U.S. patent application number 09/971709 was filed with the patent office on 2002-02-28 for pyrrolo[3,4-d]pyrimidinone derivatives and their use as medicaments.
This patent application is currently assigned to AstraZeneca AB.. Invention is credited to Cheshire, David R., Cooper, Martin E., Donald, David K., Furber, Mark, Harrison, Richard P., Perry, Matthew W.D., Tomkinsson, Nicholas P..
Application Number | 20020025966 09/971709 |
Document ID | / |
Family ID | 10804862 |
Filed Date | 2002-02-28 |
United States Patent
Application |
20020025966 |
Kind Code |
A1 |
Cooper, Martin E. ; et
al. |
February 28, 2002 |
Pyrrolo[3,4-d]pyrimidinone derivatives and their use as
medicaments
Abstract
The invention provides certain novel 5-substituted
pyrrolo[3,4-d]pyrimidin- e-2,4-diones, processes for their
preparation, pharmaceutical compositions containing them, a process
for preparing the pharmaceutical compositions, and methods of
treatment involving their use.
Inventors: |
Cooper, Martin E.;
(Loughborough, GB) ; Cheshire, David R.;
(Loughborough, GB) ; Donald, David K.;
(Loughborough, GB) ; Furber, Mark; (Loughborough,
GB) ; Perry, Matthew W.D.; (Loughborough, GB)
; Harrison, Richard P.; (Loughborough, GB) ;
Tomkinsson, Nicholas P.; (Loughborough, GB) |
Correspondence
Address: |
NIXON & VANDERHYE P.C.
8th Floor
1100 North Glebe Road
Arlingtion
VA
22201-4714
US
|
Assignee: |
AstraZeneca AB.
|
Family ID: |
10804862 |
Appl. No.: |
09/971709 |
Filed: |
October 9, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09971709 |
Oct 9, 2001 |
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09707880 |
Nov 8, 2000 |
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6306863 |
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09707880 |
Nov 8, 2000 |
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09505862 |
Feb 17, 2000 |
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6211368 |
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09505862 |
Feb 17, 2000 |
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09011780 |
Feb 24, 1998 |
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6046204 |
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Current U.S.
Class: |
514/265.1 ;
544/280 |
Current CPC
Class: |
A61P 17/08 20180101;
A61P 17/00 20180101; A61P 17/06 20180101; A61P 9/10 20180101; A61P
17/14 20180101; A61P 25/00 20180101; A61P 31/00 20180101; A61P
37/06 20180101; A61P 21/04 20180101; A61P 25/06 20180101; A61P
29/00 20180101; A61P 3/10 20180101; A61P 1/00 20180101; C07D 487/04
20130101; A61P 19/02 20180101; A61P 27/00 20180101; A61P 11/00
20180101; A61P 11/06 20180101 |
Class at
Publication: |
514/258 ;
544/280 |
International
Class: |
A61K 031/519; C07D
487/04 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 21, 1996 |
GB |
9626643.2 |
Dec 18, 1997 |
SE |
PCT/SE97/02157 |
Claims
1. A compound according to the general formula: 36wherein W
represents --CH.sub.2-- or a bond; Q represents Ar.sup.1 or
Ar.sup.2; in the case where W represents --CH.sub.2--, Q represents
an aryl group Ar.sup.1 wherein Ar.sup.1 represents naphthyi,
phenyl. quinolyl, isoquinolyl, indolyl, benzofuranyl
orbenzothienyl; in the case where W represents a bond, Q represents
an aryl group Ar.sup.2 wherein Ar.sup.2 represents acenaphthenyl,
fluorenyl or indanyl; wherein the ring systems which Ar.sup.1 and
Ar.sup.2 represent may all be optionally substituted by one or more
substituents selected from C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
halogen, or trifluoromethyl; R.sup.10 represents X-(A).sub.p--Y; X
represents S(O).sub.n, C.ident.C, (CH.sub.2).sub.2, CH.dbd.CH or
CH.sub.2CH.dbd.CH; n represents 0, 1 or 2; A represents C.sub.1-6
alkylene; p is 0 or 1; Y represents CN, OR.sup.11,
CO.sub.2R.sup.12, CONR.sup.13R.sup.14, NR.sup.15R.sup.16,
NHSO.sub.2R.sup.17, NHCOR.sup.18 or an optionally substituted aryl
or heteroaryl group, provided that when X represents S(O).sub.n and
Y is other than an optionally substituted aryl or heteroaryl group,
then p is 1 and also provided that when X represents S(O).sub.n, p
is 1 and Y represents OH, then n is not 0; R.sup.13 and R.sup.14
independently represent H, C.sub.1-5 alkyl or phenyl, which latter
group may be substituted by one or more substituents selected from
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halogen, or CO.sub.2R.sup.21;
and R.sup.1, R.sup.2, R.sup.11, R.sup.12, R.sup.15, R.sup.16,
R.sup.17, R.sup.18 and R.sup.21 independently represent H or
C.sub.1-5 alkyl; or a pharmaceutically acceptable derivative
thereof.
2. A compound according to claim 1, wherein in formula (I), W
represents --CH.sub.2-- and Q represents an aryl group Ar.sup.1
wherein Ar.sup.1 represents a naphthyl or phenyl group, each of
which may be optionally substituted by one or more substituents
selected from C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halogen or
trifluoromethyl.
3. A compound according to claim l, wherein, in formula (I), W
represents a bond and represents an aryl group Ar.sup.2 wherein
Ar.sup.2 represents an indanyl group which may be optionally
substituted by one or more substituents selected from C.sub.1-4
alkyl, C.sub.1-4 alkoxy, halozen or trifluoromethyl.
4. A compound according to any one of claims 1 to 3, wherein, in
formula (I), X represents S(O).sub.n wherein n is 0, 1 or 2,
C.ident.C, (CH.sub.2).sub.2 or CH.sub.2CH.dbd.CH.
5. A compound according to any one of claims 1 to 4, wherein, in
formula (I), X represents S(O).sub.n wherein n is 0, 1 or 2.
6. A compound according to any one of claims 1 to 5, wherein, in
formula (I), A represents C.sub.1-4 alkylene.
7. A compound according to any one of claims 1 to 6, wherein, in
formula (I), each of groups R.sup.1, R.sup.2, R.sup.11, R.sup.12,
R.sup.15, R.sup.16, R.sup.17, R.sup.18 and R.sup.21 represents H or
a C.sub.1-4 alkyl group.
8. A compound according to any one of claims 1 to 7, wherein, in
formula (I), each of groups R.sup.13 and R.sup.14 represents H,
C.sub.1-3 alkyl or phenyl, which latter group may be substituted by
one or more substituents selected from C.sub.1-4 alkyl, C.sub.1-4
alkoxy, halogen or CO.sub.2R.sup.21.
9. A compound according to claim 1, wherein, in formula (I), W
represents --CH.sub.2-- or a bond; Q represents Ar.sup.1 or
Ar.sup.2; in the case where W represents --CH.sub.2--, Q represents
an aryl group Ar.sup.1 wherein Ar.sup.1 represents naphthyl or
phenyl; in the case where W represents a bond, Q represents an aryl
group Ar.sup.2 wherein Ar.sup.2 represents indanyl; wherein the
ring systems which Ar.sup.1 and Ar.sup.2 represent may all be
optionally substituted by one or more, e.g. one, two, three or
four, substituents selected from C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
halogen, or trifluoromethyl; R.sup.10 represents X-(A).sub.p--Y, X
represents S(O).sub.nC.ident.C, (CH.sub.2).sub.2 or
CH.sub.2CH.dbd.CH; n represents 0, 1 or 2; A represents C.sub.1-6
alkylene; p is 0 or 1; Y represents CN, OR.sup.11,
CO.sub.2R.sup.12, CONR.sup.13R.sup.14, NR.sup.15R.sup.16 or an
optionally substituted phenyl, pyridyl or tetrazolyl group,
provided that when X represents S(O).sub.n and Y is other than an
optionally substituted aryl or heteroaryl group, then p is 1 and
also provided that when X represents S(O).sub.n,p is 1and Y
represents OH, then n is not 0; R.sup.13 and R.sup.14 independently
represent H, C.sub.1-5 alkyl or phenyl, which latter group may be
substituted by one or more substituents selected from C.sub.1-4
alkyl, C.sub.1-4 alkoxy, halogen, or CO.sub.2R.sup.21; and R.sup.1,
R.sup.2, R.sup.11, R.sup.12, R.sup.15, R.sup.16 and R.sup.21
independently represent H or C.sub.1-5 alkyl.
10. A compound according to claim 1, wherein, in formula (I), W
represents --CH.sub.2-- or a bond: Q represents Ar.sup.1 or
Ar.sup.2; in the case where W represents --CH.sub.2--, Q represents
an aryl group Ar.sup.2 wherein Ar.sup.1 represents naphthyl; in the
case where W represents a bond. Q represents an aryl group Ar.sup.2
wherein Ar.sup.2 represents indanyl; R.sup.10 represents
X-(A).sub.p--Y; X represents S(O).sub.n,C.ident.C, (CH.sub.2).sub.2
or CH.sub.2CH.dbd.CH; n represents 0, 1 or 2; A represents
C.sub.1-3 alkylene; p is 0 or 1; Y represents CN, OR.sup.11,
CO.sub.2R.sup.12, CONR.sup.13R.sup.14, NR.sup.15R.sup.16 or a
phenyl, pyridyl or tetrazolyl group optionally substituted by a
hydroxyl or methoxy group. proylded that when X represents
S(O).sub.n and Y is other than an optionally substituted aryl or
heteroaryl group, then p is 1 and also provided that when X
represents S(O).sub.n, p is 1 and Y represents OH, then n is not 0;
R.sup.13 and R.sup.14 independently represent H; and R.sup.1,
R.sup.2, R.sup.11, R.sup.12, R.sup.15 and R.sup.16 independently
represent H or C.sub.1-4 alkyl.
11. A compound according to claim 1 being:
5-[(3-hydroxypropyl)sulphinyl]--
3-methyl-1-(2-methylpropyl)-6-(1-naphthalenyl-methyl)-1H-pyrrolo[3,4-d]pyr-
imidine-2,4(3H,6H)-dione; or
5-[(3-hydroxypropyl)sulphonyl]-3-methyl-1-(2--
methylpropyl)-6-(1-naphthalenyl-methyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H-
,6H)-dione; or methyl
4[(2,3,4,6-tetrahydro-3-methyl-1-(2-methylpropyl)-6--
(1-naphthalenyl-methyl)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)thio]but-
anoate; or
5-[(3-methoxypropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naph-
thalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione; or
5-[(2-hydroxyethyl)sulphinyl]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalen-
yl-methyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione; or
4-[(2,3,4,6-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethy-
l)-2,4-dioxo-1H-pyrrolo[(3,4-d]pyrimidin-5-yl)thio]butanoic acid;
or
4-[(2,3,4,6-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethy-
l)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)thio]butanoic acid,
sodium salt; or
5-[(2-dimethylaminoethyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1--
naphthaleny-methyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione:
or
6-(2,3-dihydro-1H-inden-2-yl)-5-[(3-hydroxypropyl)sulphinyl]-3-methyl-1-(-
1-methylethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione; or
6-(2,3-dihydro-1H-inden-2-yl)-5-[(3-hydroxypropyl)sulphonyl]-3-methyl-1-(-
1-methylethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione; or
5-[(3-hydroxypropyl)sulphinyl]-3-methyl-1-(1-methylethyl)6-(1-naphthaleny-
l-methyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione; or
4-[(2,3,4,6-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethy-
l)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)thio]butanamide; or
5-(2,3,4,6-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl-
)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)pent-3-enoic acid; or
5-(5-hydroxypent-1-ynyl)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmet-
hyl)-1H-pvrrolo[3,4-d]pyrimidine-2,4(3H 6H)-dione; or
5-(5-hydroxypentyl)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)--
1H-pyrroIo[3,4-d]pyrimidine-2,4(3H,6H)-dione; or
5-(4-hydroxybut-1-ynyl)-3-
-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrim-
idine-2,4(3H,6H)-dione; or
5-(4-hydroxybutyl)-3-methyl-1-(2-methylpropyl)--
6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione;
5-(2,3,4,6-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl-
)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)pentanoic acid;
4-[(2,3,4,6-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenyimethy-
l)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)thio]butanenitrile;
5-[(3-{1H-tetrazol-5-yl}propyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-nap-
hthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione;
3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(2-pyridiny)thio]-
-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione;
3-methyl-1-(2-methylpropyl)-
-6-(1-naphthalenylmethyl)-5-[(2-pyridinyl)sulphinyl]-1H-pyrrolo[3,4-d]pyri-
midine-2,4(3H,6H)-dione;
3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmeth-
yl)-5-[(4-pyridinylyhio]-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione;
5-([3-methoxyphenyl]thio)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylme-
thyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione;
5-([3-hydroxyphenyl]thio)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylme-
thyl)-1H -pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)dione;
5-([4methoxyphenyl]thio)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmet-
hyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione;
5-([4hydroxyphenyl]thio-
)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]py-
rimidine-2,4(3H,6H)dione;
5-([2-methoxyphenyl]thio)-3-methyl-1-(2-methylpr-
opyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4
(3H,6H)-dione; or
5-([2-hydroxyphenyl]thio)-3-methyl-1-(2-methylpropyl)-6-
-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione.
12. A process for the preparation of a compound of formula (I) as
defined in claim 1, which comprises: (a) when X represents
S(O).sub.n and n is 1 or 2, oxidising a compound of general formula
37wherein R.sup.1, R.sup.2, A, p, Y, W and Q are as defined in
claim 1 including the provisos; (b) when Y represents OR.sup.11 and
R.sup.11 represents C.sub.1-5 alkyl, reacting a corresponding
compound of formula (I) in which Y represents OH, with an alkyl
halide of general formulaR.sup.11aHal (III)wherein R.sup.11a
represents C.sub.1-5 alkyl and Hal represents a halogen atom; (c)
when Y represents CO.sub.2R.sup.12 and R.sup.12 represents
C.sub.1-5 alkyl, esterifying a corresponding compound of formula
(I) in which Y represents CO.sup.2H with an alcohol of general
formulaR.sup.12aOH (IV)wherein R.sup.12a represents C.sub.1-5
alkyl; (d) when Y represents CONR.sup.13R.sup.14, reacting a
corresponding compound of formula (I) in which Y represents
CO.sub.2H with an amine of general formulaR.sup.13R.sup.14NH
(V)wherein R.sup.13 and R.sup.14 are as defined in claim 1; (e)
when Y represents CO.sub.2H, hydrolysing a corresponding compound
of formula (I) in which Y represents CO.sub.2R.sup.12 and R.sup.12
represents C.sub.1-5 alkyl; (f) when X represents S, A represents a
C.sub.1-6 alkylene group, Y represents CO.sub.2R.sup.12 and
R.sup.12 represents C.sub.1-5 alkyl, reacting a compound of general
formula 38in which R.sup.1, R.sup.2, W and Q are as defined in
claim 1, with a compound of general formulaL-S--A--C(OR.sup.12-
).sub.3 (VII)wherein L is a leaving group and A and R.sup.12 are as
defined in claim 1, followed by hydrolysis of the resulting ortho
ester; (g) when X represents S, A represents a C.sub.2-6 alkylene
group, Y represents NR.sup.15R.sup.16 and R.sup.15 and R.sup.16 are
as defined in claim 1, reducing a corresponding compound of formula
(II) as hereinbefore defined in which A represents a C.sub.1-5
alkylene group, Y represents CONR.sup.13R.sup.14 and R.sup.13 and
R.sup.14 are respectively equal to R.sup.15 and R.sup.16; (h) when
X represents S, A represents a C.sub.1-6 alkylene group, Y
represents NR.sup.15R.sup.16 and R.sup.15 and R.sup.16 are as
defined in claim 1, reacting a corresponding compound of general
formula 39wherein L' represents a leaving group and R.sup.1,
R.sup.2, A, W and Q are as defined in claim 1, with a compound of
formula (V) wherein R.sup.13 and R.sup.14 are respectively equal to
R.sup.15 and R.sup.16; (j) when X represents C.ident.C, CH.dbd.CH
or CH.sub.2CH.dbd.CH, reacting a compound of general formula 40in
which Hal represents a halogen atom and R.sup.1, R.sup.2, W and Q
are as defined in claim 1, with a compound of general formula (X),
H-X'-(A).sub.p--Y, in which X' represents C.ident.C, CH.dbd.CH or
CH.dbd.CHCH.sub.2 and A, p and Y are as defined in claim 1, in the
presence of a palladium catalyst, and optionally hydrogenating the
compound of formula (I) obtained wherein X represents C.ident.C or
CH.dbd.CH in the presence of a palladium on carbon catalyst to
produce a further compound of formula (I) wherein X represent
(CH.sub.2).sub.2; (k) when X represents S, A represents a C.sub.1-6
alkylene group and Y represents CN, reacting a compound of formula
(VIII) as hereinbefore defined with sodium cyanide; (l) when X
represents S, A represents a C.sub.1-6 alkylene group and Y
represents NHSO.sub.2R.sup.17, reacting a corresponding compound of
formula (I) in which Y represents NH.sub.2 with a compound of
general formula (XI), R.sup.17SO.sub.2Cl, wherein R.sup.17 is as
defined in claim 1; (m) when X represents S, A represents a
C.sub.1-6 alkylene group and Y represents NHCOR.sup.18, reacting a
corresponding compound of formula (I) in which Y represents
NH.sub.2 with a compound of general formula (XII), R.sup.18COCl,
wherein R.sup.18 is as defined in claim 1; (n) when X represents S
and Y represents an optionally substituted aryl or heteroaryl
group, reacting a compound of formula (VI) as hereinbefore defined
with a compound of general formulaY'--(A).sub.p--S--S-(A).sub.p---
Y' (XIII)wherein Y' represents an optionally substituted aryl or
heteroaryl group and p and A are as defined in claim 1; or (p) when
X represents S, A represents a C.sub.1-6 alkylene group and Y
represents a tetrazolyl group, reacting a compound of formula (I)
in which X represents S, A represents a C.sub.1-6 alkylene group
and Y represents CN, with trialkyltin azide; and optionally forming
a pharmaceutically acceptable derivative thereof.
13. A pharmaceutical composition comprising a compound of formula
(I) or a pharmaceutically acceptable derivative thereof as defined
in claim 1, in admixture with a pharmaceutically acceptable
adjuvant, diluent or carrier.
14. A process for the preparation of a pharmaceutical composition
according to claim 13, which comprises admixin a compound of
formula (I) or a pharmaceutically acceptable derivative thereof as
defined in claim 1, with a pharmaceutically acceptable adjuvant,
diluent or carrier.
15. A compound of formula (I) or a pharmaceutically accptable
derivative thereof as defined in claim 1 for use in therapy.
16. Use of a compound of formula (I) or a pharmaceutically
acceptable derivative thereof as defined in claim 1 in the
manufacture of a medicament for use in therapy.
17. A method of effecting immunosuppression which comprises
administering to a patient a therapeutically effective amount of a
compound of formula (I) or a pharmaceutically acceptable derivative
thereof as defined in claim 1.
18. A method of treating, or reducing the risk of, a reversible
obstructive airways disease in a patient suffering from, or at risk
of, said disease, which comprises administering to the patient a
therapeutically effective amount of a compound of formula (I) or a
pharmaceutically acceptable derivative thereof as defined in claim
1.
Description
[0001] The present invention provides certain novel 5-substituted
pyrrolo[3,4-d]-pyrimidine-2,4diones, processes for their
preparation, pharmaceutical compositions containing them, a process
for preparing the pharmaceutical compositions, and methods of
treatment involving their use.
[0002] T-cells play an important role in the immune response,
however in autoimmune disease T-cells are activated against
particular tissues, e.g. causing the inflammation associated with
rheumatoid arthritis. Interleukin-2 (IL-2) is an essential
autocrine growth factor for T-cells and hence inhibition of IL-2
transcription is beneficial in the modulation of autoimmune
disease. Formation of a transcriptional complex of the protein
nuclear factor of activated T-celIs-1 (NFAT-1) on the IL-2 promoter
is essential for IL-2 transcription. NFAT-1 mediated transcription
has therefore been proposed as appropriate molecular target for
immunomodulation, Y. Baine et al., J. Immunol., 1995, 154,
3667-3677.
[0003] W. F. Michne et al., in J. Med. Chem (1995) 38, 2557-2569
disclose a number of quinazoline-2,4diones and
pyrrolo[3,4-d]pyrimidine-2,4diones which inhibit transcription
regulated by the DNA region bound by the NFAT-1 protein.
[0004] WO 96/17610 discloses the use of compounds of the following
general formula and their salts as anti-ischaemic agents, 1
[0005] wherein R1, R2 and R3 which may be the same or different are
N or CH; X1 and X2 which may be the same or different are hydrogen,
hydroxy or an optionally substituted alkyl, alkenyl, alkynyl,
cycloalkyl, aryl or heterocyclyl group and Z1 and Z2 which may be
the same or different are hydrogen, hydroxy, keto or an optionally
substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl or
heterocyclyl group or one of Z1 and X1 and Z2 and X2 form the
second bond of a double bond at the 1,6 or 2,3 positions, with the
proviso that at least one of the groupings R1Z1X1, R2Z2X2 and
R1X1Z2 form a hydroxamate moiety (--N(OH)C(.dbd.O)-) in which R1
and/or R2 is N, Z1 and/or Z2 is .dbd.O and X1 and/or X2 is OH or R1
is N, Z2 is =O and X1 is OH and B is a 5- or 6-membered ring of
formula 2
[0006] in which R4, R5, R6, R7, R8, R9 and R10 which may be the
same or different are CH or N with the proviso that ring B cannot
contain more than 3 ring members which are nitrogen and the ring B
may optionally be substituted by one or more of hydroxy, keto and
an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl
or heterocyclyl group. Preferred compounds of WO 96/17610 include
those compounds in which the ring B contains no substiment
groups.
[0007] In accordance with the present invention, there is provided
a compound according to the general formula: 3
[0008] wherein--
[0009] W represents --CH.sub.2-- or a bond; Q represents Ar.sup.1
or Ar.sup.2; in the case where W represents --CH.sub.2--, Q
represents an aryl group A.sup.1 wherein Ar.sup.1 represents
naphthyl, phenyl, quinolyl, isoquinolyl, indolyl, benzofuranyl
orbenzothienyl; in the case where W represents a bond, Q represents
an aryl group Ar.sup.2 wherein Ar.sup.2 represents acenaphthenyl,
fluorenyl or indanyl; wherein the ring systems which Ar.sup.1 and
Ar.sup.2 represent may all be optionally substituted by one or more
substituents selected from C.sub.1-4 alky, C.sub.1-4 alkoxy,
halogen, or trifluoromethyl; R.sup.10 represents X-(A).sub.p--Y; X
represents S(O).sub.n, C.ident.C, (CH.sub.2).sub.2, CH.dbd.CH or
CH.sub.2CH.dbd.CH; n represents 0, 1 or 2; A represents C.sub.1-6
alkylene; p is 0 or 1; Y represents CN, OR.sub.11,
CO.sub.2R.sup.12, CONR.sup.13R.sup.14, NR.sup.15R.sup.16,
NHSO.sub.2R.sup.17, NHCOR.sup.18 or an optionally substituted aryl
or heteroaryl group, provided that when X represents S(O).sub.n and
Y is other than an optionally substituted aryl or heteroaryl group,
then p is 1 and also provided that when X represents S(O).sub.n, p
is 1 and Y represents OH, then n is not 0; R.sup.13 and R.sup.14
independently represent H, C.sub.1-5 alkyl or phenyl, which latter
group may be substituted by one or more substituents selected from
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halogen, or CO.sub.2R.sup.21;
and R.sup.1, R.sup.2, R.sup.11, R.sup.12, R.sup.15, R.sup.16,
R.sup.17, R.sup.18 and R.sup.21 independently represent H or
C.sub.1-5 alkyl; or a pharmaceutically acceptable derivative
thereof.
[0010] In the present specification, unless otherwise indicated, an
alkyl substituent or alkyl moiety in an alkoxy, alkoxycarbonyl,
alkylsulphonamido. (di)alkylamido, (di)alkylamino or acylamino
substituent group may be linear or branched.
[0011] When W in formula (I) represents --CH.sub.2--, then Q
represents an aryl group Ar.sup.1 wherein Ar.sup.1 preferably
represents a naphthyl or phenyl group, especially a naphthyl group,
which aryl group may be optionally substituted by one or more,
preferably one to four, particularly one or two, substituents
selected from C.sub.1-4 alkyl, e.g., methyl or ethyl, C.sub.1-4
alkoxy, e.g. methoxy or ethoxy, halogen, e.g. fluorine, chlorine or
bromine, or trifluoromethyl. Ar.sup.1 is preferably an
unsubstituted naphthyl group.
[0012] When W in formula (I) represents a bond, then Q represents
an aryl group Ar.sup.2 wherein Ar.sup.2 preferably represents an
indanyl group, which may be optionally substituted by one or more,
preferably one to four, particularly one or two, substituents
selected from C.sub.1-4 alkyl, e.g. methyl or ethyl, C.sub.1-4
alkoxy, e.g. methoxy or ethoxy, halogen, e.g. fluorine, chlorine or
bromine, or trifluoromethyl. Ar.sup.2 is preferably an
unsubstituted indanyl group.
[0013] Preferably, X represents S(O).sub.m wherein n is 0, 1 or 2,
C.ident.C, (CH.sub.2).sub.2 or CH.sub.2CH.dbd.CH. Particularly
advantageous compounds of formula (I) are those in which X
represents S(O).sub.m wherein n is 0, 1 or 2.
[0014] When p is 1, A preferably represents C.sub.1-4 alkylene,
more preferably CH.sub.2 (CH.sub.2).sub.2 or (CH.sub.2).sub.3.
[0015] Each of groups R.sup.1, R.sup.2, R.sup.11, R.sup.12,
R.sup.15, R.sup.16, R.sup.17, R.sup.18 and R.sup.21 preferably
represents H or a C.sub.1-4 alkyl group. R.sup.1 is most preferably
a cyclic or branched C.sub.3-4 alkyl group, e.g., a 1-methylethyl
or 2-methylpropyl group, and R.sup.2 is most preferably a methyl
group.
[0016] Each of groups R.sup.13 and R.sup.14 preferably represents
H, C.sub.1-3 alkyl or phenyl, which latter group may be substituted
by one or more, e.g. one to four, substituents selected from
C.sub.1-4 alkyl, e.g., methyl or ethyl, C.sub.1-4 alkoxy, e.g.,
methoxy or ethoxy, halogen, e.g. fluorine, chlorine or bromine. or
CO.sub.2R.sup.21.
[0017] More preferably, each of groups R.sup.13 and R.sup.14
represents H, C.sub.1-3 alkyl or phenyl, which latter group may be
substituted by one or two substituents selected from C.sub.1-4
alkyl, C.sub.1-4 alkoxy, halogen, or CO.sub.2R.sup.21.
[0018] Most preferably. each of groups R.sup.13 and R.sup.14
represents H, C.sub.1-3 alkyl or phenyl, especially H.
[0019] The group Y may represent an optionally substituted aryl or
heteroaryl group Preferably p is 0 when Y represents an optionally
substituted aryl or heteroaryl group. Examples of aryl and
heteroaryl groups include phenyl, furyl, imidazolyl, pyrazinyl,
pyrazolyl, pyridazinyl, pyridyl, pyrinidinyl, pyrrolyl, tetrazolyl
and thienyl groups. The groups phenyl, 2-pyridyl, 4-pyridyl and
5-tetrazolyl are most preferred. Examples of substituents that may
be present in the aryl or heteroaryl group include C.sub.1-4 alkyl,
e.g. methyl or ethyl, C.sub.1-4 alkoxy, e.g. methoxy or ethoxy,
halogen, e.g. fluorine, chlorine or bromine, hydroxyl and
trifluoromethyl. One or more, e.g,. 1, 2, 3 or 4, substituent
groups may be present but preferably only one substituent group is
present.
[0020] A preferred subset of compounds of formula (I) is one in
which W represents --CH.sub.2-- or a bond; Q represents Ar.sup.1 or
Ar.sup.2; in the case where W represents --CH.sub.2--, Q represents
an aryl group Ar.sup.1 wherein Ar.sup.1 represents naphthyl or
phenyl; in the case where W represents a bond, Q represents an,
aryl group A.sup.2 wherein Ar.sup.2 represents indanyl; wherein the
ring systems which Ar.sup.1 and Ar.sup.2 represent may all be
optionally substituted bv one or more, e.g. one, two, three or
four, substituents selected from C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
halogen, or trifluoromethyl; R.sup.10 represents X-(A).sub.p--Y; X
represents S(O).sub.n, C.ident.C, (CH.sub.2).sub.2 or
CH.sub.2CH.dbd.CH; n represents 0, 1 or 2; A represents C.sub.1-6
alkylene; p is 0 or 1; Y represents CN, OR.sup.11, OR.sup.11,
CO.sub.2R.sup.12 , CONR.sup.13R.sup.14, NR.sup.15R.sup.17 or an
optionally substituted phenyl, pyridyl or tetrazolyl group,
provided that when X represents S(O).sub.n and Y is other than an
optionally substituted aryl or heteroaryl group, then p is 1 and
also provided that when X represents S(O).sub.n, p is 1 and Y
represents OH, then n is not 0; R.sup.13 and R.sup.14 independently
represent H, C.sub.1-5 alkyl or phenyl, which latter group may be
substituted by one or more, e.g. one, two, three or four,
substituents selected from C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
halogen, or CO.sub.2R.sup.21; and R.sup.1, R.sup.2, R.sup.11,
R.sup.12, R.sup.15, R.sup.16 and R.sup.21 independently represent H
or C.sub.1-5 alkyl.
[0021] An especially preferred subset of compounds of formula (I)
is one in which W represents --CH.sub.2-- or a bond; Q represents
Ar.sup.1 or A.sup.2 ; in the case where W represents --CH.sub.2--,
Q represents an aryl group A.sup.1 wherein Ar.sup.1 represents
naphthyl; in the case where W represents a bond, Q represents an
aryl group Ar.sup.2 wherein Ar.sup.2 represents indanyl; R.sup.10
represents X-(A).sub.p--Y; X represents S(O).sub.n, C.ident.C,
(CH.sub.2).sub.2 or CH.sub.2CH.dbd.CH; n represents 0, 1 or 2; A
represents C.sub.1-3 alkylene: p is 0 or 1; Y represents CN,
OR.sup.11, CO.sub.2R.sup.12, CONR.sup.13R.sup.14,NR.sup.15-
R.sup.16 or a phenyl, pyridyl or tetrazolyl group optionally
substituted by a hydroxyl or methoxy group, provided that when X
represents S(O).sub.n,and Y is other than an optionally substituted
aryl or heteroaryl group, then p is 1.and also provided that when X
represents S(O).sub.n, p is 1 and Y represents OH, then n is not 0;
R.sup.13 and R.sup.14 independently represent H; and R.sup.1,
R.sup.2, R.sup.11, R.sup.12, R.sup.15 and R.sup.16 independently
represent H or C.sub.1-4 alkyl.
[0022] Specific examples of preferred compounds of formula (I)
are:
[0023] (i)
5-[(3-hydroxypropyl)sulphinyl]-3-methyl-1-(2-methylpropyl)-6-(1-
-naphthalenyl-methyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione;
[0024] (ii)
5-[(3-hydroxypropyl)sulphonyl]-3-methyl-1-(2-methylpropyl)-6-(-
1-naphthalenyl-methyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione;
[0025] (iii) methyl
4-[(2,3,4,6-terrahydro3-methyl-1-(2-methylpropyl)6-(1--
naphthalenyl-methyl)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)thio]butano-
ate;
[0026] (iv)
5-[(3-methoxypropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-nap-
hthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione;
[0027] (v)
5-[(2-hydroxyethyl)sulphinyl]-3-methyl-1-(2-methylpropyl)-6-(1--
naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione;
[0028] (vi)
4-[(2,3,4,6-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphth-
alenylmethyl)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)thio]butanoic
acid;
[0029] (vii)
4-[(2,3,4,6-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-napht-
halenylmethyl)-2,4-dioxo-1H-pyrrolo(3,4pyrdin-5-yl)thio]butanoic
acid, sodium salt;
[0030] (viii)
5-[(2-dimethylaminoethyl)thio]-3-methyl-(2-methylpropyl)-6-(-
1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione;
[0031] (ix)
6-(2,3-dihydro-1H-inden-2-yl)-5-[(3-hydroxypropyl)sulphinyl]-3-
-methyl-1-(1-methylethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione;
[0032] (x)
6-(2,3-dihydro-1H-inden-2-yl)-5-[(3-hydroxypropyl)sulphonyl]-3--
methyl-1-(1-methylethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione;
[0033] (xi)
5-[(3-hydroxypropyl)sulphinyl]-3-methyl-1-(1-methylethyl)-6-(1-
-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidin-2,4(3H,6H)-dione;
[0034] (xii)
4-[(2,3,4,6-tetrahydro-3-methlyl-1-(2-methylpropyl)-6-(1-naph-
thalenylmethyl)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)thio]butanamide;
[0035] (xiii)
5-(2,3,4,6-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-napht-
halenylmethyl)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)pent-3-enoic
acid;
[0036] (xiv)
5-(5-hydroxypent-1-ynyl)-3-methyl-1-(2-methylpropyl)-6-(1-nap-
hthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione,
[0037] (xv)
5-(5-hydroxypentyl)-3-methyl-1-(2-methylpropyl)-6-(1-naphthale-
nylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione;
[0038] (xvi)
5-(4-hydroxybut-1-ynyl)-3-methyl-1-(2-methylpropyl)-6-(1-naph-
thalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)dione;
[0039] (xvii)
5-(hydroxybutyl)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalen-
ylmethyl)-1H-pyrrolo[3,4-d]pyrimidin-2,4(3H,6H)-dione;
[0040] (xviii)
5-(2,3,4,6-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naph-
thalenylmethyl)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)pentanoic
acid;
[0041] (xix)
4-[(2,3,4,6-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-napht-
halenylmethyl)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)thio]butanenitril-
e;
[0042] (xx)
5-[(3-{1H-tetrazol-5-yl}propyl)thio]-3-methyl-1-(2-methylpropy-
l)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidirne-2,4(3H,6H)dione;
[0043] (xxi)
3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(2-py-
ridinyl)thio]-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione;
[0044] (xxii)
3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(2-p-
yridinyl)sulphinyl]-1H-pyrrolo[3,4d]pyrimidine-2,4(3H,6H)-dione;
[0045] (xxiii)
3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(4--
pyridinyl)thio]-1H-pyrrolo[3,4d]pyrimidine-2,4(3H,6H)-dione;
[0046] (xxiv)
5-([3-methoxyphenyl]thio)-3-methyl-1-(2-methylpropyl)-6-(1-n-
aphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimdine-2,4(3H,6H)-dione;
[0047] (xxv)
5-([3-hydroxyphenyl]thio)-3-methyl-1-(2-methylpropyl)-6-(1-na-
phthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione;
[0048] (xxvi)
5-([4methoxyphenyl]thio)-3-methyl-1-(2-methylpropyl)-6-(1-na-
phthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione;
[0049] (xxvii)
5-([4hydroxyphenyl]thio)-3-methyl-1-(2-methylpropyl)-6-(1-n-
aphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione;
[0050] (xxviii)
5-([2-methoxyphenyl]thio)-3-methyl-1-(2-methylpropyl)-6-(1-
-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione;
and
[0051] (xxix)
5-([2-hydroxyphenyl]thio)-3-methyl-1-(2-methylpropyl)-6-(1-n-
aphthalenylnethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione.
[0052] According to the invention there is also provided a process
for the preparation of a compound of formula I which comprises:
[0053] (a) when X represents S(O).sub.n and n is 1 or 2, oxidising
a compound of general formula 4
[0054] wherein R.sup.1, R.sup.2, A, p, Y, W and Q are as
hereinbefore defined including the provisos, in the presence of an
appropriate quantity of a suitable oxidising agent (e.g.
3chloroperoxybenzoic acid or potassium peroxymonosulphate,
commercially sold under the trade mark "Oxone") and an appropriate
organic solvent (e.g. dichloromethane) under conditions which are
well known to those skilled in the art;
[0055] (b) when Y represents OR.sup.11 and R.sup.11 represents
C.sub.1-5 alkyl, reacting a corresponding compound of formula (I)
in which Y represents OH, with an alkyl halide of general
formula
R.sup.11aHal (III)
[0056] wherein R.sup.11a represents C.sub.1-5 alkyl and Hal
represents a halogen atom such as bromine or iodine, for example,
at 25.degree. C. in the presence of a suitable base (e.g sodium
hydride) and a suitable organic solvent (e.g. tetrahydrofuran);
[0057] (c) when Y represents CO.sub.2R.sup.12 and R.sup.12
represents C.sub.1-5 alkyl, esterifying a corresponding compound of
formula (I) in which Y represents CO.sub.2H with an alcohol of
general formula
R.sup.12aOH (IV)
[0058] wherein R.sup.12a represents C.sub.1-5 alkyl, under
conditions that are well cnown to those skilled in the art;
[0059] (d) when Y represents CONR.sup.13R.sup.14, reacting a
corresponding compound of formula (I) in wnich Y represents
CO.sub.2H with an amine of general forula
R.sup.13R.sup.14NH (V)
[0060] wherein R.sup.13 and R.sup.14 are as hereinbefore defined,
for example, at 25.degree. C. in the presence of an appropriate
peptide synthesis agent (e.g. diisopropylcarbodiimide and
N,N-dimethyl-aminopyrid- ine or, alternatively, ethyl chloroformate
and triethylamine) and a suitable organic solvent (e.g.
dichloromethane);
[0061] (e) when Y represents CO.sub.2H, hydrolysing a corresponding
compound of formula (I) in which Y represents CO.sub.2R.sup.12 and
R.sup.12 represents C.sub.1-5 alkyl, using a suitable base (e.g.
lithium or sodium hydroxide) in a suitable solvent (e.g. aqueous
tetrahydrofuran) at a temperature of from 0.degree. C. to
80.degree. C.;
[0062] (f) when X represents S, A represents a C.sub.1-6 alkylene
group, Y represents CO.sub.2R.sup.12 and R.sup.12 represents
C.sub.1-5 alkyl, reacting a compound of general formula 5
[0063] in which R.sup.1, R.sup.2, W and Q are as hereinbefore
defined, with a compound of general formula
L--S--A--C(OR.sup.12).sub.3 (VII)
[0064] wherein L is a suitable leaving group. for example
para-toluenesulphinate, and A and R.sup.12 are as hereinbefore
defined, in the presence of a suitable base, for example lithium
diisopropylamide, in an appropriate solvent, for example
tetrahydrofuran, at from -78 .degree. C. to room temperature,
followed by hydrolysis of the resulting ortho ester;
[0065] (g) when X represents S, A represents a C.sub.2-6 alkylene
group, Y represents NR.sup.15R.sup.16 and R.sup.15 and R.sup.16 are
as hereinbefore defined reducing a corresponding compound of
formula (II) as hereinbefore defined in which A represents a
C.sub.1-5 alkylene group, Y represents CONR.sup.13R.sup.14 and
R.sup.13 and R.sup.14 are respectively equal to R.sup.15 and
R.sup.16, with a suitable reducing agent, for example diborane, in
a suitable solvent, for example tetrahydrofuran;
[0066] (h) when X represents S, A represents a C.sub.1-6 alkylene
group, Y represents NR.sup.15R.sup.16 and R.sup.15and R.sup.16 are
as hereinbefore defined, reacting a corresponding compound of
general formula 6
[0067] wherein L' represents a leaving group such as
para-toluenesulphonate and R.sup.1, R.sup.2, A, W and Q are as
hereinbefore defined, with a compound of formula (V) wherein
R.sup.13 and R.sup.14 are respectively equal to R.sup.15 and
R.sup.16, typically in a suitable solvent, such as
dimethylformamide, in the presence of a suitable base, such as
triethylamine;
[0068] (j) when X represents C.ident.C, CH.dbd.CH or
CH.sub.2CH.dbd.CH, reacting a compound of general formula 7
[0069] in which Hal represents a halogen atom, e.g. bromine or
iodine, and R.sup.1, R.sup.2, W and Q are as hereinbefore defined,
with a compound of general formula (X), H-X'-(A).sub.p-Y, in which
X' represents C.ident.C, CH.dbd.CH or CH.dbd.CHCH.sub.2 and A, p
and Y are as hereinbefore defined in the presence of a palladium
catalyst (e.g. bis-triphenylphosphinepalla- dium (II) chloride),
and optionally hydrogenating the compound of formula (I) obtained
wherein X represents C.ident.C or CH.dbd.CH in the presence of a
palladium on carbon catalyst to produce a further compound of
formula (I) wherein X represents (CH.sub.2).sub.2;
[0070] (k) when X represents S, A represents a C.sub.1-6 alkylene
group and Y represents CN, reacting a compound of formula (VIII) as
hereinbefore defined with sodium cyanide (NaCN);
[0071] (l) when X represents S, A represents a C.sub.1-6 alkylene
group and Y represents NHSO.sub.2R.sup.17, reacting a corresponding
compound of formula (I) in which Y represents NH.sub.2 with a
compound of general formula (XI), R.sup.17SO.sub.2Cl, wherein
R.sup.17 is as hereinbefore defined;
[0072] (m) when X represents S, A represents a C.sub.1-6 alkylene
group and Y represents NHCOR.sup.18, reacting a corresponding
compound of formula (I) in which Y rpresents NH.sub.2 with a
compound of general formula (XII), R.sup.18COCl, wherein R.sup.18
is as hereinbefore defined;
[0073] (n) when X represents S and Y represents an optionally
substituted aryl or heteroaryl group, reacting a compound of
formula (VI) as hereinbefore defined with a compound of general
formula
Y'--(A).sub.p--S--S-(A).sub.p--Y' (XIII)
[0074] wherein Y' represents an optionally substituted aryl or
heteroaryl group and p and A are as hereinbefore defined; or
[0075] (p) when X represents S, A represents a C.sub.1-6 alkylene
group and Y represents a tetrazolyl group, reacting a compound of
formula (I) in which X represents S, A represents C.sub.1-6
alkylene group and Y represents CN, with trialkyltin azide (e.g.
tmethyltin azide), typically in a solvent such as toluene under
reflux conditions; and optionally forming a pharmaceutically
acceptable derivative thereof.
[0076] Compounds of formula (II) wherein Y represents OH may be
prepared by reaction of a compound of formula (VI) as hereinbefore
defined with a compound of general formula
L"--S--A--OR.sup.22 (XIV)
[0077] wherein L" is a suitable leaving group, for example
para-toluenesulphinate, A is as hereinbefore defined, and R.sup.22
is H or a suitable protecting group such as
tert-butyldimethylsilyl, in the presence of a suitable base, for
example lithium diisopropylamide, in a suitable solvent, for
example tetrahydrofuran at around -70.degree. C.
[0078] Compounds of formula (II), wherein Y represents OR.sup.11,
CO.sub.2R.sup.12, CONR.sup.13R.sup.14, NHSO.sub.2R.sup.17 or
NHCOR.sup.18 and wherein R.sup.11 or R.sup.12 as appropriate
represent C.sub.1-5 alkyl and R.sup.13 and R.sup.14 or R.sup.17 or
R.sup.18 as appropriate are as hereinbefore defined, may be
prepared from corresponding compounds of formula (II) wherein Y
represent OH, CO.sub.2H or NH.sub.2 as appropriate in accordance
with the methods described in steps (b) to (d), (l) and (m)
hereinbefore.
[0079] Compounds of formula (VI) are known from J. Med. Chem.
(1995) 38, 2557, or may be prepared analogously by methods
described therein.
[0080] Compounds of formula (VIII) may be prepared from compounds
of formula (II) where Y represents OH by techniques known to those
skilled in the art.
[0081] Compounds of formula (IX) may be prepared by reacting a
compound of formula (VI) with lithium diisopropylamide at
-78.degree. C., followed by the addition of a halogen.
[0082] Other compounds of formula (II), (III), (IV), (V), (VII),
(X), (XI), (XII), (XIII) and (XIV) are either commercially
available, are well known in the literature or may be prepared
easily using known techniques.
[0083] It will be appreciated by those skilled in the art that in
the processes described above the functional groups (e.g. hydroxy
or amino groups) of intermediate compounds may need to be protected
by protecting aroups. The final stage in the preparation of the
compounds of formula (I) may involve the removal of one or more
protecting groups.
[0084] 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
Orgranic Synthesis`, 2nd edition, T. W. Greene & P. G. M. Wuts,
Wiley-Interscience (1991).
[0085] Pharmaceutically acceptable derivatives of the compounds of
formula (I) include solvates and salts.
[0086] Salts of the compounds of formula (I) may be formed by
reacting the free acid, or a salt thereof, or the free base, or a
salt or derivative thereof, with one or more equivalents of the
appropriate base or acid. The reaction may be carried out in a
solvent or medium in which the salt is insoluble or in a solvent in
which the salt is soluble, e.g. ethanol, tetrahydrofuran or diethyl
ether, which may be removedin vacuo, or by freeze drying. The
reaction may also be a metathetical process or it may be carried
out on an ion exchange resin. The non-toxic physiologically
acceptable salts are preferred, although other salts may be useful,
e.g. in isolating or purifying the product.
[0087] Particular salts which may be mentioned include sodium,
potassium, hydrochloride, hydrobromide, sulphonate, tosylate and
methanesulphonate.
[0088] The compounds of formula (I) may exhibit tautomerism. All
tautomeric forms and mixtures thereof are included within the scope
of the invention.
[0089] The compounds of formula (I) have a number of chiral centres
and may exist in a variety of stereoisomers. The invention provides
all optical and stereoisomers. as well as racermic mixtures. Tne
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, e.g. chiral HPLC, techniques.
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.
[0090] The compounds of formula (I) may be isolated from their
reaction mixtures using conventional techniques.
[0091] The compounds of formula (I) are useful because they possess
pharmacological activity in human and non-human animals. They are
therefore indicated as pharmaceuticals. In particular they are
useful because they possess immunosuppressive activity, for example
as demonstrated in the test described below.
[0092] The compounds are thus indicated for use in the treatment or
prevention of resistance to transplanted organs or tissues, such as
kidney, heart, lung, bone marrow, skin and cornea; and of
autoimmune, inflammatory, proliferative and hyperproliferative
diseases including cancer, and of cutaneous manifestations of
immunologicaliy-mediated diseases: for example rheumatoid
arthritis, lupus erythematosus, systemic lupus erythematosus,
Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis,
type 1 diabetes, uveitis, nephrotic syndrome, psoriasis, atopical
dermatitis, contact dermatitis and further eczematous dermatitides,
seborrhoeic dermatitis, Lichen planus, Pemphigus, bullous
Pemphigoid, Epidermolysis bullosa, urticaria, angioedemas,
vasculitides, erythemas, cutaneous eosinophilias, Alopecia areata,
eosinophilic fasciitis and atherosclerosis.
[0093] The compounds of formula (I) are also indicated in the
treatment of respiratory diseases, for example sarcoidosis,
farmer's lung and related diseases, fibroid lung, idiopathic
interstitial pneumonia and reversible obstructive airways diseases
which latter includes conditions such as asthma (e.g. bronchial
asthma, allergic asthma, intrinsic asthma, extrinsic asthma and
dust asthma), particularly chronic or inveterate asthma (e.g. late
asthma and airway hyperresponsiveness) and bronchitis.
[0094] Further, the compounds of formula (I) are indicated in the
treatment of a disease selected from intestinal
inflammations/allergies such as Coeliac disease, proctitis,
eosinophilic gastro-enteritis, mastocytosis, Crohn's disease and
ulcerative colitis; and food related allergic diseases which have
symptomatic manifestation remote from the gastrointestinal tract,
for example, migraine, rhinitis and eczema.
[0095] 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 disease
indicated.
[0096] The compounds of formula (I) and pharmaceutically acceptable
derivatives thereof, may be used on their own but will generally be
administered in the form of a pharmaceutical composition in which
the compound or derivative (active ingredient) is in admixture with
a pharmaceutically acceptable adjuvant, diluent or carrier. The
pharmaceutical composition will preferably comprise from 0.05 to
80% w (percent by weight), more preferably from 0.10 to 50% w, of
active ingredient, and, from 20 to 99.95 % w, more preferably from
50 to 99.90% w, of a pharmaceutically acceptable adjuvant, diluent
or carrier.
[0097] Thus, the present invention also provides a pharmaceutical
composition comprising a compound of formula (I), or a
pharmaceutically acceptable derivative thereof, in admixture with a
pharmaceutically acceptable adjuvant, diluent or carrier.
[0098] The invention further provides a process for the preparation
of a pharmaceutical composition according to the invention which
comprises admixing a compound of formula (1) or a pharmaceutically
acceptable derivative thereof, with a pharmaceutically acceptable
adjuvant, diluent or carrier.
[0099] According to a further aspect of the invention, there is
provided a method of effecting irnmunosuppression which comprises
administering a therapeutically effective amount of a compound of
formula (I), or a pharmaceutically acceptable derivative thereof,
to a patient.
[0100] The invention also provides a method of treating, or
reducing the risk of, a reversible obstructive airways disease in a
patient suffering from, or at risk of, said disease, which
comprises administering to the patient a therapeutically effective
amount of a compound of fornula (I), or a pharmnaceutically
acceptable derivative thereof.
[0101] The invention will be further illustrated by reference to
the following examples in which MS and NMR are the abbreviations
for Mass Spectrometry and Nuclear Magnetic Resonance
respectively.
EXAMPLE 1
[0102]
5-[(3-Hydroxypropyl)sulphinyl]-3-methyl-1-(2-methylpropyl)-6-(1-nap-
hthalenyl-methyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione(1)
and
5-[(3-hydroxy-propyl)sulphonyl]-3-methyl-1-(2-methylpropyl)-6-(1-naphthal-
enylmethyl)-1H-pyrrolo [3,4-d]pyrimidine-2,4(3H,6H)-dione (2) 8
[0103] To a stirred solution of
5-[(3-hydroxypropyl)thio]-3-methyl-1-(2
methypropyl)-6-(1-naphthalenylmethyl)-pyrrolo-[3,4-d]-pyrimidine-2,4-dion-
e (0.39 g; 0.864 mmol; J. Med. Chem. (1995) 38, 2557) in
dichloromethane (20 ml) was added 3chloro-peroxybenzoic acid
(55-60%; 0.526 g). After 30 minutes the reaction was diluted with
dichioromethane (80 ml) and washed with sodium bicarbonate solution
(50 ml) containinig sodium metabisulphite (1 g). The organic layer
was dried over magnesium sulphate (MgSO.sub.4), concentrated in
vacuo and chromatographed on silica eluting with hexane: acetone
(3:2) to give separately the two title compounds which were each
subsequently recrystallised from hexane: ethyl acetate [1:2].
[0104] Title Compound 1
[0105] Melting point: 204-206.degree. C. Elemental Analysis (in %):
Theory: C 64.22, H 6.25, N 8.99, S 6.86 Found: C 64.10, H 6.51, N
9.22, S 6.53 MS(FAB) 468 (M+H).sup.+
[0106] Title Compound 7
[0107] Melting point: 201-202.degree. C. Elemental Analysis (in %):
Theory: C 62.09, H 6.04, N 8.69, S 6.63 Found: C 61.84, H 6.21, N
8.62, S 6.22 MS(FAB) 484 (M+H).sup.+
EXAMPLE 2
[0108] Methyl
4-[(2,3,4,6-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naph-
thalenylmethyl)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)thio]butanoate
9
[0109] a) 4,4,4-Trimethoxybutyl para-toluenethiosulphonate
[0110] A mixture of para-toluenethiosulphonic acid potassium salt
(24 mmol), trimethyl 4-bromoorthobutyrate (22 mmol) and
hexamethylphosphoramide (30 ml) was stirred at room temperature for
48h before being poured into 10:1 hexane/diethyl ether (500 ml) and
shaken vigorously. The mixture was washed with water (2.times.200
ml) and then brine. The organic phase was collected and dried over
magnesium sulphate (MgSO.sub.4) and evaporated to dryness in vacuo
to yield the sub-tide ester as an oil (5.3 g) containing ca 7%
4,4,4tnmethoxybutylparatoluene(d- ithioperoxy)sulphonate. .sup.1H
NMR (CDCl.sub.3) .delta. 1.95 (2H, m), 2.37 (2H, t), 2,44 (3H, s),
3.02 (2H. t), 3.16 (9H, s), 7.33 (2H, d), 7.80 (2H, d)
[0111] b)
Methyl-1-[(2,3.4,6-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-n-
aphthalenyl-methyl)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)thio]butanoa-
te
[0112] To a solution of
3-methyl-1-(2-methylpropyl)-6-(1-naphthalenymethyl-
)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (1.4 mmol) in
tetrahydrofuran (4 ml) at -78.degree. C. under nitrogen was added a
freshly prepared 1M solution of lithium diisopropylamide (8.5 mmol)
in tetrahydrofuran followed by 4,4,4,-trimethoxybutyl
para-toluenethiosulphonate (2.3 mmol). The reaction was allowed to
warm to room temperature and then quenched via addition of
saturated aqueous NH.sub.4Cl and then brine. The mixture was
extracted into diethyl ether which was collected, dried over
magnesium sulphate (MgSO.sub.4) and evaporated to dryness in vacuo.
The residual oil was redissolved in methanol/water and treated with
glacial acetic acid for 0.5 h. The reaction was then basified via
addition of solid sodium hydrogencarbonate. The mixture was
extracted into diethyl ether, washed with brine, dried over
magnesium sulphate (MgSO.sub.4) and evaporated to dryness in vacuo.
The resultant oil was chromatographed twice (silica) eluting with
1:3 hexanes/diethyl ether to yield the title compound as an oil
(133 mg).
[0113] MS (APCI+ve) 464 (M+H).sup.+1H NMR (CDCl.sub.3) .delta. 0.88
(6H, d), 1.85 (2H, m), 2.12 (1H, m), 2,40 (2H, m), 3.04 (2H, m),
3.42 (3H, s), 3.55 (2H, d), 3.62 (3H, s), 5.84 (2H, s), 6.35 (1H,
s), 6.80 (1H, d), 7.39 (1H, t), 7.57 (2H, m), 7.82 (1H, d), 7.91
(2H, m)
EXAMPLE 3
[0114]
5-[(3-Methoxypropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthal-
enylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione 10
[0115] To a 60% dispersion of sodium hydride in mineral oil (0.035
g, 0.886 mmol) under nitrogen was added a solution of
5-[3-hydroxypropyl)thio]3-methyl-1-(2methylpropyl)-6-(1-naphthalenylmethy-
l)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (0.20 g) in
anhydrous tetrahydrofuran (10 ml). The mixture was stirred at room
temperature for 30 minutes, iodomethane (0.055 ml) was added, and
stirring was continued for 18 hours. The miture was added to
saturated sodium bicarbonate solution (20 ml) and extracted with
ethyl acetate (20 ml). The 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 hexane:acetone (4:1), and then by column
chromatography over silica, eluting with hexane:ethyl acetate
(2:1). The resulting oil was crystallised from an ethyl
acetate/hexane mixture to give the title compound (95 mg).
[0116] Melting point: 92-94.degree. C. MS (FAB) 466 (M+H).sup.+1H
NMR (CDCl.sub.3) .delta. 0.8 7 (6H, d), 1.81 (2H, quin), 2.12 (1H,
m), 3.07 (2H, t), 3.25 (3H, s), 3.38 (2H, t), 3.43 (3H, s), 3.54
(2H, d), 5.84 (2H, s), 6.34 (1H, s), 6.82 (1H, d), 7.39 (1H, t),
7.53-759 (2H, m), 7.83 (1H, d), 7.91-7.93 (2H, m)
EXAMPLE 4
[0117]
5-[(2-Hydroxyethyl)sulphinyl]-3-methyl-1-(2-methylpropyl)-6-(1-naph-
thalenyl-methyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)dione 11
[0118] a) Bis-[dimethyl(1.1-dimethyl)silyloxyethyl] disulphide
[0119] To a stirred solution of 2-hydroxyethyl disulphide (2 g) and
imidazole (5.3 g) in dichloromethane (100 ml) was added
dimethyl(1,1-dimethylethyl)silyl chloride. The solution was stirred
overnight and then diluted with diethyl ether. The mixture was
washed with dilute hydrochloric acid, then with sodium bicarbonate
solution and then dried over magnesium sulphate. Concentration in
vacuo followed by chromatography on silica gel (hexane:diethyl
ether/20:1) gave the subtitle compound as a clear oil (3.75 g). MS
(EI) 382 ((M-CH.sub.3).sup.+).
[0120] b)
5-(2-Hydroxyethyl)thio-3-methyl-1-(2-methylpropyl)-6-(1-naphthal-
enylmethyl1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
[0121] To a stirred solution of
3-methyl-1-(2-methylpropyl)-6-(1-naphthale-
nylmethyl)-pyrrolo[3,4-d]pyrimidine-4,6-dione ((J. Med. Chem.,
1995, 38, 2557; 0.50 g,) and
bis-[dimethyl(1,1-dimethylethyl)silyloxyethy] disulphide(1.06 g) in
anhydrous tetrahydroffuran (15 ml) at -78.degree. C. was added
dropwise a solution of lithium diisopropylamide (2.78 mmol) in
tetrahydrofuran (5 ml). The solution was stirred for a further 0.5
h at -78.degree. C. and then allowed to warm to ambient
temperature. Saturated aqueous sodium bicarbonate solution (10 ml)
was added and the solution was extracted with ethyl acetate. The
organic extracts were dried over magnesium sulphate and
concentrated in vacuo. The residue was redissolved in acetonitrile
(10 ml) and treated with 40% aqueous hydrofluoric acid at ambient
temperature. The solution was stirred for 1 hour, then neutralised
with aqueous sodium bicarbonate solution anid extracted with ethyl
acetate. The organic extracts were dried over magnesium sulphate
and concentrated in vacuo. Chromatography on silica gel (diethyl
ether) gave the subtitle compound (0.47 g) as a white solid.
[0122] Melting point: 138-141.degree. C. MS (FAB) 353
((M+H).sup.-).
[0123] c)
5-[(2-Hydroxyethyl)sulphinyl]-3-methyl-1-(2-methylpropyl)-6-(1-n-
aphthalenyl-methyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
[0124] To a stirred solution of
5-(2-hydroxyethyl)thio-3-methyl-1-(2-methy-
lpropyl)-6-(1-naphthalenylmethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-di-
one (100 mg) in methanol (20 ml) was added potassium
peroxymonosulphate (commercially sold under the trade mark "OXONE")
(300 mg) in water (10 ml). After stirring for 10 minutes the
reaction mixture was diluted with water and extracted with ethyl
acetate. The organic extracts were dried over magnesium sulphate
and concentrated in vacuo. Chromatography on silica gel (ethyl
acetate) cave the title compound (70 mg) as a white foam.
[0125] MS (FAB) 454 ((M+H).sup.+). .sup.1H NMR (CDCl.sub.3) .delta.
0.85 (3H, d), 0.87 (3H, d), 2.05-2.13 (1H, m), 3.21-3.33 (1H, m),
3.36 (3H, s), 3.49-3.61 (2H, m), 3.65-3.73 (1H, m), 3.84-4.05 (2H,
m), 6.17-6.27 (2H, m), 6.42 (1H, s), 6.95 (1H, d), 7.44 (1H, t),
7.54-7.66 (2H, m) and 7.87-7.98 (3H, m).
EXAMPLE 5
[0126]
4-[(2,3,4,6-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthaleny-
lmethyl)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)thio]butanoic
acid 12
[0127] The compound of Example 2, methyl
4-[(2,3,4,6-Tetrahydro-3-mehyl-1--
(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxo-1H-pyrrolo[3,4-d]-pyri-
midin-5-yl)thio]butanoate (400 mg), was dissolved in 3:1:1
tetrahydrofuran/methanol/1M lithium hydroxide and stirred for 1.5h
before being acidified by dropwise addition of concentrated
hydrochloric acid (HCl). The mixture was then extracted with ethyl
acetate. The organic phase was washed with brine, dried over
magnesium sulphate (MgSO.sub.4) and evaporated to dryness in vacuo.
The resultant yellow oil was chromatographed (silica), elutin with
200:10:1 dichloromethanelmethanol/g- lacial acetic acid. The
resultant red oil was dissolved in toluene and then evaporated,
then similarly with trichloromethane to yield a pink foam. The foam
was recrystallised from ethyl acetate/hexane to yield 129 mg of the
title compound.
[0128] MS (APCl+ve) (M+H).sup.+480 Elemental Analysis (in %):
Theory: C 65.11,H 6.10, N 8.76, S 6.69 Found: C 65.15, H 6.24, N
8.83, S 6.70 .sup.1H NMR (CDCl.sub.3) .delta. 0.88 (6H, d), 1.85
(2H, quin), 2.10 (1H, m), 2,47 (2H, t), 3.02 (2H, t), 3.42 (3H, s),
3.55 (2H, d), 5.84 (2H, s), 6.37 (1H, s), 6.79 (1H, d), 7.38 (1H,
t), 7.56 (2H, m), 7.82 (1H, d), 7.91 (2H, m)
EXAMPLE 6
[0129]
4-[(2,3,4,6-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthaleny-
lmethyl)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)thio]butanoic
acid. sodium salt 13
[0130] The compound of Example 5,
4-[(2,3,4,6-tetrahydro-3-methyl-1-(2-met-
hylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-
-yl)thio]butanoic acid (200 mg), was dissolved in dioxane (5 ml)
and sodium hydroxide solution (2.5 M) (0.163 ml) was added. The
solvent was removed by evaporation and freeze drying to give the
title compound as a 1:1 mixture with sodium carbonate.
[0131] Elemental Analysis for
C.sub.27H.sub.28N.sub.3Na.sub.3O.sub.7S (in %): Theory: C 53.37, H
4.65, N 6.92, S 5.28 Found: C 53.51, H 5.15, N 6.65, S 5.07 Melting
point: >163.degree. C. slow melt MS (APCI) 480 (M+H).sup.+1H NMR
(DMSO) .delta. 0.85 (6H,d), 1.4-1.6 (2H,m), 1.80 (2H,t), 2.0-2.2
(1H,m), 2.88 (2H,t), 3.57 (2H,d), 5.89 (2H,s), 6.57 (1H,d), 7.12
(1H,s), 7.41 (1H,t), 7.5-7.7 (2H,m), 7.86 (1H,d), 7.99 (1H,d), 8.18
(1H,d)
EXAMPLE 7
[0132]
5-[(2-Dimethylaminoethyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-nap-
hthalenyl-methyl)-1H-Pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
14
[0133]
3-Methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo-[3,-
4-d]pyrimidine-2,4(3H,6H)-dione (J. Med. Chem., 1995, 38, 2557)
(473 mg) and bis(2-dimethylaminoethyl)disulphide (0.6ml) were
dissolved in tetrahydrofuran (10 ml) and cooled to -78.degree. C.
Lithium diisopropylamide in tetrahydrofuran (2.5 eq) was added
dropwise and the resultant deep red solution was stirred for 75
minutes at -78.degree. C. The cooling bath was removed and the
solution allowed to stir for a further 60 minutes. Sodium
bicarbonate (aqueous) was added followed by ether and the phases
were separated. The aqueous phase was extracted twice with ether.
The organic phases were combined and washed twice with brine before
being dried, filtered and concentrated. The resultant oil was
purified by column chromatography (eluant,
dichloromethane:methanol:t- riethylamine 450:50:0.2) and then
recrystallised from ether-isohexane to give the title compound (230
mg).
[0134] Melting point: 140-144.degree. C. MS (APCl+ve) 465
(M+H).sup.-.sup.1H NMR (DMSO d6) .delta. 0.87 (6H, d), 2.01 (6H,
s), 2.10-2.16 (1H, m), 2.25 (1H, t), 2.99 (2H, t), 3.25 (3H, s),
3.59 (2H, d), 5.92 (2H, s), 6.54 (1H, d), 7.18 (1H, s), 7.41 (1H,
t), 7.58-7.67 (2H, m), 7.86 (1H, d), 7.99 (1H, d), 8.17 (1H, d)
EXAMPLE 8
[0135]
6-(2,3-Dihydro-1H-inden-2-yl)-5-[(3-hydroxypropyl)sulphinyl]3-methy-
l-1-(1-methylethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
15
[0136] a)
6-(2,3-Dihydro-1H-inden-2-yl)-3-methyl-1-(1-methylethyl)-1H-pyrr-
olo-[3,4-d]pyrimidine-2,4(3H,6H)-dione
[0137] 3,6-Dimethyl-5-formyl-1-(1-methylethyl)pyrimidine-2,4dione
(J. Med. Chem., 1995, 38, 2557; 1.70 g) was dissolved in chloroform
(25 ml) and the solution was heated to 50.degree. C. A solution of
bromine (0.413 ml) in chloroform (20 ml) was added dropwise to the
aldehyde solution over 24 minutes. The reaction was maintained at
50.degree. C. for a further 15 minutes, then allowed to cool to
ambient temperature. The reaction mixture was diluted with
dichloromethane and was washed successively with water, dilute
sodium thiosulphate solution (twice) and brine. The resultant
solution was dried, filtered and evaporated to a crude oil which
was dissolved in ethanol (50 ml). Triethylamine (3.38 ml) was added
to the solution followed by 2-aminoindane (1.49 g) and the mixture
was stirred under nitrogen overnight. The reaction mixture was
filtered, the white solid collected was washed with a little
ethanol and the filtrate was evaporated to give a brown oil. Ethyl
acetate was added to the oil and the resultant precipitate was
collected by filtration and was washed with a little ethyl acetate.
The filtrate was washed with hydrochloric acid (HCl) (2.5 M) and
then brine. The resultant ethyl acetate phase was dried, filtered
and evaporated to an oil. The oil was purified by chromatography,
eluting with isohexane:acetone (4:1) to give a solid which was
triturated with hot ethyl acetate: isohexane (3:1) to give the
subtitle compound (0.50 g).
[0138] Melting point: 158-160.degree. C. MS (APCI+ve) 3.24
(M+H).sup.-
[0139] b)
6-(2,3-Dihydro-1H-inden-2-yl)-5-[(3-hydroxypropyl)thio]-3-methyl-
-1-(1-methylethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
[0140]
6-(2,3-Dihydro-1H-inden-2-yl)-3-methyl-1-(1-methylethyl)-1H-pyrrolo-
-[3,4-d]pyrimidine-2,4(3H,6H)-dione (165 mg) and
S-{3-[1,1-dimethylethyl)d- imethylsilyl]oxypropyl}
toluenethiosulphonate (J. Med. Chem., 1995,38, 2557) (362 mg) were
dissolved in tetrahydrofuran (6 ml) and the resulting solution was
cooled to -78.degree. C. Lithium diisopropylamide in
tetrahydrofuran (3 eq) was added dropwise to the cold solution and
the resulting solution was stirred for 75 minutes at -78.degree. C.
and then the cooling batch was removed. The solution tas stirred
for a further 75 minutes and then sodium bicarbonate (aqueous) was
added. The reaction mixture was extracted thrice with ether. The
organic phases were combined and washed twice with brine before
being dried, filtered and evaporated. The resultant oil was
purified by column chromatography (eluant, isohexane:ethyl acetate
7:2).
[0141] The product was dissolved in acetonitrile (10 ml) and
hydrofluoric acid (40%, 6 drops) was added. The solution was
stirred at ambient temperature for 30 minutes then sodium
bicarbonate (aqueous) was added. Ether-ethyl acetate mixture (ca
1:1) was added to the reaction mixture and the phases were
separated. The aqueous phase was extracted twice with ether-ethyl
acetate mixtures. The organic phases were combined and washed twice
with brine before being dried, filtered and concentrated.
Crystallisation from ether-cyclohexane gave the subtitle compound
(141 mg).
[0142] Melting point: 123-125.degree. C. MS (APCI+ve) 414
(M+H).sup.+
[0143] c)
6-(2,3-Dihydro-1H-inden-2-yl)-5-[(3-hydroxypropyl)sulphinyl]-3-m-
ethyl-1-(1-methylethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
[0144]
6-(2,3-Dihydro-1H-inden-2-yl)-5-[(3-hydroxypropyl)thio]-3-methyl-1--
(1-methylethyl)-1H-pyrrolo[3,4615 -d]pyrimidine-2,4(3H,6H)-dione
(100 mg) was dissolved in methanol (40 ml). Water (10 ml) and
potassium peroxymonosulphate (commercially sold under the trade
mark "OXONE") (185 mg) were added and the solution was stirred for
15 minutes. The reaction mixture was diluted with water and then
extracted with ethyl acetate thrice. The extracts were combined,
washed with brine, then dried, filtered and the solvent was
evaporated. The resultant oil was triturated with isohexane, then
recrystallised from ethyl acetate--isohexane mixtures to give the
title compound (15 mg).
[0145] Melting point: 164-165.degree. C. MS (APCI+ve) 430
(M+H).sup.+1H (DMSO d6) .delta.1.35 (6H, d), 1.73 (2H, quin), 3.19
(3H, s), 3.26-3.56 (8H, m), 4.65 (1H, t), 4.71 (1H, sept),
6.08-6.12 (1H, m), 7.22-7.32 (4H, m), 7.50 (1H, s)
EXAMPLE 9
[0146]
6-(2,3-Dihydro-1H-inden-2yl)-5-[(3-hydroxypropyl)sulphonyl]-3methyl-
-1-(methylethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
16
[0147] The compound of Example 8,
6-(2,3-Dihydro-1H-inden-2-yl)-5-[(3-hydr-
oxypropyl)sulphinyl]-3-methyl-1-(1-methylethyl)-1H-pyrrolo[3,4-d]pyrimidin-
e-2,4(3H,6H)-dione (80 mg.), was dissolved in dichloromethane (5
ml) and 3-chloroperoxybenzoic acid (57-85%) (50 mg) was added. The
reaction mixture was stirred for 75 minutes then water and sodium
metabisulphite (45 mg,) were added and the mixture was stirred for
5 minutes. The phases were separated and the organic phase was
washed with sodium bicarbonate (aqueous), then dried, filtered and
evaporated. The resultant foam was recrystallised from
isohexanie-ethyl acetate-ether to give the title compound (15
mg).
[0148] Melting point: 171-172.degree. C. MS (APCI+ve) 446
(M+H).sup.+1H NMR (DMSO d6) .delta. 1.34 (6H, d), 1.73-1.83 (2H,
m), 3.22 (3H, s), 3.39-3.50 (6H, m), 3.77-3.83 (2H, m), 4.66 (1H,
t), 4.64-472 (1H, m), 6.24 (1H, quin), 7.22-7.32 (4H, m), 7.54
(1H,s)
EXAMPLE 10
[0149]
5-[(3-Hydroxypropyl)sulphinyl]-3-methyl-1-(1-methylethyl)-6-(1-naph-
thalenyl-methyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
17
[0150] The title compound was prepared from
5-[(3-Hydroxypropyl)thio]-3-me-
thyl-1-(1-methylethyl)6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-
-2,4 (3H,6H)-dione (J. Med. Chem., 1995, 38, 2557) in a manner
analogous to the method of Example 8 (c) above.
[0151] Melting point: 184-185.degree. C. MS (APCI+ve) (M+H).sup.+1H
NMR (CDCl.sub.3) .delta. 1.35 (3H, d), 1.37 (3H, d), 1.97-2.07 (2H,
m), 2.60 (1H, t), 3.24-3.51 (2H, m), 3.72-3.86 (2H, m), 4.68-4.70
(1H, m), 6.23 (2H, s), 6.48 (1H, s), 7.00 (1H, d), 7.44 (1H, t),
7.53-7.62 (2H, m), 7.86-7.94 (2H, m), 7.99-8.02 (1H, m)
EXAMPLE 11
[0152]
4-[(2,3,4,6-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthaleny-
lmethyl)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)thio]butanamide
18
[0153] The compound of Example 5,
4-[(2,3,4,6-tetrahydro-3-methyl-1-(2-met-
hylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-
-yl)thio]butanoic acid (100 mg), was dissolved in tetrahydrofuran
(3 ml) and the solution was cooled in ice. Triethylamine (30 .mu.l)
was added followed by ethyl chloroformate (21 .mu.l); the ice bath
was removed and the solution was allowed to stir for 15 minutes and
was then cooled in ice again. Aqueous ammonia (0.88 specific
gravity, 1 ml) was added and the mixture was stirred for 3 days.
The mixture was poured onto water and extracted thrice with
dichioromethane. The organic extracts were combined, washed with
brine, dried, filtered and evaporated to give an oil which was
purified by chromatography, eluting first with ethyl
acetate:isohexane: acetic acid (75:25:1) and then with ethyl
acetate:acetic acid (199:1) to give the title compound (70 mg).
[0154] Melting point: 162-165.degree. C. MS (APCI+ve) 479
(M+H).sup.+1H NMR (CDCl3) .delta. 0.94 (6H, d), 1.86 (2H, quin),
2.12-2.16 (1H, m), 2,45 (2H, t), 2.90 (2H, t), 3.41 (3H, t), 3.56
(2H, d), 5.30 (1H, br), 5.86 (2H, s), 6.08 (1H, br), 6.39 (1H, s),
6.81 (1H, d), 7.40 (1H, dd), 7.58 (2H, m), 7.84 (1H, d), 7.91 (2H,
m)
EXAMPLE 12
[0155]
5-(2,3,4,6-Tetrahydro-3methyl-1-(2-methylpropyl)-6-(1-naphthalenylm-
ethyl)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)pent-3-enoic acid
19
[0156] a)
5-Iodo-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-p-
yrrolo-[3,4-d]pyrimidine-2,4(3H,6H)-dione
[0157]
3-Methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo
-[3,4-d]pyrimidine-2,4(3H,6H)-dione ((J. Med. Chem., 1995, 38,
2557; 500 mg) was dissolved in tetrahydrofuran (15 ml) and cooled
to -78.degree. C. A solution of lithium diisopropylamide (2 eq) in
tetrahydrofuran (5 ml) was added dropwise with stirring at
-78.degree. C. Iodine (350 mg) was added and the reaction mixture
was allowed to stir at -78.degree. C. for 1 hour and was then
allowed to warm to room temperature. The mixture was then poured
into saturated ammonium chloride solution and extracted twice with
ethyl acetate. The combined organic phases were washed with sodium
thiosuiphate solution, and with brine, before being dried and
evaporated. The resultant foam was chromatographed using
isohexane:diethyl ether (1:3) to give a foam which was
recrystallised from diethyl ether/isohexane to give the subtitle
compound as a pale yellow solid (350 mg).
[0158] Melting point: 140-142.degree. C. MS (APCI+ve) 488
(M+H).sup.-1H NMR (CDCl.sub.3) .delta. 0.85 (d, 6H), 2.09 (m, 1H),
3.41 (s, 3H), 3.53 (d, 2H), 5.65 (s, 2H), 6.51 (s, 1H), 6.35
(d,1H), 7.42 (dd, 1H), 7.58 (m, 2H), 7.84-7.95 (m, 3H)
[0159] b)
Trans-5-(2,3,4,6-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-nap-
hthalenylmethyl)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5yl)pent-3-enoic
acid
[0160]
5-Iodo-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenytmethyl)-1H-pyrr-
olo[3,4-d]pyrimidine-2,4(3H,6H)-dione (100 mg), 4-pentenoic acid
(0.042 ml), palladium acetate (5 mg) and tri(o-tolyl)phosphine (13
mg) were dissolved in triethylamine (1 ml) and acetonitrile (5 ml)
and heated to 95.degree. C. in a sealed pressure tube for 3 hours.
The reaction mixture was allowed to cool to room temperature and
was then evaporated to leave a residue which was chromatographed
using ethyl acetate containing 1% acetic acid to give an oil (160
mg). Recrystallisation from diethyl ether/isohexane gave the title
compound as a pale brown solid (48 mg).
[0161] Meltingl point: 176-180.degree. C. MS (APCI+ve) 460
(M+H).sup.- (APCI-ve) 458 (M-H).sup.-1H NMR (CDCl.sub.3) .delta.
0.89 (d, 6H), 2.14 (m,1H), 2.98 (d, 2H), 3,40 (s, 3H), 3.56 (d.
2H), 3.82 (d, 2H), 5.50 (dt, [J=15 Hz, 6 Hz]1H), 5.57 (s, 2H), 5.65
(dt, [J=15 Hz, 7 Hz] 1H), 6.17 (s,1H), 6.69 (d, 1H), 7.39 (m, 1H),
7.55 (m, 2H), 7.80-7.93 (m, 3H)
EXAMPLE 13
[0162]
5-(5-Hydroxypent-1-ynyl)-3-methyl-1-(2-methylpropyl)-6-(1-naphthale-
nylmethyl)1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione 20
[0163]
5-Iodo-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrr-
olo-[3,4-d]pyrimidine-2,4(3H,6H)-dione (100 mg), 4-pentyn-1-ol
(0.080 ml), bis-triphenylphosphinepalladium (II) chloride (3 mg)
and copper (I) iodide (1 mg) were dissolved in triethylamine (3 ml)
and acetonitrile (1 ml) and heated to 90.degree. C. in a sealed
pressure tube for 3 hours. The reaction mixture was allowed to cool
to room temperature and was then evaporated to leave a residue
which was recrystallised from ethyl acetate. The resultant brown
solid was chromatographed, eluting with ethyl acetate to oive a
white solid which was triturated with ethyl acetate to give the
title compound (45 mg).
[0164] Melting point: 176-177.degree. C. MS (APCI+ve) 444
(M+H).sup.+1H NMR (CDCl3) .delta. 0.84 (d, 6H), 1.82 (m, 2H), 2.08
(m, 1H), 2.36 (t,1H), 2.65 (t, 2H), 3,40 (s, 3H), 3.50 (d, 2H),
3.77 (q, 2H), 5.67 (s, 2H), 6.10 (s, 1H), 7.08 (d,1H), 7.47 (dd,
1H), 7.55 (m, 2H), 7.86-7.94 (m, 3H)
EXAMPLE 14
[0165]
5-(5-Hydroxypentyl)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylme-
thyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione 21
[0166] The compound ofExampie 13, 5-(5-hydroxypent-4
-ynyl)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,-
4-d]pyrimidine-2,4(3H, 6H)-dione (75 mg) was suspended in ethanol
(50 ml). A suspension of 10% palladium on carbon (7 mg) in ethanol
(3 ml) was added and the mixture was hydrogenated. When hydrogen
uptake ceased, the reaction mixture was filtered and the solvent
was removed by rotary evaporation. The crude product was purified
by chromatography on silica eluting with ethyl acetate: isohexane
(3:1) to give the title compound (29 mg) as an oil.
[0167] MS (APCI+ve) 448 (M+H).sup.-; (APCI-ve) 446 (M-H).sup.-1H
NMR (CDCl.sub.3) .delta. 0.90 (6H, d), 1.3-1.65 (6H, m), 2.17 (1H,
m), 3.01 (2H, t), 3,41 (3H, s), 3.55-3.58 (4H, m), 3.64 (1H, t),
5.57 (2H, s), 6.70 (1H, d), 7.39 (1H, t), 7.56-7.60 (2H, m),
7.85-7.95 (3H, m)
EXAMPLE 15
[0168]
5-(4-Hydroxybut-1-ynyl)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalen-
ylmethyl))-1H-pyrrol[3,4-d]pyrimidine-2,4(3H,6H)dione 22
[0169] The title compound was prepared from
5-iodo-3-methyl-1-(2-methylpro-
pyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
and 3-butyn-1-ol in a manner analogous to the method of Example 13
above.
[0170] Melting point: 170-171.degree. C. MS (APCI+ve) 430
(M+H).sup.+1H NMR (CDCl.sub.3) .delta. 0.84 (d, 6H), 2.09 (m, 1H),
2.74 (t, 2H), 3.40 (s, 3H), 3.50 (d, 2H), 3.88 (m, 3H), 5.68 (s,
2H), 6.08 (s,1H), 7.10 (d,1H), 7.46 (t, 1H), 7.55 (m, 2H),
7.87-7.94 (m, 3H)
EXAMPLE 16
[0171]
5-(4-Hydroxybutyl)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmet-
hyl)-1H-pyrrolo[3,4-d]primidine-2,4(3H,6H)-dione 23
[0172] The title compound was prepared from the compound of Example
15,
5-(4hydroxybut-1-ynyl)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethy-
l)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione, in a manner
analogous to the method of Example 14 above.
[0173] MS (APCI+ve) 434 (M+H).sup.+; (APCI-ve) 432 (M-H.sup.-1H ,
NMR (CDCl3) .delta. 0.88 (6H, d), 1.56-1.72 (4H, m), 2.18 (1H, m),
2.3 (1H, br), 3.01 (2H, t), 3,41 (3H, s), 3.57 (2H, d), 3.65-3.70
(2H, m), 5.58 (2H, s), 6.69 (1H, d), 7.41 (1H, t), 7.56-7.62 (2H,
m), 7.84 (1H, d), 7.88-7.95 (2H, m)
EXAMPLE 17
[0174]
5-(2,3,4,6-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenyl-
methyl)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin5-yl)pentanoic acid
24
[0175]
5-(2,3,4,6-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenyl-
methyl)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)pent-4-ynoic
acid
[0176] The sub-title compound was prepared from
5-iodo-3-methyl-1-(2-methy-
lpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-d-
ione, and 4-pentynoic acid in the presence of
bistrimethylsilyltrifluoroac- etamide in a manner analogous to the
method of Example 13 above.
[0177] MS (APCI+ve) 458 (M+H).sup.+, (APCI-ve) 456 (M-H).sup.-1H
NMR (CDCl.sub.3) .delta. 0.85 (d, 6H), 2.07 (m,1H), 2.61 (m, 2H),
2.80 (t, 2H), 3.39 (s, 3H), 3,48 (d, 2H), 5.65 (s, 2H), 6.09
(s,1H1), 7.11 (d,1H), 7.44 (dd,1H), 7.53 (m, 2H), 7.88-7.94 (m,
3H)
[0178] b)
5-(2,3,4,6-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthale-
nylmethyl)-2,4,-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)pentanoic
acid
[0179] The title compound was prepared from
5-(2,3,4,6-tetrahydro-3-methyl-
-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxo-1H-pyrrolo[3,4-d]py-
rimidin-5-yl)-pent-4-ynoic acid in a manner analogous to the method
of Example 14 above.
[0180] Melting point: 146-147.degree. C. MS (APCI+ve) 462 (M+H),
(APCI-ve) 460 (M-H) .sup.1H NMR (CDCl.sub.3) .delta. 0.90 (d,
6H),1.66 (m, 4H), 2.16 (m, 1H), 2.34 (t, 2H), 3.02 (t, 2H), 3.40
(s. 3H), 3.56 (d, 2H), 5.56 (s, 2H), 6.15 (s,1H), 6.69.(d,1H), 7.38
(t, 1H), 753-7.62 (m, 2H), 7.82-7.94 (m, 3H)
EXAMPLE 18
[0181]
4-[(2,3,4,6-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthaleny-
lmethyl)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)thio]butanenitrile
25
[0182] a)
5-[(3-{Methanesulphonyloxy}propyl)thio]-3-methyl-1-(2-methylprop-
yl)-6-(1-nahthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
[0183]
5-[(3-Hydroxypropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthal-
enylmethyl)-1H-pyrrolo[3,4-d]pyrimdine-2,4(3H,6H)-dione (J. Med.
Chem., 1995, 38, 2557) (260 mg), methanesulphonyl chloride (54
.mu.l) and triethylamine (97 .mu.l) were dissolved in
dichloromethane (15 ml) and the mixture was stirred overnight. The
reaction mixture was poured onto sodium bicarbonate (aqueous) and
extracted twice with ethyl acetate. The extracts were combined,
dried, filtered and evaporated to give the subtitle compound as a
gum (391 mg).
[0184] MS (+ve APCI) (M+H).sup.+ 530
[0185] b)
4-[(2,3,4,6-Tetrahydro-3-methyl-1-(2methylpropyl)-6-(1-naphthale-
nylmethyl)2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)thio]butanenitrile
[0186]
5-[(3-{Methanesulphonyloxy}propyl)thio]-3-methyl-1-(2-methylpropyl)-
6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,
6H)-dione (391 mg) was dissolved in dimethyfomamide (15 ml) and
sodium cyanide (254 mg) was added. The mixture was sonicated for 4
hours and then poured onto sodium bicarbonate (aqueous). The
mixture was extracted thrice with ethyl acetate, the extracts were
combined, washed twice with water and once with brine, then dried,
filtered and evaporated. The resultant oil was chromatographed,
eluting with ethyl acetate:isohexane (4:5) and then triturated with
cyclohexane-ethyl acetate to give the title compound (95 mg).
[0187] Melting point: 127-128.degree. C. MS (+ve APCI) (M+H).sup.-
461 .sup.1H NMR (CDCl.sub.3) .delta. 0.89 (6H, d), 1.86 (2H, quin),
2.07-2.19 (1H, m), 2,48 (2H, t), 3.02 (2H, t), 3,42 (3H, s), 3.57
(2H, d), 5.85 (2H, s), 6.42 (1H, s), 6.77 (1H, d), 7.37 (1H, t),
7.56-7.63 (2H, m), 7.85 (1H, d), 7.91-7.95 (2H, m)
EXAMPLE 19
[0188]
5-[(3-{1H-Tetrazol-5-yl}propyl)thio]-3-methyl-1-(2-methylpropyl)-6--
(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)dione
26
[0189] The compound of Example 18,
4-[(2,3,4,6-tetrahydro-3-methyl-1-(2-me-
thylpropyl)-6-(1-naphthalenylmethyl)-2,4dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-
-yl)thio]butanenitrile (98 mg) was dissolved in toluene (20 ml) and
trimethyltin azide (100 mg) was added. The solution was heated
under reflux for 110 hours, then the solvent was evaporated and the
residue was chromatographed, eluting with ethanol:dichloromethane
(1:19), to give the title compound (30 mg).
[0190] MS (+ve APCI) (M+H).sup.+ 504 .sup.1H NMR (DMSO d-6) .delta.
0.86 (6H, d), 1.79 (2H, quin), 2.05-2.16 (1H, m), 2.87 (2H, t),
2.91 (2H, t), 3.23 (3H, s), 3.59 (2H, d), 5.90 (2H, s), 6.54 (1H,
d), 7.19 (1H, s), 7.38 (1H, t), 7.57-7.66 (2H, m), 7.85 (1H, d),
7.99 (1H, d), 8.17 (1H, d)
EXAMPLE 20
[0191]
3-Methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)methyl)-5-[(2-p-
yridinyl)thio]-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione 27
[0192] Prepared from
3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)--
1H-pyrrolo-[3,4-d]pyrimidine-2,4(3H,6H)-dione (J. Med. Chem., 1995,
38, 2557) and 2,2'-pyridyl disulphide following the method of
Example 7.
[0193] Melting point: 146-148.degree. C. MS (FAB) ((M+H).sup.+) 471
.sup.1H NMR (CDCl.sub.3) .delta. 0.85 (6H, d), 2.08 (1H, m), 3.38
(3H, s), 3.52 (2H, d), 5.78 (2H, s), 6.39 (1H, s), 7.03 (1H, m),
7.10 (2H, m), 7.44 (4H, m), 7.86 (3H, m), 8.38 (1H, d)
EXAMPLE 21
[0194]
3-Methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(2-pyridiny-
l)sulphinyl]-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione 28
[0195] Prepared from the compound of Example 20,
3-methyl-1-(2-methylpropy-
l)-6-(1-naphthalenylmethyl)-5-[(2-pyridinyl)thio]-1H-pyrrolo[3,4-d]pyrimid-
ine-2,4(3H,6H)-dione and potassium peroxymonosulphate (commercially
sold under the trade mark "OXONE") following the method of Example
8 c).
[0196] MS (FAB) ((M+H).sup.+) 487 .sup.1H NMR (CDCl.sub.3) .delta.
0.81 (6H, d), 2.04 (1H, m), 3,43 (3H, s), 3,49 (2H, m), 5.83 (1H,
d), 5.94 (1H, d), 6.24 (1H, s), 6.64 (1H, d), 7.07 (1H, m), 7.20
(1H, t), 7.47 (3H, m), 7.70 (2H, m), 7.84 (1H, d), 7.92 (1H, d),
8.48 (1H, d)
EXAMPLE 22
[0197]
3-Methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(4-pyridiny-
l)thio]-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione 29
[0198] Prepared from
3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)--
1H-pyrrolo-[3,4-d]pyrimidine-2,4(3H,6H)-dione (J. Med. Chem., 1995,
38, 2557) and 4,4'-pyridyl disulphide following the method of
Example 7.
[0199] Melting point: 154-156.degree. C. MS (FAB) 471 ((M+H).sup.+)
.sup.1H NMR (CDCl.sub.3) .delta. 0.87(6H, d), 2.11 (1H, m), 3.38
(3H, s), 3.56 (2H, d), 5.70 (2H, s), 6.51 (1H, s), 6.88 (2H, m),
6.92 (1H, d), 7.35 (1H, t), 7.48 (2H, m), 7.75 (1H, d), 7.81 (1H,
d), 7.87 (1H, d), 8.34 (2H, d)
EXAMPLE 23
[0200]
5-([3-Methoxyphenyl]thio)-3-methyl-1-(2-methylpropyl)-6-(1-naphthal-
enylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione 30
[0201] a) 3-Methoxyphenyldisulphide
[0202] 4Toluenesulphonylchloride (8 g) was added portionwise to a
solution of 3-methoxythiophenol (5 ml) and triethylamine (5.6 ml)
in dichloromethane (50 ml) at 0.degree. C. After 3.5 hours the
reaction mixture was diluted with dichloromethane and washed once
with water, twice with dilute hydrochloric acid, twice with
saturated sodium hydrogen carbonate solution and once with brine.
The organic layer was dried over magnesium sulphate, filtered and
evaporated in vacuo. Purification of the residue by chromatography
on silica gel, eluting with isohexane/ethyl acetate (19:1), gave
the subtitle compound as an oil (2.65 g).
[0203] MS (EI) (M.sup.+) 278 .sup.1H NMR (CDCl.sub.3) .delta. 3.77
(6H, s), 6.75 (2H, dd), 7.06 (2H, s), 7.07 (2H, d), 7.21 (2H,
t)
[0204] b)
5-([3-Methoxyphenyl]thio)-3-methyl-1-(2-methylpropyl)-6-(1-napht-
halenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
[0205] To a stirred solution of
3-methyl-1-(2-methylpropyl)-6-(1-naphthale-
nylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (0.50 g)
(J. Med. Chem., 1995, 38, 2557) and 3-methoxyphenyldisulphide(0.77
g) in anhydrous tetrahydrofuran (20 ml) at -70.degree. C. was added
dropwise a solution of lithium diisopropylamide (2.79 mmol) in
tetrahydrofuran (7 ml). The solution was stirred for a further 2
hours at -70.degree. C. and then allowed to warm to ambient
temperature. Water (10 ml) was added and the solution was extracted
with ethyl acetate. The organic phase was separated and washed once
with water, twice with dilute hydrochloric acid, twice with
saturated sodium hydrogen carbonate solution and once with brine.
The organic layer was dried over magnesium sulphate and evaporated
in vacuo. Purification by chromatography on silica gel, eluting
with isohexane/ethyl acetate (4:1 to 2:1) followed by
recrystallisation from isohexane/ethyl acetate (4:1), gave the
title compound (430 mg).
[0206] Melting point: 130-133.degree. C. MS (APCI) 500
((M+H).sup.+) .sup.1H NMR (DMSO) .delta. 0.86 (6H, d), 2.1-2.2 (1H,
m), 3.22 (3H, s), 3.60 (3H, s), 3.62 (2H, d), 5.36 (2H, s),
6.55-6.65 (3H, m), 6.73 (1H, dd), 7.16 (1H, t), 7.33 (2H, t),
7.50-7.60 (2H, m), 7.83 (1H, d), 7.96 (1H, dd), 8.05 (1H, dd)
EXAMPLE 24
[0207]
5-([3-Hydroxyphenyl]thio)-3-methyl-1-(2-methylpropyl-)6-(1-naphthal-
enylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione 31
[0208] A solution of boron tribromide in dichloromethane (1M, 3 ml)
was added to a solution of
5-([3-methoxyphenyl]thio)-3-methyl-1-(2-methylprop-
yl)-6-(1-naphthalenyl-methyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
(200 mg) (compound of Example 23) in dichloromethane (20 ml) at
ambient temperature. After 6 hours, water (10 ml) was added
carefully and the reaction mixture was partitioned between
dichloromethane and brine. The organic phase was dried over
magnesium sulphate, filtered and evaporated in vacuo. Purification
by chromatography on silica gel, eluting with isohexane/ethyl
acetate (2:1 to 1:1) followed by recrystallisation from
isohexane/ethyl acetate (3:1), gave the title compound (120
mg).
[0209] Melting point: 150-151.degree. C. MS (APCI) 486
((M+H).sup.30 ) .sup.1H NMR (DMSO) .delta. 0.86 (6H, d), 2.1-2.2
(1H, m), 3.23 (3H, s), 3.61 (2H, d), 5.83 (2H, s), 6.45 (1H, t),
6.53 (2H, dt), 6.63 (1H, d), 7.03 (1H. t), 7.30 (1H, s), 7.36 (1H,
t), 7.50-7.60 (2H, m), 7.85 (1H, d), 7.96 (1H, dd), 8.05 (1H, dd),
9.51 (1H, brs)
EXAMPLE 25
[0210]
5-([4-Methoxylhenyl]thio)-3-methyl-1-(2-methylpropyl)-6-(1-naphthal-
enylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione 32
[0211] Prepared from
3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)--
1H-pyrrolo[3,4-d]pyrimdine-2,4(3H,6H)-dione (0.50 g) (J. Med.
Chem., 1995, 38, 2557) and 4methoxyphenyldisulphide following, the
method of Example 23.
[0212] Melting point: 60-63.degree. C. (foam) MS (APCI) 500
((M+H).sup.+) .sup.1H NMR (DMSO) .delta. 0.81(6H, d), 2.1-2.2 (1H,
m), 3.24 (3H, s), 3.58 (2H, d), 3.68 (3H, s), 5.91 (2H, s), 6.50
(1H, d), 6.80 (2H, d), 7.20 (3H, d), 7.31 (1H, t), 7.55-7.60 (2H,
m), 7.83 (1H, d), 7.98 (1H, dd), 3.08 (1H, dd)
EXAMPLE 26
[0213]
5-([4-Hydroxyphenyl]thio)-3-methyI-1-(2-methylpropyl)-6-(1-naphthal-
enylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione 33
[0214] Prepared from the compound of Example 25 following the
method of Example 24.
[0215] Melting point: 228-230.degree. C. MS (APCI) 486
((M+H).sup.+) .sup.1H NMR (DMSO) .delta. 0.83 (6H, d), 2.1-2.2 (1H,
m), 3.24 (3H, s), 3.56 (2H, d), 5.91 (2H, s), 6.52 (1H, d), 6.63
(2H, d), 7.14-7.16 (3H, m), 7.35 (1H, t), 7.55-7.60 (2H, m), 7.84
(1H, d), 7.97 (1H, dd), 8.06 (1H, dd), 9.59 (1H, s)
EXAMPLE 27
[0216]
5-([2-Methoxyphenyl]thio)-3-methyl-1-(2-methylpropyl)-6-(1-naphthal-
enylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione 34
[0217] Prepared following the method of Example 23 using
3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyr-
imidine-2,4(3H,6H)-dione (0.50 g) (J. Med. Chem., 1995, 38, 2557)
and 2-methoxyphenyldisulphide.
[0218] Melting point: 153.degree. C. MS (APCI) 500 ((M+H).sup.+)
.sup.1H NMR (DMSO) .delta. 0.87 (6H, d), 2.1-2.2 (1H, m), 3.21 (3H,
s), 3.61 (2H, d), 3.69 (3H, s), 5.85 (2H, s), 6.59 (1H, d), 6.69
(1H, dd), 6.81(1H, dt), 6.91 (1H, dd), 7.12(1H, dt), 7.34 (2H, t),
7.55-7.60 (2H, m), 7.82 (1H, d), 7.96 (1H, dd), 8.05 (1H, dd)
EXAMPLE 28
[0219]
5-([2-Hydroxyphenyl]thio)-3-methyl-1-(2-methylpropyl)-6-(1-naphthal-
enylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione 35
[0220] Prepared from the compound of Example 27 following the
method of Example 24.
[0221] Melting point: 190-192.degree. C. MS (APCL) 486
((M+H).sup.+) .sup.1H NMR (DMSO) .delta. 0.85 (6H, d), 2.1-2.2 (1H,
m), 3.22 (3H, s), 3.59 (2H, d), 5.88 (2H, s), 6.63 (1H, d), 6.69
(1H, dd), 6.79 (2H, dt), 7.00 (1H, dt), 7.26 (1H, s), 7.37 (1H, t),
7.55-7.60 (2H, m), 7.85 (1H, d), 7.96 (1H, dd), 8.05 (1H, dd),
10.02 (1H, s)
EXAMPLE 29
[0222] Inhibition of Human Mixed Lymphocyte Reaction (MLR)
[0223] The MLR test was performed in 96well flat bottomed
microtiter plates. Compounds were prepared as 10 mM stock solution
in dimethyl sulphoxide. A 50 fold dilution of this was prepared in
a cell culture solution obtained from the Roswell Park Memorial
Institute (RPMI 1640 medium). Serial dilutions were prepared from
this solution. 10 .mu.l of the 50 fold diluted stock, or dilutions
of it, were added to the wells to give concentrations in the assay
starting at 9.5 .mu.m and decreasing. Into each well was placed
1.5.times.10.sup.5 cells from each of two responding donors in a
final volume of 0.2 ml RPMI 1640 medium supplemented with 10% human
serum, 2 mM L-glutamine and penicillin/streptomycin. The cells were
incubated at 37.degree. C. in a humidified atmosphere at 5% carbon
dioxide for 120 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, which is a measure
of T-ceIl proliferation.
[0224] The tide compounds of Examples 1 to 28 were found to exhibit
an IA.sub.50 value of less than 1.times.10.sup.-6 M in the above
test.
* * * * *