U.S. patent application number 12/049801 was filed with the patent office on 2008-07-24 for selective antagonists of a2a adenosine receptors.
This patent application is currently assigned to Adenosine Therapeutics, LLC. Invention is credited to Anthony Beauglehole, Jayson M. Riegar, Robert D. Thompson.
Application Number | 20080176858 12/049801 |
Document ID | / |
Family ID | 35125609 |
Filed Date | 2008-07-24 |
United States Patent
Application |
20080176858 |
Kind Code |
A1 |
Beauglehole; Anthony ; et
al. |
July 24, 2008 |
SELECTIVE ANTAGONISTS OF A2A ADENOSINE RECEPTORS
Abstract
Selective antagonists of A.sub.2A adenosine receptors like those
of formula I are provided, wherein Y forms a ring. ##STR00001## The
novel A.sub.2A Blockers are useful for the treatment of Parkinson's
disease and other diseases.
Inventors: |
Beauglehole; Anthony;
(Charlottesville, VA) ; Riegar; Jayson M.;
(Charlottesville, VA) ; Thompson; Robert D.;
(Charlottesville, VA) |
Correspondence
Address: |
WILLIAMS MULLEN
222 CENTRAL PARK AVENUE, SUITE 1700
VIRGINIA BEACH
VA
23462
US
|
Assignee: |
Adenosine Therapeutics, LLC
Charlottesville
VA
|
Family ID: |
35125609 |
Appl. No.: |
12/049801 |
Filed: |
March 17, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11803312 |
May 14, 2007 |
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12049801 |
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11097251 |
Apr 4, 2005 |
7217702 |
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11803312 |
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60559159 |
Apr 2, 2004 |
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Current U.S.
Class: |
514/252.16 ;
514/255.05; 514/263.21; 514/263.22; 514/263.4 |
Current CPC
Class: |
A61P 25/36 20180101;
C07D 473/34 20130101; A61P 25/16 20180101; A61P 25/14 20180101;
A61P 9/00 20180101; A61P 35/00 20180101; A61P 25/00 20180101; A61P
25/30 20180101; A61P 37/04 20180101; A61K 31/52 20130101; A61P
25/04 20180101; A61P 43/00 20180101; A61P 25/28 20180101 |
Class at
Publication: |
514/252.16 ;
514/263.4; 514/263.22; 514/255.05; 514/263.21 |
International
Class: |
A61K 31/52 20060101
A61K031/52 |
Claims
1. A method for treating cancer, comprising: administering a
therapeutically effective amount of an A.sub.2A antagonist compound
of formula I a mammal in need of such treatment: ##STR00115##
wherein: R.sup.1 and R.sup.2 are each independently selected from
the group consisting of hydrogen, halogen, --NH.sub.2, --OH, --SH,
--NHCH.sub.3, --N(CH.sub.3).sub.2, --OCH.sub.3, --SCH.sub.3,
(C.sub.1-C.sub.8)alkyl, aryl and aryl(C.sub.1-C.sub.8)alkyl,
wherein R.sup.1 and R.sup.2 are optionally substituted with 1 to 4
substituents of R.sup.a, wherein the alkyl is optionally
interrupted by 1-4 heteroatoms selected from --O--, --S--, --SO--,
S(O).sub.2-- or amino (--NR.sup.a--), or where R.sup.1 and R.sup.2
are independently absent, with the proviso that R.sup.a is not SH
or halogen when the R.sup.1 or R.sup.2 to which R.sup.a is bound is
halogen, --NH.sub.2, --OH, --SH, --NHCH.sub.3, --N(CH.sub.3).sub.2,
--OCH.sub.3 or --SCH.sub.3; R.sup.3 is selected from the group
consisting of hydrogen, halo, --OR.sup.a, --SR.sup.a,
(C.sub.1-C.sub.8)alkyl, cyano, nitro, trifluoromethyl,
trifluoromethoxy, (C.sub.3-C.sub.8)cycloalkyl, heterocycle,
heterocycle(C.sub.1-C.sub.8)alkyl, aryl,
aryl(C.sub.1-C.sub.8)alkyl, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkyl, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.bN--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, R.sup.aOC(.dbd.S)--,
R.sup.aC(.dbd.S)--, --SSR.sup.a, R.sup.aS(.dbd.O)--, and
R.sup.aS(.dbd.O).sub.2--; or if the ring formed from the group
CR.sup.3R.sup.4R.sup.5 is aryl or heteroaryl or partially
unsaturated, then R.sup.3 can be absent; R.sup.4 and R.sup.5
together with the atom to which they are attached form a saturated
or partially unsaturated, mono-, bi- or tricyclic or aromatic ring
having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, wherein the
ring atoms are optionally interrupted by 1, 2, 3 or 4 heteroatoms
selected from the group consisting of --O--, --S--, --SO--,
--S(O).sub.2-- or amine (--NR.sup.a--) in the ring, wherein any
ring comprising R.sup.4 and R.sup.5 is optionally further
substituted with from 1 to 14 R.sup.6 groups; wherein each R.sup.6
is independently selected from the group consisting of halo,
--OR.sup.a, --SR.sup.3, substituted or unsubstituted
(C.sub.1-C.sub.8)alkyl, cyano, nitro, trifluoromethyl,
trifluoromethoxy, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.6-C.sub.12)bicycloalkyl, heterocycle,
heterocyclyl(C.sub.1-C.sub.8)alkyl, aryl,
aryl(C.sub.1-C.sub.8)alkyl, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkyl, --CO.sub.2R.sup.3,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.bN--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, R.sup.aOC(.dbd.S)--,
R.sup.aC(.dbd.S)--, --SSR.sup.a, and R.sup.aS(.dbd.O)-- or two
R.sup.6 groups and the atom to which they are attached combined to
form C.dbd.O or C.dbd.S, or wherein two R.sup.6 groups together
with the atom or atoms to which they are attached can form a
carbocyclic or heterocyclic ring; R.sup.7 and R.sup.8 are each
independently hydrogen, (C.sub.1-C.sub.8)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, aryl aryl(C.sub.1-C.sub.8)alkylene,
heteroaryl, and heteroaryl(C.sub.1-C.sub.8)alkylene; or wherein
R.sup.7 and R.sup.8 together with the nitrogen atom to which they
attach form a heterocycle or heteroaromatic ring; R.sup.9 and
R.sup.10 are each independently selected from the group consisting
of hydrogen, halogen, --NH.sub.2, --OH, --SH, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --OCH.sub.3, --SCH.sub.3,
(C.sub.1-C.sub.8)alkyl, aryl and aryl(C.sub.1-C.sub.8)alkyl,
wherein R.sup.9 and R.sup.10 are optionally substituted with 1 to 4
substituents of R.sup.a, wherein the alkyl is optionally
interrupted by 1 to 4 heteroatoms selected from --O--, --S--,
--SO--, --S(O).sub.2-- or amino (--NR.sup.a--), or where R.sup.9
and R.sup.10 are independently absent, with the proviso that
R.sup.3 is not SH or halogen in the case where the R.sup.9 or
R.sup.10 to which R.sup.a is bound is halogen, --NH.sub.2, --OH,
--SH, --NHCH.sub.3, --N(CH.sub.3).sub.2, --OCH.sub.3 or
--SCH.sub.3; Y is --CR.sup.3R.sup.4R.sup.5 or NR.sup.4R.sup.5; Z is
selected from the group consisting of halogen, vinyl, allyl,
1-propenyl, isopropenyl, ethynyl, 1-propynyl, 2-propynyl,
1,3-butadienyl, penta-1,3-dienyl, penta-1,4-dienyl,
hexa-1,3-dienyl, hexa-1,3,5-trienyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.6-C.sub.12)bicycloalkyl, (C.sub.6-C.sub.20)polycyclyl,
heterocyclyl, cycloalkyl(C.sub.1-C.sub.8)alkyl,
bicycloalkyl(C.sub.6-C.sub.12)alkyl,
heterocyclyl(C.sub.1-C.sub.8)alkyl, aryl,
aryl(C.sub.1-C.sub.8)alkyl, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkyl, --NR.sup.aR.sup.b, --SR.sup.a,
cyano, nitro, trifluoromethyl, trifluoromethoxy, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)NR.sup.a--,
R.sup.aR.sup.bNC(.dbd.O)--, R.sup.aC(.dbd.O)NR.sup.b--,
R.sup.aR.sup.bNC(.dbd.O)NR.sup.b--,
R.sup.aR.sup.bNC(.dbd.S)NR.sup.b--, R.sup.aOC(.dbd.S)--,
R.sup.aC(.dbd.S), --SSR.sup.a, R.sup.aS(.dbd.O),
--OS(O.sub.2)R.sup.a, OS(.dbd.O)OR.sup.a, --OS(O.sub.2)OR.sup.a and
--O(SO.sub.2)NR.sup.aR.sup.b; R.sup.a and R.sup.b are each
independently selected from the group consisting of hydrogen,
halogen, --NH.sub.2, --OH, --SH, --NHCH.sub.3, --N(CH.sub.3).sub.2,
--OCH.sub.3, --SCH.sub.3, propargyl, cyano, --OS(O.sub.2)H,
--OS(O.sub.2)OH, --OS(O.sub.2)CH.sub.3, --OS(O.sub.2)OCH.sub.3,
(C.sub.1-C.sub.8)alkyl, aryl, aryl(C.sub.1-C.sub.8)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.6-C.sub.12)bicycloalkyl,
cycloalkyl(C.sub.1-C.sub.8)alkyl,
bicycloalkyl(C.sub.6-C.sub.12)alkyl, heteroaryl and
heteroaryl(C.sub.1-C.sub.8)alkyl, wherein the alkyl and cycloalkyl
are optionally interrupted with 1-4 heteroatoms selected from the
group consisting of --O--, --S--, --SO--, --S(O).sub.2-- and amino
(--NR.sup.c--); and wherein the alkyl, cycloalkyl, aryl and
heteroaryl are optionally substituted with 1, 2, 3 or 4
substituents selected from the group consisting of --OR.sup.c,
--NR.sup.cR.sup.c, SR.sup.c, cyano, --OS(O.sub.2)H,
--OS(O.sub.2)OH, --OS(O.sub.2)CH.sub.3 and --OS(O.sub.2)OCH.sub.3,
provided that the point of attachment of R.sup.a or R.sup.b is not
a heteroatom when it is attached to another heteroatom; R.sup.c is
selected from the group consisting of hydrogen and
(C.sub.1-C.sub.8)alkyl; and m is 0 to 8; n is 0, 1, 2 or 3,
provided that when m is 0, Z is not halogen, cyano, or nitro or is
not attached via a heteroatom, and when n is 0, Y is not
--NR.sup.4R.sup.5; or a pharmaceutically acceptable salt thereof,
optionally in the form of a single stereoisomer or mixture of
stereoisomers thereof.
2. The method of claim 1, wherein Z is selected from aryl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.6-C.sub.12)bicycloalkyl, or
(C.sub.6-C.sub.20)polycyclyl, wherein the ring atoms are optionally
interrupted by 1 to 8 heteroatoms selected from the group
consisting of --O--, --S--, --SO--, --S(O).sub.2-- and amino
(--NR.sup.a--).
3. The method of claim 1, wherein R.sup.3 is selected from the
group consisting of hydrogen, OH, OCH.sub.3, OAc, NH.sub.2,
NHCH.sub.3, N(CH.sub.3).sub.2 and NHAc.
4. The method of claim 1, wherein the ring comprising R.sup.4 and
R.sup.5 and the atom to which they are attached is selected from
the group consisting of cyclopentane, cyclohexane, piperidine,
dihydro-pyridine, tetrahydro-pyridine, pyridine, piperazine,
decaline, tetrahydro-pyrazine, dihydro-pyrazine, pyrazine,
dihydro-pyrimidine, tetrahydro-pyrimidine, hexahydro-pyrimidine,
pyrazine, imidazole, dihydro-imidazole, imidazolidine, pyrazole,
dihydro-pyrazole, pyrazolidine, norbornane and adamantane, each
unsubstituted or substituted.
5. The method of claim 4, wherein the ring comprising R.sup.4 and
R.sup.5 and the atom to which they are attached is selected from
the group consisting of cyclohexane, piperidine, piperazine,
norbornane, adamantane, each unsubstituted or substituted.
6. The method of claim 1, wherein number of R.sup.6 groups
substituted on the R.sup.4R.sup.5 ring is from 1 to 4 and each
R.sup.6 is independently selected from the group consisting of OH,
OCH.sub.3, methyl, ethyl, t-butyl, --CO.sub.2R.sup.3,
--CON.sup.aR.sup.b, OAc, NH.sub.2, NHCH.sub.3, N(CH.sub.3).sub.2,
NHEt and N(Et).sub.2, provided that when the ring comprising
R.sup.4 and R.sup.5 contains a ring heteroatom that is O or S, the
ring heteroatom that is O or S is not substituted with R.sup.6.
7. The method of claim 1, wherein --NR.sup.7R.sup.8 is selected
from the group consisting of amino, methylamino, dimethylamino,
ethylamino, 3-pentylamino, (diphenylethyl)-amino,
(pyridylmethyl)-amino, diethylamino and benzylamino.
8. The method of claim 1, wherein R.sup.9 is independently selected
from the group consisting of hydrogen, fluoro, --OH, --CH.sub.2OH,
--OCH.sub.3, --NH.sub.2, --NHCH.sub.3, and --N(CH.sub.3).sub.2.
9. The method of claim 1, wherein R.sup.10 is hydrogen.
10. The method of claim 1, wherein R.sup.a and R.sup.b are each
independently selected from the group consisting of hydrogen,
(C.sub.1-C.sub.4)alkyl, aryl and aryl(C.sub.1-C.sub.8)alkylene.
11. The method of claim 1, wherein Y is --CR.sup.3R.sup.4R.sup.5 or
NR.sup.4R.sup.5, and is selected from the group consisting of:
##STR00116## wherein q is 0, 1, 2, 3 or 4; R.sup.3 is selected from
the group consisting of hydrogen, halo, --OR.sup.a, --SR.sup.a,
(C.sub.1-C.sub.8)alkyl, cyano, nitro, trifluoromethyl,
trifluoromethoxy, (C.sub.3-C.sub.8)cycloalkyl, heterocycle,
heterocycle(C.sub.1-C.sub.8)alkyl, aryl,
aryl(C.sub.1-C.sub.8)alkyl, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkyl, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.bN--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR NC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, R.sup.aOC(.dbd.S)--,
R.sup.aC(.dbd.S)--, --SSR.sup.a, R.sup.aS(.dbd.O)--, and
R.sup.aS(.dbd.O).sub.2--; and each R.sup.6 is independently
selected from the group consisting of halo, --OR.sup.3, --SR.sup.a,
substituted or unsubstituted (C.sub.1-C.sub.8)alkyl, cyano, nitro,
trifluoromethyl, trifluoromethoxy, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.6-C.sub.12)bicycloalkyl, heterocycle,
heterocyclyl(C.sub.1-C.sub.8)alkyl, aryl,
aryl(C.sub.1-C.sub.8)alkyl, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkyl, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.3,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.bN--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, R.sup.aOC(.dbd.S)--,
R.sup.aC(.dbd.S)--, --SSR.sup.a, and R.sup.aS(.dbd.O)--, provided
that R.sup.6 is not halogen or a heteroatom when R.sup.6 is
attached to a heteroatom.
12. The method of claim 1, wherein Y is --CR.sup.3R.sup.4R.sup.5 or
NR.sup.4R.sup.5 and is selected from the group consisting of:
##STR00117## wherein R.sup.3 is selected from the group consisting
of hydrogen, halo, --OR.sup.a, --SR.sup.a, (C.sub.1-C.sub.8)alkyl,
cyano, nitro, trifluoromethyl, trifluoromethoxy,
(C.sub.3-C.sub.8)cycloalkyl, heterocycle,
heterocycle(C.sub.1-C.sub.8)alkyl, aryl,
aryl(C.sub.1-C.sub.8)alkyl, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkyl, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.aOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.bN--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, R.sup.aOC(.dbd.S)--,
R.sup.aC(.dbd.S)--, --SSR.sup.3, R.sup.aS(.dbd.O)--, and
R.sup.aS(.dbd.O).sub.2--; and each R.sup.6 is independently
selected from the group consisting of halo, --OR.sup.a, --SR.sup.3,
substituted or unsubstituted (C.sub.1-C.sub.8)alkyl, cyano, nitro,
trifluoromethyl, trifluoromethoxy, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.6-C.sub.12)bicycloalkyl, heterocycle,
heterocyclyl(C.sub.1-C.sub.8)alkyl, aryl,
aryl(C.sub.1-C.sub.8)alkyl, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkyl, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.bN--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, R.sup.aOC(.dbd.S)--,
R.sup.aC(.dbd.S)--, --SSR.sup.a, and R.sup.aS(.dbd.O)--.
13. A method for treating cancer, comprising: administering a
therapeutically effective amount of an A.sub.2A antagonist compound
of formula IIa mammal in need of such treatment: ##STR00118##
wherein: R.sup.1 and R.sup.2 are each independently selected from
the group consisting of hydrogen, halogen, --NH.sub.2, --OH, --SH,
--NHCH.sub.3, --N(CH.sub.3).sub.2, --OCH.sub.3, --SCH.sub.3,
(C.sub.1-C.sub.8)alkyl, aryl and aryl(C.sub.1-C.sub.8)alkyl,
wherein R.sup.1 and R.sup.2 are optionally substituted with 1 to 4
substituents of R.sup.a, wherein the alkyl is optionally
interrupted by 1 to 4 heteroatoms selected from --O--, --S--,
--SO--, --S(O).sub.2-- or amino (--NR.sup.a--), or where R.sup.1
and R.sup.2 are independently absent, with the proviso that R.sup.a
is not SH or halogen when the R.sup.1 or R.sup.2 to which R.sup.a
is bound is halogen, --NH.sub.2, --OH, --SH, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --OCH.sub.3 or --SCH.sub.3; R.sup.3 is
selected from the group consisting of hydrogen, halo, --OR.sup.a,
--SR.sup.a, (C.sub.1-C.sub.8)alkyl, cyano, nitro, trifluoromethyl,
trifluoromethoxy, (C.sub.3-C.sub.8)cycloalkyl, heterocycle,
heterocycle(C.sub.1-C.sub.8)alkyl, aryl,
aryl(C.sub.1-C.sub.8)alkyl, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkyl, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.bN--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, R.sup.aOC(.dbd.S)--,
R.sup.aC(.dbd.S)--, --SSR.sup.a, R.sup.aS(.dbd.O)--, and
R.sup.aS(.dbd.O).sub.2--; or if the ring formed from the group
CR.sup.3R.sup.4R.sup.5 is aryl or heteroaryl or partially
unsaturated, then R.sup.3 can be absent; R.sup.4 and R.sup.5
together with the atom to which they are attached form a saturated
or partially unsaturated, mono-, bi- or tricyclic, or aromatic ring
having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, wherein the
ring atoms are optionally interrupted by 1, 2, 3 or 4 heteroatoms
selected from the group consisting of --O--, --S--, --SO--,
--S(O).sub.2-- or amine (--NR.sup.c--) in the ring, wherein any
ring comprising R.sup.4 and R.sup.5 is optionally further
substituted with from 1 to 14 R.sup.6 groups; wherein each R.sup.6
is independently selected from the group consisting of hydrogen,
halo, --OR.sup.3, --SR.sup.a, substituted or unsubstituted
(C.sub.1-C.sub.8)alkyl, cyano, nitro, trifluoromethyl,
trifluoromethoxy, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.6-C.sub.12)bicycloalkyl, heterocycle,
heterocyclyl(C.sub.1-C.sub.8)alkyl, aryl,
aryl(C.sub.1-C.sub.8)alkyl, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkyl, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.b--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, R.sup.aOC(.dbd.S)--,
R.sup.aC(.dbd.S)--, --SSR.sup.a, and R.sup.aS(.dbd.O)--, or two
R.sup.6 groups and the atom to which they are attached combined to
form C.dbd.O or C.dbd.S, or wherein two R.sup.6 groups together
with the atom or atoms to which they are attached can form a
carbocyclic or heterocyclic ring; R.sup.7 and R.sup.8 are each
independently hydrogen, (C.sub.1-C.sub.8)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, aryl or aryl(C.sub.1-C.sub.8)alkylene,
heteroaryl, heteroaryl(C.sub.1-C.sub.8)alkylene-; or wherein
R.sup.7 and R.sup.8 together with the nitrogen atom to which they
attach form a heterocycle or heteroaromatic ring; R.sup.9 and
R.sup.10 are each independently selected from the group consisting
of hydrogen, halogen, --NH.sub.2, --OH, --SH, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --OCH.sub.3, --SCH.sub.3,
(C.sub.1-C.sub.8)alkyl, aryl and aryl(C.sub.1-C.sub.8)alkyl,
wherein R.sup.9 and R.sup.10 are optionally substituted with 1 to 4
substituents of R.sup.a, wherein the alkyl is optionally
interrupted by 1 to 4 heteroatoms selected from --O--, --S--, SO--,
--S(O).sub.2-- or amino (--NR.sup.a--), or where R.sup.9 and
R.sup.10 are independently absent, with the proviso that R.sup.a is
not SH or halogen in the case where R.sup.9 and R.sup.10 to which
R.sup.a is bound is halogen, --NH.sub.2, --OH, --SH, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --OCH.sub.3 and --SCH.sub.3; L is a linker
selected from the group consisting of
--(C.sub.1-C.sub.3)alkyl-C.ident.C--,
--C.ident.C--(C.sub.1-C.sub.3)alkyl-,
--(CH.sub.2).sub.1-3--CH.dbd.CH--,
--CH.dbd.CH--(CH.sub.2).sub.1-3--,
--(CH.sub.2).sub.1-2--CH.dbd.CH--CH.sub.2-- and
--CH.sub.2--CH.dbd.CH--(CH.sub.2).sub.1-2--; Y is
--CR.sup.3R.sup.4R.sup.5 or NR.sup.4R.sup.5; Z is selected from the
group consisting of halogen, vinyl, allyl, 1-propenyl, isopropenyl,
ethynyl, 1-propynyl, 2-propynyl, 1,3-butadienyl, penta-1,3-dienyl,
penta-1,4-dienyl, hexa-1,3-dienyl, hexa-1,3,5-trienyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.6-C.sub.12)bicycloalkyl,
(C.sub.6-C.sub.20)polycyclyl, heterocyclyl,
cycloalkyl(C.sub.1-C.sub.8)alkyl,
bicycloalkyl(C.sub.6-C.sub.12)alkyl,
heterocyclyl(C.sub.1-C.sub.8)alkyl, aryl,
aryl(C.sub.1-C.sub.8)alkyl, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkyl, --NR.sup.aR.sup.b, --SR.sup.a,
cyano, nitro, trifluoromethyl, trifluoromethoxy, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)NR.sup.a--,
R.sup.aR.sup.bNC(.dbd.O)--, R.sup.aC(.dbd.O)NR.sup.b--,
R.sup.aR.sup.bNC(.dbd.O)NR.sup.b--,
R.sup.aR.sup.bNC(.dbd.S)NR.sup.b, R.sup.aOC(.dbd.S)--,
R.sup.aC(.dbd.S)--, --SSR.sup.a, R.sup.aS(.dbd.O)--,
--OS(O.sub.2)R.sup.a, --OS(.dbd.O)OR.sup.a, --OS(O.sub.2)OR.sup.a
and --O(SO.sub.2)NR.sup.aR.sup.b; R.sup.a and R.sup.b are each
independently selected from the group consisting of hydrogen,
halogen, --NH.sub.2, --OH, --SH, --NHCH.sub.3, --N(CH.sub.3).sub.2,
--OCH.sub.3, --SCH.sub.3, propargyl, cyano, --OS(O.sub.2)H,
--OS(O.sub.2)OH, --OS(O.sub.2)CH.sub.3, --OS(O.sub.2)OCH.sub.3,
(C.sub.1-C.sub.8)alkyl, aryl, aryl(C.sub.1-C.sub.8)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.6-C.sub.12)bicycloalkyl,
cycloalkyl(C.sub.1-C.sub.8)alkyl,
bicycloalkyl(C.sub.6-C.sub.12)alkyl, heteroaryl and
heteroaryl(C.sub.1-C.sub.8)alkyl, wherein the alkyl and cycloalkyl
are optionally interrupted with 1 to 4 heteroatoms selected from
the group consisting of --O--, --S--, --SO--, --S(O).sub.2-- and
amino (--NR.sup.c--); and wherein the alkyl, cycloalkyl, aryl and
heteroaryl are optionally substituted with 1, 2, 3 or 4
substituents selected from the group consisting of --OR.sup.c,
--NR.sup.cR.sup.c, SR.sup.c, cyano, --OS(O.sub.2)H,
--OS(O.sub.2)OH, --OS(O.sub.2)CH.sub.3 and --OS(O.sub.2)OCH.sub.3,
provided that the point of attachment of R.sup.a or R.sup.b is not
a heteroatom when it is attached to another heteroatom; R.sup.c is
selected from the group consisting of hydrogen and
(C.sub.1-C.sub.8)alkyl; and m is 0 to 8; n is 0, 1, 2 or 3 provided
that when m is 0, Z is not halogen, cyano, or nitro or is not
attached via or a heteroatom; or a pharmaceutically acceptable salt
thereof, optionally in the form of a single stereoisomer or mixture
of stereoisomers thereof.
14. A method for treating cancer, comprising: administering a
therapeutically effective amount of an A.sub.2A antagonist compound
of formula I a mammal in need of such treatment: ##STR00119##
wherein: (CR.sup.1R.sup.2).sub.m-Z together is selected from the
group consisting of --CH.sub.2CH.dbd.CH.sub.2,
--CH.sub.2C.ident.CH, --CH.sub.2C.ident.CCH.sub.3 or
--CH.sub.2CH.sub.2C.ident.CH; Y is --CR.sup.3R.sup.4R.sup.5 or
NR.sup.4R.sup.5; R.sup.3 is selected from the group consisting of
hydrogen, halo, --OR.sup.a, --SR.sup.a, (C.sub.1-C.sub.8)alkyl,
cyano, nitro, trifluoromethyl, trifluoromethoxy,
(C.sub.3-C.sub.8)cycloalkyl, heterocycle,
heterocycle(C.sub.1-C.sub.8)alkyl, aryl,
aryl(C.sub.1-C.sub.8)alkyl, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkyl, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.bN--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, R.sup.aOC(.dbd.S)--,
R.sup.aC(.dbd.S)--, --SSR.sup.a, R.sup.aS(.dbd.O)--, and
R.sup.aS(.dbd.O).sub.2--; or if the ring formed from the group
CR.sup.3R.sup.4R.sup.5 is aryl or heteroaryl or partially
unsaturated, then R.sup.3 can be absent; R.sup.4 and R.sup.5
together with the atom to which they are attached form a saturated
or partially unsaturated, mono-, bi- or tricyclic or aromatic ring
having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, wherein the
ring atoms are optionally interrupted by 1, 2, 3 or 4 heteroatoms
selected from the group consisting of --O--, --S--, --SO--,
--S(O).sub.2-- or amine (--NR.sup.a--) in the ring, wherein any
ring comprising R.sup.4 and R.sup.5 is optionally further
substituted with from 1 to 14 R.sup.6 groups; wherein each R.sup.6
is independently selected from the group consisting of halo,
--OR.sup.a, --SR.sup.3, substituted or unsubstituted
(C.sub.1-C.sub.8)alkyl, cyano, nitro, trifluoromethyl,
trifluoromethoxy, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.6-C.sub.12)bicycloalkyl, heterocycle,
heterocyclyl(C.sub.1-C.sub.8)alkyl, aryl,
aryl(C.sub.1-C.sub.8)alkyl, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkyl, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.bN--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, R.sup.aOC(.dbd.S)--,
R.sup.aC(.dbd.S)--, --SSR.sup.a, and R.sup.aS(.dbd.O)--, or two
R.sup.6 groups and the atom to which they are attached combine to
form C.dbd.O or C.dbd.S, or wherein two R.sup.6 groups together
with the atom or atoms to which they are attached can form a
carbocyclic or heterocyclic ring; R.sup.7 and R.sup.8 are each
independently hydrogen, (C.sub.1-C.sub.8)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, aryl or aryl(C.sub.1-C.sub.8)alkylene,
heteroaryl, heteroaryl(C.sub.1-C.sub.8)alkylene-; or wherein
R.sup.7 and R.sup.8 together with the nitrogen atom to which they
attach form a heterocycle or heteroaromatic ring; R.sup.9 and
R.sup.10 are each independently selected from the group consisting
of hydrogen, halogen, --NH.sub.2, --OH, --SH, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --OCH.sub.3, --SCH.sub.3,
(C.sub.1-C.sub.8)alkyl, aryl and aryl(C.sub.1-C.sub.8)alkyl,
wherein R.sup.9 and R.sup.10 are optionally substituted with 1 to 4
substituents of R.sup.a, wherein the alkyl is optionally
interrupted by 1 to 4 heteroatoms selected from --O--, --S--,
--SO--, --S(O).sub.2-- or amino (--NR.sup.a--), or where R.sup.9
and R.sup.10 are independently absent, with the proviso that
R.sup.a is not SH or halogen in the case where the R.sup.9 or
R.sup.10 to which R.sup.a is bound is halogen, --NH.sub.2, --OH,
--SH, --NHCH.sub.3, --N(CH.sub.3).sub.2, --OCH.sub.3 or
--SCH.sub.3; R.sup.a and R.sup.b are each independently selected
from the group consisting of hydrogen, halogen, --NH.sub.2, --OH,
--SH, --NHCH.sub.3, --N(CH.sub.3).sub.2, --OCH.sub.3, --SCH.sub.3,
propargyl, cyano, --OS(O.sub.2)H, --OS(O.sub.2)OH,
--OS(O.sub.2)CH.sub.3, --OS(O.sub.2)OCH.sub.3,
(C.sub.1-C.sub.8)alkyl, aryl, aryl(C.sub.1-C.sub.8)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.6-C.sub.12)bicycloalkyl,
cycloalkyl(C.sub.1-C.sub.8)alkyl,
bicycloalkyl(C.sub.6-C.sub.12)alkyl, heteroaryl and
heteroaryl(C.sub.1-C.sub.8)alkyl, wherein the alkyl and cycloalkyl
are optionally interrupted with 1-4 heteroatoms selected from the
group consisting of --O--, --S--, --SO--, --S(O).sub.2-- and amino
(--NR.sup.c--); and wherein the alkyl, cycloalkyl, aryl and
heteroaryl are optionally substituted with 1, 2, 3 or 4
substituents selected from the group consisting of --OR.sup.a,
--NR.sup.cR.sup.c, SR.sup.c, cyano, --OS(O.sub.2)H,
--OS(O.sub.2)OH, --OS(O.sub.2)CH.sub.3 and --OS(O.sub.2)OCH.sub.3,
provided that the point of attachment of R.sup.a or R.sup.b is not
a heteroatom when it is attached to another heteroatom; R.sup.c is
selected from the group consisting of hydrogen and
(C.sub.1-C.sub.8)alkyl; and n is 0, 1, 2 or 3; or a
pharmaceutically acceptable salt thereof, optionally in the form of
a single stereoisomer or mixture of stereoisomers thereof.
15. A method for treating cancer, comprising: administering a
therapeutically effective amount of an A.sub.2A antagonist compound
of formula I a mammal in need of such treatment: ##STR00120##
wherein Z is selected from the group consisting of cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl
ring optionally substituted with 1 to 4 substituents of R.sup.a; Y
is --CR.sup.3R.sup.4R.sup.5 or NR.sup.4R.sup.5; R.sup.1 and R.sup.2
are each independently selected from the group consisting of
hydrogen, halogen, --NH.sub.2, --OH, --SH, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --OCH.sub.3, --SCH.sub.3,
(C.sub.1-C.sub.8)alkyl, aryl and aryl(C.sub.1-C.sub.8)alkyl,
wherein R.sup.1 and R.sup.2 are optionally substituted with 1 to 4
substituents of R.sup.a, wherein the alkyl is optionally
interrupted by 1-4 heteroatoms selected from --O--, --S--, --SO--,
--S(O).sub.2-- or amino (--NR.sup.a), or where R.sup.1 and R.sup.2
are independently absent, with the proviso that R.sup.a is not SH
or halogen when the R.sup.1 or R.sup.2 to which R.sup.a is bound is
halogen, --NH.sub.2, --OH, --SH, --NHCH.sub.3, --N(CH.sub.3).sub.2,
--OCH.sub.3 or --SCH.sub.3; R.sup.3 is selected from the group
consisting of hydrogen, halo, --OR.sup.a, --SR.sup.a,
(C.sub.1-C.sub.8)alkyl, cyano, nitro, trifluoromethyl,
trifluoromethoxy, (C.sub.3-C.sub.8)cycloalkyl, heterocycle,
heterocycle(C.sub.1-C.sub.8)alkyl, aryl,
aryl(C.sub.1-C.sub.8)alkyl, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkyl, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.b--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, R.sup.aOC(.dbd.S)--,
R.sup.aC(.dbd.S)--, --SSR.sup.a, R.sup.aS(.dbd.O)--, and
R.sup.aS(.dbd.O).sub.2--; or if the ring formed from the group
CR.sup.3R.sup.4R.sup.5 is aryl or heteroaryl or partially
unsaturated, then R.sup.3 can be absent; R.sup.4 and R.sup.5
together with the atom to which they are attached form a saturated
or partially unsaturated, mono-, bi- or tricyclic or aromatic ring
having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, wherein the
ring atoms are optionally interrupted by 1, 2, 3 or 4 heteroatoms
selected from the group consisting of --O--, --S--, --SO--,
--S(O).sub.2-- or amine (--NR.sup.a--) in the ring, wherein any
ring comprising R.sup.4 and R.sup.5 is optionally further
substituted with from 1 to 14 R.sup.6 groups; wherein each R.sup.6
is independently selected from the group consisting of halo,
--OR.sup.a, --SR.sup.a, substituted or unsubstituted
(C.sub.1-C.sub.8)alkyl, cyano, nitro, trifluoromethyl,
trifluoromethoxy, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.6-C.sub.12)bicycloalkyl, heterocycle,
heterocyclyl(C.sub.1-C.sub.8)alkyl, aryl,
aryl(C.sub.1-C.sub.8)alkyl, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkyl, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.bN--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, R.sup.aOC(.dbd.S)--,
R.sup.aC(.dbd.S)--, --SSR.sup.a, and R.sup.aS(.dbd.O)-- or two
R.sup.6 groups and the atom to which they are attached combine to
form C.dbd.O or C.dbd.S, or wherein two R.sup.6 groups together
with the atom or atoms to which they are attached can form a
carbocyclic or heterocyclic ring; R.sup.7 and R.sup.8 are each
independently hydrogen, (C.sub.1-C.sub.8)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, aryl or aryl(C.sub.1-C.sub.8)alkylene,
heteroaryl, heteroaryl(C.sub.1-C.sub.8)alkylene-; or wherein
R.sup.7 and R.sup.8 together with the nitrogen atom to which they
attach form a heterocycle or heteroaromatic ring; R.sup.9 and
R.sup.10 are each independently selected from the group consisting
of hydrogen, halogen, --NH.sub.2, --OH, --SH, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --OCH.sub.3, --SCH.sub.3,
(C.sub.1-C.sub.8)alkyl, aryl and aryl(C.sub.1-C.sub.8)alkyl,
wherein R.sup.9 and R.sup.10 are optionally substituted with 1 to 4
substituents of R.sup.a, wherein the alkyl is optionally
interrupted by 1 to 4 heteroatoms selected from --O--, --S--,
--SO--, --S(O).sub.2-- or amino (--NR.sup.a--), or where R.sup.9
and R.sup.10 are independently absent, with the proviso that
R.sup.a is not SH or halogen in the case where the R.sup.9 or
R.sup.10 to which R.sup.a is bound is halogen, --NH.sub.2, --OH,
--SH, --NHCH.sub.3, --N(CH.sub.3).sub.2, --OCH.sub.3 or
--SCH.sub.3; R.sup.a and R.sup.b are each independently selected
from the group consisting of hydrogen, halogen, --NH.sub.2, --OH,
--SH, --NHCH.sub.3, --N(CH.sub.3).sub.2, --OCH.sub.3, --SCH.sub.3,
propargyl, cyano, --OS(O.sub.2)H, --OS(O.sub.2)OH,
--OS(O.sub.2)CH.sub.3, --OS(O.sub.2)OCH.sub.3,
(C.sub.1-C.sub.8)alkyl, aryl, aryl(C.sub.1-C.sub.8)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.6-C.sub.12)bicycloalkyl,
cycloalkyl(C.sub.1-C.sub.8)alkyl,
bicycloalkyl(C.sub.6-C.sub.12)alkyl, heteroaryl and
heteroaryl(C.sub.1-C.sub.8)alkyl, wherein the alkyl and cycloalkyl
are optionally interrupted with 1-4 heteroatoms selected from the
group consisting of --O--, --S--, --SO--, S(O).sub.2-- and amino
(--NR.sup.c--); and wherein the alkyl, cycloalkyl, aryl and
heteroaryl are optionally substituted with 1, 2, 3 or 4
substituents selected from the group consisting of --OR.sup.c,
--NR.sup.cR.sup.c, SR.sup.c, cyano, --OS(O.sub.2)H,
--OS(O.sub.2)OH, --OS(O.sub.2)CH.sub.3 and --OS(O.sub.2)OCH.sub.3,
provided that the point of attachment of R.sup.a or R.sup.b is not
a heteroatom when it is attached to another heteroatom; R.sup.c is
selected from the group consisting of hydrogen and
(C.sub.1-C.sub.8)alkyl; and m is 0 to 8; n is 0, 1, 2 or 3,
provided that when n is 0, Y is not --NR.sup.4R.sup.5; or a
pharmaceutically acceptable salt thereof, optionally in the form of
a single stereoisomer or mixture of stereoisomers thereof.
16. The method of claim 15, wherein Z is selected from the group
consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,
where m is 0 or 1.
17. The method of claim 1, wherein: Y is selected from the group
consisting of ##STR00121## wherein Y optionally comprises 1, 2 or 3
double bonds; each carbon in the ring is optionally replaced by or
interrupted by 1 to 6 heteroatoms selected from --O--, --S--,
--SO--, S(O).sub.2--, or amino (--NR.sup.a--), and is optionally
further substituted with from 1 to 10 R.sup.6 groups, provided that
the Y ring is not attached at a bridgehead carbon atom or at a
trisubstituted carbon atom; Z is selected from the group consisting
of halogen, vinyl, allyl, 1-propenyl, isopropenyl, ethynyl,
1-propynyl, 2-propynyl, 1,3-butadienyl, penta-1,3-dienyl,
penta-1,4-dienyl, hexa-1,3-dienyl, hexa-1,3,5-trienyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.6-C.sub.12)bicycloalkyl,
(C.sub.6-C.sub.20)polycyclyl, heterocyclyl,
cycloalkyl(C.sub.1-C.sub.8)alkyl,
bicycloalkyl(C.sub.6-C.sub.12)alkyl,
heterocyclyl(C.sub.1-C.sub.8)alkyl, aryl,
aryl(C.sub.1-C.sub.8)alkyl, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkyl, --NR.sup.aR.sup.b, --SR.sup.3,
cyano, nitro, trifluoromethyl, trifluoromethoxy, --CO.sub.2R.sup.3,
R.sup.aC(.dbd.O)--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)NR.sup.a--,
R.sup.aR.sup.bNC(.dbd.O)--, R.sup.aC(.dbd.O)NR.sup.b--,
R.sup.aR.sup.bNC(.dbd.O)NR.sup.1--,
R.sup.aR.sup.bNC(.dbd.S)NR.sup.b--, R.sup.aOC(.dbd.S)--,
R.sup.aC(.dbd.S)--, --SSR.sup.a, R.sup.aS(.dbd.O)--,
--OS(O.sub.2)R.sup.a, --OS(.dbd.O)OR.sup.a, --OS(O.sub.2)OR.sup.a
and --O(SO.sub.2)NR.sup.aR.sup.b; R.sup.1 and R.sup.2 are each
independently selected from the group consisting of hydrogen,
halogen, --NH.sub.2, --OH, --SH, --NHCH.sub.3, --N(CH.sub.3).sub.2,
--OCH.sub.3, --SCH.sub.3, (C.sub.1-C.sub.8)alkyl, aryl and
aryl(C.sub.1-C.sub.8)alkyl, wherein R.sup.1 and R.sup.2 are
optionally substituted with 1 to 4 substituents of R.sup.a, wherein
the alkyl is optionally interrupted by 1-4 heteroatoms selected
from --O--, --S--, --SO--, S(O).sub.2-- or amino (--NR.sup.a--), or
where R.sup.1 and R.sup.2 are independently absent, with the
proviso that R.sup.a is not SH or halogen when the R.sup.1 or
R.sup.2 to which R.sup.a is bound is halogen, --NH.sub.2, --OH,
--SH, --NHCH.sub.3, --N(CH.sub.3).sub.2, --OCH.sub.3 or
--SCH.sub.3; R.sup.6 is independently selected from the group
consisting of halo, --OR.sup.a, --SR.sup.a, substituted or
unsubstituted (C.sub.1-C.sub.8)alkyl, cyano, nitro,
trifluoromethyl, trifluoromethoxy, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.6-C.sub.12)bicycloalkyl, heterocycle,
heterocyclyl(C.sub.1-C.sub.8)alkyl, aryl,
aryl(C.sub.1-C.sub.8)alkyl, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkyl, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.bN--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, R.sup.aOC(.dbd.S)--,
R.sup.aC(.dbd.S)--, --SSR.sup.a, and R.sup.aS(.dbd.O)-- or two
R.sup.6 groups and the atom to which they are attached combined to
form C.dbd.O or C.dbd.S, or wherein two R.sup.6 groups together
with the atom or atoms to which they are attached can form a
carbocyclic or heterocyclic ring; R.sup.7 and R.sup.8 are each
independently hydrogen, (C.sub.1-C.sub.8)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, aryl or aryl(C.sub.1-C.sub.8)alkylene,
heteroaryl, heteroaryl(C.sub.1-C.sub.8)alkylene-; or wherein
R.sup.7 and R.sup.8 together with the nitrogen atom to which they
attach form a heterocycle or heteroaromatic ring; R.sup.9 and
R.sup.10 are each independently selected from the group consisting
of hydrogen, halogen, --NH.sub.2, --OH, --SH, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --OCH.sub.3, --SCH.sub.3,
(C.sub.1-C.sub.8)alkyl, aryl and aryl(C.sub.1-C.sub.8)alkyl,
wherein R.sup.9 and R.sup.10 are optionally substituted with 1 to 4
substituents of R.sup.a, wherein the alkyl is optionally
interrupted by 1 to 4 heteroatoms selected from --O--, --S--,
--SO--, --S(O).sub.2-- or amino (--NR.sup.a--), or where R.sup.9
and R.sup.10 are independently absent, with the proviso that
R.sup.a is not SH or halogen in the case where the R.sup.9 or
R.sup.10 to which R.sup.a is bound is halogen, --NH.sub.2, --OH,
--SH, --NHCH.sub.3, --N(CH.sub.3).sub.2, --OCH.sub.3 or
--SCH.sub.3; R.sup.a and R.sup.b are each independently selected
from the group consisting of hydrogen, halogen, --NH.sub.2, --OH,
--SH, --NHCH.sub.3, --N(CH.sub.3).sub.2, --OCH.sub.3, --SCH.sub.3,
propargyl, cyano, --OS(O.sub.2)H, --OS(O.sub.2)OH,
--OS(O.sub.2)CH.sub.3, --OS(O.sub.2)OCH.sub.3,
(C.sub.1-C.sub.8)alkyl, aryl, aryl(C.sub.1-C.sub.8)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.6-C.sub.12)bicycloalkyl,
cycloalkyl(C.sub.1-C.sub.8)alkyl,
bicycloalkyl(C.sub.6-C.sub.12)alkyl, heteroaryl and
heteroaryl(C.sub.1-C.sub.8)alkyl, wherein the alkyl and cycloalkyl
are optionally interrupted with 1-4 heteroatoms selected from the
group consisting of --O--, --S--, --SO--, --S(O).sub.2-- and amino
(--NR.sup.c--); and wherein the alkyl, cycloalkyl, aryl and
heteroaryl are optionally substituted with 1, 2, 3 or 4
substituents selected from the group consisting of --OR.sup.c,
--NR.sup.cR.sup.c, SR.sup.c, cyano, --OS(O.sub.2)H,
--OS(O.sub.2)OH, --OS(O.sub.2)CH.sub.3 and --OS(O.sub.2)OCH.sub.3,
provided that the point of attachment of R.sup.a or R.sup.b is not
a heteroatom when it is attached to another heteroatom; R.sup.c is
selected from the group consisting of hydrogen and
(C.sub.1-C.sub.8)alkyl; and m is 0 to 8; n is 0, 1, 2 or 3,
provided that when m is 0, Z is not halogen, cyano, or nitro or
attached via a heteroatom; or a pharmaceutically acceptable salt
thereof, optionally in the form of a single stereoisomer or mixture
of stereoisomers thereof.
18. A method for treating cancer, comprising: administering a
therapeutically effective amount of an A.sub.2A antagonist compound
of formula I a mammal in need of such treatment: ##STR00122##
wherein: R.sup.1 and R.sup.2 are hydrogen, m is 0, 1, 2 or 3 and Z
is the moiety derived from the ring selected from the group
consisting of furan, dihydro-furan, thiophene, pyrrole, 2H-pyrrole,
2-pyrroline, 3-pyrroline, pyrrolidine, 1,3-dioxolane, oxazole,
thiazole, imidazole, dihydro-imidazole, 2-imidazoline,
imidazolidine, pyrazole, 2-pyrazoline, pyrazolidine, isoxazole,
isothiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,3-triazole,
1,2,4-triazole, 1,3,4-thiadiazole, 2H-pyran, 1H-tetrazole,
4H-pyran, pyridine, dihydro-pyridine, tetrahydro-pyridine,
piperidine, 1,4-dioxane, morpholine, 1,4-dithiane, thiomorpholine,
pyridazine, pyrimidine, dihydro-pyrimidine, tetrahydro-pyrimidine,
hexahydro-pyrimidine, pyrazine, dihydro-pyrazine,
tetrahydro-pyrazine, piperazine, 1,3,5-triazine and
1,3,5-trithiane, wherein each Z group is optionally substituted
with from 1 to 10 R.sup.a groups; Y is --CR.sup.3R.sup.4R.sup.5 or
NR.sup.4R.sup.5; R.sup.3 is selected from the group consisting of
hydrogen, halo, --OR.sup.a, --SR.sup.a, (C.sub.1-C.sub.8)alkyl,
cyano, nitro, trifluoromethyl, trifluoromethoxy,
(C.sub.3-C.sub.8)cycloalkyl, heterocycle,
heterocycle(C.sub.1-C.sub.8)alkyl, aryl,
aryl(C.sub.1-C.sub.8)alkyl, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkyl, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.bN--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, R.sup.aOC(.dbd.S)--,
R.sup.aC(.dbd.S)--, --SSR.sup.a, R.sup.aS(.dbd.O)--, and
R.sup.aS(.dbd.O).sub.2--; or if the ring formed from the group
CR.sup.3R.sup.4R.sup.5 is aryl or heteroaryl or partially
unsaturated, then R.sup.3 can be absent; R.sup.4 and R.sup.5
together with the atom to which they are attached form a saturated
or partially unsaturated, mono-, bi- or tricyclic or aromatic ring
having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, wherein the
ring atoms are optionally interrupted by 1, 2, 3 or 4 heteroatoms
selected from the group consisting of --O--, --S--, --SO--,
--S(O).sub.2-- or amine (--NR.sup.a--) in the ring, wherein any
ring comprising R.sup.4 and R.sup.5 is optionally further
substituted with from 1 to 14 R.sup.6 groups; wherein each R.sup.6
is independently selected from the group consisting of halo,
--OR.sup.a, --SR.sup.a, substituted or unsubstituted
(C.sub.1-C.sub.8)alkyl, cyano, nitro, trifluoromethyl,
trifluoromethoxy, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.6-C.sub.12)bicycloalkyl, heterocycle,
heterocyclyl(C.sub.1-C.sub.8)alkyl, aryl,
aryl(C.sub.1-C.sub.8)alkyl, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkyl, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.bN--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, R.sup.aOC(.dbd.S)--,
R.sup.aC(.dbd.S)--, --SSR.sup.a, and R.sup.aS(.dbd.O)-- or two
R.sup.6 groups and the atom to which they are attached combined to
form C.dbd.O or C.dbd.S, or wherein two R.sup.6 groups together
with the atom or atoms to which they are attached can form a
carbocyclic or heterocyclic ring; R.sup.7 and R.sup.8 are each
independently hydrogen, (C.sub.1-C.sub.8)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, aryl or aryl(C.sub.1-C.sub.8)alkylene,
heteroaryl, heteroaryl(C.sub.1-C.sub.8)alkylene-; or wherein
R.sup.7 and R.sup.8 together with the nitrogen atom to which they
attach form a heterocycle or heteroaromatic ring; R.sup.9 and
R.sup.10 are each independently selected from the group consisting
of hydrogen, halogen, --NH.sub.2, --OH, --SH, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --OCH.sub.3, --SCH.sub.3,
(C.sub.1-C.sub.8)alkyl, aryl and aryl(C.sub.1-C.sub.8)alkyl,
wherein R.sup.9 and R.sup.10 are optionally substituted with 1 to 4
substituents of R.sup.a, wherein the alkyl is optionally
interrupted by 1 to 4 heteroatoms selected from --O--, --S--,
--SO--, --S(O).sub.2-- or amino (--NR.sup.a--), or where R.sup.9
and R.sup.10 are independently absent, with the proviso that
R.sup.a is not SH or halogen in the case where the R.sup.9 or
R.sup.10 to which R.sup.a is bound is halogen, --NH.sub.2, --OH,
--SH, --NHCH.sub.3, --N(CH.sub.3).sub.2, --OCH.sub.3 or
--SCH.sub.3; R.sup.a and R.sup.b are each independently selected
from the group consisting of hydrogen, halogen, --NH.sub.2, --OH,
--SH, --NHCH.sub.3, --N(CH.sub.3).sub.2, --OCH.sub.3, --SCH.sub.3,
propargyl, cyano, --OS(O.sub.2)H, --OS(O.sub.2)OH,
--OS(O.sub.2)CH.sub.3, --OS(O.sub.2)OCH.sub.3,
(C.sub.1-C.sub.8)alkyl, aryl, aryl(C.sub.1-C.sub.8)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.6-C.sub.12)bicycloalkyl,
cycloalkyl(C.sub.1-C.sub.8)alkyl,
bicycloalkyl(C.sub.6-C.sub.12)alkyl, heteroaryl and
heteroaryl(C.sub.1-C.sub.8)alkyl, wherein the alkyl and cycloalkyl
are optionally interrupted with 1-4 heteroatoms selected from the
group consisting of --O--, --S--, --SO--, --S(O).sub.2-- and amino
(--NR.sup.c--); and wherein the alkyl, cycloalkyl, aryl and
heteroaryl are optionally substituted with 1, 2, 3 or 4
substituents selected from the group consisting of --OR.sup.c,
--NR.sup.cR.sup.c, SR.sup.c, cyano, --OS(O.sub.2)H,
--OS(O.sub.2)OH, --OS(O.sub.2)CH.sub.3 and --OS(O.sub.2)OCH.sub.3,
provided that the point of attachment of R.sup.a or R.sup.b is not
a heteroatom when it is attached to another heteroatom; R.sup.c is
selected from the group consisting of hydrogen and
(C.sub.1-C.sub.8)alkyl; and m is 0 to 8; n is 0, 1, 2 or 3,
provided that when m is 0, Z is not attached via a heteroatom, and
when n is 0, Y is not --NR.sup.4R.sup.5; or a pharmaceutically
acceptable salt thereof, optionally in the form of a single
stereoisomer or mixture of stereoisomers thereof.
19. The method of claim 18, wherein R.sup.1 and R.sup.2 are
hydrogen, m is 0 or 1, and Z is the moiety derived from the ring
selected from the group consisting of furan, thiophene, pyrrole,
2H-pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole,
isothiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,3-triazole,
1,2,4-triazole, 1,3,4-thiadiazole and 1H-tetrazole, wherein each Z
group is optionally substituted with from 1 to 3 R.sup.a groups
selected from the group consisting of methyl, ethyl, propyl,
iso-propyl, --NH.sub.2, --OH, --SH, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --OCH.sub.3 and --SCH.sub.3.
20. A method for treating cancer, comprising: administering a
therapeutically effective amount of an A.sub.2A antagonist compound
of formula I a mammal in need of such treatment: ##STR00123##
wherein: R.sup.7 and R.sup.8 are each independently selected from
the group consisting of hydrogen, (C.sub.1-C.sub.8)alkyl-,
aryl(C.sub.1-C.sub.8)alkylene-, mono- or bicyclic-, aromatic or
nonaromatic ring having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms,
wherein the ring atoms are optionally interrupted by 1, 2, 3 or 4
heteroatoms selected from the group consisting of --O--, --S--,
--SO--, --S(O).sub.2-- or amine (--NR.sup.a--) in the ring, and
each is optionally substituted with from 1, 2, 3 or 4 R.sup.a
groups; Y is --CR.sup.3R.sup.4R.sup.5 or NR.sup.4R.sup.5; Z is
selected from the group consisting of halogen, vinyl, allyl,
1-propenyl, isopropenyl, ethynyl, 1-propynyl, 2-propynyl,
1,3-butadienyl, penta-1,3-dienyl, penta-1,4-dienyl,
hexa-1,3-dienyl, hexa-1,3,5-trienyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.6-C.sub.12)bicycloalkyl, (C.sub.6-C.sub.20)polycyclyl,
heterocyclyl, cycloalkyl(C.sub.1-C.sub.8)alkyl,
bicycloalkyl(C.sub.6-C.sub.12)alkyl,
heterocyclyl(C.sub.1-C.sub.8)alkyl, aryl,
aryl(C.sub.1-C.sub.8)alkyl, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkyl, --NR.sup.aR.sup.b, --SR.sup.a,
cyano, nitro, trifluoromethyl, trifluoromethoxy, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)NR.sup.a--,
R.sup.aR.sup.bNC(.dbd.O)--, R.sup.aC(.dbd.O)NR.sup.b--,
R.sup.aR.sup.bNC(.dbd.O)NR.sup.b--,
R.sup.aR.sup.bNC(.dbd.S)NR.sup.b--, R.sup.aOC(.dbd.S)--,
R.sup.aC(.dbd.S)--, --SSR.sup.a, R.sup.aS(.dbd.O)--,
--OS(O.sub.2)R.sup.a, OS(.dbd.O)OR.sup.a, --OS(O.sub.2)OR.sup.a and
--O(SO.sub.2)NR.sup.aR.sup.b; R.sup.1 and R.sup.2 are each
independently selected from the group consisting of hydrogen,
halogen, --NH.sub.2, --OH, --SH, --NHCH.sub.3, --N(CH.sub.3).sub.2,
--OCH.sub.3, --SCH.sub.3, (C.sub.1-C.sub.8)alkyl, aryl and
aryl(C.sub.1-C.sub.8)alkyl, wherein R.sup.1 and R.sup.2 are
optionally substituted with 1 to 4 substituents of R.sup.a, wherein
the alkyl is optionally interrupted by 1-4 heteroatoms selected
from --O--, --S--, --SO--, --S(O).sub.2-- or amino (--NR.sup.a), or
where R.sup.1 and R.sup.2 are independently absent, with the
proviso that R.sup.a is not SH or halogen when the R.sup.1 or
R.sup.2 to which R.sup.a is bound is halogen, --NH.sub.2, --OH,
--SH, --NHCH.sub.3, --N(CH.sub.3).sub.2, --OCH.sub.3 or
--SCH.sub.3; R.sup.3 is selected from the group consisting of
hydrogen, halo, --OR.sup.a, --SR.sup.a, (C.sub.1-C.sub.8)alkyl,
cyano, nitro, trifluoromethyl, trifluoromethoxy,
(C.sub.3-C.sub.8)cycloalkyl, heterocycle,
heterocycle(C.sub.1-C.sub.8)alkyl, aryl,
aryl(C.sub.1-C.sub.8)alkyl, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkyl, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.bN--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, R.sup.aOC(.dbd.S)--,
R.sup.aC(.dbd.S)--, --SSR.sup.a, R.sup.aS(.dbd.O)--, and
R.sup.aS(.dbd.O).sub.2--; or if the ring formed from the group
CR.sup.3R.sup.4R.sup.5 is aryl or heteroaryl or partially
unsaturated, then R.sup.3 can be absent; R.sup.4 and R.sup.5
together with the atom to which they are attached form a saturated
or partially unsaturated, mono-, bi- or tricyclic or aromatic ring
having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, wherein the
ring atoms are optionally interrupted by 1, 2, 3 or 4 heteroatoms
selected from the group consisting of --O--, --S--, --SO--,
--S(O).sub.2-- or amine (--NR.sup.a--) in the ring, wherein any
ring comprising R.sup.4 and R.sup.5 is optionally further
substituted with from 1 to 14 R.sup.6 groups; wherein each R.sup.6
is independently selected from the group consisting of halo,
--OR.sup.a, --SR.sup.a, substituted or unsubstituted
(C.sub.1-C.sub.8)alkyl, cyano, nitro, trifluoromethyl,
trifluoromethoxy, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.6-C.sub.12)bicycloalkyl, heterocycle,
heterocyclyl(C.sub.1-C.sub.8)alkyl, aryl,
aryl(C.sub.1-C.sub.8)alkyl, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkyl, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.b--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, R.sup.aOC(.dbd.S)--,
R.sup.aC(.dbd.S)--, --SSR.sup.a, and R.sup.aS(.dbd.O)-- or two
R.sup.6 groups and the atom to which they are attached combined to
form C.dbd.O or C.dbd.S, or wherein two R.sup.6 groups together
with the atom or atoms to which they are attached can form a
carbocyclic or heterocyclic ring; R.sup.9 and R.sup.10 are each
independently selected from the group consisting of hydrogen,
halogen, --NH.sub.2, --OH, --SH, --NHCH.sub.3, --N(CH.sub.3).sub.2,
--OCH.sub.3, --SCH.sub.3, (C.sub.1-C.sub.8)alkyl, aryl and
aryl(C.sub.1-C.sub.8)alkyl, wherein R.sup.9 and R.sup.10 are
optionally substituted with 1 to 4 substituents of R.sup.a, wherein
the alkyl is optionally interrupted by 1 to 4 heteroatoms selected
from --O--, --S--, --SO--, --S(O).sub.2-- or amino (--NR.sup.a--),
or where R.sup.9 and R.sup.10 are independently absent, with the
proviso that R.sup.3 is not SH or halogen in the case where the
R.sup.9 or R.sup.10 to which R.sup.a is bound is halogen,
--NH.sub.2, --OH, --SH, --NHCH.sub.3, --N(CH.sub.3).sub.2,
--OCH.sub.3 or --SCH.sub.3; R.sup.a and R.sup.b are each
independently selected from the group consisting of hydrogen,
halogen, --NH.sub.2, --OH, --SH, --NHCH.sub.3, --N(CH.sub.3).sub.2,
--OCH.sub.3, --SCH.sub.3, propargyl, cyano, --OS(O.sub.2)H,
--OS(O.sub.2)OH, --OS(O.sub.2)CH.sub.3, --OS(O.sub.2)OCH.sub.3,
(C.sub.1-C.sub.8)alkyl, aryl, aryl(C.sub.1-C.sub.8)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.6-C.sub.12)bicycloalkyl,
cycloalkyl(C.sub.1-C.sub.8)alkyl,
bicycloalkyl(C.sub.6-C.sub.12)alkyl, heteroaryl and
heteroaryl(C.sub.1-C.sub.8)alkyl, wherein the alkyl and cycloalkyl
are optionally interrupted with 1-4 heteroatoms selected from the
group consisting of --O--, --S--, --SO--, --S(O).sub.2-- and amino
(--NR.sup.c--); and wherein the alkyl, cycloalkyl, aryl and
heteroaryl are optionally substituted with 1, 2, 3 or 4
substituents selected from the group consisting of --OR.sup.c,
--NR.sup.cR.sup.c, SR.sup.c, cyano, --OS(O.sub.2)H,
--OS(O.sub.2)OH, --OS(O.sub.2)CH.sub.3 and --OS(O.sub.2)OCH.sub.3,
provided that the point of attachment of R.sup.a or R.sup.b is not
a heteroatom when it is attached to another heteroatom; R.sup.c is
selected from the group consisting of hydrogen and
(C.sub.1-C.sub.8)alkyl; and m is 0 to 8; n is 0, 1, 2 or 3,
provided that when m is 0, Z is not halogen, cyano, or nitro or is
not attached via a heteroatom, and when n is 0, Y is not
--NR.sup.4R.sup.5; or a pharmaceutically acceptable salt thereof,
optionally in the form of a single stereoisomer or mixture of
stereoisomers thereof.
21. The method of claim 20, wherein R.sup.7 is selected from the
group consisting of benzyl, phenethyl, phenylpropyl and each is
optionally substituted with from 1, 2 or 3 substituents of
R.sup.a.
22. The method of claim 1, wherein the compound selected from the
group:
9-Cyclopropylmethyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-y-
l}adenine (1);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-propargyladenin-
e (2);
9-Cyclopentyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-y-
l}adenine (3);
9-Cyanomethyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}aden-
ine (4);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(4-meth-
oxybenzyl)adenine (5);
9-(3,4-Dichlorobenzyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn--
1-yl}adenine (6);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(4-trifluoromet-
hylbenzyl)adenine (7);
9-(3,5-Dimethyl-isoxazol-4-ylmethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyc-
lohexyl]ethyn-1-yl}adenine (8);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-[2-(trifluorome-
thylphenyl)thiazol-4-ylmethyl]adenine (9);
2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-(3-(thiophen-2-yl)prop-2-ynyl)-
adenine (10);
9-Cyclopropylmethyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-y-
l}-N-6-(3-pentyl)adenine (14);
9-Cyclopentyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-
-(3-pentyl)adenine (15);
9-Allyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pe-
ntyl)adenine (16);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pentyl)-9--
(propargyl)adenine (17);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pentyl)-9--
(pent-4-ynyl)adenine (18);
9-(2-Chloroethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-
-N-6-(3-pentyl)adenine (21);
9-([1,3]-Dioxolan-2-ylmethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl-
]ethyn-1-yl}-N-6-(3-pentyl)adenine (22);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pentyl)-9--
(tetrahydro-pyran-2-ylmethyl)adenine (23);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pentyl)-9--
(isopropylcarboxylate)adenine (24); 9-(Acetic acid ethyl
ester)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pen-
tyl)adenine (25);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(2-oxo-oxazolid-
in-5-ylmethyl)-N-6-(3-pentyl)adenine (26);
9-Benzyl-2-{2-[1(S)-hydroxy-3
(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pentyl)adenine (27);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pentyl)-9--
(pyridin-3-ylmethyl)adenine (28);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(4-nitrobenzyl)-
-N-6-(3-pentyl)adenine (29);
9-(3,5-Dimethyl-isoxazol-4-ylmethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyc-
lohexyl]ethyn-1-yl}-N-6-(3-pentyl)adenine (30);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(2-methyl-thiaz-
ol-5-ylmethyl)-N-6-(3-pentyl)adenine (31);
N6-[(S)-(+)-sec-Butyl]-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn--
1-yl}-9-propargyl-adenine (32);
N6-[(s)-(+)-sec-Butyl]-9-(3,5-dimethyl-isoxazol-4-ylmethyl)-2-{2-[1(S)-hy-
droxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (33);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-[(s)-(-)-alph-
a-napthalen-1-yl-ethyl]-9-(propargyl)adenine (35);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-methoxyben-
zyl)-9-(propargyl)adenine (36);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(propargyl)-N-6-
-(pyridin-2-ylmethyl)adenine (37);
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-[(methyl)(2-p-
henethyl)]-9-(propargyl)adenine (38);
9-Cyclopropylmethyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine
(45);
9-Cyclobutylmethyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine
(46);
9-Cyclopentylmethyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine
(47);
9-Cyclohexylmethyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine
(48); 9-Cyclobutyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine
(49); 9-Cyclopentyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine
(50); 2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-propargyl-adenine
(51); 2-{2-[Hydroxy-norbornan-2-yl]ethyn-1-yl}-9-propargyladenine;
9-(But-3-ynyl)-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine
(62); and
2-{3-[1-(Methoxycarbanoyl)piperidin-4-yl]propyn-1-yl}-9-propargyladenine
(63); or a pharmaceutically acceptable salt thereof, optionally in
the form of a single stereoisomer or mixture of stereoisomers
thereof.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] The present application is a continuation of "Selective
Antagonists of A.sub.2A Adenosine Receptors," U.S. application Ser.
No. 11/803,312 filed May 14, 2007, which is a continuation of
"Selective Antagonists of A.sub.2A Adenosine Receptors," U.S.
application Ser. No. 11/097,251 filed Apr. 4, 2005, now U.S. Pat.
No. 7,217,702 which claims benefit of U.S. Provisional Application
No. 60/559,159, filed Apr. 2, 2004, entitled "Selective Antagonists
of A.sub.2A Adenosine Receptors," the disclosures of which are
herein incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to compounds and
pharmaceutical compositions that are selective antagonists of the
A.sub.2A adenosine receptor (AR). These compounds are useful as
pharmaceutical agents.
[0003] Selective antagonists of A.sub.2A adenosine receptors have
proven to be effective for the treatment of Parkinson's disease
(PD) both in animal models and in a human trial..sup.1 However, the
initial clinical trial was stopped in phase 3 due to detection of
animal toxicity of the investigational drug, KW6002. Other
investigational compounds lack sufficient potency, selectivity or
bioavailability to be considered clinical candidates.
BACKGROUND OF THE INVENTION
[0004] Parkinson's disease is the second most common
neurodegenerative disorder and affects over 1 million people in
North America..sup.2 The pathological process, degeneration of the
dopaminergic neurons in the substantial nigra, causes profound
depletion of striatal dopamine and motor impairment. This insight
led to the introduction of L-dopa as a dopamine-replacement
treatment for PD.sup.3 Today, L-dopa continues to be the "Gold
Standard" treatment for the motor symptoms of PD..sup.4,5 Despite
the considerable symptomatic relief it affords, long-term treatment
with L-dopa has major limitations..sup.6 After five to ten years of
treatment with L-dopa, up to 60% of patients experience loss of
L-dopa effectiveness and some debilitating complications,.sup.7,8
notably, an "on" and "off" motor fluctuation and involuntary
choreic or dystonic movements, dyskinesia. This has become the
limiting factor in management of patients in the later stages of
PD..sup.9 The development of dyskinesia might reflect
desensitization of dopamine receptors..sup.10 Most importantly,
there is no clear evidence that L-dopa slows or halts the
degeneration of dopaminergic neurons. In fact, in vitro cell
culture studies suggested that dopamine and its oxidative
metabolites are toxic to dopaminergic neurons, and raised the
concern that L-dopa may actually accelerate the degeneration of
dopaminergic neurons. Because of this concern, many clinicians
avoid prescribing L-dopa early in the course of PD..sup.11
[0005] These major limitations of L-dopa therapy are linked to the
activation of dopamine receptors. This has prompted a search for
alternative treatment for PD not targeting the dopaminergic
system..sup.12 Striatal neuromodulators and transmitters other than
dopamine are increasingly appreciated as critical regulators of
motor function and offer new therapeutic opportunities to
complement dopamine-replacement.
[0006] Over the last 10 years, the A.sub.2A adenosine receptor
(A.sub.2AAR) has received increasing attention as a treatment for
PD..sup.13,14 This contention is based on our understanding of the
role of the A.sub.2AAR in the basal ganglia and on the recent
development of new, more selective A.sub.2AAR antagonists.
Anatomical, neurochemical and behavioral evidence of
adenosine-dopamine interactions underlie this new therapeutic
approach..sup.15-17 Anatomically, A.sub.2AAR density is high in the
striatum, where receptor mRNA is co-expressed with D.sub.2 receptor
mRNA in the striatopallidal neurons..sup.18-20 This unique cellular
distribution of A.sub.2A receptors suggests that A.sub.2A receptor
antagonists can selectively modulate the "indirect" striatopallidal
pathway to affect motor activity. At the neurochemical level,
activation of the A.sub.2AAR reduces the binding affinity of
D.sub.2 receptors in the striatum, .sup.21 and antagonizes many
neurochemical and cellular changes brought about by the activation
of striatal D.sub.2 receptors, including release of acetylcholine
and GABA and expression of c-Fos. Furthermore, behavioral studies
have demonstrated that the unselective adenosine antagonists
caffeine and theophylline stimulate locomotor activity.sup.22,23
whereas the unselective agonist NECA.sup.24 inhibits spontaneous
locomotor activity as well as motor activity induced by dopamine
agonists. Thus, A.sub.2AAR agonists and antagonists function as
dopamine antagonists and agonists, respectively, in modulating
motor activity. The three possible mechanisms have been proposed to
explain for motor enhancement by the A.sub.2A antagonists: (1) a
direct receptor-receptor (A.sub.2A-D.sub.2) antagonistic
interaction,.sup.25,26 (2) an opposing but independent of A.sub.2A
and D.sub.2 receptor signaling.sup.27-29 or (3) A.sub.2AAR
modulation of GABA release in the basal ganglia..sup.30-32 These
receptors also form A.sub.2AAR-D2 heterodimers,.sup.33 but how
dimerization affects receptor function is unclear.
A.sub.2A Receptor Antagonists May Offer Multiple Therapeutic
Benefits for PD Patients
[0007] First, A.sub.2A antagonists stimulate motor activity in
normal as well as dopamine-depleted animals. In rodent models of
PD, unselective adenosine antagonists (caffeine and
theophylline).sup.22,34 and the A.sub.2AAR-selective antagonists
SCH58261, KW6002 and CSC can reverse motor deficits induced by
MPTP, 6-hydroxydopamine, haloperidol or reserpine.sup.35-41 as well
as by genetic deletion of D.sub.2 receptors. More recently, the
A.sub.2A antagonists KW6002 reversed motor deficit in MPTP-treated
non-human primates..sup.43,44 Furthermore, A.sub.2A antagonists can
stimulate motor activity when combined with sub-threshold doses of
dopaminergic agents such as L-dopa or D.sub.1 and D.sub.2 agonists
such as aporphormine or quinpirole..sup.45 For example, combining
KW6002 with L-dopa reduces the dose of L-dopa, thereby reducing the
complications associated with L-dopa. In contrast to some
non-specific adenosine antagonists or some dopamine agonists, motor
stimulation was observed after acute treatment and persisted
following treatment continued for 15 days..sup.44,46,47 Thus,
tolerance to the motor stimulant effect of A.sub.2A antagonists did
not develop.
[0008] Second, studies of the MPTP-treated monkey model of PD
revealed a novel feature of A.sub.2A antagonists, namely,
stimulation of motor activity without dyskinesia..sup.43,44,48 In
contrast to L-dopa, repeated treatment with KW6002 reversed the
motor deficit but did not induce dyskinesia, even in monkeys primed
with L-dopa. Further, our recent findings in A.sub.2AAR knockout
mice suggest that development of behavioral sensitization by
chronic treatment of L-dopa requires activation of the A.sub.2AAR.
Genetic inactivation of the A.sub.2A receptor attenuated
L-dopa-induced rotational behavior..sup.49 This is consistent with
a recent study showing that co-administration of KW6002 with
apomorphine to MPTP-treated monkeys completely abolished the
development of apomorphine-induced dyskinesia..sup.50 Further
studies are warranted to explore the molecular mechanism underlying
this novel aspect of A.sub.2AAR function.
[0009] Third, accumulating evidence suggests that the specific
inactivation of A.sub.2AARs consistently attenuates brain damage
induced by ischemia.sup.51-53 and excitoxicity,.sup.54,55 as well
as in animal models of Huntington's disease.sup.56 and Alzheimer's
disease..sup.57 The neuroprotection by A.sub.2AAR antagonists has
been recently extended to a rodent model of PD. Co-administration
of A.sub.2AAR antagonists, such as CSC, DMPX, SCH58261 and KW6002
(but not the A.sub.1AR antagonist DPCPX) attenuated dopaminergic
neurotoxicity in several neurotoxin models of PD..sup.58 A.sub.2AAR
antagonists provided not only functional protection (such as
reduced dopamine content and expression of molecular markers for
the dopaminergic terminals), but also reduced the loss of
dopaminergic neurons in substantia nigra in both MPTP- and 6-OHDA
models of PD..sup.59,60 Likewise, knockout of A.sub.2AARs
attenuated MPTP-induced dopaminergic neurotoxicity in mice..sup.59
Together with the demonstration of neuroprotection by A.sub.2AAR
antagonists against a wide range of neuronal injury models. These
results raise the possibility that A.sub.2A antagonists may offer a
neuroprotection, slowing or even halting degeneration of
dopaminergic neurons.
[0010] Finally, in contrast to the widespread distribution of other
neurotransmitter receptors, for example, glutamate receptors, the
expression of the A.sub.2AAR is almost exclusively in striatum,
which might allow selective modulation of dopamine-mediated motor
pathways without serious side effects due to drug actions outside
the basal ganglia (a serious problem for drugs such as glutamate
antagonists). It is important to emphasize that ambient adenosine
levels and A.sub.2AAR density are normal in PD patients,.sup.61
indicating that A.sub.2A antagonists might remain effective, even
in the later stages of PD.
[0011] The prospective use of A.sub.2AR antagonists as potential
neuroprotective agents against dopaminergic neuron degeneration was
markedly enhanced by a May 2000 report of an epidemiological study
of the relationship between caffeine and PD. Ross et al described a
large prospective study with a 30-year follow-up of 8004
Japanese-American men that showed that in this population there is
an inverse relationship between caffeine consumption and the risk
of developing PD. .sup.62 Two other ongoing, large-cohort studies
(Heath Professional Follow-up Studies and Nurse's Heath Study)
involving 47,351 men and 88,565 women also showed that moderate
caffeine consumption (3-5 cups/day) reduced their risk of
developing PD..sup.63 Thus, the inverse relationship of caffeine
consumption and the risk of developing PD seem firmly established
by these two large, prospective epidemiological studies. These
results are consistent with the animal studies showing
neuroprotection by A.sub.2AAR antagonists and strongly argue that
A.sub.2A antagonists including caffeine may offer an opportunity to
slow down or halt the degeneration of dopaminergic neurons.
[0012] Initial clinical trial results of KW6002 indicated that
(20-80 mg/day) enhanced motor activity in one study and potentiated
a motor stimulant effect by low (but not high) doses of L-dopa in
another study..sup.64,65 KW6002 was well tolerated and had few side
effects. Unfortunately, trials with KW6002 have been stopped
because this compound was found to produce a long-term toxicity in
rats. Hence, there is a pressing need to develop alternative
molecules that lack toxicity.
[0013] The first relatively selective A.sub.2AAR antagonists, the
8-styrylxanthines, appeared about ten years ago. This class
includes KW-6002, which has low nanomolar affinity for the
A.sub.2AAR and >100-fold selectivity for the A.sub.2AAR over the
A.sub.1AR. KW-6002, entered clinical trials in 2002 as an agent for
the treatment of PD..sup.1,66 SCH58261, a pyrazolo[4,3-e]-1,2,4
triazolo[1,5-c]pyrimidine was a prototype for a series of
second-generation derivatives that appeared over the next several
years. These, too, had low nanomolar affinity and good selectivity
for the A.sub.2AAR in vitro..sup.67 The third class of antagonists
to appear, the 1,2,4-triazolo[4,5-e]-1,3,5-triazines, was typified
by ZM241385, which was active at the A.sub.2AAR in the
sub-nanomolar range but less selective, interacting with A.sub.2BAR
as well..sup.68 These potent A.sub.2A antagonists have been
important research tools, greatly facilitating pharmacological
investigations of A.sub.2AAR function in vitro as well as in vivo
significantly enhancing our understanding of the neurobiology of
the A.sub.2AAR. However, each of these antagonists has important
drawbacks. KW-6002 is light-sensitive, undergoing
photoisomerization from the active E-isomer to the 800-fold less
active Z-isomer..sup.69 SCH58261 is very poorly soluble and even
its second-generation derivatives have marginal
bioavailability..sup.70 As mentioned above, ZM241385 is unselective
and, additionally, has poor bioavailability. Other nitrogen
heterocycles such as the
1,2,4-triazolo[4,3-a]quinoxalin-1-ones.sup.71 and the
oxazolo[4,5-d]pyrimidines from ICI are also unselective, and their
bioavailability is unknown. Therefore a continuing need exists for
compounds that are selective A.sub.2A AR antagonists.
SUMMARY OF THE INVENTION
[0014] In one aspect, there is provided a compound of the formula
I:
##STR00002##
wherein R.sup.1 and R.sup.2 are each independently selected from
the group consisting of hydrogen, halogen, --NH.sub.2, --OH, --SH,
--NHCH.sub.3, --N(CH.sub.3).sub.2, --OMe, --SMe,
(C.sub.1-C.sub.8)alkyl, aryl and aryl(C.sub.1-C.sub.8)alkyl,
wherein R.sup.1 and R.sup.2 are optionally substituted with 1 to 4
substituents of R.sup.a, wherein the alkyl is optionally
interrupted by 1-4 heteroatoms selected from --O--, --S--, --SO--,
--S(O).sub.2-- or amino (--NR.sup.a), or where R.sup.1 and R.sup.2
are independently absent, with the proviso that R.sup.a is not thio
or halogen in the case where R.sup.1 and R.sup.2 to which R.sup.a
is bound is halogen, --NH.sub.2, --OH, --SH, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --OMe and --SMe; R.sup.3 is selected from the
group consisting of hydrogen, halo, --OR.sup.a, --SR.sup.a,
(C.sub.1-C.sub.8)alkyl, cyano, nitro, trifluoromethyl,
trifluoromethoxy, (C.sub.3-C.sub.8)cycloalkyl, heterocycle,
hetrocycle(C.sub.1-C.sub.8)alkyl, aryl, aryl(C.sub.1-C.sub.8)alkyl,
heteroaryl, heteroaryl(C.sub.1-C.sub.8)alkyl, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.bN--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, --OPO.sub.3R.sup.a,
R.sup.aOC(.dbd.S)--, R.sup.aC(.dbd.S)--, --SSR.sup.a,
R.sup.aS(.dbd.O)--, R.sup.aS(.dbd.O).sub.2--, --NNR.sup.a and
--OPO.sub.2R.sup.a; or if the ring formed from the group
CR.sup.3R.sup.4R.sup.5 is aryl or heteroaryl or partially
unsaturated, then R.sup.3 can be absent; R.sup.4 and R.sup.5
together with the atoms to which they are attached form a saturated
or partially unsaturated, mono-, bi- or tricyclic- or aromatic ring
having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, wherein the
ring atoms are optionally interrupted by 1, 2, 3 or 4 heteroatoms
selected from the group consisting of --O--, --S--, --SO--,
--S(O).sub.2-- or amine (--NR.sup.a--) in the ring, wherein any
ring comprising R.sup.4 and R.sup.5 is optionally further
substituted with from 1 to 14 R.sup.6 groups; wherein each R.sup.6
is independently selected from the group consisting of halo,
--OR.sup.a, --SR.sup.a, substituted or unsubstituted
(C.sub.1-C.sub.8)alkyl, cyano, nitro, trifluoromethyl,
trifluoromethoxy, (C.sub.1-C.sub.8)cycloalkyl,
(C.sub.6-C.sub.12)bicycloalkyl, heterocycle,
hetrocyclyl(C.sub.1-C.sub.8)alkyl, aryl,
aryl(C.sub.1-C.sub.8)alkyl, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkyl, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.bN--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, --OPO.sub.3R.sup.a,
R.sup.aOC(.dbd.S)--, R.sup.aC(.dbd.S)--, --SSR.sup.a,
R.sup.aS(.dbd.O)--, --NNR.sup.a and --OPO.sub.2R.sup.a or two
R.sup.6 groups and the atom to which they are attached combined to
form C.dbd.O or C.dbd.S, or wherein two R.sup.6 groups together
with the atom or atoms to which they are attached can form a
carbocyclic or heterocyclic ring; R.sup.7 and R.sup.8 are each
independently hydrogen, (C.sub.1-C.sub.8)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, aryl or aryl(C.sub.1-C.sub.8)alkylene,
heteroaryl, heteroaryl(C.sub.1-C.sub.8)alkylene-; or wherein
R.sup.7 and R.sup.8 together with the nitrogen atom to which they
attach form a heterocycle or heteroaromatic ring; R.sup.9 and
R.sup.10 are each independently selected from the group consisting
of hydrogen, halogen, --NH.sub.2, --OH, --SH, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --OMe, --SMe, (C.sub.1-C.sub.8)alkyl, aryl and
aryl(C.sub.1-C.sub.8)alkyl, wherein R.sup.9 and R.sup.10 are
optionally substituted with 1 to 4 substituents of R.sup.a, wherein
the alkyl is optionally interrupted by 1 to 4 heteroatoms selected
from --O--, --S--, --SO--, --S(O).sub.2-- or amino (--NR.sup.a--),
or where R.sup.9 and R.sup.10 are independently absent, with the
proviso that R.sup.a is not thio or halogen in the case where
R.sup.9 and R.sup.10 to which R.sup.a is bound is halogen,
--NH.sub.2, --OH, --SH, --NHCH.sub.3, --N(CH.sub.3).sub.2, --OMe
and --SMe; Y is --CR.sup.3R.sup.4R.sup.5 or NR.sup.4R.sup.5; Z is
selected from the group consisting of hydrogen, halogen,
(C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)cycloalkyl,
(C.sub.6-C.sub.12)bicycloalkyl, (C.sub.6-C.sub.20)polycyclyl,
heterocyclyl, cycloalkyl(C.sub.1-C.sub.8)alkyl,
bicycloalkyl(C.sub.6-C.sub.12)alkyl,
heterocyclyl(C.sub.1-C.sub.8)alkyl, aryl, aryl(C.sub.5-C.sub.14),
aryl(C.sub.1-C.sub.8)alkyl, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkyl, --NR.sup.aR.sup.b, --OR.sup.a,
--SR.sup.a, cyano, nitro, trifluoromethyl, trifluoromethoxy,
--CO.sub.2R.sup.a, R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--,
--OCO.sub.2R.sup.a, R.sup.aR.sup.bNC(.dbd.O)O--,
R.sup.bOC(.dbd.O)NR.sup.a--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)NR.sup.b--, R.sup.aR.sup.bNC(.dbd.O)NR.sup.b,
R.sup.aR.sup.bNC(.dbd.S)NR.sup.b--, --OPO.sub.3R.sup.a,
R.sup.aOC(.dbd.S)--, R.sup.aC(.dbd.S)--, --SSR.sup.a,
R.sup.aS(.dbd.O)--, --NNR.sup.a, --OPO.sub.2R.sup.a,
OS(O.sub.2)R.sup.a, --OS(.dbd.O)OR.sup.a, --OS(O.sub.2)OR.sup.a and
--O(SO.sub.2)NR.sup.aR.sup.b; R.sup.a and R.sup.b are each
independently selected from the group consisting of hydrogen,
halogen, --NH.sub.2, --OH, --SH, --NHCH.sub.3, --N(CH.sub.3).sub.2,
--OMe, --SMe, propargyl, cyano, --NNH, --NNCH.sub.3, --OPO.sub.2H,
--OPO.sub.2CH.sub.3, --OS(O.sub.2)H, --OS(O.sub.2)OH,
--OS(O.sub.2)CH.sub.3, --OS(O.sub.2)OCH.sub.3,
(C.sub.1-C.sub.8)alkyl, aryl, aryl(C.sub.1-C.sub.8)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.6-C.sub.12)bicycloalkyl,
cycloalkyl(C.sub.1-C.sub.8)alkyl,
bicycloalkyl(C.sub.6-C.sub.12)alkyl, heteroaryl and
heteroaryl(C.sub.1-C.sub.8)alkyl, wherein the alkyl and cycloalkyl
are optionally interrupted with 1-4 heteroatoms selected from the
group consisting of --O--, --S--, --SO--, --S(O).sub.2-- and amino
(--NR.sup.c--); and wherein the alkyl, cycloalkyl, aryl and
heteroaryl are optionally substituted with 1, 2, 3 or 4
substituents selected from the group consisting of --OR.sup.c,
--NR.sup.cR.sup.c, --SR.sup.c, cyano, --NNH, --NNCH.sub.3,
--OPO.sub.2H, --OPO.sub.2CH.sub.3, --OS(O.sub.2)H, --OS(O.sub.2)OH,
--OS(O.sub.2)CH.sub.3 and --OS(O.sub.2)OCH.sub.3, provided that
R.sup.a is not a heteroatom when it is attached to another
heteroatom; R.sup.c is selected from the group consisting of
hydrogen and (C.sub.1-C.sub.8)alkyl; and m is 0 to 8; n is 0, 1, 2
or 3, provided that when m is 0, Z is not halogen, cyano, nitro or
a heteroatom, and when n is 0, Y is not --NR.sup.4R.sup.5; or a
pharmaceutically acceptable salt thereof, optionally in the form of
a single stereoisomer or mixture of stereoisomers thereof.
[0015] In another aspect, there is provided a compound of the
formula II:
##STR00003##
wherein R.sup.1, R.sup.2, R.sup.7, R.sup.8, R.sup.9, R.sup.10, m,
n, Y and Z are as defined above; and L is a linker selected from
the group consisting of --(C.sub.1-C.sub.3)alkyl-C.ident.C--,
--C.ident.C--(C.sub.1-C.sub.3)alkyl-,
--(CH.sub.2).sub.1-3--CH.dbd.CH--,
--CH.dbd.CH--CH.sub.2).sub.1-3--,
--(CH.sub.2).sub.1-2--CH.dbd.CH--CH.sub.2-- and
--CH.sub.2--CH.dbd.CH--(CH.sub.2).sub.1-2--; or a pharmaceutically
acceptable salt thereof, optionally in the form of a single
stereoisomer or mixture of stereoisomers thereof.
[0016] In another aspect, there is provided a compound of the
formula III:
##STR00004##
wherein R.sup.1, R.sup.2, R.sup.7, R.sup.8, R.sup.9, R.sup.10, m,
n, Y and Z are as defined above; and L is a linker selected from
the group consisting of --NH--, --N.dbd.N--, --NH--N.dbd., --O--,
--S--, --SO.sub.2-- and pyrazolyl; a pharmaceutically acceptable
salt thereof, optionally in the form of a single stereoisomer or
mixture of stereoisomers thereof.
[0017] In one variation of each of the above compound of formulae
I, II and III, the group (CR.sup.1R.sup.2).sub.m together is
selected from the group consisting of methylene, ethylene,
propylene, butylene, pentylene, hexylene, heptylene, octylene,
iso-propylene, iso-butylene, sec-butylene and tert-butylene. In
another variation, (CR.sup.1R.sup.2).sub.m together is selected
from the group consisting of methylene, ethylene, propylene and
iso-propylene. In another variation, (CR.sup.1R.sup.2).sub.m-Z
together is selected from the group consisting of
--CH.sub.2CH.dbd.CH.sub.2--, --CH.sub.2C.ident.CH,
--CH.sub.2C.ident.CCH.sub.3 or --CH.sub.2CH.sub.2C.ident.CH. In yet
another variation, (CR.sup.1R.sup.2).sub.m-Z together is
--CH.sub.2C.ident.CH.
[0018] In another variation of the above formulae, R.sub.1 and
R.sub.2 are hydrogen or are absent, m is 2 to 8 and the group
(CR.sup.1R.sup.2).sub.m optionally comprises 1 to 4 alkenyl or
alkynyl conjugated or unconjugated groups. In another variation, m
is 1 to 8 and Z is selected from the group consisting of
--NH.sub.2, --OH, --SH, --NR.sup.aR.sup.b, --OR.sup.a, --SR.sup.a
and cyano. In another particular variation,
(CR.sup.1R.sup.2).sub.m-Z together is selected from the group
consisting of methanol, ethanol, propanol, butanol, pentanol,
hexanol, iso-propanol, iso-butanol, sec-butanol and tert-butanol.
In yet another variation, (CR.sup.1R.sup.2).sub.m-Z together is
selected from the group consisting of methanol, ethanol, propanol
and --CH.sub.2CN.
[0019] In one variation of each of the above, R.sup.1 and R.sup.2
are hydrogen, and the group (CR.sup.1R.sup.2).sub.m is linear or
branched, m is 1 to 6, and Z is selected from the group consisting
of methoxy, ethoxy, propoxy, butoxy, pentoxy and hexyloxy. In
another variation, Z is selected from the group consisting of
methoxy, ethoxy and propoxy. In another variation, Z is a mono-,
bicyclic-, tricyclic- or aromatic or non-aromatic
(C.sub.3-C.sub.20)cycloalkyl ring, wherein the ring atoms are
optionally interrupted by 1 to 8 heteroatoms selected from the
group consisting of --O--, --S--, --SO--, --S(O).sub.2-- and amino
(--NR.sup.a--). In yet another variation, Z is selected from the
group consisting of cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl and cyclooctyl ring optionally substituted
with 1 to 4 substituents of R.sup.3. In yet another variation, Z is
selected from the group consisting of cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl, where m is 0 or 1. In another
variation, Z is cyclopentyl and where m is 0. In a particular
variation, Z is cyclobutyl, m is 1 and R.sup.1 and R.sup.2 are
hydrogen.
[0020] In one particular variation of each of the above; Y and Z
are each independently selected from the group consisting of
hydrogen, or
##STR00005##
wherein each Y or Z group is optionally comprises 1, 2 or 3 double
bonds; each carbon in the ring is optionally replaced by or
interrupted by 1 to 6 heteroatoms selected from --O--, --S--,
--SO--, --S(O).sub.2--, or amino (--NR.sup.a--), and is optionally
further substituted with from 1 to 10 R.sup.6 groups, provided that
the Y or Z ring is not attached at a bridgehead carbon atom or at a
trisubstituted carbon atom. In another variation, each Y or Z is
independently hydrogen or a bicyclic ring selected from the group
consisting of
##STR00006##
wherein any two adjacent carbon ring atom is optionally interrupted
with 1 to 6 heteroatoms selected from --O--, --S--, --SO--,
--S(O).sub.2-- or amino (--NR.sup.a--), and the ring is optionally
substituted with from 1 to 7 R.sup.a groups selected from the group
consisting of --NH.sub.2, --OH, --SH, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --OMe, --SMe, propargyl, cyano, --NNH,
--NNCH.sub.3, --OPO.sub.2H, --OPO.sub.2CH.sub.3, --OS(O.sub.2)H,
--OS(O.sub.2)OH, --OS(O.sub.2)CH.sub.3 and --OS(O.sub.2)OCH.sub.3,
and m and n are each independently 0 or 1. In another variation,
each Y or Z is independently selected from the group consisting of
hydrogen, or
##STR00007##
wherein m and n are each independently 0 or 1, and R.sup.1,
R.sup.2, R.sup.9 and R.sup.10 are each independently absent or
selected from the group consisting of hydrogen, --NH.sub.2, --OH,
--SH, --NHCH.sub.3, --N(CH.sub.3).sub.2--OMe and --SMe, and each Z
group is optionally substituted with from 1 to 7 R.sup.a groups
selected from the group consisting of halo, --NH.sub.2, --OH, --SH,
--NHCH.sub.3, --N(CH.sub.3).sub.2, --OMe, --SMe, propargyl, cyano,
--NNH, --NNCH.sub.3, --OPO.sub.2H, --OPO.sub.2CH.sub.3,
--S(SO.sub.2)H, --S(SO.sub.2)OH, --S(SO.sub.2)CH.sub.3 and
--S(SO.sub.2)OCH.sub.3.
[0021] In another variation of the above, R.sup.1 and R.sup.2 are
hydrogen, m is 0, 1, 2 or 3 and Z is selected from the group
consisting of furan, dihydro-furan, tetrahydrofuran, thiophene,
pyrrole, 2H-pyrrole, 2-pyrroline, 3-pyrroline, pyrrolidine,
1,3-dioxolane, oxazole, thiazole, imidazole, dihydro-imidazole,
2-imidazoline, imidazolidine, pyrazole, 2-pyrazoline, pyrazolidine,
isoxazole, isothiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole,
1,2,3-triazole, 1,2,4-triazole, 1,3,4-thiadiazole, 2H-pyran,
1H-tetrazole, 4H-pyran, pyridine, dihydro-pyridine,
tetrahydro-pyridine, piperidine, 1,4-dioxane, morpholine,
1,4-dithiane, thiomorpholine, pyridazine, pyrimidine,
dihydro-pyrimidine, tetrahydro-pyrimidine, hexahydro-pyrimidine,
pyrazine, dihydro-pyrazine, tetrahydro-pyrazine, piperazine,
1,3,5-triazine and 1,3,5-trithiane, wherein each Z group is
optionally substituted with from 1 to 10 R.sup.a groups.
[0022] In yet another variation, R.sup.1 and R.sup.2 are hydrogen,
m is 0 or 1, and Z is selected from the group consisting of furan,
thiophene, pyrrole, 2H-pyrrole, oxazole, thiazole, imidazole,
pyrazole, isoxazole, isothiazole, 1,2,3-oxadiazole,
1,2,4-oxadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-thiadiazole
and 1H-tetrazole, wherein each Z group is optionally substituted
with from 1 to 3 R.sup.a groups selected from the group consisting
of methyl, ethyl, propyl, iso-propyl, --NH.sub.2, --OH, --SH,
--NHCH.sub.3, --N(CH.sub.3).sub.2, --OCH.sub.3 and --SCH.sub.3. In
another variation, Z is selected from the group consisting of
--CO.sub.2R.sup.3, R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--,
--OCO.sub.2R.sup.a, R.sup.aR.sup.bNC(.dbd.O)O--,
R.sup.bOC(.dbd.O)NR.sup.a--, R.sup.aR.sup.bN--,
R.sup.aR.sup.bNC(.dbd.O)--, R.sup.aC(.dbd.O)NR.sup.b--,
R.sup.aR.sup.bNC(.dbd.O)NR.sup.b,
R.sup.aR.sup.bNC(.dbd.S)NR.sup.b1, --OPO.sub.3R.sup.a,
R.sup.aOC(.dbd.S)--, R.sup.aC(.dbd.S)--, --SSR.sup.a,
R.sup.aS(.dbd.O)--, R.sup.aS(O.sub.2)--, --N.dbd.NR.sup.a,
--OPO.sub.2R.sup.a, --OS(O.sub.2)R.sup.a, --OS(.dbd.O)OR.sup.a,
--OS(O.sub.2)OR.sup.a and --OS(O.sub.2)NR.sup.aR.sup.b, wherein m
is 1 to 8, and the group (CR.sup.1R.sup.2).sub.m is optionally
saturated or partially unsaturated. In yet another variation, Z is
selected from the group consisting of --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)NR.sup.a--,
R.sup.aR.sup.bN--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)NR.sup.b--, R.sup.aR.sup.bNC(.dbd.O)NR.sup.b--,
R.sup.aR.sup.bNC(.dbd.S)NR.sup.b--, --OPO.sub.3R.sup.a,
R.sup.aOC(.dbd.S)--, R.sup.aC(.dbd.S)--, --SSR.sup.a,
R.sup.aS(.dbd.O)--, R.sup.aS(.dbd.O).sub.2--, --N.dbd.NR.sup.a,
--OPO.sub.2R.sup.a, --OS(O.sub.2)R.sup.a, --OS(.dbd.O)OR.sup.a,
--OS(O.sub.2)OR.sup.a and --O(SO.sub.2)NR.sup.aR.sup.b, and wherein
(R.sup.1R.sup.2).sub.m together is selected from the group
consisting of --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
--CH.dbd.CHCH.sub.2--, --CH.sub.2CH.dbd.CH--,
--CH.dbd.CHCH.sub.2CH.sub.2--, --CH.sub.2CH.dbd.CHCH.sub.2--,
--CH.sub.2CH.sub.2CH.dbd.CH--, --C--CCH.sub.2--,
--CH.sub.2C.ident.C--, --C.ident.CCH.sub.2CH.sub.2--,
--CH.sub.2C.ident.CCH.sub.2-- and --CH.sub.2CH.sub.2C--C--. In
still another variation of the above, Z is independently
--CO.sub.2R.sup.a, R.sup.aC(.dbd.O)--, R.sup.aR.sup.bN--,
--OPO.sub.3R.sup.a, R.sup.aOC(.dbd.S)--, R.sup.aC(.dbd.S)--,
R.sup.aS(.dbd.O)--, R.sup.aS(.dbd.O).sub.2--, --OPO.sub.2R.sup.a,
--OS(O.sub.2)R.sup.a, --OS(.dbd.O)OR.sup.a, --OS(O.sub.2)OR.sup.3
or --OS(O.sub.2)NR.sup.aR.sup.b, and wherein
(CR.sup.1R.sup.2).sub.m together is selected from the group
consisting of --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
--CH.dbd.CHCH.sub.2, --CH.sub.2CH.dbd.CH--,
--CH.dbd.CHCH.sub.2CH.sub.2--, --CH.sub.2CH.dbd.CHCH.sub.2--,
--CH.sub.2CH.sub.2CH.dbd.CH--, --C--CCH.sub.2--, --CH.sub.2C--C--,
--C--CCH.sub.2CH.sub.2--, --CH.sub.2C--CCH.sub.2-- and
--CH.sub.2CH.sub.2C--C--.
[0023] In one particular variation of each of the above; each
R.sup.9 is independently selected from the group consisting of
hydrogen, halo, --OR.sup.a, --SR.sup.a, (C.sub.1-C.sub.8)alkyl,
cyano, nitro, trifluoromethyl, trifluoromethoxy,
(C.sub.3-C.sub.8)cycloalkyl, heterocyclyl,
hetrocyclyl(C.sub.1-C.sub.8)alkylene-, aryl,
aryl(C.sub.1-C.sub.8)alkylene-, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkylene-, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.bN--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, --OPO.sub.3R.sup.a,
R.sup.aOC(.dbd.S)--, R.sup.aC(.dbd.S)--, --SSR.sup.a,
R.sup.aS(.dbd.O)--, R.sup.aS(.dbd.O).sub.2--, --N.dbd.NR.sup.a and
--OPO.sub.2R.sup.3. In another variation, R.sup.1 and R.sup.2
together with the carbon atom to which they are attached is
C.dbd.O, C.dbd.S or C.dbd.NR.sup.c. In yet another variation,
R.sup.3 is selected from the group consisting of hydrogen, halo,
--OR.sup.a, --SR.sup.a, cyano, nitro, trifluoromethyl,
trifluoromethoxy, --CO.sub.2R.sup.a, R.sup.aC(.dbd.O)O--,
R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.bN--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, --OPO.sub.3R.sup.a,
R.sup.aOC(.dbd.S)--, R.sup.aC(.dbd.S)--, --SSR.sup.a,
R.sup.aS(.dbd.O)--, R.sup.aS(.dbd.O).sub.2--, --NNR.sup.a and
--OPO.sub.2R.sup.a; or if the ring formed from the group
CR.sup.3R.sup.4R.sup.5 is aryl or heteroaryl or partially
unsaturated then R.sup.3 can be absent. In another variation of the
above, R.sup.3 is selected from the group consisting of hydrogen,
OH, OMe, OAc, NH.sub.2, NHMe, NMe.sub.2 and NHAc. In a particular
variation, R.sup.3 is hydrogen or OH.
[0024] In one particular variation of each of the above; R.sup.4
and R.sup.5 together with the atom to which they are attached form
a saturated or partially unsaturated, mono-, bi- or tricyclic ring,
or aromatic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring
atoms, wherein the ring atoms are optionally interrupted by 1, 2, 3
or 4 heteroatoms selected from the group consisting of --O--,
--S--, --SO--, --S(O).sub.2-- or amine (--NR.sup.a--) in the ring,
wherein any ring comprising R.sup.4 and R.sup.5 is optionally
further substituted with from 1 to 14 R.sup.6 groups; wherein each
R.sup.6 is independently selected from the group consisting of
halo, --OR.sup.a, --SR.sup.a, (C.sub.1-C.sub.8)alkyl, cyano, nitro,
trifluoromethyl, trifluoromethoxy, (C.sub.1-C.sub.8)cycloalkyl,
(C.sub.6-C.sub.12)bicycloalkyl, heterocycle,
hetrocyclyl(C.sub.1-C.sub.8)alkyl, aryl,
aryl(C.sub.1-C.sub.8)alkyl, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkyl, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR NC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.b--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, --OPO.sub.3R.sup.a,
R.sup.aOC(.dbd.S)--, R.sup.aC(.dbd.S)--, --SSR.sup.a,
R.sup.aS(.dbd.O)--, --NNR.sup.a, --OPO.sub.2R.sup.a, or two R.sup.6
groups and the atom to which they are attached combined to form
C.dbd.O or C.dbd.S, or wherein two R.sup.6 groups together with the
atom or atoms to which they are attached can form a carbocyclic or
heterocyclic ring. In another variation, the ring comprising
R.sup.4 and R.sup.5 and the atom to which they are attached is
selected from the group consisting of cyclopentane, cyclohexane,
piperidine, dihydro-pyridine, tetrahydro-pyridine, pyridine,
piperazine, decaline, tetrahydro-pyrazine, dihydro-pyrazine,
pyrazine, dihydro-pyrimidine, tetrahydro-pyrimidine,
hexahydro-pyrimidine, pyrazine, imidazole, dihydro-imidazole,
imidazolidine, pyrazole, dihydro-pyrazole, pyrazolidine, norbornane
and adamantane, each unsubstituted or substituted.
[0025] In one particular variation of each of the above, R.sup.6 is
selected from the group consisting of substituted or unsubstituted
(C.sub.1-C.sub.8)alkyl, --OR.sup.a, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)--, R.sup.aC(.dbd.O)O--, R.sup.aR.sup.bN--,
R.sup.aR.sup.bNC(.dbd.O)-- and aryl, provided that when the ring
comprising R.sup.4 and R.sup.5 contains a heteroatom that is O or
S, the heteroatom is not substituted with R.sup.6. In another
variation, R.sup.6 is selected from the group consisting of OH,
OMe, methyl, ethyl, t-butyl, --CO.sub.2R.sup.a,
--CONR.sup.aR.sup.b, OAc, NH.sub.2, NHMe, NMe.sub.2, NHEt and
N(Et).sub.2, provided that when the ring comprising R.sup.4 and
R.sup.5 contains a heteroatom that is O or S, the heteroatom is not
substituted with R.sup.6. In yet another variation, R.sup.6 is
selected from the group consisting of methyl, ethyl,
--CO.sub.2R.sup.a, --CONR.sup.aR.sup.b and OAc, provided that when
the ring comprising R.sup.4 and R.sup.5 contains a heteroatom, the
heteroatom is not substituted with OAc. In yet another variation,
R.sup.6 is selected from the group consisting
of --(CH.sub.2).sub.1-2OR.sup.a,
--(CH.sub.2).sub.1-2C(.dbd.O)OR.sup.3,
--(CH.sub.2).sub.1-2OC(.dbd.O)R.sup.a,
--(CH.sub.2).sub.1-2C(.dbd.O)R.sup.a, --(CH.sub.2).sub.1-2OCO.sub.2
R.sup.3, --(CH.sub.2).sub.1-2NHR.sup.a,
--(CH.sub.2).sub.1-2NR.sup.aR.sup.b,
--(CH.sub.2).sub.1-2OC(.dbd.O)NHR.sup.3 and
--(CH.sub.2).sub.1-2OC(.dbd.O)NR.sup.aR.sup.b. In yet another
variation, R.sup.6
is --CH.sub.2C(.dbd.O)OR.sup.a, --CH.sub.2C(.dbd.O)OR.sup.a,
--CH.sub.2OH, --CH.sub.2OAc, --CH.sub.2NH(CH.sub.3)
[0026] and --(CH.sub.2).sub.1-2N(CH.sub.3).sub.2. In another
variation, the number of R.sub.6 groups substituted on the
R.sub.4R.sub.5 ring is from 1 to 4.
[0027] In another variation, R.sup.7 and R.sup.5 is selected from
the group consisting of hydrogen, (C.sub.1-C.sub.8)alkyl-, aryl,
aryl(C.sub.1-C.sub.8)alkylene-, mono-, bicyclic- or aromatic or
nonaromatic ring having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms,
wherein the ring atoms are optionally interrupted by 1, 2, 3 or 4
heteroatoms selected from the group consisting of --O--, --S--,
--SO--, --S(O).sub.2-- or amine (--NR.sup.a--) in the ring, and
each is optionally substituted with from 1, 2, 3 or 4 R.sup.a
groups. In yet another variation, R.sup.7 is selected from the
group consisting of hydrogen, methyl, ethyl, propyl, butyl,
3-pentyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, phenyl and
benzyl, or wherein R.sup.7 is hydrogen, methyl or sec-butyl. In
another variation, R.sup.7 and R.sup.5 are each independently
selected from the group consisting of hydrogen,
(C.sub.1-C.sub.8)alkyl, (C.sub.3-C.sub.8)cycloalkyl, aryl,
aryl(C.sub.1-C.sub.8)alkylene, heteroaryl and
heteroaryl(C.sub.1-C.sub.8)alkylene-; or wherein R.sup.7 and
R.sup.8 together with the nitrogen atom to which they attach form a
heterocycle or heteroaromatic ring.
[0028] In one particular variation of each of the above,
--NR.sup.7R.sup.8 is selected from the group consisting of amino,
methylamino, dimethylamino, ethylamino, pentylamino,
diphenylethylamino, pyridylmethylamino, diethylamino and
benzylamino. In another variation, --NR.sup.7R.sup.8 is selected
from the group consisting of amino, methylamino, dimethylamino,
ethylamino, diethylamino and benzylamino, or wherein
--NR.sup.7R.sup.8 is amino.
[0029] In one particular variation of each of the above; R.sup.a
and R.sup.b are each independently selected from the group
consisting of hydrogen, (C.sub.1-C.sub.8)alkyl and
(C.sub.1-C.sub.8)alkyl substituted with 1 to 3
(C.sub.1-C.sub.8)alkoxy, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.1-C.sub.8)alkylthio, aryl, aryl(C.sub.1-C.sub.8)alkylene,
heteroaryl, or heteroaryl(C.sub.1-C.sub.8)alkylene; or R.sup.a and
R.sup.b together with the nitrogen to which they are attached, form
a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
R.sup.c is hydrogen or (C.sub.1-C.sub.6)alkyl; m is 0 to about 8
and p is 0 to 2; and Y is --CR.sup.3R.sup.4R.sup.5 or
NR.sup.4R.sup.5.
[0030] In another variation, R.sup.7 is selected from the group
consisting of benzyl, phenethyl, phenylpropyl and each is
optionally substituted with from 1, 2 or 3 substituents of R.sup.a.
In a particular variation, R.sup.7 is selected from the group
consisting of benzyl, phenethyl, phenylpropyl and each is
optionally substituted with from 1, 2 or 3 substituents of R.sup.a
selected from the group consisting of methyl, ethyl, propyl,
methoxy, ethoxy and propoxy; or wherein R.sup.7 is benzyl and
R.sup.a is methoxy.
[0031] In another aspect of the above, R.sup.9 is selected from the
group consisting of hydrogen, fluoro, --OH, --CH.sub.2OH, --OMe,
--OAc, --NH.sub.2, --NHMe, --NMe.sub.2 and --NHAc; or wherein
R.sup.9 is hydrogen or OH. In one variation, each R.sup.10 is
independently selected from the group consisting of hydrogen,
fluoro, (C.sub.1-C.sub.8)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
heterocyclyl, heterocycle(C.sub.1-C.sub.8)alkylene-, aryl,
aryl(C.sub.1-C.sub.8)alkylene-, heteroaryl and
heteroaryl(C.sub.1-C.sub.8)alkylene-. In another variation,
R.sup.10 is selected from the group consisting of hydrogen,
(C.sub.1-C.sub.8)alkyl, cyclopropyl, cyclohexyl and benzyl; or
wherein R.sup.10 is hydrogen. In yet another variation of the
above, R.sup.9 and R.sup.10 and the carbon atom to which they are
attached is a C.dbd.O group.
[0032] In a variation of the above compound, R.sup.a and R.sup.b
are each independently selected from the group consisting of
hydrogen, (C.sub.1-C.sub.4)alkyl, aryl and
aryl(C.sub.1-C.sub.8)alkylene. In a particular variation, R.sup.a
and R.sup.b are each independently selected from the group
consisting of hydrogen, methyl, ethyl, phenyl and benzyl. In
another variation, R.sup.a is (C.sub.1-C.sub.8)alkyl. In yet
another variation, R.sup.a is selected from the group consisting of
methyl, ethyl, propyl and butyl. In yet another variation, R.sup.a
is selected from the group consisting of methyl, ethyl, i-propyl,
i-butyl and tert-butyl. In still another variation, R.sup.a and
R.sup.b is a ring.
[0033] In one variation of each of the above, Y is
--CR.sub.3R.sub.4R.sub.5 or NR.sub.4R.sub.5, and is selected from
the group consisting of:
##STR00008##
wherein q is 0, 1, 2, 3 or 4; R.sup.3 is selected from the group
consisting of hydrogen, halo, --OR.sup.a, --SR.sup.a,
(C.sub.1-C.sub.8)alkyl, cyano, nitro, trifluoromethyl,
trifluoromethoxy, (C.sub.3-C.sub.8)cycloalkyl, heterocycle,
hetrocycle(C.sub.1-C.sub.8)alkyl, aryl, aryl(C.sub.1-C.sub.8)alkyl,
heteroaryl, heteroaryl(C.sub.1-C.sub.8)alkyl, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR NC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.bN--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, OPO.sub.3R.sup.a,
R.sup.aOC(.dbd.S)--, R.sup.aC(.dbd.S)--, --SSR.sup.a,
R.sup.aS(.dbd.O)--, R.sup.aS(.dbd.O).sub.2--, --NNR.sup.a and
--OPO.sub.2R.sup.a; and each R.sup.6 is independently selected from
the group consisting of halo, --OR.sup.3, --SR.sup.3, substituted
or unsubstituted (C.sub.1-C.sub.8)alkyl, cyano, nitro,
trifluoromethyl, trifluoromethoxy, (C.sub.1-C.sub.8)cycloalkyl,
(C.sub.6-C.sub.12)bicycloalkyl, heterocycle,
hetrocyclyl(C.sub.1-C.sub.8)alkyl, aryl,
aryl(C.sub.1-C.sub.8)alkyl, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkyl, --CO.sub.2R.sup.3,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.bN--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, --OPO.sub.3R.sup.a,
R.sup.aOC(.dbd.S)--, R.sup.aC(.dbd.S)--, --SSR.sup.a,
R.sup.aS(.dbd.O)--, --NNR.sup.a and --OPO.sub.2R.sup.a, provided
that R.sup.6 is not halogen or a heteroatom when R.sup.6 is
attached to a heteroatom.
[0034] In another variation, Y is --CR.sup.3R.sup.4R.sup.5 or
NR.sup.4R.sup.5 and is selected from the group consisting of:
##STR00009##
wherein R.sup.3 is selected from the group consisting of hydrogen,
halo, --OR.sup.a, --SR.sup.a, (C.sub.1-C.sub.8)alkyl, cyano, nitro,
trifluoromethyl, trifluoromethoxy, (C.sub.3-C.sub.8)cycloalkyl,
heterocycle, hetrocycle(C.sub.1-C.sub.8)alkyl, aryl,
aryl(C.sub.1-C.sub.8)alkyl, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkyl, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR NC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.bN--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, --OPO.sub.3R.sup.a,
R.sup.aOC(.dbd.S)--, R.sup.aC(.dbd.S)--, --SSR.sup.a,
R.sup.aS(.dbd.O)--, R.sup.aS(.dbd.O).sub.2--, --NNR.sup.a and
--OPO.sub.2R.sup.a; and each R.sup.6 is independently selected from
the group consisting of halo, --OR.sup.3, --SR.sup.3, substituted
or unsubstituted (C.sub.1-C.sub.8)alkyl, cyano, nitro,
trifluoromethyl, trifluoromethoxy, (C.sub.1-C.sub.8)cycloalkyl,
(C.sub.6-C.sub.12)bicycloalkyl, heterocycle,
hetrocyclyl(C.sub.1-C.sub.8)alkyl, aryl,
aryl(C.sub.1-C.sub.8)alkyl, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkyl, --CO.sub.2R.sup.3,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.bN--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, --OPO.sub.3R.sup.3,
R.sup.aOC(.dbd.S)--, R.sup.aC(.dbd.S)--, --SSR.sup.a,
R.sup.aS(.dbd.O)--, --NNR.sup.a and --OPO.sub.2R.sup.a.
[0035] In another variation, the ring comprising
--C(R.sup.3)R.sup.4R.sup.5 is 2-methylcyclohexan-1-yl,
2,2-dimethylcyclohexan-1-yl, 2-ethylcyclohexan-1-yl,
2,2-diethylcyclohexan-1-yl, 2-tert-butylcyclohexan-1-yl,
2-phenylcyclohexan-1-yl, 3-methylcyclohexan-1-yl,
3-ethylcyclohexan-1-yl, 3,3-dimethylcyclohexan-1-yl,
4-methylcyclohexan-1-yl, 4-ethylcyclohexan-1-yl,
4,4-dimethylcyclohexan-1-yl, 4-tert-butylcyclohexan-1-yl,
4-phenylcyclohexan-1-yl, 3,3,5,5-tetramethylcyclohexan-1-yl,
2,4-dimethylcyclopentan-1-yl, 4-(carboxyl)cyclohexan-1-yl,
4-(carboxymethyl)cyclohexan-1-yl and
4-(carboxyethyl)cyclohexan-1-yl. In yet another variation, the ring
comprises --C(R.sup.3)R.sup.4R.sup.5 is piperidin-4-yl,
1-carboxypiperiden-4-yl, 1-(methoxycarbonyl)piperidin-4-yl,
1-(ethoxycarbonyl)piperidin-4-yl,
1-(n-propoxycarbonyl)piperidin-4-yl,
1-(2,2-dimethylpropoxycarbonyl)piperidin-4-yl, piperidin-1-yl,
4-carboxypiperiden-1-yl, 4-(methoxycarbonyl)piperidine-1-yl,
4-(ethoxycarbonyl)piperidine-1-yl, 4-(n-propoxy)piperidine-1-yl,
4-(2,2-dimethylpropoxycarbonyl)piperidine-1-yl, piperidin-3-yl,
1-carboxypiperidene-3-yl, 1-(methoxycarbonyl)piperidine-3-yl,
1-(ethoxycarbonyl)piperidine-3-yl,
1-(n-propoxycarbonyl)piperidine-3-yl,
1-(2,2-dimethylpropoxycarbonyl)piperidine-3-yl,
3-carboxypiperidene-1-yl, 3-(methoxycarbonyl)piperidine-1-yl,
3-(ethoxycarbonyl)piperidine-1-yl,
3-(n-propoxycarbonyl)piperidine-1-yl,
3-(2,2-dimethylpropoxycarbonyl)piperidine-1-yl, piperazin-1-yl,
1-caboxypiperazin-4-yl, 1-(methoxycarbonyl)piperazin-4-yl,
1-(ethoxycarbonyl)piperazin-4-yl and
1-(n-propoxycarbonyl)piperazin-4-yl.
[0036] In another variation, the ring comprising
--C(R.sup.3)R.sup.4R.sup.5 is selected from the group consisting of
2-methylcyclohexan-1-yl, 2,2-dimethylcyclohexan-1-yl,
2-ethylcyclohexan-1-yl, 2,2-diethylcyclohexan-1-yl,
2-tert-butylcyclohexan-1-yl, 2-phenylcyclohexan-1-yl,
3-methylcyclohexan-1-yl, 3-ethylcyclohexan-1-yl,
3,3-dimethylcyclohexan-1-yl, 4-methylcyclohexan-1-yl,
4-ethylcyclohexan-1-yl, 4,4-dimethylcyclohexan-1-yl,
4-tert-butylcyclohexan-1-yl, 4-phenylcyclohexan-1-yl,
3,3,5,5-tetramethylcyclohexan-1-yl, 2,4-dimethylcyclopentan-1-yl,
4-(carboxyl)cyclohexan-1-yl, 4-(carboxymethyl)cyclohexan-1-yl,
4-(carboxyethyl)cyclohexan-1-yl, piperidin-4-yl,
1-(methoxycarbonyl)piperidin-4-yl,
1-(2,2-dimethylpropoxycarbonyl)piperidin-4-yl, piperidin-1-yl,
4-(methoxycarbonyl)piperidine-1-yl,
4-(2,2-dimethylpropoxycarbonyl)piperidine-1-yl, piperidin-3-yl,
1-(methoxycarbonyl)piperidine-3-yl,
1-(2,2-dimethylpropoxycarbonyl)piperidine-3-yl,
3-(methoxycarbonyl)piperidine-1-yl and
3-(2,2-dimethylpropoxycarbonyl)piperidine-1-yl.
[0037] In a particular variation, Z is a mono-, bicyclic-,
tricyclic- or aromatic or non-aromatic (C.sub.3-C.sub.20)cycloalkyl
ring, wherein the ring atoms are optionally interrupted by 1-8
heteroatoms selected from the group consisting of --O--, --S--,
--SO--, --S(O).sub.2-- and amino (--NR.sup.a--). In one variation
of the above, R.sup.1 and R.sup.2 are hydrogen, m is 0, 1, 2 or 3
and Z is selected from the group consisting of furan,
dihydro-furan, tetrahydrofuran, thiophene, pyrrole, 2H-pyrrole,
2-pyrroline, 3-pyrroline, pyrrolidine, 1,3-dioxolane, oxazole,
thiazole, imidazole, dihydro-imidazole, 2-imidazoline,
imidazolidine, pyrazole, 2-pyrazoline, pyrazolidine, isoxazole,
isothiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,3-triazole,
1,2,4-triazole, 1,3,4-thiadiazole, 2H-pyran, 1H-tetrazole,
4H-pyran, pyridine, dihydro-pyridine, tetrahydro-pyridine,
piperidine, 1,4-dioxane, morpholine, 1,4-dithiane, thiomorpholine,
pyridazine, pyrimidine, dihydro-pyrimidine, tetrahydro-pyrimidine,
hexahydro-pyrimidine, pyrazine, dihydro-pyrazine,
tetrahydro-pyrazine, piperazine, 1,3,5-triazine and
1,3,5-trithiane, wherein each Z group is optionally substituted
with from 1 to 10 R.sup.a groups. In another variation, Z is a
mono-, bicyclic-, tricyclic- or aromatic or non-aromatic
(C.sub.3-C.sub.20)cycloalkyl ring, wherein the ring atoms are
optionally interrupted by 1-8 heteroatoms selected from the group
consisting of --O--, --S--, --SO--, --S(O).sub.2-- and amino
(--NR.sup.a--).
[0038] In a particular variation, R.sup.1 and R.sup.2 are hydrogen,
m is 0, 1, 2 or 3 and Z is selected from the group consisting of
furan, dihydro-furan, tetrahydrofuran, thiophene, pyrrole,
2H-pyrrole, 2-pyrroline, 3-pyrroline, pyrrolidine, 1,3-dioxolane,
oxazole, thiazole, imidazole, dihydro-imidazole, 2-imidazoline,
imidazolidine, pyrazole, 2-pyrazoline, pyrazolidine, isoxazole,
isothiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,3-triazole,
1,2,4-triazole, 1,3,4-thiadiazole, 2H-pyran, 1H-tetrazole,
4H-pyran, pyridine, dihydro-pyridine, tetrahydro-pyridine,
piperidine, 1,4-dioxane, morpholine, 1,4-dithiane, thiomorpholine,
pyridazine, pyrimidine, dihydro-pyrimidine, tetrahydro-pyrimidine,
hexahydro-pyrimidine, pyrazine, dihydro-pyrazine,
tetrahydro-pyrazine, piperazine, 1,3,5-triazine and
1,3,5-trithiane, wherein each Z group is optionally substituted
with from 1 to 10 R.sup.a groups.
[0039] In another aspect, there is provided a compound of the
formula:
##STR00010##
wherein R.sup.7 and R.sup.8 are each independently selected from
the group consisting of hydrogen, (C.sub.2-C.sub.4)alkyl, 3-pentyl,
aryl(C.sub.2-C.sub.4)alkyl, heteroaryl(C.sub.2-C.sub.4)alkyl, each
unsubstituted or substituted, R.sup.8 is selected from the group
consisting of hydrogen or (C.sub.1-C.sub.4)alkyl; and R.sup.11 is
selected from the group consisting of (C.sub.1-C.sub.4)alkyl,
propargyl, (C.sub.3-C.sub.6)cycloalkyl,
(C.sub.3-C.sub.6)cycloalkyl(C.sub.1-C.sub.4)alkyl,
aryl(C.sub.1-C.sub.4)alkyl, heteroaryl(C.sub.1-C.sub.4)alkyl,
heterocyclyl(C.sub.1-C.sub.4)alkyl, HO(C.sub.1-C.sub.4)alkyl,
halo(C.sub.1-C.sub.4)alkyl, --COO(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkylCOO(C.sub.1-C.sub.4)alkyl, each unsubstituted
or substituted; R.sup.13 is methyl, iso-propyl, iso-butyl, or
tert-butyl; and R.sup.1, R.sup.2 and m are as defined herein; or a
pharmaceutically acceptable salt thereof, optionally in the form of
a single stereoisomer or mixture of stereoisomers thereof.
[0040] In another aspect, there is provided a pharmaceutical
composition comprising a therapeutically effective amount of a
compound of each of the above, and a pharmaceutically acceptable
excipient. Some of the compounds of formulae I, II, and III may
further form pharmaceutically acceptable salts and esters. All of
these forms are included within the scope of the present invention.
Pharmaceutically acceptable base addition salts of the compounds of
formulae I, II, and III include salts which may be formed when
acidic protons present in the parent compound are capable of
reacting with inorganic or organic bases as known in the art.
Acceptable inorganic bases, include for example, aluminum
hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate
and sodium-hydroxide. Salts may also be prepared using organic
bases, such as choline, dicyclohexylamine, ethylenediamine,
ethanolamine, diethanolamine, triethanolamine, procaine,
N-methylglucamine, and the like [see, for example, Berge et al.,
"Pharmaceutical Salts," J. Pharma. Sci. 66:1 (1977)].
Pharmaceutically acceptable acid addition salts of the compounds of
formulae I, II, and III include salts which may be formed when the
parent compound contains a basic group. Acid addition salts of the
compounds may be prepared in a suitable solvent from the parent
compound and an excess of a non-toxic inorganic acid, such as
hydrochloric acid, hydrobromic acid, sulfuric acid (giving the
sulfate and bisulfate salts), nitric acid, phosphoric acid and the
like, or a non-toxic organic acid such as aceticacid, propionic
acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic
acid, succinic acid, maleic acid, fumaric acid, tartaric acid,
citric acid, benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, camphorsulfonic acid,
tert-butylacetic acid, laurylsulfuric acid, glucuronic acid,
glutamic acid, and the like. The free base form may be regenerated
by contacting the acid addition salt with a base and isolating the
free base in the conventional manner. The free base forms can
differ from their respective salt forms somewhat in certain
physical properties such as solubility in polar solvents.
[0041] Also included in the above embodiments, aspects and
variations are salts of amino acids such as arginate and the like,
gluconate, and galacturonate. Some of the compounds of the
invention may form inner salts or Zwitterions. Certain of the
compounds of the present invention can exist in unsolvated forms as
well as solvated forms, including hydrated forms, and are intended
to be within the scope of the present invention. Certain of the
above compounds may also exist in one or more solid or crystalline
phases or polymorphs, the variable biological activities of such
polymorphs or mixtures of such polymorphs are also included in the
scope of this invention. Also provided are pharmaceutical
compositions comprising pharmaceutically acceptable excipients and
a therapeutically effective amount of at least one compound of this
invention.
[0042] Pharmaceutical compositions of the compounds of this
invention, or derivatives thereof, may be formulated as solutions
or lyophilized powders for parenteral administration. Powders may
be reconstituted by addition of a suitable diluent or other
pharmaceutically acceptable carrier prior to use. The liquid
formulation is generally a buffered, isotonic, aqueous solution.
Examples of suitable diluents are normal isotonic saline solution,
5% dextrose in water or buffered sodium or ammonium acetate
solution. Such formulations are especially suitable for parenteral
administration but may also be used for oral administration.
Excipients, such as polyvinylpyrrolidinone, gelatin,
hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium
chloride, or sodium citrate, may also be added. Alternatively,
these compounds may be encapsulated, tableted, or prepared in an
emulsion or syrup for oral administration. Pharmaceutically
acceptable solid or liquid carriers may be added to enhance or
stabilize the composition, or to facilitate preparation of the
composition. Liquid carriers include syrup, peanut oil, olive oil,
glycerin, saline, alcohols, or water. Solid carriers include
starch, lactose, calcium sulfate, dihydrate, terra alba, magnesium
stearate or stearic acid, talc, pectin, acacia, agar, or gelatin.
The carrier may also include a sustained release material such as
glyceryl monostearate or glyceryl distearate, alone or with a wax.
The amount of solid carrier varies but, preferably, will be between
about 20 mg to about 1 g per dosage unit. The pharmaceutical
preparations are made following the conventional techniques of
pharmacy involving milling, mixing, granulation, and compressing,
when necessary, for tablet forms; or milling, mixing, and filling
for hard gelatin capsule forms. When a liquid carrier is used, the
preparation will be in the form of a syrup, elixir, emulsion, or an
aqueous or non-aqueous suspension. Such a liquid formulation may be
administered directly p.o. or filled into a soft gelatin capsule.
Suitable formulations for each of these methods of administration
may be found in, for example, Remington: The Science and Practice
of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams
& Wilkins, Philadelphia, Pa.
[0043] In one variation, there is provided the above compound, or a
pharmaceutically acceptable salt thereof, optionally in the form of
a single stereoisomer or mixture of stereoisomers thereof. In one
aspect, there is provided a method for stimulating motor activity
without dyskinesia in a mammal, comprising administering a
therapeutically effective amount of an A.sub.2A anatagonist
compound of the above to the mammal in need of such treatment. In
one variation of the above method, the therapeutically effective
amount is effective to treat ischemia, brain damage induced by
ischemia and excitoxicity, Huntington disease, catalepsy, cancer,
drug addiction and withdrawal, Parkinson's disease (drug induced,
post-encephalitic, poison induced or post-traumatic induced), acute
or chronic pain, narcolepsy and Alzheimer's disease. In another
variation of the above, the therapeutically effective amount is
effective to stimulate motor activity for treating a movement
disorder, where the disorder is progressive supemuclear palsy,
Huntington's disease, multiple system atrophy, corticobasal
degeneration, Wilsons disease, Hallerrorden-Spatz disease,
progressive pallidal atrophy, Dopa-responsive
dystonia-Parkinsonism, spasticity or other disorders of the basal
ganglia which result in dyskinesias. In another variation of the
above, the compound is used in combination with one or more
additional drugs in the treatment of movement disorders (i.e.
L-DOPA or dopamine agonist), addiction, or cancer with the
components being in the same formulation or in a separate
formulation for administration simultaneously or sequentially. In
yet another variation of the method, the therapeutically effective
amount is effective to provide neuroprotection and slow or halt the
degeneration of dopaminergic neurons. In yet another variation, the
therapeutically effective amount is effective to enhance the immune
response by increasing the activity of an immune cell in a mammal.
In one variation, the activity is pro-inflammatory cytokine
production. In another variation, the activity of the immune cell
results in an increase in inflammation. In yet another variation of
the above method, the mammal is human.
[0044] In another embodiment of the invention, there is provided a
method for stimulating motor activity without dyskinesia in a
mammal, comprising administering a therapeutically effective amount
of an A.sub.2A antagonist compound of the above to the mammal in
need of such treatment. In one variation of the above embodiment,
there is provided a method as described above wherein the A.sub.2A
antagonist is selected from a compound of each of the above
embodiments, aspects and variations.
[0045] In another embodiment, there is provided a method to
evaluate novel A.sub.2A antagonists in four mouse models of PD.
These include: A) motor function in normal and dopamine-depleted
mice; B) synergistic activity with L-dopa to stimulate motor
activity in dopamine-depleted mice; C) attenuation MPTP-induced
neurotoxicity by inhibiting MPTP metabolism; and D) delayed
L-dopa-induced locomotor sensitization in unilateral
6-OHDA-lesioned mice.
[0046] In another embodiment, there is provided a method comprising
contacting a compound of each of the above formula with an isotope
such as those from hydrogen, carbon, nitrogen, oxygen, phosphorous,
fluorine, chlorine, or iodine (e.g. .sup.2H, .sup.3H, .sup.13C,
.sup.14C, .sup.15N, .sup.18O, .sup.31P, .sup.32P, .sup.35S,
.sup.18F, .sup.36Cl, .sup.123I, .sup.125I) optionally being a
radioactive isotope (radionuclide), such as, for example, tritium,
radioactive iodine (for example, .sup.125I for binding assays or
.sup.123I for Spect Imaging) or other non-radioactive isotope (such
as deuterium) and the like. Isotopically labeled compounds may be
useful for drug/tissue distribution assays and/or manipulating
oxidative metabolism via the primary kinetic isotope effect. They
are also valuable in identifying potential therapeutic agents for
the treatment of diseases or conditions associated with
target-receptor mediation, by contacting said agents with said
radioligands and receptors, and measuring the extent of
displacement of the radioligand and/or binding of the agent.
Representative references for Deuterium-for hydrogen substitution
include Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990; Reider
et al., J. Org. Chem. 52, 3326-3334, 1987; Foster, Adv. Drug Res.
14 1-40, 1985; Gillette et al., Biochemistry 33(10) 2927-2937,
1994; and Jarman et al. Carcinogenesis 16(4) 683-688, 1993, the
references of which are incorporated herein in their entirety. The
use of radiolabelled compounds that may be detected using imaging
techniques, such as, for instance, Single Photon Emission
Computerized Tomography (SPECT) or Positron Emission Tomography
(PET) and the like, are known in the art. See for example, U.S.
Pat. Nos. 6,395,742; 6,472,667 and references cited therein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0047] FIG. 1 shows locomotors stimulant activity of A.sub.2AAR
antagonists injected into mice.
[0048] FIG. 2 shows the effect of A.sub.2A AR gene deletion on
locomotor effect of ATL-2.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0049] Unless specifically noted otherwise herein, the definitions
of the terms used are standard definitions used in the art of
organic synthesis and pharmaceutical sciences.
[0050] Where a carbonyl group or a carbonyl derivative such as a
thio carbonyl or an imine and the like, is represented by a group
such as --C(.dbd.O)O-- or --C(.dbd.O)NR--, for example, it is
intended that the corresponding isomeric group that is
--OC(.dbd.O)-- or --NR.sup.aC(.dbd.O)-- is also included.
[0051] An "alkyl" group is a straight, branched, saturated or
unsaturated, aliphatic group having a chain of carbon atoms,
optionally with oxygen, nitrogen or sulfur atoms inserted between
the carbon atoms in the chain or as indicated. A
(C.sub.1-C.sub.20)alkyl, for example, includes alkyl groups that
have a chain of between 1 and 20 carbon atoms, and include, for
example, the groups methyl, ethyl, propyl, isopropyl, vinyl, allyl,
1-propenyl, isopropenyl, ethynyl, 1-propynyl, 2-propynyl,
1,3-butadienyl, penta-1,3-dienyl, penta-1,4-dienyl,
hexa-1,3-dienyl, hexa-1,3,5-trienyl, and the like. An alkyl group
may also be represented, for example, as a
--(CR.sup.1R.sup.2).sub.m-- group where R.sup.1 and R.sup.2 are
independently hydrogen or are independently absent, and for
example, m is 1 to 8, and such representation is also intended to
cover both saturated and unsaturated alkyl groups. An alkyl as
noted with another group such as an aryl group, represented as
"arylalkyl" for example, is intended to be a straight, branched,
saturated or unsaturated aliphatic divalent group with the number
of atoms indicated in the alkyl group (as in
(C.sub.1-C.sub.20)alkyl, for example) and/or aryl group (as in
(C.sub.5-C.sub.14)aryl, for example) or when no atoms are indicated
means a bond between the aryl and the alkyl group. Nonexclusive
examples of such group include benzyl, phenethyl and the like.
[0052] An "alkylene" group is a straight, branched, saturated or
unsaturated aliphatic divalent group with the number of atoms
indicated in the alkyl group (as in --(C.sub.1-C.sub.20)alkylene-
or --(C.sub.1-C.sub.20)alkylenyl-, for example), optionally with
one or more oxygen, nitrogen or sulfur atoms inserted (or
"interrupted") between the carbon atoms in the chain or as
indicated.
[0053] A "cyclyl" such as a monocyclyl or polycyclyl group includes
monocyclic, or linearly fused, angularly fused or bridged
polycycloalkyl, or combinations thereof. Such cyclyl group is
intended to include the heterocyclyl analogs. A cyclyl group may be
saturated, partically saturated or aromatic.
[0054] "Halogen" or "halo" means fluorine, chlorine, bromine or
iodine.
[0055] A "heterocyclyl" or "heterocycle" is a cycloalkyl wherein
one or more of the atoms forming the ring is a heteroatom that is a
N, O, or S, Non-exclusive examples of heterocyclyl include
piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl,
1,4-diazaperhydroepinyl, 1,3-dioxanyl, and the like.
[0056] "Pharmaceutically acceptable salts" means salt compositions
that is generally considered to have the desired pharmacological
activity, is considered to be safe, non-toxic and is acceptable for
veterinary and human pharmaceutical applications. Such salts
include acid addition salts formed with inorganic acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric
acid, and the like; or with organic acids such as acetic acid,
propionic acid, hexanoic acid, malonic acid, succinic acid, malic
acid, citric acid, gluconic acid, salicylic acid and the like.
[0057] "Substituted or unsubstituted" means that a group such as,
for example, alkyl, aryl, heterocyclyl,
(C.sub.1-C.sub.8)cycloalkyl, (C.sub.6-C.sub.12)bicycloalkyl,
hetrocyclyl(C.sub.1-C.sub.8)alkyl, aryl(C.sub.1-C.sub.8)alkyl,
heteroaryl, heteroaryl(C.sub.1-C.sub.8)alkyl, the mono-, bi- or
polycyclic rings that define the Z group, and the like, unless
specifically noted otherwise, may be unsubstituted or, may
substituted by 1, 2, 3, 4 or 5 substitutents selected from the
group such as halo, nitro, trifluoromethyl, trifluoromethoxy,
methoxy, carboxy, --NH.sub.2, --OH, --SH, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --SMe, propargyl, cyano, --NNH, --NNCH.sub.3,
--OPO.sub.2H, --OPO.sub.2CH.sub.3, --S(SO.sub.2)H, --S(SO.sub.2)OH,
--S(SO.sub.2)CH.sub.3 and --S(SO.sub.2)OCH.sub.3, and the like.
Representative A.sub.2AAR Antagonists:
TABLE-US-00001 [0058] TABLE 1 Binding Affinity and Selectivity of
A.sub.2AAR Ligands.sup.a ##STR00011## ##STR00012## ##STR00013## ATL
Ki, nM # R.sup.12 R.sup.7 (CR.sup.1R.sup.2).sub.m-Z A.sub.1AR
A.sub.2AAR A.sub.2BAR A.sub.3AR Antagonists 11 A 3-P Me 172 (1.3)
137 20% 30% 17 A 3-P Proparg 11 (2) 5 147 (29) 188 (38) 2 A
NH.sub.2 Proparg 4.6 (5) 0.95 50 (11) 599 (630) 3 A NH.sub.2 cPent
368 (37) 10 357 (36) 633 (63) 51 B NH.sub.2 Proparg 25 (16) 1.6 155
(97) >650 (>400) 50 B NH.sub.2 cPent >325 (>27) 12 40%
40% .sup.aAbbreviations: 3-P, 3-pentyl; Me, methyl; Proparg,
prop-2-ynyl; cPent, cyclopentyl. Numbers in parentheses are
selectivity ratios vs. the A.sub.2AAR. Activities expressed as
percentage are displacement of radioligand by 1 .mu.M candidate
ligand.
.sup.aAbbreviations: 3-P, 3-pentyl; Me, methyl; Proparg,
prop-2-ynyl; cPent, cyclopentyl. Numbers in parentheses are
selectivity ratios vs. the A.sub.2AAR. Activities expressed as
percentage are displacement of radioligand by 1 .mu.M candidate
ligand.
Motor Enhancement by the Lipophilic A.sub.2A Receptor Antagonist
ATL-2 in Normal Mice
[0059] The ability of compounds to stimulate motor activity in
normal mice was measured using a simple, computer-assisted
locomotor activity cage system. C57BL/6 mice (n=6-8 purchased from
the Jackson's lab) were habituated for the testing environment for
120 minute prior to drug treatment. The test compounds were
dissolved in vehicle (10% DMSO, 10% castrol oil EL-620 and 80%
saline). The drug was administrated intraperitoneally at a dose of
15 mg/kg, and locomotor activity was recorded for 2 hours before
and after drug administration.
[0060] FIG. 1 shows that ATL-2 produced strong motor stimulation,
reaching peak within 20 minutes and lasting for about 60 minutes
(arrow marks the injection). From our previous experience with
other A.sub.2AR antagonists, the motor stimulant effect of ATL2 is
comparable or stronger than other A.sub.2AR antagonists such as
SCH58261 and KW6002.
Absence of Motor Stimulant Effect of ATL-2 in Mice Lacking the
A.sub.2A Receptor
[0061] We validated that ATL-2 acts on the A.sub.2A receptor to
stimulate motor activity by using A.sub.2AR KO mice (in both mixed
(129sv .times.C57BL/6) as well as congenic (C57BL/6 genetic
background) developed over the last several years. We evaluated the
motor stimulant effect of ATL-2 in A.sub.2A receptor KO and their
WT littermates. WT and A.sub.2A KO mice (n=4) were habituated for
60 minutes and treated with ATL-2 (15 mg/kg) and recorded for motor
activity for 120 minutes.
[0062] FIG. 2 shows that ATL-2 produced motor activity in WT mice
(relatively high basal locomotion is likely due to short
habituation time (60 minute instead of 120 minutes) and
demonstrates relatively higher basal locomotion in WT compared to
KO mice as we noted previously,.sup.35 but this motor stimulation
was absent in A.sub.2A receptor KO mice.
EXPERIMENTAL
Synthesis of A.sub.2AAR Antagonists
[0063] The following procedures may be employed for the preparation
of the compounds of the present invention. The starting materials
and reagents used in preparing these compounds are either available
from commercial suppliers such as the Aldrich Chemical Company
(Milwaukee, Wis.), Bachem (Torrance, Calif.), Sigma (St. Louis,
Mo.), or are prepared by methods well known to a person of ordinary
skill in the art, following procedures described in such references
as Fieser and Fieser's Reagents for Organic Synthesis, vols. 1-17,
John Wiley and Sons, New York, N.Y., 1991; Rodd's Chemistry of
Carbon Compounds, vols. 1-5 and supps., Elsevier Science
Publishers, 1989; Organic Reactions, vols. 1-40, John Wiley and
Sons, New York, N.Y., 1991; March J.: Advanced Organic Chemistry,
4th ed., John Wiley and Sons, New York, N.Y.; and Larock:
Comprehensive Organic Transformations, VCH Publishers, New York,
1989. In some cases, protective groups may be introduced and
finally removed. Suitable protective groups for amino, hydroxy, and
carboxy groups are described in Greene et al., Protective Groups in
Organic Synthesis, Second Edition, John Wiley and Sons, New York,
1991. Standard organic chemical reactions can be achieved by using
a number of different reagents, for examples, as described in
Larock: Comprehensive Organic Transformations, VCH Publishers, New
York, 1989.
[0064] In one variation, the compounds of this invention can be
synthesized by the steps outlined in Scheme 1. Guanosine, A', is
acetylated to protect the ribose during reductive chlorination by
POCl.sub.3/diethylaniline to form 6-chloroguanosine, C'.
Non-aqueous diazotization in the presence of elemental iodine in
diiodomethane is a standard route to the protected
6-chloro-2-iodonebularine, D'. Heating in methanolic ammonia
deprotects the sugar and displaces the 6-chloro substituent to form
2-iodoadenosine, E'. Palladium-catalyzed coupling of E' with a
terminal alkyne generates 2-alkynyladenosine F', which undergoes
acid hydrolysis to form 9H-adenine G'. Alkylation with an
appropriate halide (alkyl, cycloalkyl or heterocyclic) completes
the synthesis of target 2,9-disubstituted adenine H'.
##STR00014##
[0065] Preparation of the terminal alkynes
(S)-1-ethynyl-1-hydroxy-(R)-3-methylcyclohexane and
2-ethynyladamantan-2-ol is achieved by treatment of the
corresponding ketone with ethynylmagnesium bromide.
[0066] Preparation of the Substituted Piperidine-Carboxylate
Terminal Alkynes (Scheme 2) starts with 4-carboxypiperidine
(isonipecotic acid) I' in anticipation of acylating the methyl
ester, J', with the appropriate alkyl chloroformate to form the
N-carbamoyl ester K'. Borohydride reduction of the ester generates
the 4-hydroxymethylpiperidine, L', which undergoes tosylation to M'
in preparation for condensation with lithium acetylide to form
terminal alkyne N'.
##STR00015##
##STR00016##
##STR00017##
TABLE-US-00002 ##STR00018## Compound Human K.sub.i No. R.sup.7
R.sup.8 (CR.sup.1R.sup.2).sub.m-Z (nM) 1 H H ##STR00019## ++++ 2 H
H Propargyl ++++ 3 H H Cyclopentyl ++++ 4 H H --CH.sub.2CN ++++ 5 H
H 4-Methoxybenzyl 6 H H 3,4-Dichlorobenzyl 7 H H
4-(Trifluoromethyl)benzyl 8 H H ##STR00020## ++++ 9 H H
##STR00021## 10 H H ##STR00022## +++ 11 Pent-3-yl H --CH.sub.3 +++
12 Pent-3-yl H --CH.sub.2CH.sub.2CH.sub.3 ++++ 13 Pent-3-yl H
Iso-propyl +++ 14 Pent-3-yl H ##STR00023## ++++ 15 Pent-3-yl H
Cyclopentyl ++++ 16 Pent-3-yl H Allyl ++++ 17 Pent-3-yl H Propargyl
++++ 18 Pent-3-yl H --(CH.sub.2).sub.3C.ident.CH ++++ 19 Pent-3-yl
H --CH.sub.2CH.sub.2OH ++++ 20 Pent-3-yl H
--CH.sub.2CH.sub.2CH.sub.2OH +++ 21 Pent-3-yl H
--CH.sub.2CH.sub.2Cl 22 Pent-3-yl H ##STR00024## +++ 23 Pent-3-yl H
##STR00025## 24 Pent-3-yl H ##STR00026## 25 Pent-3-yl H
##STR00027## +++ 26 Pent-3-yl H ##STR00028## 27 Pent-3-yl H Benzyl
++++ 28 Pent-3-yl H ##STR00029## ++++ 29 Pent-3-yl H 4-Nitrobenzyl
30 Pent-3-yl H ##STR00030## ++++ 31 Pent-3-yl H ##STR00031## 32
##STR00032## H Propargyl ++++ 33 ##STR00033## H ##STR00034## ++++
34 ##STR00035## H --CH.sub.3 +++ 35 ##STR00036## H Propargyl +++ 36
3-Methoxybenzyl H Propargyl ++++ 37 ##STR00037## H Propargyl ++++
38 ##STR00038## --CH.sub.3 Propargyl + K.sub.i < 10,000 nM; ++
K.sub.i < 1,000 nM; +++ K.sub.i < 500 nM; ++++ K.sub.i <
100 nM. ##STR00039## Compound Human K.sub.i No. R.sup.7
(CR.sup.1R.sup.2).sub.m-Z (nM) 39 H --CH.sub.3 ++++ 40 H
--CH.sub.2CH.sub.3 ++++ 41 H --CH.sub.2CH.sub.2CH.sub.3 ++++
##STR00040## Compound Human K.sub.i No. (CR.sup.9R.sup.10).sub.n-Y
(CR.sup.1R.sup.2).sub.m-Z (nM) 61 ##STR00041## Propargyl ++++ 63
##STR00042## Propargyl ++++ + K.sub.i < 10,000 nM; ++ K.sub.i
< 1,000 nM; +++ K.sub.i < 500 nM; ++++ K.sub.i < 100
nM.
Synthesis:
##STR00043##
[0068] (S)-1,1-Ethynyl-hydroxy-(R)-3-methylcyclohexane. A solution
of 0.5 M ethynylmagnesium bromide in THF (150.0 mL, 0.0750 mol) was
added to an ice cold solution of (R)-(+)-3-methylcyclohexanone
(2.77 g, 0.02469 mol) in anhydrous THF (100 mL). The ice bath was
removed and the mixture stirred at room temperature 24 h. The
mixture was cooled over ice and quenched with water (15.0 mL). The
volume of THF was reduced to approximately 50 mL and the mixture
filtered through a bed of celite/sand, washing with ether. The
solution is then evaporated to dryness and the crude purified by
column chromatography, eluting with a gradient of hexanes to
hexanes/ethyl acetate (10%) to afford the pure product as a white
crystalline solid: yield 1.412 g, 41%. .sup.1H NMR (CDCl.sub.3)
.delta. 0.73-0.95, 1.10-1.19, 1.35-1.45, 1.51-1.84, 1.93-2.03
(5.times.m, 9H, cyclohexyl), 0.93 (d, 3H, --CH.sub.3), 2.48 (s, 1H,
alkyne).
##STR00044##
[0069] 2-Ethynyl-adamantan-2-ol. A solution of 0.5 M
ethynylmagnesium bromide in THF (400.0 mL, 0.2000 mol) was added to
an ice cold solution of 2-adamantone (7.706 g, 0.05130 mol) in
anhydrous THF (250 mL). The mixture was stirred over ice 0.5 h and
then at room temperature 21 h. The volume was reduced to half and
the solution cooled over ice. The reaction was quenched with water
(5.0 mL), filtered through a bed of celite/sand and evaporated to
dryness. The crude was taken up in ether (400 mL) and washed with
water (2.times.40 mL) and brine (50 mL), dried over MgSO.sub.4,
filtered, and evaporated to dryness to afford the pure product as a
crystalline white solid: yield 8.961 g, 99%. .sup.1H NMR
(CDCl.sub.3) .delta. 1.54-1.61, 1.68-1.72, 1.76-1.99, 2.11-2.21
(4.times.m, 14H, adamantly), 2.53 (s, 1H, alkyne).
##STR00045##
[0070] Representative procedure for N6-amino substitution:
2-Iodoadenosine. A suspension of
6-chloro-2-iodo-9-(2',3',5'-O-triacetylfuranosyl)-9H-purine (14.70
g, 0.02729 mol) in MeOH (300 mL) was cooled over an ice bath.
Ammonia gas was then bubbled through the mixture until it was
saturated. The reaction vessel was sealed and heated at 40.degree.
C. for 18 h and at 60.degree. C. for 5 days. The mixture was cooled
over ice and nitrogen gas bubbled through the solution, the mixture
being allowed to warm to room temperature. The solvent was then
removed under reduced pressure and the crude recrystallized from
water containing 3-4 drops of glacial acetic acid. The resulting
precipitate was filtered and washed with water and ether to afford
a white solid: yield 7.167 g, 67%.
##STR00046##
[0071] Representative procedure for N6-alkylamino substitution:
2-Iodo-6-(3-pentyl)adenosine.
6-chloro-2-iodo-9-(2',3',5'-O-triacetylfuranosyl)-9H-purine (6.723
g, 0.01248 mol), 3-aminopentane (1.673 mL, 0.01436 mol) and
diisopropylethylamine (2.725 mL, 0.01560 mol) were stirred in
denatured ethanol (150 mL) at 90.degree. C. in a pressure apparatus
for 21 h. The reaction was then cooled over ice and ammonia gas
bubbled through the mixture until it was saturated. The reaction
vessel was closed and the mixture stirred at room temperature 21 h.
The mixture was cooled over ice and nitrogen gas bubbled through
the solution, the mixture being allowed to warm to room
temperature. The solvent was removed under reduced pressure and the
crude purified by column chromatography, eluting with a gradient of
DCM/MeOH (0-4%) to afford the pure product as an off white solid:
yield 4.838 g, 84%.
##STR00047##
[0072] Representative procedure for C2 coupling:
2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenosine. To a solution of
2-iodoadenosine (3.105 g, 7.898 mmol) in freshly degassed
acetonitrile/DMF (100 mL, 1:1) was added degassed triethylamine
(11.0 mL, 78.9 mmol), Pd(PPh.sub.3).sub.4 (113 mg, 0.09779 mmol),
CuI (catalytic), and 2,2-ethynyl-hydroxy-adamantanyl (1.516 g,
8.601 mmol). The mixture was stirred at room temperature under and
inert atmosphere for 71 h. Silica bound Pd(II) scavenger Si-thiol
(561 mg) and Pd(0) scavenger Si-TAAcOH (541 mg) were added and
stirring continued a further 4.5 h. The suspension was filtered
through celite and the resulting solution evaporated to dryness.
The crude was purified by column chromatography, eluting with a
gradient of DCM/MeOH (0-15%) to afford the pure product as a white
solid: yield 3.476 g, 100%.
##STR00048##
[0073] Representative procedure for ribose cleavage:
2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine. A solution of
2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenosine (3.486 g, 7.896
mmol) in methanol (100 mL) and 1.0 M HCl (10.0 mL) was stirred at
90.degree. C. in a pressure apparatus for 18-50 h. The pH was
adjusted to 4.2 with 5.0 M NaOH and the volume was reduced to half
under reduced pressure. After cooling the resulting precipitate was
filtered and washed with methanol to afford the pure product as a
white solid: yield 2.153 g, 88%. .sup.1H NMR (DMSO-d.sub.6) .delta.
8.13 (s, 1H), 7.25 (br s, 2H), 5.56 (s, 1H), 2.18-2.09, 1.94-1.89,
1.82-1.64, 1.52-1.45 (4.times.m, 12H). LRMS ESI (M+H.sup.+)
310.1.
##STR00049##
[0074]
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pent-
yl)adenine. Using the representative procedure for ribose cleavage
above
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pentyl)ade-
nosine (1.03 g) gave the product as a white solid: yield 0.725 g,
98%. LRMS ESI (M+H.sup.+) 342.2.
Synthesis of C2, N9-Adenines:
[0075] Representative Procedure for N9-Alklation Using an
Appropriate Alkyl Halide:
An appropriate 9-unsubstituted adenine (1.649 mmol) was dissolved
in DMF (80 mL). Anhydrous potassium carbonate (358 mg, 2.590 mmol)
and an appropriate alkyl halide (3.295 mmol) were added and the mix
stirred at between 25-100.degree. C. for 5-100 h. The reaction
mixture was adhered to silica and purified by column
chromatography, eluting with a gradient of DCM/MeOH (0-10%) to
afford the pure product.
##STR00050##
[0076]
9-Cyclopropylmethyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]eth-
yn-1-yl}adenine (1). Using the representative procedure for
N9-alkylation above
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (29
mg) gave 1 as a white solid: yield 19 mg, 55%. .sup.1H NMR
(CD.sub.3OD) .delta. 8.21 (s, 1H), 4.06 (d, 2H, J=7.3 Hz),
2.13-2.05, 1.94-1.66, 1.49-1.28, 0.92-0.80, 0.66-0.59, 0.49-0.44
(6.times.m, 14H), 1.17 (t, 1H, J=12.3 Hz), 0.96 (d, 2H, J=6.6 Hz).
LRMS ESI (M+H.sup.+) 326.1.
##STR00051##
[0077]
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-propargyl-
adenine (2). Using the representative procedure for N9-alkylation
above
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (112
mg) gave 2 as an off white solid: yield 88 mg, 69%. .sup.1H NMR
(CD.sub.3OD) .delta. 8.23 (s, 1H), 5.04 (s, 2H), 2.98 (t, 1H, J=2.6
Hz), 2.13-2.05, 1.94-1.65, 1.49-1.38, 0.91-0.80, (4.times.m, 7H),
1.17 (t, 1H, J=12.3 Hz), 0.95 (d, 2H, J=6.6 Hz). LRMS ESI
(M+H.sup.+) 310.1.
##STR00052##
[0078]
9-Cyclopentyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-y-
l}adenine (3). Using the representative procedure for N9-alkylation
above
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (34
mg) gave 3 as a white solid: yield 21 mg, 50%. .sup.1H NMR
(CD.sub.3OD) .delta. 8.21 (s, 1H), 4.91 (tt, 1H, J=7.0 Hz),
2.31-2.19, 2.13-1.65, 1.49-1.38, 0.92-0.79 (4.times.m, 17H), 1.15
(t, 1H, J=12.3 Hz), 0.96 (d, 2H, J=6.6 Hz). LRMS ESI (M+H.sup.+)
340.2.
##STR00053##
[0079]
9-Acetonitrile-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1--
yl}adenine (4). Using the representative procedure for
N9-alkylation above
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (43
mg) gave 4 as a white solid: yield 25 mg, 51%. .sup.1H NMR
(CD.sub.3OD) .delta. 8.20 (s, 1H), 5.35 (s, 1H), 2.33-2.05,
1.93-1.66, 1.49-1.38, 0.92-0.80 (4.times.m, 9H), 1.18 (t, 1H,
J=12.3 Hz), 0.96 (d, 2H, J=6.6 Hz). LRMS ESI (M+H.sup.+) 311.1.
##STR00054##
[0080]
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(4-methox-
ybenzyl)adenine (5). Using the representative procedure for
N9-alkylation above
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (24
mg) gave 5 as a white solid: yield 29 mg, 84%. .sup.1H NMR
(CD.sub.3OD) .delta. 8.10 (s, 1H), 7.26 (d, 2H, J=8.8 Hz), 6.88 (d,
2H, J=8.8 Hz), 5.32 (s, 2H), 3.75 (s, 3H), 2.33-2.05, 1.92-1.66,
1.49-1.38, 0.92-0.80 (4.times.m, 9H), 1.17 (t, 1H, J=12.3 Hz), 0.95
(d, 2H, J=6.6 Hz). LRMS ESI (M+H.sup.+) 392.2.
##STR00055##
[0081]
9-(3,4-Dichlorobenzyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]-
ethyn-1-yl}adenine (6). Using the representative procedure for
N9-alkylation above
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (26
mg) gave 6 as a white solid: yield 28 mg, 68%. .sup.1H NMR
(CD.sub.3OD) .delta. 8.20 (s, 1H), 7.52 (d, 1H, J=2.1 Hz), 7.48 (d,
1H, J=8.3 Hz), 7.19 (dd, 1H, J=2.1 Hz, J=8.3 Hz), 5.40 (s, 2H),
2.11-2.04, 1.92-1.64, 1.48-1.37, 0.92-0.79 (4.times.m, 9H), 1.16
(t, 1H, J=12.3 Hz), 0.94 (d, 2H, J=6.6 Hz). LRMS ESI (M+H.sup.+)
430.2.
##STR00056##
[0082]
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(4-triflu-
oromethylbenzyl)adenine (7). Using the representative procedure for
N9-alkylation above
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (30
mg) gave 7 as a white solid: yield 33 mg, 70%. .sup.1H NMR
(CD.sub.3OD) .delta. 8.20 (s, 1H), 7.64 (d, 2H, J=8.2 Hz), 7.44 (d,
2H, J=8.1 Hz), 5.52 (s, 2H), 2.10-2.03, 1.90-1.63, 1.47-1.36,
0.90-0.78 (4.times.m, 9H), 1.15 (t, 1H, J=12.3 Hz), 0.93 (d, 2H,
J=6.6 Hz). LRMS ESI (M+H.sup.+) 430.1.
##STR00057##
[0083]
9-(3,5-Dimethyl-isoxazol-4-ylmethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-
-1-cyclohexyl]ethyn-1-yl}adenine (8). Using the representative
procedure for N9-alkylation above
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (32
mg) gave 8 as a white solid: yield 36 mg, 80%. .sup.1H NMR
(CD.sub.3OD) .delta. 8.15 (s, 1H), 5.20 (s, 2H), 2.50 (s, 3H), 2.22
(s, 3H), 2.11-2.03, 1.92-1.65, 1.49-1.38, 0.92-0.81 (4.times.m,
9H), 1.18 (t, 1H, J=12.2 Hz), 0.96 (d, 2H, J=6.6 Hz). LRMS ESI
(M+H.sup.+) 381.1.
##STR00058##
[0084]
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-[2-(trifl-
uoromethylphenyl)thiazol-4-ylmethyl]adenine (9). Using the
representative procedure for N9-alkylation above
2-{2-[1(S)-hydroxy-3 (R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (26
mg) gave 9 as a white solid: yield 30 mg, 61%. .sup.1H NMR
(CD.sub.3OD) .delta. 8.31 (s, 1H), 8.09 (d, 2H, J=8.8 Hz), 7.74 (d,
2H, J=8.3 Hz), 7.55 (s, 1H), 5.58 (s, 2H), 2.12-2.04, 1.91-1.64,
1.48-1.37, 0.91-0.78 (4.times.m, 9H), 1.16 (t, 1H, J=12.4 Hz), 0.94
(d, 2H, J=6.6 Hz). LRMS ESI (M+H.sup.+) 513.1.
##STR00059##
[0085]
2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-(3-(thiophen-2-yl)prop-2-
-ynyl)adenine (10). To a solution of
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-propargyladenin-
e (30 mg, 0.09697 mmol) in freshly degassed acetonitrile/DMF (15
mL, 2:1) was added degassed triethylamine (1.0 mL, 7.0175 mmol),
Pd(PPh.sub.3).sub.4 (30 mg, 0.02596 mmol), CuI (catalytic), and
98+% 2-bromothiophene (13.7 .mu.L, 0.1161 mmol). The mixture was
stirred at room temperature under and inert atmosphere for 28 h.
Silica bound Pd(II) scavenger Si-thiol (240 mg) and Pd(0) scavenger
Si-TAAcOH (155 mg) were added and stirring continued a further 72
h. The suspension was filtered through celite and the resulting
solution evaporated to dryness. The crude was purified by column
chromatography, eluting with a gradient of DCM/MeOH (0-6%) to
afford the impure product (27 mg). The product was further purified
by reverse phase column chromatography, eluting with a gradient of
H.sub.2O/MeOH (50-75%) to afford the pure product 10 as a white
solid: yield 8.5 mg, 22%. .sup.1H NMR (CD.sub.3OD) .delta. 8.27 (s,
1H), 7.41 (dd, 1H, J=1.1 Hz, J=5.3 Hz), 7.25 (dd, 2H, J=1.1 Hz,
J=3.5 Hz), 6.99 (dd, 1H, J=3.7 Hz, J=5.0 Hz), 5.29 (s, 2H),
2.14-2.05, 1.94-1.65, 1.49-1.37, 0.99-0.79 (4.times.m, 12H), 1.17
(t, 1H, J=12.2 Hz). LRMS ESI (M+H.sup.+) 392.1.
##STR00060##
[0086]
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-methyl-N--
6-(3-pentyl)adenine (11). Using the representative procedure for
N9-alkylation above
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pentyl)ade-
nine (20 mg) gave 11 as a white solid: yield 9 mg, 43%. .sup.1H NMR
(CD.sub.3OD) .delta. 8.02 (s, 1H), 4.23 (m, 1H), 3.79 (s, 3H),
2.14-2.06, 1.96-1.38, 0.99-0.80 (3.times.m, 20H), 1.17 (t, 1H,
J=12.3 Hz). LRMS ESI (M+H.sup.+) 356.3.
##STR00061##
[0087]
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pent-
yl)-9-propyladenine (12). Using the representative procedure for
N9-alkylation above
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pentyl)ade-
nine (29 mg) gave 12 as a white solid: yield 26 mg, 80%. .sup.1H
NMR (CD.sub.3OD) .delta. 8.08 (s, 1H), 4.28-4.13 (m, 3H),
2.15-2.06, 1.95-1.38, 0.99-0.80 (3.times.m, 26H), 1.17 (t, 1H,
J=12.3 Hz). LRMS ESI (M+H.sup.+) 384.3.
##STR00062##
[0088]
9-Isobutyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}--
N-6-(3-pentyl)adenine (13). Using the representative procedure for
N9-alkylation above
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pentyl)ade-
nine (27 mg) gave 13 as a white solid: yield 23 mg, 73%. .sup.1H
NMR (CD.sub.3OD) .delta. 8.06 (s, 1H), 4.21 (m, 1H), 4.01 (d, 2H,
J=7.4 Hz), 2.21 (septet, 1H, J=6.8 Hz), 2.12-2.05, 1.96-1.38,
0.98-0.81 (3.times.m, 27H), 1.17 (t, 1H, J=12.2 Hz). LRMS ESI
(M+H.sup.+) 398.2.
##STR00063##
[0089]
9-Cyclopropylmethyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]eth-
yn-1-yl}-N-6-(3-pentyl)adenine (14). Using the representative
procedure for N9-alkylation above
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pentyl)ade-
nine (30 mg) gave 14 as a white solid: yield 17 mg, 57%. .sup.1H
NMR (CD.sub.3OD) .delta. 8.15 (s, 1H), 4.22 (m, 1H), 4.05 (d, 2H,
J=7.3 Hz), 2.14-2.05, 1.96-1.28, 0.98-0.79 (3.times.m, 22H), 1.17
(t, 1H, J=12.2 Hz), 0.65-0.58 (m, 2H), 0.48-0.44 (m, 2H). LRMS ESI
(M+H.sup.+) 396.3.
##STR00064##
[0090]
9-Cyclopentyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-y-
l}-N-6-(3-pentyl)adenine (15). Using the representative procedure
for N9-alkylation above 2-{2-[1(S)-hydroxy-3
(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pentyl)adenine (37 mg)
gave 15 as a white solid: yield 29 mg, 65%. .sup.1H NMR
(CD.sub.3OD) .delta. 8.15 (s, 1H), 4.91 (tt, 1H, J=7.0 Hz), 4.21
(m, 1H), 2.31-2.17, 2.14-1.35, 0.98-0.79 (3.times.m, 29H), 1.17 (t,
1H, J=12.2 Hz). LRMS ESI (M+H.sup.+) 410.3.
##STR00065##
[0091]
9-Allyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-
-(3-pentyl)adenine (16). Using the representative procedure for
N9-alkylation above
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pentyl)ade-
nine (33 mg) gave 16 as a white solid: yield 26 mg, 71%. .sup.1H
NMR (CDCl.sub.3) .delta. 7.77 (br s, 1H), 6.09-5.95 (m, 1H),
5.34-5.20 (m, 2H), 4.79 (dt, 2H, J=5.8 Hz, J=1.5 Hz), 4.28 (m, 1H),
2.21-2.11, 1.96-1.42, 0.96-0.78 (3.times.m, 21H), 1.23 (t, 1H,
J=12.2 Hz). LRMS ESI (M+H.sup.+) 382.3.
##STR00066##
[0092]
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pent-
yl)-9-(propargyl)adenine (17). Using the representative procedure
for N9-alkylation above
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pentyl)ade-
nine (134 mg) gave 17 as a white solid: yield 79 mg, 53%. .sup.1H
NMR (CD.sub.3OD) .delta. 8.17 (s, 1H), 5.03 (d, 2H, J=2.6 Hz), 4.22
(m, 1H), 2.97 (t, 1H, J=2.6), 2.14-2.06, 1.95-1.38, 0.98-0.80
(3.times.m, 21H), 1.17 (t, 1H, J=12.4 Hz). LRMS ESI (M+H.sup.+)
380.2.
##STR00067##
[0093]
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pent-
yl)-9-(pent-4-yne)adenine (18). Using the representative procedure
for N9-alkylation above
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pentyl)ade-
nine (35 mg) gave 18 as a white solid: yield 31 mg, 74%. .sup.1H
NMR (CD.sub.3OD) .delta. 8.07 (s, 1H), 4.32 (t, 2H, J=6.9 Hz), 4.21
(m, 1H), 2.31-2.19, 2.14-2.00, 1.95-1.38, 1.00-0.79 (4.times.m,
21H), 1.17 (t, 1H, J=12.3 Hz). LRMS ESI (M+H.sup.+) 408.1.
##STR00068##
[0094]
9-(2-Hydroxyethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethy-
n-1-yl}-N-6-(3-pentyl)adenine (19). Using the representative
procedure for N9-alkylation above
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pentyl)ade-
nine (103 mg) gave 19 as a white solid: yield 60 mg, 52%. .sup.1H
NMR (CD.sub.3OD) .delta. 8.06 (s, 1H), 4.30 (t, 2H, J=5.1 Hz), 4.22
(m, 1H), 3.86 (t, 2H, J=5.1 Hz), 2.14-2.05, 1.95-1.38, 0.99-0.80
(3.times.m, 21H), 1.17 (t, 1H, J=12.2 Hz). LRMS ESI (M+H.sup.+)
386.2.
##STR00069##
[0095]
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(3-hydrox-
ypropyl)-N-6-(3-pentyl)adenine (20). Using the representative
procedure for N9-alkylation above
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pentyl)ade-
nine (59 mg) gave 20 as a white solid: yield 35 mg, 51%. .sup.1H
NMR (CD.sub.3OD) .delta. 8.11 (s, 1H), 4.32 (t, 2H, J=7.0 Hz), 4.20
(m, 1H), 3.56 (t, 2H, J=5.9 Hz), 2.14-2.00, 1.93-1.38, 0.99-0.80
(3.times.m, 23H), 1.17 (t, 1H, J=12.2 Hz). LRMS ESI (M+H.sup.+)
400.3.
##STR00070##
[0096]
9-(2-Chloroethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-
-1-yl}-N-6-(3-pentyl)adenine (21). Using the representative
procedure for N9-alkylation above
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pentyl)ade-
nine (38 mg) gave 21 as a white solid: yield 28 mg, 62%. .sup.1H
NMR (CD.sub.3OD) .delta. 8.11 (s, 1H), 4.55 (t, 2H, J=5.7 Hz), 4.22
(m, 1H), 3.96 (t, 2H, J=5.7 Hz), 2.14-2.05, 1.94-1.38, 0.99-0.79
(3.times.m, 21H), 1.17 (t, 1H, J=12.1 Hz). LRMS ESI (M+H.sup.+)
404.2.
##STR00071##
[0097]
9-([1,3]-Dioxolan-2-ylmethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cycl-
ohexyl]ethyn-1-yl}-N-6-(3-pentyl)adenine (22). Using the
representative procedure for N9-alkylation above
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pentyl)ade-
nine (37 mg) gave 22 as a white solid: yield 32 mg, 69%. .sup.1H
NMR (CD.sub.3OD) .delta. 8.04 (s, 1H), 5.20 (t, 1H, J=3.3 Hz), 4.40
(d, 2H, J=3.3 Hz), 4.21 (m, 1H), 3.88-3.76 (m, 4H), 2.14-2.06,
1.92-1.38, 0.98-0.79 (3.times.m, 21H), 1.17 (t, 1H, J=12.2 Hz).
LRMS ESI (M+H.sup.+) 428.3.
##STR00072##
[0098]
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pent-
yl)-9-(tetrahydro-pyran-2-ylmethyl)adenine (23). Using the
representative procedure for N9-alkylation above
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pentyl)ade-
nine (32 mg) gave 23 as a white solid: yield 27 mg, 66%. .sup.1H
NMR (CD.sub.3OD) .delta. 8.01 (s, 1H), 4.31-4.07 (m, 3H), 3.96-3.87
(m, 1H), 3.67-3.58 (m, 1H), 3.93-3.32 (m, 1H), 2.14-2.06,
1.95-1.38, 1.31-1.12, 0.99-0.80 (4.times.m, 28H). LRMS ESI
(M+H.sup.+) 440.4.
##STR00073##
[0099]
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pent-
yl)-9-(isopropylcarboxylate)adenine (24). A 1.0 M solution of
isopropyl chloroformate in toluene (150 .mu.L, 0.1500 mmol) was
added to an ice cold solution of
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pentyl)ade-
nine (34 mg) in anhydrous pyridine (2.0 mL). After stirring over
ice 1.5 h the solvent was removed under reduced pressure and the
crude purified by column chromatography, eluting with a gradient of
DCM/MeOH (0-5%) to afford the pure product 24 as an off white
solid: yield 18 mg, 42%. .sup.1H NMR (CD.sub.3OD) .delta. 8.44 (s,
1H), 5.29 (septet, 1H, J=6.4, J=6.2 Hz), 4.21 (m, 1H), 2.14-2.05,
1.97-1.37, 1.00-0.79 (3.times.m, 27H), 1.16 (t, 1H, J=12.2 Hz).
LRMS ESI (M+H.sup.+) 427.9.
##STR00074##
[0100] 9-(Acetic acid ethyl
ester)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pen-
tyl)adenine (25). Using the representative procedure for
N9-alkylation above
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6
##STR00075##
-(3-pentyl)adenine (38 mg) gave 25 as a white solid: yield 9 mg,
19%. .sup.1H NMR (CD.sub.3OD) .delta. 8.06 (s, 1H), 5.06 (s, 2H),
4.24 (br q, 3H, J=7.0, 7.3 Hz), 2.15-2.05, 1.95-1.37, 1.05-0.79
(3.times.m, 22H), 1.29 (t, 3H, J=7.0, 7.3 Hz), 1.17 (t, 1H, J=12.2
Hz). LRMS ESI (M+H.sup.+) 428.2.
##STR00076##
[0101]
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(2-oxo-ox-
azolidin-5-ylmethyl)-N-6-(3-pentyl)adenine (26). Using the
representative procedure for N9-alkylation above
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pentyl)ade-
nine (56 mg) gave 26 as a white solid: yield 43 mg, 60%. .sup.1H
NMR (CD.sub.3OD) .delta. 8.09 (s, 1H), 5.04 (m, 1H), 4.52 (d, 2H,
J=4.8 Hz), 4.21 (m, 1H), 3.79-3.70 (m, 1H), 3.47-3.39 (m, 1H),
2.13-2.04, 1.95-1.38, 0.99-0.79 (3.times.m, 21H), 1.17 (t, 1H,
J=12.2 Hz). LRMS ESI (M+H.sup.+) 441.3.
##STR00077##
[0102]
9-Benzyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N--
6-(3-pentyl)adenine (27). Using the representative procedure for
N9-alkylation above
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pentyl)ade-
nine (37 mg) gave 27 as a white solid: yield 31 mg, 66%. .sup.1H
NMR (CD.sub.3OD) .delta. 8.06 (s, 1H), 7.37-7.25 (m, 5H), 5.40 (s,
2H), 4.22 (m, 1H), 2.14-2.05, 1.95-1.37, 0.99-0.79 (3.times.m,
21H), 1.16 (t, 1H, J=12.3 Hz). LRMS ESI (M+H.sup.+) 432.3.
##STR00078##
[0103]
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pent-
yl)-9-(pyridin-3-ylmethyl)adenine (28). Using the representative
procedure for N9-alkylation above
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pentyl)ade-
nine (34 mg) gave 28 as a white solid: yield 8 mg, 19%. .sup.1H NMR
(CD.sub.3OD) .delta. 8.57 (m, 1H), 8.48 (m, 1H), 8.17 (s, 1H), 7.77
(m, 1H), 7.41 (m, 1H), 5.49 (s, 2H), 4.22 (m, 1H), 2.13-2.04,
1.93-1.37, 0.99-0.79 (3.times.m, 21H), 1.16 (t, 1H, J=12.3 Hz).
LRMS ESI (M+H.sup.+) 433.3.
##STR00079##
[0104]
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(4-nitrob-
enzyl)-N-6-(3-pentyl)adenine (29). Using the representative
procedure for N9-alkylation above
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pentyl)ade-
nine (33 mg) gave 29 as a white solid: yield 36 mg, 78%. .sup.1H
NMR (CD.sub.3OD) .delta. 8.19 (d, 2H, J=8.8 Hz), 8.16 (s, 1H), 7.46
(d, 2H, J=8.8 Hz), 5.55 (s, 2H), 4.22 (m, 1H), 2.12-2.02,
1.92-1.36, 1.00-0.78 (3.times.m, 21H), 1.15 (t, 1H, J=12.2 Hz).
LRMS ESI (M+H.sup.+) 477.3.
##STR00080##
[0105]
9-(3,5-Dimethyl-isoxazol-4-ylmethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-
-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pentyl)adenine (30). Using the
representative procedure for N9-alkylation above
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pentyl)ade-
nine (50 mg) gave 30 as a white crystalline solid: yield 50 mg,
76%. .sup.1H NMR (CD.sub.3OD) .delta. 8.08 (s, 1H), 5.18 (s, 2H),
4.19 (m, 1H), 2.50 (s, 3H), 2.23 (s, 3H), 2.13-2.04, 1.94-1.38,
0.99-0.80 (3.times.m, 21H), 1.18 (t, 1H, J=12.1 Hz). LRMS ESI
(M+H.sup.+) 451.3.
##STR00081##
[0106]
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(2-methyl-
-thiazol-5-ylmethyl)-N-6-(3-pentyl)adenine (31).
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-pentyl)ade-
nine (56 mg, 0.1640 mmol) and 4-chloromethyl-2-methylthiazole
hydrochloride (127 mg, 0.6899 mmol) were stirred in DMF (8 mL) at
150.degree. C. for 22 h. The reaction mixture was adhered to silica
and purified by column chromatography, eluting with a gradient of
DCM/MeOH (0-6%) to afford pure 31 as an off white solid: yield 2
mg, 3%. .sup.1H NMR (CD.sub.3OD) .delta. 8.12 (s, 1H), 7.29 (s,
1H), 5.44 (s, 2H), 4.22 (m, 1H), 2.65 (s, 3H), 2.14-2.05,
1.94-1.37, 0.99-0.80 (3.times.m, 21H), 1.18 (t, 1H, J=12.2 Hz).
LRMS ESI (M+H.sup.+) 453.2.
##STR00082##
[0107]
N6-[(S)-(+)-sec-Butyl]-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]-
ethyn-1-yl}-9-propargyl-adenine (32). Using the representative
procedure for N9-alkylation above
N6-[(S)-(+)-sec-butyl]-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn--
1-yl}-N-6-(3-pentyl)adenine (29 mg) gave 32 as a white solid: yield
20 mg, 62%. .sup.1H NMR (CD.sub.3OD) .delta. 8.17 (s, 1H), 5.03 (d,
2H, J=2.6 Hz), 4.32 (m, 1H), 2.97 (t, 1H, J=2.6 Hz), 2.14-2.06,
1.95-1.58, 1.49-1.38, 1.00-0.79 (4.times.m, 16H), 1.25 (d, 3H,
J=6.4 Hz), 1.17 (t, 1H, J=12.2 Hz). LRMS ESI (M+H.sup.+) 366.1.
##STR00083##
[0108]
N6-[(s)-(+)-sec-Butyl]-9-(3,5-dimethyl-isoxazol-4-ylmethyl)-2-{2-[1-
(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (33). Using
the representative procedure for N9-alkylation above
N6-[(S)-(+)-sec-butyl]-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn--
1-yl}-N-6-(3-pentyl)adenine (42 mg) gave 33 as a white solid: yield
31 mg, 55%. .sup.1H NMR (CD.sub.3OD) .delta. 8.08 (s, 1H), 5.19 (s,
2H), 4.29 (m, 1H), 2.50 (s, 3H), 2.22 (s, 3H), 2.14-2.04,
1.95-1.57, 1.49-1.38, 0.99-0.82 (4.times.m, 16H), 1.24 (d, 3H,
J=6.4 Hz), 1.18 (t, 1H, J=12.2 Hz). LRMS ESI (M+H.sup.+) 437.2.
##STR00084##
[0109]
N6-(2-Diphenylethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]et-
hyn-1-yl}-9-methyladenine (34). Using the representative procedure
for N9-alkylation above
N6-(2-diphenylethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1--
yl}adenine (14 mg) gave 34 as a white solid: yield 5 mg, 35%. LRMS
ESI (M+H.sup.+) 466.3.
##STR00085##
[0110]
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-[(s)-(--
)-alpha-napthalen-1-yl-ethyl]-9-(propargyl)adenine (35). Using the
representative procedure for N9-alkylation above
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-[(S)-(-)-alph-
a-napthalen-1-yl-ethyl]adenine (29 mg) gave 35 as a white solid:
yield 22 mg, 70%. .sup.1H NMR (CD.sub.3OD) .delta. 8.23 (m, 1H),
8.15 (s, 1H), 7.88-7.84 (m, 1H), 7.76 (d, 1H, J=8.4 Hz), 7.64 (d,
1H, J=7.0 Hz), 7.53-7.40 (m, 3H), 6.33 (br s, 1H), 5.00 (d, 2H,
J=2.6 Hz), 2.96 (t, 1H, J=2.6 Hz), 2.08-1.99, 1.87-1.59, 1.45-1.33,
1.18-1.08, 0.95-0.70 (5.times.m, 12H). LRMS ESI (M+H.sup.+)
464.1.
##STR00086##
[0111]
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-meth-
oxybenzyl)-9-(propargyl)adenine (36). Using the representative
procedure for N9-alkylation above
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(3-methoxyben-
zyl)adenine (48 mg) gave 36 as a white solid: yield 40 mg, 76%.
.sup.1H NMR (CD.sub.3OD) .delta. 8.14 (s, 1H), 7.18 (t, 1H, J=7.9
Hz), 6.96-6.90 (m, 2H), 6.77 (m, 1H), 5.01 (d, 2H, J=2.6 Hz), 4.75
(br s, 2H), 3.74 (s, 3H), 2.97 (t, 1H, J=2.6 Hz), 2.13-2.04,
1.94-1.64, 1.48-1.37, 1.21-1.11, 0.96-0.77 (5.times.m, 12H). LRMS
ESI (M+H.sup.+) 430.2.
##STR00087##
[0112]
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(propargy-
l)-N6-(pyridin-2-ylmethyl)adenine (37). Using the representative
procedure for N9-alkylation above
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-(pyridin-2-yl-
methyl)adenine (29 mg) gave 37 as a white solid: yield 27 mg, 84%.
.sup.1H NMR (CD.sub.3OD) .delta. 8.49 (d, 1H, J=4.4 Hz), 8.20 (s,
1H), 7.76 (dt, 1H, J=1.8 Hz, J=7.7 Hz), 7.43 (d, 1H, J=7.9 Hz),
7.29 (m, 1H), 5.04 (d, 2H, J=2.6 Hz), 4.91 (br s, 2H), 2.98 (t, 1H,
J=2.6 Hz), 2.10-2.03, 1.90-1.63, 1.47-1.36, 1.20-1.10, 0.96-0.73
(5.times.m, 12H). LRMS ESI (M+H.sup.+) 401.2.
##STR00088##
[0113]
2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-[(methy-
l)(2-phenethyl)]-9-(propargyl)adenine (38). Using the
representative procedure for N9-alkylation above
2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N-6-[(methyl)(2-p-
henethyl)]adenine (54 mg) gave 38 as a white solid: yield 47 mg,
79%. .sup.1H NMR (CD.sub.3OD) .delta. 8.09 (s, 1H), 7.30-7.11 (m,
5H), 5.00 (d, 2H, J=2.6 Hz), 4.19 (br s, 2H), 3.35 (br s, 3H),
2.98-2.91 (m, 3H), 2.14-2.06, 1.96-1.66, 1.50-1.39, 1.27-1.13,
0.98-0.80 (5.times.m, 12H). LRMS ESI (M+H.sup.+) 428.3.
##STR00089##
[0114] 2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-methyladenine
(39). Using the representative procedure for N9-alkylation above
2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (58 mg) gave 39 as
a white solid: yield 39 mg, 64%. .sup.1H NMR (CD.sub.3OD) .delta.
8.08 (s, 1H), 3.80 (s, 3H), 2.37-2.22, 2.08-2.03, 1.89-1.74,
1.64-1.57 (4.times.m, 14H). LRMS ESI (M+H.sup.+) 324.2.
##STR00090##
[0115] 9-Ethyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine
(40). Using the representative procedure for N9-alkylation above
2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (59 mg) gave 40 as
a white solid: yield 42 mg, 65%. .sup.1H NMR (CD.sub.3OD) .delta.
8.15 (s, 1H), 4.25 (t, 2H, J=7.4 Hz), 2.36-2.22, 2.08-2.03,
1.89-1.74, 1.64-1.57 (4.times.m, 14H), 1.47 (t, 3H, J=7.3 Hz). LRMS
ESI (M+H.sup.+) 338.2.
##STR00091##
[0116] 2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-propyladenine
(41). Using the representative procedure for N9-alkylation above
2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (56 mg) gave 41 as
a white solid: yield 46 mg, 72%. .sup.1H NMR (CD.sub.3OD) .delta.
8.13 (s, 1H), 4.17 (t, 2H, J=7.2 Hz), 2.36-2.22, 2.08-2.03,
1.92-1.74, 1.64-1.57 (4.times.m, 16H), 0.93 (t, 3H, J=7.5 Hz). LRMS
ESI (M+H.sup.+) 352.2.
##STR00092##
[0117] 9-Hexyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine
(42). Using the representative procedure for N9-alkylation above
2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (50 mg) gave 42 as
a white solid: yield 43 mg, 68%. .sup.1H NMR (CD.sub.3OD) .delta.
8.13 (s, 1H), 4.21 (t, 2H, J=7.0, 7.5 Hz), 2.37-2.22, 2.08-2.03,
1.91-1.74, 1.65-1.57, 1.37-1.27 (5.times.m, 22H), 0.88 (t, 3H).
LRMS ESI (M+H.sup.+) 394.1.
##STR00093##
[0118] 2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-nonyladenine
(43). Using the representative procedure for N9-alkylation above
2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (43 mg) gave 43 as
a white solid: yield 47 mg, 78%. .sup.1H NMR (CD.sub.3OD) .delta.
8.13 (s, 1H), 4.20 (t, 2H, J=7.3 Hz), 2.36-2.22, 2.08-2.03,
1.90-1.74, 1.64-1.56, 1.35-1.23 (5.times.m, 28H), 0.87 (t, 3H,
J=7.0 Hz). LRMS ESI (M+H.sup.+) 436.1.
##STR00094##
[0119] 2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-isobutyl-adenine
(44). Using the representative procedure for N9-alkylation above
2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (52 mg) gave 44 as
a white solid: yield 46 mg, 75%. .sup.1H NMR (CD.sub.3OD) .delta.
8.11 (s, 1H), 4.02 (d, 2H, J=7.5 Hz), 2.36-2.16, 2.08-2.03,
1.88-1.73, 1.64-1.56, (4.times.m, 15H), 0.91 (d, 6H, J=6.6 Hz).
LRMS ESI (M+H.sup.+) 366.2.
##STR00095##
[0120]
9-Cyclopropylmethyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine
(45). Using the representative procedure for N9-alkylation above
2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (33 mg) gave 45 as
a white solid: yield 11 mg, 28%. .sup.1H NMR (CD.sub.3OD) .delta.
8.21 (s, 1H), 4.06 (d, 2H, J=7.3 Hz), 2.36-2.22, 2.08-2.03,
1.89-1.74, 1.65-1.57, (4.times.m, 14H), 1.42-1.27 (m, 1H),
0.65-0.58, 0.49-0.43 (2.times.m, 4H). LRMS ESI (M+H.sup.+)
364.2.
##STR00096##
[0121]
9-Cyclobutylmethyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine
(46). Using the representative procedure for N9-alkylation above
2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (54 mg) gave 46 as
a white crystalline solid: yield 21 mg, 32%. .sup.1H NMR
(CD.sub.3OD) .delta. 8.12 (s, 1H), 4.22 (d, 2H, J=7.5 Hz), 2.87
(quintet, 1H, J=7.7 Hz), 2.37-2.22, 2.09-1.74, 1.65-1.57,
(3.times.m, 20H). LRMS ESI (M+H.sup.+) 378.2.
##STR00097##
[0122]
9-Cyclopentylmethyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine
(47). 2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (44 mg,
0.1422 mmol) was dissolved in DMF (20 mL) with heating. Anhydrous
potassium carbonate (51 mg, 0.3690 mmol) and cyclopentylmethyl
4-methylbenzenesulfonate (54 mg, 0.2123 mmol) were added and the
mixture stirred at 70.degree. C. for 72 h. Extra cyclopentylmethyl
4-methylbenzenesulfonate (82 mg, 0.3224 mmol) was added and
stirring continued at 100.degree. C. a further 4.5 h. The reaction
mixture was adhered to silica and purified by column
chromatography, eluting with a gradient of DCM/MeOH (0-6%) to
afford the pure 47 as a white solid: yield 38 mg, 68%. .sup.1H NMR
(CD.sub.3OD) .delta. 8.15 (s, 1H), 4.14 (d, 2H, J=7.7 Hz), 2.48
(quintet, 1H, J=7.5 Hz), 2.37-2.22, 2.08-2.02, 1.89-1.58, 1.37-1.24
(4.times.m, 22H). LRMS ESI (M+H.sup.+) 392.0.
##STR00098##
[0123]
9-Cyclohexylmethyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine
(48). Using the representative procedure for N9-alkylation above
2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (49 mg) gave 48 as
a white solid: yield 45 mg, 70%. .sup.1H NMR (CD.sub.3OD) .delta.
8.10 (s, 1H), 4.04 (d, 2H, J=7.3 Hz), 2.37-2.22, 2.09-2.03,
1.92-1.54, 1.31-0.96, (4.times.m, 25H). LRMS ESI (M+H.sup.+)
406.3.
##STR00099##
[0124] 9-Cyclobutyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine
(49). Using the representative procedure for N9-alkylation above
2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (34 mg) gave 49 as
a white solid: yield 18 mg, 45%. .sup.1H NMR (CD.sub.3OD) .delta.
8.32 (s, 1H), 5.03 (m, 1H), 2.72-2.49, 2.38-2.22, 2.04-1.74,
1.64-1.57 (4.times.m, 20H). LRMS ESI (M+H.sup.+) 364.2.
##STR00100##
[0125]
9-Cyclopentyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (50).
Using the representative procedure for N9-alkylation above
2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (473 mg) gave 50 as
a white solid: yield 371 mg, 64%. .sup.1H NMR (CD.sub.3OD) .delta.
8.21 (s, 1H), 4.90 (m, 1H), 2.37-2.20, 2.08-1.73, 1.64-1.57
(4.times.m, 22H). LRMS ESI (M+H.sup.+) 378.2.
##STR00101##
[0126] 2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-propargyl-adenine
(51). Using the representative procedure for N9-alkylation above
2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (510 mg) gave 51 as
a white solid: yield 416 mg, 73%. .sup.1H NMR (CD.sub.3OD) .delta.
8.22 (s, 1H), 5.04 (d, 2H, J=2.6 Hz), 2.98 (t, 1H, J=2.5 Hz),
2.36-2.22, 2.08-2.03, 1.89-1.75, 1.65-1.57 (4.times.m, 14H). LRMS
ESI (M+H.sup.+) 348.2.
##STR00102##
[0127]
2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-(2-hydroxyethyl)adenine
(52). Using the representative procedure for N9-alkylation above
2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (49 mg) gave 52 as
a white solid: yield 21 mg, 38%. .sup.1H NMR (CD.sub.3OD) .delta.
8.12 (s, 1H), 4.31 (t, 2H, J=5.2 Hz), 3.87 (t, 2H, J=4.7 Hz),
2.36-2.21, 2.08-2.01, 1.89-1.73, 1.65-1.57 (4.times.m, 14H). LRMS
ESI (M+H.sup.+) 354.2.
##STR00103##
[0128]
2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-(2-hydroxypropyl)adenine
(53). Using the representative procedure for N9-alkylation above
2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (55 mg) gave 53 as
a white solid: yield 37 mg, 57%. .sup.1H NMR (CD.sub.3OD) .delta.
8.13 (s, 1H), 4.32 (t, 2H, J=7.0 Hz), 3.55 (t, 2H, J=5.9, 6.2 Hz),
2.36-2.21, 2.11-2.00, 1.89-1.73, 1.65-1.57 (4.times.m, 16H). LRMS
ESI (M+H.sup.+) 368.2.
##STR00104##
[0129] 2-{2-[Hydroxy-norbornan-2-yl]ethyn-1-yl}-9-propargyladenine:
Isomer A (60). Using the representative procedure for N9-alkylation
above 2-{2-[hydroxy-norbornan-2-yl]ethyn-1-yl}adenine (42 mg) gave
60 as a white solid: yield 18 mg, 38%. .sup.1H NMR (CD.sub.3OD)
.delta. 8.22 (s, 1H), 5.03 (s, 2H), 2.47-2.51 (m, 1H), 2.19-2.30
(m, 2H), 1.90-2.08 (m, 2H), 1.53-1.66 (m, 1H), 1.27-1.47 (m, 4H).
LRMS ESI (M+H.sup.+) 308.1.
##STR00105##
[0130] 2-{2-[Hydroxy-norbornan-2-yl]ethyn-1-yl}-9-propargyladenine:
Isomer B (61). Using the representative procedure for N9-alkylation
above 2-{2-[hydroxy-norbornan-2-yl]ethyn-1-yl}adenine (31 mg) gave
61 as a white solid: yield 10 mg, 29%. .sup.1H NMR (CD.sub.3OD)
.delta. 8.22 (s, 1H), 5.03 (s, 2H), 2.47-2.51 (m, 1H), 2.19-2.30
(m, 2H), 1.90-2.08 (m, 2H), 1.53-1.66 (m, 1H), 1.27-1.47 (m, 4H).
LRMS ESI (M+H.sup.+) 308.1.
##STR00106##
[0131]
9-(But-3-ynyl)-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine
(62). Using the representative procedure for N9-alkylation above
2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (52 mg) gave 62 as
a white solid: yield 14 mg, 24%. .sup.1H NMR (CD.sub.3OD) .delta.
8.18 (s, 1H), 4.36 (t, 2H, J=6.6 Hz), 2.77 (dt, 2H, J=2.6, 6.6 Hz),
2.36 (t, 1H, J=2.6 Hz), 2.36-2.22, 2.08-2.03, 1.89-1.74, 1.64-1.57
(4.times.m, 16H). LRMS ESI (M+H.sup.+) 362.0.
##STR00107##
[0132]
2-{3-[1-(Methoxycarbanoyl)piperidin-4-yl]propyn-1-yl}-9-propargylad-
enine (63). Using the representative procedure for N9-alkylation
above 2-{3-[1-(methoxycarbanoyl)piperidin-4-yl]propyn-1-yl}adenine
(53 mg) gave 63 as a white solid: yield 18 mg, 30%. .sup.1H NMR
(CD.sub.3OD) .delta. 8.21 (s, 1H), 5.02 (s, 2H), 4.21-4.09 (m, 2H),
3.66 (s, 3H), 2.94-2.74 (m, 2H), 2.47-2.40 (m, 3H), 1.95-1.74 (m,
3H), 1.38-1.20 (m, 2H). LRMS ESI (M+H.sup.+) 353.1.
[0133] The compounds in tables 1 to 7, or their pharmaceutically
acceptable salts either as single stereoisomers or mixtures are
representative examples of the invention.
TABLE-US-00003 TABLE 1 ##STR00108## Compound
(CR.sup.1R.sup.2).sub.m-Z R.sup.6 NC100 Propargyl CH.sub.2OH NC101
c-Pentyl CH.sub.2OH NC102 Propargyl CO.sub.2H NC103 c-Pentyl
CO.sub.2H NC104 Propargyl CO.sub.2Me NC105 c-Pentyl CO.sub.2Me
NC106 Propargyl CH.sub.2OAc NC107 c-Pentyl CH.sub.2OAc NC108
Propargyl CH.sub.2N(CH.sub.3).sub.2 NC109 c-Pentyl
CH.sub.2N(CH.sub.3).sub.2 NC110 Propargyl COOCH.sub.2CH.sub.2NHBoc
NC111 c-Pentyl COOCH.sub.2CH.sub.2NHBoc NC112 Propargyl
COOCH.sub.2CH.sub.2NH.sub.2 NC113 c-Pentyl
COOCH.sub.2CH.sub.2NH.sub.2 NC114 Propargyl CONHCH.sub.2CH.sub.3
NC115 c-Pentyl CONHCH.sub.2CH.sub.3 NC116 Propargyl CONH.sub.2
NC117 c-Pentyl CONH.sub.2 NC118 Propargyl CONHMe NC119 c-Pentyl
CONHMe NC120 Propargyl Me, cis CO.sub.2Me NC121 c-Pentyl Me, cis
CO.sub.2Me NC122 Propargyl Me, trans CO.sub.2Me NC123 c-Pentyl Me,
trans CO.sub.2Me NC124 Propargyl CH.sub.2CH.sub.3 NC125 c-Pentyl
CH.sub.2CH.sub.3 NC126 Propargyl H NC127 c-Pentyl H NC128 Propargyl
COCH.sub.3 NC129 c-Pentyl COCH.sub.3 NC130 Propargyl CHCH.sub.3(OH)
NC131 c-Pentyl CHCH.sub.3(OH)
TABLE-US-00004 TABLE 2 ##STR00109## Compound
(CR.sup.1R.sup.2).sub.m-Z R.sup.6 NC132 Propargyl H NC133 c-Pentyl
H NC134 Propargyl CO.sub.2tBu NC135 c-Pentyl CO.sub.2tBu NC136
Propargyl CO.sub.2Et NC137 c-Pentyl CO.sub.2Et NC138 Propargyl
CO.sub.2iBu NC139 c-Pentyl CO.sub.2iBu NC140 Propargyl CO.sub.2iPr
NC141 c-Pentyl CO.sub.2iPr 63 Propargyl COMe NC142 c-Pentyl COMe
NC143 Propargyl COC(CH.sub.3).sub.3 NC144 c-Pentyl
COC(CH.sub.3).sub.3 NC145 Propargyl COCH.sub.2(CH.sub.3).sub.3
NC146 c-Pentyl COCH.sub.2(CH.sub.3).sub.3 NC147 Propargyl
C(O)N(CH.sub.3).sub.2 NC148 c-Pentyl C(O)N(CH.sub.3).sub.2 NC149
Propargyl C(O)N(CH.sub.3)Et NC150 c-Pentyl C(O)N(CH.sub.3)Et NC142
Propargyl C(O)N(CH.sub.3)iPr NC143 c-Pentyl C(O)N(CH.sub.3)iPr
NC144 Propargyl C(O)N(CH.sub.3)iBu NC145 c-Pentyl
C(O)N(CH.sub.3)iBu NC146 Propargyl C(O)NH(CH.sub.3) NC147 c-Pentyl
C(O)NH(CH.sub.3) NC148 Propargyl C(O)NH(Et) NC149 c-Pentyl
C(O)NH(Et) NC150 Propargyl C(O)NH(iPr) NC142 c-Pentyl C(O)NH(iPr)
NC143 Propargyl C(O)NH(iBu) NC144 c-Pentyl C(O)NH(iBu)
TABLE-US-00005 TABLE 3 ##STR00110## Compound
(CR.sup.1R.sup.2).sub.m-Z R.sup.6 NC151 Propargyl H NC152 c-Pentyl
H NC153 Propargyl 2-CH.sub.3 NC154 c-Pentyl 2-CH.sub.3 NC155
Propargyl 2-C(CH.sub.3).sub.3 NC156 c-Pentyl 2-C(CH.sub.3).sub.3
NC157 Propargyl 2-C.sub.6H.sub.5 NC158 c-Pentyl 2-C.sub.6H.sub.5 2
Propargyl 3-CH.sub.3 3 c-Pentyl 3-CH.sub.3 NC159 Propargyl
3-(CH.sub.3).sub.2 NC160 c-Pentyl 3-(CH.sub.3).sub.2 NC161
Propargyl 3-CH.sub.2CH.sub.3 NC162 c-Pentyl 3-CH.sub.2CH.sub.3
NC163 Propargyl 3-(CH.sub.3).sub.2, 5-(CH.sub.3).sub.2 NC164
c-Pentyl 3-(CH.sub.3).sub.2, 5-(CH.sub.3).sub.2 NC165 Propargyl
4-CH.sub.3 NC166 c-Pentyl 4-CH.sub.3 NC167 Propargyl
4-C.sub.2H.sub.5 NC168 c-Pentyl 4-C.sub.2H.sub.5 NC169 Propargyl
4-C(CH.sub.3).sub.3 NC170 c-Pentyl 4-C(CH.sub.3).sub.3 NC171
Propargyl 4-C.sub.6H.sub.5 NC172 c-Pentyl 4-C.sub.6H.sub.5
TABLE-US-00006 TABLE 4 ##STR00111## Compound
(CR.sup.1R.sup.2).sub.m-Z R.sup.6 NC173 Propargyl H NC174 c-Pentyl
H NC175 Propargyl cyclohexyl NC176 c-Pentyl cyclohexyl NC177
Propargyl CO.sub.2Et NC178 c-Pentyl CO.sub.2Et NC179 Propargyl
CO.sub.2tBu NC180 c-Pentyl CO.sub.2tBu NC181 Propargyl COMe NC182
c-Pentyl COMe NC183 Propargyl CO.sub.2iBu NC184 c-Pentyl
CO.sub.2iBu NC185 Propargyl 2-Pyrimidinyl NC186 c-Pentyl
2-Pyrimidinyl NC187 Propargyl COC(CH.sub.3).sub.3 NC188 c-Pentyl
COC(CH.sub.3).sub.3 NC189 Propargyl COMe NC190 c-Pentyl COMe NC191
Propargyl COCH.sub.2(CH.sub.3).sub.3 NC192 c-Pentyl
COCH.sub.2(CH.sub.3).sub.3 NC193 Propargyl COCH.sub.3 NC194
c-Pentyl COCH.sub.3 NC195 Propargyl C(O)N(CH.sub.3).sub.2 NC196
c-Pentyl C(O)N(CH.sub.3).sub.2 NC197 Propargyl C(O)N(CH.sub.3)Et
NC198 c-Pentyl C(O)N(CH.sub.3)Et NC199 Propargyl C(O)N(CH.sub.3)iPr
NC200 c-Pentyl C(O)N(CH.sub.3)iPr NC201 Propargyl
C(O)N(CH.sub.3)iBu NC202 c-Pentyl C(O)N(CH.sub.3)iBu NC203
Propargyl C(O)NH(CH.sub.3) NC204 c-Pentyl C(O)NH(CH.sub.3) NC205
Propargyl C(O)NH(Et) NC206 c-Pentyl C(O)NH(Et) NC207 Propargyl
C(O)NH(iPr) NC208 c-Pentyl C(O)NH(iPr) NC209 Propargyl C(O)NH(iBu)
NC210 c-Pentyl C(O)NH(iBu)
TABLE-US-00007 TABLE 5 ##STR00112## Compound
(CR.sup.1R.sup.2).sub.m-Z R.sup.6 NC211 Propargyl CH.sub.2OH NC212
c-Pentyl CH.sub.2OH NC213 Propargyl CO.sub.2H NC214 c-Pentyl
CO.sub.2H NC215 Propargyl CO.sub.2Me NC216 c-Pentyl CO.sub.2Me
NC217 Propargyl CO.sub.2Et NC218 c-Pentyl CO.sub.2Et NC219
Propargyl CH.sub.2OAc NC220 c-Pentyl CH.sub.2OAc NC221 Propargyl
CH.sub.2N(CH.sub.3).sub.2 NC222 c-Pentyl CH.sub.2N(CH.sub.3).sub.2
NC223 Propargyl COOCH.sub.2CH.sub.2NHBoc NC224 c-Pentyl
COOCH.sub.2CH.sub.2NHBoc NC225 Propargyl
COOCH.sub.2CH.sub.2NH.sub.2 NC226 c-Pentyl
COOCH.sub.2CH.sub.2NH.sub.2 NC227 Propargyl CONHCH.sub.2CH.sub.3
NC228 c-Pentyl CONHCH.sub.2CH.sub.3 NC229 Propargyl CONH.sub.2
NC230 c-Pentyl CONH.sub.2 NC231 Propargyl CONHMe NC232 c-Pentyl
CONHMe NC233 Propargyl CH.sub.2CH.sub.3 NC234 c-Pentyl
CH.sub.2CH.sub.3 NC235 Propargyl COCH.sub.3 NC236 c-Pentyl
COCH.sub.3 NC237 Propargyl CHCH.sub.3(OH) NC238 c-Pentyl
CHCH.sub.3(OH)
TABLE-US-00008 TABLE 6 ##STR00113## Compound
(CR.sup.1R.sup.2).sub.m-Z R.sup.6 NC239 Propargyl CH.sub.2OH NC240
c-Pentyl CH.sub.2OH NC241 Propargyl CO.sub.2H NC242 c-Pentyl
CO.sub.2H NC243 Propargyl CO.sub.2Me NC244 c-Pentyl CO.sub.2Me
NC245 Propargyl CH.sub.2OAc NC246 c-Pentyl CH.sub.2OAc NC247
Propargyl CH.sub.2N(CH.sub.3).sub.2 NC248 c-Pentyl
CH.sub.2N(CH.sub.3).sub.2 NC249 Propargyl COOCH.sub.2CH.sub.2NHBoc
NC250 c-Pentyl COOCH.sub.2CH.sub.2NHBoc NC251 Propargyl
COOCH.sub.2CH.sub.2NH.sub.2 NC252 c-Pentyl
COOCH.sub.2CH.sub.2NH.sub.2 NC253 Propargyl CONHCH.sub.2CH.sub.3
NC254 c-Pentyl CONHCH.sub.2CH.sub.3 NC255 Propargyl CONH.sub.2
NC256 c-Pentyl CONH.sub.2 NC257 Propargyl CONHMe NC258 c-Pentyl
CONHMe NC259 Propargyl CH.sub.2CH.sub.3 NC260 c-Pentyl
CH.sub.2CH.sub.3 NC261 Propargyl COCH.sub.3 NC262 c-Pentyl
COCH.sub.3 NC263 Propargyl CHCH.sub.3(OH) NC264 c-Pentyl
CHCH.sub.3(OH)
TABLE-US-00009 TABLE 7 ##STR00114## Compound
(CR.sup.1R.sup.2).sub.m-Z W W' R.sup.6 NC265 Propargyl CH CH
CO.sub.2Me NC266 c-Pentyl CH N CO.sub.2Me NC267 Propargyl N CH
CO.sub.2Me NC268 c-Pentyl N N CO.sub.2Me NC269 Propargyl CH CH
CO.sub.2Me NC270 c-Pentyl CH N CO.sub.2Me NC271 Propargyl N CH
CO.sub.2Me NC272 c-Pentyl N N CO.sub.2Me NC273 Propargyl CH CH
CH.sub.2OH NC274 c-Pentyl CH N CH.sub.2OH NC275 Propargyl N CH
CH.sub.2OH NC276 c-Pentyl N N CH.sub.2OH NC277 Propargyl CH CH
CH.sub.2OH NC278 c-Pentyl CH N CH.sub.2OH NC279 Propargyl N CH
CH.sub.2OH NC280 c-Pentyl N N CH.sub.2OH NC281 Propargyl CH CH
CO.sub.2H NC282 c-Pentyl CH N CO.sub.2H NC283 Propargyl N CH
CO.sub.2H NC284 c-Pentyl N N CO.sub.2H NC285 Propargyl CH CH
CO.sub.2H NC286 c-Pentyl CH N CO.sub.2H NC287 Propargyl N CH
CO.sub.2H NC288 c-Pentyl N N CO.sub.2H NC289 Propargyl CH CH
CH.sub.2OAc NC290 c-Pentyl CH N CH.sub.2OAc NC291 Propargyl N CH
CH.sub.2OAc NC292 c-Pentyl N N CH.sub.2OAc NC293 Propargyl CH CH
CH.sub.2OAc NC294 c-Pentyl CH N CH.sub.2OAc NC295 Propargyl N CH
CH.sub.2OAc NC296 c-Pentyl N N CH.sub.2OAc NC297 Propargyl CH CH
CONH.sub.2 NC298 c-Pentyl CH N CONH.sub.2 NC299 Propargyl N CH
CONH.sub.2 NC300 c-Pentyl N N CONH.sub.2 NC301 Propargyl CH CH
CONH.sub.2 NC302 c-Pentyl CH N CONH.sub.2 NC303 Propargyl N CH
CONH.sub.2 NC304 c-Pentyl N N CONH.sub.2 NC305 Propargyl CH CH
CONHMe NC306 c-Pentyl CH N CONHMe NC307 Propargyl N CH CONHMe NC308
c-Pentyl N N CONHMe NC309 Propargyl CH CH CONHMe NC310 c-Pentyl CH
N CONHMe NC311 Propargyl N CH CONHMe NC312 c-Pentyl N N CONHMe
NC313 Propargyl CH CH CO.sub.2tBu NC314 c-Pentyl CH N CO.sub.2tBu
NC315 Propargyl N CH CO.sub.2tBu NC316 c-Pentyl N N CO.sub.2tBu
NC317 Propargyl CH CH CO.sub.2tBu NC318 c-Pentyl CH N CO.sub.2tBu
NC319 Propargyl N CH CO.sub.2tBu NC320 c-Pentyl N N CO.sub.2tBu
NC321 Propargyl CH CH CO.sub.2Et NC322 c-Pentyl CH N CO.sub.2Et
NC323 Propargyl N CH CO.sub.2Et NC324 c-Pentyl N N CO.sub.2Et NC325
Propargyl CH CH CO.sub.2Et NC326 c-Pentyl CH N CO.sub.2Et NC327
Propargyl N CH CO.sub.2Et NC328 c-Pentyl N N CO.sub.2Et NC329
Propargyl CH CH CO.sub.2iBu NC330 c-Pentyl CH N CO.sub.2iBu NC331
Propargyl N CH CO.sub.2iBu NC332 c-Pentyl N N CO.sub.2iBu NC333
Propargyl CH CH CO.sub.2iBu NC334 c-Pentyl CH N CO.sub.2iBu NC335
Propargyl N CH CO.sub.2iBu NC336 c-Pentyl N N CO.sub.2iBu NC337
Propargyl CH CH CO.sub.2iPr NC338 c-Pentyl CH N CO.sub.2iPr NC339
Propargyl N CH CO.sub.2iPr NC340 c-Pentyl N N CO.sub.2iPr NC341
Propargyl CH CH CO.sub.2iPr NC342 c-Pentyl CH N CO.sub.2iPr NC343
Propargyl N CH CO.sub.2iPr NC344 c-Pentyl N N CO.sub.2iPr NC345
Propargyl CH CH COMe NC346 c-Pentyl CH N COMe NC347 Propargyl N CH
COMe NC348 c-Pentyl N N COMe NC349 Propargyl CH CH COMe NC350
c-Pentyl CH N COMe NC351 Propargyl N CH COMe NC352 c-Pentyl N N
COMe NC353 Propargyl CH CH COC(CH.sub.3).sub.3 NC354 c-Pentyl CH N
COC(CH.sub.3).sub.3 NC355 Propargyl N CH COC(CH.sub.3).sub.3 NC356
c-Pentyl N N COC(CH.sub.3).sub.3 NC357 Propargyl CH CH
COC(CH.sub.3).sub.3 NC358 c-Pentyl CH N COC(CH.sub.3).sub.3 NC359
Propargyl N CH COC(CH.sub.3).sub.3 NC360 c-Pentyl N N
COC(CH.sub.3).sub.3 NC361 Propargyl CH CH
COCH.sub.2(CH.sub.3).sub.3 NC362 c-Pentyl CH N
COCH.sub.2(CH.sub.3).sub.3 NC363 Propargyl N CH
COCH.sub.2(CH.sub.3).sub.3 NC364 c-Pentyl N N
COCH.sub.2(CH.sub.3).sub.3 NC365 Propargyl CH CH
COCH.sub.2(CH.sub.3).sub.3 NC366 c-Pentyl CH N
COCH.sub.2(CH.sub.3).sub.3 NC367 Propargyl N CH
COCH.sub.2(CH.sub.3).sub.3 NC368 c-Pentyl N N
COCH.sub.2(CH.sub.3).sub.3 NC369 Propargyl CH CH
C(O)N(CH.sub.3).sub.2 NC370 c-Pentyl CH N C(O)N(CH.sub.3).sub.2
NC371 Propargyl N CH C(O)N(CH.sub.3).sub.2 NC372 c-Pentyl N N
C(O)N(CH.sub.3).sub.2 NC373 Propargyl CH CH C(O)N(CH.sub.3).sub.2
NC374 c-Pentyl CH N C(O)N(CH.sub.3).sub.2 NC375 Propargyl N CH
C(O)N(CH.sub.3).sub.2 NC376 c-Pentyl N N C(O)N(CH.sub.3).sub.2
NC377 Propargyl CH CH C(O)N(CH.sub.3)Et NC378 c-Pentyl CH N
C(O)N(CH.sub.3)Et NC379 Propargyl N CH C(O)N(CH.sub.3)Et NC380
c-Pentyl N N C(O)N(CH.sub.3)Et NC381 Propargyl CH CH
C(O)N(CH.sub.3)Et NC382 c-Pentyl CH N C(O)N(CH.sub.3)Et NC383
Propargyl N CH C(O)N(CH.sub.3)Et NC384 c-Pentyl N N
C(O)N(CH.sub.3)Et NC385 Propargyl CH CH C(O)N(CH.sub.3)iPr NC386
c-Pentyl CH N C(O)N(CH.sub.3)iPr NC387 Propargyl N CH
C(O)N(CH.sub.3)iPr NC388 c-Pentyl N N C(O)N(CH.sub.3)iPr NC389
Propargyl CH CH C(O)N(CH.sub.3)iPr NC390 c-Pentyl CH N
C(O)N(CH.sub.3)iPr NC391 Propargyl N CH C(O)N(CH.sub.3)iPr NC392
c-Pentyl N N C(O)N(CH.sub.3)iPr NC393 Propargyl CH CH
C(O)N(CH.sub.3)iBu NC394 c-Pentyl CH N C(O)N(CH.sub.3)iBu NC395
Propargyl N CH C(O)N(CH.sub.3)iBu NC396 c-Pentyl N N
C(O)N(CH.sub.3)iBu NC397 Propargyl CH CH C(O)N(CH.sub.3)iBu NC398
c-Pentyl CH N C(O)N(CH.sub.3)iBu NC399 Propargyl N CH
C(O)N(CH.sub.3)iBu NC400 c-Pentyl N N C(O)N(CH.sub.3)iBu NC401
Propargyl CH CH C(O)NH(Et) NC402 c-Pentyl CH N C(O)NH(Et) NC403
Propargyl N CH C(O)NH(Et) NC404 c-Pentyl N N C(O)NH(Et) NC405
Propargyl CH CH C(O)NH(Et) NC406 c-Pentyl CH N C(O)NH(Et) NC407
Propargyl N CH C(O)NH(Et) NC408 c-Pentyl N N C(O)NH(Et) NC409
Propargyl CH CH C(O)NH(iPr) NC410 c-Pentyl CH N C(O)NH(iPr) NC411
Propargyl N CH C(O)NH(iPr) NC412 c-Pentyl N N C(O)NH(iPr) NC413
Propargyl CH CH C(O)NH(iPr) NC414 c-Pentyl CH N C(O)NH(iPr) NC415
Propargyl N CH C(O)NH(iPr) NC416 c-Pentyl N N C(O)NH(iPr) NC417
Propargyl CH CH C(O)NH(iBu) NC418 c-Pentyl CH N C(O)NH(iBu) NC419
Propargyl N CH C(O)NH(iBu) NC420 c-Pentyl N N C(O)NH(iBu) NC421
Propargyl CH CH C(O)NH(iBu) NC422 c-Pentyl CH N C(O)NH(iBu) NC423
Propargyl N CH C(O)NH(iBu) NC424 c-Pentyl N N C(O)NH(iBu) NC425
Propargyl CH CH CH.sub.2OCOCH.sub.3 NC426 c-Pentyl CH N
CH.sub.2OCOCH.sub.3 NC427 Propargyl N CH CH.sub.2OCOCH.sub.3 NC428
c-Pentyl N N CH.sub.2OCOCH.sub.3 NC429 Propargyl CH CH
CH.sub.2OCOCH.sub.3 NC430 c-Pentyl CH N CH.sub.2OCOCH.sub.3 NC431
Propargyl N CH CH.sub.2OCOCH.sub.3 NC432 c-Pentyl N N
CH.sub.2OCOCH.sub.3 NC433 Propargyl CH CH CH.sub.2OCOEt NC434
c-Pentyl CH N CH.sub.2OCOEt NC435 Propargyl N CH CH.sub.2OCOEt
NC436 c-Pentyl N N CH.sub.2OCOEt NC437 Propargyl CH CH
CH.sub.2OCOEt NC438 c-Pentyl CH N CH.sub.2OCOEt NC439 Propargyl N
CH CH.sub.2OCOEt NC440 c-Pentyl N N CH.sub.2OCOEt NC441 Propargyl
CH CH CH.sub.2OCOiPr NC442 c-Pentyl CH N CH.sub.2OCOiPr NC443
Propargyl N CH CH.sub.2OCOiPr NC444 c-Pentyl N N CH.sub.2OCOiPr
NC445 Propargyl CH CH CH.sub.2OCOiPr NC446 c-Pentyl CH N
CH.sub.2OCOiPr NC447 Propargyl N CH CH.sub.2OCOiPr NC448 c-Pentyl N
N CH.sub.2OCOiPr NC449 Propargyl CH CH CH.sub.2OCOiBu NC450
c-Pentyl CH N CH.sub.2OCOiBu NC451 Propargyl N CH CH.sub.2OCOiBu
NC452 c-Pentyl N N CH.sub.2OCOiBu NC453 Propargyl CH CH
CH.sub.2OCOiBu NC454 c-Pentyl CH N CH.sub.2OCOiBu NC455 Propargyl N
CH CH.sub.2OCOiBu NC456 c-Pentyl N N CH.sub.2OCOiBu
Evaluation of Novel A.sub.2A Antagonists in Four Mouse Models of
PD: The A.sub.2A Receptor Antagonist ATL-2 Enhances Motor Function
in a Dose-Dependent Manner in Normal and Dopamine-Depleted
Mice.
[0134] In the set of experiments, we perform a dose response study
of ATL-2 in stimulating motor activity in normal mice, and then we
further extend this to dopamine-depleted mice. Adult male mice are
habituated for 120 minutes and treated (i.p.) with saline or
varying doses of compound, and their locomotor activity recorded
for 120 minutes.
[0135] In a second set of experiments, we utilize the MPTP
treatment paradigm to create animal model of PD by severely
depleting dopamine in mice. We use a single MPTP treatment paradigm
(40 mg/kg) which has been reproducibly reducing dopamine to 30-40%
of normal dopamine contents in striatum in our previous
studies..sup.35,74 Adult male mice (.beta.25 mg/kg) are treated
with single dose of MPTP (40 mg/kg). Thirty minutes after the MPTP
treatment, mice are injected (i.p.) with vehicle or compounds of
the invention at the same doses discussed above. Their motor
activity is recorded for 180 minutes.
[0136] Results: Based on our previous experiments with other
A.sub.2AR antagonists and our pilot study, we observe the maximal
stimulant dose as well as sub-threshold doses of ATL compounds in
normal and MPTP-treated mice. Without being bound by any theory, it
is proposed that motor stimulant effect may manifest best in
dopamine-depleted animals than normal animals, indicating that
A.sub.2AR antagonists preferentially act at the A.sub.2AR in a PD
condition to stimulate motor activity.
[0137] A.sub.2A receptor antagonists synergize with L-dopa to
stimulate motor activity in dopamine-depleted mice.
[0138] We further tested the ability of these compounds to
synergistically enhance motor function in conjunction with L-dopa,
the standard therapy. Mice are injected (i.p.) with MPTP at a dose
(1-2.5 mg/kg) that markedly decreases striatal dopamine levels.
Thirty minutes later (when the mice exhibit an immobility), the
mice are then randomly assigned to the following different
treatment groups (n=10): (1) L-dopa (25 mg/kg); (2) ATL-2 (0.3, 1,
3, and 10 mg/kg), and (3) L-dopa (25 mg/kg)+ATL-2 (0.3, 1, 3, and
10 mg/kg). Locomotor behavior is monitored for 120 min before and
after the treatment.
[0139] Results: Based on the Preliminary Results and on the known
feature of other A.sub.2AR antagonists, a synergistic effect of
ATL-2 with L-dopa in stimulating locomotor activity in
dopamine-depleted mice is observed. This synergistic effect of
ATL-2 and L-dopa is exhibited in a left-shift of the dose-response
curve.
A.sub.2A Antagonists Potently and Specifically Attenuate
MPTP-Induced Neurotoxicity by Inhibiting MPTP Metabolism.
[0140] C57Bl/6 mice (n=10-12 mice per group) are pretreated with
the A.sub.2A antagonist ATL-2 (0.3, 1.0, 3.0 and 10.0 mg/kg, i.p) 5
min prior to each of four MPTP (40 mg/kg) injections at 2 hr
intervals. These doses are selected based on our preliminary
results (with CSC) and on motor and neuroprotective effects
(against ischemia) by SCH58261 and DPCPX. The specificities for the
A.sub.2AR in these dose ranges of ATL-2 have been confirmed using
A.sub.2A KO mice. Seven days after the MPTP (.+-.CSC, SCH58261 or
CPA) treatment, the striatum from one side are dissected out and
processed for HPLC analysis of dopamine and DOPAC levels. The other
half brain is quickly frozen for sectioning coronally through the
striatum and substantial nigra. DAT binding density in striatum may
be determined by receptor autoradiography using .sup.3H-mazindol as
a specific ligand. Quantitation of DAT (3H-mazindol) binding
autoradiography may be performed by densitometry analysis. The
numbers of dopaminergic neurons may be determined by TH
immunohistochemistry in the substantial nigra. Stereological
methods may be used to estimate the absolute reduction in THV
nigral neurons in MPTP-treated WT mice and any attenuation in those
pretreated with ATL-2. In the same sections, cell counts may also
be performed for TH.sup.+ neurons in the more medial VTA, which is
less affected in MPTP treated mice as well as in PD.
[0141] Results: Guided by our preliminary results, neuroprotection
in a dose-dependent manner (at least from 0.5 to 5 mg/kg range) may
be observed. The potency of A.sub.2A antagonists for
neuroprotection may be observed with their potency for motor
stimulation and for possible attenuation of behavioral
sensitization (see above). Similarly, the potency of CSC or
SCH58261 for neuroprotection against MPTP may be compared to that
for neuroprotection against ischemic injury and excitoxicity. A
significant difference in an A.sub.2A antagonist's potency in
neuroprotection against MPTP and against ischemia or excitoxicity
may suggest different mechanisms and sites of action (e.g. glial
versus neuronal compartments which may have different G-protein
coupling mechanisms). On the other hand, the same potency of
A.sub.2A antagonists for motor stimulation, neuroprotection and
possibly delayed sensitization to L-dopa would suggest that the
same type of A.sub.2AR is responsible for all these potential
benefits of A.sub.2A antagonists in different animal models of
PD.
A.sub.2A Antagonists Delay and A.sub.2A Agonists Accelerate
L-dopa-Induced Locomotor Sensitization in Unilateral
6-OHDA-Lesioned Mice.
[0142] The ability of ATL-2 to modify the development of
L-dopa-induced locomotor sensitization in hemiparkinsonian mice are
tested. C57BL/6 mice (from the Jackson's lab, Bar Harbor, Mich.)
are lesioned with 6-OHDA by unilateral intrastriatal using a
standard lesioning protocol. Seven days after the 6-OHDA (or
MPP.sup.+) treatment, mice are injected with L-dopa (2.0 mg/kg,
daily) for 14 days. Five min prior to each L-dopa treatment, the
mice receive intraperitoneal pretreatment with: (1) vehicle, (2)
ATL-2 (3 mg/kg) or (3) ATL-2 (10 mg/kg). In these dose ranges, the
selective A.sub.2A antagonists have been shown to produce motor
stimulant effects (see Preliminary Results). Rotational responses
to L-dopa are recorded on the days 1, 3, 5, 7, 10 and 15. Following
the behavioral measurement, mice may be sacrificed and their brains
sectioned through striatum and substantial nigra. Striatal
enkephalin mRNA levels are determined by in situ hybridization
histochemistry. Similarly, DAT (3H-mazindol) binding is measured by
receptor autoradiography to ensure successful and equivalent
lesions among different experimental groups.
[0143] Results: Based on our previous study with SCH58261 in this
repeated L-dopa-induced sensitization model, ATL-2 delays or
prevent the development of locomotor sensitization. The prevention
or delayed appearance with L-dopa locomotor sensitization by
co-injection of an A.sub.2A antagonist indicates an important role
of the A.sub.2AR in the development of L-dopa-induced behavioral
sensitization. Furthermore, this helps exclude the possibility that
an attenuated behavioral sensitization to chronic L-dopa observed
in A.sub.2A KO mice results from a developmental effect of
A.sub.2AR deficiency. Thus combined genetic and pharmacological
approaches provide the clearest assessment of the A.sub.2AR's role
in the development of behavioral sensitization to L-dopa, and
provides insights into its role in L-dopa-induced dyskinesia.
Methods
Animal Treatments and Catalepsy Behavioral Assessments:
[0144] WT and A.sub.2A KO mice (generated as above) as well as
commercially procured C57Bl/6 mice (Taconic, N.Y.) may be used for
this study. Since our pilot study and other reports [40,88]
indicate that animal age is a critical factor in determining the
extent of an MPTP lesion, animal body weight around 25-30 grams
(corresponding to approximately 10 weeks of age) is tightly
controlled. The mice are housed in temperature and
humidity-controlled rooms with a 24-hour 1:1 light:dark cycle.
Adenosinergic and dopaminergic agents are injected at the volume of
0.1 ml/10 gram body weight of mice. Other adenosinergic and
dopaminergic drugs are purchased from RBI (Natick, Mass.). From our
previous work, we have adapted a special solvent (15% DMSO, 15%
Alkamuls-EL 620 and 70% saline) for dissolving A.sub.2A
antagonists, including CSC and SCH58261.
[0145] Catalepsy behavior may be induced by haloperidol (1 mg/kg,
i.p.) or reserpine (5 mg/kg, i.p. see below). Catalepsy score may
be determined by the bar and grid tests. For the bar test, both
mouse forepaws are placed on a 6 cm-high horizontal bar (diameter
0.7 cm). In the grid test, mice are allowed to cling to a
metal-framed vertical grid (1.3 cm squares). The latency from paw
placement until the first complete removal of one paw from the
support is measured (maximal test duration 180 sec). Upon the
completion of behavioral assessment, mice are sacrificed and the
brains are processed for neurochemical and histochemical
analyses.
Dopamine Depletion by the Treatment with MPTP or 6-OHDA:
[0146] a) Intraperitoneal Injection of MPTP: The MPTP
administration regimen (20 mg/kg.times.4 at 2 hr interval) has been
shown to produce severe dopamine depletion (consistently greater
than .about.80% in our Preliminary Results FIGS. 6 and 7). Naive
C57Bl/6 mice are pretreated with adenosine antagonists 5 min prior
to MPTP treatment.
[0147] b) Intrastriatal Injection of 6-OHDA: Wild-type C57Bl/6 or
A.sub.2AR mutant mice are anesthetized with Avertin and positioned
in a stereotaxic frame. Three microliters of 6-OHDA (3 .mu.g/.mu.l)
are injected into the left striatum (coordinates from bregma:
AP+0.0, L+2.5.0, DV-4.4) via a infusion minipump over a 4 min
period. Due to its photolability, 6-OHDA is dissolved in 0.01%
ascorbic acid and injected under a light-protected environment.
[0148] c) Post-treatment Care: Dopamine-depleted mice may be
continually monitored, and special care may be taken to maintain
mouse body temperature with a heating blanket or warming lights.
During the first 48 hours post-operation, mashed food pellets and
water are provided to the mice inside the cage at floor-level for
easy access.
Neurochemical Analysis:
[0149] (a) Measurements of Catecholamines and Indoleamines in
Striatum by HPLC: To measure tissue catecholamine and indoleamine
levels, mice are decapitated, their brains are removed rapidly, and
striata are dissected out and frozen on dry ice. Striata are
weighed frozen and then homogenized in 200 .mu.l of 150 mM
trichloroacetic acid containing 0.1 mM EDTA and 1 .mu.M epinephrine
(as an internal standard). Homogenates are centrifuged for 5 min at
15,000 g. The catecholamines in the supernatant are separated over
a reverse-phase hydrophobic interaction C-18 HPLC column (Beckman,
5.mu. ODS) and measured using an electrochemical detector (ESA
Coulochem 5100A) with electrodes set in series at oxidizing (+0.22
V) and then reducing (-0.35 V) potentials. Both the retention time
and the ratio of oxidation to reduction currents for given sample
peaks are compared against those for external standards to ensure
proper identification of analytes.
[0150] (b) Stereologic quantitation of neuronal loss in substantia
nigra: One week after lesioning, mice may be perfusion-fixed and
their brains may be microtome-cut into 40 .mu.m coronal
free-floating sections. Every sixth section may be processed for TH
immunohistochemistry using a 1:1,000 dilution of a polyclonal
rabbit antiserum against rat TH (Eugene Tech. Intl., NJ).
Immunostaining is completed using standard avidin-biotin procedures
described previously [18,130]. A non-biased stereological technique
is employed to quantify the effect of treatment on total TH+ nigra
(pars compacta) cell counts as described previously [81]. All
counts are performed by a single observer who is unaware of the
treatment group at the time of neuronal estimates. Based on our
pilot studies in WT mice MPP+ at this dose (3 .mu.g/striatum)
produced a .about.40% loss of ipsilateral TH+nigral neurons.
[0151] (c) A2A receptor binding autoradiography: Twenty micron
striatal sections are preincubated for 5 minutes with ice-cold
buffer (509 mM Tris-HCl, 5 mM KCl and 300 mM NaCl, pH 7.9) and then
incubated for 60 minutes in the same buffer containing 6 nM
3H-SCH58261 (provided generously by Dr. E. Ongini) [131]. The
slides are washed twice and then air-dried before exposure to
Hyperfilm (Amersham, Ill.) for 2-4 weeks. The films are analyzed
with a video-based image analysis system (MultiAnalyst; Biorad),
and total striatal 3H-SCH58261 binding (fmol/mg tissue) is
calculated using a tritium-labeled calibration standard
[17,131]
Statistical Analysis
[0152] Single statistical comparisons of an A.sub.2AR KO group to
its WT control are generally performed using a Student's t test,
two-tailed. Comparison of more than two factors (e.g. genotype,
drug treatment and time course) and their interactions are made
using 2-way ANOVA followed by Newman-Keuls post hoc analysis. If
data are not normally distributed, non-parametric tests
(Kruskal-Wallis or Mann-Whitney U test) are used.
[0153] Vertebrate Animals. Mice are the only animals that are be
used in experiments. The mice are monitored daily (co-investigators
or technician) under the supervision of a staff veterinarian. In
the majority of the experiments the mice are kept under SPF
conditions with no more than 5 mice/cage of females and 4 mice/cage
of males. All husbandry and veterinary care meets NIH and AAALAC
standards for humane care for use of laboratory animals. In
addition, because of daily observation of all animals, any moribund
animal is humanely euthanized by CO.sub.2-Models of PD are used to
investigate pre-clinical efficacy and pharmacokinetics of A2AAR
antagonist. Because we have used these model in our laboratory, the
model is now well characterized and the experimental manipulation
of mice for these studies are well established.
REFERENCES
[0154] 1. Hauser R A, Hubble J P, Truong D D. Randomized trial of
the adenosine A(2A) receptor antagonist istradefylline in advanced
PD. Neurology. 2003; 61:297-303. [0155] 2. Lang A E, Lozano A M.
Parkinson's disease. Second of two parts. N Engl J. Med. 1998;
339:1130-1143. [0156] 3. Agid Y, Cervera P, Hirsch E, Javoy-Agid F,
Lehericy S, Raisman R, Ruberg M. Biochemistry of Parkinson's
disease 28 years later: a critical review. Mov Disord. 1989; 4
Suppl 1:S126-S144. [0157] 4. Lang A E, Lozano A M. Parkinson's
disease. Second of two parts. N Engl J. Med. 1998; 339:1130-1143.
[0158] 5. Lang A E, Lozano A M. Parkinson's disease. First of two
parts. N Engl J. Med. 1998; 339: 1044-1053. [0159] 6. Obeso J A,
Olanow C W, Nutt J G. Levodopa motor complications in Parkinson's
disease. Trends Neurosci. 2000; 23:S2-S7. [0160] 7. Bezard E,
Brotchie J M, Gross C E. Pathophysiology of levodopa-induced
dyskinesia: potential for new therapies. Nat Rev Neurosci. 2001;
2:577-588. [0161] 8. Fahn S. The spectrum of levodopa-induced
dyskinesias. Ann Neurol. 2000; 47:S2-S9. [0162] 9. Fahn S. The
spectrum of levodopa-induced dyskinesias. Ann Neurol. 2000;
47:S2-S9. [0163] 10. Jenner P. Pathophysiology and biochemistry of
dyskinesia: clues for the development of non-dopaminergic
treatments. J Neurol. 2000; 247 Suppl 2: 1143-1150. [0164] 11.
Melamed E, Offen D, Shirvan A, Djaldetti R, Barzilai A, Ziv I.
Levodopa toxicity and apoptosis. Ann Neurol. 1998; 44:S149-S154.
[0165] 12. Jenner P. Pathophysiology and biochemistry of
dyskinesia: clues for the development of non-dopaminergic
treatments. J Neurol. 2000; 247 Suppl 2: 1143-1150. [0166] 13. Chen
J F. The adenosine A(2A) receptor as an attractive target for
Parkinson's disease treatment. Drug News Perspect. 2003;
16:597-604. [0167] 14. Schwarzschild M A, Chen J F, Ascherio A.
Caffeinated clues and the promise of adenosine A(2A) antagonists in
PD. Neurology. 2002; 58: 1154-1160. [0168] 15. Ferre S, Fredholm B
B, Morelli M, Popoli P, Fuxe K. Adenosine-dopamine
receptor-receptor interactions as an integrative mechanism in the
basal ganglia. Trends Neurosci. 1997; 20:482-487. [0169] 16.
Richardson P J, Gubitz A K, Freeman T C, Dixon A K. Adenosine
receptor antagonists and Parkinson's disease: actions of the A2A
receptor in the striatum. Adv Neurol. 1999; 80:111-119. [0170] 17.
Schwarzschild M A, Chen J F, Ascherio A. Caffeinated clues and the
promise of adenosine A(2A) antagonists in PD. Neurology. 2002; 58:
1154-1160. [0171] 18. Fink J S, Weaver D R, Rivkees S A,
Peterfreund R A, Pollack A E, Adler E M, Reppert S M. Molecular
cloning of the rat A2 adenosine receptor: selective co-expression
with D2 dopamine receptors in rat striatum. Brain Res Mol Brain
Res. 1992; 14:186-195. [0172] 19. Schiffmann S N, Jacobs O,
Vanderhaeghen J J. Striatal restricted adenosine A2 receptor (RDC8)
is expressed by enkephalin but not by substance P neurons: an in
situ hybridization histochemistry study. J. Neurochem. 1991;
57:1062-1067. [0173] 20. Schiffmann S N, Vanderhaeghen J J.
Adenosine A2 receptors regulate the gene expression of
striatopallidal and striatonigral neurons. J. Neurosci. 1993;
13:1080-1087. [0174] 21. Ferre S, Rubio A, Fuxe K. Stimulation of
adenosine A2 receptors induces catalepsy. Neurosci Lett. 1991;
130:162-164. [0175] 22. Ferre S, Fuxe K, Von Euler G, Johansson B,
Fredholm BB. Adenosine-dopamine interactions in the brain.
Neurosci. 1992; 51:501-512. [0176] 23. Fredholm B B, Battig K,
Holmen J, Nehlig A, Zvartau E E. Actions of caffeine in the brain
with special reference to factors that contribute to its widespread
use. Pharmacol Rev. 1999; 51:83-133. [0177] 24. Barraco R A,
Martens K A, Parizon M, Normile H J. Adenosine A2a receptors in the
nucleus accumbens mediate locomotor depression. Brain Res Bull.
1993; 31:397-404. [0178] 25. Ferre S, Von Euler G, Johansson B,
Fredholm B B, Fuxe K. Stimulation of high-affinity adenosine A2
receptors decreases the affinity of dopamine D2 receptors in rat
striatal membranes. Proc Natl Acad Sci USA. 1991; 88:7238-7241.
[0179] 26. Fuxe K, Ferre S, Zoli M, Agnati L F. Integrated events
in central dopamine transmission as analyzed at multiple levels.
Evidence for intramembrane adenosine A2A/dopamine D2 and adenosine
A1/dopamine D1 receptor interactions in the basal ganglia. Brain
Res Brain Res Rev. 1998; 26:258-273. [0180] 27. Aoyama S, Kase H,
Borrelli E. Rescue of locomotor impairment in dopamine D2
receptor-deficient mice by an adenosine A2A receptor antagonist. J.
Neurosci. 2000; 20:5848-5852. [0181] 28. Chen J F, Moratalla R,
Impagnatiello F, Grandy D K, Cuellar B, Rubinstein M, Beilstein M
A, Hackett E, Fink J S, Low M J, Ongini E, Schwarzschild M A. The
role of the D(2) dopamine receptor (D(2)R) in A(2A) adenosine
receptor (A(2A)R)-mediated behavioral and cellular responses as
revealed by A(2A) and D(2) receptor knockout mice. Proc Natl Acad
Sci USA. 2001; 98:1970-1975. [0182] 29. Thompson R D, Secunda S,
Daly J W, Olsson R A. N6,9-disubstituted adenines: potent,
selective antagonists at the A1 adenosine receptor. J Med. Chem.
1991; 34:2877-2882. [0183] 30. Mori A, Shindou T, Ichimura M,
Nonaka H, Kase H. The role of adenosine A2a receptors in regulating
GABAergic synaptic transmission in striatal medium spiny neurons.
J. Neurosci. 1996; 16:605-611. [0184] 31. Richardson P J, Gubitz A
K, Freeman T C, Dixon A K. Adenosine receptor antagonists and
Parkinson's disease: actions of the A2A receptor in the striatum.
Adv Neurol. 1999; 80:111-119. [0185] 32. Svenningsson P, Le Moine
C, Fisone G, Fredholm B B. Distribution, biochemistry and function
of striatal adenosine A2A receptors. Prog Neurobiol. 1999;
59:355-396. [0186] 33. Canals M, Marcellino D, Fanelli F, Ciruela
F, de Benedetti P, Goldberg S R, Neve K, Fuxe K, Agnati L F, Woods
A S, Ferre S, Lluis C, Bouvier M, Franco R. Adenosine A2A-dopamine
D2 receptor-receptor heteromerization: qualitative and quantitative
assessment by fluorescence and bioluminescence energy transfer. J
Biol. Chem. 2003; 278:46741-46749. [0187] 34. Fredholm B B, Battig
K, Holmen J, Nehlig A, Zvartau E E. Actions of caffeine in the
brain with special reference to factors that contribute to its
widespread use [Review]. Pharmacol Rev. 1999; 51:83-133. [0188] 35.
Chen J F, Moratalla R, Impagnatiello F, Grandy D K, Cuellar B,
Rubinstein M, Beilstein M A, Hackett E, Fink J S, Low M J, Ongini
E, Schwarzschild M A. The role of the D(2) dopamine receptor
(D(2)R) in A(2A) adenosine receptor (A(2A)R)-mediated behavioral
and cellular responses as revealed by A(2A) and D(2) receptor
knockout mice. Proc Natl Acad Sci USA. 2001; 98:1970-1975. [0189]
36. Grondin R, Bedard P J, Hadj T A, Gregoire L, Mori A, Kase H.
Antiparkinsonian effect of a new selective adenosine A2A receptor
antagonist in MPTP-treated monkeys. Neurology. 1999; 52: 1673-1677.
[0190] 37. Kanda T, Jackson M J, Smith L A, Pearce R K, Nakamura J,
Kase H, Kuwana Y, Jenner P. Combined use of the adenosine A(2A)
antagonist KW-6002 with L-DOPA or with selective D1 or D2 dopamine
agonists increases antiparkinsonian activity but not dyskinesia in
MPTP-treated monkeys. Exp Neurol. 2000; 162:321-327. [0191] 38.
Kanda T, Jackson M J, Smith L A, Pearce R K, Nakamura J, Kase H,
Kuwana Y, Jenner P. Adenosine A2A antagonist: a novel
antiparkinsonian agent that does not provoke dyskinesia in
parkinsonian monkeys. Ann Neurol. 1998; 43:507-513. [0192] 39.
Kanda T, Tashiro T, Kuwana Y, Jenner P. Adenosine A2A receptors
modify motor function in MPTP-treated common marmosets.
Neuroreport. 1998; 9:2857-2860. [0193] 40. Pinna A, Fenu S, Morelli
M. Motor stimulant effects of the adenosine A(2A) receptor
antagonist SCH 58261 do not develop tolerance after repeated
treatments in 6-hydroxydopamine-lesioned rats. Synapse. 2001;
39:233-238. [0194] 41. Pinna A, di Chiara G, Wardas J, Morelli M.
Blockade of A2a adenosine receptors positively modulates turning
behaviour and c-Fos expression induced by D1 agonists in
dopamine-denervated rats. Eur J. Neurosci. 1996; 8: 1176-1181.
[0195] 42. Aoyama S, Kase H, Borrelli E. Rescue of locomotor
impairment in dopamine D2 receptor-deficient mice by an adenosine
A2A receptor antagonist. Journal of Neuroscience. 2000;
20:5848-5852. [0196] 43. Grondin R, Bedard P J, Hadj T A, Gregoire
L, Mori A, Kase H. Antiparkinsonian effect of a new selective
adenosine A2A receptor antagonist in MPTP-treated monkeys.
Neurology. 1999; 52:1673-1677. [0197] 44. Kanda T, Jackson M J,
Smith L A, Pearce R K, Nakamura J, Kase H, Kuwana Y, Jenner P.
Adenosine A2A antagonist: a novel antiparkinsonian agent that does
not provoke dyskinesia in parkinsonian monkeys. Ann Neurol. 1998;
43:507-513. [0198] 45. Kanda T, Jackson M J, Smith L A, Pearce R K,
Nakamura J, Kase H, Kuwana Y, Jenner P. Combined use of the
adenosine A(2A) antagonist KW-6002 with L-DOPA or with selective D1
or D2 dopamine agonists increases antiparkinsonian activity but not
dyskinesia in MPTP-treated monkeys. Exp Neurol. 2000; 162:321-327.
[0199] 46. Halldner L, Lozza G, Lindstrom K, Fredholm B B. Lack of
tolerance to motor stimulant effects of a selective adenosine A(2A)
receptor antagonist. Eur J. Pharmacol. 2000; 406:345-354. [0200]
47. Pinna A, Fenu S, Morelli M. Motor stimulant effects of the
adenosine A(2A) receptor antagonist SCH 58261 do not develop
tolerance after repeated treatments in 6-hydroxydopamine-lesioned
rats. Synapse. 2001; 39:233-238. [0201] 48. Kanda T, Jackson M J,
Smith L A, Pearce R K, Nakamura J, Kase H, Kuwana Y, Jenner P.
Combined use of the adenosine A(2A) antagonist KW-6002 with L-DOPA
or with selective D1 or D2 dopamine agonists increases
antiparkinsonian activity but not dyskinesia in MPTP-treated
monkeys. Exp Neurol. 2000; 162:321-327. [0202] 49. Fredduzzi S,
Moratalla R, Monopoli A, Cuellar B, Xu K, Ongini E, Impagnatiello
F, Schwarzschild M A, Chen J F. Persistent behavioral sensitization
to chronic L-DOPA requires A2A adenosine receptors. J Neurosci.
2002; 22:1054-1062. [0203] 50. Bibbiani F, Oh J D, Petzer J P,
Castagnoli N, Jr., Chen J F, Schwarzschild M A, Chase T N. A2A
antagonist prevents dopamine agonist-induced motor complications in
animal models of Parkinson's disease. Exp Neurol. 2003;
184:285-294. [0204] 51. Chen J F, Huang Z, Ma J, Zhu J, Moratalla
R, Standaert D, Moskowitz M A, Fink J S, Schwarzschild M A. A(2A)
adenosine receptor deficiency attenuates brain injury induced by
transient focal ischemia in mice. J. Neurosci. 1999; 19:9192-9200.
[0205] 52. Monopoli A, Casati C, Lozza G, Forlani A, Ongini E.
Cardiovascular pharmacology of the A2A adenosine receptor
antagonist, SCH 58261, in the rat. J Pharmacol Exp Ther. 1998;
285:9-15. [0206] 53. Phillis J W. The effects of selective A1 and
A2a adenosine receptor antagonists on cerebral ischemic injury in
the gerbil. Brain Res. 1995; 705:79-84. [0207] 54. Jones P A, Smith
R A, Stone T W. Protection against hippocampal kainate
excitotoxicity by intracerebral administration of an adenosine
A.sub.2A receptor antagonist. Brain Res. 1998; 800:328-335. [0208]
55. Jones P A, Smith R A, Stone T W. Protection against
kainate-induced excitotoxicity by adenosine A2A receptor agonists
and antagonists. Neuroscience. 1998; 85:229-237. [0209] 56. Popoli
P, Pintor A, Domenici M R, Frank C, Tebano M T, Pezzola A,
Scarchilli L, Quarta D, Reggio R, Malchiodi-Albedi F, Falchi M,
Massotti M. Blockade of striatal adenosine A2A receptor reduces,
through a presynaptic mechanism, quinolinic acid-induced
excitotoxicity: possible relevance to neuroprotective interventions
in neurodegenerative diseases of the striatum. J Neurosci. 2002;
22:1967-1975. [0210] 57. Dall'Igna O P, Porciuncula L O, Souza D O,
Cunha R A, Lara D R, Dall'lgna O P. Neuroprotection by caffeine and
adenosine A2A receptor blockade of beta-amyloid neurotoxicity. Br
J. Pharmacol. 2003; 138:1207-1209. [0211] 58. Chen J F, Xu K,
Petzer J P, Staal R, Xu Y H, Beilstein M, Sonsalla P K, Castagnoli
K, Castagnoli N, Jr., Schwarzschild M A. Neuroprotection by
caffeine and A(2A) adenosine receptor inactivation in a model of
Parkinson's disease. J. Neurosci. 2001; 21:RC143. [0212] 59. Chen J
F, Xu K, Petzer J P, Staal R, Xu Y H, Beilstein M, Sonsalla P K,
Castagnoli K, Castagnoli N, Jr., Schwarzschild M A. Neuroprotection
by caffeine and A(2A) adenosine receptor inactivation in a model of
Parkinson's disease. J. Neurosci. 2001; 21:RC143. [0213] 60. Ikeda
K, Kurokawa M, Aoyama S, Kuwana Y. Neuroprotection by adenosine A2A
receptor blockade in experimental models of Parkinson's disease. J.
Neurochem. 2002; 80:262-270. [0214] 61. Martinez-Mir M I, Probst A,
Palacios J M. Adenosine A2 receptors: selective localization in the
human basal ganglia and alterations with disease. Neuroscience.
1991; 42:697-706. [0215] 62. Ross G W, Abbott R D, Petrovitch H,
Morens D M, Grandinetti A, Tung K H, Tanner C M, Masaki K H,
Blanchette P L, Curb J D, Popper J S, White L R. Association of
coffee and caffeine intake with the risk of Parkinson disease.
JAMA. 2000; 283:2674-2679. [0216] 63. Ascherio A, Zhang S M, Heman
M A, Kawachi I, Colditz G A, Speizer F E, Willett W C. Prospective
study of caffeine consumption and risk of Parkinson's disease in
men and women. Ann Neurol. 2001; 50:56-63. [0217] 64. Hauser R A,
Hubble J P, Truong D D. Randomized trial of the adenosine A(2A)
receptor antagonist istradefylline in advanced PD. Neurology. 2003;
61:297-303. [0218] 65. Bara-Jimenez W, Sherzai A, Dimitrova T,
Favit A, Bibbiani F, Gillespie M, Morris M J, Mouradian M M, Chase
T N. Adenosine A(2A) receptor antagonist treatment of Parkinson's
disease. Neurology. 2003; 61:293-296. [0219] 66. Bara-Jimenez W,
Sherzai A, Dimitrova T, Favit A, Bibbiani F, Gillespie M, Morris M
J, Mouradian M M, Chase T N. Adenosine A(2A) receptor antagonist
treatment of Parkinson's disease. Neurology. 2003; 61:293-296.
[0220] 67. Zocchi C, Ongini E, Ferrara S, Baraldi P G, Dionisotti
S. Binding of the radioligand [3H]-SCH 58261, a new non-xanthine
A2A adenosine receptor antagonist, to rat striatal membranes. Br J.
Pharmacol. 1996; 117: 1381-1386. [0221] 68. Keddie J R, Poucher S
M, Shaw G R, Brooks R, Collis M G. In vivo characterisation of ZM
241385, a selective adenosine A2A receptor antagonist. Eur J.
Pharmacol. 1996; 301:107-113. [0222] 69. Mori A, Shindou T,
Ichimura M, Nonaka H, Kase H. The role of adenosine A2a receptors
in regulating GABAergic synaptic transmission in striatal medium
spiny neurons. J. Neurosci. 1996; 16:605-611. [0223] 70. Todde S,
Moresco R M, Simonelli P, Baraldi P G, Cacciari B, Spalluto G,
Varani K, Monopoli A, Matarrese M, Carpinelli A, Magni F, Kienle M
G, Fazio F. Design, radiosynthesis, and biodistribution of a new
potent and selective ligand for in vivo imaging of the adenosine
A(2A) receptor system using positron emission tomography. J Med.
Chem. 2000; 43:4359-4362. [0224] 71. Colotta V, Catarzi D, Varano
F, Cecchi L, Filacchioni G, Martini C, Trincavelli L, Lucacchini A.
4-Amino-6-benzylamino-1,2-dihydro-2-phenyl-1,2,4-triazolo[4,3-alpha]-quin-
oxalin-1-one: a new A2A adenosine receptor antagonist with high
selectivity versus A1 receptors. Arch Pharm (Weinheim). 1999;
332:39-41.
[0225] 72. Thompson R D, Secunda S, Daly J W, Olsson R A.
N6,9-disubstituted adenines: potent, selective antagonists at the
A1 adenosine receptor. J Med. Chem. 1991; 34:2877-2882. [0226] 73.
Iwasaki K, Kusachi S, Tominaga Y, Kita T, Taniguchi G. Coronary
artery spasm demonstrated by coronary angiography in a patient with
acute myocarditis resembling acute myocardial infarction; a case
report. Jpn J. Med. 1991; 30:573-577. [0227] 74. Chen J F, Steyn S,
Staal R, Petzer J P, Xu K, Van Der Schyf C J, Castagnoli K,
Sonsalla P K, Castagnoli N, Jr., Schwarzschild M A.
8-(3-Chlorostyryl)caffeine may attenuate MPTP neurotoxicity through
dual actions of monoamine oxidase inhibition and A.sub.2A receptor
antagonism. J Biol. Chem. 2002; 277:36040-36044.
[0228] The entire disclosure of all documents cited throughout this
application are incorporated herein by reference.
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