U.S. patent application number 12/124319 was filed with the patent office on 2008-09-11 for thienopyrimidinediones and their use in modulation of autoimmune disease.
Invention is credited to Simon David Guile.
Application Number | 20080221131 12/124319 |
Document ID | / |
Family ID | 32775326 |
Filed Date | 2008-09-11 |
United States Patent
Application |
20080221131 |
Kind Code |
A1 |
Guile; Simon David |
September 11, 2008 |
THIENOPYRIMIDINEDIONES AND THEIR USE IN MODULATION OF AUTOIMMUNE
DISEASE
Abstract
The invention relates to thienopyrimidinediones of formula (I):
##STR00001## in which R.sup.1, R.sup.2, Q are as defined in the
specification, and Ar and Ar.sup.2 are selected from certain
aromatic ring systems which may be optionally substituted, as
defined in the specification. Processes for the preparation of
compounds of formula (I), pharmaceutical compositions containing
them and their use in therapy are also described.
Inventors: |
Guile; Simon David;
(Loughborough, GB) |
Correspondence
Address: |
FISH & RICHARDSON P.C.
P.O BOX 1022
MINNEAPOLIS
MN
55440-1022
US
|
Family ID: |
32775326 |
Appl. No.: |
12/124319 |
Filed: |
May 21, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10542457 |
Jul 14, 2005 |
7393854 |
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PCT/SE2004/000053 |
Jan 15, 2004 |
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12124319 |
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Current U.S.
Class: |
514/260.1 |
Current CPC
Class: |
A61P 17/14 20180101;
A61P 25/02 20180101; A61P 19/02 20180101; A61P 25/00 20180101; A61P
27/16 20180101; A61P 35/00 20180101; A61P 3/10 20180101; C07D
495/04 20130101; A61P 37/06 20180101; A61P 37/08 20180101; A61P
31/18 20180101; A61P 21/04 20180101; A61P 17/00 20180101; A61P
37/04 20180101; A61P 11/00 20180101; A61P 27/02 20180101; A61P
35/04 20180101; A61P 5/14 20180101; A61P 37/02 20180101; A61P 17/06
20180101; A61P 9/10 20180101; A61P 29/00 20180101; A61P 1/00
20180101; A61P 11/06 20180101; A61P 7/04 20180101; A61P 9/00
20180101; A61P 1/04 20180101 |
Class at
Publication: |
514/260.1 |
International
Class: |
A61K 31/519 20060101
A61K031/519; A61P 11/00 20060101 A61P011/00; A61P 9/00 20060101
A61P009/00; A61P 35/04 20060101 A61P035/04 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 17, 2003 |
SE |
0300117-9 |
Jan 17, 2003 |
SE |
0300118-7 |
Claims
1. A method of inhibiting the proliferation of T cells, comprising
administering to a patient in need thereof a therapeutically
effective amount of a compound of formula (I): ##STR00018## wherein
R.sup.1 and R.sup.2 each independently represent 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; Q is CR.sup.4R.sup.5, in which R.sup.4 is
hydrogen, fluorine or C.sub.1-6 alkyl and R.sup.5 is hydrogen,
fluorine or hydroxy; 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 substituents independently selected from the group
consisting of C.sub.1-4alkyl (optionally substituted by 1, 2 or 3
hydroxy or halo groups), C.sub.1-4alkoxy, halogen,
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, SO.sub.2N(R.sup.8)R.sup.9; Ar.sup.2 is a 5 or 6 membered
aromatic ring containing up to 4 heteroatoms independently selected
from the group consisting of nitrogen, sulphur or oxygen, and which
is optionally substituted by one or more groups independently
selected from the group consisting of C.sub.1-4alkyl (optionally
substituted by 1, 2 or 3 hydroxy or halo groups), C.sub.1-4alkoxy,
halogen, 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, SO.sub.2N(R.sup.8)R.sup.9; 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 group, or together with the
nitrogen atom to which they are attached form a 5- to 7-membered
saturated heterocyclic ring optionally containing a further O, S,
NH or N-alkyl group; R.sup.8 and R.sup.9 each independently
represent a hydrogen atom, C.sub.1-4alkanoyl or C.sub.1-4alkyl
group, or together with the nitrogen atom to which they are
attached form a 5- to 7-membered saturated heterocyclic ring
optionally containing a further O, S, NH or N-alkyl group; or a
pharmaceutically acceptable salt thereof, provided that the
compound is other than
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,
6-[[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl]methyl]-5-[(4S)-4-hydroxyiso-
xazolidin-2-ylcarbonyl]-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione or
6-[[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl]methyl]-5-[(4S)-4-hydroxyisoxaz-
olidin-2-ylcarbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-d-
ione or a pharmaceutically acceptable salt thereof.
2. The method of claim 1, wherein R.sup.1 is C.sub.1-6 alkyl.
3. The method of claim 1, wherein R.sup.2 is methyl.
4. The method of claim 1, wherein Q is CH.sub.2.
5. The method of claim 1, wherein Ar is a 5 or 6-membered aromatic
ring system wherein up to 2 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 substituents independently selected from the group
consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy, halogen,
dihaloC.sub.1-4alkyl, trihaloC.sub.1-4alkyl, oxo, thioxo, cyano and
C.sub.1-4alkylsulphonyl.
6. The method of claim 5, wherein Ar is a group of sub-formula (I):
##STR00019## wherein R.sup.10 and R.sup.11 are independently
selected from H, C.sub.1-4alkyl, or haloC.sub.1-4alkyl.
7. The method of claim 1, wherein Ar.sup.2 is other than
phenyl.
8. The method of claim 7, wherein Ar.sup.2 contains at least one
heteroatom.
9. The method of claim 1, wherein Ar.sup.2 is a 5 or 6-membered
aromatic ring system wherein up to 3 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 substituents independently selected from
C.sub.1-4alkyl, C.sub.1-4alkoxy, halogen, dihaloC.sub.1-4alkyl,
trihaloC.sub.1-4alkyl, oxo, thioxo, cyano and
C.sub.1-4alkylsulphonyl.
10. The method of claim 9, wherein Ar.sup.2 is pyridinyl or
pyrimidinyl.
11. The method of claim 9, wherein Ar.sup.2 is thiazolyl.
12. The method of claim 1, wherein the compound is selected from
the group consisting of
(S)-2-[[6-[[3,5-Dimethyl-1-(2-thiazolyl)-1H-pyrazol-4-yl]methyl]-1,2,3,4--
tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl-
]carbonyl]-4-isoxazolidinol and pharmaceutically acceptable salts
thereof.
13. A method of effecting immunosuppression, comprising
administering to a patient in need thereof a therapeutically
effective amount of a compound of formula (I): ##STR00020## wherein
R.sup.1 and R.sup.2 each independently represent 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; Q is CR.sup.4R.sup.5, in which R.sup.4 is
hydrogen, fluorine or C.sub.1-6 alkyl and R.sup.5 is hydrogen,
fluorine or hydroxy; 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 substituents independently selected from the group
consisting of C.sub.1-4alkyl (optionally substituted by 1, 2 or 3
hydroxy or halo groups), C.sub.1-4alkoxy, halogen,
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, SO.sub.2N(R.sup.8)R.sup.9; Ar.sup.2 is a 5 or 6 membered
aromatic ring containing up to 4 heteroatoms independently selected
from the group consisting of nitrogen, sulphur or oxygen, and which
is optionally substituted by one or more groups independently
selected from the group consisting of C.sub.1-4alkyl (optionally
substituted by 1, 2 or 3 hydroxy or halo groups), C.sub.1-4alkoxy,
halogen, 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, SO.sub.2N(R.sup.8)R.sup.9; 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 group, or together with the
nitrogen atom to which they are attached form a 5- to 7-membered
saturated heterocyclic ring optionally containing a further O, S,
NH or N-alkyl group; R.sup.8 and R.sup.9 each independently
represent a hydrogen atom, C.sub.1-4alkanoyl or C.sub.1-4alkyl
group, or together with the nitrogen atom to which they are
attached form a 5- to 7-membered saturated heterocyclic ring
optionally containing a further O, S, NH or N-alkyl group; or a
pharmaceutically acceptable salt thereof, provided that the
compound is other than
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,
6-[[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl]methyl]-5-[(4S)-4-hydroxyiso-
xazolidin-2-ylcarbonyl]-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione or
6-[[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl]methyl]-5-[(4S)-4-hydroxyisoxaz-
olidin-2-ylcarbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-d-
ione or a pharmaceutically acceptable salt thereof.
14. The method of claim 13, wherein R.sup.1 is C.sub.1-6 alkyl.
15. The method of claim 13, wherein R.sup.2 is methyl.
16. The method of claim 13, wherein Q is CH.sub.2.
17. The method of claim 13, wherein Ar is a 5 or 6-membered
aromatic ring system wherein up to 2 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 substituents independently selected from
the group consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy, halogen,
dihaloC.sub.1-4alkyl, trihaloC.sub.1-4alkyl, oxo, thioxo, cyano and
C.sub.1-4alkylsulphonyl.
18. The method of claim 17, wherein Ar is a group of sub-formula
(I): ##STR00021## wherein R.sup.10 and R.sup.11 are independently
selected from H, C.sub.1-4alkyl, or haloC.sub.1-4alkyl.
19. The method of claim 13, wherein Ar.sup.2 is other than
phenyl.
20. The method of claim 19, wherein Ar.sup.2 contains at least one
heteroatom.
21. The method of claim 13, wherein Ar.sup.2 is a 5 or 6-membered
aromatic ring system wherein up to 3 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 substituents independently selected from
C.sub.1-4alkyl, C.sub.1-4alkoxy, halogen, dihaloC.sub.1-4alkyl,
trihaloC.sub.1-4alkyl, oxo, thioxo, cyano and
C.sub.1-4alkylsulphonyl.
22. The method of claim 21, wherein Ar.sup.2 is pyridinyl or
pyrimidinyl.
23. The method of claim 21, wherein Ar.sup.2 is thiazolyl.
24. The method of claim 13, wherein the compound is selected from
the group consisting of
(S)-2-[[6-[[3,5-Dimethyl-1-(2-thiazolyl)-1H-pyrazol-4-yl]methyl]-1,2,3,4--
tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl-
]carbonyl]-4-isoxazolidinol and pharmaceutically acceptable salts
thereof.
25. 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 (I): ##STR00022## wherein R.sup.1 and R.sup.2 each
independently represent 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; Q is
CR.sup.4R.sup.5, in which R.sup.4 is hydrogen, fluorine or
C.sub.1-6 alkyl and R.sup.5 is hydrogen, fluorine or hydroxy; 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 substituents
independently selected from the group consisting of C.sub.1-4alkyl
(optionally substituted by 1, 2 or 3 hydroxy or halo groups),
C.sub.1-4alkoxy, halogen, 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,
SO.sub.2N(R.sup.8)R.sup.9; Ar.sup.2 is a 5 or 6 membered aromatic
ring containing up to 4 heteroatoms independently selected from the
group consisting of nitrogen, sulphur or oxygen, and which is
optionally substituted by one or more groups independently selected
from the group consisting of C.sub.1-4alkyl (optionally substituted
by 1, 2 or 3 hydroxy or halo groups), C.sub.1-4alkoxy, halogen,
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, SO.sub.2N(R.sup.8)R.sup.9; 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 group, or together with the
nitrogen atom to which they are attached form a 5- to 7-membered
saturated heterocyclic ring optionally containing a further O, S,
NH or N-alkyl group; R.sup.8 and R.sup.9 each independently
represent a hydrogen atom, C.sub.1-4alkanoyl or C.sub.1-4alkyl
group, or together with the nitrogen atom to which they are
attached form a 5- to 7-membered saturated heterocyclic ring
optionally containing a further O, S, NH or N-alkyl group; or a
pharmaceutically acceptable salt thereof, provided that the
compound is other than
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,
6-[[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl]methyl]-5-[(4S)-4-hydroxyiso-
xazolidin-2-ylcarbonyl]-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione or
6-[[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl]methyl]-5-[(4S)-4-hydroxyisoxaz-
olidin-2-ylcarbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-d-
ione or a pharmaceutically acceptable salt thereof.
26. The method of claim 25, wherein the obstructive airways disease
is chronic obstructive pulmonary disease.
27. The method of claim 25, wherein R.sup.1 is C.sub.1-6 alkyl.
28. The method of claim 25, wherein R.sup.2 is methyl.
29. The method of claim 25, wherein Q is CH.sub.2.
30. The method of claim 25, wherein Ar is a 5 or 6-membered
aromatic ring system wherein up to 2 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 substituents independently selected from
the group consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy, halogen,
dihaloC.sub.1-4alkyl, trihaloC.sub.1-4alkyl, oxo, thioxo, cyano and
C.sub.1-4alkylsulphonyl.
31. The method of claim 30, wherein Ar is a group of sub-formula
(I): ##STR00023## wherein R.sup.10 and R.sup.11 are independently
selected from H, C.sub.1-4alkyl, or haloC.sub.1-4alkyl.
32. The method of claim 25, wherein Ar.sup.2 is other than
phenyl.
33. The method of claim 32, wherein Ar.sup.2 contains at least one
heteroatom.
34. The method of claim 25, wherein Ar.sup.2 is a 5 or 6-membered
aromatic ring system wherein up to 3 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 substituents independently selected from
C.sub.1-4alkyl, C.sub.1-4alkoxy, halogen, dihaloC.sub.1-4alkyl,
trihaloC.sub.1-4alkyl, oxo, thioxo, cyano and
C.sub.1-4alkylsulphonyl.
35. The method of claim 34, wherein Ar.sup.2 is pyridinyl or
pyrimidinyl.
36. The method of claim 34, wherein Ar.sup.2 is thiazolyl.
37. The method of claim 25, wherein the compound is selected from
the group consisting of
(S)-2-[[6-[[3,5-Dimethyl-1-(2-thiazolyl)-1H-pyrazol-4-yl]methyl]-1,2,3,4--
tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl-
]carbonyl]-4-isoxazolidinol and pharmaceutically acceptable salts
thereof.
38. A method of treating cancer in a patient suffering from the
cancer, comprising administering to the patient a therapeutically
effective amount of a compound of formula (I): ##STR00024## wherein
R.sup.1 and R.sup.2 each independently represent 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; Q is CR.sup.4R.sup.5, in which R.sup.4 is
hydrogen, fluorine or C.sub.1-6 alkyl and R.sup.5 is hydrogen,
fluorine or hydroxy; 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 substituents independently selected from the group
consisting of C.sub.1-4alkyl (optionally substituted by 1, 2 or 3
hydroxy or halo groups), C.sub.1-4alkoxy, halogen,
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, SO.sub.2N(R.sup.8)R.sup.9; Ar.sup.2 is a 5 or 6 membered
aromatic ring containing up to 4 heteroatoms independently selected
from the group consisting of nitrogen, sulphur or oxygen, and which
is optionally substituted by one or more groups independently
selected from the group consisting of C.sub.1-4alkyl (optionally
substituted by 1, 2 or 3 hydroxy or halo groups), C.sub.1-4alkoxy,
halogen, 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, SO.sub.2N(R.sup.8)R.sup.9; 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 group, or together with the
nitrogen atom to which they are attached form a 5- to 7-membered
saturated heterocyclic ring optionally containing a further O, S,
NH or N-alkyl group; R.sup.8 and R.sup.9 each independently
represent a hydrogen atom, C.sub.1-4alkanoyl or C.sub.1-4alkyl
group, or together with the nitrogen atom to which they are
attached form a 5- to 7-membered saturated heterocyclic ring
optionally containing a further O, S, NH or N-alkyl group; or a
pharmaceutically acceptable salt thereof, provided that the
compound is other than
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,
6-[[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl]methyl]-5-[(4S)-4-hydroxyiso-
xazolidin-2-ylcarbonyl]-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione or
6-[[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl]methyl]-5-[(4S)-4-hydroxyisoxaz-
olidin-2-ylcarbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-d-
ione or a pharmaceutically acceptable salt thereof.
39. The method of claim 38, wherein R.sup.1 is C.sub.1-6 alkyl.
40. The method of claim 38, wherein R.sup.2 is methyl.
41. The method of claim 38, wherein Q is CH.sub.2.
42. The method of claim 38, wherein Ar is a 5 or 6-membered
aromatic ring system wherein up to 2 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 substituents independently selected from
the group consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy, halogen,
dihaloC.sub.1-4alkyl, trihaloC.sub.1-4alkyl, oxo, thioxo, cyano and
C.sub.1-4alkylsulphonyl.
43. The method of claim 42, wherein Ar is a group of sub-formula
(I): ##STR00025## wherein R.sup.10 and R.sup.11 are independently
selected from H, C.sub.1-4alkyl, or haloC.sub.1-4alkyl.
44. The method of claim 38, wherein Ar.sup.2 is other than
phenyl.
45. The method of claim 44, wherein Ar.sup.2 contains at least one
heteroatom.
46. The method of claim 38, wherein Ar.sup.2 is a 5 or 6-membered
aromatic ring system wherein up to 3 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 substituents independently selected from
C.sub.1-4alkyl, C.sub.1-4alkoxy, halogen, dihaloC.sub.1-4alkyl,
trihaloC.sub.1-4alkyl, oxo, thioxo, cyano and
C.sub.1-4alkylsulphonyl.
47. The method of claim 46, wherein Ar.sup.2 is pyridinyl or
pyrimidinyl.
48. The method of claim 46, wherein Ar.sup.2 is thiazolyl.
49. The method of claim 38, wherein the compound is selected from
the group consisting of
(S)-2-[[6-[[3,5-Dimethyl-1-(2-thiazolyl)-1H-pyrazol-4-yl]methyl]-1,2,3,4--
tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl-
]carbonyl]-4-isoxazolidinol and pharmaceutically acceptable salts
thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 10/542,457, filed on Jul. 14, 2005, which is the national phase
application of International Application No. PCT/SE2004/000053,
filed Jan. 15, 2004, which claims the benefit of Swedish Patent
Application Serial No. 0300117-9, filed Jan. 17, 2003 and Swedish
Patent Application Serial No. 0300118-7, filed Jan. 17, 2003. The
contents of all parent applications are hereby incorporated by
reference in their entireties.
BACKGROUND
[0002] The present invention relates to thienopyrimidinediones,
processes for their preparation, pharmaceutical compositions
containing them and their use in therapy. The invention also
relates to their use in the modulation of autoimmune disease.
[0003] T-cells play an important role in the immune response,
however in auto-immune disease T-cells are inappropriately
activated against particular tissues and proliferate, e.g., causing
the inflammation associated with rheumatoid arthritis. Inhibition
of the proliferation of T-cells is beneficial in the modulation of
autoimmune disease. The present invention relates to compounds
which are beneficial in the modulation of autoimmune disease.
DETAILED DESCRIPTION
[0004] In accordance with the present invention, there is provided
a compound of formula (I):
##STR00002##
in which R.sup.1 and R.sup.2 each independently represent
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; Q is CR.sup.4R.sup.5 where R.sup.4 is
hydrogen, fluorine or C.sub.1-6 alkyl and R.sup.5 is hydrogen,
fluorine or hydroxy; Ar is a 5- to 10-membered aromatic ring system
in which up to 4 ring atoms are 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 or halo groups),
C.sub.1-4alkoxy, halogen, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylthio, C.sub.1-4alkoxycarbonyl, C.sub.2-4alkanoyl,
oxo, thioxo, nitro, cyano, --N(R.sup.6)R.sup.7,
--(CH.sub.2)pN(R.sup.8)R.sup.9, hydroxy, C.sub.1-4alkylsulphonyl,
C.sub.1-4alkylsulphinyl, carbamoyl, C.sub.1-4alkylcarbamoyl,
di-(C.sub.1-4alkyl)carbamoyl, carboxy, SO.sub.2N(R.sup.8)R.sup.9;
Ar.sup.2 is a 5 or 6 membered aromatic ring containing up to 4
hetero atoms independently selected from the group consisting of
nitrogen, sulphur or oxygen, and which is optionally substituted by
one or more groups independently selected from the group consisting
of C.sub.1-4alkyl (optionally substituted by 1,2 or 3 hydroxy or
halo groups), C.sub.1-4alkoxy, halogen,
C.sub.1-4alkoxyC.sub.1-4alkyl, C.sub.1-4alkylthio,
C.sub.1-4alkoxycarbonyl, C.sub.2-4alkanoyl, oxo, thioxo, nitro,
cyano, --N(R.sup.6)R.sup.7, --(CH.sub.2)pN(R.sup.8)R.sup.9,
hydroxy, C.sub.1-4alkylsulphonyl, C.sub.1-4alkylsulphinyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di-(C.sub.1-4alkyl)carbamoyl,
carboxy, SO.sub.2N(R.sup.8)R.sup.9; 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 group, or together with the
nitrogen atom to which they are attached form a 5- to 7-membered
saturated heterocyclic ring optionally containing a further O, S,
NH or N-alkyl group; R.sup.8 and R.sup.9 each independently
represent a hydrogen atom, C.sub.1-4alkanoyl or C.sub.1-4alkyl
group, or together with the nitrogen atom to which they are
attached form a 5- to 7-membered saturated heterocyclic ring
optionally containing a further O, S, NH or N-alkyl group; and
pharmaceutically acceptable salts and solvates thereof, provided
that the compound is other than
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,
6-[[3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl]methyl]-5-[(4S)-4-hydroxyiso-
xazolidin-2-ylcarbonyl]-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,-
3H)-dione or
6-[[3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl]methyl]-5-[(4S)-4-hydroxyisoxaz-
olidin-2-ylcarbonyl]-3-methyl-1-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-d-
ione or a pharmaceutically acceptable salt or solvate thereof.
[0005] Suitably R.sup.1 is C.sub.1-6 alkyl or C.sub.3-6 cycloalkyl,
and in particular C.sub.1-6 alkyl. More preferably R.sup.1 is
ethyl, propyl, butyl or cyclopropyl. Most preferably R.sup.1 is
ethyl, isobutyl, isopropyl or cyclopropyl.
[0006] More preferably R.sup.1 is C.sub.1-4 alkyl such as isobutyl
or isopropyl.
[0007] Preferably R.sup.2 is C.sub.1-6alkyl such as ethyl or
methyl, more preferably methyl.
[0008] Suitably Q is CR.sup.5R.sup.6 where R.sup.5 is hydrogen,
C.sub.1-6 alkyl and R.sup.6 is hydrogen. Preferably Q is
CR.sup.4R.sup.5 where R.sup.4 and R.sup.5 are both hydrogen.
[0009] Examples of 5-10 membered mono- or bi-cyclic aromatic ring
systems for Ar include thienyl, furanyl, pyrrolyl, pyrrolopyridino,
imidazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl,
oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, oxadiazolyl,
thiadiazolyl, triazolyl, tetrazolyl and quinolyl.
[0010] Examples of 5- to 7-membered saturated heterocyclic rings
formed by R.sup.6 and R.sup.7 and R.sup.8 and R.sup.9 include
morpholine, piperidine, N-alkyl piperidine, piperazine, pyrrolidine
and the like. Preferably Ar is a 5 or 6-membered aromatic ring
system wherein up to 2 ring atoms may be heteroatoms independently
selected from nitrogen, oxygen and sulphur, the ring system being
optionally substituted by one or more substituents independently
selected from C.sub.1-4alkyl, C.sub.1-4alkoxy, halogen,
haloC.sub.1-4alkyl, dihaloC.sub.1-4alkyl, trihaloC.sub.1-4alkyl,
oxo, thioxo, cyano, or C.sub.1-4alkylsulphonyl.
[0011] More preferably Ar is 5-membered aromatic ring containing
two nitrogen atoms and substituted as above.
[0012] A particular example of Ar is an optionally substituted
pyrazole ring. Preferably Ar is a substituted pyrazole ring.
[0013] Most preferably Ar is a pyrazole ring di-substituted by
C.sub.1-4alkyl, especially methyl.
[0014] For instance, Ar is suitably a group of sub-formula (I):
##STR00003##
where R.sup.10 and R.sup.11 are independently selected from H,
C.sub.1-4alkyl, haloC.sub.1-4alkyl, dihaloC.sub.1-4alkyl, or
trihaloC.sub.1-4alkyl, and Ar.sup.2 is as defined above.
[0015] In R.sup.10 and R.sup.11 are selected from H or
C.sub.1-3alkyl, such as methyl. In particular, both R.sup.10 and
R.sup.11 is C.sub.1-3alkyl such as methyl.
[0016] Ar.sup.2 is suitably a 5 or 6-membered aromatic ring system
wherein up to 3 ring atoms may be heteroatoms independently
selected from nitrogen, oxygen and sulphur, the ring system being
optionally substituted by one or more substituents independently
selected from C.sub.1-4alkyl, C.sub.1-4alkoxy, halogen,
dihaloalkyl, trihaloalkyl, oxo, thioxo, cyano,
C.sub.1-4alkylsulphonyl.
[0017] Preferably Ar.sup.2 is other than phenyl. In particular
Ar.sup.2 includes at least one heteroatom.
[0018] Examples of haloalkyl groups are haloC.sub.1-4alkyl groups
which include halomethyl groups such as fluoroethyl groups.
Examples of dihaloalkyl groups are dihaloC.sub.1-4alkyl groups
including difluoromethyl and dichloromethyl. Examples of
trihaloalkyl groups are trihaloC.sub.1-4alkyl groups such as
trifluoromethyl.
[0019] In a preferred embodiment, Ar.sup.2 is 5-membered aromatic
ring containing a nitrogen and sulphur atom and substituted as
above. Most preferably Ar.sup.2 is a thiazole ring substituted by
halogen, especially fluoro.
[0020] In an alternative embodiment of the invention, Ar.sup.2 is
pyridine or pyrimidine. The rings carry at least one substituent,
but are preferably unsubstituted.
[0021] Preferably Ar.sup.2 is pyridinyl or pyrimidinyl.
[0022] Preferred compounds of formula (I) include
6-[[3,5-dimethyl-1-(2-pyrimidinyl)-1H-pyrazol-4-yl]methyl]-5-[[(4S)-4-hyd-
roxy-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyr-
imidine-2,4(1H,3H)-dione, and
6-[[3,5-dimethyl-1-(2-pyridinyl)-1H-pyrazol-4-yl]methyl]-5-[[(4S)-4-hydro-
xy-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrim-
idine-2,4(1H,3H)-dione, and pharmaceutically acceptable salts
thereof.
[0023] Other preferred compounds of formula (I) include
(S)-2-[[6-[[3,5-dimethyl-1-(2-thiazolyl)-1H-pyrazol-4-yl]methyl]-1,2,3,4--
tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl-
]carbonyl]-4-isoxazolidinol and pharmaceutically acceptable salts
thereof.
[0024] Alkyl groups, whether alone or as part of another group, can
be straight chained or branched. Unless otherwise stated, they may
contain from 1 to 6, and preferably from 1 to 4 carbon atoms.
[0025] It will be understood that a compound of the formula (I) or
a salt thereof may exhibit the phenomenon of tautomerism and that
the drawings within this specification represent only one of the
possible tautomeric forms. It is to be understood that the
invention encompasses any tautomeric form.
[0026] Certain compounds of formula (I) 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 (I) and mixtures thereof including racemates. These also
form an aspect of the present invention.
[0027] 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 (I) and their
pharmaceutically acceptable salts. Pharmaceutically acceptable
salts of the invention may, for example, include acid addition
salts of the compounds of formula (I) 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 (I) 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.
[0028] 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.
[0029] In a further aspect the invention provides a process for the
preparation of a compound of formula (I) which comprises:
[0030] (a) reaction of a compound of formula (II):
##STR00004##
in which R.sup.1 and R.sup.2 are as defined in formula (I) or are
protected derivatives thereof, and X and Y are selected from
C.sub.1-4alkyl (optionally substituted by 1, 2 or 3 hydroxy
groups), C.sub.1-4alkoxy, haloalkyl, dihaloalkyl, trihaloalkyl,
C.sub.1-4alkoxyC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl, or
--(CH.sub.2)pN(R.sup.8)R.sup.9, with a compound of formula (III):
Ar.sup.2-G1-G2 (III), where Ar.sup.2 is as defined in formula (I)
or are protected derivatives thereof and G1 is NH, G2 is NH.sub.2,
SH or OH, or
[0031] (b) reacting a compound of formula (IV):
##STR00005##
in which R.sup.1, R.sup.2, Ar and Ar.sup.2 are as defined in
formula (I) or are protected derivatives thereof, with a compound
of formula (V):
##STR00006##
in which P is a protecting group, or
[0032] (c) for compounds of formula (I) where Ar has an NH group,
reacting a compound of formula (VI):
##STR00007##
in which R.sup.1 and R.sup.2 and as defined in formula (I) and Ar
is as defined in formula (I) provided Ar has an NH group, or are
protected derivatives thereof, with a compound of formula (VII):
Ar.sup.2-L (VII), in which Ar.sup.2 is as defined in formula (I) or
is a protected derivative thereof and L is a leaving group,
[0033] and optionally thereafter process (a), (b) or (c) in any
order
[0034] removing any protecting groups
[0035] forming a pharmaceutically acceptable salt.
[0036] Reaction of compounds (II) and (III) is suitably carried out
in an inert solvent (e.g., ethanol) at a temperature of from
0.degree. C. to 100.degree. C., preferably 10.degree. C. to
50.degree. C., optionally in the presence of a catalytic quantity
of an acid (e.g., trifluoroacetic acid).
[0037] Reaction of compounds (IV) and (V) is carried out by
conversion of the carboxylic acid function to an activated form by
reaction with a coupling agent (e.g., EDCI and
1-hydroxybenzotriazole) in an inert solvent (e.g., dichloromethane)
in the presence of a base, preferably triethylamine or
ethyldiisopropylamine, at a temperature of from 0.degree. C. to
100.degree. C., preferably 10.degree. C. to 50.degree. C., in the
presence of compound (V).
[0038] Reaction of compounds (VI) and (VII) is carried out either
by heating in an inert solvent such as NMP in the presence of a
base, for example a metal carbonate, under microwave irradiation;
or by use of catalytic (or stoicheiometric) Buchwald conditions
using a Cu(I) salt with a diamine ligand in a solvent such as
dioxan at a temperature of about 100.degree. C. The group L is any
suitable leaving group, preferably L is halogen.
[0039] Compounds of formula (II) can be prepared by reacting a
compound of formula (VIII):
##STR00008##
in which R.sup.1, R.sup.2 and P are as defined above and L is a
leaving group with a nucleophilic fragment of a the group Ar such
as a zinc salt of a beta-diketone. L is preferably a halogen such
as bromo.
[0040] Compounds of formula (VIII) can be prepared from compounds
of formula (IX):
##STR00009##
in which R.sup.1, R.sup.2 and P are as defined above by, for
example, bromination using N-bromosuccinimide in an inert solvent
such as chloroform under a light source at a temperature of from
15.degree. C. to 80.degree. C., preferably at 50.degree. C. to
70.degree. C.
[0041] Compounds of formula (IX) can be prepared by protection of
the corresponding alcohols of formula (X):
##STR00010##
in which R.sup.1, R.sup.2 and P are as defined above by, for
example, reacting with a trialkylsilyl halide in an inert solvent
such as dichloromethane at a temperature of from 0.degree. C. to
60.degree. C., preferably 10.degree. C. to 30.degree. C., in the
presence of a base such as imidazole.
[0042] Compounds of formula (X) can be prepared from acids of
formula (XI):
##STR00011##
in which R.sup.1, R.sup.2 and P are as defined above by forming an
acid chloride by treating with a reagent such as oxalyl chloride in
an inert solvent such as dichloromethane at a temperature of from
0.degree. C. to 60.degree. C., preferably 10.degree. C. to
30.degree. C., followed by treatment of the resulting acid chloride
with the hydroxyisooxazolidine in a solvent such as dichloromethane
at a temperature of from 0.degree. C. to 60.degree. C., preferably
10.degree. C. to 30.degree. C. in the presence of a base such as
triethylamine.
[0043] Compounds of formula (XI) are prepared from the
corresponding esters using standard conditions.
[0044] Compounds of formula (IV) can be prepared from compounds of
formula (XII):
##STR00012##
in which R.sup.1, R.sup.2 and Ar are as defined above, provided
that Ar contains an NH group, and R.sup.20 is an ester forming
group by, for example, reacting with a compound of formula (XIII):
Ar.sup.2-halogen (XIII), in which Ar.sup.2 is as defined above or
by reaction with a compound Ar.sup.2 where Ar is as defined above
provided that Ar contains a nitrogen centre.
[0045] Reaction of compounds (XII) and (XIII) can be carried out in
an inert solvent such as dioxan at a temperature of 10.degree. C.
to 120.degree. C. in the presence of a copper (I) salt and an
alkylene diamine. The group R.sup.20 is an ester forming group such
as alkyl, especially methyl.
[0046] Reaction of compounds (XII) and Ar.sup.2 can be carried out
in a solvent such as dimethyl acetamide at a temperature of
10.degree. C. to 200.degree. C. in the presence of a base such as
potassium carbonate optionally with microwave irradiation.
[0047] A compound of formula (XII) can be prepared from a compound
of formula (XV):
##STR00013##
in which R.sup.1, R.sup.2 and R.sup.20 are as defined above by
reaction with a strong base such as lithium diisopropylamide in a
solvent such as THF at -78.degree. C. to 0.degree. C. followed by
the addition of a compound of formula (XVI): Ar--CHO (XVI).
[0048] Compounds of formula (IV) are prepared from compounds of
formula (XVII):
##STR00014##
in which R.sup.1, R.sup.2, R.sup.20, Ar and Ar.sup.2 are as defined
above, either by deoxygenation using a strong acid such as TFA in
the presence of a hydride source such as triethylsilane, optionally
in a solvent such as dichloromethane at a temperature of 10.degree.
C. to 40.degree. C., or by activation of the hydroxyl group by
esterification with an activated carboxylic acid such as
trifluoroacetic anhydride or methane sulphonyl chloride in an inert
solvent such as ethyl acetate followed by hydrogenolysis, for
example using palladium on carbon at 1 to 5 bar at 10.degree. C. to
80.degree. C.
[0049] Compounds of formula (XVII) are prepared from compounds of
formula (XV) as defined above by reacting with compounds (XVIII):
Ar.sup.2-Ar--CHO (XVIII), in which Ar and Ar.sup.2 are as defined
above using conditions analogous to those above for the reaction of
compounds (XV) and (XVI).
[0050] Compounds of formula (VI) may be made from compounds of
formula (XII) by hydrolysis of the ester function (using an alkali
metal or alkaline earth hydroxide in a solvent containing water,
e.g., aqueous ethanol or aqueous methanol) at a temperature of from
0.degree. C. to 100.degree. C., or using aqueous mineral acid in an
inert solvent at a temperature of from 20.degree. C. to 100.degree.
C., and then coupling the acid residue with a compound of formula
(V) in the presence of a condensing agent (e.g., PyBrOP) in an
inert solvent (e.g., THF) in the presence of a base such as
triethylamine at a temperature of from 0.degree. C. to 30.degree.
C.
[0051] Starting materials as defined above are available
commercially or can be prepared using routine chemistry known in
the art.
[0052] 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).
[0053] Examples of these conditions are:
[0054] (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 scrofulous rhinitis;
seasonal rhinitis including rhinitis nervosa (hay fever) and
vasomotor rhinitis; sarcoidosis, farmer's lung and related
diseases, fibroid lung and idiopathic interstitial pneumonia;
[0055] (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;
[0056] (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 areata and vernal
conjunctivitis;
[0057] (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;
[0058] (5) (other tissues and systemic disease) multiple sclerosis,
atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), lupus
erythematosus, systemic lupus, erythematosus, Hashimoto's
thyroiditis, myasthenia gravis, type I diabetes, nephrotic
syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous
leprosy, sezary syndrome and idiopathic thrombocytopenia
pupura;
[0059] (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
[0060] (7) cancer.
[0061] Accordingly, the present invention provides a compound of
formula (I) or a pharmaceutically acceptable salt thereof as
hereinbefore defined for use in therapy.
[0062] In another aspect, the invention provides the use of a
compound of formula (I) or a pharmaceutically acceptable salt
thereof as hereinbefore defined in the manufacture of a medicament
for use in therapy.
[0063] 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.
[0064] 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.
[0065] 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 (I) or a pharmaceutically
acceptable salt thereof as hereinbefore defined.
[0066] 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 (I) or a
pharmaceutically-acceptable salt thereof as hereinbefore
defined.
[0067] 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 (I) will be in the
range from 0.1 mg/kg, preferably from 0.3 mg/kg, more preferably
from 0.5 mg/kg and still more preferably 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 (I) will typically be in
the range from 0.001 mg/kg to 30 mg/kg.
[0068] The compounds of formula (I) 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 (I) 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 preferably comprise from 0.05 to
99% w (percent by weight), more preferably less than 80% w, e.g.
from 0.10 to 70% w, and even more preferably less than 50% w, of
active ingredient, all percentages by weight being based on total
composition.
[0069] Thus, the present invention also provides a pharmaceutical
composition comprising a compound of formula (I) or a
pharmaceutically acceptable salt thereof as hereinbefore defined,
in association with a pharmaceutically acceptable adjuvant, diluent
or carrier.
[0070] The invention further provides a process for the preparation
of a pharmaceutical composition of the invention which comprises
mixing a compound of formula (I) or a pharmaceutically acceptable
salt thereof as hereinbefore defined, with a pharmaceutically
acceptable adjuvant, diluent or carrier.
[0071] 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.
[0072] 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.
[0073] The invention will now be illustrated in the following
Examples in which, unless otherwise stated:
[0074] (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;
[0075] (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;
[0076] (iii) yields are given for illustration only and are not
necessarily the maximum attainable;
[0077] (iv) the structures of the end-products of the formula (I)
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;
[0078] (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;
[0079] Abbreviations
TABLE-US-00001 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DDQ
Dimethylformamide DMF Tetrahydrofuran THF
[0080] The following examples illustrate the invention.
EXAMPLE 1
6-[[3,5-dimethyl-1-(2-pyrimidinyl)-1H-pyrazol-4-yl]methyl]-5-[[(4S)-4-hydr-
oxy-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyri-
midine-2,4(1H,3H)-dione
##STR00015##
[0081] a) Ethyl methyl
2-methyl-5-(N,N-methylethylamino)-thiophene-3,4-dicarboxylate
[0082] 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 warm 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 sub-title compound (23.5 g).
[0083] .delta. .sup.1H.sub.CDC13 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
[0084] 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 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 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 hours at room temperature. The
mixture was poured into water (2 L), acidified and extracted into
ether. Washing with brine, drying and evaporation gave a solid
which was boiled in isohexane (200 ml) containing ethyl acetate (3
ml). On cooling the precipitated pale yellow solid was collected
and dried, to afford the sub-title compound (10.5 g).
[0085] MS (APCI) [M+H].sup.+ 297.
[0086] .delta. .sup.1H.sub.CDC13 1.6 (6H, d), 2.44 (3H, s), 3.37
(3H, s), 3.95 (3H, s), 4.66 (1H, br).
c)
1,2,3,4-Tetrahydro-3,6-dimethyl-1-(1-methylethyl)-2,4-dioxo-thieno[2,3--
d]pyrimidine-5-carboxylic acid
[0087] To a solution of the product of step b) (3.81 g) in THF (50
ml) and methanol (5 ml) was added 1N NaOH (25.7 ml) and the mixture
stirred under nitrogen for 18 hours. It was acidified with 2.5 N
HCl and extracted with DCM, the organic extracts washed with water,
dried over anhydrous magnesium sulfate, filtered and evaporated
under reduced pressure to give the sub-title compound as a solid
(3.40 g).
[0088] MS (ESI) 283 [M+H].sup.+.
d)
5-[[(4S)-4-Hydroxy-2-isoxazolidinyl]carbonyl]-3,6-dimethyl-1-(1-methyle-
thyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0089] To a suspension of the product of part c) (3.40 g) in DCM
(50 ml) was added oxalyl chloride (1.16 ml) and DMF (10 .mu.l) and
the mixture stirred under nitrogen for 2 hours. The acid chloride
solution was added to a suspension of (S)-4-isoxazolidinol
hydrochloride (1.51 g) and triethylamine (3.52 ml) in DCM (20 ml)
at 0.degree. C. under nitrogen and the mixture stirred at room
temperature for 3 hours. It was washed with water, dried over
anhydrous magnesium sulfate, filtered and evaporated under reduced
pressure. The residue was purified by column chromatography over
silica, eluting with ethyl acetate to give the sub-title compound
as a solid (2.52 g).
[0090] MS (ESI) 354 [M+H].sup.+.
[0091] .delta. .sup.1H.sub.DMSO 1.50-1.52 (6H, m), 2.30-2.34 (3H,
m), 3.18-3.19 (3H, m), 3.42-4.08 (4H, m), 4.59-4.74 (2H, m),
5.49-5.50 (1H, m).
e)
5-[[(4S)-4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-2-isoxazolidinyl]car-
bonyl]-3,6-dimethyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-di-
one
[0092] To a solution of the product of part d) (2.52 g) in DCM (30
ml) was added imidazole (0.53 g) and tert-butyldimethylsilyl
chloride (1.18 g) and the mixture stirred under nitrogen for 24
hours. It was acidified with 1N HCl and extracted with DCM, the
organic extracts washed with water, dried over anhydrous magnesium
sulfate, filtered and evaporated under reduced pressure. The
residue was purified by column chromatography over silica, eluting
with i-hexane/ethyl acetate (3:1) followed by i-hexane/ethyl
acetate (1:1) to give the sub-title compound (2.42 g).
[0093] .delta..sup.1H.sub.DMSO 0.09 (6H, d), 0.86 (9H, s), 1.50
(6H, d), 2.31-2.34 (3H, m), 3.18-3.19 (3H, m), 3.44-4.15 (4H, m),
4.50-4.97 (2H, m).
f)
6-Bromomethyl-5-[[(4S)-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-isox-
azolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4-
(1H,3H)-dione
[0094] to a solution of the product of part e) (2.42 g) in
chloroform (100 ml) was added N-bromosuccinimide (1.01 g) and the
mixture heated under reflux whilst being irradiated with a 300 W
tungsten lamp for 2 hours. It was cooled, washed with 1 N NaOH
solution, washed with water, dried over anhydrous magnesium
sulfate, filtered and evaporated under reduced pressure to give the
sub-title compound (2.83 g).
[0095] MS (ESI) 546 and 548 [M+H].sup.+.
g)
6-(2-Acetyl-3-oxobutyl)-5-[[(4S)-4-[[(1,1-dimethylethyl)dimethylsilyl]o-
xy]-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyri-
midine-2,4(1H,3H)-dione
[0096] A solution of the product of part f) (2.83 g) and zinc
acetylacetonate hydrate (1.47 g) in chloroform (50 ml) was heated
under reflux for 1 hour. It was cooled, washed with sodium
bicarbonate solution, filtered through celite, washed with brine,
dried over anhydrous magnesium sulfate, filtered and evaporated
under reduced pressure to give the sub-title compound (2.93 g).
[0097] MS (ESI) 566 [M+H].sup.+.
h)
5-[[(4S)-4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-2-isoxazolidinyl]car-
bonyl]-6-[[3,5-dimethyl-1-(2-pyrimidinyl)-1H-pyrazol-4-yl]methyl]-3-methyl-
-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0098] To a solution of the product of part g) (0.73 g) in
chloroform (25 ml) was added pyrimidin-2-ylhydrazine (0.27 g) and
the mixture stirred for 48 hours. It was washed with water, dried
over anhydrous magnesium sulfate, filtered and evaporated under
reduced pressure. The residue was purified by column chromatography
over silica, eluting with i-hexane/ethyl acetate (1:1) followed by
i-hexane/ethyl acetate (1:4) to give the sub-title compound (0.43
g).
[0099] MS (ESI) 640 [M+H].sup.+.
i)
6-[[3,5-Dimethyl-1-(2-pyrimidinyl)-1H-pyrazol-4-yl]methyl]-5-[[(4S)-4-h-
ydroxy-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]p-
yrimidine-2,4(1H,3H)-dione
[0100] A solution of the product of part h) (0.43 g) and
trifluoroacetic acid (0.5 ml) in DCM (10 ml) was stirred for 72
hours. It was concentrated in vacuo, diluted with sodium
bicarbonate solution, and extracted with ethyl acetate, the organic
extracts washed with water, dried over anhydrous magnesium sulfate,
filtered and evaporated under reduced pressure. The residue was
purified by column chromatography over silica, eluting with ethyl
acetate then ethyl acetate/methanol (9:1) to give the title
compound (30 mg).
[0101] MS (APCI) 526 [M+H].sup.+.
[0102] .delta..sup.1H.sub.DMSO 1.44-1.46 (6H, m), 2.16-2.19 (3H,
m), 2.53-2.55 (3H, m), 3.17-3.19 (3H, m), 3.48-4.14 (6H, m), 4.38
(1H, s, br), 4.60-4.80 (1H, m), 5.48-5.52 (1H, m), 7.46 (1H, dt),
8.87 (2H, t).
EXAMPLE 2
6-[[3,5-dimethyl-1-(2-pyridinyl)-1H-pyrazol-4-yl]methyl]-5-[[(4S)-4-hydrox-
y-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimi-
dine-2,4(1H,3H)-dione
##STR00016##
[0103] a)
5-[[(4S)-4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-2-isoxazolidi-
nyl]carbonyl]-6-[[3,5-dimethyl-1-(2-pyridinyl)-1H-pyrazol-4-yl]methyl]-3-m-
ethyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
[0104] To a solution of the product of example 1 part g) (0.73 g)
in chloroform (25 ml) was added pyridin-2-ylhydrazine (0.28 g) and
the mixture stirred for 48 hr. It was washed with water, dried over
anhydrous magnesium sulfate, filtered and evaporated under reduced
pressure. The residue was purified by column chromatography over
silica, eluting with i-hexane followed by i-hexane/ethyl acetate
(1:1) to give the sub-title compound (0.28 g).
[0105] MS (ESI) 639 [M+H].sup.+.
b)
6-[[3,5-Dimethyl-1-(2-pyridinyl)-1H-pyrazol-4-yl]methyl]-5-[[(4S)-4-hyd-
roxy-2-isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyr-
imidine-2,4(1H,3H)-dione
[0106] A solution of the product of part a) (0.28 g) and
trifluoroacetic acid (0.5 ml) in DCM (10 ml) was stirred for 72
hours. It was concentrated in vacuo, diluted with sodium
bicarbonate solution, and extracted with ethyl acetate, the organic
extracts washed with water, dried over anhydrous magnesium sulfate,
filtered and evaporated under reduced pressure. The residue was
purified by column chromatography over silica, eluting with ethyl
acetate then ethyl acetate/methanol (49:1) to give the title
compound (88 mg).
[0107] MS (APCI) 525 [M+H].sup.+.
[0108] .delta. .sup.1H.sub.DMSO 1.44-1.47 (6H, m), 2.17-2.19 (3H,
m), 2.56-2.58 (3H, m), 3.47-4.14 (6H, m), 4.38 (1H, s, br),
4.60-4.80 (1H, m), 5.51-5.52 (1H, m), 7.30-7.34 (1H, m), 7.80 (1H,
d), 7.95 (1H, dt), 8.45-8.47 (1H, m).
EXAMPLE 3
(S)-2-[[6-[[3,5-Dimethyl-1-(2-thiazolyl)-1H-pyrazol-4-yl]methyl]-1,2,3,4-t-
etrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]-
carbonyl]-4-isoxazolidinol
##STR00017##
[0110] A mixture of
(S)-2-[[6-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-1,2,3,4-tetrahydro-3-met-
hyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-iso-
xazolidinol (237 mg), 2-bromothiazole (237 mg), copper(I) iodide
(20 mg), trans-cyclohexane-1,2-diamine (15 mg) and potassium
carbonate (145 mg) were heated at 100.degree. C. in 1,4-dioxane(1
ml) for 24 hours. The reaction mixture was concentrated to dryness
and purified by chromatography on SiO.sub.2 (Biotage cartridge)
(eluting with EtOAc to 5% MeOH in EtOAc) and subsequently reverse
phase chromatography to give the title compound as a white solid
(110 mg).
[0111] MS (APCI+ve) M+H=531.1.
[0112] .delta. .sup.1H.sub.DMSO, 120.degree. C. 1.47 (6H, d), 2.17
(3H, s), 2.60 (3H, s), 3.20 (3H, s), 3.46 (1H, d), 3.75 (1H, d),
3.89-3.95 (2H, m), 3.89 (2H, s), 4.46 (1H, sep), 4.70 (1H, s), 5.08
(1H, s), 7.38 (1H, d), 7.56 (1H, d).
Pharmacological Data
Inhibition of PMA/Ionomycin-Stimulated Peripheral Blood Mononuclear
Cell Proliferation
[0113] 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.
[0114] 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.
Of the specific examples, examples 1 had a PIA.sub.50 of 8.3 and
Example 3 had a PIA.sub.50 of 9.07 in the above test.
* * * * *