U.S. patent application number 12/063432 was filed with the patent office on 2010-07-15 for xanthine derivatives as selective hm74a agonists.
Invention is credited to Richard Jonathan Daniel Hatley, Jag Paul Heer, John Liddle, Andrew McMurtrie Mason, Ivan Leo Pinto, Shahzad Sharooq Rahman, Ian Edward David Smith.
Application Number | 20100179128 12/063432 |
Document ID | / |
Family ID | 37189397 |
Filed Date | 2010-07-15 |
United States Patent
Application |
20100179128 |
Kind Code |
A1 |
Hatley; Richard Jonathan Daniel ;
et al. |
July 15, 2010 |
XANTHINE DERIVATIVES AS SELECTIVE HM74A AGONISTS
Abstract
The present invention relates to compounds of formula (I) which
are xanthine derivatives, processes for the manufacture of said
derivatives, pharmaceutical formulations containing these active
compounds and the use of the compounds in therapy, for example, in
the treatment of diseases where under-activation of the HM74A
receptor contributes to the disease or where activation of the
receptor will be beneficial ##STR00001##
Inventors: |
Hatley; Richard Jonathan
Daniel; (Hertfordshire, GB) ; Heer; Jag Paul;
(Essex, GB) ; Liddle; John; (Hertfordshire,
GB) ; Mason; Andrew McMurtrie; (Hertfordshire,
GB) ; Pinto; Ivan Leo; (Essex, GB) ; Rahman;
Shahzad Sharooq; (Essex, GB) ; Smith; Ian Edward
David; (Hertfordshire, GB) |
Correspondence
Address: |
GlaxoSmithKline;GLOBAL PATENTS -US, UW2220
P. O. BOX 1539
KING OF PRUSSIA
PA
19406-0939
US
|
Family ID: |
37189397 |
Appl. No.: |
12/063432 |
Filed: |
August 8, 2006 |
PCT Filed: |
August 8, 2006 |
PCT NO: |
PCT/EP06/07869 |
371 Date: |
February 9, 2008 |
Current U.S.
Class: |
514/214.02 ;
514/234.2; 514/248; 514/263.2; 514/263.21; 514/263.22; 514/263.23;
514/263.24; 514/263.36; 540/578; 544/118; 544/234; 544/267;
544/268; 544/269; 544/270 |
Current CPC
Class: |
A61P 9/08 20180101; A61P
3/04 20180101; A61P 7/02 20180101; A61P 1/14 20180101; A61P 3/00
20180101; A61P 9/00 20180101; A61P 29/00 20180101; A61P 9/04
20180101; C07D 473/04 20130101; C07D 473/06 20130101; A61P 5/50
20180101; A61P 3/10 20180101; A61P 3/06 20180101; A61P 13/12
20180101; A61P 9/10 20180101 |
Class at
Publication: |
514/214.02 ;
544/267; 514/263.36; 544/269; 514/263.23; 514/263.22; 544/270;
514/263.2; 514/263.24; 544/268; 514/263.21; 540/578; 514/248;
544/234; 544/118; 514/234.2 |
International
Class: |
A61K 31/55 20060101
A61K031/55; C07D 473/04 20060101 C07D473/04; A61K 31/522 20060101
A61K031/522; C07D 519/00 20060101 C07D519/00; A61K 31/5377 20060101
A61K031/5377; A61P 3/06 20060101 A61P003/06; A61P 3/10 20060101
A61P003/10; A61P 3/04 20060101 A61P003/04; A61P 9/04 20060101
A61P009/04; A61P 9/10 20060101 A61P009/10; A61P 7/02 20060101
A61P007/02; A61P 13/12 20060101 A61P013/12 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 10, 2005 |
GB |
0516464.5 |
Apr 19, 2006 |
GB |
0607736.6 |
Jul 21, 2006 |
GB |
0614569.2 |
Claims
1-19. (canceled)
20. A compound of formula (I): ##STR01033## and pharmaceutically
acceptable derivatives thereof, wherein: R.sup.1 represents
-(alkylene).sub.m-X-(alkylene).sub.n-Y; wherein X represents A, A1,
A2 or a direct link; wherein: A represents a group selected from
cycloalkylene, cycloalkenylene, aryl, heteroaryl, heterocyclyl, and
--CH.sub.2--OC(O)--; A1 represents a group selected from
--CH.sub.2--O--(CH.sub.2).sub.qaryl-O--,
--CH.sub.2--O--(CH.sub.2).sub.wN(R.sup.5)C(O)O--,
--CH.sub.2--N(R.sup.5)C(O)O--, --CH.sub.2--N(R.sup.5)C(O)--,
--CH.sub.2--(O).sub.p--(CH.sub.2).sub.qC(O)NR.sup.5--,
--CH.sub.2--N(R.sup.5)C(O)N(R.sup.5)--,
--CH.sub.2--C(O)N((CH.sub.2).sub.wOH)--,
--CH.sub.2--NR.sup.5--S(O).sub.2--, CH.sub.2--S(O).sub.2NR.sup.5--,
--CH.sub.2--C(O)O--, --O--, --NR.sup.5--, and --S--; and A2
represents --CH(OH)--; R.sup.2 is selected from hydrogen,
C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl,
cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl, each
of which may be optionally substituted by one or more of a group
independently selected from: C.sub.1-10 alkyl, C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,
C.sub.1-6 haloalkyl, halogen, --CN, --OR.sup.4,
--(CH.sub.2).sub.nCOR.sup.4, --C(O)OR.sup.4, --OCOR.sup.4,
--(CH.sub.2).sub.nNR.sup.5R.sup.6, --(NH).sub.pCONR.sup.5R.sup.6,
--OCONR.sup.5R.sup.7, and --NR.sup.5C(O)OR.sup.7; R.sup.3
represents a group selected from halogen and CN; wherein: R.sup.4
is selected from hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, --(CH.sub.2).sub.n cycloalkyl,
--(CH.sub.2).sub.n cycloalkenyl, --(CH.sub.2).sub.n heterocyclyl,
--(CH.sub.2).sub.n aryl, and --(CH.sub.2).sub.n heteroaryl; R.sup.5
and R.sup.6 are independently selected from hydrogen and C.sub.1-4
alkyl; R.sup.7 represents a group selected from H, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, --(CH.sub.2).sub.t
cycloalkyl, --(CH.sub.2).sub.ncycloalkenyl, --(CH.sub.2).sub.t
heterocyclyl, --(CH.sub.2).sub.t aryl, and --(CH.sub.2).sub.t
heteroaryl; R.sup.8 represents a group selected from C.sub.1-4
alkyl; R.sup.9 represents a group selected from C.sub.1-6 alkyl
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, --(CH.sub.2).sub.n
cycloalkyl, --(CH.sub.2).sub.ncycloalkenyl,
--(CH.sub.2).sub.nheterocyclyl, --(CH.sub.2).sub.naryl,
--(CH.sub.2).sub.nheteroaryl, and CN; m represents an integer
selected from 1, 2, 3, 4 and 5; n represents an integer selected
from 0, 1, 2, 3, 4 and 5; p represents an integer selected from 0
and 1; q represents an integer selected from 0, 1 and 2; t
represents an integer selected from 1 and 2; w represents an
integer selected from 2, 3 and 4; and provided that: when X is A,
A1 or A2, Y is a group selected from heteroaryl, heterocyclyl,
aryl, cycloalkyl, cycloalkenyl, --NH-aryl,
--O(CH.sub.2).sub.n-aryl, --O-heteroaryl, --OR.sup.5,
--C(O)OR.sup.5, --C(O)O--C.sub.6 aryl, --OC(O)R.sup.4,
--CH(aryl).sub.2, --CH(heteroaryl).sub.2, and --C.sub.1-6
haloalkyl; when X is A1 and Y is selected from
--O(CH.sub.2).sub.n-aryl, --O-heteroaryl, --OR.sup.5,
--OC(O)R.sup.4, or --NH-aryl, and n is an integer selected from 2,
3, 4 and 5; when X is A1 and Y is --C.sub.1-6 haloalkyl; when X is
A2, n is an integer selected from 1, 2, 3, 4 and 5; when X is a
direct link, (m+n) is an integer selected from 2 to 10; when X is a
direct link and (m+n) is an integer selected from 3 to 10, Y
represents a group selected from --C(O)(CH.sub.2).sub.qOR.sup.4,
--C(O)-aryl, --C(O)-heteroaryl, --C(O)-heterocyclyl, heteroaryl,
heterocyclyl, Aryl, 3 or 4 ring fused system, --CH(aryl).sub.2,
--CH(heteroaryl).sub.2, --OR.sup.5, --NR.sup.5R.sup.6,
--NR.sup.5C(O)OR.sup.7, --(O).sub.pC(O)NR.sup.5R.sup.7, and
--NR.sup.5C(O)R.sup.7; when X is a direct link and (m+n) is 2, Y
represents a group selected from --OR.sup.5, --NH.sub.2, and
--NR.sup.5C(O)OR.sup.8; when Y incorporates a ring, that ring may
be optionally substituted by one or more of C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen,
--(CH.sub.2).sub.qNR.sup.5R.sup.7,
--(CH.sub.2).sub.q--(O).sub.p--(CH.sub.2).sub.q--N(R.sup.5)C(O)OR.sup.8,
--(CH.sub.2).sub.q--N(R.sup.5)C(O)R.sup.8,
--(CH.sub.2).sub.q--(O).sub.p--(CH.sub.2).sub.q--C(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.q--N(R.sup.5)C(O)N(R.sup.5)R.sup.6,
--(CH.sub.2).sub.q--C(O)N((CH.sub.2).sub.mOH)R.sup.5,
--(CH.sub.2).sub.q--N(R.sup.5)--S(O).sub.2R.sup.8,
--CH.sub.2--S(O).sub.2N(R.sup.5)R.sup.6, --C.sub.1-6 haloalkyl,
--OCF.sub.3, --OCH(F).sub.2, --OCH.sub.2F, --C(O)OR.sup.5,
--OR.sup.5, --R.sup.8CN, --CN, --SO.sub.2R.sup.9,
--(CH.sub.2).sub.nheteroaryl, --(CH.sub.2).sub.nheterocycyl,
--(CH.sub.2).sub.ncycloalkyl, --(CH.sub.2).sub.ncycloalkenyl, and
--(CH.sub.2).sub.naryl; and when X is A1, A1 is --O-- and Y is a
ring which is substituted by aryl or heteroaryl, then m is an
integer selected from 3, 4 and 5.
21. A compound according to claim 20, wherein X is selected from A
and A1.
22. A compound according to claim 20, wherein R.sup.2 is selected
from C.sub.3-6 alkyl.
23. A compound according to claim 20, wherein X is selected from A
and A1; wherein: A represents a group selected from heteroaryl and
heterocyclyl, and A1 represents a group selected from
CH.sub.2--O--(CH.sub.2).sub.wN(R.sup.5)C(O)O--,
CH.sub.2--N(R.sup.5)C(O)O--, CH.sub.2--N(R.sup.5)C(O)--,
CH.sub.2--(O).sub.p--(CH.sub.2).sub.gC(O)NR.sup.5--,
CH.sub.2--N(R.sup.5)C(O)N(R.sup.5)--,
CH.sub.2--C(O)N((CH.sub.2).sub.mOH)--,
CH.sub.2--NR.sup.5--S(O).sub.2--, CH.sub.2--S(O).sub.2NR.sup.5--,
and CH.sub.2--C(O)O--.
24. A compound according to claim 23, wherein X represents A and A
is heteroaryl.
25. A compound according to claim 24, wherein A is a heteroaryl
comprising a nitrogen heteroatom.
26. A compound according to claim 20, wherein Y is selected from
aryl, heteroaryl and O-aryl.
27. A compound according to claim 20, wherein R.sup.3 is
halogen.
28. A compound according to claim 20, wherein R.sup.3 is
chlorine.
29. A method for treatment of disorders of lipid metabolism, which
comprises administering a compound of formula (I) of claim 20.
30. A method according to claim 29, wherein disorders of lipid
metabolism are selected from diabetic dyslipidaemia, mixed
dyslipidaemia, heart failure, hypercholesteraemia, cardiovascular
disease, atherosclerosis, arteriosclerosis, hypertriglyceridaemia,
type II diabetes mellitus, type I diabetes, insulin resistance,
hyperlipidaemia, anorexia nervosa, obesity, coronary artery
disease, thrombosis, angina, chronic renal failure, peripheral
vascular disease or stroke.
31. A method according to claim 30, wherein disorders of lipid
metabolism are selected from diabetic dyslipidaemia, mixed
dyslipidaemia, hypercholesteraemia, hypertriglyceridaemia, or
hyperlipidaemia.
32. A method according to claim 30, wherein the cardiovascular
disease is selected from heart failure, atherosclerosis and
arteriosclerosis, coronary artery disease, thrombosis, angina,
peripheral vascular disease or stroke.
33. A method for treatment of dyslipidaemia and
hyperlipoproteinaemia, which comprises administering a compound of
formula (I) of claim 20.
34. A method for treatment of inflammatory diseases or conditions,
which comprises administering a compound of formula (I) of claim
20.
35. A method for treatment of a human or animal subject having a
condition where under-activation of HM74A receptor contributes to
the condition in which activation of the receptor is agonistic,
which comprises administering an effective amount of a compound of
formula (I) according to claim 20.
36. A pharmaceutical formulation, which comprises at least one
chemical entity according to claim 20 and at least one
pharmaceutically acceptable diluent, excipient or carrier.
37. A combination for administration together or separately,
sequentially or simultaneously in separate or combined
pharmaceutical formulations, which comprises at least one chemical
entity according to claim 20 together with another therapeutically
active agent.
38. A pharmaceutical formulation, which comprises: (i) at least one
chemical entity according to claim 20; (ii) one or more
therapeutically active agent selected from statins, fibrates,
bile-acid binding resins and nicotinic acid; and (iii) one or more
pharmaceutically acceptable diluents, excipients or carriers.
Description
[0001] The present invention relates to compounds which are
xanthine derivatives, processes for the manufacture of said
derivatives, pharmaceutical formulations containing these compounds
and the use of the compounds in therapy, for example, in the
treatment of diseases where under-activation of the HM74A receptor
contributes to the disease or where activation of the receptor will
be beneficial.
[0002] Dyslipidaemia is a general term used to describe individuals
with aberrant lipoprotein profiles. Clinically, the main classes of
compounds used for the treatment of patients with dyslipidaemia,
and therefore at risk of cardiovascular disease are the statins,
fibrates, bile-acid binding resins and nicotinic acid. Nicotinic
acid (Niacin, a B vitamin) has been used clinically for over 40
years in patients with various forms of dyslipidaemia. The primary
mode of action of nicotinic acid is via inhibition of
hormone-sensitive triglyceride lipase (HSL), which results in a
lowering of plasma non-esterified fatty acids (NEFA) which in turn
alters hepatic fat metabolism to reduce the output of LDL and VLDL
(low and very low density lipoprotein). Reduced VLDL levels are
thought to lower cholesterol ester transfer protein (CETP) activity
to result in increased HDL (high density lipoprotein) levels which
may be the cause of the observed cardiovascular benefits. Thus,
nicotinic acid produces a very desirable alteration in lipoprotein
profiles; reducing levels of VLDL and LDL whilst increasing HDL.
Nicotinic acid has also been demonstrated to have disease modifying
benefits, reducing the progression and increasing the regression of
atherosclerotic lesions and reducing the number of cardiovascular
events in several trials.
[0003] The observed inhibition of HSL by nicotinic acid treatment
is mediated by a decrease in cellular cyclic adenosine
monophosphate (cAMP) caused by the G-protein-mediated inhibition of
adenylyl cyclase. Recently, the G-protein coupled receptors HM74
and HM74A have been identified as receptors for nicotinic acid (PCT
patent application WO02/84298; Wise et. al. J Biol. Chem., 2003,
278 (11), 9869-9874). The DNA sequence of human HM74A may be found
in Genbank; accession number AY148884. Two further papers support
this discovery, (Tunaru et. al. Nature Medicine, 2003, 9(3),
352-255 and Soga et. al. Biochem Biophys Res Commun., 2003, 303 (1)
364-369), however the nomenclature differs slightly. In the Tunaru
paper what they term human HM74 we term HM74A and in the Soga paper
HM74b is identical to HM74A. Cells transfected to express HM74A
and/or HM74 gain the ability to elicit G.sub.i G-protein mediated
responses following exposure to nicotinic acid. In mice lacking the
homologue of HM74A (m-PUMA-G) nicotinic acid fails to reduce plasma
NEFA levels.
[0004] Certain xanthine derivatives have been synthesised and
disclosed in the prior art. For example, EP0389282 discloses
xanthine derivatives as potential mediators of cerebrovascular
disorders. A range of xanthine derivatives were identified as
adenosine receptor antagonists by Jacobson et. al. in J. Med.
Chem., 1993, 36, 2639-2644.
[0005] We now present a group of xanthine derivatives which are
selective agonists of the nicotinic acid receptor HM74A and are
thus of potential benefit in the treatment, prophylaxis and
suppression of diseases where under-activation of this receptor
either contributes to the disease or where activation of the
receptor will be beneficial.
SUMMARY OF THE INVENTION
[0006] The present invention provides xanthine derivatives and the
use of these derivatives in therapy, for example, in the treatment
of diseases where under-activation of the HM74A receptor
contributes to the disease or where activation of the receptor will
be beneficial. For example, in treatment of diseases of lipid
metabolism including dyslipidaemia or hyperlipoproteinaemia such as
diabetic dyslipidaemia and mixed dyslipidaemia, heart failure,
hypercholesteraemia, cardiovascular disease including
atherosclerosis, arteriosclerosis, and hypertriglyceridaemia. As
such, the compounds may also find favour as therapeutics for
coronary artery disease, thrombosis, angina, chronic renal failure,
peripheral vascular disease and stroke, as well as the
cardiovascular indications associated with type II diabetes
mellitus, type I diabetes, insulin resistance, hyperlipidaemia,
anorexia nervosa, obesity. The compounds may also be of use in the
treatment of inflammatory diseases or conditions, as set out
further below.
[0007] Intermediates, formulations, methods and processes described
herein form further embodiments of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0008] According to one aspect of this invention we provide at
least one chemical entity selected from compounds of formula
(I)
##STR00002## [0009] and pharmaceutically acceptable derivatives
thereof, wherein [0010] R.sup.1 represents
-(alkylene).sub.m-X-(alkylene).sub.n-Y; [0011] Wherein X represents
A, A1, A2 or a direct link;
[0012] A represents a group selected from [0013] cycloalkylene,
cycloalkenylene, aryl, heteroaryl, heterocyclyl, and
--CH.sub.2--OC(O)--; [0014] A1 represents a group selected from
[0015] --CH.sub.2--O--(CH.sub.2).sub.qaryl-O--,
--CH.sub.2--O--(CH.sub.2).sub.wN(R.sup.5)C(O)O--,
--CH.sub.2--N(R.sup.5)C(O)O--, --CH.sub.2--N(R.sup.5)C(O)--,
--CH.sub.2--(O).sub.p--(CH.sub.2).sub.qC(O)NR.sup.5--,
--CH.sub.2--N(R.sup.5)C(O)N(R.sup.5)--,
--CH.sub.2--C(O)N((CH.sub.2).sub.wOH)--,
--CH.sub.2--NR.sup.5--S(O).sub.2--, CH.sub.2--S(O).sub.2NR.sup.5--,
--CH.sub.2--C(O)O--, --O--, --NR.sup.5--, and --S--; [0016] A2
represents --CH(OH)--; [0017] When X is A, A1 or A2, Y represents a
group selected from [0018] heteroaryl, heterocyclyl, aryl,
cycloalkyl, cycloalkenyl, --NH-aryl, --O(CH.sub.2).sub.n-aryl,
--O-heteroaryl, --OR.sup.5, --C(O)OR.sup.5, --C(O)O--C.sub.6aryl,
--OC(O)R.sup.4, --CH(aryl).sub.2, --CH(heteroaryl).sub.2, and
--C.sub.1-6 haloalkyl; [0019] When X is A1 and Y is selected from
[0020] --O(CH.sub.2).sub.n-aryl, --O-heteroaryl, --OR.sup.5,
--OC(O)R.sup.4, and --NH-aryl, [0021] n is an integer selected from
2, 3, 4 and 5; [0022] When X is A1 and Y is --C.sub.1-6 haloalkyl,
or when X is A2, n is an integer selected from 1, 2, 3, 4 and 5;
[0023] When X is a direct link, (m+n) is an integer selected from 2
to 10; [0024] When X is a direct link and (m+n) is an integer
selected from 3 to 10, Y represents a group selected from [0025]
--C(O)(CH.sub.2).sub.qOR.sup.4, --C(O)-aryl, --C(O)-heteroaryl,
--C(O)-heterocyclyl, heteroaryl, heterocyclyl, Aryl, 3 or 4 ring
fused system, --CH(aryl).sub.2, --CH(heteroaryl).sub.2, --OR.sup.5,
--NR.sup.5R.sup.6, --NR.sup.5C(O)OR.sup.7,
--(O).sub.pC(O)NR.sup.5R.sup.7, and --NR.sup.5C(O)R.sup.7; [0026]
When X is a direct link and (m+n) is 2, Y represents a group
selected from --OR.sup.5, --NH.sub.2, and --NR.sup.5C(O)OR.sup.8;
[0027] When Y incorporates a ring, that ring may be optionally
substituted by one or more of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, halogen, --(CH.sub.2).sub.qNR.sup.5R.sup.7,
--(CH.sub.2).sub.q--(O).sub.p--(CH.sub.2).sub.q--N(R.sup.5)C(O)OR.sup.8,
--(CH.sub.2).sub.q--N(R.sup.5)C(O)R.sup.8,
--(CH.sub.2).sub.q--(O).sub.p--(CH.sub.2).sub.q--C(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.q--N(R.sup.5)C(O)N(R.sup.5)R.sup.6,
(CH.sub.2).sub.q--C(O)N((CH.sub.2).sub.mOH)R.sup.5,
--(CH.sub.2).sub.q--N(R.sup.5)--S(O).sub.2R.sup.8,
--CH.sub.2--S(O).sub.2N(R.sup.5)R.sup.6, --C.sub.1-6 haloalkyl,
--OCF.sub.3, --OCH(F).sub.2, --OCH.sub.2F, --C(O)OR.sup.5,
--OR.sup.5, --R.sup.8CN, --CN, --SO.sub.2R.sup.9,
--(CH.sub.2).sub.nheteroaryl, --(CH.sub.2).sub.nheterocycyl,
--(CH.sub.2).sub.ncycloalkyl, --(CH.sub.2).sub.ncycloalkenyl, and
--(CH.sub.2).sub.naryl;
[0028] Provided that when X is A1, A1 is --O-- and Y is a ring
which is substituted by aryl or heteroaryl, then m is an integer
selected from 3, 4 and 5;
[0029] R.sup.2 is selected from hydrogen, C.sub.1-10 alkyl,
C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, cycloalkyl, cycloalkenyl,
heterocyclyl, aryl, and heteroaryl, each of which may be optionally
substituted by one or more of a group independently selected from:
C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl,
cycloalkyl, heterocyclyl, aryl, heteroaryl, C.sub.1-6 haloalkyl,
halogen, --CN, --OR.sup.4, --(CH.sub.2).sub.nCOR.sup.4,
--C(O)OR.sup.4, --OCOR.sup.4, --(CH.sub.2).sub.nNR.sup.5R.sup.6,
--(NH).sub.pCONR.sup.5R.sup.6, --OCONR.sup.5R.sup.7, and
--NR.sup.5C(O)OR.sup.7; [0030] R.sup.3 represents a group selected
from halogen and CN; [0031] R.sup.4 is selected from hydrogen,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
--(CH.sub.2).sub.ncycloalkyl, --(CH.sub.2).sub.n cycloalkenyl,
--(CH.sub.2).sub.n heterocyclyl, --(CH.sub.2).sub.n aryl, and
--(CH.sub.2).sub.n heteroaryl; [0032] R.sup.5 and R.sup.6 are
independently selected from hydrogen and C.sub.1-4 alkyl; [0033]
R.sup.7 represents a group selected from H, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, --(CH.sub.2).sub.t
cycloalkyl, --(CH.sub.2).sub.n cycloalkenyl, --(CH.sub.2).sub.t
heterocyclyl, --(CH.sub.2).sub.t aryl, and --(CH.sub.2).sub.t
heteroaryl; [0034] R.sup.8 represents a group selected from
C.sub.1-4 alkyl; [0035] R.sup.9 represents a group selected from
C.sub.1-6 alkyl C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
--(CH.sub.2).sub.n cycloalkyl, --(CH.sub.2).sub.ncycloalkenyl,
--(CH.sub.2).sub.nheterocyclyl, --(CH.sub.2).sub.n aryl,
--(CH.sub.2).sub.nheteroaryl, and CN; [0036] m represents an
integer selected from 1, 2, 3, 4 and 5; [0037] n represents an
integer selected from 0, 1, 2, 3, 4 and 5; [0038] p represents an
integer selected from 0 and 1; [0039] q represents an integer
selected from 0, 1 and 2; [0040] t represents an integer selected
from 1 and 2; and [0041] w represents an integer selected from 2, 3
and 4.
[0042] The compounds are of use in the treatment of diseases where
under-activation of the HM74A receptor contributes to the disease
or where activation of the receptor will be beneficial. For example
in treatment of diseases of lipid metabolism including
dyslipidaemia or hyperlipoproteinaemia such as diabetic
dyslipidaemia and mixed dyslipidaemia, heart failure,
hypercholesteraemia, cardiovascular disease including
atherosclerosis, arteriosclerosis, and hypertriglyceridaemia. As
such, the compounds may also find favour as therapeutics for
coronary artery disease, thrombosis, angina, chronic renal failure,
peripheral vascular disease and stroke, as well as the
cardiovascular indications associated with type II diabetes
mellitus, type I diabetes, insulin resistance, hyperlipidaemia,
anorexia nervosa, obesity. As such the compounds of the present
invention may find use as agonists or partial agonists of
HM74A.
[0043] According to another aspect of this invention we provide at
least one chemical entity selected from compounds of formula
(I)
##STR00003##
and pharmaceutically acceptable derivatives thereof, wherein
R.sup.1 represents -(alkylene).sub.m-X-(alkylene).sub.n-Y Wherein X
represents A, A1, A2 or a direct link;
[0044] A represents a group selected from;
cycloalkylene, cycloalkenylene, aryl, heteroaryl, heterocyclyl, and
--CH.sub.2--OC(O)--;
[0045] A1 represents a group selected from:
--CH.sub.2--O--(CH.sub.2).sub.qaryl-O--,
--CH.sub.2--O--(CH.sub.2).sub.wN(R.sup.5)C(O)O--,
--CH.sub.2--N(R.sup.5)C(O)O--, --CH.sub.2--N(R.sup.5)C(O)--,
--CH.sub.2--(O).sub.p--(CH.sub.2).sub.qC(O)NR.sup.5--,
--CH.sub.2--N(R.sup.5)C(O)N(R.sup.5)--,
--CH.sub.2--C(O)N((CH.sub.2).sub.mOH)--,
--CH.sub.2--NR.sup.5--S(O).sub.2--, CH.sub.2--S(O).sub.2NR.sup.5--,
--CH.sub.2--C(O)O--, --O--, --NH--, and --S--;
[0046] A2 represents:
--CH(OH)--;
[0047] When X is A, A1 or A2, Y represents a group selected
from:
heteroaryl, heterocyclyl, aryl, cycloalkyl, cycloalkenyl,
--NH-aryl, --O(CH.sub.2).sub.n-aryl, --O-heteroaryl, --OR.sup.5,
--C(O)OR.sup.5, --C(O)O--C.sub.6 aryl, --OC(O)R.sup.5,
--CH(aryl).sub.2, --CH(heteroaryl).sub.2, and --C.sub.1-6
haloalkyl;
[0048] When X is A1 and Y is selected from:
--O(CH.sub.2).sub.n-aryl, --O-heteroaryl, --OR.sup.5,
--OC(O)R.sup.5, and --NH-aryl, n is an integer selected from 2, 3,
4 and 5;
[0049] When X is A1 and Y is --CF.sub.3, or when X is A2, n is an
integer selected from 1, 2, 3, 4 and 5;
[0050] When X is a direct link, (m+n) is an integer selected from 2
to 10;
[0051] When X is a direct link and (m+n) is an integer selected
from 3 to 10, Y represents a group selected from:
--C(O)(CH.sub.2).sub.qOR.sup.5, --C(O)-aryl, --C(O)-heteroaryl,
--C(O)-heterocyclyl, heteroaryl, heterocyclyl, Aryl, 3 or 4 ring
fused system, --CH(aryl).sub.2, --CH(heteroaryl).sub.2, --OR.sup.5,
--NR.sup.5R.sup.6, --NC(O)OR.sup.8, --(O).sub.pC(O)NR.sup.5R.sup.6,
and --NR.sup.5C(O)R.sup.8;
[0052] When X is a direct link and (m+n) is 2, Y represents a group
selected from: --OR.sup.5, --NH.sub.2, and --NC(O)OR.sup.8;
[0053] When Y incorporates a ring, that ring may be optionally
substituted by one or more of: C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, halogen, --NH.sub.2,
--(CH.sub.2).sub.q--(O).sub.p--(CH.sub.2).sub.p--N(R.sup.5)C(O)OR.sup.8,
--(CH.sub.2).sub.p--N(R.sup.5)C(O)R.sup.8,
--(CH.sub.2).sub.q--(O).sub.p--(CH.sub.2).sub.p--C(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.p--N(R.sup.5)C(O)N(R.sup.5)R.sup.6,
--(CH.sub.2).sub.p--C(O)N((CH.sub.2).sub.mOH)R.sup.5,
--(CH.sub.2).sub.p--N(R.sup.5)--S(O).sub.2R.sup.8,
--CH.sub.2--S(O).sub.2N(R.sup.5)R.sup.6, --C.sub.1-6 haloalkyl,
--OCF.sub.3, --OCH(F).sub.2, --OCH.sub.2F, --C(O)OR.sup.5,
--OR.sup.5, --(R.sup.8).sub.pCN, --SO.sub.2R.sup.9,
--(CH.sub.2).sub.nheteroaryl, --(CH.sub.2).sub.nheterocycyl,
--(CH.sub.2).sub.ncycloalkyl, --(CH.sub.2).sub.ncycloalkenyl, and
--(CH.sub.2).sub.naryl;
[0054] Provided that when X is A1, A1 is --O-- and Y is a ring
which is substituted by aryl or heteroaryl, then m is an integer
selected from 3, 4 and 5;
R.sup.2 is selected from: H; or C.sub.1-10 alkyl, C.sub.2-10
alkenyl, C.sub.2-10 alkynyl, cycloalkyl, cycloalkenyl heterocyclyl,
aryl, and heteroaryl, each of which may be optionally substituted
by one or more of: C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10
alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C.sub.1-6
haloalkyl, halogen, --CN, --OR.sup.4, --(CH.sub.2).sub.nCOR.sup.4,
--C(O)OR.sup.4, --OCOR.sup.4, --(CH.sub.2).sub.nNR.sup.5R.sup.6,
--(NH).sub.pCONR.sup.5R.sup.6, --OCONR.sup.5R.sup.7, and
--NHC(O)OR.sup.7; R.sup.3 is selected from: halogen and CN; R.sup.4
is selected from: H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, --(CH.sub.2), cycloalkyl, --(CH.sub.2).sub.r,
cycloalkenyl, --(CH.sub.2).sub.nheterocyclyl, --(CH.sub.2).sub.n
aryl, and --(CH.sub.2).sub.nheteroaryl; R.sup.5 and R.sup.6 are
selected from: hydrogen and C.sub.1-4 alkyl;
[0055] R.sup.7 is selected from: H, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, --(CH.sub.2).sub.t cycloalkyl,
--(CH.sub.2).sub.ncycloalkenyl, --(CH.sub.2).sub.t heterocyclyl,
--(CH.sub.2).sub.t aryl, and --(CH.sub.2).sub.t heteroaryl;
R.sup.8 is selected from C.sub.1-4 alkyl; R.sup.9 is selected from,
C.sub.1-6 alkyl C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
--(CH.sub.2).sub.n cycloalkyl, --(CH.sub.2).sub.ncycloalkenyl,
--(CH.sub.2).sub.nheterocyclyl, --(CH.sub.2).sub.n aryl, and
--(CH.sub.2).sub.nheteroaryl, CN; m represents an integer selected
from: 1, 2, 3, 4 and 5; n represents an integer selected from: 0,
1, 2, 3, 4 and 5; p represents an integer selected from: 0 and 1; q
represents an integer selected from: 0, 1 and 2; t represents an
integer selected from: 1 and 2; w represents an integer selected
from: 2, 3 and 4.
[0056] In one embodiment, X represents A or A1. In a further
embodiment, A is selected from heteroaryl, heterocyclyl, and A1 is
selected from CH.sub.2--O--(CH.sub.2).sub.wN(R.sup.5)C(O)O--, for
example CH.sub.2--O--(CH.sub.2).sub.2NHC(O)O--,
CH.sub.2--N(R.sup.5)C(O)O-- for example CH.sub.2--NHC(O)O,
CH.sub.2--N(R.sup.5)C(O)-- for example, CH.sub.2--NHC(O)--,
CH.sub.2--(O).sub.p--(CH.sub.2).sub.qC(O)NR.sup.5-- for example
CH.sub.2C(O)NCH.sub.3--, CH.sub.2--N(R.sup.5)C(O)N(R.sup.5)-- for
example CH.sub.2--NHC(O)NCH.sub.3--,
CH.sub.2--C(O)N((CH.sub.2).sub.mOH)-- for example
CH.sub.2--C(O)N((CH.sub.2).sub.2OH)--,
CH.sub.2--NR.sup.5--S(O).sub.2-- for example
CH.sub.2--NH--S(O).sub.2--, C.sub.1-12--S(O).sub.2NR.sup.5-- for
example CH.sub.2--S(O).sub.2NCH.sub.3--, and CH.sub.2--C(O)O--. In
another embodiment, X represents A and A represents a heteroaryl.
In another embodiment A represents a heteroaryl comprising a
nitrogen heteroatom, for example, triazolyl, furazanyl,
oxadiazolyl, tetrazolyl, imidazolyl or pyrazolyl.
[0057] In one embodiment, Y represents an optionally substituted
group selected from: aryl, for example phenyl or napthyl,
heteroaryl, for example pyridinyl, thiazolyl, thienyl, benzofuranyl
or indolyl, and O-aryl, for example O-phenyl.
[0058] In a further embodiment, Y is substituted by one or more
groups selected from OR.sup.5 for example OH or OCH.sub.3, halogen,
for example F or Cl, aryl, for example phenyl, C.sub.1-6 haloalkyl
for example CF.sub.3 or CH.sub.2CF.sub.3, OCF.sub.3,
(R.sup.8).sub.PCN for example CN,
(CH.sub.2).sub.p--N(R.sup.5)--S(O).sub.2R.sup.8, for example
NHSO.sub.2CH.sub.3 and SO.sub.2R.sup.9, for example
SO.sub.2CH.sub.3.
[0059] In yet a further embodiment Y is substituted by one or more
groups selected from OR.sup.5, halogen, C.sub.1-6 haloalkyl, and
--(CH.sub.2).sub.q--N(R.sup.5)C(O)R.sup.8.
[0060] In another embodiment, Y is substituted by one or more
groups selected from halogen, and C.sub.1-4 haloalkyl.
[0061] In yet a further embodiment, wherein Y is a ring, it is not
further substituted.
[0062] In one embodiment of the invention, when X represents A or
A1, and A represents cycloalkyl, cycloalkenyl, aryl, heteroaryl or
heterocyclyl, and A1 represents
--CH.sub.2--O--(CH.sub.2).sub.wN(R.sup.5)C(O)O--,
--CH.sub.2--N(R.sup.5)C(O)O--, --CH.sub.2--N(R.sup.5)C(O)--,
--CH.sub.2--(O).sub.p--(CH.sub.2).sub.qC(O)NR.sup.5--,
--CH.sub.2--N(R.sup.5)C(O)N(R.sup.5)--, or
--CH.sub.2--C(O)N((CH.sub.2).sub.mOH)--, and Y represents a ring,
for example when X represents oxadizolyl, tetrazolyl or pyrazolyl
and Y represents phenyl, pyridinyl, or thienyl, m is an integer
selected from 3 and 4 and n is an integer selected from 0 and 1,
for example m is 4 and n is 0, or m is 3 and n is 1;
[0063] In one embodiment R.sup.2 represents C.sub.1-10 alkyl which
may be optionally substituted by one or more of: cycloalkyl,
heterocyclyl, aryl, heteroaryl, C.sub.1-6 haloalkyl, halogen, --CN,
--OR.sup.4, --(CH.sub.2).sub.nCOR.sup.5, --C(O)OR.sup.4,
--OCOR.sup.4, --(CH.sub.2).sub.nNR.sup.5R.sup.5, and
--(NH).sub.pCONR.sup.5R.sup.6. In a further embodiment, R.sup.2 is
selected from C.sub.1-10 alkyl which may be optionally substituted
by one or more of: cycloalkyl, aryl, heteroaryl, C.sub.1-6
haloalkyl, halogen, --CN, --OR.sup.4, --(CH.sub.2).sub.nCOR.sup.5,
--C(O)OR.sup.4 and --OCOR.sup.4. In yet a further embodiment
R.sup.2 is selected from C.sub.1-6 alkyl which may be optionally
substituted by one or more of: cycloalkyl, C.sub.1-6 haloalkyl,
halogen, --CN or --OR.sup.4. In yet another further embodiment,
R.sup.2 is selected from C.sub.3-6 alkyl, for example butyl or
pentyl.
[0064] In one embodiment, R.sup.3 represents halogen. In a further
embodiment, R.sup.3 is selected from: chlorine and bromine. In
another embodiment, R.sup.3 represents chlorine.
[0065] With regard to stereoisomers, the compounds of formula (I)
may have one or more asymmetric carbon atom and may occur as
recemates, racemic mixtures and as individual enantiomers or
diastereomers. All such isomeric forms are included within the
present invention, including mixtures thereof.
[0066] Where a compound of formula (I) contains an alkenyl or
alkenylene group, cis (E) and trans (Z) isomerism may also occur.
The present invention includes the individual stereoisomers of the
compound of the invention and, where appropriate, the individual
tautomeric forms thereof, together with mixtures thereof.
[0067] Separation of diastereoisomers or cis and trans isomers may
be achieved by conventional techniques, e.g. by fractional
crystallisation, chromatography or HPLC of a stereoisomeric mixture
of the agent may also be prepared from a corresponding optically
pure intermediate or by resolution, such as HPLC of the
corresponding racemate using a suitable chiral support or by
fractional crystallisation of the diastereoisomeric salts formed by
reaction of the corresponding racemate with a suitable optically
active acid or base, as appropriate.
[0068] Furthermore, some of the crystalline forms of the compounds
of formula (I) may exist as polymorphs, which are included in the
present invention. One form may have an advantage over another
form, for example one form may have improved stability over another
form.
[0069] It is to be understood that the present invention includes
any combination of particular embodiments and covers all
combinations of particular substituents described hereinabove.
[0070] Throughout the present specification and the accompanying
claims the words "comprise" and "include" and variations such as
"comprises", "comprising", "includes" and "including" are to be
interpreted inclusively. That is, these words are intended to
convey the possible inclusion of other elements or integers not
specifically recited, where the context allows.
[0071] As used herein, the term "alkyl" (when used as a group or as
part of a group) refers to a straight or branched hydrocarbon chain
unless specified otherwise, containing the specified number of
carbon atoms. For example, C.sub.3-C.sub.10alkyl means a straight
or branched hydrocarbon chain containing at least 3 and at most 10
carbon atoms. Examples of alkyl as used herein include, but are not
limited to methyl (Me), ethyl (Et), n-propyl and i-propyl.
[0072] The term "alkylene" or as used herein means both straight
and branched chain, or cyclic saturated hydrocarbon linker groups.
Examples of alkylene groups include methylene (--CH.sub.2--),
ethylene (--CH.sub.2CH.sub.2--), ethene (--CH.dbd.CH--), or
cyclopropylene and the like. For example, as used herein,
-(alk).sub.n-, where n is 3 represents --(CH.sub.2).sub.3--,
--C(CH.sub.3).sub.2--, --CH.sub.2CH.dbd.CH--, or -cyclopropylene-
and the like. For example as used herein, -(alk).sub.m- where m is
4 represents --(CH.sub.2).sub.4--, --CH.sub.2C(CH.sub.3).sub.2--,
--CH.sub.2CH.dbd.CHCH.sub.2--, or --CH.sub.2cyclopropylene- and the
like.
[0073] The term "alkenyl" as used herein refers to a straight or
branched hydrocarbon chain containing the specified number of
carbon atoms which contains one or more double bonds.
[0074] The term "alkynyl" as used herein refers to a straight or
branched hydrocarbon chain containing the specified number of
carbon atoms which contains one or more triple bonds.
[0075] The term "cycloalkyl" as used herein refers to a saturated
monocyclic hydrocarbon ring of 3 to 8 carbon atoms. Examples of
such groups include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl or cyclooctyl and the like.
[0076] The term "cycloalkylene" as used herein refers to a
saturated monocyclic hydrocarbon ring of 3 to 8 carbon linker
groups. Examples of such groups include cyclopropylene,
cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene or
cyclooctylene and the like.
[0077] The term "cycloalkenyl" as used herein refers to an
unsaturated non-aromatic monocyclic hydrocarbon ring of 3 to 8
carbon atoms containing one or more carbon-carbon double bonds.
Examples of such groups include cyclopropenyl, cyclobutenyl,
cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl and the
like.
[0078] The term "cycloalkenylene" as used herein refers to an
unsaturated non-aromatic monocyclic hydrocarbon ring of 3 to 8
carbon linker groups containing one or more carbon-carbon double
bonds. Examples of such groups include cyclopropenylene,
cyclobutenylene, cyclopentenylene, cyclohexenylene,
cycloheptenylene or cyclooctenylene and the like.
[0079] The term "aryl" as used herein refers to a C.sub.6-12
monocyclic, bicyclic or tricyclic hydrocarbon ring wherein at least
one ring is aromatic. Examples of such groups include phenyl,
naphthyl or tetrahydronaphthalenyl and the like.
[0080] The term "heteroaryl" as used herein refers to a 5-6
membered monocyclic aromatic ring or a fused 8-10 membered bicyclic
aromatic ring, containing 1 to 4 heteroatoms selected from oxygen,
nitrogen and sulphur. There may be one or more optional oxo
substituents on the ring carbon atoms. Examples of such monocyclic
aromatic rings include thienyl, furyl, furazanyl, pyrrolyl,
triazolyl, tetrazolyl, imidazolyl, oxazolyl, thiazolyl,
oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyranyl,
pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl, pyridyl, triazinyl,
tetrazinyl and the like. Examples of such fused aromatic rings
include quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,
pteridinyl, cinnolinyl, phthalazinyl, naphthyridinyl, indolyl,
isoindolyl, azaindolyl, indolizinyl, indazolyl, purinyl,
pyrrolopyridinyl, furopyridinyl, benzofuranyl, isobenzofuranyl,
benzothienyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl,
benzothiazolyl, benzoisothiazolyl, benzoxadiazolyl,
benzothiadiazolyl and the like.
[0081] The term "heterocyclyl" as used herein refers to a 4-7
membered monocyclic ring or a fused 8-12 membered bicyclic ring
which may be saturated or partially unsaturated containing 1 to 4
heteroatoms selected from oxygen, nitrogen or sulphur. There may be
one or more optional oxo substituents on the ring carbon atoms.
Examples of such monocyclic rings include pyrrolidinyl, azetidinyl,
pyrazolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl,
thiomorpholinyl, thiazolidinyl, hydantoinyl, valerolactamyl,
oxiranyl, oxetanyl, dioxolanyl, dioxanyl, oxathiolanyl, oxathianyl,
dithianyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl,
tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl,
tetrahydrothiophenyl, tetrahydrothiopyranyl, diazepanyl, azepanyl
and the like. Examples of such bicyclic rings include indolinyl,
isoindolinyl, benzopyranyl, quinuclidinyl,
2,3,4,5-tetrahydro-1H-3-benzazepine, tetrahydroisoquinolinyl and
the like.
[0082] The term "3 or 4 ring fused system" as used herein refers to
a fused 12-18 membered tricyclic or tetracyclic ring which contains
1 to 4 heteroatoms of N and wherein at least one ring is aromatic.
There may be one or more optional oxo substituents on the ring
carbon atoms. Examples of such fused aromatic rings include
carbazolyl, acenaphthyl, naphthotriazolyl and the like.
[0083] The terms "halogen" or "halo" as used herein refer to a
fluorine, chlorine, bromine or iodine atom.
[0084] The term "C.sub.1-6 haloalkyl" as used herein refers to a
C.sub.1-6 alkyl group as defined herein wherein at least one
hydrogen atom is replaced with halogen. Examples of such groups
include fluoroethyl, trifluoromethyl or trifluoroethyl and the
like.
[0085] As used herein, where a group is referred to as being
"substituted" by another group or having "one or more substituents"
unless a particular position for such a substitution is specified
it is to be understood that a substitution may be present at any
position in the group.
[0086] The term "pharmaceutically acceptable derivative" as used
herein refers to any pharmaceutically acceptable derivative of a
compound of the present invention, for example, salts, solvates or
esters, which upon administration to a mammal, such as a human, is
capable of providing (directly or indirectly) such a compound or an
active metabolite thereof. Such derivatives are clear to those
skilled in the art, without undue experimentation, and with
reference to the teaching of Burger's Medicinal Chemistry And Drug
Discovery, 5th Edition, Vol 1: Principles And Practice, which is
incorporated herein by reference.
[0087] As used herein, the term "pharmaceutically acceptable" used
in relation to an ingredient (active ingredient, diluent, excipient
or carrier) which may be included in a pharmaceutical formulation
for administration to a patient, refers to that ingredient being
acceptable in the sense of being compatible with any other
ingredients present in the pharmaceutical formulation and not being
deleterious to the recipient thereof.
[0088] As used herein, the term "solvate" refers to a complex of
variable stoichiometry formed by a solute (in this invention, a
compound of formula (I) or a pharmaceutically acceptable derivative
thereof) and a solvent. Such solvents for the purposes of the
present invention may not interfere with the biological activity of
the solute. The solvent used may be a pharmaceutically acceptable
solvent. Examples of suitable pharmaceutically acceptable solvents
include water, ethanol and acetic acid. An example of a solvent
that may be used is water, in which case the solvate may be
referred to as a hydrate of the solute in question.
[0089] It will be appreciated that, for pharmaceutical use, the
"salt or solvate" referred to above will be a pharmaceutically
acceptable salt or solvate. However, other salts or solvates may
find use, for example, in the preparation of a compound of formula
(I) or in the preparation of a pharmaceutically acceptable salt or
solvate thereof.
[0090] Pharmaceutically acceptable salts include those described by
Berge, Bighley and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19.
Suitable pharmaceutically acceptable salts include alkali metal
salts formed from the addition of alkali metal bases such as alkali
metal hydroxides. Examples of suitable alkali metal salts include
sodium salts and potassium salts. Other suitable pharmaceutically
acceptable salts include alkaline earth metal salts such as calcium
salts and magnesium salts, ammonium salts; or salts with organic
bases such as ethanolamine, triethanolamine, ethylene diamine,
triethylmine, choline and meglumine; or salts with amino acids such
as arginine, lysine and histidine.
[0091] Esters may be active in their own right and/or be
hydrolysable under in vivo conditions in the human body. Suitable
pharmaceutically acceptable in vivo hydrolysable ester groups
include those which break down readily in the human body to leave
the parent acid or its salt. An ester may be formed at a carboxylic
acid (--C(O)OH) group, by methods well known in the art involving
reaction with the corresponding alcohol. For example, esters may be
C.sub.1-6alkyl esters, e.g. methyl esters, ethyl esters, and the
like.
[0092] As used herein, the term "compounds of the invention" means
the compounds according to Formula I and the pharmaceutically
acceptable derivatives thereof. The term "a compound of the
invention" means any one of the compounds of the invention as
defined above.
[0093] As used herein the term "at least one chemical entity" means
at least one chemical substance chosen from the group of compounds
consisting of compounds of formula I and pharmaceutically
acceptable derivatives thereof.
[0094] In one aspect of the invention there is provided
substantially crystalline
3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-di-
hydro-1H-purine-2,6-dione form 1. In another aspect of the
invention there is provided substantially crystalline
3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-di-
hydro-1H-purine-2,6-dione form 2.
[0095] Thermal analysis on samples of substantially crystalline
3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-di-
hydro-1H-purine-2,6-dione forms 1 and 2 was carried out. Thus,
there is provided substantially crystalline
3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-di-
hydro-1H-purine-2,6-dione (form 1 or form 2) having a melting point
onset measured by DSC (.+-.0.5.degree. C.) of: 160.degree. C. or
greater and 147.degree. C. or greater, respectively.
[0096] Samples of substantially crystalline
3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-di-
hydro-1H-purine-2,6-dione form 1, and
3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-di-
hydro-1H-purine-2,6-dione form 2, prepared as described
hereinafter, gave the X-ray powder diffraction patterns of FIGS.
1-2. The X-ray diffraction pattern is unique to the crystalline
form. The substantially crystalline forms exhibit diffraction
patterns with a unique set of diffraction peaks which can be
expressed in 2 theta angles (.degree.).
[0097] 2 Theta diffraction anglet account for positions of various
peaks in the X-ray diffraction pattern. Slight variations in
observed 2 theta angles are expected based on the specific
diffractometer employed and the analyst's sample preparation
technique.
[0098] The substantially crystalline forms of
3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-di-
hydro-1H-purine-2,6-dione can be identified by the presence of a
characteristic 2 theta angle peak, or by multiple 2 theta angles
which are reasonably characteristic of the particular crystalline
forms. To identify substantially crystalline
3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-di-
hydro-1H-purine-2,6-dione (form 1), these peaks occur at the
following positions, expressed in 2 theta angles (.+-.0.1 degrees):
5.4, 6.7, 9.7, 11.1, 12.9, 14.0, 15.6, 16.3, 16.7, 23.1 degrees. To
identify substantially crystalline
3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-di-
hydro-1H-purine-2,6-dione (form 2), these peaks occur at the
following positions, expressed in 2 theta angles (.+-.0.1 degrees):
5.2, 6.6, 10.4, 11.2, 13.4, 15.6, 18.1, 19.5, 20.9 degrees. In one
embodiment at least one of the foregoing 2 theta angles are
employed to identify substantially crystalline
3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-di-
hydro-1H-purine-2,6-dione form 1 and substantially crystalline
3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-di-
hydro-1H-purine-2,6-dione form 2. In other embodiments at least 2,
3, 4 or 5 (where applicable) of the foregoing 2 theta angles are
employed to identify substantially crystalline
3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-di-
hydro-1H-purine-2,6-dione form 1, substantially crystalline
3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-di-
hydro-1H-purine-2,6-dione form 2.
[0099] Some margin of error is present in each of the 2 theta angle
assignments. The margin of error in the foregoing 2 theta angles is
approximately .+-.0.1 degrees for each of the foregoing peak
assignments.
[0100] Since some margin of error is possible in the assignment of
2 theta angles, the preferred method of comparing X-ray powder
diffraction patterns in order to identify a particular crystalline
form is to overlay the X-ray powder diffraction pattern of the
unknown form over the X-ray powder diffraction pattern of a known
form. For example, one skilled in the art can overlay an X-ray
powder diffraction pattern of an unidentified form of
3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-di-
hydro-1H-purine-2,6-dione, obtained using the methods described
herein, see FIG. 3 for example, and readily determine whether the
X-ray diffraction pattern of the unidentified form is substantially
the same as the X-ray powder diffraction pattern of substantially
crystalline
3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-di-
hydro-1H-purine-2,6-dione Form 1 or 2. If the X-ray powder
diffraction pattern is substantially the same as that shown in any
of FIGS. 1-2, the previously form can be readily and accurately
identified.
[0101] As used herein, the term "substantially crystalline form"
means that it is substantially free of amorphous form
3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-di-
hydro-1H-purine-2,6-dione. By "substantially free" is meant
containing less than 50% of the amorphous form, in one aspect less
than 20% of the amorphous form, in another aspect less than 10% of
the amorphous form, in another aspect less than 5% of the amorphous
form, in another aspect less than 2% of the amorphous form, in
another aspect less than 1% of the amorphous form.
[0102] The present invention provides a method for the preparation
of substantially crystalline
3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-di-
hydro-1H-purine-2,6-dione form as described herein.
[0103] Compounds of formula (I) are of potential therapeutic
benefit in the treatment and amelioration of the symptoms of many
diseases of lipid metabolism including dyslipidaemia and
hyperlipoproteinaemia such as diabetic dyslipidaemia and mixed
dyslipidaemia, heart failure, hypercholesteraemia, cardiovascular
disease including atherosclerosis, arteriosclerosis, and
hypertriglyceridaemia, type II diabetes mellitus, type I diabetes,
insulin resistance, hyperlipidaemia, anorexia nervosa, obesity. As
such, the compounds may also find favour as therapeutics for
coronary artery disease, thrombosis, angina, chronic renal failure,
peripheral vascular disease and stroke.
[0104] It has been reported that the HM74 and HM74A receptors are
involved in inflammation (WO02084298). Inflammation represents a
group of vascular, cellular and neurological responses to trauma.
Inflammation can be characterised as the movement of inflammatory
cells such as monocytes, neutrophils and granulocytes into the
tissues. This is usually associated with reduced endothelial
barrier function and oedema into the tissues. Inflammation with
regards to disease typically is referred to as chronic
inflammation. Such chronic inflammation may manifest itself through
disease symptoms. The aim of anti-inflammatory therapy is therefore
to reduce this chronic inflammation and allow for the physiological
process of healing and tissue repair to progress.
[0105] Examples of inflammatory diseases or conditions for which
the compounds of the present invention may demonstrate utility
include those of the joint, for example arthritis (e.g. rheumatoid
arthritis, osteoarthritis, prosthetic joint failure), or the
gastrointestinal tract (e.g. ulcerative colitis, Crohn's disease,
and other inflammatory bowel and gastrointestinal diseases,
gastritis and mucosal inflammation resulting from infection, the
enteropathy provoked by non-steroidal anti-inflammatory drugs), of
the lung (e.g. adult respiratory distress syndrome, asthma, cystic
fibrosis, or chronic obstructive pulmonary disease), of the heart
(e.g. myocarditis), of nervous tissue (e.g. multiple sclerosis), of
the pancreas, (e.g. inflammation associated with diabetes melitus
and complications thereof, of the kidney (e.g. glomerulonephritis),
of the skin (e.g. dermatitis, psoriasis, eczema, urticaria, burn
injury), of the eye (e.g. glaucoma) as well as of transplanted
organs (e.g. rejection) and multi-organ diseases (e.g. systemic
lupus erythematosis, sepsis) and inflammatory sequelae of viral or
bacterial infections and inflammatory conditions associated with
atherosclerosis and following hypoxic or ischaemic insults (with or
without reperfusion), for example in the brain or in ischaemic
heart disease.
[0106] In one embodiment, the compounds of this invention are
useful in the treatment and prevention of inflammation, diabetes
and cardiovascular diseases or conditions including
atherosclerosis, arteriosclerosis, hypertriglyceridemia, and mixed
dyslipidaemia.
[0107] Nicotinic acid has a significant side effect profile,
possibly because it is dosed at high level (gram quantities daily).
The most common side effect is an intense cutaneous flushing. In
certain embodiments of the present invention the compounds may
exhibit reduced side effects compared to nicotinic acid. HM74A has
been identified as a high affinity receptor for nicotinic acid
whilst HM74 is a lower affinity receptor. The compounds of the
present invention show greater affinity for HM74A than for HM74
therefore may find use as selective HM74A agonists or partial
agonists.
[0108] The potential for compounds of formula (I) to activate HM74A
may be demonstrated, for example, using the following in vitro
whole cell assays:
In-Vitro Testing
[0109] For transient transfections, HEK293T cells (HEK293 cells
stably expressing the SV40 large T-antigen) were maintained in DMEM
containing 10% foetal calf serum and 2 mM glutamine. Cells were
seeded in 90 mm culture dishes and grown to 60-80% confluence
(18-24 h) prior to transfection. Human HM74A (GenBank.TM. accession
number AY148884) was subcloned in to a mammalian expression vector
(pcDNA3; Invitrogen) and transfected using Lipofectamine reagent.
For transfection, 9 .mu.g of DNA was mixed with 30 .mu.l
Lipofectamine in 0.6 ml of Opti-MEM (Life Technologies Inc.) and
was incubated at room temperature for 30 min prior to the addition
of 1.6 ml of Opti-MEM. Cells were exposed to the Lipofectamine/DNA
mixture for 5 h and 6 ml of 20% (v/v) foetal calf serum in DMEM was
then added. Cells were harvested 48 h after transfection. Pertussis
toxin treatment was carried out by supplementation into media at 50
ngml.sup.-1 for 16 h. All transient transfection studies involved
co-transfection of receptor together with the G.sub.i/o G protein,
G.sub.o1.alpha..
[0110] For generation of stable cell lines the above method was
used to transfect CHO-K1 cells seeded in six well dishes grown to
30% confluence. These cells were maintained in DMEM F-12 HAM media
containing 10% foetal calf serum and 2 mM glutamine. 48 h
post-transfection the media was supplemented with 400 .mu.g/ml
Geneticin (G418, Gibco) for selection of antibiotic resistant
cells. Clonal CHO-K1 cell lines stably expressing HM74A were
confirmed by [.sup.35S]-GTP.gamma.S binding measurements, following
the addition of nicotinic acid.
[0111] P2 membrane preparation--Plasma membrane-containing P2
particulate fractions were prepared from cell pastes frozen at
-80.degree. C. after harvest. All procedures were carried out at
4.degree. C. Cell pellets were resuspended in 1 ml of 10 mM
Tris-HCl and 0.1 mM EDTA, pH 7.5 (buffer A) and by homogenisation
for 20 s with a Ultra Turrax followed by passage (5 times) through
a 25-gauge needle. Cell lysates were centrifuged at 1,000 g for 10
min in a microcentrifuge to pellet the nuclei and unbroken cells
and P2 particulate fractions were recovered by microcentrifugation
at 16,000 g for 30 min. P2 particulate fractions were resuspended
in buffer A and stored at -80.degree. C. until required.
[0112] [.sup.35S]-GTP.gamma.S binding--assays were performed at
room temperature in 384-well format based on methods described
previously, (Wieland, T. and Jakobs, K. H. (1994) Methods Enzymol.
237, 3-13). Briefly, the dilution of standard or test compounds
were prepared and added to a 384-well plate in a volume of 10
.mu.l. Membranes (HM74A or HM74) were diluted in assay buffer (20
mM HEPES, 100 mM NaCl, 10 mM MgCl.sub.2, pH7.4) supplemented with
saponin (60 .mu.g/ml), Leadseeker WGA beads (Amersham; 250
.mu.g/well) and 10 .mu.M GDP, so that the 20 .mu.l volume added to
each well contains 5 .mu.g of membranes. [.sup.35S]-GTP.gamma.S
(1170 Ci/mmol, Amersham) was diluted (1:1500) in assay buffer and
20 .mu.l added to each well. Following the addition of the
radioligand, the plates were sealed, pulse spun and incubated for 4
hours at room temperature. At the end of the incubation period the
plates were read on a Leadseeker machine (VIEWLUX PLUS;
Perkin-Elmer) to determine the levels of specific binding.
[0113] These assays were refined by reducing the final assay volume
to 10 .mu.l. For this 10 .mu.l assay a revised protocol was used.
This involved the use of only 100 nl of standard or test compound
per well of a 384-well plate and 1.5 .mu.g membrane and 100 .mu.g
Leadseeker WGA beads. For the low volume protocol, membrane, beads
and [.sup.35S]-GTP.gamma.S were mixed together and then 10 .mu.l of
this mix were dispensed to each well. Incubation and plate read
were identical for the 10 .mu.l and 50 .mu.l assays.
[0114] All exemplified compounds were tested in one or both of the
[.sup.35S]-GTP.gamma.S binding assays described above (i.e. the 10
.mu.l and 50 .mu.l assays).
[0115] Data was analysed by curve fitting as carried out using a
Four Parameter Logistical equation using the XC50 software package
(max 2 points deleted from any one curve). Specific binding is
expressed as pEC.sub.50 and as % efficacy compared to the maximal
response of nicotinic acid binding.
In-Vivo Testing
[0116] HM74A agonists can be tested in male Spague-Dawley rats
(200-250 g) which have been fasted for at least 12 hours prior to
the study. The compounds are dosed intravenously at either 1 or 3
mg/kg (5 ml/kg) or by oral gavage at doses ranging from 1-30 mg/kg
(10 ml/kg). Blood samples (0.3 ml tail vein bleed) can be taken
pre-dose and at three times post-dose (times ranging from 15
minutes to 6 hours post-dose). Each blood sample is transferred to
a heparin tube (Becton Dickinson Microtainer, PST LH) and
centrifuged (10,000 g for 5 minutes) to produce a plasma sample.
The plasma samples are assayed for levels of non-esterified fatty
acids (NEFA) using a commercially available kit (Randox).
Inhibition of plasma NEFA levels, relative to pre-dose levels, are
used as a surrogate for HM74A agonist activity.
[0117] In order to determine whether HM74A compounds exhibit the
flushing response associated with nicotinic acid they can be dosed
to conscious guinea-pigs. Male Dunkin Hartley guinea pigs (300-600
g; n=10-20 per group) are fasted for at least 12 hours, but not in
excess of 24 hours prior to experimention. Pre-study blood samples
(0.5 ml) are taken from each animal by cardiac puncture under
recovery anaesthesia (Isoflurane 3.5% with additional O2 (1
L/min)). Ear temperature measurements are taken by placing the left
ear of each animal over an infra-red temperature probe.
Measurements are taken at one minute intervals from 5 minutes
pre-dose to 30 minutes post-dose. Temperature measurements are then
taken at 15 minute intervals up to 2 hours post-dose. Animals
receive test compounds by oral gavage (5 ml/kg). Blood samples (0.5
ml) are taken by cardiac puncture under terminal anaesthesia. Blood
samples are taken from individual animals to provide data at 0.5,
1, 2, 3, and 4 hours post-dose. All blood samples are placed on a
blood roller for 5 minutes then stored on ice until the end of the
study. Following centrifugation (12000 g for 5 min) the plasma is
transferred into fresh tubes and stored at -20.degree. C. until
assayed for NEFA concentrations.
[0118] Compounds according to Formula (I) have been synthesised
(see synthetic examples below) and tested in the
[.sup.35S]-GTP.gamma.S binding assays discussed above.
[0119] Some compounds according to formula (I) including: [0120]
3-butyl-8-chloro-[3-(dimethylamino)propyl]-3,7-dihydro-1H-purine-2,6-dion-
e; [0121]
8-chloro-3-(3,3-dimethylbutyl)-1-[2-(ethyloxy)ethyl]-3,7-dihydro-
-1H-purine-2,6-dione; [0122]
3-butyl-8-chloro-1-[3-(5-phenyl-1,2,4-oxadiazol-3-yl)propyl]-3,7-dihydro--
1H-purine-2,6-dione; [0123]
1-[3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl-
]-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione; [0124]
2-({4-[3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pr-
opyl]phenyl}oxy)ethyl acetate. have utility as intermediates in the
production of other compounds according to formula (I).
[0125] The exemplified compounds (Examples 1-894) have a pEC.sub.50
of 4.3 (+/-0.3 log unit) or greater and an efficacy of 30% or
greater (in relation to nicotinic acid) in the
[.sup.35S]-GTP.gamma.S binding assays described above, in which
they were tested.
[0126] The following compounds were tested and found to have
activity lower than a pEC.sub.50 of 4.3 (+/-0.3 log unit) and an
efficacy of less than 30% (in relation to nicotinic acid) in the
[.sup.35S]-GTP.gamma.S binding assays described above, in which
they were tested. [0127]
8-chloro-1-(3-{3-[(2,4-difluorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl-
)-3-[2-(1-piperidinyl)ethyl]-3,7-dihydro-1H-purine-2,6-dione;
[0128]
8-chloro-1-(3-{3-[(2,4-difluorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl-
)-3-[2-(hexahydro-1H-azepin-1-yl)ethyl]-3,7-dihydro-1H-purine-2,6-dione;
[0129]
8-chloro-1-(3-{3-[(2,4-difluorophenyl)methyl]-1,2,4-oxadiazol-5-yl-
}propyl)-3-[2-(1-pyrrolidinyl)ethyl]-3,7-dihydro-1H-purine-2,6-dione;
[0130]
8-chloro-1-(3-{3-[(2,4-difluorophenyl)methyl]-1,2,4-oxadiazol-5-yl-
}propyl)-3-[2-(dimethylamino)-2-methylpropyl]-3,7-dihydro-1H-purine-2,6-di-
one; [0131]
8-chloro-1-(3-{3-[(2,4-difluorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl-
)-3-[3-(dimethylamino)propyl]-3,7-dihydro-1H-purine-2,6-dione;
[0132]
8-chloro-1-(3-{3-[(2,4-difluorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl-
)-3-[3-(4-methyl-1-piperazinyl)propyl]-3,7-dihydro-1H-purine-2,6-dione;
[0133]
8-chloro-1-(3-{3-[(2,4-difluorophenyl)methyl]-1,2,4-oxadiazol-5-yl-
}propyl)-3-[2-(dimethylamino)ethyl]-3,7-dihydro-1H-purine-2,6-dione
General Purification and Analytical Methods:
LC/MS: Method
[0134] Analytical HPLC was conducted on a Supelcosil.TM. ABZ+PLUS
column (Supelco) (3 .mu.m, 3.3 cm.times.4.6 mm ID) eluting with
0.1% HCO.sub.2H and 0.01 M ammonium acetate in water (solvent A),
and 95% MeCN and 5% water (containing 0.5% HCO.sub.2H) (solvent B),
using the following elution gradient 0-0.7 min 0% B, 0.7-4.2 min
0.fwdarw.100% B, 4.2-4.6 minutes 100% B, 4.6-4.8 min 100.fwdarw.0%
B at a flow rate of 3 ml/min. The diode array UV detection was
carried out in the range 215 to 330 nm. The mass spectra (MS) were
recorded on a Waters ZQ mass spectrometer using electrospray
positive ionisation [(ES+ve to give MH.sup.+ and M(NH.sub.4).sup.+
molecular ions] or electrospray negative ionisation [(ES-ve to give
(M-H).sup.- molecular ion] modes. Only the parent ion of major
isotopes quoted.
[0135] .sup.1H NMR spectra were recorded using a Bruker DPX 400 MHz
spectrometer using tetramethylsilane as the standard.
[0136] Biotage.TM. chromatography refers to purification carried
out using either the Flash 40i or Flash 150i purification systems,
sold by Biotage AB, using cartridges pre-packed with KPSil
(silica).
[0137] Companion.TM. system refers to the Teledyne Isco Combiflash
Companion.TM. purification system. This is a gradient controlled
purification system with integral, variable wavelength UV detection
with the capability to trigger automated fraction collection by UV
threshold.
[0138] Mass directed autoprep (MDAP) refers to methods where the
material was purified by high performance liquid chromatography
using either a Supelcosil ABZ+5 .mu.m column (10 cm.times.20 mm
i.d.) or a Supelcosil ABZ+10 .mu.m column (15 cm.times.30 mm i.d.)
with a suitable gradient of solvent A: 0.1% HCO.sub.2H in water and
solvent B: 95% MeCN, 5% water (containing 0.5% HCO.sub.2H). The
Waters 2767 inject/collector was triggered by a MicroMass ZQ Mass
Spectrometer on detecting the mass of interest (using Micromass
MassLynx software).
[0139] Preparative HPLC (Autoprep HPLC or Autoprep) refers to
methods where the material was purified by high performance liquid
chromatography on a Supelcosil ABZ+5 .mu.m column (10 cm.times.21.2
mm i.d.) with a suitable gradient of 0.1% HCO.sub.2H in water and
MeCN (with 0.5% HCO.sub.2H). The Gilson 233 fraction collector was
triggered by UV detection.
[0140] SPE (solid phase extraction) refers to the use of
polyethylene cartridges which are pre-packed with sorbent used for
purification. The sorbent contained in these cartridges will be
specified. Examples used are detailed below:
[0141] C18 SPE refers to the use of cartridges pre-packed with 40
.mu.M C18 funtionalised silica sorbent (sold by Varian Inc.). The
compound was loaded, typically in 50:50 DMSO/MeOH, onto a cartridge
previously conditioned with MeCN and equilibrated with 5% MeCN in
water. The product was eluted with a suitable gradient of 0.1%
HCO.sub.2H in water and MeCN (0.5% HCO.sub.2H).
[0142] Aminopropyl SPE or column refers to the use of cartridges
pre-packed with 40 .mu.m-120 .mu.m aminopropyl functionalized
silica (sold by Varian Inc.). The crude product is typically loaded
in DCM/MeOH mixtures onto a cartridge previously conditioned with
MeOH. The neutral components were eluted with MeOH and/or DCM (3 or
4 column volumes) and the acidic components usually eluted with an
eluent containing a proportion of AcOH (2-20%).
[0143] Oasis.TM. Cartridges/Oasis.TM. SPE's refer to SPE cartridges
packed with a polymeric sorbent manufactured by the Waters
Corporation. These are typically conditioned with 3 column volumes
of MeOH and equilibrated with water before the sample is loaded.
Salts and inorganics are eluted with water and the product
typically eluted with MeOH or MeCN.
[0144] GreenHouse.TM. refers to a 24 reaction parallel synthesiser
platform available from RDT Ltd, UK
[0145] As indicated above, compounds of Formula (I) may find use in
human or veterinary medicine, for example as activators of HM74A,
in the management of dyslipidaemia and hyperlipoproteinaemia.
[0146] Thus, there is provided as another embodiment of the present
invention at least one compound of formula (I) or a
pharmaceutically acceptable derivative thereof, for use in human or
veterinary medicine, for example in the treatment of disorders of
lipid metabolism including dyslipidaemia and hyperlipoproteinaemia
such as diabetic dyslipidaemia and mixed dyslipidaemia, heart
failure, hypercholesteraemia, cardiovascular disease including
atherosclerosis, arteriosclerosis, and hypertriglyceridaemia, type
II diabetes mellitus, type I diabetes, insulin resistance,
hyperlipidaemia, anorexia nervosa and obesity. As such, the
compounds are also provided for use in the treatment of coronary
artery disease, thrombosis, angina, chronic renal failure,
peripheral vascular disease and stroke.
[0147] There is provided as a further embodiment of the present
invention at least one compound of formula (I) or a
pharmaceutically acceptable derivative thereof, for use in the
manufacture of a medicament for the treatment of disorders of lipid
metabolism including dyslipidaemia and hyperlipoproteinaemia such
as diabetic dyslipidaemia and mixed dyslipidaemia, heart failure,
hypercholesteraemia, cardiovascular disease including
atherosclerosis, arteriosclerosis, and hypertriglyceridaemia, type
II diabetes mellitus, type I diabetes, insulin resistance,
hyperlipidaemia, anorexia nervosa, obesity. As such, the compounds
are also provided for use in the treatment of coronary artery
disease, thrombosis, angina, chronic renal failure, peripheral
vascular disease and stroke.
[0148] It will be appreciated that references herein to treatment
extend to prophylaxis, prevention of recurrence and suppression of
symptoms as well as the treatment of established conditions.
[0149] In one embodiment of the invention, there is provided at
least one compound of formula (I) or a pharmaceutically acceptable
derivative thereof for use in the treatment of disorders of lipid
metabolism including dyslipidaemia and hyperlipoproteinaemia. For
example, the use is provided of at least one compound of Formula
(I) or a pharmaceutically acceptable derivative thereof in the
treatment of diabetic dyslipidaemia, mixed dyslipidaemia, heart
failure, hypercholesteraemia, type II diabetes mellitus, type I
diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa,
obesity, coronary artery disease, thrombosis, angina, chronic renal
failure, stroke and cardiovascular disease including
atherosclerosis, arteriosclerosis, and hypertriglyceridaemia.
[0150] It is to be understood that this embodiment of the present
invention includes any combination of particular embodiments and
covers all combinations of particular substituents described herein
above for compounds of Formula (I).
[0151] Additionally, the present invention provides the use of at
least one compound of formula (I) or a pharmaceutically acceptable
derivative thereof, in the manufacture of a medicament for the
treatment of inflammatory diseases or conditions of the joint, for
example, arthritis (e.g. rheumatoid arthritis, osteoarthritis,
prosthetic joint failure), or of the gastrointestinal tract (e.g.
ulcerative colitis, Crohn's disease, and other inflammatory bowel
and gastrointestinal diseases, gastritis and mucosal inflammation
resulting from infection, the enteropathy provoked by non-steroidal
anti-inflammatory drugs), of the lung (e.g. adult respiratory
distress syndrome, asthma, cystic fibrosis, or chronic obstructive
pulmonary disease), of the heart (e.g. myocarditis), of nervous
tissue (e.g. multiple sclerosis), of the pancreas, (e.g.
inflammation associated with diabetes melitus and complications
thereof, of the kidney (e.g. glomerulonephritis), of the skin (e.g.
dermatitis, psoriasis, eczema, urticaria, burn injury), of the eye
(e.g. glaucoma) as well as of transplanted organs (e.g. rejection)
and multi-organ diseases (e.g. systemic lupus erythematosis,
sepsis) and inflammatory sequelae of viral or bacterial infections
and inflammatory conditions associated with atherosclerosis and
following hypoxic or ischaemic insults (with or without
reperfusion), for example in the brain or in ischaemic heart
disease.
[0152] In a further or alternative embodiments there is provided a
method for the treatment of a human or animal subject with a
condition where under-activation of the HM74A receptor contributes
to the condition or where activation of the receptor will be
beneficial, which method comprises administering to said human or
animal subject an effective amount of at least one compound of
formula (I) or a pharmaceutically acceptable derivative
thereof.
[0153] Again, it is to be understood that this embodiment of the
present invention includes any combination of particular
embodiments and covers all combinations of particular substituents
described herein above for compounds of Formula (I).
[0154] In one embodiment, the present invention provides a method
for the treatment of disorders of lipid metabolism including
dyslipidaemia and hyperlipoproteinaemia such as diabetic
dyslipidaemia and mixed dyslipidaemia, heart failure,
hypercholesteraemia, cardiovascular disease including
atherosclerosis, arteriosclerosis, and hypertriglyceridaemia, type
II diabetes mellitus, type I diabetes, insulin resistance,
hyperlipidaemia, anorexia nervosa and obesity, which method
comprises administering to said human or animal subject an
effective amount of at least one compound of formula (I) or a
pharmaceutically acceptable derivative thereof. As such, these
compounds may also find favour in methods for the treatment of
coronary artery disease, thrombosis, angina, chronic renal failure,
peripheral vascular disease and stroke, which methods comprise
administering to said human or animal subject an effective amount
of at least one compound of formula (I) or a pharmaceutically
acceptable derivative thereof.
[0155] The amount of a compound of formula (I) or a
pharmaceutically acceptable derivative thereof which is required to
achieve the desired biological effect will, of course, depend on a
number of factors, for example, the mode of administration and the
precise clinical condition of the recipient. In general, the daily
dose will be in the range of 0.1 mg-1-g/kg, typically 0.1-100
mg/kg. An intravenous dose may, for example, be in the range of
0.01 mg to 0.1 g/kg, typically 0.01 mg to 10 mg/kg, which may
conveniently be administered as an infusion of from 0.1 .mu.g to 1
mg, per minute. Infusion fluids suitable for this purpose may
contain, for example, from 0.01 .mu.g to 0.1 mg, per millilitre.
Unit doses may contain, for example, from 0.01 .mu.g to 1 g of a
compound of the invention. Thus ampoules for injection may contain,
for example, from 0.01 .mu.g to 0.1 g and orally administrable unit
dose formulations, such as tablets or capsules, may contain, for
example, from 0.1 mg to 1 g, for example from 5 mg to 50 mg.
[0156] A compound of formula (I) or a pharmaceutically acceptable
derivative thereof may be employed as the compound per se in the
treatment of a disease where under-activation of the HM74A receptor
contributes to the disease or where activation of the receptor will
be beneficial, an example of this is where a compound of the
present invention is presented with an acceptable carrier in the
form of a pharmaceutical formulation. The carrier must, of course,
be acceptable in the sense of being compatible with the other
ingredients of the formulation and must not be deleterious to the
recipient. The carrier may be a solid or a liquid, or both, and may
be formulated with the compound of the invention as a unit-dose
formulation, for example, a tablet, which may contain from 0.05% to
95% by weight of the compound of the invention.
[0157] The formulations include those suitable for oral, rectal,
topical, buccal (e.g. sub-lingual) and parenteral (e.g.
subcutaneous, intramuscular, intradermal or intravenous)
administration.
[0158] There is also provided according to the invention a process
for preparation of such a pharmaceutical composition which
comprises mixing the ingredients.
[0159] Formulations suitable for oral administration may be
presented in discrete units, such as capsules, cachets, lozenges or
tablets, each containing a predetermined amount of a a compound of
formula (I) or a pharmaceutically acceptable derivative thereof; as
a powder or granules; as a solution or a suspension in an aqueous
or non-aqueous liquid; or as an oil-in-water or water-in-oil
emulsion. In general, the formulations are prepared by uniformly
and intimately admixing the compound of formula (I) or a
pharmaceutically acceptable derivative thereof, with a liquid or
finely divided solid carrier, or both, and then, if necessary,
shaping the product. For example, a tablet may be prepared by
compressing or moulding a powder or granules of the compound of
formula (I) or a pharmaceutically acceptable derivative thereof
optionally with one or more accessory ingredients. Compressed
tablets may be prepared by compressing, in a suitable machine, the
compound in a free-flowing form, such as a powder or granules
optionally mixed with a binder, lubricant, inert diluent and/or
surface active/dispersing agent(s). Moulded tablets may be made by
moulding, in a suitable machine, the powdered compound moistened
with an inert liquid diluent.
[0160] Tablets and capsules for oral administration may contain
conventional excipients such as binding agents, for example syrup,
acacia, gelatin, sorbitol, tragacanth, mucilage of starch or
polyvinyl pyrrolidone; fillers, for example, lactose,
microcrystalline cellulose, sugar, maize-starch, calcium phosphate
or sorbitol; lubricants, for example, magnesium stearate, stearic
acid, talc, polyethylene glycol or silica; disintegrants, for
example, potato starch, croscarmellose sodium or sodium starch
glycollate; or wetting agents such as sodium lauryl sulphate. The
tablets may be coated according to methods well known in the art.
Oral liquid preparations may be in the form of, for example,
aqueous or oily suspensions, solutions, emulsions, syrups or
elixirs, or may be presented as a dry product for constitution with
water or other suitable vehicle before use. Such liquid
preparations may contain conventional additives such as suspending
agents, for example, sorbitol syrup, methyl cellulose,
glucose/sugar syrup, gelatin, hydroxymethyl cellulose,
hydroxypropylmethyl cellulose, carboxymethyl cellulose, aluminium
stearate gel or hydrogenated edible fats; emulsifying agents, for
example, lecithin, sorbitan mono-oleate or acacia; non-aqueous
vehicles (which may include edible oils), for example almond oil,
fractionated coconut oil, oily esters, propylene glycol or ethyl
alcohol; or preservatives, for example, methyl or propyl
p-hydroxybenzoates or sorbic acid. The preparations may also
contain buffer salts, flavouring, colouring and/or sweetening
agents (e.g. mannitol) as appropriate.
[0161] Formulations suitable for buccal (sub-lingual)
administration include lozenges comprising a compound of the
invention in a flavoured base, usually sucrose and acacia or
tragacanth, and pastilles comprising the compound of the invention
in an inert base such as gelatin and glycerin or sucrose and
acacia.
[0162] Formulations of the present invention suitable for
parenteral administration conveniently comprise sterile aqueous
preparations of a compound of formula (I) or a pharmaceutically
acceptable derivative thereof, the formulation may be isotonic with
the blood of the intended recipient. These preparations could be
administered intravenously, although administration may also be
effected by means of subcutaneous, intramuscular, or intradermal
injection. Such preparations may conveniently be prepared by
admixing the compound of formula (I) or a pharmaceutically
acceptable derivative thereof with water and rendering the
resulting solution sterile and isotonic with the blood. Injectable
compositions according to the invention will generally contain from
0.1 to 5% w/w of the compound of formula (I) or a pharmaceutically
acceptable derivative thereof.
[0163] Thus, formulations of the present invention suitable for
parenteral administration comprising a compound of formula (I) or a
pharmaceutically acceptable derivative thereof may be formulated
for parenteral administration by bolus injection or continuous
infusion and may be presented in unit dose form, for instance as
ampoules, vials, small volume infusions or pre-filled syringes, or
in multi-dose containers with an added preservative. The
compositions may take such forms as solutions, suspensions, or
emulsions in aqueous or non-aqueous vehicles, and may contain
formulatory agents such as anti-oxidants, buffers, antimicrobial
agents and/or toxicity adjusting agents. Examples of formulations
suitable for oral administration include formulations comprising a
compound of formula (I) or a pharmaceutically acceptable derivative
thereof, in 10% DMSO and 90% sodium hydrogen carbonate in sterile
saline. Examples of formulations suitable for intravenous
administration include formulations comprising a compound of
formula (I) or a pharmaceutically acceptable derivative thereof, in
5% or 10% DMSO and 95% or 90% sodium hydrogen carbonate in sterile
water. Alternatively, the therapeutically active agent may be in
powder form for constitution with a suitable vehicle, e.g. sterile,
pyrogen-free water, before use. The dry solid presentation may be
prepared by filling a sterile powder aseptically into individual
sterile containers or by filling a sterile solution aseptically
into each container and freeze-drying.
[0164] Formulations suitable for rectal administration may be
presented as unit-dose suppositories. These may be prepared by
admixing a a compound of formula (I) or a pharmaceutically
acceptable derivative thereof with one or more conventional solid
carriers, for example, cocoa butter or glycerides and then shaping
the resulting mixture.
[0165] Formulations suitable for topical application to the skin
may take the form of an ointment, cream, lotion, paste, gel, spray,
aerosol, or oil. Carriers which may be used include vaseline,
lanolin, polyethylene glycols, alcohols, and combinations of two or
more thereof. The compound of formula (I) or a pharmaceutically
acceptable derivative thereof is generally present at a
concentration of from 0.1 to 15% w/w of the composition, for
example, from 0.5 to 2%.
[0166] By topical administration as used herein, we include
administration by insufflation and inhalation. Examples of various
types of preparation for topical administration include ointments,
creams, lotions, powders, pessaries, sprays, aerosols, capsules or
cartridges for use in an inhaler or insufflator or drops (e.g. eye
or nose drops).
[0167] Ointments and creams may, for example, be formulated with an
aqueous or oily base with the addition of suitable thickening
and/or gelling agents and/or solvents. Such bases may thus, for
example, include water and/or an oil such as liquid paraffin or a
vegetable oil such as arachis oil or castor oil or a solvent such
as a polyethylene glycol. Thickening agents which may be used
include soft paraffin, aluminium stearate, cetostearyl alcohol,
polyethylene glycols, microcrystalline wax and beeswax.
[0168] Lotions may be formulated with an aqueous or oily base and
will in general also contain one or more emulsifying agents,
stabilising agents, dispersing agents, suspending agents or
thickening agents.
[0169] Powders for external application may be formed with the aid
of any suitable powder base, for example, talc, lactose or starch.
Drops may be formulated with an aqueous or non-aqueous base also
comprising one or more dispersing agents, solubilising agents or
suspending agents.
[0170] Spray compositions may be formulated, for example, as
aqueous solutions or suspensions or as aerosols delivered from
pressurised packs, with the use of a suitable propellant, e.g.
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane,
1,1,1,2-tetrafluorethane, carbon dioxide or other suitable gas.
[0171] Capsules and cartridges for use in an inhaler or
insufflator, of for example gelatin, may be formulated containing a
powder mix of a compound of the invention and a suitable powder
base such as lactose or starch.
[0172] The pharmaceutical compositions according to the invention
may also be used in combination with other therapeutic agents, for
example in combination with other classes of dyslipidaemic drugs
(e.g. statins, fibrates, bile-acid binding resins or nicotinic
acid).
[0173] The compounds of the instant invention may be used in
combination with one or more other therapeutically active agents
for example in combination with other classes of dyslipidaemic
drugs e.g. 3-hydroxy-3-methylglutaryl-coenzyme A reductase
inhibitors (statins) or fibrates or bile acid binding resins or
nicotinic acid. The invention thus provides, in a further
embodiment, the use of such a combination in the treatment of
diseases where under-activation of the HM74A receptor contributes
to the disease or where activation of the receptor will be
beneficial and the use of at least one compound of formula (I) or a
pharmaceutically acceptable derivative thereof in the manufacture
of a medicament for the combination therapy of disorders of lipid
metabolism including dyslipidaemia and hyperlipoproteinaemia such
as diabetic dyslipidaemia and mixed dyslipidaemia, heart failure,
hypercholesteraemia, cardiovascular disease including
atherosclerosis, arteriosclerosis, and hypertriglyceridaemia, type
II diabetes mellitus, type I diabetes, insulin resistance,
hyperlipidaemia, anorexia nervosa and obesity.
[0174] When the compounds of the present invention are used in
combination with other therapeutically active agents, the compounds
may be administered either together or separately, sequentially or
simultaneously by any convenient route.
[0175] The combinations referred to above may conveniently be
presented for use in the form of a pharmaceutical formulation and
thus pharmaceutical formulations comprising a combination as
defined above optimally together with a pharmaceutically acceptable
carrier or excipient comprise a further embodiment of the
invention. The individual components of such combinations may be
administered either together or separately, sequentially or
simultaneously in separate or combined pharmaceutical
formulations.
[0176] When combined in the same formulation it will be appreciated
that the two components must be stable and compatible with each
other and the other components of the formulation and may be
formulated for administration. When formulated separately they may
be provided in any convenient formulation, conveniently in such a
manner as are known for such compounds in the art.
[0177] When in combination with a second therapeutic agent active
against the same disease, the dose of each component may differ
from that when the compound is used alone. Appropriate doses will
be readily appreciated by those skilled in the art.
[0178] The invention thus provides, in a further embodiment, a
combination comprising at least one compound of formula (I) or a
pharmaceutically acceptable derivative thereof together with
another therapeutically active agent.
[0179] The combination referred to above may conveniently be
presented for use in the form of a pharmaceutical formulation and
thus pharmaceutical formulations comprising a combination as
defined above together with a pharmaceutically acceptable carrier
thereof represent a further embodiment of the invention.
[0180] The compounds of the present invention and pharmaceutically
acceptable derivatives thereof may be prepared by the methodology
described hereinafter, constituting a further embodiment of this
invention.
[0181] In one embodiment the present invention provides a method
for the preparation of compound(s) of formula (I) from an
appropriate starting material, for example compound(s) of formula
(II):
##STR00004##
wherein PG=protecting group, the method comprising: [0182] (i)
alkylation at N1 of an N7 protected xanthine; [0183] (ii)
alkylation at N3 of an N7 protected xanthine; [0184] (iii)
halogenation at C8; and [0185] (iv) de-protection of N7; in any
order providing de-protection is carried out after alkylation.
Process 1:
[0186] A process according to the invention for preparing
compound(s) of formula (I) in which R1 incorporates a cycloalkyl,
heterocyclyl, cycloalkenyl, heteroaryl or aryl.
##STR00005##
i) Alkylation of guanine with allyl bromide ii) Diazotisation with
sodium nitrite followed by hydrolysis to form the xanthine iii)
Chlorination
iv) Alkylation at N3
v) Alkylation at N1
[0187] vi) Palladium catalysed removal of the allyl group wherein L
represents a leaving group, for example halogen.
Process 2:
[0188] A process according to the invention for preparing
compound(s) of formula (I) in which R1 incorporates an amide,
carbamate or urea
##STR00006## [0189] wherein L represents a leaving group, for
example halogen, d represents (m-1) (i.e. d together with the
preceding methylene=m), R represents -(alkylene).sub.n-Y and Q may
or may not be present, and if present represents either O or
NR5.
Process 3:
[0190] A process according to the invention for preparing
compound(s) of formula (I) in which R1 incorporates a `reverse`
carbamate or ester
##STR00007##
wherein L represents a leaving group, for example halogen, d
represents (m-1), and R represents -(alk).sub.n-Y.
Process 4:
[0191] A process according to the invention for preparing
compound(s) of formula (I) in which R1 incorporates an ester or
amide
##STR00008##
wherein L represents a leaving group, for example halogen, d
represents (m-1), and R represents --NR.sup.5R.sup.7 or
--OR.sup.5.
Process 5:
[0192] A process according to the invention for preparing
compound(s) of formula (I) in which R1 incorporates a pyrazole,
imidazole or tetrazole.
##STR00009##
wherein L represents a leaving group, for example halogen, d
represents (m-1), and R represents -(alk).sub.n-Y.
Process 6:
[0193] A process according to the invention for preparing
compound(s) of formula (I) in which R1 incorporates an
oxadiazole.
##STR00010##
wherein L represents a leaving group, for example halogen, d
represents (m-1), R represents an alkyl group and R' represents
-(alk).sub.n-Y.
Process 7:
[0194] A process according to the invention for preparing
compound(s) of formula (I) in which R1 incorporates an
oxadiazole
##STR00011##
wherein L represents a leaving group, for example halogen, d
represents (m-1), R represents an alkyl group and R' represents
-(alk).sub.n-Y.
Process 8:
[0195] A process according to the invention for preparing
compound(s) of formula (I) in which R.sup.3 is CN comprises steps
(i) and (ii) of Process 1 followed by:
##STR00012##
iii) Alkylation at N3
iv) Alkylation at Ni
[0196] v) Formation of aldehyde at C8 by lithiation with LiHMDS and
DMF quench vi) Conversion of the aldehyde to the nitrile vii)
Palladium catalysed removal of the allyl group , wherein L
represents a leaving group.
Process 9:
[0197] A process according to the invention for preparing
compound(s) of formula (I) in which R.sup.3 is Cl or Br comprises
steps (i) to (iv) of Process 8 followed by:
##STR00013##
i) Halogenation at C8 using NCS or NBS ii) Palladium catalysed
removal of the allyl group
Process 10:
[0198] A process according to the invention for preparing
compound(s) of formula (I) in which R.sup.3 is CN comprises steps
(i) to (iv) of Process 8 followed by:
##STR00014##
v) Formation of ester vi) Hydrolysis of the methyl ester vii)
Conversion of the acid to the amide. viii) Conversion of the amide
to the nitrile ix) Palladium catalysed removal of the allyl
group
Process 11:
[0199] A process according to the invention for preparing
compound(s) of formula (I) in which R.sup.3 is Cl comprises:
##STR00015##
i) Alkylation at N3
ii) Alkylation at N1
[0200] iii) Debenzylation iii) Chlorination at C8 wherein L
represents a leaving group
Process 12:
[0201] A process according to the invention for preparing
compound(s) of formula (I) in which R.sup.1 differs from R.sup.2
and R.sup.3 is Cl comprises steps (i) to (v) of Process 1 (where
R.sup.2 from process 1 is specifically SEM or MEM) followed by:
##STR00016##
vi) Cleavage of MEM or SEM protecting group group vii) Alkylation
of N3 followed by palladium catalysed removal of the allyl group
wherein L represents a leaving group
Process 13:
[0202] A process according to the invention for preparing
compound(s) of formula (I) in which R.sup.3 is Cl, Br or I
comprises steps (i) to (iv) of Process 8 followed by:
##STR00017##
v) Palladium catalysed removal of allyl group vi) Halogenation at
C8 using NCS, NBS or NIS
Process 14:
[0203] A process according to the invention for preparing
compound(s) of formula (I) comprises:
##STR00018##
i) Pyrimidinedione formation
ii) Alkylation at N1
[0204] iii) Nitrosation iv) Reduction using Na.sub.2S.sub.2O.sub.4
or a similar reducing agent v) Xanthine formation vi) Halogenation
at C8 using NCS wherein L represents a leaving group
Process 15:
[0205] A process according to the invention for preparing
compound(s) of formula (I):
##STR00019##
wherein L represents a leaving group.
[0206] As an additional step to the general processes described
above, and in particular for use in the preparation of the examples
below, there are several ways of purifying resulting compounds, one
or more of which may be of use in the present invention, for
example the use of MDAP, by recrystallisation from one or more
suitable solvents such as ethyl acetate, absolute ethanol,
acetonitrile or methanol, or by use of purification column such as
Silica Redisep cartridges and subsequent eluting with a suitable
solvent such as dichloromethane containing ethyl acetate.
[0207] Where desired or necessary, as a final stage in any of the
above synthetic processes, a resultant compound of formula (I) can
be converted into a pharmaceutically acceptable salt form or vice
versa or converting one salt form into another pharmaceutically
acceptable salt form.
ABBREVIATIONS
[0208] AcOH Acetic acid [0209] atm Atmosphere [0210] br Broad (NMR)
[0211] CDI Carbonyldiimidazole [0212] d Doublet (NMR) [0213] DBAD
Di-t-butylazodicarboxylate [0214] DCM Dichloromethane [0215] DIPEA
Diisopropylethylamine [0216] DMSO Dimethylsulfoxide [0217] DMF
N,N-Dimethylformamide [0218] EtOAc Ethyl acetate [0219] EtOH
Ethanol [0220] h Hour(s) [0221] IPA Isopropyl alcohol [0222] m
Multiplet (NMR) [0223] MDAP Mass directed autoprep [0224] MeCN
Acetonitrile [0225] MeOH Methanol [0226] min Minute(s) [0227] NCS
N-Chlorosuccinimide [0228] NBS N-bromosuccinimide [0229] NIS
N-iodosuccinimide [0230] q Quartet (NMR) [0231] rt Room temperature
[0232] RT Retention time [0233] s Singlet (NMR) [0234] SPE Solid
phase extraction cartridge [0235] t Triplet (NMR) [0236] TFA
Trifluoroacetic acid [0237] THF Tetrahydrofuran [0238] DMEM
Dulbecco's Modified Eagle's Medium [0239] HEPES
4-(2-Hydroxyethyl)piperazine-1-ethanesulphonic acid [0240] LiHMDS
Lithium hexamethyldisilylamide [0241] .DELTA. Heat [0242] SEM
2-(trimethylsilyl)ethoxymethyl [0243] MEM 2-methoxyethoxymethyl
[0244] Boc t-butoxycarbonyl [0245] THP tetrahydropyran
BRIEF DESCRIPTION OF FIGURES
[0246] FIG. 1: XRPD data of substantially crystalline
3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-di-
hydro-1H-purine-2,6-dione form 1.
[0247] FIG. 2: XRPD data of substantially crystalline
3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-di-
hydro-1H-purine-2,6-dione form 2.
[0248] FIG. 3: Overlay of XRPD data for substantially crystalline
3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-di-
hydro-1H-purine-2,6-dione Form 1 and Form 2.
[0249] The following non-limiting examples illustrate the present
invention:
SYNTHETIC EXAMPLES
[0250] It should be noted that the assignment of
(Z)-stereochemistry set out in the compounds exemplified below has
not been confirmed by experimental data. The person skilled in the
art will also recognise that there can be interconversion between E
& Z isomers. (Dondoni, Alessandro; Lunazzi, Lodovico;
Giorgianni, Patrizia; Macciantelli, Dante. Carbon-nitrogen
rotational barrier as a stereochemical probe of benzamidoximes.
Journal of Organic Chemistry (1975), 40(20), 2979-80)
Example 1
8-Chloro-1-(2-hydroxyethyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione
a)
8-Chloro-1-(2-hydroxyethyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione
##STR00020##
[0252]
8-Chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(1.5 g, 5.1 mmol), Cs.sub.2CO.sub.3 (1.8 g, 5.6 mmol) and
2-chloroethanol (509 .mu.L, 7.7 mmol) were reacted together in DMF
(20 ml) at 60.degree. C. for 18 h. The reaction was allowed to cool
to it and the mixture was degassed by applying a vacuum and then
nitrogen was introduced. Pd(PPh.sub.3).sub.4 (428 mg, 0.37 mmol)
was added and the mixture degassed once more. Morpholine (2.1 ml,
24.7 mmol) was added and the mixture was stirred under nitrogen for
3 h, and then partitioned between 2M HCl (aq) and EtOAc. The
organic layer was separated, washed with brine, dried (MgSO.sub.4)
and concentrated. The residue was taken up into MeOH and then
passed down an aminopropyl column with the product eluting with 3%
AcOH/MeOH. The product fractions were combined and concentrated
then purified by recrystallisation from EtOAc. The resulting solid
was collected by filtration and washed with EtOAc to give the title
compound as a white solid (713 mg, 47%).
[0253] LC/MS: m/z 301 [MH].sup.+, RT 2.7 min.
[0254] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.86 (t, 3H, J=7 Hz),
1.22-1.36 (m, 4H), 1.63 (m, 2H), 3.50 (br t, 2H, J=6 Hz), 3.90 (t,
2H, J=7.5 Hz), 3.95 (t, 2H, J=6.5 Hz), 4.75 (br s, 1H), 14.5 (br s,
1H).
b)
8-Chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
##STR00021##
[0256] To a solution of
8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (100 mg,
0.44 mmol) in anhydrous DMF (3 ml) was added sodium carbonate
(0.051 g, 0.484 mmol). After 10 min stirring at rt pentyl iodide
(0.063 ml, 0.484 mmol) was added and stirring continued under
nitrogen at rt for 18 h. The reaction mixture was diluted with
water (25 ml) and extracted with EtOAc (2.times.25 ml). The
combined organic extracts were dried (MgSO.sub.4) filtered and
evaporated. Purification by SPE (Si, 5 g) eluting with 4:1
EtOAc/cyclohexane afforded the title compound as a white solid (96
mg, 74%).
[0257] LC/MS: m/z 297 [MH].sup.+.
c) 8-Chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
##STR00022##
[0259] To a solution of
7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione) (10.52 g, 54.7
mmol) in anhydrous DMF (60 ml) was added NCS (8.04 g, 60.2 mmol).
The reaction mixture was left to stir under nitrogen at 20.degree.
C. for 6 h. The reaction mixture was concentrated in vacuo to give
an amber oil. MeOH was added and left to stand for 18 h. The
resulting residue was filtered and dried under vacuum to give the
title compound (7.69 g, 62%).
[0260] LC/MS: m/z 227 [MH].sup.+.
d) 7-(2-Propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
##STR00023##
[0262] A mixture of
2-amino-7-(2-propen-1-yl)-1,7-dihydro-6H-purin-6-one (40 g, 0.209
mol) in AcOH (900 ml) and water (100 ml) was heated at 55.degree.
C. Sodium nitrite (57.74 g, 0.837 mol) in water (100 ml) was added
dropwise. Care; toxic fumes. After the addition was complete (ca.
25 min) the reaction mixture was allowed to cool to ambient
temperature and then concentrated to ca. 1/3 of its original
volume. Water (500 ml) was added and the resulting precipitate
collected by filtration. The residue was washed with water then
dried at 50.degree. C. over P.sub.2O.sub.5 and under vacuum for 2 h
to give the title compound (17.20 g). The aqueous fraction was
concentrated and water added (100 ml). Again the resulting solid
was filtered and dried. This gave more of the title compound (2.31
g). Combined product (19.52 g, 49%).
[0263] LC/MS: m/z 193 [MH].sup.+.
e) 2-Amino-7-(2-propen-1-yl)-1,7-dihydro-6H-purin-6-one
##STR00024##
[0265] A mixture of guanosine (20 g, 0.071 mol), allyl bromide
(14.7 ml, 0.169 mol) and anhydrous DMSO (100 ml) was stirred at rt,
under nitrogen, for 18 h. Conc. HCl (50 ml of 37%) was added in one
portion and the mixture stirred for 45 min then poured into MeOH
(600 ml). The methanolic solution was neutralised with 2M NaOH (aq)
solution and the resulting white precipitate collected by
filtration. The white solid was dried under vacuum at 50.degree. C.
for 18 h to afford the title compound (16 g) which was used without
further purification.
[0266] LC/MS: m/z 192 [MH].sup.+.
Example 2
8-Chloro-3-(2-cyclobutylethyl)-1-(2-hydroxyethyl)-3,7-dihydro-1H-purine-2,-
6-dione
##STR00025##
[0268] 7-(2-Propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (575 mg,
2.54 mmol) was stirred in dry THF (20 ml) with 2-cyclobutylethanol
(c.73 mol %, remainder 1-butanol) (254 mg). Dibenzyl
azodicarboxylate (94%, 1.57 g, 4.95 mmol) was added, the mixture
cooled to 0.degree. C. and a solution of triphenylphosphine (1.302
g, 4.97 mmol) in dry THF (10 ml) was added dropwise. The mixture
was stirred for 30 min. at 0.degree. C. then at rt for 18 h under
nitrogen. The solvent was evaporated and the residue purified on a
Biotage system (100 g) eluting with EtOAc-cyclohexane (2:3). The
material thus obtained (0.53 g) was a mixture of the required
compound, the corresponding n-butyl analogue and dibenzyl
hydrazinedicarboxylate, and was alkylated without further
purification.
[0269] This mixture (256 mg) and Cs.sub.2CO.sub.3 (326 mg, 1 mmol)
were stirred in dry DMF (5 ml). 2-Chloroethanol (80.5 mg, 1 mmol)
was added and the mixture was stirred and heated at 55.degree. C.
for 65 h. After cooling, it was thoroughly degassed,
tetrakis(triphenylphosphine)palladium(0) (200 mg) and morpholine
(0.7 ml) were added, and the mixture was stirred for 6 h. EtOAc and
2M HCl were added and the mixture filtered, the organic phase
washed with brine, dried (Na.sub.2SO.sub.4) and evaporated and the
residue separated from non-acidic material by aminopropyl SPE (5 g,
MeOH-THF and MeOH wash, elution with DCM-MeOH with 5% added AcOH).
The material obtained from the acid wash (105 mg) was further
purified by MDAP to provide the title compound (42.7 mg).
[0270] LC/MS: m/z 313 [MH].sup.+, RT 2.58 min.
[0271] .sup.1H NMR (DMSO-d.sub.6) .delta.: 1.53-1.64 (m, 2H),
1.71-1.84 (m, 4H), 1.94-2.02 (m, 2H), 2.21-2.30 (m, 1H), 3.47-3.53
(m, 2H), 3.84 (t, 2H, J=7 Hz), 3.95 (t, 2H, J=7 Hz), 4.76 (br s,
1H), 14.45 (br s, 1H)
Example 3
8-Chloro-1-[3-(2-furanyl)propyl]-3-pentyl-3,7-dihydro-1H-purine-2,6-dione,
sodium salt
##STR00026##
[0273] A GreenHouse.TM. tube equipped with a stirrer was charged
with a 0.25 ml aliquot of a 0.54M solution of
8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(0.13 mmol) in THF. To the mixture was added
3-(2-furanyl)-1-propanol (21 mg, 0.16 mmol, 1.2 eq) in THF (0.25
ml), followed by a 0.25 ml aliquot of a 0.71M solution of
bis(1,1-dimethylethyl) (E)-1,2-diazenedicarboxylate (0.18 mmol) in
THF and then a 0.25 ml aliquot of a 0.71M solution of
triphenylphosphine (0.18 mmol) in THF. The solution was stirred in
a GreenHouse.TM. under nitrogen for 16 h. To the mixture was added
a further 0.25 ml aliquot of a 1.4M solution of
bis(1,1-dimethylethyl) (E)-1,2-diazenedicarboxylate (0.36 mmol) in
THF and then a further 0.25 ml aliquot of a 1.4M solution of
triphenylphosphine (0.36 mmol) in THF. The mixture was stirred for
16 h under a stream of nitrogen.
[0274] Tetrakis(triphenylphosphine)palladium(0) (16 mg, 0.014 mmol)
and morpholine (0.12 ml, 1.35 mmol) were added to the mixture which
was stirred for 16 h under a stream of nitrogen. The reaction
mixture was concentrated under nitrogen and the crude material
dissolved in aqueous NaOH solution (0.5 ml, 2M). The resulting
solution was purified using aminopropyl SPE (eluting with AcOH in
DCM and MeOH). Further purification using C18 SPE (eluting with a
water, ammonia and MeCN mixture) afforded the title compound as a
clear gum (22 mg, 45%).
[0275] LC/MS: m/z 365 [MH].sup.+, RT 3.48 min.
[0276] NMR (DMSO-d.sub.6) .delta.: 0.85 (t, 3H, J=7 Hz), 1.35-1.19
(m, 4H), 1.62 (m, 2H), 1.79 (m, 2H), 2.59 (t, 2H, J=8 Hz),
3.93-3.80 (m, 4H), 6.14 (d, 1H, J=3 Hz), 6.32 (dd, 1H, J=3 and 2
Hz), 7.48 (d, 1H, J=2 Hz).
Example 4
5-(8-Chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-[(3-met-
hylphenyl)methyl]pentanamide
a)
5-(8-Chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-[(3--
methylphenyl)methyl]pentanamide
##STR00027##
[0278] A mixture of
5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic
acid (50 mg, 0.14 mmol) in DCM (3 ml) was treated with CDI (27 mg,
0.17 mmol) and left to stir at rt for 1 h.
[(3-Methylphenyl)methyl]amine (25 .mu.l, 0.20 mmol) was added and
left to stir for a further 1 h. The mixture was concentrated then
purified by aminopropyl SPE. The title compound was eluted with
2-3% AcOH/MeOH then concentrated to give the title compound as a
white solid (56 mg, 87%).
[0279] LC/MS: m/z 460 [MH].sup.+, RT 3.3 min.
b)
5-(8-Chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentano-
ic acid
##STR00028##
[0281] A mixture of methyl
5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoat-
e (8.40 g, 0.023mol), LiOH (1.63 g, 0.068mol), MeOH (150 ml) and
water (10 ml) was left to stir at ambient temperature for 64 h. The
mixture was partitioned between water and EtOAc and the aqueous
acidified. The organic layer was separated and the aqueous
extracted again with EtOAc. The combined extracts were washed with
brine, dried (MgSO.sub.4) and concentrated, giving the title
compound as an off-white solid (9.09 g).
[0282] LC/MS: m/z 357 [MH].sup.+, RT 3.0 min.
c) Methyl
5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-
pentanoate
##STR00029##
[0284] A solution of
8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(2.0 g, 6.7 mmol) in anhydrous DMF (40 ml) was treated with
Cs.sub.2CO.sub.3 (2.42 g, 7.4 mmol) and methyl 5-bromovalerate
(1.16 ml, 8.1 mmol). The mixture was heated at 50.degree. C. for 18
h then allowed to cool to rt and degassed under a gentle vacuum,
then nitrogen introduced. This was repeated twice.
Pd(PPh.sub.3).sub.4 (779 mg, 0.67 mmol) was added and the mixture
degassed once more. Morpholine (5.9 ml, 67 mmol) was added and left
to stir for 3 h at rt. The mixture was partitioned between 2M HCl
(aq) and EtOAc. The organic layer was separated, washed with brine,
dried (MgSO.sub.4) and concentrated, giving a yellow residue/oil
(5.16 g). The residue was taken up in MeOH and divided into two
equal portions, and then each passed down an aminopropyl SPE (20
g), eluting with MeOH followed by 5% AcOH/MeOH then 10% AcOH/MeOH
and finally 15% AcOH/MeOH. The product fractions were combined and
concentrated giving the title compound as an off-white solid (2.28
g, 91%).
[0285] LC/MS: m/z 371 [MH].sup.+, RT 3.1 min.
Example 5
5-(8-Chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-[(3-eth-
ylphenyl)methyl]pentanamide
##STR00030##
[0287] A mixture of
5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic
acid (50 mg, 0.14 mmol) in DCM (3 ml) was treated with CDI (27 mg,
0.17 mmol) and left to stir at rt for 1 h.
[(3-ethylphenyl)methyl]amine (25 .mu.l 0.20 mmol) was added and
left to stir for a further 1 h. The mixture was concentrated then
purified on an aminopropyl SPE. The title compound was eluted with
2-3% AcOH/MeOH to give a white solid (61 mg, 92%).
[0288] LC/MS: m/z 474 [MH].sup.+, RT 3.5 min.
Example 6
5-(8-Chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-[(4-flu-
oro-3-methylphenyl)methyl]pentanamide
##STR00031##
[0290] A mixture of
5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic
acid (50 mg, 0.14 mmol) and DCM (3 ml) was treated with CDI (27 mg,
0.17 mmol) and stirred at rt for 1 h.
1-(4-Fluoro-3-methylphenyl)methanamine (27 mg, 0.20 mmol) and DIPEA
(24 .mu.l 0.14 mmol) were added. After 1 h the mixture was
concentrated and then the residue taken up into MeOH and passed
down an aminopropyl SPE. The product was eluted with 2% AcOH/MeOH
and further purified by MDAP to give the title compound as a solid
(15 mg, 22%).
[0291] LC/MS: m/z 478 [MH].sup.+, RT 3.4 min.
Example 7
Phenylmethyl
5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoat-
e
##STR00032##
[0293] A mixture of
5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic
acid (50 mg, 0.14 mmol) in DCM (3 ml) was treated with CDI (27 mg,
0.17 mmol) and left to stir at rt for 1 h. Benzyl alcohol (21
.mu.l, 0.20 mmol) was added and left to stir for a further 1 h. The
reaction mixture was concentrated and DMF (3 ml) was added then
heated at 50.degree. C. for 2 h. The mixture was concentrated then
purified by MDAP giving the title compound as a white solid (33 mg,
53%).
[0294] LC/MS: m/z 447 [MH].sup.+, RT 3.7 min.
Example 8
(3-Methylphenyl)methyl
[3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]c-
arbamate
a) (3-Methylphenyl)methyl
[3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]c-
arbamate
##STR00033##
[0296] A solution of 3-methylbenzyl alcohol (16 .mu.l, 0.13 mmol)
in DCM (3 ml) was treated with CDI (24 mg, 0.15 mmol) and allowed
to stir at rt for 1 h.
1-(3-aminopropyl)-8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-di-
one trifluoroacetate (50 mg, 0.16 mmol) was added followed by DIPEA
(28 .mu.l, 0.16 mmol) then heated at 50.degree. C. for 56 h. The
reaction mixture was concentrated, the residue taken up into MeOH
and purified by aminopropyl SPE. The title compound eluted with 2%
AcOH/MeOH and a white solid collected (40 mg, 58%).
[0297] LC/MS: m/z 462 [MH].sup.+, RT 3.6 min.
b)
1-(3-Aminopropyl)-8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione
trifluoroacetate
##STR00034##
[0299] A solution of 1,1-dimethylethyl
[3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]c-
arbamate (1.59 g, 4.38 mmol) in DCM (16 ml) was treated with TFA
(16 ml) and stirred at rt for 2 h then concentrated in vacuo.
Residual TFA was removed by azeotroping with DCM then the residue
was triturated with Et.sub.2O to give the title compound as a solid
(1.48 g, quant.).
[0300] LC/MS: m/z 314 [MH].sup.+, RT 2.1 min.
c) 1,1-Dimethylethyl
[3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]c-
arbamate
##STR00035##
[0302] A solution of 1,1-dimethylethyl (3-hydroxypropyl)carbamate
(1.0 ml, 6.1 mmol) in THF (40 ml) was treated with
8-chloro-3-pentyl-1-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3,7-dihydro-1-
H-purine-2,6-dione (1.5 g, 5.1 mmol) and PPh.sub.3 (1.73 g, 6.6
mmol) at rt under nitrogen. DBAD (1.52 g, 6.6 mmol) was added in
one portion and stirred for 18 h. The mixture was degassed by
applying a vacuum and then nitrogen was introduced.
Pd(PPh.sub.3).sub.4 (586 mg, 0.51 mmol) was added and the mixture
degassed once more. Morpholine (4.4 ml, 50.7 mmol) was added and
the mixture was stirred under nitrogen for 3 h, then partitioned
between 2M HCl (aq) and EtOAc. The organic layer was separated,
washed with brine, dried (MgSO.sub.4) and concentrated, giving a
yellow oil. MeOH was added and then passed down an aminopropyl SPE
with the product eluting with 2-3% AcOH/MeOH. The product fractions
were combined and concentrated, giving the title compound as a
clear gummy solid (1.59 g, 75%).
[0303] LC/MS: m/z 414 [MH].sup.+, RT 3.4 min.
Example 9
Phenylmethyl
[3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]c-
arbamate
##STR00036##
[0305]
1-(3-Aminopropyl)-8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione
trifluoroacetate (50 mg, 0.12 mmol) in DCM (3 ml) was treated with
DIPEA (51 .mu.l, 0.29 mmol) and benzyl chloroformate (20 .mu.l,
0.14 mmol). After 1 h the reaction mixture was concentrated and
purified on an aminopropyl SPE. The title compound eluted with 2%
AcOH/MeOH and a white solid collected (35 mg, 67%).
[0306] LC/MS: m/z 448 [MH].sup.+, RT 3.4 min.
Example 10
(2-Fluorophenyl)methyl
[3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]c-
arbamate
##STR00037##
[0308] (2-Fluorophenyl)methanol (11 .mu.l, 0.10 mmol) in DCM (3 ml)
was reacted with CDI (17 mg, 0.11 mmol) under nitrogen for 1 h.
1-(3-Aminopropyl)-8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione
trifluoroacetate (50 mg, 0.16 mmol) was added followed by DIPEA (20
.mu.l, 0.12 mmol) then heated at reflux for 18 h. THF (3 ml) was
added and heated at 75.degree. C. for 5 h. After cooling, the
mixture was concentrated in vacuo and purified by MDAP to give the
title compound as a solid (21 mg, 39%).
[0309] LC/MS: m/z 466 [MH].sup.+, RT 3.4 min.
Example 11
(2,4-Difluorophenyl)methyl
[3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]c-
arbamate
##STR00038##
[0311] (2,4-Difluorophenyl)methanol (11 .mu.L, 0.10 mmol) in DCM (3
ml) was reacted with CDI (17 mg, 0.11 mmol) under nitrogen for 1 h.
1-(3-Aminopropyl)-8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione
trifluoroacetate (50 mg, 0.16 mmol) was added followed by DIPEA (20
.mu.l, 0.12 mmol) then heated at reflux for 18 h. THF (3 ml) was
added and heated at 75.degree. C. for 5 h. After cooling, the
mixture was concentrated in vacuo and purified by MDAP to give the
title compound as a solid (29 mg, 21%).
[0312] LC/MS: m/z 484 [MH].sup.+, RT 3.4 min.
Example 12
2-(3-Pyridinyl)ethyl
[3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]c-
arbamate
a) 2-(3-Pyridinyl)ethyl
[3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]c-
arbamate
##STR00039##
[0314] A solution of CDI (21 mg, 0.13 mmol) in THF (2 ml) was
treated with 2-(3-pyridinyl)ethanol (16 mg, 0.13 mmol) and heated
at reflux for 1 h before the addition of
1-(3-aminopropyl)-8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione
hydrochloride (50 mg, 0.14 mmol) and DIPEA (25 .mu.l, 0.14 mmol).
The reaction was left at reflux for 18 h then concentrated and
purified by MDAP to provide the title compound as a solid (30 mg,
24%).
[0315] LC/MS: m/z 463 [MH].sup.+, RT 2.6 min.
b)
1-(3-Aminopropyl)-8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione
hydrochloride
##STR00040##
[0317] A mixture of 1,1-dimethylethyl
[3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]c-
arbamate (5.19 g, 12.5 mmol) and 4M HCl in 1,4-dioxane (80 ml) was
stirred at rt for 3 h. The mixture was concentrated in vacuo and
dried under vacuum to provide the title product as a white solid
(4.49 g, quant.).
[0318] LC/MS: m/z 314 [MH].sup.+, RT 2.2 min.
Example 13
2-(3-Fluorophenyl)ethyl
[3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]c-
arbamate
##STR00041##
[0320] A solution of CDI (21 mg, 0.13 mmol) in THF (2 ml) was
treated with 2-(3-fluorophenyl)ethanol (16 .mu.l, 0.13 mmol) and
heated at reflux for 1 h before the addition of
1-(3-aminopropyl)-8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione
hydrochloride (50 mg, 0.14 mmol) and DIPEA (25 .mu.L, 0.14 mmol).
The reaction was left at reflux for 18 h then concentrated and
purified by MDAP to provide the title compound as a solid (27 mg,
39%).
[0321] LC/MS: m/z 480 [MH].sup.+, RT 3.5 min.
Example 14
2-(2-Thienyl)ethyl
[3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]c-
arbamate
##STR00042##
[0323] A solution of CDI (21 mg, 0.13 mmol) in THF (2 ml) was
treated with 2-(2-thienyl)ethanol (15 .mu.l, 0.13 mmol) and heated
at reflux for 1 h before the addition of
1-(3-aminopropyl)-8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione
hydrochloride (50 mg, 0.14 mmol) and DIPEA (25 .mu.L, 0.14 mmol).
The reaction was left at reflux for 18 h then concentrated and
purified by MDAP to provide the title compound as a solid (34 mg,
51%).
[0324] LC/MS: m/z 468 [MH].sup.+, RT 3.4 min.
Example 15
3-(8-Chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl
(1-phenylcyclopropyl)carbamate
a)
3-(8-Chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl
(1-phenylcyclopropyl)carbamate
##STR00043##
[0326] A solution of
8-chloro-1-(3-hydroxypropyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione
(50 mg, 0.16 mmol) was treated with CDI (28 mg, 0.18 mmol) and
allowed to stir at rt for 1 h. 1-Phenylcyclopropanamine (30 mg,
0.20 mmol) was added and the mixture heated at reflux under
nitrogen for 18 h. Another aliquot of 1-phenylcyclopropanamine (30
mg, 0.20 mmol) was added followed by THF (3 ml). The reaction was
heated at 75.degree. C. for 18 h then concentrated and purified by
MDAP. This gave the title compound as a white solid (13 mg,
18%).
[0327] LC/MS: m/z 474 [MH].sup.+, RT 3.5 min.
b)
8-Chloro-1-(3-hydroxypropyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione
##STR00044##
[0329] A solution of
8-chloro-3-pentyl-1-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3,7-dihydro-1-
H-purine-2,6-dione (5.87 g, 14.8 mmol) in EtOH (100 ml) was treated
with pTsOH (2.8 g, 14.8 mmol) and stirred at rt for 18.5 h. The
mixture was partitioned between 1M HCl (aq) and EtOAc. The organic
layer was separated and the aqueous layer extracted once more. The
combined extracts were washed with water (.times.5), brine, then
dried (MgSO.sub.4) and concentrated, giving a pale yellow solid.
The solid was washed with Et.sub.2O and collected by filtration
giving a white solid (2.42 g, 52%).
[0330] LC/MS: m/z 315 [MH].sup.+, RT 2.7 min.
c)
8-Chloro-3-pentyl-1-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3,7-dihydro-
-1H-purine-2,6-dione
##STR00045##
[0332]
8-Chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(5.0 g, 16.8 mmol), Cs.sub.2CO.sub.3 (6.0 g, 18.5 mmol) and
2-(3-bromopropoxy)tetrahydro-2H-pyran (3.4 ml, 20 mmol) were
reacted together in DMF (100 ml) at 50.degree. C. under nitrogen
for 24 h. The reaction was allowed to cool to rt and the mixture
was degassed by applying a vacuum and then nitrogen was introduced.
Pd(PPh.sub.3).sub.4 (1.4 g, 1.2 mmol) was added and the mixture
degassed once more. Morpholine (14.7 ml, 170 mmol) was added and
the mixture was stirred under nitrogen for 3 h, then partitioned
between 2M HCl (aq) and EtOAc. The organic layer was separated,
washed with brine, dried (MgSO.sub.4) and concentrated, giving a
yellow residue (5.16 g). MeOH was added and then passed down an
aminopropyl SPE with the product eluting with 5% AcOH/MeOH. The
product fractions were combined and concentrated, giving the title
compound as a pale yellow solid (5.97 g, 89%).
[0333] LC/MS: m/z 399 [MH].sup.+, RT 3.3 min.
Example 16
3-(8-Chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl
(phenylmethyl)carbamate
##STR00046##
[0335] A solution of
8-chloro-1-(3-hydroxypropyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione
(50 mg, 0.16 mmol) in THF (3 ml) was treated with triphosgene (47
mg, 0.16 mmol) and pyridine (13 .mu.l, 0.16 mmol). After 30 min
benzylamine (217 .mu.l, 2.0 mmol) was added and left to stir for a
further 30 min. The mixture was partitioned between 2M HCl (aq) and
EtOAc. The organic layer was separated, washed with brine, dried
(MgSO.sub.4) and concentrated. The residue was taken up into MeOH
and purified by passing down an aminopropyl SPE, the product eluted
with 2-5% AcOH/MeOH. The title compound was obtained as an
off-white solid (67 mg, 94%).
[0336] LC/MS: m/z 448 [MH].sup.+, RT 3.2 min.
Example 17
3-(8-Chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl
[(3-methylphenyl)methyl]carbamate
##STR00047##
[0338] A solution of
8-chloro-1-(3-hydroxypropyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione
(50 mg, 0.16 mmol) in DCM (3 ml) was treated with CDI (31 mg, 0.19
mmol) and stirred at rt for 1 h. 3-Methylbenzylamine (26 .mu.l,
0.21 mmol) was added and heated at reflux for 18 h. Another aliquot
of methylbenzylamine (4 .mu.l, 0.03 mmol) was added and the mixture
left for 4 h at reflux. The mixture was concentrated then taken up
into MeOH and passed down an aminopropyl SPE. The product was,
eluted with 2% AcOH/MeOH and then purified further by MDAP. This
gave the title compound as a white solid (42 mg, 57%).
[0339] LC/MS: m/z 462 [MH].sup.+, RT 3.5 min.
Example 18
8-Chloro-1-(3-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-4-yl}propyl)-
-3-pentyl-3,7-dihydro-1H-purine-2,6-dione
a)
8-Chloro-1-(3-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-4-yl}prop-
yl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione
##STR00048##
[0341]
8-Chloro-3-pentyl-7-(2-propen-1-yl)-1-[3-(1H-pyrazol-4-yl)propyl]-3-
,7-dihydro-1H-purine-2,6-dione (61 mg, 0.15 mmol) in dry DMF (2 ml)
was stirred with sodium carbonate (64 mg, 0.6 mmol) and
2-chloro-6-fluorobenzyl bromide (134 mg, 0.6 mmol) and heated at
45.degree. C. for 18 h under nitrogen. After cooling to rt the
mixture was degassed by evacuating and readmitting nitrogen, and
stirred with tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.303
mmol) and morpholine (0.13 ml) for 5.5 h. The mixture was
partitioned between EtOAc and 2M HCl, the organic phase separated
and evaporated and the residue purified by aminopropyl SPE (5 g,
washing with THF-MeOH (1:1) then neat MeOH and finally eluting with
DCM-MeOH (1:1) containing 5% AcOH) to give the title compound (57
mg) as a solid.
[0342] LC/MS: m/z 507 [MH].sup.+, RT 3.64 min.
b)
8-Chloro-3-pentyl-7-(2-propen-1-yl)-1-[3-(1H-pyrazol-4-yl)propyl]-3,7-d-
ihydro-1H-purine-2,6-dione
##STR00049##
[0344]
3-Pentyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(5 g, 16.86 mmol) and 3-(1H-pyrazol-4-yl)propan-1-ol (2.12 g, 16.8
mmol) were stirred in dry THF (150 ml) at 3.degree. C. Dibenzyl
azodicarboxylate (10.05 g, 33.7 mmol) was added followed by the
dropwise addition of triphenylphosphine (8.83 g, 33.7 mmol) in dry
THF (70 ml). The mixture was allowed to warm to rt and stirred for
18 h. Water (1 ml) was added and the solvents evaporated. The
residue was taken up in Et.sub.2O (200 ml) from which a white
solid, mostly triphenylphosphine oxide, crystallised and was
filtered off. The filtrate was concentrated and further by-products
crystallised from ether-cyclohexane. The remaining filtrate was
concentrated (19.2 g) and purified on a Biotage.TM. system (400 g)
eluting with EtOAc-cyclohexane (2:1) to afford the title compound
as a white solid (2.89 g).
[0345] LC/MS: m/z 405 [MH].sup.+, RT 3.19 min.
[0346] The following compounds (Table 1) were prepared using a
method analogous to that for Example 18, from the corresponding
benzyl halides.
TABLE-US-00001 TABLE 1 Yield Example structure (mg) LC/MS: 19
##STR00050## 68 m/z 509 [MH].sup.+ RT 3.58 min
8-chloro-3-pentyl-1-(3-{1-[(2,4,6-
trifluorophenyl)methyl]-1H-pyrazol-4-yl}propyl)-3,7-
dihydro-1H-purine-2,6-dione 20 ##STR00051## 56 m/z 507 [MH].sup.+
RT 3.73 min 8-chloro-1-(3-{1-[(2-chloro-4-fluorophenyl)methyl]-1H-
pyrazol-4-yl}propyl)-3-pentyl-3,7-dihydro-1H-purine- 2,6-dione 21
##STR00052## 29 m/z 491 [MH].sup.+ RT 3.53 min
8-chloro-1-(3-{1-[(2,6-difluorophenyl)methyl]-1H-
pyrazol-4-yl}propyl)-3-pentyl-3,7-dihydro-1H-purine- 2,6-dione 22
##STR00053## 32* m/z 473 [MH].sup.+ RT 3.55 min
8-chloro-1-(3-{1-[(2-fluorophenyl)methyl]-1H-pyrazol-
4-yl}propyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione *after
additional purification by MDAP.
NMR Details for Selected Examples from Table 1
Example 19
8-chloro-3-pentyl-1-(3-{1-[(2,4,6-trifluorophenyl)methyl]-1H-pyrazol-4-yl}-
propyl)-3,7-dihydro-1H-purine-2,6-dione
[0347] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.85 (t, 3H, J=7 Hz),
1.20-1.40 (m, 4H), 1.60-1.70 (m, 2H), 1.70-1.82 (m, 2H), 2.39 (t,
2H, J=8 Hz), 3.83-3.94 (m, 4H), 5.24 (s, 2H), 7.18-7.30 (m, 3H),
7.57 (s, 1H).
Example 23
8-Chloro-1-(3-{1-[(2,4-difluorophenyl)methyl]-1H-pyrazol-4-yl}propyl)-3-pe-
ntyl-3,7-dihydro-1H-purine-2,6-dione
##STR00054##
[0349]
8-Chloro-3-pentyl-7-(2-propen-1-yl)-1-[3-(1H-pyrazol-4-yl)propyl]-3-
,7-dihydro-1H-purine-2,6-dione (81 mg, 0.2 mmol) and sodium
carbonate (85 mg, 0.8 mmol) were stirred in dry DMF (2 ml) with
2,4-difluorobenzyl bromide (166 mg, 0.8 mmol) at 45.degree. C. for
18 h. The mixture was degassed and stirred with
tetrakis(triphenylphosphine)palladium(0) (46 mg, 0.04 mmol) and
morpholine (176 mg, 2 mmol) at rt for 6 h. The reaction was worked
up and purified by aminopropyl SPE (5 g, washing with THF-MeOH
(1:1) then neat MeOH, eluting with DCM-MeOH (1:1) with 5% added
AcOH) to yield the title compound (37.7 mg) as a solid.
[0350] LC/MS: m/z 491 [MH].sup.+, RT 3.42 min.
[0351] .sup.1H NMR (d.sup.6 DMSO) 0.85 (3H, t, J=7 Hz), 1.21-1.34
(4H, m), 1.58-1.68 (2H, m), 1.71-1.80 (2H, m), 2.41 (2H, t, J=8
Hz), 3.84-3.93 (4H, m), 5.26 (2H, s), 7.02-7.09 (1H, m), 7.15-7.29
(2H, m), 7.31 (1H, s), 7.61 (1H, s).
[0352] The following compounds (Table 1) were prepared using a
method analogous to that for Example 23, from the corresponding
benzyl halides.
TABLE-US-00002 TABLE 2 Yield Example Structure (mg) LC/MS: 24
##STR00055## 17* m/z 455 [MH].sup.+ RT 3.52 min
8-chloro-3-pentyl-1-{3-[1-(phenylmethyl)-1H-pyrazol-4-
yl]propyl}-3,7-dihydro-1H-purine-2,6-dione 25 ##STR00056## 11.6*
m/z 489 [MH].sup.+ RT 3.52 min
8-chloro-1-(3-{1-[(3-chlorophenyl)methyl]-1H-pyrazol-4-
yl}propyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 26 ##STR00057##
33 m/z 469 [MH].sup.+ RT 3.54 min
8-chloro-1-(3-{1-[(3-methylphenyl)methyl]-1H-pyrazol-4-
yl}propyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 27 ##STR00058##
42 m/z 473 [MH].sup.+ RT 3.44 min
8-chloro-1-(3-{1-[(4-fluorophenyl)methyl]-1H-pyrazol-4-
yl}propyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione *after
additional purification by MDAP.
NMR Details for Selected Examples from Table 2
Example 24
8-chloro-3-pentyl-1-{3-[1-(phenylmethyl)-1H-pyrazol-4-yl]propyl}-3,7-dihyd-
ro-1H-purine-2,6-dione
[0353] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.87 (t, 3H, J=7 Hz),
1.20-1.36 (m, 4H), 1.60-1.70 (m, 2H), 1.72-1.85 (m, 2H), 2.42 (t,
2H, J=8 Hz), 3.83-3.95 (m, 4H), 5.24 (s, 2H), 7.13-7.38 (m, 6H),
7.61 (s, 1H).
Example 28
8-Chloro-1-(3-{1-[(2-chlorophenyl)methyl]-1H-pyrazol-4-yl}propyl)-3-pentyl-
-3,7-dihydro-1H-purine-2,6-dione
##STR00059##
[0355] Prepared by the method for
8-chloro-1-(3-{1-[(2,4-difluorophenyl)methyl]-1H-pyrazol-4-yl}propyl)-3-p-
entyl-3,7-dihydro-1H-purine-2,6-dione but from 2-chlorobenzyl
bromide (164 mg, 0.8 mmol). However, in order to complete the
deprotection step further tetrakis(triphenylphosphine)palladium(0)
(40 mg) and morpholine (0.15 ml) were added and stirring continued
for a further 5.5 h. Purification by aminopropyl SPE as above
afforded the title compound as a solid (42 mg).
[0356] LC/MS: m/z 489 [MH].sup.+, RT 3.67 min.
Example 29
3-Butyl-8-chloro-1-{3-[1-(phenylmethyl)-1H-imidazol-4-yl]propyl}-3,7-dihyd-
ro-1H-purine-2,6-dione
a)
3-Butyl-8-chloro-1-{3-[1-(phenylmethyl)-1H-imidazol-4-yl]propyl}-3,7-di-
hydro-1H-purine-2,6-dione
##STR00060##
[0358] A solution of
3-butyl-8-chloro-1-[4-(1H-imidazol-4-yl)butyl]-7-(2-propen-1-yl)-3,7-dihy-
dro-1H-purine-2,6-dione (300 mg, 0.77 mmol) in anhydrous THF (5 ml)
was treated with benzyl bromide (144 mg, 0.84 mmol) and DIPEA (147
.mu.l, 0.84 mmol). The mixture was left to stir at rt under
nitrogen for 4 days. The mixture was partitioned between EtOAc and
2M HCl (aq). The organic layer was separated, washed with brine,
dried (MgSO.sub.4) and concentrated. The crude was purified by a
silica SPE column using a 0.5-5% MeOH/DCM gradient. The product
fractions were combined and concentrated under high vacuum. The
product was dissolved in THF (5 ml) then Pd(PPh.sub.3).sub.4 (88
mg, 0.077 mmol) and morpholine (670 .mu.l, 7.67 mmol) were added
and the mixture left to stir at rt under nitrogen for 3 h. 88 mg of
Pd(PPh.sub.3).sub.4 (0.077 mmol) was added and the mixture was left
to stir at rt under nitrogen for 16 h. The mixture was partitioned
between EtOAc and H.sub.2O. The organic layer was separated and the
aqueous layer was extracted with EtOAc (.times.2). The organic
layers were combined, washed with brine, dried (MgSO.sub.4) and
concentrated. The crude product was purified by MDAP to give the
title compound as a white solid (9 mg, 2%).
[0359] LC/MS: m/z 441 [MH].sup.+, RT 2.50 min.
[0360] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.89 (t, 3H, J=7.5 Hz),
1.28 (m, 2H), 1.60 (m, 2H), 1.79 (m, 2H), 2.48 (t overlapping with
DMSO, 2H, J=7.5 Hz), 3.89 (m, 4H), 5.17 (s, 2H), 7.08 (s, 1H),
7.31, (m, 6H), 8.03 (s, 1H).
b)
3-Butyl-8-chloro-1-[3-(1H-imidazol-4-yl)propyl]-7-(2-propen-1-yl)-3,7-d-
ihydro-1H-purine-2,6-dione
##STR00061##
[0362] A solution of
3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(2.8 g, 9.9 mmol) in anhydrous THF (60 ml) was treated with
3-(1H-imidazol-4-yl)-1-propanol (1.5 g, 12 mmol) in anhydrous THF
(10 ml) and PPh.sub.3 (3.4 g, 13 mmol). DBAD (2.9 g, 13 mmol) was
added in one portion and the mixture was left to stir at rt, under
nitrogen for 18 h. The mixture was partitioned between EtOAc and
H.sub.2O. The aqueous layer was extracted and washed with EtOAc.
The organic layers were combined, washed with brine, dried
(MgSO.sub.4) and concentrated. The crude product was purified by a
silica SPE cartridge using a MeOH/EtOAc gradient (0.5%-7% MeOH).
The product fractions were combined and concentrated by to give the
title compound as a white solid (2.16 g, 55%).
[0363] LC/MS: m/z 391 [MH].sup.+, RT 2.40 min.
c)
3-Butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
##STR00062##
[0365] To a solution of
3-butyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (3.34 g,
13.4 mmol) in anhydrous DMF (19 ml) was added NCS (1.97 g, 14.8
mmol) and left to stir at rt under nitrogen for 22 h. The mixture
was concentrated in vacuo to give a yellow solid which was filtered
and washed with MeOH to provide a first crop. The filtrate was
concentrated to a solid and washed with MeOH to provide a second
crop and repeated a further two occasions to provide the title
compound. On the final wash the filtrate was further purified by
SPE (Si, 20 g) cartridge eluting with EtOAc:cyclohexane (1:1). The
combined solids were dried under vacuum to afford the title
compound (2.42 g, 64%).
[0366] LC/MS: m/z 283 [MH].sup.+.
Example 30
3-Butyl-8-chloro-1-(3-{1-[(2,3-difluorophenyl)methyl]-1H-imidazol-4-yl}pro-
pyl)-3,7-dihydro-1H-purine-2,6-dione
##STR00063##
[0368] A solution of
3-butyl-8-chloro-1-[4-(1H-imidazol-4-yl)butyl]-7-(2-propen-1-yl)-3,7-dihy-
dro-1H-purine-2,6-dione (150 mg, 0.38 mmol) in anhydrous DMF (3 ml)
was treated with 1-(bromomethyl)-2,4-difluorobenzene (54 .mu.l,
0.42 mmol) and DIPEA (73 .mu.l, 0.42 mmol). The mixture was left to
stir at rt under nitrogen for 3 days. The mixture was partitioned
between EtOAc and 2M HCl (aq). The organic layer was separated,
washed with brine, dried (MgSO.sub.4) and concentrated. The crude
product was purified on a silica SPE column using a DCM to load the
material onto the column and wash through the impurities then a
0-5% MeOH/DCM gradient to elute the compound. The product fractions
were combined and concentrated and the residues dissolved in
anhydrous DMF (3 ml). The solution was degassed then
Pd(PPh.sub.3).sub.4 (39 mg, 0.034 mmol) and morpholine (200 .mu.l,
2.3 mmol) were added and the mixture left to stir at rt under
nitrogen for 3 h. The crude product was purified by an aminopropyl
SPE using MeOH to load the compound onto the column and wash
through the impurities then a 0-5% AcOH/MeOH gradient to elute the
product. The product fractions were combined and concentrated by
high vacuum to leave the title compound as a white solid (14 mg,
7%).
[0369] LC/MS: m/z 477 [MH].sup.+, RT 2.54 min.
Example 31
3-Butyl-8-chloro-1-[3-(1-{[2-(trifluoromethyl)phenyl]methyl}-1H-imidazol-4-
-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione
##STR00064##
[0371] A solution of
3-butyl-8-chloro-1-[4-(1H-imidazol-4-yl)butyl]-7-(2-propen-1-yl)-3,7-dihy-
dro-1H-purine-2,6-dione (150 mg, 0.38 mmol) in anhydrous DMF (3 ml)
was treated with 1-(chloromethyl)-2-(trifluoromethyl)benzene (61
.mu.l, 0.42 mmol) and DIPEA (73 .mu.l, 0.42 mmol). The mixture was
left to stir at rt under nitrogen for 3 days. The mixture was
partitioned between EtOAc and 2M HCl (aq). The organic layer was
separated, washed with brine, dried (MgSO.sub.4) and concentrated.
The crude product was purified on a silica SPE column using DCM to
load the material onto the column and wash through the impurities
then a 0-5% MeOH/DCM gradient to elute the compound. The product
fractions were combined and concentrated and the residues dissolved
in anhydrous DMF (3 ml). The solution was degassed then
Pd(PPh.sub.3).sub.4 (35 mg, 0.030 mmol) and morpholine (174 .mu.l,
2.0 mmol) were added and the mixture left to stir at rt under
nitrogen for 3 h. The crude product was purified by an aminopropyl
SPE using MeOH to load the compound onto the column and wash
through the impurities then a 0-5% AcOH/MeOH gradient to elute the
product. The product fractions were combined and concentrated by
high vacuum to leave the title compound as a white solid (50 mg,
26%).
[0372] LC/MS: m/z 509 [MH].sup.+, RT 2.64 min.
Example 32
3-Butyl-8-chloro-1-[3-(1-{[3-(trifluoromethyl)phenyl]methyl}-1H-imidazol-4-
-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione
##STR00065##
[0374] A solution of
3-butyl-8-chloro-1-[4-(1H-imidazol-4-yl)butyl]-7-(2-propen-1-yl)-3,7-dihy-
dro-1H-purine-2,6-dione (150 mg, 0.38 mmol) in anhydrous DMF (3 ml)
was treated with 1-(chloromethyl)-3-(trifluoromethyl)benzene (65
.mu.l, 0.42 mmol) and DIPEA (73 .mu.l, 0.42 mmol). The mixture was
left to stir at rt under nitrogen for 3 days. The mixture was
partitioned between EtOAc and 2M HCl (aq). The organic layer was
separated, washed with brine, dried (MgSO.sub.4) and concentrated.
The crude product was purified on a silica SPE column using a DCM
to load the material onto the column and wash through the
impurities then a 0-5% MeOH/DCM gradient to elute the compound. The
product fractions were combined and concentrated and the residues
dissolved in anhydrous DMF (3 ml). The solution was degassed then
Pd(PPh.sub.3).sub.4 (30 mg, 0.027 mmol) and morpholine (156 .mu.l,
1.8 mmol) were added and the mixture left to stir at rt under
nitrogen for 3 h. The crude product was purified by an aminopropyl
SPE using MeOH to load the compound onto the column and wash
through the impurities then a 0-5% AcOH/MeOH gradient to elute the
product. The product fractions were combined and concentrated by
high vacuum to leave the title compound as a white solid (18 mg,
9%).
[0375] LC/MS: m/z 509 [MH].sup.+, RT 2.78 min.
Example 33
3-Butyl-8-chloro-1-{3-[3-(phenylmethyl)-1H-1,2,4-triazol-1-yl]propyl}-3,7--
dihydro-1H-purine-2,6-dione
a)
3-Butyl-8-chloro-1-{3-[3-(phenylmethyl)-1H-1,2,4-triazol-1-yl]propyl}-3-
,7-dihydro-1H-purine-2,6-dione
##STR00066##
[0377] A solution of
3-butyl-8-chloro-1-{3-[3-(phenylmethyl)-1H-1,2,4-triazol-1-yl]propyl}-7-(-
2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (669 mg, 1.39 mmol)
in THF (7 ml) was degassed by applying a vacuum and then nitrogen
was introduced. Pd(PPh.sub.3).sub.4 (160 mg, 0.14 mmol) was added
and the mixture degassed once more. Morpholine (1.2 ml, 13.9 mmol)
was added and the mixture was stirred under nitrogen for 18 h, then
partitioned between 2M HCl (aq) and EtOAc. The organic layer was
separated and the aqueous layer extracted again with EtOAc. The
combined extracts were washed with brine, dried (MgSO.sub.4) and
concentrated, giving a yellow residue. MeOH was added and then
passed down an aminopropyl SPE with the product eluting with 2-3%
AcOH/MeOH. The product fractions were combined and concentrated
giving a pale yellow solid (380 mg). Approximately a quarter of the
material was purified by autoprep HPLC and rest was crystallised
from MeOH:DMSO (1:1) giving the title compound as a white solid
(125 mg, 31%).
[0378] LC/MS: m/z 442 [MH].sup.+, RT 3.0 min.
[0379] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.89 (t, 3H, J=7 Hz),
1.30 (m, 2H), 1.62 (m, 2H), 2.07 (m, 2H), 3.90 (m, 6H), 4.13 (t,
2H, J=7 Hz), 7.24 (m, 5H), 8.36 (1H, s), 14.5 (br s, 1H).
b)
3-Butyl-8-chloro-1-{3-[3-(phenylmethyl)-1H-1,2,4-triazol-1-yl]propyl}-7-
-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
##STR00067##
[0381] A solution of 3-(phenylmethyl)-1H-1,2,4-triazole (2.1 g,
13.2 mmol) in MeOH (40 ml) was treated with 0.5M NaOMe in MeOH (29
ml) followed by 1,3-dibromopropane (1.7 ml). After stirring for 5 h
at 50.degree. C. the mixture was partitioned between 2M HCl (aq)
and EtOAc. The organic layer was separated, washed with brine,
dried (MgSO.sub.4) and concentrated, giving an oily residue (1.0
g). To this was added
butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(917 mg, 3.2 mmol) and Cs.sub.2CO.sub.3 (1.2 g, 3.6 mmol). DMF (15
ml) was added and the mixture was stirred at 50.degree. C. for 20 h
then partitioned between 2M HCl (aq) and EtOAc. The organic layer
was separated, washed with brine, dried (MgSO.sub.4) and
concentrated. The resulting oil (1.52 g) was passed down a silica
SPE (50 g) column eluting with EtOAc/cyclohexane mixtures. Two
isomeric products of the triazole were obtained as a 2:1 mixture,
in favour of the title compound, as a yellow paste (697 mg, 67%
based on ratio of isomers present).
[0382] LC/MS: m/z 482 [MH].sup.+, RT 3.3 min.
Example 34
8-Chloro-3-pentyl-1-{3-[5-(phenylmethyl)-2H-tetrazol-2-yl]propyl}-3,7-dihy-
dro-1H-purine-2,6-dione
##STR00068##
[0384] A solution of 5-benzyl-1H-tetrazole (1.0 g, 6.24 mmol) in
MeOH (5 ml) was treated with 1-chloro-3-iodopropane (1.0 ml, 9.36
mmol) and a solution of 0.5M NaOMe in MeOH (4.7 ml, 9.36 mmol). The
reaction was heated at reflux for 18 h then partitioned between 2M
HCl (aq) and EtOAc. The organic layer was separated and the aqueous
layer extracted once more with EtOAc. The combined extracts were
washed with brine, dried (MgSO.sub.4) and concentrated, giving a
yellow solid. (796 mg). 700 mg of this material was reacted with
8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(732 mg, 2.47 mmol) and Cs.sub.2CO.sub.3 (967 mg, 3.0 mmol) in DMF
(20 ml) at 75.degree. C. for 24 h. The reaction was allowed to cool
to rt and the mixture was degassed by applying a vacuum and then
nitrogen was introduced. Pd(PPh.sub.3).sub.4 (428 mg, 0.37 mmol)
was added and the mixture degassed once more. Morpholine (2.1 ml,
24.7 mmol) was added and the mixture was stirred under nitrogen for
3 h, then partitioned between 2M HCl (aq) and EtOAc. The organic
layer was separated and the aqueous layer extracted once more. The
combined extracts were concentrated, giving a yellow residue. MeOH
was added and then passed down an aminopropyl SPE, the product
eluting with 2-3% AcOH/MeOH. The product fractions were combined
and concentrated then purified by the MDAP to give the title
compound as a white solid (35 mg, 3%).
[0385] LC/MS: m/z 457 [MH].sup.+, RT 3.5 min.
[0386] .sup.1H NMR; (DMSO-d.sub.6) .delta.: 0.85 (t, 3H, J=7 Hz),
1.21-1.34 (m, 4H), 1.62 (m, 2H), 2.22 (m, 2H), 3.88 (t, 2H, J=7
Hz), 3.97 (t, 2H, J=7 Hz), 4.17 (s, 2H), 4.67 (t, 2H, J=7 Hz),
7.20-7.32 (m, 5H), 14.5 (br s, 1H).
Example 35
3-Butyl-8-chloro-1-{3-[5-(phenylmethyl)-2H-tetrazol-2-yl]propyl}-3,7-dihyd-
ro-1H-purine-2,6-dione
##STR00069##
[0388] A solution of 5-benzyl-1H-tetrazole (1.8 g, 11.2 mmol) in
MeOH (30 ml) was treated with 1,3-dibromopropane (5.7 ml, 56.2
mmol) and 0.5M NaOMe in MeOH (31.5 ml) then stirred at 40.degree.
C. under nitrogen for 60 h. The mixture was partitioned between 2M
HCl (aq) and EtOAc. The organic layer was separated, washed with
brine, dried (MgSO.sub.4) and concentrated. Partial purification by
SPE (20 g silica, cyclohexane/EtOAc mixtures) and by the
Companion.TM. system (silica SPE, cyclohexane/EtOAc mixtures) gave
an oil (1.98 g, 62% of a mixture of isomers, 2:1 in favour of
2-(3-bromopropyl)-5-(phenylmethyl)-2H-tetrazole) which was taken on
crude in the next step.
[0389] A mixture of
3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(1.74 g, 6.1 mmol), crude
2-(3-bromopropyl)-5-(phenylmethyl)-2H-tetrazole) (1.9 g, 6.8 mmol),
Cs.sub.2CO.sub.3 (2.2 g, 6.8 mmol) and DMF (60 ml) was stirred at
45.degree. C. under nitrogen for 24 h. The mixture was degassed by
applying a vacuum and then nitrogen was introduced.
Pd(PPh.sub.3).sub.4 (705 mg, 0.61 mmol) was added and the mixture
degassed once more. Morpholine (5.4 ml, 61.4 mmol) was added and
the mixture was stirred under nitrogen for 4 h, and then
partitioned between 2M HCl (aq) and EtOAc. The organic layer was
separated, washed with brine, dried (MgSO.sub.4) and concentrated,
giving a yellow residue. MeOH was added and then passed down an
aminopropyl column with the product eluting with 2% AcOH/MeOH. The
product was further purified by the Companion.TM. system using
EtOAc/cyclohexane mixtures. The resulting solid was stirred with
boiling Et.sub.2O and filtered after cooling to rt. The title
compound was collected as a white solid (1.01 g, 37%) and dried at
50.degree. C. under vacuum.
[0390] LC/MS: m/z 443 [MH].sup.+, RT 3.3 min.
[0391] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.89 (t, 3H, J=7 Hz),
1.29 (m, 2H), 1.61 (m, 2H), 2.22 (m, 2H), 3.89 (t, 2H, J=7 Hz),
3.97 (t, 2H, J=7 Hz), 4.17 (s, 2H), 4.67 (t, 2H, J=7 Hz), 7.20-7.32
(m, 5H), 14.5 (br s, 1H).
Example 36
8-Chloro-1-(3-{5-[(4-fluorophenyl)methyl]-2H-tetrazol-2-yl}propyl)-3-(4,4,-
4-trifluorobutyl)-3,7-dihydro-1H-purine-2,6-dione
a)
8-Chloro-1-(3-{5-[(4-fluorophenyl)methyl]-2H-tetrazol-2-yl}propyl)-3-(4-
,4,4-trifluorobutyl)-3,7-dihydro-1H-purine-2,6-dione
##STR00070##
[0393] 5-[(4-Fluorophenyl)methyl]-1H-tetrazole (75 mg, 0.4 mmol)
was treated with potassium carbonate (100 mg, 0.7 mmol) and DMF (3
ml). The mixture was treated with a solution of
3-[8-chloro-2,6-dioxo-7-(2-propen-1-yl)-3-(4,4,4-trifluorobutyl)-2,3,6,7--
tetrahydro-1H-purin-1-yl]propyl methanesulfonate (100 mg, 0.2 mmol)
in DMF (0.5 ml). The mixture was stirred and heated at 60.degree.
C. 3 hours then cooled and evaporated. The residue was partitioned
between chloroform (4 ml) and water (2 cm.sup.3). 1 cm.sup.3 of
saturated aqueous sodium bicarbonate (3 ml) was added to each. The
mixture was separated and the organic phase evaporated. The residue
was dissolved in anhydrous THF (3 ml) and the mixture degassed by
the cautious successive application of vacuum and nitrogen pressure
to the mixture. The mixture was treated with
tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.008 mmol) and
morpholine (0.2 ml, 2.3 mmol) and then stirred in a nitrogen
atmosphere for 2 h. The mixture was evaporated and partitioned
between chloroform (4 ml) and saturated aqueous ammonium chloride
(3 ml). The mixture was separated, and the aqueous phase
re-extracted with chloroform. The organic phase was evaporated and
the residue dissolved in MeOH (3 ml). The solution was added to the
top of a 2 g aminopropyl SPE and washed with MeOH (15 ml). The
desired product was eluted from the cartridge with a 3% v/v
solution of AcOH in MeOH (20 ml). Product containing fractions were
combined and evaporated and the residue subjected to purification
by flash column chromatography (gradient elution from 10:1
cyclohexane/EtOAc to EtOAc). Product-containing fractions were
combined and evaporated to yield the product as a colourless oil.
Trituration in minimal diethyl ether caused the product to solidify
and this was thoroughly dried to yield the title compound as a
white solid (18.7 mg, 18%).
[0394] LC/MS: m/z 515 [MH].sup.+, RT 3.31 min.
[0395] .sup.1H NMR (CDCl.sub.3) .delta.: 2.06 (m, 2H), 2.21 (m,
2H), 2.45 (m, 2H), 4.17 (m, 4H), 4.24 (t, 2H, J=7.0 Hz), 4.70 (t,
2H, J=7.2 Hz), 6.96 (m, 2H), 7.25 (m, 2H).
b)
3-[8-Chloro-2,6-dioxo-7-(2-propen-1-yl)-3-(4,4,4-trifluorobutyl)-2,3,6,-
7-tetrahydro-1H-purin-1-yl]propyl methanesulfonate
##STR00071##
[0397] A solution of
8-chloro-1-(3-hydroxypropyl)-7-(2-propen-1-yl)-3-(4,4,4-trifluorobutyl)-3-
,7-dihydro-1H-purine-2,6-dione (0.82 g, 2.1 mmol) in DCM (20 ml)
was treated with triethylamine (0.42 ml, 3.1 mmol) and
methanesulfonic anhydride (0.40 g, 2.3 mmol). After 1 h the mixture
was treated with saturated aqueous sodium bicarbonate (20 ml). The
mixture was separated and the organic phase dried (MgSO.sub.4),
filtered and evaporated to give the title compound (0.91 g), which
was used without further purification.
[0398] LC/MS: m/z 473 [MH].sup.+, RT 3.17 min.
c)
8-Chloro-1-(3-hydroxypropyl)-7-(2-propen-1-yl)-3-(4,4,4-trifluorobutyl)-
-3,7-dihydro-1H-purine-2,6-dione
##STR00072##
[0400] A solution of
8-chloro-7-(2-propen-1-yl)-3-(4,4,4-trifluorobutyl)-3,7-dihydro-1H-purine-
-2,6-dione (1.0 g, 3.0 mmol) in DMF (15 ml) was treated with
caesium carbonate (1.16 g, 3.6 mmol) and 3-bromo-1-propanol (0.3
ml, 3.3 mmol). The mixture was heated at 60.degree. C. for 4 h and
then cooled and evaporated. The residue was partitioned between
EtOAc (50 ml) and water (50 ml). The organic phase was dried
(MgSO.sub.4), filtered and evaporated. The product was purified by
flash chromatography using a gradient elution from cyclohexane to
EtOAc. Product-containing fractions were combined and evaporated to
give the title compound as a colourless oil (0.82 g, 75%).
[0401] LC/MS: m/z 395 [MH].sup.+, RT 2.90 min.
d)
8-Chloro-7-(2-propen-1-yl)-3-(4,4,4-trifluorobutyl)-3,7-dihydro-1H-puri-
ne-2,6-dione
##STR00073##
[0403] A solution of
8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (2.0 g,
8.8 mmol) in DMF (20 ml) was treated with sodium carbonate (1.15 g,
10.8 mmol) and 4-bromo-1,1,1-trifluorobutane (1.86 g, 9.7 mmol).
The mixture was stirred at 50.degree. C. for 18 h then cooled and
evaporated. The residue was partitioned between EtOAc (100 ml) and
saturated aqueous sodium bicarbonate (50 ml). The organic phase was
dried (MgSO.sub.4), filtered and evaporated. The residue was
triturated in a mixture of diethyl ether and cyclohexane then the
product filtered off and dried to yield the title compound as a
white solid (1.18 g, 40%).
[0404] LC/MS: m/z 337 [MH].sup.+, RT 2.83 min.
e) 5-[(4-Fluorophenyl)methyl]-1H-tetrazole
##STR00074##
[0406] A mixture of triethylammonium chloride (4.14 g, 30 mmol) and
sodium azide (1.95 g, 30 mmol) was treated with a solution of
(4-fluorophenyl)acetonitrile (1.35 g, 10 mmol) in toluene (14 ml)
and the mixture was stirred and heated at 100.degree. C. for 5 h.
The cooled mixture was treated with water (10 ml) and the mixture
separated. The aqueous phase was stirred and treated dropwise with
concentrated hydrochloric acid until the product had precipitated
from solution. The precipitated product was filtered off, washed
with water and dried to yield the title compound as a white solid
(1.27 g, 72%).
[0407] LC/MS: m/z 179 [MH].sup.+, RT 2.24 min.
[0408] The compounds in Table 3 were prepared using a method
analogous to that for Example 36:
8-chloro-1-(3-{5-[(4-fluorophenyl)methyl]-2H-tetrazol-2-yl}propyl)-3-(4,4-
,4-trifluorobutyl)-3,7-dihydro-1H-purine-2,6-dione, with the
appropriate methanesulfonate and tetrazole. MDAP was employed to
further purify those compounds insufficiently pure following normal
phase chromatography.
[0409] Methanesulfonates intermediates and their precursor alcohols
were prepared according to the following procedures:
3-[8-Chloro-2,6-dioxo-7-(2-propen-1-yl)-3-propyl-2,3,6,7-tetrahydro-1H-pur-
in-1-yl]propyl methanesulfonate
##STR00075##
[0411] A solution of
8-chloro-1-(3-hydroxypropyl)-7-(2-propen-1-yl)-3-propyl-3,7-dihydro-1H-pu-
rine-2,6-dione (1.99 g, 6.1 mmol) in DCM (50 ml) was treated with
triethylamine (1.2 ml, 8.6 mmol) and methanesulfonic anhydride (1.2
g, 6.9 mmol). After 1.5 h the mixture was treated with water (50
ml). The mixture was separated and the aqueous phase extracted with
DCM (25 ml), the combined organic phases dried (MgSO.sub.4),
filtered and evaporated to give the title compound as a pale yellow
oil (2.38 g), which was used without further purification.
[0412] LC/MS: m/z 405 [MH].sup.+, RT 2.93 min.
3-[3-Butyl-8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-puri-
n-1-yl]propyl methanesulfonate
##STR00076##
[0414] Prepared according to the method used for
3-[8-chloro-2,6-dioxo-7-(2-propen-1-yl)-3-propyl-2,3,6,7-tetrahydro-1H-pu-
rin-1-yl]propyl methanesulfonate to give the title compound as a
pale yellow oil (2.44 g).
[0415] LC/MS: m/z 419 [MH].sup.+, RT 3.14 min.
8-Chloro-1-(3-hydroxypropyl)-7-(2-propen-1-yl)-3-propyl-3,7-dihydro-1H-pur-
ine-2,6-dione
##STR00077##
[0417] A solution of
8-chloro-7-(2-propen-1-yl)-3-propyl-3,7-dihydro-1H-purine-2,6-dione
(3.0 g, 11.1 mmol) in DMF (20 ml) was treated with caesium
carbonate (3.7 g, 11.4 mmol) and 3-bromo-1-propanol (1.6 g, 11.5
mmol). The mixture was heated at 60.degree. C. for 4 h and then
cooled and evaporated. The residue was partitioned between EtOAc
(60 ml) and saturated aqueous sodium bicarbonate (50 ml). The
aqueous phase was extracted with EtOAc (60 ml), the combined
organic phases were dried (MgSO.sub.4), filtered and evaporated.
The product was purified using the Companion.TM. system and a
gradient elution from cyclohexane to EtOAc. Product containing
fractions were combined and evaporated to give the title compound
as a colourless oil (2.6 g).
[0418] LC/MS: m/z 327 [MH].sup.+, RT 2.62 min.
3-Butyl-8-chloro-1-(3-hydroxypropyl)-7-(2-propen-1-yl)-3,7-dihydro-1H-puri-
ne-2,6-dione
##STR00078##
[0420] Prepared according to the method used for
8-chloro-1-(3-hydroxypropyl)-7-(2-propen-1-yl)-3-propyl-3,7-dihydro-1H-pu-
rine-2,6-dione to give the title compound as a colourless oil (2.3
g).
[0421] LC/MS: m/z 341 [MH].sup.+, RT 2.85 min.
TABLE-US-00003 TABLE 3 # Structure Name Yield LC/MS: 37
##STR00079## 8-chloro-1-(3-{5-[(4-
fluorophenyl)methyl]-2H-tetrazol-2-
yl}propyl)-3-propyl-3,7-dihydro-1H- purine-2,6-dione 12.4 mg (14%)
m/z 447 [MH].sup.+ RT 3.14 min 38 ##STR00080##
8-chloro-3-propyl-1-[3-(5-{[3- (trifluoromethyl)phenyl]methyl}-2H-
tetrazol-2-yl)propyl]-3,7-dihydro-1H- purine-2,6-dione 8.0 mg (8%)
m/z 497 [MH].sup.+ RT 3.36 min 39 ##STR00081##
8-chloro-3-(4,4,4-trifluorobutyl)-1-[3- (5-{[3-
(trifluoromethyl)phenyl]methyl}-2H-
tetrazol-2-yl)propyl]-3,7-dihydro-1H- purine-2,6-dione 21.0 mg
(19%) m/z 565 [MH].sup.+ RT 3.34 min 40 ##STR00082##
8-chloro-3-(4,4,4-trifluorobutyl)-1-(3-
{-5-[(2,4,6-trifluorophenyl)methyl]-
2H-tetrazol-2-yl}propyl)-3,7-dihydro- 1H-purine-2,6-dione 17.0 mg
(15%) m/z 551 [MH].sup.+ RT 3.27 min 41 ##STR00083##
8-chloro-1-(3-{5-[(3,4- difluorophenyl)methyl]-2H-tetrazol-
2-yl}propyl)-3-(4,4,4-trifluorobutyl)-
3,7-dihydro-1H-purine-2,6-dione 19.1 mg (18%) m/z 533 [MH].sup.+ RT
3.36 min 42 ##STR00084## 3-butyl-8-chloro-1-[3-(5-{[2-fluoro-5-
(trifluoromethyl)phenyl]methyl}-2H-
tetrazol-2-yl)propyl]-3,7-dihydro-1H- purine-2,6-dione 23.9 mg
(23%) m/z 529 [MH].sup.+ RT 3.50 min 43 ##STR00085##
8-chloro-1-(3-{5-[(2- fluorophenyl)methyl]-2H-tetrazol-2-
yl}propyl)-3-(4,4,4-trifluorobutyl)-
3,7-dihydro-1H-purine-2,6-dione 19.8 mg (19%) m/z 515 [MH].sup.+ RT
3.31 min 44 ##STR00086## 8-chloro-1-(3-{5-[(2,6-
dichlorophenyl)methyl]-2H-tetrazol-
2-yl}propyl)-3-propyl-3,7-dihydro- 1H-purine-2,6-dione 50.7 mg
(51%) m/z 497 [MH].sup.+ RT 3.33 min 45 ##STR00087##
3-butyl-8-chloro-1-(3-{5-[(2- fluorophenyl)methyl]-2H-tetrazol-2-
yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 46.4 mg (48%) m/z 461
[MH].sup.+ RT 3.27 min 46 ##STR00088##
3-butyl-8-chloro-1-(3-{5-[(2- chlorophenyl)methyl]-2H-tetrazol-2-
yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 25.4 mg (27%) m/z 477
[MH].sup.+ RT 3.40 min 47 ##STR00089##
3-butyl-8-chloro-1-(3-{5-[(3- fluorophenyl)methyl]-2H-tetrazol-2-
yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 36.8 mg (40%) m/z 461
[MH].sup.+ RT 3.31 min 48 ##STR00090##
3-butyl-8-chloro-1-(3-{5-[(3- chlorophenyl)methyl]-2H-tetrazol-2-
yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 38.5 mg (40%) m/z 477
[MH].sup.+ RT 3.45 min 49 ##STR00091##
3-butyl-8-chloro-1-(3-{5-[(4- fluorophenyl)methyl]-2H-tetrazol-2-
yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 31.6 mg (34%) m/z 461
[MH].sup.+ RT 3.31 min 50 ##STR00092##
3-butyl-8-chloro-1-(3-{5-[(4- chlorophenyl)methyl]-2H-tetrazol-2-
yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 33.1 mg (35%) m/z 477
[MH].sup.+ RT 3.46 min 51 ##STR00093##
3-butyl-8-chloro-1-(3-{5-[(2- methylphenyl)methyl]-2H-tetrazol-2-
yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 39.5 mg (43%) m/z 457
[MH].sup.+ RT 3.37 min 52 ##STR00094##
3-butyl-8-chloro-1-(3-{5-[(3- methylphenyl)methyl]-2H-tetrazol-2-
yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 36.5 mg (40%) m/z 457
[MH].sup.+ RT 3.40 min 53 ##STR00095##
3-butyl-8-chloro-1-[3-(5-{[3- (trifluoromethyl)phenyl]methyl}-2H-
tetrazol-2-yl)propyl]-3,7-dihydro-1H- purine-2,6-dione 43.7 mg
(43%) m/z 511 [MH].sup.+ RT 3.50 min 54 ##STR00096##
3-butyl-8-chloro-1-[3-(5-{[2- (methyloxy)phenyl]methyl}-2H-
tetrazol-2-yl)propyl]-3,7-dihydro-1H- purine-2,6-dione 28.6 mg
(30%) m/z 473 [MH].sup.+ RT 3.29 min 55 ##STR00097##
3-butyl-8-chloro-1-{3-[5-(1- phenylcyclopropyl)-2H-tetrazol-2-
yl]propyl}-3,7-dihydro-1H-purine- 2,6-dione 44.2 mg (47%) m/z 469
[MH].sup.+ RT 3.41 min 56 ##STR00098## 3-butyl-8-chloro-1-{3-[5-(2-
phenylethyl)-2H-tetrazol-2- yl]propyl}-3,7-dihydro-1H-purine-
2,6-dione 39.2 mg (43%) m/z 457 [MH].sup.+ RT 3.36 min 57
##STR00099## 3-butyl-8-chloro-1-{3-[5-(2-
thienylmethyl)-2H-tetrazol-2- yl]propyl}-3,7-dihydro-1H-purine-
2,6-dione 33.4 mg (37%) m/z 449 [MH].sup.+ RT 3.20 min 58
##STR00100## 3-butyl-8-chloro-1-(3-{5-[(2,6-
dichlorophenyl)methyl]-2H-tetrazol-
2-yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 36.4 mg (36%) m/z 511
[MH].sup.+ RT 3.49 min 59 ##STR00101## 8-chloro-1-(3-{5-[(2-
fluorophenyl)methyl]-2H-tetrazol-2-
yl}propyl)-3-propyl-3,7-dihydro-1H- purine-2,6-dione 5.6 mg (6%)
m/z 447 [MH].sup.+ RT 3.10 min 60 ##STR00102##
8-chloro-1-(3-{5-[(3- chlorophenyl)methyl]-2H-tetrazol-2-
yl}propyl)-3-propyl-3,7-dihydro-1H- purine-2,6-dione 5.9 mg (6%)
m/z 463 [MH].sup.+ RT 3.29 min 61 ##STR00103##
8-chloro-1-(3-{5-[(4- chlorophenyl)methyl]-2H-tetrazol-2-
yl}propyl)-3-propyl-3,7-dihydro-1H- purine-2,6-dione 14.9 mg (16%)
m/z 463 [MH].sup.+ RT 3.30 min 62 ##STR00104##
8-chloro-1-(3-{5-[(3- methylphenyl)methyl]-2H-tetrazol-2-
yl}propyl)-3-propyl-3,7-dihydro-1H- purine-2,6-dione 17.5 mg (20%)
m/z 443 [MH].sup.+ RT 3.23 min 63 ##STR00105##
8-chloro-1-[3-(5-{[2- (methyloxy)phenyl]methyl}-2H-
tetrazol-2-yl)propyl]-3-propyl-3,7- dihydro-1H-purine-2,6-dione
14.5 mg (16%) m/z 459 [MH].sup.+ RT 3.12 min 64 ##STR00106##
8-chloro-3-propyl-1-{3-[5-(2- thienylmethyl)-2H-tetrazol-2-
yl]propyl}-3,7-dihydro-1H-purine- 2,6-dione 17.0 mg (20%) m/z 435
[MH].sup.+ RT 3.02 min 65 ##STR00107## 8-chloro-1-(3-{5-[(2,6-
difluorophenyl)methyl]-2H-tetrazol-
2-yl}propyl)-3-propyl-3,7-dihydro- 1H-pyrine-2,6-dione 18.4 mg
(20%) m/z 465 [MH].sup.+ RT 3.11 min 66 ##STR00108##
8-chloro-1-(3-{5-[(3,4- dichlorophenyl)methyl]-2H-tetrazol-
2-yl}propyl)-3-propyl-3,7-dihydro- 1H-purine-2,6-dione 19.4 mg
(20%) m/z 497 [MH].sup.+ RT 3.44 min 67 ##STR00109##
8-chloro-1-(3-{5-[(2,4- difluorophenyl)methyl]-2H-tetrazol-
2-yl}propyl)-3-propyl-3,7-dihydro- 1H-purine-2,6-dione 19.1 mg
(21%) m/z 465 [MH].sup.+ RT 3.16 min 68 ##STR00110##
8-chloro-1-(3-{5-[(3,4- difluorophenyl)methyl]-2H-tetrazol-
2-yl}propyl)-3-propyl-3,7-dihydro- 1H-purine-2,6-dione 21.5 mg
(23%) m/z 465 [MH].sup.+ RT 3.19 min 69 ##STR00111##
8-chloro-1-(3-{5-[(2,5- difluorophenyl)methyl]-2H-tetrazol-
2-yl}propyl)-3-propyl-3,7-dihydro- 1H-purine-2,6-dione 8.5 mg (9%)
m/z 465 [MH].sup.+ RT 3.14 min 70 ##STR00112##
8-chloro-3-propyl-1-(3-{5-[(2,4,6-
trifluorophenyl)methyl]-2H-tetrazol-
2-yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 17.4 mg (18%) m/z 483
[MH].sup.+ RT 3.09 min 71 ##STR00113##
8-chloro-1-[3-(5-{[2-fluoro-6- (trifluoromethyl)phenyl]methyl}-2H-
tetrazol-2-yl)propyl]-3-propyl-3,7- dihydro-1H-purine-2,6-dione
22.3 mg (22%) m/z 515 [MH].sup.+ RT 3.28 min 72 ##STR00114##
8-chloro-1-[3-(5-([4-fluoro-3- (trifluoromethyl)phenyl]methyl}-2H-
tetrazol-2-yl)propyl]-3-propyl-3,7- dihydro-1H-purine-2,6-dione
17.2 mg (17%) m/z 515 [MH].sup.+ RT 3.30 min 73 ##STR00115##
8-chloro-1-[3-(5-{[2-fluoro-5- (trifluoromethyl)phenyl]methyl}-2H-
tetrazol-2-yl)propyl]-3-propyl-3,7- dihydro-1H-purine-2,6-dione
18.2 mg (18%) m/z 515 [MH].sup.+ RT 3.34 min 74 ##STR00116##
3-butyl-8-chloro-1-(3-{5-[(2,6- difluorophenyl)methyl]-2H-tetrazol-
2-yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 18.2 mg (19%) m/z 479
[MH].sup.+ RT 3.29 min 75 ##STR00117##
3-butyl-8-chloro-1-(3-{5-[(3,4- dichlorophenyl)methyl]-2H-tetrazol-
2-yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 20.1 mg (20%) m/z 511
[MH].sup.+ RT 3.58 min 76 ##STR00118##
3-butyl-8-chloro-1-(3-{5-[(2,4- difluorophenyl)methyl]-2H-tetrazol-
2-yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 19.3 mg (20%) m/z 479
[MH].sup.+ RT 3.33 min 77 ##STR00119##
3-butyl-8-chloro-1-(3-{5-[(2-chloro-
6-fluorophenyl)methyl]-2H-tetrazol-
2-yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 18.9 mg (19%) m/z 495
[MH].sup.+ RT 3.33 min 78 ##STR00120##
3-butyl-8-chloro-1-(3-{5-[(3,4- difluorophenyl)methyl]-2H-tetrazol-
2-yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 21.7 mg (23%) m/z 479
[MH].sup.+ RT 3.33 min 79 ##STR00121##
3-butyl-8-chloro-1-[3-(5-{[2- (trifluoromethyl)phenyl]methyl}-2H-
tetrazol-2-yl)propyl]-3,7-dihydro-1H- purine-2,6-dione 18.1 mg
(18%) m/z 511 [MH].sup.+ RT 3.32 min 80 ##STR00122##
3-butyl-8-chloro-1-(3-{5-[(2,5- difluorophenyl)methyl]-2H-tetrazol-
2-yl)propyl)-3,7-dihydro-1H-purine- 2,6-dione 24.0 mg (25%) m/z 479
[MH].sup.+ RT 3.31 min 81 ##STR00123##
3-butyl-8-chloro-1-(3-{5-[(3,5- difluorophenyl)methyl]-2H-tetrazol-
2-yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 15.9 mg (17%) m/z 479
[MH].sup.+ RT 3.38 min 82 ##STR00124##
3-butyl-8-chloro-1-{3-[5-({2- [(trifluoromethyl)oxy]phenyl}methyl)-
2H-tetrazol-2-yl]propyl}-3,7-dihydro- 1H-purine-2,6-dione 32.8 mg
(31%) m/z 527 [MH].sup.+ RT 3.51 min 83 ##STR00125##
3-butyl-8-chloro-1-(3-{5-[(2,4,6-
trifluorophenyl)methyl]-2H-tetrazol-
2-yl)propyl)-3,7-dihydro-1H-purine- 2,6-dione 20.7 mg (21%) m/z 497
[MH].sup.+ RT 3.35 min 84 ##STR00126##
3-butyl-8-chloro-1-[3-(5-{[2-fluoro-6-
(trifluoromethyl)phenyl]methyl}-2H-
tetrazol-2-yl)propyl]-3,7-dihydro-1H- purine-2,6-dione 23.9 mg
(23%) m/z 529 [MH].sup.+ RT 3.44 min 85 ##STR00127##
3-butyl-8-chloro-1-[3-(5-{[4-fluoro-3-
(trifluoromethyl)phenyl]methyl}-2H-
tetrazol-2-yl)propyl]-3,7-dihydro-1H- purine-2,6-dione 13.9 mg
(13%) m/z 529 [MH].sup.+ RT 3.53 min 86 ##STR00128##
3-butyl-8-chloro-1-(3-{5-[(2,4- dichlorophenyl)methyl]-2H-tetrazol-
2-yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 17.5 mg (17%) m/z 511
[MH].sup.+ RT 3.63 min
NMR Details for Selected Examples from Table 3:
Example 37
8-Chloro-1-(3-{5-[(4-fluorophenyl)methyl]-2H-tetrazol-2-yl}propyl)-3-propy-
l-3,7-dihydro-1H-purine-2,6-dione
[0422] .sup.1H NMR (CDCl.sub.3) .delta.: 0.99 (t, 3H, J=7.5 Hz),
1.80 (m, 2H), 2.46 (m, 2H), 4.06 (m, 2H), 4.18 (s, 2H), 4.25 (t,
2H, J=7 Hz), 4.70 (t, 2H, J=7.5 Hz), 6.96 (m, 2H), 7.26 (m, 2H),
13.15 (br s, 1H).
Example 40
8-Chloro-3-(4,4,4-trifluorobutyl)-1-(3-{5-[(2,4,6-trifluorophenyl)methyl]--
2H-tetrazol-2-yl}propyl)-3,7-dihydro-1H-purine-2,6-dione
[0423] .sup.1H NMR (CDCl.sub.3) .delta.: 2.07 (m, 2H), 2.21 (m,
2H), 2.44 (m, 2H), 4.18 (t, 2H, J=7.1 Hz), 4.20 (s, 2H), 4.24, (t,
2H, J=6.8 Hz), 4.68 (t, 2H, J=7.3 Hz), 6.67 (t, 2H, J=8.1 Hz),
13.04 (br s, 1H).
Example 41
[0424] .sup.1H NMR (CDCl.sub.3): 2.03-2.10 (m, 2H), 2.16-2.28 (m,
2H), 2.43-2.50 (m, 2H), 4.16-4.19 (m, 2H), 4.17 (s, 2H), 4.24 (t,
2H, J=7.1 Hz), 4.71 (t, 2H, J=7.1 Hz), 7.00-7.13 (m, 3H), 13.06
(bs, 1H).
Example 44
[0425] .sup.1H NMR (CDCl.sub.3): 0.99 (t, 3H, J=7.5 Hz), 1.76-1.86
(m, 2H), 2.40-2.47 (m, 2H), 4.05-4.09 (m, 2H), 4.23-4.26 (m, 2H),
4.54 (s, 2H), 4.65-4.69 (m, 2H), 7.14-7.18 (m, 1H), 7.31-7.33, (m,
2H), 13.18 (bs, 1H).
Example 45
[0426] .sup.1H NMR (CDCl.sub.3): 0.97 (t, 3H, J=7.5 Hz), 1.36-1.46
(m, 2H), 1.71-1.79 (m, 2H), 2.42-2.49 (m, 2H), 4.08-4.11 (m, 2H),
4.25 (s, 2H), 4.24-4.27 (m, 2H), 4.68-4.71 (m, 2H), 7.02-7.09 (m,
2H), 7.20-7.26, (m, 2H), 13.14 (bs, 1H).
Example 46
[0427] .sup.1H NMR (CDCl.sub.3): 0.97 (t, 3H, J=7.5 Hz), 1.36-1.45
(m, 2H), 1.71-1.79 (m, 2H), 2.42-2.49 (m, 2H), 4.09 (t, 2H, J=7.5
Hz), 4.26 (t, 2H, J=7.5 Hz), 4.34 (s, 2H), 4.70 (t, 2H, J=7.3 Hz),
7.18-7.21 (m, 2H), 7.25-7.27, (m, 1H), 7.35-7.37, (m, 1H), 13.34
(bs, 1H).
Example 47
3-Butyl-8-chloro-1-(3-{5-[(3-fluorophenyl)methyl]-2H-tetrazol-2-yl}propyl)-
-3,7-dihydro-1H-purine-2,6-dione
[0428] .sup.1H NMR (CDCl.sub.3) .delta.: 0.97 (t, 3H, J=7 Hz), 1.40
(m, 2H), 1.75 (m, 2H), 2.46 (m, 2H), 4.10 (t, 2H, J=7.5 Hz), 4.21
(s, 2H), 4.26 (t, 2H , J=6.5 Hz), 4.70 (t, 2H, J=7.5 Hz), 6.90 (m,
1H), 6.99 (m, 1H), 7.07 (m, 1H), 7.25 (m, 1H), 13.25 (br s,
1H).
Example 48
[0429] .sup.1H NMR (CDCl.sub.3): 0.99 (t, 3H, J=7.5 Hz), 1.38-1.48
(m, 2H), 1.73-1.81 (m, 2H), 2.44-2.51 (m, 2H), 4.12 (t, 2H, J=7.5
Hz), 4.20 (s, 2H), 4.27 (t, 2H, J=7.5 Hz), 4.70 (t, 2H, J=7.3 Hz),
6.95-7.00 (m, 2H), 7.26-7.30, (m, 2H), 13.35 (bs, 1H).
Example 49
3-Butyl-8-chloro-1-(3-{5-[(4-fluorophenyl)methyl]-2H-tetrazol-2-yl}propyl)-
-3,7-dihydro-1H-purine-2,6-dione
[0430] .sup.1H NMR (CDCl.sub.3) .delta.: 0.99 (t, 3H, J=7 Hz), 1.43
(m, 2H), 1.77 (m, 2H), 2.48 (m, 2H), 4.12 (t, 2H, J=7.5 Hz), 4.20
(s, 2H), 4.27 (t, 2H, J=7 Hz), 4.72 (t, 2H, J=7.5 Hz), 6.98 (m,
2H), 7.27 (m, 2H), 13.35 (br s, 1H).
Example 50
3-Butyl-8-chloro-1-(3-{5-[(4-chlorophenyl)methyl]-2H-tetrazol-2-yl}propyl)-
-3,7-dihydro-1H-purine-2,6-d lone
[0431] .sup.1H NMR (CDCl.sub.3) .delta.: 1.02 (t, 3H, J=7.5 Hz),
1.45 (m, 2H), 1.79 (m, 2H), 2.50 (m, 2H), 4.14 (t, 2H, J=7.5 Hz),
4.22 (s, 2H), 4.29 (t, 2H, J=7 Hz), 4.75 (t, 2H, J=7.5 Hz), 7.27
(s, 4H), 13.35 (br s, 1H).
Example 55
3-Butyl-8-chloro-1-{3-[5-(1-phenylcyclopropyl)-2H-tetrazol-2-yl]propyl}-3,-
7-dihydro-1H-purine-2,6-dione
[0432] .sup.1H NMR (CDCl.sub.3) .delta.: 0.93 (t, 3H, J=7.3 Hz),
1.36 (m, 4H), 1.55 (m, 2H), 1.71 (m, 2H), 2.38 (m, 2H), 4.06 (t,
2H, J=7.5 Hz), 4.20 (t, 2H, J=6.7 Hz), 4.59 (t, 2H, J=7.5 Hz), 7.25
(m, 3H), 7.36 (m, 2H), 13.30 (br s, 1H).
Example 67
8-Chloro-1-(3-{5-[(2,4-difluorophenyl)methyl]-2H-tetrazol-2-yl}propyl)-3-p-
ropyl-3,7-dihydro-1H-purine-2,6-dione
[0433] .sup.1H NMR (CDCl.sub.3) .delta.: 0.99 (t, 3H, J=7.5 Hz),
1.80 (m, 2H), 2.45 (m, 2H), 4.06 (m, 2H), 4.20 (s, 2H), 4.25 (t,
2H, J=7 Hz), 4.70 (t, 2H, J=7.5 Hz), 6.80 (m, 2H), 7.23 (m,
1H).
Example 70
8-Chloro-3-propyl-1-(3-(5-[(2,4,6-trifluorophenyl)methyl]-2H-tetrazol-2-yl-
)propyl)-3,7-dihydro-1H-purine-2,6-dione
[0434] .sup.1H NMR (CDCl.sub.3) .delta.: 0.99 (t, 3H, J=7.3 Hz),
1.80 (m, 2H), 1.98 (m, 2H), 2.01 (m, 2H), 4.20 (s, 2H), 4.25 (t,
2H, J=6.5 Hz), 4.67 (t, 2H, J=7.3 Hz), 6.68 (t, 2H, J=8.1 Hz).
Example 71
[0435] .sup.1H NMR (CDCl.sub.3): 0.99 (t, 3H, J=7.3 Hz), 1.76-1.85
(m, 2H), 2.39-2.46 (m, 2H), 4.05-4.08 (m, 2H), 4.24 (t, 2H, J=7.1
Hz), 4.39 (s, 2H), 4.64 (t, 2H, J=7.1 Hz), 7.29-7.32 (m, 1H),
7.38-7.44, (m, 1H), 7.49-7.51, (m, 1H), 13.17 (bs, 1H).
Example 78
[0436] .sup.1H NMR (CDCl.sub.3): 0.99 (t, 3H, J=7.6 Hz), 1.36-1.45
(m, 2H), 1.71-1.79 (m, 2H), 2.42-2.49 (m, 2H), 4.09 (t, 2H, J=7.5
Hz), 4.17 (s, 2H), 4.24 (t, 2H, J=7.5 Hz), 4.71 (t, 2H, J=7.3 Hz),
7.00-7.14 (m, 3H), 13.07 (bs, 1H).
Example 80
[0437] .sup.1H NMR (CDCl.sub.3): 0.96 (t, 3H, J=7.2 Hz), 1.32-1.47
(m, 2H), 1.68-1.80 (m, 2H), 2.40-2.51 (m, 2H), 4.06-4.12 (m, 2H),
4.22 (s, 2H), 4.22-4.27 (m, 2H), 4.67-4.73 (m, 2H), 6.84-7.04 (m,
3H), 13.05 (bs, 1H).
Example 83
3-Butyl-8-chloro-1-(3-{5-[(2,4,6-trifluorophenyl)methyl]-2H-tetrazol-2-yl}-
propyl)-3,7-dihydro-1H-purine-2,6-dione
[0438] .sup.1H NMR (CDCl.sub.3) .delta.: 0.97 (t, 3H, J=7.3 Hz),
1.41 (m, 2H), 1.75 (m, 2H), 2.44 (m, 2H), 4.10 (t, 2H, J=7.5 Hz),
4.20 (s, 21-1), 4.25 (t, 2H, J=6.5 Hz), 4.67 (t, 2H, J=7.4 Hz),
6.67 (t, 2H, J=8.0 Hz), 13.25 (br s, 1H).
Example 87
8-Chloro-3-pentyl-1-{3-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]propyl}-3,7--
dihydro-1H-purine-2,6-dione
a)
8-Chloro-3-pentyl-1-(3-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]propyl)-3-
,7-dihydro-1H-purine-2,6-dione
##STR00129##
[0440] A solution of
3-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]-1-propanol (88 mg, 0.4
mmol) in THF (4 ml) was treated with
8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(100 mg, 0.34 mmol) and PPh.sub.3 (115 mg, 0.44 mmol) under
nitrogen. DBAD (101 mg, 0.44 mmol) was added in one portion and the
reaction left to react for 5 h. The mixture was degassed by
applying a vacuum and then nitrogen was introduced.
Pd(PPh.sub.3).sub.4 (39 mg, 0.034 mmol) was added and the mixture
degassed once more. Morpholine (294 .mu.l, 3.4 mmol) was added and
the mixture was stirred under nitrogen for 3 h. The mixture was
partitioned between 2M HCl (aq) and EtOAc. The organic layer was
separated, washed with brine, dried (MgSO.sub.4) and concentrated.
The title compound was obtained as a white solid after purification
by MDAP (64 mg, 42%).
[0441] LC/MS: m/z 457 [MH].sup.+, RT 3.4 min.
[0442] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.85 (t, 3H, J=7 Hz),
1.22-1.34 (m, 4H), 1.62 (m, 2H), 2.02 (m, 2H), 2.91 (t, 2H, J=7
Hz), 3.88 (t, 2H, J=7 Hz), 3.95-4.00 (m, 4H), 7.22-7.33 (m, 5H),
14.5 (br s, 1H).
b) 3-[3-(Phenylmethyl)-1,2,4-oxadiazol-5-yl]-1-propanol
##STR00130##
[0444] A mixture of .gamma.-butyrolactone (223 .mu.l, 2.9 mmol),
benzamidine oxime (480 mg, 3.2 mmol), 21% solution of NaOEt in EtOH
(1.3 ml) and EtOH (3 ml) was heated in the microwave at 140.degree.
C. for 10 min. The mixture was partitioned between 2M HCl (aq) and
EtOAc. The organic layer was separated, washed with brine, dried
(MgSO.sub.4) and concentrated. The title product was purified over
silica using the Companion.TM. system to give a pale yellow oil
(143 mg, 23%).
[0445] LC/MS: m/z 219 [MH].sup.+, RT 2.4 min.
Example 88
8-Chloro-1-(3-{3-[(4-chlorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-3-p-
entyl-3,7-dihydro-1H-purine-2,6-dione
a)
8-Chloro-1-(3-{3-[(4-chlorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)--
3-pentyl-3,7-dihydro-1H-purine-2,6-dione
##STR00131##
[0447] A solution of
8-chloro-1-(3-{3-[(4-chlorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-3--
pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.18 g,
0.34 mmol) in DMF (5 ml) was degassed by sequential evacuation of
the flask and admission of nitrogen (.times.3) and morpholine (0.5
ml, 5.8 mmol), and Pd(PPh.sub.3).sub.4 (80 mg, 0.068 mmol) added.
The solution was stirred for 72 h then concentrated and the
residues loaded onto an aminopropyl SPE (10 g) with MeOH. Elution
with MeOH followed by 5% AcOH/MeOH provided the title compound as a
pale yellow solid, which was washed with ether to yield a white
solid (0.053 g, 32%).
[0448] LC/MS: m/z 491 [MH].sup.+, RT 3.69 min
b)
8-Chloro-1-(3-{3-[(4-chlorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)--
3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
##STR00132##
[0450] i) A mixture of .gamma.-butyrolactone (8 ml, 104 mmol),
4-chlorobenzamidine oxime (3.0 g, 16.25 mmol), 30% solution of
NaOMe in MeOH (5 ml) and MeOH (80 ml) was refluxed for 30 h, cooled
and concentrated. The residues were purified by flash
chromatography over silica eluting with DCM/EtOH/0.88 aq ammonia
(200:8:1) to provide a yellow oil (13 g). This material was
dissolved in DCM (150 ml) and washed with 2M sodium hydroxide (100
ml) and the organics separated, dried and concentrated to yield
3-{3-[(4-chlorophenyl)methyl]-1,2,4-oxadiazol-5-yl}-1-propanol as a
viscous oil (3.95 g, 96%) which was used in the next step.
[0451] ii) To a solution of
8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(0.10 g, 0.34 mmol),
3-{3-[(4-chlorophenyl)methyl]-1,2,4-oxadiazol-5-yl}-1-propanol
(0.086 g, 0.34 mmol) and triphenylphosphine (0.186 g, 0.69 mmol) in
THF (5 ml) was added dibenzylazodicarboxylate (0.204 g, 0.68 mmol)
and the solution stirred for 18 h. The solution was then
concentrated and the residues chromatographed over silica (20 g,
SPE) eluting with DCM initially then DCM/Et.sub.2O mixtures to
yield the title compound contaminated with dibenzylazodicarboxylate
by-products (0.18 g). Material used crude in deprotection step.
[0452] LC/MS: m/z 531 [MH].sup.+, RT 3.83 min.
Example 89
8-Chloro-3-pentyl-1-{3-[3-(2-phenylethyl)-1,2,4-oxadiazol-5-yl]propyl}-3,7-
-dihydro-1H-purine-2,6-dione
a)
8-Chloro-3-pentyl-1-{3-[3-(2-phenylethyl)-1,2,4-oxadiazol-5-yl]propyl}--
3,7-dihydro-1H-purine-2,6-dione
##STR00133##
[0454] A solution of
3-[3-(2-phenylethyl)-1,2,4-oxadiazol-5-yl]-1-propanol (150 mg, 0.65
mmol) in THF (6 ml) was treated with
8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(160 mg, 0.54 mmol) and PPh.sub.3 (183 mg, 0.70 mmol) under
nitrogen. DBAD (161 mg, 0.70 mmol) was added in one portion and the
reaction left to react for 18 h. The mixture was degassed by
applying a vacuum and then nitrogen was introduced.
Pd(PPh.sub.3).sub.4 (39 mg, 0.034 mmol) was added and the mixture
degassed once more. Morpholine (294 .mu.l, 3.4 mmol) was added and
the mixture was stirred under nitrogen for 3 h. The mixture was
partitioned between 2M HCl (aq) and EtOAc. The organic layer was
separated, washed with brine, dried (MgSO.sub.4) and concentrated.
The residue was taken up into MeOH and purified by passing down an
aminopropyl SPE, the product eluted with 2-5% AcOH/MeOH. The title
compound was obtained as an off-white solid (185 mg, 73%).
[0455] LC/MS: m/z 471 [MH].sup.+, RT 3.6 min.
[0456] .sup.1H NMR; (DMSO-d.sub.6) .delta.: 0.85 (t, 3H, J=7 Hz),
1.23-1.34 (m, 4H), 1.63 (m, 2H), 2.06 (m, 2H), 2.87 (m, 4H), 2.93
(t, 2H, J=7 Hz), 3.89 (t, 2H, J=7 Hz), 4.00 (t, 2H, J=6.5 Hz),
7.16-7.29 (m, 5H), 14.5 (br s, 1H).
b) 3-[3-(2-Phenylethyl)-1,2,4-oxadiazol-5-yl]-1-propanol
##STR00134##
[0458] A mixture of .gamma.-butyrolactone (426 .mu.l, 5.5 mmol),
phenethylamidine oxime (1.0 g, 6.1 mmol), 21% solution of NaOEt in
EtOH (2 ml) and EtOH (3 ml) was heated in the microwave at
140.degree. C. for 10 min. The mixture was partitioned between 2M
HCl (aq) and EtOAc. The organic layer was separated, washed with
brine, dried (MgSO.sub.4) and concentrated. The title product was
purified by Si-SPE eluting with EtOAc/cyclohexane mixtures to give
the title compound as a pale yellow oil (390 mg, 31%).
[0459] LC/MS: m/z 233 [MH].sup.+, RT 2.5 min.
Example 90
8-Chloro-1-{3-[3-(Phenylmethyl)-1,2,4-oxadiazol-5-yl]propyl}-3-propyl-3,7--
dihydro-1H-purine-2,6-dione
a)
8-Chloro-1-{3-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]propyl}-3-propyl-3-
,7-dihydro-1H-purine-2,6-dione
##STR00135##
[0461] A solution of
8-chloro-7-(2-propen-1-yl)-3-propyl-3,7-dihydro-1H-purine-2,6-dione
(200 mg, 0.74 mmol) in THF (4 ml) was treated with
3-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]-1-propanol (195 mg, 0.89
mmol) and PPh.sub.3 (254 mg, 0.96 mmol). DBAD (223 mg, 0.96 mmol)
was added in one portion and the mixture was left to stir at rt
under nitrogen for 18 h. The mixture was partitioned between EtOAc
and 2M HCl (aq). The organic layer was separated, washed with
brine, dried (MgSO.sub.4) and concentrated. The crude product was
purified by a silica SPE column using a 0-70% cyclohexane/EtOAc
gradient. The product fractions were combined, concentrated and
further purified by a silica SPE column using a 0-60%
cyclohexane/EtOAc gradient. The product fractions were combined and
concentrated then dissolved in anhydrous THF (4 ml). The solution
was degassed by high vacuum then Pd(PPh.sub.3).sub.4 (86 mg, 0.074
mmol) and morpholine (644 .mu.l, 7.4 mmol) were added and the
mixture left to stir at rt under nitrogen for 1 day. The mixture
was partitioned between EtOAc and HCl (aq). The organic layer was
separated, washed with brine, dried (MgSO.sub.4) and concentrated
by high vacuum. The crude product was purified by an aminopropyl
SPE using MeOH to load the compound onto the column and wash
through the impurities then a 2-4% AcOH/MeOH gradient to elute the
product. The product fractions were combined and concentrated by
high vacuum to leave the title compound as a white solid (74 mg,
23%).
[0462] LC/MS: m/z 429 [MH].sup.+, RT 3.14 min.
[0463] .sup.1H NMR; (DMSO-d.sub.6) .delta.: 0.87 (t, 3H, J=7.5 Hz),
1.65 (m, 2H), 2.02 (m, 2H), 2.91 (t, 2H, J=7.5 Hz), 3.86 (t, 2H,
J=7 Hz), 3.97 (s,t overlapping, 4H), 7.27 (m, 5H) 14.46 (s,
1H).
b)
8-Chloro-7-(2-propen-1-yl)-3-propyl-3,7-dihydro-1H-purine-2,6-dione
##STR00136##
[0465] A mixture of
8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (1.5 g,
6.6 mmol), 1-iodopropane (1.2 g, 6.9 mmol) and sodium carbonate
(0.9 g, 8.5 mmol) in DMF (40 ml) was heated at 50.degree. C. for 18
h. The reaction mixture was concentrated in vacuo and the residue
treated with water (60 ml) and extracted with EtOAc (3.times.80
ml). The combined organic extracts were dried (MgSO.sub.4) filtered
and evaporated. The residue was triturated with ether/cyclohexane,
the solid was filtered off and dried to afford the title compound
(0.82 g, 46%).
[0466] LC/MS: m/z 269 [MH].sup.+.
Example 91
8-Chloro-3-pentyl-1-{3-[3-(3-thienylmethyl)-1,2,4-oxadiazol-5-yl]propyl}-3-
,7-dihydro-1H-purine-2,6-dione
a)
8-Chloro-3-pentyl-1-{3-[3-(3-thienylmethyl)-1,2,4-oxadiazol-5-yl]propyl-
}-3,7-dihydro-1H-purine-2,6-dione
##STR00137##
[0468] A mixture of ethyl
4-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate
(70 mg, 0.19 mmol), N-hydroxy-2-(3-thienyl)ethanimidamide (36 mg,
0.23 mmol), 21% solution of NaOEt in EtOH (78 .mu.l, 0.21 mmol) and
EtOH (1.5 ml) was heated in the microwave at 140.degree. C. for 10
min. After cooling the reaction was partitioned between 2M HCl (aq)
and EtOAc. The organic layer was separated and the aqueous layer
extracted again with EtOAc. The combined extracts were concentrated
and purified by MDAP. The title compound was freeze dried from
1,4-dioxane to give a white solid (27 mg, 31%).
[0469] LC/MS: m/z 463 [MH].sup.+, RT 3.4 min.
b) Ethyl
4-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)b-
utanoate
##STR00138##
[0471] A solution of
8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(3.0 g, 10.1 mmol) in anhydrous DMF (35 ml) was treated with
Cs.sub.2CO.sub.3 (3.6 g, 11.1 mmol) and ethyl 4-bromobutyrate (1.6
ml, 11.1 mmol). The mixture was stirred at rt for 18 h then
degassed under a gentle vacuum, then nitrogen introduced. This was
repeated twice. Pd(PPh.sub.3).sub.4 (1.17 g, 1.0 mmol) was added
and the mixture degassed once more. Morpholine (8.8 ml, 101 mmol)
was added and left to stir for 3 h at rt. The mixture was
partitioned between 2M HCl (aq) and EtOAc. The organic layer was
separated, washed with brine, dried (MgSO.sub.4) and concentrated,
giving a yellow solid (5.16 g). The residue was taken up in MeOH
and divided into two equal portions, and then each passed down an
aminopropyl SPE (20 g), eluting with MeOH followed by 5% AcOH/MeOH.
The product fractions were combined and concentrated giving the
title compound as a near white solid (3.01 g, 80%).
[0472] LC/MS: m/z 371 [MH].sup.+, RT 3.2 min.
Example 92
8-Chloro-3-pentyl-1-{3-[3-(1-phenylethyl)-1,2,4-oxadiazol-5-yl]propyl}-3,7-
-dihydro-1H-purine-2,6-dione
##STR00139##
[0474] A mixture of ethyl
4-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate
(70 mg, 0.19 mmol), N-hydroxy-2-phenylpropanimidamide (38 mg, 0.23
mmol), 21% solution of NaOEt in EtOH (78 .mu.l, 0.21 mmol) and EtOH
(1.5 ml) was heated in the microwave at 140.degree. C. for 10 min.
After cooling the reaction was partitioned between 2M HCl (aq) and
EtOAc. The organic layer was separated and the aqueous layer
extracted again with EtOAc. The combined extracts were concentrated
and purified by the MDAP. The title compound was freeze dried from
1,4-dioxane to give a white solid (44 mg, 49%).
[0475] LC/MS: m/z 471 [MH].sup.+, RT 3.6 min.
Example 93
3-Butyl-8-chloro-1-{3-[3-(2,3-difluorobenzyl)-1,2,4-oxadiazol-5-yl]propyl}-
-3,7-dihydro-1H-purine-2,6-dione
a)
3-Butyl-8-chloro-1-{3-[3-(2,3-difluorobenzyl)-1,2,4-oxadiazol-5-yl]prop-
yl}-3,7-dihydro-1H-purine-2,6-dione
##STR00140##
[0477] 2,3-Difluorophenylacetonitrile (23 mg, 0.15 mmol) was
dissolved in EtOH (1 ml). Hydroxylamine hydrochloride (14 mg, 0.20
mmol) was added, followed by water (0.5 ml) and potassium carbonate
(41 mg, 0.3 mmol). The mixture was heated at reflux overnight and
then cooled and partitioned between EtOAc and brine. The organic
phase was evaporated and the crude amidoxime thus obtained was
dissolved in EtOH (1 ml). Ethyl
4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate
(43 mg, 0.12 mmol) and 21% by wt. ethanolic sodium ethoxide ((0.067
ml, 0.18 mmol) was added and the mixture heated in the microwave
reactor at 140.degree. C. for 10 min. The mixture was partitioned
between EtOAc and 2M HCl, the organic phase evaporated and the
product purified by MDAP to provide the title compound as a solid
(13 mg).
[0478] LC/MS: m/z 479 [MH].sup.+, RT 3.52 min.
[0479] .sup.1H NMR (MeOH-d.sub.4) .delta.: 0.96 (t, 3H, J=7 Hz),
1.34-1.45 (m, 2H), 1.65-1.75 (m, 2H), 2.13-2.22 (m, 2H), 2.97 (t,
2H, J=7 Hz), 4.00 (t, 2H, J=7 Hz), 4.05 (s, 2H), 4.12 (t, 2H, J=7
Hz), 7.03-7.25 (m, 3H).
b) Ethyl
4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)bu-
tanoate
##STR00141##
[0481] To
3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dio-
ne (6.0 g, 21.24 mmol) in dry DMF (100 ml) was added
Cs.sub.2CO.sub.3 (7.62 g, 23.36 mmol) followed by ethyl
4-bromobutyrate (4.556 g, 23.36 mmol). The mixture was heated at
55.degree. C. for 18 h and allowed to cool then degassed by
repeatedly evacuating and readmitting nitrogen. Morpholine (14.9 g,
171 mmol) was added followed by
tetrakis(triphenylphosphine)palladium(0) (4.0 g, 3.46 mmol) and the
mixture was stirred for 4 h. EtOAc (300 ml) and 2M HCl (150 ml) and
water (100 ml) were added and the organic phase separated, washed
with brine (3.times.100 ml) and filtered. The filtrate was dried
(Na.sub.2SO.sub.4) and evaporated. The crude product (10 g) was
purified by aminopropyl SPE (3.times.20 g), loading in THF/MeOH
(1:1), washing with THF/MeOH (1:1) and neat MeOH and eluting the
product with DCM/MeOH (1:1) containing 5% added AcOH to afford the
title compound (5.08 g).
[0482] LC/MS: m/z 357 [MH].sup.+, RT 3.06 min.
[0483] .sup.1H NMR (d.sup.4 MeOH) 0.96 (3H, t, J=7 Hz), 1.33-1.42
(2H, m), 1.64-1.74 (2H, m), 2.12-2.21 (2H, m), 2.95 (2H, t, J=8
Hz), 3.99 (2H, t, J=7 Hz), 4.03 (2H, s), 4.11 (2H, t, J=7 Hz),
7.03-7.21 (3H, m).
Example 94
3-Butyl-8-chloro-1-{3-[3-(2-chlorobenzyl)-1,2,4-oxadiazol-5-yl]propyl}-3,7-
-dihydro-1H-purine-2,6-dione
##STR00142##
[0485] Ethyl
4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate
(53 mg, 0.15 mmol) and
(1Z)-2-(2-chlorophenyl)-N-hydroxyethanimidamide (30 mg, 0.18 mmol;
Entry 1, table 7) were heated in EtOH (0.75 ml) with 21% ethanolic
sodium ethoxide (0.083 ml, 0.22 mmol) at 140.degree. C. for 10 min.
The mixture was then partitioned between EtOAc and 2M HCl and the
organic phase evaporated. The product was purified by MDAP to yield
the title compound as a solid (34.8 mg).
[0486] LC/MS: m/z 477 [MH].sup.+, RT 3.59 min.
[0487] .sup.1H NMR (d.sup.6 DMSO) 0.89 (3H, t, J=8 Hz), 1.24-1.34
(2H, m), 1.56-1.65 (2H, m), 1.98-2.07 (2H, m), 2.92 (2H, t, J=7
Hz), 3.89 (2H, t, J=7 Hz), 3.98 (2H, t, J=7 Hz), 4.09 (2H, s),
7.28-7.48 (4H, m).
Example 95
3-Butyl-8-chloro-1-{3-[3-(4-fluorobenzyl)-1,2,4-oxadiazol-5-yl]propyl}-3,7-
-dihydro-1H-purine-2,6-dione
##STR00143##
[0489] Starting from
(1Z)-2-(4-fluorophenyl)-N-hydroxyethanimidamide (28 mg, 0.18 mmol;
Entry 2, Table 7) was similarly obtained the title compound as a
solid (10.0 mg).
[0490] LC/MS: m/z 461 [MH].sup.+, RT 3.49 min.
Example 96
3-Butyl-8-chloro-1-{3-[3-(2,3-dichlorobenzyl)-1,2,4-oxadiazol-5-yl]propyl}-
-3,7-dihydro-1H-purine-2,6-dione
##STR00144##
[0492] Ethyl
4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate
(53 mg, 0.15 mmol) and
(1Z)-2-(2,3-dichlorophenyl)-N-hydroxyethanimidamide (36 mg, 0.165
mmol; Entry 3, Table 7) and 21% ethanolic sodium ethoxide (0.083
ml, 0.22 mmol) were heated together in EtOH (0.75 ml) in the
microwave reactor at 140.degree. C. for 10 min. The mixture was
then partitioned between EtOAc and 2M HCl, the organic phase
separated, evaporated and the product purified by MDAP to give the
title compound as a solid (42.1 mg).
[0493] LC/MS: m/z 511, 513, 515 (isotopes) [MH].sup.+, RT 3.66
min.
[0494] The following compounds (Table 4) were prepared using a
method analogous to that for Example 96, using the appropriate
amidoxime, (with the exceptions that for Example 110 (Table 4)
during workup the pH was adjusted to 5 prior to extraction with
EtOAc; and in the case of Example 111 (Table 4) the crude product
was stirred for 18 h with EtOH (1 ml) and 2M NaOH (0.5 ml) and
Example 112 (Table 4) was stirred for 18 h with EtOH (0.75 ml) and
2M NaOH (0.5 ml) prior to repeat workup and purification by
MDAP).
TABLE-US-00004 TABLE 4 Amidoxime Wt of (see table amidoxime Yield
Example Structure 7) Mg mg LC/MS: 97 ##STR00145## 4 28 32.4 m/z 461
[MH].sup.+ RT 3.41 min 3-butyl-8-chloro-1-{3-[3-(3-
fluorobenzyl)-1,2,4-oxadiazol-5-
yl]propyl}-3,7-dihydro-1H-purine-2,6- dione 98 ##STR00146## 5 31
28.3 m/z 479 [MH].sup.+ RT 3.46 min 3-butyl-8-chloro-1-{3-[3-(3,4-
difluorobenzyl)-1,2,4-oxadiazol-5-
yl]propyl}-3,7-dihydro-1H-purine-2,6- dione 99 ##STR00147## 6 33
32.3 m/z 495 [MH].sup.+ RT 3.55 min
3-butyl-8-chloro-1-{3-[3-(3-chloro-2-
fluorobenzyl)-1,2,4-oxadiazol-5-
yl]propyl}-3,7-dihydro-1H-purine-2,6- dione 100 ##STR00148## 8 29
35 m/z 469 [MH].sup.+ RT 3.43 min 3-butyl-8-chloro-1-{3-[3-(1-
phenylcyclopropyl)-1,2,4-oxadiazol-5-
yl]propyl}-3,7-dihydro-1H-purine-2,6- dione 101 ##STR00149## 9 42
2.6 m/z 551 [MH].sup.+ RT 3.71 min 1-(3-{3-[1-(3-bromophenyl)-1-
methylethyl]-1,2,4-oxadiazol-5-
yl}propyl)-3-butyl-8-chloro-3,7-dihydro- 1H-purine-2,6-dione 102
##STR00150## 10 32 30.5 m/z 487 [MH].sup.+ RT 3.27 min
1-{3-[3-(1,3-benzodioxol-5-ylmethyl)-
1,2,4-oxadiazol-5-yl]propyl}-3-butyl-8-
chloro-3,7-dihydro-1H-purine-2,6-dione 103 ##STR00151## 19 33 26.2
m/z 495 [MH].sup.+ RT 3.47 min
3-butyl-8-chloro-1-(3-{3-[(2-chloro-5-
fluorophenyl)methyl]-1,2,4-oxadiazol-
5-yl}propyl)-3,7-dihydro-1H-purine-2,6- dione 104 ##STR00152## 21
26 33.4 m/z 449 [MH].sup.+ RT 3.23 min 3-butyl-8-chloro-1-{3-[3-(2-
thienylmethyl)-1,2,4-oxadiazol-5-
yl]propyl)-3,7-dihydro-1H-purine-2,6- dione 105 ##STR00153## 22 31
27.3 m/z 483 [MH].sup.+ RT 3.47 min
1-{3-[3-(1-benzofuran-3-ylmethyl)-
1,2,4-oxadiazol-5-yl]propyl}-3-butyl-8-
chloro-3,7-dihydro-1H-purine-2,6-dione 106 ##STR00154## 15 42 29.8
m/z 545 [MH].sup.+ RT 3.79 min 3-butyl-8-chloro-1-(3-{3-[(2,3,4-
trichlorophenyl)methyl]-1,2,4-
oxadiazol-5-yl}propyl)-3,7-dihydro-1H- purine-2,6-dione 107
##STR00155## 16 31 34.8 m/z 479 [MH].sup.+ RT 3.35 min
3-butyl-8-chloro-1-(3-{3-[(2,5-
difluorophenyl)methyl]-1,2,4-oxadiazol-
5-yl}propyl)-3,7-dihydro-1H-purine-2,6- dione 108 ##STR00156## 17
31 38.2 m/z 479 [MH].sup.+ RT 3.31 min
3-butyl-8-chloro-1-(3-{3-[(2,6-
difluorophenyl)methyl]-1,2,4-oxadiazol-
5-yl}propyl)-3,7-dihydro-1H-purine-2,6- dione 109 ##STR00157## 18
31 35.4 m/z 479 [MH].sup.+ RT 3.39 min
3-butyl-8-chloro-1-(3-{3-[(3,5-
difluorophenyl)methyl]-1,2,4-oxadiazol-
5-yl}propyl)-3,7-dihydro-1H-purine-2,6- dione 110 ##STR00158## 20
31 16.1 m/z 482 [MH].sup.+ RT 3.31 min
3-butyl-8-chloro-1-{3-[3-(1H-indol-3-
ylmethyl)-1,2,4-oxadiazol-5-yl]propyl}-
3,7-dihydro-1H-purine-2,6-dione 111 ##STR00159## 7 28 10 m/z 459
[MH].sup.+ RT 3.07 min 3-butyl-8-chloro-1-(3-{3-[(3-
hydroxyphenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3,7-dihydro-1H-
purine-2,6-dione 112 ##STR00160## 25 40 28.4 m/z 536 [MH].sup.+ RT
3.03 min N-[3-({5-[3-(3-butyl-8-chloro-2,6-dioxo-
2,3,6,7-tetrahydro-1H-purin-1- yl)propyl]-1,2,4-oxadiazol-3-
yl}methyl)phenyl]methanesulfanamide 113 ##STR00161## (1S,2S)-N-
hydroxy-2- phenylcyclo- propane- carboximid- amide 29 29.6 m/z 469
[MH].sup.+ RT 3.51 min 3-butyl-8-chloro-1-(3-{3-[(1S,2S)-2-
phenylcyclopropyl]-1,2,4-oxadiazol-5-
yl}propyl)-3,7-dihydro-1H-purine-2,6- dione
NMR Details for Selected Examples from Table 4:
Example 97
3-butyl-8-chloro-1-{3-[3-(3-fluorobenzyl)-1,2,4-oxadiazol-5-yl]propyl}-3,7-
-dihydro-1H-purine-2,6-dione
[0495] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.90 (t, 3H, J=7 Hz),
1.25-1.36 (m, 2H), 1.56-1.67 (m, 2H), 2.0-2.1 (m, 2H), 2.94 (t, 2H,
J=7 Hz), 3.90 (t, 2H, J=7 Hz), 3.98 (t, 2H, J=7 Hz), 4.02 (s, 2H),
7.05-7.15 (m, 3H), 7.32-7.40 (m, 1H).
Example 98
3-Butyl-8-chloro-1-{3-[3-(3,4-difluorobenzyl)-1,2,4-oxadiazol-5-yl]propyl}-
-3,7-dihydro-1H-purine-2,6-dione
[0496] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.89 (t, 3H, J=7.5 Hz),
1.25-1.34 (m, 2H), 1.56-1.65 (m, 2H), 1.99-2.07 (m, 2H), 2.92 (t,
2H, J=7 Hz), 3.89 (t, 2H, J=7 Hz), 3.98 (t, 2H, J=7 Hz), 4.02 (s,
2H), 7.10-7.15 (m, 1H), 7.32-7.39 (m, 2H), 14.45 (br s, 1H).
Example 100
3-butyl-8-chloro-1-{3-[3-(1-phenylcyclopropyl)-1,2,4-oxadiazol-5-yl]propyl-
}-3,7-dihydro-1H-purine-2,6-dione
[0497] .sup.1H NMR (MeOH-d.sub.4) .delta.: 0.95 (t, 3H, J=7 Hz),
1.25-1.30 (m, 2H), 1.30-1.45 (m, 4H), 1.64-1.75 (m, 2H), 2.15-2.25
(m, 2H), 2.94 (t, 2H, J=7 Hz), 3.98 (t, 2H, J=7 Hz), 4.10 (t, 2H,
J=7 Hz), 7.20-7.37 (m, 5H).
Example 102
1-{3-[3-(1,3-benzodioxol-5-ylmethyl)-1,2,4-oxadiazol-5-yl]propyl}-3-butyl--
8-chloro-3,7-dihydro-1H-purine-2,6-dione
[0498] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.90 (t, 3H, J=7 Hz),
1.25-1.36 (m, 2H), 1.58-1.68 (m, 2H), 1.98-2.09 (m, 2H), 2.92 (t,
2H, J=7 Hz), 3.88-3.95 (m, 4H), 3.99 (t, 2H, J=7 Hz), 5.98 (s, 2H),
6.70-6.86 (m, 3H).
Example 110
3-butyl-8-chloro-1-{3-[3-(1H-indol-3-ylmethyl)-1,2,4-oxadiazol-5-yl]propyl-
}-3,7-dihydro-1H-purine-2,6-dione
[0499] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.89 (t, 3H, J=7 Hz),
1.23-1.36 (m, 2H), 1.56-1.67 (m, 2H), 1.96-2.08 (m, 2H), 2.90 (t,
2H, J=7 Hz), 3.90 (t, 2H, J=7 Hz), 3.99 (t, 2H, J=7 Hz), 4.04 (s,
2H), 6.92-7.50 (m, 5H), 10.95 (s, 1H).
Example 111
3-butyl-8-chloro-1-(3-{3-[(3-hydroxyphenyl)methyl]-1,2,4-oxadiazol-5-yl}pr-
opyl)-3,7-dihydro-1H-purine-2,6-dione
[0500] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.90 (t, 3H, J=7 Hz),
1.25-1.38 (m, 2H), 1.57-1.68 (m, 2H), 1.96-2.07 (m, 2H), 2.92 (t,
2H, J=7 Hz), 3.86 (s, 2H), 3.89 (t, 2H, J=7 Hz), 3.99 (t, 2H, J=7
Hz), 6.58-6.68 (m, 3H), 7.08 (m, 1H), 9.40 (s, 1H).
Example 112
N-[3-({5-[3-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)p-
ropyl]-1,2,4-oxadiazol-3-yl}methyl)phenyl]methanesulfonamide
[0501] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.89 (t, 3H, J=7.5 Hz),
1.24-1.34 (m, 2H), 1.56-1.65 (m, 2H), 1.97-2.06 (m, 2H), 2.91 (t,
2H, J=7.5 Hz), 2.97 (s, 3H), 3.90 (t, 2H, J=7.5 Hz), 3.96 (s, 2H),
3.97 (t, 2H, J=7 Hz), 6.96-6.99 (m, 1H), 7.06-7.13 (m, 2H), 7.26
(t, 1H, J=8 Hz), 9.75 (s, 1H), 14.45 (br s, 1H).
Example 114
3-Butyl-8-chloro-1-(3-{3-[(3,4-dichlorophenyl)methyl]-1,2,4-oxadiazol-5-yl-
}propyl)-3,7-dihydro-1H-purine-2,6-dione
##STR00162##
[0503] Ethyl
4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate
(71 mg, 0.2 mmol),
(1Z)-2-(3,4-dichlorophenyl)-N-hydroxyethanimidamide (48 mg, 0.22
mmol) and 21% by wt. ethanolic sodium ethoxide (0.111 ml, 0.3 mmol)
were heated together in EtOH (1 ml) in the microwave reactor at
140.degree. C. for 10 min. The mixture was then partitioned between
EtOAc and 2M HCl, the organic phase separated and evaporated, and
the crude product was purified by MDAP to give the title compound
as a solid (48.8 mg).
[0504] LC/MS: m/z 511, 513 [MH].sup.+, RT 3.65 min.
[0505] The following compounds (Table 5) were prepared using a
method analogous to that for Example 114, using the appropriate
amidoxime (with the exception that for Example 115 and Example 125,
0.185 ml, (0.5 mmol) of 21% sodium ethoxide was added in order to
allow for the amidoximes being the hydrochloride salts).
TABLE-US-00005 TABLE 5 Wt of amidoxime Yield Example Structure
Amidoxime mg mg LC/MS: 115 ##STR00163## (1Z)-N- hydroxy-2-[3-
(trifluoromethyl) phenyl] ethanimidamide hydrochloride 56 46.5 m/z
511 [MH].sup.+ RT 3.63 min 3-butyl-8-chloro-1-[3-(3-{[3-
(trifluoromethyl)phenyl]methyl}- 1,2,4-oxadiazol-5-yl)propyl]-
3,7-dihydro-1H-purine-2,6- dione 116 ##STR00164## (1Z)-2-(2,6-
dichlorophenyl)- N- hydroxy- ethanimidamide 48 53.8 m/z 511
[MH].sup.+ RT 3.64 min 3-butyl-8-chloro-1-(3-{3-[(2,6-
dichlorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3,7-
dihydro-1H-purine-2,6-dione 117 ##STR00165## (1Z)-N- hydroxy-2-
phenyl- propanimidamide 36 45.4 m/z 457 [MH].sup.+ RT 3.51 min
3-butyl-8-chloro-1-{3-[3-(1- phenylethyl)-1,2,4-oxadiazol-
5-yl]propyl}-3,7-dihydro-1H- purine-2,6-dione 118 ##STR00166##
(1Z)-N- hydroxy-2-(1- naphthalenyl) ethanimidamide 44 48.6 m/z 493
[MH].sup.+ RT 3.67 min 3-butyl-8-chloro-1-{3-[3-(1-
naphthalenylmethyl)-1,2,4- oxadiazol-5-yl]propyl}-3,7-
dihydro-1H-purine-2,6-dione 119 ##STR00167## (1Z)-2-(4-
chlorophenyl)- N- hydroxy- ethanimidamide 41 35.6 m/z 477
[MH].sup.+ RT 3.60 min 3-butyl-8-chloro-1-(3-{3-[(4-
chlorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3,7-
dihydro-1H-purine-2,6-dione 120 ##STR00168## (1Z)-N- hydroxy-3-
phenyl- propanimidamide 36 29.6 m/z 457 [MH].sup.+ RT 3.55 min
3-butyl-8-chloro-1-{3-[3-(2- phenylethyl)-1,2,4-oxadiazol-
5-yl]propyl}-3,7-dihydro-1H- purine-2,6-dione 121 ##STR00169##
(1Z)-2-(3- chlorophenyl)- N- hydroxy- ethanimidamide 41 39.4 m/z
477 [MH].sup.+ RT 3.64 min 3-butyl-8-chloro-1-(3-{3-[(3-
chlorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3,7-
dihydro-1H-purine-2,6-dione 122 ##STR00170## (1Z)-N-hydroxy- 2-(4-
hydroxyphenyl) ethanimidamide 36 53.5 m/z 459 [MH].sup.+ RT 3.08
min 3-butyl-8-chloro-1-(3-{3-[(4- hydroxyphenyl)methyl]-1,2,4-
oxadiazol-5-yl}propyl)-3,7- dihydro-1H-purine-2,6-dione 123
##STR00171## (1Z)-N- hydroxy-2-[3- (trifluoromethyl)- 1H-pyrazol-
1- yl]ethanimidamide 46 58.1 m/z 501 [MH].sup.+ RT 3.33 min
3-butyl-8-chloro-1-[3-(3-{[3- (trifluoromethyl)-1H-pyrazol-
1-yl]methyl}-1,2,4-oxadiazol- 5-yl)propyl]-3,7-dihydro-1H-
purine-2,6-dione 124 ##STR00172## (1Z)-N- hydroxy-2-(3- thienyl)
ethanimidamide 34 32.6 m/z 449 [MH].sup.+ RT 3.31 min
3-butyl-8-chloro-1 -{3-[3-(3- thienylmethyl)-1,2,4-
oxadiazol-5-yl]propyl}-3,7- dihydro-1H-purine-2,6-dione 125
##STR00173## (1Z)-2-(4- chlorophenyl)- N- hydroxy- propanimidamide
hydrochloride 52 30.3 m/z 491 [MH].sup.+ RT 3.67 min
3-butyl-8-chloro-1-(3-{3-[1-(4- chlorophenyl)ethyl]-1,2,4-
oxadiazol-5-yl}propyl)-3,7- dihydro-1H-purine-2,6-dione
NMR Details for Selected Examples from Table 5
Example 115
[0506] .sup.1H NMR (d.sup.6 DMSO) 0.88 (3H, t, J=7 Hz), 1.24-1.33
(2H, m), 1.56-1.65 (2H, m), 1.98-2.06 (2H, m), 2.92 (2H, t, J=7
Hz), 3.89 (2H, t, J=7 Hz), 3.97 (2H, t, J=7 Hz), 4.14 (2H, s),
7.52-7.70 (4H, m).
Example 117
3-butyl-8-chloro-1-{3-[3-(1-phenylethyl)-1,2,4-oxadiazol-5-yl]propyl}-3,7--
dihydro-1H-purine-2,6-dione
[0507] .sup.1H NMR (DMSO-d.sub.8) .delta.: 0.89 (t, 31-1, J=7 Hz),
1.22-1.35 (m, 2H), 1.52 (d, 31-1, J=8 Hz), 1.56-1.68 (m, 2H),
1.95-2.08 (m, 2H), 2.91 (t, 2H, J=7 Hz), 3.89 (t, 2H, J=7 Hz), 3.95
(t, 2H, J=7 Hz), 4.18 (q, 1H, J=8 Hz), 7.17-7.32 (m, 5H).
Example 119
3-butyl-8-chloro-1-(3-{3-[(4-chlorophenyl)methyl]-1,2,4-oxadiazol-5-yl}pro-
pyl)-3,7-dihydro-1H-purine-2,6-dione
[0508] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.89 (t, 3H, J=7 Hz),
1.23-1.37 (m, 2H), 1.55-1.67 (m, 2H), 1.97-2.09 (m, 2H), 2.90 (t,
2H, J=7 Hz), 3.88 (t, 2H, J=7 Hz), 3.97 (t, 2H, J=7 Hz), 4.00 (s,
2H), 7.27-7.40 (m, 4H).
Example 122
3-butyl-8-chloro-1-(3-{3-[(4-hydroxyphenyl)methyl]-1,2,4-oxadiazol-5-yl}pr-
opyl)-3,7-dihydro-1H-purine-2,6-dione
[0509] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.90 (t, 3H, J=7 Hz),
1.23-1.37 (m, 2H), 1.57-1.68 (m, 2H), 1.96-2.08 (m, 2H), 2.90 (t,
2H, J=7 Hz), 3.82 (s, 2H), 3.90 (t, 2H, J=7 Hz), 3.98 (t, 2H, J=7
Hz), 6.68 (d, 2H, J=9 Hz), 7.04 (d, 2H, J=9 Hz), 9.32 (s, 1H).
Example 123
3-butyl-8-chloro-1-[3-(3-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,2-
,4-oxadiazol-5-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione
[0510] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.90 (t, 3H, J=7 Hz),
1.23-1.36 (m, 2H), 1.57-1.69 (m, 2H), 1.95-2.08 (m, 2H), 2.95 (t,
2H, J=7 Hz), 3.91 (t, 2H, J=7 Hz), 3.97 (t, 2H, J=7 Hz), 5.62 (s,
2H), 6.79 (s, 1H), 8.10 (s, 1H).
Example 125
3-butyl-8-chloro-1-(3-{3-[1-(4-chlorophenyl)ethyl]-1,2,4-oxadiazol-5-yl}pr-
opyl)-3,7-dihydro-1H-purine-2,6-dione
[0511] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.90 (t, 3H, J=7 Hz),
1.23-1.38 (m, 2H), 1.51 (d, 3H, J=6 Hz), 1.55-1.69 (m, 2H),
1.96-2.10 (m, 2H), 2.92 (t, 2H, J=7 Hz), 3.89 (t, 2H, J=7 Hz), 3.98
(t, 2H, J=7 Hz), 4.24 (q, 1H, J=6 Hz), 7.27-7.40 (m, 4H).
Example 126
3-Butyl-8-chloro-1-[3-(3-{[3-(ethyloxy)-4-hydroxyphenyl]methyl}-1,2,4-oxad-
iazol-5-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione
##STR00174##
[0513] Ethyl
4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate
(53 mg, 0.15 mmol) and
(1Z)-2-[3-(ethyloxy)-4-hydroxyphenyl]-N-hydroxyethanimidamide (35
mg, 0.165 mmol; entry 11, Table 7) were mixed in EtOH (0.75 ml).
Ethanolic sodium ethoxide (21% by wt., 0.083 ml, 0.22 mmol) was
added and the mixture was heated in the microwave at 140.degree. C.
for 10 min. A further 0.055 ml (0.15 mmol) of NaOEt solution was
then added and the mixture heated for a further 10 min period at
140.degree. C. The mixture was partitioned between EtOAc and 2M HCl
and the organic phase evaporated and purified by MDAP to give the
title compound as a solid (29.6 mg).
[0514] LC/MS: m/z 503 [MH].sup.+, RT 3.15 min.
[0515] The following compounds (Table 6) were prepared using a
method analogous to that for Example 126, using the appropriate
amidoxime (with the exception that for Example 127 (Table 6), the
crude product after workup was stirred with EtOH (1 ml) and 2M NaOH
(0.5 ml) overnight in order to hydrolyse residual starting ester,
prior to repeat HCl workup and purification by MDAP).
TABLE-US-00006 TABLE 6 Wt of Amidoxime aldoxime Yield Example
Structure (see table 7) mg mg LC/MS: 127 ##STR00175## 12 32 19.3
m/z 489 [MH].sup.+ RT 2.98 min 3-butyl-8-chloro-1-[3-(3-{(4-
hydroxy-3- (methyloxy)phenyl]methyl}-1,2,4-
oxadiazol-5-yl)propyl]-3,7-dihydro- 1H-purine-2,6-dione 128
##STR00176## 13 32 37.2 m/z 487 [MH].sup.+ RT 3.23 min
3-butyl-8-chloro-1-(3-{3-[1-(4- hydroxyphenyl)-1-methytethyl]-
1,2,4-oxadiazol-5-yl}propyl)-3,7- dihydro-1H-purine-2,6-dione 129
##STR00177## 14 34 23.6 m/z 500 [MH].sup.+ RT 2.94 min
N-[3-({5-[3-(3-butyl-8-chloro-2,6-
dioxo-2,3,6,7-tetrahydro-1H-purin- 1-yl)propyl]-1,2,4-oxadiazol-3-
yl}methyl)phenyl]acetamide
NMR Details for Selected Examples from Table 6
Example 129
N-[3-({5-[3-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)p-
ropyl]-1,2,4-oxadiazol-3-yl}methyl)phenyl]acetamide
[0516] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.90 (t, 3H, J=7 Hz),
1.25-1.38 (m, 2H), 1.57-1.68 (m, 2H), 1.95-2.07 (m, 5H), 2.92 (t,
2H, J=7 Hz), 3.91 (t, 2H, J=7 Hz), 3.94 (s, 2H), 3.98 (m, 2H),
6.88-7.50 (m, 4H), 9.90 (s, 1H).
Example 130
3-Butyl-8-chloro-1-(3-{3-[(2-chloro-4-fluorophenyl)methyl]-1,2,4-oxadiazol-
-5-yl}propyl)-3,7-dihydro-1H-purine-2,6-dione
##STR00178##
[0518] Ethyl
4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate
(100 mg, 0.28 mmol) and
(1Z)-2-(2-chloro-4-fluorophenyl)-N-hydroxyethanimidamide (62.4 mg,
0.308 mmol) and 21% by wt. ethanolic sodium ethoxide (0.157 ml,
0.42 mmol) were heated together in a microwave reactor in EtOH (1.5
ml) at 140.degree. C. for 10 min. The mixture was worked up by
partitioning between EtOAc and 2M HCl. The organic phase was
evaporated and purified by MDAP to afford the title compound as a
solid (73 mg).
[0519] LC/MS: m/z 495 [MH].sup.+, RT 3.55 min.
Example 131
8-Chloro-3-ethyl-1-{(3-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]propyl}-3,7--
dihydro-1H-purine-2,6-dione
a)
8-Chloro-3-ethyl-1-{3-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]propyl}-3,-
7-dihydro-1H-purine-2,6-dione
##STR00179##
[0521] A solution of
8-chloro-3-ethyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(150 mg, 0.59 mmol) in anhydrous THF (4 ml) was treated with
3-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]-1-propanol (154 mg, 0.71
mmol) and triphenylphosphine (200 mg, 0.76 mmol). DBAD (162 mg,
0.71 mmol) was added in one portion and the mixture was left to
stir at rt, under nitrogen for 18 h. The mixture was degassed by
high vacuum then Pd(PPh.sub.3).sub.4 (68 mg, 0.059 mmol) and
morpholine (515 .mu.l, 5.9 mmol) were added. The mixture was left
to stir at rt, under nitrogen, for 3 h. The mixture was partitioned
between EtOAc and 2M HCl (aq). The organic layer was separated,
washed with brine, dried (MgSO.sub.4) and concentrated by high
vacuum. The crude material was purified by an aminopropyl SPE using
MeOH to load the compound onto the column and wash through the
impurities, then with 2% AcOH/MeOH to elute the compound. The UV
active fractions were combined and concentrated by high vacuum. The
product was further purified by MDAP. The product fractions were
combined and concentrated to give the title compound as a white
solid (61 mg, 25%).
[0522] LC/MS: m/z 415 [MH].sup.+, RT 3.01 min
[0523] .sup.1H NMR; (DMSO-d.sub.6) .delta.: 1.19 (t, 3H, J=7 Hz),
2.93 (m, 2H), 2.91 (t, 2H, J=7.5 Hz), 3.96 (m, 6H), 7.27 (m, 5H)
14.46 (s, 1H).
b)
8-Chloro-3-ethyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
##STR00180##
[0525] A solution of
8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (10 g,
0.044 mol) in anhydrous DMF (100 ml) was treated with iodoethane
(5.4 ml, 0.068 mol) and Na.sub.2CO.sub.3 (4.9 g, 0.046 mol). The
reaction mixture was left to stir at it under nitrogen for 2 days.
Iodoethane (0.35 ml, 0.0044 mol) was added and the mixture was left
to stir at it for 1 day. The mixture was partitioned between EtOAc
and 2M HCl. The organic layer was separated, washed sequentially
with saturated sodium sulphite solution and brine, dried
(MgSO.sub.4) and concentrated. The crude solid was washed with
Et.sub.2O to give the title compound as a white solid (8.37 g,
75%).
[0526] LC/MS: m/z 255 [MH].sup.+, RT 2.35 min.
Example 132
8-Chloro-3-pentyl-1-(3-{3-[(1S,2S)-2-phenylcyclopropyl]-1,2,4-oxadiazol-5--
yl}propyl)-3,7-dihydro-1H-purine-2,6-dione
##STR00181##
[0528] Ethyl
5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoat-
e (70 mg, 0.19 mmol) was dissolved in EtOH (1.5 ml). The solution
was treated with a 21% solution of NaOEt in EtOH (78 .mu.l, 0.21
mmol) and (1S,2S)--N-hydroxy-2-phenylcyclopropanecarboximidamide
(37 mg, 0.21 mmol). The reaction was heated in the microwave at
140.degree. C. for 10 min. The mixture was partitioned between EtOH
and 2M HCl (aq). The organic layer was separated and concentrated,
the resulting crude product was purified by MDAP. The product
fractions were combined and concentrated to give the title compound
as a white solid (35 mg, 38%).
[0529] LC/MS: m/z 483 [MH].sup.+, RT 3.67 min.
Example 133
8-Chloro-1-(3-{3-[(3-chlorophenyl)methyl]-1,2,4-oxadiazol-5-yl}Propyl)-3-p-
entyl-3,7-dihydro-1H-purine-2,6-dione
##STR00182##
[0531] Ethyl
5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoat-
e (70 mg, 0.19 mmol) was dissolved in EtOH. The solution was
treated with a 21% solution of NaOEt in EtOH (78 .mu.l, 0.21 mmol)
and (1Z)-2-(3-chlorophenyl)-N-hydroxyethanimidamide (38 mg, 0.21
mmol). The reaction was heated in the microwave at 140.degree. C.
for 10 min. The mixture was partitioned between EtOH and 2M HCl
(aq). The organic layer was decanted off and concentrated. The
crude product was purified on the MDAP. The product fractions were
combined and concentrated to give the title compound as a white
solid (46 mg, 49%).
[0532] LC/MS: m/z 491 [MH].sup.+, RT 3.64 min.
[0533] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.85 (t, 3H, J=7 Hz),
1.27 (m, 4H), 1.62 (m, 2H), 2.02 (m, 2H), 2.92 (t, 2H, J=7.5 Hz),
3.88 (t, 2H, J=7 Hz), 3.97 (t, 2H, J=6.5 Hz), 4.02 (s, 2H), 7.23
(d, 1H, J=7 Hz), 7.34 (m, 3H).
Example 134
8-Chloro-1-(3-{3-[(3,4-dichlorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-
-3-pentyl-3,7-dihydro-1H-purine-2,6-dione
##STR00183##
[0535] Ethyl
5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoat-
e (70 mg, 0.19 mmol) was dissolved in EtOH. The solution was
treated with a 21% solution of NaOEt in EtOH (78 .mu.l, 0.21 mmol)
and (1Z)-2-(3,4-dichlorophenyl)-N-hydroxyethanimidamide (46 mg,
0.21 mmol). The reaction was heated in the microwave at 140.degree.
C. for 10 min. The mixture was partitioned between EtOH and 2M HCl
(aq). The organic layer was decanted off and concentrated. The
crude product was purified on the MDAP. The product fractions were
combined and concentrated to give the title compound as a white
solid (66 mg, 66%).
[0536] LC/MS: m/z 527 [MH].sup.+, RT 3.80 min.
Example 135
8-Chloro-1-(3-{3-[(2,6-dichlorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-
-3-pentyl-3,7-dihydro-1H-purine-2,6-dione
##STR00184##
[0538] Ethyl
5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoat-
e (70 mg, 0.19 mmol) was dissolved in EtOH. The solution was
treated with a 21% solution of NaOEt in EtOH (78 .mu.l, 0.21 mmol)
and (1Z)-2-(2,6-dichlorophenyl)-N-hydroxyethanimidamide (46 mg,
0.21 mmol). The reaction was heated in the microwave at 140.degree.
C. for 10 min. The mixture was partitioned between EtOH and 2M HCl
(aq). The organic layer was decanted off and concentrated by
nitrogen blowdown. The crude product was purified on the MDAP. The
product fractions were combined and concentrated to give the title
compound as a white solid (80 mg, 80%).
[0539] LC/MS: m/z 526 [MH].sup.+, RT 3.6 min.
Example 136
8-Chloro-1-(3-{3-[(2-chloro-4-fluorophenyl)methyl]-1,2,4-oxadiazol-5-yl}pr-
opyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione
##STR00185##
[0541] Ethyl
5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoat-
e (70 mg, 0.19 mmol) was dissolved in EtOH. The solution was
treated with a 21% solution of NaOEt in EtOH (78 .mu.l, 0.21 mmol)
and (1Z)-2-(2-chloro-4-fluorophenyl)-N-hydroxyethanimidamide (42
mg, 0.21 mmol). The reaction was heated in the microwave at
140.degree. C. for 10 min. The mixture was partitioned between EtOH
and 2M HCl (aq). The organic layer was decanted off and
concentrated. The crude product was purified on the MDAP. The
product fractions were combined and concentrated to give the title
compound as a white solid (65 mg, 67%).
[0542] LC/MS: m/z 509 [MH].sup.+, RT 3.63 min.
Example 137
3-Butyl-8-chloro-1-{3-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]propyl}-3,7-d-
ihydro-1H-purine-2,6-dione
##STR00186##
[0544] A solution of
3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(205 mg, 0.73 mmol) in anhydrous THF (4 ml) was treated with
3-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]-1-propanol (190 mg, 0.87
mmol) and PPh.sub.3 (247 mg, 0.94 mmol). DBAD (217 mg, 0.94 mmol)
was added in one portion and the mixture was stirred at it under
nitrogen for 18 h. The mixture was degassed by high vacuum then
Pd(PPh.sub.3).sub.4 (84 mg, 0.073 mmol) and morpholine (636 .mu.l,
7.3 mmol) were added. The mixture was stirred at it under nitrogen
for 3 h. The mixture was partitioned between EtOAc and 2M HCl (aq)
and the organic layer separated, washed with brine, dried
(MgSO.sub.4) and concentrated. The crude material was purified by
an aminopropyl column using MeOH to load the compound onto the
column and wash through the impurities, then with 2-4% AcOH/MeOH
gradient to remove the compound from the column. Further
purification was effected by MDAP to give the title compound as a
white solid (75 mg, 23%).
[0545] LC/MS: m/z 443 [MH].sup.+, RT 3.37 min.
[0546] .sup.1H NMR; (DMSO-d.sub.6) .delta.: 0.89 (t, 3H, J=7.5 Hz),
1.29 (m, 2H), 1.61 (m, 2H), 2.02 (m, 2H), 2.91 (t, 2H, J=7.5 Hz),
3.89 (t, 2H, J=7 Hz), 3.97 (m, 4H), 7.27 (m, 5H) 14.46 (s, 1H).
Example 138
8-Chloro-1-(3-{3-[(4-hydroxyphenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-3--
pentyl-3,7-dihydro-1H-purine-2,6-dione
##STR00187##
[0548] Ethyl
5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoat-
e (29 mg, 0.078 mmol) and
(1Z)-N-hydroxy-2-(4-hydroxyphenyl)ethanimidamide (14 mg, 0.084
mmol) were heated in EtOH (1 ml) with 21% ethanolic sodium ethoxide
(0.043 ml, 0.117 mmol) under microwave irradiation at 140.degree.
C. for 10 min. The mixture was partitioned between EtOAc and 2M HCl
and the organic phase evaporated. This material was stirred with
EtOH (1 ml) and 2M NaOH (0.5 ml) for 18 h, before being worked up
again by partition between EtOAc and 2M HCl. Purification by MDAP
afforded the title compound (6.5 mg).
[0549] LC/MS: m/z 473 [MH].sup.+, RT 3.34 min.
[0550] .sup.1H NMR (MeOH-d.sub.4) .delta.: 0.92 (t, 3H, J=7 Hz),
1.25-1.45 (m, 4H), 1.68-1.78 (m, 2H), 2.11-2.21 (m, 2H), 2.93 (t,
2H, J=7 Hz), 3.82 (s, 2H), 3.98 (t, 2H, J=7 Hz), 4.10 (t, 2H, J=7
Hz), 6.70 (d, 2H, J=10 Hz), 7.02 (d, 2H, J=10 Hz).
Example 139
3-Butyl-8-chloro-1-(3-{3-[(phenyloxy)methyl]-1,2,4-oxadiazol-5-yl}propyl)--
3,7-dihydro-1H-purine-2,6-dione
##STR00188##
[0552] To ethyl
4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate
(26 mg, 0.073 mmol) and (1Z)-N-hydroxy-2-(phenyloxy)ethanimidamide
hydrochloride (16 mg, 0.079 mmol) in EtOH (1 ml) was added 21% wt.
ethanolic sodium ethoxide solution (0.068 ml, 0.183 mmol) and the
mixture was heated under microwave irradiation at 140.degree. C.
for 10 min. The mixture was partitioned between EtOAc and 2M HCl,
the organic phase dried (Na.sub.2SO.sub.4) evaporated and purified
by MDAP to give title compound as a gum which solidified upon
trituration with ether (5.9 mg).
[0553] LC/MS: m/z 459 [MH].sup.+, RT 3.39 min.
[0554] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.90 (t, 3H, J=8 Hz),
1.22-1.36 (m, 2H), 1.57-1.68 (m, 2H), 2.02-2.14 (m, 2H), 3.00 (t,
2H, J=8 Hz), 3.90 (t, 2H, J=7 Hz), 4.00 (t, 2H, J=7 Hz), 5.18 (s,
2H), 6.95-7.35 (m, 5H).
Example 140
3-Butyl-8-chloro-1-(3-{3-[(3,5-dichlorophenyl)methyl]-1,2,4-oxadiazol-5-yl-
}propyl)-3,7-dihydro-1H-purine-2,6-dione
##STR00189##
[0556] To ethyl
4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate
(185 mg, 0.52 mmol) and
(1Z)-2-(3,5-dichlorophenyl)-N-hydroxyethanimidamide (126 mg, 0.58
mmol; Entry 23, Table 7) in dry EtOH (2 ml) was added 21% wt.
ethanolic sodium ethoxide solution (0.29 ml, 0.78 mmol) and the
mixture was heated by microwaves at 140.degree. C. for 10 min. The
reaction was worked up by partition between EtOAc and 2M HCl and
evaporating the organic phase. Purification by MDAP afforded the
title compound as a solid (135 mg).
[0557] LC/MS: m/z 511 [MH].sup.+, RT 3.71 min.
Example 141
3-Butyl-8-chloro-1-(3-{3-[(2,4,6-trifluorophenyl)methyl]-1,2,4-oxadiazol-5-
-yl}propyl)-3,7-dihydro-1H-purine-2,6-dione
##STR00190##
[0559] Similarly prepared starting from
(1Z)-N-hydroxy-2-(2,4,6-trifluorophenyl)ethanimidamide (119 mg,
0.58 mmol; Entry 24, Table 7) in a yield of 135 mg.
[0560] LC/MS: m/z 497 [MH].sup.+, RT 3.39 min.
[0561] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.90 (t, 3H, J=7 Hz),
1.24-1.36 (m, 2H), 1.55-1.66 (m, 2H), 1.96-2.06 (m, 2H), 2.91 (t,
2H, J=8 Hz), 3.91 (t, 2H, J=8 Hz), 3.94-4.02 (m, 4H), 7.18-7.28 (m,
2H).
Amidoximes:
[0562] These are available by the methods detailed below and
exemplified by analogues in Table 7.
TABLE-US-00007 TABLE 7 (Intermediates) Yield Entry Structure Name
Method mg LC/MS: 1 ##STR00191## (1Z)-2-(2-chlorophenyl)-N-
hydroxyethanimidamide G 38 m/z 185 [MH].sup.+ RT 1.04 min 2
##STR00192## (1Z)-2-(4-fluorophenyl)-N- hydroxyethanimidamido G 42
m/z 169 [MH].sup.+ RT 0.72 min 3 ##STR00193##
(1Z)-2-(2,3-dichlorophenyl)-N- hydroxyethanimidamide B 64 m/z 219
[MH].sup.+ RT 1.83 min 4 ##STR00194## (1Z)-2-(3-fluorophenyl)-N-
hydroxyethanimidamide A 78 m/z 169 [MH].sup.+ RT 0.62 min 5
##STR00195## (1Z)-2-(3,4-difluorophenyl)-N- hydroxyethanimidamide A
88 m/z 187 [MH].sup.+ RT 0.74 min 6 ##STR00196##
(1Z)-2-(3-chloro-2- fluorophenyl)-N- hydroxyethanimidamide A 92 m/z
203 [MH].sup.+ RT 1.40 min 7 ##STR00197## (1Z)-N-hydroxy-2-(3-
hydroxyphenyl)ethanimidamide A 67 m/z 167 [MH].sup.+ RT 0.46 min 8
##STR00198## N-hydroxy-1- phenylcyclopropanecarboximi- damide C 75
m/z 177 [MH].sup.+ RT 1.06 min 9 ##STR00199##
(1Z)-2-(3-bromophenyl)-N- hydroxy-2- methylpropanimidamide D 74 m/z
257 [MH].sup.+ RT 2.04 min 10 ##STR00200##
(1Z)-2-(1,3-benzodioxol-5-yl)- N-hydroxyethanimidamide C 98 m/z 195
[MH].sup.+ RT 0.73 min 11 ##STR00201## (1Z)-2-[3-(ethyloxy)-4-
hydroxyphenyl]-N- hydroxyethanimidamide C 109 m/z 211 [MH].sup.+ RT
0.76 min 12 ##STR00202## (1Z)-N-hydroxy-2-[4-hydroxy-3-
(methyloxy)phenyl]ethanimidamide C 98 m/z 197 [MH].sup.+ RT 0.50
min 13 ##STR00203## (1Z)-N-hydroxy-2-(4- hydroxyphenyl)-2-
methylpropanimidamide D 66 m/z 195 [MH].sup.+ RT 0.85 min 14
##STR00204## N-{3-((2Z)-2-(hydroxyamino)-2-
iminoethyl]phenyl}acetamide C 91 m/z 208 [MH].sup.+ RT 0.73 min 15
##STR00205## (1Z)-N-hydroxy-2-(2,3,4-
trichlorophenyl)ethanimidamide C 124 m/z 253 [MH].sup.+ RT 2.29 min
16 ##STR00206## (1Z)-2-(2,5-difluorophenyl)-N-
hydroxyethanimidamide C 89 m/z 187 [MH].sup.+ RT 0.66 min 17
##STR00207## (1Z)-2-(2,6-difluorophenyl)-N- hydroxyethanimidamide C
86 m/z 187 [MH].sup.+ RT 0.62 min 18 ##STR00208##
(1Z)-2-(3,5-difluorophenyl)-N- hydroxyethanimidamido C 96 m/z 187
[MH].sup.+ RT 0.80 min 19 ##STR00209## (1Z)-2-(2-chloro-5-
fluorophenyl)-N- hydroxyethanimidamide C 97 m/z 203 [MH].sup.+ RT
0.90 min 20 ##STR00210## (1Z)-N-hydroxy-2-(1H-indol-3-
yl)ethanimidamide C 95 m/z 190 [MH].sup.+ RT 0.90 min 21
##STR00211## (1Z)-N-hydroxy-2-(2- thienyl)ethanimidamide C 74 m/z
157 [MH].sup.+ RT 0.38 min 22 ##STR00212##
(1Z)-2-(1-benzofuran-3-yl)-N- hydroxyethanimidamide C 87 m/z 191
[MH].sup.+ RT 1.46 min 23 ##STR00213##
(1Z)-2-(3,5-dichlorophonyl)-N- hydroxyethanimidamide E 165 m/z 219
[MH].sup.+ RT 2.03 min 24 ##STR00214## (1Z)-N-hydroxy-2-(2,4,6-
trifluorophenyl)ethanimidamide F 297 m/z 205 [MH].sup.+ RT 0.66 min
25 ##STR00215## (1Z)-N-hydroxy-2-{3- [(methylsulfonyl)amino]phenyl}
ethanimidamide C 125 m/z 244 [MH].sup.+ RT 0.63 min
Method A
[0563] The corresponding nitrile (0.5 mmol) was stirred in EtOH
(1.5 ml) with 50% aqueous hydroxylamine solution (0.08 ml, 1.3
mmol) and heated at 65.degree. C. for 4.5 h. After cooling the
crude reaction mixture was loaded onto an SCX SPE cartridge (2 g)
and washed with MeOH, then the amidoxime product was eluted with 2M
ammonia in MeOH.
Method B
[0564] Similar to Method A except that the product crystallised out
from the crude reaction mixture and was isolated by filtration
instead of by SCX.
Method C
[0565] Similar to Method A except that the product was purified on
a 5 g SCX cartridge.
Method D
[0566] Similar to Method C except that the heating period was 18
h.
Method E
[0567] Similar to Method C except that the scale was 0.753 mmol of
nitrile.
Method F
[0568] Similar to Method A except that the scale was 1.5 mmol of
nitrile and purification was on a 10 g SCX cartridge.
Method G
[0569] Similar to Method A except that the heating time was 2.75 h
and the scale was 0.25 mmol of nitrile.
[0570] It should be noted that the above assignment of
(Z)-stereochemistry has not been confirmed by experimental data.
The person skilled in the art will also recognise that there can be
interconversion between E & Z isomers. (Dondoni, Alessandro;
Lunazzi, Lodovico; Giorgianni, Patrizia; Macciantelli, Dante.
Carbon-nitrogen rotational barrier as a stereochemical probe of
benzamidoximes. Journal of Organic Chemistry (1975), 40(20),
2979-80)
Example 142
3-Butyl-8-chloro-1-(3-{5-[(3-chlorophenyl)methyl]-1,2,4-oxadiazol-3-yl}pro-
pyl)-3,7-dihydro-1H-purine-2,6-dione
a)
3-Butyl-8-chloro-1-(3-{5-[(3-chlorophenyl)methyl]-1,2,4-oxadiazol-3-yl}-
Propyl)-3,7-dihydro-1H-purine-2,6-dione
##STR00216##
[0572] (3-Chlorophenyl)acetic acid (0.1 mmol),
N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride (21
mg, 0.11 mmol) and 1H-1,2,3-benzotriazol-1-ol (15 mg, 0.11 mmol)
were stirred in 1-methyl-2-pyrrolidinone (1 ml). To this was added
(1Z)-4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hy-
droxybutanimidamide (34 mg, 0.1 mmol) and the mixture stirred at rt
for 17 h and then at 80.degree. C. for 24 h. The reaction mixture
was purified, without further modification, by preparative HPLC
(auto prep) to give the title compound (13 mg, 27%).
[0573] LC/MS: m/z 477, 479 [MH].sup.+, RT 3.5 min.
[0574] .sup.1H NMR (CDCl.sub.3) .delta.: 0.96 (t, 3H, J=7 Hz),
1.32-1.47 (m, 2H), 1.68-1.80 (m, 2H), 2.12-2.24 (m, 2H), 2.83 (t,
2H, J=7.5 Hz), 4.05-4.24 (m, 6H), 7.16-7.30 (m, 4H).
b)
(1Z)-4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N--
hydroxybutanimidamide
##STR00217##
[0576]
4-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)buta-
nenitrile (1 g, 0.0032 mol) was stirred in EtOH (3.5 ml) and water
(1.8 ml). Hydroxylamine hydrochloride (344 mg, 0.0049mol) and
potassium carbonate (652 mg, 0.0049mol) were added and the mixture
heated at 80.degree. C. for 3 days. After cooling the crude
reaction mixture was evaporated. The crude product was dissolved in
water, neutralised to pH7 with HCl, and loaded onto an Oasis.TM.
cartridge (2 g). This was eluted with water to remove the salts and
then with MeOH, to give the title compound (957 mg, 86%).
[0577] LC/MS: m/z 343, 345 [M].sup.+, RT 2.04 min.
c)
4-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butaneni-
trile
##STR00218##
[0579]
4-[3-Butyl-8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro--
1H-purin-1-yl]butanenitrile (2.1 g, 6 mmol) was stirred in a
mixture of nitrogen degassed DCM (20 ml) and AcOH (2 ml).
Tetrakis(triphenylphosphine)palladium (675 mg, 0.6 mmol) and phenyl
silane (7.4 ml, 60 mmol) were added and the mixture stirred at rt
for 2d. This was then evaporated and the residue triturated with a
mixture of diethylether:cyclohexane (1:1) to afford the title
compound (1.47 g, 60%) as a white solid.
[0580] LC/MS: m/z 310 [MH].sup.+, RT 2.66 min.
d)
4-[3-Butyl-8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-p-
urin-1-yl]butanenitrile
##STR00219##
[0582]
3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(2.0 g, 0.0072 mol) in dry MeCN (20 ml) was added Cs.sub.2CO.sub.3
(4.68 g, 0.0144 mol) followed by bromobutyronitrile (1.38 g, 0.0094
mol). The mixture was heated at 80.degree. C. for 18 h and then
allowed to cool. The reaction mixture was evaporated and the crude
product partitioned between EtOAc and HCl (2N). The organic phase
was separated and washed with brine, dried (MgSO.sub.4) and
evaporated to give the crude product. This was purified by silica
SPE (50 g), eluting with cyclohexane:ethylacetate (2:1 to 1:1) to
afford the title compound as a clear oil (2.1 g, 85%).
[0583] LC/MS: m/z 350 [MH].sup.+, RT 3.10 min.
[0584] The following compounds (Table 8) were prepared using a
method analogous to that for Example 142, from the corresponding
acids and
(1Z)-4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hy-
droxybutanimidamide.
TABLE-US-00008 TABLE 8 ##STR00220## Example Compound: R1 = Yield %
LC/MS: 143 3-butyl-8-chloro-1-(3-{5-[(3-
chlorophenyl)methyl]-1,2,4- oxadiazol-3-yl}propyl)-3,7-
dihydro-1H-purine-2,6-dione ##STR00221## 27 m/z 477 [MH].sup.+ RT
3.5 min 144 3-butyl-8-chloro-1-[3-(5-{[3-
(methyloxy)phenyl]methyl}- 1,2,4-oxadiazol-3-yl)propyl]-
3,7-dihydro-1H-purine-2,6- dione ##STR00222## 22 m/z 473 [MH].sup.+
RT 3.3 min 145 3-butyl-8-chloro-1-[3-(5-{[3-
(trifluoromethyl)phenyl]methyl}- 1,2,4-oxadiazol-3-
yl)propyl]-3,7-dihydro-1H- purine-2,6-dione ##STR00223## 23 m/z 511
[MH].sup.+ RT 3.5 min 146 3-butyl-8-chloro-1-(3-{5-[(2- chloro-4-
fluorophenyl)methyl]-1,2,4- oxadiazol-3-yl}propyl)-3,7-
dihydro-1H-purine-2,6-dione ##STR00224## 28 m/z 495 [MH].sup.+ RT
3.5 min 147 3-butyl-8-chloro-1-{3-[5- (cyclopentylmethyl)-1,2,4-
oxadiazol-3-yl]propyl}-3,7- dihydro-1H-purine-2,6-dione
##STR00225## 15 m/z 435 [MH].sup.+ RT 3.5 min 148
1-{3-[5-(1,3-benzodioxol-5- ylmethyl)-1,2,4-oxadiazol-3-
yl]propyl}-3-butyl-8-chloro- 3,7-dihydro-1H-purine-2,6- dione
##STR00226## 27 m/z 487 [MH].sup.+ RT 3.3 min 149
3-butyl-8-chloro-1-(3-{5-[(4- fluorophenyl)methyl]-1,2,4-
oxadiazol-3-yl}propyl)-3,7- dihydro-1H-purine-2,6-dione
##STR00227## 28 m/z 461 [MH].sup.+ RT 3.3 min 150
3-butyl-8-chloro-1-[3-(5-{[2- (methyloxy)phenyl]methyl}-
1,2,4-oxadiazol-3-yl)propyl]- 3,7-dihydro-1H-purine-2,6- dione
##STR00228## 21 m/z 473 [MH].sup.+ RT 3.3 min 151
1-{3-[5-(1-benzofuran-4- ylmethyl)-1,2,4-oxadiazol-3-
yl]propyl}-3-butyl-8-chloro- 3,7-dihydro-1H-purine-2,6- dione
##STR00229## 24 m/z 483 [MH].sup.+ RT 3.4 min
NMR Details for Selected Examples from Table 8
Example 145
[0585] .sup.1H NMR (CDCl.sub.3) 0.96 (3H, t, J=7.5 Hz), 1.32-1.47
(2H, m), 1.65-1.81 (2H, m), 2.12-2.25 (2H, m), 2.84 (2H, t, J=7.5
Hz), 4.02 (2H, t, 7.5 Hz), 4.22 (2H, t, 7 Hz), 4.24 (2H, s),
7.40-7.62 (4H, m).
Example 152
8-Chloro-3-pentyl-1-{3-[5-(phenylmethyl)-1,2,4-oxadiazol-3-yl]propyl}-3,7--
dihydro-1H-purine-2,6-dione
a)
8-Chloro-3-pentyl-1-{3-[5-(phenylmethyl)-1,2,4-oxadiazol-3-yl]propyl}-3-
,7-dihydro-1H-purine-2,6-dione
##STR00230##
[0587] To a stirred solution of
8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(0.20, 0.67 mmol) in THF (5 ml) was added
3-[5-(phenylmethyl)-1,2,4-oxadiazol-3-yl]-1-propanol (0.162 g, 0.74
mmol), DBAD (0.186 g, 0.81 mmol) and triphenylphosphine (0.212 g,
0.81 mmol) and the solution stirred for 18 h. To the solution was
added Pd(PPh.sub.3).sub.4 (75 mg, 0.067 mmol) and morpholine (600
.mu.l, 6.7 mmol) were added and stirred for at rt under nitrogen
for a further 3 h. 75 mg of Pd(PPh.sub.3).sub.4 was added and the
mixture left to stir for another 3 h. The mixture was partitioned
between EtOAc and 2M HCl (aq). The organic layer was separated,
washed with brine, dried (MgSO.sub.4) and concentrated. The crude
material was purified by an aminopropyl SPE using MeOH to load the
compound onto the column and wash through the impurities, then with
2-4% AcOH/MeOH to elute the compound. The product fractions were
combined and concentrated then further purified by MDAP. The
product fractions were combined and concentrated give the title
compound as a white solid (51 mg, 20%).
[0588] LC/MS: m/z 457 [MH].sup.+, RT 3.54 min.
b) 3-[5-(Phenylmethyl)-1,2,4-oxadiazol-3-yl]-1-propanol
##STR00231##
[0590] A mixture of (1E)-4,4-bis(ethyloxy)-N-hydroxybutanimidamide
(3.2 g, 16.8 mmol), ethyl phenylacetate (2.3 ml, 14.4 mmol) and
sodium ethoxide (21% solution in EtOH, 6.4 ml) was heated in a
microwave at 140.degree. C. for 10 min. The material was combined
with that from a second reaction (using 1.2 g of
(1E)-4,4-bis(ethyloxy)-N-hydroxybutanimidamide and conducted as
above) and partitioned between 1M HCl solution and EtOAc. The
organic layer was separated, washed with brine, dried and
concentrated to provide
5-[3,3-bis(ethyloxy)propyl]-5-(phenylmethyl)-1,2,4-oxadiazole which
was used without purification in the next stage.
[0591] Crude
3-[3,3-bis(ethyloxy)propyl]-5-(phenylmethyl)-1,2,4-oxadiazole (5.63
g, 19.4 mmol) in EtOH (75 ml) was stirred with p-toluenesulphonic
acid (0.738 g, 3.9 mmol) for 21 h and the mixture partitioned
between EtOAc and water. The organics were isolated washed with
water and brine, dried and concentrated to a red oil. This material
contained significant amounts of acetal, therefore the oil was
dissolved in THF (15 ml) and treated with 2M HCl solution for 2 h
then partitioned between EtOAc and water. The organics were
isolated washed with brine, dried and concentrated to yield
3-[5-(phenylmethyl)-1,2,4-oxadiazol-3-yl]propanal as a red/brown
oil (3.77 g) which was used crude in the next stage.
[0592] A solution of crude
3-[5-(phenylmethyl)-1,2,4-oxadiazol-3-yl]propanal (3.76 g, 17.4
mmol) in MeOH (60 ml) was cooled to 0.degree. C. and sodium
borohydride (0.724 g, 19.1 mmol) added portionwise over 30 min. The
cooling bath was removed and the solution stirred for a further 1 h
then partitioned between 1M HCl and EtOAc. The organic layer was
separated and the aqueous extracted with EtOAc. The combined
extracts were washed with brine, dried and concentrated to an
orange liquid. This was purified on a 50 g silica SPE eluting with
cyclohexane/EtOAc (20% to 80% gradient elution) to provide the
title compound as a yellow oil (2.24 g).
[0593] LC/MS: m/z 210 [MH].sup.+.
c) (1E)-4,4-bis(ethyloxy)-N-hydroxybutanimidamide
##STR00232##
[0595] A mixture of 3-cynopropionaldehyde diethylacetal (6.12 g, 39
mmol), hydroxylamine hydrochloride (4.06 g, 58.4 mmol), potassium
carbonate (10.76 g, 77.9 mmol) in water (20 ml) and EtOH (40 ml)
was refluxed for 24 h. The mixture was allowed to cool and then
partitioned between water and EtOAc. The organic layer was
separated and the aqueous extracted with EtOAc. The combined
organic fractions were washed with brine, dried and concentrated to
provide the title compound as a colourless oil contaminated with
.about.20% starting nitrile (6.03 g, 81%).
[0596] LC/MS: m/z 191 [MH].sup.+.
Example 153
8-Chloro-1-{3-[5-(phenylmethyl)-1,2,4-oxadiazol-3-yl]propyl}-3-propyl-3,7--
dihydro-1H-purine-2,6-dione
##STR00233##
[0598] A solution of
8-chloro-7-(2-propen-1-yl)-3-propyl-3,7-dihydro-1H-purine-2,6-dione
(200 mg, 0.74 mmol) in THF (4 ml) was treated with
3-[5-(phenylmethyl)-1,2,4-oxadiazol-3-yl]-1-propanol (195 mg, 0.89
mmol) and PPh.sub.3 (254 mg, 0.96 mmol). DBAD (223 mg, 0.96 mmol)
was added in one portion and the mixture was left to stir at rt
under nitrogen for 18 h. The mixture was partitioned between EtOAc
and 2M HCl (aq). The organic layer was separated, washed with
brine, dried (MgSO.sub.4) and concentrated by high vacuum. The
crude product was purified on a silica SPE column using a 0-70%
cyclohexane/EtOAc gradient. The product fractions were combined,
concentrated by high vacuum and purified on a silica SPE column
using a 0-60% cyclohexane/EtOAc gradient. The product fractions
were combined and concentrated then dissolved in anhydrous THF (4
ml). The solution was degassed by high vacuum then
Pd(PPh.sub.3).sub.4 (61 mg, 0.053 mmol) and morpholine (460 .mu.l,
5.3 mmol) were added and the mixture left to stir at rt under
nitrogen for 1 day. The mixture was partitioned between EtOAc and
2M HCl (aq). The organic layer was separated, washed with brine,
dried (MgSO.sub.4) and concentrated by high vacuum. The crude
product was purified by an aminopropyl SPE using MeOH to load the
compound onto the column and wash through the impurities then a
2-4% AcOH/MeOH gradient to elute the product. The product fractions
were combined and concentrated to leave the title compound as a
white solid (36 mg, 11%).
[0599] LC/MS: m/z 429 [MH].sup.+, RT 3.14 min.
[0600] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.86 (t, 3H, J=7.5 Hz),
1.65 (m, 2H), 1.93 (m, 2H), 2.70 (t, 2H, J=7.5 Hz), 3.86 (t, 2H,
J=7 Hz), 3.96 (t, 2H, J=7 Hz), 4.28 (s, 2H), 7.32 (m, 5H).
Example 154
3-Butyl-8-chloro-1-{3-[3-(phenylmethyl)-1,2,4-oxadiazol-3-yl]propyl}-3,7-d-
ihydro-1H-purine-2,6-dione
##STR00234##
[0602] A solution of
3-[5-(phenylmethyl)-1,2,4-oxadiazol-3-yl]-1-propanol (594 mg, 2.7
mmol) in THF (25 ml) was treated with
3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(700 mg, 2.48 mmol) and PPh.sub.3 (779 mg, 2.97 mmol) under
nitrogen. DBAD (684 mg, 2.97 mmol) was added in one portion and the
reaction left to react for 60 h. The mixture was partitioned
between 2M HCl (aq) and EtOAc. The organic layer was separated,
washed with brine, dried (MgSO.sub.4) and concentrated. MeOH was
added to the residue and then passed down an aminopropyl column
with the product eluting with 2-4% AcOH/MeOH. Product fractions
were combined and concentrated. The off-white residue was
recrystallised from EtOAc:cyclohexane (1:1), giving the title
compound as a white solid (696 mg, 63%).
[0603] LC/MS: m/z 443 [MH].sup.+, RT 3.4 min.
[0604] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.89 (t, 3H, J=7 Hz),
1.29 (m, 2H), 1.61 (m, 2H), 1.93 (m, 2H), 2.70 (t, 2H, J=7.5 Hz),
3.90 (t, 2H, J=7 Hz), 3.96 (t, 2H, J=7 Hz), 4.28 (2H, s), 7.31 (m,
5H), 14.4 (br s, 1H).
Example 155
3-Butyl-8-chloro-1-(3-{5-[(3-chloro-4-hydroxyphenyl)methyl]-1,2,4-oxadiazo-
l-3-yl}propyl)-3,7-dihydro-1H-purine-2,6-dione
##STR00235##
[0606] A solution of 3-chloro-4-hydroxyphenylacetic acid (24 mg,
0.13 mmol) in DMSO (1 ml) was treated with CDI (21 mg, 0.13 mmol)
and left to react for 30 min.
(1Z)-4-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hy-
droxybutanimidamide (50 mg, 0.15 mmol) was added and the mixture
heated in the microwave at 120.degree. C. for 15 min. The solution
was directly purified by MDAP to obtain the title compound as a
white solid (12 mg, 17%).
[0607] LC/MS: m/z 493 [MH].sup.+, RT 3.2 min.
Example 156
3-Butyl-8-chloro-1-[3-(5-{[3-chloro-2-(methyloxy)phenyl]methyl}-1,2,4-oxad-
iazol-3-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione
##STR00236##
[0609] A mixture of [3-chloro-2-(methyloxy)phenyl]acetic acid (32
mg, 0.16 mmol) in DMF (1.5 ml) was treated with CDI (26 mg, 0.16
mmol) and left to react for 45 min.
(1Z)-4-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hy-
droxybutanimidamide (60 mg, 0.18 mmol) was added and the mixture
heated in the microwave at 140.degree. C. for 15 min. After
cooling, the reaction was partitioned between 2M HCl (aq) and
EtOAc. The organic layer was separated then concentrated and
purified by the MDAP. The title compound was obtained as a white
solid (25 mg, 28%).
[0610] LC/MS: m/z 507 [MH].sup.+, RT 3.5 min.
Example 157
3-Butyl-8-chloro-1-(3-{5-[(3-fluoro-4-hydroxyphenyl)methyl]-1,2,4-oxadiazo-
l-3-yl}propyl)-3,7-dihydro-1H-purine-2,6-dione
##STR00237##
[0612] A mixture of (3-fluoro-4-hydroxyphenyl)acetic acid (27 mg,
0.16 mmol) in DMF (1.5 ml) was treated with CDI (26 mg, 0.16 mmol)
and left to react for 45 min.
(1Z)-4-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hy-
droxybutanimidamide (60 mg, 0.18 mmol) was added and the mixture
heated in the microwave at 140.degree. C. for 15 min. After
cooling, the reaction was partitioned between 2M HCl (aq) and
EtOAc. The organic layer was separated then concentrated and
purified by MDAP. The title compound was obtained as a white solid
(10 mg, 12%).
[0613] LC/MS: m/z 477 [MH].sup.+, RT 3.2 min.
Example 158
8-chloro-3-pentyl-1-[4-(5-phenyl-1,2,4-oxadiazol-3-yl)butyl]-3,7-dihydro-1-
H-purine-2,6-dione
a) Preparation of
8-chloro-3-pentyl-1-[4-(5-phenyl-1,2,4-oxadiazol-3-yl)butyl]-3,7-dihydro--
1H-purine-2,6-dione
##STR00238##
[0615] Benzoic acid (18 mg, 0.15 mmol) was treated with a solution
of 1H-1,2,3-benzotriazol-1-ol hydrate (25 mg, 0.19 mmol) in DMSO
(0.3 ml). To this was added a solution/suspension of
N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride (29
mg, 0.15 mmol) in DMSO (0.3 ml) followed by a solution of
5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydrox-
ypentanimidamide (55 mg, 0.15 mmol) in DMSO (0.3 ml). The mixture
was heated at 40.degree. C. for 1 h, then at 80.degree. C. for 5 h
and then cooled. The mixture was subjected to purification by MDAP.
Product-containing fractions were blown to dryness by a stream of
nitrogen to yield the title compound as a white solid (17.2 mg,
25%).
[0616] LC/MS: m/z 457 [MH].sup.+, RT 3.67 min.
[0617] .sup.1H NMR (CDCl.sub.3) .delta.: 0.90 (t, 3H, J=6.8 Hz),
1.35 (m, 4H), 1.76 (m, 2H), 1.89 (m, 4H), 2.88 (t, 2H, J=7.2 Hz),
4.08 (t, 2H, J=7.5 Hz), 4.17 (t, 2H, J=6.7 Hz), 7.50 (m, 2H), 7.57
(m, 1H), 8.08, (d, 2H, J=7.3 Hz).
b)
5-(8-Chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydr-
oxypentanimidamide
##STR00239##
[0619] A solution of
5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentaneni-
trile (3.0 g, 8.9 mmol) in EtOH (30 ml) was treated with water (15
ml), potassium carbonate (1.48 g, 10.7 mmol) and hydroxylamine
hydrochloride (0.74 g, 10.7 mmol) and then heated at 70.degree. C.
overnight. A further potassium carbonate (1.5 g, 10.9 mmol) and
hydroxylamine hydrochloride (1.0 g, 14.5 mmol) were cautiously
added to the mixture which was then heated to 90.degree. C. for 24
h. The mixture was cooled and concentrated in vacuo to remove most
of the EtOH. The residual mixture was treated with water (30 ml)
and acidified to pH 7 by the cautious addition of 2M aqueous
hydrochloric acid. The precipitated solid was filtered off, washed
with water, then with diethyl ether and thoroughly dried to yield
the title compound as a white solid (2.80 g, 85%).
[0620] LC/MS: m/z 371 [MH].sup.+, RT 2.27 min.
c)
5-(8-Chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentane-
nitrile
##STR00240##
[0622] A solution of
8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(4.0 g, 13.5 mmol) in DMF (100 ml) was treated with caesium
carbonate (4.83 g, 14.8 mmol) and 5-bromopentanenitrile (1.73 ml,
14.8 mmol). The mixture was heated at 50.degree. C. in a nitrogen
atmosphere for 19 h and then cooled. The mixture was then degassed
by the repeated successive application of a vacuum and then
nitrogen pressure. The mixture was then treated with
tetrakis(triphenylphosphine)palladium(0) (1.1 g, 0.94 mmol) and
morpholine (11.8 ml, 136 mmol). The mixture was stirred in a
nitrogen atmosphere for 3 h and then partitioned between EtOAc and
2M aqueous hydrochloric acid. The organic layer was separated,
washed with brine, dried (MgSO.sub.4) and concentrated to reveal a
yellow, oily residue. This was dissolved in MeOH, divided equally
into four portions and each portion applied to a 20 g aminopropyl
SPE which was then washed through with MeOH. The desired product
was eluted from the cartridge with a 5% v/v solution of AcOH in
MeOH. The product-containing fractions were combined and
concentrated to yield the title compound as a pale yellow solid
(4.03 g, 88%).
[0623] LC/MS: m/z 338 [MH].sup.+, RT 3.05 min.
[0624] The following compounds were prepared using a method
analogous to that for Example 158
(8-chloro-3-pentyl-1-[4-(5-phenyl-1,2,4-oxadiazol-3-yl)butyl]-3,7-dihydro-
-1H-purine-2,6-dione) from the corresponding acids:
TABLE-US-00009 TABLE 9 # Structure Name Yield LC/MS: 159
##STR00241## 8-chloro-3-pentyl-1-{4-[5-(2-
pyridinyl)-1,2,4-oxadiazol-3- yl]butyl}-3,7-dihydro-1H-
purine-2,6-dione 7.3 mg (11%) m/z 458 [MH].sup.+ RT 3.21 min 160
##STR00242## 8-chloro-1-{4-[5-(2- chlorophenyl)-1,2,4-
oxodiazol-3-yl]butyl}-3-pentyl- 3,7-dihydro-1H-purine-2,6- dione
12.8 mg (17%) m/z 491 [MH].sup.+ RT 3.77 min 161 ##STR00243##
8-chloro-1-(4-{5-[2- (methyloxy)phenyl]-1,2,4-
oxodiazol-3-yl}butyl)-3- pentyl-3,7-dihydro-1H-purine- 2,6-dione
21.7 mg (30%) m/z 487 [MH].sup.+ RT 3.54 min 162 ##STR00244##
8-chloro-1-(4-[5-(2- fluorophenyl)-1,2,4-
oxadiazol-3-yl]butyl}-3-pentyl- 3,7-dihydro-1H-purine-2,6- dione
16.6 mg (23%) m/z 475 [MH].sup.+ RT 3.62 min
[0625] In addition Example 159,
8-chloro-3-pentyl-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-d-
ihydro-1H-purine-2,6-dione has the following spectral data: .sup.1H
NMR (CDCl.sub.3) .delta.: 0.89 (t, 3H, J=6.9 Hz), 1.75 (m, 4H),
1.89 (m, 6H), 2.92 (t, 2H, J=7.1 Hz), 4.07 (t, 2H, J=7.4 Hz), 4.16
(t, 2H, J=6.9 Hz), 7.52 (m, 1H), 7.92 (m, 1H), 8.18 (m, 1H), 8.83
(m, 1H), 13.40 (br s, 1H).
Example 163
8-Chloro-1-{4-[5-(4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl]butyl}-3-propyl-3,-
7-dihydro-1H-purine-2,6-dione
##STR00245##
[0627] 4-Hydroxybenzoic acid (18 mg, 0.13 mmol) and CDI (24 mg,
0.15 mmol) were stirred in anhydrous DMSO (0.9 ml) at it for 1 h.
(1Z)-5-(8-Chloro-2,6-dioxo-3-propyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-h-
ydroxypentanimidamide (50 mg, 0.15 mmol; prepared in a manner
similar to
(1Z)-5-(8-Chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-h-
ydroxypentanimidamide as described in Example 158(b)) was added and
the mixture was stirred at 90.degree. C. for 2 h. The reaction
mixture was purified by MDAP. The product fraction was combined and
concentrated under high vacuum to give the title compound as a
white solid (7 mg, 11%).
[0628] LC/MS: m/z 443 [MH].sup.+, RT 3.28 min.
Example 164
3-Butyl-8-chloro-1-{4-[5-(2,6-difluorophenyl)-1,2,4-oxadiazol-3-yl]butyl}--
3,7-dihydro-1H-purine-2,6-dione
##STR00246##
[0630] 2,6-Difluorobenzoic acid (40 mg, 0.25 mmol) and CDI (45 mg,
0.28 mmol) were stirred in anhydrous DMSO (0.9 ml) at it for 1 h.
(1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hy-
droxypentanimidamide (100 mg, 0.28 mmol) was added and the mixture
was stirred at 90.degree. C. for 16 h. The reaction mixture was
purified by MDAP. The product fraction was combined and
concentrated to give the title compound as a white solid (18 mg,
15%).
[0631] LC/MS: m/z 479 [MH].sup.+, RT 3.40 min.
Example 165
3-Butyl-8-chloro-1-{4-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7--
dihydro-1H-purine-2,6-dione
##STR00247##
[0633] 2-Fluorobenzoic acid (36 mg, 0.25 mmol) and CDI (45 mg, 0.28
mmol) were stirred in anhydrous DMSO (0.9 ml) at rt for 1 h.
(1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hy-
droxypentanimidamide (100 mg, 0.28 mmol) was added and the mixture
was stirred at 90.degree. C. for 16 h. The mixture was purified by
MDAP. The product, fraction was combined and concentrated to give
the title compound as a white solid (33 mg, 29%).
[0634] LC/MS: m/z 461 [M11].sup.+, RT 3.44 min.
Example 166
3-Butyl-8-chloro-1-{4-[5-(4-chloro-2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl-
}-3,7-dihydro-1H-purine-2,6-dione
##STR00248##
[0636] 4-Chloro-2-pyridinecarboxylic acid (40 mg, 0.25 mmol) and
CDI (45 mg, 0.28 mmol) were stirred in anhydrous DMSO (0.9 ml) at
rt for 1 h.
(1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hy-
droxypentanimidamide (100 mg, 0.28 mmol) was added and the mixture
was stirred at 90.degree. C. for 16 h. The reaction mixture was
purified by MDAP. The product fraction was combined and
concentrated to give the title compound as a white solid (13 mg,
11%).
[0637] LC/MS: m/z 478 [MH].sup.+, RT 3.31 min.
[0638] .sup.1H NMR (DMSO-d.sub.6) .delta..sub.H 14.4 (br. s, 1H),
8.79 (d, 1H, J=6 Hz), 8.24 (d, 1H, J=2 Hz), 7.88 (dd, 1H, J=6 Hz
& 2 Hz), 3.91 (m, 4H), 2.85 (t, 2H, J=7.5 Hz), 1.56-1.76 (m,
6H), 1.28 (m, 2H), 0.87 (t, 3H, J=7.5 Hz) ppm.
Example 167
3-Butyl-8-chloro-1-{4-[5-(3-methyl-2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl-
}-3,7-dihydro-1H-purine-2,6-dione
##STR00249##
[0640] 3-Methyl-2-pyridinecarboxylic acid (35 mg, 0.25 mmol) and
CDI (45 mg, 0.28 mmol) were stirred in anhydrous DMSO (0.9 ml) at
rt for 1 h.
(1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hy-
droxypentanimidamide (100 mg, 0.28 mmol) was added and the mixture
was stirred at 90.degree. C. for 16 h. The reaction mixture was
purified by MDAP. The product fraction was combined and
concentrated to give the title compound as a white solid 14 mg,
12%).
[0641] LC/MS: m/z 458 [MH].sup.+, RT 3.13 min.
Example 168
3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dih-
ydro-1H-purine-2,6-dione
Method A
##STR00250##
[0643] 2-Pyridinecarboxylic acid (31 mg, 0.25 mmol) and CDI (45 mg,
0.28 mmol) were stirred in anhydrous DMSO (0.5 ml) at rt for 1 h. A
solution of
(1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-
-hydroxypentanimidamide (100 mg, 0.28 mmol) in DMSO (0.4 ml) was
added and the mixture was stirred at 90.degree. C. for 16 h. The
reaction mixture was purified directly by MDAP. The product
fractions were combined and concentrated to give the title compound
as a white solid (14 mg, 12%).
[0644] LC/MS: m/z 444 [MH].sup.+, RT 3.01 min.
[0645] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.87 (t, 3H, J=7 Hz),
1.27 (m, 2H), 1.65 (m, 6H), 2.84 (t, 2H, J=7 Hz), 3.91 (m, 4H),
7.70 (dd 1H, J=5 & 7 Hz), 8.07 (m, 1H), 8.19 (d, 1H, J=8 Hz),
8.81 (d, 1H, J=5 Hz), 14.5 (br. s, 1H).
Method B
##STR00251##
[0647] 2-Pyridinecarboxylic acid (675 mg, 5.3 mmol) and CDI (909
mg, 5.6 mmol) were stirred in anhydrous DMF (30 ml) at rt under
nitrogen for 90 mins.
(1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl-
)-N-hydroxypentanimidamide (2.0 g, 5.6 mmol) and DMF (10 ml) were
added and the mixture was stirred at 100.degree. C. for 20 h. The
reaction mixture was cooled to rt then partitioned between sat.
NH.sub.4Cl(aq) solution and EtOAc. The organic layer was separated,
and the aqueous solution extracted with EtOAc. The combined
extracts were washed with brine, dried MgSO.sub.4 and concentrated
giving an orange liquid. This was purified using the Companion.TM.
system giving two identical white solids (649 mg; 240 mg).
[0648] LC/MS: m/z 444 [MH].sup.+, RT 3.04 min.
Method C
##STR00252##
[0650] A 12-L, round-bottom flask was equipped with an overhead,
mechanical stirrer, a temperature probe with a J-KEM temperature
controller, a condenser and a nitrogen inlet adapter. The flask was
charged with picolinic acid (0.180 kg, 1.46 mol), MIBK (4.0 L),
1,1'-carbonyldiimidazole (0.23 kg, 1.42 mol) and more MIBK (0.66
L). The mixture was stirred and warmed to 50.degree. C. over
approximately 1 hour, and the temperature overshot to 56.degree. C.
The solids dissolved during the heat up to 50.degree. C. and carbon
dioxide was generated. After 1 hour at 50.degree. C.,
(1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hy-
droxypentanimidamide (0.467 kg, 1.31 mol) was added to the
reaction. The mixture was then warmed to 90.degree. C. over 1 hour.
HPLC analysis of the reaction after heating at 90.degree. C. for
5.5 hours indicated that the reaction was complete. The heat was
turned off, and 1.0 N hydrochloric acid solution (2.33 L) was
added. The temperature dropped to 61.degree. C. After stirring
overnight, the product precipitated and was filtered. The
filtercake was washed with water (1.times.2.23 L, 1.times.2.43 L)
and heptanes (1.40 L). The wet cake was dried in a vacuum oven at
50.degree. C. for 22 hours to give 396 g of product (68%) HPLC
analysis 97.7% (AUC) t.sub.R=18.6 min.
Method D
Formation of
3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-di-
hydro-1H-purine-2,6-dione Form 1
[0651] The reaction vessel was charged with
3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-di-
hydro-1H-purine-2,6-dione (1 wt), acetone (20vol) and water
(0.6vol). The mixture was stirred and warmed to 50-60.degree. C.
and agitated for a minimum of 1 hour. A solution was formed which
is clarified at this temperature by filtration through a 1 micron
filter into a 2.sup.nd reaction vessel. The solution was cooled
over approximately 3 hours to 33-38.degree. C. and seeded at this
temperature with
3-Butyl-8-chloro-1-{4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-di-
hydro-1H-purine-2,6-d lone (Form 1, 0.01 wt). The thin suspension
was agitated at this temperature for a minimum of 1 hour then
cooled to 20-25.degree. C. and held at this temperature for a
minimum of 12 hours. The suspension thus formed was cooled to
13-17.degree. C. and held at this temperature for a minimum of 1
hour. The suspension was then sampled, and the solid collected by
filtration in the laboratory. The solid was dried and analysed by
xrpd/DSC to check form. If the form is as required (Form 1) the
batch is filtered, washed (2.times.3vol acetone) and dried in a
vacuum oven at 50.degree. C. The batch is offloaded once analysis
shows solvent levels (acetone, water) to be at acceptable.
[0652] Expected yield (75-80% w/w).
[0653] If the form of the sample taken at is shown to be other than
pure Form 1, then the batch is reheated to 35-45.degree. C. and
agitated at this temperature for a minimum of 1 hour. The thin
suspension is then cooled to 20-25.degree. C. and held at this
temperature for a minimum of 12 hours. The suspension thus formed
is then cooled to 13-17.degree. C. and held at this temperature for
a minimum of 1 hour. The suspension is then sampled, and the solid
collected by filtration in the laboratory. The solid is dried and
analysed by xrpd/DSC to check form. If the form is as required
(Form 1) the batch is filtered, washed and dried as described
previously. If the form is not pure Form 1, then the cycle from is
repeated until a satisfactory result is obtained.
X-Ray Powder Diffraction (XRPD)
[0654] X-ray powder diffraction (XRPD) data are shown in FIGS. 1-3.
The data were acquired on a PANalytical X'Pert Pro powder
diffractometer, model PW3040/60, serial number DY1850 using an
X'Celerator detector. The acquisition conditions were: radiation:
Cu K.alpha., generator tension: 40 kV, generator current: 45 mA,
start angle: 2.0.degree.2.theta., end angle: 40.0.degree.2 .theta.,
step size: 0.0167.degree.2 .theta., time per step: 31.75 seconds.
The samples were prepared by mounting a few milligrams of sample on
a Si wafer (zero background) plates, resulting in a thin layer of
powder.
Example 169
3-Butyl-8-chloro-1-{4-[5-(4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-
-dihydro-1H-purine-2,6-dione
##STR00253##
[0656] 4-Hydroxybenzoic acid (35 mg, 0.25 mmol) and CDI (45 mg,
0.28 mmol) were stirred in anhydrous DMSO (0.9 ml) at rt for 1 h.
(1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hy-
droxypentanimidamide (100 mg, 0.28 mmol) was added and the mixture
was stirred at 90.degree. C. for 16 h. The mixture was purified by
MDAP to give the title compound as a white solid (5 mg, 4%).
[0657] LC/MS: m/z 459 [MH].sup.+, RT 3.24 min.
Example 170
8-Chloro-1-[4-(5-phenyl-1,2,4-oxadiazol-3-yl)butyl]-3-propyl-3,7-dihydro-1-
H-purine-2,6-dione
##STR00254##
[0659] Benzoic acid (9 mg, 0.074 mmol) and CDI (13 mg, 0.081 mmol)
were stirred in anhydrous DMSO (0.9 ml) at rt for 1 h.
(1Z)-5-(8-Chloro-2,6-dioxo-3-propyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-h-
ydroxypentanimidamide (28 mg, 0.081 mmol) was added and the mixture
was stirred at 80.degree. C. for 4 h. The mixture was purified by
MDAP to give the title compound as a white solid (0.6 mg, 2%).
[0660] LC/MS: m/z 429 [MH].sup.+, RT 3.21 min.
[0661] .sup.1H NMR (MeOH-d.sub.4) .delta.: 0.93 (t, 3H, J=7.5 Hz),
1.74 (m, 4H), 1.84 (m, 2H), 2.84 (t, 2H, J=7 Hz), 3.97 (t, 2H,
J=7.5 Hz), 4.08 (t, 2H, J=7 Hz), 7.57 (dd, 2H, J=7 & 7.5 Hz),
7.65 (dd, 1H, J=7 & 7.5 Hz), 8.08 (d, 2H, J=7.5 Hz).
Example 171
3-Butyl-8-chloro-1-{4-[5-(2-chloro-6-fluorophenyl)-1,2,4-oxadiazol-3-yl]bu-
tyl}-3,7-dihydro-1H-purine-2,6-dione
##STR00255##
[0663] 2-Chloro-6-fluorobenzoic acid (44 mg, 0.25 mmol) and CDI (45
mg, 0.28 mmol) were stirred in anhydrous DMSO (0.9 ml) at rt for 1
h.
(1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hy-
droxypentanimidamide (100 mg, 0.28 mmol) was added and the mixture
was stirred at 90.degree. C. for 16 h. The mixture was purified by
MDAP. The product fraction was combined and concentrated to give
the title compound as a white solid (6.4 mg, 5%).
[0664] LC/MS: m/z 495 [MH].sup.+, RT 3.58 min.
Example 172
3-Butyl-8-chloro-1-{4-[5-(5-hydroxy-2-pyridinyl)-1,2,4-oxadiazol-3-yl]buty-
l}-3,7-dihydro-1H-purine-2,6-dione
##STR00256##
[0666] 5-Hydroxy-2-pyridinecarboxylic acid (24 mg, 0.17 mmol) and
CDI (31 mg, 0.19 mmol) were stirred in anhydrous DMSO (0.9 ml) at
rt for 1 h.
(1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hy-
droxypentanimidamide (68 mg, 0.19 mmol) was added and the mixture
was stirred at 90.degree. C. for 16 h. The mixture was purified by
MDAP and the product fractions concentrated to give the title
compound as a white solid (19 mg, 24%).
[0667] LC/MS: m/z 459 [MH].sup.+, RT 3.03 min.
Example 173
8-Chloro-3-pentyl-1-{4-[5-(3-thienyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihy-
dro-1H-purine-2,6-dione
##STR00257##
[0669] A solution of
(1Z)-5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-h-
ydroxypentanimidamide (50 mg, 0.13 mmol) in EtOH (1 ml) was treated
with a 21% solution of NaOEt in EtOH (55 .mu.l, 0.21 mmol) and
ethyl 3-thiophenecarboxylate (18 .mu.l, 0.13 mmol). The mixture was
heated in the microwave at 150.degree. C. for 10 min. After
cooling, the reaction was partitioned between 2M HCl (aq) and
EtOAc. The organic layer was separated and the aqueous extracted
again with EtOAc. The combined extracts were concentrated and
purified by the MDAP. The title compound was obtained as an
off-white solid (20 mg, 32%).
[0670] LC/MS: m/z 463 [MH].sup.+, RT 3.6 min.
Example 174
8-Chloro-3-pentyl-1-{4-[5-(2-thienyl)-1,2,4-oxadiazol-3-yl]butyl}-3,7-dihy-
dro-1H-purine-2,6-dione
##STR00258##
[0672] 2-Thiophenecarboxylic acid (14 mg, 0.11 mmol) was dissolved
in NMP (0.9 ml) and treated with CDI (18 mg, 0.11 mmol). After 1 h,
(1Z)-5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-h-
ydroxypentanimidamide (50 mg, 0.13 mmol) was added and the mixture
heated in the microwave at 150.degree. C. for 15 min. The solution
was directly purified by MDAP to obtain the title compound which
was then freeze dried from 1,4-dioxane to give the title compound
as a white solid (19 mg, 31%).
[0673] LC/MS: m/z 463 [MH].sup.+, RT 3.5 min.
Example 175
8-Chloro-3-pentyl-1-{4-[5-(1,3-thiazol-2-yl)-1,2,4-oxadiazol-3-yl]butyl}-3-
,7-dihydro-1H-purine-2,6-dione
##STR00259##
[0675] A solution of
(1Z)-5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-h-
ydroxypentanimidamide (50 mg, 0.13 mmol) in EtOH (1.5 ml) was
treated with a 21% solution of NaOEt in EtOH (50 .mu.l, 0.13 mmol)
and ethyl 1,3-thiazole-2-carboxylate (18 mg, 0.11 mmol). The
mixture was heated in the microwave at 170.degree. C. for 10 min.
After cooling, the reaction was partitioned between 2M HCl (aq) and
EtOAc. The organic layer was separated then concentrated and
purified by the MDAP. The title compound was obtained as a white
solid (13 mg, 21%).
[0676] LC/MS: m/z 464 [MH].sup.+, RT 3.3 min.
[0677] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.83 (t, 3H, J=7 Hz),
1.21-1.32 (m, 4H), 1.60-1.77 (m, 6H), 2.84 (t, 2H, J=7 Hz), 3.91
(m, 4H), 8.23 (d, 1H, J=3 Hz), 8.27 (d, 1H, J=3 Hz), 14.4 (br s,
1H).
Example 176
3-butyl-8-chloro-1-{4-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]butyl}-3,7-dih-
ydro-1H-purine-2,6-dione
a) Preparation of
3-butyl-8-chloro-1-{-4-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]butyl}-3,7-d-
ihydro-1H-purine-2,6-dione
##STR00260##
[0679] To a mixture of ethyl
5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate
(120 mg, 0.32 mmol) and of N-hydroxy-2-pyridinecarboximidamide (50
mg, 0.36 mmol) in EtOH (2 ml) was added a 21% (w/v) solution of
sodium ethoxide in EtOH (0.225 ml, 0.62 mmol) and then heated in a
sealed vial in a microwave oven at 140.degree. C. for 10 min. The
cooled mixture was evaporated to dryness and the residue
partitioned between chloroform (5 ml) and saturated aqueous
ammonium chloride (5 ml). The organic phase was evaporated to
dryness and the crude product subjected to purification by MDAP.
Product containing fractions were combined and evaporated to
dryness. The product was triturated to a solid in a small amount of
diethyl ether then dried to reveal the title compound as a white
solid (44 mg, 31%).
[0680] LC/MS: m/z 444 [MH].sup.+, RT 3.03 min.
[0681] .sup.1H NMR (CDCl.sub.3) .delta.: 0.96 (t, 3H, J=7.3 Hz),
1.40 (m, 2H), 1.74 (m, 2H), 1.88 (m, 2H), 1.99 (m, 2H), 3.07 (t,
2H, J=7.5 Hz), 4.09 (t, 2H, J=7.5 Hz), 4.17 (t, 2H, J=7.0 Hz), 7.43
(m, 1H), 7.64 (m, 1H), 8.10 (m, 1H), 8.79 (m, 1H).
b) Preparation of N-hydroxy-2-pyridinecarboximidamide
##STR00261##
[0683] To a mixture of 2-pyridinecarbonitrile (3 g, 29 mmol) and
potassium carbonate (4.1 g, 30 mmol)in EtOH (30 ml) was added water
(15 ml) and, cautiously, hydroxylamine hydrochloride (2.9 g, 42
mmol) and then heated at reflux for 6 h, cooled and evaporated to
dryness. The residue was treated with water (100 ml) and the
suspended solid product filtered off, washed with water and dried
to yield the title compound as a white solid (2.28 g, 57%).
[0684] .sup.1H NMR (DMSO-d.sub.6) .delta.: 5.85 (br s, 2H), 7.40
(m, 1H), 7.79 (m, 1H), 7.86 (m, 1H), 8.55 (m, 1H), 9.92 (s, 1H)
Example 177
3-Butyl-8-chloro-1-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)butyl]-3,7-dihydro-1H-
-purine-2,6-dione
Method A
a)
3-Butyl-8-chloro-1-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)butyl]-3,7-dihydro-
-1H-purine-2,6-dione
##STR00262##
[0686] Ethyl
5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate
(74 mg, 0.2 mmol) and benzamidoxime (30 mg, 0.22 mmol) were
suspended in dry EtOH (1 ml) and ethanolic sodium ethoxide (21% by
wt., 0.111 ml, 0.3 mmol) was added. The mixture was gently warmed
until solids were dissolved and then heated in the microwave
reactor at 140.degree. C. for 10 min. The mixture was then
partitioned between EtOAc and 2M HCl and the organic phase dried
(Na.sub.2SO.sub.4) and evaporated. MDAP afforded the pure title
compound (40.7 mg).
[0687] LC/MS: m/z 443 [MH].sup.+, RT 3.67 min.
[0688] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.89 (t, 3H, J=7 Hz),
1.22-1.34 (m, 2H), 1.57-1.75 (m, 4H), 1.75-1.86 (m, 2H), 3.05 (t,
2H, J=7 Hz), 3.88-3.98 (m, 4H), 7.52-7.63 (m, 3H), 7.95-8.0 (m,
2H).
b) Ethyl
5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pe-
ntanoate
##STR00263##
[0690] To
3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dio-
ne (1.5 g, 5.31 mmol) in dry DMF (25 ml) was added Cs.sub.2CO.sub.3
(1.905 g, 5.84 mmol), followed by ethyl 5-bromovalerate (1.46 g,
6.99 mmol). The mixture was heated at 55.degree. C. for 18 h then
allowed to cool. It was degassed by repeatedly evacuating and
readmitting nitrogen, then morpholine (3.70 ml, 42.5 mmol) and
tetrakis(triphenylphosphine)palladium(0) (1.0 g, 0.865 mmol) were
added and the mixture stirred for 5 h. EtOAc (75 ml), 2M HCl (40
ml) and water (20 ml) were added and the organic phase was
separated, washed with brine (3.times.25 ml), filtered to remove
some insoluble yellow solid, dried (Na.sub.2SO.sub.4) and
evaporated. The residue (2.5 g) was purified by aminopropyl SPE (20
g), loading in THF-MeOH (1:1), washing with MeOH and eluting the
product with DCM-MeOH (1:1) containing 5% added AcOH to afford the
title compound (1.53 g).
[0691] LC/MS: m/z 371 MH.sup.+, RT 3.18 min
Method B
a)
3-Butyl-8-chloro-1-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)butyl]-3,7-dihydro-
-1H-purine-2,6-dione
##STR00264##
[0693] CDI (0.98 g, 6.1 mmol) was added to a solution of
5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic
acid (1.89 g, 5.5 mmol) in DMF (15 ml) and stirred under nitrogen
for 1.5 h. Benzamidoxime (0.91 g, 6.1 mmol) was added and the
mixture stirred at 110.degree. C. overnight. The reaction mixture
was partitioned between EtOAc and 2M HCl. The organic layer was
separated, washed with brine, dried (MgSO.sub.4) and evaporated.
The crude product was crystallised from methanol and then further
purified using the Companion.TM. system and a gradient elution from
cyclohexane to EtOAc. Product containing fractions were combined
and evaporated to give the title compound as a white solid (850
mg).
[0694] LC/MS: m/z 443 [MH].sup.+, RT 3.52 min.
[0695] .sup.1H NMR (MeOH-d.sub.4) .delta.: 0.94 (t, 3H, J=7.5 Hz),
1.31-1.41 (m, 2H), 1.65-1.73 (m, 2H), 1.75-1.83 (m, 2H), 1.87-1.96
(m, 2H), 3.04 (t, 2H, J=7.5 Hz), 4.01 (t, 2H, J=7.5 Hz), 4.06 (t,
2H, J=7 Hz), 7.46-7.55 (m, 3H), 7.98-8.02 (m, 2H).
b)
5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoi-
c acid
##STR00265##
[0697] A mixture of ethyl
5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate
(2.8 g, 7.55 mmol), LiOH (542 mg, 22.7 mmol), water (2.5 ml) and
methanol (50 ml) was stirred at rt for 60 h. The mixture was
portioned between water and EtOAc and the pH of the aqueous phase
adjusted to pH 4-5. The organic layer was separated, washed with
brine, dried (MgSO.sub.4) and evaporated to give the title compound
as a white solid (2.18 g).
[0698] LC/MS: m/z 343 [MH].sup.+, RT 2.69 min.
Example 178
8-Chloro-3-pentyl-1-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)butyl]-3,7-dihydro-1-
H-purine-2,6-dione
##STR00266##
[0700] A mixture of methyl
5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoat-
e (50 mg, 0.13 mmol), benzamidine oxime (20 mg, 0.15 mmol) and a
21% solution of NaOEt in EtOH 0.20 mmol) in EtOH (1.5 ml) was
heated in the microwave at 140.degree. C. for 10 min. After cooling
the reaction was partitioned between 2M HCl (aq) and EtOAc. The
organic layer was separated, dried (MgSO.sub.4) and concentrated.
Purification by the MDAP gave the title compound as a white solid
(25 mg, 41%).
[0701] LC/MS: m/z 457 [MH].sup.+, RT 3.7 min.
[0702] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.82 (t, 3H, J=7 Hz),
1.25 (m, 4H), 1.66 (m, 4H), 1.79 (m, 2H), 3.04 (t, 2H, J=7 Hz),
3.92 (4H, m), 7.57 (m, 3H), 7.97 (m, 2H), 14.5 (br s, 1H).
Example 179
3-Butyl-8-chloro-1-{4-[3-(3-hydroxyphenyl)-1,2,4-oxadiazol-5-yl]butyl}-3,7-
-dihydro-1H-purine-2,6-dione
##STR00267##
[0704] A mixture of ethyl
5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate
(50 mg, 0.13 mmol), N,3-dihydroxybenzenecarboximidamide (25 mg,
0.16 mmol), 21% solution of NaOEt in EtOH (55 .mu.l, 0.15 mmol) and
EtOH (1.5 ml) was heated in the microwave at 180.degree. C. for 10
min. Another aliquot of 21% solution of NaOEt in EtOH (55 .mu.l,
0.21 mmol) was added and the mixture heated in the microwave at
175.degree. C. for 30 min. After cooling the reaction was
partitioned between 2M HCl (aq) and EtOAc. The organic layer was
separated, concentrated and purified by the MDAP. The title
compound was obtained as an off-white solid (20 mg, 32%).
[0705] LC/MS: m/z 459 [MH].sup.+, RT 3.3 min.
Example 180
8-Chloro-1-{(4-[3-(4-hydroxyphenyl)-1,2,4-oxadiazol-5-yl]butyl}-3-pentyl-3-
,7-dihydro-1H-purine-2,6-dione
##STR00268##
[0707] A solution of
5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic
acid (50 mg, 0.14 mmol) in DMF (2 ml) was treated with CDI (23 mg,
0.14 mmol) and stirred at rt for 30 min.
N,4-dihydroxybenzenecarboximidamide (26 mg, 0.17 mmol) was added
and the mixture heated in the microwave at 120.degree. C. for 15
min. After cooling the reaction was partitioned between 2M HCl (aq)
and EtOAc. The organic layer was separated, concentrated and
purified by the MDAP. The title compound was obtained as an
off-white solid (17 mg, 26%).
[0708] LC/MS: m/z 473 [MH].sup.+, RT 3.5 min.
Example 181
3-Butyl-8-chloro-1-[4-(5-phenyl-2H-tetrazol-2-yl)butyl]-3,7-dihydro-1H-pur-
ine-2,6-dione
##STR00269##
[0710] A mixture of
4-[3-butyl-8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-pur-
in-1-yl]butyl methanesulfonate (50 mg, 0.12 mmol), Cs.sub.2CO.sub.3
(45 mg, 0.14 mmol) and DMF (3 ml) was treated with
5-phenyl-1H-tetrazole (20 mg, 0.14 mmol) and stirred for 60 h at
50.degree. C. After cooling, the mixture was degassed by applying a
vacuum and then nitrogen was introduced. Pd(PPh.sub.3).sub.4 (20
mg, 0.017 mmol) was added and the mixture degassed once more.
Morpholine (150 .mu.l, 1.7 mmol) was added and the mixture was
stirred under nitrogen for 18 h, then partitioned between 2M HCl
(aq) and EtOAc. The organic layer was separated and the aqueous
layer extracted again with EtOAc. The combined extracts were
concentrated, giving a yellow residue. MeOH was added and then
passed down an NH.sub.2-propyl column with the product eluting with
2% AcOH/MeOH. Further purification by MDAP gave the title compound
as an off-white solid (15 mg, 29%).
[0711] LC/MS: m/z 443 [MH].sup.+, RT 3.4 min.
[0712] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.86 (t, 3H, J=7 Hz),
1.26 (m, 2H), 1.59 (m, 4H), 1.97 (m, 2H), 3.90 (m, 4H), 4.76 (t,
2H, J=7 Hz), 7.54 (m, 3H), 8.02 (m, 2H), 14.4 (br s, 1H).
Example 182
3-Butyl-8-chloro-1-[4-(5-oxo-4-phenyl-4,5-dihydro-1H-tetrazol-1-yl)butyl]--
3,7-dihydro-1H-purine-2,6-dione
##STR00270##
[0714] A mixture of
4-[3-butyl-8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-pur-
in-1-yl]butyl methanesulfonate (50 mg, 0.12 mmol), Cs.sub.2CO.sub.3
(45 mg, 0.14 mmol) and DMF (3 ml) was treated with
1-phenyl-1,2-dihydro-5H-tetrazol-5-one (23 mg, 0.14 mmol) and
stirred for 60 h at 50.degree. C. After cooling, the mixture was
degassed by applying a vacuum and then nitrogen was introduced.
Pd(PPh.sub.3).sub.4 (20 mg, 0.017 mmol) was added and the mixture
degassed once more. Morpholine (150 .mu.l, 1.7 mmol) was added and
the mixture was stirred under nitrogen for 18 h, then partitioned
between 2M HCl (aq) and EtOAc. The organic layer was separated and
the aqueous layer extracted again with EtOAc. The combined extracts
were concentrated, giving a yellow residue. MeOH was added and then
passed down an aminopropyl column with the product eluting with 2%
AcOH/MeOH. Further purification by MDAP gave the title compound as
an off-white solid (27 mg, 51%). NB. ca. 10% O-alkylated material
present.
[0715] LC/MS: m/z 459 [MH].sup.+, RT 3.1 min.
[0716] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.88 (t, 3H, J=7 Hz),
1.28 (m, 2H), 1.62 (m, 4H), 1.79 (m, 2H), 3.91 (m, 4H), 4.03 (m,
2H), 7.44 (m, 1H), 7.57 (m, 2H), 7.85 (m, 2H), 14.5 (br s, 1H).
Example 183
3-Butyl-8-chloro-1-[4-(4-methyl-2,5-dioxo-3-phenyl-1-imidazolidinyl)butyl]-
-3,7-dihydro-1H-purine-2,6-dione
a)
3-Butyl-8-chloro-1-[4-(4-methyl-2,5-dioxo-3-phenyl-1-imidazolidinyl)but-
yl]-3,7-dihydro-1H-purine-2,6-dione
##STR00271##
[0718] A mixture of
4-[3-butyl-8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-pur-
in-1-yl]butyl methanesulfonate (88 mg, 0.20 mmol), Cs.sub.2CO.sub.3
(80 mg, 0.24 mmol) and DMF (2 ml) was treated with
5-methyl-1-phenyl-2,4-imidazolidinedione (46 mg, 0.24 mmol) and
stirred for 18 h at 70.degree. C. After cooling, the mixture was
degassed by applying a vacuum and then nitrogen was introduced.
Pd(PPh.sub.3).sub.4 (25 mg, 0.022 mmol) was added and the mixture
degassed once more. Morpholine (174 .mu.L, 2.0 mmol) was added and
the mixture was stirred under nitrogen for 5 h, then partitioned
between 2M HCl (aq) and EtOAc. The organic layer was separated and
the aqueous layer extracted again with EtOAc. The combined extracts
were concentrated, giving a yellow residue. MeOH was added and then
passed down an aminopropyl SPE with the product eluting with 2%
AcOH/MeOH. Further purification by MDAP gave the title compound as
a solid (70 mg, 71%).
[0719] LC/MS: m/z 487 [MH].sup.+, RT 3.2 min.
b)
4-[3-Butyl-8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-p-
urin-1-yl]butyl methanesulfonate
##STR00272##
[0721] A solution of
3-butyl-8-chloro-1-(4-hydroxybutyl)-7-(2-propen-1-yl)-3,7-dihydro-1H-puri-
ne-2,6-dione (1.30 g, 3.66 mmol) in DCM (10 ml) was treated with
triethylamine (0.77 ml, 5.50 mmol) followed by portionwise addition
of methanesulfonic anhydride (702 mg, 4.03 mmol). CARE,
effervescence. The reaction mixture was stirred at rt for 10 min
then partitioned between sat. NaHCO.sub.3 (aq) solution and DCM.
The organic layer was separated and washed with 1M HCl (aq) and
then brine. It was dried (MgSO.sub.4) and concentrated, giving the
title compound as a viscous oil (1.60 g, quant.).
[0722] LC/MS: m/z 433 [MH].sup.+, RT 3.3 min.
c)
3-Butyl-8-chloro-1-(4-hydroxybutyl)-7-(2-propen-1-yl)-3,7-dihydro-1H-pu-
rine-2,6-dione
##STR00273##
[0724] A stirred solution of
3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(5.0 g, 17.7 mmol) in DMF (100 ml) was treated with
Cs.sub.2CO.sub.3 (6.3 g, 19.5 mmol) and 4-bromo-1-butanol (3.0 ml,
21.2 mmol). The mixture was heated at 50.degree. C. for 5 h then
partitioned between 2M HCl (aq) and EtOAc. The organic layer was
separated, washed with brine, dried (MgSO.sub.4) and concentrated,
giving a yellow solid. Purification by silica SPE
(EtOAc/cyclohexane mixtures as the eluent) and then by the
Companion.TM. system (IPA/DCM mixtures as the eluent) gave the
title compound as a colourless oil (1.35 g, 21%).
[0725] LC/MS: m/z 355 [MH].sup.+, RT 2.9 min.
Example 184
8-Chloro-1-{4-[4-(cyclopentylsulfonyl)phenyl]butyl}-3-pentyl-3,7-dihydro-1-
H-purine-2,6-dione
##STR00274##
[0727]
8-Chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(100 mg, 0.34 mmol) was dissolved in DMF (1 ml) and sequentially
treated with 4-[4-(cyclopentylsulfonyl)phenyl]-1-butanol (105 mg,
0.37 mmol), PPh.sub.3 (404 .mu.l of a 1M solution in DMF) and DBAD
(404 .mu.l of a 1M solution in DMF). After stirring for 24 h under
nitrogen, the mixture was degassed by applying a vacuum and then
nitrogen was introduced. Pd(PPh.sub.3).sub.4 (39 mg, 0.034 mmol)
was added and the mixture degassed once more. Morpholine (297
.mu.l, 3.4 mmol) was added and the mixture was stirred under
nitrogen for 63 h, then partitioned between 2M HCl (aq) and EtOAc.
The organic layer was separated, washed with brine, dried
(MgSO.sub.4) and concentrated, giving a yellow residue. MeOH was
added and then passed down an aminopropyl SPE with the product
eluting with 2% AcOH/MeOH. The product was further purified by MDAP
giving the title compound as a beige solid (5 mg, 3%).
[0728] LC/MS: m/z 521 [MH.sup.+], RT 3.7 min.
Example 185
8-Chloro-1-{4-[4-(methyloxy)phenyl]butyl}-3-pentyl-3,7-dihydro-1H-purine-2-
,6-dione
##STR00275##
[0730] A solution of 4-(4-bromobutyl)phenyl methyl ether (88 mg,
0.36 mmol) in DMF (3 ml) was reacted with
8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(90 mg, 0.30 mmol) and Cs.sub.2CO.sub.3 (109 mg, 0.33 mmol) for 5 h
at 50.degree. C. The mixture was degassed by applying a vacuum and
then nitrogen was introduced. Pd(PPh.sub.3).sub.4 (35 mg, 0.030
mmol) was added and the mixture degassed once more. Morpholine
(0.26 ml, 3.0 mmol) was added and the mixture was stirred under
nitrogen for 3 h. Another aliquot of Pd(PPh.sub.3).sub.4 (35 mg,
0.030 mmol) was added and left for a further 3 h. The mixture was
partitioned between 2M HCl (aq) and EtOAc. The organic layer was
separated and the aqueous layer extracted again with EtOAc. The
combined extracts were concentrated, giving a yellow residue. MeOH
was added and then passed down an aminopropyl SPE with the product
eluting with 3% AcOH/MeOH. The product was further purified by MDAP
giving the title compound as a solid (2 mg, 1.5%).
[0731] LC/MS: m/z 419 [MH].sup.+, RT 3.7 min.
[0732] .sup.1H NMR; (MeOH-d.sub.4) .delta.: 0.90 (t, 3H, J=7 Hz),
1.28-1.40 (m, 4H), 1.57-1.75 (m, 6H), 2.57 (t, 2H, J=7 Hz), 3.73
(s, 3H), 3.97-4.02 (4H, m), 6.77 (m, 2H), 7.06 (m, 2H).
Example 186
8-Chloro-3-pentyl-1-{3-[3-(methyloxy)phenyl]propyl}-3,7-dihydro-1H-purine--
2,6-dione
a)
8-Chloro-3-pentyl-1-{3-[3-(methyloxy)phenyl]propyl}-3,7-dihydro-1H-puri-
ne-2,6-dione
b)
##STR00276##
[0734]
8-Chloro-3-pentyl-1-{3-[3-(methyloxy)phenyl]propyl}-7-(2-propen-1-y-
l)-3,7-dihydro-1H-purine-2,6-dione (2.94 g) was dissolved in
anhydrous THF (40 ml). The solution was degassed using a
nitrogen/vacuum purge 6 times. Tetrakis(triphenylphosphine)
palladium (0.66 g) was added followed by morpholine (5 ml). After
stirring for 18 hr, the reaction mixture was diluted with EtOAc and
was washed with 1N HCl and brine (.times.2), dried (MgSO.sub.4) and
evaporated in vacuo. This crude material was purified on an
aminopropyl SPE (70 g) eluting with MeOH then MeOH containing 3%
AcOH to give the title compound as a pale yellow solid (1.56
g).
[0735] LC/MS: m/z 405 [MH].sup.+, RT 3.51 min.
b)
8-Chloro-3-pentyl-1-{3-[3-(methyloxy)phenyl]propyl}-7-(2-propen-1-yl)-3-
,7-dihydro-1H-purine-2,6-dione
##STR00277##
[0737]
8-Chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(1.76 g, 5.94 mmol) and 3-[3-(methyloxy)phenyl]-1-propanol (1.00 g,
6.04 mmol) were dissolved in anhydrous THF (50 ml) under an
atmosphere of nitrogen. After 5 min triphenylphosphine (1.87 g,
7.12 mmol) was added. After a further 5 min di-tert-butyl
azodicarboxylate (1.64 g, 7.1 mmol) was added. The solution was
stirred for 20 h at rt. The cloudy solution was concentrated in
vacuo and purified on a 50 g Silica II SPE (IST) using a Biotage
FlashMaster.TM. Personal, eluting with cyclohexane /EtOAc 5:1 the
appropriate fractions were concentrated in vacuo to give the title
compound as a pale cream oil containing minor impurities (2.94
g).
[0738] LC/MS: m/z 445 [MH].sup.+, RT 3.88 min.
Example 187
8-Chloro-1-[3-(3-hydroxyphenyl)propyl]-3-pentyl-3,7-dihydro-1H
purine-2,6-dione
##STR00278##
[0740] To a suspension of
8-chloro-3-pentyl-1-{3-[3-(methyloxy)phenyl]propyl}-3,7-dihydro-1H-purine-
-2,6-dione (1.52 g, 3.86 mmol) in anhydrous DCM (40 ml) at
-73.degree. C. was slowly added 1N borontribromide in DCM (4.6 ml).
The reaction mixture was stirred at -70.degree. C. for 2 hours and
then at rt for 96 h. The reaction mixture was cooled in ice, and
water (6.8 ml) was added slowly. The reaction mixture was then
diluted with EtOAc and water, and the organic phase was washed with
saturated, sodium hydrogen carbonate (.times.3) and brine then
dried (MgSO.sub.4) and evaporated in vacuo. A portion of this crude
material (90 mg) was purified by MDAP to give the title compound
after freeze drying as a white solid (40 mg).
[0741] LC/MS: m/z 391 [MH].sup.+, RT 3.43 min.
[0742] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.85 (t, 3H, J=7 Hz);
1.27 (m, 4H); 1.63 (m, 2H); 1.80 (m, 2H); 2.50 (m, 2H); 3.89 (m,
4H); 6.57 (m, 3H); 7.02 (t, 1H, J=8 Hz); 9.22 (s, 1H); 14.39 (s,
1H)
Example 188
3-butyl-8-chloro-1-{4-[3-(4-hydroxyphenyl)-1,2,4-oxadiazol-5-yl]butyl}-3,7-
-dihydro-1H-purine-2,6-dione
##STR00279##
[0744] A stirred solution of
5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic
acid (100 mg, 0.29 mmol) in DMF (4 ml) was treated with CDI (52 mg,
0.32 mmol). After 1 h, N,4-dihydroxybenzenecarboximidamide was
added and the mixture heated at 100.degree. C. for 6 h. On cooling,
the reaction mixture was partitioned between 2M HCl (aq) and EtOAc.
The organic layer was separated, washed with brine, dried (MgSO4)
and concentrated. Purification by MDAP afforded the title compound
as a pale grey solid (72 mg).
[0745] LC/MS: m/z 459 [MH].sup.+, RT 3.27 min.
[0746] The following compounds (Table 10) were prepared using a
method analogous to that for Example 177, using the appropriate
amidoxime.
TABLE-US-00010 TABLE 10 Yield Example Structure (mg) LC/MS 189
##STR00280## 48.4 m/z 457 [MH].sup.+ RT 3.56 min
3-butyl-8-chloro-1-{4-[3-(phenylmethyl)-
1,2,4-oxadiazol-5-yl]butyl}-3,7-dihydro- 1H-purine-2,6-dione 190
##STR00281## 35.8 m/z 461 [MH].sup.+ RT 3.74 min
3-butyl-8-chloro-1-{4-[3-(4-fluorophenyl)-
1,2,4-oxadiazol-5-yl]butyl}-3,7-dihydro- 1H-purine-2,6-dione 191
##STR00282## 48.2 m/z 509 [MH].sup.+ RT 3.74 min
3-butyl-8-chloro-1-(4-{3-[(2-chloro-4-
fluorophenyl)methyl]-1,2,4-oxadiazol-5-
yl}butyl)-3,7-dihydro-1H-purine-2,6-dione
Example 192
3-Butyl-8-chloro-1-{3-[3-(1-phenylcyclopentyl)-1,2,4-oxadiazol-5-yl]propyl-
}-3,7-dihydro-1H-purine-2,6-dione
##STR00283##
[0748] Ethyl
4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate
(53 mg, 0.15 mmol), N-hydroxy-1-phenylcyclopentanecarboximidamide
(34 mg, 0.165 mmol) and sodium methoxide (20 mg, 0.37 mmol) in dry
MeOH (0.75 ml) were heated at 140.degree. C. in the microwave
reactor for 10 min. The mixture was then partitioned between ethyl
acetate and 2M HCl, the organic phase evaporated and the product
purified by MDAP to give the title compound as a solid (29.1
mg).
[0749] LC/MS: m/z 497 [MH].sup.+, RT 3.76 min.
[0750] The following compounds (Table 11) were prepared using a
method analogous to that for Example 192, using the appropriate
amidoxime [with the exception that for Examples 210, 211 and 212
EtOH was used as reaction solvent; for Examples 210, 211 and 212
the reactions were worked up by adding 2M HCl until neutral and
evaporating the solvent; for Example 206 the scale was 32 mg of
starting ethyl ester; Example 208 the scale was 42 mg of starting
ethyl ester].
TABLE-US-00011 TABLE 11 Yield Example Structure (mg) LC/MS 193
##STR00284## 17.4 m/z 485 [MH].sup.+ RT 3.74 min
3-butyl-8-chloro-1-{3-[3-(2-methyl-
1-phenylpropyl)-1,2,4-oxadiazol-5-
yl]propyl}-3,7-dihydro-1H-purine- 2,6-dione 194 ##STR00285## 33.7
m/z 515 [MH].sup.+ RT 3.73 min 3-butyl-8-chloro-1-(3-{3-[1-(2-
fluorophenyl)cyclopentyl}-1,2,4-
oxadiazol-5-yl)propyl)-3,7-dihydro- 1H-purine-2,6-dione 195
##STR00286## 28.8 m/z 455 [MH].sup.+ RT 3.43 min
1-[3-(3-bicyclo[4.2.0]octa-1,3,5- trien-7-yl-1,2,4-oxadiazol-5-
yl)propyl]-3-butyl-8-chloro-3,7- dihydro-1H-purine-2,6-dione 196
##STR00287## 33.4 m/z 507 [MH].sup.+ RT 3.59 min
3-butyl-8-chloro-1-(3-{3-[1-(2,4- difluorophenyl)-1-methylethyl]-
1,2,4-oxadiazol-5-yl}propyl)-3,7- dihydro-1H-purine-2,6-dione 197
##STR00288## 33.8 m/z 517 [MH].sup.+ RT 3.85 min
3-butyl-8-chloro-1-(3-{3-[1-(4- chlorophenyl)cyclobutyl]-1,2,4-
oxadiazol-5-yl}propyl)-3,7-dihydro- 1H-purine-2,6-dione 198
##STR00289## 34.2 m/z 515 [MH].sup.+ RT 3.80 min
3-butyl-8-chloro-1-(3-{3-[1-(3- fluorophenyl)cyclopentyl]-1,2,4-
oxadiazol-5-yl}propyl)-3,7-dihydro- 1H-purine-2,6-dione 199
##STR00290## 16.3 m/z 505 [MH].sup.+ RT 3.80 min
3-butyl-8-chloro-1-(3-{3-[1-(4- chlorophenyl)propyl]-1,2,4-
oxadiazol-5-yl)propyl)-3,7-dihydro- 1H-purine-2,6-dione 200
##STR00291## 34.9 m/z 549 [MH].sup.+ RT 3.72 min 1-(3-{3-[1-(3-
bromophenyl)cyclopropyl]-1,2,4- oxadiazol-5-yl}propyl)-3-butyl-8-
chloro-3,7-dihydro-1H-purine-2,6- dione 201 ##STR00292## 30.4 m/z
507 [MH].sup.+ RT 3.59 min 3-butyl-8-chloro-1-(3-{3-[1-(2,3-
difluorophenyl)-1-methylethyl]- 1,2,4-oxadiazol-5-yl]propyl)-3,7-
dihydro-1H-purine-2,6-dione 202 ##STR00293## 3 m/z 535 [MH].sup.+
RT 3.69 min. 3-butyl-8-chloro-1-(3-{3-
(phenoxy(phenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3,7-dihydro-
1H-purine-2,6-dione 203 ##STR00294## 38.8 m/z 577 [MH].sup.+ RT
3.99 min. 1-(3-{3-[1-(3- bromophenyl)cyclopentyl]-1,2,4-
oxadiazol-5-yl}propyl)-3-butyl-8- chloro-3,7-dihydro-1H-purine-2,6-
dione 204 ##STR00295## 41.4 m/z 535 [MH].sup.+ RT 3.79 min.
3-butyl-8-chloro-1-(3-{3-[1-(2- chloro-5-fluorophenyl)cyclobutyl]-
1,2,4-oxadiazol-5-yl}propyl)-3,7- dihydro-1H-purine-2,6-dione 205
##STR00296## 12.9 m/z 499 [MH].sup.+ RT 3.42 min.
3-butyl-8-chloro-1-{3-[3-(1,3,4,5- tetrahydro-2-benzoxepin-1-yl)-
1,2,4-oxadiazol-5-yl]propyl}-3,7- dihydro-1H-purine-2,6-dione 206
##STR00297## 12.9 m/z 563 [MH].sup.+ RT 4.02 min.
3-butyl-8-chloro-1-(3-{3-[1-(2- chloro-6-fluorophenyl)cyclohexyl]-
1,2,4-oxadiazol-5-yl}propyl)-3,7- dihydro-1H-purine-2,6-dione 207
##STR00298## 34.8 m/z 511 [MH].sup.+ RT 3.88 min.
3-butyl-8-chloro-1-{3-[3-(1- phenylcyclohexyl)-1,2,4-oxadiazol-
5-yl]propyl}-3,7-dihydro-1H-purine- 2,6-dione 208 ##STR00299## 19
m/z 563 [MH].sup.+ RT 4.00 min. 3-butyl-8-chloro-1-(3-{3-[1-(2-
chloro-4-fluorophenyl)cyclohexyl]-
1,2,4-oxadiazol-5-yl]propyl)-3,7- dihydro-1H-purine-2,6-dione 209
##STR00300## 30.5 m/z 483[MH].sup.+ RT 3.64 min.
3-butyl-8-chloro-1-{3-[3-(1- phenylcyclobutyl)-1,2,4-oxadiazol-
5-yl]propyl}-3,7-dihydro-1H-purine- 2,6-dione
Example 210
3-Butyl-8-chloro-1-[3-(3-{[4-(methyloxy)phenyl]methyl}-1,2,4-oxadiazol-5-y-
l)propyl]-3,7-dihydro-1H-purine-2,6-dione
##STR00301##
[0752] Prepared using a method analogous to that used for Example
93, except an additional final purification step using HPLC was
employed. Yield 6.0 mg.
[0753] LC/MS: m/z 473 [MH].sup.+, RT 3.27 min.
[0754] The following compounds (Table 12) were prepared using a
method analogous to that for Example 96, using the appropriate
amidoxime [with the exception that for Example 211 the scale was
0.12 mmol instead of 0.15 mmol; for Example 216 the crude product
was stirred in EtOH (0.75 ml) with 2M NaOH (0.5 ml) overnight prior
to the usual EtOAc/HCl workup and MDAP; Example 218 was isolated as
an impurity from the preparation of Example 219 and was separated
from it by HPLC; for Examples 221, 222 and 223 the pH during
aqueous workup was adjusted to approximately 5 prior to extraction;
additionally Example 223 was further purified by silica SPE (2 g,
DCM-MeOH 40:1 then 20:1) after MDAP].
TABLE-US-00012 TABLE 12 Yield Example Structure (mg) LC/MS 211
##STR00302## 23.8 m/z 537 [MH].sup.+ RT 3.83 min
3-butyl-8-chloro-1-(3-{3-[1-(2,4-
dichlorophenyl)cyclopropyl]-1,2,4-
oxadiazol-5-yl}propyl)-3,7-dihydro-1H- purine-2,6-dione 212
##STR00303## 39.5 m/z 507 [MH].sup.+ RT 3.58 min
3-butyl-8-chloro-1-[3-(3-{[5-chloro-2-
(methyloxy)phenyl]methyl}-1,2,4-
oxadiazol-5-yl)propyl]-3,7-dihydro-1H- purine-2,6-dione 213
##STR00304## 35.8 m/z 529 [MH].sup.+ RT 3.41 min
1-(3-{3-[4,5-bis(methyloxy)-2,3- dihydro-1H-inden-1-yl]-1,2,4-
oxadiazol-5-yl}propyl)-3-butyl-8- chloro-3,7-dihydro-1H-purine-2,6-
dione 214 ##STR00305## 9.7 m/z 511 [MH].sup.+ RT 3.63 min
3-butyl-8-chloro-1-(3-{3-[(2,5- dichlorophenyl)methyl]-1,2,4-
oxadiazol-5-yl}propyl)-3,7-dihydro-1H- purine-2,6-dione 215
##STR00306## 18.0 m/z 446 [MH].sup.+ RT 3.15 min
3-butyl-8-chloro-1-(3-{3-[(1-methyl-1H-
pyrrol-2-yl)methyl]-1,2,4-oxadiazol-5-
yl}propyl)-3,7-dihydro-1H-purine-2,6- dione 216 ##STR00307## 15.5
m/z 464 [MH].sup.+ RT 2.94 min 3-butyl-8-chloro-1-(3-{3-[(4-methyl-
1,3-thiazol-2-yl)methyl]-1,2,4-
oxadiazol-5-yl}propyl)-3,7-dihydro-1H- purine-2,6-dione 217
##STR00308## 33.5 m/z 479 [MH].sup.+ RT 3.35 min
3-butyl-8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4-
oxadiazol-5-yl}propyl)-3,7-dihydro-1H- purine-2,6-dione 218
##STR00309## 4.6 m/z 545 [MH].sup.+ RT 3.71 min
3-butyl-8-chloro-1-(3-{3-[(2,3,6- trichlorophenyl)methyl]-1,2,4-
oxadiazol-5-yl}propyl)-3,7-dihydro-1H- purine-2,6-dione 219
##STR00310## 17.7 m/z 545 [MH].sup.+ RT 3.79 min
3-butyl-8-chloro-1-(3-{3-[(2,4,5- trichlorophenyl)methyl]-1,2,4-
oxadiazol-5-yl}propyl)-3,7-dihydro-1H- purine-2,6-dione 220
##STR00311## 17.8 m/z 455 [MH].sup.+ RT 3.49 min
3-butyl-8-chloro-1-(3-{3-[(E)-2- phenylethenyl]-1,2,4-oxadiazol-5-
yl}propyl)-3,7-dihydro-1H-purine-2,6- dione 221 ##STR00312## 39.2
m/z 467 [MH].sup.+ RT 3.24 min
3-butyl-8-chloro-1-(3-{3-[(4-chloro-1H-
pyrazol-1-yl)methyl]-1,2,4-oxadiazol-
5-yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 222 ##STR00313## 27.0
m/z 452 [MH].sup.+ RT 2.56 min 3-butyl-8-chloro-1-{3-[3-(4-
morpholinylmethyl)-1,2,4-oxadiazol-5-
yl]propyl}-3,7-dihydro-1H-purine-2,6- dione 223 ##STR00314## 23.6
m/z 444 [MH].sup.+ RT 2.92 min 3-butyl-8-chloro-1-{3-[3-(2-
pyridinylmethyl)-1,2,4-oxadiazol-5-
yl]propyl}-3,7-dihydro-1H-purine-2,6- dione 224 ##STR00315## 38.8
m/z 495 [MH].sup.+ RT 3.43 min
3-butyl-8-chloro-1-(3-{3-[(2-chloro-6-
fluorophenyl)methyl]-1,2,4-oxadiazol-
5-yl}propyl)-3,7-dihydro-1H-purine- 2,6-dione 225 ##STR00316## 27
m/z 491 [MH].sup.+ RT 3.31 min
3-butyl-8-chloro-1-[3-(3-{[3-fluoro-4-
(methyloxy)phenyl]methyl)-1,2,4-
oxadiazol-5-yl)propyl]-3,7-dihydro-1H- purine-2,6-dione
[0755] The following compounds (Table 13) were prepared using a
method analogous to that for Example 114, using the appropriate
amidoxime [with the exception that Example 226 was conducted on
half the scale of Example 114 and during workup the aqueous phase
was neutralised prior to extraction; Example 227 was conducted on
half the scale of Example 114 and the crude product stirred with 2M
NaOH (0.5 ml) in EtOH (1 ml) for 5 h prior to workup and MDAP; for
Example 232 0.185 ml (0.5 mmol) of 21% NaOEt was used].
TABLE-US-00013 TABLE 13 Yield Example Structure (mg) LC/MS 226
##STR00317## 20 m/z 444 [MH].sup.+ RT 2.74min
3-butyl-8-chloro-1-{3-[3-(3- pyridinylmethyl)-1,2,4-oxadiazol-5-
yl]propyl}-3,7-dihydro-1H-purine-2,6- dione 227 ##STR00318## 7.2
m/z 448 [MH].sup.+ RT 3.13 min
3-butyl-8-chloro-1-(3-{3-[(5-methyl-3-
isoxazolyl)methyl]-1,2,4-oxadiazol-5-
yl}propyl)-3,7-dihydro-1H-purine-2,6- dione 228 ##STR00319## 47.4
m/z 519 [MH].sup.+ RT 3.71 min
3-butyl-8-chloro-1-{3-[3-(diphenylmethyl)-
1,2,4-oxadiazol-5-yl]propyl}-3,7-dihydro- 1H-purine-2,6-dione 229
##STR00320## 36.7 m/z 429 [MH].sup.+ RT 3.36 min
3-butyl-8-chloro-1-[3-(3-phenyl-1,2,4-
oxadiazol-5-yl)propyl]-3,7-dihydro-1H- purine-2,6-dione 230
##STR00321## 41.1 m/z 447 [MH].sup.+ RT 3.42 min
3-butyl-8-chloro-1-{3-[3-(4-fluorophenyl)-
1,2,4-oxadiazol-5-yl]propyl}-3,7-dihydro- 1H-purine-2,6-dione 231
##STR00322## 36.7 m/z 469 [MH].sup.+ RT 3.60 min
3-butyl-8-chloro-1-{3-[3-(5-chloro-2-
thienyl)-1,2,4-oxadiazol-5-yl]propyl)-3,7-
dihydro-1H-purine-2,6-dione 232 ##STR00323## 47.0 m/z 503
[MH].sup.+ RT 3.14 min 1-[3-(3-{[3,4-
bis(methyloxy)phenyl]methyl}-1,2,4-
oxadiazol-5-yl)propyl]-3-butyl-8-chloro-
3,7-dihydro-1H-purine-2,6-dione 233 ##STR00324## 29.2 m/z 533
[MH].sup.+ RT 3.62 min 3-butyl-8-chloro-1-(3-{3-
[(pentafluorophenyl)methyl]-1,2,4-
oxadiazol-5-yl}propyl)-3,7-dihydro-1H- purine-2,6-dione 234
##STR00325## 29.8 m/z 500 [MH].sup.+ RT 3.01 min
N-[4-({5-[3-(3-butyl-8-chloro-2,6-dioxo-
2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]- 1,2,4-oxadiazol-3-
yl}methyl)phenyl]acetamide 235 ##STR00326## 37.7 m/z 511 [MH].sup.+
RT 3.65 min 3-butyl-8-chloro-1-[3-(3-{[4-
(trifluoromethyl)phenyl]methyl}-1,2,4-
oxadiazol-5-yl)propyl]-3,7-dihydro-1H- purine-2,6-dione 236
##STR00327## 47.5 m/z 493 [MH].sup.+ RT 3.69 min
3-butyl-8-chloro-1-{3-[3-(2- naphthalenylmethyl)-1,2,4-oxadiazol-5-
yl]propyl)-3,7-dihydro-1H-purine-2,6- dione
Example 237
3-Butyl-8-chloro-1-(3-{3-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)methyl]--
1,2,4-oxadiazol-5-yl}propyl)-3,7-dihydro-1H-purine-2,6-dione
##STR00328##
[0757] Synthesised by a method analogous to that for Example 126
with the exception that a further 2 equivalents of 21% sodium
ethoxide (0.11 ml) was used, the extra heating time was 20 min. and
the product was isolated by filtration followed by trituration with
hot MeOH. Yield 14.5 mg.
[0758] LC/MS: m/z 499 [MH].sup.+, RT 2.78 min.
[0759] The following compounds (Table 14) were prepared by a method
analogous to that for Example 18 [with the exception that Examples
238-243 were all synthesised on a scale starting from 50 mg of
8-chloro-3-pentyl-7-(2-propen-1-yl)-1-[3-(1H-pyrazol-4-yl)propyl]-3,7-dih-
ydro-1H-purine-2,6-dione; Examples 241, 243, 245, 246 and 247 were
additionally purified by MDAP following aminopropyl SPE; Example
242 was additionally purified by recrystallisation from MeOH
following aminopropyl SPE; for Example 248, 128 mg (1.2 mmol) of
sodium carbonate was used; during workup the aqueous phase was
adjusted to pH6 prior to extraction; and the product was purified
by MDAP then by further HPLC; for Example 241 solids which
precipitated during workup were combined with the EtOAc extracts
prior to SPE].
TABLE-US-00014 TABLE 14 Example Structure Yield (mg) LC/MS 238
##STR00329## 36.0 m/z 480 [MH].sup.+ RT 3.24 min
4-({4-[3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-1H-
purin-1-yl)propyl]-1H-pyrazol- 1-yl}methyl)benzonitrile 239
##STR00330## 7.6 m/z 536 [MH].sup.+ RT 3.03 min
8-chloro-1-(3-{1-[(1-methyl-2- oxo-1,2-dihydro-6-
quinolinyl)methyl]-1H-pyrazol- 4-yl}propyl)-3-pentyl-3,7-
dihydro-1H-purine-2,6-dione 240 ##STR00331## 34.0 m/z 526
[MH].sup.+ RT 3.11 min 8-chloro-1-(3-{1-[(3-methyl-2-
oxo-2,3-dihydro-1,3- benzoxazol-6-yl)methyl]-1H-
pyrazol-4-yl}propyl)-3-pentyl- 3,7-dihydro-1H-purine-2,6- dione 241
##STR00332## 26.2 m/z 473 [MH].sup.+ RT 3.38 min
8-chloro-1-(3-{1-[(3- fluorophenyl)methyl]-1H-
pyrazol-4-yl}propyl)-3-pentyl- 3,7-dihydro-1H-purine-2,6- dione 242
##STR00333## 16.2 m/z 520 [MH].sup.+ RT 3.12 min methyl
3-({4-[3-(8-chloro-2,6- dioxo-3-pentyl-2,3,6,7-
tetrahydro-1H-purin-1- yl)propyl]-1H-pyrazol-1- yl}methyl)-4-
isothiazolecarboxylate 243 ##STR00334## 21.0 m/z 512 [MH].sup.+ RT
3.36 min 1-{3-[1-(1,3-benzothiazol-2- ylmethyl)-1H-pyrazol-4-
yl]propyl)-8-chloro-3-pentyl- 3,7-dihydro-1H-purine-2,6- dione 244
##STR00335## 65.0 m/z 523, 525 [Cl isotopes MH.sup.+] RT 3.77 min
8-chloro-1-(3-{1-[(2,6- dichlorophenyl)methyl]-1H-
pyrazol-4-yl}propyl)-3-pentyl- 3,7-dihydro-1H-purine-2,6- dione 245
##STR00336## 35.0 m/z 491 [MH].sup.+ RT 3.61 min
8-chloro-1-(3-{1-[(3,4- difluorophenyl)methyl]-1H-
pyrazol-4-yl}propyl)-3-pentyl- 3,7-dihydro-1H-purine-2,6- dione 246
##STR00337## 17.0 m/z 541 [MH].sup.+ RT 3.76 min
8-chloro-1-[3-(1-{[4-fluoro-3- (trifluoromethyl)phenyl]methyl)-
1H-pyrazol-4-yl)propyl]-3- pentyl-3,7-dihydro-1H-purine 2,6-dione
247 ##STR00338## 27.0 m/z 507 [MH].sup.+ RT 3.73 min
8-chloro-1-(3-{1-[(3-chloro-4- fluorophenyl)methyl]-1H-
pyrazol-4-yl}propyl)-3-pentyl- 3,7-dihydro-1H-purine-2,6- dione 248
##STR00339## 11.4 m/z 456 [MH].sup.+ RT 3.13 min
8-chloro-3-pentyl-1-{3-[1-(2- pyridinylmethyl)-1H-pyrazol-4-
yl]propyl}-3,7-dihydro-1H- purine-2,6-dione
Example 249
8-Chloro-1-(3-{1-[(4-chlorophenyl)methyl]-1H-pyrazol-4-yl}propyl)-3-pentyl-
-3,7-dihydro-1H-purine-2,6-dione
##STR00340##
[0761]
8-Chloro-3-pentyl-7-(2-propen-1-yl)-1-[3-(1H-pyrazol-4-yl)propyl]-3-
,7-dihydro-1H-purine-2,6-dione (50 mg, 0.123 mmol) in dry DMF (1.5
ml) was stirred with sodium carbonate (75 mg, 0.708 mmol) and
4-chlorobenzyl bromide (150 mg, 0.73 mmol) at 40.degree. C. for 18
h. The mixture was partitioned between EtOAc and water, the organic
phase washed with brine, dried and evaporated. The product was
purified by normal phase chromatography on silica (Companion
System, EtOAc--cyclohexane gradient) giving an oil (44 mg). This
was stirred in degassed, dry DMF (1 ml) with
tetrakis(triphenylphosphine)palladium(0) (19 mg) and morpholine
(0.072 ml) under nitrogen for 6 h. The mixture was partitioned
between EtOAc and 2M HCl and the organic phase evaporated and
purified by the usual aminopropyl SPE procedure. Yield 21.0 mg.
[0762] LC/MS: m/z 489 [MH.sup.+], RT 3.59 min.
[0763] The following compounds (Table 15) were prepared by a method
analogous to that for Example 23 [with the exception that for
Example 250 a second portion of Pd(PPh.sub.3).sub.4 was added after
5 h, stirring was continued overnight, and final purification was
achieved by HPLC; for Example 252 required additional purification
by MDAP; Example 257 required additional purification by
recrystallisation from MeOH; Example 258 required additional
purification by trituration with MeOH].
TABLE-US-00015 TABLE 15 Yield Example Structure (mg) LC/MS 250
##STR00341## 7.3 m/z 447 [MH].sup.+ RT 3.06 min
8-chloro-1-{3-[1-(1,2,4-oxadiazol-3-
ylmethyl)-1H-pyrazol-4-yl]propyl)-3-
pentyl-3,7-dihydro-1H-purine-2,6-dione 251 ##STR00342## 23.7 m/z
469 [MH].sup.+ RT 3.49 min 8-chloro-1-(3-{1-[(4-
methylphenyl)methyl]-1H-pyrazol-4-
yl)propyl)-3-pentyl-3,7-dihydro-1H- purine-2,6-dione 252
##STR00343## 29.0 m/z 460 [MH].sup.+ RT 3.10 min
8-chloro-1-(3-{1-[(5-methyl-3- isoxazolyl)methyl]-1H-pyrazol-4-
yl)propyl)-3-pentyl-3,7-dihydro-1H- purine-2,6-dione 253
##STR00344## 56.0 m/z 485 [MH].sup.+ RT 3.41 min
8-chloro-1-[3-(1-{[3- (methyloxy)phenyl]methyl)-1H-pyrazol-4-
yl)propyl]-3-pentyl-3,7-dihydro-1H-purine- 2,6-dione 254
##STR00345## 47.0 m/z 523 [MH].sup.+ RT 3.61 min
8-chloro-3-pentyl-1-[3-(1-{[3- (trifluoromethyl)phenyl]methyl}- 1H-
pyrazol-4-yl)propyl]-3,7-dihydro-1H- purine-2,6-dione 255
##STR00346## 44.0 m/z 469 [MH].sup.+ RT 3.54 min
8-chloro-1-(3-{1-[(2- methylphenyl)methyl]-1H-pyrazol-4-
yl}propyl)-3-pentyl-3,7-dihydro-1H- purine-2,6-dione 256
##STR00347## 51.0 m/z 480 [MH].sup.+ RT 3.32 min
3-({4-[3-(8-chloro-2,6-dioxo-3-pentyl-
2,3,6,7-tetrahydro-1H-purin-1-yl)propyl]-
1H-pyrazol-1-yl}methyl)benzonitrile 257 ##STR00348## 36.7 m/z 483
[MH].sup.+ RT 3.66 min 8-chloro-1-(3-{1-[(3,5-
dimethylphenyl)methyl]-1H-pyrazol-4-
yl)propyl)-3-pentyl-3,7-dihydro-1H- purine-2,6-dione 258
##STR00349## 21.2 m/z 522 [MH].sup.+ RT 3.09 min
8-chloro-3-pentyl-1-[3-(1-([4-(1H-1,2,4-
triazol-1-yl)phenyl]methyl}-1H-pyrazol-4-
yl)propyl]-3,7-dihydro-1H-purine-2,6- dione
Example 259
8-Chloro-3-pentyl-1-[3-(1-pentyl-1H-pyrazol-4-yl)propyl]-3,7-dihydro-1H-pu-
rine-2,6-dione
##STR00350##
[0765]
8-Chloro-3-pentyl-7-(2-propen-1-yl)-1-[3-(1H-pyrazol-4-yl)propyl]-3-
,7-dihydro-1H-purine-2,6-dione (61 mg, 0.15 mmol) and sodium
carbonate (32 mg, 0.3 mmol) in dry DMF (1.5 ml) was heated with
1-iodopentane (238 mg, 1.2 mmol) in the microwave reactor at
120.degree. C. for 25 min. After cooling the mixture was degassed
and stirred with tetrakis(triphenylphosphine)palladium(0) (40 mg,
0.0346 mmol) and morpholine (0.2 ml) for 7 h. A further 20 mg of
Pd(PPh.sub.3).sub.4 was then added and stirring continued
overnight. The mixture was stirred with EtOAc and 2M HCl for 1 h
and the organic phase separated and evaporated. The product was
purified by aminopropyl SPE (5 g) washing with MeOH-THF (1:1), then
MeOH, and eluting the product with DCM-MeOH (1:1) containing 5%
added AcOH to give the title compound (25 mg).
[0766] LC/MS: m/z 435 [MH].sup.+, RT 3.65 min.
[0767] The following compounds (Table 16) were prepared by a method
analogous to that for Example 259 [with the exception that the
compounds were purified by MDAP and for Example 261 the total
heating time in the microwave reactor was 50 min].
TABLE-US-00016 TABLE 16 Example Structure Yield (mg) LC/MS 260
##STR00351## 15.1 m/z 451 [MH].sup.+ RT 3.21 min ethyl
{4-[3-(5-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-1H-purin-1-
yl)propyl]-1H-pyrazol-1-yl}acetate 261 ##STR00352## 1.34 m/z 421
[MH].sup.+ RT 3.48 min 8-chloro-1-(3-[1-(2-methylpropyl)-1H-
pyrazol-4-yl]propyl}-3-pentyl-3,7- dihydro-1H-purine-2,6-dione 262
##STR00353## 0.32 m/z 409 [MH].sup.+ RT 2.79 min
8-chloro-1-{3-[1-(2-hydroxyethyl)-1H-
pyrazol-4-yl]propyl}-3-pentyl-3,7- dihydro-1H-purine-2,6-dione 263
##STR00354## 9.6 m/z 404 [MH].sup.+ RT 3.12 min
{4-[3-(8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin-1-
yl)propyl]-1H-pyrazol-1-yl}acetonitrile
Example 264
8-Chloro-3-pentyl-1-{3-[1-(2-phenylethyl)-1H-pyrazol-4-yl]propyl}-3,7-dihy-
dro-1H-purine-2,6-dione
##STR00355##
[0769]
8-Chloro-3-pentyl-7-(2-propen-1-yl)-1-[3-(1H-pyrazol-4-yl)propyl]-3-
,7-dihydro-1H-purine-2,6-dione (81 mg, 0.2 mmol), sodium carbonate
(42 mg, 0.4 mmol) and (2-iodoethyl)benzene (0.174 ml, 1.2 mmol)
were heated together in dry DMF (1 ml) under microwave irradiation
at 120.degree. C. for 25 min.
Tetrakis(triphenylphosphine)palladium(0) (46 mg, 0.04 mmol) and
morpholine (0.174 ml) were added and the mixture stirred for 6 h.
Further quantities (46 mg and 0.174 ml) of these reagents were
added and stirring continued for a further 60 h. Workup and
purification as for the examples in Table 16 gave the title
compound (15.5 mg).
[0770] LC/MS: m/z 469 [MH].sup.+, RT 3.60 min.
Example 265
8-Chloro-3-pentyl-1-(3-{1-[2-(1-pyrrolidinyl)ethyl]-1H-pyrazol-4-yl}propyl-
)-3,7-dihydro-1H-purine-2,6-dione
##STR00356##
[0772]
8-Chloro-3-pentyl-7-(2-propen-1-yl)-1-[3-(1H-pyrazol-4-yl)propyl]-3-
,7-dihydro-1H-purine-2,6-dione (61 mg, 0.15 mmol), sodium carbonate
(159 mg, 1.5 mmol) and 1-(2-chloroethyl)pyrrolidine hydrochloride
(127 mg, 0.75 mmol) were heated together in dry DMF (2 ml) at
80.degree. C. for 65 h. Tetrabutylammonium iodide (55 mg, 0.15
mmol) was added and heating continued for another 18 h. A further
quantity of 1-(2-chloroethyl)pyrrolidine hydrochloride (127 mg,
0.75 mmol) was added and the mixture heated by microwaves at
120.degree. C., then a 3.sup.rd aliquot of
1-(2-chloroethyl)pyrrolidine hydrochloride (100 mg) was added, with
a further 25 min at 120.degree. C. in the microwave. The mixture
was partitioned between water and EtOAc, the organic phase
separated, washed with brine and evaporated. This material was
partitioned between EtOAc and 2M HCl. The separated aqueous phase
was basified to pH9, saturated with NaCl and extracted with EtOAc
(.times.2). The extracts were evaporated and the residue (28 mg)
stirred in dry degassed DMF (1.5 ml) with
tetrakis(triphenylphosphine)palladium(0) (50 mg) and morpholine
(0.2 ml) for 6 h. The mixture was partitioned between EtOAc and 2M
HCl, the aqueous phase filtered, extracted twice with EtOAc and
evaporated to dryness. The residue was purified by the aminopropyl
SPE procedure, followed by MDAP to yield the title compound (1.9
mg).
[0773] LC/MS: m/z 462 [MH].sup.+, RT 2.46 min.
Example 266
8-Chloro-1-(3-{1-[(5-chloro-2-thienyl)methyl]-1H-pyrazol-4-yl}propyl)-3-pe-
ntyl-3,7-dihydro-1H-purine-2,6-dione
##STR00357##
[0775] To
8-chloro-3-pentyl-7-(2-propen-1-yl)-1-[3-(1H-pyrazol-4-yl)propyl-
]-3,7-dihydro-1H-purine-2,6-dione (61 mg, 0.15 mmol) in dry THF (1
ml) at -78.degree. C., under nitrogen, was added potassium
t-butoxide (1M in THF, 0.15 ml), followed by
2-chloro-5-(chloromethyl)thiophene (25 mg, 0.15 mmol). Stirring was
continued at -78.degree. C. for 15 min, then at room temperature
for 1 h and finally at 60.degree. C. for 18 h. The solution was
degassed and morpholine (0.13 ml) and
tetrakis(triphenylphosphine)palladium(0) (35 mg) added and stirring
continued for 6 h. Further quantities (0.2 ml morpholine, 50 mg
Pd(PPh.sub.3).sub.4) were added and stirring continued overnight.
Worked up by partition between EtOAc and 2M HCl, the organic phase
evaporated and purified by the standard aminopropyl SPE procedure
followed by MDAP yielding title compound as a white solid (5.1
mg).
[0776] LC/MS: m/z 495 [MH].sup.+, RT 3.68 min.
Example 267
8-Chloro-3-pentyl-1-[3-(1H-pyrazol-4-yl)propyl]-3,7-dihydro-1H-purine-2,6--
dione acetate
##STR00358##
[0778]
8-Chloro-3-pentyl-7-(2-propen-1-yl)-1-[3-(1H-pyrazol-4-yl)propyl]-3-
,7-dihydro-1H-purine-2,6-dione (50 mg, 0.124 mmol) in dry degassed
THF (1.5 ml) was stirred with
tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) and
morpholine (0.108 ml) under nitrogen for 5 h. The mixture was
partitioned between EtOAc and 0.5M citric acid and the organic
phase separated. Two further EtOAc extractions were performed and
the combined organics were evaporated and the product purified by
aminopropyl SPE (2 g), loading and washing with THF-MeOH (1:1) then
washing with MeOH and eluting with DCM-MeOH (1:1) containing 5%
AcOH. Yield 28.3 mg.
[0779] LC/MS: m/z 365 [M].sup.+, RT 2.89 min.
Example 268
8-Chloro-3-hexyl-1-(2-hydroxyethyl)-3,7-dihydro-1H-purine-2,6-dione
a)
8-Chloro-3-hexyl-1-(2-hydroxyethyl)-3,7-dihydro-1H-purine-2,6-dione
##STR00359##
[0781]
8-Chloro-3-hexyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-d lone
(100 mg, 0.322 mmol), cesium carbonate (126 mg, 0.387 mmol) and
2-chloroethanol (29.8 mg, 0.37 mmol) in dry DMF (3 ml) were heated
together under nitrogen at 55.degree. C. for 42 h. The cooled
mixture was degassed thoroughly and stirred with
tetrakis(triphenylphosphine)palladium(0) (74 mg) and morpholine
(0.28 ml) for 5 h. The reaction was worked up by partition between
EtOAc and 2M HCl, the organic phase being separated and evaporated.
The residue was loaded onto an aminopropyl SPE cartridge (5 g) in
THF-MeOH (1:1), washed with the same solvent, then with neat MeOH,
and the product eluted with DCM-MeOH (1:1) containing AcOH (2.5%
rising to 5%). The product thus obtained was further purified by
MDAP to afford the title compound (38 mg).
[0782] LC/MS: m/z 315 [MH].sup.+, RT 2.79 min.
b)
8-Chloro-3-hexyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
##STR00360##
[0784] To
8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (226 mg,
1 mmol) and sodium carbonate (117 mg, 1.1 mmol) in dry DMF (7 ml)
was added 1-iodohexane (223 mg, 1.05 mmol). The mixture was stirred
and heated at 50.degree. C. for 2 days. After cooling, the mixture
was partitioned between EtOAc and water, the organic phase washed
with brine, dried over Na.sub.2SO.sub.4 and evaporated. The crude
product was recrystallised from EtOAc-cyclohexane (1:2). Yield 146
mg.
[0785] LC/MS: m/z 311 [MH].sup.+, RT 3.12 min.
[0786] The following compounds (Table 17) were prepared by a method
analogous to that for Example 268, except for Example 270 the scale
was reduced to 75 mg (0.243 mmol) of the precursor
8-chloro-3-(3-cyclopropylpropyl)-7-(2-propen-1-yl)-3,7-dihydro-1H-purine--
2,6-dione.
TABLE-US-00017 TABLE 17 Yield Example Structure Precursor (mg)
LC/MS 269 ##STR00361## 8-chloro-3-(4- methylpentyl)-7-(2-
propen-1-yl)-3,7- dihydro-1H-purine- 2,6-dione 37 m/z 315
[MH].sup.+ RT 2.74 min 8-chloro-1-(2-hydroxyethyl)-
3-(4-methylpentyl)-3,7- dihydro-1H-purine-2,6-dione 270
##STR00362## 8-chloro-3-(3- cyclopropylpropyl)- 7-(2-propen-1-yl)-
3,7-dihydro-1H- purine-2,6-dione 26 m/z 313 [MH].sup.+ RT 2.58 min
8-chloro-3-(3- cyclopropylpropyl)-1-(2- hydroxyethyl)-3,7-dihydro-
1H-purine-2,6-dione
[0787] The intermediates were prepared according to the method of
Example 268b, except that
8-chloro-3-(3-cyclopropylpropyl)-7-(2-propen-1-yl)-3,7-dihydro-1H-purine--
2,6-dione was purified by silica SPE (5 g) eluting with
EtOAc-cyclohexane (2:3).
TABLE-US-00018 Scale Yield Intermediate Name (mmol) Alkylating
agent (mg) LC/MS ##STR00363## 8-chloro-3-(4- methylpentyl)-7-
(2-propen-1-yl)- 3,7-dihydro-1H- purine-2,6-dione 1 1-bromo-4-
methylpentane (173 mg) 210 m/z 311 [MH].sup.+ RT 3.08 min
##STR00364## 8-chloro-3-(3- cyclopropylpropyl)- 7-(2-propen-1-
yl)-3,7-dihydro- 1H-purine-2,6- dione 0.662 3-cyclopropylpropyl 4-
methylbenzenesulfonate (170 mg) 125 m/z 309 [MH].sup.+ RT 2.93
min
Example 271
3-Butyl-8-chloro-1-{3-[5-(phenylmethyl)-1,3,4-oxadiazol-2-yl]propyl}-3,7-d-
ihydro-1H-purine-2,6-dione
##STR00365##
[0789] To
3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dio-
ne (99 mg, 0.35 mmol) in dry DMF (2 ml) was added cesium carbonate
(137 mg, 0.42 mmol) followed by a solution in dry DMF (1 ml) of
2-(3-chloropropyl)-5-(phenylmethyl)-1,3,4-oxadiazole (99 mg, 0.42
mmol). The mixture was stirred under nitrogen and heated at
55.degree. C. for 2.5 h then stirred at room temperature overnight.
The mixture was degassed by repeatedly evacuating and admitting
nitrogen and then tetrakis(triphenylphosphine)palladium(0) (81 mg,
0.07 mmol) and morpholine (0.305 ml, 3.5 mmol) were added and
stirring was continued for 5 h EtOAc and 2M HCl were added and the
mixture stirred for 20 min then filtered. The organic phase was
separated and evaporated, and the product was purified by
aminopropyl SPE (5 g) washing with THF-MeOH (1:1) then with MeOH
and eluting the acidic product with DCM-MeOH (1:1) containing 5%
added AcOH. The product thus obtained was purified further by MDAP
to yield the title compound (92 mg).
[0790] LC/MS: m/z 443 [MH].sup.+, RT 3.18 min.
[0791] The following compounds (Table 18) were prepared by a method
analogous to that for Example 271, with the exception that Example
279 was further purified by HPLC.
TABLE-US-00019 TABLE 18 Xanthine Alkylating Yield Example Product
structure precursor agent (mg) LC/MS 272 ##STR00366## 3-butyl-8-
chloro-7-(2- propen-1-yl)- 3,7-dihydro-1H- purine-2,6- dione (99
mg) 2-[(2-chloro-4- fluorophenyl) methyl]-5-(3- chloropropyl)-
1,3,4- oxadiazole (121 mg) 90 m/z 495 [MH].sup.+ RT 3.34 min
3-butyl-8-chloro-1-(3-{5- [(2-chloro-4- fluorophenyl)methyl]-
1,3,4-oxadiazol-2- yl)propyl)-3,7-dihydro-1H- purine-2,6-dione 273
##STR00367## 8-chloro-3- pentyl-7-(2- propen-1-yl)- 3,7-dihydro-1H-
purine-2,6- dione (104 mg) 2-(3- chloropropyl)- 5- (phenylmethyl)-
1,3,4- oxadiazole (99 mg) 98 m/z 457 [MH].sup.+ RT 335 min
8-chloro-3-pentyl-1-{3-[5- (phenylmethyl)-1,3,4-
oxadiazol-2-yl]propyl}- 3,7-dihydro-1H-purine- 2,6-dione 274
##STR00368## 8-chloro-3- pentyl-7-(2- propen-1-yl)- 3,7-dihydro-1H-
purine-2,6- dione (104 mg) 2-[(2-chloro-4- fluorophenyl)
methyl]-5-(3- chloropropyl)- 1,3,4- oxadiazole (121 mg) 98 m/z 509
[MH].sup.+ RT 3.52 min 8-chloro-1-(3-{5-[(2- chloro-4-
fluorophenyl)methyl]- 1,3,4-oxadiazol-2- yl}propyl)-3-pentyl-3,7-
dihydro-1H-purine-2,6- dione 275 ##STR00369## 8-chloro-3-
pentyl-7-(2- propen-1-yl)- 3,7-dihydro-1H- purine-2,6- dione (104
mg) 2-(3- chloropropyl)- 5-[(2,4- difluorophenyl) methyl]-1,3,4-
oxadiazole (111 mg) 43 m/z 493 [MH].sup.+ RT 3.40 min
8-chloro-1-(3-{5-[(2,4- difluorophenyl)methyl]- 1,3,4-oxadiazol-2-
yl}propyl)-3-pentyl-3,7- dihydro-1H-purine-2,6- dione 276
##STR00370## 8-chloro-3-(3- cyclopropylpropyl)- 7-(2-propen-
1-yl)-3,7- dihydro-1H- purine-2,6- dione (108 mg) 2-(3-
chloropropyl)- 5- (phenylmethyl)- 1,3,4- oxadiazole (99 mg) 95 m/z
469 [MH].sup.+ RT 3.34 min 8-chloro-3-(3- cyclopropylpropyl)-1-{3-
[5-(phenylmethyl)-1,3,4- oxadiazol-2-yl]propyl}-
3,7-dihydro-1H-purine- 2,6-dione 277 ##STR00371## 8-chloro-3-(3-
cyclopropylpropyl)- 7-(2-propen- 1-yl)-3,7- dihydro-1H- purine-2,6-
dione (108 mg) 2-[(2-chloro-4- fluorophenyl) methyl]-5-(3-
chloropropyl)- 1,3,4- oxadiazole (121 mg) 99 m/z 521 [MH].sup.+ RT
3.51 min 8-chloro-1-(3-{5-[(2- chloro-4- fluorophenyl)methyl]-
1,3,4-oxadiazol-2- yl}propyl)-3-(3- cyclopropylpropyl)-3,7-
dihydro-1H-purine-2,6- dione 278 ##STR00372## 8-chloro-3-(3-
cyclopropylpropyl)- 7-(2-propen- 1-yl)-3,7- dihydro-1H- purine-2,6-
dione (108 mg) 2-(3- chloropropyl)- 5-[(2,4- difluorophenyl)
methyl]-1,3,4- oxadiazole (111 mg) 49 m/z 505 [MH].sup.+ RT 3.40
min 8-chloro-3-(3- cyclopropylpropyl)-1-(3- {5-[(2,4-
difluorophenyl)methyl]- 1,3,4-oxadiazol-2-
yl}propyl)-3,7-dihydro-1H- purine-2,6-dione 279 ##STR00373##
3-butyl-8- chloro-7-(2- propen-1-yl)- 3,7-dihydro-1H- purine-2,6-
dione (99 mg) 2-(3- chloropropyl)- 5-[(2,4- difluorophenyl)
methyl]-1,3,4- oxadiazole (111 mg) 38.9 m/z 479 [MH].sup.+ RT 3.31
min 3-butyl-8-chloro-1-(3-{5- [(2,4- difluorophenyl)methyl]-
1,3,4-oxadiazol-2- yl}propyl)-3,7-dihydro-1H- purine-2,6-dione
Synthesis of Chloropropyl 1,3,4-oxadiazole Intermediates from Table
18 [0792]
2-[(2-chloro-4-fluorophenyl)methyl]-5-(3-chloropropyl)-1,3,4-oxadi-
azole [0793]
2-(3-chloropropyl)-5-[(2,4-difluorophenyl)methyl]-1,3,4-oxadiazole
[0794] 2-(3-chloropropyl)-5-(phenylmethyl)-1,3,4-oxadiazole
[0795] Diacyl hydrazines (500 mg, synthesis below) were stirred in
dry toluene (4 ml) and phosphorus oxychloride (4 ml) was added. The
mixtures were heated at 90.degree. C. for 2 h then allowed to cool
and the solvents evaporated. The residues were dissolved in dry
toluene, evaporated and then partitioned between EtOAc and aqueous
NaHCO.sub.3. The organic phases were washed with brine, dried over
Na.sub.2SO.sub.4 and evaporated to give the required oxadiazoles as
colourless oils. These were not purified further but reacted
directly with the xanthines as above.
TABLE-US-00020 Yield Diacyl hydrazine Oxadiazole product (mg) LC/MS
##STR00374## 4-chloro-N'- (phenylacetyl)butanohydrazide
##STR00375## 2-(3-chloropropyl)-5- (phenylmethyl)-1,3,4- oxadiazole
446 m/z 237 [MH].sup.+ RT 2.94 min ##STR00376##
4-chloro-N'-[(2-chloro-4- fluorophenyl)acetyl]butanohydrazide
##STR00377## 2-[(2-chloro-4- fluorophenyl)methyl]-5-
(3-chloropropyl)-1,3,4- oxadiazole 405 m/z 289 [MH].sup.+ RT 3.17
min ##STR00378## N-chloro-N'-[(2,4-
difluorophenyl)acetyl]butanohydrazide ##STR00379##
2-(3-chloropropyl)-5- [(2,4- difluorophenyl)methyl]-
1,3,4-oxadiazole 333 m/z 273 [MH].sup.+ RT 3.03 min
Preparation of 4-chloro-N'-(phenylacetyl)butanohydrazide
##STR00380##
[0797] To 4-chlorobutyryl chloride (1.12 ml, 10 mmol) in dry DCM
(10 ml) was added, dropwise, over 40 min, a mixture of phenylacetic
hydrazide (1.5 g, 10 mmol) and DIPEA (1.77 ml, 10.2 mmol) in dry
DCM (40 ml) at room temperature. A dense white precipitate formed.
After a further 20 min. 2M HCl (30 ml) was added and the title
compound (white solid) was filtered off, washed with water and
dried (2.24 g).
[0798] LC/MS: m/z 255 [MH].sup.+, RT 2.20 min.
Preparation of
4-chloro-N'-[(2-chloro-4-fluorophenyl)acetyl]butanohydrazide
##STR00381##
[0800] (i) A solution of 2-chloro-4-fluorophenylacetyl chloride (10
mmol) in dry DCM (15 ml) was added over 20 min to a mixture of
t-butyl carbazate (1.32 g, 10 mmol) and DIPEA (1.77 ml, 10.2 mmol)
in dry DCM (20 ml). After stirring for a further 2 h, the mixture
was washed with 1M HCl then with aqueous NaHCO.sub.3. A white solid
precipitated at this point, which was filtered off, washed with
water and DCM then dried to yield 1,1-dimethylethyl
2-[(2-chloro-4-fluorophenyl)acetyl]hydrazinecarboxylate (1.94
g).
[0801] (ii) This compound (1.92 g, 6.34 mmol) was suspended in
dioxan (2 ml) and 4M HCl in dioxan (5 ml) was added. A dense white
precipitate formed. After 1 h the mixture was partitioned between
EtOAc and saturated aqueous NaHCO.sub.3 and the organic phase
washed with brine, dried (Na.sub.2SO.sub.4) and evaporated giving
2-(2-chloro-4-fluorophenyl)acetohydrazide as a white solid (1.07
g).
[0802] (iii) A mixture of 2-(2-chloro-4-fluorophenyl)acetohydrazide
(909 mg, 4.5 mmol) and DIPEA (0.817 ml, 4.7 mmol) in dry DCM (65
ml) was added over 20 min to 4-chlorobutyryl chloride (0.505 ml,
4.5 mmol) in dry DCM (5 ml). After 1.5 h, 2M HCl was added and the
precipitated
4-chloro-N'-[(2-chloro-4-fluorophenyl)acetyl]butanohydrazide was
filtered off, washed with water and dried (1.24 g).
[0803] LC/MS: m/z 307 [MH].sup.+, RT 2.61 min.
Preparation of
2-(3-chloropropyl)-5-[(2,4-difluorophenyl)methyl]-1,3,4-oxadiazole
##STR00382##
[0805] (i) A solution of 2,4-difluorophenylacetyl chloride (10
mmol) in dry DCM (15 ml) was added over 10 min. to a mixture of
t-butyl carbazate (1.32 g, 10 mmol) and DIPEA (1.77 ml, 10.2 mmol)
in dry DCM (20 ml). After stirring for 1.5 h the mixture was washed
with 1M HCl then with aqueous NaHCO.sub.3. The organic phase was
evaporated to afford 1,1-dimethylethyl
2-[(2,4-difluorophenyl)acetyl]hydrazinecarboxylate as a white
solid.
[0806] (ii) 1,1-dimethylethyl
2-[(2,4-difluorophenyl)acetyl]hydrazinecarboxylate (10 mmol) in
dioxan (5 ml) was stirred with 4M HCl in dioxan (8 ml) for 1.5 h.
The mixture was partitioned between EtOAc and saturated aqueous
NaHCO.sub.3 and the organic phase washed with brine, dried
(Na.sub.2SO.sub.4) and evaporated. Reaction was incomplete so the
residue was stirred again with 4M HCl in dioxan (10 ml) for 2.5 h.
Workup as previously gave 2-(2,4-difluorophenyl)acetohydrazide as a
solid (570 mg).
[0807] (iii) A mixture of 2-(2,4-difluorophenyl)acetohydrazide (570
mg, 3.06 mmol) and DIPEA (0.553 ml, 3.2 mmol) in dry DCM (30 ml)
was added to 4-chlorobutyryl chloride (0.343 ml, 3.06 mmol) in dry
DCM (5 ml) over 15 min. An immediate white precipitate formed.
After stirring for 1 h, 2M HCl (20 ml) was added and the solid
2-(3-chloropropyl)-5-[(2,4-difluorophenyl)methyl]-1,3,4-oxadiazole
was filtered off, washed with water and dried (726 mg).
[0808] LC/MS: m/z 291 [MH].sup.+, RT 2.45 min.
Example 280
3-Butyl-8-chloro-1-[4-(3-phenyl-5-isoxazolyl)butyl]-3,7-dihydro-1H-purine--
2,6-dione
a)
3-Butyl-8-chloro-1-[4-(3-phenyl-5-isoxazolyl)butyl]-3,7-dihydro-1H-puri-
ne-2,6-dione
##STR00383##
[0810]
3-Butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(100 mg, 0.354 mmol) and 4-(3-phenyl-5-isoxazolyl)-1-butanol (77
mg, 0.355 mmol) were dissolved in dry THF (4 ml) under nitrogen. A
solution of dibenzyl azodicarboxylate (94%, 224 mg, 0.708 mmol) in
dry THF (2 ml) was added. The mixture was cooled to 0.degree. C.
and a solution of triphenylphosphine (185 mg, 0.708 mmol) in dry
THF (1 ml) was added. The mixture was stirred for 20 min at
0.degree. C. then at room temperature overnight. The mixture was
degassed then stirred with morpholine (0.308 ml) and
tetrakis(triphenylphosphine)palladium(0) (82 mg) for 4.5 h. A
further 60 mg of tetrakis(triphenylphosphine)palladium(0) was added
and stirring continued overnight. The reaction was worked up by
partition between EtOAc and 2M HCl, the organic phase evaporated
and purified by aminopropyl SPE (5 g) washing with THF-MeOH (1:1),
MeOH and eluting with DCM-MeOH (1:1) containing 5% AcOH. Further
purification by MDAP afforded the title compound (56 mg).
[0811] LC/MS: m/z 442 [MH].sup.+, RT 3.59 min.
b) 4-(3-Phenyl-5-isoxazolyl)-1-butanol
##STR00384##
[0813] To N-hydroxybenzenecarboximidoyl chloride (622 mg, 4 mmol)
in dry DCM (6 ml) was added 5-hexyn-1-ol (431 mg, 4.4 mmol). The
mixture was cooled to 0.degree. C. under nitrogen as triethylamine
(0.612 ml, 4.4 mmol) was added dropwise over 10 min. Stirred for a
further 20 min at 0.degree. C. then at room temperature overnight.
The mixture was washed with water and the organic phase evaporated.
The product was purified by silica SPE (20 g) eluting with
EtOAc-cyclohexane (1:2, then 3:1) to give a white waxy solid (443
mg).
[0814] LC/MS: m/z 218 [MH].sup.+, RT 2.74 min.
Example 281
3-Butyl-8-chloro-1-{3-[3-(Phenylmethyl)-5-isoxazolyl]propyl}-3,7-dihydro-1-
H-purine-2,6-dione
a)
3-Butyl-8-chloro-1-{3-[3-(phenylmethyl)-5-isoxazolyl]propyl}-3,7-dihydr-
o-1H-purine-2,6-dione
##STR00385##
[0816] Prepared analogously to
3-butyl-8-chloro-1-[4-(3-phenyl-5-isoxazolyl)butyl]-3,7-dihydro-1H-purine-
-2,6-dione (Example 280) using half the molar quantities, starting
from
3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(50 mg, 0.177 mmol) and
3-[3-(phenylmethyl)-5-isoxazolyl]-1-propanol (38.4 mg, 0.177 mmol).
Yield 24.2 mg,
[0817] LC/MS: m/z 442 [MH].sup.+, RT 3.43 min.
b) 3-[3-(Phenylmethyl)-5-isoxazolyl]-1-propanol
##STR00386##
[0819] Synthesised as with 4-(3-phenyl-5-isoxazolyl)-1-butanol,
using N-hydroxy-2-phenylethanimidoyl chloride (253 mg, 1.5 mmol)
and 4-pentyn-1-ol (139 mg, 1.65 mmol). Yield 61 mg of pale yellow
oil.
[0820] LC/MS: m/z 218 [MH].sup.+, RT 2.62 min.
Example 282
3-Butyl-8-chloro-1-{3-[(3-phenyl-1,2,4-oxadiazol-5-yl)thio]propyl}-3,7-dih-
ydro-1H-purine-2,6-dione
a)
3-Butyl-8-chloro-1-{3-[(3-phenyl-1,2,4-oxadiazol-5-yl)thio]propyl}-3,7--
dihydro-1H-purine-2,6-dione
##STR00387##
[0822] Prepared by the method of
3-butyl-8-chloro-1-[4-(3-phenyl-5-isoxazolyl)butyl]-3,7-dihydro-1H-purine-
-2,6-dione starting from
3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(100 mg, 0.354 mmol) and
3-[(3-phenyl-1,2,4-oxadiazol-5-yl)thio]-1-propanol (83.5 mg, 0.354
mmol) except that a 2.sup.nd aliquot of 250 mg of
tetrakis(triphenylphosphine)palladium(0) was added during the
deprotection step. Yield 19.6 mg
[0823] LC/MS: m/z 461 [MH].sup.+, RT 3.75 min.
b) 3-[(3-phenyl-1,2,4-oxadiazol-5-yl)thio]-1-propanol
##STR00388##
[0825] To 3-phenyl-1,2,4-oxadiazole-5(2H)-thione (178 mg, 1 mmol)
in dry THF (3 ml) was added DIPEA (0.174 ml, 1 mmol) and
3-bromo-1-propanol (139 mg, 1 mmol). Stirring was continued for 65
h then the mixture was partitioned between EtOAc and water. The
organic phase was washed with brine, dried (Na.sub.2SO.sub.4) and
evaporated to give title compound as an oil (235 mg).
[0826] LC/MS: m/z 237 [MH].sup.+, RT 2.94 min.
Example 283
3-Butyl-8-chloro-1-{2-[(3-phenyl-1,2,4-oxadiazol-5-yl)thio]ethyl}-3,7-dihy-
dro-1H-purine-2,6-dione
a)
3-Butyl-8-chloro-1-{2-[(3-phenyl-1,2,4-oxadiazol-5-yl)thio]ethyl}-3,7-d-
ihydro-1H-purine-2,6-dione
##STR00389##
[0828] Prepared by a method analogous to that used for Example 270
(3-Butyl-8-chloro-1-[4-(3-phenyl-5-isoxazolyl)butyl]-3,7-dihydro-1H-purin-
e-2,6-dione) starting from
3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(141 mg, 0.5 mmol) and
2-[(3-phenyl-1,2,4-oxadiazol-5-yl)thio]ethanol (111 mg, 0.5 mmol).
A single portion of tetrakis(triphenylphosphine)palladium(0) (232
mg) was used in the deprotection step, however, stirring being
continued for 6 h. Purification by aminopropyl SPE followed by MDAP
afforded the title compound as a white solid (33.1 mg).
[0829] LC/MS: m/z 447 [MH].sup.+, RT 3.67 min.
b) 2-[(3-phenyl-1,2,4-oxadiazol-5-yl)thio]ethanol
##STR00390##
[0831] The title compound was obtained in a similar manner to
3-[(3-phenyl-1,2,4-oxadiazol-5-yl)thio]-1-propanol, from
2-bromoethanol, after a reaction time of 24 h and purification by
silica SPE (ethyl acetate-cyclohexane 1:1). Yield 176 mg.
[0832] LC/MS: m/z 223 [MH].sup.+, RT 2.98 min.
Example 284
3-Butyl-8-chloro-1-(2-{[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]amino}ethyl)-
-3,7-dihydro-1H-purine-2,6-dione
a)
3-Butyl-8-chloro-1-(2-{[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]amino}eth-
yl)-3,7-dihydro-1H-purine-2,6-dione
##STR00391##
[0834]
3-Butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(64.4 mg, 0.228 mol),
2-{[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]amino}ethanol (50 mg,
0.228 mmol) and dibenzyl azodicarboxylate (136 mg, 0.456 mmol) were
stirred in dry THF (3 ml) at 0.degree. C. as triphenylphosphine
(119 mg, 0.456 mmol) in dry THF (1 ml) was added dropwise. The
mixture was stirred at 0.degree. C. for 10 min. then at room
temperature for 2 overnight periods. It was thoroughly degassed and
stirred with morpholine (0.2 ml) and
tetrakis(triphenylphosphine)palladium(0) (53 mg, 0.046 mmol) for 5
h. A further 53 mg of the catalyst was then added and stirring
continued overnight. The reaction was worked up by partition
between EtOAc and 2M HCl, the organic phase evaporated and purified
by aminopropyl SPE (5 g) washing with THF-MeOH (1:1), MeOH and
eluting with DCM-MeOH (1:1) containing 5% AcOH. Further
purification by MDAP afforded the title compound (11.8 mg).
[0835] LC/MS: m/z 444 [MH].sup.+, RT 3.12 min.
b) 2-{[3-(Phenylmethyl)-1,2,4-oxadiazol-5-yl]amino}ethanol
##STR00392##
[0836] 3-(Phenylmethyl)-5-(trichloromethyl)-1,2,4-oxadiazole (140
mg, 0.505 mmol) in dry DMF (2 ml) was stirred with ethanolamine
(0.25 ml) for 1.5 h. The mixture was partitioned between EtOAc and
water, the organic phase washed with water, brine, dried
(Na.sub.2SO.sub.4) and evaporated to give a white waxy solid (87
mg).
[0837] LC/MS: m/z 220 [MH].sup.+, RT 2.22 min.
Example 285
3-Butyl-8-chloro-1-(2-{[3-(Phenylmethyl)-1,2,4-oxadiazol-5-yl]thio}ethyl)--
3,7-dihydro-1H-purine-2,6-dione
a)
3-Butyl-8-chloro-1-(2-{[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]thio}ethy-
l)-3,7-dihydro-1H-purine-2,6-dione
##STR00393##
[0839]
3-Butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(150 mg, 0.531 mmol) and
2-{[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]thio}ethanol (125 mg,
0.530 mmol) in dry THF (4 ml) were cooled to 0.degree. C. and
dibenzyl azodicarboxylate (94%, 336 mg, 1.06 mmol) in dry THF (2
ml) was added followed by triphenylphosphine (278 mg, 1.06 mmol).
The mixture was stirred at 0.degree. C. for 15 min. then at room
temperature for 2 overnight periods. Morpholine (1 g) and
tetrakis(triphenylphosphine)palladium(0) (250 mg, 0.216 mmol) were
added to the degassed solution, and after 5 h a further 100 mg of
Pd(PPh.sub.3).sub.4 was added and stirring continued for 3
overnight periods. The reaction was worked up by partition between
EtOAc and 2M HCl, the organic phase evaporated and purified by
aminopropyl SPE (5 g) washing with THF-MeOH (1:1), MeOH and eluting
with DCM-MeOH (1:1) containing 5% AcOH. Further purification by
MDAP afforded the title compound afforded title compound (26
mg).
[0840] LC/MS: m/z 461 [MH].sup.+, RT 3.47 min.
b) 2-{[3-(Phenylmethyl)-1,2,4-oxadiazol-5-yl]thio}ethanol
##STR00394##
[0842] To 3-(phenylmethyl)-1,2,4-oxadiazole-5(2H)-thione (384 mg, 2
mmol) in dry THF (5 ml) was added DIPEA (0.348 ml, 2 mmol) and
2-bromoethanol (250 mg, 2 mmol). The mixture was stirred at room
temperature overnight and then partitioned between EtOAc and 1M
HCl. The organic phase was washed with brine, dried, evaporated and
purified by silica SPE (10 g) eluting with EtOAc-cyclohexane (1:2)
to give title compound (315 mg) as a colourless oil.
[0843] LC/MS: m/z 237 [MH].sup.+, RT 2.74 min.
Example 286
3-Butyl-8-chloro-1-{[3-(3-Phenylpropyl)-1,2,4-oxadiazol-5-yl]methyl}-3,7-d-
ihydro-1H-purine-2,6-dione
a)
3-Butyl-8-chloro-1-{[3-(3-phenylpropyl)-1,2,4-oxadiazol-5-yl]methyl}-3,-
7-dihydro-1H-purine-2,6-dione
##STR00395##
[0845] Ethyl
(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetate
(66 mg, 0.2 mmol) and (1Z)-N-hydroxy-4-phenylbutanimidamide (39 mg,
0.22 mmol) were stirred in dry ethanol (1 ml) with ethanolic sodium
ethoxide (21% wt. solution, 0.111 ml, 0.3 mmol) and heated under
microwave irradiation at 140 C for 10 min. The cooled mixture was
partitioned between ethyl acetate and 2M hydrochloric acid, the
organic phase separated and evaporated. The product was purified by
MDAP to give the title compound as a solid (31.5 mg).
[0846] LC/MS: m/z 443 [MH].sup.+, RT 3.56 min.
b) Ethyl
(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acet-
ate
##STR00396##
[0848]
3-Butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(1.5 g, 5.31 mmol) and cesium carbonate (1.903 g, 5.84 mmol) were
stirred together in dry DMF (25 ml). Ethyl bromoacetate (0.648 ml,
5.84 mmol) was added and the mixture was stirred at 55 C overnight.
The cooled mixture was degassed using nitrogen and stirred with
tetrakis(triphenylphosphine)palladium(0) (1 g) and morpholine (3.73
ml) for 4.5 h. The mixture was partitioned between ethyl acetate
(80 ml) and 2M HCl (50 ml). The organic phase was washed with
3.times.80 ml brine, filtered, dried over Na.sub.2SO.sub.4 and
evaporated. The product was purified by aminopropyl SPE (20 g),
washing with THF-MeOH (1:1), then neat MeOH and eluting the product
with DCM-MeOH (1:1) containing acetic acid (2.5% rising to 5%),
which gave pure title compound (1.16 g).
[0849] LC/MS: m/z 329 [MH].sup.+, RT 2.87 min.
Example 287
3-Butyl-8-chloro-1-{[3-(2-phenylethyl)-1,2,4-oxadiazol-5-yl]methyl}-3,7-di-
hydro-1H-purine-2,6-dione
##STR00397##
[0851] Synthesised by a method analogous to that for Example 286,
starting from (1Z)-N-hydroxy-3-phenylpropanimidamide. Yield 22.6
mg.
[0852] LC/MS: m/z 429 [MH].sup.+, RT 3.43 min.
Example 288
3-Butyl-8-chloro-1-{2-[3-(2-phenylethyl)-1,2,4-oxadiazol-5-yl]ethyl}-3,7-d-
ihydro-1H-purine-2,6-dione
##STR00398##
[0854] Synthesised by a method analogous to that for Example 286,
starting from (1Z)-N-hydroxy-3-phenylpropanimidamide and ethyl
3-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)propanoate-
. Yield 23.3 mg.
[0855] LC/MS: m/z 443 [MH].sup.+, RT 3.40 min.
Example 289
Ethyl
3-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)propa-
noate
##STR00399##
[0857] Synthesised as for ethyl
(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetate
starting from ethyl 3-bromopropanoate (0.749 ml, 5.84 mmol), except
that, after the initial overnight heating period, further ethyl
3-bromopropanoate (1.5 ml) was added, heating was resumed for a
further 4 h, then a further portion of cesium carbonate (1.903 g),
followed 2 h later by a third portion of ethyl 3-bromopropanoate
(1.5 ml) were added. Heating at 55 C was then continued for a
second overnight period before workup and deprotection as above.
Yield 0.404 g.
[0858] LC/MS: m/z 343 [MH].sup.+, RT 2.90 min.
[0859] The following compounds (Table 19) were prepared by a method
analogous to that for Example 3, with any modification noted in the
method A-F.
TABLE-US-00021 TABLE 19 Yield Example Structure (mg) LC/MS Method
290 ##STR00400## 10 m/z 495 [MH].sup.+ RT 3.30 min A
1-[3-(8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin-1-
yl)propyl]-1H-naphtho[2,3-d]imidazole- 4,9-dione, sodium salt 291
##STR00401## 24 m/z 414 [MH].sup.+ RT 3.72 min A
8-chloro-1-[3-(1H-indol-3-yl)propyl]-3-
pentyl-3,7-dihydro-1H-purine-2,6- dione, sodium salt 292
##STR00402## 27 m/z 437 [MH].sup.+ RT 2.41 min A
5-amino-1-[3-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro-1H-purin-1-
yl)propyl]-2-methyl-1H-imidazole-4- carboxamide, sodium salt 293
##STR00403## 21 m/z 382 [MH].sup.+ RT 2.86min A
8-chloro-1-[3-(2-oxo-1- pyrrolidinyl)propyl]-3-pentyl-3,7-
dihydro-1H-purine-2,6-dione, sodium salt 294 ##STR00404## 9 m/z 487
[MH].sup.+ RT 3.15 min A 8-chloro-1-{3-[2,5-dioxo-4-
(phenylmethyl)-1-imidazolidinyl]propyl}-
3-pentyl-3,7-dihydro-1H-purine-2,6- dione, sodium salt 295
##STR00405## 39 m/z 538 [MH].sup.+ RT 3.46 min A
2-({[3-(8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin-1-
yl)propyl]amino}carbonyl)-1,2-dihydro 1-acenaphthylenecarboxylic
acid, sodium salt 296 ##STR00406## 18 m/z 381 [MH].sup.+RT 2.33 min
A 1-[3-(3-amino-1H-1,2,4-triazol-5-
yl)propyl]-8-chloro-3-pentyl-3,7- dihydro-1H-purine-2,6-dione,
sodium salt 297 ##STR00407## 22 m/z 369 [MH].sup.+ RT 3.2 min A
8-chloro-3-pentyl-1-[3-(tetrahydro-2-
furanyl)propyl]-3,7-dihydro-1H-purine- 2,6-dione, sodium salt 298
##STR00408## 8 m/z 446 [MH].sup.+ RT 2.55 min A
1-[3-(2-amino-6-methyl-9H-purin-9-
yl)propyl]-8-chloro-3-pentyl-3,7- dihydro-1H-purine-2,6-dione,
sodium salt 299 ##STR00409## 21 m/z 431 [MH].sup.+ RT 3.9 min A
1-[3-(1-benzothien-2-yl)propyl]-8-
chloro-3-pentyl-3,7-dihydro-1H-purine- 2,6-dione, sodium salt 300
##STR00410## 31 m/z 508 [MH].sup.+ RT 3.56 min A
N-[3-(8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin-1-
yl)propyl]-2,2-diphenylacetamide, sodium salt 301 ##STR00411## 22
m/z 382 [MH].sup.+ RT 2.76 min A 8-chloro-1-[3-(5-oxo-2-
pyrrolidinyl)propyl]-3-pentyl-3,7- dihydro-1H-purine-2,6-dione,
sodium salt 302 ##STR00412## 33 m/z 455 [MH].sup.+ RT 4.01 min A
8-chloro-1-{3-[5-(methyloxy)-1- naphthalenyl]propyl}-3-pentyl-3,7-
dihydro-1H-purine-2,6-dione, sodium salt 303 ##STR00413## 5 m/z 405
[MH].sup.+ RT 3.71 min A 8-chloro-1-{3-[2-
(methyloxy)phenyl]propyl}-3-pentyl-3,7-
dihydro-1H-purine-2,6-dione, sodium salt 304 ##STR00414## 15 m/z
393 [MH].sup.+ RT 3.7 min A
8-chloro-1-[3-(2-fluorophenyl)propyl]-3-
pentyl-3,7-dihydro-1H-purine-2,6- dione, sodium salt 305
##STR00415## 15 m/z 425 [MH].sup.+ RT 4.04 min A
8-chloro-1-[3-(1-naphthalenyl)propyl]-
3-pentyl-3,7-dihydro-1H-purine-2,6- dione, sodium salt 306
##STR00416## 13 m/z 400 [MH].sup.+ RT 3.51 min A
3-[3-(8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin-1-
yl)propyl]benzonitrile, sodium salt 307 ##STR00417## 19 m/z 451
[MH].sup.+ RT 4.06 min A 1-[3-(4-biphenylyl)propyl]-8-chloro-3-
pentyl-3,7-dihydro-1H-purine-2,6- dione, sodium salt 308
##STR00418## 30 m/z 453 [MH].sup.+ RT 3.2 min A 8-chloro-1-{3-[4-
(methylsulfonyl)phenyl]propyl}-3- pentyl-3,7-dihydro-1H-purine-2,6-
dione, sodium salt 309 ##STR00419## 2 m/z 376 [MH].sup.+ RT 2.41
min A 8-chloro-3-pentyl-1-[3-(4-
pyridinyl)propyl]-3,7-dihydro-1H-purine- 2,6-dione 310 ##STR00420##
46 m/z 566 [MH].sup.+ RT 4.23 min A
8-chloro-1-[3-(2,3-diphenyl-1H-indol-1-
yl)propyl]-3-pentyl-3,7-dihydro-1H- purine-2,6-dione, sodium salt
311 ##STR00421## 1 m/z 513 [MNH4].sup.+ RT 3.38 min B
2-(3-(8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin-1-
yl)propyl]-2H-naphtho[2,3- d][1,2,3]triazole-4,9-dione 312
##STR00422## 21 m/z 542 [MH].sup.+ RT 3.62 min B
8-chloro-1-(3-{6-[(4- chlorophenyl)amino]-9H-purin-9-
yl)propyl)-3-pentyl-3,7-dihydro-1H- purine-2,6-dione 313
##STR00423## 7 m/z 381 [MH].sup.+ RT 2.33 min B
1-[3-(3-amino-1H-1,2,4-triazol-5- yl)propyl]-8-chloro-3-pentyl-3,7-
dihydro-1H-purine-2,6-dione 314 ##STR00424## 17 m/z 463 [MH].sup.+
RT 3.24 min B 1-{4-[3,4-bis(methyloxy)phenyl]-4-
oxobutyl}-8-chloro-3-pentyl-3,7- dihydro-1H-purine-2,6-dione,
sodium salt 315 ##STR00425## 2 m/z 582 [MH].sup.+ RT 3.79 min B
8-chloro-1-{4-oxo-4-(1-(phenylsulfonyl)-
1H-indol-2-yl]butyl}-3-pentyl-3,7- dihydro-1H-purine-2,6-dione 316
##STR00426## 14 m/z 415 [MH].sup.+ RT 2.45 min B
1-[3-(1H-benzimidazol-2-yl)propyl]-8-
chloro-3-pentyl-3,7-dihydro-1H-purine- 2,6-dione 317 ##STR00427## 5
m/z 433 [MH].sup.+ RT 2.69 min C
1-[3-(7-amino-3H-[1,2,3]triazolo[4,5-
d]pyrimidin-3-yl)propyl]-8-chloro-3-
pentyl-3,7-dihydro-1H-purine-2,6-dione 318 ##STR00428## 2 m/z 508
[MH].sup.+ RT 4.11 min D 1-[3-(5-bromo-1-methyl-1H-indol-2-
yl)propyl]-8-chloro-3-pentyl-3,7- dihydro-1H-purine-2,6-dione 319
##STR00429## 17 m/z 443 [MH].sup.+ RT 2.59 min E
8-chloro-1-[3-(1-ethyl-1H- benzimidazol-2-yl)propyl]-3-pentyl-3,7-
dihydro-1H-purine-2,6-dione 320 ##STR00430## 25 m/z 443 [MH].sup.+
RT 2.61 min F 8-chloro-1-[3-(5,6-dimethyl-1H-
benzimidazol-2-yl)propyl]-3-pentyl-3,7-
dihydro-1H-purine-2,6-dione
[0860] Method A: Analogous to that for Example 3
[0861] Method B: Similar to Method A, except material was purified
using autopreparative HPLC after purification by aminopropyl
SPE.
[0862] Method C: Similar to Method A, except material was purified
by washing with water after purification by aminopropyl SPE.
[0863] Method D: Similar to Method A, except material was purified
by MDAP after purification by aminopropyl SPE.
[0864] Method E: Similar to Method A, except material was purified
by SCX SPE after initial purification using aminopropyl SPE.
[0865] Method F: Similar to Method A, except material was purified
using preparative HPLC using a Zorbax Phenyl column.
Example 321
8-Chloro-1-[3-(ethyloxy)ethyl]-3-(2,2,2-trifluoroethyl)-3,7-dihydro-1H-pur-
ine-2,6-dione
a)
8-Chloro-1-[3-(ethyloxy)ethyl]-3-(2,2,2-trifluoroethyl)-3,7-dihydro-1H--
purine-2,6-dione
##STR00431##
[0867] To a greenhouse tube equipped with a stirrer was added
caesium carbonate (85 mg, 0.26 mmol), followed by a solution of
8-chloro-7-(2-propen-1-yl)-3-(2,2,2-trifluoroethyl)-3,7-dihydro-1H-purine-
-2,6-dione (69 mg, 0.22 mmol) in dry DMF (1 ml) and then a solution
of 1-bromo-3-(ethyloxy)ethane (60 mg, 0.39 mmol) in dry DMF (1 ml).
The mixture was heated to 80.degree. C. for 5 h under nitrogen,
then allowed to cool to room temperature for 16 h. The reaction
mixture was concentrated using a vacuum centrifuge. THF (2.5 ml)
was added to the mixture, followed by Pd(PPh.sub.3).sub.4 (30 mg,
0.026 mmol) and morpholine (190 uL, 2.2 mmol) and the mixture
stirred at rt under nitrogen for 72 h. The mixture was partitioned
between 2N HCl (2 ml) and chloroform (4 ml), the organic layer
separated using a hydrophobic frit, and the aqueous layer extracted
with chloroform (2.times.4 ml). Combined organic layers were
concentrated under reduced pressure then loaded in 1:1 DCM/MeOH
onto an aminopropyl SPE (5 g), washing with 1:1 DCM/MeOH and
eluting with 20% to 80% acetic acid in 1:1 DCM/MeOH. Solvent was
removed under reduced pressure to afford the title compound as a
solid (70 mg, 93%).
[0868] .sup.1H NMR (MeOD) .delta.: 1.11 (t, 3H, J=7 Hz), 3.51 (q,
2H, J=7 Hz), 3.64 (t, 2H, J=6 Hz), 4.18 (t, 21-1, J=6 Hz), 4.73 (q,
2H, J=9 Hz).
[0869] LC/MS: m/z 341 [MH].sup.+, RT 2.72 min.
b)
8-Chloro-7-(2-propen-1-yl)-3-(2,2,2-trifluoroethyl)-3,7-dihydro-1H-puri-
ne-2,6-dione
##STR00432##
[0871] 8-Chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(1.5 g, 6.62 mmol) in dry DMF (50 ml) was stirred with sodium
carbonate (980 mg, 9.25 mmol) and 1,1,1-trifluoro-2-iodoethane (1.2
g, 5.71 mmol) at room temperature for 18 h under nitrogen. The
mixture was heated at 50.degree. C. for 6 h then cooled to rt and
stirred for a further 10 h. The mixture was heated at 120.degree.
C. for 4 h, further 1,1,1-trifluoro-2-iodoethane (426 mg, 2.03
mmol) added, and the reaction mixture heated at 120.degree. C. for
a further 3 h. The reaction mixture was concentrated under reduced
pressure.
[0872] A further amount of
8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (3.8 g,
16.8 mmol) in dry DMF (125 ml) was stirred with sodium carbonate
(2.5 g, 23.1 mmol) and 1,1,1-trifluoro-2-iodoethane (4.1 g, 19.5
mmol) and the reaction mixture heated at 120.degree. C. for 16 h
under nitrogen. This reaction mixture was combined with the
previous crude material and concentrated under reduced pressure.
The residue was triturated with DCM, the mixture filtered, and the
filtrate concentrated under reduced pressure then dissolved in DCM
(20 ml). 10 ml of this material was purified by silica
chromatography using a 100 g Silica column, eluting the title
compound with a suitable gradient of ethyl acetate/cyclohexane. The
remaining 10 ml was purified using a Silica RediSep cartridge (130
g) on a Companion, eluting the title compound with a suitable
gradient of ethyl acetate/cyclohexane. Fractions containing the
title compound from both purification modes were combined and
concentrated under reduced pressure to give the title compound as a
white solid (1.6 g, 22% overall yield).
[0873] LC/MS: m/z 309 [MH].sup.+, RT 2.59 min.
Example 322
8-Chloro-1-[3-(2,6-dichlorophenyl)propyl]-3-pentyl-3,7-dihydro-1H-purine-2-
,6-dione, sodium salt
##STR00433##
[0875] To a solution of
8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(40 mg, 0.14 mmol) in dry DMF (0.25 ml) was added caesium carbonate
(49 mg, 0.15 mmol) followed by a solution of
2-(3-bromopropyl)-1,3-dichlorobenzene (54 mg, 0.20 mmol) in dry DMF
(0.25 ml). The mixtures were stirred at 60.degree. C. for 16 h,
then Pd(PPh.sub.3).sub.4 (16 mg, 0.014 mmol) added, followed by
morpholine (118 uL, 1.4 mmol) and the mixtures stirred for a
further 16 h. Solvent was removed using a vacuum centrifuge and the
sample dissolved in DMSO (0.25 ml) then loaded onto a C18 SPE (5
g). 2N NaOH (0.5 ml) was added and a suitable gradient of
ammonia/water/MeCN used to elute the product. The title compound
was isolated as a solid (52 mg, 83%).
[0876] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.84 (t, 3H, J=7 Hz),
1.18-1.36 (m, 4H), 1.55-1.69 (m, 2H), 1.69-1.85 (m, 2H), 2.78-2.89
(m, 2H), 3.85 (t, 2H, J=7 Hz), 3.95 (t, 2H, J=7 Hz), 7.23 (dd, 1H,
J=9 and 7 Hz), 7.41 (d, 2H, J=7 Hz).
[0877] LC/MS: m/z 445 [MH].sup.+, RT 4.05 min.
[0878] The following compounds (Table 20) were prepared using a
method analogous to that for the Example 322, from the
corresponding alkyl halides:
TABLE-US-00022 TABLE 20 Yield Example Structure (mg) LC/MS: Method
323 ##STR00434## 57 m/z 505 [MH].sup.+ RT 3.14 min A
N-({[3-(8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin-1-
yl)propyl]amino}carbonyl)-N- (phenylmethyl)glycine, sodium 324
##STR00435## 16 m/z 530 [MH].sup.+ RT 3.36 min A 8-chloro-1-[3-(9H-
dibenzo[c,f][1,2,4]triazolo[4,3-a]azepin-3-
yl)propyl]-3-pentyl-3,7-dihydro-1H-purine- 2,6-dione, sodium 325
##STR00436## 18 m/z 430 [MH].sup.+ RT 3.12 min A
8-chloro-1-[3-(1-oxo-1,3-dihydro-2H-
isoindol-2-yl)propyl]-3-pentyl-3,7-dihydro- 1H-purine-2,6-dione,
sodium salt 326 ##STR00437## 18 m/z 467 [MH].sup.+ RT 2.99 min A
8-chloro-3-pentyl-1-(3-[1,2,4]triazolo[3,4-
a]phthalazin-3-ylpropyl)-3,7-dihydro-1H- purine-2,6-dione, sodium
salt 327 ##STR00438## 30 m/z 464 [MH].sup.+ RT 4.03 min A
1-[3-(9H-carbazol-9-yl)propyl]-8-chloro-3-
pentyl-3,7-dihydro-1H-purine-2,6-dione, sodium salt 328
##STR00439## 42 m/z 396 [MH].sup.+ RT 3.17 min A
8-chloro-1-[3-(4-methyl-1,3-thiazol-5-
yl)propyl]-3-pentyl-3,7-dihydro-1H-purine 2,6-dione, sodium salt
329 ##STR00440## 31 m/z 477 [MH].sup.+ RT 2.83 min A
7-[3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-
tetrahydro-1H-purin-1-yl)propyl]-1,3-
dimethyl-3,7-dihydro-1H-purine-2,6- dione, sodium salt 330
##STR00441## 50 m/z 439 [MH].sup.+ RT 3.56 min A
1-[3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-
tetrahydro-1H-purin-1-yl)propyl]-1H- indole-3-carbonitrile, sodium
salt 331 ##STR00442## 10 m/z 527 [MH].sup.+ RT 4.3 min A
8-chloro-1-{3-[3-ethyl-6-(trifluoromethyl)-
1-benzothien-2-yl]propyl}-3-pentyl-3,7-
dihydro-1H-purine-2,6-dione, sodium 332 ##STR00443## 5 m/z 495
[MH].sup.+ RT 2.21 min A 3-[3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-
tetrahydro-1H-purin-1-yl)propyl]-1-[3-(3-
pyridinyl)propyl]pyridinium 333 ##STR00444## 45 m/z 501 [MH].sup.+
RT 4.01 min A 1-[4,4-bis(4-fluorophenyl)butyl]-8-chloro-
3-pentyl-3,7-dihydro-1H-purine-2,6- dione, sodium salt 334
##STR00445## 33 m/z 494 [MH].sup.+ RT 3.69 min A
N-(3-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-
tetrahydro-1H-purin-1-yl)propyl)-4- biphenylcarboxamide, sodium
salt 335 ##STR00446## 18 m/z 376 [MH].sup.+ RT 2.5 min A
8-chloro-3-pentyl-1-[3-(3- pyridinyl)propyl]-3,7-dihydro-1H-purine-
2,6-dione, sodium salt 336 ##STR00447## 39 m/z 431 [MH].sup.+ RT
3.13 min A 8-chloro-1-[3-(2-oxo-2,3-dihydro-1H-
benzimidazol-1-yl)propyl]-3-pentyl-3,7-
dihydro-1H-purine-2,6-dione, sodium salt 337 ##STR00448## 4 m/z 432
[MH].sup.+ RT 2.53 min B 1-[3-(6-amino-9H-purin-9-yl)propyl]-8-
chloro-3-pentyl-3,7-dihydro-1H-purine- 2,6-dione, sodium salt 338
##STR00449## 1 m/z 444 [MH].sup.+ RT 3.39 min C
8-chloro-1-[3-(1,3-dioxo-1,3-dihydro-2H-
isoindol-2-yl)propyl]-3-pentyl-3,7-dihydro- 1H-purine-2,6-dione 339
##STR00450## 3 m/z 416 [MH].sup.+ RT 2.87 min C
8-chloro-1-[3-(1,3-dihydro-2H-isoindol-2-
yl)propyl]-3-pentyl-3,7-dihydro-1H-purine- 2,6-dione 340
##STR00451## 8 m/z 431 [MH].sup.+ RT 2.83 min D
8-chloro-1-[3-(6-methyl[1,2,4]triazolo[4,3-
b]pyridazin-3-yl)propyl]-3-pentyl-3,7- dihydro-1H-purine-2,6-dione
341 ##STR00452## 3 m/z 414 [MH].sup.+ RT 2.64 min E
8-chloro-1-[3-(6-methyl[1,2,4]triazolo[4,3-
b]pyridazin-3-yl)propyl]-3-pentyl-3,7-
dihydro-1H-purine-2,6-dione
[0879] Method A: Analogous to that for Example 3
[0880] Method B: Similar to Method A, except after concentration by
vacuum centrifuge, material was partitioned between 2M HCl and DCM,
the aqueous layer isolated then purified using C18 SPE in the
manner described in Method A.
[0881] Method C: Similar to Method A, except after concentration by
vacuum centrifuge, material was partitioned between 2M HCl and DCM,
and the product was isolated from the organic layer after
autopreparative HPLC.
[0882] Method D: Similar to Method A, except product was isolated
using aminopropyl SPE.
[0883] Method E: Similar to Method A, except material was further
purified on a phenyl HPLC using a suitable gradient of
water/MeOH/MeCN/TFA, then autopreparative HPLC, using a suitable
gradient of water/acetonitrile.
[0884] The following compounds (Table 21) were prepared using a
method analogous to that for Example 142, from the corresponding
acids and
(1Z)-4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hy-
droxybutanimidamide.
TABLE-US-00023 TABLE 21 ##STR00453## Example Name Compound: R1 =
LC/MS 342 3-butyl-8-chloro-1-[3-(5-methyl-
1,2,4-oxadiazol-3-yl)propyl]-3,7- dihydro-1H-purine-2,6-dione
##STR00454## m/z 367 [MH].sup.+ RT 2.7 min 343
3-butyl-8-chloro-1-{3-[5- (cyclopropylmethyl)-1,2,4-
oxadiazol-3-yl]propyl}-3,7- dihydro-1H-purine-2,6-dione
##STR00455## m/z 407 [MH].sup.+ RT 3.11 min 344
3-butyl-8-chloro-1-{3-[5-(3- methylphenyl)-1,2,4-oxadiazol-
3-yl]propyl}-3,7-dihydro-1H- purine-2,6-dione ##STR00456## m/z 443
[MH].sup.+ RT 3.47 min 345 3-butyl-8-chloro-1-{3-[5-(4-
methylphenyl)-1,2,4-oxadiazol- 3-yl]propyl}-3,7-dihydro-1H-
purine-2,6-dione ##STR00457## m/z 443 [MH].sup.+ RT 3.34 min 346
3-butyl-8-chloro-1-(3-{5-[2-(2,3- difluorophenyl)ethyl]-1,2,4-
oxadiazol-3-yl}propyl)-3,7- dihydro-1H-purine-2,6-dione
##STR00458## m/z 493 [MH].sup.+ RT 3.47 min 347
3-butyl-8-chloro-1-(3-{1,2,4- oxadiazol-3-yl)propyl]-3,7-
dihydro-1H-purine-2,6-dione ##STR00459## m/z 381 [MH].sup.+ RT 2.9
min 348 3-butyl-1-[3-(5-butyl-1,2,4-
oxadiazol-3-yl)propyl]-8-chloro- 3,7-dihydro-1H-purine-2,6-dione
##STR00460## m/z 409 [MH].sup.+ RT 3.27 min 349
3-butyl-8-chloro-1-[3-(5- cyclopentyl-1,2,4-oxadiazol-3-
yl)propyl]-3,7-dihydro-1H-purine- 2,6-dione ##STR00461## m/z 421
[MH].sup.+ RT 3.29 min 350 3-butyl-8-chloro-1-[3-(5-{[4-
(dimethylamino)phenyl]methyl}- 1,2,4-oxadiazol-3-yl)propyl]-3,7-
dihydro-1H-purine-2,6-dione ##STR00462## m/z 486 [MH].sup.+ RT 3.24
min 351 3-butyl-8-chloro-1-{3-[5-(3-
thienylmethyl)-1,2,4-oxadiazol-3- yl]propyl}-3,7-dihydro-1H-purine-
2,6-dione ##STR00463## m/z 449 [MH].sup.+ RT 3.24 min 352
3-butyl-8-chloro-1-{3-[5-(1H- indol-3-ylmethyl)-1,2,4-
oxadiazol-3-yl]propyl}-3,7- dihydro-1H-purine-2,6-dione
##STR00464## m/z 482 [MH].sup.+ RT 3.29 min
Example 353
3-Butyl-8-chloro-1-(2-{[4-(2-thienyl)phenyl]oxy}ethyl)-3,7-dihydro-1H-puri-
ne-2,6-dione
##STR00465##
[0886] A microwave vial containing a magnetic stirrer bar was
charged with 2-thienylboronic acid (16 mg, 0.125 mmol),
1-{2-[(4-bromophenyl)oxy]ethyl}-3-butyl-8-chloro-3,7-dihydro-1H-purine-2,-
6-dione (50 mg, 0.113 mmol), aqueous sodium carbonate (1 ml, 1M
solution) and dimethoxyethane (1 ml). This mixture was degassed
with nitrogen and then Pd(PPh.sub.3).sub.2Cl.sub.2 (4 mg,
5.6.times.10.sup.-6 mol) was added. The reaction mixture was capped
and heated at 140.degree. C. in a microwave for 15 min (pressure
reached 7 bar). The crude reaction mixture was acidified with HCl
(2M, 1.5 ml), washed with chloroform (2.times.1 ml) and the phases
separated. The combined organics were evaporated and the crude
product purified by MDAP to afford the title compound (10 mg).
[0887] LC/MS: m/z 445 [MH].sup.+, RT 3.76 min
Example 354
3-Butyl-8-chloro-1-(2-{[4-(4-methyl-2-thienyl)Phenyl]oxy}ethyl)-3,7-dihydr-
o-1H-purine-2,6-dione
##STR00466##
[0889] A microwave vial containing a magnetic stirrer bar was
charged with (4-methyl-2-thienyl)boronic acid (18 mg, 0.125 mmol),
1-{2-[(4-bromophenyl)oxy]ethyl}-3-butyl-8-chloro-3,7-dihydro-1H-purine-2,-
6-dione (50 mg, 0.113 mmol), aqueous sodium carbonate (1 ml, 1M
solution) and dimethoxyethane (1 ml). This mixture was degassed
with nitrogen and then Pd(PPh.sub.3).sub.2Cl.sub.2 (4 mg, 0.0056
mmol) was added. The reaction mixture was capped and heated at
140.degree. C. in a microwave for 15 min (pressure reached 7 bar).
The crude reaction mixture was acidified with HCl (2M, 1.5 ml),
washed with chloroform (2.times.1 ml) and the phases separated. The
combined organics were evaporated and the crude product purified by
MDAP to afford the title compound (17 mg).
[0890] LC/MS: m/z 459 [MH].sup.+, RT 3.9 min
Example 355
1-{2-[(4-Bromophenyl)oxy]ethyl}-3-butyl-8-chloro-3,7-dihydro-1H-purine-2,6-
-dione
a)
1-{2-[(4-Bromophenyl)oxy]ethyl}-3-butyl-8-chloro-3,7-dihydro-1H-purine--
2,6-dione
##STR00467##
[0892]
1-{2-[(4-Bromophenyl)oxy]ethyl}-3-butyl-8-chloro-7-(2-propen-1-yl)--
3,7-dihydro-1H-purine-2,6-dione (2.3 g, 4.8 mmol) was stirred in a
mixture of nitrogen degassed DCM (40 ml) and AcOH (4 ml).
Tetrakis(triphenylphosphine)palladium (1.1 g, 0.896 mmol) and
phenylsilane (5.9 ml, 48 mmol) were added and the mixture stirred
at rt for 2 h. This was then evaporated and the residue triturated
with a mixture of diethylether:cyclohexane (1:2) to afford the
title compound (1.02 g, 49%) as a white solid.
[0893] LC/MS: m/z 441/443 [MH].sup.+, RT 3.6 min
b)
1-{2-[(4-bromophenyl)oxy]ethyl}-3-butyl-8-chloro-7-(2-propen-1-yl)-3,7--
dihydro-1H-purine-2,6-dione
##STR00468##
[0895]
3-Butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(2.8 g, 9.8 mmol) in dry DMF (50 ml) was added Cs.sub.2CO.sub.3
(6.4 g, 19.6 mmol) followed by 2-bromoethyl 4-bromophenyl ether
(3.6 g, 13 mmol). The mixture was heated at 80.degree. C. for 17 h
and then allowed to cool. The reaction mixture was evaporated and
the crude product partitioned between EtOAc and HCl (2N). The
organic phase was separated and washed with brine, dried
(MgSO.sub.4) and evaporated to give the crude product. This was
purified by silica SPE (50 g), eluting with
cyclohexane:ethylacetate (10:1 to 1:1) to afford the title compound
as a cream coloured solid (2.9 g, 62%).
[0896] LC/MS: m/z 381/483 [MH].sup.+, RT 3.87 min.
Example 356
1,1'-(1,4-Butanediyl)bis(3-butyl-8-chloro-3,7-dihydro-1H-purine-2,6-dione)
[0897] a)
1,1'-(1,4-Butanediyl)bis(3-butyl-8-chloro-3,7-dihydro-1H-purine--
2,6-dione)
##STR00469##
[0898]
1,1'-(1,4-Butanediyl)bis[3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dih-
ydro-1H-purine-2,6-dione] (24 mg, 0.039 mmol) was stirred in a
mixture of nitrogen degassed DCM (2 ml) and AcOH (0.2 ml).
Tetrakis(triphenylphosphine)palladium (38 mg, 0.033 mmol) and
phenylsilane (42 uL, 0.39 mmol) were added and the mixture stirred
at rt for 2 h. This was then evaporated and the crude product
purified by reverse phase chromatography (5-95% gradient, H.sub.2O:
CH.sub.3CN) to afford the title compound (2 mg).
[0899] LC/MS: m/z 539 [MH].sup.+, RT 3.33 min
b)
1,1'-(1,4-Butanediyl)bis[3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-
-1H-purine-2,6-dione]
##STR00470##
[0901]
3-Butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(60 mg, 0.212 mmol) in dry DMF (1 ml) was added Cs.sub.2CO.sub.3
(207 mg, 0.636mol) followed by 1,4-diiodobutane (16 uL, 0.106
mmol). The mixture was heated at 80.degree. C. for 17 h and then
allowed to cool. The reaction mixture was partitioned between DCM
and HCl (2M). The organic phase was separated and washed with
brine, dried (MgSO.sub.4) and evaporated to give the crude product.
This was purified by MDAP to afford the title compound as a cream
coloured solid (24 mg).
[0902] LC/MS: m/z 619 [MH].sup.+, RT 3.95 min.
[0903] The following compounds (Table 22) were prepared using a
method analogous to that for Example 356.
TABLE-US-00024 TABLE 22 Example Name Structure Yield LC/MS: 357
3-butyl-1-[5-(3-butyl-8- chloro-2,6-dioxo-2,3,6,9-
tetrahydro-1H-purin-1- yl)pentyl]-8-chloro-3,7-
dihydro-1H-purine-2,6- dione ##STR00471## 2.4 mg m/z 553 [MH].sup.+
RT 3.43 min 358 3-butyl-1-[7-(3-butyl-8- chloro-2,6-dioxo-2,3,6,9-
tetrahydro-1H-purin-1- yl)heptyl]-8-chloro-3,7-
dihydro-1H-purine-2,6- dione ##STR00472## 3.6 m/z 581 [MH].sup.+ RT
3.72 min
Example 359
8-Chloro-1-[2-(ethyloxy)ethyl]-3-(4,4,4-trifluorobutyl)-3,7-dihydro-1H-pur-
ine-2,6-dione
##STR00473##
[0905] A solution of
8-chloro-7-(2-propen-1-yl)-3-(4,4,4-trifluorobutyl)-3,7-dihydro-1H-purine-
-2,6-dione (84 mg, 0.25 mmol) in DMF (1 ml) was treated with
caesium carbonate (163 mg, 0.5 mmol) and 1-bromo-2-(ethyloxy)ethane
(42 mg, 0.275 mmol). The mixture was heated at 80.degree. C. for 4
h and then cooled.
[0906] The reaction mixture was degassed with nitrogen and then
treated with morpholine (220 uL) and
tetrakis(triphenylphosphine)palladium (29 mg, 0.025 mmol) and
stirred for 4 h. The reaction mixture was partitioned between
chloroform and HCl (2M). The organic phase was separated and
evaporated. The crude product was loaded on to an aminopropyl SPE.
The non acidic impurities were eluted with a mixture of DCM and
MeOH and the desired product eluted with 10% AcOH in DCM.
Evaporation afforded the title compound (77 mg).
[0907] LC/MS: m/z 369 [MH].sup.+, RT 1.96 min.
Example 360
8-Chloro-3-propyl-1-{4-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]butyl}-3,7-di-
hydro-1H-purine-2,6-dione
a)
8-Chloro-3-propyl-1-{4-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]butyl}-3,7-
-dihydro-1H-purine-2,6-dione
##STR00474##
[0909] A solution of
8-chloro-7-(2-propen-1-yl)-1-{4-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]but-
yl}-3,7-dihydro-1H-purine-2,6-dione (40 mg, 0.09 mmol) in DMF (3
ml) was treated with potassium carbonate (15 mg, 0.11 mmol) and
1-iodopropane (19 mg, 0.11 mmol). The mixture was heated at
40.degree. C. for 3 h then at 70.degree. C. for a further 3 h. The
mixture was cooled and degassed by the successive application of
vacuum and nitrogen gas. The mixture was then treated with a
solution of tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.009
mmol) and morpholine (0.1 ml, 1.2 mmol) and then stirred overnight.
The mixture was evaporated and partitioned between chloroform (2
ml) and water (2 ml). The aqueous phase was extracted with further
chloroform (2 ml) and the combined organics evaporated and the
residue dissolved in methanol (2 ml). The solution was applied to a
1 g aminopropyl SPE and eluted with methanol and then with 5%
acetic acid in methanol. Product-containing fractions were pooled
and evaporated and the product further purified by MDAP to reveal
8-chloro-3-propyl-1-{4-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]butyl}-3,7-d-
ihydro-1H-purine-2,6-dione (1.4 mg) as a white solid.
[0910] LC/MS: m/z 430 [MH].sup.+, RT 2.84 min.
b)
8-Chloro-7-(2-propen-1-yl)-1-{4-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]b-
utyl}-3,7-dihydro-1H-purine-2,6-dione
##STR00475##
[0912] A suspension of N-hydroxy-2-pyridinecarboximidamide (1.15 g,
8.4 mmol) in anhydrous THF (20 ml) was treated with sodium
methoxide (0.38 g, 7.0 mmol) and the mixture stirred for 5 min. The
mixture was treated with ethyl
5-[8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purin-
-1-yl]pentanoate (2 g, 5.6 mmol) and the stirred for about 5 min
until all the material had dissolved. The mixture was then sealed
and heated in a microwave at 120.degree. C. for 15 min then cooled
and partitioned between ethyl acetate (100 ml) and saturated
aqueous sodium bicarbonate (50 ml). The aqueous phase was extracted
with further ethyl acetate (50 ml) and the combined organics dried
(MgSO.sub.4), filtered and evaporated. The product was purified by
flash chromatography using a gradient elution from 1:9 ethyl
acetate/cyclohexane to ethyl acetate to reveal
8-chloro-7-(2-propen-1-yl)-1-{4-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-
-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione (1.49 g) as a white
solid.
[0913] LC/MS: m/z 428 [MH].sup.+, RT 2.70 min.
[0914] Similarly prepared was
8-chloro-1-(3-{3-[(2,4-difluorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl-
)-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione using ethyl
4-[8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purin-1-yl]-
butanoate.
[0915] LC/MS: m/z 463 [MH].sup.+, RT 3.09 min.
c) Ethyl
5-[8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-pur-
in-1-yl]pentanoate
##STR00476##
[0917] A solution of
8-chloro-7-(2-propen-1-yl)-3-({[2-(trimethylsilyl)ethyl]oxy}methyl)-3,7-d-
ihydro-1H-purine-2,6-dione (10 g, 28 mmol) in DMF (10 ml) was
treated with potassium carbonate (4.8 g, 35 mmol) and ethyl
5-bromopentanoate (6.5 g, 31 mmol) and then heated to 70.degree. C.
for 3 h, cooled and evaporated. The residue was partitioned between
ethyl acetate (100 ml) and water (50 ml). The organic phase was
dried (MgSO.sub.4), filtered and evaporated and the crude
intermediate dissolved in dichloromethane (90 ml), treated with
trifluoroacetic acid (17 ml) and the mixture stirred at ambient
temperature overnight. Toluene (50 ml) was added and the mixture
evaporated to dryness. The product was purified by flash
chromatography using a gradient elution from cyclohexane to ethyl
acetate to reveal 8.65 g of ethyl
5-[8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purin-1-yl]-
pentanoate as a white solid.
[0918] LC/MS: m/z 355 [MH].sup.+, RT 2.75 min.
[0919] Similarly prepared was ethyl
4-[8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purin-1-yl]-
butanoate.
[0920] LC/MS: m/z 341 [MH].sup.+, RT 2.61 min.
d)
8-Chloro-7-(2-propen-1-yl)-3-({[2-(trimethylsilyl)ethyl]oxy}methyl)-3,7-
-dihydro-1H-purine-2,6-dione
##STR00477##
[0922] To a solution of
8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (5 g,
22.1 mmol) in DMF (80 ml) was added
2-2-(trimethylsilyl)ethoxymethyl chloride (4.3 ml, 24.2 mmol) and
sodium carbonate (2.6 g, 24.2 mmol). After stirring at room
temperature overnight further 2-2-(trimethylsilyl)ethoxymethyl
chloride (4.3 ml, 24.2 mmol) and sodium carbonate (1.3 g, 12.1
mmol) were added and stirring continued for 2 h. The reaction
mixture was then partitioned between 5% LiCl aq and ethyl acetate.
The organic extract was separated, washed with brine, dried
(MgSO.sub.4) and concentrated. Purification by Biotage.TM.
chromatogratphy using a silica cartridge eluting 1:4-1:2 ethyl
acetate/cyclohexane afforded the title compound (3.14 g, 40%).
[0923] m/z 374 [MNH.sub.4.sup.+]
[0924] The following compounds (Table 23) were prepared by a method
analogous to that for Example 360, from
8-chloro-7-(2-propen-1-yl)-1-{4-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]but-
yl}-3,7-dihydro-1H-purine-2,6-dione and the appropriate alkylating
agent.
TABLE-US-00025 TABLE 23 ##STR00478## Example R = Name Yield (mg)
m/z RT (min) 361 ##STR00479## 8-chloro-1-{4-[3-(2-
pyridinyl)-1,2,4- oxadiazol-5-yl]butyl}- 3,7-dihydro-1H-purine-
2,6-dione 2.5 388 2.37 362 ##STR00480## 8-chloro-3-methyl-1-{4-
[3-(2-pyridinyl)-1,2,4- oxadiazol-5-yl]butyl}-
3,7-dihydro-1H-purine- 2,6-dione 1.7 402 2.53 363 ##STR00481##
8-chloro-3-ethyl-1-{4-[3- (2-pyridinyl)-1,2,4-
oxadiazol-5-yl]butyl}- 3,7-dihydro-1H-purine- 2,6-dione 1.4 416
2.66 364 ##STR00482## 8-chloro-3- (phenylmethyl)-1-{4-[3-
(2-pyridinyl)-1,2,4- oxadiazol-5-yl]butyl}- 3,7-dihydro-1H-purine-
2,6-dione 1.3 478 3.09 365 ##STR00483## 8-chloro-3-(2-
methylpropyl)-1-{4-[3- (2-pyridinyl)-1,2,4- oxadiazol-5-yl]butyl}-
3,7-dihydro-1H-purine- 2,6-dione 2.0 444 2.99 366 ##STR00484##
8-chloro-3-(3- methylbutyl)-1-{4-[3-(2- pyridinyl)-1,2,4-
oxadiazol-5-yl]butyl)- 3,7-dihydro-1H-purine- 2,6-dione 1.6 458
3.21 367 ##STR00485## 8-chloro-3-(2- phenylethyl)-1-{4-[3-(2-
pyridinyl)-1,2,4- oxadiazol-5-yl]butyl)- 3,7-dihydro-1H-purine-
2,6-dione 2.1 492 3.18 368 ##STR00486## 8-chloro-1-{4-[3-(2-
pyndinyl)-1,2,4- oxadiazol-5-yl]butyl}-3-
(4,4,4-trifluorobutyl)-3,7- dihydro-1H-purine-2,6- dione 2.1 498
3.07 369 ##STR00487## 8-chloro-1-{4-{3-(2- pyridinyl)-1,2,4-
oxadiazol-5-yl]butyl}-3- [2-(1H-pyrrol-1-yl)ethyl]-
3,7-dihydro-1H-purine- 2,6-dione 2.7 481 2.89 370 ##STR00488##
8-chloro-3-[2- (phenyloxy)ethyl]-1-{4- [3-(2-pyridinyl)-1,2,4-
oxadiazol-5-yl]butyl}- 3,7-dihydro-1H-purine- 2,6-dione 1.7 508
3.11 371 ##STR00489## 8-chloro-1-{4-[3-(2- pyridinyl)-1,2,4-
oxadiazol-5-yl]butyl}-3- [3-(1H-pyrrol-1- yl)propyl]-3,7-dihydro-
1H-purine-2,6-dione 2.1 495 3.01 372 ##STR00490##
8-chloro-3-(2-propen-1- yl)-1-{4-[3-(2-pyridinyl)-
1,2,4-oxadiazol-5- yl]butyl)-3,7-dihydro-1H- purine-2,6-dione 1.3
428 2.73 373 ##STR00491## 8-chloro-3-[3- (methyloxy)propyl]-1-{4-
[3-(2-pyridinyl)-1,2,4- oxadiazol-5-yl]butyl}-
3,7-dihydro-1H-purine- 2,6-dione 1.0 460 2.65
[0925] The following compounds (Table 24) were prepared by a method
analogous to that for Example 360, from
8-chloro-1-(3-{3-[(2,4-difluorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl-
)-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione and the
appropriate alkylating agent.
TABLE-US-00026 TABLE 24 ##STR00492## Yield RT Example R = Name (mg)
m/z (min) 374 ##STR00493## 8-chloro-1-(3-{3-[(2,4-
difluorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3,7-
dihydro-1H-purine-2,6-dione 2.5 423 2.71 375 ##STR00494##
8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4-
oxadiazol-5-yl}propyl)-3- methyl-3,7-dihydro-1H-purine- 2,6-dione
1.7 437 2.92 376 ##STR00495## 8-chloro-1-(3-{3-[(2,4-
difluorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3-ethyl-
3,7-dihydro-1H-purine-2,6- dione 1.4 451 3.06 377 ##STR00496##
8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4-
oxadiazol-5-yl}propyl)-3- propyl-3,7-dihydro-1H-purine- 2,6-dione
2.2 465 3.22 378 ##STR00497## 8-chloro-1-(3-{3-[(2,4-
difluorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3-pentyl-
3,7-dihydro-1H-purine-2,6- dione 2.6 493 3.54 379 ##STR00498##
8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4-
oxadiazol-5-yl}propyl)-3-(2- hydroxyethyl)-3,7-dihydro-1H-
purine-2,6-dione 2.7 467 2.72 380 ##STR00499##
8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4-
oxadiazol-5-yl}propyl)-3-(3- hydroxypropyl)-3,7-dihydro-
1H-purine-2,6-dione 2.0 481 2.77 381 ##STR00500##
8-chloro-1-(3-{3-((2,4- difluorophenyl)methyl]-1,2,4-
oxadiazol-5-yl}propyl)-3-(4- hydroxybutyl)-3,7-dihydro-1H-
purine-2,6-dione 1.4 495 2.80 382 ##STR00501##
8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4-
oxadiazol-5-yl)propyl)-3- (phenylmethyl)-3,7-dihydro-
1H-purine-2,6-dione 1.6 513 3.43 383 ##STR00502##
8-chloro-3-(cyclopropylmethyl)- 1-(3-{3-[(2,4-
difluorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3,7-
dihydro-1H-purine-2,6-dione 1.8 477 3.30 384 ##STR00503##
8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4-
oxadiazol-5-yl)propyl)-3-(2- methylpropyl)-3,7-dihydro-1H-
purine-2,6-dione 3.5 479 3.36 385 ##STR00504##
8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4-
oxadiazol-5-yl)propyl)-3-(3- methylbutyl)-3,7-dihydro-1H-
purine-2,6-dione 3.1 493 3.53 386 ##STR00505##
8-chloro-3-(cyclobutylmethyl)- 1-(3-{3-[(2,4-
difluorophenyl)methyl]-1,2,4- oxadiazol-5-yl}propyl)-3,7-
dihydro-1H-purine-2,6-dione 2.2 491 3.45 387 ##STR00506##
8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4-
oxadiazol-5-yl}propyl)-3-(2- phenylethyl)-3,7-dihydro-1H-
purine-2,6-dione 2.4 527 3.50 388 ##STR00507##
8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4-
oxadiazol-5-yl)propyl)-3-(3- methyl-2-buten-1-yl)-3,7-
dihydro-1H-purine-2,6-dione 3.1 491 3.46 389 ##STR00508##
8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4-
oxadiazol-5-yl}propyl)-3-(4,4,4- trifluorobutyl)-3,7-dihydro-1H-
purine-2,6-dione 3.0 533 3.39 390 ##STR00509##
8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4-
oxadiazol-5-yl}propyl)-3-(3,3,3- trifluoropropyl)-3,7-dihydro-1H-
purine-2,6-dione 2.7 519 3.34 391 ##STR00510##
8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4-
oxadiazol-5-yl)propyl)-3-[2- (1H-pyrrol-1-yl)ethyl]-3,7-
dihydro-1H-purine-2,6-dione 2.0 516 3.27 392 ##STR00511##
8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4-
oxadiazol-5-yl)propyl)-3-[2- 1H-purine-2,6-dione 1.6 543 3.44 393
##STR00512## 8-chloro-1-(3-{3-((2,4- difluorophenyl)methyl]-1,2,4-
oxadiazol-5-yl}propyl)-3-[2- (ethyloxy)ethyl]-3,7-dihydro-
1H-purine-2,6-dione 2.8 495 3.11 394 ##STR00513##
8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4-
oxadiazol-5-yl}propyl)-3-[2- (methyloxy)ethyl]-3,7-dihydro-
1H-purine-2,6-dione 2.6 481 2.98 395 ##STR00514##
8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4-
oxadiazol-5-yl}propyl)-3-(2- propen-1-yl)-3,7-dihydro-1H-
purine-2,6-dione 3.1 463 3.17 396 ##STR00515##
8-chloro-1-(3-{3-[(2,4- difluorophenyl)methyl]-1,2,4-
oxadiazol-5-yl}propyl)-3-[3- (methyloxy)propyl)-3,7-
dihydro-1H-purine-2,6-dione 2.1 495 3.04 397 ##STR00516##
8-chloro-3-cyclopentyl-1-(3-{3- [(2,4-difluorophenyl)methyl]-
1,2,4-oxadiazol-5-yl}propyl)- 3,7-dihydro-1H-purine-2,6- dione 2.5
491 3.52
Example 398
1-[3-(3-Bromophenyl)propyl]-8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-di-
one
##STR00517##
[0927] A solution of 3-(3-bromophenyl)-propan-1-ol (1.627 g, 7.56
mmol) in THF (65 ml) was treated with
8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(2.04 g, 6.87 mmol) under nitrogen. PPh.sub.3 (2.164 g, 8.25 mmol)
was added to the stirred mixture after 2 min and after a further 6
min DBAD (1.9 g, 8.25 mmol) was added in one portion. The mixture
was stirred for 2.5 h and then left to react for 16 h. The mixture
was degassed by applying a vacuum and then nitrogen was introduced.
Pd(PPh.sub.3).sub.4 (794 mg, 0.69 mmol) was added and the mixture
degassed once more. Morpholine (6 ml, 68.8 mmol) was added and the
mixture was stirred under nitrogen for 6 h. The mixture was
partitioned between 2M HCl (aq) and EtOAc. The organic layer was
separated, washed with brine, dried (MgSO.sub.4) and concentrated.
The residue was taken up into MeOH and purified by passing down an
aminopropyl SPE, the product eluted with 2-5% AcOH/MeOH. The title
compound was obtained as an off-white solid (2.48 g, 79%).
[0928] LC/MS: m/z 455, 453 [MH].sup.+, RT 3.85 min.
Example 399
8-Chloro-1-{2-[(3-hydroxyphenyl)oxy]ethyl}-3-pentyl-3,7-dihydro-1H-purine--
2,6-dione and
Example 400
8-chloro-1-(2-{[3-({2-[(3-hydroxyphenyl)oxy]ethyl}oxy)phenyl]oxy}ethyl)-3--
pentyl-3,7-dihydro-1H-purine-2,6-dione
##STR00518##
[0930] A solution of 2-(2-hydroxyethyl)-resorcinol (1.156 g, 7.5
mmol) in THF (60 ml) was treated with
8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(2.016 g, 6.79 mmol) under nitrogen. PPh.sub.3 (2.138 g, 8.15 mmol)
was added to the stirred mixture after 4 min and after a further 8
min DBAD (1.88 g, 8.16 mmol) was added in one portion. The mixture
was stirred for 1 h 50 min and then left to react for 16 h. The
mixture was degassed by applying a vacuum and then nitrogen was
introduced. Pd(PPh.sub.3).sub.4 (785 mg, 0.68 mmol) was added and
the mixture degassed once more. Morpholine (5.9 ml, 67.7 mmol) was
added and the mixture was stirred under nitrogen for 4.5 h. The
mixture was partitioned between 2M HCl (aq) and EtOAc. The organic
layer was separated, washed with brine, dried (MgSO.sub.4) and
concentrated. The residue was taken up into MeOH and purified by
passing it down an aminopropyl SPE, the product gradient elution
with 2-5% AcOH/MeOH. The fractions containing product were
evaporated to give a pale yellow foam (2.39 g) and a pale yellow
gum (213 mg). The foam was dissolved in dichloromethane (50 ml) and
passed through a hydrophobic frit. The solution was evaporated and
dried in vacuo to give
8-chloro-1-{2-[(3-hydroxyphenyl)oxy]ethyl}-3-pentyl-3,7-dihydro-1H-p-
urine-2,6-dione as a white solid (1.919 g, containing 15%
8-chloro-1-(2-([3-({2-[(3-hydroxyphenyl)oxy]ethyl}oxy)phenyl]oxy)ethyl)-3-
-pentyl-3,7-dihydro-1H-purine-2,6-dione).
[0931] The gum was purified by MDAP to give
8-chloro-1-{2-[(3-hydroxyphenyl)oxy]ethyl}-3-pentyl-3,7-dihydro-1H-purine-
-2,6-dione as a white solid (126 mg).
[0932] LC/MS: m/z 393 [MH].sup.+, RT 3.23 min as well as
8-chloro-1-(2-{[3-({2-[(3-hydroxyphenyl)oxy]ethyl}oxy)phenyl]oxy}ethyl)-3-
-pentyl-3,7-dihydro-1H-purine-2,6-dione as a pale yellow solid (38
mg).
[0933] LC/MS: m/z 529 [MH].sup.+, RT 3.62 min.
[0934] The following compounds (Table 25) were prepared using a
method analogous to that for
8-chloro-1-(2-[(3-hydroxyphenyl)oxy]ethyl)-3-pentyl-3,7-dihydro-1H-purine-
-2,6-dione above, from the corresponding alcohol.
TABLE-US-00027 TABLE 25 Yield Example Structure (mg) LC/M: 401
##STR00519## 58 m/z 391 [MH].sup.+ RT 3.38 min
8-chloro-1-[3-(4-hydroxyphenyl)propyl]-3-pentyl-
3,7-dihydro-1H-purine-2,6-dione 402 ##STR00520## 12 m/z 525
[MH].sup.+ RT 4.07 min 8-chloro-1-[3-(4-{[3-(4-
hydroxyphenyl)propyl]oxy}phenyl)propyl]-3-
pentyl-3,7-dihydro-1H-purine-2,6-dione
Example 403
8-Chloro-1-(3-{3-[(3-chlorophenyl)oxy]phenyl}propyl)-3-pentyl-3,7-dihydro--
1H-purine-2,6-dione
##STR00521##
[0936]
1-[3-(3-Bromophenyl)propyl]-8-chloro-3-pentyl-3,7-dihydro-1H-purine-
-2,6-dione (100 mg, 0.22 mmol) was dissolved in dioxan (0.75 ml).
Copper (1) iodide (9 mg, 0.05 mmol), N,N-dimethylglycine
hydrochloride (9 mg, 0.06 mmol), cesium carbonate (215 mg, 0.66
mmol) and 3-chlorophenol (52 mg, 0.4 mmol) were added to the
solution. The mixture was heated under microwave irradiation at
200.degree. C. for 10 min, followed by another 10 min at
200.degree. C. after which the cooled mixture was filtered and the
residue washed with EtOAc and MeOH. The filtrate and washings were
combined and evaporated under reduced pressure to leave a red/brown
solid. The solid was partitioned between DCM and water. The phases
were separated by hydrophobic frit and the organic evaporated under
reduced pressure to leave a solid. The solid was purified by MDAP
to give the title compound as a yellow solid/gum (27 mg, 24%).
[0937] LC/MS: m/z 501 [MH].sup.+, RT 4.25 min.
Example 404
8-Chloro-3-pentyl-1-{3-[3-(phenyloxy)phenyl]propyl}-3,7-dihydro-1H-purine--
2,6-dione
##STR00522##
[0939]
1-[3-(3-Bromophenyl)propyl]-8-chloro-3-pentyl-3,7-dihydro-1H-purine-
-2,6-dione (100 mg, 0.22 mmol), copper (1) iodide (4 mg, 0.02
mmol), N,N-dimethylglycine hydrochloride (9 mg, 0.06 mmol) cesium
carbonate (144 mg, 0.44 mmol) and phenol (31 mg, 0.33 mmol) were
placed in dioxan (0.44 ml). Then the mixture was heated in the
microwave at 150.degree. C. for 3.3 min, then further quantities of
cesium carbonate (72 mg, 0.22 mmol), copper (1) iodide (6 mg, 0.03
mmol) and dioxan (0.44 ml) were added to the mixture and heated in
the microwave at 170.degree. C. for 10 min, followed by another 10
min at 200.degree. C. The cooled mixture was filtered and the
residue washed with EtOAc. The filtrate and washings were combined
and evaporated under reduced pressure to leave a dark brown gum.
The gum was purified by MDAP to give the title compound as a pale
cream solid (44 mg, 42%).
[0940] LC/MS: m/z 467 [MH].sup.+, RT 4.14 min.
Example 405
8-Chloro-1-[3-(3'-chloro-3-biphenylyl)propyl]-3-pentyl-3,7-dihydro-1H-puri-
ne-2,6-dione
##STR00523##
[0942] A mixture of
1-[3-(3-bromophenyl)propyl]-8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-d-
ione (100 mg, 0.22 mmol) and 3-chlorophenyl boronic acid (35 mg,
0.22 mmol) was stirred in isopropanol (0.35 ml). A solution of
sodium carbonate (70 mg, 0.66 mmol) in water (0.35 ml) was added to
the mixture followed by 10% palladium on carbon (6 mg, Degussa type
E101 NE/W). The mixture was heated in the microwave at 160.degree.
C. for 10 min, then filtered (glass fibre filter) and the residues
washed with IPA. The filtrate and washings were combined and
evaporated under reduced pressure to leave a gum. The gum was
partitioned between DCM and water. The organic phase was separated
and the aqueous phase extracted with EtOAc. The combined organic
phases were dried (MgSO.sub.4) and concentrated to leave a foam.
The foam was purified by MDAP to give the title compound as a
colourless gum (40 mg, 37%).
[0943] LC/MS: m/z 485 [MH].sup.+, RT 4.27 min.
[0944] The following compounds (Table 26) were prepared using a
method analogous to that for
8-chloro-1-[3-(3'-chloro-3-biphenylyl)propyl]-3-pentyl-3,7-dihydro-1H-pur-
ine-2,6-dione (Example 405) above, from the corresponding boronic
acid, except that the 2-chlorophenyl analogue was heated in the
microwave at 160.degree. C. for 10 min twice while in the work up
1M hydrochloric acid was used instead of water. Also the EtOAc
extraction was omitted.
TABLE-US-00028 TABLE 26 Yield Example Structure (mg) LC/MS: 406
##STR00524## 51 m/z 451 [MH].sup.+ RT 4.02 min
1-[3-(3-biphenylyl)propyl]-8-chloro-3-pentyl-
3,7-dihydro-1H-purine-2,6-dione 407 ##STR00525## 56 m/z 485
[MH].sup.+ RT 4.15 min
8-chloro-1-[3-(2'-chloro-3-biphenylyl)propyl]-
3-pentyl-3,7-dihydro-1H-purine-2,6-dione
Example 408
3-Butyl-8-chloro-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dione
a)
3-Butyl-8-chloro-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dione
##STR00526##
[0945] 3-Butyl-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dione
(100 mg, 0.31 mmol) and NCS (41 mg, 0.31 mmol) were suspended in
MeCN (5 ml) and heated at 120.degree. C. under microwave
irradiation for 10 min. The reaction mixture was concentrated under
reduced pressure and the title compound isolated using HPLC.
[0946] .sup.1H NMR (CDCl.sub.3) .delta.: 0.96 (3H, t), 1.37-1.43
(2H, m), 1.70-1.78 (2H, m), 2.00-2.09 (2H, m), 2.73 (2H, t), 4.08
(2H, t), 4.14 (2H, t), 7.13-7.26 (5H, m), 12.6 (1H, br.s).
[0947] LC/MS: m/z 361 [MH].sup.+.
b) 3-Butyl-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dione
##STR00527##
[0949]
3-Butyl-7-(phenylmethyl)-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2-
,6-dione (0.6 g, 1.44 mmol) was dissolved in acetic acid (35 ml),
20% palladium hydroxide on carbon (0.366 g) was added, and the
mixture was shaken under hydrogen (at 50 psi) overnight. The
catalyst was removed by filtration through Celite.RTM. and washed
with acetic acid. The filtrate was concentrated under reduced
pressure and the title compound isolated using HPLC (0.385 g,
82%).
[0950] LC/MS: m/z 327 [MH].sup.+.
c)
3-Butyl-7-(phenylmethyl)-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-d-
ione
##STR00528##
[0952] 7-Benzyl-3-butyl-3,7-dihydro-1H-purine-2,6-dione (0.5 g,
1.68 mmol) and potassium carbonate (0.347 g, 2.5 mmol) were
suspended in DMF (20 ml), (3-bromopropyl)benzene (390 mg, 1.96
mmol) was added. The reaction mixture was stirred at ambient
temperature overnight. The reaction mixture was evaporated to
dryness and the residue was partitioned between water and ethyl
acetate. The organic layer was washed with water, followed by
brine, dried over anhydrous sodium sulphate and concentrated under
reduced pressure to yield the title compound.
[0953] .sup.1H NMR (CDCl.sub.3) .delta.: 0.95 (3H, t), 1.34-1.43
(2H, m), 1.68-1.76 (2H, m), 1.98-2.07 (2H, m), 2.71 (2H, t),
4.05-4.10 (4H, m), 5.49 (2H, s), 7.19-7.24 (5H, m), 7.33-7.38 (5H,
m), 7.52 (1H, s).
[0954] LC/MS: m/z 417 [MH].sup.+.
d) 7-Benzyl-3-butyl-3,7-dihydro-1H-purine-2,6-dione
##STR00529##
[0956] 7-Benzyl-3,7-dihydro-1H-purine-2,6-dione (17.14 g, 70.8
mmol) [Synthetic Communications, 20(16), 2459-2467, 1990] and
potassium carbonate (11.43 g, 82.8 mmol) were suspended in DMF (400
ml) at 40.degree. C. After stirring for thirty minutes, butyl
iodide (8.76 ml, 77.0 mmol) was added, and the mixture was stirred
at 40.degree. C. overnight. 50% Aqueous acetic acid (60 ml) was
added, and the solution was concentrated under reduced pressure.
The residue was suspended in water (500 ml), and the products were
extracted into chloroform. The organics were collected,
concentrated, and product was isolated using flash chromatography
eluting with 1% methanol in dichloromethane (9.49 g, 45%).
[0957] .sup.1H NMR (CDCl.sub.3) .delta.: 0.95 (3H, t), 1.34-1.41
(2H, m), 1.70-1.78 (2H, m), 4.05 (2H, t), 5.46 (2H, s), 7.31-7.40
(5H, m), 7.56 (1H, s), 8.21 (1H, br.s).
[0958] LC/MS: m/z 299 [MH].sup.+.
Example 409
3-Butyl-8-chloro-1-[2-(phenyloxy)ethyl]-3,7-dihydro-1H-purine-2,6-dione
a)
3-Butyl-8-chloro-1-[2-(phenyloxy)ethyl]-3,7-dihydro-1H-purine-2,6-dione
##STR00530##
[0960] The title compound was prepared using the procedure for
3-butyl-8-chloro-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dione,
from 3-butyl-1-[2-(phenyloxy)ethyl]-3,7-dihydro-1H-purine-2,6-dione
and NCS.
[0961] .sup.1H NMR (CDCl.sub.3) .delta.: 0.95 (3H, t), 1.36-1.45
(2H, m), 1.71-1.79 (2H, m), 4.11 (2H, t), 4.29 (2H, t), 4.54 (2H,
t), 6.87-6.94 (3H, m), 7.21-7.27 (2H, m), 13.10 (1H, br.s).
[0962] LC/MS: m/z 363 [MH].sup.+.
b)
3-Butyl-1-[2-(phenyloxy)ethyl]-3,7-dihydro-1H-purine-2,6-dione
##STR00531##
[0964] The title compound was prepared using the procedure outlined
for 3-butyl-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dione,
from
3-butyl-7-(phenylmethyl)-1-[2-(phenyloxy)ethyl]-3,7-dihydro-1H-purine-2,6-
-dione.
[0965] LC/MS: m/z 329 [MH].sup.+.
c)
3-Butyl-7-(phenylmethyl)-1-[2-(phenyloxy)ethyl]-3,7-dihydro-1H-purine-2-
,6-dione
##STR00532##
[0967] The title compound was prepared using the procedure outlined
for
3-butyl-7-(phenylmethyl)-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dio-
ne, from 7-benzyl-3-butyl-3,7-dihydro-1H-purine-2,6-dione and
2-bromoethyl phenyl ether.
[0968] .sup.1H NMR (CDCl.sub.3) .delta.: 0.95 (3H, t), 1.35-1.44
(2H, m), 1.69-1.78 (2H, m), 4.07-4.11 (2H, m), 4.26 (2H, t), 4.434
(2H, t), 5.49 (2H, s), 6.87-7.38 (10H, m), 7.55 (1H, s).
[0969] LC/MS: m/z 419 [MH].sup.+.
Example 410
8-Chloro-3-methyl-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dione
a)
8-Chloro-3-methyl-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dione
##STR00533##
[0971] The title compound was prepared using the procedure outlined
for
3-butyl-8-chloro-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dione,
from 3-methyl-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dione
and NCS.
[0972] .sup.1H NMR (CDCl.sub.3) .delta.: 2.01-2.12 (2H, m), 2.74
(2H, t), 3.57 (3H, s), 4.14 (2H, t), 6.99-7.24 (5H, m), 12.5 (1H,
br.s).
[0973] LC/MS: m/z 319 [MH].sup.+.
b) 3-Methyl-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dione
##STR00534##
[0975] The title compound was prepared using the procedure outlined
for 3-butyl-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dione,
from
3-methyl-7-(phenylmethyl)-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-di-
one.
[0976] LC/MS: m/z 285 [MH].sup.+.
c)
3-Methyl-7-(phenylmethyl)-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6--
dione
##STR00535##
[0978] The title compound was prepared using the procedure outlined
for
3-butyl-7-(phenylmethyl)-1-(3-phenylpropyl)-3,7-dihydro-1H-purine-2,6-dio-
ne, from 3-methyl-7-(phenylmethyl)-3,7-dihydro-1H-purine-2,6-dione
and (3-bromopropyl)benzene.
[0979] LC/MS: m/z 375 [MH].sup.+.
d) 3-Methyl-7-(phenylmethyl)-3,7-dihydro-1H-purine-2,6-dione
##STR00536##
[0981] The title compound was prepared using the procedure
described for 7-benzyl-3-butyl-3,7-dihydro-1H-purine-2,6-dione
using methyl iodide (0.28 ml, 4.46 mmol). Purification was achieved
by trituration. The product was isolated as a solid, insoluble in
chloroform and water (0.334 g, 57%).
[0982] .sup.1H NMR (DMSO-d.sub.6) .delta.: 3.34 (3H, s), 5.44 (2H,
s), 7.26-7.37 (5H, m), 8.21 (1H, s), 11.13 (1H, s).
[0983] LC/MS: m/z 257 [MH].sup.+.
Example 411
8-Chloro-3-pentyl-1-{[1-(phenylmethyl)-1H-indol-5-yl]methyl}-3,7-dihydro-1-
H-purine-2,6-dione
a)
8-Chloro-3-pentyl-1-{[1-(phenylmethyl)-1H-indol-5-yl]methyl}-3,7-dihydr-
o-1H-purine-2,6-dione
##STR00537##
[0985] 8-Chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione (156 mg,
0.5 mmol) was dissolved in anhydrous THF (5 ml) under nitrogen and
[1-(phenylmethyl)-1H-indol-5-yl]methanol (138 mg, 0.58 mmol) was
added. After several minutes triphenylphosphine (168 mg, 0.63 mmol)
was added followed 5-10 min later by DBAD (155 mg, 0.67 mmol) and
the solution stirred for 18 h. The mixture was degassed by applying
a vacuum and then nitrogen was introduced. Pd(PPh.sub.3).sub.4 (63
mg, 0.054 mmol) was added and the mixture degassed once more.
Morpholine (0.461 ml, 5.3 mmol) was added and the mixture was
stirred under nitrogen for 24 h. A further quantity of
Pd(PPh.sub.3).sub.4 (58 mg, 0.05 mmol) was added and the mixture
was stirred under nitrogen for 96 h. The mixture was diluted with
EtOAc and washed with 2M HCl (5 ml) then brine (15 ml), dried
(MgSO.sub.4) and concentrated. The crude material was purified by
an aminopropyl SPE (eluent MeOH to wash through the impurities,
then with 3-4% AcOH/MeOH). The product fractions were combined and
concentrated to give the title compound as a white solid (43 mg,
17%).
[0986] LC/MS: m/z 476 [MH].sup.+, RT 3.78 min.
b) [1-(Phenylmethyl)-1H-indol-5-yl]methanol
##STR00538##
[0988] Methyl 1-(phenylmethyl)-1H-indole-5-carboxylate (1.17 g, 4.4
mmol) was dissolved in anhydrous THF under nitrogen and cooled to
-5.degree. C. 1M Lithium aluminumhydride in diethylether (4.0 ml)
was added slowly. The cooling bath was removed and the reaction
mixture was left overnight at room temperature. The reaction was
quenched by the sequential addition of water (0.15 ml), 15% NaOH
(0.15 ml) followed by water (0.45 ml) then ethyl acetate and sodium
sulphate were added and the mixture stirred for 0.5 h. The
insoluble material was filtered and washed well with ethyl acetate.
The filtrate was concentrated in vacuo to give the title compound
as a cream solid which darkened on standing (1.04 g, 100%).
[0989] LC/MS: m/z 238 [MH].sup.+, RT 3.03 min.
[0990] The following alcohols were prepared by reduction of the
corresponding methyl ester in a similar manner:
[1-(Phenylmethyl)-1H-indol-4-yl]methanol
##STR00539##
[0992] LC/MS: m/z 238 [MH].sup.+, RT 3.03 min.
[2-(Phenylmethyl)-1,3-benzoxazol-4-yl]methanol
##STR00540##
[0994] LC/MS: m/z 240 [MH].sup.+, RT 2.02 min.
c) Methyl 1-(phenylmethyl)-1H-indole-5-carboxylate
##STR00541##
[0996] Methyl 1H-indole-5-carboxylate (1.0 g, 5.7 mmol) was
dissolved in anhydrous DMF under nitrogen and cooled to 2.degree.
C. Sodium hydride (0.25 g, 6.3 mmol, 60% in paraffin) was added.
After 0.5 h benzyl bromide (0.75 ml, 6.0 mmol) was added and the
reaction mixture stirred for 4 hr at room temperature, then left
overnight. The reaction mixture was poured into water (50 ml) and
ethyl acetate (10 ml). The aqueous phase was extracted further with
ethyl acetate (50 ml). The combined organic phases were washed with
dil. ammonia then brine, dried (MgSO.sub.4) and concentrated in
vacuo. The crude product was purified on a 50 g Si SPE (gradient
elution cyclohexane/ethyl acetate 8% to 16%). The relevant
fractions were concentrated in vacuo to give the title compound as
a white solid (1.17 g, 77%)
[0997] LC/MS: m/z 266 [MH].sup.+, RT 3.60 min.
Methyl 1-(phenylmethyl)-1H-indole-4-carboxylate was prepared in a
similar manner
##STR00542##
[0999] LC/MS: m/z 266 [MH].sup.+, RT 3.58 min.
Methyl 2-(phenylmethyl)-1,3-benzoxazole-5-carboxylate
##STR00543##
[1001] Trimethylbenzylorthoformate (1.34 g, 6.8 mmol) was dissolved
in methanol (2 ml) and methyl-3-amino-hydroxybenzoate (0.56 g, 3.35
mmol) was added followed by conc. hydrochloric acid (9.1 ml). The
mixture was stirred at reflux for 4.75 h, allowed to cool and
evaporated in vacuo. The residue was partitioned between diethyl
ether (10 ml) and 2M NaOH solution (5 ml). The organic phase was
washed with water (5 ml) and the combined aqueous phases were back
extracted with ether (10 ml). The combined organic phases were
dried (MgSO.sub.4) and concentrated in vacuo to leave an orange oil
(1.37 g). The crude product was purified on silica (40 g SPE,
gradient elution cyclohexane/ethyl acetate 0-100%) to give the
title compound as a white solid (0.72 g, 80%).
[1002] LC/MS: m/z 268 [MH].sup.+, RT 3.27 min.
3-[3-(Phenylmethyl)phenyl]-1-propanol
##STR00544##
[1004] 3-[3-(phenylcarbonyl)phenyl]propanoic acid (491 mg, 1.96
mmol) was dissolved in anhydrous THF under nitrogen and cooled to
0.degree. C. 1M LiAlH.sub.4 in ether (2.13 ml) was added slowly and
the reaction mixture was stirred at room temperature for 20 h. The
reaction was cooled in ice and tetrahydrofuran (5 ml) and 1M
LiAlH.sub.4 in ether solution (2.2 ml) added. The reaction mixture
was heated at reflux for 7 hr then left at room temperature for 3
days. The reaction was quenched with sequentially, water (0.16 ml),
15% NaOH (0.16 ml) and water (0.47 ml) then diluted with ethyl
acetate and dried with sodium sulphate. The insoluble material was
filtered and thoroughly washed with ethyl acetate. The filtrate was
concentrated in vacuo to give
3-{3-[hydroxy(phenyl)methyl]phenyl}-1-propanol as a white opaque
oil (0.42 g, 90%)
[1005] LC/MS: m/z 243 [MH].sup.+, RT 2.71 min.
[1006] The above material (200 mg, 0.82 mmol) was dissolved in
anhydrous dichloromethane (5 ml) and triethylsilane (0.53 ml, 3.2
mmol) followed by trifluoroacetic acid (0.36 ml, 4.1 mmol) were
added. The reaction mixture was stirred for 1 h then washed with
saturated sodium hydrogen carbonate solution. The organic phase was
filtered through a hydrophobic fit and concentrated in vacuo. The
crude product was purified over silica (4 g SPE, gradient elution
cyclohexane/ethyl acetate 0-30%) to give the title compound as a
colourless oil (68 mg, 37%).
[1007] LC/MS: m/z 227 [MH].sup.+, RT 3.25 min.
[1008] The following compounds (Table 27) were prepared using a
method analogous to that for
8-chloro-3-pentyl-1-{[1-(phenylmethyl)-1H-indol-5-yl]methyl}-3,7-dihydro--
1H-purine-2,6-dione from the corresponding alcohols as described
above.
TABLE-US-00029 TABLE 27 Yield Example Structure (mg) LC/MS: 412
##STR00545## 49 m/z 476 [MH].sup.+ RT 3.82 min
8-chloro-3-pentyl-1-{[1-(phenylmethyl)-1H-indol-
4-yl]methyl}-3,7-dihydro-1H-purine-2,6-dione 413 ##STR00546## 70
m/z 465 [MH].sup.+ RT 4.01 min 8-chloro-3-pentyl-1-{3-[3-
(phenylmethyl)phenyl]propyl}-3,7-dihydro-1H- purine-2,6-dione 414
##STR00547## 174 m/z 478 [MH].sup.+ RT 3.70 min
8-chloro-3-pentyl-1-{[2-(phenylmethyl)-1,3-
benzoxazol-5-yl]methyl}-3,7-dihydro-1H-purine- 2,6-dione
Example 415
8-Chloro-1-(2-hydroxy-6-phenylhexyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-di-
one
a)
8-Chloro-1-(2-hydroxy-6-phenylhexyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-
-dione
##STR00548##
[1010] A solution of
8-chloro-1-(2-hydroxy-6-phenylhexyl)-3-pentyl-7-(2-propen-1-yl)-3,7-dihyd-
ro-1H-purine-2,6-dione (0.084 g, 0.18 mmol) and Pd(PPh.sub.3).sub.4
(0.042 g, 0.035 mmol) in THF (5 ml) was degassed (sequential
evacuation followed by addition of nitrogen.times.3) then
morpholine (0.25 ml, 2.8 mmol) added and the mixture stirred
overnight. The solution was loaded onto an aminopropyl SPE (5 g)
and eluted with MeOH to remove by-products then with 5% AcOH/MeOH
to isolate the title compound, after concentration, as an oil
(0.022 g, 29%).
[1011] LC/MS: m/z 433 [MH].sup.+
b)
8-Chloro-1-(2-hydroxy-6-phenylhexyl)-3-pentyl-7-(2-propen-1-yl)-3,7-dih-
ydro-1H-purine-2,6-dione
##STR00549##
[1013] To a solution of
8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(0.107 g, 0.36 mmol) and 1-chloro-6-phenyl-2-hexanol (0.107 g, 0.5
mmol) in DMF (5 ml) was added cesium carbonate (0.24 g, 0.74 mmol)
and the mixture heated at 60.degree. C. for 3 h, whereupon a
further 80 mg of cesium carbonate was added and heating continued
at 100.degree. C. for 18 h. The solution was allowed to cool,
concentrated and the residues purified by chromatography over
silica (20 g SPE, eluting with first with DCM then DCM/10% ether)
to yield the title compound as a yellow oil (0.085 mg, 53%).
[1014] LC/MS: m/z 473 [MH].sup.+
Example 416
8-Chloro-1-{4-[2-oxo-3-(phenylmethyl)-1-pyrrolidinyl]butyl}-3-pentyl-3,7-d-
ihydro-1H-purine-2,6-dione
a)
8-Chloro-1-{4-[2-oxo-3-(phenylmethyl)-1-pyrrolidinyl]butyl}-3-pentyl-3,-
7-dihydro-1H-purine-2,6-dione
##STR00550##
[1016] A solution of
8-chloro-1-{4-[2-oxo-3-(phenylmethyl)-1-pyrrolidinyl]butyl}-3-pentyl-7-(2-
-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.35 g, 0.67 mmol),
Pd(PPh.sub.3).sub.4 (0.082 g, 0.07 mmol) and morpholine (0.6 ml,
6.7 mmol) in THF (10 ml) was degassed (sequential evacuation
followed by addition of nitrogen.times.3) then stirred for 4 h. The
solution was then loaded onto an aminopropyl SPE (5 g) and eluted
first with MeOH then 5% AcOH/MeOH to provide the title compound
containing a small impurity. Further purification over silica (10 g
SPE, gradient elution ether/ethyl acetate 1:0 to 0:1) provided the
title compound as a clear oil (0.10 g, 31%).
[1017] LC/MS: m/z 486 [MH].sup.+
b)
8-Chloro-1-{4-[2-oxo-3-(phenylmethyl)-1-pyrrolidinyl]butyl}-3-pentyl-7--
(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
##STR00551##
[1019] Prepared as with
8-chloro-1-(2-hydroxy-6-phenylhexyl)-3-pentyl-7-(2-propen-1-yl)-3,7-dihyd-
ro-1H-purine-2,6-dione using
1-(4-bromobutyl)-3-(phenylmethyl)-2-pyrrolidinone as the alkylating
agent, potassium carbonate as base and heating at 50.degree. C. for
18 h. Yield 86%.
[1020] LC/MS: m/z 526 [MH].sup.+
c) 1-(4-bromobutyl)-3-(phenylmethyl)-2-pyrrolidinone
##STR00552##
[1022] To a solution of 3-(phenylmethyl)-2-pyrrolidinone (0.23 g,
1.3 mmol) and 1,4-dibromobutane (0.57 g, 4.2 mmol) in DMF (5 ml)
was added sodium t-butoxide (0.151 g, 1.6 mmol) and the solution
stirred for 18 h. The solution was concentrated and the residues
chromatographed over silica (20 g SPE, eluting first with
cyclohexane then with DCM) to provide the title compound as a
colourless oil containing a trace of DMF (0.25 g, 61%).
LC/MS: m/z 311 [MH].sup.+
Example 417
8-Chloro-1-{4-[2-oxo-1-(phenylmethyl)-3-pyrrolidinyl]butyl}-3-pentyl-3,7-d-
ihydro-1H-purine-2,6-dione
a)
8-Chloro-1-{4-[2-oxo-1-(phenylmethyl)-3-pyrrolidinyl]butyl}-3-pentyl-3,-
7-dihydro-1H-purine-2,6-dione
##STR00553##
[1024] To a solution of
8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(0.086 g, 0.29 mmol) and
3-(4-bromobutyl)-1-(phenylmethyl)-2-pyrrolidinone (0.17 g, 0.55
mmol, 1:1 mixture with 2-(phenylmethyl)-2-azaspiro[4.4]nonan-1-one)
in THF (5 ml) was added potassium carbonate (0.08 g, 0.58 mmol) and
the mixture heated and stirred at 50.degree. C. for 18 h. The
solution was allowed to cool then degassed (sequential evacuation
followed by addition of nitrogen.times.3) and Pd(PPh.sub.3).sub.4
(0.09 g, 0.077 mmol) followed by morpholine (0.2 ml, 2.2 mmol)
added and the solution stirred at ambient temperature for 18 h. The
solution was separated between ethyl acetate and dil HCl and the
organics washed with brine, dried and concentrated. Purification of
the residues using an aminopropyl SPE (5 g) eluting first with MeOH
then 5% AcOH/MeOH yielded the title compound as a yellow oil which
crystallised on standing under ether (0.031 g, 22%).
[1025] LC/MS: m/z 486 [MH].sup.+
b) 3-(4-Bromobutyl)-1-(phenylmethyl)-2-pyrrolidinone
##STR00554##
[1027] To a solution of 1-(phenylmethyl)-2-pyrrolidinone (0.47 g,
2.7 mmol) in THF (10 ml) at -78.degree. C. was added lithium
hexamethyldisilylazine (2.8 ml, 2.7 mmol, 1M solution) over 5 min.
After 15 min 1,4-dibromobutane (0.32 ml, 2.7 mmol) was added and
the solution allowed to attain ambient temperature over 2 h then
stirred for a further 18 h. The solution was separated between
ethyl acetate and water and the organics isolated, dried and
concentrated. Chromatography over silica (20 g SPE) eluting with
cyclohexane then DCM and finally ether provided a clear oil which
was a 1:1 mixture of the title compound and
2-(phenylmethyl)-2-azaspiro[4.4]nonan-1-one (0.17 g). This was used
in the next step without further purification.
[1028] LC/MS: m/z 310, 312 [MH].sup.+
Example 418
8-Chloro-1-(5-{5-[(3,4-dichlorophenyl)methyl]-2H-tetrazol-2-yl}pentyl)-3-p-
entyl-3,7-dihydro-1H-purine-2,6-dione
##STR00555##
[1030] To a solution of
8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(0.18 g, 0.61 mmol) in THF (5 ml) was added
5-{5-[(3,4-dichlorophenyl)methyl]-2H-tetrazol-2-yl}-1-pentanol
(0.191 g, 0.61 mmol; prepared in similar fashion to Example 35),
triphenylphosphine (0.36 g, 1.3 mmol) and finally
dibenzylazodicarboxylate (0.40 g, 1.3 mmol). The solution was
stirred for 18 h after which Pd(PPh.sub.3).sub.4 (0.16 g, 0.137
mmol) followed by morpholine (0.75 ml, 8.3 mmol) was added and the
solution stirred at ambient temperature for 6 h. The solution was
loaded onto an aminopropyl SPE (5 g) and eluted with MeOH then 5%
AcOH/MeOH to yield the title compound containing minor impurities.
Further chromatography (silica SPE, 20 g) eluting with ether
yielded the title compound as a white solid (0.061 g, 18%).
LC/MS: m/z 553 [MH].sup.+
Example 419
8-Chloro-3-pentyl-1-{5-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]pentyl}-3,7--
dihydro-1H-purine-2,6-dione
##STR00556##
[1032] To a solution of
8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(0.093 g, 0.3 mmol) in THF (5 ml) was added
5-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]-1-pentanol (0.077 g, 0.3
mmol; prepared in similar fashion to Example 87b),
triphenylphosphine (0.17 g, 0.6 mmol) and finally
dibenzylazodicarboxylate (0.20 g, 0.6 mmol). The solution was
stirred for 18 h, degassed, after which Pd(PPh.sub.3).sub.4 (0.08
g, 0.07 mmol) followed by morpholine (0.35 ml, 3.9 mmol) was added
and the solution stirred at ambient temperature for 6 h. The
solution was loaded onto an aminopropyl SPE (5 g) and eluted with
MeOH then 5% AcOH/MeOH to yield the title compound as a cream solid
(0.051 g. 34%).
[1033] LC/MS: m/z 485 [MH].sup.+
Example 420
8-Chloro-1-{3-[5-(4-chlorophenyl)-1H-pyrazol-3-yl]propyl}-3-pentyl-3,7-dih-
ydro-1H-purine-2,6-dione
##STR00557##
[1035] Prepared as with
8-chloro-1-(5-{5-[(3,4-dichlorophenyl)methyl]-2H-tetrazol-2-yl}pentyl)-3--
pentyl-3,7-dihydro-1H-purine-2,6-dione using
3-[5-(4-chlorophenyl)-1H-pyrazol-3-yl]-1-propanol. The final
product material was washed with ether to yield the title compound
as a cream solid (30%).
LC/MS: m/z 475 [MH].sup.+
Example 421
3-Butyl-8-chloro-1-{4-[5-(1-methyl-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol--
3-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione
##STR00558##
[1037] A solution of the 1-methyl-1H-1,2,3-triazole-4-carboxylic
acid (18 mg, 0.14 mmol) in DMF (0.5 ml) was treated with CDI (23
mg, 0.14 mmol) at rt for 1 h. A solution of
(1Z)-5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hy-
droxypentanimidamide (50 mg, 0.14 mmol) in DMSO (0.4 ml) was added
to the mixture then heated to 100.degree. C. for 18 h. The reaction
mixture was purified by MDAP to give the title compound as a white
solid (18 mg).
[1038] LC/MS: m/z 448 [MH].sup.+, RT 2.86 min.
[1039] The following compounds (Table 28) were prepared using a
method analogous to that for Example 421, using the appropriate
carboxylic acid.
TABLE-US-00030 TABLE 28 Exam- Yield ple Structure Name (mg) LC/MS
422 ##STR00559## 3-butyl-8-chloro-1- {4-[5-(1H-imidazol-2-
yl)-1,2,4-oxadiazol- 3-yl]butyl}-3,7- dihydro-1H-purine- 2,6-dione
16 m/z 433 [MH].sup.+ RT 2.79 min 423 ##STR00560##
3-butyl-8-chloro-1- (4-{5-[4- (trifluoromethyl)-1H-
pyrazol-5-yl]-1,2,4- oxadiazol-3-yl}butyl)- 3,7-dihydro-1H-
purine-2,6-dione 19 m/z 501 [MH].sup.+ RT 3.28 min 424 ##STR00561##
3-butyl-8-chloro-1- {4-[5-(2-chloro-3- thienyl)-1,2,4-
oxadiazol-3-yl]butyl)- 3,7-dihydro-1H- purine-2,6-dione 26 m/z 483
[MH].sup.+ RT 3.59 min 425 ##STR00562## 3-butyl-8-chloro-1-
{4-[5-(3-methyl-5- isoxazolyl)-1,2,4- oxadiazol-3-yl]butyl}-
3,7-dihydro-1H- purine-2,6-dione 25 m/z 448 [MH].sup.+ RT 3.21 min
426 ##STR00563## 3-butyl-8-chloro-1- {4-[5-(1-methyl-1H-
imidazol-4-yl)-1,2,4- oxadiazol-3-yl]butyl}- 3,7-dihydro-1H-
purine-2,6-dione 16 m/z 447 [MH].sup.+ RT 2.74 min 427 ##STR00564##
3-butyl-8-chloro-1- {4-(5-(1-methyl-1H- imidazol-2-yl)-1,2,4-
oxadiazol-3-yl]butyl}- 3,7-dihydro-1H- purine-2,6-dione 9 m/z 447
[MH].sup.+ RT 2.91 min 428 ##STR00565## 3-butyl-8-chloro-1-
{4-[5-(1H-1,2,4- triazol-3-yl)-1,2,4- oxadiazol-3-yl]butyl}-
3,7-dihydro-1H- purine-2,6-dione 10 m/z 434 [MH].sup.+ RT 2.73 min
429 ##STR00566## 3-butyl-8-chloro-1- {4-[5-(5-isothiazolyl)-
1,2,4-oxadiazol-3- yl]butyl}-3,7-dihydro- 1H-purine-2,6-dione 17
m/z 450 [MH].sup.+ RT 3.34 min 430 ##STR00567## 3-butyl-8-chloro-1-
{4-[5-(2-furanyl)- 1,2,4-oxadiazol-3- yl]butyl}-3,7-dihydro-
1H-purine-2,6-dione 26 m/z 433 [MH].sup.+ RT 3.27 min 431
##STR00568## 3-butyl-8-chloro-1- {4-[5-(5-methyl-2- thienyl)-1,2,4-
oxadiazol-3-yl]butyl}- 3,7-dihydro-1H- purine-2,6-dione 29 m/z 463
[MH].sup.+ RT 3.61 min 432 ##STR00569## 3-butyl-8-chloro-1-
{4-[5-(3-chloro-4- methyl-2-thienyl)- 1,2,4-oxadiazol-3-
yl]butyl}-3,7-dihydro- 1H-purine-2,6-dione 30 m/z 497 [MH].sup.+ RT
3.76 min 433 ##STR00570## 3-butyl-8-chloro-1- {4-[5-(4-methyl-1,3-
oxazol-5-yl)-1,2,4- oxadiazol-3-yl]butyl}- 3,7-dihydro-1H-
purine-2,6-dione 25 m/z 448 [MH].sup.+ RT 3.13 min 434 ##STR00571##
3-butyl-8-chloro-1- {4-[5-(3-isoxazolyl)- 1,2,4-oxadiazol-3-
yl]butyl}-3,7-dihydro- 1H-purine-2,6-dione 23 m/z 434 [MH].sup.+ RT
3.20 min 435 ##STR00572## 1-{4-[5-(5-acetyl-2- thienyl)-1,2,4-
oxadiazol-3-yl]butyl}- 3-butyl-8-chloro-3,7- dihydro-1H-purine-
2,6-dione 28 m/z 491 [MH].sup.+ RT 3.43 min 436 ##STR00573##
3-butyl-8-chloro-1- {4-[5-(5-chloro-2- furanyl)-1,2,4-
oxadiazol-3-yl]butyl}- 3,7-dihydro-1H- purine-2,6-dione 27 m/z 467
[MH].sup.+ RT 3.51 min 437 ##STR00574## 3-butyl-8-chloro-1-
(4-{5-[5- (trifluoromethyl)-2- furanyl]-1,2,4-
oxadiazol-3-yl}butyl)- 3,7-dihydro-1H- purine-2,6-dione 27 m/z 501
[MH].sup.+ RT 3.61 min 438 ##STR00575## 3-butyl-8-chloro-1-
{4-[5-(3-methyl-2- furanyl)-1,2,4- oxadiazol-3-yl]butyl}-
3,7-dihydro-1H- purine-2,6-dione 27 m/z 447 [MH].sup.+ RT 3.43 min
439 ##STR00576## 3-butyl-8-chloro-1- {4-[5-(1-methyl-1H-
pyrazol-3-yl)-1,2,4- oxadiazol-3-yl]butyl}- 3,7-dihydro-1H-
purine-2,6-dione 25 m/z 447 [MH].sup.+ RT 3.02 min 440 ##STR00577##
3-butyl-8-chloro-1- {4-[5-(1-methyl-1H- pyrazol-4-yl)-1,2,4-
oxadiazol-3-yl]butyl}- 3,7-dihydro-1H- purine-2,6-dione 8 m/z 447
[MH].sup.+ RT 2.99 min 441 ##STR00578## 3-butyl-8-chloro-1-
{4-[5-(3-thienyl)- 1,2,4-oxadiazol-3- yl]butyl}-3,7-dihydro-
1H-purine-2,6-dione 19 m/z 449 [MH].sup.+ RT 3.43 min 442
##STR00579## 3-butyl-8-chloro-1- {4-[5-(5-methyl-1H-
pyrazol-3-yl)-1,2,4- oxadiazol-3-yl]butyl}- 3,7-dihydro-1H-
purine-2,6-dione 26 m/z 447 [MH].sup.+ RT 3.03 min 443 ##STR00580##
3-butyl-8-chloro-1- {4-[5-(3-methyl-2- thienyl)-1,2,4-
oxadiazol-3-yl]butyl}- 3,7-dihydro-1H- purine-2,6-dione 27 m/z 463
[MH].sup.+ RT 3.62 min 444 ##STR00581## 3-butyl-8-chloro-1-
{4-[5-(1H-pyrrol-2- yl)-1,2,4-oxadiazol- 3-yl]butyl}-3,7-
dihydro-1H-purine- 2,6-dione 13 m/z 432 [MH].sup.+ RT 3.26 min 445
##STR00582## 3-butyl-8-chloro-1- {4-[5-(2-methyl-3- thienyl)-1,2,4-
oxadiazol-3-yl]butyl}- 3,7-dihydro-1H- purine-2,6-dione 18 m/z 463
[MH].sup.+ RT 3.64 min 446 ##STR00583## 3-butyl-8-chloro-1-
{4-[5-(4-methyl-1,3- thiazol-5-yl)-1,2,4- oxadiazol-3-yl]butyl}-
3,7-dihydro-1H- purine-2,6-dione 24 m/z 464 [MH].sup.+ RT 3.26 min
447 ##STR00584## 3-butyl-8-chloro-1- {4-[5-(1H-pyrazol-3-
yl)-1,2,4-oxadiazol- 3-yl]butyl}-3,7- dihydro-1H-purine- 2,6-dione
20 m/z 433 [MH].sup.+ RT 3.00 min 448 ##STR00585##
3-butyl-8-chloro-1- {4-[5-(3-ethyl-5- isoxazolyl)-1,2,4-
oxadiazol-3-yl]butyl}- 3,7-dihydro-1H- purine-2,6-dione 20 m/z 462
[MH].sup.+ RT 3.43 min 449 ##STR00586## 3-butyl-8-chloro-1-
{4-[5-(5-ethyl-3- isoxazolyl)-1,2,4- oxadiazol-3-yl]butyl}-
3,7-dihydro-1H- purine-2,6-dione 23 m/z 462 [MH].sup.+ RT 3.46 min
450 ##STR00587## 3-butyl-8-chloro-1- {4-[5-(1,3-thiazol-5-
yl)-1,2,4-oxadiazol- 3-yl]butyl}-3,7- dihydro-1H-purine- 2,6-dione
20 m/z 450 [MH].sup.+ RT 3.13 min 451 ##STR00588##
3-butyl-8-chloro-1- {4-[5-(1H-indazol-3- yl)-1,2,4-oxadiazol-
3-yl]butyl}-3,7- dihydro-1H-purine- 2,6-dione 24 m/z 483 [MH].sup.+
RT 3.50 min 452 ##STR00589## 1-{4-[5-(1- benzofuran-2-yl)-
1,2,4-oxadiazol-3- yl]butyl}-3-butyl-8- chloro-3,7-dihydro-
1H-purine-2,6-dione 6 m/z 483 [MH].sup.+ RT 3.72 min 453
##STR00590## 3-butyl-8-chloro-1- {4-[5-(5-methyl-3-
isoxazolyl)-1,2,4- oxadiazol-3-yl]butyl}- 3,7-dihydro-1H-
purine-2,6-dione 13 m/z 448 [MH].sup.+ RT 3.30 min 454 ##STR00591##
3-butyl-8-chloro-1- {4-[5-(2-methyl-1,3- thiazol-4-yl)-1,2,4-
oxadiazol-3-yl]butyl}- 3,7-dihydro-1H- purine-2,6-dione 20 m/z 464
[MH].sup.+ RT 3.14 min 455 ##STR00592## 3-butyl-8-chloro-1-
{4-[5-(4-methyl- 1,2,3-thiadiazol-5- yl)-1,2,4-oxadiazol-
3-yl]butyl)-3,7- dihydro-1H-purine- 2,6-dione 14 m/z 465 [MH].sup.+
RT 3.40 min 456 ##STR00593## 3-butyl-8-chloro-1- {4-[5-(3-methyl-2-
thioxo-2,3-dihydro- 1H-imidazol-4-yl)- 1,2,4-oxadiazol-3-
yl]butyl}-3,7-dihydro- 1H-purine-2,6-dione 16 m/z 479 [MH].sup.+ RT
3.08 min 457 ##STR00594## 3-butyl-8-chloro-1- {5-[5-(1,2,5-
thiadiazol-3-yl)- 1,2,4-oxadiazol-3- yl]butyl)-3,7-dihydro-
1H-purine-2,6-dione 24 m/z 451 [MH].sup.+ RT 3.27 min 458
##STR00595## 3-butyl-8-chloro-1- {4-[5-(3-furanyl)-
1,2,4-oxadiazol-3- yl]butyl}-3,7-dihydro- 1H-purine-2,6-dione 21
m/z 433 [MH].sup.+ RT 3.29 min 459 ##STR00596## 3-butyl-8-chloro-1-
{4-[5-(1-methyl-1H- pyrazol-5-yl)-1,2,4- oxadiazol-3-yl]butyl}-
3,7-dihydro-1H- purine-2,6-dione 23 m/z 447 [MH].sup.+ RT 3.22 min
460 ##STR00597## 3-butyl-8-chloro-1- {4-[5-(1,3-thiazol-4-
yl)-1,2,4-oxadiazol- 3-yl]butyl}-3,7- dihydro-1H-purine- 2,6-dione
20 m/z 450 [MH].sup.+ RT 3.06 min 461 ##STR00598##
N-(4-{3-[4-(3-butyl-8- chloro-2,6-dioxo- 2,3,6,7-tetrahydro-
1H-purin-1-yl)butyl]- 1,2,4-oxadiazol-5- yl}-3-
chlorophenyl)acetamide 23 m/z 534 [MH].sup.+ RT 3.44 min 462
##STR00599## N-(4-{3-(4-(3-butyl-8- chloro-2,6-dioxo-
2,3,6,7-tetrahydro- 1H-purin-1-yl)butyl]- 1,2,4-oxadiazol-5-
yl}phenyl)acetamide 16 m/z 500 [MH].sup.+ RT 3.23 min 463
##STR00600## 3-butyl-8-chloro-1- {4-[5-(2-thienyl)-
1,2,4-oxadiazol-3- yl]butyl}-3,7-dihydro- 1H-purine-2,6-dione 27
m/z 449 [MH].sup.+ RT 3.45 min 464 ##STR00601## 3-butyl-8-chloro-1-
{4-[5-(1-methyl-1H- pyrrol-2-yl)-1,2,4- oxadiazol-3-yl]butyl}-
3,7-dihydro-1H- purine-2,6-dione 15 m/z 446 [MH].sup.+ RT 3.45
min
Example 465
1-{4-[1,3-Benzoxazol-2-yl(methyl)amino]butyl}-8-chloro-3-ethyl-3,7-dihydro-
-1H-purine-2,6-dione
##STR00602##
[1041] A solution of 2-chloro-1,3-benzoxazole (0.46 g, 3 mmol) in
THF (20 ml) was treated with 1-methylpyrrolidine (0.26 g, 3 mmol)
and the reaction mixture heated at reflux for 6 h, then cooled and
evaporated to dryness. Purification by flash chromatography [Isco
Companion, 12 g Redisep cartridge, gradient elution from
cyclohexane to cyclohexane/diethyl ether (3:2)] revealed 0.52 g
(73% yield) of N-(4-chlorobutyl)-N-methyl-1,3-benzoxazol-2-amine as
a colourless oil. LC/MS: m/z 239 [MH].sup.+, RT 3.12 min.
[1042] A solution of
8-chloro-3-ethyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(0.112 g, 0.44 mmol) in DMF (10 ml) was treated with potassium
carbonate (0.08 g, 0.6 mmol) and
N-(4-chlorobutyl)-N-methyl-1,3-benzoxazol-2-amine (0.12 g, 0.5
mmol). The reaction mixture was heated at 75.degree. C. for 18 h
and then cooled to ambient temperature. The mixture was degassed by
the repeated application of vacuum followed by backfilling with
nitrogen gas and then treated with
tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.026 mmol) and
morpholine (0.5 ml, 5.7 mmol). Stirred for 4 h under a nitrogen
atmosphere at ambient temperature after which time the mixture was
evaporated to dryness and the residue partitioned between
chloroform (40 ml) and saturated aqueous ammonium chloride (40 ml).
The organic phase was evaporated to dryness and the residue
dissolved in methanol (5 ml) and added to a 5 g aminopropyl SPE
cartridge which was subsequently washed with methanol and the
product eluted with a 5% solution of acetic acid in methanol.
Combined product-containing fractions were evaporated to dryness
and the product purified by MDAP to give the title compound as a
white solid (0.043 g, 23%).
[1043] LC/MS: m/z 417 [MH].sup.+, RT 2.91 min.
[1044] The following compounds (Table 29) were prepared by a method
analogous to that for Example 465.
TABLE-US-00031 TABLE 29 Yield Example Structure Precursor (mg)
LC/MS 466 ##STR00603## 8-chloro-7-(2- propen-1-yl)-3-
propyl-3,7-dihydro- 1H-purine-2,6- dione 47 m/z 431 [MH].sup.+ RT
3.09 min 1-{4-[1,3-benzoxazol-2- yl(methyl)amino]butyl}-8-
chloro-3-propyl-3,7-dihydro- 1H-purine-2,6-dione 467 ##STR00604##
3-butyl-8-chloro-7- (2-propen-1-yl)- 3,7-dihydro-1H-
purine-2,6-dione 61 m/z 445 [MH].sup.+ RT 3.28 min
1-{4-[1,3-benzoxazol-2- yl(methyl)amino]butyl}-3-
butyl-8-chloro-3,7-dihydro- 1H-purine-2,6-dione
Example 468
3-Butyl-8-chloro-1-[5-(1,3-dioxo-1,3-dihydro-2H-Isoindol-2-yl)
pentyl]-3,7-dihydro-1H-purine-2,6-dione
##STR00605##
[1046] A solution of
3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(0.5 g, 1.8 mmol) in DMF (20 ml) was treated with potassium
carbonate (0.3 g, 2.1 mmol) and 1,5-dibromopentane (1.2 ml, 8.9
mmol) and then heated at 50.degree. C. for 2 h. The mixture was
cooled and evaporated to dryness. The residue was partitioned
between ethyl acetate (30 ml) and saturated aqueous sodium
bicarbonate (30 ml). The aqueous phase was extracted with a further
ethyl acetate (30 ml) and the combined organics dried over
magnesium sulfate, filtered and evaporated to dryness. The product
was purified by flash chromatography [Isco Companion, 40 g Redisep
cartridge, gradient elution from cyclohexane to cyclohexane/ethyl
acetate (1:1)] to reveal 0.663 g (87%) of
1-(5-bromopentyl)-3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purin-
e-2,6-dione as a colourless oil. LC/MS: m/z 431/433 [MH].sup.+, RT
3.76 min.
[1047] To a solution of
1-(5-bromopentyl)-3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purin-
e-2,6-dione (0.642 g, 1.5 mmol) in DMF (10 ml) was added potassium
phthalimide (0.303 g, 1.6 mmol) and the mixture heated at
50.degree. C. for 2 h then cooled. The mixture was degassed by the
repeated application of vacuum followed by backfilling with
nitrogen gas and then treated with
tetrakis(triphenylphosphine)palladium(0) (0.173 g, 0.15 mmol) and
morpholine (1.3 ml, 15 mmol). The mixture was allowed to stand at
ambient temperature under a blanket of nitrogen for 18 h after
which time the mixture was evaporated and the residue partitioned
between chloroform (30 ml) and saturated aqueous ammonium chloride
(30 ml). The aqueous phase was extracted with a further chloroform
(30 ml) and the combined organics dried over magnesium sulfate,
filtered and evaporated. The residue was dissolved in methanol (5
ml) and added to a 10 g aminopropyl SPE cartridge which was
subsequently washed with methanol and the product eluted with a 5%
solution of acetic acid in methanol. Product-containing fractions
were evaporated and then purification by MDAP to give
N-[5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentyl]-
-2-(4-morpholinylcarbonyl)benzamide as a white solid (0.137 g,
LC/MS: m/z 545 [MH].sup.+, RT 2.77 min) and the title compound as a
white solid (0.239 g, 35%).
[1048] LC/MS: m/z 458 [MH].sup.+, RT 3.33 min.
Example 469
8-Chloro-1-{4-[3-(2,4-difluorophenyl)-1,2,4-oxadiazol-5-yl]butyl}-3-ethyl--
3,7-dihydro-1H-purine-2,6-dione
a)
8-Chloro-1-{4-[3-(2,4-difluorophenyl)-1,2,4-oxadiazol-5-yl]butyl}-3-eth-
yl-3,7-dihydro-1H-purine-2,6-dione
##STR00606##
[1050] A solution of
5-(8-chloro-3-ethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic
acid (0.05 g, 0.16 mmol) in DMSO (1 ml) was treated with CDI (0.029
g, 0.18 mmol) and the mixture stirred at room temperature for 1 h.
Subsequently, the mixture was treated with
2,4-difluorobenzamidoxime (0.03 g, 0.18 mmol) and then heated to
120.degree. C. for 30 min. The product was purified from the crude
mixture using MDAP. Product-containing fractions were evaporated
using a stream of nitrogen and the resulting colourless gum
triturated in ether and dried to reveal the title compound as a
white solid (50 mg, 70%).
[1051] LC/MS: m/z 451 [MH].sup.+, RT 2.23 min.
b)
5-(8-chloro-3-ethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoi-
c acid
##STR00607##
[1053] A solution of ethyl
5-(8-chloro-3-ethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate
(2.3 g, 6.7 mmol) in methanol (75 ml) was treated with water (3 ml)
and lithium hydroxide (0.481 g, 20.1 mmol) and the mixture stirred
at 40.degree. C. for 17 h. The mixture was evaporated to dryness
and the residue treated with 50 ml of ethyl acetate and 50 ml of
water. The 2 phases were separated and the aqueous phase adjusted
to pH5 using 2M aqueous hydrochloric acid. The precipitated product
was filtered off and dried to yield
5-(8-chloro-3-ethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic
acid as a white solid (1.99 g, 95%).
[1054] LC/MS: m/z 315 [MH].sup.+, RT 2.34 min.
c) Ethyl
5-(8-chloro-3-ethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pe-
ntanoate
##STR00608##
[1056] A solution of
8-chloro-7-(2-propen-1-yl)-3-ethyl-3,7-dihydro-1H-purine-2,6-dione
(3 g, 11.8 mmol) in DMF (40 ml) was treated with potassium
carbonate (1.9 g, 14.1 mmol) and ethyl 5-bromopentanoate (2.24 ml,
14.1 mmol) and the mixture heated in a nitrogen atmosphere at
70.degree. C. for 5 h and then cooled. The mixture was degassed by
the repeated application of vacuum followed by backfilling with
nitrogen gas and then treated with
tetrakis(triphenylphosphine)palladium(0) (1.36 g, 1.1 mmol) and
morpholine (10.3 ml, 118 mmol). The mixture was stirred in a
nitrogen atmosphere for 4 h and then evaporated to dryness. The
residue was partitioned between 100 ml of ethyl acetate and 100 ml
of water. The aqueous phase was re-extracted with 100 ml of ethyl
acetate and the combined organics dried over magnesium sulfate,
filtered and evaporated. The residue was triturated in diethyl
ether, filtered and dried to reveal ethyl
5-(8-chloro-3-ethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pent-
anoate compound as a white solid (2.3 g, 57%).
[1057] LC/MS: m/z 343 [MH].sup.+, RT 2.73 min.
[1058] The following compounds (Table 30) were prepared by a method
analogous to that for Example 469.
TABLE-US-00032 TABLE 30 Yield Example Structure Precursor (mg)
LC/MS 470 ##STR00609## 5-(8-chloro-3- ethyl-2,6-dioxo-
2,3,6,7-tetrahydro- 1H-purin-1- yl)pentanoic acid 33 m/z 449
[MH].sup.+ RT 3.27 min 8-chloro-1-{4-[3-(2- chlorophenyl)-1,2,4-
oxadiazol-5-yl]butyl}-3-ethyl- 3,7-dihydro-1H-purine-2,6- dione 471
##STR00610## 5-(8-chloro-3- ethyl-2,6-dioxo- 2,3,6,7-tetrahydro-
1H-purin-1- yl)pentanoic acid 32 m/z 415 [MH].sup.+ RT 3.22 min
8-chloro-1-[4-(3-phenyl- 1,2,4-oxadiazol-5-yl)butyl]-3-
ethyl-3,7-dihydro-1H-purine- 2,6-dione 472 ##STR00611##
5-(8-chloro-3- ethyl-2,6-dioxo- 2,3,6,7-tetrahydro- 1H-purin-1-
yl)pentanoic acid 31 m/z 433 [MH].sup.+ RT 3.26 min
8-chloro-3-ethyl-1-{4-[3-(4- fluorophenyl)-1,2,4-
oxadiazol-5-yl]butyl}-3,7- dihydro-1H-purine-2,6-dione 473
##STR00612## 5-(8-chloro-3- ethyl-2,6-dioxo- 2,3,6,7-tetrahydro-
1H-purin-1- yl)pentanoic acid 2 m/z 417 [MH].sup.+ RT 2.54 min
8-chloro-3-ethyl-1-{4-[3-(2- pyrazinyl)-1,2,4-oxadiazol-5-
yl]butyl}-3,7-dihydro-1H- purine-2,6-dione 474 ##STR00613##
5-(8-chloro-3- ethyl-2,6-dioxo- 2,3,6,7-tetrahydro- 1H-purin-1-
yl)pentanoic acid 38 [MH].sup.+ RT 3.12 min
8-chloro-3-ethyl-1-{4-[3-(2- fluorophenyl)-1,2,4-
oxadiazol-5-yl]butyl}-3,7- dihydro-1H-purine-2,6-dione 475
##STR00614## 5-(8-chloro-3- propyl-2,6-dioxo- 2,3,6,7-tetrahydro-
1H-purin-1- yl)pentanoic acid 29 m/z 447 [MH].sup.+ RT 3.28 min
8-chloro-1-{4-[3-(2- fluorophenyl)-1,2,4- oxadiazol-5-yl]butyl}-3-
propyl-3,7-dihydro-1H- purine-2,6-dione 476 ##STR00615##
5-(8-chloro-3- propyl-2,6-dioxo- 2,3,6,7-tetrahydro- 1H-purin-1-
yl)pentanoic acid 11 m/z 429 [MH].sup.+ RT 3.35 min
8-chloro-1-[4-(3-phenyl- 1,2,4-oxadiazol-5-yl)butyl]-3-
propyl-3,7-dihydro-1H- purine-2,6-dione 477 ##STR00616##
5-(8-chloro-3- propyl-2,6-dioxo- 2,3,6,7-tetrahydro- 1H-purin-1-
yl)pentanoic acid 32 m/z 465 [MH].sup.+ RT 3.40 min
8-chloro-1-{4-[3-(2,4- difluorophenyl)-1,2,4-
oxadiazol-5-yl]butyl}-3- propyl-3,7-dihydro-1H- purine-2,6-dione
478 ##STR00617## 5-(8-chloro-3- propyl-2,6-dioxo-
2,3,6,7-tetrahydro- 1H-purin-1- yl)pentanoic acid 25 m/z 463
[MH].sup.+ RT 3.40 min 8-chloro-1-{4-[3-(2- chlorophenyl)-1,2,4-
oxadiazol-5-yl]butyl}-3- propyl-3,7-dihydro-1H- purine-2,6-dione
479 ##STR00618## 5-(8-chloro-3- propyl-2,6-dioxo-
2,3,6,7-tetrahydro- 1H-purin-1- yl)pentanoic acid 26 m/z 447
[MH].sup.+ RT 3.44 min 8-chloro-1-{4-[3-(4- fluorophenyl)-1,2,4-
oxadiazol-5-yl]butyl}-3- propyl-3,7-dihydro-1H- purine-2,6-dione
480 ##STR00619## 5-(8-chloro-3- propyl-2,6-dioxo-
2,3,6,7-tetrahydro- 1H-purin-1- yl)pentanoic acid 25 m/z 431
[MH].sup.+ RT 3.09 min 8-chloro-3-propyl-1-{4-[3-(2-
pyrazinyl)-1,2,4-oxadiazol-5- yl]butyl}-3,7-dihydro-1H-
purine-2,6-dione
[1059] The following compounds (Table 31) were prepared using a
method analogous to that for Example 158, using the appropriate
acid.
TABLE-US-00033 TABLE 31 Yield Example Structure Name (mg) LC/MS 481
##STR00620## 8-chloro-3-pentyl-1-{4- [5-(4-pyridinyl)-1,2,4-
oxadiazol-3-yl]butyl}- 3,7-dihydro-1H-purine- 2,6-dione 8.0 m/z 458
[MH].sup.+ RT 3.25 min 482 ##STR00621## 8-chloro-1-{4-[5-(3-
fluorophenyl)-1,2,4- oxadiazol-3-yl]butyl}-3-
pentyl-3,7-dihydro-1H- purine-2,6-dione 9.1 m/z 475 [MH].sup.+ RT
3.73 min 483 ##STR00622## 8-chloro-1-{4-[5-(4- fluorophenyl)-1,2,4-
oxadiazol-3-yl]butyl}-3- pentyl-3,7-dihydro-1H- purine-2,6-dione
16.1 m/z 475 [MH].sup.+ RT 3.69 min 484 ##STR00623##
8-chloro-1-{4-[5-(2- methylphenyl)-1,2,4- oxadiazol-3-yl]butyl}-3-
pentyl-3,7-dihydro-1H- purine-2,6-dione 22.9 m/z 471 [MH].sup.+ RT
3.82 min 485 ##STR00624## 8-chloro-1-{4-[5-(3- methylphenyl)-1,2,4-
oxadiazol-3-yl]butyl}-3- pentyl-3,7-dihydro-1H- purine-2,6-dione
18.0 m/z 471 [MH].sup.+ RT 3.81 min 486 ##STR00625##
8-chloro-1-{4-[5-(4- methylphenyl)-1,2,4- oxadiazol-3-yl]butyl}-3-
pentyl-3,7-dihydro-1H- purine-2,6-dione 25.0 m/z 471 [MH].sup.+ RT
3.80 min 487 ##STR00626## 8-chloro-1-{4-[5-(4- chlorophenyl)-1,2,4-
oxadiazol-3-yl]butyl}-3- pentyl-3,7-dihydro-1H- purine-2,6-dione
16.6 m/z 491 [MH].sup.+ RT 3.89 min 488 ##STR00627##
8-chloro-1-{4-[5-(3- chlorophenyl)-1,2,4- oxadiazol-3-yl]butyl}-3-
pentyl-3,7-dihydro-1H- purine-2,6-dione 12.8 m/z 491 [MH].sup.+ RT
3.91 min 489 ##STR00628## 8-chloro-1-(4-{5-[3- (methyloxy)phenyl]-
1,2,4-oxadiazol-3- yl}butyl)-3-pentyl-3,7- dihydro-1H-purine-2,6-
dione 23.0 m/z 487 [MH].sup.+ RT 3.71 min 490 ##STR00629##
8-chloro-1-(4-{5-[4- (methyloxy)phenyl]- 1,2,4-oxadiazol-3-
yl}butyl)-3-pentyl-3,7- dihydro-1H-purine-2,6- dione 15.8 m/z 487
[MH].sup.+ RT 3.67 min 491 ##STR00630## 8-chloro-1-[4-(5-
cyclohexyl-1,2,4- oxadiazol-3-yl)butyl]-3- pentyl-3,7-dihydro-1H-
purine-2,6-dione 16.1 m/z 468 [MH].sup.+ RT 3.73 min 492
##STR00631## 8-chloro-1-[4-(5- cyclopentyl-1,2,4-
oxadiazol-3-yl)butyl]-3- pentyl-3,7-dihydro-1H- purine-2,6-dione
11.7 m/z 449 [MH].sup.+ RT 3.59 min 493 ##STR00632##
8-chloro-1-{4-[5-(1,1- dimethylethyl)-1,2,4-
oxadiazol-3-yl]butyl}-3- pentyl-3,7-dihydro-1H- purine-2.6-dione
19.8 m/z 437 [MH].sup.+ RT 3.52 min 494 ##STR00633##
8-chloro-3-pentyl-1-{4- [5-(phenylmethyl)- 1,2,4-oxadiazol-3-
yl]butyl}-3,7-dihydro- 1H-purine-2,6-dione 21.0 m/z 471 [MH].sup.+
RT 3.55 min 495 ##STR00634## 8-chloro-3-pentyl-1-(4- {5-[(2,4,6-
trifluorophenyl)methyl]- 1,2,4-oxadiazol-3- yl}butyl)-3,7-dihydro-
1H-purine-2.6-dione 29.3 m/z 525 [MH].sup.+ RT 3.62 min 496
##STR00635## 8-chloro-3-pentyl-1-{4- [5-(2-phenylethyl)-
1,2,4-oxadiazol-3- yl]butyl}-3,7-dihydro- 1H-purine-2,6-dione 18.4
m/z 485 [MH].sup.+ RT 3.64 min 497 ##STR00636##
8-chloro-3-pentyl-1-{4- [5-(3-pyridinyl)-1,2,4-
oxadiazol-3-yl]butyl}- 3,7-dihydro-1H-purine- 2,6-dione 8.2 m/z 458
[MH].sup.+ RT 3.23 min
[1060] The following compounds (Table 32) were prepared using a
method analogous to that for Example 36, using the appropriate
tetrazole and
3-[3-alkyl-8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-pur-
in-1-yl]propyl methanesulfonate. MDAP was employed to further
purify those compounds insufficiently pure following normal phase
chromatography.
TABLE-US-00034 TABLE 32 Yield Example Structure Name (mg) LC/MS 498
##STR00637## 3-butyl-8-chloro-1- (3-{5-[(4- methylphenyl)methyl]-
2H-tetrazol-2- yl}propyl)-3,7- dihydro-1H-purine- 2,6-dione 35.1
m/z 457 [MH].sup.+ RT 3.40 min 499 ##STR00638## 3-butyl-8-chloro-1-
[3-(5-{(4- (trifluoromethyl) phenyl]methyl}-2H- tetrazol-2-
yl)propyl]-3,7- dihydro-1H-purine- 2,6-dione 43.6 m/z 511
[MH].sup.+ RT 3.52 min 500 ##STR00639## 3-butyl-8-chloro-1-
[3-(5-{[4- (methyloxy)phenyl] methyl}-2H-tetrazol-
2-yl)propyl]-3,7- dihydro-1H-purine- 2,6-dione 38.2 m/z 473
[MH].sup.+ RT 3.24 min 501 ##STR00640## 3-butyl-8-chloro-1-
(3-{5-[(2- fluorophenyl)methyl]- 1H-tetrazol-1- yl}propyl)-3,7-
dihydro-1H-purine- 2,6-dione 13.7 m/z 461 [MH].sup.+ RT 3.07 min
502 ##STR00641## 3-butyl-8-chloro-1- (3-{5-[(3-
fluorophenyl)methyl]- 1H-tetrazol-1- yl}propyl)-3,7-
dihydro-1H-purine- 2,6-dione 15.0 m/z 461 [MH].sup.+ RT 3.10 min
503 ##STR00642## 3-butyl-8-chloro-1- (3-{5-[(4-
fluorophenyl)methyl]- 1H-tetrazol-1- yl}propyl)-3,7-
dihydro-1H-purine- 2,6-dione 17.7 m/z 461 [MH].sup.+ RT 3.10 min
504 ##STR00643## 3-butyl-8-chloro-1- (3-{5-[(2-
chlorophenyl)methyl]- 1H-tetrazol-1- yl}propyl)-3,7-
dihydro-1H-purine- 2,6-dione 8.4 m/z 477 [MH].sup.+ RT 3.17 min 505
##STR00644## 3-butyl-8-chloro-1- (3-{5-[(3- chlorophenyl)methyl]-
1H-tetrazol-1- yl}propyl)-3,7- dihydro-1H-purine- 2,6-dione 16.4
m/z 477 [MH].sup.+ RT 3.23 min 506 ##STR00645## 3-butyl-8-chloro-1-
(3-{5-[(4- chlorophenyl)methyl]- 1H-tetrazol-1- yl}propyl)-3,7-
dihydro-1H-purine- 2,6-dione 17.0 m/z 477 [MH].sup.+ RT 3.24 min
507 ##STR00646## 3-butyl-8-chloro-1- (3-{5-[(2-
methylphenyl)methyl]- 1H-tetrazol-1- yl}propyl)-3,7-
dihydro-1H-purine- 2,6-dione 15.1 m/z 457 [MH].sup.+ RT 3.15 min
508 ##STR00647## 3-butyl-8-chloro-1- (3-{5-[(3-
methylphenyl)methyl]- 1H-tetrazol-1- yl}propyl)-3,7-
dihydro-1H-purine- 2,6-dione 18.6 m/z 457 [MH].sup.+ RT 3.18 min
509 ##STR00648## 3-butyl-8-chloro-1- (3-{5-[(4-
methylphenyl)methyl]- 1H-tetrazol-1 yl}propyl)-3,7-
dihydro-1H-purine- 2,6-dione 16.3 m/z 457 [MH].sup.+ RT 3.19 min
510 ##STR00649## 3-butyl-8-chloro-1- [3-(5-{[3- (trifluoromethyl)
phenyl]methyl}-1H- tetrazol-1- yl)propyl]-3,7- dihydro-1H-purine-
2,6-dione 17.7 m/z 511 [MH].sup.+ RT 3.31 min 511 ##STR00650##
3-butyl-8-chloro-1- [3-(5-{[4- (trifluoromethyl) phenyl]methyl}-1H-
tetrazol-1- yl)propyl]-3,7- dihydro-1H-purine- 2,6-dione 21.6 m/z
511 [MH].sup.+ RT 3.33 min 512 ##STR00651## 3-butyl-8-chloro-1-
[3-(5-{[2- (methyloxy)phenyl] methyl}-1H-tetrazol-
1-yl)propyl]-3,7- dihydro-1H-purine- 2,6-dione 16.3 m/z 473
[MH].sup.+ RT 3.10 min 513 ##STR00652## 3-butyl-8-chloro-1-
[3-(5-{[4- (methyloxy)phenyl] methyl}-1H-tetrazol-
1-yl)propyl]-3,7- dihydro-1H-purine- 2,6-dione 20.8 m/z 473
[MH].sup.+ RT 3.05 min 514 ##STR00653## 3-butyl-8-chloro-1-
{3-[5-(1- phenylcyclopropyl)- 1H-tetrazol-1- yl]propyl}-3,7-
dihydro-1H-purine- 2,6-dione 14.1 m/z 468 [MH].sup.+ RT 3.16 min
515 ##STR00654## 3-butyl-8-chloro-1- {3-[5-(2- phenylethyl)-1H-
tetrazol-1- yl]propyl)-3,7- dihydro-1H-purine- 2,6-dione 21.0 m/z
457 [MH].sup.+ RT 3.15 min 516 ##STR00655## 3-butyl-8-chloro-1-
{3-[5-(2- thienylmethyl)-1H- tetrazol-1- yl]propyl)-3,7-
dihydro-1H-purine- 2,6-dione 11.8 m/z 448 [MH].sup.+ RT 3.02 min
517 ##STR00656## 3-butyl-8-chloro-1- (3-{5-[(2,6- dichlorophenyl)
methyl]-1H-tetrazol-1- yl}propyl)-3,7- dihydro-1H-purine- 2,6-dione
12.4 m/z 512 [MH].sup.+ RT 3.27 min 518 ##STR00657##
8-chloro-3-propyl-1- [3-(5-{[4- (trifluoromethyl)
phenyl]methyl}-2H- tetrazol-2- yl)propyl]3,7- dihydro-1H-purine-
2,6-dione 15.5 m/z 497 [MH].sup.+ RT 3.38 min 519 ##STR00658##
8-chloro-1-(3-{5-[(2- chlorophenyl)methyl]-1H-tetrazol-1-
yl}propyl)-3-propyl- 3,7-dihydro-1H- purine-2,6-dione 1.6 m/z 463
[MH].sup.+ RT 3.00 min 520 ##STR00659## 8-chloro-1-(3-{5-[(3-
chlorophenyl)methyl]-1H-tetrazol-1- yl}propyl)-3-propyl-
3,7-dihydro-1H- purine-2,6-dione 7.1 m/z 463 [MH].sup.+ RT 3.06 min
521 ##STR00660## 8-chlorol-(3-{5-[(2- methylphenyl)methyl]-
1H-tetrazol-1- yl}propyl)-3-propyl- 3,7-dihydro-1H-
purine-2,6-dione 7.2 m/z 443 [MH].sup.+ RT 2.97 min 522
##STR00661## 8-chloro-1-(3-{5-[(3- methylphenyl)methyl]-
1H-tetrazol-1- yl}propyl)-3-propyl- 3,7-dihydro-1H-
purine-2,6-dione 5.7 m/z 443 [MH].sup.+ RT 3.01 min 523
##STR00662## 8-chloro-1-(3-{5-[(4- methylphenyl)methyl]-
1H-tetrazol-1- yl}propyl)-3-propyl- 3,7-dihydro-1H-
purine-2,6-dione 5.5 m/z 443 [MH].sup.+ RT 3.01 min 524
##STR00663## 8-chloro-3-propyl-1- [3-(5-{[3- (trifluoromethyl)
phenyl]methyl}-1H- tetrazol-1- yl)propyl]-3,7- dihydro-1H-purine-
2,6-dione 3.3 m/z 497 [MH].sup.+ RT 3.16 min 525 ##STR00664##
8-chloro-1-(3-{5-[(2- methylphenyl)methyl}- 2H-tetrazol-2-
propyl)-3-propyl- 3,7-dihydro-1H- purine-2,6-dione 24.1 m/z 443
[MH].sup.+ RT 3.20 min 526 ##STR00665## 8-chloro-1-(3-{5-[(2-
fluorophenyl)methyl]- 1H-tetrazol-1- yl}propyl)-3-propyl-
3,7-dihydro-1H- purine-2,6-dione 1.3 m/z 447 [MH].sup.+ RT 2.89 min
527 ##STR00666## 8-chloro-3-propyl-1- {3-[5-(2- thienylmethyl)-1H-
tetrazol-1- yl]propyl}-3,7- dihydro-1H-purine- 2,6-dione 5.2 m/z
435 [MH].sup.+ RT 2.83 min 528 ##STR00667## 8-chloro-1-[3-(5-{[4-
(methyloxy)phenyl] methyl}-1H-tetrazol- 1-yl)propyl]-3-
propyl-3,7-dihydro- 1H-purine-2,6- dione 1.2 m/z 459 [MH].sup.+ RT
2.87 min 529 ##STR00668## 8-chloro-1-[3-(5-{[4- (methyloxy)phenyl]
methyl}-2H-tetrazol- 2-yl)propyl]-3- propyl-3,7-dihydro-
1H-purine-2,6- dione 19.7 m/z 459 [MH].sup.+ RT 3.07 min 530
##STR00669## 8-chloro-1-[3-(5-{[2- (methyloxy)phenyl]
methyl}-1H-tetrazol- 1-yl)propyl]-3- propyl-3,7-dihydro-
1H-purine-2,6- dione 1.9 m/z 459 [MH].sup.+ RT 2.92 min 531
##STR00670## 3-butyl-8-chloro-1- {2-[5-(2- phenylethyl)-2H-
tetrazol-2-yl]ethyl}- 3,7-dihydro-1H- purine-2,6-dione 44.0 m/z 443
[MH].sup.+ RT 3.31 min 532 ##STR00671## 3-butyl-8-chloro-1-
{2-[5-(2- phenylethyl)-1H- tetrazol-1-yl]ethyl}- 3,7-dihydro-1H-
purine-2,6-dione 10.4 m/z 443 [MH].sup.+ RT 3.12 min 533
##STR00672## 3-butyl-8-chloro-1- [3-(5-{[2-fluoro-4-
(trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3,7-
dihydro-1H-purine- 2,6-dione 24.5 m/z 529 [MH].sup.+ RT 3.22 min
534 ##STR00673## 3-butyl-8-chloro-1- [3-(5-{(5-fluoro-2-
(trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3,7-
dihydro-1H-purine- 2,6-dione 25.3 m/z 529 [MH].sup.+ RT 3.51 min
535 ##STR00674## 3-butyl-8-chloro-1- [3-(5-{[3-fluoro-4-
(trifluoromethyl) phenyl]methyl)-2H- tetrazol-2- yl)propyl]-3,7-
dihydro-1H-purine- 2,6-dione 11.5 m/z 529 [MH].sup.+ RT 3.56 min
536 ##STR00675## 3-butyl-8-chloro-1- (3-{5-[(3,4,5-
trifluorophenyl) methyl]-2H-tetrazol-2- yl}propyl)-3,7-
dihydro-1H-purine- 2,6-dione 19.4 m/z 497 [MH].sup.+ RT 3.45 min
537 ##STR00676## 3-butyl-8-chloro-1- {3-[5-({3-
[(trifluoromethyl)oxy] phenyl}methyl)-2H- tetrazol-2-
yl]propyl}-3,7- dihydro-1H-purine- 2,6-dione 27.2 m/z 527
[MH].sup.+ RT 3.55 min 538 ##STR00677## 3-butyl-8-chloro-1-
[3-(5-{(3-fluoro-5- (trifluoromethyl) phenyl]methyl}-2H-
tetrazol-2- yl)propyl]-3,7- dihydro-1H-purine- 2,6-dione 19.8 m/z
529 [MH].sup.+ RT 3.56 min 539 ##STR00678## 1-[3-(5-{[2,4-
bis(trifluoromethyl) phenyl]methyl}-2H- tetrazol-2-
yl)propyl]-3-butyl-8- chloro-3,7-dihydro- 1H-purine-2,6- dione 36.6
m/z 579 [MH].sup.+ RT 3.72 min 540 ##STR00679## 1-[3-(5-{[2,5-
bis(trifluoromethyl) phenyl]methyl}-2H- tetrazol-2-
yl)propyl]-3-butyl-8- chloro-3,7-dihydro- 1H-purine-2,6- dione 50.3
m/z 579 [MH].sup.+ RT 3.65 min 541 ##STR00680##
8-chloro-1-[3-(5-{[4- fluoro-2- (trifluoromethyl)
phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3-(4,4,4-
trifluorobutyl)-3,7- dihydro-1H-purine- 2,6-dione 25.0 m/z 583
[MH].sup.+ Rt 3.50 min 542 ##STR00681## 8-chloro-1-[3-(5-{(4-
fluoro-2- (trifluoromethyl) phenyl]methyl}-2H- (trifluoromethyl)
phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3-[2- (methyloxy)ethyl]-
3,7-dihydro-1H- purine-2,6-dione 23.0 m/z 531 [MH].sup.+ RT 3.16
min 543 ##STR00682## 8-chloro-3-[2- (ethyloxy)ethyl]-1-
[3-(5-{[4-fluoro-2- (trifluoromethyl) phenyl]methyl}-2H-
tetrazol-2- yl)propyl]-3,7- dihydro-1H-purine- 2,6-dione 13.1 m/z
545 [MH].sup.+ RT 3.30 min 544 ##STR00683## 8-chloro-1-[3-(5-{[4-
fluoro-2- (trifluoromethyl) phenyl]methyl}-2H- tetrazol-2-
yl)propy]-3-(3,3,3- trifluoropropyl)-3,7- dihydro-1H-purine-
2,6-dione 36.3 m/z 569 [MH].sup.+ RT 3.46 min 545 ##STR00684##
8-chloro-1-[3-(5-{[4- fluoro-2- (trifluoromethyl)
phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3-propyl- 3,7-dihydro-1H-
purine-2,6-dione 32.0 m/z 515 [MH].sup.+ RT 3.37 min 546
##STR00685## 3-butyl-8-chloro-1- [3-(5-{[4-fluoro-2-
(trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3,7-
dihydro-1H-purine- 2,6-dione 30.3 m/z 529 [MH].sup.+ RT 3.53 min
547 ##STR00686## 1-[3-(5-{[3,5- bis(trifluoromethyl)
phenyl]methyl}-2H- tetrazol-2- yl)propyl]-8-chloro- 3-propyl-3,7-
dihydro-1H-purine- 2,6-dione 22.9 m/z 565 [MH].sup.+ RT 3.54 min
548 ##STR00687## 8-chloro-3-propyl-1- {3-[5-({4-
[(trifluoromethyl)oxy]- phenyl}methyl)-2H- tetrazol-2-
yl]propyl}-3,7- dihydro-1H-purine- 2,6-dione 21.6 m/z 513
[MH].sup.+ RT 3.42 min 549 ##STR00688## 8-chloro-1-(3-{5-[(2-
chloro-6- fluorophenyl)methyl]- 2H-tetrazol-2- yl}propyl)-3-propyl-
3,7-dihydro-1H- purine-2,6-dione 12.4 m/z 481 [MH].sup.+ RT 3.20
min 550 ##STR00689## 8-chloro-3-propyl-1- [3-(5-{[2-
(trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3,7-
dihydro-1H-purine- 2,6-dione 17.7 m/z 497 [MH].sup.+ RT 3.26 min
551 ##STR00690## 8-chloro-1-(3-{5- [(3,5- difluorophenyl)
methyl]-2H-tetrazol-2- yl}propyl)-3-propyl- 3,7-dihydro-1H-
purine-2,6-dione 21.6 m/z 465 [MH].sup.+ RT 3.16 min 552
##STR00691## 8-chloro-3-propyl-1- {3-[5-({2- [(trifluoromethyl)oxy]
phenyl}methyl)-2H- tetrazol-2- yl]propyl}-3,7- dihydro-1H-purine-
2,6-dione 22.3 m/z 513 [MH].sup.+ RT 3.27 min 553 ##STR00692##
8-chloro-1-[3-(5-{[2- fluoro-4- (trifluoromethyl)
phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3-propyl- 3,7-dihydro-1H-
purine-2,6-dione 9.7 m/z 515 [MH].sup.+ RT 3.40 min 554
##STR00693## 8-chloro-1-[3-(5-{[5- fluoro-2- (trifluoromethyl)
phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3-propyl- 3,7-dihydro-1H-
purine-2,6-dione 26.8 m/z 515 [MH].sup.+ RT 3.26 min 555
##STR00694## 8-chloro-1-[3-(5-{[3- fluoro-4- (trifluoromethyl)
phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3-propyl- 3,7-dihydro-1H-
purine-2,6-dione 20.7 m/z 515 [MH].sup.+ RT 3.31 min 556
##STR00695## 8-chloro-3-propyl-1- (3-{5-[(3,4,5- trifluorophenyl)
methyl]-2H-tetrazol-2- yl}propyl)-3,7- dihydro-1H-purine- 2,6-dione
10.2 m/z 483 [MH].sup.+ RT 3.23 min 557 ##STR00696##
8-chloro-3-propyl-1- {3-[5-({3- [(trifluoromethyl)oxy]
phenyl}methyl)-2H- tetrazol-2- yl]propyl}-3,7- dihydro-1H-purine-
2,6-dione 9.8 m/z 513 [MH].sup.+ RT 3.35 min 558 ##STR00697##
8-chloro-1-(3-{5- [(2,4- dichlorophenyl) methyl]-2H-tetrazol-2-
yl}propy)-3-propyl- 3,7-dihydro-1H- purine-2,6-dione 27.6 m/z 497
[MH].sup.+ RT 3.40 min
559 ##STR00698## 8-chloro-1-[3-(5-{[3- fluoro-5- (trifluoromethyl)
phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3-propyl- 3,7-dihydro-1H-
purine-2,6-dione 17.6 m/z 515 [MH].sup.+ RT 3.23 min 560
##STR00699## 1-[3-(5-{[2,4- bis(trifluoromethyl) phenyl]methyl}-2H-
tetrazol-2- yl)propyl]-8-chloro- 3-propyl-3,7- dihydro-1H-purine-
2,6-dione 21.0 m/z 565 [MH].sup.+ RT 3.40 min 561 ##STR00700##
1-[3-(5-{[2,5- bis(trifluoromethyl) phenyl]methyl}-2H- tetrazol-2-
yl)propyl]-8-chloro- 3-propyl-3,7- dihydro-1H-purine- 2,6-dione 9.7
mz 565 [MH].sup.+ RT 3.50 min 562 ##STR00701## 1-[3-(5-{[3,5-
bis(trifluoromethyl) phenyl]methyl}-2H- tetrazol-2-
yl)propyl]-3-butyl-8- chloro-3,7-dihydro- 1H-purine-2,6- dione 28.1
m/z 579 [MH].sup.+ RT 3.68 min 563 ##STR00702## 3-butyl-8-chloro-1-
{3-[5-({4- [(trifluoromethyl)oxy] phenyl}methyl)-2H- tetrazol-2-
yl]propyl}-3,7- dihydro-1H-purine- 2,6-dione 32.1 m/z 527
[MH].sup.+ RT 3.57 min 564 ##STR00703## 8-chloro-1-(3-{5-[(4-
fluorophenyl)methyl]- 2H-tetrazol-2- yl}propyl)-3-[2-
(methyloxy)ethyl]- 3,7-dihydro-1H- purine-2,6-dione 15.0 m/z 463
[MH].sup.+ RT 2.89 min 565 ##STR00704## 8-chloro-3-[2-
(ethyloxy)ethyl]-1- (3-{5-[(4- fluorophenyl)methyl]- 2H-tetrazol-2-
yl)propyl)-3,7- dihydro-1H-purine- 2,6-dione 12.6 m/z 477
[MH].sup.+ RT 3.03 min 566 ##STR00705## 8-chloro-1-(3-{5-[(4-
fluorophenyl)methyl]- 2H-tetrazol-2- yl}propyl)-3-(3,3,3-
trifluoropropyl)-3,7- dihydro-1H-purine- 2,6-dione 17.8 m/z 501
[MH].sup.+ RT 3.21 min 567 ##STR00706## 8-chloro-3-[2-
(methyloxy)ethyl]-1- [3-(5-{[2- (trifluoromethyl)
phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3,7- dihydro-1H-purine-
2,6-dione 14.2 m/z 513 [MH].sup.+ RT 3.10 min 568 ##STR00707##
8-chloro-3-[2- (ethyloxy)ethyl]-1- [3-(5-{[2- (trifluoromethyl)
phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3,7- dihydro-1H-purine-
2,6-dione 20.8 m/z 527 [MH].sup.+ RT 3.18 min 569 ##STR00708##
8-chloro-1-[3-(5-{[2- (trifluoromethyl) phenyl]methyl}-2H-
tetrazol-2- yl)propyl]-3-(3,3,3- trifluoropropyl)-3,7-
dihydro-1H-purine- 2,6-dione 35.8 m/z 551 [MH].sup.+ RT 3.35 min
570 ##STR00709## 8-chloro-3-[2- (methyloxy)ethyl]-1- [3-(5-{[3-
(trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3,7-
dihydro-1H-purine- 2,6-dione 15.3 m/z 513 [MH].sup.+ RT 3.14 min
571 ##STR00710## 8-chloro-1-[3-(5-{[3- (trifluoromethyl)
phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3-(3,3,3-
trifluoropropyl)-3,7- dihydro-1H-purine- 2,6-dione 29.4 m/z 551
[MH].sup.+ RT 3.42 min 572 ##STR00711## 8-chloro-1-(3-{5- [(2,4-
difluorophenyl) methyl]-2H-tetrazol-2- yl}propyl)-3-(2-
(methyloxy)ethyl]- 3,7-dihydro-1H- purine-2,6-dione 17.8 m/z 481
[MH].sup.+ RT 2.96 min 573 ##STR00712## 8-chloro-1-(3-{5- [(2,4-
difluorophenyl) methyl]-2H-tetrazol-2- yl}propyl)-3-[2-
(ethyloxy)ethyl]-3,7- dihydro-1H-purine- 2,6-dione 14.4 m/z 495
[MH].sup.+ RT 2.86 min 574 ##STR00713## 8-chloro-1-(3-{5- [(2,4-
difluorophenyl) methyl]-2H-tetrazol-2- yl}propyl)-3-(3,3,3-
trifluoropropyl)-3,7- dihydro-1H-purine- 2,6-dione 29.9 m/z 518
[MH].sup.+ RT 3.19 min 575 ##STR00714## 8-chloro-3-(2-
(methyloxy)ethyl]-1- (3-{5-[(2,4,6- trifluorophenyl)
methyl]-2H-tetrazol-2- yl}propyl)-3,7- dihydro-1H-purine- 2,6-dione
21.3 m/z 499 [MH].sup.+ RT 2.93 min 576 ##STR00715## 8-chloro-3-[2-
(ethyloxy)ethyl]-1- (3-{5-[(2,4,6- trifluorophenyl)
methyl]-2H-tetrazol-2- yl}propyl)-3,7- dihydro-1H-purine- 2,6-dione
15.5 m/z 513 [MH].sup.+ RT 2.93 min 577 ##STR00716##
8-chloro-1-(3-{5- [(2,4,6- trifluorophenyl) methyl]-2H-tetrazol-2-
yl}propyl)-3-(3,3,3- trifluoropropyl)-3,7- dihydro-1H-purine-
2,6-dione 32.3 m/z 537 [MH].sup.+ RT 3.29 min 578 ##STR00717##
8-chloro-1-(3-{5- [(3,4- difluorophenyl) methyl]-2H-tetrazol-2-
yl}propyl)-3-[2- (methyloxy)ethyl]- 3,7-dihydro-1H-
purine-2,6-dione 14.5 m/z 481 [MH].sup.+ RT 2.97 min 579
##STR00718## 8-chloro-1-(3-{5- [(3,4- difluorophenyl)
methyl]-2H-tetrazol-2- yl}propyl)-3-[2- (ethyloxy)ethyl]-3,7-
dihydro-1H-purine- 2,6-dione 7.2 m/z 495 [MH].sup.+ RT 3.06 min 580
##STR00719## 8-chloro-1-(3-{5- [(3,4- difluorophenyl)
methyl]-2H-tetrazol-2- yl}propyl)-3-(3,3,3- trifluoropropyl)-3,7-
dihydro-1H-purine- 2,6-dione 27.8 m/z 519 [MH].sup.+ RT 3.27 min
581 ##STR00720## 8-chloro-1-(3-{5- [(2,5- difluorophenyl)
methyl]-2H-tetrazol-2- yl}propyl)-3-[2- (methyloxy)ethyl]-
3,7-dihydro-1H- purine-2,6-dione 17.1 m/z 481 [MH].sup.+ RT 2.89
min 582 ##STR00721## 8-chloro-1-(3-{5- [(2,5- difluorophenyl)
methyl]-2H-tetrazol-2- yl}propyl)-3-[2- (ethyloxy)ethyl]-3,7-
dihydro-1H-purine- 2,6-dione 13.5 m/z 495 [MH].sup.+ RT 3.05 min
583 ##STR00722## 8-chloro-3-[2- (ethyloxy)ethyl]-1- [3-(5-{[3-
(trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3,7-
dihydro-1H-purine 2,6-dione 14.6 m/z 527 [MH].sup.+ RT 3.26 min 584
##STR00723## 8-chloro-3-(4,4,4- trifluorobutyl)-1-[3- (5{[4-
(trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3,7-
dihydro-1H-purine- 2,6-dione 12.1 m/z 565 [MH].sup.+ RT 3.51 min
585 ##STR00724## 8-chloro-3-[2- (methyloxy)ethyl]-1- [3-(5-{[4-
(trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3,7-
dihydro-1H-purine- 2,6-dione 17.3 m/z 513 [MH].sup.+ RT 3.17 min
586 ##STR00725## 8-chloro-3-[2- (ethyloxy)ethyl]-1- [3-(5-{[4-
(trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3,7-
dihydro-1H-purine- 2,6-dione 15.2 m/z 527 [MH].sup.+ RT 3.30 min
587 ##STR00726## 8-chloro-3-(4,4,4- trifluorobutyl)-1-[3- (5-{[2-
(trifluoromethyl) phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3,7-
dihydro-1H-purine- 2,6-dione 5.8 m/z 565 [MH].sup.+ RT 3.46 min 588
##STR00727## 8-chloro-1-(3-{5- [(2,5- difluorophenyl)
methyl]-2H-tetrazol-2- yl}propyl)-3-(4,4,4- trifluorobutyl)-3,7-
dihydro-1H-purine- 2,6-dione 14.7 m/z 533 [MH].sup.+ RT 3.34 min
589 ##STR00728## 8-chloro-1-[3-(5-{[4- (trifluoromethyl)
phenyl]methyl}-2H- tetrazol-2- yl)propyl]-3-(3,3,3-
trifluoropropyl)-3,7- dihydro-1H-purine- 2,6-dione 26.1 m/z 551
[MH].sup.+ RT 3.46 min 590 ##STR00729## 8-chloro-1-(3-{5- [(2,5-
difluorophenyl) methyl]-2H-tetrazol-2- yl}propyl)-3-(3,3,3-
trifluoropropyl)-3,7- dihydro-1H-purine- 2,6-dione 18.0 m/z 519
[MH].sup.+ RT 3.29 min 591 ##STR00730## 8-chloro-1-(3-{5-[(2-
fluorophenyl)methyl]- 2H-tetrazo-2- yl}propyl)-3-[2-
(methyloxy)ethyl]- 3,7-dihydro-1H- purine-2,6-dione 3.4 m/z 463
[MH].sup.+ RT 2.84 min 592 ##STR00731## 8-chloro-3-[2-
(ethyloxy)ethyl]-1- (3-{5-[(2- fluorophenyl)methyl]- 2H-tetrazol-2-
yl}propyl)-3,7- dihydro-1H-purine- 2,6-dione 8.2 m/z 477 [MH].sup.+
RT 2.85 min 593 ##STR00732## 8-chloro-1-(3-{5-[(2-
fluorophenyl)methyl]- 2H-tetrazol-2- yl}propyl)-3-(3,3,3-
trifluoropropyl)-3,7- dihydro-1H-purine- 2,6-dione 32.7 m/z 501
[MH].sup.+ RT 3.25 min 594 ##STR00733## 8-chloro-3-[2-
(methyloxy)ethyl]-1- {3-[5-(1- phenylcyclopropyl)- 2H-tetrazol-2-
yl]propyl}-3,7- dihydro-1H-purine- 2,6-dione 10.2 m/z 471
[MH].sup.+ RT 2.93 min 595 ##STR00734## 8-chloro-3-[2-
(ethyloxy)ethyl]-1- {3-[5-(1- phenylcyclopropyl)- 2H-tetrazol-2-
yl]propyl}-3,7- dihydro-1H-purine- 2,6-dione 15.2 m/z 485
[MH].sup.+ RT 2.96 min 596 ##STR00735## 8-chloro-1-{3-[5-(1-
phenylcyclopropyl)- 2H-tetrazol-2- yl]propyl}-3-(3,3,3-
trifluoropropyl)-3,7- dihydro-1H-purine- 2,6-dione 4.6 m/z 509
[MH].sup.+ RT 3.00 min
Example 597
1-[5-(1,3-Benzoxazol-2-yl)pentyl]-8-chloro-3-ethyl-3,7-dihydro-1H-purine-2-
,6-dione
a)
1-[5-(1,3-Benzoxazol-2-yl)pentyl]-8-chloro-3-ethyl-3,7-dihydro-1H-purin-
e-2,6-dione
##STR00736##
[1062] a) A solution of
3-ethyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(0.095 g, 0.37 mmol) in DMF (10 ml) was treated with potassium
carbonate (0.0615 g, 0.45 mmol) and
2-(5-chloropentyl)-1,3-benzoxazole (0.091 g, 0.41 mmol) and the
mixture heated at 70.degree. C. for 4.5 h. The mixture was cooled
and degassed by the repeated application of vacuum to the reaction
mixture and subsequent backfilling with nitrogen gas and then
treated with tetrakis(triphenylphosphine)palladium(0) (0.043 g,
0.037 mmol) and morpholine (0.32 ml, 3.7 mmol) and the mixture
stirred for 4 h in a nitrogen atmosphere. The mixture was
evaporated to dryness and the residue partitioned between 25 ml of
ethyl acetate and 25 ml of brine. The aqueous phase was
re-extracted with 25 ml of ethyl acetate and the combined organics
dried over magnesium sulfate, filtered and evaporated. The residue
was dissolved in 5 ml of methanol and added to a 5 g aminopropyl
SPE which was subsequently washed with methanol and the product
eluted with a 5% solution of acetic acid in methanol.
Product-containing fractions were pooled and evaporated to reveal a
colourless gum which was triturated with diethyl ether and dried to
give the title compound as a white solid (0.0538 g, 36%).
[1063] LC/MS: m/z 402 [MH].sup.+, RT 3.06 min
[1064] b) 2-(5-Chloropentyl)-1,3-benzoxazole
##STR00737##
[1065] 6-Chloro-N-(2-hydroxyphenyl)hexanamide (0.95 g, 3.9 mmol)
was treated with toluene (20 ml) and 4-toluenesulfonic acid
monohydrate (0.05 g, 0.26 mmol) and the mixture heated in the
microwave at 160.degree. C. for 1 h then cooled and evaporated. The
residue was partition between 25 ml of ethyl acetate and 25 ml of
saturates aqueous sodium bicarbonate. The aqueous phase was
extracted twice more with 25 ml ethyl acetate and the combined
organics dried over magnesium sulfate, filtered and evaporated to
dryness. The product was then purified by flash chromatography
(gradient elution: cyclohexane to cyclohexane/ethyl acetate 1:1) to
give 2-(5-chloropentyl)-1,3-benzoxazole as a colourless oil which
solidified upon standing (0.47 g, 53%).
[1066] LC/MS: m/z 224 [MH].sup.+, RT 3.32 min
c) 6-chloro-N-(2-hydroxyphenyl)hexanamide
##STR00738##
[1068] 2-Aminophenol (0.5 g, 4.6 mmol) was stirred in ethyl acetate
(15 ml) and treated dropwise with 6-chlorohexanoyl chloride (0.664
ml, 5.5 mmol) and then dropwise with triethylamine (0.95 ml, 6.9
mmol). After 1 h the mixture was washed with 2.times.25 ml of
saturated aqueous sodium bicarbonate and the organic phase dried
over magnesium sulfate, filtered and evaporated to dryness to give
6-chloro-N-(2-hydroxyphenyl)hexanamide as a pale brown solid (0.05
g, 86%).
[1069] LC/MS: m/z 242 [M].sup.+, RT 2.95 min.
[1070] The following compounds (Table 33) were prepared using a
method analogous to that for Example 597.
TABLE-US-00035 TABLE 33 Yield Example Structure Name (mg) LC/MS 598
##STR00739## 1-[5-(1,3- benzoxazol-2- yl)pentyl]-8-
chloro-3-propyl- 3,7-dihydro-1H- purine-2,6-dione 60.5 m/z 416
[MH].sup.+ RT 3.23 mins 599 ##STR00740## 1-[5-(1,3- benzoxazol-2-
yl)pentyl]-3-butyl- 8-chloro-3,7- dihydro-1H- purine-2,6-dione 55.1
m/z 428 [MH].sup.+ RT 3.42 mins 600 ##STR00741##
3-butyl-8-chloro-1- [5-(6-methyl-1,3- benzoxazol-2- yl)pentyl]-3,7-
dihydro-1H- purine-2,6-dione 68.9 m/z 444 [MH].sup.+ RT 3.56
mins
Example 601
1-[5-(1,3-Benzothiazol-2-yl)pentyl]-3-butyl-8-chloro-3,7-dihydro-1H-purine-
-2,6-dione
a)
1-[5-(1,3-Benzothiazol-2-yl)pentyl]-3-butyl-8-chloro-3,7-dihydro-1H-pur-
ine-2,6-dione
##STR00742##
[1072] A solution of
3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(0.053 g, 0.19 mmol) in DMF (5 ml) was treated with potassium
carbonate (0.026 g, 0.19 mmol) and
2-(5-chloropentyl)-1,3-benzothiazole (0.0498 g, 0.21 mmol) and the
mixture heated at 60.degree. C. for 3 days. The mixture was cooled
and degassed by the repeated application of vacuum to the reaction
mixture and subsequent backfilling with nitrogen gas and then
treated with tetrakis(triphenylphosphine)palladium(0) (0.0294 g,
0.025 mmol) and morpholine (0.164 ml, 1.9 mmol) and the mixture
stirred for 18 hours in a nitrogen atmosphere. The mixture was
evaporated to dryness and the residue partitioned between 25 ml of
ethyl acetate and 25 ml of saturated aqueous sodium bicarbonate.
The organic phase was dried over magnesium sulfate, filtered and
evaporated. The residue was dissolved in 5 ml of methanol and added
to a 5 g aminopropyl SPE which was subsequently washed with
methanol and the product eluted with a 5% solution of acetic acid
in methanol. Product-containing fractions were pooled and
evaporated and the residue subjected to purification by MDAP to
give the title compound as a white solid (0.0101 g, 12%).
[1073] LC/MS: m/z 446 [MH].sup.+, RT 3.55 min.
b) 2-(5-Chloropentyl)-1,3-benzothiazole
##STR00743##
[1075] An ice-cooled solution of 2-aminothiophenol (0.376 ml, 3.54
mmol) in anhydrous THF (5 ml) was treated with
diisopropylethylamine (0.62 ml, 3.54 mmol) followed by
6-chlorohexanoyl chloride (0.36 ml, 2.95 mmol). The mixture was
stirred at ambient temperature for 2 h then heated at reflux for 19
h and then cooled and diluted with DCM (10 ml). The solution was
washed with 10 ml of 2M aqueous hydrochloric acid, 10 ml of 2M
aqueous sodium hydroxide and 10 ml of brine; dried over magnesium
sulfate, filtered and evaporated to reveal 0.4122 g of a pale
yellow oil. The product was purified by flash chromatography using
a gradient elution from cyclohexane to cyclohexane/ethyl acetate
(7:3) to give 2-(5-chloropentyl)-1,3-benzothiazole as a colourless
oil (0.0541 g, 6%).
[1076] LC/MS: m/z 240 [MH].sup.+, RT 3.48 min.
Example 602
3-Butyl-8-chloro-1-{3-[4-(phenylmethyl)-1-piperazinyl]propyl}-3,7-dihydro--
1H-purine-2,6-dione
##STR00744##
[1078] A solution of
3-[3-butyl-8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-pur-
in-1-yl]propyl methanesulfonate (0.08 g, 0.19 mmol) in DMF (5 ml)
was treated with potassium carbonate (0.08 g, 0.6 mmol) and
1-benzylpiperazine (0.04 g, 0.23 mmol) and then heated at
70.degree. C. for 2 h. The mixture was cooled, evaporated to
dryness and partitioned between 10 ml of DCM and 10 ml of water.
The organic phase was evaporated to dryness and the residue
dissolved in anhydrous THF (5 ml). The solution was cautiously
degassed by the repeated application of vacuum to the reaction
mixture and subsequent backfilling with nitrogen gas and then
treated with tetrakis(triphenylphosphine)palladium(0) (0.010 g,
0.009 mmol) and morpholine (0.200 ml, 2.3 mmol) and the mixture
stirred for 2 h in a nitrogen atmosphere. The mixture was
evaporated and the residue taken up in 5 ml of methanol and added
to a 2 g aminopropyl SPE cartridge which was then washed with
methanol and the product eluted using a 3% solution of acetic acid
in methanol. Product-containing fractions were pooled and
evaporated to dryness. The product was then purified by flash
chromatography using a gradient elution from DCM/2% Acetic acid to
DCM/20% MeOH/2% Acetic acid and the final product freeze-dried from
1,4-dioxan to give the title compound as a white solid (0.021 g,
24%).
[1079] LC/MS: m/z 459 [MH].sup.+, RT 2.37 min.
[1080] The following compounds (Table 34) were prepared by the
appropriate general methodology described above.
TABLE-US-00036 TABLE 34 Example Structure Name LC/MS 603
##STR00745## 8-chloro-3-(2- cyclopropylethyl)-1-[2-
(ethyloxy)ethyl]-3,7-dihydro- 1H-purine-2,6-dione m/z 327
[MH].sup.+ RT 2.80 min 604 ##STR00746## 8-chloro-1-[2-
(ethyloxy)ethyl]-3-(3- methylbutyl)-3,7-dihydro-
1H-purine-2,6-dione m/z 329 [MH].sup.+ RT 3.02 min 605 ##STR00747##
4-{8-chloro-1-[2- ethyloxy)ethyl]-2,6-dioxo-
1,2,6,7-tetrahydro-3H-purin- 3-yl}butanenitrile m/z 326 [MH].sup.+
RT 2.33 min 606 ##STR00748## 8-chloro-1-(3-{3-[(2,4-
difluorophenyl)methyl]-m 1,2,4-oxadiazol-5-yl}propyl)-
3-[3-(1-piperidinyl)propyl]- 3,7-dihydro-1H-purine-2,6- dione m/z
548 [MH].sup.+ RT 2.44 min 607 ##STR00749## 3-butyl-8-chloro-1-[2-
(methyloxy)ethyl]-3,7- dihydro-1H-purine-2,6-dione m/z 301
[MH].sup.+ RT 2.31 min 608 ##STR00750## 3-butyl-8-chloro-1-[3-
(ethyloxy)propyl]-3,7- dihydro-1H-purine-2,6-dione m/z 329
[MH].sup.+ RT 2.95 min 609 ##STR00751## 3-butyl-8-chloro-1-[3-
(methyloxy)propyl]-3,7- dihydro-1H-purine-2,6-dione m/z 315
[MH].sup.+ RT 2.36 min 610 ##STR00752## 3-butyl-8-chloro-1-[2-
(ethyloxy)ethyl]-3,7-dihydro- 1H-purine-2,6-dione m/z 315
[MH].sup.+ RT 2.34 min 611 ##STR00753## 3-butyl-8-chloro-1-[2-
(propyloxy)ethyl]-3,7- dihydro-1H-purine-2,6-dione m/z 329
[MH].sup.+ RT 2.71 min 612 ##STR00754## methyl 4-(3-butyl-8-chloro-
2,6-dioxo-2,3,6,7- tetrahydro-1H-purin-1- yl)butanoate m/z 343
[MH].sup.+ RT 2.56 min 613 ##STR00755## methyl 5-(3-butyl-8-chloro-
2,6-dioxo-2,3,6,7- tetrahydro-1H-purin-1- yl)pentanoate m/z 357
[MH].sup.+ RT 2.66 min 614 ##STR00756## 5-(3-butyl-8-chloro-2,6-
dioxo-2,3,6,7-tetrahydro-1H- purin-1-yl)pentanamide m/z 342
[MH].sup.+ RT 2.41 min 615 ##STR00757## 5-(3-butyl-8-chloro-2,6-
dioxo-2,3,6,7-tetrahydro-1H- purin-1-yl)-N-
(phenylmethyl)pentanamide m/z 432 [MH].sup.+ RT 2.97 min 616
##STR00758## 4-(3-butyl-8-chloro-2,6- dioxo-2,3,6,7-tetrahydro-1H-
purin-1-yl)butanamide m/z 328 [MH].sup.+ RT 2.34 min 617
##STR00759## 4-(3-butyl-8-chloro-2,6- dioxo-2,3,6,7-tetrahydro-1H-
purin-1-yl)-N- (phenylmethyl)butanamide m/z 418 [MH].sup.+ RT 2.93
min 618 ##STR00760## 5-(3-butyl-8-chloro-2,6-
dioxo-2,3,6,7-tetrahydro-1H- purin-1-yl)-N,N- dimethylpentanamide
m/z 370 [MH].sup.+ RT 2.26 min 619 ##STR00761##
5-(3-butyl-8-chloro-2,6- dioxo-2,3,6,7-tetrahydro-1H-
purin-1-yl)-N- methylpentanamide m/z 356 [MH].sup.+ RT 2.56 min 620
##STR00762## 4-(3-butyl-8-chloro-2,6- dioxo-2,3,6,7-tetrahydro-1H-
purin-1-yl)-N,N- dimethylbutanamide m/z 356 [MH].sup.+ RT 2.59 min
621 ##STR00763## 4-(3-butyl-8-chloro-2,6-
dioxo-2,3,6,7-tetrahydro-1H- purin-1-yl)-N- methylbutanamide m/z
342 [MH].sup.+ RT 2.48 min 622 ##STR00764## 3-butyl-8-chloro-1-(4-
morpholin-4-yl-4-oxobutyl)- 3,7-dihydro-1H-purine-2,6- dione m/z
398 [MH].sup.+ RT 2.58 min 623 ##STR00765##
3-butyl-8-chloro-1-[3-(4- methyl-1,3-thiazol-5-
yl)propyl]-3,7-dihydro-1H- purine-2,6-dione m/z 382 [MH].sup.+ RT
3.00 min 624 ##STR00766## 5-(3-butyl-8-chloro-2,6-
dioxo-2,3,6,7-tetrahydro-1H- purin-1-yl)-N-[(4-
chlorophenyl)methyl] pentanamide m/z 466 [MH].sup.+ RT 3.26 min 625
##STR00767## 8-chloro-1-{3-[4- (methyloxy)phenyl]propyl}-
3-pentyl-3,7-dihydro-1H- purine-2,6-dione m/z 405 [MH].sup.+ RT
3.65 min 626 ##STR00768## 8-chloro-1-[3-(4-
cyclohexylphenyl)propyl]-3- pentyl-3,7-dihydro-1H- purine-2,6-dione
m/z 457 [MH].sup.+ RT 4.42 min 627 ##STR00769## methyl
4-[3-(8-chloro-2,6- dioxo-3-pentyl-2,3,6,7- tetrahydro-1H-purin-1-
yl)propyl]benzoate m/z 433 [MH].sup.+ RT 3.59 min 628 ##STR00770##
8-chloro-1-[3-(3,4- dichlorophenyl)propyl]-3-
pentyl-3,7-dihydro-1H- purine-2,6-dione m/z 443 [MH].sup.+ RT 4.03
min 629 ##STR00771## 8-chloro-3-pentyl-1-(4-
phenylbutyl)-3,7-dihydro- 1H-purine-2,6-dione m/z 389 [MH].sup.+ RT
3.87 min 630 ##STR00772## ethyl 6-(8-chloro-2,6-dioxo-
3-pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)hexanoate m/z 399
[MH].sup.+ RT 3.47 min 631 ##STR00773## 5-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N- phenylpentanamide m/z
432 [MH].sup.+ RT 3.36 min 632 ##STR00774##
5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)-N-(2- phenylethyl)pentanamide m/z 460 [MH].sup.+ RT
3.29 min 633 ##STR00775## 8-chloro-1-[5-(1,3-dihydro-
2H-isoindol-2-yl)-5- oxopentyl]-3-pentyl-3,7-
dihydro-1H-purine-2,6-dione m/z 458 [MH].sup.+ RT 3.35 min 634
##STR00776## 5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)-N-(1H- imidazol-2- ylmethyl)pentanamide m/z 436
[MH].sup.+ RT 2.32 min 635 ##STR00777## 5-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-[(2-
chlorophenyl)methyl] pentanamide m/z 480 [MH].sup.+ RT 2.77 min 636
##STR00778## 5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)-N-[(3- chlorophenyl)methyl] pentanamide m/z 480
[MH].sup.+ RT 3.42 min 637 ##STR00779## 5-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-[(1-methyl-
1H-imidazol-2- yl)methyl]pentanamide m/z 450 [MH].sup.+ RT 2.32 min
638 ##STR00780## 5-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-(pyridin-2-
ylmethyl)pentanamide m/z 447 [MH].sup.+ RT 2.70 min 639
##STR00781## 5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)-N-methyl-N- (phenylmethyl)pentanamide m/z 460
[MH].sup.+ RT 3.38 min 640 ##STR00782## 5-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-(pyridin-4-
ylmethyl)pentanamide m/z 447 [MH].sup.+ RT 2.42 min 641
##STR00783## 5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)-N-(pyridin-3- ylmethyl)pentanamide m/z 447
[MH].sup.+ RT 2.54 min 642 ##STR00784## 5-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-{[3-
(trifluoromethyl)phenyl] methyl}pentanamide m/z 514 [MH].sup.+ RT
3.45 min 643 ##STR00785## 5-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-{[4-
(trifluoromethyl)phenyl] methyl}pentanamide m/z 514 [MH].sup.+ RT
3.47 min 644 ##STR00786## 5-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-{(4-
(methyloxy)phenyl]methyl} pentanamide m/z 476 [MH].sup.+ RT 2.67
min 645 ##STR00787## 5-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-[(4-
fluorophenyl)methyl] pentanamide m/z 464 [MH].sup.+ RT 3.26 min 646
##STR00788## 5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)-N-{[3- (methyloxy)phenyl]methyl} pentanamide m/z 326
[MH].sup.+ RT 3.21 min 647 ##STR00789## 5-(8-chloro-2,6-dioxo-3-
pentyl-2,3.6,7-tetrahydro- 1H-purin-1-yl)-N-[(3,4-
dichlorophenyl)methyl] pentanamide m/z 514 [MH].sup.+ RT 3.56 min
648 ##STR00790## 5-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-{[3-
(methylsulfonyl)phenyl] methyl}pentanamide m/z 524 [MH].sup.+ RT
2.97 min 649 ##STR00791## 5-(8-chloro-2,6-dioxo-3-
pentyl-2.3,6,7-tetrahydro- 1H-purin-1-yl)-N-{[6-
(methyloxy)pyridin-3- yl]methyl}pentanamide m/z 477 [MH].sup.+ RT
3.01 min 650 ##STR00792## 5-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-[(3,4-
difluorophenyl)methyl] pentanamide m/z 482 [MH].sup.+ RT 3.33 min
651 ##STR00793## 5-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-{[3-
(dimethylamino)phenyl] methyl}pentanamide m/z 489 [MH].sup.+ RT
3.01 min 652 ##STR00794## N-(1-benzothien-2-
ylmethyl)-5-(8-chloro-2,6- dioxo-3-pentyl-2,3,6,7-
tetrahydro-1H-purin-1- yl)pentanamide m/z 502 [MH].sup.+ RT 3.48
min 653 ##STR00795## 5-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-(3-
thienylmethyl)pentanamide m/z 452 [MH].sup.+ RT 3.18 min 654
##STR00796## 5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)-N-[(3- hydroxyphenyl)methyl] pentanamide m/z 462
[MH].sup.+ RT 3.04 min 655 ##STR00797## 5-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-[(3-
fluorophenyl)methyl] pentanamide m/z 464 [MH].sup.+ RT 3.28 min 656
##STR00798## 5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)-N-({4- [(difluoromethyl)oxy]phenyl}
methyl)pentanamide m/z 512 [MH].sup.+ RT 3.34 min 657 ##STR00799##
5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)-N-({4- [(trifluoromethyl)oxy]phenyl}
methyl)pentanamide m/z 530 [MH].sup.+ RT 3.50 min 658 ##STR00800##
5-(8-chloro-2,6-dioxo-3- pentyl-2.3,6,7-tetrahydro-
1H-purin-1-yl)-N-(pyrazin-2- ylmethyl)pentanamide m/z 448
[MH].sup.+ RT 2.74 min 659 ##STR00801## 5-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-[(2,3
dichlorophenyl)methyl] pentanamide m/z 514 [MH].sup.+ RT 3.55 min
660 ##STR00802## N-(biphenyl-3-ylmethyl)-5-
(8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin-
1-yl)pentanamide m/z 522 [MH].sup.+ RT 3.61 min 661 ##STR00803##
5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)-N-(1- phenylethyl)pentanamide m/z 460 [MH].sup.+ RT
3.30 min 662 ##STR00804## N-[(3-aminophenyl)methyl]-
5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)pentanamide m/z 461 [MH].sup.+ RT 2.79 min 663
##STR00805## 5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)-N-[(4- methylphenyl)methyl] pentanamide m/z 460
[MH].sup.+ RT 3.36 min 664 ##STR00806## N-(biphenyl-4-ylmethyl)-5-
(8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin-
1-yl)pentanamide m/z 522 [MH].sup.+ RT 3.63 min 665 ##STR00807##
5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)-N- (naphthalen-1- ylmethyl)pentanamide m/z 496
[MH].sup.+ RT 3.48 min 666 ##STR00808## 5-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N- (naphthalen-2-
ylmethyl)pentanamide m/z 496 [MH].sup.+ RT 3.50 min 667
##STR00809## 5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)-N-[(3,5- dimethylphenyl)methyl] pentanamide m/z 474
[MH].sup.+ RT 3.48 min 668 ##STR00810## (3-methylphenyl)methyl 5-
(8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin-
1-yl)pentanoate m/z 461 [MH].sup.+ RT 3.78 min 669 ##STR00811##
5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)-N- (phenylmethyl)pentanamide m/z 46 [MH].sup.+ RT
3.12 min
670 ##STR00812## 5-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-[(2-
methylphenyl)methyl] pentanamide m/z 460 [MH].sup.+ RT 3.22 min 671
##STR00813## 5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)-N-[(3,4- dimethylphenyl)methyl] pentanamide m/z 474
[MH].sup.+ RT 3.34 min 672 ##STR00814## 5-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-[(3-
cyanophenyl)methyl] pentanamide m/z 471 [MH].sup.+ RT 3.14 min 673
##STR00815## 8-chloro-1-(2- hydroxypropyl)-3-pentyl-3,7-
dihydro-1H-purine-2,6-dione m/z 315 [MH].sup.+ RT 2.73 min 674
##STR00816## 8-chloro-1-(2-hydroxybutyl)- 3-pentyl-3,7-dihydro-1H-
purine-2,6-dione m/z 329 [MH].sup.+ RT 2.91 min 675 ##STR00817##
N-[(3-bromophenyl)methyl]- 5-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)pentanamide m/z 524
[MH].sup.+ RT 3.43 min 676 ##STR00818## 5-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-methyl-N- {[3-
(trifluoromethyl)phenyl] methyl}pentanamide m/z 528 [MH].sup.+ RT
3.55 min 677 ##STR00819## 1,1-dimethylethyl [2-(8-
chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin-
1-yl)ethyl]carbamate m/z 400 [MH].sup.+ RT 3.21 min 678
##STR00820## 1-(2-aminoethyl)-8-chloro-3- pentyl-3,7-dihydro-1H-
purine-2,6-dione m/z 300 [MH].sup.+ RT 2.14 min 679 ##STR00821##
8-chloro-1-(2-hydroxy-4- phenylbutyl)-3-pentyl-3,7-
dihydro-1H-purine-2,6-dione m/z 405 [MH].sup.+ RT 3.43 min 680
##STR00822## 8-chloro-1-(2-hydroxy-3- phenylpropyl)-3-pentyl-3,7-
dihydro-1H-purine-2,6-dione m/z 391 [MH].sup.+ RT 3.17 min 681
##STR00823## N-[2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1- yl)ethyl]acetamide m/z 342 [MH].sup.+ RT 2.61 min 682
##STR00824## 4-(3-butyl-8-chloro-2,6- dioxo-2,3,6,7-tetrahydro-1H-
purin-1-yl)-N-(2- phenylethyl)butanamide m/z 432 [MH].sup.+ RT 3.06
min 683 ##STR00825## 4-(3-butyl-8-chloro-2,6-
dioxo-2,3,6,7-tetrahydro-1H- purin-1-yl)-N-[2-(3-
methylphenyl)ethyl]butanamide m/z 446 [MH].sup.+ RT 3.19 min 684
##STR00826## 4-(3-butyl-8-chloro-2,6- dioxo-2,3,6,7-tetrahydro-1H-
purin-1-yl)-N-[(3- methylphenyl)methyl]butanamide m/z 432
[MH].sup.+ RT 3.14 min 685 ##STR00827## 8-chloro-1-(2-hydroxy-1-
methylethyl)-3-pentyl-3,7- dihydro-1H-purine-2,6-dione m/z 315
[MH].sup.+ RT 2.80 min 686 ##STR00828##
2-{[2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)ethyl]oxy}-N- (2-phenylethyl)acetamide m/z 462
[MH].sup.+ RT 3.23 min 687 ##STR00829##
2-{[2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)ethyl]oxy}-N- [(3- methylphenyl)methyl]acetamide m/z
462 [MH].sup.+ RT 3.28 min 688 ##STR00830##
2-{[2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)ethyl]oxy}-N- [(4- methylphenyl)methyl]acetamide m/z
462 [MH].sup.+ RT 3.27 min 689 ##STR00831##
2-{[2-(8-chloro-2,6-dioxo-3- pentyl-2,3,67-tetrahydro-
1H-purin-1-yl)ethyl]oxy}-N- methyl-N- (phenylmethyl)acetamide m/z
462 [MH].sup.+ RT 3.27 min 690 ##STR00832##
2-{(2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)ethyl]oxy}-N- {[3- (trifluoromethyl)phenyl]methyl}
acetamide m/z 516 [MH].sup.+ RT 3.39 min 691 ##STR00833##
2-{[2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)ethyl]oxy}-N- [2-(3- methylphenyl)ethyl]acetamide m/z
476 [MH].sup.+ RT 3.36 min 692 ##STR00834##
2-{[2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)ethyl]oxy}-N- methyl-N-{[3-
(trifluoromethyl)phenyl]methyl} acetamide m/z 462 [MH].sup.+ RT
3.27 min 693 ##STR00835## N-[(3-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1- yl)propyl]benzenesulfonamide
m/z 454 [MH].sup.+ RT 3.29 min 694 ##STR00836##
N-[3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)propyl]-3- phenylpropanamide m/z 446 [MH].sup.+ RT
3.27 min 695 ##STR00837## N-[3-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl]-1-
phenylmethanesulfonamide m/z 468 [MH].sup.+ RT 3.29 min 696
##STR00838## N-[3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)propyl]-2- phenylacetamide m/z 432 [MH].sup.+ RT 3.18
min 697 ##STR00839## 1-[3-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl]-3-[(3-
methylphenyl)methyl]urea m/z 461 [MH].sup.+ RT 3.29 min 698
##STR00840## 1-[3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)propyl]-3-[(4- methylphenyl)methyl]urea m/z 461
[MH].sup.+ RT 3.29 min 699 ##STR00841## 3-[3-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl]-1- methyl-1-{[3-
(trifluoromethyl)phenyl]methyl} urea m/z 529 [MH].sup.+ RT 3.51 min
700 ##STR00842## 1-[3-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl]-3-
(phenylmethyl)urea m/z 447 [MH].sup.+ RT 3.17 min 701 ##STR00843##
2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)ethyl (phenylmethyl)carbamate m/z 434 [MH].sup.+ RT
3.24 min 702 ##STR00844## 2-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)ethyl [(4-
methylphenyl)methyl]carbamate m/z 448 [MH].sup.+ RT 3.34 min 703
##STR00845## 2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)ethyl (2- phenylethyl)carbamate m/z 448 [MH].sup.+ RT
3.34 min 704 ##STR00846## 2-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)ethyl [2-(3-
methylphenyl)ethyl]carbamate m/z 462 [MH].sup.+ RT 3.48 min 705
##STR00847## 2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)ethyl [2-(4- methylphenyl)ethyl]carbamate m/z 462
[MH].sup.+ RT 3.48 min 706 ##STR00848## 2-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)ethyl [(3-
methylphenyl)methyl]carbamate m/z 448 [MH].sup.+ RT 3.37 min 707
##STR00849## 3-butyl-8-chloro-1-(2- hydroxyethyl)-3,7-dihydro-
1H-purine-2,6-dione m/z 287 [MH].sup.+ RT 2.42 min 708 ##STR00850##
5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)-N-(4- propylphenyl)pentanamide m/z 474 [MH].sup.+ RT
3.73 min 709 ##STR00851## 5-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-(2-
ethylphenyl)pentanamide m/z 460 [MH].sup.+ RT 3.41 min 710
##STR00852## 5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)-N-(3- ethylphenyl)pentanamide m/z 460 [MH].sup.+ RT
3.58 min 711 ##STR00853## 3-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl [(4-
fluorophenyl)methyl]carbamate m/z 466 [MH].sup.+ RT 3.43 min 712
##STR00854## 3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)propyl methyl(phenylmethyl)carbamate m/z 462
[MH].sup.+ RT 3.54 min 713 ##STR00855## 3-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl [(4-
methylphenyl)methyl]carbamate 714 ##STR00856##
3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)propyl [(2- methylphenyl)methyl]carbamate m/z 462
[MH].sup.+ RT 3.50 min 715 ##STR00857## (4-fluorophenyl)methyl
[3-(8- chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin-
1-yl)propyl]carbamate m/z 466 [MH].sup.+ RT 3.36 min 716
##STR00858## 3-thienylmethyl [3-(8-chloro-
2,6-dioxo-3-pentyl-2,3,6,7- tetrahydro-1H-purin-1-
yl)propyl]carbamate m/z 454 [MH].sup.+ RT 3.27 min 717 ##STR00859##
(4-methylphenyl)methyl [3- (8-chloro-2,6-dioxo-3-pentyl-
2,3,6,7-tetrahydro-1H-purin- 1-yl)propyl]carbamate m/z 462
[MH].sup.+ RT 3.45 min 718 ##STR00860## (2-methylphenyl)methyl [3-
(8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin-
1-yl)propyl]carbamate m/z 462 [MH].sup.+ RT 3.42 min 719
##STR00861## 2-(4-fluorophenyl)ethyl [3-
(8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin-
1-yl)propyl]carbamate m/z 480 [MH].sup.+ RT 3.49 min 720
##STR00862## 3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)propyl (2- phenylethyl)carbamate m/z 462 [MH].sup.+
RT 3.50 min 721 ##STR00863## 3-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl propylcarbamate m/z
400 [MH].sup.+ RT 3.20 min 722 ##STR00864##
3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)propyl (2- methyl-2- phenylpropyl)carbamate m/z 490
[MH].sup.+ RT 3.66 min 723 ##STR00865## 3-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl (1- methyl-1-
phenylethyl)carbamate m/z 476 [MH].sup.+ RT 3.59 min 724
##STR00866## 5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)-N-(2-methyl- 2- phenylpropyl)pentanamide m/z 488
[MH].sup.+ RT 3.53 min 725 ##STR00867## 5-(8-chloro-2,6-dioxo-3-
pentyl-2,36,7-tetrahydro- 1H-purin-1-yl)-N-[(4-
fluorophenyl)methyl]-N- methylpentanamide m/z 478 [MH].sup.+ RT
3.46 min 726 ##STR00868## 5-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-[(2-
fluorophenyl)methyl]pentanamide m/z 464 [MH].sup.+ RT 3.32 min 727
##STR00869## N-[3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)propyl]-2-(3- methylphenyl)acetamide m/z 446
[MH].sup.+ RT 3.37 min 728 ##STR00870## N-[3-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl]-2-(4-
fluorophenyl)acetamide m/z 450 [MH].sup.+ RT 3.28 min 729
##STR00871## N-[3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)propyl]-2-(4- methylphenyl)acetamide m/z 446
[MH].sup.+ RT 3.36 min 730 ##STR00872## N-[3-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl]-2- methyl-2-
phenylpropanamide m/z 460 [MH].sup.+ RT 3.50 min 731 ##STR00873##
N-[3-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)propyl]-3- methyl-3-phenylbutanamide m/z 474
[MH].sup.+ RT 3.51 min 732 ##STR00874## N-[3-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl]-3-(3-
methylphenyl)propanamide m/z 460 [MH].sup.+ RT 3.45 min 733
##STR00875## 5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)-N-(1- phenylcyclopropyl)pentanamide m/z 472
[MH].sup.+ RT 3.29 min 734 ##STR00876## 5-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-methyl-N-
phenylpentanamide m/z 446 [MH].sup.+ RT 3.27 min 735 ##STR00877##
5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)-N-(3- methylphenyl)pentanamide m/z 446 [MH].sup.+ RT
3.41 min
736 ##STR00878## 5-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-methyl-N- (3-
methylphenyl)pentanamide m/z 460 [MH].sup.+ RT 3.41 min 737
##STR00879## 5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)-N-(4- methylphenyl)pentanamide m/z 446 [MH].sup.+ RT
3.40 min 738 ##STR00880## 5-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N-
(cyclohexylmethyl)pentanamide m/z 452 [MH].sup.+ RT 3.40 min 739
##STR00881## 8-chloro-3-pentyl-1-[2- (phenylamino)ethyl]-3,7-
dihydro-1H-purine-2,6-dione m/z 376 [MH].sup.+ RT 3.55 min 740
##STR00882## 5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)-N-methyl-N- (4- methylphenyl)pentanamide m/z 460
[MH].sup.+ RT 3.41 min 741 ##STR00883## 5-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)-N- cyclohexylpentanamide
m/z 438 [MH].sup.+ RT 3.25 min 742 ##STR00884##
N-[2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-
yl)ethyl]benzenesulfonamide m/z 440 [MH].sup.+ RT 3.08 min 743
##STR00885## N-[2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)ethyl]-1- phenylmethanesulfonamide m/z 454 [MH].sup.+
RT 3.15 min 744 ##STR00886## phenyl [2-(8-chloro-2,6-
dioxo-3-pentyl-2,3,6,7- tetrahydro-1H-purin-1- yl)ethyl]carbamate
m/z 420 [MH].sup.+ RT 3.18 min 745 ##STR00887## phenylmethyl
[2-(8-chloro- 2,6-dioxo-3-pentyl-2,3,6,7- tetrahydro-1H-purin-1-
yl)ethyl]carbamate m/z 434 [MH].sup.+ RT 3.23 min 746 ##STR00888##
N-[2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-
yl)ethyl]benzamide m/z 404 [MH].sup.+ RT 3.04 min 747 ##STR00889##
N-[2-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)ethyl]-2- phenylacetamide m/z 418 [MH].sup.+ RT 2.99
min 748 ##STR00890## N-[2-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)ethyl]-3-
phenylpropanamide m/z 432 [MH].sup.+ RT 3.14 min 749 ##STR00891##
8-chloro-1-[(1- hydroxycyclopropyl)methyl]-
3-pentyl-3,7-dihydro-1H- purine-2,6-dione m/z 327 [MH].sup.+ RT
2.82 min 750 ##STR00892## phenyl [3-(8-chloro-2,6-
dioxo-3-pentyl-2,3,6,7- tetrahydro-1H-purin-1- yl)propyl]carbamate
m/z 434 [MH].sup.+ RT 3.31 min 751 ##STR00893## 2-phenylethyl
[3-(8-chloro- 2,6-dioxo-3-pentyl-2,3,6,7- tetrahydro-1H-purin-1-
yl)propyl]carbamate m/z 462 [MH].sup.+ RT 3.48 min 752 ##STR00894##
2-pyridin-4-ylethyl [3-(8- chloro-2,6-dioxo-3-pentyl-
2,3,6,7-tetrahydro-1H-purin- 1-yl)propyl]carbamate m/z 463
[MH].sup.+ RT 2.44 min 753 ##STR00895## 2-pyridin-2-ylethyl [3-(8-
chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin-
1-yl)propyl]carbamate m/z 480 [MH].sup.+ RT 2.44 min 754
##STR00896## 2-(2-fluorophenyl)ethyl [3-
(8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin-
1-yl)propyl]carbamate m/z 480 [MH].sup.+ RT 3.46 min 755
##STR00897## 2-(1H-imidazol-1-yl)ethyl [3-
(8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin-
1-yl)propyl]carbamate m/z 452 [MH].sup.+ RT 2.30 min 756
##STR00898## 2-(1H-imidazol-2-yl)ethyl [3-
(8-chloro-2,6-dioxo-3-pentyl- 2,3,6,7-tetrahydro-1H-purin-
1-yl)propyl]carbamate m/z 452 [MH].sup.+ RT 2.31 min 757
##STR00899## 8-chloro-3-pentyl-1-{3-[5- (phenylmethyl)-1H-tetrazol-
1-yl]propyl}-3,7-dihydro-1H- purine-2,6-dione m/z 457 [MH].sup.+ RT
3.32 min 758 ##STR00900## 8-chloro-1-[3-(1H-imidazol-
4-yl)propyl]-3-pentyl-3,7- dihydro-1H-purine-2,6-dione m/z 365
[MH].sup.+ RT 2.27 min 759 ##STR00901## 8-chloro-3-pentyl-1-{3-[1-
(phenylmethyl)-1H-imidazol- 4-yl]propyl}-3,7-dihydro-1H-
purine-2,6-dione m/z 455 [MH].sup.+ RT 2.61 min 760 ##STR00902##
8-chloro-3-pentyl-1-[3-(3- thienyl)propyl]-3,7-dihydro-
1H-purine-2,6-dione m/z 381 [MH].sup.+ RT 3.61 min 761 ##STR00903##
8-chloro-3-pentyl-1-[3-(2- thienyl)propyl]-3,7-dihydro-
1H-purine-2,6-dione m/z 381 [MH].sup.+ RT 3.69 min 762 ##STR00904##
3-butyl-8-chloro-1-{3-[5- (phenylmethyl)-1H-1,2,4-
triazol-1-yl]propyl}-3,7- dihydro-1H-purine-2,6-dione m/z 442
[MH].sup.+ RT 2.94 min 763 ##STR00905## 8-chloro-1-{3-[5-
(phenylmethyl)-2H-tetrazol- 2-yl]propyl}-3-propyl-3,7-
dihydro-1H-purine-2,6-dione m/z 429 [MH].sup.+ RT 3.14 min 764
##STR00906## 8-chloro-3-methyl-1-{3-[5- (phenylmethyl)-1,2,4-
oxadiazol-3-yl]propyl}-3,7- dihydro-1H-purine-2,6-dione m/z 401
[MH].sup.+ RT 2.88 min 765 ##STR00907## 8-chloro-3-methyl-1-{3-[3-
(phenylmethyl)-1,2,4- oxadiazol-5-yl]propyl}-3,7-
dihydro-1H-purine-2,6-dione m/z 401 [MH].sup.+ RT 2.89 min 766
##STR00908## 8-chloro-3-ethyl-1-{3-[5- (phenylmethyl)-1,2,4-
oxadiazol-3-yl]propyl}-3,7- dihydro-1H-purine-2,6-dione m/z 415
[MH].sup.+ RT 2.97 min 767 ##STR00909## 4-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)butanoic acid m/z 343
[MH].sup.+ RT 2.81 min 768 ##STR00910##
8-chloro-3-pentyl-1-[3-(3-{[3- (trifluoromethyl)-1H-pyrazol-
1-yl]methyl}-1,2,4- oxadiazol- 5-yl)propyl]-3,7-dihydro-1H-
purine-2,6-dione m/z 515 [MH].sup.+ RT 3.43 min 769 ##STR00911##
8-chloro-1-{4-[3-(4- fluorophenyl)-1,2,4- oxadiazol-5-yl]butyl}-3-
pentyl-3,7-dihydro-1H- purine-2,6-dione m/z 475 [MH].sup.+ RT 3.71
min 770 ##STR00912## 8-chloro-3-pentyl-1-(4-{3-[4-
(trifluoromethyl)phenyl]- 1,2,4-oxadiazol-5-yl}butyl)-
3,7-dihydro-1H-purine-2,6- dione m/z 525 [MH].sup.+ RT 3.92 min 771
##STR00913## 8-chloro-1-(4-{3-[4- (dimethylamino)phenyl]-
1,2,4-oxadiazol-5-yl}butyl)- 3-pentyl-3,7-dihydro-1H-
purine-2,6-dione m/z 500 [MH].sup.+ RT 3.73 min 772 ##STR00914##
8-chloro-1-{4-[3-(5-chloro-2- thienyl)-1 2,4-oxadiazol-5-
yl]butyl}-3-pentyl-3,7- dihydro-1H-purine-2,6-dione m/z 497
[MH].sup.+ RT 3.88 min 773 ##STR00915## 8-chloro-3-pentyl-1-[3-(3-
phenyl-1,2,4-oxadiazol-5- yl)propyl]-3,7-dihydro-1H-
purine-2,6-dione m/z 443 [MH].sup.+ RT 3.51 min 774 ##STR00916##
8-chloro-1-{4-[3-(3,4- dichlorophenyl)-1,2,4-
oxadiazol-5-yl]butyl}-3- pentyl-3,7-dihydro-1H- purine-2,6-dione
m/z 525 [MH].sup.+ RT 4.12 min 775 ##STR00917##
8-chloro-3-pentyl-1-{4-[3- (pyridin-3-ylmethyl)-1,2,4-
oxadiazol-5-yl]butyl}-3,7- dihydro-1H-purine-2,6-dione m/z 472
[MH].sup.+ RT 2.90 min 776 ##STR00918##
8-chloro-3-pentyl-1-(2-{[(3- phenyl-1,2,4-oxadiazol-5-
yl)methyl]oxy}ethyl)-3,7- dihydro-1H-purine-2,6-dione m/z 459
[MH].sup.+ RT 3.45 min 777 ##STR00919##
8-chloro-3-pentyl-1-[3-(3-{[4- (trifluoromethyl)phenyl]
methyl}-1,2,4-oxadiazol-5- yl)propyl]-3,7-dihydro-1H-
purine-2,6-dione m/z 525 [MH].sup.+ RT 3.69 min 778 ##STR00920##
8-chloro-1-(3-{3- [(pentafluorophenyl)methyl]-
1,2,4-oxadiazol-5-yl}propyl)- 3-pentyl-3,7-dihydro-1H-
purine-2,6-dione m/z 547 [MH].sup.+ RT 3.66 min 779 ##STR00921##
1-{3-[3-(1-benzothien-2-yl)- 1,2,4-oxadiazol-5-yl]propyl}-
8-chloro-3-pentyl-3,7- dihydro-1H-purine-2,6-dione m/z 499
[MH].sup.+ RT 3.77 min 780 ##STR00922## 8-chloro-1-{3-[3-(2-
methylphenyl)-1,2,4- oxadiazol-5-yl]propyl}-3-
pentyl-3,7-dihydro-1H- purine-2,6-dione m/z 457 [MH].sup.+ RT 3.62
min 781 ##STR00923## 8-chloro-1-(2,3- dihydroxypropyl)-3-pentyl-
3,7-dihydro-1H-purine-2,6- dione m/z 331 [MH].sup.+ RT 2.48 min 782
##STR00924## 1-(4-biphenyl-4-ylbutyl)-8-
chloro-3-pentyl-3,7-dihydro- 1H-purine-2,6-dione m/z 465 [MH].sup.+
RT 4.18 min 783 ##STR00925## 8-chloro-1-{3-[3-
(phenylmethyl)-1,2,4- oxadiazol-5-yl]propyl}-3,7-
dihydro-1H-purine-2,6-dione m/z 387 [MH].sup.+ RT 2.63 min 784
##STR00926## 8-chloro-1-{3-[5- (phenylmethyl)-1,2,4-
oxadiazol-3-yl]propyl}-3,7- dihydro-1H-purine-2,6-dione m/z 387
[MH].sup.+ RT 2.65 min 785 ##STR00927## 8-chloro-3-pentyl-1-{4-[5-
(1H-tetrazol-5-yl)-1,2,4- oxadiazol-3-yl]butyl}-3,7-
dihydro-1H-purine-2,6-dione m/z 449 [MH].sup.+ RT 4.03 min 786
##STR00928## 3-butyl-8-chloro-1-{3-[5- (phenylmethyl)-1H-tetrazol-
1-yl]propyl}-3,7-dihydro-1H- purine-2,6-dione m/z 443 [MH].sup.+ RT
3.11 min 787 ##STR00929## 8-chloro-1-{4-[5-(2-
hydroxyphenyl)-1,2,4- oxadiazol-3-yl]butyl}-3-
pentyl-3,7-dihydro-1H- purine-2,6-dione m/z 473 [MH].sup.+ RT 3.84
min 788 ##STR00930## 8-chloro-1-{4-[5-(3-chloro-4-
hydroxyphenyl)-1,2,4- oxadiazol-3-yl]butyl}-3-
pentyl-3,7-dihydro-1H- purine-2,6-dione m/z 507 [MH].sup.+ RT 3.74
min 789 ##STR00931## 1-[3-(1-benzofuran-2-
yl)propyl]-8-chloro-3-pentyl- 3,7-dihydro-1H-purine-2,6- dione m/z
415 [MH].sup.+ RT 5.10 min 790 ##STR00932## 1-[4-(1-benzofuran-2-
yl)butyl]-8-chloro-3-pentyl- 3,7-dihydro-1H-purine-2,6- dione m/z
429 [MH].sup.+ RT 3.88 min 791 ##STR00933## 8-chloro-1-{4-[5-(5-
chloropyridin-2-yl)-1,2,4- oxadiazol-3-yl]butyl}-3-
propyl-3,7-dihydro-1H- purine-2,6-dione m/z 464 [MH].sup.+ RT 3.30
min 792 ##STR00934## 8-chloro-1-{4-(5-(2,4- difluorophenyl)-1,2,4-
oxadiazol-3-yl]butyl}-3- propyl-3,7-dihydro-1H- purine-2,6-dione
m/z 465 [MH].sup.+ RT 3.48 min 793 ##STR00935##
8-chloro-1-{4-[5-(3- hydroxypropyl)-1,2,4- oxadiazol-3-yl]butyl}-3-
pentyl-3,7-dihydro-1H- purine-2,6-dione m/z 439 [MH].sup.+ RT 2.93
min 794 ##STR00936## 3-[4-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1- yl)butyl]benzonitrile m/z
414 [MH].sup.+ RT 3.62 min 795 ##STR00937## 8-chloro-1-[4-(3-
hydroxyphenyl)butyl]-3- pentyl-3,7-dihydro-1H- purine-2,6-dione m/z
405 [MH].sup.+ RT 3.48 min 796 ##STR00938## 1-{4-[6,7-
bis(methyloxy)naphthalen-1- yl]butyl}-8-chloro-3-pentyl-
3,7-dihydro-1H-purine-2,6- dione m/z 499 [MH].sup.+ RT 3.78 min 797
##STR00939## 1-[4-(4-aminophenyl)butyl]- 8-chloro-3-pentyl-3,7-
dihydro-1H-purine-2,6-dione m/z 404 [MH].sup.+ RT 3.02 min 798
##STR00940## 8-chloro-1-[4-(3-hydroxy-
2,4,6-trimethylphenyl)butyl]- 3-pentyl-3,7-dihydro-1H-
purine-2,6-dione m/z 447 [MH].sup.+ RT 3.78 min 799 ##STR00941##
8-chloro-1-[4-(2,6- dichlorophenyl)butyl]-3- pentyl-3,7-dihydro-1H-
purine-2,6-dione m/z 457 [MH].sup.+ RT 4.10 min 800 ##STR00942##
8-chloro-1-{4-[3- (methylsulfonyl)phenyl]butyl}-
3-pentyl-3,7-dihydro-1H- purine-2,6-dione m/z 467 [MH].sup.+ RT
3.33 min 801 ##STR00943## 8-chloro-1-{4-[3-
(cyclopentylsulfonyl)phenyl] butyl}-3-pentyl-3,7-dihydro-
1H-purine-2,6-dione m/z 521 [MH].sup.+ RT 3.65 min 802 ##STR00944##
4-[4-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro- 1H-purin-1-
yl)butyl]benzonitrile m/z 414 [MH].sup.+ RT 3.61 min 803
##STR00945## 8-chloro-1-(4-naphthalen-1- ylbutyl)-3-pentyl-3,7-
dihydro-1H-purine-2,6-dione m/z 439 [MH].sup.+ RT 4.00 min 804
##STR00946## 8-chloro-3-pentyl-1-(4-{4-
[(phenylmethyl)oxy]phenyl}
butyl)-3,7-dihydro-1H-purine- 2,6-dione m/z 495 [MH].sup.+ RT 4.06
min 805 ##STR00947## 8-chloro-1-[4-(4-
fluorophenyl)butyl]-3-pentyl- 3,7-dihydro-1H-purine-2,6- dione m/z
407 [MH].sup.+ RT 3.78 min 806 ##STR00948##
N-[4-{[4-(8-chloro-2,6-dioxo- 3-pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)butyl]oxy}-3- (methyloxy)phenyl]acetamide m/z 492
[MH].sup.+ RT 3.09 min 807 ##STR00949## 3-butyl-8-chloro-1-[4-(5-
phenyl-1,2,4-oxadiazol-3- yl)butyl]-3,7-dihydro-1H-
purine-2,6-dione m/z 443 [MH].sup.+ RT 3.49 min 808 ##STR00950##
1-(4-biphenyl-3-ylbutyl)-8- chloro-3-pentyl-3,7-dihydro-
1H-purine-2,6-dione m/z 465 [MH].sup.+ RT 4.13 min 809 ##STR00951##
3-butyl-8-chloro-1-(4-{5-[2- fluoro-4- (trifluoromethyl)phenyl]-
1,2,4-oxadiazol-3-yl}butyl)- 3,7-dihydro-1H-purine-2,6- dione m/z
529 [MH].sup.+ RT 3.71 min 810 ##STR00952##
3-butyl-8-chloro-1-{4-[5-(4- chloro-2-fluorophenyl)-1,2,4-
oxadiazol-3-yl]butyl}-3,7- dihydro-1H-purine-2,6-dione m/z 495
[MH].sup.+ RT 3.64 min 811 ##STR00953##
3-butyl-8-chloro-1-{4-[5-(2,4- difluorophenyl)-1,2,4-
oxadiazol-3-yl]butyl)-3,7- dihydro-1H-purine-2,6-dione m/z 479
[MH].sup.+ RT 3.49 min 812 ##STR00954##
3-butyl-8-chloro-1-{4-[5-(2,3- difluorophenyl)-1,2,4-
oxadiazol-3-yl]butyl)-3,7- dihydro-1H-purine-2,6-dione m/z 479
[MH].sup.+ RT 3.53 min 813 ##STR00955##
3-butyl-8-chloro-1-{4-[5-(2- fluoro-4-methylphenyl)-
1,2,4-oxadiazol-3-yl]butyl}- 3,7-dihydro-1H-purine-2,6- dione m/z
475 [MH].sup.+ RT 3.51 min 814 ##STR00956## 3-butyl-8-chloro-1-(4-
hydroxybutyl)-3,7-dihydro- 1H-purine-2,6-dione m/z 315 [MH].sup.+
RT 2.54 min 815 ##STR00957## 3-butyl-8-chloro-1-{4-[5-(2,5-
difluorophenyl)-1,2,4- oxadiazol-3-yl]butyl}-3,7-
dihydro-1H-purine-2,6-dione m/z 479 [MH].sup.+ RT 3.50 min 816
##STR00958## 3-butyl-8-chloro-1-{4-[5-(3,5-
dichlorophenyl)-2H-tetrazol- 2-yl]butyl)-3,7-dihydro-1H-
purine-2,6-dione m/z 511 [MH].sup.+ RT 3.92 min 817 ##STR00959##
3-butyl-8-chloro-1-{4-[5-(6- methylpyridin-2-yl)-1,2,4-
oxadiazol-3-yl]butyl}-3,7- dihydro-1H-purine-2,6-dione m/z 458
[MH].sup.+ RT 3.12 min 818 ##STR00960##
3-butyl-8-chloro-1-(4-{5-]2- fluoro-5-(methyloxy)phenyl]-
1,2,4-oxadiazol-3-yl}butyl)- 3,7-dihydro-1H-purine-2,6- dione m/z
491 [MH].sup.+ RT 3.51 min 819 ##STR00961##
3-butyl-8-chloro-1-{4-(2,4- dioxo-5-(phenylmethyl)-1,3-
thiazolidin-3-yl]butyl}-3,7- dihydro-1H-purine-2,6-dione m/z 504
[MH].sup.+ RT 3.36 min 820 ##STR00962## 3-butyl-8-butyl-1-[4-(3,5-
dioxo1-phenyl-1,2,4- triazolidin-4-yl)-butyl]-3,7-
dihydro-1H-purine-2,6-dione m/z 474 [MH].sup.+ RT 2.91 min 821
##STR00963## 3-butyl-8-chloro-1-{4-[5-(6-
oxo-1,6-dihydropyridin-2-yl)- 1,2,4-oxadiazol-3-yl]butyl}-
3,7-dihydro-1H-purine-2,6- dione m/z 460 [MH].sup.+ RT 2.86 min 822
##STR00964## 3-butyl-8-chloro-1-{4-[5-(6-
fluoropyridin-2-yl)-1,2,4- oxadiazol-3-yl]butyl}-3,7-
dihydro-1H-purine-2,6-dione m/z 462 [MH].sup.+ RT 3.23 min 823
##STR00965## 3-butyl-8-chloro-1-{4-[5-(3-
chloro-2-fluorophenyl)-1,2,4- oxadiazol-3-yl]butyl}-3,7-
dihydro-1H-purine-2,6-dione m/z 495 [MH].sup.+ RT 3.69 min 824
##STR00966## 3-butyl-8-chloro-1-{4-[5-(3- methylphenyl-1,2,4-
oxadiazol-3-yl]butyl}-3,7- dihydro-1H-purine-2,6-dione m/z 457
[MH].sup.+ RT 3.67 min 825 ##STR00967##
3-butyl-8-chloro-1-{4-[5-(3,5- dichloro-4-hydroxyphenyl)-
1,2,4-oxadiazol-3-yl]butyl}- 3,7-dihydro-1H-purine-2,6- dione m/z
527 [MH].sup.+ RT 3.92 min 826 ##STR00968##
3-butyl-8-chloro-1-(4-{5-[4- hydroxy-3- (methyloxy)phenyl]-1,2,4-
oxadiazol-3-yl}butyl)-3,7- dihydro-1H-purine-2,6-dione m/z 489
[MH].sup.+ RT 3.27 min 827 ##STR00969##
3-butyl-8-chloro-1-{4-[5-(3- chloro-4-hydroxyphenyl)-
1,2,4-oxadiazol-3-yl]butyl}- 3,7-dihydro-1H-purine-2,6- dione m/z
493 [MH].sup.+ RT 3.61 min 828 ##STR00970##
3-butyl-8-chloro-1-{4-[5-(1H- indol-6-yl)-1,2,4-oxadiazol-
3-yl]butyl}-3,7-dihydro-1H- purine-2,6-dione m/z 482 [MH].sup.+ RT
3.55 min 829 ##STR00971## 3-butyl-8-chloro-1-{4-(5-(2-
methylphenyl)-1,2,4- oxadiazol-3-yl]butyl}-3,7-
dihydro-1H-purine-2,6-dione m/z 457 [MH].sup.+ RT 3.67 min 830
##STR00972## 3-butyl-8-chloro-1-(4-{-5[4- (methyloxy)phenyl]-1,2,4-
oxadiazol-3-yl}butyl)-3,7- dihydro-1H-purine-2,6-dione m/z 473
[MH].sup.+ RT 3.51 min 831 ##STR00973##
3-butyl-8-chloro-1-{4-[5-(4- fluorophenyl)-1,2,4-
oxadiazol-3-yl]butyl}-3,7- dihydro-1H-purine-2,6-dione m/z 461
[MH].sup.+ RT 3.54 min 832 ##STR00974## 3-butyl-8-chloro-1-[4-(5-
pyrazin-2-yl-1,2,4-oxadiazol- 3-yl)butyl]-3,7-dihydro-1H-
purine-2,6-dione m/z 445 [MH].sup.+ RT 2.96 min 833 ##STR00975##
3-butyl-8-chloro-1-{4-[5-(6- oxo-1,6-dihydropyridin-3-yl)-
1,2,4-oxadiazol-3-yl]butyl)- 3,7-dihydro-1H-purine-2,6- dione m/z
460 [MH].sup.+ RT 2.78 min 834 ##STR00976##
1-{4-[5-(1H-benzimidazol-2- yl)-1,2,4-oxadiazol-3-
yl]butyl}-3-butyl-8-chloro- 3,7-dihydro-1H-purine-2,6- dione m/z
483 [MH].sup.+ RT 3.22 min 835 ##STR00977##
3-butyl-8-chloro-1-{4-[5-(3- fluorophenyl)-1,2,4-
oxadiazol-3-yl]butyl}-3,7- dihydro-1H-purine-2,6-dione m/z 461
[MH].sup.+ RT 3.58 min 836 ##STR00978## 3-butyl-8-chloro-1-[4-(5-
pyrimidin-2-yl-1,2,4- oxadiazol-3-yl)butyl]-3,7-
dihydro-1H-purine-2,6-dione m/z 445 [MH].sup.+ RT 2.84 min
Example 837
3-Butyl-8-chloro-1-{4-[5-(2-fluoro-4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl]b-
utyl}-3,7-dihydro-1H-purine-2,6-dione
a)
3-Butyl-8-chloro-1-{4-[5-(2-fluoro-4-hydroxyphenyl)-1,2,4-oxadiazol-3-y-
l]butyl}-3,7-dihydro-1H-purine-2,6-dione
##STR00979##
[1082] CDI (45 mg, 0.28 mmol) in anhydrous DMSO (0.5 ml) was added
to 2-fluoro-4-hydroxybenzoic acid (40 mg, 0.25 mmol) and stirred at
rt for 2 h.
5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydr-
oxypentanimidamide (100 mg, 0.28 mmol) in DMSO (0.4 ml) was added
and the resulting mixture heated at 90.degree. C. for 18 h.
Purification by MDAP afforded the title compound as a solid (38 mg,
28%).
[1083] LC/MS: m/z 477 [MH].sup.+, RT 3.39 min.
[1084] .sup.1H NMR (DMSO-d.sub.6) .delta.: 0.87 (t, 3H, J=7 Hz),
1.27 (m, 2H), 1.56-1.78 (m, 6H), 2.77 (t, 2H, J=7 Hz), 3.90 (m,
4H), 6.80 (m, 2H), 7.91 (t, 1H, J=9 Hz), 11.01 (s, 1H), 14.45 (br
s, 1H).
b)
5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydro-
xypentanimidamide
##STR00980##
[1086]
5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pent-
anenitrile (8.5 g, 26 mmol) was dissolved in EtOH (100 ml).
Hydroxylamine (50% in water; 2.6 ml, 39 mmol) was added and the
mixture heated at 80.degree. C. for 48 h under nitrogen. The
reaction mixture was concentrated in vacuo, the resultant solid
washed with methanol and dried to give the title compound as a
solid (5.9 g, 47%).
[1087] LC/MS: m/z 357 [MH].sup.+, RT 2.17 min.
c)
5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanen-
itrile
##STR00981##
[1089] 5-Bromopentanenitrile (4.54 ml, 39 mmol) and cesium
carbonate (12.7 g) were added to a solution of
3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(10 g, 35 mmol) in DMF (100 ml) and the mixture stirred under
nitrogen at 40.degree. C. overnight and allowed to cool.
[1090] The mixture was then degassed by the repeated successive
application of a vacuum and then nitrogen pressure. The mixture was
then treated with tetrakis(triphenylphosphine)palladium(0) (2.86 g,
2.5 mmol) and morpholine (30.8 ml, 350 mmol). The mixture was
stirred in a nitrogen atmosphere for 3 h and then partitioned
between EtOAc and 2M aqueous hydrochloric acid. The aqueous layer
was separated and extracted with EtOAc (.times.2). The combined
organic phases were concentrated in vacuo to give a solid that was
washed with ether, filtered and dried. The filtrate was
concentrated and purified on an aminopropyl column eluting with
MeOH followed by 3% AcOH/MeOH. The product-containing fractions
were combined and concentrated to give a solid, which was combined
with the filtered product. The title compound was obtained as a
solid (10.5 g, 93%).
[1091] LC/MS: m/z 324 [MH].sup.+, RT 2.75 min.
[1092] The following compounds (Table 35) were prepared using a
method analogous to that for Example 837, using the appropriate
carboxylic acid.
TABLE-US-00037 844 ##STR00982## 3-butyl-8-chloro-1-[4-(5-
isoquinolin-1-yl-1,2,4- oxadiazol-3-yl)butyl]-3,7-
dihydro-1H-purine-2,6-dione m/z 494 [MH].sup.+ RT 3.49 min 845
##STR00983## 3-butyl-8-chloro-1-[4-(2-oxo- 3-phenylimidazolidin-1-
yl)butyl]-3,7-dihydro-1H- purine-2,6-dione m/z 459 [MH].sup.+ RT
3.23 min 846 ##STR00984## 3-butyl-8-chloro-1-[4-(2,5-
dioxo-3-phenylimidazolidin- 1-yl)butyl]-3,7-dihydro-1H-
purine-2,6-dione m/z 473 [MH].sup.+ RT 3.19 min 847 ##STR00985##
3-butyl-8-chloro-1-[4-(2-oxo- 3-phenylpyrrolidin-1-
yl)butyl]-3,7-dihydro-1H- purine-2,6-dione m/z 458 [MH].sup.+ RT
3.12 min 848 ##STR00986## N-[4-(3-butyl-8-chloro-2,6-
dioxo-2,3,6,7-tetrahydro-1H- purin-1-yl)butyl]-N-
methylbenzenesulfonamide m/z 468 [MH].sup.+ RT 3.28 min 849
##STR00987## 3-butyl-8-chloro-1-[4-(4- phenyl-1H-imidazol-1-
yl)butyl]-3,7-dihydro-1H- purine-2,6-dione m/z 441 [MH].sup.+ RT
2.60 min 850 ##STR00988## 3-butyl-8-chloro-1-[4-(2,5-
dioxo-3-phenylpyrrolidin-1- yl)butyl]-3,7-dihydro-1H-
purine-2,6-dione m/z 472 [MH].sup.+ RT 3.20 min 851 ##STR00989##
3-butyl-8-chloro-1-[4-(4- phenylpiperidin-1-yl)butyl]-
3,7-dihydro-1H-purine-2,6- dione m/z 458 [MH].sup.+ RT 2.56 min 852
##STR00990## 3-butyl-8-chloro-1-[4-(4- phenylpiperazin-1-yl)butyl]-
3,7-dihydro-1H-purine-2,6- dione m/z 459 [MH].sup.+ RT 2.49 min 853
##STR00991## 3-butyl-8-chloro-1-(4- mopholin-4-ylbutyl)-3,7-
dihydro-1H-purine-2,6-dione m/z 384 [MH].sup.+ RT 2.11 min 854
##STR00992## 3-butyl-8-chloro-1-[4-(3,4- dihydroisoquinolin-2(1H)-
yl)butyl]-3,7-dihydro-1H- purine-2,6-dione m/z 430 [MH].sup.+ RT
2.40 min 855 ##STR00993## 3-butyl-8-chloro-1-[4-(1,3-
dihydro-2H-isoindol-2- yl)butyl]-3,7-dihydro-1H- purine-2,6-dione
m/z 416 [MH].sup.+ RT 2.33 min 856 ##STR00994##
3-butyl-8-chloro-1-(4-{5-[2- fluoro-6-(methyloxy)phenyl]-
1,2,4-oxadiazol-3-yl}butyl]- 3,7-dihydro-1H-purine-2,6- dione m/z
491 [MH].sup.+ RT 3.33 min 857 ##STR00995##
3-butyl-8-chloro-1-{4-[5-(2- cyclohexylphenyl)-1,2,4-
oxadiazol-3-yl]butyl}-3,7- dihydro-1H-purine-2,6-dione m/z 525
[MH].sup.+ RT 4.18 min 858 ##STR00996## 3-butyl-8-chloro-1-[4-(5-
phenyl-1,3-oxazol-2- yl)butyl]-3,7-dihydro-1H- purine-2,6-dione m/z
442 [MH].sup.+ RT 3.46 min 859 ##STR00997##
3-butyl-8-chloro-1-[4-(4- phenyl-1,3-oxazol-2-
yl)butyl]-3,7-dihydro-1H- purine-2,6-dione m/z 442 [MH].sup.+ RT
3.48 min 860 ##STR00998## 3-butyl-8-chloro-1-[4-oxo-4-
(3-phenylpyrrolidin-1- yl)butyl]-3,7-dihydro-1H- purine-2,6-dione
m/z 458 [MH].sup.+ RT 3.16 min 861 ##STR00999##
3-butyl-8-chloro-1-{4-[3-(2- fluorophenyl)-1,2,4-
oxadiazol-5-yl]butyl}-3,7- dihydro-1H-purine-2,6-dione m/z 461
[MH].sup.+ RT 3.45 min 862 ##STR01000##
3-butyl-8-chloro-1-{4-[5-(4- fluorophenyl)-2H-tetrazol-2-
yl]butyl}-3,7-dihydro-1H- purine-2,6-dione m/z 461 [MH].sup.+ RT
3.47 min 863 ##STR01001## 3-butyl-8-chloro-1-{4-[5-(2,6-
difluorophenyl)-2H-tetrazol- 2-yl]butyl}-3,7-dihydro-1H-
purine-2,6-dione m/z 479 [MH].sup.+ RT 3.32 min 864 ##STR01002##
3-butyl-8-chloro-1-[4-(5- pyridin-2-yl-1H-tetrazol-1-
yl)butyl]-3,7-dihydro-1H- purine-2,6-dione m/z 444 [MH].sup.+ RT
2.94 min 865 ##STR01003## 3-butyl-8-chloro-1-[4-(5-
pyridin-2-yl-2H-tetrazol-2- yl)butyl]-3,7-dihydro-1H-
purine-2,6-dione m/z 444 [MH].sup.+ RT 3.07 min 866 ##STR01004##
3-butyl-8-chloro-1-{4-[5-(2- methylphenyl)-2H-tetrazol-
2-yl]butyl}-3,7-dihydro-1H- purine-2,6-dione m/z 457 [MH].sup.+ RT
3.54 min 867 ##STR01005## 3-butyl-8-chloro-1-{4-[5-(3-
methylphenyl)-2H-tetrazol- 2-yl]butyl}-3,7-dihydro-1H-
purine-2,6-dione m/z 457 [MH].sup.+ RT 3.56 min 868 ##STR01006##
3-butyl-8-chloro-1-{4-[5-(2- chlorophenyl)-2H-tetrazol-2-
yl]butyl}-3,7-dihydro-1H- purine-2,6-dione m/z 477 [MH].sup.+ RT
3.68 min 869 ##STR01007## 3-butyl-8-chloro-1-(4-{5-[4-
(methyloxy)phenyl]-2H- tetrazol-2-yl}butyl)-3,7-
dihydro-1H-purine-2,6-dione m/z 473 [MH].sup.+ RT 3.40 min 870
##STR01008## 3-butyl-8-chloro-1-{4-[5-(4-
chlorophenyl)-2H-tetrazol-2- yl]butyl}-3,7-dihydro-1H-
purine-2,6-dione m/z 477 [MH].sup.+ RT 3.68 min 871 ##STR01009##
3-butyl-8-chloro-1-{4-[5-(3- fluorophenyl)-2H-tetrazol-2-
yl]butyl}-3,7-dihydro-1H- purine-2,6-dione m/z 461 [MH].sup.+ RT
3.51 min 872 ##STR01010## 3-butyl-8-chloro-1-{4-[5-(2-
fluorophenyl)-2H-tetrazol-2- yl]butyl}-3,7-dihydro-1H-
purine-2,6-dione m/z 461 [MH].sup.+ RT 3.34 min 873 ##STR01011##
5-(3-butyl-8-chloro-2,6- dioxo-2,3,6,7-tetrahydro-1H-
purin-1-yl)pentanoic acid m/z 343 [MH].sup.+ RT 2.76 min 874
##STR01012## 5-(3-butyl-8-chloro-2,6- dioxo-2,3,6,7-tetrahydro-1H-
purin-1-yl)pentanoic acid m/z 315 [MH].sup.+ RT 2.74 min 875
##STR01013## 3-butyl-8-chloro-1-[4-(3-
phenyl-1-pyrrolidinyl)butyl]- 3,7-dihydro-1H-purine-2,6- dione m/z
444 [MH].sup.+ RT 2.51 min 876 ##STR01014##
3-butyl-8-chloro-1-{4-[5-(2- methylphenyl)-1H-tetrazol-
1-yl]butyl}-3,7-dihydro-1H- purine-2,6-dione m/z 457 [MH].sup.+ RT
3.16 min 877 ##STR01015## 3-butyl-8-chloro-1-[4-(5-
phenyl-1H-tetrazol-1- yl)butyl]-3,7-dihydro-1H- purine-2,6-dione
m/z 443 [MH].sup.+ RT 3.08 min 878 ##STR01016##
3-butyl-8-chloro-1-(4-{5-[4- (methyloxy)phenyl]-1H-
tetrazol-1-yl}butyl)-3,7- dihydro-1H-purine-2,6-dione m/z 473
[MH].sup.+ RT 3.10 min 879 ##STR01017##
3-butyl-8-chloro-1-(4-{5-[3- (methyloxy)phenyl]-2H-
tetrazol-2-yl}butyl)-3,7- dihydro-1H-purine-2,6-dione m/z 473
[MH].sup.+ RT 3.40 min 880 ##STR01018##
8-chloro-3-ethyl-1-(3-{(5Z)- 5-[(4- fluorophenyl)methylidene]-
2,4-dioxo-1,3-thiazolidin-3- yl}propyl)-3,7-dihydro-1H-
purine-2,6-dione m/z 478 [MH].sup.+ RT 3.31 min 881 ##STR01019##
3-butyl-8-chloro-1-(3-{(5Z)- 5-[(4- fluorophenyl)methylidene]-
2,4-dioxo-1,3-thiazolidin-3- yl}propyl)-3,7-dihydro-1H-
purine-2,6-dione m/z 506 [MH].sup.+ RT 3.63 min 882 ##STR01020##
8-chloro-1-[4-(3-phenyl- 1,2,4-oxadiazol-5-yl)butyl]-
3-(2-propen-1-yl)-3,7- dihydro-1H-purine-2,6-dione m/z 427
[MH].sup.+ RT 3.20 min 883 ##STR01021## 8-chloro-3-
(cyclopropylmethyl)-1-[4-(5- phenyl-1,2,4-oxadiazol-3-
yl)butyl]-3,7-dihydro-1H- purine-2,6-dione m/z 441 [MH].sup.+ RT
3.38 min 884 ##STR01022## 8-chloro-3- (cyclobutylmethyl)-1-[4-(5-
phenyl-1,2,4-oxadiazol-3- yl)butyl]-3,7-dihydro-1H-
purine-2,6-dione m/z 455 [MH].sup.+ RT 3.53 min 885 ##STR01023##
8-chloro-1-[4-(5-phenyl- 1,2,4-oxadiazol-3-yl)butyl]-
3-(4,4,4-trifluorobutyl)-3,7- dihydro-1H-purine-2,6-dione m/z 497
[MH].sup.+ RT 3.46 min 886 ##STR01024##
8-chloro-3-(4-fluorobutyl)-1- [4-(5-phenyl-1,2,4-
oxadiazol-3-yl)butyl]-3,7- dihydro-1H-purine-2,6-dione m/z 461
[MH].sup.+ RT 3.26 min 887 ##STR01025## 8-chloro-3-[2-
(ethyloxy)ethyl]-1-[4-(5- phenyl-1,2,4-oxadiazol-3-
yl)butyl]-3,7-dihydro-1H- purine-2,6-dione m/z 459 [MH].sup.+ RT
3.16 min 888 ##STR01026## 8-chloro-3-(2-methylpropyl)-
1-[4-(5-phenyl-1,2,4- oxadiazol-3-yl)butyl]-3,7-
dihydro-1H-purine-2,6-dione m/z 443 [MH].sup.+ RT 3.44 min 889
##STR01027## 8-chloro-3-(3- cyclopropylpropyl)-1-[4-(5-
phenyl-1,2,4-oxadiazol-3- yl)butyl]-3,7-dihydro-1H-
purine-2,6-dione m/z 469 [MH].sup.+ RT 3.63 min 890 ##STR01028##
8-chloro-3-methyl-1-[4-(5- phenyl-1,2,4-oxadiazol-3-
yl)butyl]-3,7-dihydro-1H- purine-2,6-dione m/z 401 [MH].sup.+ RT
2.98 min 891 ##STR01029## 3-(8-chloro-2,6-dioxo-3-
pentyl-2,3,6,7-tetrahydro- 1H-purin-1-yl)propyl[(2-
fluorophenyl)methyl]carbamate m/z 466 [MH].sup.+ RT 3.44 min 892
##STR01030## methyl 6-{3-[4-(3-butyl-8- chloro-2,6-dioxo-2,3,6,7-
tetrahydro-1H-purin-1- yl)butyl]-1,2,4-oxadiazol-5-
yl}-3-pyridinecarboxylate m/z 502 [MH].sup.+ RT 3.22 min 893
##STR01031## 5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)-N-(3- hydroxypropyl)-N- (phenylmethyl)pentanamide
m/z 504 [MH].sup.+ RT 2.64 min 894 ##STR01032##
5-(8-chloro-2,6-dioxo-3- pentyl-2,3,6,7-tetrahydro-
1H-purin-1-yl)-N-(2- hydroxyethyl)-N- (phenylmethyl)pentanamide m/z
490 [MH].sup.+ RT 3.13 min
[1093] All publications, including but not limited to patents and
patent applications, cited in this specification are herein
incorporated by reference as if each individual publication were
specifically and individually indicated to be incorporated by
reference herein as though fully set forth.
* * * * *