U.S. patent number RE44,205 [Application Number 13/441,140] was granted by the patent office on 2013-05-07 for adenosine a.sub.2a receptor antagonists.
This patent grant is currently assigned to Merck Sharp & Dohme Corp.. The grantee listed for this patent is Craig D. Boyle, Samuel Chackalamannil, William J. Greenlee, Neil Lindo, Bernard R. Neustadt, Lisa S. Silverman, Deen Tulshian, Yan Xia. Invention is credited to Craig D. Boyle, Samuel Chackalamannil, William J. Greenlee, Neil Lindo, Bernard R. Neustadt, Lisa S. Silverman, Deen Tulshian, Yan Xia.
United States Patent |
RE44,205 |
Neustadt , et al. |
May 7, 2013 |
Adenosine A.sub.2a receptor antagonists
Abstract
Compounds having the structural formula I ##STR00001## or a
pharmaceutically acceptable salt thereof, wherein R is optionally
substituted phenyl, cycloalkenyl, or heteroaryl; X is alkylene or
--C(O)CH.sub.2--; Y is --N(R.sup.2)CH.sub.2CH.sub.2N(R).sup.3)--,
--OCH.sub.2CH.sub.2N(R.sup.2)--, --O--, --S--, --CH.sub.2S--,
--(CH.sub.2).sub.2--NH--, or optionally substituted ##STR00002## m
and n are 2-3, and Q is nitrogen or optionally substituted carbon;
and Z is optionally substituted phenyl, phenylalkyl or heteroaryl,
diphenylmethyl, R.sup.6--C(O)--, R.sup.6--SO.sub.2--,
R.sup.6--OC(O)--, R.sup.7--N(R.sup.8)--C(O)--,
R.sup.7--N(R.sup.8)--C(S)--, ##STR00003## phenyl-CH(OH)--, or
phenyl-C(.dbd.NOR.sup.2)--; or when Q is CH, phenylamino or
pyridylamino; or Z and Y together are substituted piperidinyl or
substituted phenyl; and R.sup.2, R.sup.3, R.sup.6, R.sup.7, and
R.sup.8 are as defined in the specification are disclosed, their
use in the treatment of Parkinson's disease, alone or in
combination with other agents for treating Parkinson's disease, and
pharmaceutical compositions comprising them; also disclosed are a
processes for preparing intermediates useful for preparing
compounds of formula I.
Inventors: |
Neustadt; Bernard R. (West
Orange, NJ), Lindo; Neil (New Providence, NJ), Greenlee;
William J. (Teaneck, NJ), Tulshian; Deen (Lebanon,
NJ), Silverman; Lisa S. (Maryville, TN), Xia; Yan
(Edison, NJ), Boyle; Craig D. (Branchburg, NJ),
Chackalamannil; Samuel (Califon, NJ) |
Applicant: |
Name |
City |
State |
Country |
Type |
Neustadt; Bernard R.
Lindo; Neil
Greenlee; William J.
Tulshian; Deen
Silverman; Lisa S.
Xia; Yan
Boyle; Craig D.
Chackalamannil; Samuel |
West Orange
New Providence
Teaneck
Lebanon
Maryville
Edison
Branchburg
Califon |
NJ
NJ
NJ
NJ
TN
NJ
NJ
NJ |
US
US
US
US
US
US
US
US |
|
|
Assignee: |
Merck Sharp & Dohme Corp.
(Rahway, NJ)
|
Family
ID: |
22769372 |
Appl.
No.: |
13/441,140 |
Filed: |
April 6, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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60207143 |
May 26, 2000 |
|
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Reissue of: |
09865071 |
May 24, 2001 |
6630475 |
Oct 7, 2003 |
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Current U.S.
Class: |
514/257; 514/267;
514/252.16; 540/553; 540/470; 514/211.15; 544/61; 544/238;
514/255.05; 514/252.11; 514/233.2; 514/211.08; 544/115; 544/230;
514/218; 514/228.5; 540/601; 514/252.02; 540/480; 514/217.06;
540/575; 544/251; 540/466; 540/513 |
Current CPC
Class: |
A61P
43/00 (20180101); A61P 25/24 (20180101); A61P
25/00 (20180101); C07D 487/14 (20130101); A61P
25/28 (20180101); A61P 25/16 (20180101); A61P
25/08 (20180101) |
Current International
Class: |
C07D
471/04 (20060101); C07D 471/22 (20060101); C07D
487/04 (20060101) |
Field of
Search: |
;544/251 ;514/267 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0217748 |
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Feb 1991 |
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EP |
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WO 95/01356 |
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Jan 1995 |
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WO |
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WO 9501356 |
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Jan 1995 |
|
WO |
|
WO 97/05138 |
|
Feb 1997 |
|
WO |
|
WO97/05138 |
|
Feb 1997 |
|
WO |
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WO 98/52568 |
|
Nov 1998 |
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WO |
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WO98/52568 |
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Nov 1998 |
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WO |
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Other References
R Bertorelli et al., 37 Drug Development Research 65-72 (1996).
cited by examiner .
C. Zocchi et al., 117 British Journal of Pharmacology 1381-1386
(1996). cited by examiner .
P.G. Baraldi et al., 39 Journal of Medicinal Chemistry 1164-1171
(1996). cited by examiner .
Baraldi et al. "Pyrozolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine
Derivatives: Potent and Selective A2a Adenosine Antagonists", J.
Med. Chem, 39, pp. 1164-1171 (1996). cited by applicant .
Seela et al. "168. Synthesis of 2'-Deoxyriboforanosides of
8-Aza-7-deazaguanine and Related Pyrazolol[3,4-d] pyrimidines",
Helvetica Chicima Acta, vol. 69, pp. 1602-1613. (1986). cited by
applicant .
Ungerstedt et al. "Quantitative Recording of Rotational Behaviour
in Rats after 6-Hydroxy Dopamine Lesions of the Nigrostriatal
Dopahmine System", Brian Research, vol. 24, pp. 485-493 (1970).
cited by applicant .
Ungerstedt et al. "6-Hydorxy-Dopamine induced Degeneration of
Central Monoamine Neurons", European Journal of Pharmacology, 5,
pp. 107-110 (1968). cited by applicant .
Adami et al. "The Adenosine A Receptor Blocker, SCH 58261, IS
Effective over a 2-Week Treatment in Haloperiodol-Induced
Catalepsy", British Journal of Pharmacology, 126, pp. 283 (Mar.
1999). cited by applicant .
Baraldi et al, J. Med. Chem., 39 (1996), pp. 1164-1171. cited by
applicant .
Seela et al, Helvetica Chimca Acta, 69 (1986), pp. 1602-1613. cited
by applicant .
Ungerstedt et al, Brian Research, 24 (1970), pp. 485-493. cited by
applicant .
Ungerstedt, Eur. J. Pharmacol., 5 (1968), pp. 107-110. cited by
applicant .
Adami et al, Br. J. Pharmacol., 126, (Mar. 1999), 283P. cited by
applicant.
|
Primary Examiner: Wilson; James O
Assistant Examiner: Pagano; Alexander R
Attorney, Agent or Firm: Devlin; Gerard M. Fischer; H.
Eric
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATION
This application claims the benefit of U.S. Provisional Application
No. 60/207,143, filed May 26, 2000.
Claims
We claim:
1. A compound having the structural formula ##STR00306## or a
pharmaceutically acceptable salt thereof, wherein R is
R.sup.1-furanyl, R.sup.1-thienyl, R.sup.1-pyridyl, R.sup.1-pyridyl
N-oxide, R.sup.1-oxazolyl, R.sup.10-phenyl, R.sup.1-pyrrolyl or
C.sub.4-C.sub.6 cycloalkenyl; X is C.sub.2-C.sub.6 alkylene or
--C(O)CH.sub.2--; Y is --N(R.sup.2)CH.sub.2CH.sub.2N(R.sup.3)--,
--OCH.sub.2CH.sub.2N(R.sup.2)--, .[.--O--,.]. --S--, --CH.sub.2S--,
--(CH.sub.2).sub.2--NH--, or ##STR00307## and Z is R.sup.5-phenyl,
R.sup.5-phenyl(C.sub.1-C.sub.6)alkyl, R.sup.5-heteroaryl,
diphenylmethyl, R.sup.6--C(O)--, R.sup.6--SO.sub.2--,
R.sup.6--OC(O)--, R.sup.7--N(R.sup.8)--C(O)--,
R.sup.7--N(R.sup.8)--C(S)--, ##STR00308## phenyl-CH(OH)--, or
phenyl-C(.dbd.NOR.sup.2)--; or when Q is ##STR00309## Z is also
phenylamino or pyridylamino; or Z and Y together are ##STR00310##
R.sup.1 is 1 to 3 substituents independently selected from
hydrogen, C.sub.1-C.sub.6-alkyl, --CF.sub.3, halogen, --NO.sub.2,
--NR.sup.12R.sup.13, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkylthio, C.sub.1-C.sub.6 alkylsulfinyl, and C.sub.1-C.sub.6
alkylsulfonyl; R.sup.2 and R.sup.3 are independently selected from
the group consisting of hydrogen and C.sub.1-C.sub.6 alkyl; m and n
are independently 2-3; Q is ##STR00311## R.sup.1 is 1-2
substituents independently selected from the group consisting of
hydrogen and C.sub.1-C.sub.6alkyl, or two R.sup.4 substituents on
the same carbon can form .dbd.O; R.sup.5 is 1 to 5 substituents
independently selected from the group consisting of hydrogen,
halogen, C.sub.1-C.sub.6 alkyl, hydroxy, C.sub.1-C.sub.6 alkoxy,
--CN, di-((C.sub.1-C.sub.6)alkyl)amino, --CF.sub.3, --OCF.sub.3,
acetyl, --NO.sub.2, hydroxy(C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)-alkoxy(C.sub.1-C.sub.6)alkoxy,
di-((C.sub.1-C.sub.6)-alkoxy)(C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)-alkoxy(C.sub.1-C.sub.6)alkoxy-(C.sub.1-C.sub.6)-alkoxy,
carboxy(C.sub.1-C.sub.6)-alkoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl(C.sub.1-C.sub.6)alkoxy,
(C.sub.3-C.sub.6)cycloalkyl(C.sub.1-C.sub.6)alkoxy,
di-((C.sub.1-C.sub.6)alkyl)amino(C.sub.1-C.sub.6)alkoxy,
morpholinyl, (C.sub.1-C.sub.6)alkyl-SO.sub.2-,
(C.sub.1-C.sub.6)alkyl-SO_-(C.sub.1-C.sub.6)alkoxy,
tetrahydropyranyloxy,
(C.sub.1-C.sub.6)alkylcarbonyl(C.sub.1-C.sub.6)-alkoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl,
(C.sub.1-C.sub.6)alkylcarbonyloxy(C.sub.1-C.sub.6)-alkoxy,
--SO.sub.2NH.sub.2, phenoxy, ##STR00312## or adjacent R.sup.5
substituents together are --O--CH.sub.2--O--,
--O--CH.sub.2CH.sub.2--O--, --O--CF.sub.2--O-- or
--O--CF.sub.2CF.sub.2--O-- and form a ring with the carbon atoms to
which they are attached; R.sup.6 is (C.sub.1-C.sub.6)alkyl,
R.sup.5-phenyl, R.sup.5-phenyl(C.sub.1-C.sub.6)alkyl, thienyl,
pyridyl, (C.sub.3-C.sub.6)-cycloalkyl,
(C.sub.1-C.sub.6)alkyl-OC(O)-NH-(C.sub.1-C.sub.6)alkyl-,
di-((C.sub.1-C.sub.6)alkyl)aminomethyl, or ##STR00313## R.sup.7 is
(C.sub.1-C.sub.6)alkyl, R.sup.5-phenyl or
R.sup.5-phenyl(C.sub.1-C.sub.6)alkyl; R.sup.8 is hydrogen or
C.sub.1-C.sub.6 alkyl; or R.sup.7 and R.sup.8 together are
--(CH.sub.2).sub.p--A--(CH.sub.2).sub.q, wherein p and q are
independently 2 or 3 and A is a bond, --CH.sub.2--, --S-- or --O--,
and form a ring with the nitrogen to which they are attached;
R.sup.9 is 1-2 groups independently selected from hydrogen,
C.sub.1-C.sub.6 alkyl, hydroxy, C.sub.1-C.sub.6 alkoxy, halogen,
--CF.sub.3 and (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkoxy;
R.sup.10 is 1 to 5 substituents independently selected from the
group consisting of hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
hydroxy, C.sub.1-C.sub.6 alkoxy, --CN, --NH.sub.2,
C.sub.1-C.sub.6alkylamino, di-((C.sub.1-C.sub.6)alkyl)amino,
--CF.sub.3, --OCF.sub.3 and --S(O).sub.0-2(C.sub.1-C.sub.6)alkyl;
R.sup.11 is H, C.sub.1-C.sub.6 alkyl, phenyl, benzyl,
C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6
alkoxy(C.sub.1-C.sub.6)alkyl,
di-((C.sub.1-C.sub.6)alkyl)amino(C.sub.1-C.sub.6)alkyl,
pyrrolidinyl(C.sub.1-C.sub.6)alkyl or
piperidino(C.sub.1-C.sub.6)alkyl; R.sup.12 is H or C.sub.1-C.sub.6
alkyl; and R.sup.13 is (C.sub.1-C.sub.6)alkyl-C(O)- or
(C.sub.1-C.sub.6)alkyl-SO.sub.2--; wherein heteroaryl is a single
ring or benzofused heteroaromatic group, or an N-oxide thereof, of
5 to 10 atoms comprised of 2 to 9 carbon atoms and 1 to 4
heteroatoms independently selected from the group consisting of N,
O and S, provided that the rings do not include adjacent oxygen
atoms, adjacent sulfur atoms, or adjacent oxygen and sulfur
atoms.
2. A compound of claim 1 wherein R is R.sup.1-furanyl.
3. A compound of claim 1 wherein X is C.sub.2-C.sub.6 alkylene.
4. A compound of claim 1 wherein Y is ##STR00314##
5. A compound of claim 4 wherein Q is ##STR00315##
6. A compound of claim 5 wherein m and n are each 2, and R.sup.4 is
H.
7. A compound of claim 1 wherein Z is R.sup.5-phenyl,
R.sup.5-heteroaryl, R.sup.6--C(O)-- or R.sup.6--SO.sub.2--.
8. A compound of claim 7 wherein R.sup.5 is H, halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy(C.sub.1-C.sub.6)alkoxy or
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkoxy, or R.sup.6 is
R.sup.5-phenyl.
9. A compound of claim 1 wherein R is R.sup.1-furanyl, X is
C.sub.2-C.sub.6 alkylene, Y is ##STR00316## Q is ##STR00317## m and
n are each 2, R.sup.4 is H, Z is R.sup.5-phenyl,
R.sup.5-heteroaryl, R.sup.6--C(O)-- or R.sup.6--SO.sub.2--, R.sup.5
is H, halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy(C.sub.1-C.sub.6)alkoxy or (C.sub.1-C.sub.6)alkoxy
(C.sub.1-C.sub.6)alkoxy, and R.sup.6 is R.sup.5-phenyl.
10. A compound of claim 1 selected from the group consisting of
compounds of the formula ##STR00318## wherein R and Z--Y are as
defined in the following table: TABLE-US-00016 Z--Y-- R
##STR00319## ##STR00320## ##STR00321## ##STR00322## ##STR00323##
##STR00324## ##STR00325## ##STR00326## ##STR00327## ##STR00328##
##STR00329## ##STR00330## ##STR00331## ##STR00332## ##STR00333##
##STR00334## ##STR00335## ##STR00336## ##STR00337## ##STR00338##
##STR00339## ##STR00340## ##STR00341## ##STR00342##
11. A compound of claim 1 wherein Z is R.sup.5-heteroaryl and
heteroaryl is selected from the group consisting of pyridyl,
oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl,
imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazolyl,
thiadiazolyl, pyrazinyl, pyrimidyl, pyridazinyl, triazolyl,
indolyl, quinolyl, isoquinolyl, phthalazinyl, benzothienyl,
benzimidazolyl, benzofuranyl, benzoxazolyl and benzofurazanyl, or
an N-oxide thereof.
12. A compound of claim 11 wherein heteroaryl is selected from the
group consisting of pyridyl, pyridyl N-oxide, thiazolyl, pyrazinyl,
pyrimidyl, quinolyl and benzimidazolyl.
13. The compound having the structure ##STR00343##
14. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of claim 1 in a pharmaceutically
acceptable carrier.
15. A method of treating central nervous system diseases or stroke,
comprising administering an effective amount of a compound of
.[.formula I.]. .Iadd.claim 1, or a pharmaceutically acceptable
salt thereof, .Iaddend.to a mammal in need of such treatment.
16. A method of claim 15 for treating depression, cognitive
diseases and neurodegenerative diseases.
17. A method of claim 16 for treating Parkinson's disease, senile
dementia or psychoses of organic origin.
.Iadd.18. A pharmaceutical composition of claim 14 wherein said
compound has the structure: ##STR00344## or a pharmaceutically
acceptable salt thereof..Iaddend.
.Iadd.19. The method of claim 15 wherein said compound, or
pharmaceutically acceptable salt thereof, is a compound having the
structure: ##STR00345## or a pharmaceutically acceptable salt
thereof..Iaddend.
.Iadd.20. The method of claim 19 wherein said central nervous
system disease is Parkinson's disease, senile dementia, or
psychoses of organic origin..Iaddend.
.Iadd.21. A pharmaceutically acceptable salt of a compound having
the structure: ##STR00346## .Iaddend.
Description
BACKGROUND
The present invention relates to substituted
5-amino-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine adenosine
A.sub.2a receptor antagonists, the use of said compounds in the
treatment of central nervous system diseases, in particular
Parkinson's disease, and to pharmaceutical compositions comprising
said compounds. The invention also relates to a process for
preparing
5-amino-2-(substituted)pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidines,
intermediates useful in preparing the claimed compounds.
Adenosine is known to be an endogenous modulator of a number of
physiological functions. At the cardiovascular system level,
adenosine is a strong vasodilator and a cardiac depressor. On the
central nervous system, adenosine induces sedative, anxiolytic and
antiepileptic effects. On the respiratory system, adenosine induces
bronchoconstriction. At the kidney level, it exerts a biphasic
action, inducing vasoconstriction at low concentrations and
vasodilation at high doses. Adenosine acts as a lipolysis inhibitor
on fat cells and as an antiaggregant on platelets.
Adenosine action is mediated by the interaction with different
membrane specific receptors which belong to the family of receptors
coupled with G proteins. Biochemical and pharmacological studies,
together with advances in molecular biology, have allowed the
identification of at least four subtypes of adenosine receptors:
A.sub.1, A.sub.2a, A.sub.2b and A.sub.3. A.sub.1 and A.sub.3 are
high-affinity, inhibiting the activity of the enzyme adenylate
cyclase, and A.sub.2a and A.sub.2b, are low-affinity, stimulating
the activity of the same enzyme. Analogs of adenosine able to
interact as antagonists with the A.sub.1, A.sub.2a, A.sub.2b and
A.sub.3 receptors have also been identified.
Selective antagonists for the A.sub.2a receptor are of
pharmacological interest because of their reduced level of side
affects. In the central nervous system, A.sub.2a antagonists can
have antidepressant properties and stimulate cognitive functions.
Moreover, data has shown that A.sub.2a receptors are present in
high density in the basal ganglia, known to be important in the
control of movement. Hence, A.sub.2a antagonists can improve motor
impairment due to neurodegenerative diseases such as Parkinson's
disease, senile dementia as in Alzheimer's disease, and psychoses
of organic origin.
Some xanthine-related compounds have been found to be A.sub.1
receptor selective antagonists, and xanthine and non-xanthine
compounds have been found to have high A.sub.2a affinity with
varying degrees of A.sub.2a vs. A.sub.1 selectivity.
Triazolo-pyrimidine adenosine A.sub.2a receptor antagonists with
different substitution at the 7-position have been disclosed
previously, for example in WO 95/01356; U.S. Pat. No. 5,565,460; WO
97/05138; and WO 98/52568.
SUMMARY OF THE INVENTION
The present invention relates to compounds having the structural
formula I
##STR00004## or a pharmaceutically acceptable salt thereof,
wherein
R is R.sup.1-furanyl, R.sup.1-pyridyl, R.sup.1-pyridyl N-oxide,
R.sup.1-oxazolyl, R.sup.10-phenyl, R.sup.1-pyrrolyl or
C.sub.4-C.sub.6 cycloalkenyl;
X is C.sub.2-C.sub.6 alkylene or --C(O)CH.sub.2--;
Y is --N(R.sup.2)CH.sub.2CH.sub.2N(R.sup.3)--,
--OCH.sub.2CH.sub.2N(R.sup.2)--, --O--, --S--, --CH.sub.2S--,
--(CH.sub.2).sub.2--NH--, or
##STR00005## and
Z is R.sup.5-phenyl, R.sup.5-phenyl(C.sub.1-C.sub.6)alkyl,
R.sup.5-heteroaryl, diphenylmethyl, R.sup.6--C(O)--,
R.sup.6--SO.sub.2--, R.sup.6--OC(O)--, R.sup.7--N(R.sup.8)--C(O)--,
R.sup.7--N(R.sup.8)--C(S)--,
##STR00006## phenyl--CH(OH)--, or phenyl-C(.dbd.NOR.sup.2)--; or
when Q is
##STR00007## Z is also phenylamino or pyridylamino; or
Z and Y together are
##STR00008##
R.sup.1 is 1 to 3 substituents independently selected from
hydrogen, C.sub.1-C.sub.6-alkyl, --CF.sub.3, halogen, --NO.sub.2,
--NR.sup.12R.sup.13, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkylthio, C.sub.1-C.sub.6 alkylsulfinyl, and C.sub.1-C.sub.6
alkylsulfonyl;
R.sup.2 and R.sup.3 are independently selected from the group
consisting of hydrogen and C.sub.1-C.sub.6 alkyl;
m and n are independently 2-3;
O is
##STR00009##
R.sup.4 is 1-2 substituents independently selected from the group
consisting of hydrogen and C.sub.1-C.sub.6alkyl, or two R.sup.4
substituents on the same carbon can form .dbd.O;
R.sup.3 is 1 to 5 substituents independently selected from the
group consisting of hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
hydroxy, C.sub.1-C.sub.6 alkoxy, --CN,
di-((C.sub.1-C.sub.6)alkyl)amino, --CF.sub.3, --OCF.sub.3, acetyl,
--NO.sub.2, hydroxy(C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)-alkoxy(C.sub.1-C.sub.6)alkoxy,
di-((C.sub.1-C.sub.6)-alkoxy) (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)-alkoxy(C.sub.1-C.sub.6)alkoxy-(C.sub.1-C.sub.6)-alkoxy,
carboxy(C.sub.1-C.sub.6)-alkoxy, (C.sub.1-C.sub.6)-alkoxycarbonyl
(C.sub.1-C.sub.6)alkoxy,
(C.sub.3-C.sub.6)cycloalkyl(C.sub.1-C.sub.6)alkoxy,
di((C.sub.1-C.sub.6)alkyl)amino(C.sub.1-C.sub.6)alkoxy,
morpholinyl, (C.sub.1-C.sub.6) alkyl-SO.sub.2--,
(C.sub.1-C.sub.6)alkyl-SO--(C.sub.1-C.sub.6)alkoxy,
tetrahydropyranyloxy,
(C.sub.1-C.sub.6)alkylcarbonyl(C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, (C.sub.1-C.sub.6)alkylcarbonyloxy
(C.sub.1-C.sub.6)-alkoxy, --SO.sub.2NH.sub.2, phenoxy,
##STR00010## or adjacent R.sup.5 substituents together are
--O--CH.sub.2--O--, --O--CH.sub.2CH.sub.2--O--, --O--CF.sub.2--O--
or --O--CF.sub.2CF.sub.2--O-- and form a ring with the carbon atoms
to which they are attached;
R.sup.6 is (C.sub.1-C.sub.6)alkyl, R.sup.5-phenyl,
R.sup.5-phenyl(C.sub.1-C.sub.6)alkyl, thienyl, pyridyl,
(C.sub.3-C.sub.6)-cycloalkyl, (C.sub.1-C.sub.6)alkyl-OC
(O)--NH--(C.sub.1-C.sub.6)alkyl-,
di((C.sub.1-C.sub.6)alkyl)aminomethyl, or
##STR00011##
R.sup.7 is (C.sub.1-C.sub.6)alkyl, R.sup.5-phenyl or
R.sup.5-phenyl(C.sub.1-C.sub.6)alkyl;
R.sup.8 is hydrogen or C.sub.1-C.sub.6 alkyl; or R.sup.7 and
R.sup.8 together are --(CH.sub.2).sub.p--A--(CH.sub.2).sub.q,
wherein p and q are independently 2 or 3 and A is a bond,
--CH.sub.2--, --S-- or --O--, and form a ring with the nitrogen to
which they are attached;
R.sup.9 is 1-2 groups independently selected from hydrogen,
C.sub.1-C.sub.6 alkyl, hydroxy, C.sub.1-C.sub.6 alkoxy, halogen,
--CF.sub.3 and (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkoxy;
R.sup.10 is 1 to 5 substituents independently selected from the
group consisting of hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
hydroxy, C.sub.1-C.sub.6 alkoxy, --CN, --NH.sub.2,
C.sub.1-C.sub.6alkylamino, di-((C.sub.1-C.sub.6)alkyl)amino,
--CF.sub.3, --OCF.sub.3 and
--S(O).sub.0-2(C.sub.1-C.sub.6)alkyl;
R.sup.11 is H, C.sub.1-C.sub.6 alkyl, phenyl, benzyl,
C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6
alkoxy(C.sub.1-C.sub.6)alkyl, di-((C.sub.1-C.sub.6)alkyl)amino
(C.sub.1-C.sub.6)alkyl, pyrrolidinyl(C.sub.1-C.sub.6)alkyl or
piperidino (C.sub.1-C.sub.6)alkyl;
R.sup.12 is H or C.sub.1-C.sub.6 alkyl; and
R.sup.13 is (C.sub.1-C.sub.6)alkyl-C(O)-- or
(C.sub.1-C.sub.6)alkyl-SO.sub.2--.
Preferred compounds of formula I are those wherein R is
R.sup.1-furanyl, R.sup.1-thienyl, R.sup.1-pyrrolyl or
R.sup.10-phenyl, more preferably R.sup.1-furanyl. R.sup.1 is
preferably hydrogen or halogen. Another group of preferred
compounds is that wherein X is alkylene, preferably ethylene. Y is
preferably
##STR00012## wherein Q is
##STR00013## with Q preferably being nitrogen. Preferably, m and n
are each 2, and R.sup.4 is H. A preferred definition for Z is
R.sup.5-phenyl, R.sup.5-heteroaryl, R.sup.6--C(O)-- or
R.sup.6--SO.sub.2--. R.sup.5 is preferably H, halogen, alkyl,
alkoxy, hydroxyalkoxy or alkoxyalkoxy. R.sup.6 is preferably
R.sup.5-phenyl.
Another aspect of the invention is a pharmaceutical composition
comprising a therapeutically effective amount of a compound of
formula I in a pharmaceutically acceptable carrier.
Yet another aspect of the invention is a method of treating central
nervous system diseases such as depression, cognitive diseases and
neurodegenerative diseases such as Parkinson's disease, senile
dementia or psychoses of organic origin, and stroke, comprising
administering a compound of formula I to a mammal in need of such
treatment. In particular, the invention is drawn to the method of
treating Parkinson's disease comprising administering a compound of
formula I to a mammal in need of such treatment.
Another aspect of the invention is a process for preparing
5-amino-2-(R-substituted)-pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidin-
es of formula II, which are intermediates useful in the preparation
of compounds of formula I. The process of preparing compounds of
formula II
##STR00014## wherein R is as defined above, comprises
(1) treating 2-amino-4,6-dihydroxypyrimidine
##STR00015## with POCl.sub.3 in dimethylformamide (DMF) to obtain
2-amino-4,6-dichloropyrimidine-5-carboxaldehyde
##STR00016##
(2) treating carboxaldehyde VII with a hydrazide of the formula
H.sub.2N--NH--C(O)--R, wherein R is defined above, to obtain
##STR00017##
(3) treating the intermediate of formula VII with hydrazine hydrate
to form a pyrazolo ring, thus obtaining the intermediate of formula
IX
##STR00018##
(4) forming the. desired compound of formula II by dehydrative
rearrangement.
A preferred aspect of the process is the dehydrative rearrangement
of the intermediate of formula IX to obtain the
5-amino-2-(R-substituted)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine
of formula II. Preferred embodiments of the process use 2-furoic
hydrazide or 2-thienoylhydrazide in step 2, thus preparing
compounds of formula II wherein R is 2-furyl or 2-thienyl.
Another aspect of the invention is a process for preparing
7-bromoalkyl-5-amino-2-(R-substituted)-pyrazolo[4,3-e]-1,2,4-triazolo-[1,-
5-c]pyrimidines of formula IIIa, which are intermediates useful in
the preparation of compounds of formula I. The process of preparing
compounds of formula IIIa
##STR00019## wherein R is as defined above, comprises
(1) treating a chloride of formula VIII
##STR00020## with a hydroxyalkyl hydrazine of the formula
IIO--(CH.sub.2).sub.r--NHNH.sub.2, wherein r is 2-6, to obtain
##STR00021##
(2) cyclizing the intermediate of formula X by dehydrative
rearrangement to obtain the tricyclic intermediate of formula
XI
##STR00022##
(3) converting the hydroxy compound of formula XI to the bromide of
formula IIIa.
Still another aspect of the invention is a method of treating
Parkinson's disease with a combination of a compound of formula I
and one or more agents known to be useful in the treatment of
Parkinson's disease, for example dopamine; a dopaminergic agonist;
an inhibitor of monoamine oxidase, type B (MAO-B); a DOPA
decarboxylase inhibitor (DCI); or a catechol-O-methyltransferase
(COMT) inhibitor.
Also claimed is a pharmaceutical composition comprising a compound
of formula I and one or more agents known to be useful in the
treatment of Parkinson's in a pharmaceutically acceptable
carrier.
DETAILED DESCRIPTION
As used herein, the term alkyl includes straight or branched
chains. Alkylene, referring to a divalent alkyl group, similarly
refers to straight or branched chains. Cycloalkylene refers to a
divalent cycloalkyl group. Cycloalkenyl refers to a C.sub.4-C.sub.6
cycloalkyl ring comprising one double bond.
Heteroaryl means a single ring, bicyclic or benzofused
heteroaromatic group of 5 to 10 atoms comprised of 2 to 9 carbon
atoms and 1 to 4 heteroatoms independently selected from the group
consisting of N, O and S, provided that the rings do not include
adjacent oxygen and/or sulfur atoms. N-oxides of the ring nitrogens
are also included. Examples of single-ring heteroaryl groups are
pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl,
thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl,
isothiazolyl, thiadiazolyl, pyrazinyl, pyrimidyl, pyridazinyl and
triazolyl. Examples of bicyclic heteroaryl groups are naphthyridyl
(e.g., 1, 5 or 1,7), imidazopyridyl, pyrido[2,3]imidazolyl,
pyridopyrimidinyl and 7-azaindolyl. Examples of benzo-fused
heteroaryl groups are indolyl, quinolyl, isoquinolyl, phthalazinyl,
benzothienyl (i.e., thionaphthenyl), benzimidazolyl, benzofuranyl,
benzoxazolyl and benzofurazanyl. All positional isomers are
contemplated, e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl.
R.sup.5-substituted heteroaryl refers to such groups wherein
substitutable ring carbon atoms have a substituent as defined
above.
Certain compounds of the invention may exist in different
stereoisomeric forms (e.g., enantiomers, diastereoisomers and
atropisomers). The invention contemplates all such stereoisomers
both in pure form and in mixture, including racemic mixtures.
Certain compounds will be acidic in nature, e.g. those compounds
which possess a carboxyl or phenolic hydroxyl group. These
compounds may form pharmaceutically acceptable salts. Examples of
such salts may include sodium, potassium, calcium, aluminum, gold
and silver salts. Also contemplated are salts formed with
pharmaceutically acceptable amines such as ammonia, alkyl amines,
hydroxyalkylamines, N-methylglucamine and the like.
Certain basic compounds also form pharmaceutically acceptable
salts, e.g., acid addition salts. For example, pyrido-nitrogen
atoms may form salts with strong acid, while compounds having basic
substituents such as amino groups also form salts with weaker
acids. Examples of suitable acids for salt formation are
hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic,
malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic,
methanesulfonic and other mineral and carboxylic acids well known
to those skilled in the art. The salts are prepared by contacting
the free base form with a sufficient amount of the desired acid to
produce a salt in the conventional manner. The free base forms may
be regenerated by treating the salt with a suitable dilute aqueous
base solution such as dilute aqueous NaOH, potassium carbonate,
ammonia and sodium bicarbonate. The free base forms differ from
their respective salt forms somewhat in certain physical
properties, such as solubility in polar solvents, but the acid and
base salts are otherwise equivalent to their respective free base
forms for purposes of the invention.
All such acid and base salts are intended to be pharmaceutically
acceptable salts within the scope of the invention and all acid and
base salts are considered equivalent to the free forms of the
corresponding compounds for purposes of the invention.
Compounds of formula I can be prepared by known methods from
starting materials either known in the art or prepared by methods
known in the art; see, for example, WO 95/01356 and J. Med. Chem.,
39 (1996) 1164-1171.
Preferably, the compounds of formula I are prepared by the methods
shown in the following reaction schemes. In Scheme 1, alkylation of
a 5-amino-pyrazolo[4,3-c]-[1,2,4]-triazolo[1,5-c]pyrimidine of
formula II is used to prepare compounds of formula I:
##STR00023##
Starting materials of formula II can be reacted with an alkyl diol
ditosylate and a base such as NaH in an inert solvent such as
dimethylformamide (DMF), or with a chloro-bromo- or dibromo-alkyl
compound under similar conditions, to obtain the alkyl-substituted
intermediate of formula II. The compound of formula III is then
reacted with an amine of the formula Z--Y--H in an inert solvent
such as DMF at an elevated temperature to obtain a compound of
formula Ia, i.e., a compound of formula I wherein X is
alkylene.
Alternatively, staring materials of formula II can be reacted with
a compound of formula Z--Y--X--Cl and a base such as NaH in an
inert solvent such as DMF to obtain a mixture of a 7-substituted
compound of formula I and the corresponding 8-substituted
compound.
To prepare compounds of formula I wherein Y is piperazinyl and Z is
R.sup.6--C(O)--, R.sup.6--SO.sub.2--, R.sup.6--OC(O)--,
R.sup.7--N(R.sup.8)--C(O)-- or R.sup.7--N(R.sup.8)--C(S)--, a
compound of formula I wherein Z--Y is
4-t-butoxycarbonyl-1-piperazinyl is deprotected, for example by
reaction with an acid such as HCl. The resultant free piperazinyl
compound, IV, is treated according to procedures well known in the
art to obtain the desired compounds. The following Scheme 2
summarizes such procedures:
##STR00024##
Another method for preparing compounds of formula I is shown in
Scheme 3:
##STR00025##
In this procedure, chloropyrazolo-pyrimidine V is reacted with a
compound of formula Z--Y--X--Cl in a manner similar to the
alkylation procedure of Scheme 1, and the resultant intermediate is
reacted with a hydrazide of formula H.sub.2N--NH--C(O)--R (or with
hydrazine hydrate, followed by a compound of formula Cl--C(O)--R).
The resultant hydrazide undergoes dehydrative rearrangement, e.g.,
by treatment with N,O-bis-(trimethylsilyl)acetamide (BSA) or a
combination of BSA and hexamethyldisilazane (HMDS) and at elevated
temperatures.
Starting materials are known or can be prepared by processes known
in the art. However, compounds of formula II are preferably
prepared by the novel process disclosed above and described in
further detail here.
In the first step of the process, 2-amino-4,6-dihydroxypyrimidine
(VI) is converted to the corresponding
4,6-dichloro-5-carboxaldehyde by treatment with POCl.sub.3 or
SOCl.sub.2 in DMF as described in Helv. Chim. Acta, 69 (1986),
1602-1613. The reaction is carried out at an elevated temperature,
preferably about 100.degree. C., for 2 to 8 hours, preferably about
5 hours.
In the second step, 2-amino-4,6-dichloropyrimidine-5-carboxaldehyde
(VII) is treated with a hydrazide of the formula
H.sub.2N--NH--C(O)--R, wherein R is as defined above, to obtain the
compound of formula VIII; the compound of formula VI and the
hydrazide are used in a molar ratio of approximately 1:1, with a
slight excess of the hydrazide being preferred. The reaction is
carried out at room temperature or up to about 80.degree. C. in a
solvent such as CH.sub.3CN or DMF. The reaction time is about 16
hours (e.g., overnight).
In the third step, the compound of formula VIII is heated at
60-100.degree. C. with 1-5 equivalents of hydrazine hydrate in a
solvent such as CH.sub.3CN or DMF for 1-24 hours to obtain the
compound of formula IX.
In the last step, the compound of formula IX undergoes dehydrative
rearrangement by treatment with a mixture of HMDS and BSA or with
BSA alone. The reaction is carried out at elevated temperatures,
preferably about 120.degree. C., for about 16 hours (e.g.,
overnight)
After each step of the process, the crude material is purified by
conventional methods, e.g., extraction and/or
recrystallization.
Compared to previously published methods for preparing the
intermediate of formula II, this method proceeds in fewer steps,
under milder reaction conditions and with much higher yield.
The compounds of formulas V and VII are known (Helv. Chim. Acta, 69
(1986), 1602-1613).
Another method for preparing compounds of formula I is illustrated
in the following Scheme 4.
##STR00026##
Chloride VIII is treated with a hydroxyalkyl-hydrazine in an inert
solvent such as ethanol at temperatures from ambient to 100.degree.
C. to furnish derivative X. This is subjected to dehydrative
cyclization, similarly to IX, such as with BSA, to provide
tricyclic XI. Tricyclic XI is then converted to bromide IIIa with
PBr.sub.3 at elevated temperature from 80.degree. C. to 150.degree.
C. for 1 to 24 hours. Intermediate XI can also be converted into
the tosylate analogous to IIIa by toluenesulfonyl chloride and
base. Bromide IIIa is converted to compounds of formula I as
described above for III.
Another method for preparing compounds of formula I is illustrated
in the following Scheme 5:
##STR00027##
In analogy to Scheme 1, chloride V is converted into alkylated
compound XII, and this is further reacted with carbazate XIV, where
R' is preferably t-butyl or benzyl, to obtain derivative XIII. A
solvent such as DMF may be employed at a temperature of
60-120.degree. C. This is then reacted as in Scheme 1 to furnish
XV. The R' group is next removed, such as removal of a t-butyl
group with HCl or TFA, furnishing hydrazine XVI. Acylation of XVI
furnishes XVII, which is subjected to dehydrative cyclization as
described above to provide desired Ia. Alternatively, XII may be
reacted with a hydrazide XVIII to obtain XIX, which can be
converted to XVII analogously to preparation of XV.
Using the above procedures, the following compounds were
prepared.
Preparation 1
##STR00028##
Step 1: Stir POCl.sub.3 (84 ml, 0.9 mol) and chill to 5-10.degree.
C. while adding DMF (17.8 ml, 0.23 mol) drop-wise. Allow the
mixture to warm to room temperature (RT) and add
2-amino-4,6-dihydroxypyrimidine VI (14 g, 0.11 mol) portion-wise.
Heat at 100.degree. C. for 5 h. Strip off excess POCl.sub.3 under
vacuum, pour the residue into ice water, and stir overnight.
Collect solids by filtration and recrystallize the dried material
from a filtered ethyl acetate (EtOAc) solution to give the
aldehyde, VII, m.p. 230.degree. (dec). Mass spectrum: M+=192. PMR
(DMSO): .delta. 8.6(.delta., 2H); .delta. 10.1(s,1H).
Step 2: Stir a mixture of the product of Step 1 (0.38 g, 2 mmol)
and 2-furoic hydrazide (0.31 g, 2.5 mmol) in CH.sub.3CN (50 ml)
containing N,N-diisopropylethylamine (0.44 ml, 2.5 mmol) overnight
at RT. Solvent strip the reaction mixture, and partition the
residue between EtOAc and water. Dry the organic layer over
MgSO.sub.4, remove the solvent, and recrystallize the residue from
CH.sub.3CN to give the desired compound VIII. Mass spectrum:
MH+=282.
Step 3: Add hydrazine hydrate (75 mg, 1.5 mmol) to a hot CH.sub.3CN
solution of the product of Step 2 (0.14 g, 0.5 mmol). Reflux 1 h.
Cool to RT and collect the yellow product IX. Mass spectrum:
MH+=260.
Step 4: Heat the product of Step 3 (5.4 g, 0.021 mol) in a mixture
of hexamethyl-disilazine (100 ml) and N,O-bis (trimethylsilyl)
acetamide (35 ml) at 120.degree. C. overnight. Remove volatiles
under vacuum and slurry the residue in hot water to give a solid
precipitate. Recrystallize from 80% aqueous acetic acid to give the
title compound.
M.P.>300.degree. C. Mass spectrum: MH+=242.
Preparation 2
##STR00029##
Combine the product of Preparation 1 (6.0 g, 25 mmol), ethylene
glycol ditosylate (11.1 g, 30 mmol), and NaH (60% in oil,1.19 g, 30
mmol) in dry DMF (30 ml). Stir under N.sub.2 for 24 h and filter to
obtain the title compound as a cream solid (PMR in DMSO:
.delta.4.47+4.51 triplets, 8.03 s). Isolate additional material by
chromatography of the filtrate.
Preparation 3
##STR00030##
In a similar manner to Preparation 1, but employing
2-thienoylhydrazide, prepare the title compound as a yellow solid,
mass spectrum: MH+=258.
Preparation 4
##STR00031##
In a similar manner to Preparation 2, but using the product of
Preparation 3, prepare the title compound as a yellow solid, PMR
(DMSO) .delta. 4.49+4.54 triplets, 8.05 s.
Preparation 5
Arylpiperazines
1-(2,4-Difluorophenyl)piperazine is prepared from
2,4-difluorobromobenzcne. To the bromide (8.0 g, 41.4 mmol),
piperazine (21.4 g, 249 mmol), sodium t-butoxide (5.6 g, 58 mmol)
and BINAP (1.55 g, 2.5 mmol) in toluene (20 ml), add
Pd.sub.2(dba).sub.3 (0.477 g, 0.83 mmol). Heat the mixture at
110.degree. C. under N.sub.2 for 20 h. Allow to cool and extract
with 1N HCl. Basify the extract with NaOH to pH=10, extract with
CH.sub.2Cl.sub.2, dry and concentrate to obtain the title compound
as a brown oil.
In a similar fashion, prepare the following arylpiperazines (Me is
methyl):
##STR00032## ##STR00033## ##STR00034## ##STR00035## ##STR00036##
##STR00037##
1-(5-Ethyl-2-pyrimidinyl)piperazine is prepared from
2-chloro-5-ethylpyrimidine. Heat the chloride (2.0 g, 14 mmol) and
piperazine (3.0 g, 35 mmol) in EtOH (70 ml) at 90.degree. C. for 2
h in a sealed vessel. Concentrate and partition between
CH.sub.2Cl.sub.2 and 2N NaOH. Dry the organic with MgSO.sub.4 and
concentrate. Chromatograph the crude product on silica
(CH.sub.2Cl.sub.2--CH.sub.3OH) to obtain the piperazine as a yellow
oil.
In a similar fashion, prepare the following piperazines from the
appropriate chloride:
##STR00038##
1-(4-Cyano-2-fluorophenyl)piperazine is prepared from
3,4-difluorobenzonitrile. Heat the nitrile (2.0 g, 14.4 mmol),
piperazine (6.2 g, 72 mmol) and K.sub.2CO.sub.3 (2.4 g, 17 mmol) in
toluene (10 ml) at reflux for 22 h. Allow to cool, and extract with
1N HCl. Basify with NaOH to pH=10. Extract with CH.sub.2Cl.sub.2
and wash with water and then brine. Dry the organic with MgSO.sub.4
and concentrate to give the piperazine as a white solid.
In a similar fashion, prepare the following piperazines from the
appropriate fluoride (Et is ethyl):
##STR00039##
1-(4-(2-Methoxyethoxy)phenyl)piperazine is prepared from
4-(4-hydroxy-phenyl)-1-acetylpiperazine. To NaH (60% in mineral
oil, 0.79 g, 20 mmol) in DMF (25 ml) add the phenol (3.0 g, 13.6
mmol), followed by 2-bromoethyl methyl ether (2.27 g, 16.3 mmol).
Stir at RT 18 h, concentrate, and partition between EtOAc and 5%
citric acid. Wash the organic with 1N NaOH, then brine. Dry over
MgSO.sub.4, and concentrate to obtain the alkylated product as a
white solid. Heat this material (2.2 g, 7.9 mmol) in 6N HCl (30 ml)
at reflux for 1 h. Allow to cool and basify to pH=10 with NaOH.
Extract with CH.sub.2Cl.sub.2 and wash with water and then brine.
Dry the organic with MgSO.sub.4 and concentrate to give the
piperazine as a yellow oil.
In a similar fashion (except basic hydrolysis is employed for the
cyclopropyl-methyl ether) prepare the following piperazines:
##STR00040##
4-(2-Methylaminoethoxy)fluorobenzene is prepared from
4-(2-bromo-ethoxy)-fluorobenzene. Combine the bromide (1.0 g, 4.6
mmol) in CH.sub.3OH (5 ml) with CH.sub.3NH.sub.2 in CH.sub.2OH (2M,
46 ml, 92 mmol) in a sealed vessel. Heat at 60.degree. C. for 18 h,
concentrate, and partition between EtOAc and sat, NaHCO.sub.3. Wash
the organic with brine, dry with MgSO.sub.4, and concentrate to
obtain the amine as a yellow oil.
N-methyl-2-(4-(2-methoxyethoxy)phenoxy)ethylamine was prepared in
two steps. Combine 4-(2-methoxyethoxy)phenol (1.68 g, 10.0 mmol),
1,2-dibromoethane (16.9 g, 90 mmol), and K.sub.2CO.sub.3 (2.76 g,
20 mmol) in CH.sub.3CN (20 ml) and DMF (10 ml). Heat at reflux 22
h, allow to cool, filter, and partition between ether (Et.sub.2O)
and 1N NaOH. Wash with brine, dry over MgSO.sub.4, and concentrate
to provide the bromoethyl ether as beige solid. Combine this (0.97
g, 3.5 mmol) with 2M CH.sub.3NH.sub.2/CH.sub.3OH (35 ml). Heat in a
sealed tube (65.degree. C., 18 h), concentrate, and partition
between Et.sub.2O and 1N NaHCO.sub.3. Wash with brine, dry
MgSO.sub.4, and concentrate to provide the amine as an orange
oil.
1-Phenyl-2-piperazinone is prepared from
4-benzyloxycarbonyl-1-phenyl-2-piperazinone. Combine this material
(1.61 g, 5.2 mmol) with 10% Pd/C (0.4 g) in EtOH (50 ml) and 1N HCl
(6 ml). Hydrogenate at 45 psi for 2 h and filter. Concentrate and
chromatograph the residue on silica (eluting with
CH.sub.2Cl.sub.2:CH.sub.3OH:NH.sub.4OH) to obtain the piperazinone
as a cream solid.
Preparation 6
##STR00041##
Step 1: Dissolve the product of Preparation 1, Step 2 (0.56 g, 2.0
mmol) in hot CH.sub.3CN (200 ml). Add 2-hydroxyethylhydrazine (0.51
g, 6.0 mmol). Heat at reflux 2 h and concentrate. Treat with 25 ml
water and stir to give a solid. Collect and dry to give the
alcohol, MS: m/e=304 (M+1).
Step 2: Heat the product of Step 1 (0.10 g, 0.33 mmol) in BSA (10
ml) for 4 h at 115.degree. C. Concentrate in vacuo and warm with
aqueous CH.sub.3OH. Collect and dry to give the cyclization
product, MS: m/e=286 (M+1).
Step 3: Combine the product of Step 2 (0.285 g, 1.0 mmol) and
PBr.sub.3 (2.0 ml, 21 mmol). Heat at 145.degree. C. for 2 h, cool,
and pour onto ice. Filter and dry the solid. Recrystallize from
CH.sub.3OH to obtain the title compound, MS: m/e=348+350 (M+1).
Preparation 7
##STR00042##
Combine 5-bromo-2-furoic acid (0.50 g, 2.6 mmol) and NaHCO.sub.3
(0.44 g, 5.2 mmol) in hexane (6 ml) and water (5.2 ml). Add
Selectfluor.RTM. (0.98 g, 2.8 mmol) and stir 2 h. Separate the
hexane layer and dry over MgSO.sub.4 to provide a solution of
2-bromo-5-fluorofuran. Dilute with THF (6 ml) and cool to
-78.degree. C. Add 2.5M n-BuLi/hexane (4.2 ml, 11 mmol). Stir 10
min., add excess dry ice, and stir 1 h additional. Treat with 1N
HCl, extract with CH.sub.2Cl.sub.2, and dry over MgSO.sub.4.
Concentrate and dry to obtain the title compound as a white solid,
PMR (CDCl.sub.3) .delta.6.70+7.28.
EXAMPLE 1
##STR00043##
Combine the tosylate of Preparation 2 (0.55 g, 1.25 mmol) and
1-(2,4-difluorophenyl)piperazine (0.50 g, 2.5 mmol) in DMF (7 ml)
and heat at 80.degree. C. for 20 h. Concentrate and purify by flash
column chromatography (CH.sub.2Cl.sub.2, CH.sub.3OH+NH.sub.3) to
obtain the title compound as a cream solid, mass spectrum m/e=466
(M+H).
In similar fashion, prepare the following compounds:
TABLE-US-00001 ##STR00044## Ex- MS, am- [M + 1] ple Z--Y-- m/e 1-2
##STR00045## 430 1-3 ##STR00046## 498, 500, 502 1-4 ##STR00047##
498 1-5 ##STR00048## 444 1-6 ##STR00049## 431 1-7 ##STR00050## 460
1-8 ##STR00051## 448 1-9 ##STR00052## 404 1-10 ##STR00053## 520
1-11 ##STR00054## 498 1-12 ##STR00055## 532, 534 1-13 ##STR00056##
478, 480 1-14 ##STR00057## 494, 496 1-15 ##STR00058## 444 1-16
##STR00059## 478, 480 1-17 ##STR00060## 464, 466 1-18 ##STR00061##
432 1-19 ##STR00062## 468 1-20 ##STR00063## 431 1-21 ##STR00064##
472 1-22 ##STR00065## 508, 510 1-23 ##STR00066## 490 1-24
##STR00067## 490 1-25 ##STR00068## 445 1-26 ##STR00069## 460 1-27
##STR00070## 455 1-28 ##STR00071## 533, 535 1-29 ##STR00072## 437
1-30 ##STR00073## 481 1-31 ##STR00074## 498, 500, 502 1-32
##STR00075## 448 1-33 ##STR00076## 432 1-34 ##STR00077## 444 1-35
##STR00078## 474 1-36 ##STR00079## 498, 500, 502 1-37 ##STR00080##
470 1 -38 ##STR00081## 466 1-39 ##STR00082## 462 1-40 ##STR00083##
460 1-41 ##STR00084## 484 1-42 ##STR00085## 499 1 43 ##STR00086##
480 1-44 ##STR00087## 462 1-45 ##STR00088## 474 1-46 ##STR00089##
478 1-47 ##STR00090## 484 1-48 ##STR00091## 517 1-49 ##STR00092##
473 1-50 ##STR00093## 478 1-51 ##STR00094## 484 1-52 ##STR00095##
474 1-53 ##STR00096## 492 1-54 ##STR00097## 514 1-55 ##STR00098##
450 1-56 ##STR00099## 493 1-57 ##STR00100## 473 1-58 ##STR00101##
500 1-59 ##STR00102## 462 1-60 ##STR00103## 447 1-61 ##STR00104##
445 1-62 ##STR00105## 504 1-63 ##STR00106## 488 1-64 ##STR00107##
502 1-65 ##STR00108## 510 1-66 ##STR00109## 482, 484 1-67
##STR00110## 478 1-68 ##STR00111## 534 1-69 ##STR00112## 480 1-70
##STR00113## 496 1-71 ##STR00114## 496 1-72 ##STR00115## 444 1-73
##STR00116## 491 1-74 ##STR00117## 578 1-75 ##STR00118## 520 1-76
##STR00119## 522 1-77 ##STR00120## 560 1-78 ##STR00121## 500 1-79
##STR00122## 508 1-80 ##STR00123## 532 1-81 ##STR00124## 540 1-82
##STR00125## 468 1-83 ##STR00126## 490 1-84 ##STR00127## 572 1-85
##STR00128## 540 1-86 ##STR00129## 522 1-87 ##STR00130## 518 1-88
##STR00131## 529 1-89 ##STR00132## 574 1-90 ##STR00133## 572 1-91
##STR00134## 528 1-92 ##STR00135## 572 1-93 ##STR00136## 529 1-94
##STR00137## 522 1-95 ##STR00138## 548 1-96 ##STR00139## 548 1 -97
##STR00140## 437 1-98 ##STR00141## 518 1-99 ##STR00142## 532 1-100
##STR00143## 504 1-101 ##STR00144## 518 1-102 ##STR00145## 479, 501
1-103 ##STR00146## 401 1-104 ##STR00147## 454 1-105 ##STR00148##
507, 509 1-106 ##STR00149## 443 1-107 ##STR00150## 471 1-108
##STR00151## 457 1-109 ##STR00152## 401 1-110 ##STR00153## 440
1-111 ##STR00154## 485 1-112 ##STR00155## 429 1-113 ##STR00156##
499 1-114 ##STR00157## 461 1-115 ##STR00158## 446 1-116
##STR00159## 475 1-117 ##STR00160## 473 1-118 ##STR00161## 474
1-119 ##STR00162## 458 1-120 ##STR00163## 446 1-121 ##STR00164##
446 1-122 ##STR00165## 490 1-123 ##STR00166## 528, 530, 532
1-124 ##STR00167## 460 1-125 ##STR00168## 458 1-126 ##STR00169##
458 1-127 ##STR00170## 445 1-128 ##STR00171## 523, 525 1-129
##STR00172## 515 1-130 ##STR00173## 518 1-131 ##STR00174## 493
1-132 ##STR00175## 548 1-133 ##STR00176## 493 1-134 ##STR00177##
530 1-135 ##STR00178## 507 1-136 ##STR00179## 487 1-137
##STR00180## 531 1-138 ##STR00181## 487 1-139 ##STR00182## 531
1-140 ##STR00183## 494 1-141 ##STR00184## 419 1-142 ##STR00185##
461, 463 1-143 ##STR00186## 459 1-144 ##STR00187## 441 1-145
##STR00188## 457 1-146 ##STR00189## 431 1-147 ##STR00190## 407
EXAMPLE 2
##STR00191## Step 1:
##STR00192##
Combine the product of Preparation 1 (0.60 g, 2.5 mmol),
1,3-dibromopropane (0.60 g, 3.0 mmol), and NaH (60% in oil, 0.119
g, 3.0 mmol) in dry DMF (9 ml). Stir under N.sub.2 for 2 h,
concentrate and flash chromatograph to obtain the title compound as
a solid (PMR in CDCl.sub.3+CD.sub.3OD: .delta. 2.43 quint.,
3.38+4.51 triplets, 8.09 s), as well as 8-substituted isomer.
Step 2:
Combine the product of Step 1 (0.050 g, 0.14 mmol) and
1-phenylpiperazine (0.045 g, 0.28 mmol) in DMF (2 ml) and heat at
80.degree. C. for 4 h. Concentrate and purify by flash column
chromatography (CH.sub.2Cl.sub.2, CH.sub.3OH+NH.sub.3) to obtain
the title compound as a cream solid, mass spectrum m/e=443
(M+H).
Similarly prepare the following compounds:
TABLE-US-00002 ##STR00193## Example Z MS, [M + 1] m/e 2-2
##STR00194## 478, 480 2-3 ##STR00195## 474
EXAMPLE 3
The compound of Example 1-2 was also prepared by the following
procedure:
Combine the product of Preparation 1 (0.15 g, 0.62 mmol),
1-phenyl-4-(2-chloroethyl)piperazine (0.17 g, 0.75 mmol), and NaH
(60% in oil, 0.035 g, 0.87 mmol) in dry DMF (7 ml). Stir under
N.sub.2 for 48 h, add additional chloride (0.03 g) and NaH (0.005
g) and stir another 72 h. Concentrate and purify by flash column
chromatography (CH.sub.2Cl.sub.2, CH.sub.2OH+NH.sub.3) to obtain
the title compound as a cream solid, mass spectrum m/e=429
(M+H).
The compound of Example 1-3 is similarly prepared, as are the
following compounds:
TABLE-US-00003 ##STR00196## Example Z--Y--X-- MS, m/e 3-1
##STR00197## 454 3-2 ##STR00198## 444 3-3 ##STR00199## 429
EXAMPLE 4
##STR00200## Step 1:
##STR00201##
Combine 1-(2,4-difluorophenyl)piperazine (1.5 g, 7.6 mmol), ethyl
2-bromopropionate (1.65 g, 9.1 mmol) and DIPEA (1.1 g, 8.3 mmol) in
DMF (8 ml). Stir 4 h, concentrate, and partition between Et.sub.2O
and water. Wash with brine, dry (MgSO.sub.4), and concentrate to
obtain the ester as a yellow oil, NMR (CDCl.sub.3) consistent.
Step 2:
##STR00202##
To the product of Step 1 (2.15 g, 7.2 mmol) in THF (10 ml), add
LiAlH.sub.4 (1.0 M in THF, 4.4 ml, 4.4 mmol) dropwise. Heat at
60.degree. C. 1 h, add water (0.16 ml), 15% NaOH (0.16 ml), and
then water (0.49 ml). Filter and concentrate to obtain the alcohol
as a yellow oil, NMR (CDCl.sub.3) consistent.
Step 3:
##STR00203##
To the product of Step 2 (0.90 g, 3.5 mmol) in CH.sub.2Cl.sub.2 (10
ml) at 5.degree. C., add SOCl.sub.2 (0.38 ml, 5.3 mmol). Allow to
warm and stir 16 h. Concentrate and partition between
CH.sub.2Cl.sub.2 and 1N NaOH, wash with water, dry (MgSO.sub.4) and
concentrate to obtain the crude product as a yellow oil.
Step 4: Combine the product of Preparation 1 (0.20 g, 0.83 mmol),
the product of Step 3 (0.34 g, 1.2 mmol) and NaH (60% in oil, 0.040
g, 1.0 mmol) in dry DMF (5 ml). Heat at 60.degree. C. for 24 h, add
additional chloride (0.15 g) and NaH (0.02 g), and heat another 4
h. Concentrate and purify by flash column chromatography
(CH.sub.2Cl.sub.2, CH.sub.3OH+NH.sub.3) to obtain the title
compound as a yellow solid, mass spectrum m/e 479 (M+H).
Similarly, prepare the following:
##STR00204##
EXAMPLE 5
Using the procedure of Example 1, substituting the tosylate of
Preparation 4 for the tosylate of Preparation 2, prepare the
following compounds:
TABLE-US-00004 ##STR00205## Ex. Z MS, [M + 1] m/e 5-1 ##STR00206##
482 5-2 ##STR00207## 520 5-3 ##STR00208## 538
EXAMPLE 6
##STR00209##
Step 1: To a solution of the product of Example 3-1 (4.17 g, 9.2
mmol) in CH.sub.2Cl.sub.2 (500 ml), add anhydrous HCl (120 ml of
4.0 M dioxane solution) and stir 2 h. Concentrate to dryness under
vacuum and take up the residue in water. Make alkaline with aqueous
NaOH and collect the precipitated de-protected product. Mass
spectrum: MH+=354.
Step 2: Stir a mixture of the product of Step 1 (71 mg, 0.2 mmol)
and 4-methoxy-benzoyl chloride (51 mg, 0.3 mmol) in dry DMF (10 ml)
containing N,N-diisopropyl-ethylamine (52 mg, 0.4 mmol) for 6 h at
RT. Pour the solution into water and collect the precipitated title
compound. Mass spectrum: MH+=488.
In a similar fashion, prepare the following:
TABLE-US-00005 ##STR00210## Example Z-- MS, [M + 1] m/e 6-2
##STR00211## 502 6-3 ##STR00212## 396 6-4 ##STR00213## 594 6-5
##STR00214## 464 6-6 ##STR00215## 438 6-7 ##STR00216## 464 6-8
##STR00217## 459 6-9 ##STR00218## 472 6-10 ##STR00219## 452 6-11
##STR00220## 539 6-12 ##STR00221## 532 6-13 ##STR00222## 508 6-14
##STR00223## 551 6-15 ##STR00224## 439 6-16 ##STR00225## 492
EXAMPLE 7
##STR00226##
To a solution of the product of Example 6, Step 1 (53 mg, 0.15
mmol) in NMP (10 ml) add 4-chlorophenylisocyanate (25.3 mg, 0.165
mmol) at RT. Stir overnight, add an additional 25.3 mg of the
isocyanate, and stir 1 h to complete conversion of all starting
material. Pour into water and collect the precipitated title
compound. Mass spectrum: MH+=507.
In a similar fashion, prepare the following from the appropriate
isocyanate, isothiocyanate or carbamoyl chloride:
TABLE-US-00006 ##STR00227## Example Z-- MS, [M + 1] m/e 7-2
##STR00228## 517 7-3 ##STR00229## 451 7-4 ##STR00230## 453 7-5
##STR00231## 491 7-6 ##STR00232## 509 7-7 ##STR00233## 467
EXAMPLE 8
##STR00234##
Slurry the product of Example 6, Step 1 (53 mg, 0.15 mmol) in dry
DMF (20 ml) containing triethylamine (77 mg, 0.76 mmol); add
2,4-difluorobenzenesulfonyl chloride (37 .mu.l, 0.225 mmol). Stir
at RT 2 days. Pour into water and collect the precipitated title
compound. Mass spectrum: M+=529.
In a similar fashion, prepare the following:
TABLE-US-00007 ##STR00235## Example Z-- MS, [M + 1] m/e 8-2
##STR00236## 561, 563, 565 8-3 ##STR00237## 529 8-4 ##STR00238##
571, 573 8-5 ##STR00239## 511 8-6 ##STR00240## 554 8-7 ##STR00241##
524 8-8 ##STR00242## 446
EXAMPLE 9
##STR00243##
Add 4-methoxyphenyl chloroformate (56 mg, 0.3 mmol) to a slurry of
the product of Example 6, Step 1 (71 mg, 0.2 mmol) in warm DMF (25
ml) containing triethylamine (101 mg, 1.0 mmol). Stir the mixture
overnight at RT. Concentrate the solution to 1/3 its volume and
pour into water. Collect the precipitate, wash with water, and dry
in vacuo. Recrystallize from CH.sub.3OH/CH.sub.2Cl.sub.2 to give
the title compound. Mass spectrum: MH+=504.
EXAMPLE 10
##STR00244##
Step 1: Combine 1-bromo-2,4-difluorobenzene (1.00 g, 5.18 mmol),
N,N'-dimethyl-ethylenediamine (2.74 g, 31.1 mmol), NaO-t-Bu (0.70
g, 7.2 mmol), Pd(dba).sub.2 (0.060 g, 0.10 mmol) and (.+-.)-BINAP
(0.19 g, 0.31 mmol) in toluene (10 ml). Heat at 110.degree. for 18
h, allow to cool, and extract with 1N HCl. Basify the aqueous
solution with NaOH and extract with CH.sub.2Cl.sub.2. Dry,
concentrate, and purify by PLC to give
N-(2,4-difluoro-phenyl)-N,N'-dimethylethylenediamine.
Step 2: Combine the product of Preparation 2 (0.100 g, 0.23 mmol)
with the product of Step 1 (0.091 g, 0.46 mmol) in DMF (2 ml). Heat
at 80.degree. for 90 h, allow to cool, concentrate, and purify by
column chromatography to obtain the title compound as an oil, mass
spec m/e=467.
EXAMPLE 11
The compound of Example 1-2 was also prepared by the following
procedure.
Step 1:
##STR00245##
To a solution of the product of Preparation 1, Step 1, (768 mg, 4
mmol) in DMF (20 ml) add N,N-diisopropylethylamine (0.88 ml, 5
mmol), followed by hydrazine hydrate (0.2 ml, 4.1 mmol). The
solution warms and a solid precipitates which gradually dissolves
over 1 h. After stirring 3 h, concentrate the solution under vacuum
to about 1/3 its volume, and pour into water. Collect the
precipitate and recrystallize it from CH.sub.3OH to give the
chloropyrazolopyrimidine. Mass spectrum: MH+=170.
Step 2:
##STR00246##
To a stirred solution of 1-phenylpiperazine (6.5 g, 40 mmol) and
50% aqueous chloroacetaldehyde (6.4 ml, 48 mmol) in
CH.sub.2Cl.sub.2 (125 ml) at 5-10.degree. C. add, portionwise,
Na(OAc).sub.3BH (12.72 g, 60 mmol). When foaming ceases, allow the
mixture to warm to RT and stir for 3 h. Dilute with
CH.sub.2Cl.sub.2 (100 ml), and shake with 1N aq NaOH to bring pH
above 8. Wash organic layer with water and brine, dry over
MgSO.sub.4, and solvent strip. Chromatograph on silica and elute
with 1% CH.sub.3OH/CH.sub.2Cl.sub.2 to give the title compound.
Mass spectrum: MH+=225.
Step 3:
##STR00247##
To a slurry of 60% NaH (0.14 g, 3.5 mmol) in DMF (30 ml) at ice
bath temperature add, portionwise, the product of Step 1 (0.51 g, 3
mmol). When gas evolution ceases, add the product of Step 2. Stir
the resulting mixture at RT overnight. Filter off dark red
insoluble matter, and concentrate the filtrate to dryness under
vacuum. Triturate the gummy residue with CH.sub.3OH to give the
title compound as a light yellow solid. Mass spectrum: MH+=358.
The product of Step 3 was treated as described in Preparation 1,
Steps 2 and 4, to obtain the compound of Example 1-2.
EXAMPLE 12
##STR00248##
Step 1: To NaH (60% in oil, 142 mg, 3.5 mmol) in DMF (15 ml) add
the chloride of Example 11, Step 1 (500 mg, 2.9 mmol). Add to this
1-(2-chloroethyl)-4-(2,4-difluorophenyl) piperazine (846 mg, 3.5
mmol). Stir at RT 90 h and concentrate. Chromatograph to obtain the
desired compound as a white solid. PMR in DMSO: .delta.2.57 (4H,
s), 2.76 (2H, t), 2.85 (4H, s), 4.30 (2H, t), 7.0 (2H, m), 7.15
(1H, dxt), 7.26 (2H, s), 7.97(1H, s).
Step 2: Treat the chloride of Step 1 (37 mg, 0.095 mmol) in DMF (95
ml) with hydrazine hydrate (9.2 .mu.l, 0.19 mmol). After 4 h,
concentrate and chromatograph on PLC to obtain the hydrazine as a
brown oil. Mass spectrum: MH+=390.
Step 3: Treat the hydrazine from Step 2 (18 mg, 0.047 mmol) in DMF
(2 ml) with thiophene-2-carbonyl chloride (5.2 .mu.l, 0.047 mmol)
and DIPEA (12.2 .mu.l, 0.07 mmol). After 4 h, concentrate and
chromatograph on PLC to obtain the hydrazide as a yellow oil. Mass
spectrum: MH+=500.
Step 4: Heat the hydrazide from Step 3 (13 mg, 0.026 mmol) in
N,O-bis(trimethyl-silyl)acetamide (1 ml) for 2 h at 100.degree. C.
Concentrate and chromatograph on PLC to obtain the title compound
as a white solid. Mass spectrum: MH+=482.
The 1-(2-chloroethyl)-4-(2,4-difluorophenyl)piperazine employed in
this sequence is prepared in two steps. Add chloroacetyl chloride
(1.76 ml, 22.1 mmol) and N-methylmorpholine (2.65 ml, 24.1 mmol) to
1-(2,4-difluorophenyl)piperazine (3.98 g, 20.1 mmol) in
CH.sub.2Cl.sub.2 (15 ml) at 0.degree. C. Stir at RT 1 h,
concentrate, partition EtOAc-water, dry, and concentrate to obtain
the amide as a brown oil. To a 0.degree. C. solution of this (4.71
g, 17.1 mmol) in THF (25 ml) add dropwise
BH.sub.3.circle-solid.CH.sub.3S/THF (2M, 12.8 ml, 25.6 mmol). Stir
at RT overnight, quench with CH.sub.3OH, concentrate, and partition
with CH.sub.2Cl.sub.2-water. Dry and concentrate the organic layer.
Treat the crude product a second time with
BH.sub.3.circle-solid.CH.sub.3S/THF and work up as above to provide
the chloroethylpiperazine as a brown oil.
EXAMPLE 13
##STR00249##
Step 1: To NaH (2.14 g, 60% in oil, 53 mmol) in DMF (20 ml), add
the product of Example 11, Step 1 (7.55 g, 45 mmol). Add
1-bromo-2-chloroethane (14.8 ml, 178 mmol). Stir 1.5 h and
concentrate. Chromatograph to give the dichloride as a white
solid.
Step 2: In the product of Step 1 (3.7 g, 16 mmol) in DMF (20 ml)
add 1-butyl carbazate (2.53 g, 19 mmole). Heat at 80.degree. C. for
18 h and concentrate. Chromatograph to obtain the carbazate as a
while solid.
Step 3: To the product of Step 2 (3.16 g, 9.6 mmol) and KI (1.6 g,
9.6 mmol) in DMF (25 ml) add 1-(2,4-difluorophenyl)piperazine (3.82
g, 19 mmol). Heat at 90.degree. C. for 68 h and concentrate.
Chromatograph to obtain the piperazine as a brown solid.
Step 4: Dissolve the product of Step 3 (3.38 g, 6.9 mmol) in 1:1
CH.sub.3OH--CH.sub.2Cl.sub.2 (50 ml). Add 4M HCl in dioxane (20
ml). Stir 16 h and add aq. NH.sub.3 to pH 11-12. Concentrate and
chromatograph to obtain the hydrazine as a yellow solid.
Step 5: Combine the product of Step 4 (0.120 g, 0.31 mmol) with
5-bromo-2-furoic acid (0.071 g, 0.37 mmol) and HOBt.H.sub.2O (0.050
g, 0.37 mmol) in DMF (6 ml). Add EDCl (0.071 g, 0.37 mmol) and stir
1 h. Concentrate and chromatograph to obtain the hydrazide as a
yellow solid.
Step 6: Dissolve the product of Step 5 (0.163 g, 0.28 mmol) in
N,O-bis(trimethylsilyl) acetamide (6 ml). Heat at 120.degree. C.
for 16 h and pour into CH.sub.3OH. Concentrate and chromatograph to
obtain the title product as an off-white solid: MS m/e 544+546
(M+1).
Similarly prepare compounds of the following structure, wherein R
is as defined in the table:
TABLE-US-00008 ##STR00250## Example R MS m/e 13-2 ##STR00251## 480
13-3 ##STR00252## 500, 502 13-4 ##STR00253## 465 13-5 ##STR00254##
479 13-6 ##STR00255## 544, 546 13-7 ##STR00256## 466 13-8
##STR00257## 512 13-9 ##STR00258## 476 13-10 ##STR00259## 484
EXAMPLE 14
##STR00260##
Treat the product of Example 13, Step 4 (0.080 g, 0.20 mmol) with
nicotinoyl chloride hydrochloride (0.044 g, 0.25 mmol) and
diisopropylethylamine (0.086 ml, 0.49 mmol) in DMF (4 ml). Stir 2
h, concentrate and chromatograph to obtain the hydrazide as a white
solid.
Treat this material with BSA as in Example 13, Step 6 to obtain the
title compound as a white solid: MS m/e 477 (M+1).
Similarly prepare compounds of the following structure, wherein R
is as defined in the table:
TABLE-US-00009 ##STR00261## Example R MS, m/e 14-2 ##STR00262## 511
14-3 ##STR00263## 494
EXAMPLE 15
##STR00264##
Step 1: To the product of Example 13, Step 2 (3.54 g, 10.8 mmol)
and KI (1.79 g, 10.8 mmol) in DMF (35 ml) add
1-(4-(2-methoxyethoxy)phenyl)piperazine (5.1 g, 22 mmol). Heat at
90.degree. C. for 90 h and concentrate. Chromatograph to obtain the
piperazine as a brown solid.
Step 2: Treat the product of Step 1 with HCl as in Example 13, Step
4, to obtain the hydrazine as a yellow solid.
Step 3: Treat the product of Step 2 with 5-chloro-2-furoic acid as
in Example 13, Step 5, to obtain the hydrazide as a yellow
solid.
Step 4: Treat the product of Step 3 with BSA as in Example 13, Step
6. Chromatograph to obtain the title compound as a white solid, MS
m/e 538+540 (M+1).
Similarly prepare compounds of the following structure, wherein R
is as defined in the table:
TABLE-US-00010 ##STR00265## Example R MS, m/e 15-2 ##STR00266##
582, 584 15-3 ##STR00267## 532 15-4 ##STR00268## 550 15-5
##STR00269## 522 15-6 ##STR00270## 518
EXAMPLE 16
##STR00271##
Combine the product of Example 1-83 (0.080 g, 0.16 mmol) with
Ac.sub.2O (0.028 ml, 0.28 mmol) and 4-dimethylaminopyridine (0.004
g, 0.03 mmol) in DMF (5 ml). Stir 4 h, concentrate, and
chromatograph to obtain the acetate ester as a white solid, MS:
m/e=532 (M+1).
EXAMPLE 17
##STR00272##
Combine the product of Example 1-21 (0.100 g, 0.21 mmol) with
H.sub.2NHOH.circle-solid.HCl 0.029 g, 0.42 mmol) in 95% EtOH (9
ml). Add 10 drops conc. HCl, heat at reflux 5 h, add DMF (1.5 ml),
heat 18 h, allow to cool, and filter to obtain the oxime as a white
solid, MS: m/e=487 (M+1). Chromatograph the mother liquor to obtain
additional product.
Similarly prepare the methoxime, a white solid, MS: m/e=501
(M+1):
##STR00273##
EXAMPLE 18
##STR00274##
Step 1: To a solution of 4-bromophenethyl alcohol (0.600 g, 2.98
mmol) and 3-pyridinylboronic acid (0.734 g, 5.97 mmol) in toluene
(35 ml) and EtOH (9 ml), add a solution of K.sub.2CO.sub.3 (0.8826
g, 5.97 mmol) in H.sub.2O (16 ml) and
tetrakis(triphenyl-phosphine)palladium(0) (0.172 g, 0.149 mmol).
Heat in a sealed tube 18 h at 120.degree. C. and cool. Extract with
EtOAc, wash with brine, dry (K.sub.2CO.sub.3) and concentrate.
Chromatograph on silica (30-50% EtOAc/hexanes) to obtain the biaryl
alcohol.
Step 2: To the product of Step 1 (0.540 g, 2.71 mmol) in
CH.sub.2Cl.sub.2 (15 ml) at 0.degree. C. add mesyl chloride (0.35
ml, 3.52 mmol) and Et.sub.3N (0.57 ml, 4.00 mmol). Stir 2.5 h and
extract with CH.sub.2Cl.sub.2. Dry (Na.sub.2SO.sub.4) and
concentrate to obtain the mesylate.
Step 3: Add the product of Preparation 4 (0.347 g, 1.44 mmol) to
the mesylate of Step 2 (0.480 g, 1.73 mmol) in DMF (4.5 ml),
followed by NaH (60%. in oil, 0.082 g, 4.04 mmol). Stir 18 h and
extract with EtOAc. Wash with H.sub.2O dry (K.sub.2CO.sub.3) and
concentrate. Purify by PTLC (5% CH.sub.3OH/CH.sub.2Cl.sub.2,
developed twice) to obtain the title compound as a white solid, MS:
423 (M+1).
By the above method, prepare the following (Example 18-8 from
commercial biphenylethanol):
TABLE-US-00011 ##STR00275## Example Z--Y-- MS, m/e 18-2
##STR00276## 468 18-3 ##STR00277## 452 18-4 ##STR00278## 466 18-5
##STR00279## 506 18-6 ##STR00280## 453 18-7 ##STR00281## 423 18-8
##STR00282## 422 18-9 ##STR00283## 423
EXAMPLE 19
##STR00284##
Step 1: Combine 4-bromophenethyl alcohol (3.00 g, 14.9 mmol),
triethylamine (2.68 ml, 19.2 mmol), dimethylaminopyridine (0.180 g,
1.47 mmol) and t-butyidimethylsilyl chloride (2.45 g, 16.3 mmol) in
CH.sub.2Cl.sub.2 (75 ml). Stir 1 h, wash with H.sub.2O, dry
(K.sub.2CO.sub.3), and concentrate. Chromatograph on silica
(hexanes) to obtain the silyl ether.
Step 2: To the compound of Step 1 (0.300 g, 0.95 mmol) in dry
toluene (15 ml) add 2-(tri-butylstannyl)pyridine (1.05 g, 2.86
mmol) and tetrakis(triphenylphosphine)-palladium (0.11 g, 0.095
mmol). Flush with N.sub.2 and heat 16 h at 120.degree. C. Cool,
filter through Celite, and wash with NH.sub.4Cl, brine and then
water. Dry (K.sub.2CO.sub.3) and concentrate. Chromatograph on
silica (3-5% EtOAc/hexanes) to obtain the biaryl, MS 314 (M+1).
Step 3: Combine the biaryl of Step 2 (0.180 g, 0.57 mmol) and TBAF
(1.0 M in THF, 1.7 ml) in THF (5.7 ml). Stir 2 h, wash with
saturated NH.sub.4Cl, and extract with EtOAc. Wash with H.sub.2O
several times, dry (K.sub.2CO.sub.3) and concentrate to obtain the
alcohol. Steps 4 and 5: Conduct as in Example 18, Steps 2 and 3, to
obtain the title compound as a white solid, MS: 423 (M+1).
Similarly prepare the following compounds:
##STR00285##
EXAMPLE 20
##STR00286##
To the product of Example 18 (0.055 g, 0.13 mmol) in
CH.sub.2Cl.sub.2 (1.5 ml) at -78.degree. C. add m-CPBA (0.050 g,
0.29 mmol). Allow to warm, stir 5 h, and wash successively with
sat. Na.sub.2S.sub.2O.sub.3, 5% K.sub.2CO.sub.3, and H.sub.2O. Dry
(Na.sub.2SO.sub.4) and concentrate. Purify by PTLC (10%
CH.sub.3OH/CH.sub.2Cl.sub.2) to obtain the title compound, MS: 439
(M+1).
Similarly, oxidize the product of Example 18-2 at 0.degree. C. or
RT to produce the sulfoxide, MS: 484 (M+1), or the sulfone, MS: 500
(M+1).
##STR00287##
EXAMPLE 21
##STR00288##
Combine the product of Preparation 6 (0.104 g, 0.30 mmol),
4-methyl-benzenethiol (0.075 g, 0.60 mmol), and K.sub.2CO.sub.3
(0.091 g, 0.66 mmol) in DMF (20 ml). Heat at 80.degree. C. for 5 h
and concentrate. Partition between EtOAc and water, wash with
brine, dry over MgSO.sub.4 and concentrate. Recrystallize from
CH.sub.3OH to obtain the title compound, MS: m/e=392 (M+1).
Similarly prepare the following compounds:
TABLE-US-00012 ##STR00289## Example Z MS, m/e 21-2 ##STR00290## 408
21-3 ##STR00291## 426, 428 21-4 ##STR00292## 394 21-5 ##STR00293##
379
EXAMPLE 22
##STR00294##
Combine the product of Preparation 6 (0.11 g, 0.25 mmol),
3,4-dimethoxy-phenol (0.154 g, 1.0 mmol), and K.sub.2CO.sub.3
(0.138 g, 1.0 mmol) in DMF (5 ml). Heat at 90.degree. C. for 48 h
and concentrate. Partition between EtOAc and water, wash with 1 N
NaOH and then brine, dry over MgSO.sub.4, and concentrate.
Chromatograph on silica (1.5% CH.sub.3OH/CH.sub.2Cl.sub.2) to
obtain the title compound, MS: m/e=422 (M+1).
Similarly prepare the following compound, MS: m/e=454 (M+1).
##STR00295##
EXAMPLE 23
##STR00296##
Step 1: To NaH (60% in oil,1.32 g, 33 mmol) in DMF (25 ml) at
5.degree. C. add dropwise, with stirring, 3,4-dimethoxyphenol (4.77
g, 30 mmol). After 0.5 h, add 1,5-dibromo-pentane (20.7 g, 90
mmol). Stir 2 h and concentrate. Chromatograph on silica
(CH.sub.2Cl.sub.2) to obtain the monobromide, MS: m/e=303
(M+1).
Step 2: To NaH (60% in oil, 0.044 g, 1.1 mmol) in DMF (25 ml) at
5.degree. C. add the product of Preparation 1 (0.241 g, 1.1 mmol).
After 0.5 h, add the compound from Step 1. Allow to warm, stir 18
h, and concentrate. Partition between EtOAc and water, wash with 1N
NaOH and then brine, dry over MgSO.sub.4, and concentrate.
Chromatograph on silica (2% CH.sub.3OH/CH.sub.2Cl.sub.2) and
recrystallize the appropriate fraction from CH.sub.3CN to obtain
the title compound, MS: m/e=464 (M+1).
EXAMPLE 24
##STR00297##
Step 1: Combine 1,4-dioxa-8-azaspiro(4,5)decane (0.48 ml, 3.8 mmol)
with the product of Preparation 2 (0.66 g, 1.5 mmol) in DMF (10
ml). Heat at 90.degree. C. for 16 h, allow to cool, filter and wash
with CH.sub.3OH to give off-white solid, MS: m/e 411 (M+1).
Step 2: Heat the product of Step 1 (0.476 g, 1.16 mmol) in acetone
(10 ml) and 5% HCl (10 ml) at 100.degree. C. for 16 h. Cool,
neutralize with sat. NaHCO.sub.3, and extract with 10% CH.sub.3OH
in CH.sub.2Cl.sub.2. Dry (MgSO.sub.4), concentrate and
chromatograph on silica with CH.sub.3OH--CH.sub.2Cl.sub.2 to obtain
the ketone as a white powder, MS: m/e 367 (M+1).
Step 3: Combine the product of Step 2 (0.050 g, 0.13 mmol) with
O-methylhydroxyl-amine hydrochloride (0.033 g, 0.39 mmol) in
pyridine (3 ml). Stir for 16 h and concentrate. Partition between
NaHCO.sub.3 (sat.) and 5% CH.sub.3OH in CH.sub.2Cl.sub.2. Dry
(MgSO.sub.4), concentrate and chromatograph on silica with 5%
CH.sub.3OH--CH.sub.2Cl.sub.2 to obtain the title compound as a
white solid, MS: m/e 396 (M+1).
Similarly prepare the following compounds:
TABLE-US-00013 ##STR00298## Example R.sup.11 MS, m/e 24-2
--CH.sub.2CH.sub.3 410 24-3 --CH.sub.2CH.sub.2CH.sub.3 424 24-4
--CH.sub.2CHCH.sub.2 422 24-5 --C(CH.sub.3).sub.3 438 24-3
--C.sub.6H.sub.5 458 24-4 --CH.sub.2C.sub.6H.sub.5 472
EXAMPLE 25
##STR00299##
Step 1: Combine benzyl 4-oxo-1-piperidinecarboxylate (1.0 g, 4.3
mmol) with H.sub.2NOH.HCl (0.89 g, 13 mmol) in pyridine (5 ml).
Stir 16 h and concentrate. Partition between NaHCO.sub.3 (sat.) and
EtOAc, dry (MgSO.sub.4) and concentrate to give the oxime.
Step 2: Combine the product of Step 1 (0.44 g, 1.8 mmol) with
2-bromoethyl methyl ether (0.20 ml, 2.2 mmol) and NaH (0.10 g, 2.7
mmol) in DMF (8 ml). Stir 16 h and concentrate. Partition between
NH.sub.4Cl (sat.) and ether, dry (MgSO.sub.4), and concentrate.
Chromatograph the residue on silica with 20% EtOAc-hexane to obtain
the alkylated oxime.
Step 3: Stir the product of Step 2 (0.45 g, 1.47 mmol) over 5% Pd/C
(0.045 g) in EtOAc (25 ml) under H.sub.2 for 6 h. Filter and
concentrate to obtain the amine.
Step 4: Treat the amine of Step 3 with the product of Preparation 2
as in Example 24, Step 1, to obtain the title compound as a white
solid, MS: m/e 440 (M+1).
EXAMPLE 26
##STR00300##
Add sodium triacetoxyborohydride (0.083 g, 0.39 mmol) to a mixture
of the product of Example 24, Step 2 (0.050 g, 0.13 mmol), aniline
(0.035 ml, 0.39 mmol), and AcOH (0.045 ml, 0.78 mmol) in
dichloroethane (3 ml). Stir 16 h and partition between NaHCO.sub.3
(sat.) and 5% CH.sub.3OH in CH.sub.2Cl.sub.2. Dry (MgSO.sub.4) and
concentrate. Chromatograph (5% CH.sub.3OH--CH.sub.2Cl.sub.2) to
obtain the title compound as a white solid, MS: m/e 444 (M+1).
In similar fashion, prepare the following compound, MS: m/e 445
(M+1).
##STR00301##
EXAMPLE 27
##STR00302##
Step 1: Combine 4-bromophenol (3.46 g, 20.0 mmol) with 2-bromoethyl
methyl ether (2.82 ml, 30.0 mmol) and K.sub.2CO.sub.3 (8.30 g, 60.0
mmol) in acetone (50 ml). Heat at reflux 16 h, cool, filter, and
concentrate. Chromatograph on silica with 5% EtOAc/hexane to give
the ether as a clear oil. To this ether (2.73 g, 11.8 mmol) in dry
THF (50 ml) at -78.degree. C. add n-BuLi (1.6 M in hexane, 7.4 ml,
11.8 mmol). Stir for 10 min. and add a solution of benzyl
4-oxo-1-piperidinecarboxylate (2.5 g, 10.7 mmol) in dry THF (5 ml).
Stir for 2 h and allow to warm. Partition between sat. NH.sub.4Cl
and EtOAc, dry (MgSO.sub.4) and concentrate. Chromatograph on
silica with EtOAc/hexane (20:80, then 40:60) to obtain the
alcohol.
Step 2: To a solution of the product of Step 1 (0.386 g, 1.0 mmol)
and triethylsilane (0.80 ml, 5.0 mmol) in dry CH.sub.2Cl.sub.2 (10
ml) at -78.degree. C. add trifluoroacetic acid (0.38 ml, 5.0 mmol).
Allow to warm over 2 h and partition between sat. NaHCO.sub.3 and
CH.sub.2Cl.sub.2. Dry (MgSO.sub.4) and concentrate. Chromatograph
on silica with 20% EtOAc/hexane to obtain the reduction product,
MS: m/e 370 (M+1).
Step 3: Stir the product of Step 2 (0.300 g, 0.758 mmol) over 5%
Pd/C (0.030 g) in EtOAc (5 ml) and CH.sub.3OH (5 ml) under H.sub.2
for 2 h. Filter and concentrate to obtain the amine.
Step 4: Treat the amine of Step 3 with the product of Preparation 2
as in Example 24, Step 1, to obtain the title compound as a white
solid, MS: m/e 503 (M+1).
EXAMPLE 28
##STR00303##
Treat the product of Example 1-145 (0.020 g, 0.044 mmol) in EtOH
(0.5 ml) at 0.degree. C. with sodium borohydride (0.005 g, 0.13
mmol) and with an equal amount again after 0.75 h. After another
0.75 h, partition between CH.sub.2Cl.sub.2 and sat. NH.sub.4Cl. Dry
(Na.sub.2SO.sub.4) and concentrate. Purify by PTLC (10%
CH.sub.3OH/CH.sub.2Cl.sub.2) to obtain the title compound as a
white solid, MS: 459 (M+1).
EXAMPLE 29
##STR00304##
Treat the product of Example 1-145 (0.020 g, 0.044 mmol) in
pyridine (0.5 ml) with methoxyamine hydrochloride (0.011 g, 0.13
mmol). Stir 16 h and concentrate. Partition between
CH.sub.2Cl.sub.2 and sat. NaHCO.sub.3. Dry (Na.sub.2SO.sub.4) and
concentrate. Purify by PTLC (5% CH.sub.3OH/CH.sub.2Cl.sub.2) to
obtain the title compound as a white solid, MS: 486 (M+1).
Similarly, prepare the oxime 29-2 as two separated geometric
isomers, each a white solid, MS: 472 (M+1).
##STR00305##
Because of their adenosine A.sub.2a receptor antagonist activity,
compounds of the present invention are useful in the treatment of
depression, cognitive function diseases and neurodegenerative
diseases such as Parkinson's disease, senile dementia as in
Alzheimer's disease, and psychoses of organic origin. In
particular, the compounds of the present invention can improve
motor-impairment due to neurodegenerative diseases such as
Parkinson's disease.
The other agents known to be useful in the treatment of Parkinson's
disease which can be administered in combination with the compounds
of formula I include: L-DOPA; dopaminergic agonists such as
quinpirole, ropinirole, pramipexole, pergolide and bromocriptine;
MAO-B inhibitors such as deprenyl and selegiline; DOPA
decarboxylase inhibitors such as carbidopa and benserazide; and
COMT inhibitors such as tolcapone and entacapone. One to three
other agents can be used in combination with the compounds of
formula I, preferably one.
The pharmacological activity of the compounds of the invention was
determined by the following in vitro and in vivo assays to measure
A.sub.2a receptor activity.
Human Adenosine A.sub.2a and A.sub.1 Receptor Competition Binding
Assay Protocol
Membrane sources:
A.sub.2a: Human A.sub.2a Adenosine Receptor membranes, Catalog
#RB-HA2a, Receptor Biology, Inc., Beltsville, Md. Dilute to 17
.mu.g/100 .mu.l in membrane dilution buffer (see below).
Assay Buffers:
Membrane dilution buffer: Dulbecco's Phosphate Buffered Saline
(Gibco/BRL)+10 mM MgCl.sub.2.
Compound Dilution Buffer: Dulbecco's Phosphate Buffered Saline
(Gibco/BRL)+10 mM MgCl.sub.2 supplemented with 1.6 mg/ml methyl
cellulose and 16% DMSO. Prepared fresh daily.
Ligands:
A.sub.2a: [3H]-SCH 58261, custom synthesis, AmershamPharmacia
Biotech, Piscataway, N.J. Stock is prepared at 1 nM in membrane
dilution buffer. Final assay concentration is 0.5 nM.
A.sub.1: [3H]-DPCPX, AmershamPharmacia Biotech, Piscataway, N.J.
Stock is prepared at 2 nM in membrane dilution buffer. Final assay
concentration is 1 nM.
Non-specific Binding:
A.sub.2a: To determine non-specific binding, add 100 nM CGS 15923
(RBI, Natick, Mass.). Working stock is prepared at 400 nM in
compound dilution buffer.
A.sub.1: To determine non-specific binding, add 100 .mu.M NECA
(RBI, Natick, Mass). Working stock is prepared at 400 .mu.M in
compound dilution buffer.
Compound Dilution:
Prepare 1 mM stock solutions of compounds in 100% DMSO. Dilute in
compound dilution buffer. Test at 10 concentrations ranging from 3
.mu.M to 30 pM. Prepare working solutions at 4.times. final
concentration in compound dilution buffer.
Assay procedure:
Perform assays in deep well 96 well plates. Total assay volume is
200 .mu.l. Add 50 .mu.l compound dilution buffer (total ligand
binding) or 50 .mu.l CGS 15923 working solution (A.sub.2a
non-specific binding) or 50 .mu.l NECA working solution (A.sub.1
non-specific binding) or 50 .mu.l of drug working solution. Add 50
.mu.l ligand stock ([3H]-SCH 58261 for A.sub.2a, [3H]-DPCPX for
A.sub.1). Add 100 .mu.l of diluted membranes containing the
appropriate receptor. Mix. Incubate at room temperature for 90
minutes. Harvest using a Brandel cell harvester onto Packard GF/B
filter plates. Add 45 .mu.l Microscint 20 (Packard), and count
using the Packard TopCount Microscintillation Counter. Determine
IC.sub.50 values by fitting the displacement curves using an
iterative curve fitting program (Excel). Determine Ki values using
the Cheng-Prusoff equation.
Haloperidol-induced catalepsy in the rat
Male Sprague-Dawley rats (Charles River, Calco, Italy) weighing
175-200 g are used. The cataleptic state is induced by the
subcutaneous administration of the dopamine receptor antagonist
haloperidol (1 mg/kg, sc), 90 min before testing the animals on the
vertical grid test. this test, the rats are placed on the wire mesh
cover of a 25.times.43 plexiglass cage placed at an angle of about
70 degrees with the bench table. The rat is placed on the grid with
all four legs abducted and extended ("frog posture"). The use of
such an unnatural posture is essential for the specificity of this
test for catalepsy. The time span from placement of the paws until
the first complete removal of one paw (decent latency) is measured
maximally for 120 sec.
The selective A.sub.2A adenosine antagonists under evaluation are
administered orally at doses ranging between 0.03 and 3 mg/kg, 1
and 4 h before scoring the animals.
In separate experiments, the anticataleptic effects of the
reference compound, L-DOPA (25, 50 and 100 mg/kg, ip), were
determined.
6-OHDA Lesion of the Middle Forebrain Bundle in Rats
Adult male Sprague-Dowley rats (Charles River, Calco, Como, Italy),
weighing 275-300 g, are used in all experiments. The rats are
housed in groups of 4 per cage, with free access to food and water,
under controlled temperature and 12 hour light/dark cycle. The day
before the surgery the rats are fasted over night with water ad
libitum.
Unilateral 6-hydroxydopamine (6-OHDA) lesion of the middle
forebrain bundle is performed according to the method described by
Ungerstedt et al. (Brain Research, 1971, 6-OHDA and Cathecolamine
Neurons, North Holland, Amsterdam, 101-127), with minor changes.
Briefly, the animals are anaesthetized with chloral hydrate (400
mg/kg, ip) and treated with desipramine (10 mpk, ip) 30 min prior
to 6-OHDA injection in order to block the uptake of the toxin by
the noradrenergic terminals. Then, the animals are placed in a
stereotaxic frame. The skin over the skull is reflected and the
stereotaxic coordinates (-2.2 posterior from bregma (AP), +1.5
lateral from bregma (ML), 7.8 ventral from dura (DV) are taken,
according to the atlas of Pellegrino et al (Pellegrino L. J.,
Pellegrino A. S. and Cushman A. J., A Stereotaxic Atlas of the Rat
Brain, 1979, New York: Plenum Press). A burr hole is then placed in
the skull over the lesion site and a needle, attached to a Hamilton
syringe, is lowered into the left MFB. Then 8 .mu.g 6-OHDA-HCl is
dissolved in 4 .mu.l of saline with 0.05% ascorbic acid as
antioxidant, and infused at the constant flow rate of 1 .mu.l/1 min
using an infusion pump. The needle is withdrawn after additional 5
min and the surgical wound is closed and the animals left to
recover for 2 weeks.
Two weeks after the lesion the rats are administered with L-DOPA
(50 mg/kg, ip) plus Benserazide (25 mg/kg, ip) and selected on the
basis of the number of full contralateral turns quantified in the 2
h testing period by automated rotameters (priming test). Any rat
not showing at least 200 complete turns/2 h is not included in the
study.
Selected rats receive the test drug 3 days after the priming test
(maximal dopamine receptor supersensitivity). The new receptor
antagonists are administered orally at dose levels ranging between
0.1 and 3 mg/kg at different time points (i.e., 1, 6, 12 h) before
the injection of a subthreshold dose of L-DOPA (4 mpk, ip) plus
benserazide (4 mpk, ip) and the evaluation of turning behavior.
Using the above test procedures, the following results were
obtained for preferred and/or representative compounds of the
invention.
Results of the binding assay on compounds of the invention showed
A.sub.2a, Ki vaules of 0.3 to 57 nM, with preferred compounds
showing Ki values between 0.3 and 5.0 nM.
Selectivity is determined by dividing Ki for A1 receptor by Ki for
A2a receptor. Preferred compounds of the invention have a
selectivity ranging from about 100 to about 2000.
Preferred compounds showed a 50-75% decrease in descent latency
when tested orally at 1 mg/kg for anti-cataleptic activity in
rats.
In the 6-OHDA lesion test, rats dosed orally with 1 mg/kg of the
preferred compounds performed 170-440 turns in the two-hour assay
period.
In the haloperidol-induced catalepsy test, a combination of
sub-threshold amount of a compound of formula I and a sub-threshold
amount of L-DOPA showed a significant inhibition of the catalepsy,
indicating a synergistic effect. In the 6-OHDA lesion test, test
animals administered a combination of a compound of formula I and a
sub-threshold amount of L-DOPA demonstrated significantly higher
contralateral turning.
For preparing pharmaceutical compositions from the compounds
described by this invention, inert, pharmaceutically acceptable
carriers can be either solid or liquid. Solid form preparations
include powders, tablets, dispersible granules, capsules, cachets
and suppositories. The powders and tablets may be comprised of from
about 5 to about 70 percent active ingredient. Suitable solid
carriers are known in the art, e.g. magnesium carbonate, magnesium
stearate, talc, sugar, lactose. Tablets, powders, cachets and
capsules can be used as solid dosage forms suitable for oral
administration.
For preparing suppositories, a low melting wax such as a mixture of
fatty acid glycerides or cocoa butter is first melted, and the
active ingredient is dispersed homogeneously therein as by
stirring. The molten homogeneous mixture is then poured into
convenient sized molds, allowed to cool and thereby solidify.
Liquid form preparations include solutions, suspensions and
emulsions. As an example may be mentioned water or water-propylene
glycol solutions for parenteral injection.
Liquid form preparations may also include solutions for intranasal
administration.
Aerosol preparations suitable for inhalation may include solutions
and solids in powder form, which may be in combination with a
pharmaceutically acceptable carrier, such as an inert compressed
gas.
Also included are solid form preparations which are intended to be
converted, shortly before use, to liquid form preparations for
either oral or parenteral administration. Such liquid forms include
solutions, suspensions and emulsions.
The compounds of the invention may also be deliverable
transdermally. The transdermal compositions can take the form of
creams, lotions, aerosols and/or emulsions and can be included in a
transdermal patch of the matrix or reservoir type as are
conventional in the art for this purpose.
Preferably the compound is administered orally.
Preferably, the pharmaceutical preparation is in unit dosage form.
In such form, the preparation is subdivided into unit doses
containing appropriate quantities of the active component, e.g., an
effective amount to achieve the desired purpose.
The quantity of active compound of formula I in a unit dose of
preparation may be varied or adjusted from about 0.1 mg to 1000 mg,
more preferably from about 1 mg to 300 mg, according to the
particular application.
The actual dosage employed may be varied depending upon the
requirements of the patient and the severity of the condition being
treated. Determination of the proper dosage for a particular
situation is within the skill of the art. Generally, treatment is
initiated with smaller dosages which are less than the optimum dose
of the compound. Thereafter, the dosage is increased by small
increments until the optimum effect under the circumstances is
reached. For convenience, the total daily dosage may be divided and
administered in portions during the day if desired.
The amount and frequency of administration of the compounds of the
invention and the pharmaceutically acceptable salts thereof will be
regulated according to the judgment of the attending clinician
considering such factors as age, condition and size of the patient
as well as severity of the symptoms being treated. A typical
recommended dosage regimen for compounds of formula I is oral
administration of from 10 mg to 2000 mg/day preferably 10 to 1000
mg/day, in two to four divided doses to provide relief from central
nervous system diseases such as Parkinson's disease. The compounds
are non-toxic when administered within this dosage range.
The doses and dosage regimen of the dopaminergic agents will be
determined by the attending clinician in view of the approved doses
and dosage regimen in the package insert, taking into consideration
the age, sex and condition of the patient and the severity of the
disease. It is expected that when the combination of a compound of
formula I and a dopaminergic agent is administered, lower doses of
the components will be effective compared to the doses of the
components administered as monotherapy.
The following are examples of pharmaceutical dosage forms which
contain a compound of the invention. Those skilled in the art will
recognize that dosage forms can be modified to contain both a
compound of formula I and a dopaminergic agent.
The scope of the invention in its pharmaceutical composition aspect
is not to be limited by the examples provided.
TABLE-US-00014 No. Ingredients mg/tablet mg/tablet 1. Active
compound 100 500 2. Lactose USP 122 113 3. Corn Starch, Food Grade,
as a 30 40 10% paste in Purified Water 4. Corn Starch, Food Grade
45 40 5. Magnesium Stearate 3 7 Total 300 700
Method of Manufacture
Mix Item Nos. 1 and 2 in a suitable mixer for 10-15 minutes.
Granulate the mixture with Item No. 3. Mill the damp granules
through a coarse screen (e.g., 1/4'', 0.63 cm) if necessary. Dry
the damp granules. Screen the dried granules if necessary and mix
with Item No. 4 and mix for 10-15 minutes. Add Item No. 5 and mix
for 1-3 minutes. Compress the mixture to appropriate size and weigh
on a suitable tablet machine.
TABLE-US-00015 No. Ingredient mg/capsule mg/capsule 1. Active
compound 100 500 2. Lactose USP 106 123 3. Corn Starch, Food Grade
40 70 4. Magnesium Stearate NF 7 7 Total 253 700
Method of Manufacture
Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 minutes.
Add Item No. 4 and mix for 1-3 minutes. Fill the mixture into
suitable two-piece hard gelatin capsules on a suitable
encapsulating machine.
While the present invention has been described in conjunction with
the specific embodiments set forth above, many alternatives,
modifications and variations thereof will be apparent to those of
ordinary skill in the art. All such alternatives, modifications and
variations are intended to fall within the spirit and scope of the
present invention.
* * * * *