method of claim 25, wherein Ar contains at least 2 ring
nitrogen.
37. The method of claim 25, wherein Ar is selected from the group
consisting of 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 25.
38. The method of claim 25, wherein Ar is substituted by 1, 2 or 3
substituents independently selected from the group consisting of
C.sub.1-4alkyl optionally substituted by 1 or 2 hydroxy groups,
C.sub.1-4alkoxy, halogen, trihaloalkyl, C.sub.1-4alkylthio,
C.sub.1-4alkoxycarbonyl, C.sub.2-4alkanoyl, oxo, thioxo, cyano,
--NHR.sup.7, --(CH.sub.2)pN(R.sup.8)R.sup.9 wherein p is 1 or 2,
hydroxy, C.sub.1-4alkylsulphonyl, carbamoyl,
C.sub.1-4alkylcarbamoyl, di-(C.sub.1-4alkyl)carbamoyl, carboxy, and
a 5 or 6 membered aromatic ring containing up to 4 heteroatoms
independently selected from the group consisting of nitrogen,
oxygen and sulphur.
39. A method of treating or reducing the risk of cancer in a
patient suffering from, or at risk of, the cancer, comprising
administering to a patient a therapeutically effective amount of a
compound of formula (1) ##STR00033## wherein R.sup.1 and R.sup.2
each independently represent a C.sub.1-6alkyl, C.sub.3-6alkenyl,
C.sub.3-6cycloalkylC.sub.1-3alkyl or C.sub.3-6cycloalkyl; each of
which is optionally substituted by 1 to 3 halogen atoms; R.sup.3 is
a group --CON(R.sup.10)YR.sup.11 or --SO.sub.2N(R.sup.10)YR.sup.11;
in which Y is O, S or NR.sub.12, R.sup.12 being hydrogen or
C.sub.1-6alkyl; and R.sup.10 and R.sup.11 are independently
C.sub.1-6alkyl optionally substituted by halo, hydroxy, amino,
C.sub.1-6alkylamino or di-(C.sub.1-6alkyl)amino; Q is --CO-- or
--C(R.sup.4)(R.sup.5)--; in which R.sup.4 is a hydrogen atom or
C.sub.1-4alkyl and R.sup.5 is a hydrogen atom or a hydroxy group;
Ar is a 5- to 10-membered aromatic ring system, in which up to 4
ring atoms are optionally heteroatoms independently selected from
the group consisting of nitrogen, oxygen and sulphur, and the ring
system is optionally substituted by one or more substituents
independently selected from the group consisting of C.sub.1-4alkyl
optionally substituted by 1, 2 or 3 hydroxy groups,
C.sub.1-4alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl,
C.sub.1-4alkoxyC.sub.1-4alkyl, C.sub.1-4alkylthio,
C.sub.1-4alkoxycarbonyl, C.sub.2-4alkanoyl, oxo, thioxo, nitro,
cyano, --N(R.sup.6)R.sup.7, --(CH.sub.2)pN(R.sup.8)R.sup.9,
hydroxy, C.sub.1-4alkylsulphonyl, C.sub.1-4alkylsulphinyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di-(C.sub.1-4alkyl)carbamoyl,
carboxy, and a 5 or 6 membered aromatic ring containing up to 4
heteroatoms independently selected from the group consisting of
nitrogen, oxygen and sulphur; p is 1 to 4; R.sup.6 and R.sup.7 each
independently represent a hydrogen atom, C.sub.1-4alkanoyl or
C.sub.1-4alkyl, or together with the nitrogen atom to which they
are attached form a 5- to 7-membered saturated heterocyclic ring;
R.sup.8 and R.sup.9 each independently represent a hydrogen atom,
C.sub.1-4alkanoyl or C.sub.1-4 alkyl, or together with the nitrogen
atom to which they are attached form a 5- to 7-membered saturated
heterocyclic ring; or a pharmaceutically acceptable salt
thereof.
40. The method of claim 39, wherein R.sup.2 is methyl or ethyl.
41. The method of claim 39, wherein R.sup.2 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.
42. The method of claim 39, wherein Q is --CO-- or
--CH.sub.2--.
43. The method of claim 39, wherein R.sup.10 is C.sub.1-4alkyl
optionally substituted by is hydroxy.
44. The method of claim 39, wherein R.sup.11 is C.sub.1-4alkyl
optionally substituted by hydroxy.
45. The method of claim 39, wherein Y is O.
46. The method of claim 39, wherein R.sup.3 is --CON(Me)OMe,
--CON(Et)OMe, --CON(OEt)Me, --CON(Et)OEt,
--CON(CH.sub.2CH.sub.2OH)OEt, --CON(CH.sub.2CH.sub.2OH)Me,
--CON(OCH.sub.2CH.sub.2OH)Me, or --CON(OCH.sub.2CH.sub.2OH)Et.
47. The method of claim 39, wherein Ar contains at least 1 ring
nitrogen.
48. The method of claim 39, wherein Ar contains at least 2 ring
nitrogen.
49. The method of claim 39, wherein Ar is selected from the group
consisting of 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 39.
50. The method of claim 39, wherein Ar is substituted by 1, 2 or 3
substituents independently selected from the group consisting of
C.sub.1-4alkyl optionally substituted by 1 or 2 hydroxy groups,
C.sub.1-4alkoxy, halogen, trihaloalkyl, C.sub.1-4alkylthio,
C.sub.1-4alkoxycarbonyl, C.sub.2-4alkanoyl, oxo, thioxo, chicano,
--NHR.sup.7, --(CH.sub.2)pN(R.sup.8)R.sup.9 wherein p is 1 or 2,
hydroxy, C.sub.1-4alkylsulphonyl, carbamoyl,
C.sub.1-4alkylcarbamoyl, di-(C.sub.1-4alkyl)carbamoyl, carboxy, and
a 5 or 6 membered aromatic ring containing up to 4 heteroatoms
independently selected from the group consisting of nitrogen,
oxygen and sulphur.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 10/483,161, filed on Jan. 8, 2004, which is the national phase
application under 35 U.S.C. .sctn. 371 of PCT International
Application No. PCT/GB02/03250 having an International filing date
of Jul. 16, 2002, which in turn claims priority to United Kingdom
Application Serial No. 0117583.5, filed Jul. 19, 2001. The contents
of all parent applications are incorporated by reference in their
entirety.
BACKGROUND
[0002] The present invention relates to
thieno[2,3-d]pyrimidinediones, processes for their preparation,
pharmaceutical compositions containing them and their use in
therapy. In particular, in their use in the modulation of
autoimmune disease.
[0003] T-cells play an important role in the immune response,
however in auto-immune disease T-cells are inappropriately
activated against particular tissues and proliferate, e.g., causing
the inflammation associated with rheumatoid arthritis. Inhibition
of the proliferation of T-cells is beneficial in the modulation of
autoimmune disease. The present invention relates to compounds
which are beneficial in the modulation of autoimmune disease.
[0004] The compounds of WO 2000/12514 and WO2001/038489 are known
to be useful in modulating the immune response. These applications
encompass compounds having an amidic --C--N-- at the 5-position of
the thienopyrimidine ring system. These compounds exist as
slowly-interconverting rotamers, because of the combination of slow
rotations around the amidic C--N link and around the bond from the
amidic carbonyl to the thienopyrimidine core; the rate of
interconversion is such that the isomers may be separated by HPLC.
Such hindered rotation presents significant problems for the
development of a pharmaceutical compound: long equilibration times
imply that different initial rotameric mixtures may be expected to
arise if the conditions of the final step of the synthesis is
varied, leading to problems in assaying purity and reproducing the
solid form of the raw drug. Moreover rotameric forms having
lifetimes comparable to biological half lives may be expected to be
handled by metabolic processes in different ways, potentially
giving rise to structurally dissimilar metabolites, the biological
activity and safety of all of which must be fully studied and
documented. We have now found a class of compounds which have an
amidic --C--N-- group or sulphonamidic --S--N-- group at the
5-position of the thienopyrimidine ring system, have interesting
potency and yet do not have the problems associated with the
compounds existing as separate rotamers under ambient
conditions.
DETAILED DESCRIPTION
[0005] In accordance with the present invention, there is provided
a compound of formula (1)
##STR00002##
in which R.sup.1 and R.sup.2 each independently represent a
C.sub.1-6alkyl, C.sub.3-6alkenyl, C.sub.3-6cycloalkylC.sub.1-3alkyl
or C.sub.3-6cycloalkyl; each of which may be optionally substituted
by 1 to 3 halogen atoms; R.sup.3 is a group
--CON(R.sup.10)YR.sup.11 or --SO.sub.2N(R.sup.10)YR.sup.11, in
which Y is O, S or NR.sub.12 (R.sup.12 being hydrogen or
C.sub.1-6alkyl), and R.sup.10 and R.sup.11 are independently
C.sub.1-6alkyl optionally substituted by halo, hydroxy, amino,
C.sub.1-6alkylamino or di-(C.sub.1-6alkyl)amino; Q is --CO-- or
--C(R.sup.4)(R.sup.5)-- (R.sup.4 being a hydrogen atom or
C.sub.1-4alkyl and R.sup.5 being a hydrogen atom or is hydroxy
group); Ar is a 5- to 10-membered aromatic ring system in which 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 independently selected from
C.sub.1-4alkyl (optionally substituted by 1, 2 or 3 hydroxy
groups), C.sub.1-4alkoxy, halogen, haloalkyl, dihaloalkyl,
trihaloalkyl, C.sub.1-4alkoxyC.sub.1-4alkyl, C.sub.1-4alkylthio,
C.sub.1-4alkoxycarbonyl, C.sub.2-4alkanoyl, oxo, thioxo, nitro,
cyano, --N(R.sup.6)R.sup.7 and --(CH.sub.2)pN(R.sup.8)R.sup.9,
hydroxy, C.sub.1-4alkylsulphonyl, C.sub.1-4alkylsulphinyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di-(C.sub.1-4alkyl)carbamoyl,
carboxy, or a 5 or 6 membered aromatic ring containing up to 4
heteroatoms independently selected from nitrogen, oxygen and
sulphur; p is 1 to 4; R.sup.1 and R.sup.7 each independently
represent a hydrogen atom, C.sub.1-4alkanoyl or C.sub.1-4alkyl, or
together with the nitrogen atom to which they are attached form a
5- to 7-membered saturated heterocyclic ring; and R.sup.8 and
R.sup.9 each independently represent a hydrogen atom,
C.sub.1-4alkanoyl or C.sub.1-4 alkyl, or together with the nitrogen
atom to which they are attached form a 5- to 7-membered saturated
heterocyclic ring; or a pharmaceutically acceptable salt or prodrug
thereof.
[0006] In another aspect the invention relates to a compound of the
formula (1) as hereinabove defined or to a
pharmaceutically-acceptable salt thereof.
[0007] Within the present invention it is to be understood that a
compound of the formula 1 or a salt thereof may exhibit the
phenomenon of tautomerism and that the formulae drawings within
this specification can represent only one of the possible
tautomeric forms. It is to be understood that the invention
encompasses any tautomeric form and is not to be limited merely to
any one tautomeric form utilised within the formulae drawings. The
formulae drawings within this specification can represent only one
of the possible tautomeric forms and it is to be understood that
the specification encompasses all possible tautomeric forms of the
compounds drawn not just those forms which it has been possible to
show graphically herein.
[0008] The present invention relates to the compounds of formula 1
as hereinbefore defined as well as to the salts thereof. Salts for
use in pharmaceutical compositions will be pharmaceutically
acceptable salts, but other salts may be useful in the production
of the compounds of formula 1 and their pharmaceutically acceptable
salts. Pharmaceutically acceptable salts of the invention may, for
example, include acid addition salts of the compounds of formula 1
as hereinbefore defined which are sufficiently basic to form such
salts. Such acid addition salts include for example salts with
inorganic or organic acids affording pharmaceutically acceptable
anions such as with hydrogen halides (especially hydrochloric or
hydrobromic acid of which hydrochloric acid is particularly
preferred) or with sulphuric or phosphoric acid, or with
trifluoroacetic, citric or maleic acid. Suitable salts include
hydrochlorides, hydrobromides, phosphates, sulphates, hydrogen
sulphates, alkylsulphonates, arylsulphonates, acetates, benzoates,
citrates, maleates, fumarates, succinates, lactates and tartrates.
In addition where the compounds of formula 1 are sufficiently
acidic, pharmaceutically acceptable salts may be formed with an
inorganic or organic base which affords a pharmaceutically
acceptable cation. Such salts with inorganic or organic bases
include for example an alkali metal salt, such as a sodium or
potassium salt, an alkaline earth metal salt such as a calcium or
magnesium salt, an ammonium salt or for example a salt with
methylamine, dimethylamine, trimethylamine, piperidine, morpholine
or tris-(2-hydroxyethyl)amine.
[0009] Preferred salts include an acid addition salt such as a
hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate,
tartrate, citrate, oxalate, methanesulfonate or p-toluenesulfonate,
or an alkali metal salt such as a sodium or potassium salt.
[0010] Various forms of prodrugs are known in the art. For examples
of such prodrug derivatives, see:
a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and
Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et
al. (Academic Press, 1985); b) A Textbook of Drug Design and
Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter
5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191
(1991);
c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38
(1992);
d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77,
285 (1988); and
[0011] e) N. Kakeya, et al., Chem. Pharm. Bull. 32, 692 (1984).
[0012] Examples of such pro-drugs may be used to form
in-vivo-cleavable esters of a compound of the Formula 1. An in vivo
hydrolysable ester of a compound of the formula (1) containing a
hydroxy group is, for example, a pharmaceutically acceptable ester
which is hydrolysed in the human or animal body to produce the
parent alcohol. The term includes inorganic esters such as
phosphate esters and .alpha.-acyloxyalkyl ethers and related
compounds which as a result of the in vivo hydrolysis of the ester
breakdown to give the parent hydroxy group. Examples of
.alpha.-acyloxyalkyl ethers include acetoxymethoxy and
2,2-dimethylpropionyloxymethoxy. A selection of in vivo
hydrolysable ester forming groups for hydroxy include alkanoyl,
benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl,
alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl
and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),
dialkylaminoacetyl and carboxyacetyl.
[0013] It is also to be understood that certain compounds of the
formula (1) can exist in solvated forms as well as unsolvated
forms, for example, hydrated forms. It is to be understood that the
invention encompasses all such solvated forms, which are useful in
therapy, in particular for the particular therapeutic purposes
mentioned hereinafter.
[0014] In the present specification, unless otherwise indicated, an
alkyl, alkenyl or alkynyl group or an alkyl, alkenyl or alkynyl
moiety in a substituent group may be linear or branched.
[0015] Ar may be bonded to the --C(R.sup.4)(R.sup.5)-- group by a
ring carbon atom or a ring nitrogen providing this does not lead to
quaternisation.
[0016] It will be appreciated that in a group
--C(R.sup.4)(R.sup.5)Ar, R.sup.5 may represent a hydroxy group only
when Ar is bonded to --C(R.sup.4)(R.sup.5) through a carbon atom
and not a heteroatom. Furthermore, it should be understood that in
--C(O)Ar, Ar is bonded through a carbon atom and not a heteroatom
to the moiety --C(O). A hydroxyalkyl may contain more than one
hydroxy group but a single hydroxy group is preferred.
[0017] For the avoidance of doubt, when Ar is substituted by an oxo
or thioxo group, it is intended that Ar includes the
dihydro-versions of aromatic ring systems. For example, it
encompasses thiazolyl and 2,3-dihydrothiazolyl (when the latter is
substituted by an oxo or thioxo group). Similarly Ar encompasses,
for example, 2,3-dihydrobenzoxazolyl, 2,3-dihydrobenzothiazolyl,
2,3-dihydropyrazinyl and 2,3-dihydrobenzimidazolyl (when these are
substituted by an oxo or thioxo group).
[0018] 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, two, three or four substituents independently
selected from C.sub.1-4alkyl (optionally substituted by 1, 2 or 3
hydroxy groups) (e.g. methyl, ethyl, n-propyl, n-butyl,
hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl or 3-hydroxypropyl),
C.sub.1-4alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy),
halogen (e.g. fluorine, chlorine, bromine or iodine), haloalkyl,
(e.g. fluoromethyl, chloromethyl, bromomethyl, 2-fluoroethyl,
2-fluoropropyl or 3-fluoropropyl), dihaloalkyl, (e.g.
difluoromethyl, dichloromethyl, chlorofluoromethyl, dibromomethyl,
2,2-difluoroethyl, 2,2-difluoropropyl or 2,3-difluoropropyl),
trihaloalkyl, (e.g. trifluoromethyl, trichloromethyl,
2,2,2-trifluoroethyl, 2,2,2-trifluoropropyl or
2,2,3-trifluoropropyl), C.sub.1-4alkoxyC.sub.1-4alkyl, (e.g.
methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-methoxypropyl or
3-methoxypropyl), C.sub.1-4alkylthio (e.g. methylthio, ethylthio,
n-propylthio or n-butylthio), C.sub.1-4alkoxycarbonyl (e.g.
methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,
isopropoxycarbonyl or n-butoxycarbonyl), C.sub.2-4alkanoyl (e.g.
acetyl or propionyl), oxo, thioxo, nitro, cyano,
--N(R.sup.6)R.sup.7 (e.g. amino, N-methylamino, N-ethylamino,
di-N,N-methylamino or N-ethyl-N-methylamino),
--(CH.sub.2).sub.pN(R.sup.8)R.sup.9 [e.g.
--CH.sub.2N(R.sup.8)R.sup.9, --CH.sub.2CH.sub.2N(R.sup.8)R.sup.9 or
CH.sub.2CH.sub.2CH.sub.2N(R.sup.8)R.sup.9], hydroxy,
C.sub.1-4alkylsulphonyl (e.g. methylsulphonyl, ethylsulphonyl or
propylsulphonyl), C.sub.1-4alkylsulphinyl (methylsulphinyl,
ethylsulphinyl or propylsulphinyl), carbamoyl,
C.sub.1-4alkylcarbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl and
propylcarbamoyl) di-C.sub.1-4alkylcarbamoyl (e.g.
di-N,N-methylcarbamoyl, N-ethyl-N-methylcarbamoyl or
di-N,N-ethylcarbamoyl), carboxy and or a 5 or 6 membered aromatic
ring containing up to 4 heteroatoms independently selected from
nitrogen, oxygen and sulphur (e.g. phenyl, pyrimidyl, thienyl and
furanyl).
[0019] The aromatic ring system may be monocyclic or polycyclic
(e.g. bicyclic), examples of which include phenyl, naphthyl,
quinolyl, pyrazolyl, thienyl, oxazolyl, imidazolyl, pyridinyl,
pyrrolo[2,3-b]pyridyl, benzimidazolyl, indazolyl, benzothiazolyl,
2,3-dihydrobenzothiazolyl, benzoxazolyl, thiazolyl,
2,3-dihydrothiazolyl, 2,3-dihydrobenzimidazolyl,
2,3-dihydrobenzoxazolyl, thiazolo[5,4-b]pyridyl and
benzotriazolyl.
[0020] Further values of R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11,
R.sup.12, p, Q and Ar and substituents on Ar are further defined
hereinafter. Such values may be used where appropriate with any of
the definitions, claims or embodiments defined hereinafter or
hereinbefore.
[0021] In one aspect Ar is a 5 or 6 membered monocyclic ring.
[0022] In another aspect Ar is a 8, 9 or 10 bicyclic ring.
[0023] In yet another aspect Ar is a 9 or 10 bicyclic ring.
[0024] In one aspect the invention relates to compounds of the
formula 1 wherein Ar is a 5- to 10-membered aromatic ring system
containing up to 4 ring heteroatoms selected from nitrogen, oxygen
and sulphur providing that there is at least 1 ring nitrogen, the
ring being optionally substituted as defined above. These compound
have been found to be advantageous.
[0025] In another aspect Ar is a 5- to 10-membered aromatic ring
system containing 1 or 2 ring nitrogen atoms and optionally one
ring sulphur or oxygen atom or containing 3 ring nitrogen atoms,
the ring being optionally substituted as defined above.
[0026] In another aspect Ar is a 5- to 10-membered aromatic ring
system containing 1 or 2 ring nitrogen atoms and optionally one
ring sulphur atom, the ring being optionally substituted as defined
above.
[0027] In another aspect Ar is a 5- to 10-membered aromatic ring
system containing 2 ring nitrogen, the ring being optionally
substituted as defined above.
[0028] In yet another aspect 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.
[0029] In yet another aspect Ar is selected from imidazolyl,
pyrazolyl, pyrrolyl, isoxazolyl, 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.
[0030] In yet another aspect Ar is selected from imidazolyl,
pyrazolyl, benzimidazolyl, indazolyl, benztriazolyl,
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 and
2,3-dihydrobenzimidazolyl.
[0031] In yet another aspect Ar is selected from imidazolyl,
pyrazolyl, pyrrolyl, isoxazolyl, phenyl and
2,3-dihydropyrazinyl.
[0032] In yet another aspect Ar is selected from 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-dihydrobenzothiazolyl and
2,3-dihydrobenzimidazolyl.
[0033] In yet another aspect, Ar is selected from imidazolyl,
quinolyl, indolyl, benzimidazolyl, indazolyl, pyridopyrrolyl,
2,3-dihydrobenzothiazolyl, or 2,3-dihydrobenzimidazolyl.
[0034] R.sup.1 and R.sup.2 each independently represent
C.sub.1-6alkyl, particularly is C.sub.1-5alkyl (e.g. methyl, ethyl,
n-propyl, 1-methylethyl, n-butyl, 2-methylpropyl,
2,2-dimethylpropyl, n-pentyl or n-hexyl), C.sub.3-6alkenyl,
particularly C.sub.3-4alkenyl (e.g. 1-propenyl, 1-butenyl,
1-pentenyl or 1-hexenyl), C.sub.3-5cycloalkylC.sub.1-3alkyl
(cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,
2-(cyclopropyl)ethyl, 2-(cyclobutyl)ethyl or 2-(cyclopentyl)ethyl)
or C.sub.3-6cycloalkyl, particularly C.sub.5-6cycloalkyl
(cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) each of which
may be optionally substituted by 1 to 3 halogen atoms (e.g.
trifluoromethyl 2,2,2-trifluoroethyl, 2-chloroethyl, 2-chloropropyl
or 3,3,3-trifluoropropyl).
[0035] In another aspect, R.sup.1 and R.sup.2 each independently
represent C.sub.1-5alkyl or C.sub.3-6cycloalkylmethyl, each
optionally substituted by 1 to 3 halogen atoms.
[0036] In yet another aspect, R.sup.1 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.
[0037] In yet another aspect R.sup.1 is ethyl, n-propyl,
1-methylethyl, 2-methylpropyl, 2,2-dimethylpropyl or
cyclopropylmethyl.
[0038] In yet another aspect, R.sup.1 is 2-methylpropyl.
[0039] In one aspect R.sup.2 is methyl or trifluoromethyl.
[0040] In yet another aspect, R.sup.2 is methyl.
[0041] In yet another aspect, R.sup.10 and R.sup.11 are
C.sub.1-4alkyl, which is either unsubstituted or substituted by 1
or 2 substituents.
[0042] In yet another aspect, R.sup.10 is C.sub.1-4alkyl optionally
substituted by hydroxy.
[0043] In yet another aspect, R.sup.10 is methyl, ethyl,
hydroxymethyl or 2-hydroxyethyl.
[0044] In yet another aspect, R.sup.10 is methyl, ethyl or
2-hydroxyethyl.
[0045] In yet another aspect, R.sup.10 is methyl or
2-hydroxyethyl.
[0046] In yet another aspect, R.sup.10 is methyl.
[0047] In yet another aspect, R.sup.11 is C.sub.1-4alkyl optionally
substituted by hydroxy.
[0048] In yet another aspect, R.sup.11 is methyl, ethyl,
hydroxymethyl or 2-hydroxyethyl.
[0049] In yet another aspect, R.sup.11 is methyl or
2-hydroxyethyl.
[0050] In yet another aspect, R.sup.11 is C.sub.1-4alkyl. In yet
another aspect, R.sup.11 is methyl.
[0051] In another aspect R.sup.12 is methyl or ethyl.
[0052] In yet another aspect R.sup.12 is methyl.
[0053] In yet another aspect, R.sup.3 is of the formula
--CON(R.sup.10)YR.sup.11.
[0054] In yet another aspect, R.sup.3 is of the formula
--SO.sub.2N(R.sup.10)YR.sup.11.
[0055] In another aspect, Y is O.
[0056] In another aspect, R.sup.3 is --CON(Me)OMe, --CON(Et)OMe,
--CON(OEt)Me, --CON(Et)OEt, --CON(CH.sub.2CH.sub.2OH)OEt,
--CON(CH.sub.2CH.sub.2OH)Me, --CON(OCH.sub.2CH.sub.2OH)Me or
--CON(OCH.sub.2CH.sub.2OH)Et.
[0057] In yet another aspect, R.sup.3 is --CON(Me)OMe,
--CON(CH.sub.2CH.sub.2OH)OMe, --CON(OCH.sub.2CH.sub.2OH)Me or
--CON(Et)OMe.
[0058] In another aspect, R.sup.3 is --SO.sub.2N(Me)OMe,
--SO.sub.2N(Et)OMe, --SO.sub.2N(OEt)Me, --SO.sub.2N(Et)OEt,
--SO.sub.2N(CH.sub.2CH.sub.2OH)OEt,
--SO.sub.2N(CH.sub.2CH.sub.2OH)Me,
--SO.sub.2N(OCH.sub.2CH.sub.2OH)Me or
--SO.sub.2N(OCH.sub.2CH.sub.2OH)Et.
[0059] In yet another aspect, R.sup.3 is --SO.sub.2N(Me)OMe,
--SO.sub.2N(CH.sub.2CH.sub.2OH)OMe,
--SO.sub.2N(OCH.sub.2CH.sub.2OH)Me or --SO.sub.2N(Et)OMe.
[0060] In yet another aspect, R.sup.3 is --CON(Me)OMe or
--CON(CH.sub.2CH.sub.2OH)OMe.
[0061] In yet another aspect, R.sup.3 is --CON(Me)OMe.
[0062] In another aspect, R.sup.4 and R.sup.5 are independently
hydrogen or methyl.
[0063] In yet another aspect, Q is --O-- or --CH.sub.2--.
[0064] In one aspect Q is --CO--.
[0065] In another aspect Q is --CH.sub.2--.
[0066] In another aspect, Ar is unsubstituted or substituted by 1,
2 or 3 substituents.
[0067] In another aspect. Ar is unsubstituted or substituted by 1
or 2 substituents.
[0068] In another aspect, when the substituent on Ar is a 5 or 6
membered aromatic ring, this substituent on Ar contains up to 2
heteratoms independently selected from nitrogen, oxygen and
sulphur. In one aspect it is selected from furanyl, thienyl, phenyl
and pyrimidinyl. In another aspect, it is selected from pyrimidyl
and phenyl. In yet another aspect, it is phenyl.
[0069] Examples of the type of ring formed by R.sup.6 and R.sup.7
together with the nitrogen atom to which they attached include
pyrrolidino, piperidino, morpholino, piperazino, azepano,
1,4-oxepano and 1,4 diazepano. In another aspect, the ring is
selected from pyrrolidino, piperidino or morpholino.
[0070] Examples of the type of ring formed by R.sup.8 and R.sup.9
together with the nitrogen atom to which they attached include
pyrrolidino, piperidino, morpholino, piperazino, azepano,
1,4-oxepano and 1,4 diazepano. In another aspect, the ring is
selected from pyrrolidino, piperidino or morpholino.
[0071] R.sup.6 and R.sup.7 each independently represent a hydrogen
atom, C.sub.4alkanoyl (e.g. formyl, acetyl or propionyl) or
C.sub.1-4 alkyl (e.g. methyl, ethyl, n-propyl or n-butyl), or
together with the nitrogen atom to which they are attached form a
5- to 7-membered saturated heterocyclic ring.
[0072] In yet another aspect, R.sup.6 and R.sup.7 each
independently represent a hydrogen atom or C.sub.1-4 alkyl.
[0073] R.sup.8 and R.sup.9 each independently represent a hydrogen
atom, C.sub.1-4alkanoyl (e.g. formyl, acetyl or propionyl) or
C.sub.1-4 alkyl (e.g. methyl, ethyl, n-propyl or n-butyl), or
together with the nitrogen atom to which they are attached form a
5- to 7-membered saturated heterocyclic ring.
[0074] In yet another aspect, R.sup.8 and R.sup.9 each
independently represent a hydrogen atom or C.sub.1-4 alkyl.
[0075] In yet another aspect, substituents for Ar include
C.sub.1-4alkyl (optionally substituted by 1 or 2 hydroxy groups),
C.sub.1-4alkoxy, halogen, trihaloalkyl, C.sub.1-4alkylthio,
C.sub.1-4alkoxycarbonyl, C.sub.2-4alkanoyl, oxo, thioxo, cyano,
--NHR.sup.7 and --(CH.sub.2)pN(R.sup.8)R.sup.9 (wherein p is 1 or
2), hydroxy, C.sub.1-4alkylsulphonyl, carbamoyl,
C.sub.1-4alkylcarbamoyl, di-(C.sub.1-4alkyl)carbamoyl, carboxy, or
a 5 or 6 membered aromatic ring containing up to 4 heteroatoms
independently selected from nitrogen, oxygen and sulphur.
[0076] In yet another aspect, substituents for Ar include methyl,
ethyl, n-propyl, iso-propyl, tert-butyl, hydroxymethyl,
trifluoromethyl, chloro, fluoro, bromo, hydroxymethyl, acetyl,
methylthio, methoxycarbonyl, amino, methylamino, furanyl, thienyl,
pyrimidyl, phenyl, cyano, thioxo and oxo.
[0077] In yet another aspect, substituents for Ar include methyl,
ethyl, propyl, isopropyl, tert-butyl, hydroxymethyl,
trifluoromethyl, chloro, fluoro, bromo, acetyl, methylthio,
methoxycarbonyl, amino, methylamino, phenyl, pyrimidyl, cyano,
thioxo and oxo.
[0078] In one aspect, substituents are C.sub.1-4alkyl, halogen and,
especially, trifluoromethyl, oxo and alkylthio.
[0079] In another aspect, substituents include methyl, ethyl,
propyl, 1-methylethyl, chloro, fluoro, bromo, acetyl, methylthio,
amino, methylamino and oxo.
[0080] In yet another aspect, substituents include methyl, propyl,
1-methylethyl, chloro, acetyl, methylthio, methyl, amino and
oxo.
[0081] In yet another aspect, substituents are methyl, chloro, oxo
and methylthio.
[0082] Particular values for Ar include
2,4,5-trichloroimidazol-1-yl, 2-(1-methylethyl)imidazol-1-yl,
2-chloroimidazol-1-yl, 4,5-dichloro-2-methylimidazol-1-yl,
4,5-dichloro-2-hydroxymethylimidazol-1-yl,
2,4,5-trichloro-2-methylimidazol-1-yl, 4,5-dichloroimidazol-2-yl,
2-bromo-4,5-dichloroimidazol-2-yl, 2-methylthio-imidazoyl-1-yl,
3,5-dimethylpyrazol-4-yl, 1,3,5-trimethylpyrazol-4-yl,
3,5-dimethylpyrazol-4-yl, 3-tert-butyl-5-methylpyrazol-4-yl,
3,5-dimethylpyrazol-1-yl, 5-methyl-3-phenylpyrazol-4-yl,
5-methyl-3-(trifluoromethyl)pyrazol-4-yl,
5-methyl-3-(prop-2-yl)pyrazol-4-yl,
3,5-methyl-1-phenylpyrazol-4-yl,
5-dichloro-2,3-dihydro-2-oxothiazol-3-yl,
4-chloro-2,3-dihydro-2-oxothiazol-3-yl, 3,5-dimethylisoxazol-4-yl,
2,4-dimethyl-1-(prop-2-yl)pyrrol-3-yl,
2-methoxycarbonyl-4-methylpyrrol-3-yl,
3-methoxycarbonyl-2,5-dimethylpyrrol-3-yl, phenyl,
2-(trifluoromethyl)phenyl, 2,3-dihydro-6-methyl-3-oxopyrazinyl,
quinol-4-yl, quinol-5-yl, 6-fluoroquinol-4-yl, 8-fluoroquinol-4-yl,
2-methylquinol-4-yl, 3-chloroquinol-4-yl, 2-methylindol-3-yl,
7-methylindol-3-yl, 5-cyanoindol-1-yl, 1-acetylindol-3-yl,
indazol-3-yl, 2-methylbenzimidazol-1-yl, 2-ethylbenzimidazol-1-yl,
2-propylbenzimidazol-1-yl, 2-methylthiobenzimidazol-1-yl,
2-hydroxymethylbenzimidazol-1-yl, 2-methylaminobenzimidazol-1-yl,
2-aminobenzimidazol-1-yl, 2-oxo-2,3-dihydrobenzoxazol-3-yl,
pyrrolo[2,3-b]pyridin-3-yl, 2-methylpyrrolo[2,3-b]pyridin-1-yl,
2-methylpyrrolo[2,3-b]pyridin-3-yl, imidazo[1,2-a]pyrid-3-yl,
2-(methylthio)imidazo[4,5-b]pyrid-1-yl,
2-(methylthio)imidazo[4,5-b]pyrid-3-yl, 1H-1,2,3-benzotriazol-1-yl,
1-methyl-2-oxo-2,3-dihydrobenzimidazol-1-yl,
2-oxo-2,3-dihydrobenzothiazol-3-yl,
2-thioxo-2,3-dihydrobenzothiazol-3-yl,
2-oxo-2,3-dihydrobenzoxazol-1-yl,
2-oxo-2,3-dihydrobenzimidazol-3-yl,
2-oxo-2,3-dihydrobenzimidazol-1-yl,
5,6-difluoro-2-oxo-2,3-dihydrobenzimidazol-1-yl and
2-oxo-1,3-thiazolo[5,4-b]pyridin-3-yl.
[0083] Particular values for Ar include quinol-4-yl,
2-(1-methylethyl)imidazol-1-yl, 2-chloroimidazol-1-yl,
2-(methylthio)imidazol-1-yl, 3-chloroquinol-4-yl,
1-acetylindol-3-yl, 2-methylthiobenzimidazol-1-yl,
2-methylaminobenzimidazol-1-yl, 2-propylbenzimidazol-1-yl,
indazol-3-yl, 2-methylpyrrolo[2,3-b]pyridin-3-yl,
2-oxo-2,3-dihydrobenzothiazol-3-yl and
1-methyl-2-oxo-2,3-dihydrobenzimidazol-1-yl.
[0084] A particular class of compound is of the formula (1) in
which R.sup.1 is C.sub.1-5alkyl or C.sub.3-6cycloalklmethyl;
R.sup.2 is C.sub.1-5alkyl; R.sup.3 is a group
--ON(R.sup.10)YR.sup.11 in which Y is O, S or NR.sub.12 (R.sup.12
being hydrogen or C.sub.1-6alkyl) and R.sup.10 and R.sup.11 are
independently C.sub.1-6alkyl optionally substituted by halo,
hydroxy, amino, C.sub.1-6alkylamino or di-(C.sub.1-6alkyl)amino; Q
is --CO-- or --CH.sub.2--; Ar is a 5- to 10-membered aromatic ring
system in which 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 independently
selected from C.sub.1-4alkyl (optionally substituted by 1, 2 or 3
hydroxy groups), C.sub.1-4alkoxy, halogen, haloalkyl, dihaloalkyl,
trihaloalkyl, C.sub.1-4alkoxyC.sub.1-4alkyl, C.sub.1-4alkylthio,
C.sub.1-4alkoxycarbonyl, C.sub.2-4alkanoyl, oxo, thioxo, nitro,
cyano, --N(R.sup.6)R.sup.7 and --(CH.sub.2)pN(R.sup.8)R.sup.9,
hydroxy, C.sub.1-4alkylsulphonyl, C.sub.1-4alkylsulphinyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di-(C.sub.1-4alkyl)carbamoyl,
carboxy, or a 5 or 6 membered aromatic ring containing up to 4
heteroatoms independently selected from nitrogen, oxygen and
sulphur; R.sup.6 and R.sup.7 each independently represent a
hydrogen atom or C.sub.1-4alkyl, or together with the nitrogen atom
to which they are attached form a 5- to 7-membered saturated
heterocyclic ring; and R.sup.8 and R.sup.9 each independently
represent a hydrogen atom or C.sub.1-4 alkyl, or together with the
nitrogen atom to which they are attached form a 5- to 7-membered
saturated heterocyclic ring; or a pharmaceutically-acceptable salt
thereof.
[0085] Another class of compound is of the formula (1), in which
R.sup.1 is C.sub.1-5alkyl or C.sub.3-6cycloalkylmethyl; R.sup.2 is
C.sub.1-5alkyl; R.sup.3 is a group --SO.sub.2N(R.sup.10)YR.sup.11,
in which Y is O, S or NR.sub.12 (R.sup.12 being hydrogen or
C.sub.1-6alkyl) and R.sup.10 and R.sup.11 are independently
C.sub.1-6alkyl optionally substituted by halo, hydroxy, amino,
C.sub.1-6alkylamino or di-(C.sub.1-6alkyl)amino; Q is --CO-- or
--CH.sub.2--; Ar is a 5- to 10-membered aromatic ring system in
which 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 independently selected from
C.sub.1-4alkyl (optionally substituted by 1, 2 or 3 hydroxy
groups), C.sub.1-4alkoxy, halogen, haloalkyl, dihaloalkyl,
trihaloalkyl, C.sub.1-4alkoxyC.sub.1-4alkyl, C.sub.1-4alkylthio,
C.sub.1-4alkoxycarbonyl, C.sub.2-4alkanoyl, oxo, thioxo, nitro,
cyano, --N(R.sup.6)R.sup.7 and --(CH.sub.2)pN(R.sup.8)R.sup.9,
hydroxy, C.sub.1-4alkylsulphonyl, C.sub.1-4alkylsulphinyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di-(C.sub.1-4alkyl)carbamoyl,
carboxy, or a 5 or 6-membered aromatic ring containing up to 4
heteroatoms independently selected from nitrogen, oxygen and
sulphur; R.sup.6 and R.sup.7 each independently represent a
hydrogen atom or C.sub.1-4alkyl, or together with the nitrogen atom
to which they are attached form a 5- to 7-membered saturated
heterocyclic ring; and R.sup.8 and R.sup.9 each independently
represent a hydrogen atom or C.sub.1-4 alkyl, or together with the
nitrogen atom to which they are attached form a 5- to 7-membered
saturated heterocyclic ring; or a pharmaceutically-acceptable salt
thereof.
[0086] Another particular class of compound is of the formula (1),
in which R.sup.1 is C.sub.1-5alkyl or C.sub.3-6cycloalkylmethyl;
R.sup.2 is methyl; R.sup.3 is a group --CON(R.sup.10)YR.sup.11, in
which Y is O, S or NR.sub.12 (R.sup.12 being hydrogen or
C.sub.1-6alkyl) and R.sup.10 and R.sup.11 are independently
C.sub.1-6alkyl optionally substituted by halo, hydroxy, amino,
C.sub.1-6alkylamino or di-(C.sub.1-6alkyl)amino; Q is --CO-- or
--CH.sub.2--; 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 independently
selected from C.sub.1-4alkyl (optionally substituted bar 1, 2 or 3
hydroxy groups), C.sub.1-4alkoxy, halogen, haloalkyl, is
dihaloalkyl, trihaloalkyl, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylthio, C.sub.1-4alkoxycarbonyl, C.sub.2-4alkanoyl,
oxo, thioxo, nitro, cyano, --N(R.sup.6)R.sup.7 and
--(CH.sub.2)pN(R.sup.8)R.sup.9, hydroxy, C.sub.1-4alkylsulphonyl,
C.sub.1-4alkylsulphinyl, carbamoyl, C.sub.1-4alkylcarbamoyl,
di-(C.sub.1-4alkyl)carbamoyl, carboxy, or a 5 or 6 membered
aromatic ring containing up to 4 heteroatoms independently selected
from nitrogen, oxygen and sulphur; R.sup.6 and R.sup.7 each
independently represent a hydrogen atom or C.sub.1-4alkyl, or
together with the nitrogen atom to which they are attached form a
5- to 7-membered saturated heterocyclic ring; and R.sup.8 and
R.sup.9 each independently represent a hydrogen atom or C.sub.1-4
alkyl, or together with the nitrogen atom to which they are
attached form a 5- to 7-membered saturated heterocyclic ring; or a
pharmaceutically-acceptable salt thereof.
[0087] Another particular class of compound is of the formula (1)
in which R.sup.1 is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl,
2,2-dimethylpropyl or cyclopropylmethyl; R.sup.1 is methyl; R.sup.3
is a group --CON(R.sup.10)OR.sup.11, in which R.sup.10 and R.sup.11
are independently C.sub.1-6alkyl optionally substituted by halo,
hydroxy, amino, C.sub.1-6alkylamino or di-(C.sub.1-6alkyl)amino; Q
is --CO-- or --CH.sub.2--; Ar is a 5- to 10-membered aromatic ring
system containing up to 4 ring heteroatoms selected from nitrogen,
oxygen and sulphur providing that there is at least 1 ring
nitrogen, the ring being optionally substituted by one or more
substituents independently selected from C.sub.1-4alkyl (optionally
substituted by 1, 2 or 3 hydroxy groups), C.sub.1-4alkoxy, halogen,
haloalkyl, dihaloalkyl, trihaloalkyl,
C.sub.1-4alkoxyC.sub.1-4alkyl, C.sub.1-4alkylthio,
C.sub.1-4alkoxycarbonyl, C.sub.2-4alkanoyl, oxo, thioxo, nitro,
cyano, --N(R.sup.6)R.sup.7 and --(CH.sub.2)pN(R.sup.8)R.sup.9,
hydroxy, C.sub.1-4alkylsulphonyl, C.sub.1-4alkylsulphinyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di-(C.sub.1-4alkyl)carbamoyl,
carboxy, or a 5 or 6 membered aromatic ring containing up to 4
heteroatoms independently selected from nitrogen, oxygen and
sulphur; R.sup.6 and R.sup.7 each independently represent a
hydrogen atom or C.sub.1-4alkyl, or together with the nitrogen atom
to which they are attached form a 5- to 7-membered saturated
heterocyclic ring; and R.sup.8 and R.sup.9 each independently
represent a hydrogen atom or C.sub.1-4 alkyl, or together with the
nitrogen atom to which they are attached form a 5- to 7-membered
saturated heterocyclic ring; or a pharmaceutically-acceptable salt
thereof.
[0088] Another particular class of compound is of the formula (1),
in which R.sup.1 is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl,
2,2-dimethylpropyl or cyclopropylmethyl; R.sup.2 is methyl; R.sup.3
is a group --ON(R.sup.10)OR.sup.11, in which R.sup.10 and R.sup.11
are independently C.sub.1-4alkyl optionally substituted by hydroxy;
Q is --CO-- or --CH.sub.2--; 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, the ring
being optionally substituted by one or more substituents
independently selected from C.sub.1-4alkyl (optionally substituted
by 1, 2 or 3 hydroxy groups), C.sub.1-4alkoxy, halogen, haloalkyl,
dihaloalkyl, trihaloalkyl, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylthio, C.sub.1-4alkoxycarbonyl, C.sub.2-4alkanoyl,
oxo, thioxo, nitro, cyano, --N(6)R.sup.7 and
--(CH.sub.2)pN(R.sup.8)R.sup.9, hydroxy, C.sub.1-4alkylsulphonyl,
C.sub.1-4alkylsulphinyl, carbamoyl, C.sub.1-4alkylcarbamoyl,
di-(C.sub.1-4alkyl)carbamoyl, carboxy, or a 5 or 6 membered
aromatic ring containing up to 4 heteroatoms independently selected
from nitrogen, oxygen and sulphur; R.sup.6 and R.sup.7 each
independently represent a hydrogen atom or C.sub.1-4alkyl, or
together with the nitrogen atom to which they are attached form a
5- to 7-membered saturated heterocyclic ring; and R.sup.8 and
R.sup.9 each independently represent a hydrogen atom or C.sub.1-4
alkyl, or together with the nitrogen atom to which they are
attached form a 5- to 7-membered saturated heterocyclic ring; or a
pharmaceutically-acceptable salt thereof.
[0089] Another particular class of compound is of the formula (1),
in which R.sup.1 is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl,
2,2-dimethylpropyl or cyclopropylmethyl; R.sup.2 is methyl; R.sup.3
is a group --ON(R.sup.10)OR.sup.11, in which R.sup.10 and R.sup.11
are independently C.sub.1-4alkyl optionally substituted by hydroxy;
Q is --CO-- or --CH.sub.2--; 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, the ring
being optionally substituted by one or more substituents
independently selected from methyl, ethyl, n-propyl, iso-propyl,
tert-butyl, hydroxymethyl, trifluoromethyl, chloro, fluoro, bromo,
hydroxymethyl, acetyl, methylthio, methoxycarbonyl, amino,
methylamino, furanyl, thienyl, pyrimidyl, phenyl, cyano, thioxo and
oxo; or a pharmaceutically-acceptable salt thereof.
[0090] Another particular class of compound is of the formula (1),
in which R.sup.1 is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl,
2,2-dimethylpropyl or cyclopropylmethyl; R.sup.1 is methyl; R.sup.3
is a group --CON(R.sup.10)OR.sup.11, in which R.sup.10 and R.sup.11
are independently C.sub.1-4alkyl optionally substituted by hydroxy;
Q is --CO-- or --CH.sub.2--; Ar is 2,4,5-trichloroimidazol-1-yl,
2-(1-methylethyl)imidazol-1-yl, 2-chloroimidazol-1-yl,
4,5-dichloro-2-methylimidazol-1-yl,
4,5-dichloro-2-hydroxymethylimidazol-1-yl,
2,4,5-trichloro-2-methylimidazol-1-yl, 4,5-dichloroimidazol-2-yl,
2-bromo-4,5-dichloroimidazol-2-yl, 2-methylthio-imidazoly-1-yl,
3,5-dimethylpyrazol-4-yl, 1,3,5-trimethylpyrazol-4-yl,
3,5-dimethylpyrazol-4-yl, 3-tert-butyl-5-methylpyrazol-4-yl,
3,5-dimethylpyrazol-1-yl, 5-methyl-3-phenylpyrazol-4-yl,
5-methyl-3-(trifluoromethyl)pyrazol-4-yl,
5-methyl-3-(prop-2-yl)pyrazol-4-yl,
3,5-methyl-1-phenylpyrazol-4-yl,
5-dichloro-2,3-dihydro-2-oxothiazol-3-yl,
4-chloro-2,3-dihydro-2-oxothiazol-3-yl, 3,5-dimethylisoxazol-4-yl,
2,4-dimethyl-1-(prop-2-yl)pyrrol-3-yl,
2-methoxycarbonyl-4-methylpyrrol-3-yl,
3-methoxycarbonyl-2,5-dimethylpyrrol-3-yl, phenyl,
2-(trifluoromethyl)phenyl, 2,3-dihydro-6-methyl-3-oxopyrazinyl,
quinol-4-yl, quinol-5-yl, 6-fluoroquinol-4-yl, 8-fluoroquinol-4-yl,
2-methylquinol-4-yl, 3-chloroquinol-4-yl, 2-methylindol-3-yl,
7-methylindol-3-yl, 5-cyanoindol-1-yl, 1-acetylindol-3-yl,
indazol-3-yl, 2-methylbenzimidazol-1-yl, 2-ethylbenzimidazol-1-yl,
2-propylbenzimidazol-1-yl, 2-methylthiobenzimidazol-1-yl,
2-hydroxymethylbenzimidazol-1-yl, 2-methylaminobenzimidazol-1-yl,
2-aminobenzimidazol-1-yl, 2-oxo-2,3-dihydrobenzoxazol-3-yl,
pyrrolo[2,3-b]pyridin-3-yl, 2-methylpyrrolo[2,3-b]pyridin-1-yl,
2-methylpyrrolo[2,3-b]pyridin-3-yl, imidazo[1,2-a]pyrid-3-yl,
2-(methylthio)imidazo[4,5-b]pyrid-1-yl,
2-(methylthio)imidazo[4,5-b]pyrid-3-yl, 1H-1,2,3-benzotriazol-1-yl,
1-methyl-2-oxo-2,3-dihydrobenzimidazol-1-yl,
2-oxo-2,3-dihydrobenzothiazol-3-yl,
2-thioxo-2,3-dihydrobenzothiazol-3-yl,
2-oxo-2,3-dihydrobenzoxazol-1-yl,
2-oxo-2,3-dihydrobenzimidazol-3-yl,
2-oxo-2,3-dihydrobenzimidazol-1-yl,
5,6-difluoro-2-oxo-2,3-dihydrobenzimidazol-1-yl or
2-oxo-1,3-thiazolo[5,4-b]pyridin-3-yl; or a
pharmaceutically-acceptable salt thereof.
[0091] In another aspect of the invention, there is provided a
compound of formula (1) in which R.sup.1 and R.sup.2 each
independently represent a C.sub.1-6alkyl, C.sub.3-6alkenyl,
C.sub.3-5cycloalkyl(C.sub.1-3)methyl or C.sub.3-6cycloalkyl; each
of which may be optionally substituted by 1 to 3 halogen atoms;
R.sup.3 is a group --CON(R.sup.10)YR.sup.11 or
--SO.sub.2N(R.sup.10)YR.sup.11, in which Y is O, S or NR.sub.12
(R.sup.12 being hydrogen or C.sub.1-6alkyl), and R.sup.10 and
R.sup.11 are independently C.sub.1-6alkyl optionally substituted by
halo, hydroxy, amino, C.sub.1-6alkylamino or
di-(C.sub.1-6alkyl)amino; Q is --CO-- or --C(R.sup.4)(R.sup.5)--
(R.sup.4 being a hydrogen atom or C.sub.1-4alkyl and R.sup.5 being
a hydrogen atom or hydroxy group); Ar is a 5- to 10-membered
aromatic ring system in which 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
independently selected from C.sub.1-4alkyl, C.sub.1-4alkoxy,
halogen, haloalkyl, dihaloalkyl, trihaloalkyl,
hydroxyC.sub.1-4alkyl, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylthio, C.sub.1-4alkoxycarbonyl, C.sub.2-4alkanoyl,
oxo, nitro, cyano, --N(R.sup.6)R.sup.7 and
--(CH.sub.2)pN(R.sup.8)R.sup.9, hydroxy, C.sub.1-4alkylsulphonyl,
C.sub.1-4alkylsulphinyl, carbamoyl, C.sub.1-4alkylcarbamoyl,
di-(C.sub.1-4alkyl)carbamoyl, carboxy; p is 1 to 4; R.sup.6 and
R.sup.7 each independently represent a hydrogen atom,
C.sub.1-4alkanoyl or C.sub.1-4alkyl, or together with the nitrogen
atom to which they are attached form a 5- to 7-membered saturated
heterocyclic ring; and R.sup.8 and R.sup.9 each independently
represent a hydrogen atom, C.sub.1-4alkanoyl or C.sub.1-4 alkyl, or
together with the nitrogen atom to which they are attached form a
5- to 7-membered saturated heterocyclic ring; or a pharmaceutically
acceptable salt or prodrug thereof.
[0092] A particular class of compound is of the formula (1) in
which R.sup.1 is C.sub.1-5alkyl or C.sub.3-6cycloalkylmethyl;
R.sup.2 is C.sub.1-5alkyl; R.sup.3 is a group
--CON(R.sup.10)YR.sup.11, in which Y is O, S or NR.sub.12 (R.sup.12
being hydrogen or C.sub.1-6alkyl), and R.sup.10 and R.sup.11 are
independently C.sub.1-6alkyl optionally substituted by halo,
hydroxy, amino, C.sub.1-6alkylamino or di-(C.sub.1-6alkyl)amino; Q
is --CO-- or --CH.sub.2--; Ar is a 5- to 10-membered aromatic ring
system in which up to 4 ring atoms may be heteroatoms independently
selected from nitrogen, oxygen and sulphur, the ring system being
optionally substituted by 1, 2 or 3 substituents independently
selected from C.sub.1-4alkyl, C.sub.1-4alkoxy, halogen, haloalkyl,
dihaloalkyl, trihaloalkyl, hydroxyC.sub.1-4alkyl,
C.sub.1-4alkoxyC.sub.1-4alkyl, C.sub.1-4alkylthio,
C.sub.1-4alkoxycarbonyl, C.sub.2-4alkanoyl, oxo, nitro, cyano,
NR.sup.6R.sup.7 and --CH.sub.2NR.sup.8R.sup.9; R.sup.6 and R.sup.7
each independently represent a hydrogen atom or C.sub.1-4alkyl, or
together with the nitrogen atom to which they are attached form a
5- to 7-membered saturated heterocyclic ring; and R.sup.8 and
R.sup.9 each independently represent a hydrogen atom or C.sub.1-4
alkyl, or together with the nitrogen atom to which they are
attached form a 5- to 7-membered saturated heterocyclic ring; or a
pharmaceutically-acceptable salt thereof.
[0093] Another class of compound is of the formula (1) in which
R.sup.1 is C.sub.1-5alkyl or C.sub.3-6cycloalkylmethyl; R.sup.2 is
C.sub.1-5alkyl; R.sup.3 is a group --SO.sub.2N(R.sup.10)YR.sup.11,
in which Y is O, S or NR.sub.12 (R.sup.12 being hydrogen or
C.sub.1-6alkyl) and R.sup.10 and R.sup.11 are independently
C.sub.1-6alkyl optionally substituted by halo, hydroxy, amino,
C.sub.1-6alkylamino or di-(C.sub.1-6alkyl)amino; Q is --CO-- or
--CH.sub.2--; Ar is a 5- to 10-membered aromatic ring system in
which up to 4 ring atoms may be heteroatoms independently selected
from nitrogen, oxygen and sulphur, the ring system being optionally
substituted by 1, 2 or 3 substituents independently selected from
C.sub.1-4alkyl, C.sub.1-4alkoxy, halogen, haloalkyl, dihaloalkyl,
trihaloalkyl, hydroxyC.sub.1-4alkyl, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylthio, C.sub.1-4alkoxycarbonyl, C.sub.2-4alkanoyl,
oxo, nitro, cyano, NR.sup.6R.sup.7 and --CH.sub.2NR.sup.8R.sup.9;
R.sup.6 and R.sup.7 each independently represent a hydrogen atom or
C.sub.1-4alkyl, or together with the nitrogen atom to which they
are attached form a 5- to 7-membered saturated heterocyclic ring;
and R.sup.8 and R.sup.9 each independently represent a hydrogen
atom or C.sub.1-4 alkyl, or together with the nitrogen atom to
which they are attached form a 5- to 7-membered saturated
heterocyclic ring; or a pharmaceutically-acceptable salt
thereof.
[0094] Another particular class of compound is of the formula (1)
in which R.sup.1 is C.sub.1-5alkyl or C.sub.3-6cycloalkylmethyl;
R.sup.2 is methyl; R.sup.3 is a group --CON(R.sup.10)YR.sup.11, in
which Y is O, S or NR.sub.12 (R.sup.12 being hydrogen or
C.sub.1-6alkyl), and R.sup.10 and R.sup.11 are independently
C.sub.1-6alkyl optionally substituted by halo, hydroxy, amino,
C.sub.1-6alkylamino or di-(C.sub.1-6alkyl)amino; Q is --CO-- or
--CH.sub.2--; Ar is a 5- to 10-membered aromatic ring system in
which up to 4 ring atoms may be heteroatoms independently selected
from nitrogen, oxygen and sulphur, the ring system being optionally
substituted by 1, 2 or 3 substituents independently selected from
C.sub.1-4alkyl, C.sub.1-4alkoxy, halogen, haloalkyl, dihaloalkyl,
trihaloalkyl, hydroxyC.sub.1-4alkyl, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylthio, C.sub.1-4alkoxycarbonyl, C.sub.2-4alkanoyl,
oxo, nitro, cyano, NR.sup.6R.sup.7 and --CH.sub.2NR.sup.8R.sup.9;
R.sup.6 and R.sup.7 each independently represent a hydrogen atom or
C.sub.1-4alkyl, or together with the nitrogen atom to which they
are attached form a 5- to 7-membered saturated heterocyclic ring;
and R.sup.8 and R.sup.9 each independently represent a hydrogen
atom or C.sub.1-4 alkyl, or together with the nitrogen atom to
which they are attached form a 5- to 7-membered saturated
heterocyclic ring; or a pharmaceutically-acceptable salt
thereof.
[0095] Another particular class of compound is of the formula (1)
in which R.sup.1 is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl,
2,2-dimethylpropyl or cyclopropylmethyl; R.sup.2 is methyl; R.sup.3
is a group --CON(R.sup.10)OR.sup.11, in which R.sup.10 and R.sup.11
are independently C.sub.1-6alkyl optionally substituted by halo,
hydroxy, amino, C.sub.1-6alkylamino or di-(C.sub.1-6alkyl)amino; Q
is --CO-- or --CH.sub.2--; Ar is a 5- to 10-membered aromatic ring
system in which up to 4 ring atoms may be heteroatoms independently
selected from nitrogen, oxygen and sulphur, the ring system being
optionally substituted by 1, 2 or 3 substituents independently
selected from C.sub.1-4alkyl, C.sub.1-4alkoxy, halogen, haloalkyl,
dihaloalkyl, trihaloalkyl, hydroxyC.sub.1-4alkyl,
C.sub.1-4alkoxyC.sub.1-4alkyl, C.sub.1-4alkylthio,
C.sub.1-4alkoxycarbonyl, C.sub.2-4alkanoyl, oxo, nitro, cyano,
NR.sup.6R.sup.7 and --CH.sub.2NR.sup.8R.sup.9; R.sup.6 and R.sup.7
each independently represent a hydrogen atom or C.sub.1-4alkyl, or
together with the nitrogen atom to which they are attached form a
5- to 7-membered saturated heterocyclic ring; and R.sup.8 and
R.sup.9 each independently represent a hydrogen atom or C.sub.1-4
alkyl, or together with the nitrogen atom to which they are
attached form a 5- to 7-membered saturated heterocyclic ring; or a
pharmaceutically-acceptable salt thereof.
[0096] Another particular class of compound is of the formula (1)
in which R.sup.1 is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl,
2,2-dimethylpropyl or cyclopropylmethyl; R.sup.2 is methyl; R.sup.3
is a group --CON(R.sup.10)OR.sup.11, in which R.sup.10 is
C.sub.1-4alkyl optionally substituted by hydroxy and R.sup.11 is
methyl; Q is --CO-- or --CH.sub.2--; Ar is a 5- to 10-membered
aromatic ring system in which up to 4 ring atoms may be heteroatoms
independently selected from nitrogen, oxygen and sulphur, the ring
system being optionally substituted by 1, 2 or 3 substituents
independently selected from C.sub.1-4alkyl, C.sub.1-4alkoxy,
halogen, haloalkyl, dihaloalkyl, trihaloalkyl,
hydroxyC.sub.1-4alkyl, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylthio, C.sub.1-4alkoxycarbonyl, C.sub.2-4alkanoyl,
oxo, nitro, cyano, NR.sup.6R.sup.7 and --CH.sub.2NR.sup.9R.sup.9;
R.sup.6 and R.sup.7 each independently represent a hydrogen atom or
C.sub.1-4alkyl, or together with the nitrogen atom to which they
are attached form a 5- to 7-membered saturated heterocyclic ring;
and R.sup.8 and R.sup.9 each independently represent a hydrogen
atom or C.sub.1-4 alkyl, or together with the nitrogen atom to
which they are attached form a 5- to 7-membered saturated
heterocyclic ring; or a pharmaceutically-acceptable salt
thereof.
[0097] Another particular class of compound is of the formula (1)
in which R.sup.1 is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl,
2,2-dimethylpropyl or cyclopropylmethyl; R.sup.2 is methyl; R.sup.3
is a group --CON(R.sup.10)OR.sup.11, in which R.sup.10 is
C.sub.1-4alkyl optionally substituted by hydroxy and R.sup.11 is
methyl; Q is --CO-- or --CH.sub.2--; Ar is selected from
imidazolyl, quinolyl, indolyl, benzimidazolyl, indazolyl,
pyridopyrrolyl, 2,3-dihydrobenzothiazolyl and
2,3-dihydrobenzimidazolyl, the ring system being optionally
substituted by 1, 2 or 3 substituents independently selected from
C.sub.1-4alkyl, C.sub.1-4alkoxy, halogen, haloalkyl, dihaloalkyl,
trihaloalkyl, hydroxyC.sub.1-4alkyl, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylthio, C.sub.1-4alkoxycarbonyl, C.sub.2-4alkanoyl,
oxo, nitro, cyano, NR.sup.6R.sup.7 and --CH.sub.2NR.sup.8R.sup.9;
R.sup.6 and R.sup.7 each independently represent a hydrogen atom or
C.sub.1-4alkyl, or together with the nitrogen atom to which they
are attached form a 5- to 7-membered saturated heterocyclic ring;
and R.sup.8 and R.sup.9 each independently represent a hydrogen
atom or C.sub.1-4 alkyl, or together with the nitrogen atom to
which they are attached form a 5- to 7-membered saturated
heterocyclic ring; or a pharmaceutically-acceptable salt
thereof.
[0098] Another particular class of compound is of the formula (1),
in which R.sup.1 is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl,
2,2-dimethylpropyl or cyclopropylmethyl; R.sup.2 is methyl; R.sup.3
is a group --CON(R.sup.10)OR.sup.11, in which R.sup.10 is
C.sub.1-4alkyl optionally substituted by hydroxy and R.sup.11 is
methyl; Q is --CO-- or --CH.sub.2--; Ar is selected from
imidazolyl, quinolyl, indolyl, benzimidazolyl, indazolyl,
pyridopyrrolyl, 2,3-dihydrobenzothiazolyl and
2,3-dihydrobenzimidazolyl, the ring system being optionally
substituted by 1, 2 or 3 substituents independently selected from
methyl, ethyl, propyl, 1-methylethyl, chloro, fluoro, bromo,
acetyl, methylthio, amino, methylamino and oxo; or a
pharmaceutically-acceptable salt thereof.
[0099] Particular compounds of the present invention include:
[0100]
6-[(4,5-dichloro-2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,4-tetrahydro-N-m-
ethoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-
-carboxamide; [0101]
1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-6--
(4-quinolinylmethyl)thieno[2,3-d]pyrimidine-5-carboxamide; [0102]
1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-6--
(1H-pyrrolo[2,3-b]pyridin-3-dimethyl)-thieno[2,3-d]pyrimidine-5-carboxamid-
e; [0103]
1,2,3,4-tetrahydro-6-(1H-indol-3-ylmethyl)-N-methoxy-N,3-dimethy-
l-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamide;
[0104]
1,2,3,4-tetrahydro-6-(1H-indol-3-ylcarbonyl)-N-methoxy-N,3-dimethy-
l-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamide;
[0105]
6-[(4,5-dichloro-2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,4-tetrahy-
dro-N-methoxy-N,3-dimethyl-1-(1-methylethyl)-2,4-dioxo-thieno[2,3-d]pyrimi-
dine-5-carboxamide; [0106]
1,2,3,4-tetrahydro-6-(1H-indazol-3-ylmethyl)-N-methoxy-N,3-dimethyl-1-(2--
methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamide;
[0107]
6-[(4,5-dichloro-2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,4-tetrahydro-N-m-
ethoxy-N,3-dimethyl-2,4-dioxo-1-propyl-thieno[2,3-d]pyrimidine-5-carboxami-
de; [0108]
1-(2,2-dimethylpropyl)-1,2,3,4-tetrahydro-N-methoxy-N,3-dimethy-
l-2,4-dioxo-6-(quinolin-4-ylmethyl)-thieno[2,3-d]pyrimidine-5-carboxamide;
[0109]
1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-6-[[2-(1-methylethyl)-1H-
-imidazol-1-yl]methyl]-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidin-
e-5-carboxamide; [0110]
1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-6-[[2-(methy-
lthio)-1H-imidazol-1-yl]methyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carbox-
amide-6-[(2-chloro-1H-imidazol-1-yl)methyl]-1,2,3,4-tetrahydro-N-methoxy-N-
,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxa-
mide; [0111]
1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-6-[2-(methyl-
thio)-1H-benzimidazol-1-yl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamid-
e; [0112]
1,2,3,4-tetrahydro-N-(2-hydroxyethyl)-N-methoxy-3-methyl-1-(2-me-
thylpropyl)-6-[[2-(methylthio)-1H-imidazol-1-yl]methyl]-2,4-dioxo-thieno[2-
,3-d]pyrimidine-5-carboxamide; [0113]
1,2,3,4-tetrahydro-6-[[2-(methylamino)-1H-benzimidazol-1-yl]methyl]-N-met-
hoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-c-
arboxamide; [0114]
1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-6--
[(2-propyl-1H-benzimidazol-1-yl)methyl]-thieno[2,3-d]pyrimidine-5-carboxam-
ide; [0115]
1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-6--
[(2,3-dihydro-3-methyl-2-oxo-1H-benzimidazol-1-yl)methyl]-thieno[2,3-d]pyr-
imidine-5-carboxamide; [0116]
6-[(2,3-dihydro-2-oxo-benzothiazol-3-yl)methyl]-1,2,3,4-tetrahydro-N-meth-
oxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-ca-
rboxamide; [0117]
6-[(1-acetyl-1H-indol-3-yl)methyl]-1,2,3,4-tetrahydro-N-methoxy-N,3-dimet-
hyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxamide;
[0118]
1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-6-[(2-
-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-2,4-dioxo-thieno[2,3-d]pyrim-
idine-5-carboxamide; [0119]
6-[(3-chloroquinolin-4-yl)methyl]-1,2,3,4-tetrahydro-NI-methoxy-N,3-dimet-
hyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamide;
[0120]
N-methoxy-N,3-dimethyl-2,4-dioxo-1-propyl-6-(quinolin-4-ylmethyl)--
1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxamide; [0121]
1-ethyl-N-methoxy-N,3-dimethyl-2,4-dioxo-6-(quinolin-4-ylmethyl)-1,2,3,4--
tetrahydrothieno[2,3-d]pyrimidine-5-carboxamide; [0122]
1-(cyclopropylmethyl)-N-methoxy-N,3-dimethyl-2,4-dioxo-6-(quinolin-4-ylme-
thyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxamide,
[0123]
1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-6-[(2-methyl-1H-indol-3-yl)meth-
yl]-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxamide;
[0124]
1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-6-[2-methyl-1H-indol-3-y-
lmethyl]-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxamide-
; [0125]
N-methoxy-N,3-dimethyl-2,4-dioxo-1-propyl-6-(quinolin-4-ylmethyl)-
-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxamide; [0126]
1-ethyl-N-methoxy-N,3-dimethyl-2,4-dioxo-6-(quinolin-4-ylmethyl)-1,2,3,4--
tetrahydrothieno[2,3-d]pyrimidine-5-carboxamide; [0127]
1-(cyclopropylmethyl)-N-methoxy-N,3-dimethyl-2,4-dioxo-6-(quinolin-4-ylme-
thyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxamide;
[0128]
6-[4,5-dichloro-2-(hydroxymethyl)-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahy-
dro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrim-
idine-5-carboxamide; [0129]
1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-6-[2-methyl-1H-pyrrolo[2,3-b]py-
ridin-3-ylmethyl]-2,4-dioxo-1-propyl-thieno[2,3-d]pyrimidine-5-carboxamide-
; [0130]
1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(1-methylethyl)-6-[2--
methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimid-
ine-5-carboxamide; [0131]
1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-6--
[2-(trifluoromethyl)phenylmethyl]thieno[2,3-d]pyrimidine-5-carboxamide;
[0132]
1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-d-
ioxo-6-(benzyl)thieno[2,3-d]pyrimidine-5-carboxamide; [0133] methyl
4-[1,2,3,4-tetrahydro-5-[(N-methoxy-N-methylamino)carbonyl]-3-methyl-1-(2-
-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl](hydroxy)methyl]-1-met-
hyl-1H-pyrrole-2-carboxylate; [0134] methyl
1-methyl-4-[1,2,3,4-tetrahydro-5-[(methoxymethylamino)carbonyl]-3-methyl--
1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-ylmethyl]-1H-pyrrole--
2-carboxylate; [0135] methyl
2,5-dimethyl-4-[1,2,3,4-tetrahydro-5-[(N-methoxy-N-methylamino)carbonyl]--
3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-ylmethyl]-1H-
-pyrrole-3-carboxylate; [0136]
1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-6--
[2-oxo-3(2H)-benzoxazolylmethyl]-thieno[2,3-d]pyrimidine-5-carboxamide;
[0137]
1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-d-
ioxo-6-[(2,4,5-trichloro-1H-imidazol-1-yl)methyl]-thieno[2,3-d]pyrimidine--
5-carboxamide; [0138]
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-N-(2-hydroxyethyl)-1-iso-
butyl-N-ethoxy-3-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-
e-5-carboxamide; [0139]
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-N-(2-hydroxyethoxy)-1-is-
obutyl-N,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5--
carboxamide; and [0140]
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-N-ethyl-1,2,3,4-tetrahyd-
ro-N-methoxy-3-methyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-
-5-carboxamide; [0141] and pharmaceutically-acceptable salts
thereof.
Synthesis of Compounds of the Formula 1
[0142] Compounds of formula 1 may be prepared by a number of
processes as generally described hereinbelow and more specifically
in the Examples hereinafter. Processes for the preparation of novel
compounds of formula 1, are provided as a further feature of the
invention and are as described hereinafter. Necessary starting
materials may be obtained by standard procedures of organic
chemistry. The preparation of such starting materials is described
within the accompanying non-limiting Examples. Alternatively
necessary starting materials are obtainable by analogous procedures
to those illustrated which are within the is ordinary skill of an
organic chemist.
[0143] Thus according to another aspect of the invention, a
compound of the formula (1) may be formed by deprotecting a
compound of the formula (1) wherein at least 1 functional group is
protected. For example, amino or hydroxy groups may be protected
during the reaction sequence used to prepare a compound of the
formula (1).
[0144] Protecting groups, may in general be chosen from any of the
groups described in the literature or known to the skilled chemist
as appropriate for the protection of the group in question, and may
be introduced by conventional methods.
[0145] Protecting groups may be removed by any convenient method as
described in the literature or known to the skilled chemist as
appropriate for the removal of the protecting group in question,
such methods being chosen so as to effect removal of the protecting
group with minimum disturbance of groups elsewhere in the
molecule.
[0146] A suitable protecting group for a hydroxy group is, for
example, an arylmethyl group (especially benzyl), a
tri-(1-4C)alkylsilyl group (especially trimethylsilyl or
tert-butyldimethylsilyl), an aryldi-(1-4C)alkylsilyl group
(especially dimethylphenylsilyl), a diaryl-(1-4C)alkylsilyl group
(especially tert-butyldiphenylsilyl), a (1-4C)alkyl group
(especially methyl), a (2-4C)alkenyl group (especially alkyl), a
(1-4C)alkoxymethyl group (especially methoxymethyl) or a
tetrahydropyranyl group (especially tetrahydropyran-2-yl). The
deprotection conditions for the above protecting groups will
necessarily vary with the choice of protecting group. Thus, for
example, an arylmethyl group such as a benzyl group may be removed,
for example, by hydrogenation over a catalyst such as
palladium-on-charcoal. Alternatively a trialkylsilyl or an
aryldialkylsilyl group such as a tert-butyldimethylsilyl or a
dimethylphenylsilyl group may be removed, for example, by treatment
with a suitable acid such as hydrochloric, sulphuric, phosphoric or
trifluoroacetic acid, or with an alkali metal or ammonium fluoride
such as sodium fluoride or, in particular, tetrabutylammonium
fluoride. Alternatively an alkyl group may be removed, for example,
by treatment with an alkali metal (1-4C)alkylsulphide such as
sodium thioethoxide or, for example, by treatment with an alkali
metal diarylphosphide such as lithium diphenylphosphide or, for
example, by treatment with a boron or aluminium trihalide such as
boron tribromide. Alternatively a (1-4C)alkoxymethyl group or
tetrahydropyranyl group may be removed, for example, by treatment
with a suitable acid such as hydrochloric or trifluoroacetic
acid.
[0147] Alternatively a suitable protecting group for a hydroxy
group is, for example, an acyl group, for example a (2-4C)alkanoyl
group (especially acetyl) or an aroyl group (especially benzoyl).
The deprotection conditions for the above protecting groups will
necessarily vary with the choice of protecting group. Thus, for
example, an acyl group such as an alkanoyl or an aroyl group may be
removed, for example, by hydrolysis with a suitable base such as an
alkali metal hydroxide, for example lithium or sodium
hydroxide.
[0148] A suitable protecting group for an amino, imino or
alkylamino group is, for example, an acyl group, for example a
(2-4C)alkanoyl group (especially acetyl), a (1-4C)alkoxycarbonyl
group (especially methoxycarbonyl, ethoxycarbonyl or
tert-butoxycarbonyl), an arylmethoxycarbonyl group (especially
benzyloxycarbonyl) or an aroyl group (especially benzoyl). The
deprotection conditions for the above protecting groups necessarily
vary with the choice of protecting group. Thus, for example, an
acyl group such as an alkanoyl, alkoxycarbonyl or aroyl group may
be removed for example, by hydrolysis with a suitable base such as
an alkali metal hydroxide, for example lithium or sodium hydroxide.
Alternatively an acyl group such as a tert-butoxycarbonyl group may
be removed, for example, by treatment with a suitable acid such as
hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid,
and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group
may be removed, for example, by hydrogenation over a catalyst such
as palladium-on-charcoal.
[0149] The protection and deprotection of functional groups is
fully described in `Protective Groups in Organic Chemistry`, edited
by J. W. F. McOmie, Plenum Press (1973) and `Protective Groups in
Organic Synthesis`, 2.sup.nd edition; T. W. Greene and P. G. M.
Wuts, Wiley-Interscience (1991).
[0150] A compound of the formula (1), or a compound of the formula
(1) wherein at least 1 functional group is protected, may be
prepared using one of the following processes:
a) when R.sup.3 is of the formula --CON(R.sup.3)Y(R.sup.11),
reacting a compound of the formula (10):
##STR00003##
with a compound of the formula HN(R.sup.10)Y(R.sup.11); b) when
R.sup.3 is of the formula --SO.sub.2N(R.sup.10)Y(R.sup.11),
reacting a compound of the formula (II):
##STR00004##
with a compound of the formula HN(R.sup.10)Y(R.sup.11); c) when Q
is methylene, reacting a compound of the formula (12):
##STR00005##
with a compound of the formula Ar; d) when Q is methylene, reducing
a compound of the formula (13):
##STR00006##
e) reacting a compound of the formula (14):
##STR00007##
with a compound of the formula L'-R.sup.10; or f) converting one
compound of the formula (1) into another compound of the formula
(1); wherein L and L' are leaving groups, X is --CO-- or
--SO.sub.2-- and R.sup.1, R.sup.2, R.sup.3, R.sup.10, Q and Ar are
as hereinabove defined and any functional groups are optionally
protected; and optionally after a), b), c), d), e) or f),
converting the compound of the formula (1) into a further compound
of formula (1) and/or forming a pharmaceutically-acceptable salt,
solvate and/or prodrug thereof.
[0151] The reaction between a compound of the formula (10) and
HN(R.sup.10)Y(R.sup.11) is conveniently carried out under amide
bond forming reaction conditions. For example, in the presence of a
coupling agent such as dicyclohexylcarbodiimide or
1-ethyl-3-(3-dimethylaminopropyl)ethylcarbodiimide. Optionally a
base may be used, preferably an organic base such as triethylamine.
Suitable solvents are usually aprotic solvents, for example
dimethylformamide or chlorinated solvents, for example
dichloromethane or trichloromethane. Additionally, a compound which
catalyses this type of amide bond formation reaction, such as
1-hydroxybenzotriazole, may be present. The temperature is usually
in the range of about -30.degree. C. to about 60.degree. C.,
preferably at or near ambient temperature.
[0152] The reaction between a compound of the formula (11) and
HN(R.sup.10)Y(R.sup.11) is conveniently carried out by converting
the compound of formula (11) into the corresponding sulphonyl
halide, preferably sulphonyl chloride. This may be achieved by
using a halogenating agent, for example phosphorous trichloride or
phosphorous pentachloride, in a halocarbon solvent, in a
temperature range of -10.degree. C. to 50.degree. C. The resulting
sulphonyl chloride may be reacted with the amine in a halocarbon
solvent in the presence of an organic base, such as a tertiary
amine, in the temperature range of 0.degree. C. to 60.degree. C.,
most conveniently at ambient temperature.
[0153] The reaction between a compound of the formula (12) and Ar
is normally carried out in the presence of a strong base such as
sodium hydride. Suitable leaving groups include halo, in particular
bromo. The reaction is conveniently carried out in an inert solvent
such as tetrahydrofuran, preferably at or around ambient
temperature. In some circumstances, for example when Ar contains
ring nitrogen atoms which do not need to be deprotonated, a milder
base, such as sodium bicarbonate can be used. This reaction is
conveniently used to is prepare compounds in which Ar is linked
through a ring nitrogen atom. However, it is possible to use this
process to prepare a compound in which Ar is linked via a ring
carbon atom. This can be achieved by using a strong base and a zinc
salt such as zinc chloride and optionally sodium iodide as a
catalyst.
[0154] A compound of formula (13) can be reduced to the
corresponding methylene compound using standard reduction
conditions for hydroxy groups known in the art. For example, it can
be protonated with an acid such as trifluoroacetic acid and reduced
with a trialkylsilane. Alternatively the hydroxy group could be
converted to a stronger leaving group, such as mesylate or tosylate
and the resulting compound hydrogenated in a non-hydroxylic
solvent, preferably tetrahydrofuran, with a catalyst such as
palladium on charcoal, in a temperature range of 0.degree. C. to
50.degree. C., preferably at ambient temperature and a pressure of
1 to 5 bar.
[0155] The reaction between a compound of formula (14) and a
compound of formula L'-R.sup.10 is conveniently carried out in an
organic solvent such as acetone or THF in the presence of a mild
base, for example an inorganic base such as potassium carbonate.
The reaction may be carried out in the temperature range of
0.degree. C. to reflux. In particular the leaving group, L', is
halo, for example iodo.
[0156] A compound of the formula (1) may be prepared from another
compound of formula (1) by chemical modification. For example a
compound of the formula (1) wherein Q is methylene can be oxidised
to a compound of the formula (1) wherein Q is carbonyl. A preferred
oxidising agent is 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
in an inert organic solvent such as tetrahydrofuran. In some
circumstances oxidation can be effected by exposure of the
methylene compound to air.
[0157] Intermediates of the formulae (10), (11) and (12) may be
formed from a compound of the formula (15):
##STR00008##
wherein R.sup.20 is C.sub.1-6alkyl, for example methyl or ethyl,
and R.sup.21 is either --CH.sub.2L (wherein L is as hereinabove
defined) or --CH(OH)Ar.
[0158] A compound of formula (15) wherein R.sup.21 is --CH.sub.2L
may be reacted with Ar under similar conditions to those described
for process c) above.
[0159] When Ar is linked via a ring carbon atom in a compound of
the formula (10), (11) or (12), a compound of formula (15) wherein
R.sup.21 is --CH(OH)Ar may be reduced using similar conditions to
those described for process d) above. To form a compound of the
formula (12), --XOR.sup.20 is then converted to R.sup.3 by removing
R.sup.20 and using process a) or b) described above as
appropriate.
[0160] A compound of the formula (13) or (15) wherein R.sup.21 is
--CH(OH)Ar may be formed by reacting a compound of the formula
(16):
##STR00009##
(in which R.sup.22 is R.sup.3 or --CO.sub.2R.sup.20, as
appropriate) with a compound of formula Ar--CHO in the presence of
a strong base such as a lithium dialkylamide, for example, lithium
diisopropylamide, in an inert organic solvent such as
tetrahydrofuran and initially at a low temperature, such as
-78.degree. C. and subsequently allowing it to warm to ambient
temperature.
[0161] A compound of formula (14) may be formed by reacting a
compound of formula (10) or (12) with a compound of formula
H.sub.2N(YR.sup.11) under the reaction conditions described in a)
or b) as appropriate.
[0162] The intermediates (15) are in general prepared from a
compound of the formula (17):
##STR00010##
wherein R.sup.23 is hydrogen or methyl.
[0163] A compound of the formula (15), wherein R.sup.21 is
--CH(OH)Ar, may be prepared by reacting a compound of formula (17),
wherein R.sup.23 is hydrogen, with Ar--CHO using the conditions
described above for the reaction of a compound of formula (16) with
a compound of formula Ar--CHO.
[0164] A compound of the formula (15), wherein R.sup.21 is
--CH.sub.2L, may be prepared from a compound of formula (17),
wherein R.sup.23 is methyl, by, for example, halogenation. When L
is bromo, the methyl group may be brominated using a standard
brominating agent such as N-bromosuccinimide under standard
conditions known in the art.
[0165] A compound of formula (17), wherein X is --CO-- and R.sup.23
is hydrogen, may be formed by firstly reacting a compound of
formula (18):
##STR00011##
with an alkylbromopyruvate, such as ethylbromopyruvate, in the
presence of a mild base such an alkali carbonate, fore example
potassium carbonate in a polar solvent e.g. DMF at a temperature
between 5.degree. C. and 50.degree. C. and then secondly treating
the resulting adduct with a Lewis acid preferably titanium
tetrachloride, in an inert solvent e.g. dichloromethane at a
temperature between -20.degree. C. and 50.degree. C., preferably
between 0.degree. C. and 25.degree. C.
[0166] A compound of formula (17), wherein X is --CO-- and R.sup.23
is methyl, may be formed by firstly reacting a compound of formula
(18) with an alkyl 3-bromo-2-oxobutanoate such as methyl
3-bromo-2-oxobutanoate in the presence of a mild base such as an
alkali carboxylate, for example sodium acetate in a polar solvent
such as DMF, or preferably water, at a temperature between
5.degree. C. and 50.degree. C. and then secondly treating the
resulting adduct with a Lewis acid, preferably titanium
tetrachloride, in an inert solvent e.g. dichloromethane at a
temperature between -20.degree. C. and 50.degree. C., preferably
between 0.degree. C. and 25.degree. C.
[0167] A compound of formula (17), wherein X is --CO--, may also be
formed by reacting a compound of formula (19):
##STR00012##
(in which R.sup.24 is C.sub.1-4alkyl, for example ethyl) with
acetyl cyanate in an inert solvent, for example toluene, at a
temperature of from 0.degree. C. to 50.degree. C., and then
treating the product of that conversion with a solution of a metal
alkoxide in the alkanol (e.g., sodium methoxide in methanol) at a
temperature of from 0.degree. C. to 30.degree. C., in the presence
of a compound of formula R.sup.2-L.sup.1 (in which L.sup.1 is a
leaving group, e.g., iodide).
[0168] A compound of formula (19) may be prepared by the reaction
of a compound of formula (20):
[0169] R.sup.1--N.dbd.S with a Wittig compound, for example a
compound of the formula (21):
##STR00013##
(in which R' is phenyl or substituted phenyl such as tolyl) in an
inert solvent, for example THF, at a temperature of from 20.degree.
C. to 80.degree. C., and treatment of the resulting adduct in situ
with a compound of formula (22):
##STR00014##
at a temperature of from -78.degree. C. to 60.degree. C.
[0170] Compounds of the formula (11) and (12) and (13) wherein
R.sup.3 is of the formula --SO.sub.2N(R.sup.10)Y(R.sup.11) may be
prepared using related methods known in the art.
[0171] The compounds of formula (1) above may be converted to a
pharmaceutically-acceptable salt, solvate or prodrug thereof.
[0172] The skilled person will appreciate that it may sometimes be
necessary to protect functional groups in the intermediates during
reaction to prevent side-reactions. The texts referred to
previously in the discussion on protecting group give guidance on
suitable protecting groups and their introduction and removal.
[0173] Certain compounds of formula (1) are capable of existing in
stereoisomeric forms. It will be understood that the invention
encompasses all geometric and optical isomers of the compounds of
formula (1) and mixtures thereof including racemates. Tautomers and
mixtures thereof also form an aspect of the present invention.
[0174] Isomers may be resolved or separated by conventional
techniques, e.g. chromatography or fractional crystallisation.
Enantiomers may be isolated by separation of a racemic or other
mixture of the compounds using conventional techniques (e.g.,
chiral High Performance Liquid Chromatography (HPLC)).
Alternatively the desired optical isomers may be made by reaction
of the appropriate optically active starting materials under
conditions which will not cause racemisation, or by derivatisation,
for example with a homochiral acid followed by separation ojf the
diastereomeric derivatives by conventional means (e.g., HPLC,
chromatography over silica) or may be made with achiral starting
materials and chiral reagents. All stereoisomers are included
within the scope of the invention.
[0175] The compounds of the invention may be isolated from their
reaction mixtures using conventional techniques.
[0176] The compounds of the invention are useful because they
possess pharmacological activity in human and non-human animals.
They are indicated as pharmaceuticals for use in the (prophylactic)
treatment of autoimmune, inflammatory, proliferative and
hyperproliferative diseases and immunologically-mediated diseases
including rejection of transplanted organs or tissues and Acquired
Immunodeficiency Syndrome (AIDS).
[0177] Examples of these conditions are: [0178] (1) (the
respiratory tract) airways diseases including chronic obstructive
pulmonary disease (COPD); asthma, such as bronchial, allergic,
intrinsic, extrinsic and dust asthma, particularly chronic or
inveterate asthma (e.g. late asthma and airways
hyper-responsiveness); bronchitis; acute, allergic, atrophic
rhinitis and chronic rhinitis including rhinitis caseosa,
hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and
rhinitis medicamentosa; membranous rhinitis including croupous,
fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis;
seasonal rhinitis including rhinitis nervosa (hay fever) and
vasomotor rhinitis; sarcoidosis, farmer's lung and related
diseases, fibroid lung and idiopathic interstitial pneumonia;
[0179] (2) (bone and joints) rheumatoid arthritis, seronegative
spondyloarthropathies (including ankylosing spondylitis, psoriatic
arthritis and Reiter's disease), Behcet's disease, Sjogren's
syndrome and systemic sclerosis; [0180] (3) (skin) psoriasis,
atopical dermatitis, contact dermatitis and other eczmatous
dermitides, seborrhoetic dermatitis, Lichen planus, Pemphigus,
bullous Pemphigus, Epidermolysis bullosa, urticaria, angiodermas,
vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopecia
greata and vernal conjunctivitis; [0181] (4) (gastrointestinal
tract) Coeliac disease, proctitis, eosinopilic gastro-enteritis,
mastocytosis, Crohn's disease, ulcerative colitis, food-related
allergies which have effects remote from the gut, e.g., migraine,
rhinitis and eczema; [0182] (5) (other tissues and systemic
disease) multiple sclerosis, atherosclerosis, Acquired
Immunodeficiency Syndrome (AIDS), lupus erythematosus, systemic
lupus, erythematosus, Hashimoto's thyroiditis, myasthenia gravis,
type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper
IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathic
thrombocytopenia pupura; [0183] (6) (allograft rejection) acute and
chronic following, for example, transplantation of kidney, heart,
liver, lung, bone marrow, skin and cornea; and chronic graft versus
host disease; and [0184] (7) cancer.
[0185] Accordingly, the present invention provides a compound of
formula (1) or a pharmaceutically-acceptable salt thereof as
hereinbefore defined for use in therapy.
[0186] In another aspect, the present invention provides a compound
of formula (1) or a pharmaceutically-acceptable salt thereof as
hereinbefore defined for use in inhibiting the proliferation of T
cells.
[0187] In another aspect, the invention provides the use of a
compound of formula (1) or a pharmaceutically-acceptable salt
thereof as hereinbefore defined in the manufacture of a medicament
for use in inhibiting the proliferation of T cells.
[0188] In the context of the present specification, the term
"therapy" also includes "prophylaxis" unless there are specific
indications to the contrary. The terms "therapeutic" and
"therapeutically" should be construed accordingly.
[0189] Prophylaxis is expected to be particularly relevant to the
treatment of persons who have suffered a previous episode of, or
are otherwise considered to be at increased risk of, the is disease
or condition in question. Persons at risk of developing a
particular disease or condition generally include those having a
family history of the disease or condition, or those who have been
identified by genetic testing or screening to be particularly
susceptible to developing the disease or condition.
[0190] The invention further provides a method of effecting
immunosuppression (e.g. in the treatment of allograft rejection)
which comprises administering to a patient a therapeutically
effective amount of a compound of formula (1) or a
pharmaceutically-acceptable salt thereof as hereinbefore
defined.
[0191] The invention still further provides a method of treating,
or reducing the risk of, an airways disease (e.g. asthma or COPD)
in a patient suffering from, or at risk of, said disease, which
comprises administering to the patient a therapeutically effective
amount of a compound of formula (1)i or a
pharmaceutically-acceptable salt thereof as hereinbefore
defined.
[0192] For the above-mentioned therapeutic uses the dosage
administered will, of course, vary with the compound employed, the
mode of administration, the treatment desired and the disorder
indicated. However, in general, for effecting immuno-suppression,
the daily dosage of the compound of formula (1) will be in the
range from 0.1 mg/kg, particularly from 0.3 mg/kg, more
particularly from 0.5 mg/kg and still more particularly from 1
mg/kg up to and including 30 mg/kg. For the treatment of airways
diseases, the daily dosage of the compound of formula (1) will
typically be in the range from 0.001 mg/kg to 30 mg/kg.
[0193] The compounds of formula (1) and pharmaceutically-acceptable
salts thereof may be used on their own but will generally be
administered in the form of a pharmaceutical composition in which
the formula (1) compound/salt/solvate (active ingredient) is in
association with a pharmaceutically-acceptable adjuvant, diluent or
carrier. Depending on the mode of administration, the
pharmaceutical composition will particularly comprise from 0.05 to
99% w (percent by weight), more particularly less than 80% w, e.g.
from 0.10 to 70% w, and even more particularly less than 50% w, of
active ingredient, all percentages by weight being based on total
composition.
[0194] Thus, the present invention also provides a pharmaceutical
composition comprising a compound of formula (1) or a
pharmaceutically-acceptable salt thereof as hereinbefore defined,
in association with a pharmaceutically-acceptable adjuvant, diluent
or carrier.
[0195] The invention further provides a process for the preparation
of a pharmaceutical is composition of the invention which comprises
mixing a compound of formula (1) or a pharmaceutically-acceptable
salt thereof as hereinbefore defined, with a
pharmaceutically-acceptable adjuvant, diluent or carrier.
[0196] The pharmaceutical composition of the invention may be
administered topically (e.g. to the lung and/or airways or to the
skin) in the form of solutions, suspensions, heptafluoroalkane
aerosols and dry powder formulations; or systemically, e.g. by oral
administration in the form of tablets, capsules, syrups, powders or
granules, or by parenteral administration in the form of solutions
or suspensions, or by subcutaneous administration or by rectal
administration in the form of suppositories or transdermally.
[0197] The ability of compounds which can inhibit
PMA/ionomycin-stimulated peripheral blood mononuclear cell
proliferation can be assessed, for example using the procedure set
out below:
Inhibition of PMA/Ionomycin-Stimulated Peripheral Blood Mononuclear
Cell Proliferation
[0198] The assay for Phorbol 12-myristate 13-Acetate
(PMA)/ionomycin-stimulated peripheral blood mononuclear cell (PBMC)
proliferation was performed in 96-well flat bottomed microtitre
plates. Compounds were prepared as 10 mM stock solutions in
dimethyl sulfoxide. A 50-fold dilution of this was prepared in RPMI
culture medium and serial dilutions were prepared from this
solution. 10 .mu.l of the 50-fold diluted stock, or dilutions of
it, were added to the well to give concentrations in the assay
starting at 9.5 .mu.M and going down. Into each well was placed
1.times.10.sup.5 PBMC, prepared from human peripheral blood from a
single donor, in RPMI1640 medium supplemented with 10% human serum,
2 mM glutamine and penicillin/streptomycin. PMA (0.5 ng/ml final
concentration) and ionomycin (500 ng/ml final concentration) were
added to these cells in supplemented RPMI1640 medium (as above) so
that the final volume of the assay was 0.2 ml. The cells were
incubated at 37.degree. C. in a humidified atmosphere at 5% carbon
dioxide for 72 hours. .sup.3H-Thymidine (0.5 .mu.Ci) was added for
the final 6 hours of the incubation. The level of radioactivity
incorporated by the cells was then determined and this is a measure
of proliferation.
[0199] The compounds of the Examples were found to exhibit an
IA.sub.50 value of less than 1.times.10.sup.-6 M in the above test.
In the following specific examples, Example 2 had an IA.sub.50 of
5.88.times.10.sup.-9 M and Example 7 had an IA.sub.50 of
3.46.times.10.sup.-8 M in the above test.
[0200] The invention will now be illustrated in the following
Examples in which, unless otherwise stated:
[0201] (i) evaporations were carried out by rotary evaporation in
vacuo and work-up procedures were carried out after removal of
residual solids such as drying agents by filtration;
[0202] (ii) operations were carried out at ambient temperature,
that is in the range 18-25.degree. C. and under an atmosphere of an
inert gas such as argon or nitrogen;
[0203] (iii) yields are given for illustration only and are not
necessarily the maximum attainable;
[0204] (iv) the structures of the end-products of the formula (1)
were confirmed by nuclear (generally proton) magnetic resonance
(NMR) and mass spectral techniques; proton magnetic resonance
chemical shift values were measured on the delta scale and peak
multiplicities are shown as follows: s, singlet; d, doublet; t,
triplet; m, multiplet; br, broad; q, quartet, quin, quintet;
[0205] (v) intermediates were not generally fully characterised and
purity was assessed by thin layer chromatography (TLC),
high-performance liquid chromatography (HPLC), mass spectrometry
(MS), infra-red (IR) or NMR analysis;
Abbreviations
[0206] 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DDQ
Dimethylformamide DMF
[0207] m-Chloroperoxybenzoic acid mCPBA
Tetrahydrofuran THF
EXAMPLE 1
6-[4,5-Dichloro-2-methyl-1H-imidazol-1-ylethyl]-1,2,3,4-tetrahydro-N-metho-
xy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-car-
boxamide
a) Methyl
1,2,3,4-tetrahydro-3,6-dimethyl-1-(2-methylpropyl)-2,4-dioxo-thi-
eno-[2,3-d]pyrimidine-5-carboxylate
[0208] 6-Mercapto-3-methyl-1-(2-methylpropyl)-pyrimidine-2,4(1H,
3H)-dione (50 g) was dissolved in a solution of sodium acetate
(95.6 g) in water (1.5 L), and methyl 3-bromo-2-oxo-butanoate (44.6
g) was added dropwise with stirring. After stirring 1 h at room
temperature the mixture was thoroughly extracted into ethyl
acetate. The organic solution was washed with brine, dried
(MgSO.sub.4) and evaporated to leave an oil.
[0209] The oil (75.1 g) was dissolved in methylene chloride (800
ml) and cooled in an ice-bath under an atmosphere of nitrogen. With
efficient stirring titanium tetrachloride (43.3 ml) was slowly
added dropwise. The reaction mixture was stirred 1 hr in the
ice-bath and then 3 hr at room temperature. The reaction mixture
was poured slowly into vigorously stirred ice-water (2 L), and then
the resulting suspension was extracted into methylene chloride.
After drying, the organic solvent was removed in vacuo, and the
residue was chromatographed (SiO.sub.2/1:1 ethyl acetate-isohexane)
to afford the sub-title compound (42 g). Trituration with isohexane
gave a white powder.
[0210] .delta. .sup.1H.sub.CDCl3 0.98 (6H, d), 2.23-2.41 (1H, m),
2.46 (3H, s), 3.4 (3H, s), 3.75 (2H, d), 3.96 (3H, s).
b) Methyl
6-(bromomethyl)-1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2-
,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylate
[0211] A solution of the product of step a) (10 g) and
N-bromosuccinimide (5.74 g) in chloroform (350 ml) was refluxed
under illumination from a tungsten lamp for 4 h. The solution was
washed with water, saturated sodium bicarbonate solution and then
brine. The organic layer was dried over magnesium sulfate, filtered
and concentrated in vacuo. The residue was purified by flash silica
chromatography eluting with isohexane:ether (1:1) to give the
sub-title compound as a white powder (8.29 g).
[0212] MS (APCI) 390/391 [M+H].sup.+.
[0213] .delta. .sup.1H.sub.CDCl3 1.00 (6H, d), 2.31 (1H, septet),
3.39 (3H, s), 3.76 (2H, dd), 3.99 (3H, s), 4.66 (2H, s).
c) Methyl
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahy-
dro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carbox-
ylate
[0214] 4,5-Dichloro-2-methylimidazole (1.3 g) in dry
tetrahydrofuran (20 ml) was added dropwise to a suspension of
sodium hydride (0.34 g, 60%) in dry tetrahydrofuran (20 ml) at room
temperature under nitrogen. After 15 min, a solution of the product
of step b) (3.35 g) in dry tetrahydrofuran (20 ml) was added
dropwise and the reaction was stirred for 3 h at room temperature.
The solution was poured into water and extracted with ethyl
acetate. The combined extracts were dried over magnesium sulfate,
filtered and concentrated in vacuo. The residue was purified by
flash silica chromatography eluting with a gradient 50-100% ethyl
acetate in isohexane to give the sub-title compound as a white
solid (2.28 g).
[0215] MS (APCI) 459/460 [M+H].sup.+.
[0216] .delta. .sup.1H.sub.CDCl3 0.97 (6H, d), 2.26 (1H, septet),
2.38 (3H, s), 3.39 (3H, s), 3.73 (2H, d), 3.99 (3H, s), 5.26 (2H,
s).
d)
6-[4,5-Dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahydro-3-m-
ethyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic
Acid
[0217] Sodium hydroxide (7.3 ml of 1M aqueous solution) followed by
methanol (4 ml) were added to a solution of the product of step c)
(2.28 g) in tetrahydrofuran (50 ml) and stirred at room temperature
for 3 hours. The solution was concentrated under reduced pressure.
The residue was diluted with water and extracted with ethyl
acetate. The combined extracts were dried over magnesium sulfate,
filtered and concentrated in vacuo. The residue was purified by
flash silica chromatography eluting with a gradient of 2-5% ethanol
in dichloromethane to give the sub-title compound as a white solid
(1.68 g).
[0218] MS (APCI) 445/447 [M+H].sup.+.
[0219] .delta. .sup.1H.sub.CDCl3 0.96 (6H, d), 2.22 (1H, septet),
2.37 (3H, s), 3.51 (3H, s), 3.78 (2H, d), 5.78 (2H, s), 15.51 (1H,
br.s).
e)
6-[4,5-Dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahydro-N-m-
ethoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-
-carboxamide
[0220] 1-Hydroxybenzotriazole (0.077 g) was added to a solution of
the product of step d) (0.128 g) in dichloromethane (20 ml). After
stirring for 10 min,
1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide hydrochloride (0.11
g) was added. After stirring for 30 minutes
N,O-dimethylhydroxylamine hydrochloride (0.056 g) and triethylamine
(0.08 ml) were added and stirring was continued for 20 h. The
solution was concentrated in vacuo. The residue was purified by
flash silica chromatography eluting with a gradient of 0-10%
ethanol in dichloromethane to give the title compound as a white
foam (0.095 g).
[0221] MS (ESI) 488.09 [M+H].sup.+.
[0222] .delta. .sup.1H.sub.CDCl3 0.97-0.99 (6H, m), 2.26 (1H,
septet), 2.40+2.43 (2.times.s ratio 3:1, 3H), 3.39 (3H, s),
3.11+3.43 (2.times.s ratio 1:3, 3H), 3.49+3.97 (2.times.s, ratio
3:1, 3H), 3.65 (1H, dd), 3.84 (1H, d), 5.10-5.23 (2H, m).
EXAMPLE 2
1,2,3,4-Tetrahydro-N-methoxy-N-3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-6-(-
4-quinolinylmethyl)thieno[2,3-d]pyrimidine-5-carboxamide
a) Ethyl
1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2-
,3-d]pyrimidine-5-carboxylate
[0223] 6-Mercapto-3-methyl-1-(2-methylpropyl)-pyrimidine-2,4(1H,
3H)-dione (49.5 g) was dissolved in dry DMF (900 ml) and ethyl
bromopyruvate (30 ml) was added, and then with stirring anhydrous
potassium carbonate (15.954 g) was also added. The mixture was
stirred at room temperature for 5 h, and then poured into water (5
L). The aqueous solution was acidified with dil hydrochloric acid,
and then extracted thoroughly with ethyl acetate. The organic
extract was dried (MgSO.sub.4) and evaporated at high vacuum to
leave a semisolid mass. A portion of this semisolid mass (24 g) was
dissolved in methylene chloride (500 ml) and cooled in an ice-bath
under an atmosphere of nitrogen. With efficient stirring titanium
tetrachloride (13.5 ml) was slowly added. The reaction mixture was
stirred 1 h in the ice-bath and then 3 h at room temperature. The
reaction mixture was poured slowly into vigorously stirred
ice-water (1.5 L), and then the resulting suspension was extracted
into methylene chloride. After drying the organic solvent was
concentrated in vacuo, and the residue was chromatographed
(SiO.sub.2/1:1 ethyl acetate-isohexane) to afford the sub-title
compound as a pale yellow solid (15 g).
[0224] .delta. .sup.1H.sub.CDCl3 1.0 (6H, d), 1.4 (3H, t),
2.31-2.45 (1H, m), 3.4 (3H, s), 3.8 (2H, d), 4.4 (2H, q), 7.28 (1H,
s).
b) Ethyl
1,2,3,4-tetrahydro-6-(hydroxy4-quinolinyl-methyl-3-methyl-1-(2-me-
thylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylate
[0225] A solution of lithium diisopropylamide (5.52 g) in anhydrous
THF (80 ml) was added dropwise over 1 h to a stirred solution of
the product of step a) (8.02 g) and 4-quinolinecarboxaldehyde (8.12
g) in anhydrous THF (80 ml) at -78.degree. C. under nitrogen. The
mixture was stirred for a further 1 h at -78.degree. C. then
quenched with glacial acetic acid (10 ml), allowed to warm to room
temperature, diluted with saturated sodium bicarbonate solution
(100 ml) and extracted into ethyl acetate (2.times.100 ml). The
combined extracts were dried over magnesium sulfate, filtered and
concentrated in vacuo. The residue was purified by column
chromatography, eluting with 3:2 ethyl acetate/1-hexane, to give
the sub-title compound as a white solid (7.35 g).
[0226] MS (ESI) 468 {M+H].sup.+.
[0227] .delta. .sup.1H.sub.CDCl3 0.85 (3H, d), 0.88 (3H, d), 1.43
(3H, t), 2.10-2.16 (1H, m), 3.38 (3H, s), 3.49 (1H, dd), 3.61 (1H,
s, br), 3.71 (1H, dd), 4.48 (2H, quartet), 6.78 (1H, s), 7.52 (1H,
t), 7.72 (1H, t), 7.83 (1H, d), 7.90 (1H, d), 8.17 (1H, d), 9.02
(1H, d).
c) Ethyl
1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-6-(4-qui-
nolinylmethyl)-thieno[2,3-d]pyrimidine-5-carboxylate
[0228] Trifluoroacetic anhydride (3.33 ml) was added to a solution
of the product of step b) (7.34 g) and triethylamine (6.56 ml) in
anhydrous THF (150 ml) at room temperature under nitrogen and the
mixture stirred for 15 min. 10% palladium on charcoal (500 mg) was
added and the mixture hydrogenated at 1 bar for 20 h. It was
filtered through Celite, washing with saturated sodium bicarbonate
solution (150 ml) then ethyl acetate (300 ml). The organic material
was extracted into ethyl acetate (150 ml), the combined extracts
were dried over magnesium sulfate, filtered and concentrated in
vacuo. The residue was purified by column chromatography, eluting
with 1:1 ethyl acetate/1-hexane, to give the sub-title compound as
a solid (5.90 g).
[0229] MS (ESI) 452{M+H].sup.+.
[0230] .delta. .sup.1H.sub.CDCl3 0.90 (6H, d), 1.37 (3H, t),
2.10-2.16 (1H, m), 3.39 (3H, s), 3.64 (2H, d), 4.45 (2H, q), 4.61
(2H, s), 7.29 (1H, d), 7.60 (1H, t), 7.75 (1H, t), 8.11 (1H, d),
8.16 (1H, d), 8.89 (1H, d).
d) Sodium
1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-6-(4-qu-
inolinylmethyl)-thieno[2,3-d]pyrimidine-5-carboxylate
[0231] A solution of the product of step c) (5.89 g) in THF (150
ml) and methanol (23 ml) under nitrogen was degassed by repeated
evacuation and flushing with nitrogen. 1M sodium hydroxide (18 ml)
was added and the mixture stirred for 18 h. The resulting
precipitated solid was collected by filtration, washed with THF and
concentrated in vacuo to give the sub-title compound as a solid
(5.06 g).
[0232] MS (ESI) 424 {M+H].sup.+.
[0233] .delta. .sup.1H.sub.DMSO 0.81 (6H, d), 2.10-2.15 (1H, m),
3.20 (3H, s), 3.56 (2H, d), 4.56 (2H, s), 7.52 (1H, dd), 7.57 (1H,
td), 7.74 (1H, td), 8.00 (1H, dd), 8.83 (1H, d).
e)
1,2,3,4-Tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl-2,4-dioxo-6-
-(4-quinolinylmethyl-thieno[2,3-d]pyrimidine-5-carboxamide
[0234] To a suspension of the product of step d) (157 mg) in
dichloromethane (5 ml) was added 1-hydroxybenzotriazole hydrate
(108 mg) and the mixture stirred for 15 minutes.
1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (135
mg) was added and stirring continued for 1 h.
N,O-Dimethylhydroxylamine hydrochloride (69 mg) and triethylamine
(147 .mu.l) were added and the reaction mixture stirred for 18 h
then concentrated in vacuo. The residue was purified by column
chromatography, eluting with i-hexane/ethyl acetate (10-100%
gradient) to give the title compound as a solid (136 mg).
[0235] MS (APCI) 467 {M+H].sup.+.
[0236] .delta. .sup.1H.sub.DMSO 0.83 (6H, m), 2.04-2.08 (1H, m),
2.98 (1H, s), 3.21 (3H, s), 3.22-3.27 (2H, m), 3.43 (2H, s), 3.61
(2H, d), 3.72 (1H, s), 4.60 (2H, s), 7.43-7.48 (1H, m), 7.61-7.68
(1H, m), 7.78 (1H, t), 8.04 (1H, d), 8.22-8.31 (1H, m), 8.67 (1H,
d).
EXAMPLE 3
1,2,3,4-Tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-6-(-
1H
pyrrolo[2,3-b]pyridin-3-ylmethyl)-thieno[2,3-d]pyrimidine-5-carboxamide
a) Methyl
1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-6-(1H-p-
yrrolo[2,3,b]pyridin-3-ylmethyl)-thieno[2,3,d]pyridine-5-carboxylate
[0237] To a solution of 7-azaindole (0.78 g) in dry THF (30 ml) was
added 2.5M n-butyl lithium (2.6 ml) dropwise at 10.degree. C. under
nitrogen and the resulting mixture was stirred for 15 min. 1.0M
ethereal zinc chloride (6.61 ml) was added, the mixture allowed to
warm to room temperature and stirred for 2 hours. The solvent was
removed under reduced pressure and the residue diluted with dry
toluene (20 ml). A solution of the product of example 1 part a)
(3.14 g) in dry toluene (10 ml) was added followed by a catalytic
amount of sodium iodide and the mixture stirred under nitrogen for
72 h. The solvent was decanted and the solid residue partitioned
between 2N hydrochloric acid and ethyl acetate; the aqueous phase
was basified with sodium bicarbonate and extracted into ethyl
acetate (2.times.100 ml). The combined extracts were dried over
magnesium sulfate, filtered and concentrated in vacuo. The residue
was purified by chromatography, eluting with i-hexane/ethyl acetate
(20-75% gradient), to give the sub-title compound as a yellow solid
(1.37 g).
[0238] MS (APCI) 427 [M+H].sup.+.
[0239] .delta. .sup.1H.sub.DMSO 0.83 (6H, d), 2.09 (1H, heptet),
3.20 (3H, s), 3.61 (2H, d), 3.86 (3H, s), 4.22 (2H, s), 7.02-7.05
(1H, m), 7.43 (1H, m), 7.88 (1H, d), 8.20 (1H, d), 11.56 (1H, s,
br).
b)
1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-6-(1H-pyrrolo[-
2,3,b]pyridin-3-ylmethyl)-thieno[2,3,d]pyrimidine-5-carboxylic
Acid
[0240] The sub-title compound (1.22 g) was prepared from the
product of part a, (1.37 g) by the method of example of example 1,
step c.
[0241] MS (ESI) 413 [M+H].sup.+.
c)
1,2,3,4-Tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo--
6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thieno[2,3-d]pyrimidine-5-carboxam-
ide
[0242] The title compound (100 mg) was prepared from the product of
part b), (145 mg) by the method of example 1, step d.
[0243] MS (APCI) 456 [M+H].sup.+.
[0244] .delta. .sup.1H.sub.DMSO 0.82-0.84 (6H, m), 2.07-2.10 (1H,
m), 3.02 (1H, s), 3.20-3.22 (3H, m), 3.30-3.32 (2H, m), 3.44 (2H,
s), 3.57-3.68 (2H, m), 3.78 (1H, s), 4.14-4.16 (2H, m), 7.01-7.04
(1H, m), 7.43 (1H, d), 7.95-7.97 (1H, m), 8.20 (1H, dd), 11.55 (1H,
s, br).
EXAMPLE 4
1,2,3,4-Tetrahydro-6-(1H-indol-3-ylmethyl)-N-methoxy-N,3-dimethyl-1-(2-met-
hylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamide
a) Methyl
1,2,3,4-tetrahydro-6-(1H-indol-3-ylmethyl)-3-methyl-1-(2-methylp-
ropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylate
[0245] The product from example 1 part b) (2.5 g) was dissolved in
chloroform (20 ml), then indole (1.08 g), sodium hydrogen carbonate
(1.4 g) and water (20 ml) were added and the reaction mixture was
stirred at room temperature for 3 days. The two layers were
separated and the aqueous phase was extracted with dichloromethane.
The combined organic extracts were dried over magnesium sulfate,
filtered and concentrated in vacuo. The residue was purified by
flash silica chromatography eluting with 50% ethyl acetate in
isohexane to give the sub-title compound as a white solid (1.8
g).
[0246] MS (APCI) 426 [M+H].sup.+.
b)
1,2,3,4-Tetrahydro-6-(1H-indol-3-ylmethyl)-3-methyl-1-(2-methylpropyl)--
2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic Acid
[0247] Prepared using the procedure described in example 1 part d)
from the product of part a) to give the sub-title compound as a
pale pink solid.
[0248] MS (APCI) 412 [M+H].sup.+.
c)
1,2,3,4-Tetrahydro-6-(H-indol-3-ylmethyl)-N-methoxy-N,3-dimethyl-1-(2-m-
ethylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamide
[0249] Prepared using the procedure described in example 1 part e)
from the product of part b) to give the title compound as a pale
pink solid.
[0250] MS (APCI) 454 [M+H].sup.+.
EXAMPLE 5
1,2,3,4-Tetrahydro-6-(1H-indol-3-ylcarbonyl)-N-methoxy-N,3-dimethyl-1-(2
methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamide
[0251] DDQ (0.25 g) was added to a stirred solution of the product
of example 4 (0.25 g) in THF (9 ml) and water (1 ml). The solution
was stirred for a further 2 h and the concentrated in vacuo. The
residue was purified by flash silica chromatography eluting with
ethyl acetate:isohexane (7:3) to give the title compound as a pale
pink solid (0.1 g).
[0252] MS (APCI) 469 [M+H].sup.+.
[0253] .delta. .sup.1H.sub.DMSO 0.95-1.07 (6H, m), 2.21-2.38 (1H,
m), 3.2 (3H, s), 3.29 (3H, s), 3.46 (3H, s), 3.75-3.93 (2H, m),
7.21-7.32 (2H, m), 7.55 (1H, d), 8.13 (1H, d), 8.27-8.31 (1H, m),
12.17 (1H, s).
EXAMPLE 6
6-[4,5-Dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahydro-N-meth-
oxy-N,3-dimethyl-1-(1-methylethyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-car-
boxamide
a) Ethyl methyl
2-methyl-5-((1-methylethyl)amino)-thiophene-3,4-dicarboxylate
[0254] Ethoxycarbonylmethylene triphenyl phosphorane (33.8 g) in
dry THF (200 ml) was treated with isopropyl iscthiocyanate (10.1 g)
at 65.degree. C. for 16 h under nitrogen. The mixture was cooled to
-78.degree. C. and methyl 3-bromo-2-oxo-butanoate (19.5 g) was
added. The reaction was allowed to warm slowly to room temperature.
After 24 h at room temperature more methyl 3-bromo-2-oxo-butanoate
(2.8 g) was added and the mixture was warmed to 60.degree. C. for
16 h. The cooled reaction was poured into water (1.5 L) and
extracted into ether. Drying and evaporation gave an oil which was
chromatographed (SiO2/10:1 isohexane-ethyl acetate then 5:1
isohexane-ethyl acetate) to afford the subtitle compound (23.5
g).
[0255] .delta. .sup.1H.sub.CDCl3 1.23-1.35 (9H, m), 2.26 (3H, s),
3.46 (1H, m), 3.82 (3H, s), 4.2 (2H, q), 7.42 (1H, br.s).
b) Methyl
1,2,3,4-tetrahydro-3,6-dimethyl-1-(1-methylethyl)-2,4-dioxo-thie-
no[2,3-d]pyrimidine-5-carboxylate
[0256] Silver cyanate (13.5 g) suspended in anhydrous toluene (90
ml) under nitrogen was treated dropwise with acetyl chloride (5.34
ml) and stirred vigorously for 30 min. The product of step a) (23
g) dissolved in anhydrous toluene (15 ml) was added and the mixture
was stirred for 72 h. Ether (360 ml) was added and the insoluble
material was filtered off and washed with a small volume of ether.
The combined organic solutions were washed with saturated sodium
bicarbonate solution, dried and evaporated. The residue was treated
with a solution of sodium methoxide in methanol (25 wt %, 64 ml) at
room temperature for 72 h. The reaction was cooled in ice and
treated with trimethylsilyl chloride (50.8 ml) and stirred at room
temperature overnight. All volatiles were removed in vacuo and the
residue partitioned between water and ethyl acetate. Drying and
evaporation of the organic solution left a residue, which was
chromatographed (SiO.sub.2/2:1 isohexane-ethyl acetate then 3:2
isohexane-ethyl acetate) to isolate the major component (12.2 g).
This was taken in dry DMF (150 ml) with potassium carbonate (6.95
g) and methyl iodide (7.1 g) for 72 h at room temperature. The
mixture was poured into water (2 L), acidified and extracted into
ether. Washing with brine, drying and evaporation gave a solid
which was boiled in isohexane (200 ml) containing ethyl acetate (3
ml). On cooling the precipitated pale yellow solid was collected
and dried, to afford the sub-title compound (10.5 g).
[0257] .delta. .sup.1H.sub.CDCl3 1.6 (6H, d), 2.44 (3H, s), 3.37
(3H, s), 3.95 (3H, s), 4.66 (1H, br). MS (APCI) (M.sup.++H).
c)
6-(Bromomethyl)-1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxo-
thieno[2,3-d]pyrimidine-5-carboxylic Acid Methyl Ester
[0258] Prepared using the procedure described in example 1 part b)
from the product of example 6 part b) to give the subtitle
compound.
[0259] .delta. .sup.1H.sub.CDCl3 1.62-1.64 (6H, m), 3.37 (3H, s),
3.99 (3H, s), 4.60-4.70 (3H, m).
d) Methyl
6-[4,5-Dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahy-
dro-3-methyl-1-(1-methylethyl-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxyl-
ate
[0260] Prepared using the procedure described in example 1 part c)
from the product of example 6 part c) to give the subtitle
compound.
[0261] MS (APCI) 445/446 [M+H].sup.+.
[0262] .delta. .sup.1H.sub.CDCl3 1.56-1.61 (6H, m), 2.37-2.38 (3H,
m), 3.37 (3H, s), 3.98 (3H, s), 4.40-4.50 (1H, br.s), 5.25 (2H,
s).
e) Sodium
6-[4,5-Dichloro-2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,4-tetrah-
ydro-3-methyl-1-(1-methylethyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carbox-
ylate
[0263] Prepared using the procedure described in example 2 part d)
from the product of example 6 part d) to give the sub-title
compound.
[0264] MS (APCI) 431/433 [M+H].sup.+.
[0265] .delta. .sup.1H.sub.D2O 1.53 (6H, d), 2.39 (3H, s), 3.31
(3H, s), 3.54-3.69 (1H, m), 5.32 (2H, s).
f)
6-[4,5-Dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahydro-N-m-
ethoxy-N,3-dimethyl-1-(1-methylethyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5--
carboxamide
[0266] Prepared using the procedure described in example 1 part e)
from the product of example 6 part e) to give the title
compound.
[0267] MS (APCI) 474/475 [M+H].sup.+.
[0268] .delta. .sup.1H.sub.CDCl3 1.54-1.61 (6H, m), 2.40-2.44 (3H,
m), 3.36 (3H, s), 3.11 and 3.43 (3H, 2.times.s ratio 1:5),
3.49+3.97 (3H, 2.times.s ratio 5:1), 4.47 (1, br.s), 5.15-5.24 (2H,
m).
EXAMPLE 7
6-[4,5-Dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahydro-N-meth-
oxy-N,3-dimethyl-2,4-dioxo-1-propyl-thieno[2,3-d]pyrimidine-5-carboxamide
##STR00015##
[0269] a) 6-Mercapto-3-methyl-1-propyl-pyrimidine-2,4 (1H,
3H)-dione
[0270] A mixture of 6-chloro-3-methyl-1-propyl-pyrimidine-2,4(1H,
3H)-dione (3.76 g), sodium hydrosulphide hydrate (6.0 g) and
ethanol (100 ml) was stirred at room temperature for 48 h then
concentrated under reduced pressure. The residue was dissolved in
water (500 ml) and washed with ethyl acetate (2.times.100 ml). The
aqueous phase was acidified with dilute hydrochloric acid, then
extracted with ethyl acetate (3.times.100 ml). The combined organic
phase was dried (MgSO.sub.4) and concentrated in vacuo to give a
pale yellow solid which was used directly in the next step.
b) Methyl
1,2,3,4-tetrahydro-3,6-dimethyl-2,4-dioxo-1-propyl-thieno[2,3-d]-
pyrimidine-5-carboxylate
[0271] Prepared from the product of step a) following the procedure
of example 1, step a).
[0272] .delta. .sup.1H.sub.CDCl3 1.00 (3H, t), 1.81 (2H, sextet),
2.46 (3H, s), 3.39 (3H, s), 3.87-3.90 (2H, m), 3.96 (3H, s).
c) Methyl
6-(Bromomethyl)-1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-1-propylth-
ieno[2,3-d]pyrimidine-5-carboxylate
[0273] Prepared using the procedure described in example 1, part b)
from the product of part b) to give the subtitle compound.
[0274] .delta. .sup.1H.sub.CDCl3 1.02 (3H, t), 1.82 (2H, sextet),
3.39 (3H, s), 3.91 (2H, t), 4.00 (3H, s), 4.68 (2H, s).
d) Methyl
6-[4,5-Dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahy-
dro-3-methyl-2,4-dioxo-1-propyl-thieno[2,3-d]pyrimidine-5-carboxylate
[0275] Prepared using the procedure described in example 1, part c)
from the product of part c) to give the subtitle compound.
[0276] MS (APCI) 445/447 [M+H].sup.+.
[0277] .delta. .sup.1H.sub.CDCl3 0.99 (3H, t), 1.76 (2H, sextet),
2.38 (3H, s), 3.39 (3H, s), 3.85 (2H, td), 3.99 (3H, s), 5.26 (2H,
s).
[0278] Mpt. 155-156.degree. C.
e) Sodium
6-[(4,5-Dichloro-2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,4-tetra-
hydro-3-methyl-2,4-dioxo-1-propyl-thieno[2,3-d]pyrimidine-5-carboxylate
[0279] Prepared using the procedure described in example 1, part d)
from the product of part d) to give the sub-title compound.
[0280] MS (APCI) 431/433 [M+H].sup.+.
[0281] .delta. .sup.1H.sub.DMSO 0.87 (3H, t), 1.67 (2H, sextet),
2.38 (3H, s), 3.19 (3H, s), 3.78 (2H, t), 5.23 (2H, s).
f)
6-[4,5-Dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahydro-N-m-
ethoxy-N,3-dimethyl-2,4-dioxo-1-propyl-thieno[2,3-d]pyrimidine-5-carboxami-
de
[0282] Prepared using the procedure described in example 1, part e)
from the product of part e) to give the title compound.
[0283] MS (APCI) 474/475/476 [M+H].sup.+.
[0284] .delta. .sup.1H.sub.CDCl3 1.00 (3H, t), 1.80 (2H, sextet),
2.40 (3H, s), 3.11+3.43 (3H, 2.times.s ratio 1:3), 3.38 (3H, s),
3.49+3.99 (3H, 2.times.s ratio 3:1), 3.75-3.82 (1H, m), 3.86-3.99
(1H, m), 5.09-5.24 (2H, m).
EXAMPLE 8
1,2,3,4-Tetrahydro-6-(1H-indazol-3-ylmethyl)-N-methoxy-N,3-dimethyl-1-(2-m-
ethylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamide
a)
1,2,3,4-Tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo--
thieno[2,3-d]pyrimidine-5-carboxamide
[0285] Trimethylaluminium (2M solution in toluene, 7.5 ml) was
added dropwise to methoxylamin hydrochloride (1.5 g) in dry toluene
(10 ml) and anhydrous THF (5 ml) at 0.degree. C. under a nitrogen
atmosphere. The solution was stirred for 1 h at 0.degree. C. and
then allowed to reach room temperature. The product of example 2
part a) (3 g, 9.7 mmol) was added portionwise and stirred for 1 h.
The resulting solution was poured into ice/dilute HCl and then
extracted with ethyl acetate (.times.3). The combined organic
extracts were washed with brine and concentrated in vacuo, to
afford the sub-title compound as a gum (3 g), which was used in the
next step without further purification.
b)
3-[1,2,3,4-Tetrahydro-5-[(N-methoxy-N-methylamino)carbonyl]-3-methyl-1--
(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl](hydroxymethyl)-1H-i-
ndazole-1-carboxylic Acid, Phenylmethyl Ester
[0286] Prepared by the method of example 2 part a) using the
product of part a) and 3-formyl-1H-indazole-1-carboxylic acid
phenylmethyl ester.
[0287] LCMS (ESI) 606 (M.sup.++H).
c)
3-[1,2,3,4-Tetrahydro-5-[(N-methoxy-N-methylamino)carbonyl]-3-methyl-1--
(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-ylmethyl]-1H-indazole-1-
-carboxylic Acid, Phenylmethyl Ester
[0288] Trifluoroacetic acid (2 ml) was added to the crude product
of part b) (1.7 g) in dichloromethane (5 ml) and triethylsilane (2
ml). The reaction mixture was stirred for 2 h and then poured into
sodium bicarbonate solution and extracted with dichloromethane. The
organic phase was washed with water and then dried over magnesium
sulfate and concentrated in vacuo. The residue was purified by
chromatography (SiO.sub.2) eluting with ethyl acetate:isohexane
(2:3), to give the sub-title compound as a colourless foam.
[0289] LCMS (ESI) 460 (M.sup.++H).
d)
1,2,3,4-Tetrahydro-6-(1H-indazol-3-ylmethyl)-N-methoxy-N,3-dimethyl-1-(-
2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamide
[0290] The product of part c) (0.5 g) was dissolved in ethanol,
treated with 10% palladium on charcoal (0.1 g) and stirred under an
atmosphere of hydrogen (4 bar) for 1.5 h. The reaction mixture was
filtered (celite) and concentrated in vacuo. The reaction mixture
was purified by chromatography (SiO.sub.2) eluting with ethyl
acetate:hexane (3:1) to give the title compound as a clear gum (0.3
g).
[0291] LCMS (ESI) 456 (M.sup.++H).
[0292] .delta. .sup.1H.sub.CDCl3 0.92 (6H, d), 2.23 (1H, m),
3.08-3.43 (3H, m), 3.46 and 3.99 (3H, m, rotamers), 4.49 (2H, s),
7.17 (1H, t), 7.4 (1H, t), 7.46 (1H, d), 7.81 (1H, d).
EXAMPLE 9
1-(2,2-Dimethylpropyl)-1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-2,4-dioxo-
-6-(quinolin-4-ylmethyl)-thieno[2,3-d]pyrimidine-5-carboxamide
a) 6-Chloro-1-(2,2-dimethylpropyl)-3-methyl-pyrimidine-2,4(1H,
3)-dione
[0293] 6-Chloro-3-methyl uracil (10.0 g) and potassium carbonate
(10.34 g) in DMF (70 ml) under nitrogen were treated with neopentyl
iodide (9.9 ml) and stirred for 48 h. Neopentyl iodide (7.4 ml) was
added and the reaction was stirred under reflux for a further 37 h.
The reaction was poured into water (700 ml) and extracted with
ethyl acetate. The combined organics were dried and concentrated in
vacuo to afford the subtitle compound an orange oil, 8.1 g.
[0294] .delta. .sup.1H.sub.CDCl3 1.00 (9H, s), 3.34 (3H, s), 4.01
(2H, d), 8.02 (1H, s).
b) 1-(2,2-Dimethylpropyl)-6-mercapto-3-methyl-pyrimidine-2,4(1H,
3H)-dione
[0295] The product of step a) (8.1 g) in ethanol (300 ml) was
treated with NaSH (3.9 g) under nitrogen. After 48 h at room
temperature the solvent was evaporated and the residue diluted with
water. The aqueous phase was washed with ethyl acetate then
acidified with 2M HCl. This was then extracted with ethyl acetate
and the combined organics dried and concentrated in vacuo to afford
the subtitle compound as an orange oil, 6.5 g.
[0296] .delta. .sup.1H.sub.CDCl3 1.09 (9H, s), 3.27 (3H, s), 3.78
(0.5H, s), 4.18 (2H, s), 4.49 (1H, s), 5.79 (0.5H, s).
c) Ethyl
1-(2,2-dimethylpropyl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydrothien-
o[2,3-d]pyrimidine-5-carboxylate
[0297] To the product of step b) (6.3 g) in dry dimethylformamide
(100 ml) was added potassium carbonate (1.9 g) and stirred for 10
min. Ethyl bromopyruvate (4 ml) was added and was stirred under
nitrogen at room temperature for 2 h. The reaction was poured into
water (1 L) and acidified (2M HCl) and extracted with ethyl
acetate. The combined organics were washed with brine (100 ml).
Drying and evaporation afforded an oil. The oil was dissolved in
dichloromethane (100 ml) and cooled in ice whilst stirring.
Titanium tetrachloride (6 ml) was added and stirring continued
under nitrogen for 2 hours. The reaction was poured into water (1
L) and extracted with dichloromethane (.times.2). The combined
organics were dried and concentrated in vacuo. The residue was
purified by chromatography (SiO.sub.2/ethyl acetate-dichloromethane
0-8%) to afford the subtitle compound as an orange oil, 6.2 g
[0298] .delta. .sup.1H.sub.CDCl3 1.05 (9H, s), 1.40 (3H, t), 3.42
(3H, s), 3.85 (2H, s), 4.42 (2H, q), 7.25 (1H, s).
[0299] MS (APCI) 325.1 (M.sup.++H).
d) Ethyl
1-(2,2-dimethylpropyl)-6-[hydroxy(quinolin-4-yl)methyl]-3-methyl--
2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate
[0300] The subtitle compound was prepared by the method of example
2, part b) using the product of part c) and
4-quinolinecarboxaldehyde.
[0301] .delta. .sup.1H.sub.CDCl3 0.91 (9H, s), 1.40 (3H, t), 3.38
(3H, s), 3.53 (1H, s), 3.70 (1H, s), 4.47 (2H, q), 6.76 (1H, s),
7.51 (1H, m), 7.71 (1H, m), 7.81 (1H, m) 7.88 (1H, m), 8.16 (1H,
m), 9.01 (1H, d).
e) Ethyl
1-(2,2-dimethylpropyl)-3-methyl-2,4-dioxo-6-(quinolin-4-ylmethyl)-
-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate
[0302] The sub-title compound was prepared using the method of
example 2, part c) using the product of part d).
[0303] MS (ESI) 466 (M.sup.++H).
f) Sodium
1-(2,2-dimethylpropyl)-3-methyl-2,4-dioxo-6-(quinolin-4-ylmethyl-
)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate
[0304] The sub-title compound was prepared by the method of example
2, part d) using the product of part e)
[0305] MS (ESI) 438.0 (M.sup.++H).
g)
1-(2,2-Dimethylpropyl)-N-methoxy-N,3-dimethyl-2,4-dioxo-6-(quinolin-4-y-
lmethyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxamide
[0306] Prepared following the method of example 2 part e) to afford
the title compound as a white solid (61 mg).
[0307] MS (APCI) 481.1 (M.sup.++H).
[0308] .delta. .sup.1H.sub.DMSO 0.91 (9H, d), 2.97 (1H, s), 3.21
(3H, d), 3.29 (2H, d), 3.42 (2H, s), 3.65 (2H, s), 3.71 (1H, s),
4.59 (2H, s), 7.43 (1H, m), 7.63 (1H, t) 7.77 (1H, m), 8.05 (1H,
d), 8.29 (1H, m), 8.50 (1H, m), 8.87 (1H, d).
EXAMPLE 10 i)
1,2,3,4-Tetrahydro-N-methoxy-N,3-dimethyl-6-[2-(1-methylethyl)-1H-imidazol-
-1-ylmethyl]-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carbox-
amide
a)
1,2,3,4-Tetrahydro-3-methyl-6-[[2-(1-methylethyl)-1H-imidazol-1-yl]meth-
yl]-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic
Acid, Methyl Ester
[0309] The subtitle compound was prepared by the method of Example
1 step c).
[0310] MS (APCI) 419 [M+H].sup.+.
[0311] .delta. .sup.1H.sub.CDCl3 0.94 (6H, d); 1.31 (6H, d); 2.22
(1H, septet); 3.0 (1H, quintet); 3.39 (3H, s); 3.70 (2H, d); 4.0
(3H, s); 5.25 (2H, s); 6.86 (1H, m); 7.02 (1H, m).
b)
1,2,3,4-Tetrahydro-3-methyl-6-[2-(1-methylethyl)-1H-imidazol-1-ylmethyl-
]-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic
Acid, Sodium Salt
[0312] The sub-title compound was prepared by the method of example
2 step d).
[0313] MS (APCI) 405 [M+H].sup.+.
[0314] .delta. .sup.1H.sub.DMSO 0.93 (6H, d); 1.33 (6H, d); 2.17
(1H, septet); 3.26 (3H, s); 3.53 (1H, septet); 3.74 (2H, d);
3.80-4.0 (1H, br.s); 6.0 (2H, s); 7.50-7.58 (1H, m); 7.64-7.69 (1H,
m); 14.83 (1H, br.s).
c)
1,2,3,4-Tetrahydro-N-methoxy-N,3-dimethyl-6-[2-(1-methylethyl)-1H-imida-
zol-1-yl]methyl]-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-ca-
rboxamide
[0315] The title compound was prepared by the method of Example 1,
step e).
[0316] MS (APCI) 448 [M+H].sup.+.
[0317] .delta. .sup.1H.sub.CDCl3 0.96 (6H, d); 1.23-1.42 (6H, m);
2.23 (1H, septet); 2.98-3.08 (1H, m); 3.39 (3H, s); 3.43+3.98 (6H,
2.times.s ratio 5:1); 3.62 (1H, dd); 3.83 (1H, dd): 5.09-5.24 (2H,
m); 6.87-6.89 (1H, m); 6.99-7.01 (1H, m).
EXAMPLE 10 ii)
1,2,3,4-Tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-6-[2-(methylt-
hio)-1H-imidazol-1-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxami-
de
a) 2-Methylthio-imidazole
[0318] Iodomethane (0.55 ml) was added to a solution of
2-mercaptoimidazole (0.89 g) in potassium hydroxide solution (8.90
ml, 1M) and stirred at room temperature for 3 h. The solution was
partitioned between water and ethyl acetate. The organic layer was
washed with brine, dried over magnesium sulfate, filtered and
concentrated in vacuo to give the sub-title compound as a cream
solid (0.87 g).
[0319] .delta. .sup.1H.sub.CDCl3 2.60 (3H, s); 5.30 (1H, s); 7.07
(2H, s).
b)
1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-[2-(methylthio)-1H-imi-
dazol-1-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic
Acid Methyl Ester
[0320] The sub title compound was prepared by the method of Example
1, step c).
[0321] MS (APCI) 423 [M+H].sup.+.
[0322] .delta. .sup.1H.sub.CDCl3 0.96 (6H, dd); 2.24 (1H, septet);
2.62 (3H, s); 3.39 (3H, s); 3.72 (2H, d); 4.01 (3H, s); 5.26 (2H,
s); 7.06 (1H, m); 7.10 (1H, m).
c)
1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-[2-(methylthio)-1H-imi-
dazol-1-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic
acid sodium salt
[0323] The sub-title compound was prepared by the method of example
2, part d).
[0324] MS (APCI) 409/410 [M+H].sup.+.
[0325] .delta. .sup.1H.sub.DMSO 0.87 (6H, d); 2.16 (1H, septet);
3.19 (3H, s); 3.29 (3H, s); 3.66 (2H, d); 5.14 (2H, s); 6.88 (1H,
s); 7.47 (1H, s).
d)
1,2,3,4-Tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-6-[2-(meth-
ylthio)-1H-imidazol-1-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carbox-
amide
[0326] The title compound was prepared by the method of Example 1,
step e).
[0327] MS (APCI) 452 [M+H].sup.+.
[0328] .delta. .sup.1H.sub.CDCl3 0.96-0.98 (6H, m); 2.27 (1H,
septet); 2.63 (3H, s); 3.38 (3H, s); 3.44+3.99 (3H, 2.times.s,
ratio 5:1); 3.44+3.08 (3H, 2.times.s ratio 5:1); 3.63 (1H, m); 3.84
(1H, m); 5.12 (1H, d); 5.28 (1H, d); 7.08 (1H, s); 7.10 (1H,
s).
EXAMPLE 10 iii)
6-[2-Chloro-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahydro-N-methoxy-N-3-dimet-
hyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamide
a)
6-[2-Chloro-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahydro-3-methyl-1-(2-me-
thylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic Acid,
Methyl Ester
[0329] The sub-title compound was prepared by the method of Example
1 step c) using 2-chloro-imidazole.
[0330] MS (APCI) 411 [M+H].sup.+.
[0331] .delta. .sup.1H.sub.CDCl3 0.96 (6H, d); 2.25 (1H, septet);
3.39 (3H, s); 3.73 (2H, d); 4.01 (3H, s); 5.25 (2H, s); 6.98 (1H,
s); 7.06 (1H, s).
b)
6-[2-Chloro-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahydro-3-methyl-1-(2-me-
thylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic Acid,
Sodium Salt
[0332] The sub-title compound was prepared by the method of Example
1, step d).
[0333] MS (APCI) 397 [M+H].sup.+.
[0334] .delta. .sup.1H.sub.DMSO 0.88 (6H, d); 2.17 (1H, septet);
3.20 (3H, s); 3.67 (2H, d); 5.18 (2H, s); 6.83 (1H, d); 7.53 (1H,
d).
c)
6-[2-Chloro-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahydro-N-methoxy-N,3-di-
methyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamide
[0335] The subtitle compound was prepared by the method of Example
1, step e).
[0336] MS (APCI) 440 [M+H].sup.+.
[0337] .delta. .sup.1H.sub.CDCl3 0.97 (6H, dd); 2.27 (1H, septet);
3.39 (3H, s); 3.44+3.08+3.99 (3.times.s, ratio 1:4:1, 6H); 3.65
(1H, dd); 3.85 (1H, dd); 5.09 (1H, d); 5.29 (1H, d); 6.96 (1H, s);
7.10 (1H, s).
EXAMPLE 10 iv)
1,2,3,4-Tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-6-[2-(methylt-
hio)-1H-benzimidazol-1-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carbo-
xamide
a) Methyl
1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-[2-(methylthio)-
-1H-benzimidazol-1-ylmethyl]-2,4-dioxo-methyl ester
thieno[2,3-d]pyrimidine-5-carboxylate
[0338] Prepared using the procedure described in example 1, part c)
from the product of example 1 step b) and
2-methylthiobenzimidazole, to give the subtitle compound.
[0339] MS (APCI) 474 [M+H].sup.+.
b)
1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-[2-(methylthio)-1H-ben-
zimidazol-1-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic
Acid
[0340] Prepared using the procedure described in example 1, part d)
from the product of step a), to give the subtitle compound as a
white solid.
[0341] MS (APCI) 459 [M+H].sup.+.
c)
1,2,3,4-Tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-6-[2-(meth-
ylthio)-1H-benzimidazol-1-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-ca-
rboxamide
[0342] Prepared using the procedure described in example 1, part
e), from the product of step b) to give the title compound.
[0343] MS (APCI) 502 [M+H].sup.+.
[0344] .delta. .sup.1H.sub.DMSO 0.87 (3H, s), 0.84 (3H, s),
2.07-2.2 (1H, m), 2.76 (3H, s), 2.99 (3H, s), 3.17 (3H, s), 3.21
(3H, s), 3.62-3.7 (2H, m), 5.43 (2H, d), 7.13-7.2 (2H, m), 7.5-7.6
(2H, m).
EXAMPLE 10 v)
[0345]
1,2,3,4-Tetrahydro-N-(2-hydroxyethyl)-N-methoxy-3-methyl-1-(2-methy-
lpropyl)-6-[2-(methylthio)-1H-imidazol-1-ylmethyl]-2,4-dioxo-thieno[2,3-d]-
pyrimidine-5-carboxamide
a)
1,2,3,4-Tetrahydro-N-methoxy-3-methyl-1-(2-methylpropyl)-6-[[2-(methylt-
hio)-1H-imidazol-1-yl]methyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxam-
ide
[0346] The sub-title compound was prepared by the method of example
1, part e) using the product of example 10 ii), part b) and
methoxylamine.hydrochloride.
[0347] MS (APCI) 499 [M+H].sup.+.
[0348] .delta. .sup.1H.sub.CDCl3 0.92 (3H, s), 0.95 (3H, s),
2.04-2.26 (1H, m), 2.61 (3H, s), 3.46 (3H, s), 3.74 (2H, d), 3.9
(3H, s), 5.3 (2H, s), 7.12 (2H, t) and 7.17 (2H, t).
b)
1,2,3,4-Tetrahydro-N-methoxy-3-methyl-1-(2-methylpropyl)-6-[2-(methylth-
io)-1H-imidazol-1-ylmethyl]-2,4-dioxo-N-[2-[(tetrahydro-2H-pyran-2-yl)oxy]-
ethyl]-thieno[2,3-d]pyrimidine-5-carboxamide
[0349] The product of part a) (180 mg),
2-(2-bromoethoxy)tetrahydro-2H-pyran (0.28 g), potassium carbonate
(0.17 g), acetone (3 ml) and DMF (0.5 ml) were heated at 60.degree.
C. for 24 h. The reaction was quenched with water and then
extracted with ethyl acetate (.times.2). The combined organic
extracts were washed (brine), dried (MgSO.sub.4) and concentrated
in vacuo to afford the sub-title compound as an oil (130 mg).
[0350] MS (APCI) 566/494 [M+H].sup.+.
c)
1,2,3,4-Tetrahydro-N-(2-hydroxyethyl)-N-methoxy-3-methyl-1-(2-methylpro-
pyl)-6-[2-(methylthio)-1H-imidazol-1-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyri-
midine-5-carboxamide
[0351] The product of part b) was treated with p-toluenesulfonic
acid and methanol for 24 h. Water was added to the reaction mixture
and then extracted with dichloromethane (.times.3). The combined
organic extracts were dried (MgSO.sub.4) and concentrated in vacuo
to give a viscous oil. The oil was triturated with diethyl ether to
afford the title compound (15 mg).
[0352] MS (APCI) 482 [M+H].sup.+.
[0353] .delta. .sup.1H.sub.DMSO 0.85 (3H, s), 0.91 (3H, s),
2.06-2.2 (1H, m), 3.2 (3H, s), 3.27-3.32 (7H, m), 3.61-3.84 (4H,
m), 3.84-3.95 (1H, m), 4.82-4.9 (1H, m (br)), 5.2-5.3 (2H, m), 6.97
(1H, d) and 7.24 (1H, d).
EXAMPLE 10 vi)
1,2,3,4-Tetrahydro-6-[2-(methylamino)-1H-benzimidazol-1-ylmethyl]-N-methox-
y-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carb-
oxamide
a)
1,2,3,4-Tetrahydro-3-ethyl-6-[2-(methylamino)-1H-benzimidazol-1-ylmethy-
l]-1-(2-methylpropyl)-2,2-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic
Acid, Methyl Ester
[0354] Prepared by the method of example 1 part c) and
2-(methylamino)benzimidazole to give the title compound as a white
solid (0.85 g).
[0355] MS (APCI) 456 [M+H].sup.+.
[0356] .delta. .sup.1H.sub.DMSO 0.83-0.85 (6H, d), 2.05 (1H, m),
2.94-2.95 (3H, d), 3.19 (3H, s), 3.60-3.63 (2H, d), 3.84 (3H, s),
5.39 (2H, s), 6.83-6.87 (2H, m), 6.90-6.99 (1H, t), 7.08-7.11 (1H,
d), 7.20-7.22 (1H, d).
b)
1,2,3,4-Tetrahydro-3-methyl-6-[2-(methylamino)-1H-benzimidazol-1-ylmeth-
yl]-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic
Acid
[0357] Prepared by the method of example 1 part d) to give the
sub-title compound as a beige solid (0.54 g).
[0358] MS (APCI) 442 [M+H].sup.+.
c)
1,2,3,4-Tetrahydro-6-[2-(methylamino)-1H-benzimidazol-1-ylmethyl]-N-met-
hoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-c-
arboxamide
[0359] N,O-Dimethylhydroxylamine hydrochloride (0.09 g) and
triethylamine (0.12 ml) were added to a solution of the product of
step c) (0.2 g) in dichloromethane (5 ml). 1-Hydroxybenzotriazole
(0.12 g) was added as well as
1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide hydrochloride (0.17
g). The reaction mixture was stirred for 12 h at room temperature.
The solution was concentrated in vacuo. The residue was purified by
flash silica chromatography eluting with a gradient of 0-3%
methanol in dichloromethane. The product obtained was
recrystallised from dichloromethane/isohexane to give the title
compound as a white solid (0.024 g).
[0360] MS (ES.sup.+) 485.19657 [M+H].sup.+.
[0361] .delta. .sup.1H.sub.DMSO 0.82-0.86 (6H, m), 2-2.1 (1H, m),
2.93 (3H, d), 3 (1H, s), 3.2 (3H, s), 3.34 (2H, s), 3.43 (2H, s),
3.61-3.64 (2H, d), 3.82 (1H, s), 5.12-5.53 (2H, ABq), 6.83-6.99
(3H, m), 7.19-7.28 (2H, m).
EXAMPLE 10 vii)
1,2,3,4-Tetrahydro-N-methoxy
N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-6-[2-propyl-1H-benzimidazol-1-y-
lmethyl]-thieno[2,3-d]pyrimidine-5-carboxamide
a)
1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-6-[2-propyl-1H-
-benzimidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-5-carboxylic
Acid, Methyl Ester
[0362] Prepared using the procedure described in example 1 part c)
from the product of example 1 part b) and 2-n-propylbenzimidazole
to give the subtitle compound after purification by flash silica
chromatography eluting with isohexane:ethyl acetate (1:1).
[0363] MS (APCI) 469 [M+H].
[0364] .delta. .sup.1H.sub.DMSO 0.81-0.83 (6H, d), 0.94-0.99 (3H,
t), 1.72-1.82 (2H, sext), 2.01-2.08 (1H, m), 2.80-2.85 (2H, t),
3.19 (3H, s), 3.59-3.61 (2H, d), 3.78 (3H, s), 5.65 (2H,
s),7.15-7.23 (2H, m), 7.53-7.59 (2H, m).
b)
1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-6-[2-propyl-1H-
-benzimidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-5-carboxylic
Acid
[0365] Prepared using the procedure described in example 1 part d)
from the product of part a) to give the subtitle compound.
[0366] MS (APCI) 455 [M+H].
[0367] .delta. .sup.1H.sub.DMSO 0.78-0.85 (6H, d), 0.94-1 (3H, t),
1.74-1.86 (2H, sext), 2-2.07 (1H, m), 2.87-2.92 (2H, t), 3.25 (3H,
s), 3.58-3.6 (2H, d), 5.82 (2H, s), 7.21-7.27 (2H, m), 7.58-7.65
(2H, m).
c)
1,2,3,4-Tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl-2,4-dioxo-6-
-[2-propyl-1H-benzimidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-5-carboxami-
de
[0368] 1-Hydroxybenzotriazole (0.14 g) was added to a solution of
the product of step b) (0.25 g) in dichloromethane (5 ml). After
stirring for 5 minutes,
1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide hydrochloride (0.21
g) was added. After stirring for 10 minutes, N,
O-dimethylhydroxylamine hydrochloride (0.1 g) and triethylamine
(0.15 ml) were added The reaction mixture was stirred for 12 h at
room temperature. The solution was concentrated in vacuo. The
residue was purified by flash silica chromatography eluting with a
gradient of 0-3% methanol in dichloromethane to give the title
compound as a yellow solid (0.118 g).
[0369] MS (APCI) 498.2 [M+H].
[0370] .delta. .sup.1H.sub.DMSO 0.80-0.34 (6H, m), 0.95-1 (3H, t),
1.76-1.85 (2H, sext), 2-2.1 (1H, m), 2.84-2.93 (2H, t), 2.96 (1H,
s), 3.2 (3H, s), 3.27 (2H, s), 3.41 (2H, s), 3.62-3.64 (2H, d),
3.76 (1H, s), 5.41-5.68 (2H, m), 7.14-7.21 (2H, m), 7.55-7.66 (2H,
m).
EXAMPLE 10 viii)
1,2,3,4-Tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-6-[-
2,3-dihydro-3-methyl-2-oxo-1H-benzimidazol-1-ylmethyl]-thieno[-2,3-d]pyrim-
idine-5-carboxamide
a) Methyl
6-[2,3-dihydro-3-methyl-2-oxo-1H-benzimidazol-1-ylmethyl]-1,2,3,-
4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-
-5-carboxylate
[0371] The subtitle compound was prepared by the method of example
1 step c) using the product of example 1 step b) and
N-methylbenzimidazolone.
[0372] MS (APCI) 457 [M+H].sup.+.
[0373] .delta. .sup.1H.sub.DMSO 0.88 (6H, d), 2.13 (1H, non), 3.19
(3H, s), 3.27 (3H, s), 3.36 (3H, s), 3.67 (2H, d), 3.85 (2H, s),
6.95-7.20 (4H, m).
b)
6-[2,3-Dihydro-3-methyl-2-oxo-1H-benzimidazol-1-ylmethyl]-1,2,3,4-tetra-
hydro-3-methyl-1-(2-methylpropyl-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carbo-
xylic Acid
[0374] The subtitle compound was prepared by the method of example
1 step d).
using the product of step a).
[0375] MS (APCI) 443 [M+H].sup.+.
[0376] .delta. .sup.1H.sub.DMSO 0.85 (6H, d), 2.10 (1H, non), 3.25
(3H, s), 3.35 (3H, s), 3.67 (2H, d), 5.34 (2H, s), 6.95-7.21 (4H,
m), 10.80 (1H, s).
c)
6-[2,3-Dihydro-3-methyl-2-oxo-1H-benzimidazol-1-methyl]-1,2,3,4-tetrahy-
dro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrim-
idine-5-carboxamide
[0377] The title compound was prepared by the method of example 1
step e).
using the product of step b).
[0378] MS (ES.sup.+) 486 [M+H].sup.+.
[0379] .delta. .sup.1H.sub.DMSO (90.degree. C.) 0.88 (6H, d), 2.16
(1H, non), 3.00 (3H, s), 3.22 (3H, s), 3.35 (3H, s), 3.41 (3H, s),
3.67 (2H, d), 4.97 (1H, d), 5.18 (1H, d), 7.01-7.23 (4H, m).
EXAMPLE 10 ix)
6-[2,3-Dihydro-2-oxo-benzothiazol-3-ylmethyl]-1,2,3,4-tetrahydro-N-methoxy-
-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carbo-
xamide
a) Methyl
1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-6-[2,3--
dihydro-2-oxo-benzothiazol-3-ylmethyl]-thieno[2,3-d]pyrimidine-5-carboxyla-
te
[0380] The subtitle compound was prepared by the method of example
1 step c) using the product of example 1 step b) and
benzothiazolone.
[0381] MS (APCI) 460 [M+H].sup.+.
[0382] .delta. .sup.1H.sub.DMSO 0.88 (6H, d), 2.13 (1H, non), 3.19
(3H, s), 3.67 (2H, d), 3.84 (3H, s), 5.32 (2H, s), 7.23-7.70 (4H,
m).
b)
6-[2,3-Dihydro-2-oxo-benzothiazol-3-ylmethyl]-1,2,3,4-tetrahydro-3-meth-
yl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic
Acid
[0383] The subtitle compound was prepared by the method of example
1 step d).
using the product of step a).
[0384] MS (APCI) 468 [M+H].sup.+.
[0385] .delta. .sup.1H.sub.DMSO 0.86 (6H, d), 2.13 (1H, non), 3.19
(3H, s), 3.64 (2H, d), 5.20 (2H, s), 7.18 (1H, dt), 7.28 (1H, dt),
7.63 (1H, dt), 8.18 (1H, d).
c)
6-[2,3-Dihydro-2-oxo-benzothiazol-3-ylmethyl]-1,2,3,4-tetrahydro-N-meth-
oxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-ca-
rboxamide
[0386] The title compound was prepared by the method of example 1
step e).
using the product of step 1b).
[0387] MS (ES.sup.+) 489 [M+H].sup.+.
[0388] .delta. .sup.1H.sub.DMSO (90.degree. C.) 0.89 (6H, d), 2.16
(1H, non), 3.00 (3H, s), 3.09 (1H, d), 3.32 (1H, d), 3.21 (3H, s),
3.41 (3H, s), 3.67-3.70 (2H, m), 4.97 (1H, d), 5.18 (1H, d), 7.20
(1H, t), 7.33-7.43 (2H, m), 7.63 (1H, d).
EXAMPLE 11 i)
6-[(1-Acetyl-1H-indol-3-yl)methyl]-1,2,3,4-tetrahydro-N-methoxy-N,3-dimeth-
yl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxamide
a)
6-[(1-Acetyl-1H-indol-3-yl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(2-met-
hylpropyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic Acid
[0389] Acetic anhydride (134 .mu.l) was added to a solution of
example 5 part b), (0.45 g), 4-dimethylaminopyridine (catalytic
amount), and triethylamine (183 .mu.l), in dichloromethane (2 ml)
at ambient temperature with stirring under nitrogen. After stirring
for 48 h the mixture was concentrated in vacuo. The residue was
purified by column chromatography, eluting with ethyl
acetate/acetic acid (1%) to give the sub-title compound as a solid
(0.18 g).
[0390] MS (ES.sup.+) 454 [M+H].sup.+.
b)
6-[(1-Acetyl-1H-indol-3-yl)methyl]-1,2,3,4-tetrahydro-N-methoxy-N,3-dim-
ethyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxamide
[0391] Prepared by the method of example 1 part e) using the
product of step a). The crude material was purified by reverse
phase preparative HPLC (50-95% acetonitrile) to give the title
compound (23 mg).
[0392] MS (APCI) 497 [M+H].sup.+.
[0393] .delta. .sup.1H.sub.DMSO 0.90-0.92 (6H, m), 2.15-2.19 (1H,
m), 2.70 (3H, s), 3.05 (1H, s), 3.27 (3H, s), 3.52 (2H, s),
3.62-3.69 (3H, m), 3.83 (1H, s), 4.17-4.19 (3H, m), 7.28-7.42 (2H,
m), 7.68-7.75 (1H, m), 7.87-7.89 (1H, m), 8.36 (1H, d).
EXAMPLE 11 ii)
1,2,3,4-Tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-6-[2-methyl-1-
H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-ca-
rboxamide
a)
1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-[2-methyl-1H-pyrrolo[2-
,3,b]pyridin-3-ylmethyl]-2,4-dioxothieno[2,3,d]pyrimidine-5-carboxylic
Acid Methyl Ester
[0394] The sub-title compound (0.7 g) was prepared from the product
of example 1 part b) and 2-methyl-7-azaindole (0.68 g) by the
method of example 3, part a).
[0395] MS (ES.sup.+) 441 [M+H].sup.+.
b)
1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-[2-methyl-1H-pyrrolo[2-
,3,b]pyridin-3-ylmethyl]-2,4-dioxothieno[2,3,d]pyrimidine-5-carboxylic
Acid
[0396] The sub-title compound (0.66 g) was prepared from the
product of part a) (0.7 g) by the method of example 1, part b).
[0397] MS (ES.sup.+) 427 [M+H].sup.+.
c)
1,2,3,4-Tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-6-[2-methy-
l-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-
-carboxamide
[0398] The title compound was prepared from the product of example
step b), by the method of example 1, part d).
[0399] MS (APCI) 470 [M+H].sup.+.
[0400] .delta. .sup.1H.sub.DMSO 0.81-0.83 (6H, m), 2.07 (1H,
heptet), 2.39 (3H, s), 2.98 (1H, s), 3.2-3.21 (3H, m), 3.43 (2H,
s), 3.54-3.66 (3H, m), 3.78 (1H, m), 4.06-4.16 (2H, m), 6.95-6.98
(1H, m), 7.77-7.83 (1H, m), 8.08 (1H, d), 11.45 (1H, s).
EXAMPLE 12
1,2,3,4-Tetrahydro-N-methoxy-N,3-dimethyl-6-[2-methyl-1H-indol-3-ylmethyl]-
-1-(2-methylpropyl)-2,4-dioxothieno[-2,3-d]pyrimidine-5-carboxamide
##STR00016##
[0401] a) Methyl
1,2,3,4-tetrahydro-3-methyl-6-[2-methyl-1H-indol-3-ylmethyl]-1-(2-methylp-
ropyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate
[0402] A solution of methyl
1,2,3,4-tetrahydro-3,6-dimethyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d-
]pyrimidine-5-carboxylate [example 1 step a), 7.00 g) and
N-bromosuccinimide (4.42 g) in chloroform (140 ml) was refluxed
under illumination from a tungsten lamp for 2 hours. The solution
was cooled to room temperature, saturated aqueous sodium
bicarbonate solution (140 ml) and 2-methylindole (5.92 g) were
added and the mixture stirred rapidly for 48 hours. The phases were
separated and the aqueous phase extracted with dichloromethane (100
ml). Combined organic extracts were dried over anhydrous magnesium
sulfate, filtered and evaporated under reduced pressure. The
residue was purified by column chromatography over silica, eluting
with ethyl acetate/i-hexane (1:3) to give the sub-title compound as
a pale brown solid (6.68 g).
[0403] MS (ES.sup.+) 440 [M+H].sup.+.
[0404] NMR .delta. .sup.1H.sub.CDCl3 0.87 (6H, d), 2.11-2.21 (1H,
m), 2.42 (3H, s), 3.38 (3H, s), 3.61 (2H, d), 3.99 (3H, s), 4.22
(2H, s), 7.08 (1H, t), 7.15 (1H, t), 7.31 (1H, d), 7.46 (1H, d),
7.91 (1H, s, br).
b)
1,2,3,4-Tetrahydro-3-methyl-6-[2-methyl-1H-indol-3-ylmethyl]-1-(2-methy-
lpropyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic Acid
[0405] Sodium hydroxide solution (1M, 13.6 ml) and methanol (25 ml)
were added to a stirred solution of the product from step a) (4.00
g) in tetrahydrofuran (100 ml). After 28 hours, the solution was
concentrated under reduced pressure to 20 ml volume, diluted with
water (200 ml) and extracted with ether (2.times.100 ml). The
aqueous phase was acidified to pH 2 by addition of concentrated
hydrochloric acid and extracted with ethyl acetate/methanol (19:1,
2.times.200 ml). Organic extracts were dried over anhydrous
magnesium sulfate, filtered and evaporated under reduced pressure
to give the sub-title compound as a white solid (4.00 g).
[0406] MS (ES.sup.+) 426 [M+H].sup.+.
[0407] NMR .delta. .sup.1H.sub.DMSO 0.80 (6H, d), 1.99-2.09 (1H,
m), 2.37 (3H, s), 3.18 (3H, s), 3.59 (2H, d), 4.32 (2H, s), 6.91
(1H, t), 7.00 (1H, t), 7.26 (1H, d), 10.96 (1H, s), 14.05 (1H, s,
br).
c)
1,2,3,4-Tetrahydro-N-methoxy-N,3-dimethyl-6-[2-methyl-1H-indol-3-ylmeth-
yl]-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxamide
[0408] The title compound was prepared from the product of part b)
by the method of example 1, part e).
[0409] MS (APCI) 469 [M+H].sup.+.
[0410] .sup.1H NMR (DMSO) .delta. 0.81-0.83 (6H, m), 2.04-2.08 (1H,
m), 2.37 (3H, s), 2.99 (1H, s), 3.20 (3H, s), 3.25-3.40 (2H, m),
3.53-3.66 (2H, m), 3.79 (1H, m), 4.03-4.13 (2H, m), 6.91 (1H, t),
7.00 (1H, t),7.24 (1H, d),7.37-7.44 (1H, m).
EXAMPLE 13
6-[3-Chloroquinolin-4-ylmethyl]-1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl--
1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamide
a) 3-Chloro-4-quinolinecarboxaldehyde
[0411] A solution of selenium dioxide (1.90 g) in 1,4-dioxan (5 ml)
and water (1.2 ml) was added dropwise over 15 min to a stirred
solution of 3-chloro-4-methylquinoline (2.91 g) in 1,4-dioxan (10
ml) at 60-70.degree. C. The mixture was heated at reflux for 6 h,
allowed to warm to room temperature, then concentrated in vacuo.
The residue was purified by column chromatography (SiO.sub.2),
eluting with dichloromethane to 5% methanol in dichloromethane by a
stepwise gradient, to give the sub-title compound as a yellow solid
(1.19 g).
[0412] MS (ES.sup.+) 192/194 {M+H].sup.+.
[0413] .delta. .sup.1H.sub.CDCl3 7.73 (1H, ddd), 7.79 (1H, ddd),
8.15 (1H, dd), 8.89 (1H, dd), 8.98 (1H, s), 10.88 (1H, s).
b) Ethyl
6-[3-chloro-4-quinolinylhydroxymethyl]1,2,3,4-tetrahydro-3-methyl-
-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylate
[0414] The subtitle compound was prepared by the method of example
2, part b) using the product of part a) and example 2, part a)
[0415] MS (ES.sup.+) 502/504 {M+H].sup.+.
[0416] .delta. .sup.1H.sub.CDCl3 0.91 (3H, d), 1.22 (3H, t), 2.19
(1H, sex), 3.36 (3H, s), 3.60-3.73 (2H, m), 3.89 (1H, d), 4.03-4.27
(2H, m), 7.04 (1H, s), 7.37 (1H, t), 7.57 (1H, t), 8.14 (1H, d),
8.52 (1H, d), 8.56 (1H, d).
c) Ethyl
1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-6-(4-qui-
nolinylmethyl)-thieno[2,3-d]pyrimidine-5-carboxylate
[0417] Methanesulfonyl chloride (0.07 ml) was added to a solution
of the product of part b) (0.42 g) and triethylamine (0.23 ml) in
anhydrous THF (10 ml) at room temperature under nitrogen and the
mixture stirred for 30 min. 10% palladium on charcoal (30 mg) was
added and the mixture hydrogenated at 5 bar for 2 h. It was
filtered through celite washing with methanol (100 ml). The organic
material was concentrated in vacuo and the residue purified by
column chromatography (,SiO.sub.2), eluting with 1:1 ethyl
acetate/1-hexane, to give the sub-title compound as a solid (0.31
g).
[0418] MS (ES.sup.+) 486/488 {M+H].sup.+.
[0419] .delta. .sup.1H.sub.CDCl3 0.86 (6H, d), 1.47 (3H, t), 2.12
(1H, non), 3.38 (3H, s), 3.59 (2H, d), 4.53 (2H, q), 4.80 (2H, s),
7.63 (1H, ddd), 7.74 (1H, ddd), 8.12-8.17 (2H, m), 8.91 (1H,
s).
d) Sodium
6-[3-chloro-4-quinolinylmethyl]-1,2,3,4-tetrahydro-3-methyl-1-(2-
-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylate
[0420] The subtitle compound was prepared by the method of example
2, step d) using the product of step c).
[0421] MS (ES.sup.+) 458/460 {M+H].sup.+.
[0422] .delta. .sup.1H.sub.DMSO 0.77 (6H, d), 2.03 (1H, non), 3.18
(3H, s), 3.52 (2H, d), 4.70 (2H, s), 7.61 (1H, ddd), 7.76 (1H,
ddd), 8.02 (1H, d), 8.85 (1H, d), 8.95 (1H, s).
e)
6-[3-Chloro-4-quinolinylmethyl]-1,2,3,4-tetrahydro-N-methoxy-N,3-dimeth-
yl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxamide
[0423] The subtitle compound was prepared by the method of example
1 step e) using the product of step d).
[0424] MS (APCI) 501/503 {M+H].sup.+.
[0425] .delta. .sup.1H.sub.DMSO (130.degree. C.) 0.82 (6H, m), 2.09
(1H, non), 3.17 (3H, s), 3.22 (3H, s), 3.57 (3H, s), 3.59 (2H, d),
4.70 (2H, s), 7.66 (1H, t), 7.77 (1H, t), 8.07 (1H, d), 8.23 (1H,
d), 8.89 (1H, s).
EXAMPLE 14i)
N-Methoxy-N,3-dimethyl-2,4-dioxo-1-propyl-6-(quinolin-4-ylmethyl)-1,2,3,4--
tetrahydrothieno[2,3-d]pyrimidine-5-carboxamide
a) 6-Chloro-3-methyl-1-propylpyrimidine-2,4(1H, 3H)-dione
[0426] The sub-title compound was prepared by the method of 9, part
a) using 6-chloro-3-methyl uracil and propyl iodide.
[0427] .delta. .sup.1H.sub.CDCl3 0.98 (3H, t), 1.74 (2H, sextet),
3.33 (3H, s), 4.02 (2H, t), 8.02 (1H, s).
b) 6-Mercapto-3-methyl-1-propyl-pyrimidine-2,4(1H, 3H)-dione
[0428] The sub-title compound was prepared by the method of example
9, part b) using the product of step a).
[0429] .delta. .sup.1H.sub.CDCl3 0.97 (3,H, t), 1.72 (2H, m), 3.31
(3H, s), 4.29 (2H, s).
c) Ethyl
3-methyl-2,4-dioxo-1-propyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimi-
dine-5-carboxylate
[0430] The sub-title compound was prepared by the method of example
9, part c) using the product of step b).
[0431] .delta. .sup.1H.sub.CDCl3 1.02 (3H, t), 1.83 (2H, sextet),
3.42 (3H, s), 3.95 (2H, t), 4.41 (2H, q), 7.30 (1H, s).
[0432] MS (APCI+ve) 297.1 (M.sup.++H).
d) Ethyl
6-[hydroxy(quinolin-4-yl)methyl]-3-methyl-2,4-dioxo-1-propyl-1,2,-
3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate
[0433] The sub-title compound was prepared by the method of example
9, part d) using the product of step c).
[0434] .delta. .sup.1H.sub.CDCl3 0.89 (3H, t), 1.41 (3H, t), 1.65
(2H, sextet), 3.38 (3H, s), 3.75 (1H, d), 3.64 (1H, m), 3.80 (1H,
m), 4.48 (2H, q), 6.78 (1H, d), 7.52 (1H, m), 7.72 (1H, m) 7.84
(1H, m), 7.90 (1H, d), 8.16 (1H, m), 9.02 (1H, d).
e) Ethyl
3-methyl-2,4-dioxo-1-propyl-6-(quinolin-4-ylmethyl)-1,2,3,4-tetra-
hydrothieno[2,3-d]pyrimidine-5-carboxylate
[0435] The sub-title compound was prepared by the method of example
9, part e) using the product of step d).
[0436] MS (ESI) 437.9 (M.sup.++H).
f) Sodium
3-methyl-2,4-dioxo-1-propyl-6-(quinolin-4-ylmethyl)-1,2,3,4-tetr-
ahydrothieno[2,3-d]pyrimidine-5-carboxylate
[0437] The sub-title compound was prepared by the method of example
9, part f) using the product of step e).
[0438] .delta. .sup.1H.sub.DMSO 0.80 (3H, t), 1.57 (2H, sextet),
3.68 (2H, t), 4.55 (2H, s), 3.19 (3H, s), 7.53 (2H, d), 7.57 (1H,
m) 7.74 (1H, m), 8.01 (1H, d), 8.61 (1H, d), 8.83 (1H, d).
g)
N-Methoxy-N,3-dimethyl-2,4-dioxo-1-propyl-6-(quinolin-4-ylmethyl)-1,2,3-
,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxamide
[0439] The sub-title compound was prepared by the method of example
9, part g) using the product of step f).
[0440] .delta. .sup.1H.sub.DMSO 0.83 (3H, m), 1.61 (2H, q), 2.98
(1H, s), 3.21 (3H, d), 3.30 (2H, m), 3.43 (2H, s), 3.74 (3H, d),
4.60 (2H, s), 7.46 (1H, m), 7.63 (1H, m), 7.78 (1H, m) 8.05 (1H,
d), 8.27 (1H, m), 8.88 (1H, d).
[0441] MS (APCI) 453.1 (M.sup.++H).
EXAMPLE 14 ii)
1-Ethyl-N-methoxy-N,3-dimethyl-2,4-dioxo-6-(quinolin-4-ylethyl)-1,2,3,4-te-
trahydrothieno[2,3-d]pyrimidine-5-carboxamide
a) 6-Chloro-1-ethyl-3-methylpyrimidine-2,4(1H, 3H)-dione
[0442] The sub-title compound was prepared by the method of example
9, part a) using 6-chloro-3-methyl uracil and ethyl iodide.
[0443] .delta. .sup.1H.sub.CDCl3 1.32 (3H, d), 3.33 (3H, s), 4.15
(2H, q), 5.92 (1H, s).
b) 1-Ethyl-6-mercapto-3-methyl-pyrimidine-2,4(1H, 3H)-dione
[0444] The sub-title compound was prepared by the method of example
9, part b) using the product of step c).
[0445] .delta. .sup.1H.sub.CDCl3 1.26 (3H, t), 3.31 (3H, s), 4.15
(0.5H, s), 4.49 (2H, q), 5.57 (0.5H, s).
c) Ethyl
1-ethyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimid-
ine-5-carboxylate
[0446] The sub-title compound was prepared by the method of example
9, part c) using the product of step b).
[0447] MS (APCI) 283.1 (M.sup.++H).
d) Ethyl
1-ethyl-6-[hydroxy(quinolin-4-yl)methyl]-3-methyl-2,4-dioxo-1,2,3-
,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate
[0448] The sub-title compound was prepared by the method of example
9, part d) using the product of step c).
[0449] .delta. .sup.1H.sub.CDCl3 1.21 (3H, t), 1.43 (3H, t), 3.38
(3H, s), 3.53 (1H, d), 3.75 (2H, m), 4.50 (2H, q), 6.79 (1H, d),
7.53 (2H, m), 7.85 (2H, m), 7.89 (2H, d), 9.03 (1H, d).
e) Ethyl
1-ethyl-3-methyl-2,4-dioxo-6-(quinolin-4-ylmethyl)-1,2,3,4-tetrah-
ydrothieno[2,3-d]pyrimidine-5-carboxylate
[0450] The sub-title compound was prepared by the method of example
9, part e) using the product of step d).
[0451] MS (ESI) 424.0 (M.sup.++H).
f) Sodium
1-ethyl-3-methyl-2,4-dioxo-6-(quinolin-4-ylmethyl)-1,2,3,4-tetra-
hydrothieno[2,3-d]pyrimidine-5-carboxylate
[0452] The sub-title compound was prepared by the method of example
9, part f) using the product of step e).
[0453] MS (ESI) 396.0 (M.sup.++H).
g)
1-Ethyl-N-methoxy-N,3-dimethyl-2,4-dioxo-6-(quinolin-4-ylmethyl)-1,2,3,-
4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxamide
[0454] The sub-title compound was prepared by the method of example
9, part g) using the product of step f).
[0455] .delta. .sup.1H.sub.DMSO 1.15 (3H, t), 2.99 (1H, s), 3.21
(3H, d), 3.31 (2H, d), 3.44 (2H, s), 3.73 (1H, s), 3.81 (2H, q),
4.60 (2H, s), 7.47 (1H, m), 7.78 (1H, m), 8.05 (1H, d), 8.28 (1H,
m), 8.88 (1H, d).
[0456] MS (APCI) 453.1 (M.sup.++H).
EXAMPLE 14 iii)
1-(Cyclopropylmethyl)-N-methoxy-N,3-dimethyl-2,4-dioxo-6-(quinolin-4-yleth-
yl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxamide
a) 6-Chloro-1-(cyclopropylmethyl)-3-methylpyrimidine-2,4(1H,
3H)-dione
[0457] The sub-title compound was prepared by the method of example
9, part a) using 6-chloro-3-methyl uracil and cyclopropylmethyl
bromide.
[0458] .delta. .sup.1H.sub.CDCl3 0.48 (4H, m), 1.24 (1H, m), 3.33
(3H, s), 3.85 (1H, s), 5.93 (1H, s).
b) 1-(Cyclopropylmethyl-6-mercapto-3-methylpyrimidine-2,4(1H,
3H)-dione
[0459] The sub-title compound was prepared by the method of example
9, part c) using the product of step a).
[0460] .delta. .sup.1H.sub.CDCl3 0.47 (4H, m), 1.31 (1H, m), 3.33
(3H, s), 4.18 (0.5H, s), 4.36 (2H, d), 5.77 (1.5H, s).
c) Ethyl
1-(cyclopropylmethyl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno-
[2,3-d]pyrimidine-5-carboxylate
[0461] The sub-title compound was prepared by the method of example
9, part c) using the product of step b).
[0462] MS (APCI) 309.1 (M.sup.++H).
d) Ethyl
1-(cyclopropylmethyl)-6-[hydroxy(quinolin-4-yl)methyl]-3-methyl-2-
,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate
[0463] The sub-title compound was prepared by the method of example
9, part d) using the product of step c).
[0464] .delta. .sup.1H.sub.CDCl3 0.35 (2H, m), 0.49 (2H, m), 1.11
(1H, m), 1.41 (3H, t), 3.38 (3H, d), 3.60 (1H, m), 3.77 (1H, m),
3.80 (1H, d), 4.48 (2H, q), 6.79 (1H, d), 7.52 (1H, m), 7.71 (1H,
m), 7.83 (1H, m), 7.91 (1H, m), 8.16 (1H, m), 9.01 (1H, d).
e) Ethyl
1-(cyclopropylmethyl)-3-methyl-2,4-dioxo-6-(quinolin-4-ylmethyl)--
1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate
[0465] The sub-title compound was prepared by the method of example
9, part e) using the product of step d).
[0466] MS (ESI) 450.0 (M.sup.++H).
f) Sodium
1-(cyclopropylmethyl)-3-methyl-2,4-dioxo-6-(quinolin-4-ylmethyl)-
-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate
[0467] The sub-title compound was prepared by the method of example
9, part 0 using the product of step e).
[0468] MS (ESI) 422.1 (M.sup.++H).
g)
1-Ethyl-N-methoxy-N,3-dimethyl-2,4-dioxo-6-(quinolin-4-ylmethyl)-1,2,3,-
4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxamide
[0469] The sub-title compound was prepared by the method of example
9, part g) using the product of step f).
[0470] .delta. .sup.1H.sub.DMSO 1.15 (1H, m), 2.99 (1H, s), 3.22
(3H, d), 3.30 (2H, m), 3.45 (2H, s), 3.70 (3H, m), 4.60 (2H, s),
7.47 (1H, m), 7.64 (1H, t), 7.78 (1H, m) 8.05 (1H, d), 8.28 (1H,
m), 8.88 (1H, d).
[0471] MS (APCI) 465.1 (M.sup.++H).
EXAMPLE 15
6-[4,5-Dichloro-2-(hydroxymethyl)-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahyd-
ro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimi-
dine-5-carboxamide
##STR00017##
[0472] a) 4,5-Dichloro-1H-imidazole-2-methanol
[0473] Potassium hydroxide (0.12 g, 2.14 mmol) in water (4 ml) was
added to 4,5-dichloroimidazole, and the suspension was stirred for
35 min. Paraformaldehyde (0.11 g, 3.66 mmol) was added portionwise
and the reaction mixture was stirred over night, then acidified
with dilute HCl to pH 1 and then concentrated in vacuo to give a
white solid, 0.6 g (98%).
[0474] .delta. .sup.1H.sub.CDCl3 4.36 (2H, s).
b)
6-[4,5-Dichloro-2-(hydroxymethyl)-1H-imidazol-1-ylmethyl]-1,2,3,4-tetra-
hydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carb-
oxylic Acid Methyl Ester
[0475] Potassium carbonate (0.14 g, 3.1 mmol) and the product of
part a) (0.51 g, 3.09 mmol), were added to a solution of the
product of example 1 part b) in DMF, and the reaction mixture was
stirred for 16 h. The solid precipitate formed was filtered, and
the filtrate was concentrated in vacuo to give an orange solid 0.6
g, contains DMF.
[0476] .delta. .sup.1H.sub.CDCl3 0.99 (6H, m), 2.19-2.31 (1H, m),
3.4 (3H, s), 3.72 (2H, d), 4.0 (3H, s), 4.68 (2H, s), 5.45 (2H,
s).
c)
6-[4,5-Dichloro-2-(hydroxymethyl)-1H-imidazol-1-ylmethyl]-1,2,3,4-tetra-
hydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carb-
oxylic Acid
[0477] Prepared from the product of step b) following the procedure
of example 3, step d).
[0478] MS (ESI) 484 [M+H].sup.+.
d)
6-[4,5-Dichloro-2-(hydroxymethyl)-1H-imidazol-1-ylmethyl]-5-[[(4S)-4-hy-
droxyisoxazolidin-2-yl]carbonyl]-3-methyl-1-(2-methylpropyl)-thieno[2,3-d]-
pyrimidine 2,4(1H, 3H)-dione
[0479] Prepared form the product of step c) using the procedure of
example 1 part e). The product was purified by reverse phase
preparative HPLC eluting with ammonium acetate:acetonitrile (70:30)
to give the title compound as a white solid.
[0480] .delta. .sup.1H.sub.DMSO 0.91 (6H, m), 2.16-2.22 (1H, m),
3.2-3.6 (3H, br, s), 3.23 (3H, s), 3.68-3.73 (2H, m), 4.52 (2H, s),
5.373-5.39 (3H, m).
[0481] MS (APCI) 505 [M+H].sup.+.
EXAMPLE 16
1,2,3,4-Tetrahydro-N-methoxy-N,3-dimethyl-6-[2-methyl-1H-pyrrolo[2,3-b]pyr-
idin-3-ylmethyl]-2,4-dioxo-1-propyl-thieno[2,3-d]pyrimidine-5-carboxamide
##STR00018##
[0482] a) Methyl
3-methyl-6-[2-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]2,4-dioxo-1-prop-
yl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate
[0483] The subtitle compound was prepared from the product of
example 7 part c) and 2-methyl-1H-pyrrolo[2,3-d]pyridine using the
method of example 3 part a).
[0484] MS (ESI) 427 [M+H].sup.+.
[0485] .delta. .sup.1H.sub.D6-DMSO 0.82 (6H, t), 1.59 (2H, sextet),
2.38 (3H, s), 3.19 (3H, s), 3.72 (2H, t), 3.83 (3H, s), 4.17 (2H,
s), 6.98 (1H, dd), 7.75 (1H, d), 8.10 (1H, dd), 11.48 (1H, s).
b) Sodium
3-methyl-6-[2-methyl-1H-pyrrolo[2,3-d]pyridin-3-ylmethyl]-2,4-di-
oxo-1-propyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate
[0486] The subtitle compound was prepared from the product of step
a using the method of example 1 part d.
[0487] MS (ESI) 413 [M+H].sup.+
[0488] .delta. .sup.1H.sub.D2O 0.77 (3H, t), 1.55 (1H, sextet),
2.43 (3H, s), 3.34 (3H, s), 3.63 (2H, t), 4.16 (2H, s), 7.08 (1H,
dd), 7.89 (1H, d), 8.06 (1H, d).
c)
1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-6-[2-methyl-1H-pyrrolo[2,3-b]-
pyridin-3-ylmethyl]-2,4-dioxo-1-propyl-thieno[2,3-d]pyrimidine-5-carboxami-
de
[0489] The subtitle compound was prepared by the method of example
1 part e using the product of part b.
[0490] .delta. .sup.1H.sub.DMSO 0.77 (3H, t), 1.55 (1H, sextet),
2.43 (3H, s), 3.34 (3H, s), 3.63 (2H, t), 4.16 (2H, s), 7.08 (1H,
dd), 7.89 (1H, d), 8.06 (1H, d).
EXAMPLE 17
1,2,3,4-Tetrahydro-N-methoxy-N,3-dimethyl-1-(1-methylethyl)-6-[2-methyl-1H-
-pyrrolo[2,3-b]pyridin-3-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-car-
boxamide
##STR00019##
[0491] a)
1,2,3,4-Tetrahydro-3-methyl-1-(1-methylethyl)-6-[2-methyl-1H-pyr-
rolo[2,3-b]pyridin-3-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxy-
lic Acid Methyl Ester
[0492] Prepared from the product of example 6 part c) following the
procedure of example 3 part a) to give the sub-title compound as a
solid.
[0493] MS (ESI) 427 [M+H].sup.+.
[0494] .delta. .sup.1H.sub.DMSO 1.48 (6H, d), 2.49 (3H, s), 3.36
(3H, s), 3.99 (3H, s), 4.11 (2H, s), 4.20 (1H, s, br), 7.03-7.06
(1H, m) 7.79 (1H, d), 8.23 (1H, d), 9.10 (1H, s).
b)
1,2,3,4-Tetrahydro-3-methyl-1-(1-methylethyl)-6-[2-methyl-1H-pyrrolo[2,-
3-b]pyridin-3-ylmethyl]-2,4-dioxo-thieno[-2,3-d]pyrimidine-5-carboxylic
Acid
[0495] Prepared from the product of part a) following the procedure
of example 1 part d) to give the sub-title compound as a solid.
[0496] MS (ES) 413 [M+H].sup.+.
c)
1,2,3,4-Tetrahydro-N-methoxy-N,3-dimethyl-1-(1-methylethyl)-6-[2-methyl-
-1H-pyrrolo[-2,3-b]pyridin-3-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-
-carboxamide
[0497] The title compound was prepared from the product of part b)
following the procedure of example 1 part e).
[0498] MS (APCI) 456 [M+H].sup.+.
[0499] .delta. .sup.1H.sub.DMSO 1.38-1.42 (6H, m), 2.40 (3H, s),
3.00 (3H, s), 3.17-3.18 (3H, m), 3.30 (2H, s), 3.45 (2H, s), 3.79
(1H, s), 4.00-4.15 (2H, m), 4.30 (1H, S, br), 6.96-6.99 (1H, s),
7.80-7.86 (1H, m), 8.09-8.10 (1H, m), 11.46 (1H, s).
EXAMPLE 18
1,2,3,4-Tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-6-[-
-(trifluoromethyl)phenylmethyl]thieno[2,3-d]pyrimidine-5-carboxamide
##STR00020##
[0500] a)
1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-6-[2-(t-
rifluoromethyl)-phenylmethyl]thieno[2,3-d]pyrimidine-5-carboxylic
Acid
[0501] To a solution of
5-bromo-3-methyl-1-(2-methylpropyl)-6-[[2-(trifluoromethyl)phenyl]methyl]-
-thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione (WO 0183489) in THF (60
ml) was added isopropylmagnesiumchloride (2M solution in THF, 3.35
ml) dropwise at 0.degree. C. under nitrogen. After 5 min the
mixture was treated with a stream of carbon dioxide for 10 min. The
reaction mixture was quenched with water, acidified 2N HCl and
extracted into ethyl acetate (.times.3). The combined organic
extracts were washed with dilute HCl, brine, dried (MgSO.sub.4) and
concentrated in vacuo to give the subtitle compound as a yellow
solid (2.48 g).
[0502] MS (ESI) 427 [M+H].sup.+.
b)
1,2,3,4-Tetrahydro-N-methoxy-N-3-dimethyl-1-(2-methylpropyl)-2,4-dioxo--
6-[2-(trifluoromethyl)phenylmethyl]thieno[2,3-d]pyrimidine-5-carboxamide
[0503] The title compound was prepared from the product of part a)
following the procedure of example 1 part e).
[0504] MS (APCI) 456 [M+H].sup.+.
[0505] .delta. .sup.1H.sub.DMSO 0.86-0.88 (6H, m), 2.12 (1H,
heptet), 3.00 (1H, s), 3.21 (3H, s), 3.26 (2H, s), 3.43 (2H, s),
3.59-3.73 (3H, m), 4.22 (2H, s), 7.48-7.54 (2H, m), 7.64-7.70 (1H,
m), 7.75 (1H, d).
EXAMPLE 19
1,2,3,4-Tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-6-(-
benzyl)thieno[2,3-d]pyrimidine-5-carboxamide
##STR00021##
[0506] a)
1,2,3,4-Tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-
-dioxo-6-benzyl)thieno[2,3-d]pyrimidine-5-carboxamide
[0507] The title compound was prepared from
1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-6-(phenylmethyl)-
thieno[2,3-d]pyrimidine-5-carboxylic acid (WO 9854190) following
the procedure of example 1 part e).
[0508] MS (APCI) 456 [M+H].sup.+.
[0509] .delta. .sup.1H.sub.DMSO 0.87-0.90 (6H, m), 2.10-2.17 (1H,
m), 3.21 (1H, s), 3.21-3.22 (3H, m), 3.28-3.32 (2H, m), 3.39 (2H,
m), 3.59-3.76 (3H, m), 4.02-4.05 (2H, m), 7.23-7.35 (5H, m).
EXAMPLE 20(i)
Methyl
4-[1,2,3,4-tetrahydro-5-[(N-methoxy-N-methylamino)carbonyl]-3-methy-
l-1-(2-methylpropyl]-2,4-dioxothieno[2,3-d]pyrimidin-6-yl](hydroxy)methyl]-
-1-methyl-1H-pyrrole-2-carboxylate
##STR00022##
[0510] a) 1,2,3,4-Tetrahydro-N-methoxy-N
3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxa-
mide
[0511] Trimethyl aluminium (7.55 ml of 2M solution in toluene) was
added to N,O-dimethylhydroxylamine hydrochloride (1.415 g) in dry
toluene (60 ml) at 0.degree. C. under nitrogen. After stirring at
0.degree. C. for 1 h the temperature was raised to ambient and the
mixture was stirred for a further 1 h. The product of Example 2
part a) (1.5 g) was added in portions. After 2 h the reaction was
poured onto ice-cold 2M HCl and stirred whilst it warmed to ambient
temperature. The mixture was extracted into ethyl acetate, and the
combined extracts were washed with brine, dried and evaporated to
afford the subtitle compound (1.359 g).
[0512] MS (APCI) 326 [M+H].sup.+.
[0513] .delta. .sup.1H.sub.DMSO 0.93 (6H, d), 2.22 (1H, septet),
3.22 (5H, s), 3.31 (2H, s), 3.42 (2H, br s), 4.03 (2H, d), 7.35
(1H, s).
b) Methyl
4-[1,2,3,4-tetrahydro-5-[N-methoxy-N-methylaminocarbonyl]-3-meth-
yl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl](hydroxy)methyl-
]-1-methyl-1H-pyrrole-2-carboxylate
[0514] The product of part a) (240 mg) and methyl
4-formyl-1-methyl-1H-pyrrole-2-carboxylate (250 mg) in dry THF (40
ml) at -78.degree. C. were treated with lithium diisopropylamide
(0.74 ml of 2M) for 5 h. The reaction was poured into excess
saturated aqueous ammonium chloride solution and extracted into
ethyl acetate. The combined extracts were washed with brine, dried
and evaporated to afford a solid residue which was purified by
chromatography (SiO2/50-100% ethyl acetate in isohexane) to afford
the title compound (56 mg).
[0515] MS (APCI) 475 [M-OH].sup.+.
[0516] .delta. .sup.1H.sub.CDCl3 0.95-0.98 (6H, d), 2.29 (1H,
septet), 2.88 and 3.32 (1H, 2.times.d), 3.32-3.92 (17H, m),
5.30-6.01 (1H, m), 6.86-6.88 (1H, m), 6.91-6.95 (1H, m).
EXAMPLE 20 (ii)
Methyl
1-methyl-4-[1,2,3,4-tetrahydro-5-[(methoxymethylamino)carbonyl]-3-m-
ethyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-ylmethyl]-1H-py-
rrole-2-carboxylate
##STR00023##
[0517] a) Methyl
1-methyl-4-[1,2,3,4-tetrahydro-5-[(N-methoxy-N-methylamino)carbonyl]-3-me-
thyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-ylmethyl]-1H-pyr-
role-2-carboxylate Acid
[0518] The product of Example 20 (i) part b) (95 mg) was treated
with trifluoroacetic acid (3 ml) and triethylsilane (1.5 ml) at
room temperature for 5 h. Evaporation in vacuo gave a residue which
was purified by Reverse Phase HPLC (25%-95% acetonitrile-1% aqueous
ammonium acetate eluant) to afford the title compound (63 mg).
[0519] MS (APCI) 477 [M+H].sup.+.
[0520] .delta. .sup.1H.sub.CDCl3 0.96 (6H, d), 2.27 (1H, septet),
3.10 and 3.40 (3H, 2.times.s), 3.38 (3H, s), 3.49 and 3.97 (3H,
2.times.s), 3.55-3.60 (1H, m), 3.79 (3H, s), 3.88 (3H, s),
3.97-4.01 (3H, m), 6.72 (1H, s), 6.82-6.89 (1H, m).
EXAMPLE 21
Methyl
2,5-dimethyl-4-[1,2,3,4-tetrahydro-5-[(N-methoxy-N-methylamino)carb-
onyl]-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-ylmeth-
yl]-1H-pyrrole-3-carboxylate
##STR00024##
[0521] a) 3-Methyl
1-phenylmethyl4-formyl-2,5-dimethyl-1H-pyrrole-1,3-dicarboxylate
[0522] Methyl 2,5-dimethyl-4-formyl-pyrrole-3-carboxylate (500 mg)
in THF (5 ml) under nitrogen was added to a suspension of sodium
hydride (120 mg of 60% oil dispersion) in dry THF (10 ml). When
effervescence had ceased the suspension was cooled to 10.degree.
C., and benzyl chloroformate (0.437 ml) was added. After stirring
at room temperature for 4 h, ethanol (0.5 ml) was added and then
the reaction was poured into water. Extraction into ethyl acetate,
washing the extracts with brine, drying and evaporation gave the
crude product. Purification by chromatography (SiO2/30%-50% ethyl
acetate in isohexane) afforded the subtitle compound (0.6 g).
[0523] MS (APCI) 316 [M+H].sup.+.
[0524] .delta. .sup.1H.sub.CDCl3 2.60 (3H, s), 2.62 (3H, s), 3.86
(3H, s), 5.43 (2H, s), 7.26-7.45 (5H, m), 10.31 (1H, s).
b) 3-Methyl
1-(phenylmethyl)4-[1,2,3,4-tetrahydro-5-[N-methoxy-N-methylaminocarbonyl--
3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]hydroxy)m-
ethyl]-2,5-dimethyl-1H-pyrrole-1,3-dicarboxylate
[0525] The product of step a) (0.6 g) and the product of Example
20(i) step a) were reacted together using the method of Example 2
part b) to afford the subtitle compound after purification by
chromatography (SiO2/50%-100% ethyl acetate in isohexane) (195
mg).
[0526] MS (APCI) 623 [M-OH].sup.+.
c) 3-Methyl 1-(phenylmethyl)
2,5-dimethyl-4-[1,2,3,4-tetrahydro-5-[N-methoxy-N-methylamino)carbonyl]-3-
-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-ylmethyl]-1H--
pyrrole-1'-3-dicarboxylate
[0527] The product of step b) was converted to the subtitle
compound by the method of Example 20(ii) part a), aid purified by
chromatography (SiO2/50%-100% ethyl acetate in isohexane) (125
mg).
[0528] MS (APCI) 625 [M+H].sup.+.
[0529] .delta. .sup.1H.sub.CDCl3 0.93 (6H, d), 2.21 (1H, septet),
2.29 (3H, s), 2.67 (3H, s), 3.19 and 3.36 (3H, 2.times.s), 3.41
(3H, s), 3.47 and 3.95 (3H, 2.times.s), 3.58 (1H, dd), 3.79 (1H,
dd), 3.79 (3H, s), 4.09-4.19 (2H, m), 5.38 (2H, s), 7.38-7.42 (5H,
m).
d) Methyl
2,5-dimethyl-4-[[1,2,3,4-tetrahydro-5-[N-methoxy-N-methylaminoca-
rbonyl]-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]m-
ethyl]-1H-pyrrole-3-carboxylate
[0530] The product of step c) (189 mg) in dry ethanol (18 ml) was
treated with a slurry of 10% Pd/C (20 mg) in dry ethanol (2 ml) and
hydrogenated at 4 bar for 75 min. Filtration from catalyst and
evaporation gave a residue which was purified by chromatography in
two stages: firstly (SiO2/3:1 ethyl acetate-isohexane) and secondly
(SiO2/2:1 isohexane-acetone) to afford the title compound (85
mg).
[0531] MS (APCI) 491 [M+H].sup.+.
[0532] .delta. .sup.1H.sub.CDCl3 0.94 (6H, d), 2.15 and 2.17 (3H,
2.times.s), 2.24 (1H, septet), 2.48 (3H, s), 3.10 and 3.41 (3H,
2.times.s), 3.37 (3H, s), 3.51 and 3.96 (3H, 2.times.s), 3.58-3.63
(1H, m), 3.75-3.8 (1H, m), 3.77 (3H, s), 4.01-4.07 (1H, m),
4.18-4.29 (1H, m).
EXAMPLE 22
1,2,3,4-Tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-6-[-
2-oxo-3(2H)-benzoxazolylmethyl]-thieno[2,3-d]pyrimidine-5-carboxamide
##STR00025##
[0533] a)
1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-6-[2-ox-
o-3(2H)-benzoxazolyl)methyl]-thieno[2,3-d]pyrimidine-5-carboxylic
Acid, Methyl Ester
[0534] The subtitle compound was synthesised by the method of
example 1c) using the product of example 1 part b) and
benzoxazolone. The product was isolated by SiO2 chromatography
eluting with ethyl acetate/1-hexane (3:2), followed by
recrystallisation with diethyl ether to give the sub-title
compound.
[0535] MS (ESI) 444 [M+H].sup.+.
[0536] .delta. .sup.1H.sub.CDCl3 0.95 (6H, d), 2.25 (1H, septet),
3.39 (3H, d), 3.73 (2H, d), 4.04 (3H, s), 5.18 (2H, s), 7.18 (4H,
m).
b)
1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-6-[2-oxo-3(2H)-
-benzoxazolylmethyl]-thieno[2,3-d]pyrimidine-5-carboxylic Acid
[0537] Prepared by the method of example 1 part d) using the
product of part a)
[0538] MS (ESI) 430 [M+H].sup.+.
c)
1,2,3,4-tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo--
6-[2-oxo-3
(M2H)-benzoxazolylmethyl]-thieno[2,3-d]pyrimidine-5-carboxamide
[0539] Prepared by the method of example 1 part e) using the
product of part b).
[0540] MS (ESI) 473 [M+H].sup.+.
[0541] .delta. .sup.1H.sub.DMSO 0.91 (6H, d), 2.20 (1H, septet),
3.16 (3H, s), 3.23 (3H, s), 3.49 (3H, s), 3.71 (2H, d), 5.1 (2H,
s),7.15 (2H, m) and 7.27 (2H, d).
EXAMPLE 23
1,2,3,4-Tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo-6-[-
(2,4,5-trichloro-1H-imidazol-1-yl)methyl]-thieno[2,3-d]pyrimidine-5-carbox-
amide
##STR00026##
[0542] a) Methyl
1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-6-[(2,4,5-trichl-
oro-1H-imidazol-1-yl)methyl]-thieno[2,3-d]pyrimidine-5-carboxylate
[0543] The subtitle compound was made by the method of Example 1,
part c), using 2,4,5-trichloro-imidazole, and The product of
Example 1, part b). and purified by chromatography
(SiO.sub.2/20%-50% ethyl acetate-isohexane)
[0544] MS (APCI) 479/481/483 [M+H].sup.+.
[0545] .delta. .sup.1H.sub.CDCl3 0.97 (6H, d), 2.25 (1H, septet),
3.39 (3H, s), 3.74 (2H, d), 3.99 (3H, s), 5.37 (2H, s).
b)
1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl-2,4-dioxo-6-[2,4,5-trichl-
oro-1H-imidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-5-carboxylic
Acid
[0546] The product of part a) (170 mg) was treated with lithium
hydroxide monohydrate (31 mg) in water (0.75 ml), methanol (0.75
ml) and THF (2.25 ml) for 4 h at room temperature. The reaction was
acidified with glacial acetic acid and evaporated to dryness. The
residue was dissolved in water and extracted into dichloromethane.
Drying and evaporation gave the subtitle compound (110 mg).
[0547] MS (APCI) 465/467/469 [M+H].sup.+.
c)
1,2,3,4-Tetrahydro-N-methoxy-N,3-dimethyl-1-(2-methylpropyl)-2,4-dioxo--
6-[(2,4,5-trichloro-1H-imidazol-1-yl)methyl]-thieno[2,3-d]pyrimidine-5-car-
boxamide
[0548] The title compound was prepared by the method of Example 1,
part e, using the product of step b) above and purified by
chromatography (SiO.sub.2/50%-66% ethyl acetate-isohexane).
[0549] MS (APCI) 508/510/512 [M+H].sup.+.
[0550] .delta. .sup.1H.sub.CDCl3 0.98 (6H, d), 2.28 (1H, septet),
3.39 (3H, s), 3.43 (3H, s), 3.46 (3H, s), 3.64 (1H, dd), 3.86 (1H,
dd), 5.18 (1H, d), 5.37 (1H, d).
EXAMPLE 24i)
6-[4,5-Dichloro-2-methyl-1H-imidazol-1-ylmethyl]-N-(2-hydroxyethyl)-1-isob-
utyl-N-methoxy-3-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-
e-5-carboxamide
##STR00027##
[0551] a)
6-[4,5-Dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1-isobutyl-N-me-
thoxy-3-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carbo-
xamide
[0552] Prepared from the product of example 1 part d) and
methoxylamine hydrochloride following the procedure of example 1
part e).
[0553] .delta. .sup.1H.sub.CDCl3 0.87 (6H, d), 2.21 (1H, n), 2.37
(3H, s), 3.47 (3H, s), 3.75 (2H, d), 3.91 (3H, s), 5.80 (2H, s),
13.45 (1H, s).
b)
6-[4,5-Dichloro-2-methyl-1H-imidazol-1-ylmethyl]-N-(2-hydroxyethyl)-1-i-
sobutyl-N-methoxy-3-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimi-
dine-5-carboxamide
[0554] Potassium carbonate (72 mg) and 2-iodoethanol (0.072 ml)
were added to a solution of the product of part a) (72 mg) in
acetone (3 ml). The mixture was stirred at reflux for 10 h, cooled
to room temperature then diluted with water (10 ml) and extracted
with ethyl acetate (2.times.10 ml). Organic extracts were dried
over anhydrous magnesium sulfate, filtered and evaporated under
reduced pressure. The residue was purified by normal-phase HPLC
with gradient dichloromethane/ethanol elution to give the title
compound (43 mg) as a foam.
[0555] MS (APCI) 516/518/520 [M-H].sup.-.
[0556] .delta. .sup.1H.sub.CDCl3 0.87 0.98 (6H, d), 2.27 (1H, n),
2.43 (3H, s), 3.40 (3H, s), 3.41 (3H, s), 3.58 (1H, dt), 3.67 (1H,
(id), 3.83 (1H, dd), 3.94-3.99 (2H, m), 4.03-4.07 (1H, m), 4.36
(1H, dt), 5.25 (2H, ABq).
EXAMPLE 24ii)
6-[4,5-Dichloro-2-methyl-1H-imidazol-1-ylmethyl]-N-(2-hydroxyethoxy)-1-iso-
butyl-N,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-c-
arboxamide
##STR00028##
[0557] a)
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-N-hydroxy-1-iso-
butyl-N,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-c-
arboxamide
[0558] Oxalyl chloride (0.162 ml) was added to a stirred solution
of the product of example 1 part d) (415 mg) and dimethylformamide
(0.01 ml) in dichloromethane (4 ml). After 1 h the solution was
evaporated under reduced pressure. The residue was dissolved in
anhydrous tetrahydrofuran (3 ml) and 1 ml of the solution was added
to a stirred solution of N-methylhydroxylamine hydrochloride (129
mg) in saturated aqueous sodium bicarbonate solution (2 ml). After
1 h, the mixture was diluted with water (10 ml) and extracted with
ethyl acetate (3.times.10 ml). Organic extracts were dried over
anhydrous magnesium sulfate, filtered and evaporated under reduced
pressure to give the sub-title compound (129 mg).
[0559] MS (ESI) 474/476/478 [M+H].sup.+.
[0560] .delta. .sup.1H.sub.DMSO 0.88-0.93 (6H, m), 2.10-2.20 (1H,
m), 2.32 (2.25H, s), 2.36 (0.75H, s), 2.98 (0.75H, s), 3.22 (3H,
s), 3.26 (0.75H, s), 3.63-3.78 (1H, m), 5.22 (1.5H, s), 5.26 (0.5H,
s), 9.80 (0.75H, s), 10.00 (0.25H, s).
b)
6-[4,5-Dichloro-2-methyl-1H-imidazol-1-ylmethyl]-N-(2-hydroxyethoxy)-1--
isobutyl-N,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine--
5-carboxamide
[0561] Potassium carbonate (125 mg) and 2-iodoethanol (0.125 ml)
were added to a solution of the product of part a) (125 mg) in
acetone (5 ml). The mixture was stirred for 16 h, diluted with
water (10 ml) and extracted with ethyl acetate (3.times.10 ml).
Organic extracts were dried over anhydrous magnesium sulfate,
filtered and evaporated under reduced pressure. The residue was
purified by reverse-phase HPLC with gradient 0.1% aqueous ammonium
acetate/acetonitrile elution and the resulting oil triturated with
ether to give the title compound (75 mg) as a solid.
[0562] MS (APCI) 517/519/521 [M+H].sup.+.
[0563] .delta. .sup.1H.sub.DMSO 0.89-0.91 (6H, m), 2.10-2.21 (1H,
m), 2.33 (2H, s), 2.36 (1H, s), 3.02 (1H, s), 3.21 (2H, s), 3.22
(1H, s), 3.27 (1H, s), 3.20-3.34 (1.33H, m), 3.57-3.78 (4H, m),
4.03-4.13 (0.67H, m), 4.50 (0.67H, t), 4.79 (0.33H, t), 5.20-5.32
(2H, m).
EXAMPLE 24iii)
6-[4,5-Dichloro-2-methyl-1H-imidazol-1-ylmethyl]-N-ethyl-1,2,3,4-tetrahydr-
o-N-methoxy-3-methyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine--
5-carboxamide
##STR00029##
[0564] a)
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahy-
dro-N-methoxy-3-methyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidin-
e-5-carboxamide
[0565] Prepared by the method of example 1 part e) using
methoxylaminehydrochloride and the product of example 1 part d. The
subtitle compound was obtained as a white solid after SiO.sub.2
chromatography eluting with (1-5% methanol in DCM).
[0566] .delta. .sup.1H.sub.CDCl3 0.5 (6H, d), 2.21 (1H, m), 2.37
(3H, s), 3.47 (3H, s), 3.75 (2H, d), 3.91 (3H, s), 5.8 (2H, s) and
13.45 (1H, s).
b)
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-N-ethyl-1,2,3,4-tetrah-
ydro-N-methoxy-3-methyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidi-
ne-5-carboxamide
[0567] The product of part a) (100 mg) was added to a stirred
solution of NaH (60% dispersion in mineral oil, 8.4 mg) in THF (5
ml) and the reaction mixture was stirred under nitrogen for 30 min.
Ethyl iodide (0.2 ml) was added and the reaction mixture was heated
at reflux for 16 h. The reaction mixture was quenched with ethanol
and concentrated in vacuo. The reaction mixture was dissolved in
water and extracted with ethyl acetate. The organics were washed
with brine and concentrated in vacuo. The title compound was
obtained as a white solid after SiO.sub.2 chromatography eluting
with (20% ethanol in DCM).
[0568] MS (ESI) 503 [M+H].sup.+.
[0569] .delta. .sup.1H.sub.CDCl3 0.98 (6H, d), 1.39 (3H, t), 2.26
(1H, m), 2.4 (3H, s), 3.39 (3H, s), 3.49 (3H, s), 3.63 (1H, m),
3.82 (2H, m), 3.99 (1H, m) and 5.17 (2H, m).
* * * * *