U.S. patent application number 12/111792 was filed with the patent office on 2008-08-28 for thienopyrimidinediones and their use in the modulation of autoimmune disease.
Invention is credited to Martin Edward Cooper, Simon David Guile, Anthony Howard Ingall, Rukhsana Tasneem Rasul, Rachel Heulwen Reynolds.
Application Number | 20080207642 12/111792 |
Document ID | / |
Family ID | 9919407 |
Filed Date | 2008-08-28 |
United States Patent
Application |
20080207642 |
Kind Code |
A1 |
Reynolds; Rachel Heulwen ;
et al. |
August 28, 2008 |
Thienopyrimidinediones and Their Use in the Modulation of
Autoimmune Disease
Abstract
The invention relates to a compound of formula (1): ##STR00001##
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 is optionally substituted by
1 to 3 halogen atoms; R.sup.3 is isoxazolidin-2-ylcarbonyl or
tetrahydroisoxazin-2-ylcarbonyl wherein each ring is optionally
substituted by one hydroxy group; 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 hydroxy group; and
Ar is a 5- to 10-membered aromatic ring system in which up to 4
ring atoms may be heteroatoms independently selected from the group
consisting of 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) ; Rasul; Rukhsana Tasneem;
(Loughborough, GB) ; Guile; Simon David;
(Loughborough, GB) ; Cooper; Martin Edward;
(Loughborough, GB) |
Correspondence
Address: |
FISH & RICHARDSON P.C.
P.O BOX 1022
MINNEAPOLIS
MN
55440-1022
US
|
Family ID: |
9919407 |
Appl. No.: |
12/111792 |
Filed: |
April 29, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10483162 |
Jul 21, 2004 |
7384950 |
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PCT/GB02/03399 |
Jul 24, 2002 |
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12111792 |
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Current U.S.
Class: |
514/255.05 ;
514/260.1 |
Current CPC
Class: |
A61P 25/00 20180101;
A61P 19/02 20180101; A61P 37/02 20180101; A61P 3/10 20180101; A61P
11/00 20180101; A61P 37/08 20180101; A61P 11/06 20180101; A61P
43/00 20180101; A61P 13/12 20180101; A61P 35/00 20180101; A61P
37/06 20180101; A61P 37/00 20180101; A61P 29/00 20180101; A61P 9/10
20180101; A61P 31/18 20180101; A61P 1/00 20180101; A61P 21/00
20180101; A61P 27/16 20180101; C07D 495/04 20130101; A61P 21/04
20180101; A61P 17/00 20180101; A61P 17/08 20180101 |
Class at
Publication: |
514/255.05 ;
514/260.1 |
International
Class: |
A61K 31/497 20060101
A61K031/497; A61K 31/519 20060101 A61K031/519; A61P 37/00 20060101
A61P037/00; A61P 11/00 20060101 A61P011/00; A61P 35/00 20060101
A61P035/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 28, 2001 |
GB |
0118479.5 |
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): ##STR00091## 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
isoxazolidin-2-ylcarbonyl or tetrahydroisoxazin-2-ylcarbonyl, in
which each ring is optionally substituted by one hydroxy group; 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
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, the ring system being optionally substituted by one or
more substitutes 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).sub.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;
and R.sup.8 and R.sup.9 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; 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 Ar contains at least 1 ring
nitrogen.
6. The method of claim 1, wherein Ar contains at least 2 ring
nitrogens.
7. 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.
8. 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.2-4alkanoyl, oxo, thioxo, cyano and
--(CH.sub.2).sub.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.
9. The method of claim 1, wherein the compound is:
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6--
(4-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (R)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(4-q-
uinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S)
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazoli-
dinylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3-
H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(4-q-
uinolinylcarbonyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-indol-3-y-
l)methyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(1H-
-pyrrolo[2,3-b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-ind-
ol-3-yl)carbonyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dio-
ne; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(1-methylethyl)--
6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)--
dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propyl-6-(1H--
pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
6-[4,5-dichloro-2-oxo-3(2H)-thiazolylmethyl]-5-[4-hydroxyisoxazolidin-
-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione; (S)
6-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-5-{4-hydroxyisoxazolidin-2-ylcar-
bonyl}-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-1-isobutyl-3-methyl-6-[1,3,5-trime-
thyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(R)
6-[(4,5-dichloro-2-methyl-1H-imidazol-1-yl)methyl]-5-[4-hydroxy-isoxazoli-
din-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1-
H,3H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-benzimida-
zol-1-yl)methyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e; (S)
6-[(2-ethyl-1H-benzimidazol-1-yl)methyl]-5-[4-hydroxyisoxazolidin-2-
-ylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2--
propyl-1H-benzimidazol-1-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)--
6-[2-(methylthio)-1H-benzimidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4
(1H,3H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benzimidaz-
ol-1-ylmethyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3-
H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-1H-ben-
zimidazol-1-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-amino-1H-benzimidazo-
l-1-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(2-methylpropyl)-6--
[2,4,5-trichloro-1H-imidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-t-
hioxo-3(2H)-benzothiazolylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6--
[4-chloro-2-oxo-3(2H)-thiazolylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)--
dione; (S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylprop-
yl)-6-[2-oxo-1,3-benzoxazol-3(2H)-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione; (S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[(2--
oxo[1,3]thiazolo[5,4-b]pyridin-1-(2H)-yl)methyl]thieno[2,3-d]pyrimidine-2,-
4(1H,3H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(1H--
1,2,3-benzotriazol-1-ylmethyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6--
(1H-pyrrolo[2,3-h]pyridin-1-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-di-
one; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl-
)-6-2-methyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl]thieno[2,3-d]pyrimidine-2-
,4(1H,3H)-dione; (S)
1-[1,2,3,4-tetrahydro-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(-
2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-ylmethyl-1H-indole-5-car-
bonitrile; (S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[2-o-
xo-1,3-benzothiazol-3(2H)-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e; (R)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-methyl-1H-indo-
l-3-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[7-methyl-1H-indol--
3-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-3H-
-imidazo[4,5-b]pyridin-3-ylmethyl]-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H-
,3H)-dione; (S)
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazoli-
dinylcarbonyl]-3-methyl-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-1H-
-benzimidazol-1-ylmethyl]-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione; (S)
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazoli-
dinylcarbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-5-carboxa-
mide; (S)
6-[3,5-d]ethyl-1H-pyrazol-4-ylmethyl]-5-{4-hydroxyisoxazolidin-2-
-ylcarbonyl}-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione; (S)
6-[3-(1,1-dimethylethyl)-5-methyl-1H-pyrazol-4-ylmethyl]-5-{4-hydroxyisox-
azolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine--
2,4(1H,3H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-m-
ethyl-4-quinolinylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
6-[6-fluoro-4-quinolinylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3--
methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
6-[8-fluoro-4-quinolinylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3--
methyl-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-(5-q-
uinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-propyl-6-(quinolin-4-yl-
methyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(1-methylethyl)-6-(4-qu-
inolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2--
methyl-1H-pyrrolo[2,3b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione; (R)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2--
methyl-1H-pyrrolo[2,3b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl-
)-6-[2,3-dihydro-6-methyl-3-oxo-pyrazin-2-ylmethyl]-thieno[2,3-d]pyrimidin-
e-2,4(1H,3H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl)-1H-pyrrolo[-
2,3-b]pyridin-3-ylmethyl]-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-ben-
zimidazol-1-ylmethyl]-3-methyl-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propyl-6-[2-
-amino-1H-benzimidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benz-
imidazol-1-yl
methyl]-3-methyl-1-(isopropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-am-
ino-1H-benzimidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-me-
thyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H-
)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-methyl-
-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-di-
one; (S)-6-[4,5-dichloro-2-(hydroxymethyl)-1H-imidazol-1-yl
methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thie-
no[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[3,5-dimethyl-1H-pyrazol-1-yl
methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thie-
no[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[4-hydroxyisoxazol-
idin-2-yl
carbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3-
H)-dione; (S)
6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-yl
carbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbo-
nyl]-1-isopropyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[3,5-dimethylisoxazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarb-
onyl]-1-(isobutyl)-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1-ethyl-5-[(4S)-4-hydrox-
y-2-isoxazolidinylcarbonyl]-3-methyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-di-
one;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-(1H-py-
rrolo[2,3-b]pyridin-3-ylmethyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-propyl--
1H-benzimidazol-1-yl
methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-oxo-3(2-
H)-benzothiazolylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-methyl--
1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dio-
ne;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[5-cyan-
o-1H-indol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-6-[1-isopropyl-3-
,5-dimethyl-1H-pyrazol-4-ylmethyl]-3-methylthieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-meth-
yl-6-[5-methyl-3-phenyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(-
1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-methyl-6-[5-meth-
yl-3-(trifluoromethyl)-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1-
H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-6-[3-isopropyl-5-m-
ethyl-1H-pyrazol-4-ylmethyl]-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-di-
one;
6-[3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-5-[(4S)-4-hydroxyisox-
azolidin-2-ylcarbonyl]-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3-
H)-dione;
6-[3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-5-[(4S)-4-hydrox-
yisoxazolidin-2-ylcarbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1-
H,3H)-dione;
6-(1H-1,2,3-benzotriazol-1-ylmethyl)-5-[(4S)-4-hydroxyisoxazolidinylcarbo-
nyl]-3-methyl-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4H)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isopropyl)-6-[(2-oxo-
thiazolo[5,4-b]pyridin-1(2H)-yl)methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione;
6-[2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[(S)-4-hydroxyi-
soxazolidinylcarbonyl]-3-methyl-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(-
1H,3H)-dione,
6-[5,6-difluoro-2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[(4S)-4-h-
ydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimi-
dine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-6-(imidazo[1,2-a]pyridin-3-yl-
methyl)-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
3-methyl-6-[2-methylindol-3-ylmethyl]-1-(isobutyl)-5-(tetrahydroisoxazin--
2-ylcarbonyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[2-bromo-4,5-dichloro-1H-imidazol-1-ylmethyl]-5-[(4S)-4-hydroxyisoxazol-
idinylcarbonyl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-di-
one;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[-
2-(methylthio)-1H-imidazo[4,5-b]pyridin-1-ylmethyl]-thieno[2,3-d]pyrimidin-
e-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(meth-
ylthio)-3H-imidazo[4,5-b]pyridin-3-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1-
H,3H)-dione;
6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-3-ethyl-5-[(4S)-4-hydroxy-2-isoxaz-
olidinylcarbonyl]-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(t-
rifluoromethyl)phenylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(m-
ethylthio)-1H-imidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e; or (S)
5-[4-hydroxylisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-
-[2-methyl-1H-pyrrolo[2,3-b]pyridine-3-ylmethyl]thieno[2,3-d]pyrimidine-2,-
4(1H,3H)-dione; or a pharmaceutically acceptable salt thereof.
10. A method of effecting immunosuppression, comprising
administering to a patient a therapeutically effective amount of a
compound of formula (1) ##STR00092## 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
isoxazolidin-2-ylcarbonyl or tetrahydroisoxazin-2-ylcarbonyl, in
which each ring is optionally substituted by one hydroxy group; 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
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, the ring system being optionally substituted by one or
more substitutes 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).sub.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.1-4alkyl, 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.
11. The method of claim 10, wherein R.sup.2 is methyl or ethyl.
12. The method of claim 10, 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.
13. The method of claim 10, wherein Q is --CO-- or
--CH.sub.2--.
14. The method of claim 10, wherein Ar contains at least 1 ring
nitrogen.
15. The method of claim 10, wherein Ar contains at least 2 ring
nitrogens.
16. The method of claim 10, 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.
17. The method of claim 10, 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.2-4alkanoyl, oxo, thioxo, cyano and
--(CH.sub.2).sub.pN(R)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.
18. The method of claim 10, wherein the compound is:
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6--
(4-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (R)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(4-q-
uinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S)
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazoli-
dinylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3-
H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(4-q-
uinolinylcarbonyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-indol-3-y-
l)methyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(1H-
-pyrrolo[2,3-b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-ind-
ol-3-yl)carbonyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dio-
ne; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(1-methylethyl)--
6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)--
dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propyl-6-(1H--
pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
6-[4,5-dichloro-2-oxo-3(2H)-thiazolylmethyl]-5-[4-hydroxyisoxazolidin-
-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione; (S)
6-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-5-{4-hydroxyisoxazolidin-2-ylcar-
bonyl}-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-1-isobutyl-3-methyl-6-[1,3,5-trime-
thyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(R)
6-[(4,5-dichloro-2-methyl-1H-imidazol-1-yl)methyl]-5-[4-hydroxy-isoxazoli-
din-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1-
H,3H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-benzimida-
zol-1-yl)methyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e; (S)
6-[(2-ethyl-1H-benzimidazol-1-yl)methyl]-5-[4-hydroxyisoxazolidin-2-
-ylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2--
propyl-1H-benzimidazol-1-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)--
6-[2-(methylthio)-1H-benzimidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4
(1H,3H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benzimidaz-
ol-1-ylmethyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3-
H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-1H-ben-
zimidazol-1-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-amino-1H-benzimidazo-
l-1-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(2-methylpropyl)-6--
[2,4,5-trichloro-1H-imidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-t-
hioxo-3(2H)-benzothiazolylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6--
[4-chloro-2-oxo-3(2H)-thiazolylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)--
dione; (S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylprop-
yl)-6-[2-oxo-1,3-benzoxazol-3(2H)-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione; (S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[(2--
oxo[1,3]thiazolo[5,4-b]pyridin-1-(2H)-yl)methyl]thieno[2,3-d]pyrimidine-2,-
4(1H,3H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(1H--
1,2,3-benzotriazol-1-ylmethyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6--
(1H-pyrrolo[2,3-b]pyridin-1-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-di-
one; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl-
)-6-2-methyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl]thieno[2,3-d]pyrimidine-2-
,4(1H,3H)-dione; (S)
1-[1,2,3,4-tetrahydro-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(-
2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-ylmethyl-1H-indole-5-car-
bonitrile; (S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[2-o-
xo-1,3-benzothiazol-3(2H)-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e; (R)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-methyl-1H-indo-
l-3-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[7-methyl-1H-indol--
3-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-3H-
-imidazo[4,5-b]pyridin-3-ylmethyl]-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H-
,3H)-dione; (S)
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazoli-
dinylcarbonyl]-3-methyl-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-1H-
-benzimidazol-1-ylmethyl]-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione; (S)
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazoli-
dinylcarbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-5-carboxa-
mide; (S)
6-[3,5-d]ethyl-1H-pyrazol-4-ylmethyl]-5-{4-hydroxyisoxazolidin-2-
-ylcarbonyl}-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione; (S)
6-[3-(1,1-dimethylethyl)-5-methyl-1H-pyrazol-4-ylmethyl]-5-{4-hydroxyisox-
azolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine--
2,4(1H,3H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-m-
ethyl-4-quinolinylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
6-[6-fluoro-4-quinolinylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3--
methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
6-[8-fluoro-4-quinolinylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3--
methyl-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-(5-q-
uinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-propyl-6-(quinolin-4-yl-
methyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(1-methylethyl)-6-(4-qu-
inolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2--
methyl-1H-pyrrolo[2,3b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione; (R)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2--
methyl-1H-pyrrolo[2,3b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl-
)-6-[2,3-dihydro-6-methyl-3-oxo-pyrazin-2-ylmethyl]-thieno[2,3-d]pyrimidin-
e-2,4(1H,3H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl)-1H-pyrrolo[-
2,3-b]pyridin-3-ylmethyl]-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-ben-
zimidazol-1-ylmethyl]-3-methyl-1-propyl-thieno[2,3-d]pyridine-2,4(1H,3H)-d-
ione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propyl-6-[2-a-
mino-1H-benzimidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benzim-
idazol-1-yl
methyl]-3-methyl-1-(isopropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-am-
ino-1H-benzimidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-me-
thyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H-
)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-methyl-
-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-di-
one; (S)-6-[4,5-dichloro-2-(hydroxymethyl)-1H-imidazol-1-yl
methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thie-
no[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[3,5-dimethyl-1H-pyrazol-1-yl
methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thie-
no[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[4-hydroxyisoxazol-
idin-2-yl
carbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3-
H)-dione; (S)
6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-yl
carbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbo-
nyl]-1-isopropyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[3,5-dimethylisoxazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarb-
onyl]-1-(isobutyl)-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-t1-ethyl-5-[(4S)-4-hydro-
xy-2-isoxazolidinylcarbonyl]-3-methyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-d-
ione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-(1H-p-
yrrolo[2,3-b]pyridin-3-ylmethyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-propyl--
1H-benzimidazol-1-yl
methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-oxo-3(2H-
)-benzothiazolylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-methyl--
1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dio-
ne;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[5-cyan-
o-1H-indol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-6-[1-isopropyl-3-
,5-dimethyl-1H-pyrazol-4-ylmethyl]-3-methylthieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-meth-
yl-6-[5-methyl-3-phenyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(-
1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-methyl-6-[5-meth-
yl-3-(trifluoromethyl)-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1-
H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-6-[3-isopropyl-5-m-
ethyl-1H-pyrazol-4-ylmethyl]-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-di-
one;
6-[3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-5-[(4S)-4-hydroxyisox-
azolidin-2-ylcarbonyl]-[1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione;
6-[3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-5-[(4S)-4-hydro-
xyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(-
1H,3H)-dione;
6-(1H-1,2,3-benzotriazol-1-ylmethyl)-5-[(4S)-4-hydroxyisoxazolidinylcarbo-
nyl]-3-methyl-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4H)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isopropyl)-6-[(2-oxo-
thiazolo[5,4-b]pyridin-1(2H)-yl)methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione;
6-[2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[(S)-4-hydroxyi-
soxazolidinylcarbonyl]-3-methyl-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(-
1H,3H)-dione;
6-[5,6-difluoro-2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[(4S)-4-h-
ydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimi-
dine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-6-(imidazo[1,2-a]pyridin-3-yl-
methyl)-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
3-methyl-6-[2-methylindol-3-ylmethyl]-1-(isobutyl)-5-(tetrahydroisoxazin--
2-ylcarbonyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[2-bromo-4,5-dichloro-1H-imidazol-1-ylmethyl]-5-[(4S)-4-hydroxyisoxazol-
idinylcarbonyl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-di-
one;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[-
2-(methylthio)-1H-imidazo[4,5-b]pyridin-1-ylmethyl]-thieno[2,3-d]pyrimidin-
e-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(meth-
ylthio)-3H-imidazo[4,5-b]pyridin-3-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1-
H,3H)-dione;
6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-3-ethyl-5-[(4S)-4-hydroxy-2-isoxaz-
olidinylcarbonyl]-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(t-
rifluoromethyl)phenylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(m-
ethylthio)-1H-imidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e; or (S)
5-[4-hydroxylisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-
-[2-methyl-1H-pyrrolo[2,3-b]pyridine-3-ylmethyl]thieno[2,3-d]pyrimidine-2,-
4(1H,3H)-dione; or a pharmaceutically acceptable salt thereof.
19. A method of treating a reversible obstructive airways disease
in a patient suffering from the disease, comprising administering
to the patient a therapeutically effective amount of a compound of
formula (1) ##STR00093## 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
isoxazolidin-2-ylcarbonyl or tetrahydroisoxazin-2-ylcarbonyl, in
which each ring is optionally substituted by one hydroxy group; 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
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, the ring system being optionally substituted by one or
more substitutes 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).sub.pN(R.sup.8)R.sup.9,
hydroxy, C.sub.1-4alkylsulphonyl, C.sub.1-4-alkylsulphinyl,
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.1-4alkyl, 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.
20. The method of claim 19, wherein the obstructive airways disease
is chronic obstructive pulmonary disease (COPD).
21. The method of claim 19, wherein R.sup.2 is methyl or ethyl.
22. The method of claim 19, 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.
23. The method of claim 19, wherein Q is --CO-- or
--CH.sub.2--.
24. The method of claim 19, wherein Ar contains at least 1 ring
nitrogen.
25. The method of claim 19, wherein Ar contains at least 2 ring
nitrogens.
26. The method of claim 19, 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.
27. The method of claim 19, 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.2-4alkanoyl, oxo, thioxo, cyano and
--(CH.sub.2).sub.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.
28. The method of claim 19, wherein the compound is:
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6--
(4-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (R)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(4-q-
uinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S)
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazoli-
dinylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3-
H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(4-q-
uinolinylcarbonyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-indol-3-y-
l)methyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(1H-
-pyrrolo[2,3-b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-ind-
ol-3-yl)carbonyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dio-
ne; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(1-methylethyl)--
6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)--
dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propyl-6-(1H--
pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
6-[4,5-dichloro-2-oxo-3(2H)-thiazolylmethyl]-5-[4-hydroxyisoxazolidin-
-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione; (S)
6-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-5-{4-hydroxyisoxazolidin-2-ylcar-
bonyl}-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-1-isobutyl-3-methyl-6-[1,3,5-trime-
thyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(R)
6-[(4,5-dichloro-2-methyl-1H-imidazol-1-yl)methyl]-5-[4-hydroxy-isoxazoli-
din-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1-
H,3H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-benzimida-
zol-1-yl)methyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e; (S)
6-[(2-ethyl-1H-benzimidazol-1-yl)methyl]-5-[4-hydroxyisoxazolidin-2-
-ylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2--
propyl-1H-benzimidazol-1-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)--
6-[2-(methylthio)-1H-benzimidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4
(1H,3H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benzimidaz-
ol-1
ylmethyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3-
H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-1H-ben-
zimidazol-1-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-amino-1H-benzimidazo-
l-1-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(2-methylpropyl)-6--
[2,4,5-trichloro-1H-imidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-t-
hioxo-3(2H)-benzothiazolylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6--
[4-chloro-2-oxo-3(2H)-thiazolylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)--
dione; (S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylprop-
yl)-6-[2-oxo-1,3-benzoxazol-3(2H)-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione; (S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[(2--
oxo[1,3]thiazolo[5,4-b]pyridin-1-(2H)-yl)methyl]thieno[2,3-d]pyrimidine-2,-
4(1H,3H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(1H--
1,2,3-benzotriazol-1-ylmethyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6--
(1H-pyrrolo[2,3-b]pyridin-1-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-di-
one; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl-
)-6-2-methyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl]thieno[2,3-d]pyrimidine-2-
,4(1H,3H)-dione; (S)
1-[1,2,3,4-tetrahydro-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(-
2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-ylmethyl-1H-indole-5-car-
bonitrile; (S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[2-o-
xo-1,3-benzothiazol-3(2H)-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e; (R)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-methyl-1H-indo-
l-3-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[7-methyl-1H-indol--
3-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-3H-
-imidazo[4,5-b]pyridin-3-ylmethyl]-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H-
,3H)-dione; (S)
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazoli-
dinylcarbonyl]-3-methyl-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-1H-
-benzimidazol-1-ylmethyl]-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione; (S)
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazoli-
dinylcarbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-5-carboxa-
mide; (S)
6-[3,5-d]ethyl-1H-pyrazol-4-ylmethyl]-5-1{4-hydroxyisoxazolidin--
2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H-
)-dione-(S)
6-[3-(1,1-dimethylethyl)-5-methyl-1H-pyrazol-4-ylmethyl]-5-{4-hydroxyisox-
azolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine--
2,4(1H,3H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-m-
ethyl-4-quinolinylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
6-[6-fluoro-4-quinolinylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3--
methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
6-[8-fluoro-4-quinolinylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3--
methyl-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-(5-q-
uinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-propyl-6-(quinolin-4-yl-
methyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(1-methylethyl)-6-(4-qu-
inolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2--
methyl-1H-pyrrolo[2,3b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione; (R)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2--
methyl-1H-pyrrolo[2,3b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl-
)-6-[2,3-dihydro-6-methyl-3-oxo-pyrazin-2-ylmethyl]-thieno[2,3-d]pyrimidin-
e-2,4(1H,3H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl)-1H-pyrrolo[-
2,3-b]pyridin-3-ylmethyl]-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-ben-
zimidazol-1-ylmethyl]-3-methyl-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propyl-6-[2-
-amino-1H-benzimidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benz-
imidazol-1-yl
methyl]-3-methyl-1-(isopropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-am-
ino-1H-benzimidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-me-
thyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H-
)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-methyl-
-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-di-
one; (S)-6-[4,5-dichloro-2-(hydroxymethyl)-1H-imidazol-1-yl
methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thie-
no[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[3,5-dimethyl-1H-pyrazol-1-yl
methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thie-
no[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[4-hydroxyisoxazol-
idin-2-yl
carbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3-
H)-dione; (S)
6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-yl
carbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbo-
nyl]-1-isopropyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[3,5-dimethylisoxazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarb-
onyl]-1-(isobutyl)-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1-ethyl-5-[(4S)-4-hydrox-
y-2-isoxazolidinylcarbonyl]-3-methyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-di-
one;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-(1H-py-
rrolo[2,3-b]pyridin-3-ylmethyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-propyl--
1H-benzimidazol-1-yl
methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-oxo-3(2-
H)-benzothiazolylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-methyl--
1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dio-
ne;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[5-cyan-
o-1H-indol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-6-[1-isopropyl-3-
,5-dimethyl-1H-pyrazol-4-ylmethyl]-3-methylthieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-meth-
yl-6-[5-methyl-3-phenyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(-
1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-methyl-6-[5-meth-
yl-3-(trifluoromethyl)-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1-
H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-6-[3-isopropyl-5-m-
ethyl-1H-pyrazol-4-ylmethyl]-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-di-
one;
6-[3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-5-[(4S)-4-hydroxyisox-
azolidin-2-ylcarbonyl]-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3-
H)-dione;
6-[3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-5-[(4S)-4-hydrox-
yisoxazolidin-2-ylcarbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1-
H,3H)-dione;
6-(1H-1,2,3-benzotriazol-1-ylmethyl)-5-[(4S)-4-hydroxyisoxazolidinylcarbo-
nyl]-3-methyl-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4H)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isopropyl)-6-[(2-oxo-
thiazolo[5,4-b]pyridin-1(2H)-yl)methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione;
6-[2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[(S)-4-hydroxyi-
soxazolidinylcarbonyl]-3-methyl-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(-
1H,3H)-dione;
6-[5,6-difluoro-2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[(4S)-4-h-
ydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimi-
dine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-6-(imidazo[1,2-a]pyridin-3-yl-
methyl)-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
3-methyl-6-[2-methylindol-3-ylmethyl]-1-(isobutyl)-5-(tetrahydroisoxazin--
2-ylcarbonyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[2-bromo-4,5-dichloro-1H-imidazol-1-ylmethyl]-5-[(4S)-4-hydroxyisoxazol-
idinylcarbonyl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-di-
one;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[-
2-(methylthio)-1H-imidazo[4,5-b]pyridin-1-ylmethyl]-thieno[2,3-d]pyrimidin-
e-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(meth-
ylthio)-3H-imidazo[4,5-b]pyridin-3-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1-
H,3H)-dione;
6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-3-ethyl-5-[(4S)-4-hydroxy-2-isoxaz-
olidinylcarbonyl]-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(t-
rifluoromethyl)phenylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(m-
ethylthio)-1H-imidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e; or (S)
5-[4-hydroxylisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-
-[2-methyl-1H-pyrrolo[2,3-b]pyridine-3-ylmethyl]thieno[2,3-d]pyrimidine-2,-
4(1H,3H)-dione; or a pharmaceutically acceptable salt thereof.
29. A method of treating cancer in a patient suffering from the
cancer, comprising administering to a patient a therapeutically
effective amount of a compound of formula (1) ##STR00094## 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 isoxazolidin-2-ylcarbonyl or
tetrahydroisoxazin-2-ylcarbonyl, in which each ring is optionally
substituted by one hydroxy group; 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 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, the ring system
being optionally substituted by one or more substitutes
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).sub.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.1-4alkyl, 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.
30. The method of claim 29, wherein R.sup.2 is methyl or ethyl.
31. The method of claim 29, 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.
32. The method of claim 29, wherein Q is --CO-- or
--CH.sub.2--.
33. The method of claim 29, wherein Ar contains at least 1 ring
nitrogen.
34. The method of claim 29, wherein Ar contains at least 2 ring
nitrogens.
35. The method of claim 29, 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.
36. The method of claim 29, 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.2-4alkanoyl, oxo, thioxo, cyano and
--(CH.sub.2).sub.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 or 6 membered aromatic
ring containing up to 4 heteroatoms independently selected from the
group consisting of nitrogen, oxygen, and sulphur.
37. The method of claim 29, wherein the compound is:
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6--
(4-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (R)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(4-q-
uinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S)
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazoli-
dinylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3-
H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(4-q-
uinolinylcarbonyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-indol-3-y-
l)methyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(1H-
-pyrrolo[2,3-b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-ind-
ol-3-yl)carbonyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dio-
ne; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(1-methylethyl)--
6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)--
dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propyl-6-(1H--
pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
6-[4,5-dichloro-2-oxo-3(2H)-thiazolylmethyl]-5-[4-hydroxyisoxazolidin-
-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione; (S)
6-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-5-{4-hydroxyisoxazolidin-2-ylcar-
bonyl}-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-1-isobutyl-3-methyl-6-[1,3,5-trime-
thyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(R)
6-[(4,5-dichloro-2-methyl-1H-imidazol-1-yl)methyl]-5-[4-hydroxy-isoxazoli-
din-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1-
H,3H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-benzimida-
zol-1-yl)methyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e; (S)
6-[(2-ethyl-1H-benzimidazol-1-yl)methyl]-5-[4-hydroxyisoxazolidin-2-
-ylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2--
propyl-1H-benzimidazol-1-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)--
6-[2-(methylthio)-1H-benzimidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4
(1H,3H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benzimidaz-
ol-1-ylmethyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3-
H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-1H-ben-
zimidazol-1-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-amino-1H-benzimidazo-
l-1-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(2-methylpropyl)-6--
[2,4,5-trichloro-1H-imidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-t-
hioxo-3(2H)-benzothiazolylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6--
[4-chloro-2-oxo-3(2H)-thiazolylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)--
dione; (S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylprop-
yl)-6-[2-oxo-1,3-benzoxazol-3(2H)-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione; (S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[(2--
oxo[1,3]thiazolo[5,4-b]pyridin-1-(2H)-yl)methyl]thieno[2,3-d]pyrimidine-2,-
4(1H,3H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(1H--
1,2,3-benzotriazol-1-ylmethyl)-thieno[2,3-d]pyri
idine-2,4(1H,3H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6--
(1H-pyrrolo[2,3-b]pyridin-1-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-di-
one; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl-
)-6-2-methyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl]thieno[2,3-d]pyrimidine-2-
,4(1H,3H)-dione; (S)
1-[1,2,3,4-tetrahydro-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(-
2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-ylmethyl-1H-indole-5-car-
bonitrile; (S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[2-o-
xo-1,3-benzothiazol-3(2H)-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e; (R)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-methyl-1H-indo-
l-3-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[7-methyl-1H-indol--
3-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-3H-
-imidazo[4,5-b]pyridin-3-ylmethyl]-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H-
,3H)-dione; (S)
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazoli-
dinylcarbonyl]-3-methyl-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-1H-
-benzimidazol-1-ylmethyl]-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione; (S)
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazoli-
dinylcarbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-5-carboxa-
mide; (S)
6-[3,5-d]ethyl-1H-pyrazol-4-ylmethyl]-5-{4-hydroxyisoxazolidin-2-
-ylcarbonyl}-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione; (S)
6-[3-(1,1-dimethylethyl)-5-methyl-1H-pyrazol-4-ylmethyl]-5-{4-hydroxyisox-
azolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine--
2,4(1H,3H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-m-
ethyl-4-quinolinylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
6-[6-fluoro-4-quinolinylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3--
methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
6-[8-fluoro-4-quinolinylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3--
methyl-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-(5-q-
uinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-propyl-6-(quinolin-4-yl-
methyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(1-methylethyl)-6-(4-qu-
inolinylmethyl)thieno[2,3-d]pyridine-2,4(1H,3H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2--
methyl-1H-pyrrolo[2,3b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione; (R)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2--
methyl-1H-pyrrolo[2,3b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl-
)-6-[2,3-dihydro-6-methyl-3-oxo-pyrazin-2-ylmethyl]-thieno[2,3-d]pyrimidin-
e-2,4(1H,3H)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl)-1H-pyrrolo[-
2,3-b]pyridin-3-ylmethyl]-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-ben-
zimidazol-1-ylmethyl]-3-methyl-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propyl-6-[2-
-amino-1H-benzimidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benz-
imidazol-1-yl
methyl]-3-methyl-1-(isopropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-am-
ino-1H-benzimidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-me-
thyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H-
)-dione; (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-methyl-
-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-di-
one; (S)-6-[4,5-dichloro-2-(hydroxymethyl)-1H-imidazol-1-yl
methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thie-
no[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[3,5-dimethyl-1H-pyrazol-1-yl
methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thie-
no[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[4-hydroxyisoxazol-
idin-2-yl
carbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3-
H)-dione; (S)
6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-yl
carbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)
6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbo-
nyl]-1-isopropyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
(S)-6-[3,5-dimethyhsoxazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbo-
nyl]-1-(isobutyl)-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1-ethyl-5-[(4S)-4-hydrox-
y-2-isoxazohdinylcarbonyl]-3-methyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dio-
ne;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-(1H-pyr-
rolo[2,3-b]pyridin-3-ylmethyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H-dione-1-e-
thyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-propyl-1H-b-
enzimidazol-1-yl methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-oxo-3(2H-
)-benzothiazolylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-methyl--
1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dio-
ne;
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[5-cyan-
o-1H-indol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-6-[1-isopropyl-3-
,5-dimethyl-1H-pyrazol-4-ylmethyl]-3-methylthieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-meth-
yl-6-[5-methyl-3-phenyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(-
1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-methyl-6-[5-meth-
yl-3-(trifluoromethyl)-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1-
H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-6-[3-isopropyl-5-m-
ethyl-1H-pyrazol-4-ylmethyl]-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-di-
one;
6-[3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-5-[(4S)-4-hydroxyisox-
azolidin-2-ylcarbonyl]-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3-
H)-dione;
6-[3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-5-[(4S)-4-hydrox-
yisoxazolidin-2-ylcarbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1-
H,3H)-dione;
6-(1H-1,2,3-benzotriazol-1-ylmethyl)-5-[(4S)-4-hydroxyisoxazolidinylcarbo-
nyl]-3-methyl-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4H)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isopropyl)-6-[(2-oxo-
thiazolo[5,4-b]pyridin-1(2H)-yl)methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione;
6-[2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[(S)-4-hydroxyi-
soxazolidinylcarbonyl]-3-methyl-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(-
1H,3H)-dione;
6-[5,6-difluoro-2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[(4S)-4-h-
ydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimi-
dine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-6-(imidazo[1,2-a]pyridin-3-yl-
methyl)-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
3-methyl-6-[2-methylindol-3-ylmethyl]-1-(isobutyl)-5-(tetrahydroisoxazin--
2-ylcarbonyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
6-[2-bromo-4,5-dichloro-1H-imidazol-1-ylmethyl]-5-[(4S)-4-hydroxyisoxazol-
idinylcarbonyl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-di-
one;
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[-
2-(methylthio)-1H-imidazo[4,5-b]pyridin-1-ylmethyl]-thieno[2,3-d]pyrimidin-
e-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(meth-
ylthio)-3H-imidazo[4,5-b]pyridin-3-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1-
H,3H)-dione;
6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-3-ethyl-5-[(4S)-4-hydroxy-2-isoxaz-
olidinylcarbonyl]-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(t-
rifluoromethyl)phenylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(m-
ethylthio)-1H-imidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e; or (S)
5-[4-hydroxylisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-
-[2-methyl-1H-pyrrolo[2,3-b]pyridine-3-ylmethyl]thieno[2,3-d]pyrimidine-2,-
4(1H,3H)-dione; or a pharmaceutically acceptable salt thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 10/483,162, filed Jan. 8, 2004, which is the national phase
application under 35 U.S.C. .sctn. 371 of PCT International
Application No. PCT/GB02/03399 having an International filing date
of Jul. 24, 2002, which in turn claims priority to United Kingdom
Application Serial No. 0118479.5, filed Jul. 28, 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, eg 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
incorporate an amidic --C--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 is optionally substituted by
1 to 3 halogen atoms; R.sup.3 is isoxazolidin-2-ylcarbonyl or
tetrahydroisoxazin-2-ylcarbonyl wherein each ring is optionally
substituted by one hydroxy group; 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 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 the group
consisting of nitrogen, oxygen, and sulphur, the ring system being
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).sub.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.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.1-4alkyl, 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, 7, 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 (I) 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 or a ring nitrogen providing this does not lead to
quaternization.
[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.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, benznimidazolyl, 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, 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 in which 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 1-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] More particularly, Ar is selected from imidazolyl, quinolyl,
indolyl, benzimidazolyl, indazolyl, pyrazolyl, benztriazolyl,
2,3-dihydrothiazolyl, 2,3-dihydrobenzoxazolyl,
pyrrolo[2,3-b]pyridyl, thiazolo[5,4-b]pyridyl,
2,3-dihydrobenzothiazolyl and 2,3-dihydrobenzimidazolyl.
[0032] In yet another aspect, Ar is selected from imidazolyl,
pyrazolyl, pyrrolyl, isoxazolyl, phenyl and
2,3-dihydropyrazinyl.
[0033] 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.
[0034] In another aspect, when the substituent on Ar is a 5 or 6
membered aromatic ring, this substituent on Ar contains up to 2
heteroatoms 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.
[0035] 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 1,4diazepano. In another aspect, the ring is
selected from pyrrolidino, piperidino or morpholino.
[0036] 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 1,4diazepano. In another aspect, the ring is
selected from pyrrolidino, piperidino or morpholino.
[0037] R.sup.1 and R.sup.2 each independently represent
C.sub.1-6alkyl, such as 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, such as
C.sub.3-4alkenyl (e.g. 1-propenyl, 1-butenyl, 1-pentenyl or
1-hexenyl), C.sub.3-6cycloalkylC.sub.1-3alkyl(cyclopropylmethyl,
cyclobutylmethyl, cyclopentylmethyl, 2-(cyclopropyl)ethyl,
2-(cyclobutyl)ethyl or 2-(cyclopentyl)ethyl) or
C.sub.3-6cycloalkyl, such as 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).
[0038] 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.
[0039] 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.
[0040] In yet another aspect, R.sup.1 is ethyl, n-propyl, isopropyl
or 2-methylpropyl.
[0041] In yet another aspect, R.sup.1 is 2-methylpropyl.
[0042] In one aspect, R.sup.2 is methyl or trifluoromethyl.
[0043] In yet another aspect, R.sup.2 is methyl.
[0044] In yet another aspect, R.sup.3 is
hydroxyisoxazolidin-2-ylcarbonyl, tetrahydroisoxazin-2-yl or
hydroxytetrahydroisoxazin-2-ylcarbonyl.
[0045] In yet another aspect, R.sup.3 is
hydroxyisoxazolidin-2-ylcarbonyl or
hydroxytetrahydroisoxazin-2-ylcarbonyl.
[0046] In yet another aspect, R.sup.3 is hydroxyisoxazolidin-2-yl
carbonyl.
[0047] In yet another aspect, R.sup.3 is
4-hydroxyisoxazolidin-2-yl.
[0048] In yet another aspect, R.sup.3 is
4S-hydroxyisoxazolidin-2-yl.
[0049] In another aspect, R.sup.4 and R.sup.5 are independently
hydrogen or methyl.
[0050] In another aspect, Q is --CO-- or --CH.sub.2--.
[0051] In one aspect, Q is --CO--.
[0052] In another aspect, Q is --CH.sub.2--.
[0053] In another aspect, Ar is unsubstituted or substituted by 1,
2 or 3 substituents.
[0054] In yet another aspect, Ar is unsubstituted or substituted by
1 or 2 substituents.
[0055] 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.2-4alkanoyl, oxo, thioxo, cyano and
--(CH.sub.2).sub.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.
[0056] In a particular aspect, substituents for Ar are selected
from C.sub.1-4alkyl, halogen, C.sub.2-4alkanoyl, trifluoromethyl,
oxo, thioxo, hydroxyC.sub.1-4alkyl, amino, C.sub.1-4alkylamino and
C.sub.1-4alkylthio.
[0057] In yet another aspect, substituents for Ar include methyl,
ethyl, n-propyl, iso-propyl, tert-butyl, 1-methylethyl,
trifluoromethyl, chloro, fluoro, bromo, hydroxymethyl, acetyl,
methylthio, amino, methylamino, furanyl, thienyl, pyridyl, phenyl,
cyano, thioxo and oxo.
[0058] In yet another aspect, substituents for Ar include methyl,
propyl, isopropyl, tert-butyl, 1-methylethyl, trifluoromethyl,
chloro, fluoro, bromo, methylthio, ammo, methylamino, phenyl,
pyrimidyl, cyano, thioxo and oxo.
[0059] Yet further particular substituents for Ar are selected from
methyl, ethyl, propyl, tert-butyl, 1-methylethyl, chloro, fluoro,
bromo, hydroxymethyl, acetyl, methylthio, amino, methylamino,
thioxo and oxo.
[0060] Yet further particular substituents for Ar are selected from
methyl, ethyl, propyl, tert-butyl, fluoro, chloro, oxo, thioxo,
hydroxymethyl, amino, methylamino and methylthio.
[0061] Yet further particular substituents for Ar are selected from
methyl, propyl, tert-butyl, 1-methylethyl, chloro, fluoro,
methylthio, amino, methylamino, thioxo and oxo.
[0062] Particular values for Ar include
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-trifluorophenyl,
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,
2-methylindol-3-yl, 7-methylindol-3-yl, 5-cyanoindol-1-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, 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,
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.
[0063] Further particular values for Ar include
4,5-dichloro-2-methylimidazol-1-yl,
2,4,5-trichloro-2-methylimidazol-1-yl, 4,5-dichloroimidazol-2-yl,
3,5-dimethylpyrazol-4-yl, 1,3,5-trimethylpyrazol-4-yl,
3,5-dimethylpyrazol-4-yl, 3-tert-butyl-5-methylpyrazol-4-yl,
5-dichloro-2,3-dihydro-2-oxothiazol-3-yl,
4-chloro-2,3-dihydro-2-oxothiazol-3-yl, quinol-4-yl, quinol-5-yl,
6-fluoroquinol-4-yl, 8-fluoroquinol-4-yl, 2-methylquinol-4-yl,
2-methylindol-3-yl, 7-methylindol-3-yl, 5-cyanoindol-1-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, pyrrolo[2,3-b]pyridin-3-yl,
2-methylpyrrolo[2,3-b]pyridin-1-yl,
2-methylpyrrolo[2,3-b]pyridin-3-yl, 1H-1,2,3-benzotriazol-1-yl,
2-oxo-2,3-dihydrobenzothiazol-3-yl,
2-thioxo-2,3-dihydrobenzothiazol-3-yl,
2-oxo-2,3-dihydrobenzoxazol-1-yl,
6-methyl-3-oxo-2,3-dihydropyrazin-2-yl and
2-oxo-1,3-thiazolo[5,4-b]pyridin-3-yl.
[0064] In one aspect, R.sup.6 and R.sup.7 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.
[0065] In yet another aspect, R.sup.6 and R.sup.1 each
independently represent a hydrogen atom or C.sub.1-4alkyl.
[0066] In one aspect, 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.
[0067] In yet another aspect, R.sup.8 and R.sup.9 each
independently represent a hydrogen atom or C.sub.1-4 alkyl.
[0068] 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 isoxazolidin-2-ylcarbonyl or
tetrahydroisoxazin-2-ylcarbonyl wherein each ring is optionally
substituted by one hydroxy group; Q is CO-- or CH.sub.2-- (wherein
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 may be heteroatoms
independently selected from the group consisting of nitrogen,
oxygen and sulphur, the ring system being optionally substituted by
1, 2 or 3 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, 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.
[0069] 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 hydroxyisoxazin-2-ylcarbonyl,
tetrahydroisoxazin-2-ylcarbonyl or
hydroxytetrahydroisoxazin-2-ylcarbonyl; 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 the group
consisting of nitrogen, oxygen and sulphur providing that there is
at least 1 ring nitrogen, 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).sub.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 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.
[0070] Another class of compound is of the formula (1) in which
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; R.sup.2 is methyl; R.sup.3 is
hydroxytetrahydroisoxazin-2-ylcarbonyl,
tetrahydroisoxazin-2-ylcarbonyl or
hydroxytetrahydroisoxazin-2-ylcarbonyl; 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 the group
consisting of nitrogen, oxygen and sulphur providing that there is
at least 1 ring nitrogen, the ring system being optionally
substituted by one or more substituents independently selected from
the group consisting of C.sub.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).sub.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; 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.
[0071] Another 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 hydroxyisoxazolidin-2-ylcarbonyl,
tetrahydroisoxazin-2-ylcarbonyl or
hydroxyl-tetrahydroisoxazin-2-ylcarbonyl; Q is --CH.sub.2--; and Ar
is a 5- to 10-membered aromatic ring system containing up to 4 ring
heteroatoms selected from the group consisting of nitrogen, oxygen
and sulphur, providing that there is at least 1 ring nitrogen, the
ring system being optionally substituted by 1 or 2 substituents
independently selected from the group consisting of C.sub.4alkyl
optionally substituted by 1, 2 or 3 hydroxy groups,
C.sub.1-4alkoxy, halogen, trihaloalkyl, C.sub.1-4alkylthio,
C.sub.2-4alkanoyl, oxo, thioxo, cyano,
--(CH.sub.2).sub.pN(R.sup.8)R.sup.9 in which 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; or a
pharmaceutically acceptable salt thereof.
[0072] Another 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 4-hydroxytetrahydroisoxazin-2-ylcarbonyl or
tetrahydroisoxazin-2-ylcarbonyl; Q is --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 system being optionally
substituted by 1 or 2 substituents independently selected from
methyl, ethyl, n-propyl, iso-propyl, tert-butyl, 1-methylethyl,
trifluoromethyl, chloro, fluoro, bromo, hydroxymethyl, acetyl,
methylthio, amino, methylamino, furanyl, thienyl, pyrimidyl,
phenyl, cyano, thioxo and oxo; or a pharmaceutically acceptable
salt thereof.
[0073] In another aspect, the invention relates to a compound of
general formula (1)
##STR00003##
in which R.sup.1 and R.sup.2 each independently represent a
C.sub.1-6alkyl, C.sub.3-6alkenyl, C.sub.3-5cycloalkylC.sub.1-3alkyl
or C.sub.3-6cycloalkyl; each of which is optionally substituted by
1 to 3 halogen atoms; R.sup.3 is isoxazolidin-2-ylcarbonyl or
tetrahydroisoxazin-2-ylcarbonyl wherein each ring is optionally
substituted by one hydroxy group; 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 hydroxy group; Ar is a 5- to
10-membered aromatic ring system in which up to 4 ring atoms can be
heteroatoms independently selected from the group consisting of
nitrogen, oxygen and sulphur, the ring system being 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).sub.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.
[0074] 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 isoxazolidin-2-ylcarbonyl or
tetrahydroisoxazin-2-ylcarbonyl wherein each ring is optionally
substituted by one hydroxy group; Ar is a 5- to 10-membered
aromatic ring system in which up to 4 ring atoms can be heteroatoms
independently selected from the group consisting of nitrogen,
oxygen and sulphur, the ring system being optionally substituted by
1, 2 or 3 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, 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.
[0075] 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 hydroxytetrahydroisoxazin-2-ylcarbonyl
or hydroxytetrahydroisoxazin-2-ylcarbonyl; Q is --CO-- or
--CH.sub.2--; Ar is a 5- to 10-membered aromatic ring system in
which up to 4 ring atoms can be heteroatoms independently selected
from the group consisting of nitrogen, oxygen and sulphur, the ring
system being optionally substituted by 1, 2 or 3 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.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.
[0076] 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
methyl; R.sup.3 is hydroxyisoxazolidin-2-ylcarbonyl or
hydroxytetrahydroisoxazin-2-ylcarbonyl; Q is --CO-- or
--CH.sub.2--; Ar is a 5- to 10-membered aromatic ring system in
which up to 4 ring atoms can be heteroatoms independently selected
from the group consisting of nitrogen, oxygen and sulphur, the ring
system being optionally substituted by 1, 2 or 3 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.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.
[0077] Another 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 hydroxyisoxazolidin-2-ylcarbonyl or
hydroxytetrahydroisoxazin-2-ylcarbonyl; Q is --CO-- or
--CH.sub.2--; Ar is a 5- to 10-membered aromatic ring system in
which up to 4 ring atoms can be heteroatoms independently selected
from the group consisting of nitrogen, oxygen and sulphur, the ring
system being optionally substituted by 1, 2 or 3 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, 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.
[0078] 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 hydroxyisoxazolidin-2-ylcarbonyl; Q is --CO-- or --CH.sub.2--;
Ar is a 5- to 10-membered aromatic ring system in which up to 4
ring atoms can be heteroatoms independently selected from the group
consisting of nitrogen, oxygen and sulphur, the ring system being
optionally substituted by 1, 2 or 3 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, 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; 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.
[0079] Another 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 hydroxyisoxazolidin-2-ylcarbonyl; Q is --CO-- or --CH.sub.2--;
Ar is selected from the group consisting of imidazolyl, pyrazolyl,
2,3-dihydrothiazolyl, quinolyl, indolyl, benzimidazolyl, indazolyl,
pyrrolo[2,3-b]pyridinyl, 1H-1,2,3-benzotriazolyl,
2,3-dihydrobenzothiazolyl, 2,3-dihydrobenzimidazolyl,
2,3-dihydrobenzoxazolyl and 1,3-thiazolo[5,4-b]pyridinyl, the ring
system being optionally substituted by 1, 2 or 3 substituents
independently selected from the group consisting of C.sub.1-4alkyl
optionally substituted by 1, 2 or 3 hydroxy group, 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, 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.
[0080] Another class of compound is of the formula (1) in which
R.sup.1 is n-propyl, 1-methylethyl or 2-methylpropyl; R.sup.2 is
methyl; R.sup.3 is 4-hydroxyisoxazolidin-2-ylcarbonyl; Q is --CO--
or --CH.sub.2--; and Ar is selected from the group consisting of
imidazolyl, pyrazolyl, 2,3-dihydrothiazolyl, quinolyl, indolyl,
benzimidazolyl, pyrrolo[2,3-b]pyridinyl, 1H-1,2,3-benzotriazolyl,
2,3-dihydrobenzothiazolyl, 2,3-dihydrobenzoxazolyl and
1,3-thiazolo[5,4-b]pyridinyl, the ring system being optionally
substituted by 1, 2 or 3 substituents independently selected from
methyl, ethyl, propyl, tert-butyl, chloro, fluoro, thioxo,
hydroxymethyl, methylthio, amino, methylamino and oxo; or a
pharmaceutically acceptable salt thereof.
[0081] Particular compounds of the present invention include:
[0082]
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6--
(4-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
[0083] (R)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(4-q-
uinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; [0084]
(S)
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazoli-
dinylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3-
H)-dione; [0085] (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(4-q-
uinolinylcarbonyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; [0086]
(S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-indol-3-y-
l)methyl]-1-(2-methylpropyl)thieno[2,3-d]pyridine-2,4(1H,3H)-dione;
[0087] (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6--
[(1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)--
dione; [0088] (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-indol-3-y-
l)carbonyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
[0089] (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(1-methylethyl)-6-(1H-p-
yrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
[0090] (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propyl-6-(1H-pyrrolo[2,-
3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
[0091] (S)
6-[4,5-dichloro-2-oxo-3(2H)-thiazolylmethyl]-5-[4-hydroxyisoxazolidin-
-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione; [0092] (S)
6-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-5-{4-hydroxyisoxazolidin-2-ylcar-
bonyl}-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
[0093] (S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-1-isobutyl-3-methyl-6-[1,3,5-t-
rimethyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
[0094] (R)
6-[(4,5-dichloro-2-methyl-1H-imidazol-1-yl)methyl]-5-[4-hydroxyisoxazolid-
in-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H-
,3H)-dione; [0095] (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-benzimida-
zol-1-yl)methyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e; [0096] (S)
6-[(2-ethyl-1H-benzimidazol-1-yl)methyl]-5-[4-hydroxyisoxazolidin-2-ylcar-
bonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione-
; [0097] (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2--
propyl-1H-benzimidazol-1-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e; [0098] (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-(-
methylthio)-1H-benzimidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)--
dione; [0099] (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benzimidaz-
ol-1-ylmethyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3-
H)-dione; [0100] (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-1H-ben-
zimidazol-1-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione; [0101] (S)
5-[4-hydroxysoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-amino-1H-benzimidazol-
-1-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
[0102]
(S)-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(2-methylprop-
yl)-6-[2,4,5-trichloro-1H-imidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(-
1H,3H)-dione; [0103] (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-t-
hioxo-3(2H)-benzothiazolylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
[0104] (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[4-c-
hloro-2-oxo-3(2H)-thiazolylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e; [0105] (S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[2-o-
xo-1,3-benzoxazol-3(2H)-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
[0106] (S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[(2--
oxo[1,3]thiazolo[5,4-b]pyridin-1-(2H)-yl)methyl]thieno[2,3-d]pyrimidine-2,-
4(1H,3H)-dione; [0107] (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(1H--
1,2,3-benzotriazol-1-ylmethyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
[0108] (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-(1H--
pyrrolo[2,3-b]pyridin-1-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
[0109] (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-2-me-
thyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H-
)-dione; [0110] (S)
1-[1,2,3,4-tetrahydro-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(-
2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-ylmethyl-1H-indole-5-car-
bonitrile; [0111] (S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[2-o-
xo-1,3-benzothiazol-3(2H)-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e; [0112] (R)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-methyl-1H-indol-3-yl-
methyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
[0113] (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[7-methyl-1H-indol--
3-ylmethyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
[0114] (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-3H-imi-
dazo[4,5-b]pyridin-3-ylmethyl]-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione; [0115] (S)
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazoli-
dinylcarbonyl]-3-methyl-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
[0116] (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-1H-ben-
zimidazol-1-ylmethyl]-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)--
dione; [0117] (S)
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxazoli-
dinylcarbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-5-carboxa-
mide; [0118] (S)
6-[3,5-d]ethyl-1H-pyrazol-4-ylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbon-
yl}-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
[0119] (S)
6-[3-(1,1-dimethylethyl)-5-methyl-1H-pyrazol-4-ylmethyl]-5-{4-hydroxyisox-
azolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine--
2,4(1H,3H)-dione; [0120] (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-m-
ethyl-4-quinolinylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
[0121] (S)
6-[6-fluoro-4-quinolinylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl-
}-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
[0122] (S)
6-[8-fluoro-4-quinolinylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3--
methyl-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
[0123] (S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6--
(5-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
[0124] (S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-propyl-6-(quinolin-4-yl-
methyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; [0125] (S)
5-{4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(1-methylethyl)-6-(4-qu-
inolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; [0126] (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2--
methyl-1H-pyrrolo[2,3-d]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H-
,3H)-dione; [0127] (R)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2--
methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H-
,3H)-dione; [0128]
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2,3-d-
ihydro-6-methyl-3-oxo-pyrazin-2-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3-
H)-dione; [0129] (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl)-1H-pyrrolo[-
2,3-b]pyridin-3-ylmethyl]-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e; [0130]
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-
-1H-benzimidazol-1-ylmethyl]-3-methyl-1-propyl-thieno[2,3-d]pyrimidine-2,4-
(1H,3H)-dione; [0131]
(S)-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propyl-6-[2-am-
ino-1H-benzimidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
[0132]
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-
-benzimidazol-1-yl
methyl]-3-methyl-1-(isopropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
[0133]
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)--
6-[2-amino-1H-benzimidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-d-
ione; [0134]
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-me-
thyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H-
)-dione; [0135] (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-methyl-
-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-di-
one; [0136] (S)-6-[4,5-dichloro-2-(hydroxymethyl)-1H-imidazol-1-yl
methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thie-
no[2,3-d]pyrimidine-2,4(1H,3H)-dione; [0137]
(S)-6-[3,5-dimethyl-1H-pyrazol-1-yl
methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thie-
no[2,3-d]pyrimidine-2,4(1H,3H)-dione; [0138]
(S)-6-[2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[4-hydroxyisoxazol-
idin-2-yl
carbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3-
H)-dione; [0139] (S)
6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-yl
carbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
[0140] (S)
6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbo-
nyl]-1-isopropyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
[0141]
(S)-6-[3,5-dimethylisoxazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarb-
onyl]-1-(isobutyl)-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
[0142]
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1-ethyl-5-[(4S)-4-
-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-thieno[2,3-d]pyrimidine-2,4(1H-
,3H)-dione; [0143]
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-(1H-pyrrol-
o[2,3-b]pyridin-3-ylmethyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
[0144]
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbony]-3-methyl-6-[2-p-
ropyl-1H-benzimidazol-1-yl
methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; [0145]
1-ethyl-5-[(4)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-oxo-3(2H-
)-benzothiazolylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
[0146]
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-methyl--
1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dio-
ne; [0147]
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6--
[5-cyano-1H-indol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
[0148]
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-6-[1-isop-
ropyl-3,5-dimethyl-1H-pyrazol-4-ylmethyl]-3-methylthieno[2,3-d]pyrimidine--
2,4(1H,3H)-dione; [0149]
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-methyl-6-[5-me-
thyl-3-phenyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dio-
ne; [0150]
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-methyl-
-6-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimi-
dine-2,4(1H,3H)-dione; [0151]
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-6-[3-isopropyl-5-m-
ethyl-1H-pyrazol-4-ylmethyl]-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-di-
one; [0152]
6-[3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-5-[(4S)-4-hydroxyisoxazol-
idin-2-ylcarbonyl]-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-d-
ione, [0153]
6-[3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-5-[(4S)-4-hydroxyisoxazol-
idin-2-ylcarbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dio-
ne; [0154]
6-(1H-1,2,3-benzotriazol-1-ylmethyl)-5-[(4S)-4-hydroxyisoxazoli-
dinylcarbonyl]-3-methyl-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-d-
ione; [0155]
5-[(4S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isopropyl)-6-[(2-oxo-
thiazolo[5,4-b]pyridin-1(2H)-yl)methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione; [0156]
6-[2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[(S)-4-hydroxyisoxazol-
idinylcarbonyl]-3-methyl-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)--
dione; [0157]
6-[5,6-difluoro-2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[(4S)-4-h-
ydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimi-
dine-2,4(1H,3H)-dione; [0158]
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-6-(imidazo[1,2-a]pyridin-3-yl-
methyl)-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
[0159]
3-methyl-6-[2-methylindol-3-ylmethyl]-1-(isobutyl)-5-(tetrahydrois-
oxazin-2-ylcarbonyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
[0160]
6-[2-bromo-4,5-dichloro-1H-imidazol-1-ylmethyl]-5-[(4S)-4-hydroxyisoxazol-
idinylcarbonyl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-di-
one; [0161]
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(m-
ethylthio)-1H-imidazo[4,5-b]pyridin-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,-
4(1H,3H)-dione; [0162]
5-[(4S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(meth-
ylthio)-3H-imidazo[4,5-b]pyridin-3-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1-
H,3H)-dione; [0163]
6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-3-ethyl-5-[(4S)-4-hydroxy-2-isoxaz-
olidinylcarbonyl]-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione;
[0164]
5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)--
6-[2-(trifluoromethyl)phenylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dio-
ne; [0165]
5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobuty-
l)-6-[2-(methylthio)-1H-imidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1-
H,3H)-dione; or [0166] (S)
5-[4-hydroxylisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-methy-
l-1H-pyrrolo[2,3-b]pyridine-3-ylmethyl]thieno[2,3-d]pyridine-2,4(1H,3H)-di-
one; and pharmaceutically acceptable salts thereof.
Synthesis of Compounds of the Formula (1)
[0167] 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 ordinary skill of an
organic chemist.
[0168] 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).
[0169] 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.
[0170] 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.
[0171] 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 allyl), a
(1-4C)alkoxymethyl group (especially methoxymethyl) or a
tetrahydropyranyl group (especially tetrahydroyran-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, particularly, 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.
[0172] 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.
[0173] 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.
[0174] 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).
[0175] 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:
[0176] a) reacting a compound of the formula (10):
##STR00004##
with isoxazolidine or tetrahydroisoxazine (each being optionally
substituted by a hydroxy group);
[0177] b) when Q is methylene, reacting a compound of the formula
(11):
##STR00005##
with a compound of the formula Ar;
[0178] c) when Q is methylene, reducing a compound of the formula
(12):
##STR00006##
[0179] d) reacting a compound of the formula (11) or (13) to form
Ar by primary ring synthesis:
##STR00007##
[0180] e) reacting a compound of the formula (14) with
R.sup.1-L.sup.2:
##STR00008##
in which L and L.sup.2 are leaving groups and R.sup.1, R.sup.2,
R.sup.3, Q and Ar are as hereinabove defined and optionally after
a), b), c) or d), converting the compound of the formula (1) into a
further compound of formula (1) and/or forming a pharmaceutically
acceptable salt or solvate thereof.
[0181] The reaction between a compound of the formula (10) and
isoxazolidine or tetrahydroisoxazine (optionally substituted by a
hydroxy group) 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, particularly 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.,
particularly at or near ambient temperature.
[0182] The reaction between a compound of the formula (11) 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, particularly 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 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.
[0183] A compound of formula (12) 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, particularly tetrahydrofuran, with a catalyst such as
palladium on charcoal, in a temperature range of 0.degree. C. to
50.degree. C., particularly at ambient temperature and a pressure
of 1 to 5 bar.
[0184] The group -Q-Ar is conveniently formed on a compound of
formula (11) or (13) by primary ring synthesis. Here, reference is
made to the compendiums "The Chemistry of Heterocyclic Compounds"
E. C. Taylor and A. Weissberger (published by John Wiley and Sons)
and "Comprehensive Heterocyclic Chemistry" A. R Katritzky and C. W
Rees (published by Pergamon Press (Elsevier)). For examples of the
preparation of a compound of the formula (1) wherein Ar is
3,5-dimethylpyrazol-4-yl or 1,3,5-trimethylpyrazol-4-yl see
examples 11 and 12 in the specific examples.
[0185] A compound of the formula (14) may be reacted with a
compound of formula R.sup.1-L.sup.2 in the presence of a mild base,
such as potassium carbonate, in a dipolar aprotic solvent such as
DMF, in a temperature range of ambient temperature to 170.degree.
C.
[0186] 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.
[0187] Intermediates of the formulae (10) may be formed from a
compound of the formula (15):
##STR00009##
in which 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.
[0188] A compound of formula (15) wherein R.sup.12 is --CH.sub.2L
may be reacted with Ar under similar conditions to those described
for process b) above.
[0189] When Ar is linked via a ring carbon atom, a compound of
formula (15) wherein R.sup.21 is CH(OH)Ar may be reduced using
similar conditions to those described for process c) above.
[0190] A compound of the formula (12) or (15) wherein R.sup.21 is
CH(OH)Ar may be formed by reacting a compound of the formula
(16):
##STR00010##
(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.
[0191] The intermediates are in general prepared from a compound of
the formula (17):
##STR00011##
in which R.sup.23 is hydrogen or methyl.
[0192] When R.sup.21 is --CH(OH)Ar, R.sup.23 is hydrogen and the
compound of formula (16) may be reacted with Ar--CHO as described
above for the compound of formula (15).
[0193] When R.sup.21 is --CH.sub.2L, R.sup.13 is methyl which is
converted to --CH.sub.2L 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.
[0194] A compound of formula (17) wherein R.sup.23 is hydrogen may
be formed by firstly reacting a compound of formula (18):
##STR00012##
with an alkylbromopyruvate, such as ethylbromopyruvate, in the
presence of a mild base such as an alkali carbonate, for 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 particularly titanium
tetrachloride, in an inert solvent e.g. dichloromethane at a
temperature between -20.degree. C. and 50.degree. C., particularly
between 0.degree. C. and 25.degree. C.
[0195] A compound of formula (17) wherein 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 particularly
water, at a temperature between 5.degree. C. and 50.degree. C. and
then secondly treating the resulting adduct with a Lewis acid,
particularly titanium tetrachloride, in an inert solvent e.g.
dichloromethane at a temperature between -20.degree. C. and
50.degree. C., particularly between 0.degree. C. and 25.degree.
C.
[0196] A compound of formula (17) may be formed by reacting a
compound of formula (19):
##STR00013##
(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).
[0197] A compound of formula (19) may be prepared by the reaction
of a compound of formula (20): R.sup.1--N.dbd.S with a Wittig
compound, for example a compound of the formula (21):
##STR00014##
(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):
##STR00015##
at a temperature of from -78.degree. C. to 60.degree. C.
[0198] A compound of formula (18) may be formed by reacting a
compound of formula (23):
##STR00016##
with an alkaline metal thiol, such as sodium thiol, in a polar
solvent, such as an alcohol, for example ethanol, in a temperature
range of 10 to 50.degree. C.
[0199] A compound of formula (23) may be formed by reacting a
compound of formula (24):
##STR00017##
with a compound of formula R.sup.1-L.sup.2 under conditions
described for process e) above.
[0200] The compounds of formula (1) above may be converted to a
pharmaceutically acceptable salt or solvate thereof.
[0201] 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. These also
form an aspect of the present invention.
[0202] 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 of 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.
[0203] The compounds of the invention may be isolated from their
reaction mixtures using conventional techniques.
[0204] 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).
[0205] Examples of these conditions are: [0206] (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;
[0207] (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; [0208] (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; [0209] (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; [0210] (5) (other tissues and systemic
disease) multiple sclerosis, atherosclerosis, Acquired
hnunodeficiency 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; [0211] (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 [0212] (7) cancer.
[0213] Accordingly, the present invention provides a compound of
formula (1) or a pharmaceutically acceptable salt thereof as
hereinbefore defined for use in therapy.
[0214] 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.
[0215] 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.
[0216] 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.
[0217] 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 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.
[0218] 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.
[0219] 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) or a pharmaceutically
acceptable salt thereof as hereinbefore defined.
[0220] 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 immunosuppression,
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.
[0221] 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.
[0222] 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.
[0223] The invention further provides a process for the preparation
of a pharmaceutical 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.
[0224] 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.
[0225] 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
[0226] The assay for PMA/ionomycin-stimulated 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 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. Phorbol myristate acetate (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.
[0227] 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 1 had an IA.sub.50 of
1.7.times.10.sup.-10 M and Example 20 had an IA.sub.50 of
5.times.10.sup.-9M in the above test.
[0228] The invention will now be illustrated in the following
Examples in which, unless otherwise stated:
[0229] (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;
[0230] (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;
[0231] (iii) yields are given for illustration only and are not
necessarily the maximum attainable;
[0232] (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;
[0233] (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;
TABLE-US-00001 Abbreviations
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DDQ Dimethylformamide DMF
m-Chloroperoxybenzoic acid mCPBA Tetrahydrofuran THF
EXAMPLE 1
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-(4-quin-
olinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00018##
[0234] a) (S) Methyl
2-[4-hydroxyisoxazolidin-2-yl]carbonylbenzoate
[0235] Triethylamine (0.28 ml) was added to a solution of
N-hydroxyphthalimide (5.00 g) and (R)-(+)-epichlorohydrin (2.40 ml)
in anhydrous dioxane (10 ml) under nitrogen. The mixture was
stirred at 50.degree. C. for 48 h, further (R)-(+)-epichlorohydrin
(0.24 ml) and triethylamine (0.28 ml) were added and stirring
continued at 50.degree. C. for 24 h. Methanol (10 ml) and further
triethylamine (4.27 ml) were added and stirring continued at
50.degree. C. for 2 h. The mixture was evaporated under reduced
pressure, the residue dissolved in saturated aqueous sodium
bicarbonate solution (100 ml) and extracted with ethyl acetate
(6.times.100 ml). Combined organic extracts were dried over
anhydrous magnesium sulfate, filtered and evaporated under reduced
pressure. The residue was recrystallised from ethyl acetate to give
the sub-title compound (3.4 g). MS (ESI) 252 [M+H].sup.+.
.delta..sup.1H.sub.CDCl3 3.66 (1H, d, br), 3.79 (1H, d, br),
3.89-3.99 (1H, m), 3.99-4.10 (1H, m), 4.74-4.81 (1H, m), 7.46 (1H,
d), 7.49 (1H, t), 7.62 (1H, t), 7.99 (1H, d).
b) (S)-4-Isoxazolidinol hydrochloride
[0236] Hydrochloric acid (4M, 15 ml) was added to the product of
step a) (1.87 g) and the solution heated under reflux for 3 h. The
mixture was cooled to room temperature, filtered and evaporated
under reduced pressure. The residue was recrystallised from
propan-2-ol to give the sub-title compound as white needles (0.78
g). .delta. .sup.1H.sub.CDCl3 3.35 (1H, d), 3.47 (1H, dd), 4.03
(1H, dd), 4.07 (1H, d), 4.78-4.81 (1H, m).
c) Ethyl
1,2,3,4-tetrahydro-3-methyl-1-(isobutyl-2,4-dioxothieno[2,3-d]pyr-
imidine-5-carboxylate
[0237] 6-Mercapto-3-methyl-1-(isobutyl)-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 (15.95 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 hr in the ice-bath and then 3 hr 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
removed 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. 5 .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).
d) Ethel
1,2,3,4-tetrahydro-6-[hydroxy(4-quinolin)methyl]-3-methyl-1-(isob-
utyl-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate
[0238] A solution of lithium diisopropylamide (5.52 g) in anhydrous
THF (80 ml) was added dropwise over 1 hour to a stirred solution of
the product of step c) (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 hour 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). MS (ESI) 468
{M+H].sup.+. .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)
e) Ethyl
1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-(4-quinoliny-
lmethyl)-thieno[2,3-d]pyrimidine-5-carboxylate
[0239] Trifluoroacetic anhydride (3.33 ml) was added to a solution
of the product of step d) (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 under
reduced pressure. 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). MS (ESI)
452{M+H].sup.+. .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)
f) Sodium
1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-(4-quinolin-
ylmethyl-thieno[2,3-d]pyrimidine-5-carboxylate
[0240] A solution of the product of step e) (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
dried in vacuo to give the sub-title compound as a solid (5.06 g).
MS (ESI) 424{M+H].sup.+. .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)
g) (S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-(4-q-
uinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0241] To a suspension of the product of step f) (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. (S)-4-Isoxazolidinol
hydrochloride (Example 1, part b)) (69 mg) and triethylamine (147
.mu.l) were added and the reaction mixture stirred for 18 h then
concentrated under reduced pressure. 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). MS (APCI)
495 [M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.80-0.90 (6H, m),
2.03-2.17 (1H, m), 3.21 (1.8H, s), 3.22 (1.2H, s), 3.55-3.68 (3H,
m), 3.70-4.13 (3H, m), 4.52-4.68 (2.4H, m), 4.78-4.81 (0.6H, m),
5.50 (0.4H, d), 5.54 (0.6H, d), 7.42 (0.4H, d), 7.46 (0.6H, d),
7.63 (1H, t), 7.78 (1H, t), 8.05 (OH, d), 8.24 (0.4H, d), 8.28
(0.6H, d), 8.86 (1H, d).
EXAMPLE 2
(R)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-(4-quin-
olinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00019##
[0242] a) (R) Methyl
2-[4-hdroxyisoxazolidin-2-ylcarbonyl]benzoate
[0243] Prepared from N-hydroxyphthalimide and
(S)-(+)-epichlorohydrin by the method of example 1 part a). MS
(ESI) 252 [M+H].sup.+. .delta. .sup.1H.sub.CDCl3 3.66 (1H, d, br),
3.79 (1H, d, br), 3.89-3.99 (1H, m), 3.99-4.10 (1H, m), 4.74-4.81
(1H, m), 7.46 (1H, d), 7.49 (1H, t), 7.62 (1H, t), 7.99 (1H,
d).
b) (R)-4-Isoxazolidinol hydrochloride
[0244] Prepared from the product of step a) following the procedure
of example 1b). .delta. .sup.1H.sub.DMSO 3.35 (1H, d), 3.47 (1H,
dd), 4.03 (1H, dd), 4.07 (1H, d), 4.78-4.81 (1H, m).
c) (R)
5-[[4-Hydroxyisoxazolidin-2-yl]carbonyl]-3-methyl-1-(isobutyl)-6-(4-
-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0245] To a stirred suspension of the product from example 1 part
f), (200 mg) in dichloromethane (8 ml) was added
hydroxybenzotriazole (90 mg) followed by
1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (128
mg). After 15 minutes, (R)-4-isoxazolidinol hydrochloride (84 mg)
and triethylamine (0.093 ml) were added and stirring continued for
18 h. The resulting mixture was purified by column chromatography
over silica, eluting with ethyl acetate/methanol (19:1) and the
product triturated with ether to give the title compound as a white
powder (92 mg). MS (APCI) 495 [M+H].sup.+. .sup.1H.sub.DMSO
0.80-0.90 (6H, m), 2.03-2.17 (1H, m), 3.21 (1.8H, s), 3.22 (1.2H,
s), 3.55-3.68 (3H, m), 3.70-4.13 (3H, m), 4.52-4.68 (2.4H, m),
4.78-4.81 (0.6H, m), 5.50 (0.4H, d), 5.54 (0.6H, d), 7.42 (0.4H,
d), 7.46 (0.6H, d), 7.63 (1H, t), 7.78 (1H, t), 8.05 (1H, d), 8.24
(0.4H, d), 8.28 (0.6H, d), 8.86 (1H, d).
EXAMPLE 3
(S)
6-[4,5-Dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2-isoxaz-
olidinylcarbonyl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)--
dione
##STR00020##
[0246] a) Methyl
1,2,3,4-tetrahydro-3,6-dimethyl-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimi-
dine-5-carboxylate
[0247] 6-Mercapto-3-methyl-1-(isobutyl)-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 extracted into ethyl acetate. The
organic solution was washed with brine, dried (MgSO.sub.4) and
evaporated to leave an oil. 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 h in the ice-bath and then 3 hours 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.
.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-(isobutyl)-2,4-dio-
xothieno-[2,3-d]pyrimidine-5-carboxylate
[0248] 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 hours. The solution
was washed with water, saturated sodium bicarbonate solution and
then brine. The organic layer was dried over magnesium sulfate,
filtered and concentrated 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). MS (APCI) 390/391 [M+H].sup.+. 8 .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-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate
[0249] 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 minutes, 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 hours 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). MS (APCI) 459/460 [M+H].sup.+. .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-yl)methyl]-1,2,3,4-tetrahydro-3-
-methyl-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic
acid
[0250] Sodium hydroxide (7.3 ml of 1 M 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). MS (APCI) 445/447 [M+H].sup.+. .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-yl)methyl]-5-[4-(S)-hydroxy-2-i-
soxazolidinylcarbonyl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H-
,3H)-dione
[0251] The title compound was prepared by the method of Example 1
part g). MS (APCI) 516/518 [M+H].sup.+. .delta. .sup.1H.sub.CDCl3
0.98 (6H, dd); 2.29 (1H, septet); 2.39 (3H, s); 3.38 (3H, s); 3.54
(1H, dd); 3.66-3.70 (1H, m); 3.80-3.87 (1H, m); 4.04-4.10 (2H, m);
4.56 (1H, d); 4.70-4.75 (1H, m); 4.92 (1H, d); 5.13-5.30 (2H,
m).
EXAMPLE 4
(S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-(4-quin-
olinylcarbonyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00021##
[0253] Prepared from the product of example 1 part b) (115 mg) and
the product of example 1 part f) (342 mg) by the method of example
1 g), followed by exposure of the product to air for 18 hours. The
crude material was purified by reverse-phase preparative HPLC with
gradient aqueous ammonium acetate/acetonitrile elution followed by
trituration with ether to give the title compound as a white powder
(22 mg). MS (APCI) 509 [M+H].sup.+. *.delta. .sup.1H.sub.DMSO
(130.degree. C.*) 0.97 (6H, d), 2.23-2.33 (1H, m), 2.68-2.95 (2H,
m), 3.23 (3H, s), 3.60 (1H, dd), 3.65-3.75 (1H, m), 3.81 (2H, d),
4.50 (1H, s, br), 7.56 (1H, d), 7.61 (1H, d), 7.73-7.82 (2H, m),
8.10 (1H, d), 8.97 (1H, d). (*N.B. Substance exists as a mixture of
rotamers therefore NMR complicated at room temperature but
simplified at elevated temperature)
EXAMPLE 5
(S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-indol--
3-yl)methyl]-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00022##
[0254] a) Methyl
1,2,3,4-tetrahydro-3-methyl-6-[(2-methyl-1H-indol-3-yl
methyl]-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate
[0255] A solution of the product of example 3, part a), (7 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). The 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/1-hexane (1:3) to give the sub-title
compound as a pale brown solid (6.68 g). MS (ESI) 440 [M+H].sup.+.
.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-yl)methyl]-1-(isobu-
tyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid
[0256] Sodium hydroxide solution (1 M, 13.6 ml) and methanol (25
ml) were added to a stirred solution of the product from step a) (4
g) in tetrahydrofuran (100 ml). After 28 h, 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 g). MS (ESI) 426
[M+H].sup.+. .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) (S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-ind-
ol-3-yl)methyl]-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0257] Prepared from the product of part b) and
(S)-4-isoxazolidinol hydrochloride [example 1, part b)] following
the procedure of example 1, part g) to give the title compound as a
solid. MS (APCI) 497 [M+H].sup.+. .delta. .sup.1H.sub.DMSO
0.80-0.83 (6H, m), 1.98-2.08 (1H, m), 2.37 (1H, s), 3.19 (1.5H, s),
3.21 (1.5H, s), 3.50-3.65 (3H, m), 3.70-3.93 (2H, m), 4.00-4.18
(3H, m), 4.62-4.83 (1H, m), 5.50 (0.5H, d, br), 5.54 (0.5H, d),
6.90 (1H, t), 6.98 (1H, t), 7.25 (1H, d), 7.39 (0.5H, d), 7.43
(0.5H, d), 10.91 (1H, s).
EXAMPLE 6
(S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[(1H-py-
rrolo[2,3-b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00023##
[0258] a) Methyl 1,2,3,4-tetrahydro-3-methyl-1
(isobutyl-2,4-dioxo-6-(1H-pyrrolo[2,3,b]pyridin-3-ylmethyl)thieno[2,3-d]p-
yridine-5-carboxylate
[0259] To a solution of 7-azaindole (0.78 g) in dry THF (30 ml) was
added 2.5 M n-butyl lithium (2.6 ml) dropwise at 10.degree. C.
under nitrogen and the resulting mixture was stirred for 15
minutes. 1.0 M ethereal zinc chloride (6.61 ml) was added, the
mixture was 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 example 3
part b) (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 hours. The solvent was decanted and the solid
residue partitioned between 2 N hydrochloric acid and ethyl
acetate; the organic 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 column
chromatography, eluting with i-hexane/ethyl acetate (20-75%
gradient), to give the sub-title compound as a yellow solid (1.37
g). MS (APCI) 427[M+H].sup.+. .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(isobutyl)-2,4-dioxo-6-(1H-pyrrolo[2,3b]py-
ridin-3-ylmethyl)thieno[2,3-d]pyrimidine-5-carboxylic acid
[0260] The sub-title compound was prepared from the product of step
a by the method of example 3, step d). MS (ESI) 413[M+H].sup.+.
c) (S)
5-[[4-hydroxyisoxazolidin-2-yl]carbonyl]-3-methyl-1-(isobutyl)-6-[(-
1H-pyrrolo[2,3b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dio-
ne
[0261] The title compound (55 mg) was prepared from the product of
step b, (150 mg) by the method of example 1, step g), and
(S)-4-hydroxyisoxazolidine, example 1 part b). MS (APCI)
484[M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.82-0.85 (6H, m),
2.03-2.13 (1H, m), 3.20-3.21 (3H, m), 3.53-3.68 (3H, m), 3.75-3.90
(2H, m), 4.00-4.18 (3H, m), 4.60-4.80 (1H, m), 5.50-5.55 (1H, m),
6.99-7.02 (1H, m), 7.41-7.44 (1H, m), 7.90-7.97 (1H, m), 8.18-8.20
(1H, m), 11.53 (1H, s, br).
EXAMPLE 7
(S)
5-[4-Hydroxyisoxazoldin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-indol-3-
-yl)carbonyl]-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00024##
[0263] 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (48 mg) was added
to a stirred solution of the product of example 5 part c), 48 mg in
tetrahydrofuran/water (9:1, 1 ml). After 1 hour, the solution was
evaporated under reduced pressure and the residue purified by
reverse-phase preparative HPLC with gradient aqueous ammonium
acetate/acetonitrile elution followed by recrystallisation from
ether to give the title compound as a solid (20 mg). MS (APCI) 511
[M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.90 (6H, d), 2.13-2.23 (1H,
m), 2.46 (3H, s), 3.23 (0.4H, s), 3.24 (0.6H, s), 3.18-3.25 (0.6H,
m), 3.63-3.93 (5H, m), 4.05-4.12 (0.4H, m), 4.56-4.62 (0.6H, m),
4.70-4.76 (0.4H, m), 5.46 (1H, s, br), 7.07 (1H, t), 7.15 (1H, t),
7.39 (1H, d), 7.46-7.53 (1H, m), 12.01 (1H, s).
EXAMPLE 8
(S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(1-methylethyl)-6-(1-
H-pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e
a) Ethyl methyl
2-methyl-5-(N,N-methylethylamino)-thiophene-3,4-dicarboxylate
[0264] Ethoxycarbonylmethylene triphenyl phosphorane (33.8 g) in
dry THF (200 ml) was treated with isopropyl isothiocyanate (10.1 g)
at 65.degree. C. for 16 hours under nitrogen. The mixture was
cooled to -78.degree. C. and methyl 3-bromo-2-oxo-butanoate was
added. The reaction was allowed to warn slowly to room temperature.
After 24 hours 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 hours. The cooled reaction was
poured into water (1.5 L) and extracted into ether. Drying and
evaporation gave an oil which was chromatographed (SiO.sub.2/10:1
isohexane-ethyl acetate then 5:1 isohexane-ethyl acetate) to afford
the subtitle compound (23.5 g). .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
[0265] 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 minutes. The product of step 1)
(23 g) dissolved in anhydrous toluene (15 ml) was added and the
mixture was stirred for 72 hours. 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 hours. 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 (2L), 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 title compound (10.5 g). .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) (++H) 297.
c)
6-(Bromomethyl)-1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl-2,4-dioxot-
hieno[2,3-d]pyrimidine-5-carboxylic acid methyl ester
[0266] Prepared using the procedure described in example 3 part b)
from the product of part b) to give the subtitle compound. 8
.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)
1,2,3,4-Tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxo-6-(1H-pyrrolo[2-
,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyridine-5-carboxylic acid
methyl ester
[0267] Prepared using the procedure described in example 6 part a)
from the product of part c) to give the subtitle compound. MS (ESI)
413 [M+H].sup.+.
e)
1,2,3,4-Tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxo-6-(1H-pyrrolo[2-
,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-5-carboxylic
acid
[0268] Prepared using the procedure described in example 3 part d)
from the product of part d) to give the subtitle compound. MS (ESI)
399 [M+H].sup.+.
f) (S)
5-[[4-Hydroxyisoxazolidin-2-yl]carbonyl]-3-methyl-1-(1-methylethyl)-
-6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyridine-2,4(1H,3H)-d-
ione
[0269] Prepared using the procedure described in example 3 part e)
from the product of part e) to give the title compound. MS (APCI)
470 [M+H].sup.+. .delta. .sup.1H.sub.CDCl3 1.36-1.42 (6H. m),
3.17-3.19 (3H, m), 3.32-3.42 (7H, m), 4.60-4.75 (0.5H, m),
4.78-4.82 (0.5H, m), 5.50-5.55 (1H, m), 7.00-7.03 (1H, m),
7.43-7.44 (1H, m), 7.95-7.99 (1H, m), 8.19-8.21 (1H, m), 11.54 (1H,
s, br).
EXAMPLE 9
(S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propyl-6-(1H-pyrrolo-
[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
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 g) and ethanol (100 ml) was stirred
at room temperature for 48 hours then concentrated in vacuo. 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 evaporated to leave 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-propylthieno[2,3-d]p-
yrimidine-5-carboxylate
[0271] Prepared from the product of step a) following the procedure
of example 3, step a). .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)
6-(Bromomethyl)-1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-1-propylthieno[2,-
3-d]pyrimidine-5-carboxylic acid methyl ester
[0272] Prepared using the procedure described in example 3 part b)
from the product of part b) to give the subtitle compound. .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)
1,2,3,4-Tetrahydro-3-methyl-2,4-dioxo-1-propyl-6-(1H-pyrrolo[2,3-b]pyri-
din-3-ylmethyl)thieno[2,3-d]pyrimidine-5-carboxylic acid methyl
ester
[0273] Prepared using the procedure described in example 6 part a)
from the product of part c) to give the subtitle compound. MS (ESI)
413 [M+H].sup.+.
e)
1,2,3,4-Tetrahydro-3-methyl-2,4-dioxo-1-propyl-6-(1H-pyrrolo[2,3-b]pyri-
din-3-ylmethyl thieno[2,3-d]pyridine-5-carboxylic acid
[0274] Prepared using the procedure described in example 3 part d)
from the product of part d) to give the subtitle compound. MS (ESI)
399 [M+H].sup.+.
f) (S)
5-[[4-Hydroxyisoxazolidin-2-yl]carbonyl]-3-methyl-1-propyl-6-(1H-py-
rrolo[2,3-b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0275] Prepared using the procedure described in example 3 part e)
from the product of part e) to give the title compound. MS (APCI)
470 [M+H].sup.+. .delta. .sup.1H.sub.CDCl3 0.81-0.85 (3H, m),
1.55-1.63 (2H, m), 3.20-3.21 (3H, m), 3.54-4.23 (8H, m), 4.60-4.70
(0.42H, m), 4.77-4.83 (0.58H, m), 6.99-7.03 (1H, m), 7.41-7.44 (1H,
m), 7.93-7.97 (1H, m), 8.19-8.20 (1H, m), 11.53 (1 h, s, br).
EXAMPLE 10
(S)
6-[4,5-Dichloro-2-oxo-(2H)-thiazol-3-ylmethyl]-5-[4-hydroxyisoxazolidi-
n-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-d-
ione
##STR00025##
[0276] a)
1,2,3,4-Tetrahydro-3,6-dimethyl-1-(isobutyl)-2,4-dioxothieno[2,3-
-d]pyrimidine-5-carboxylic acid
[0277] The subtitle compound was prepared by the method of example
3 step d) using the product of example 3 step a). MS (ESI)
297{M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.93 (6H, d), 2.21 (1H,
non), 2.53 (3H, s), 3.27 (3H, s), 3.75 (2H, d), 14.04 (1H, s).
b) (S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3,6-dimethyl-1-(isobutyl)thi-
eno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0278] The subtitle compound was prepared by the method of example
1 step g) using the product of step a). MS (APCI) 368
.mu.M+H].sup.+. .delta. .sup.1H.sub.CDCl3 1.00 (6H, m), 2.25-2.37
(1H, m), 2.46 (3H, s), 3.39 (3H, s), 3.53-4.09 (5H, m), 4.61 (1H,
d), 4.71 (1H, dt), 5.05 (1H, d).
c) (S)
5-[4-[(1,1-dimethylethyl)dimethylsilyloxy]isoxazolidin-2-ylcarbonyl-
]-3,6-dimethyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0279] To a solution of the product of step b) (1.2 g) and
imidazole (0.24 g) in dichloromethane (20 ml) was added
tert-butyldimethylsilyl chloride (0.54 g). After stirring at
ambient temperature for 16 hours the mixture was washed with water
and the organics poured onto a biotage column. Gradient elution
with 0 to 5% methanol in dichloromethane gave the sub-title
compound as a colourless solid (1.55 g). 5 .sup.1H.sub.CDCl3 0.09
(3H, s), 0.11 (3H, s), 0.90 (9H, s), 0.99 (6H, d),2.30 (1H, non),
2.44 (3H, s), 3.36 (3H, s), 3.54 (1H, dd), 3.64 (1H, dd), 3.75 (1H,
d), 3.84 (1H, dd), 3.98 (1H, dd), 4.47 (1H, dd), 4.89 (1H, dd).
d) (S)
6-(Bromomethyl)-5-[4-[(1,1-dimethylethyl)dimethylsilyloxy]isoxazoli-
din-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione
[0280] The subtitle compound was prepared by the method of example
3 step b) using the product of step c). .delta. .sup.1H.sub.CDCl3
0.09 (3H, s), 0.12 (3H, s), 0.98 (9H, s), 1.00 (6H, d),2.31 (1H,
non), 3.36 (3H, s), 3.63 (1H, dd), 3.68 (1H, dd), 3.81 (1H, d),
3.87 (1H, dd), 4.00 (1H, dd), 4.37 (1H, dd), 4.64 (1H, d), 4.69
(1H, d), 4.87-4.92 (1H, m).
e) (S)
6-[(4,5-Dichloro-2-oxo-3(2H)-thiazolyl)methyl]-5-[4-[(1,1-dimethyle-
thyl
dimethylsilyloxy]isoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl-thie-
no[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0281] The subtitle compound was prepared by the method of example
3 step c) using the product of step d) and
4,5-dichloro-2-oxo-3(2H)-thiazolone. 8 .sup.1H.sub.CDCl3 0.11 (3H,
s), 0.12 (3H, s), 0.91 (9H, s), 0.98 (6H, d),2.28 (1H, non), 3.36
(3H, s), 3.57 (1H, dd), 3.66 (1H, dd), 3.79 (1H, d), 3.85 (1H, dd),
3.99 (1H, dd), 4.40 (1H, dd), 4.88 (1H, dd), 5.11 (1H, d), 5.20
(1H, d).
f) (S)
6-[(4,5-Dichloro-2-oxo-3(2H)-thiazolyl)methyl]-5-[4-hydroxyisoxazol-
idin-2-ylcarbonyl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione
[0282] To a solution of the product of step e) (180 mg) in THF (5
ml) under a nitrogen atmosphere, was added glacial acetic acid
(0.10 ml) followed by 1 N tetrabutylammonium fluoride solution in
THF (0.5 ml). After 16 h at ambient temperature the mixture was
neutralised with sat sodium bicarbonate solution and extracted into
ethyl acetate. The organics were washed with water, and dried over
magnesium sulphate. Concentration in vacuo gave a white solid that
was purified by reverse phase HPLC to give the title compound as a
white solid (100 mg). .delta. .sup.1H.sub.DMSO 0.92 (6H, d), 2.18
(1H, non), 3.20 (3H, s), 3.43-4.11 (6H, m), 4.60-4.76 (1H, m),
5.04-5.11 (2H, m), 5.51 (1H, s).
EXAMPLE 11
(S)
6-[(3,5-Dimethyl-1H-pyrazol-4-yl)methyl]-5-{4-hydroxyisoxazolidin-2-yl-
carbonyl}-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00026##
[0283] a)
6-[(3,5-Dimethyl-1H-pyrazol-4-yl)methyl]-1-isobutyl-3-methyl-2,4-
-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic
acid
[0284] Potassium carbonate (3.55 g) and
dichlorobis(triphenylphosphine)cobalt (II) (0.1 g) were added to a
stirred solution of the product of example 3, part a) (1 g) and
2,4-pentanedione (2.64 ml) in dichloromethane (30 ml) under
nitrogen. After 48 hours, aqueous hydrazine (35%, 2.33 ml) was
added and the mixture stirred vigorously for 1 hour, diluted with
water (30 ml) and extracted with ethyl acetate (2.times.60 ml).
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. The product was dissolved in tetrahydrofuran (20 ml) and
methanol (3 ml) then treated with sodium hydroxide solution (1 M,
2.57 ml). After 3 days, the mixture was evaporated under reduced
pressure to ca. 5 ml, diluted with water (25 ml) and extracted with
ethyl acetate (25 ml). The aqueous phase was acidified with
hydrochloric acid and extracted with ethyl acetate (3.times.25 ml).
Organic extracts were dried over anhydrous magnesium sulfate,
filtered and evaporated under reduced pressure to give the
sub-title compound as a solid (0.23 g). MS (ESI) 391 [M+H].sup.+.
.delta. .sup.1H.sub.DMSO 0.85 (6H, d), 2.05-2.18 (1H, m), 2.08 (6H,
s), 3.17 (3H, s), 3.62 (2H, d), 3.71 (2H, s).
b) (S)
6-[(3,5-Dimethyl-1H-pyrazol-4-yl)methyl]-5-{[4-hydroxyisoxazolidin--
2-yl]carbonyl}-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0285] Prepared using the procedure described in example 1 part g)
from the product of part a) (225 mg) and (S)-4-hydroxyisoxazolidine
hydrochloride {example 1 part b)} to give the title compound as a
solid (98 mg). MS (ESI) 462 [M+H].sup.+. .delta. .sup.1H.sub.DMSO
0.87 (6H, d), 2.05-2.20 (1H, m), 3.19 (2H, s), 3.21 (1H, s), 3.48
(0.67H, d), 3.47-3.85 (6H, m), 3.90-4.05 (0.67H, m), 4.10 (0.67H,
dd), 4.57-4.78 (1H, m), 5.51 (1H, d), 12.08 (1H, s, br).
EXAMPLE 12
(S)
5-{4-Hydroxyisoxazolidin-2-ylcarbonyl}-1-(isobutyl)-3-methyl-6-[1,3,5--
trimethyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00027##
[0286] a) (S)
6-(Bromomethyl)-5-{-4-hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(isobu-
tyl)thieno[2,3-d]pyridine-2,4(1H,3H)-dione
[0287] Prepared from the product of example 10 part b) by the
method of example 3 part b). .delta..sup.1H.sub.CDCl3 1.01 (6H, d),
2.27-2.36 (1H, m), 3.39 (3H, s), 3.58 (1H, dd), 3.69-3.76 (2H, m),
3.88 (1H, dd), 4.01 (1H, d), 4.13 (1H, dd), 4.59 (1H, d), 4.60 (1H,
d), 4.72 (1H, d), 4.89 (1H, d).
b) (S)
5-{4-Hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(isobutyl)-6-[(1,-
3,5-trimethyl-1H-pyrazol-4-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-di-
one
[0288] Potassium tert.-butoxide solution (1 M in tetrahydrofuran,
2.99 ml) was added to a stirred solution of the product of part a)
(1.00 g) and 2,4-pentanedione (0.31 ml) in tetrahydrofuran (20 ml)
at room temperature under nitrogen. After 18 hours, 8 ml of this
solution was treated with methylhydrazine (64 .mu.l) and after a
further 24 hours the mixture was evaporated under reduced pressure.
The residue was purified by reverse-phase preparative HPLC with
gradient aqueous ammonium acetate/acetonitrile elution then by
column chromatography over silica, eluting with ethyl
acetate/methanol (24:1) to give the title compound as a solid (24
mg). MS (ESI) 476 [M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.88 (6H,
d), 2.02 (3H, s), 2.08-2.18 (4H, m), 3.19 (2H, s), 3.21 (1H, s),
3.47 (0.67H, d), 3.62 (3H, s), 3.55-4.03 (6.67H, m), 4.10 (0.671,
dd), 4.58-4.78 (1H, m), 5.52 (1H, d).
EXAMPLE 13i
(R)
6-[(4,5-Dichloro-2-methyl-1H-imidazol-1-yl)methyl]-5-[4-hydroxyisoxazo-
lidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H-
)-dione
[0289] The title compound was prepared by the method of Example 1
part g), from the products of example 3 part d) and example 2 part
b). MS (APCI) 516/518 [M+H].sup.+. .delta. .sup.1H.sub.CDCl3 0.98
(6H, dd); 2.29 (1H, septet); 2.39 (3H, s); 3.38 (3H, s); 3.54 (1H,
dd); 3.66-3.70 (1H, m); 3.80-3.87 (1H, m); 4.04-4.10 (2H, m); 4.56
(1H, d); 4.70-4.75 (1H, m); 4.92 (1H, d); 5.13-5.30 (2H, m).
EXAMPLE 13ii
(S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-1H-benzim-
idazol-1-yl)methyl]-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00028##
[0290] a)
1,2,3,4-Tetrahydro-3-methyl-6-[(2-methyl-1H-benzimidazol-1-yl)me-
thyl]-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic
acid, methyl ester
[0291] Prepared using the procedure described in example 3 part c)
from the product of example 3 part b) and 2-methylbenzimidazole. MS
(API) 440 [M+H].sup.+. .delta. .sup.1H.sub.CDCl3 0.9 (6H, d),
209-2.12 (1H, m), 2.63 (3H, s), 3.39 (3H, s), 3.62 (2H, d), 4.01
(3H, s), 5.49 (2H, s), 7.23-7.35 (3H, m), 7.7-7.75 (1H, m).
b)
1,2,3,4-Tetrahydro-3-methyl-6-[(2-methyl-1H-benzimidazol-1-ylmethyl]-1--
(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid
[0292] Prepared using the procedure described in example 3 part d)
from the product of part a) to give the subtitle compound. MS (ESI)
426 [M+H].sup.+.
c) (S)
5-[[4-Hydroxyisoxazolidin-2-yl]carbonyl]-3-methyl-6-[(2-methyl-1H-b-
enzimidazol-1-yl)methyl]-1-(isobutyl)thieno[2,3-d]pyrimidine-2.4
(1H,3H)-dione
[0293] Prepared using the procedure described in example 3 part e)
from the product of part b) to give the title compound. MS (APCI)
498 [M+H].sup.+. .delta. .sup.1H.sub.CDCl3 0.87-0.93 (6H, m),
2.02-2.17 (1H, m), 2.66 (3H, s), 3.24 (3H, s), 3.38 (3H, s),
3.52-3.58 (2H, m), 3.71-3.8 (1H, m), 4.01-4.07 (2H, m),4.59 (1H,
d), 4.71-4.75 (1H, m), 4.94 (1H, d), 5.3-5.54 (2H, m), 7.22-7.28
(2H, m), 7.39-7.42 (1H, m),7.69-7.71 (1H, m).
EXAMPLE 13iii
(S)
6-[(2-Ethyl-1H-benzimidazol-1-yl)methyl]-5-[4-hydroxyisoxazolidin-2-yl-
carbonyl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00029##
[0294] a)
6-[(2-Ethyl-1H-benzimidazol-1-yl)methyl]-1,2,3,4-tetrahydro-3-me-
thyl-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic
acid, methyl ester
[0295] Prepared using the procedure described in example 3 part c)
from the product of example 3 part b) and 2-methylbenzimidazole to
give the subtitle compound, which was purified by flash silica
chromatography eluting with 30% to 70% ethyl acetate in isohexane.
MS (ESI) 455 [M+H].sup.+. .delta. .sup.1H.sub.CDCl3 0.86-0.88 (6H,
d), 1.44-1.50 (3H, t), 2-2.1 (1H, m), 2.89-3(2H, q), 3.39 (3H, s),
3.59-3.62 (2H, d), 4(3H, s), 5.50 (2H, s), 7.2-7.34 (3H, m),
7.60-7.78 (1H, m).
b)
6-[(2-Ethyl-1H-benzimidazol-1-yl)methyl]-1,2,3,4-tetrahydro-3-methyl-1--
(isobutyl-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid
[0296] Prepared using the procedure described in example 3 part d)
from the product of part a) to give the subtitle compound. MS (ESI)
441 [M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.79-0.81 (6H, d),
1.30-1.35 (3H, t), 2-2.1 (1H, m), 2.88-2.95 (2H, q), 3.25 (3H, s),
3.58-3.61 (2H, d), 5.80 (2H, s), 7.2-7.23 (2H, m), 7.57-7.63 (2H,
m).
c) (S)
6-[(2-Ethyl-1H-benzimidazol-1-yl)methyl]-5-[4-hydroxyisoxazolidin-2-
-ylcarbonyl]-3-methyl-1-(isobutyl
thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0297] Prepared using the procedure described in example 3 part e)
from the product of part b) to give the title compound after
purification by flash silica chromatography eluting with 5%
methanol in ethyl acetate followed by a recrystallisation from
ethyl acetate/isohexane. MS (APCI) 512 [M+H].sup.+. .delta.
.sup.1H.sub.DMSO 0.80-0.83 (6H, m), 1.29-1.34 (3H, t), 2-2.1 (1H,
m), 2.88-2.96 (2H, q), 3.20 (3H, s), 3.55-3.71 (3H, m),3.81-3.91
(2H, m), 4-4.1 (1H, m),4.55-4.81 (1H, 2m), 5.51-5.57 (3H, m),
7.15-7.20 (2H, m), 7.55-7.58 (1H, m), 7.62-7.65 (1H, m).
EXAMPLE 13iv
(S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[(2-pro-
pyl-1H-benzimidazol-1-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a)
1,2,3,4-Tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-[(2-propyl-1H-benz-
imidazol-1-yl)methyl]thieno[2,3-d]pyrimidine-5-carboxylic acid,
methyl ester
[0298] Prepared using the procedure described in example 3 part c)
from the product of example 3 part b) and 2-n-propylbenzimidazole
to give the subtitle compound after purification by flash silica
chromatography eluting with isohexane:ethyl acetate (1:1). MS
(APCI) 469 [M+H]. .delta. .sup.1H.sub.DMSO 0.81-0.83 (6H, d),
0.94-0.99 (3H, t), 1.72-1.82 (2H, sextet), 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-(isobutyl)-2,4-dioxo-6-[(2-propyl-1H-benz-
imidazol-1-yl)methyl]thieno[2,3-d]pyrimidine-5-carboxylic acid
[0299] Prepared using the procedure described in example 1 part f)
from the product of step a) to give the subtitle compound. MS
(APCI) 455 [M+H]. .delta. .sup.1H.sub.DMSO 0.78-0.85 (6H, d),
0.94-1 (3H, t), 1.74-1.86 (2H, sextet), 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) (S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[(2--
propyl-1H-benzimidazol-1-yl)-methyl]thieno[2,3-d]pyridine-2,4(1H,3H)-dione
[0300] Prepared using the procedure described in example 3 part e)
from the product of step b) and (S)-4-hydroxyisoxalidine
hydrochloride [example 1 part b)] to give the title compound. MS
(APCI) 526.2[M+H]. .delta. .sup.1H.sub.DMSO 0.80-0.84 (6H, m),
0.95-1 (3H, t), 1.76-1.83 (2H, sextet), 2-2.1 (1H, m), 2.86-2.90
(2H, m), 3.2 (3H, s), 3.5-3.61 (3H, m), 3.7-3.92 (2.5H, m),
4.4-4.15 (0.5H, m), 4.5-4.6 (0.4H, m), 4.8 (0.6H, m), 5.52-5.57
(3H, m), 7.16-7.19 (2H, m), 7.55-7.65 (2H, 2m).
EXAMPLE 13v
(S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(met-
hylthio)-1H-benzimidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4
(1H,3H)-dione
a) Methyl
1,2,3,4-Tetrahydro-3-methyl-1-(isobutyl)-6-[2-(methylthio)-1H-be-
nzimidazol-1-ylmethyl]-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate
[0301] Prepared using the procedure described in example 3 part c)
from the product of example 3 part b) and
2-methylthiobenzimidazole, to give the sub-title compound. MS
(APCI) 474 [M+H].sup.+.
b)
1,2,3,4-Tetrahydro-3-methyl-1-(isobutyl-6-[2-(methylthio)-1H-benzimidaz-
ol-1-ylmethyl]-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic
acid
[0302] Prepared using the procedure described in example 1 part f)
from the product of step a), to give the sub-title compound as a
white solid. MS (APCI) 459 [M+H].sup.+.
c) (S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(-
methylthio)-1H-benzimidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4
(1H,3H)-dione
[0303] Prepared using the procedure described in example 3 part e)
from the product of part b) and (S)-4-isoxazolidinol hydrochloride
to give the title compound. MS (APCI) 530 [M+H].sup.+. .delta.
.sup.1H.sub.CDCl3 0.87 (3H, s), 0.81 (3H, s), 1.98-2.19 (2H, m),
2.8 (3H, s), 3.21 (3H, m), 3.58-4.17 (6H, m), 4.6-4.8 (1H, m),
5.43-5.58 (2H, m), 7.15-7.19 (2H, m), 7.54-7.6 (2H, m).
EXAMPLE 13vi
(S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-hydroxymethyl)-1H-benzimid-
azol-1-ylmethyl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-d-
ione
##STR00030##
[0304] a)
1,2,3,4-Tetrahydro-6-[2-(hydroxymethyl-1H-benzimidazol-1-ylmethy-
l]-3-methyl-1-(isobutyl-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic
acid, methyl ester
[0305] The product of example 3 part b) (0.6 g) was dissolved in
DMF (5 ml). 2-Hydroxymethyl-benzimidazole (0.28 g) and anhydrous
potassium carbonate (0.6 g) were added to the solution, which was
stirred for 16 hours. The sub-title compound was obtained as a
white solid after filtration of the reaction mixture and
evaporation (0.18 g). MS (APCI) 457 [M+H].sup.+. .delta.
.sup.1H.sub.CDCl3 0.87 (3H, s), 0.9 (3H, s), 2.1-2.2 (m, 1H), 3.38
(s, 3H), 3.57-3.64 (m, 3H), 3.96 (s, 3H), 4.97 (s, 2H), 5.64 (s,
2H), 7.26-7.38 (m, 2H), 7.22-7.3 (m, 1H) and 7.74-7.8 (m, 1H).
b)
1,2,3,4-Tetrahydro-6-[2-(hydroxymethyl)-1H-benzimidazol-1-ylmethyl]-3-m-
ethyl-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic
acid
[0306] The sub-title compound was prepared using the procedure
described in example 3 part d) from the product of part a) to give
the sub-title compound. MS (APCI) 443 [M+H].sup.+.
c) (S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benz-
imidazol-1-ylmethyl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3-
H)-dione
[0307] The title compound was prepared using the procedure
described in example 3 part e) from the product of example part b).
MS (APCI) 474/475 [M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.83 (3H,
s), 0.85 (3H, s), 2.06-2.18 (1H, m), 3.22 (3H, s), 3.42-3.98 (6H,
m), 4.7-4.8 (1H, s (br)), 4.82 (2H, s), 5.25 (1H, s), 5.49 (1H, s),
5.62 (2H, s), 7.16-7.19 (2H, m) and 7.57-7.6 (2H, m).
EXAMPLE 13vii
(S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-1H--
benzimidazol-1-ylmethyl]-1-(isobutyl)thieno[2,3
d]pyrimidine-2,4(1H,3H)-dione
##STR00031##
[0308] a)
1,2,3,4-Tetrahydro-3-methyl-6-[2-(methylamino)-1H-benzimidazol-1-
-ylmethyl]-1-(isobutyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic
acid, methyl ester
[0309] Sodium hydride (0.24 g, 60% in mineral oil) was added
portionwise to a stirred solution of 2-(methylamino)benzimidazole
(0.93 g) in DMF (50 ml) at 0.degree. C. under nitrogen. After
stirring for 30 minutes at room temperature a solution of the
product of example 3 part b) (2.16 g) in DMF (10 ml) was added
dropwise and the reaction was stirred for 16 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 recrystallised
from ethyl acetate to give the sub-title compound as a white solid,
1.5 g. MS (ESI) 456 [M+H].sup.+. .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-(isobutyl)-2,4-dioxothieno[2,3-d]pyridine-5-carboxylic
acid
[0310] The sub-title compound was prepared following the procedure
of example 3 part d) using the product of part a). MS (APCI) 442
[M+H].sup.+.
c) (S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)--
1H-benzimidazol-1-ylmethyl]-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione
[0311] (S)-4-Hydroxyisoxalidine hydrochloride (Example 1, part b))
(0.08 g) and triethylamine (0.09 ml) were added to a solution of
the product of part b) (0.13 g) in dichloromethane (5 ml).
1-Hydroxybenzotriazole (0.09 g) was added as well as
1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide hydrochloride (0.12
g). The reaction mixture was stirred for 12 hours at room
temperature. The solution was concentrated under reduced pressure.
The residue was purified by flash silica chromatography eluting
with a gradient of 0-3% methanol in ethyl acetate. The product
obtained was recrystallised from ethyl acetate/isohexane/methanol
to give the title compound as a white solid (0.07 g). MS (APCI)
513.2 [M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.82-0.86 (6H, m),
2-2.1 (1H, m), 2.9 (3H, m), 3.2 (3H, s), 3.6-3.68 (3H, m),
3.78-3.84 (1H, m), 3.9-3.94 (1H, m), 4-4.12 (1H, m), 4.6-4.8 (1H,
2m), 5.2-5.61 (3H, m), 6.86-6.99 (3H, m), 7.19-7.27 (2H, m).
EXAMPLE 13viii
(S)
5-[4-Hydroxyisoxazoldin-2-ylcarbonyl]-3-methyl-6-[2-amino-1H-benzimida-
zol-1-ylmethyl]-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00032##
[0312] a)
6-[(2-Amino-1H-benzimidazol-1-yl)methyl]-1,2,3,4-tetrahydro-3-me-
thyl-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic
acid, methyl ester
[0313] The sub-title compound was prepared by the method of example
13vii, part a) from the product of example 3 part b) (0.4 g) and
2-aminobenzimidazole (0.16 g). MS (ESI) 442 [M+H].sup.+.
b)
6-[(2-Amino-1H-benzimidazol-1-yl)methyl]-1,2,3,4-tetrahydro-3-methyl-1--
(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid
[0314] The subtitle compound was prepared using the method of
example 3 part d) from the product of part a). MS (ESI) 428
[M+H].sup.+.
c) (S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-amino-1H-benzi-
midazol-1-ylmethyl]-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0315] The title compound was prepared by the method of example
13vii) part c) from the product of part b). MS (ESI) 499
[M+H].sup.+. .delta. .sup.1H.sub.CDCl3 0.93 (6H, d), 2.16-2.28 (1H,
m), 3.36-3.4 (5H, m), 3.62-4.37 (6H, m), 4.59 (1H, d), 4.78 and 4.9
(1H, t, rotamers), 2.25 (2H, AB q) and 7.16-7.4 (4H, m).
EXAMPLE 13ix
(S)-5-[4-Hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[(2,4,5-
-trichloro-1H-imidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00033##
[0316] a) Methyl
1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-[2,4,5-trichloro-1H--
imidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-5-carboxylate
[0317] The subtitle compound was prepared by the method of Example
3 part c) using 2,4,5-trichloro-imidazole and the product of
Example 3 part b), and purified by chromatography
(SiO.sub.2/20%-50% ethyl acetate-isohexane). MS (APCI) 479/481/483
[M+H].sup.+. .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-(isobutyl-2,4-dioxo-6-[2,4,5-trichloro-1H-
-imidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-5-carboxylic acid
[0318] 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 hours 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). MS (APCI) 465/467/469 [M+H].sup.+.
c)
(S)-5-[4-Hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[4,5-
-trichloro-1H-imidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0319] The title compound was prepared by the method of Example 1
step g) using the product of step b). MS (APCI) 536/538/540
[M+H].sup.+. .delta. .sup.1H.sub.CDCl3 0.98 (6H, dd); 2.26 (1H,
septet); 3.40 (3H, s); 3.47 (1H, dd); 3.66-3.70 (1H, m); 3.80-3.87
(1H, m); 4.04-4.20 (2H, m); 4.55 (1H, d); 4.70-4.75 (1H, m); 4.90
(1H, d); 5.25 (1H, d); 5.40 (1H, d).
EXAMPLE 13x
(S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-thio-
xo-3(2H)-benzothiazolylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00034##
[0320] a) Methyl
1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-[2-thioxo-3(2H)-benz-
othiazolylmethyl]thieno[2,3-d]pyrimidine-5-carboxylate
[0321] A solution of the product of example 3 step b) (300 mg) and
2-methylthiobenzothiazole (300 mg) in diglyme (3 ml) was heated by
microwave irradiation (600 W) to 160.degree. C. After 30 minutes,
the solvent was removed by vacuum distillation and the residue
purified by gradient chromatography eluting with a gradient of
dichloromethane to 5% methanol in dichloromethane to give the
sub-title compound as a white solid (150 mg). .delta.
.sup.1H.sub.CDCl3 0.93 (6H, d), 2.22 (1H, non), 3.38 (3H, s), 3.71
(2H, d), 4.00 (3H, s), 4.80 (2H, s), 7.33 (1H, dt), 7.45 (1H, dt),
7.77 (1H, dd), 7.92 (1H, d).
b)
1,2,3,4-Tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-)-6-[(2-thioxo-3(2H)-
-benzothiazolyl)methyl]thieno[2,3-d]pyrimidine-5-carboxylic
acid
[0322] The subtitle compound was prepared by the method of example
3, step d) using the product of step a). MS (APCI) 461 {M+H].sup.+.
.delta. .sup.1H.sub.DMSO 0.86 (6H, d), 2.10 (1H, non), 3.25 (3H,
s), 3.70 (2H, d), 5.00 (2H, s), 7.39 (1H, t), 7.52 (1H, t), 7.93
(1H, d), 8.02 (1H, d).
c) (S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[(2--
thioxo-3(2H)-benzothiazolylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0323] The title compound was prepared using the method of example
3 step e) and the product of step b). MS (APCI) 533{M+H].sup.+.
.delta. .sup.1H.sub.DMSO 0.81-0.88 (6H, m), 2.10 (1H, non), 3.19
(3H, s), 4.14-4.45 (6H, m), 4.65 (1H, s), 4.77 (2H, m), 5.65-5.89
(1H, m), 7.40 (1H, t), 7.51 (1H, t), 7.95 (1H, d), 8.04 (1H,
d).
EXAMPLE 13xi
(S) 5-14
Hydroxyisoxazoldin-2-ylcarbonyl]-3-methyl-1-isobutyl)-6-[4-chloro-
-2-oxo-3(2H)-thiazolylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00035##
[0324] a) 4-Chloro-2-fluorothiazole
[0325] A suspension of 2,4-dichlorothiazole (5 g) and potassium
fluoride (5 g) in tetramethylenesulfone (20 ml) were heated at
130.degree. C. for 6 hours. Further potassium fluoride (5 g) was
added and the mixture heated at 175.degree. C. for 16 hours. Vacuum
distillation of the reaction mixture gave the sub-title compound as
a colourless oil (1.7 g). .delta. .sup.1H.sub.CDCl3 6.71 (1H,
d).
b) 4-Chloro-2(3H)-thiazolone
[0326] A mixture of the product of step a) (1.7 g) and potassium
hydroxide (1.22 g) in water (25 ml) and acetonitrile (5 ml) was
stirred at ambient temperature for 16 hours. The mixture was
partitioned between water and dichloromethane, the aqueous layer
was collected, acidified with glacial acetic acid and extracted
into dichloromethane. After drying over magnesium sulfate the
organics were filtered and concentrated to dryness to give the
sub-title compound as a colourless oil (0.35 g). 5
.sup.1H.sub.CDCl3 5.97 (1H, s), 9.47 (1H, s). MS (ESI)
135/137{M+H].sup.+
c) Methyl
6-[4-chloro-2-oxo-3(2H)-thiazolylmethyl]-1,2,3,4-tetrahydro-3-me-
thyl-1-(isobutyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylate
[0327] The subtitle compound was prepared by the method of example
3 part c) using the product of step b). .delta. .sup.1H.sub.CDCl3
0.97 (6H, d), 2.29 (1H, non), 3.39 (3H, s), 3.76 (2H, d), 3.99 (3H,
s), 5.17 (2H, s), 6.08 (1H, s).
d)
6-[4-Chloro-2-oxo-3(2H)-thiazolylmethyl]-1,2,3,4-tetrahydro-3-methyl-1--
(isobutyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid
[0328] The subtitle compound was prepared by the method of example
3 part d) using the product of step c). MS (ESI)
430/432{M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.90 (6H, d), 2.15
(1H, non), 3.25 (3H, s), 3.73 (2,3-d), 5.25 (2H, s), 6.79 (1H,
s).
e) (S)
6-[4-Chloro-2-oxo-3(2H)-thiazolylmethyl]-5-[4-hydroxyisoxazolidin-2-
-ylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e
[0329] The title compound was prepared by the method of example 3
part e) using the product of step d). MS (APCI) 501/503{M+H].sup.+.
.delta. .sup.1H.sub.DMSO 0.82-0.92 (6H, m), 2.15-2.20 (1H, m), 3.20
(3H, s), 3.40-3.60 (6H, m), 4.60-4.80 (1H, m), 5.04 (2H, s), 5.50
(1H, s), 6.72 (1H, s).
EXAMPLE 13xii
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-oxo--
1,3-benzoxazol-3(2H)-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) Methyl
1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-[(2-oxo-1,3-
-benzoxazol-3(2H)-yl)methyl]thieno[2,3-d]pyrimidine-5-carboxylate
[0330] The sub-title compound was prepared by the method of example
3 part c), using product of example 3 part b) and
1,3-benzoxazol-2(3H)-one. .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) Sodium
1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-[2-oxo-1,3--
benaoxazol-3(2H)-ylmethyl]-thieno[2,3-d]pyrimidine-5-carboxylate
[0331] The subtitle compound was prepared by the method of example
3 part d) using the product of part a). MS (ES) 430.1
(M.sup.++H).
c) (S)
5-{4-Hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(isobutyl)-6-[2-o-
xo-1,3-benzoxazol-3(2H)-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0332] The subtitle compound was prepared by the method of example
3 part e) using the product of part b). .delta. .sup.1H.sub.CDCl3
0.89 (6H, d), 2.15 (1H, m), 3.20 (3H, d), 3.81 (6H, m), 4.68 (1H,
m), 5.13 (2H, m), 5.50 (1H, m), 7.18 (2H, dd), 7.38 (2H, m). MS
(APCI) 501.1 (M.sup.++H)
EXAMPLE 13xiii
(S)-5-{4-Hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(isobutyl)-6-[(2-oxo-
[1,3]thiazolo[5,4-b]pyridin-1(2H)-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H-
,3H)-dione
##STR00036##
[0333] a) 3-Nitropyridine-2-thiol
[0334] To a solution of 3-nitro-2-chloropyridine (9.07 g) in
ethanol (120 ml) was added NaSH (6.41 g) and the mixture was
allowed to stir for 30 min, and then concentrated in vacuo. Water
was added to the residue and acidified with dilute HCl and then
extracted with ethyl acetate (x5). The organic phase was washed
with water, dried and concentrated in vacuo to afford the subtitle
compound as an orange solid (9.08 g). .sup.1H.sub.CDCl3 7.19 (dd,
J=2.7, 4.2 Hz, 1H); 8.44 (m, 2H). MS (ESI) 154.9.
b) 3-Aminopyridine-2-thiol
[0335] To a solution of the product of part a) (0.50 g) in glacial
acetic acid (5 ml) cooled in a water bath was added reduced iron
powder (0.50 g) and stirred at room temperature for 45 minutes.
Further acetic acid (5 ml) was added and stirring continued for a
further 20 minutes. The reaction mixture was added dropwise to a
solution of sodium bicarbonate and extracted into ethyl acetate
(.times.3). The organic phase was dried and concentrated in vacuo
to afford the subtitle compound as a dark green oil (0.29 g).
.delta. .sup.1H.sub.CDCl3 4.95 (s, 2H); 6.68 (t, J=6.8 Hz, 1H);
6.80 (d, J=7.7 Hz, 1H); 7.14 (d, J=5.6 Hz, 1H); 12.75 (s, 1H).
c) [1.3]Thiazolo[5,4-b]pyridin-2(1H)-one
[0336] To a solution of the product of part b) (280 mg) in toluene
(300 ml) was added 1,1-carbonyldiimidazole (392 mg) and heated to
reflux for 16 hours. The reaction mixture was concentrated in vacuo
and the residue purified by normal phase chromatography eluting
with a mixture of iso-hexane:ethyl acetate (3:2). The combined
organic fractions were concentrated in vacuo to afford the
sub-title compound as an off-white solid (214 mg). .delta.
.sup.1H.sub.CDCl3 7.23 (dd, J=7.9, 4.9 Hz, 1H); 7.38 (dd, J=8.1,
1.4 Hz, 1H); 8.31 (dd, J=4.9, 1.5 Hz, 1H); 9.50 (s, 1H). MS (ESI)
150.9 [M+H].sup.+.
d) Methyl
1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-[(2-oxo[1,3-
]thiazolo[5,4-b]pyridin-1(2H)-yl)methyl]thieno[2,3-d]pyrimidine-5-carboxyl-
ate
[0337] Prepared using the method of example 3 part c) using the
product of example 3 part b) and the product of part c). .delta.
.sup.1H.sub.CDCl3 0.95 (d, J=6.5 Hz, 6H); 2.25 (septet, J=6.9 Hz,
1H); 3.38 (s, 3H); 3.73 (d, J=7.9 Hz, 2H); 4.04 (s, 3H) 5.30 (dd,
J=0.3, 2.6 Hz, 2H); 7.26 (t, J=8.8 Hz, 1H); 7.74 (dd, J=8.4, 1.2
Hz, 1H); 8.31 (dd, J=5.0, 1.3 Hz, 1H). MS (ESI) 460.9
[M+H].sup.+.
e)
1,2,3,4-Tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-[2-oxo[1,3]thiazol-
o[5,4-b]-pyridin-1(2H)-ylmethyl]-thieno[2,3-d]pyrimidine-5-carboxylic
acid
[0338] Prepared using the method of example 3 part d) using the
product of part d). .delta. .sup.1H.sub.CDCl3 0.96 (q, J=3.3 Hz,
6H); 2.26 (septet, J=7.7 Hz, 1H); 3.51 (s, 3H); 3.81 (d, J=21.1 Hz,
2H); 6.06 (s, 2H) 7.25 (m, 1H); 7.62 (dd, J=8.1, 1.3 Hz, 1H); 8.32
(m, 1H). MS (ESI) 447 [M+H].sup.+.
f) (S)
5-{4-Hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(isobutyl)-6-[2-o-
xo[1,3]thiazolo[5,4-b]pyridin-1(2H)-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1-
H,3H)-dione
[0339] Prepared using the method of example 3 part e) using the
product of part e). 8 .sup.1H.sub.DMSO 0.89 (q, J=6.5 Hz, 6H); 2.15
(septet, J=7.8 Hz, 1H); 3.20 (d, J=4.0 Hz, 3H); 3.76 (m, 6H); 4.68
(m, 1H) 5.26 (m, 1H); 7.41 (dd, J=8.2, 4.9 Hz, 1H); 7.80 (d, J=8.3
Hz, 1H), 8.31 (d, J=4.8 Hz, 1H). MS (APCI) 518.0.
EXAMPLE 13xiv
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-(1H-1,2-
,3-benzotriazol-1-ylmethyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a)
6-(1H-1,2,3-Benzotriazol-1-ylmethyl)-1,2,3,4-tetrahydro-3-methyl-1-(iso-
butyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid, methyl
ester
[0340] Prepared using the procedure described in example 3 part c)
from the product of example 3 part b) and benzotriazole to give the
subtitle compound. MS (ESI) 309 [M-benzotriazole].sup.+. .delta.
.sup.1H.sub.CDCl3 0.9 (3H, s), 0.98 (3H, s), 2.18-2.24 (1H, m),
2.48 (3H, s), 3.38 (3H, s), 3.62 (2H, d), 4.11 (3H, s), 6.03 (2H,
s), 7.41 (1H, t), 7.49 (1H, t), 7.71 (1H, d), and 8.09 (1H, d).
b)
6-(1H-1,2,3-Benzotriazol-1-ylmethyl-1,2,3,4-tetrahydro-3-methyl-1-(isob-
utyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid
[0341] Prepared using the procedure described in example 3 Part d)
from the product of part a) to give the subtitle compound. MS (ESI)
414 [M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.87 (3H, s), 0.91 (3H,
s), 2.01-2.19 (1H, m), 3.2 (3H, s), 3.7 (2H, d), 6.3 (2H, s), 7.46
(1H, t), 7.6 (1H, t).
c)
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-(1H--
1,2,3-benzotriazol-1-ylmethyl)thieno[2,3-d]pyridine-2,4(1H,3H)-dione
[0342] The subtitle compound was prepared using the procedure
described in example 1 part g) from the product of part b). MS
(ESI) 486 [M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.87 (3H, s), 0.89
(3H, s), 2.01-2.19 (1H, m), 3.08-3.22 (3H, m), 3.62-4.17 (6H, m),
4.62-4.82 (1H, m), 5.6-5.8 (1H, m), 6.07-6.12 (2H, m), 7.42 (1H,
t), 7.6 (1H, q), 7.93 (1H, m) and 8.04 (1H, d).
EXAMPLE 13 xv
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-(1H-pyr-
rolo[2,3-b]pyridin-1-ylmethyl)thieno)[2,3-a]pyrimidine-2,4(1H,3H)-dione
##STR00037##
[0343] a)
1,2,3,4-Tetrahydro-3-methyl-1-(isobutyl-2,4-dioxo-6-(1H-pyrrolo[-
2,3-b]pyridin-1-ylmethyl)thieno[2,3-d]pyrimidine-5-carboxylic acid,
methyl ester
[0344] The subtitle compound was prepared using the procedure
described in example 3 part c) from the product of example 3 part
b) and 7-azaindole. MS (APCI) 427 [M+H].sup.+. .delta.
.sup.1H.sub.CDCl3 0.85 (3H, s), 0.92 (3H, s), 2.15-2.25 (1H, m),
3.38 (3H, s), 3.66 (3H, d), 4.03 (3H, s), 4.97 (s, 2H), 5.61 (2H,
s), 6.49-6.91 (1H, d), 7.06-7.14 (1H, m), 7.38 (1H, d), 7.91-7.95
(1H, m) and 8.31-8.37 (1H, m).
b)
1,2,3,4-Tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-(1H-pyrrolo[2,3-b]-
pyridin-1-ylmethyl)thieno[2,3-d]pyrimidine-5-carboxylic acid
[0345] The subtitle compound was prepared using the procedure
described in example 3 part d) from the product of part a). MS
(APCI) 412 [M+H].sup.+.
c)
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-(1H--
pyrrolo[2,3-b]pyridin-1-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0346] The subtitle compound prepared using the procedure described
in example 3 part e) from the product of part b). MS (ESI) 484
[M+H].sup.+. .delta. .sup.1H.sub.DMSO 1.82-1.93 (6H, m), 1.16-1.22
(1H, m), 2.02-2.09 (1H, m), 3.20 (3H, s), 3.42-3.98 (4H, m),
4.03-4.18 (1H, m), 4.9-4.81 (1H, m), 5.39-5.61 (3H, m), 6.52 (1H,
d), 7.06-7.18 (1H, m), 7.43-7.57 (1H, m), 7.99 (1H, d) and
8.28-8.33 (1H, m).
EXAMPLE 13 xvi
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[(2-met-
hyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione
##STR00038##
[0347] a)
1,2,3,4-Tetrahydro-3-methyl-1-(isobutyl)-6-[2-methyl-1H-pyrrolo[-
2,3-b]pyridin-1-ylmethyl]-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic
acid, methyl ester
[0348] The subtitle compound was prepared using the procedure
described in example 3 part c) from the product of example 3 part
b) and 2-methyl-7-azaindole. MS (ESI) 441 [M+H].sup.+. .delta.
.sup.1H.sub.CDCl3 0.87 (3H, s), 0.90 (3H, s), 2.04-2.21 (1H, m),
2.48 (3H, s), 3.38 (3H, s), 3.62 (2H, d), 3.9 (s, 3H), 4.21 (2H,
s), 7.01-7.06 (1H, m), 7.76 (1H, d), 8.22 (1H, d), and 8.8 (1H,
(br) s).
b)
1,2,3,4-Tetrahydro-3-methyl-1-(isobutyl)-6-[2-methyl-1H-pyrrolo[2,3-b]p-
yridin-1-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic
acid
[0349] The subtitle compound was prepared using the procedure
described in example 3 part d) from the product of part a). MS
(ESI) 427 [M+H].sup.+.
c) (S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-m-
ethyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3-
H)-dione
[0350] The sub-title compound was prepared using the procedure
described in example 3 part e) from the product of part b). MS
(ESI) 498 [M+H].sup.+. .delta. .sup.1H.sub.CDCl3 0.88 (3H, s), 0.91
(3H, s), 1.2-1.4 (3H, m), 2.13-2.22 (1H, m), 3.38 (3H, s),
3.41-3.59 (2H, m), 3.64-3.8 (1H, m), 4.28-4.4 (4H, m), 4.62-4.8
(2H, m), 5.07-5.18 (1H, m), 6.91-7.04 (1H, m), 7.84 (1H, d), 8.22
(1H, m) and 9.41 (1H, m).
EXAMPLE 13xvii
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[5-cyan-
o-(1H)-indol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00039##
[0351] a)
6-[5-Cyano-1H-indol-1-ylmethyl]-1,2,3,4-tetrahydro-3-methyl-1-(i-
sobutyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid,
methyl ester
[0352] Prepared using the procedure described in example 3 part c)
from the product of example 3 part b) and 5-cyanoindole to give the
subtitle compound, which was purified by flash silica
chromatography eluting with 40% ethyl acetate in isohexane. MS
(ESI) 451 [M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.84-0.86 (6H, d),
2-2.1 (1H, m), 3.2 (3H, s), 3.6-3.63 (2H, d), 4.85 (3H, s), 5.68
(2H, s), 6.67-6.68 (1H, d), 7.53-7.56 (1H, dd), 7.62-7.63 (1H,
d),7.71-7.74 (1H, d), 8.12 (1H, s).
b)
6-[5-Cyano-1H-indol-1-ylmethyl]-1,2,3,4-tetrahydro-3-methyl-1-(isobutyl-
)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid
[0353] Prepared using the procedure described in example 3 part d)
from the product of a) to give the subtitle compound. MS (ESI) 437
[M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.81-0.83 (6H, d), 2-2.1 (1H,
m), 3.19 (3H, s), 3.57-3.59 (2H, d), 5.52 (2H, s), 5.59-5.6 (1H,
d), 7.42-7.45 (1H, d), 7.81-7.82 (1H), 8 (1H, s), 8.15-8.18 (1H,
d).
c)
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[5-c-
yano-(1H)-indol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-3-dione
[0354] Prepared using the procedure described in example 3 part e)
from the product of part b) to give the title compound after
purification by flash silica chromatography eluting with 0-2%
methanol in ethyl acetate. MS (APCI) 508 [M+H].sup.+. .delta.
.sup.1H.sub.DMSO 0.82-0.86 (6H, m), 2-2.1 (1H, m), 3.2 (3H, s),
3.58-3.7 (3H, m), 3.8-3.9 (2H, m), 4-4.1 (1H, m), 4.6-4.8 (1H,
2m),5.5-5.6 (3H, m), 6.66-6.67 (1H, d), 7.49-7.53 (1H, m),
7.62-7.65 (1H, m),7.81-7.84 (1H, d), 8.11 (1H, s).
EXAMPLE 13xviii
(S)
5-{4-Hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(isobutyl)-6-[2-oxo--
1,3-benzothiazol-3(2H)-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00040##
[0355] a) Methyl
1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-[2-oxo-3(2H)-benzoth-
iazolylmethyl]thieno[2,3-d]pyrimidine-5-carboxylate
[0356] The subtitle compound was prepared by the method of example
3 step c) using the product of example 3 step b) and
benzothiazolone. MS (APCI) 460 [M+H].sup.+. .delta.
.sup.1H.sub.D6-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)
1,2,3,4-Tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-[2-oxo-3(2H)-benzt-
hiazolylmethyl]thieno[2,3-d]pyrimidine-5-carboxylic acid
[0357] The subtitle compound was prepared by the method of example
3 step d). using the product of step a). MS (APCI) 468 [M+H].sup.+.
.delta. .sup.1H.sub.D6-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) (S)
5-{4-Hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(isobutyl)-6-[2-o-
xo-1,3-benzothiazol-3(2H)-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e
[0358] The title compound was prepared by the method of example 1
step g). using the product of step b). MS (ES.sup.+)
517[M+H].sup.+. .delta. .sup.1H.sub.D6-DMSO (90.degree. C.) 0.88
(6H, d), 2.11 (1H, non), 3.20 (3H, s), 3.70 (5H, m), 4.09 (1H, dt),
4.58-4.82 (1H, m), 5.21 (2H, m), 5.54 (1H, dd), 7.22 (1H, m), 7.40
(2H, m), 7.69 (1H, d).
EXAMPLE 13 xix
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[1,2,3--
dihydro-6-methyl-3-oxo-pyrazin-2-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione
##STR00041##
[0359] a) Methyl
1,2,3,4-tetrahydro-6-[2,3-dihydro-6-methyl-3-oxo-pyrazin-2-ylmethyl]-3-me-
thyl-1-(isobutyl-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate
[0360] The subtitle compound was prepared from the product of
example 3 part b) and 2,3-dihydro-6-methyl-3-oxo-pyrazine using the
method of example 3 part c). The crude product was purified by
chromatography (SiO.sub.2/EtOAc). MS (APCI) 419 [M+H].sup.+.
.delta. .sup.1H.sub.CDCl3 0.97 (6H, d), 2.23-2.33 (1H, m), 2.29
(3H, s), 3.38 (3H, s), 3.75 (2H, d), 4.03 (3H, s), 5.39 (2H, s),
6.85 (1H, d), 7.07 (1H, d).
b)
1,2,3,4-Tetrahydro-6-[2,3-dihydro-6-methyl-3-oxo-pyrazin-2-ylmethyl]-3--
methyl-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic
acid
[0361] The product of step a) was hydrolysed by the method of
example 1 part f). The crude product was dried in vacuo and used
without further characterisation.
c)
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2,3-
-dihydro-6-methyl-3-oxo-pyrazin-2-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H-
,3H)-dione
[0362] The crude product of step b) was reacted with
(S)-4-hydroxyisoxazolidine hydrochloride using the method of
Example 1 part g), to afford the title compound. The crude product
was purified by reverse phase HPLC using an elution gradient (75%
aqueous ammonium acetate/25% acetonitrile to 100% acetonitrile). MS
(APCI) 476 [M+H].sup.+. .delta. .sup.1H.sub.CDCl3 (spectrum made
complex by existence of rotamers) 1.0 (6H, d), 2.3 (3H, s), 2.5
(1H, m), 3.4 (3H, s), 3.5-3.7 (.about.2H, m), 3.8-4.0 (.about.2H,
m), 4.0-4.2 (.about.2H, m), 4.6-5.0 (.about.2H, m), 5.3-5.6
(.about.2H, dd), 6.9 (1H, m), 7.1 (1H, m).
EXAMPLE 14i
(S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[7-methyl-1H-indol-3-
-ylmethyl]-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a)
1,2,3,4-Tetrahydro-3-methyl-6-[7-methyl-1H-indol-3-ylmethyl]-1-(isobuty-
l)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid, methyl
ester
[0363] The subtitle compound was prepared by the method of example
5 part a) using the product of example 3 part b) and 7-methyl
indole. MS (APCI) 440 [M+H].sup.+. .delta. .sup.1H.sub.CDCl3
0.85-0.89 (6H, d), 2.1-2.2 (1H, m), 2.5 (3H, s), 3.39 (3H, s),
3.62-3.65 (2H, d), 3.98 (3H, s), 4.28 (2H, s), 7.01-7.07 (2H, m),
7.13-7.14 (1H, d), 7.41-7.43 (1H, d), 8 (1H, (br) s).
b)
1,2,3,4-Tetrahydro-3-methyl-6-[7-methyl-1H-indol-3-ylmethyl]-1-(isobuty-
l)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid
[0364] Prepared using the procedure described in example 1 part c)
from the product of step a) to give the subtitle compound. MS
(APCI) 426 [M+H]. .delta. .sup.1H.sub.DMSO 0.80-0.83 (6H, d), 2-2.1
(1H, m), 2.44 (3H, s), 3.25 (3H, s), 3.6-3.62 (2H, d), 4.37 (2H,
s), 6.84-6.89 (2H, m), 7.27-7.31 (2H, m), 11 (1H, bs), 14(1H, (br),
s).
c) (S)
5-[[4-Hydroxyisoxazolidin-2-yl]carbonyl]-3-methyl-6-[7-methyl-1H-in-
dol-3-ylmethyl]-1-(isobutyl
thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0365] Prepared using the procedure described in example 1 part g)
from the product of step b) and (S)-4-hydroxyisoxazolidine
hydrochloride [Example 1 part b] to give the title compound after
purification by flash silica chromatography eluting with 0-3%
methanol in ethyl acetate and recrystallisation from ethyl
acetate:isohexane (9:1). MS (APCI) 497.1 [M+H]. .delta.
.sup.1H.sub.DMSO 0.81-0.84 (6H, m), 2-2.1 (1H, m), 2.44 (3H, s),
3.2 (3H, s), 3.5-3.9 (6H, 3m),4.1-4.2 (2H, m), 4.7-4.8 (1H, 2m),5.5
(1H, d), 6.82-6.87 (2H, m), 7.28-7.38 (2H, m), 10.95 (1H, bs).
EXAMPLE 14ii
(R)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-methyl-1H-indol-3-
-ylmethyl]-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
a) Methyl
1,2,3,4-tetrahydro-3-methyl-6-[2-methyl-1H-indol-3-ylmethyl]-1-(-
isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid,
methyl ester
[0366] Prepared by the method of example 5 part a) from the product
of example 3 part
a) and 2-methylindole. MS (ESI) 440 [M+H].sup.+. .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-(isobuty-
l)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid
[0367] Prepared by the method of example 3 part d) from the product
of part a). MS (ESI) 426 [M+H].sup.+. .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) (R)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-methyl-1H-indo-
l-3-ylmethyl]-1-(isobutyl
thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0368] Prepared by the method of example 3 part d) from the product
of part a) and (R)-4-isoxazolidinol hydrochloride [example 2b)]. MS
(APCI) 497 [M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.80-0.83 (6H, m),
1.98-2.08 (1H, m), 2.37 (1H, s), 3.19 (1.5H, s), 3.21 (1.5H, s),
3.50-3.65 (3H, m), 3.70-3.93 (2H, m), 4.00-4.18 (3H, m), 4.62-4.83
(1H, m), 5.50 (0.5H, d, br), 5.54 (0.5H, d), 6.90 (1H, t), 6.98
(1H, t), 7.25 (1H, d), 7.39 (0.5H, d), 7.43 (0.5H, d), 10.91 (1H,
s).
EXAMPLE 14iii
(S)
5-[4-Hydroxyisoxazoldin-2-ylcarbon]-3-methyl-6-[(2-methyl)-1H-pyrrolo[-
2,3-b]pyridin-3-yl)methyl]-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dio-
ne
##STR00042##
[0369] a) Methyl
3-methyl-6-[(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-2,4-dioxo-1-p-
ropyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate
[0370] The subtitle compound was prepared from the product of
example 9 part c and 2-methyl-1H-pyrrolo[2,3-b]pyridine using the
method of example 6 part b. MS (ESI) 427 [M+H].sup.+. .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-b]pyridin-3-yl)methyl]-2,4--
dioxo-1-propyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate
[0371] The subtitle compound was prepared from the product of step
a using the method of example 1 part f. MS (ESI) 413 [M+H].sup.+.
.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) (S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl)-1H-py-
rrolo[2,3-d]pyridin-3-yl)methyl]-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3-
H)-dione
[0372] Prepared from the product of part b) and
(S)-4-isoxazolidinol hydrochloride [example 1, part b)] following
the procedure of example 1, part g) to give the title compound as a
solid. MS (APCI) 484 [M+H].sup.+. .delta. .sup.1H.sub.D6-DMSO 0.84
(3H, d), 1.64 (2H, d), 2.38 (3H, s), 3.22 (3H, s), 3.41 (1H, d),
3.75 (3H, m), 3.93 (2H, s), 4.10 (2H, m), 4.70 (1H, s), 5.00 (1H,
s), 6.91 (1H, s), 7.76 (1H, d), 8.06 (1H, s), 10.92 (1H, s).
EXAMPLE 15i
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-3H--
imidazo[4,5-b]pyridin-3-ylmethyl]-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione
a)
1,2,3,4-Tetrahydro-3-methyl-6-[2-(methylamino)-3H-imidazo[4,5-b]pyridin-
-3-ylmethyl]-2,4-dioxo-1-propyl-thieno[2,3-d]pyrimidine-5-carboxylic
acid, methyl ester
[0373] The subtitle compound was prepared by the method of example
13xii) part a) using the product of example 9 part c). MS (ESI) 456
[M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.83 (3H, s), 0.85 (3H, s),
2.04-2.11 (1H, m), 2.94 (2H, d), 3.19 (3H, s), 3.6 (2H, d), 3.85
(3H, s), 5.4 (2H, s), 6.83-6.9 (2H, m), 6.97 (1H, t), 7.22 (1H,
d).
b)
1,2,3,4-Tetrahydro-3-methyl-6-[2-(methylamino)-3H-imidazo[4,5-b]pyridin-
-3-ylmethyl]-2,4-dioxo-1-propyl-thieno[2,3-d]pyrimidine-5-carboxylic
acid
[0374] Prepared using the procedure described in example 3 part d)
from the product of part a) to give the subtitle compound. MS
(APCI) 428 [M+H].sup.+.
c)
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-methylamino)-3-
H-imidazo[4,5-b]pyridin-3-ylmethyl]-1-propyl-thieno[2,3-d]pyrimidine-2,4(1-
H,3H)-dione
[0375] Prepared using the procedure described in example 3 part e)
from the product of part b) to give the title compound. MS (APCI)
499 [M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.81 (3H, m), 0.86 (2H,
m), 1.58-1.61 (3H, s), 2.9 (3H, s), 3.2 (3H, s), 3.64-4.2 (6H, m),
5.18-5.62 (3H, m), 6.88-6.99 (3H, m), 7.2-7.3 (2H, m).
EXAMPLE 15 ii
(S)-5-[4-Hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-propyl-6-[4,5-Dichlo-
ro-2-methyl-1H-imidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e
##STR00043##
[0376] a)
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-carboxylic
acid, methyl ester
[0377] Prepared using the procedure described in example 3 part c)
from the product of example 9 part c) to give the subtitle
compound. MS (APCI) 445/447 [M+H].sup.+. .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). Mpt. 155-156.degree. C.
b)
6-[4,5-Dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahydro-3-m-
ethyl-2,4-dioxo-1-propyl-thieno[2,3-d]pyrimidine-5-carboxylic acid,
sodium salt
[0378] Prepared using the procedure described in example 3 part d)
from the product of example part a) to give the sub-title compound.
MS (APCI 431/433[M+H].sup.+. .delta. .sup.1H.sub.DMSO-d6 0.87 (3H,
t), 1.67 (2H, sextet), 2.38 (3H, s), 3.19 (3H, s), 3.78 (2H, t),
5.23 (2H, s).
c)
(S)-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-propyl-6-[4,5-dic-
hloro-2-methyl-1H-imidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)--
dione
[0379] Prepared using the procedure described in example 3 part e)
from the product of example part b) to give the title compound. MS
(APCI) 502/504[M+H].sup.+. .delta. .sup.1H.sub.CDCl3 1.01 (3H, t),
1.79 (2H, sextet), 2.39 (3H, s), 3.35+3.38 (3H, 2.times.s ratio
1:4), 3.47-3.57 (1H, m), 3.81-3.96 (2H, m), 4.01-4.10 (2H, m), 4.57
(1H, d), 4.58-4.75 (1H, m), 4.93 (1H, d), 5.19-5.27 (2H, m).
EXAMPLE 15iii
5-[(4S)-4-Hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benzim-
idazol-1-ylmethyl]-3-methyl-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-di-
one
##STR00044##
[0380] a)
1,2,3,4-tetrahydro-6-[2-(hydroxymethyl)-1H-benzimidazol-1-ylmeth-
yl]-3-methyl-2,4-dioxo-1-propyl-thieno[2,3-d]pyrimidine-5-carboxylic
acid, methyl ester
[0381] Sodium hydride (60 mg, 60% suspension) was added to
2-benzimidazolemethanol (210 mg) in anhydrous DMF under nitrogen at
0.degree. C. After 10 minutes, product of example 9c (500 mg) in
DMF was added dropwise and the reaction mixture was stirred at room
temperature for 3 hours. Water was added and a precipitate occurred
which was filtered, washed with ethyl acetate then ether to give
the title compound as a yellow solid (230 mg). The filtrate was
extracted twice with dichloromethane. The organics were dried over
magnesium sulfate and concentrated in vacuo to give a brown solid
which was combined with the product obtained earlier to give the
title compound as a pale brown solid (480 mg). MS (ES) 443
[M+H].sup.+. *.delta. .sup.1H.sub.DMSO 0.79-0.84 (3H, t), 1.52-1.62
(2H, q), 3.19 (3H, s), 3.69-3.74 (2H, t), 3.85 (3H, s), 4.77-4.79
(2H, d), 5.71 (2H, s), 5.84-5.88 (1H, t), 7.17-7.26 (2H, m),
7.51-7.54 (1H, d), 7.61-7.63 (1H, d).
b) Sodium
1,2,3,4-tetrahydro-6-[2-(hydroxymethyl-1H-benzimidazol-1-ylmethy-
l]-3-methyl-2,4-dioxo-1-propyl-thieno[2,3-d]pyrimidine-5-carboxylate
[0382] Prepared from product of example 15iii part a) (420 mg)
using method of example 1 part f) to give the title compound as a
white solid (260 mg). MS (ES) 429 [M+H].sup.+.
c)
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-ben-
zimidazol-1-yl
methyl]-3-methyl-1-propyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0383] Prepared from product of example 15iii part b) using method
of example 13vii part c). The crude material was purified by
reverse-phase preparative HPLC eluting from 25% to 95% acetonitrile
in 0.1% ammonium acetate aqueous solution to give the title
compound (75 mg). MS (ES) 500. 1583 [M+H].sup.+. .delta.
.sup.1H.sub.DMSO 0.79-0.84 (3H, t), 1.54-1.59 (2H, m), 3.2 (3H, s),
3.6-4.2 (6H, range of m), 4.6-4.8 (3H, 2m), 5.4-5.9 (4H, m),
7.18-7.20 (2H, m), 7.6-7.66 (2H, m).
EXAMPLE 15iv
5-[(4S)-4-Hydroxyisoxazoldin-2-ylcarbonyl]-3-methyl-1-propyl-6-[2-amino-1H-
-benzimidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00045##
[0384] a)
6-[2-amino-1H-benzimidazol-1-ylmethyl]-1,2,3,4-tetrahydro-3-meth-
yl-2,4-dioxo-1-propyl-thieno[2,3-d]pyrimidine-5-carboxylic acid,
methyl ester
[0385] Sodium hydride (60 mg, 60% suspension) was added to
2-aminobenzimidazole (200 mg) in anhydrous DMF under Nitrogen.
After 10 minutes, product of example 9c (500 mg) in dry DMF was
added dropwise and the reaction mixture was stirred at room
temperature for 3 hours. Water was added and a precipitate occurred
which was filtered, washed with ethyl acetate then ether to give
the title compound as brown-orange crystals (220 mg). MS (ES) 428
[M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.81-0.86 (3H, t), 1.54-1.66
(2H, q), 3.19 (3H, s), 3.72-3.76 (2H, t), 3.88 (3H, s), 5.4 (2H,
s), 6.6 (2H, s), 6.84-6.89 (1H, t), 6.93-6.98 (1H, t), 7-7.15 (2H,
m).
b)
6-[2-amino-1H-benzimidazol-1-ylmethyl]-1,2,3,4-tetrahydro-3-methyl-2,4--
dioxo-1-propyl-thieno[2,3-d]pyridine-5-carboxylic acid
[0386] Prepared from product of example 15iv part a) (220 mg) by
the method of example 1 part f) to give the title compound as a
pale yellow solid (190 mg). MS (ES) 414 [M+H].sup.+.
c)
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-[1-propyl-6-[2-ami-
no-1H-benzimidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0387] Prepared from the product of example 15iv part b) (190 mg)
by the method of example 13vii part c). The crude material was
purified by reverse-phase preparative HPLC eluting from 5% to 95%
acetonitrile in 0.1% ammonium acetate aqueous, followed by
trituration and filtration with methanol to give the title compound
as a white solid (19 mg). MS (ES) 485.1631 [M+H].sup.+. .delta.
.sup.1H.sub.DMSO 0.82-0.86 (3H, t), 1.57-1.62 (2H, q), 3.19 (3H,
s), 3.65-4.15 (6H, range of m), 4.65-4.80 (1H, m), 5.26-5.60 (3H,
m), 6.63-6.69 (2H, bm), 6.84-6.87 (1H, t), 6.93-6.97 (1H, t),
7.12-7.14 (1H, d), 7.20-7.27 (1H, 2d).
EXAMPLE 16 i)
(S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-1H--
benzimidazol-1-ylmethyl]-1-(isopropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-d-
ione
##STR00046##
[0388] a)
1,2,3,4-Tetrahydro-3-methyl-6-[2-(methylamino)-1H-benzimidazol-1-
-ylmethyl]-1-(isopropyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic
acid, methyl ester
[0389] Prepared using the procedure described in example 13 vii)
part a) from the product of example 8 part c) and
2-methylaminobenzimidazole to give the sub-title compound after
trituration with ethyl acetate followed by filtration. MS (ESI) 442
[M+H].sup.+. .delta. .sup.1H.sub.DMSO 1.40-1.42 (6H, d), 2.94-2.96
(3H, d), 3.16 (3H, s), 3.85 (3H, s), 4.3 (1H, bs), 5.39 (2H, s),
6.84-6.99 (3H, m), 7.11-7.14 (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-(isopropyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic
acid
[0390] Prepared using the procedure described in example 3 part d)
from the product of part a) to give the subtitle compound. MS (ESI)
428 [M+H].sup.+.
c) (S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)--
1H-benzimidazol-1-ylmethyl]-1-(isopropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H-
)-dione
[0391] Prepared using the procedure described in example 13 vii)
part c) from the product of part b) to give the subtitle compound
after purification by flash silica chromatography eluting with 0-3%
methanol in dichloromethane followed by trituration with ether. MS
(APCI) 499 [M+H].sup.+. .delta. .sup.1H.sub.DMSO 1.41-1.42 (6H, m),
2.94-2.95 (3H, d), 3.17 (3H, s), 3.55-3.66 (1H, 2d), 3.81-3.84 (1H,
m), 3.89-4(1H, m), 4-4.1 (1H, m), 4.1-4.2 (1H, m),4.6-4.75 (1H,
2m), 5.17-5.26 (1H, m), 5.37-5.44 (1H, 2m), 5.52-5.61 (1H,
2m),6.89-6.99 (3H, m), 7.19-7.30 (2H, m).
EXAMPLE 16 ii
(S)-5-[4-Hydroxy-2-isoxazolidinylcarbonyl]-6-[4,5-dichloro-2-methyl-1HH-im-
idazol-1-ylmethyl-3-methyl-1-(isopropyl)thieno[2,3-d]pyrimidine-5-carboxam-
ide
##STR00047##
[0392] a)
6-[4,5-Dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahy-
dro-3-methyl-1-(isopropyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic
acid, methyl ester
[0393] Prepared using the procedure described in example 3 part c)
from the product of example 8 part c) to give the subtitle
compound. MS (APCI) 445/446 [M+H].sup.+. .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).
b)
6-[4,5-Dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahydro-3-m-
ethyl-1-(isopropyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic
acid, sodium salt
[0394] Prepared using the procedure described in example 3 part d)
from the product of example part a) to give the sub-title compound.
MS (APCI 431/433 [M+H].sup.+. .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).
c)
(S)-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-6-[4,5-Dichloro-2-methyl-1H--
imidazol-1-ylmethyl-3-methyl-1-(isopropyl)thieno[2,3-d]pyrimidine-5-carbox-
amide
[0395] Prepared using the procedure described in example 3 part e)
from the product of part b) to give the title compound. MS (APCI)
502/504 [M+H]. .delta. .sup.1H.sub.CDCl3 1.55-1.61 (6H, m), 2.39
(3H, s), 3.33 (3H, s), 3,51(1H, dd), 4.01-4.09 (2H, m), 4.40-4.55
(1H, br.s), 4.57 (1H, d); 4.68-4.75 (1H, m); 4.95 (1H, d);
5.15-5.28 (2H, m).
EXAMPLE 16iii
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benzimi-
dazol-1-yl
methyl]-3-methyl-1-(isopropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H-
)-dione
##STR00048##
[0396] a)
1,2,3,4-tetrahydro-6-[2-(hydroxymethyl)-1H-benzimidazol-1-ylmeth-
yl]-3-methyl-1-(isopropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic
acid, methyl ester
[0397] Sodium hydride (79 mg, 60% suspension) was added to
2-benzimidazolemethanol (280 mg) in anhydrous DMF under Nitrogen at
0.degree. C. After 10 minutes, product of example 8b (660 mg) in
DMF was added dropwise and the reaction mixture was stirred at room
temperature for 3 hours. Water was added and a precipitate occurred
which was filtered, washed with ethyl acetate then ether to give
the title compound as an off-white solid (350 mg). MS (ES) 443
[M+H].sup.+. .delta. .sup.1H.sub.DMSO 1.39-1.41 (6H, d), 3.18 (3H,
s), 3.85 (3H, s), 4.32 (1H, bs), 4.78-4.80 (2H, s), 5.71 (2H, s),
5.86 (1H, bs), 7.23 (2H, m), 7.55-7.57 (1H, d), 7.61-7.64 (1H,
d).
b) Sodium
1,2,3,4-tetrahydro-6-[2-(hydroxymethyl)-1H-benzimidazol-1-ylmeth-
yl]-3-methyl-1-(isopropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylate
[0398] Prepared from product of example 16iii part a) (350 mg)
using the method of example 1 part f) to give the title compound as
a white solid (340 mg). MS (ES) 429 [M+H].sup.+.
c)
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benz-
imidazol-1-ylmethyl-3-methyl]-1-(isopropyl)-thieno[2,3-d]pyrixndine-2,4(1H-
,3H)-dione
[0399] Prepared from product of example 16iii part b) using the
method of example 13vii part c). The crude material was purified by
reverse-phase preparative HPLC eluting from 25% to 95% acetonitrile
in 0.1% ammonium acetate aqueous solution to give the
title-compound (110 mg). MS (ES) 500.1610 [M+H].sup.+. .delta.
.sup.1H.sub.DMSO 1.37-1.40 (6H, m), 3.18 (3H, s), 3.5-4.4 (5H,
range of m), 4.6-4.8 (3H, 2m), 5.5-6.9 (4H, m), 7.17-7.21 (2H, m),
7.59-7.68 (2H, m).
EXAMPLE 16iv
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-ami-
no-1H-benzimidazol-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00049##
[0400] a)
6-[2-amino-1H-benzimidazol-1-ylmethyl]-1,2,3,4-tetrahydro-3-meth-
yl-1-(isopropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic
acid, methyl ester
[0401] Prepared from the product of example 8b (660 mg) and
2-aminobenzimidazole (250 mg) by the method of example 13vii part
a). The crude material was purified by flash silica chromatography
eluting with 50% ethyl acetate in isohexane then 4% methanol in
dichloromethane containing 0.1% triethylamine to give the title
compound as a yellow foam (360 mg). MS (ES) 428[M+H].sup.+. .delta.
.sup.1H.sub.DMSO 1.40-1.42 (6H, d), 3.17 (3H, s), 3.88 (3H, s), 4.3
(1H, bs), 5.42 (2H, s), 6.62 (2H, s), 6.87-6.90 (1H, t), 6.93-6.98
(1H, t), 7.11-7.15 (2H, m).
b) Sodium 6-[2-amino-1H-benzimidazol-1-yl
methyl]-1,2,3,4-tetrahydro-3-methyl-1-(isopropyl)-2,4-dioxo-thieno[2,3-d]-
pyrimidine-5-carboxylate
[0402] Prepared from the product of example 16iv part a) (360 mg)
by the method of example 1 part f) to give the title compound as a
white solid (190 mg). MS (ES) 414 [M+H].sup.+.
c)
(S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2--
amino-1H-benzimidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0403] Prepared from the product of example 16iv part b) (190 mg)
by the method of example 13vii part c). The crude material was
purified by reverse-phase preparative HPLC eluting from 25% to 95%
acetonitrile in 0.1% ammonium acetate aqueous, followed by
trituration with methanol and filtration to give the title compound
as a white solid (20 mg). MS (ES) 485.1623 [M+H].sup.+. .delta.
.sup.1H.sub.DMSO 1.35-1.42 (6H, m), 3.18 (3H, m), 3.6-4.4 (5H,
range of m), 4.6-4.8 (1H, m), 5.2-5.6 (3H, m), 6.7-6.8 (2H, bs),
6.86-6.90 (1H, t), 6.95-6.98 (1H, t), 7.13-7.15 (1H, d), 7.2-7.3
(1H, 2d).
EXAMPLE 16 v
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-met-
hyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione
##STR00050##
[0404] a)
1,2,3,4-Tetrahydro-3-methyl-1-(isopropyl)-6-[2-methyl-1H-pyrrolo-
[2,3-b]pyridin-1-yl
methyl]-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid
[0405] To a stirred suspension of 60% sodium hydride (0.15 g) in
THF (5 ml) was added a solution of 2-methylazaindole (0.25 g) in
THF (5 ml) dropwise under nitrogen at ambient temperature. After
stirring for 5 minutes. it was cooled to 0.degree. C. a solution of
the product of example 22, part a) (0.60 g) in THF (10 ml) was
added and the mixture warmed to room temperature and stirred for 5
hours. It was quenched with water, acidified with 2.5M HCl and
extracted with dichloromethane, the 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/1-hexane (1:1) followed by
ethyl acetate/methanol (9:1) to give the sub-title compound as a
solid (0.06 g). MS (ESI) 413 [M+H].sup.+. .delta. .sup.1H.sub.DMSO
1.36 (6H, d), 3.17 (3H, s), 4.20 (1H, s, br), 5.73 (2H, s), 6.32
(1H, s), 7.09-7.12 (1H, s), 7.88-7.90 (1H, m), 8.20-8.21 (1H,
m).
b)
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2--
methyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione
[0406] Prepared from the product of part a) and
(S)-4-isoxazolidinol hydrochloride [example 1, part b)] following
the procedure of example 1, part g) to give the title compound as a
solid. MS (APCI) 484 [M+H].sup.+. .delta. .sup.1H.sub.DMSO
1.38-1.40 (6H, m), 2.41 (3H, m), 3.16-3.19 (3H, m), 3.54-4.25 (5H,
m), 4.60 4.73 (1H, m), 5.42-5.58 (3H, m), 6.29 (1H, s), 7.09-7.13
(1H, m), 7.88 (1H, dd), 8.22-8.26 (1H, m).
EXAMPLE 17i
(S)-5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[3,5-d]-
ethyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00051##
[0407] a)
6-[3,5-Diethyl-1H-pyrazol-4-ylmethyl]-3-methyl-1-(isobutyl)-2,4--
dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic
acid
[0408] Prepared using the procedure described in example 12 part a)
from the product of example 3 part c) (1 g) and 3,5-heptanedione to
give the subtitle compound as a solid (0.37 g). MS (ESI) 419
[M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.86 (6H, d), 1.10 (6H, t),
2.05-2.15 (1H, m), 2.49 (4H, q), 3.26 (3H, s), 3.66 (2H, d), 4.06
(2H, s).
b) (S)
5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[3,5-
-diethyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,
3m)-dione
[0409] Prepared using the procedure described in example 3 part e)
from the product of part a) and (S)-4-hydroxyisoxazolidine
hydrochloride {example 1, part b)} to give the title compound as a
solid (145 mg). MS (ESI) 490 [M+H].sup.+. .delta. .sup.1H.sub.DMSO
0.86 (6H, d), 1.09 (6H, t), 2.03-2.19 (1H, m), 2.49-2.52 (4H, m),
3.19 (2H, s), 3.21 (1H, s), 3.50 (0.67H, d), 3.35-3.63 (1H, m),
3.70 (1H, dd), 3.75-3.80 (3H, m), 3.84 (0.67H, dd), 3.90-4.05 (1H,
m), 4.09 (0.67H, dd), 4.58-4.80 (1H, m), 5.51 (1H, d), 12.18 (1H,
s, br).
EXAMPLE 17 ii
(S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[3-(1-d-
imethylethyl)-5-methyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1-
H,3H)-dione
##STR00052##
[0411] Prepared using the procedure described in example 12 part b)
from the product of example 12 part a),
5,5-dimethylhexane-2,4-dione and 35% aqueous hydrazine solution to
give the title compound as a solid. MS (ESI) 504 [M+H].sup.+.
.delta. .sup.1H.sub.DMSO 0.85 (6H, d), 1.23 (9H, s), 1.99-2.06 (4H,
m), 3.19 (2.25H, s), 3.21 (0.7525H, s), 3.50-3.60 (2H, m),
3.64-3.72 (1H, m) 3.79 (1H, m), 3.83-3.96 (33H, m), 3.98-4.05
(0.25H, m), 4.07 (0.75H, dd), 4.58-4.78 (1H, m), 5.51 (1H, d),
12.08 (1H, s, br).
EXAMPLE 18i
(S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-meth-
yl-4-quinolinylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00053##
[0412] a) N-Methoxy-N,2-dimethyl-4-quinolinecarboxamide
[0413] To a solution of 2-methyl-4-quinolinecarboxylic acid (8.2 g)
in dichloromethane (100 ml) containing DMF (1 drop) was added
oxalyl chloride (4.5 ml). This mixture was heated at reflux for 1
hour. After concentrating to dryness in vacuo the residue was
redissolved in dichloromethane (50 ml), triethylamine (17 ml) was
added followed by N,O-dimethylhydroxylamine (8.2 g) and the
reaction was stirred at ambient temperature for 16 hours. The
reaction mixture was washed with water (2.times.100 ml), the
organic solution was evaporated and the residue was purified by
chromatography eluting with ethyl acetate to give the subtitle
compound as a brown oil (10 g). MS (ESI) 231 {M+H].sup.+. .delta.
.sup.1H.sub.CDCl3 2.77 (3H, s), 3.24/3.40 (3H, s), 3.47/3.74 (3H,
s), 7.26 (1H, s), 7.52 (1H, t), 7.71 (1H, t), 7.80 (1H, d), 8.06
(1H, d).
b) 2-Methyl-4-quinolinecarboxaldehyde
[0414] A solution of 2.5 N diisobutylaluminium hydride in toluene
(5.6 ml) was added to a solution of the product of step a) (1.6 g)
in anhydrous toluene (40 ml) at -78.degree. C. After 2 hours the
reaction was quenched by the addition of sodium potassium tartrate
(5 g) in water (25 ml) and allowed to warn to room temperature. The
organic phase was collected, washed with water, dried over
magnesium sulfate and concentrated to dryness in vacuo. The residue
was the purified by chromatography eluting with 30% ethyl acetate
in i-hexane to give the subtitle compound (0.82 g). .delta.
.sup.1H.sub.CDCl3 2.87 (3H, s), 7.26 (1H, s), 7.67 (1H, ddd), 7.69
(1H, s), 7.78 (1H, ddd), 8.12 (1H, d), 8.96 (1H, d), 10.49 (1H,
s).
c) 1,1-Dimethylethyl
1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-
-5-carboxylate
[0415] To a solution of the product of example 1 part c) (2.0 g) in
dichloromethane (12 ml) containing DMF (1 drop) was added oxalyl
chloride (1.0 ml). This mixture was stirred at room temperature for
1 hour. After concentrating to dryness in vacuo the residue was
redissolved in dichloromethane (8 ml), triethylamine (4 ml) was
added followed by 2-methylpropan-2-ol (8.0 ml) and the reaction
stirred at ambient temperature for 4 hours. The reaction mixture
was washed with water (2.times.100 ml), the organic phase was dried
and evaporated and the residue was purified by chromatography
eluting with i-hexane/ethyl acetate (5:1) to give the subtitle
compound as an orange oil (1.6 g). .delta. .sup.1H.sub.CDCl3 0.99
(6H, d), 1.61 (9H, s), 2.31 (1H, non), 3.42 (3H, s), 3.80 (2H, d),
7.26 (1H, s).
d) 1,1-Dimethylethyl
1,2,3,4-tetrahydro-6-[hydroxy(2-methyl-4-quinolinyl)methyl]-3-methyl-1-(i-
sobutyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate
[0416] The subtitle compound was prepared by the method of example
1 step d) using the products of step c) and step b). MS (ESI)
510{M+H].sup.+. .delta. .sup.1H.sub.CDCl3 0.85 (6H, d), 1.66 (9H,
s), 2.11 (1H, m), 2.82 (3H, s), 3.39 (3H, s), 3.48 (1H, dd), 3.53
(1H, d), 3.71 (1H, dd), 6.72 (1H, d), 7.44 (1H, t), 7.67 (1H, t),
7.72 (1H, s), 7.82 (1Hd), 8.07 (1H, d).
e) 1,1-Dimethylethyl
1,2,3,4-tetrahydro-3-methyl-1-(isobutyl-6-[(2-methyl-4-quinolinyl)methyl]-
-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate
[0417] Methane sulphonyl chloride (0.46 ml) was added to a solution
of the product of step d) (1.42 g) and triethylamine (1.54 ml) in
anhydrous THF (30 ml) at room temperature under nitrogen and the
mixture was stirred for 40 minutes. 10% palladium on charcoal (320
mg) was added and the mixture hydrogenated at 5 bar for 2 hours.
The suspension was filtered through celite, washing with methanol
(100 ml). The organic material was concentrated under reduced
pressure and the residue was purified by column chromatography,
eluting with 1:3 ethyl acetate/1-hexane, to give the sub-title
compound as a solid (1.0 g). MS (ESI) 495 {M+H].sup.+. .delta.
.sup.1H.sub.CDCl3 0.91 (6H, d), 1.61 (9H, t), 2.18 (1H, non), 2.74
(3H, s), 3.40 (3H, s), 3.64 (2H, d), 4.55 (2H, s), 7.18 (1H, s),
7.52 (1H, t), 7.71 (1H, t), 8.05-8.07 (2H, m).
f)
1,2,3,4-Tetrahydro-3-methyl-1-(isobutyl)-6-[2-methyl-4-quinolinylmethyl-
]-2,4 dioxothieno[2,3-d]pyrimidine-5-carboxylic acid
[0418] To a solution of the product of step e) (0.82 g) in
dichloromethane (15 ml) under nitrogen was added trifluoroacetic
acid (3 ml), and the mixture was stirred for 1 hour. Saturated
sodium bicarbonate solution (100 ml) was added and the mixture
extracted into dichloromethane; the organic phase was washed with
water (200 ml), dried over magnesium sulphate, filtered and
concentrated to dryness to give the sub-title compound as a red
solid (0.72 g). .delta. .sup.1H.sub.DMSO 0.87 (6H, d), 2.13 (1H,
non), 2.76 (3H, s), 3.51 (3H, s), 3.65 (2H, d), 5.21 (2H, s), 7.21
(1H, s), 7.48 (1H, t), 7.70 (1H, t), 7.89 (1H, d), 8.06 (1H,
d).
g) (S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-m-
ethyl-4-quinolinylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0419] The subtitle compound was prepared by the method of example
1 step g) using the products from part f) and example 1 part b). MS
(APCI) 509{M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.85 (6H, m),
2.00-2.12 (1H, m), 2.62 (3H, s), 3.21 (3H, s), 3.55-4.12 (6H, m),
4.47-4.63 (2H, m), 4.79 (1H, s, br), 5.54 (1H, s, br), 7.31/7.36
(1H, s), 7.54-7.56 (1H, m), 7.71 (1H, t), 7.93 (1H, d), 8.16-8.23
(1H, m).
EXAMPLE 18 ii
(S)
6-[6-Fluoro-4-quinolinylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-
-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00054##
[0420] a)
6-[6-Fluoro-4-quinolinyl(hydroxy)methyl]-3-methyl-1-(isobutyl)-2-
,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic
acid, ethyl ester
[0421] Prepared using the procedure described in example 1 part d)
from the product of example 1 part c) and
6-fluoro-4-quinolinecarbaldehyde to give the subtitle compound. MS
(ESI) 486 [M+H].sup.+. .delta. .sup.1H.sub.CDCl3 0.87 (3H, d), 0.90
(3H, d), 1.42 (3H, t), 2.07-2.21 (1H, m), 3.38 (3H, s), 3.51 (1H,
dd), 3.63 (1H, d), 3.75 (1H, dd), 4.49 (2H, q), 6.65 (1H, d), 7.48
(1H, td), 7.57 (1H, dd), 7.84 (1H, d), 8.17 (1H, dd), 8.98 (1H,
d).
b)
6-[6-Fluoro-4-quinolinylmethyl]-3-methyl-1-(isobutyl-2,4-dioxo-1,2,3,4--
tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic, acid ethyl
ester
[0422] Prepared using the procedure described in example 1 part e)
from the product of part a) to give the subtitle compound. MS (ESI)
470 [M+H].sup.+. .delta. .sup.1H.sub.CDCl3 0.91 (6H, d), 1.38 (3H,
t), 2.13-2.26 (1H, m), 3.40 (3H, s), 3.65 (2H, d), 4.46 (2H, q),
4.53 (2H, s), 7.31 (1H, d), 7.51 (1H, td), 7.75 (1H, dd), 8.16 (1H,
dd), 8.85 (1H, d).
c)
6-[6-Fluoro-4-quinolinylmethyl-3-methyl]-1-(isobutyl)-2,4-dioxo-1,2,3,4-
-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid, sodium
salt
[0423] Prepared using the procedure described in example 1 part f)
from the product of part b) to give the subtitle compound. MS
(ES)+442 [M+2H--Na].sup.+. .delta. .sup.1H.sub.DMSO 0.81 (6H, d),
2.02-2.16 (1H, m), 3.20 (3H, s), 3.56 (2H, d), 4.51 (2H, s), 7.59
(1H, d), 7.63 (1H, td), 8.06 (1H, dd), 8.61 (1H, dd), 8.82 (1H,
d).
d) (S)
6-[6-Fluoro-4-quinolinylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbon-
yl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0424] Prepared using the procedure described in example 1 part g)
from the product of part c) and (S)-4-hydroxyisoxazolidine
hydrochloride {example 1 part b)} to give the title compound. MS
(ESI) 513 [M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.82-0.85 (6H, m),
2.04-2.17 (1H, m), 3.21 (2H, s), 3.22 (1H, s), 3.55-3.68 (3H, m),
3.75-4.13 (3H, m), 4.50-4.71 (2.33H, m), 4.78-4.81 (0.67H, m),
5.50-5.56 (1H, m), 7.42-7.53 (1H, m), 7.69 (1H, td), 8.02-8.16 (2H,
m), 8.86 (1H, d). (* N.B. mixture of rotamers, minor rotamer peaks
not quoted; spectrum simplified at higher temperatures)
EXAMPLE 18iii)
(S)
6-[8-Fluoro-4-quinolinylmethyl]-5-[4-hydroxyisoxazolidin-2-Ylcarbonyl]-
-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00055##
[0425] a)
6-[8-Fluoro-4-quinolinyl(hydroxy)methyl]-3-methyl-1-(isobutyl)-2-
,4-dioxo-1,2,34-tetrahydrothieno[2,3-d]piyimidine-5-carboxylic
acid, ethyl ester
[0426] Prepared using the procedure described in example 1 part d)
from the product of example 1 part c) and
8-fluoro-4-quinolinecarbaldehyde to give the subtitle compound. MS
(ESI) 486 [M+H].sup.+. .delta. .sup.1H.sub.CDCl3 0.85 (3H, d), 0.88
(3H, d), 1.43 (3H, t), 2.05-2.19 (1H, m), 3.38 (3H, s), 3.47 (1H,
dd), 3.65 (1H, d), 3.74 (1H, dd), 4.49 (2H, q), 6.74 (1H, d),
7.38-7.50 (2H, m), 7.69 (1H, d), 7.91 (1H, dd), 9.07 (1H, d).
b)
6-[8-Fluoro-4-guinohnylmethyl]-3-methyl-1-(isobutyl)-2,4-dioxo-1,2,3,4--
tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid, ethyl
ester
[0427] Prepared using the procedure described in example 1 part e)
from the product of part a) to give the subtitle compound. MS (ESI)
470 [M+H].sup.+. .delta. .sup.1H.sub.CDCl3 0.91 (6H, d), 1.37 (3H,
t), 2.13-2.23 (1H, m), 3.39 (3H, s), 3.65 (2H, d), 4.45 (2H, q),
4.60 (2H, s), 7.31 (1H, d), 7.73 (1H, d), 7.44 (1H, td), 7.51-7.57
(1H, m), 7.91 lhd 8.94 (1H, d).
c)
6-[8-Fluoro-4-quinolinylmethyl]-3-methyl-1-(isobutyl)-2,4-dioxo-1,2,3,4-
-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid sodium
salt
[0428] Prepared using the procedure described in example 1 part f)
from the product of part b) to give the subtitle compound. MS (ESI)
442 [M+2H--Na].sup.+. .sup.1H.sub.DMSO 0.81 (6H, d), 2.03-2.13 (1H,
m), 3.20 (3H, s), 3.57 (2H, d), 4.55 (2H, s), 7.53-7.58 (2H, m),
7.63 (1H, d), 8.45-8.50 (1H, m), 8.88 (1H, d).
d) (S)
6-[8-Fluoro-4-quinolinylmethyl]-5-{4-hydroxyisoxazolidin-2-ylcarbon-
yl-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3m)-dione
[0429] Prepared using the procedure described in example 1 part e)
from the product of part c) and (S)-4-hydroxyisoxazolidine
hydrochloride {example 1 part b)} to give the title compound. MS
(ESI) 513 [M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.83-0.85 (6H, m),
2.04-2.15 (1H, m), 3.21 (2H, s), 3.22 (1H, s), 3.52-3.72 (3H, m),
3.76-4.12 (3H, m), 4.55-4.70 (2.33H, m), 4.78-4.81 (0.67H, m),
5.50-5.57 (1H, m), 7.52 (0.33H, d), 7.56 (0.67H, d), 7.58-7.63 (2H,
m), 8.05-8.13 (1H, m), 8.92 (1H, d). (* N.B. 2:1 mixture of
rotamers)
EXAMPLE 18iv
(S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-(5-quin-
olinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00056##
[0430] a)
6-[Hydroxy(5-quinolinylmethyl]-3-methyl-1-(isobutyl)-2,4-dioxo-1-
,2,34-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid, ethyl
ester
[0431] Prepared using the procedure described in example 1 part d)
from the product of example 1 part c) and 5-quinolinecarbaldehyde
to give the subtitle compound. MS (ESI) 468 [M+H].sup.+. .delta.
.sup.1H.sub.CDCl3 0.87 (3H, d), 0.89 (3H, d), 1.33 (3H, t),
2.10-2.22 (1H, m), 3.38 (3H, s), 3.52 (1H, s, br), 3.55 (1H, dd),
3.71 (1H, dd), 4.33-4.41 (2H, m), 6.75 (1H, s), 7.39 (1H, dd), 7.77
(1H, t), 7.90 (1H, d), 8.14 (1H, d), 8.39 (1H, d), 8.91 (1H,
d).
b)
3-Methyl-1-(isobutyl)-2,4-dioxo-6-(5-quinolinylmethyl)-1,2,3,4-tetrahyd-
rothieno[2,3-d]pyrimidine-5-carboxylic acid ethyl ester
[0432] Prepared using the procedure described in example 1 part e)
from the product of part a) to give the subtitle compound. MS (ESI)
452 [M+H].sup.+. .delta. .sup.1H.sub.CDCl3 0.87 (6H, d), 1.42 (3H,
t), 2.09-2.19 (1H, m), 3.38 (3H, s), 3.60 (2H, d), 4.49 (2H, q),
4.59 (2H, s), 7.43 (1H, dd), 7.50 (1H, dd), 7.70 (1H, t), 8.11 (1H,
d), 8.49 (1H, d), 8.93 (1H, dd).
c)
3-Methyl-1-(isobutyl)-2,4-dioxo-6-(5-quinolinylmethyl-1,2,3,4-tetrahydr-
othieno[2,3-d]prinidine-5-carboxylic acid sodium salt
[0433] Prepared using the procedure described in example 1 part f)
from the product of part b) to give the subtitle compound. MS (ESI)
424 [M+2H--Na].sup.+. .delta. .sup.1H.sub.DMSO 0.79 (6H, d),
2.00-2.10 (1H, m), 3.19 (3H, s), 3.53 (2H, d), 4.52 (2H, s), 7.46
(1H, dd), 7.64 (1H, d), 7.71 (1H, t), 7.93 (1H, d), 8.85 (1H, dd),
9.14 (1H, d).
d) (S)
5-{4-Hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(isobutyl)-6-(5-q-
uinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0434] Prepared using the procedure described in example 1 part g)
from the product of part c) and example 1 part b) to give the title
compound. MS (ESI) 495 [M+H].sup.+. .delta. .sup.1H.sub.DMSO
0.80-0.83 (6H, m), 1.99-2.06 (1H, m), 3.20 (2H, s), 3.21 (1H, s),
3.50-3.63 (3H, m), 3.77-4.14 (3H, m), 4.548-4.70 (2.33H, m),
4.79-4.82 (0.67H, m), 5.50 (0.33H, d), 5.56 (0.67H, d), 7.54 (1H,
dd), 7.59 (0.33H, d), 7.63 (0.67H, d), 7.75 (1H, t), 7.98 (1H, d),
8.60 (0.33H, d), 8.64 (0.67H, d), 8.91 (1H, d).
EXAMPLE 19
(S)
5-{4-Hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-propyl-6-(quinolin-4-
-ylmethyl)thieno[2,3-d]lpyrimidine-2,4(1H,3H)-dione
a) 6-Chloro-3-methyl-1-propylpyrimidine-2,4(1H,3H)-dione
[0435] 6-chloro-3-methyl uracil (10 g) and potassium carbonate
(10.34 g) in DMF (70 ml) under nitrogen was treated with n-propyl
iodide (25.4 g) and heated at reflux for 8 hours. The reaction was
cooled and then poured into water (700 ml) and extracted with ethyl
acetate. The combined organics were dried and evaporated in vacuo
to afford the subtitle compound an orange oil, 17.52 g. .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) 3-Methyl-1-propyl-6-mercaptoprimnidine-2,4(1H,3H)-dione
[0436] The product of step a) (11.43 g) in ethanol (400 ml) was
treated with NaSH (6.31 g) under nitrogen. After stirring for 48
hours at room temperature, the solvent was evaporated in vacuo 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 evaporated
in vacuo to afford the subtitle compound as an orange oil, 7 g.
.delta. .sup.1H.sub.CDCl3 0.97 (3H, 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
[0437] The product of step b) (6.95 g) in dry dimethylformamide
(100 ml) was added potassium carbonate (2.4 g) and stirred for 10
min. Ethyl bromopyruvate (5 ml) was added and was stirred under
nitrogen at room temperature for 2 hours. The reaction was poured
into water (1 L), acidified (2M HCl) and extracted with ethyl
acetate. The organic extracts 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 (7.58 ml) was added and stirring continued
under nitrogen for 2 hours. The reaction was poured into water (1
L) and extracted with dichloromethane. The organics were dried and
evaporated 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, 4.64 g. .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). MS (APCI) 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
[0438] The sub-title compound was prepared using the method of
example 1, part d) using the product of step c). .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
[0439] The sub-title compound was prepared using the method of
example 1e) using the product of step d). 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
[0440] The sub-title compound was prepared by the method of example
1 part f) using the product of step e). .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) (S)
5-{4-Hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-propyl-6-(quinoli-
n-4-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0441] Prepared as the method of example 1, part g) using the
product of step f) and (S)-isoxazolidin-4-ol hydrochloride. .delta.
.sup.1H.sub.DMSO 0.84 (3H, td), 1.60 (2H, septet), 3.21 (3H, d),
3.56 (1H, d), 3.73 (3H, m), 3.81 (1H, d), 3.90 (1H, m), 4.61 (2H,
dd), 4.79 (1H, s), 5.52 (1H, m), 7.46 (1H, dd), 7.63 (1H, m) 7.79
(1H, m), 8.05 (1H, d), 8.27 (1H, dd), 8.87 (1H, d). MS (APCI) 481.1
(M.sup.++H).
EXAMPLE 20
(S)
5-{4-Hydroxyisoxazolidin-2-ylcarbonyl}-3-methyl-1-(isopropyl)-6-(4-qui-
nolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00057##
[0442] a) Diethyl
2-(isopropyl)amino)thiophene-3,4-dicarboxylate
[0443] Ethoxycarbonylmethylene triphenyl phosphorane (33.8 g) in
dry THF (200 ml) was treated with isopropyl isothiocyanate (10.1 g)
at 65.degree. C. for 16 hours under nitrogen. The mixture was
cooled to -78.degree. C. and ethyl bromo-pyruvate (19.5 g) was
added. The reaction was allowed to warm slowly to room temperature.
After 24 hours at room temperature, more ethyl bromo-pyruvate (3.17
g) was added and the mixture was stirred at room temperature for 16
hours. The reaction was poured into water (1.5 L) and extracted
into ether. Drying and evaporation gave an oil which was
chromatographed (SiO.sub.2/5:1 isohexane-ethyl acetate) to afford
the subtitle compound (21.2 g). .delta. .sup.1H.sub.CDCl3 1.23-1.43
(12H, m), 3.46 (1H, m), 4.2-4.35 (4H, m), 6.50 (1H, s), 7.52 (1H,
br. d).
b) Ethyl
1,2,3,4-tetrahydro-3-methyl-1-(isopropyl)-2,4-dioxo-thieno[2,3-d]-
pyrimidine-5-carboxylate
[0444] Silver cyanate (4.5 g) suspended in anhydrous toluene (30
ml) under nitrogen was treated dropwise with acetyl chloride (1.78
ml) and stirred vigorously for 30 minutes. The product of step a)
(7.12 g) dissolved in anhydrous toluene (5 ml) was added and the
mixture was stirred for 24 hours. Ether (120 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 ethoxide in ethanol (prepared
from sodium 1.95 g and ethanol 35 ml) at room temperature for 24
hours. The reaction was cooled in ice and treated with
trimethylsilyl chloride (20 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. This was taken in dry DMF
(50 ml) with potassium carbonate (6.95 g) and methyl iodide (8.5 g)
for 24 hours at room temperature. The mixture was poured into water
(1 L), acidified and extracted into ether. Washing with brine,
drying and evaporation gave an oil. Chromatography (SiO.sub.2/3:1
isohexane-ethyl acetate) to afford the subtitle compound (3.1 g).
.delta. .sup.1H.sub.CDCl3 1.39 (3H, t), 1.6 (6H, d), 3.39 (3H, s),
4.4 (2H, q), 7.25 (1H, s). MS (APCI) (M.sup.++H) 297.
c) 6-[Hydroxy(4-quinolinyl)
methyl]-3-methyl-1-(isopropyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]p-
yrimidine-5-carboxylic acid ethyl ester
[0445] Prepared using the procedure described in example 1 part d)
from the product of part b) and 4-quinolinecarbaldehyde to give the
subtitle compound. MS (ESI) 454 [M+H].sup.+. .delta.
.sup.1H.sub.CDCl3 1.41 (3H, t), 1.43 (3H, d), 1.46 (3H, d), 3.35
(3H, s), 3.66 (1H, d), 4.25-4.45 (1H, m), 4.45-4.51 (2H, m), 6.78
(1H, d), 7.53 (1H, td), 7.72 (1H, td), 7.83 (1H, d), 7.92 (1H, d),
8.17 (1H, dd), 9.02 (1H, d).
d)
3-Methyl-1-(isopropyl)-2,4-dioxo-6-(4-quinolinylmethyl)-1,2,3,4-tetahyd-
rothieno[2,3-d]pyrimidine-5-carboxylic acid ethyl ester
[0446] Prepared using the procedure described in example 1 part c)
from the product of part c) to give the subtitle compound. MS (ESI)
438 [M+H].sup.+. .sup.1H.sub.CDCl3 1.37 (3H, t), 1.49 (6H, d), 3.36
(3H, s), 4.44 (2H, q), 4.60 (2H, s), 4.30-4.60 (1H, m), 7.31 (1H,
d), 7.61 (1H, td), 7.76 (1H, td), 8.13 (1H, dd), 8.16 (1H, dd),
8.81 (1H, d).
e)
3-Methyl-1-(isopropyl)-2,4-dioxo-6-(4-quinolinylmethyl)-1,2,3,4-tetrahy-
drothieno[2,3-d]pyrimidine-5-carboxylic acid, sodium salt
[0447] Prepared using the procedure described in example 1 part f)
from the product of part d) to give the subtitle compound. MS (ESI)
410 [M+2H--Na].sup.+. .delta. .sup.1H.sub.DMSO 1.36 (6H, d), 3.16
(3H, s), 4.10-4.35 (1H, m), 4.52 (2H, s), 7.53 (1H, d), 7.58 (1H,
t), 7.74 (1H, t), 8.00 (1H, d), 8.62 (1H, d), 8.82 (1H, d).
f) (S)
5-{4-Hydroxisoxazolidin-2-ylcarbonyl}-3-methyl-1-(isopropyl)-6-(4-q-
uinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0448] Prepared using the procedure described in example 1 part g)
from the product of part e) to give the title compound. MS (ESI)
481 [M+H].sup.+. * .delta. .sup.1H.sub.DMSO 1.40-1.44 (6H, m), 3.18
(2H, s), 3.19 (1H, s), 3.54 (1H, d), 3.75 (0.33H, d), 3.81 (0.67H,
d), 3.89 (0.67H, dd), 3.89-3.98 (0.33H, m), 3.99-4,05 (0.33H, m),
4.10 (0.67H, dd), 4.22-4.40 (1H, m), 4.50-4.68 (2.33H, m), 4.79
(0.67H, d), 5.50 (0.33H, d), 5.54 (0.67H, d), 7.44 (0.33H, d), 7.48
(0.67H, d), 7.64 (1H, t), 7.78 (1H, t), 8.05 (1H, d), 8.26 (0.33H,
d), 8.30 (0.67H, d), 8.87 (1H, d). (* N.B. 2:1 mixture of major
rotamers, minor rotamer peaks not quoted)
EXAMPLE 21i
(S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[(2-met-
hyl-1H-pyrrolo[2,3b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione
##STR00058##
[0449] a)
1,2,3,4-Tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-(1H-pyrrolo-
[2,3b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-5-carboxylic acid,
methyl ester
[0450] Prepared by the method of example 6 part a) using the
product of example 3 part b) and 2-methyl-7-azaindole. MS (APCI)
427[M+H].sup.+. .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-(isobutyl)-2,4-dioxo-6-(1H-pyrrolo-2,3,b]-
pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-5-carboxylic acid
[0451] The sub-title compound (1.22 g) was prepared from the
product of part a) by the method of example of example 3, step d).
MS (ES) 413[M+H].sup.+.
c) (S)
5-[[4-Hydroxyisoxazolidin-2-yl]carbonyl]-3-methyl-1-(isobutyl)-6-[(-
2-methyl-1H-pyrrolo[2,3b]pyridin-3-yl)methyl]thieno[2.3
d]pyridine-2,4(1H,3H)-dione
[0452] The title compound was prepared from the product of step b)
by the method of example 1, step g). MS (APCI) 498[M+H].sup.+.
.delta. .sup.1H.sub.DMSO 0.87-0.90 (6H, m), 2.09-2.15 (1H, m), 2.46
(3H, m), 3.25-3.27 (3H, m), 3.58-3.72 (3H, m), 3.81-3.93 (2H, m),
4.03-4.22 (3H, m), 4.72-4.86 (1H, m), 5.57-5.82 (1H, m), 7.00-7.03
(1H, m), 7.84-7.89 (1H, m), 8.14-8.15 (1H, m), 11.51 (1H, s).
EXAMPLE 21ii
(R)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[(2-met-
hyl-1H-pyrrolo[2,3b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione
##STR00059##
[0454] The title compound was prepared from the product of example
21i), step b) by the method of example 1, step g) using
(R)-4-hydroxyisoxazolidine, example 2 part b). MS (APCI)
498[M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.81-0.84 (6H, m),
2.03-2.09 (1H, m), 2.39 (3H, s), 3.16-3.19 (3H, m), 3.52-3.66 (3H,
m), 3.75-3.89 (2H, m), 3.97-4.16 (3H, m), 4.63-4.80 (1H, m),
5.53-5.55 (1H, m), 6.94-6.98 (1H, m), 7.76-7.83 (1H, m), 8.08-8.09
(1H, m), 11.45 (1H, s).
EXAMPLE 22
(S)
5-[4-Hydroxyisoxazoldin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2-meth-
yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3)-d-
ione
##STR00060##
[0455] a) Methyl
6-(bromomethyl)-1,2,3,4-tetrahydro-3-methyl-1-(isopropyl)-2,4-dioxothieno-
[2,3-d]pyrimidine-5-carboxylate
[0456] A solution of the product of example 8, part b), (1.6 g),
N-bromosuccinimide (1 g), and azoisobutyronitrile (10 mg) in ethyl
acetate (25 ml) was refluxed for 1 hour. The solution was cooled to
room temperature, washed successively with dilute sodium hydroxide
solution and water, the 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 diethyl ether/i-hexane (1:1) to give the sub-title
compound as a solid (1.5 g). .delta. .sup.1H.sub.CDCl3 1.62 (6H,
d), 3.37 (3H, s), 3.99 (3H, s), 3.60-3.70 (3H, m).
b) Methyl
1,2,3,4-tetrahydro-3-methyl-1-(isopropyl)-6-[2-methyl-1H-pyrrolo-
[2,3-b]pyridin-3-ylmethyl]-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate
[0457] To a stirred suspension of 60% sodium hydride (0.23 g) in
THF (10 ml) was added a solution of 2-methylazaindole (0.37 g) in
THF (10 ml) dropwise under nitrogen at ambient temperature, and
after 5 minutes. 1 M zinc chloride in ether (5.6 ml) was added.
After stirring for 5 minutes, a solution of the product of part a)
(0.88 g) in THF (10 ml) was added and the mixture stirred for 3
hours. It was quenched with water and extracted with ethyl acetate,
the 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/1-hexane (1:1) to give the sub-title compound as a solid
(0.4 g). MS (ESI) 427 [M+H].sup.+. .delta. .sup.1H.sub.CDCl3 1.48
(6H, d), 2.49 (3H, s), 3.36 (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).
c)
1,2,3,4-Tetrahydro-3-methyl-1-(isopropyl)-6-[2-methyl-1H-pyrrolo[2,3-b]-
pyridin-3-yl methyl]-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic
acid
[0458] Prepared from the product of part b) following the procedure
of example 1, part f) to give the sub-title compound as a solid. MS
(ESI) 413 [M+H].sup.+.
d) (S)
5-[4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)-6-[2--
methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]thieno[2,3-d]-pyridine-2,4(1H,3-
H)-dione
[0459] Prepared from the product of part c) and
(S)-4-isoxazolidinol hydrochloride [example 1, part b)] following
the procedure of example 1, part g) to give the title compound as a
solid.
[0460] MS (APCI) 484 [M+H].sup.+. .delta. .sup.1H.sub.DMSO
1.37-1.40 (6H, m), 2.40 (3H, s), 3.17-3.18 (3H, m), 3.52-4.28 (7H,
m), 4.66-4.79 (1H, m), 5.50-5.55 (1H, m), 6.95-6.99 (1H, m),
7.80-7.86 (1H, m), 8.08-8.10 (1H, m), 11.45 (1H, s).
EXAMPLE 23
(S)-6-[4,5-Dichloro-2-(hydroxymethyl)-1H-imidazol-1-yl
methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thie-
no[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00061##
[0461] a) 4,5-Dichloro-1H-imidazole-2-methanol
[0462] Potassium hydroxide (0.12 g, 2.14 mmol) in water (4 ml) was
added to 4,5-dichloromethane, 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%). .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-(isobutyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic
acid methyl ester
[0463] 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 3 part b) in DMF, and the reaction mixture was
stirred for 16 hours. The solid precipitate formed was filtered,
and the filtrate was concentrated in vacuo to give an orange solid
0.6 g, contains DMF. .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-tetr-
ahydro-3-methyl-1-(isobutyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxyli-
c acid
[0464] Prepared from the product of step b) following the procedure
of example 3, step d). MS (ESI) 484 [M+H].sup.+.
d) 6-[4,5-Dichloro-2-(h drox
methyl)-1H-imidazol-1-ylmethyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbony-
l]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0465] Prepared form the product of step c) using the procedure of
example 3 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. .delta.
.sup.1H.sub.CDCl3 0.89 (6H, m), 2.06-2.21 (1H, m), 3.21 (3H, s),
3.62-4.18 (6H, m), 4.44-4.78 (2H, m), 5.41 (2H, m), 5.53 (1H, m)
and 5.72-5.75 (1H, m).
EXAMPLE 24
(S)-6-[3,5-Dimethyl-1H-pyrazol-1-yl
methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-thie-
no[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00062##
[0466] a)
6-[3,5-Dimethyl-1H-pyrazol-1-ylmethyl]-1,2,3,4-tetrahydro-3-meth-
yl-1-(isobutyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid
methyl ester
[0467] The product of example 3 part b) (0.4 g, 1.03 mmol),
2,4-dimethylpyrazole (0.2 g, 2.06 mmol) and dimethyl acetamide
(approx. 0.5 ml) were heated in a microwave oven for 5 mins at
100.degree. C. The reaction mixture was concentrated in vacuo and
then triturated, 0.34 g (84%). MS (ESI) 405 [M+H].sup.+.
b)
6-[3,5-Dimethyl-1H-pyrazol-1-ylmethyl]-1,2,3,4-tetrahydro-3-methyl-1-(i-
sobutyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid
[0468] Prepared from the product of step a) following the procedure
of example 3, step d). MS (ESI) 391 [M+H].sup.+.
c) 6-[3,5-Dimethyl-1H-pyrazol-1-yl
methyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-
-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0469] Prepared form the product of step b) using the procedure of
example 3 part e). The product was purified by reverse phase HPLC
eluting with ammonium acetate:acetonitrile (70:30) to give the
title compound as a white solid. MS (ESI) 462 [M+H].sup.+. .delta.
.sup.1H.sub.CDCl3 0.9 (6H, m), 2.09-2.19 (1H, m), 2.2 (3H, s), 3.2
(3H, s), 3.52-4.1 (6H, m), 4.81-4.77 (1H, m), 5.16-5.23 (2H, m),
5.49-5.57 (1H, m) and 5.82 (1H, s).
EXAMPLE 25
(S)-6-[2,3-Dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[4-hydroxyisoxazoli-
din-2-yl
carbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H-
)-dione
##STR00063##
[0470] a)
6-[2,3-Dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-1,2,3,4-tetrahy-
dro-3-methyl-1-(isobutyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic
acid, methyl ester
[0471] The product of example 3 part b) (0.5 g, 1.28 mmol),
2-chlorobenzimidazole (0.21 g, 1.37 mmol), potassium carbonate
(0.36 g, 2.6 mmol) and DMF (10 ml) were stirred for 1.5 hours.
Ethyl acetate and water were added to the reaction mixture. The two
phases were separated, the organic layer was dried (MgSO.sub.4) and
then concentrated in vacuo. The residue was purified by biotage
eluting with dichloromethane to give the sub-title compound as a
pale yellow solid, 0.36 g (61%). 5 .sup.1H.sub.D6DMSO 0.83 and 0.91
(6H, d), 2.1-2.22 (1H, m), 3.38 (3H, s), 3.67 (2H, d), 4.1 (3H, s),
5.58 (2H, s), 7.26-7.38 (2H, m), 7.41-7.48 (1H, m) and 7.7-7.8 (1H,
m).
b)
6-[2,3-Dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-1,2,3,4-tetrahydro-3-m-
ethyl-1-(isobutyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic
acid
[0472] The product of step a) (0.36 g, 0.65 mmol) was added to a
solution of THF (10 ml), water (1 ml), and triethylamine (0.05 ml)
in a sealed tube, which was heated at 180.degree. C. for 3 days.
The reaction mixture was concentrated in vacuo to give the
sub-title compound (0.3 g crude yield). MS (ESI) 446
[M+H].sup.+.
c)
6-[2,3-Dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[(4S)-4-hydroxyisoxa-
zolidin-2-yl
carbonyl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0473] Prepared form the product of step b) using the procedure of
example 3 part e). The product was purified by reverse phase HPLC
eluting with ammonium acetate:acetonitrile (80:20) to give the
title compound as a pale yellow foam after trituration with diethyl
ether. .delta. .sup.1H.sub.D6DMSO 0.93 (6H, m), 2.1-2.24 (1H, m),
3. (2H, s), 3.26 (3H, s), 3.52-4.18 (5H, m), 4.62-4.82 (1H, s),
5.02-5.2 (2H, s), 6.96-7.03 (2H, m), 7.17-7.19 (1H, m).
EXAMPLE 26
(S)
6-[3,5-Dimethyl-1H-pyrazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-yl
carbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00064##
[0474] a)
6-[3,5-Dimethyl-1H-pyrazol-4-ylmethyl]-3-methyl-2,4-dioxo-1-prop-
yl-1,2,34-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid
sodium salt
[0475] Zinc bis(acetylacetonate) (0.405 g) was added to a solution
of the product of example 9, part c), (0.56 g) in chloroform (15
ml) and the resulting suspension stirred under reflux for 15
minutes then cooled to room temperature. Saturated sodium
bicarbonate solution (10 ml) was added and the mixture stirred
vigorously for 5 minutes, filtered then extracted with
dichloromethane (2.times.25 ml). Combined organic extracts were
treated with aqueous hydrazine solution (35%, 0.26 ml), stirred for
16 hours, dried over anhydrous magnesium sulphate, filtered and
evaporated under reduced pressure. The residue was dissolved in
tetrahydrofuran (15 ml) and methanol (3.1 ml) then treated with
sodium hydroxide solution (1M, 2.16 ml) and the mixture stirred for
18 hours. The resulting precipitate was collected by filtration,
washed with tetrahydrofuran and dried in vacuo to give the
sub-title compound (0.42 g), MS (ESD) 377 [M+2H--Na].sup.+. .delta.
.sup.1H.sub.DMSO 0.85 (3H, t), 1.63 (2H, sextet), 2.08 (6H, s),
3.19 (3H, s), 3.74 (4H, m).
b) (S)
6-[3,5-Dimethyl-1H-pyrazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-y-
lcarbonyl-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0476] Prepared from the product of part a) and
(S)-4-isoxazolidinol hydrochloride [example 1, part b)] following
the procedure of example 1, part g) to give the title compound as a
solid. MS (APCI) 440 [M+H].sup.+. .delta. .sup.1H.sub.DMSO
(90.degree. C.*) 0.88 (3H, t), 1.68 (1H, sex), 2.08 (6H, s), 3.21
(3H, s), 3.46 (1H, d), 3.67-4.14 (7H, m), 4.63-4.77 (1H, m), 5.23
(1H, s, br), 11.86 (1H, s, br). (*N.B. Substance exists as a
mixture of rotamers therefore NMR complicated at room temperature
but simplified at elevated temperature)
EXAMPLE 26i
(S)
6-[3,5-Dimethyl-1H-pyrazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-ylca-
rbonyl]-1-isopropyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00065##
[0477] a)
6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-1-isopropyl-3-methyl-2,4--
dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid
sodium salt
[0478] Prepared from the product of example 8, part b) following
the procedure of example 26, part a) to give the sub-title compound
as a solid. MS (ESI) 377 [M+2H--Na].sup.+. .delta. .sup.1H.sub.DMSO
1.44 (6H, d), 2.10 (6H, s), 3.17 (3H, s), 3.74 (2H, s), 4.34 (1H,
s, br), 12.01 (1H, s, br).
b) (S) 6-[3,5-Dimethyl-1H-pyrazol-4-yl
methyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isopropyl-3-methylthieno-
[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0479] Prepared from the product of part a) and
(S)-4-isoxazolidinol hydrochloride [example 1, part b)] following
the procedure of example 1, part g) to give the title compound as a
solid. MS (APCI) 448 [M+H].sup.+. .delta. .sup.1H.sub.DMSO
1.43-1.46 (6H, m), 2.09 (6H, s, br), (1.87H, s), 3.18 (1.13H, s),
3.47 (0.62H, d), 3.58 (0.38H, d), 3.70-3.79 (3H, m), 3.80-3.86 (1H,
m), 3.88-4.04 (0.38H, m), 4.10 (0.62H, dd), 4.37 (1H, s, br),
4.58-4.78 (1H, s, br), 5.50 (1H, d), 12.11 (1H, s).
EXAMPLE 27
(S)-6-[3,5-Dimethylisoxazol-4-ylmethyl]-5-[4-hydroxyisoxazolidin-2-ylcarbo-
nyl]-1-(isobutyl)-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00066##
[0480] a) Methyl
6-[3,5-dimethylisoxazol-4-ylmethyl]-1-(isobutyl)-3-methyl-2,4-dioxo-1,2,3-
,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate
[0481] Zinc bis(acetylacetonate) (0.724 g) was added to a solution
of the product of example 3, part b), (1.0 g) in chloroform (20 ml)
and the resulting suspension stirred under reflux for 30 minutes
then cooled to room temperature. Saturated sodium bicarbonate
solution (20 ml) was added and the mixture stirred vigorously for 5
minutes, filtered then extracted with dichloromethane (2.times.20
ml). Organic extracts were dried over anhydrous magnesium sulphate,
filtered and evaporated under reduced pressure. The residue was
dissolved in ethanol (10 ml), hydroxylamine hydrochloride (0.54 g)
and pyridine (0.62 ml) were added and the mixture stirred for 16
hours. Hydrochloric acid (2 M, 5 ml) was added and stirring
continued for 24 hours. The mixture was evaporated to low volume
then added to saturated sodium bicarbonate solution (25 ml) and
extracted with ethyl acetate (2.times.25 ml). Organic extracts were
dried over anhydrous magnesium sulphate, filtered and evaporated
under reduced pressure. The residue was purified by column
chromatography over silica, eluting with ethyl acetate/iso-hexane
(2:1) and the product triturated with ether to give the sub-title
compound (0.55 g). MS (ESI) 406 [M+H].sup.+. .delta.
.sup.1H.sub.CDCl3 0.95 (6H, d), 2.18 (3H, s), 2.18-2.30 (1H, m),
3.39 (3H, s), 3.70 (2H, d), 3.85 (2H, s), 3.95 (3H, s).
b)
6-[3,5-dimethylisoxazol-4-ylmethyl]-1-(isobutyl)-3-methyl-2,4-dioxo-1,2-
,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid
[0482] Prepared from the product of part a) following the procedure
of example 3, part d) to give the sub-title compound as a solid. MS
(ESI) 392 [M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.89 (6H, d), 2.09
(3H, s), 2.09-2.20 (1H, m), 2.34 (3H, s), 3.22 (3H, s), 3.70 (2H,
d), 4.04 (2H, s).
c)
6-[3,5-dimethylisoxazol-4-ylmethyl]-5-[(4S)-4-hydroxyisoxazolidin-2-yl
carbonyl]-1-(isobutyl)-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0483] Prepared from the product of part b) and
(S)-4-isoxazolidinol hydrochloride [example 1, part b)] following
the procedure of example 1, part g) to give the title compound as a
foam. MS (APCI) 463 [M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.89 (6H,
d), 2.10 (3H, s), 2.13-2.24 (1H, m), 2.30 (3H, s), 3.22 (3H, s),
3.44 (1H, d, br), 3.65-3.78 (3H, m), 3.82 (2H, s), 3.85-4.10 (2H,
m), 4.70 (1H, s, br), 5.18 (1H, d).
EXAMPLE 28
6-[4,5-Dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1-ethyl-5-[(4S)-4-hydroxy-
-2-isoxazolidinylcarbonyl]-3-methyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dio-
ne
##STR00067##
[0484] a) 1-Ethyl-3,6-dimethyl-2,4(1H, 3H)-pyrimidinedione
[0485] To a suspension of 3,6-dimethyl-2,4(1H,3H)-pyrimidinedione
(2.0 g) in DMF (15 ml) at room temperature was added potassium
carbonate (2.1 g). The mixture was stirred for 5 minutes then ethyl
iodide (1.2 ml) was added and the mixture stirred for 3 days. The
reaction mixture was partitioned between water (500 ml) and ethyl
acetate (3.times.100 ml). The combined organic phase was dried
(MgSO.sub.4) and evaporated to give the sub-title compound as a
colourless oil (2.0 g) (contains 30 mole % DMF by NMR). .delta.
.sup.1H.sub.CDCl3 1.32 (3H, t), 3.33 (3H, s), 4.15 (2H, q), 5.92
(1H, s).
b) 1-Ethyl-6-mercapto-3-methyl-2,4(1H, 3H)-pyrimidinedione
[0486] Prepared from the product of step a) following the procedure
of example 5, step a). .delta. .sup.1H.sub.CDCl3 1.28 (3H, t), 3.32
(3H, s), 4.14 (2H, s), 4.48 (2H, q).
c) Methyl
1-ethyl-1,2,3,4-tetrahydro-3,6-dimethyl-2,4-dioxo-thieno[2,3-d]--
pyrimidine-5-carboxylate
[0487] Prepared from the product of step b) following the procedure
of example 3, step a). MS (ESI) 283 [M+H].sup.+.
d) Methyl
6-(bromomethyl)-1-ethyl-1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-th-
ieno[2,3-d]pyrimidine-5-carboxylate
[0488] Prepared from the product of step c) following the procedure
of example 22, step a).
e) Methyl
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1-ethyl-1,2,3,4-
-tetrahydro-3-methyl-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylate
[0489] A mixture of the product of step d) (0.25 g), sodium
bicarbonate (0.29 g) and 4,5-dichloro-2-methyl-1H-imidazole (0.115
g) in acetonitrile (10 ml) was heated at reflex for 18 hours. The
cooled mixture was partitioned between water (50 ml) and
dichloromethane (3.times.50 ml). The combined organic phase was
dried (MgSO.sub.4) and evaporated to give the sub-title compound as
an oil which was used directly in the next step. MS (ESI)
429/431/433 [M-H.sup.+].
f)
6-[4,5-dichloro-2-methyl-1H-imidazol-1H-ylmethyl]-1-ethyl-1,2,3,4-tetra-
hydro-3-methyl-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid,
sodium salt
[0490] Prepared from the product of step e) following the procedure
of example 1, step f). MS (ESI) 417/419/421 [M+H].sup.+.
g)
6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1-ethyl-5-[(4S)-4-hydr-
oxy-2-isoxazoldinylcarbonyl]-3-methyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-d-
ione
[0491] Prepared from the product of step f) using the amine of
example 1, step b) following the procedure of example 1, step g).
MS (ESI) 488/490/492 [M+H].sup.+. .delta. .sup.1H.sub.DMSO
(90.degree. C.) 1.25 (3H, t), 2.33 (3H, s), 3.22 (3H, s), 2.99 (1H,
s), 3.34-3.55 (1H, m), 3.70-4.14 (5H, m), 4.63-4.87 (1H, m), 5.27
(2H, m). (*N.B. Substance exists as a mixture of rotamers therefore
NMR complicated at room temperature but simplified at elevated
temperature)
EXAMPLE 28i
1-Ethyl-5-[(4)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-(1H-pyrrolo[-
2,3-b]pyridin-3-ylmethyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00068##
[0492] a)
1-Ethyl-1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-6-(1H-pyrrolo[2,3--
b]pyridin-3-ylmethyl-thieno[2,3-d]pyrimidine-5-carboxylic acid,
methyl ester
[0493] The sub-title compound was prepared by the method of example
22 part b, from the product of example 28 part d). .delta.
.sup.1H.sub.CDCl3 1.26 (3H, t), 3.49 (3H, s), 3.87 (2H, q), 4.03
(3H, s), 4.28 (2H, s), 7.058 (1H, t), 7.93 (1H, d), 8.32 (1H, d)
and 8.89 (1H, s).
b)
1-Ethyl-1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-6-(1H-pyrrolo[2,3-b]pyrid-
in-3-ylmethyl)-thieno[2,3-d]pyrimidine-5-carboxylic acid
[0494] The sub-title compound was prepared by the method of example
3 part d). MS (ESI) 386 [M+H].sup.+.
c)
1-Ethyl-(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-(1H-pyrrolo-
[2,3-b]pyridin-3-ylmethyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0495] Prepared from the product of step b) using the procedure of
example 3 part e). The product was purified by reverse phase HPLC
eluting with ammonium acetate:acetonitrile (70:30) to give the
title compound as an off-white solid. .delta. .sup.1H.sub.D6DMSO
1.12 (3H, m), 3.31 (3H, s), 3.58-4.22 (6H, m), 4.62-4.75 (1H, s),
4.8 (1H, s), 5.5 (1H, s), 6.9-7.03 (1H, m), 7.45 (1H, m), 7.95-8
(1H, m), 8.19 (1H, d), 11.53 (1H, s).
EXAMPLE 28ii
1-Ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-propyl-1-
H-benzimidazol-1-yl
methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00069##
[0496] a) Methyl
1-ethyl-1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-6-[2-propyl-1H-benzimidazol-
-1-yl methyl]-thieno[2,3-d]pyrimidine-5-carboxylate
[0497] Prepared from the product of example 28 step d) following
the procedure of example 13iv, step a). MS (ESI) 441
[M+H].sup.+.
b)
1-ethyl-1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-6-[2-propyl-1H-benzimidaz-
ol-1-ylmethyl]-thieno[2,3-d]pyrimidine-5-carboxylic acid, sodium
salt
[0498] Prepared from the product of step a) following the procedure
of example 1, step f). MS (ESI) 427 [M+H].sup.+ (free acid),
c)
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-propy-
l-1H-benzimidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0499] Prepared from the product of step b) using the amine of
example 1, step b) following the procedure of example 1, step g).
MS (ESI) 498 [M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.99 (3H, t),
1.12 (3H, t), 1.80 (2H, sextet), 2.88 (2H, t), 3.20 and 3.21 (3H,
s), 3.58 (1H, d), 3.70-4.15 (5H, m), 4.63 and 4.81 (1H, t),
5.46-5.70 (3H, m), 7.15-7.22 (2H, m), 7.54-7.69 (2H, m).
EXAMPLE 28iii
1-Ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-oxo-3(2H-
)-benzothiazolylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00070##
[0500] a) Methyl
1-ethyl-1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-6-[2-oxo-3(2H)-benzothiazol-
ylmethyl]-thieno[2,3-d]pyrimidine-5-carboxylate
[0501] Prepared from the product of example 28 step d) following
the procedure of example 13xviii, step a). MS (ESI) 432
[M+H].sup.+.
b)
1-ethyl-1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-6-[2-oxo-3(2H)-benzothiaz-
olylmethyl]-thieno[2,3-d]ipyrimidine-5-carboxylic acid, sodium
salt
[0502] Prepared from the product of step a) following the procedure
of example 1, step f). MS (ESI) 418 [M+H].sup.+ (free acid).
c)
1-ethyl-5-[(4S)-4-hydroxy-2-isoxazohdinylcarbonyl]-3-methyl-6-[2-oxo-3(-
2H)-benzothiazolylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0503] Prepared from the product of step b) using the amine of
example 1, step b) following the procedure of example 1, step g).
MS (ESI) 489 [M+H].sup.+. .delta. .sup.1H.sub.DMSO 1.19 (3H, t),
3.19 and 3.20 (3H, s), 3.52-4.00 (6H, m), 4.56-4.82 (1H, m),
5.09-5.40 (3H, m), 7.19-7.25 (1H, m), 7.33-7.48 (2H, m), 7.67-7.72
(1H, m).
EXAMPLE 28iv
1-Ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-methyl-1-
H-pyrrolo[2,3-b]pyridin-3-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e
##STR00071##
[0504] a) Methyl
1-ethyl-1,2,3,4-tetrahydro-3-methyl-6-[2-methyl-1H-pyrrolo[2,3-b]pyridin--
3-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylate
[0505] Prepared from the product of example 28 step d) following
the procedure of example 14iii, step a). MS (ESI) 399
[M+H].sup.+.
b)
1-ethyl-1,2,3,4-tetrahydro-3-methyl-6-[2-methyl-1H-pyrrolo[2,3-b]pyridi-
n-3-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid,
sodium salt
[0506] Prepared from the product of step a) following the procedure
of example 1, step f). Used directly in next step.
c)
1-ethyl-5-[(4S-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-methyl-
-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-d-
ione
[0507] Prepared from the product of step b) using the amine of
example 1, step b) following the procedure of example 1, step g).
MS (ESI) 470 [M+H].sup.+. .delta. .sup.1H.sub.DMSO 1.10-1.16 (3H,
m), 2.40 (3H, s), 3.19-3.20 (3H, m), 3.50-4.83 (10H, m), 6.94-6.99
(1H, m), 7.78-7.86 (1H, m), 8.09 (1H, dd), 11.46 (1H, s).
EXAMPLE 28v)
1-Ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[5-cyano-1H-
-indol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00072##
[0508] a)
6-[5-cyano-1H-indol-1-ylmethyl]-1-ethyl-1,2,3,4-tetrahydro-3-met-
hyl-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid, methyl
ester
[0509] Prepared using the product of example 28 part d) by the
method of example 13 xvii) part a). MS (ESI) 421 [M+H].
b)
1-[1-Ethyl-1,2,3,4-tetrahydro-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbony-
l]-3-methyl-2,4-dioxothieno[2,3-d]pyrimidin-6-ylmethyl]-1H-indole-5-carbon-
itrile
[0510] Prepared using the product of part a) by the methods of
example 13 xvii part b) and part c) to give the title compound.
.delta. .sup.1H.sub.DMSO 1.10-1.23 (3H, m), 3.2 (3H, s), 3.8-4.12
(6H, m), 4.62-4.81 (1H, m), 5.5-5.64 (3H, m), 6.68 (1H, d), 7.5-7.9
(1H, m), 7.6-7.65 (1H, m), 7.77-7.84 (1H, m) and 8.1 (1H, s).
EXAMPLE 29i
5-[(4S-4-Hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-6-[1-isopropyl-3,5-
-dimethyl-1H-pyrazol-4-ylmethyl]-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H-
)-dione
##STR00073##
[0512] 2-Iodopropane (0.1 ml) and potassium carbonate (100 mg) were
added to a solution of
6-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-5-[(4S)-4-hydroxyisoxazolidin-2--
ylcarbonyl]-1-(isobutyl)-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
(example 11, 100 mg) in dimethylformamide (1 ml) and the mixture
stirred at 100.degree. C. After 2 hours, further 2-iodopropane (0.2
ml) and potassium carbonate (200 mg) were added. After a further 16
hours, the mixture was cooled to room temperature, diluted with
water (20 ml) and extracted with ethyl acetate (2.times.20 ml).
Combined organic extracts were treated with pyrrolidine (0.1 ml)
and after 1 hour were dried over anhydrous magnesium sulphate,
filtered and evaporated under reduced pressure. The residue was
purified by reverse-phase HPLC with gradient 0.1% aqueous ammonium
acetate/acetonitrile elution to give the title compound (58 mg) as
a foam. MS (APCI) 504 [M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.87
(6H, d), 1.31 (6H, d), 1.99-2.14 (7H, m), 3.19-3.21 (3H, m),
3.45-4.13 (8H, m), 4.40 (1H, sept), 4.56-4.79 (1H, m), 5.48-5.55
(1H, m).
EXAMPLE 29ii
5-[(4S)-4-Hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-methyl-6-[5-met-
hyl-3-phenyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3,H)-dio-
ne
##STR00074##
[0513] a) Methyl
1-isobutyl-3-methyl-6-[5-methyl-3-phenyl-1H-pyrazol-4-ylmethyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate
[0514] Zinc (II) acetate (88 mg) was added to a stirred solution of
methyl
6-(bromomethyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,-
3-d]pyrimidine-5-carboxylate (185 mg) and 1-benzoylacetone (154 mg)
in chloroform (10 ml) and the mixture heated at reflux for 1 hour
then cooled to room temperature. Saturated sodium bicarbonate
solution (20 ml) was added and the mixture stirred for 30 minutes
then filtered and the phases separated. The aqueous phase was
extracted with dichloromethane (10 ml). Combined organic extracts
were treated with hydrazine hydrate (0.046 ml) and methanol. After
20 hours, the solution was dried over anhydrous magnesium sulphate,
filtered and evaporated under reduced pressure to give the
sub-title compound (300 mg) contaminated with
5-methyl-3-phenyl-1H-pyrazole. MS (ESI) 467 [M+H].sup.+. .delta.
.sup.1H.sub.CDCl3 0.90 (6H, d), 2.17 (1H, non), 2.27 (3H, s), 3.38
(3H, s), 3.65 (2H, d), 3.94 (3H, s), 4.10 (2H, s), 7.35 (1H, t),
7.40 (2H, t), 7.46 (2H, d).
b)
1-Isobutyl-3-methyl-6-[5-methyl-3-phenyl-1H-pyrazol-4-ylmethyl]-2,4-dio-
xo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid
[0515] Sodium hydroxide solution (1M, 0.58 ml) was added to a
stirred solution of the product of part a) (300 mg) in
tetrahydrofuran (10 ml) and methanol (1 ml). After 48 hours, water
(20 ml) was added and the mixture extracted with ether (20 ml). The
aqueous phase was acidified to pH 5 by addition of hydrochloric
acid (2 M) and extracted with ethyl acetate (2.times.20 ml).
Organic extracts were dried over anhydrous magnesium sulphate,
filtered and evaporated under reduced pressure to give the
sub-title compound (205 mg) as a solid. MS (ESI) 453. [M+H].sup.+.
.delta. .sup.1H.sub.DMSO 0.81 (6H, d), 2.03 (1H, non), 2.20 (3H,
s), 3.25 (3H, s), 3.62 (2H, d), 4.23 (2H, s), 7.32 (1H, t), 7.39
(2H, t), 7.49 (2H, d).
c)
5-[(4S)-4-Hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-methyl-6-[5-me-
thyl-3-phenyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dio-
ne
[0516] Diethyl chloridophosphate (0.076 ml) was added to a stirred
solution of the product of part b) (200 mg), 1-hydroxybenzotriazole
hydrate (81 mg) and triethylamine (0.215 ml) in acetonitrile (2
ml). After 15 minutes, (S)-4-isoxazolidinol hydrochloride [example
1, part b), 61 mg] was added. After a further 24 hours, the mixture
was diluted with saturated aqueous sodium bicarbonate solution (10
ml) and extracted with ethyl acetate (2.times.20 ml). Organic
extracts were dried over anhydrous magnesium sulfate, filtered and
evaporated under reduced pressure. The residue was purified by
column chromatography over silica gel, eluting with ethyl
acetate/methanol (25:1) followed by recrystallisation from ethyl
acetate/iso-hexane to give the title compound (138 mg). MS (APCI)
524 [M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.82 (6H, d), 2.04 (1H,
non), 2.20 (3H, s, br), 3.30 (3H, s), 3.45-4.15 (8H, m), 4.57-4.80
(1H, m), 5.35-5.55 (1H, m), 7.33 (1H, s, br), 7.40 (2H, s, br),
7.54 (2H, s, br), 12.73 (0.5H, s, br) 12.86 (0.5H, s, br).
EXAMPLE 29iii
5-[(4S)-4-Hydroxyisoxazolidin-2-ylcarbonyl]-isobutyl-3-methyl-6-[5-methyl--
3-(trifluoromethyl)-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3-
H)-dione
##STR00075##
[0517] a) Methyl
1-isobutyl-3-methyl-6-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-ylmethyl-
]-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate
[0518] Prepared from methyl
6-(bromomethyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,-
3-d]pyrimidine-5-carboxylate (300 mg) and
1,1,1-trifluoroacetylacetonate following the procedure of example
29(ii), part a). Crude product was purified by column
chromatography over silica, eluting with ethyl acetate/iso-hexane
(2:3) to give the sub-title compound (130 mg). MS (ESI) 459
[M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.94 (6H, d), 2.22 (1H, non),
2.26 (3H, s), 3.39 (3H, s), 3.69 (2H, d), 3.96 (3H, s), 4.08 (2H,
s), 10.29 (1H, s, br).
b)
1-Isobutyl-3-methyl-6-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-ylmeth-
yl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic
acid
[0519] Prepared from the product of part a) following the procedure
of example 29(ii), part b) to give the sub-title compound as a
solid. MS (ESI) 445 [M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.86 (6H,
d), 2.09 (1H, non), 2.21 (3H, s), 3.26 (3H, s), 3.67 (2H, d), 4.20
(2H, s), 13.43 (1H, s), 14.20 (1H, s, br).
c)
5-[(4S-4-Hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-methyl-6-[5-met-
hyl-3-(trifluoromethyl)-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(-
1H,3H)-dione
[0520] Prepared from the product of part b) following the procedure
of example 29(ii), part c) to give the title compound as a solid.
MS (APCI) 516 [M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.87 (6H, d),
2.11 (1H, non), 2.18 (3H, s), 3.20 (3H, s), 3.50-4.10 (8H, m),
4.55-4.78 (1H, m).
EXAMPLE 29iv
5-[(4S)-4-Hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-6-[3-isopropyl-5-me-
thyl-1H-pyrazol-4-ylmethyl]-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dio-
ne
##STR00076##
[0521] a)
1-Isobutyl-6-[3-isopropyl-5-methyl-1H-pyrazol-4-ylmethyl]-3-meth-
yl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic
acid
[0522] Prepared from methyl
6-(bromomethyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,-
3-d]pyrimidine-5-carboxylate (450 mg) and 5-methylhexane-2,4-dione
following the procedure of example 29(iii), part a), followed by
ester hydrolysis following the procedure of example 29(ii) part b)
to give the sub-title compound (285 mg) as a solid. MS (ESI) 419
[M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.85 (6H, d), 1.13 (6H, d),
2.07 (3H, s), 2.09, (1H, non.), 2.88 (1H, sept.), 3.26 (3H, s),
3.66 (2H, d), 4.04 (2H, s).
b)
5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-6-[3-iso'roy
yl-5-methyl-1H-pyrazol-4-ylmethyl]-3-methylthieno[2,3-d]pyrimidine-2,4(1H-
,3H)-dione
[0523] Prepared from the product of part a) (281 mg) following the
procedure of example 29(ii), part c). Crude product was purified by
reverse-phase HPLC with gradient 0.1% aqueous ammonium
acetate/acetonitrile elution, then by trituration with ether to
give the title compound (170 mg) as a solid. MS (APCI) 490
[M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.86 (6H, d), 1.08-1.18 (6H,
m), 2.02-2.17 (4H, m), 2.80-2.98 (1H, m), 3.19-3.21 (3H, m),
3.48-4.12 (8H, m), 4.58-4.78 (1H, m), 5.51 (1H, d), 12.15 (1H, s,
br).
EXAMPLE 29(v)
6-[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-5-[(4S)-4-hydroxyisoxazoli-
din-2-ylcarbonyl]-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-di-
one
##STR00077##
[0524] a) Methyl
6-[3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-1-isobutyl-3-methyl-2,4-d-
ioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate
[0525] Prepared from methyl
6-(bromomethyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,-
3-d]pyrimidine-5-carboxylate (500 mg), zinc acetylacetonate hydrate
and phenyl hydrazine following the procedure of example 26, part
a). Crude product was purified by column chromatography over
silica, eluting with ethyl acetate/iso-hexane (2:3) to give the
sub-title compound (555 mg) as a solid. MS (ESI) 481 [M+H].sup.+.
.delta. .sup.1H.sub.DMSO 0.95 (6H, d), 2.24 (3H, s), 2.27 (3H, s),
2.20-2.30 (1H, m), 3.39 (3H, s), 3.71 (2H, d), 3.95 (3H, s), 3.96
(2H, s), 7.36-7.50 (5H, m).
b)
6-[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-1-isobutyl-3-methyl-2,4-
-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid
sodium salt
[0526] Prepared from the product of part a) following the procedure
of example 1 part f) to give the sub-title compound as a solid, MS
(ESI) 467 [M+H-Na].sup.+. .delta. .sup.1H.sub.DMSO 0.87 (6H, d),
2.17 (3H, s), 2.10-2.22 (1H, m), 2.17 (3H, s), 3.20 (3H, s), 3.65
(2H, d), 3.84 (2H, s), 7.34-7.39 (1H, m), 7.46-7.51 (4H, m).
c)
6-[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-5-[(4S)-4-hydroxyisoxaz-
olidin-2-ylcarbonyl]-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione
[0527] Prepared from the product of part b) following the procedure
of example 29(ii), part c) to give the title compound as a solid.
MS (APCI) 538 [M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.89 (6H, d),
0.21-0.22 (4H, m), 2.25 (3H, s), 3.20-3.22 (3H, m), 3.45-4.15 (8H,
m), 4.55-4.80 (1H, m), 5.35-5.55 (1H, m), 7.37-7.40 (1H, m),
7.44-7.54 (4H, m).
EXAMPLE 29(VI)
6-[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-5-[(4S)-4-hydroxyisoxazoli-
din-2-ylcarbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dion-
e
##STR00078##
[0529] A solution of
6-(bromomethyl)-3-methyl-1-propyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3--
d]pyrimidine-5-carboxylic acid (500 mg) and zinc acetylacetonate
hydrate (389 mg) in chloroform (10 ml) was stirred at reflux for 1
hour then cooled to room temperature. Water (10 ml) and phenyl
hydrazine (0.27 ml) were added, the mixture stirred for 3 days and
the phases separated. The aqueous phase was extracted with
dichloromethane (2.times.10 ml). Organic extracts were dried over
anhydrous magnesium sulphate, filtered and evaporated under reduced
pressure. The residue was dissolved in acetonitrile (5 ml) and
treated with 1-hydroxybenzotriazole (173 mg), triethylamine (0.63
ml) and diethyl chloridophosphate (0.22 ml). The mixture was
stirred for 1 hour then (S)-4-isoxazolidinol hydrochloride [example
1, part b), 173 mg] was added. After a further 24 hours, the
mixture was evaporated under reduced pressure and the residue
purified by reverse-phase HPLC with gradient 0.1% aqueous ammonium
acetate/acetonitrile elution. The product was further purified by
column chromatography over silica, eluting with ethyl
acetate/methanol (49:1) to give the title compound (150 mg) as a
foam. MS (APCI) 524 [M+H].sup.+. .delta. .sup.1H.sub.DMSO 0.89 (3H,
t), 1.67 (2H, sex), 2.16 (3H, s), 2.26 (3H, s), 3.20-3.22 (3H, m),
3.45-3.60 (1H, m), 3.71-4.15 (7H, m), 4.57-4.80 (1H, m), 5.46-5.57
(1H, m), 7.37-7.40 (1H, m), 7.44-7.54 (4H, m).
EXAMPLE 30
6-(1H-1,2,3-Benzotriazol-1-ylethyl)-5-[(4S)-4-hydroxyisoxazolidinylcarbony-
l]-3-methyl-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00079##
[0530] a)
6-(1H-1,2,3-benzotriazol-1-ylmethyl)-1,2,3,4-tetrahydro-3-methyl-
-1-(isopropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid,
methyl ester
[0531] To a solution of benzotriazole (0.19 g) in dry
tetrahydrofuran under nitrogen, sodium hydride (0.06 g, 60%
suspension) was added. After 10 minutes, the product from example 8
part c) (0.6 g) in dry tetrahydrofuran was added dropwise. The
reaction mixture was stirred at room temperature overnight. Water
was added and the reaction mixture was extracted with ethyl
acetate. The organics were washed with brine, dried over magnesium
sulfate then concentrated in vacuo. The residue obtained was
purified by silica chromatography eluting with 30% then 40%
isohexane in ethyl acetate to give the title compound as a white
foam (0.32 g). .delta. .sup.1H.sub.CDCl3 1.50-1.52 (6H, d), 3.35
(3H, s), 4.05 (3H, s), 4.6 (1H, bs), 6.01 (2H, s),7.4 (1H, m), 7.51
(1H, m), 7.75 (1H, m), 8.07 (1H, m).
b)
6-(1H-1,2,3-benzotriazol-1-ylmethyl)-1,2,3,4-tetrahydro-3-methyl-1-(iso-
propyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid
[0532] Sodium hydroxide (1.5 ml, 1 M) was added to a solution of
the productd of example 30a) in tetrahydrofuran under nitrogen.
Then about 1 ml of methanol were added to solubilize the reaction
mixture. The reaction mixture was stirred at room temperature for 5
hours. Hydrochloric acid (0.7 ml, 2 M) was added and the reaction
mixture was vacuumed down to dryness to give the title
compound.
c)
6-(1H-1,23-benzotriazol-1-ylmethyl)-5-[(4S)-4-hydroxyisoxazolidinylcarb-
onyl]-3-methyl-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0533] Hydroxybenzotriazole (0.23 g), (4S)-4-hydroxyisoxazolidine
hydrochloride (described in example 1 part b)) (0.16 g) and
triethylamine (0.22 ml) were added to a solution of the product of
example 30b) in dichloromethane under nitrogen. After 10 minutes,
EDCI (0.29 g) was added. The reaction mixture was stirred at room
temperature overnight. Water was added and the reaction mixture was
extracted with dichloromethane. The organics were washed with
brine, dried over magnesium sulphate and concentrated in vacuo. The
residue was first purified by silica chromatography eluting with
ethyl acetate then by reverse phase HPLC to give the title compound
as a white foam. MS (APCI) (M.sup.++H) 471.1450. .delta.
.sup.1H.sub.DMSO 1.41-1.45 (6H, m), 3.17 (3H, s), 3.36-4.13 (4H,
range of m), 4.4 (1H, bs), 4.8 (1H, 2m), 5.5 (1H, m), 6.02-6.15
(2H, m),7.4-7.44 (1H, m), 7.54-7.59 (1H, m), 7.91-7.95 (1H, m),
8.05-8.07 (1H, d).
EXAMPLE 31
5-[(4S)-4-Hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isopropyl)-6-[(2-oxot-
hiazolo[5,4-b]pyridin-1(2H)-yl)methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)--
dione
##STR00080##
[0534] a)
1,2,3,4-tetrahydro-3-methyl-1-(isopropyl)-2,4-dioxo-6-[2-oxothia-
zolo[5,4-b]pyridin-1(2H)-ylmethyl]-thieno[2,3-d]pyrimidine-5-carboxylic
acid, methyl ester
[0535] Prepared using the procedure described in example 30a) from
[1,3]thiazolo[5,4-b]pyridine-2(1H)-one (0.24 g) (described in
example 13xiii) part c)) and the product from example 8 part c)
(0.6 g). The residue was triturated with ether then filtered to
give the sub-title compound. .delta. .sup.1H.sub.CDCl3 1.57-1.59
(6H, d), 3.36 (3H, s), 4(3H, s), 4.5 (1H, bs), 5.3 (2H,
s),7.24-7.28 (1H, m), 7.73-7.76 (1H, d), 8.30-8.32 (1H, d).
b)
1,2,3,4-tetrahydro-3-methyl-1-(isopropyl)-2,4-dioxo-6-[2-oxothiazolo[5,-
4-b]pyridin-1(2H)-ylmethyl]-thieno[2,3-d]pyrimidine-5-carboxylic
[0536] Sodium hydroxide (0.78 ml, 1 M) was added to a solution of
the product of example 31 part a) (0.35 g) in tetrahydrofuran under
nitrogen. Then 1 ml of methanol was added to solubilize the mixture
and the reaction mixture was stirred at room temperature for 48
hours. The precipitate formed was filtered, washed with
tetrahydrofuran then ether to give the sub-title compound (0.18 g).
MS (ES) (N++H) 433.
c)
5-[(4S)-4-Hydroxyisoxazolidinclcarbonyl]-3-methyl-1-(isopropyl)-6-[2-ox-
othiazolo[5,4-b]pyridin-1(2H)-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione
[0537] Hydroxybenzotriazole (0.12 g) was added to a suspension of
the product of example 31b) in tetrahydrofuran under nitrogen.
After 10 minutes, EDCI (0.15 g) was added and after another 40
minutes, (4S)-4-hydroxyisoxazolidine hydrochloride (0.06 g) and
triethylamine (0.07 ml) were added. The reaction mixture was
stirred at room temperature overnight. Water was added and the
mixture was extracted with dichloromethane. The organics were
washed with brine, dried over magnesium sulfate then concentrated
in vacuo. The residue was purified by silica chromatography eluting
with 5% methanol in dichloromethane to give the title compound as a
white foam. MS (APCI) (M.sup.++H) 504.0914. .delta. .sub.D6DMSO
1.45-1.48 (6H, m), 3.16 (3H, s), 3.52-4.1 (4H, range of m), 4.4
(1H, bs), 4.6-4.8 (1H, range of m), 5.11-5.57 (3H, m),7.4-7.47 (1H,
m), 7.79-7.81 (1H, d), 8.30-8.31 (1H, d).
EXAMPLE 32
6-[2,3-Dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[(4S)-4-hydroxyisoxazol-
idin-ylcarbonyl]-3-methyl-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione
##STR00081##
[0538] a)
1,2,3,4-Tetrahydro-3-methyl-1-(isopropyl)-6-[2-(methylthio)-1H-b-
enzimidazol-1-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyridine-5-carboxylic
acid, methyl ester
[0539] Prepared using the procedure described in example 3 part c)
from the product of example 8 part c) and
2-methylmercaptobenzimidazole to give the title compound as a pale
yellow solid after purification by silica chromatography eluting
with isohexane/ethyl acetate (1/1). MS (ES) (M.sup.++H). 459.
.delta. .sup.1H.sub.D6DMSO 1.40-1.42 (6H, d), 2.73 (3H, s), 3.16
(3H, s), 3.80 (3H, s), 4.3 (1H, bs), 5.56 (2H, s), 7.15-7,23(2H,
m), 7.54-7.58 (2H, m).
b)
1,2,3,4-Tetrahydro-3-methyl-1-(isopropyl)-6-[2-(methylsulfonyl)-1H-benz-
imidazol-1-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic
acid, methyl ester
[0540] mCPBA (1.2 g) was added to a solution of the product of
example 31 part a) (0.64 g) in dichloromethane. The reaction
mixture was stirred at room temperature for 2 hours. The reaction
mixture was washed with 10% sodium metabisulphite solution (40 ml),
sodium hydrogenocarbonate then brine. The organics were dried over
magnesium sulfate then concentrated under vacuum to give the
sub-title compound. MS (ES) (M.sup.++H) 490.8.
c)
6-[2,3-Dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-1,2,3,4-tetrahydro-3-m-
ethyl-1-(isopropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic
acid
[0541] Sodium hydrogenocarbonate (0.55 g) was added to a suspension
of the product from example 32 part b) (0.54 g) in water. The
reaction mixture was heated at reflux for 17 hours. The reaction
mixture was washed with ethyl acetate and the aqueous layer was
freezed dried to give the sub-title compound (0.7 g). MS (ES)
(M.sup.++H) 415.
d)
6-[2,3-Dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[(4S)-4-hydroxyisoxa-
zolidinylcarbonyl]-3-methyl-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3-
H)-dione
[0542] Prepared using the procedure described in example 31 part c)
from the product of example 32 part c) to give the title compound
after purification by silica chromatography eluting with 0% then 1%
methanol in ethyl acetate followed by a reverse phase HPLC
purification eluting with 0.1% ammonium acetate
aqueous:acetonitrile (95:5 to 5:95). MS (APCI) (M.sup.++H)
(486.1469). .delta. .sup.1H.sub.D6DMSO 300 Mhz) 1.44-1.45 (6H, m),
3.16 (3H, s), 3.5-4.5 (5H, range of m), 4.6-5.2 (3H, range of m),
5.5-5.57 (1H, 2m), 6.99 (3H, s), 7.2 (1H, m).
EXAMPLE 33
6-[5,6-Difluoro-2,3-dihydro-2-oxo-1H-benzimidazol-1-ylmethyl]-5-[(4S)-4-hy-
droxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimid-
ine-2,4(1H,3H)-dione
##STR00082##
[0543] a) 5,6-Difluoro-2-mercaptobenzimiazole
[0544] A stirred suspension of 3,4-difluoro-6-nitroaniline (2 g)
and 5% palladium on charcoal (100 mg) in ethanol (30 ml) was
hydrogenated at 5 bar for 24 hours. The mixture was filtered
through celite and concentrated in vacuo to give a solid which was
dissolved in DMF (20 ml) and treated with carbon disulfide (10 ml).
The solution was stirred for 5 h at ambient temperature. The
solution was poured onto water and the resultant mixture was
extracted with ethyl acetate (x3). The combined organic extracts
were dried (MgSO.sub.4) and concentrated in vacuo to give a dark
red solid (2.45 g). .delta. .sup.1H.sub.D6DMSO 7.6-7.62 (2H, m),
8.3 (1H, s, br), 13 (s, 1H).
b) 5,6-Difluoro-2-(methylthio)benzimidazole
[0545] A stirred suspension of 5,6-Difluoro-2-mercaptobenzimiazole
(2.4 g) and potassium carbonate (1.78 g) in acetone was treated
with methyl iodide (0.8 ml) and stirred for 2 hours. The reaction
was evaporated to dryness and the residue suspended in water (300
ml). The mixture was extracted with ethyl acetate (x3). The
combined organic extracts were dried (MgSO.sub.4) and evaporated.
The residue was chromatographed (SiO.sub.2/2:8 ethyl
acetate-isohexane) to afford the sub-title compound (1.95 g). MS
(APCI) 215 [M+H].sup.+.
c)
6-[5,6-Difluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-ylmethyl]-5-[(4S)-4-
-hydroxyisoxazolidin-2-ylcarbonyl]-1-isobutyl-3-methylthieno[2,3-d]pyrimid-
ine-2,4(1H,3H)-dione
[0546] m-CPBA was added to dichloromethane and the reaction mixture
was stirred for 1 hour. The reaction mixture was poured onto a
solution of 10% sodium metabisulfite (160 ml). The two phases were
separated and the organic washed with sodium hydrogencarbonate,
brine then dried (MgSO.sub.4) and concentrated in vacuo to give a
yellow foam. The foam was treated with water (5 ml), THF (5 ml) and
sodium hydrogencarbonate (0.37 g). The reaction mixture was stirred
at reflux for 48 hours. A precipitate was formed which was filtered
and washed with water to give a white solid. The solid was treated
with THF (7 ml), HOBT (0.2 g) and EDCI (0.28 g). The reaction
mixture was stirred at reflux for 35 minutes and then triethylamine
(0.24 ml) and (S)-Hydroxyisoxizolidine HCl (0.18 g) were added. The
reaction mixture was stirred at reflux for 2 days. The residue was
chromatographed (SiO.sub.2/98:2 ethyl acetate-methanol) to give a
yellow solid. This was recrytallised from methanol to afford the
title compound as a white crystalline solid (0.18 g). .delta.
.sup.1H.sub.D6DMSO 0.84 (6H, m), 2.02-2.19 (1H, m), 3.19 (1H, s),
3.74-4.17 (5H, m), 4.6-4.81 (1H, m), 4.97-5.18 (2H, m), 5.7-5.61
(1H, m), 7.02-7.17 (m, 1H) and 7.35-7.41 (m, 1H).
EXAMPLE 34
5-[(4S)-4-Hydroxyisoxazolidin-2-ylcarbonyl]-6-(imidazo[1,2-a]pyridin-3-ylm-
ethyl)-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00083##
[0547] a) Methyl
6-(imidazo[1,2-a]pyridin-3-ylmethyl-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-
-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate
[0548] The product of example 3 part b (1 g),
imidazolo[1,2-a]pyridine (0.4 ml), potassium carbonate (0.35 g) and
THF (20 ml) were stirred under nitrogen for 1 hour. Warer was added
to the reaction and extracted with ethyl acetate (.times.2). The
combined organic extracts were dried (MgSO.sub.4) and concentrated
in vacuo. The residue was chromatographed (SiO.sub.2/9:1 ethyl
acetate-hexane and the ethyl acetate) to give the sub-title
compound as a colourless oil. LCMS (ESI) 4275 [M+H].sup.+.
b)
6-(Imidazo[1,2-a]pyridin-3-ylmethyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,-
3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid
[0549] The product of part a was treated with sodium hydroxide
(0.75 ml), THF (5 ml) and methanol (0.05 ml) and the resulting
solution was stirred for 2 hours under nitrogen. The reaction
mixture was washed with ethyl acetate. The aqueous phase was
concentrated in vacuo to give the subtitle compound (0.13 g).
c)
5-[(4S)-4-Hydroxyisoxazolidin-2-ylcarbonyl]-6-(imidazo[1,2-a]pyridin-3--
ylmethyl)-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0550] The product of step b (0.13 g), was dissolved in THF (3 ml).
HOBT (0.09 g) was added, followed by EDCI (0.12 g). After stirring
for 10 min triethylamine (0.05 ml) and (S)-Hydroxyisoxizolidine
.HCl (0.08 g) were added and the reaction mixture was stirred for
16 hours. Water (10 ml) and ethylacetate (10 ml) were added. The
two phases were separated and the aq layer was re-extracted with
ethyl acetate. The combined organic extracts were dried
(MgSO.sub.4) and concentrated in vacuo. The compound was purified
by
[0551] RPHPLC eluting with ammonium acetate:acetonitrile (80:20) to
afford the title compound as a white solid. LCMS (APCI) 485
[M+H].sup.+.
EXAMPLE 35
3-Methyl-6-[2-methylindol-3-ylmethyl]-1-(isobutyl)-5-(tetrahydroisoxazin-2-
-ylcarbonyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00084##
[0553] The title compound was prepared by the method of Example 1
part g) using the product of Example 5 part b) and
tetrahydro-1,2-oxazine hydrochloride. MS (APCI) 495 [M+H].sup.+.
.sup.1H.sub.DMSO, 130.degree. C. 0.82 (6H, d); 1.72 (4H, br s);
2.11 (1H, septet); 2.35 (3H, s); 3.25 (3H, s); 3.6 (2H, br d); 3.70
(2H, br s); 3.85 (2H, br s); 4.1 (2H, s); 6.9 (1H, t); 6.95 (1H,
t); 7.25 (1H, d); 7.35 (1H, d); 10.4 (1H, br s).
EXAMPLE 36
6-[2-Bromo-4,5-dichloro-1H-imidazol-1-ylmethyl]-5-[(4S)-4-hydroxyisoxazoli-
dinylcarbonyl]-3-methyl-1-(isobutyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dio-
ne
##STR00085##
[0554] a)
6-[2-bromo-4,5-dichloro-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahyd-
ro-3-methyl-1-(isobutyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic
acid, methyl ester
[0555] The product from example 3 part b) (1 g) was added to a
solution of 2-bromo-4,5-dichloroimidazole (0.73 g) and potassium
carbonate (1 g) in anhydrous dimethylformamide. The reaction was
stirred at room temperature for 2 days then diluted into water and
extracted with ethyl acetate (twice). The organics were dried over
magnesium sulfate and concentated under reduced pressure. The
residue was purified by flash silica chromatography eluting with
20% ethyl acetate in isohexane to give the subtitle compound (0.84
g). MS (APCI) 524.9 [M+H]. .delta. .sup.1H.sub.CDCl3 0.96-0.98 (6H,
d), 2.2-2.3 (1H, m), 3.39 (3H, s), 3.73-3.75 (2H, d), 4 (3H,
s),5.36 (2H, s).
b)
6-[2-bromo-4,5-dichloro-1H-imidazol-1-ylmethyl]-1,2,3,4-tetrahydro-3-me-
thyl-1-(isobutyl-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic
acid,
[0556] Sodium hydroxide (2 ml of 1 M aqueous solution) followed by
methanol (0.5 ml) were added to a solution of the product of step
a) (0.85 g) in tetrahydrofuran (7 ml) and stirred at room
temperature for 2 hours. The precipitate formed was filtered and
washed with tetrahydrofuran to give the subtitle compound as a
white solid (0.81 g). MS (APCI) 510.8 [M+H].
c)
6-[2-Bromo-4,5-dichloro-1H-imidazol-1-ylmethyl]-5-[(4S)-4-hydroxyisoxaz-
olidinylcarbonyl]-3-methyl-1-(isobutyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-
-dione
[0557] Prepared using the procedure described in example 1 part g)
from the product of step b) in example 10 and
(4S)-4-hydroxyisoxalidine hydrochloride (product of example 1b) to
give the subtitle compound after purification by flash silica
chromatography eluting with 2% methanol in dichloromethane. MS
(APCI) 581.8 [M+H]. .delta. .sup.1H.sub.DMSO 0.89-0.91 (6H, d),
2.1-2.2 (1H, m), 3.2 (3H, s), 3.6-4 (5H, m), 4-4.1 (1H, m),4.6-4.8
(1H, 2m), 5.34 (2H, s), 5.51-5.53 (1H, d).
EXAMPLE 37
5-[(4S)-4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(me-
thylthio)-1H-imidazo[4,5-b]pyridin-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4-
(1H,3H)-dione
##STR00086##
[0558] a) 2-(methylthio)-1H-imidazo[4,5-b]pyridine
[0559] Potassium ethylxanthate (4.51 g) was added to
2,3-diaminipyridine (2.51 g) in ethanol (25 ml) and water (5 ml).
The reaction mixture was refluxed for 24 hours then cooled. A
precipitate was formed which was filtered, washed with ethanol then
ether to give a pale pink solid (3.16 g).
[0560] Potassium hydroxide (23 ml, 1 M) was added to this solid and
after 5 minutes, iodomethane (1.3 ml) was added. The reaction
mixture was stirred at room temperature overnight, then extracted
with ethyl acetate. The aqueous layer was concentrated in vacuo.
The residue was triturated with methanol and the insoluble solid
was filtrated. The filtrate was concentrated under vacuum then the
residue was triturated with dichloromethane and filtered to give
the title compound as a beige solid (440 mg). MS (ES) 166
[M+H].sup.+. .delta. .sup.1H.sub.DMSO 2.56 (3H, s), 6.68-6.73 (1H,
m), 7.44-7.47 (1H, d), 7.84-7.86 (1H, d).
b)
1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-6-[2-(methylthio)-1H-imidazo[4-
,5-b]pyridin-1-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic
acid, methyl ester
[0561] Prepared from the product of example 3b (815 mg) and
2-(methylthio)-1H-imidazo[4,5-b]pyridine (example 37 part a)) (342
mg) by the method of example 13vii part a). The crude material was
purified by flash silica chromatography eluting with 50% ethyl
acetate in isohexane then 3% methanol in dichloromethane to give
the title-compound (190 mg) as well as the product of example 22i
part a) (40 mg). MS (ES) 474 [M+H].sup.+. .delta. .sup.1H.sub.CDCl3
0.89-0.90 (6H, d), 2.1-2.2 (1H, m), 2.8 (3H, s), 3.4 (3H, s), 3.6
(2H, d), 4.1 (3H, s), 5.82 (2H, s), 6.95-7 (1H, t), 7.85-7.91 (2H,
m).
c) Sodium
1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-6-[2-(methylthio)-1H-im-
idazo[4,5-b]pyridin-1-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carbox-
ylate
[0562] Sodium hydroxide (0.8 ml, 1 M) was added to a solution of
the product of example 37 part b) (190 mg) in tetrahydrofuran under
nitrogen. Methanol was added to solubilise the solution and the
reaction mixture was stirred at room temperature for 3 hours. HCl
(0.4 ml, 2 M) was added to neutralise the solution and the mixture
was concentrated in vacuo to give the title compound. MS (ES) 460
[M+H].sup.+.
d)
5-[(4S)-4-Hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2--
(methylthio)-1H-imidazo[4,5-b]pyridin-1-ylmethyl]-thieno[2,3-d]pyrimidine--
2,4(1H,3H)-dione
[0563] Prepared from product of example 37 part c) by the method of
example 1 part g). The crude material was purified by reverse-phase
preparative HPLC eluting with acetonitrile in 0.1% ammonium acetate
aqueous from 25% to 95% to give the title-compound as a colourless
oil (47 mg). MS (ES) 531.1494 [M+H].sup.+. .delta. .sup.1H.sub.DMSO
0.88-0.90 (6H, m), 2.1-2.2 (1H, m), 2.70 (3H, s), 3.18 (3H, s),
3.6-3.9 (5H, 3m), 4-4.1 (1H, m), 4.6-4.8 (1H, 3m), 5.5-5.9 (3H, m),
7.1 (1H, m), 7.9 (2H, m).
EXAMPLE 37i
5-[(4S)-4-Hydroxyisoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(methy-
lthio)-3H-imidazo[4,5-b]pyridin-3-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H-
,3H)-dione
##STR00087##
[0564] a)
1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-6-[2-(methylthio)-3H-im-
idazo[4,5-b]pyridin-3-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carbox-
ylic acid, methyl ester
[0565] Obtained from the reaction of example 37 part b). MS (ES)
474 [M+H].sup.+. .delta. .sup.1H.sub.CDCl3 0.88-0.90 (6H, d),
2.1-2.2 (1H, m), 2.8 (3H, s), 3.38 (3H, s), 3.66-3.68 (2H, d),
4(3H, s), 5.6 (2H, s), 7.19-7.23 (1H, m), 7.90-7.93 (1H, d),
8.28-8.29 (1H, d).
b)
1,2,3,4-tetrahydro-3-methyl-1-(isobutyl-6-[2-(methylthio)-3H-imidazo[4,-
5-b]pyridin-3-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic
acid
[0566] Prepared from the product of example 37i part a) (40 mg) by
the method of example 22 part c) to give the title compound. MS
(ES) 460 [M+H].sup.+.
c)
5-[(4S)-4-hydroxyisoxazolidinylcarbonyl]-3-methyl-[1-(isobutyl)-6-[2-(m-
ethylthio)-3H-imidazo-4,5-b]pyridin-3-ylmethyl]-thieno[2,3-d]pyrimidine-2,-
4(1H,3H)-dione
[0567] Prepared from product of example 37i part b) by the method
of example 1 part g). The crude material was purified by flash
silica chromatography eluting with 3% methanol in dichloromethane,
followed by trituration with isohexane to give the title compound
as a pale yellow solid (10 mg). MS (ES) 531.1583 [M+H].sup.+.
.delta. .sup.1H.sub.CDCl3 0.91-0.93 (6H, d), 2.17-2.26 (1H, m),
2.78-2.8 (3H, d), 3.36 (3H, s), 3.5-4.2 (6H, 3m), 4.6-5 (2H, 3d),
5.43-5.74 (2H, m), 7.19-7.26 (1H, m), 7.9-7.93 (1H, d), 8.26-8.28
(1H, d).
EXAMPLE 38
6-[3,5-Dimethyl-1H-pyrazol-4-ylmethyl]-3-ethyl-5-[(4S)-4-hydroxy-2-isoxazo-
lidinylcarbonyl]-1-(isopropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00088##
[0568] a)
1,2,3,4-tetrahydro-6-methyl-1-(isopropyl)-2,4-dioxo-thieno[2,3-d-
]pyrimidine-5-carboxylic acid, methyl ester
[0569] 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 minutes. The product of example 8
step a) (23 g) dissolved in anhydrous toluene (15 ml) was added and
the mixture was stirred for 72 hours. 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 hours. 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 sub-title
compound (12.2 g). MS (ES) 283 [M+H].sup.+.
b)
3-Ethyl-1,2,3,4-tetrahydro-6-methyl-1-(isopropyl)-2,4-dioxo-thieno[2,3--
d]pyrimidine-5-carboxylic acid, methyl ester
[0570] The product of part a) (0.5 g), potassium carbonate (0.34
g), ethyl iodide (0.17 ml), DMF (5 ml) and acetone (5 ml) were
heated at 50.degree. C. for 16 hours. The reaction mixture was
quenched with water (5 ml) and then extracted with ethyl acetate.
The organic extracts were dried (MgSO.sub.4) and concentrated in
vacuo. The residue was chromatographed chromatographed
(SiO.sub.2/8:1:1 isohexane-ethyl acetate-dichloromethane to give
the sub-title compound as a pale yellow oil. .sup.1H.sub.CDCl3 1.23
(3H, t), 1.59 (6H, m), 2.4 (3H, s), 3.95 (3H, t), 4.01-4.06 (2H,
q), 4.6-4.8 (1H, m).
c)
6-(Bromomethyl-3-ethyl-1,2,3,4-tetrahydro-1-(isopropyl)-2,4-dioxo-thien-
o[2,3-d]pyrimidine-5-carboxylic acid, methyl ester
[0571] The subtitle compound was prepared by the method of example
22 part a) using the product of part b). MS (ES) 327
[M+OH--Br].sup.+.
d)
6-[3,5-Dimethyl-1H-pyrazol-4-ylmethyl]-3-ethyl-1,2,3,4-tetrahydro-1-(is-
opropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid,
methyl ester
[0572] The subtitle compound was prepared by the method of example
26 part a) using the product of part c). MS (ES) 334
[M+H].sup.+.
e)
6-[3,5-Dimethyl-1H-pyrazol-4-ylmethyl]-3-ethyl-5-[(4S)-4-hydroxy-2-isox-
azolidinylcarbonyl]-1-(isopropyl)-thieno[2,3-d]-pyrimidine-2,4(1H,3H)-dion-
e
[0573] The product of part d) (0.6 mmol), diethyl chlorophosphate
(0.09 ml), 1-hydroxybenzotriazole (0.08 g), triethylamine (0.1 ml)
and acetonitrile (6 ml) were stirred for 30 minutes. The product of
example 1 part b) (0.08 g) was added and the mixture was stirred
for 16 hours. The reaction was quenched with the addition of
potassium carbonate. The reaction mixture was purified SiO.sub.2
chromatography eluting THF:methanol (98:2) to give the a yellow
foam, which was further purified by reverse phase HPLC to give the
sub-title compound as a white solid (30 mg). H.sub.DMSO 1.06-1.18
(3H, m), 1.41-1.53 (6H, m), 2.1 (6H, s), 3.42-4.18 (7H, m),
4.3-4.47 (1H, s), 4.63-4.8 (1H, m) and 5.5 (1H, m).
EXAMPLE 39
5-[(4S)-4-Hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2-(tr-
ifluoromethyl)phenylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
##STR00089##
[0574] a)
1,2,3,4-Tetrahydro-3-methyl-1-(isobutyl)-2,4-dioxo-6-[2-(trifluo-
romethyl)phenylmethyl]-thieno[2,3-d]pyrimidine-5-carboxylic
acid
[0575] To a solution of
5-Bromo-3-methyl-1-(isobutyl)-6-[2-(trifluoromethyl)phenylmethyl]-thieno[-
2,3-d]pyrimidine-2,4(1H,3H)-dione (WO 0183489) in THF (60 ml) was
added isopropylmagnesiumcholride (2 M solution in THF, 3.35 ml)
dropwise at 0.degree. C. under nitrogen. After 5 minutes, the
mixture was treated with a stream of carbon dioxide for 10 minutes.
The reaction mixture was quenched with water, acidified 2 N HCl and
extracted into ethyl acetate (x3). 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). MS (ES) 441 [M+H].sup.+.
b)
5-[(4S)-4-Hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2--
(trifluoromethyl)phenylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0576] Prepared by the method of example 1 part g) using the
product of part a). MS (APCI) 512 [M+H].sup.+. .sup.1H.sub.DMSO 0.8
(6H, m), 2.1 (1H, pentet), 3.2 (3H, m), 3.5-3.8 (4H, m), 4.2 (2H,
m), 4.6-4.7 (1H, m), 5.5 (1H, m),7.5 (2H, m),7.6 (1H, t) and 7.8
(1H, d).
EXAMPLE 40
5-[(4S)-4-Hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutvi)-6-[2-(me-
thylthio)-1H-imidazol-1-ylmethyl]-thieno[2,3-d]-pyrimidine-2,4(1H,3H)-dion-
e
##STR00090##
[0577] a)
1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-6-[2-(methylthio)-1H-im-
idazol-1-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic
acid, methyl ester
[0578] The subtitle compound was prepared by the method of example
13vi part a) using the product of example 3 part b) and
2-methylthioimidazole. MS (ESI) 423 [M+H].sup.+.
b)
1,2,3,4-tetrahydro-3-methyl-1-(isobutyl-6-[2-(methylthio)-1H-imidazol-1-
-ylmethyl]-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid
[0579] Prepared by the method of example 3 part d) using the
product of part a). MS (ESI) 409 [M+H].sup.+.
c)
5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-6-[2--
(methylthio)-1H-imidazol-1-ylmethyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-di-
one
[0580] Prepared by the method of example 3 part e) using the
product of part b). MS (APCI) 480. .sup.1H.sub.DMSO 0.89-0.91 (6H,
m), 2.11-2.18 (1H, m), 2.49-2.52 (3H, m), 3.2-3.21 (3H, m),
3.52-4.1 (6H, m), 4.62-4.78 (1H, m), 5.23-5.25 (2H, m), 5.5-5.58
(1H, m), 6.97 (1H, d) and 7.21-7.23 (1H, m).
* * * * *