PYRIDAZINONE ACETIC ACIDS AS ALDOSE REDUCTASE INHIBITORS

ACIDES PYRIDAZINONEACETIQUES UTILISES COMME INHIBITEURS DE L'ALDOSE REDUCTASE

English Abstract

2107104 9217446 PCTABS00016
Compounds having aldose reductase inhibitory activity of formula
(I) wherein X CH2, CH2CH2, -CHCH3, (a); Y=O or S; R1 is
an optionally substituted phenyl, benzothiazol-2-yl,
benzoxazol-2-yl, benzofuran-2-yl, benzothiophen-2-yl, thiazolopyridin-2-yl,
oxazolopyridin-2-yl, 3-phenyl 1,2,4-oxadiazol-5-yl, and
5-phenyl-1,2,4-oxadiazol-3-yl wherein said substituted groups are
substituted with one or more and preferably two substituents that are
independently selected from fluorine, chlorine, bromine, methyl, and
trifluoromethyl; R2 and R3 are independently selected from
hydrogen, fluorine, chlorine, bromine, (C1-C4) alkyl, methyl
(C1-C4) alkylthio, (C1-C4) alkoxy and trifluoromethyl or
R2 and R3 taken together with the carbons to which they are
attached form a group W, wherein W is (b) or (c) wherein p is 1 or
2 and U1 and U2 are independently CH2, O or S with the
proviso that both U1 and U2 are not O or S; R4 is hydrogen or a
prodrug group; or a pharmaceutically acceptable salt thereof.

Claims

-27-
CLAIMS
1. A compound of the formula
<IMG> I
wherein
X is CH2, CH2CH2, -CH(CH3), or <IMG>;
Y=O or S;
R1 is benzothiazol-2-yl optionally substituted with one
or two substitutents that are independently selected from
fluorine, chlorine, bromine, methyl, and trifluoromethyl;
R2 and R3 are independently selected from hydrogen, (C1-
C4) alkyl, fluorine, chlorine, bromine, and trifluoromethyl
or R2 and R3 taken together with the carbons to which they
are attached form a group W, wherein W is
<IMG> or <IMG>
wherein p is 1 or 2 and U1 and U2 are independently CH2,
O or S with the proviso that both U1 and U2 are not O or S;
R4 is hydrogen or a prodrug group;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 wherein X is CH2,
R1 is hydrogen and R2 and R3 are each hydrogen or methyl or R2
is hydrogen and R3 is methyl or R2 and R3 taken together form
a cyclohexyl ring or a cyclopentyl ring.

-28-
3. A compound according to claim 1 selected from the
group consisting of:
3, 4 -Dihydro-4-oxo-5,6-dimethyl-3-[(5,7-difluoro-2-
benzothiazolyl) methyl]-1-pyridazineacetic acid;
3,4,-Dihydro-4-oxo-5,6-dimethyl-3-[(5-trifluoromethyl)-
2-benzothiazolyl)methyl]-1-pyridazineacetic acid;
3;4-Dihydro-4-oxo-5,6-cyclohexano-3-[(5,7-difluoro-2-
benzothiazolyl) methyl]-1-pyridazineacetic acid;
3,4 -Dihydro-4-oxo-5, 6-cyclohexano-3-
[[5(trifluoromethyl)-2-benzo-thiazolyl]methyl]-1-
pyridazineacetic acid;
3,4-Dihydro-4-oxo-3[(5,7-difluoro-2-
benzothiazolyl ) methyl ] -1-pyridaz ineacetic acid;
3, 4-Dihydro-4-oxo-[[5-(trifluoromethyl)-2-
benzothiazolyl]methyl]-1-pyridazineacetic acid;
3,4-Dihydro-4-oxo-6-methyl-3-[[5-trifluoromethyl]-2 -
benzothiazolyl]methyl]-1-pyridazineacetic acid;
3,4 -Dihydro-4-oxo-5,6-cyclopentano-3-[(5(trifluoro-
methyl)-2-benzothiazolyl)methyl)-l-pyridazineacetic acid.
3,4-Dihydro-4-oxo-5,6-cyclohexano-3-[(5,7-dichloro-2-
benzothiazolyl)methyl]-1-pyridazineacetic acid; and
3,4-Dihydro-4-oxo-5,6-dimethyl-3-[(5,7-dichloro-2-
benzothiazolyl)methyl]-1-pyridazineacetic acid .
4. A compound of the formula
<IMG>
wherein
R5 is hydrogen or XR1 where in
X is CH2, CH2CH2, -CH(CH3), -CH2-<IMG>-NH or -CH2-<IMG>-NH; and

-29-
R1 is benzothiazol-2-yl optionally substituted with one
or two substitutents that are independently selected from
fluorine, chlorine, bromine, methyl, and trifluoromethyl;
R2 and R3 are independently selected from hydrogen, (C1-
C4) alkyl, fluorine, chlorine, bromine, and trifluoromethyl
or R2 and R3 taken together-with the carbons to which they
are attached form a group W, wherein W is
<IMG> or <IMG>
wherein p is 1 or 2 and U1 and u2 are independently CH2,
O or S with the proviso that both U1 and U2 are not O or S;
and R4 is (C1-C4)alkyl.
5. A compound according to claim 4 wherein R2 and R3
are each methyl, R4 is -C(CH3)3 and R5 is hydrogen.
6. A compound according to claim 4 wherein R2 and R3
taken together form a cyclohexyl ring, R4 is ethyl and R5 is
hydrogen.
7. A compound according to claim 4 wherein R2 and R3
are each methyl, R5 is XR1 wherein X is CH2, and R4 is
-C(CH3)3.
8. A compound according to claim 4 wherein R2 and R3
taken together form a cyclohexyl ring, R5 is XR1 wherein X is
CH2, and R4 is ethyl.
9. A pharmaceutical composition for inhibition of
aldose reductase activity comprising a compound of claim 1
in an amount effective in the inhibition of aldose reductase
activity in admixture with a pharmaceutically acceptable
carrier.
10. A method of inhibiting aldose reductase activity
comprising administering to a diabetic host an effective
amount of a compound of claim 1.
11. A pharmaceutical composition for lowering blood
uric acid levels comprising a compound of claim 1 in an

-30-
amount effective for lowering blood uric acid levels in
admixture with a pharmaceutically acceptable carrier.
12. A method for lowering blood uric acid levels in a
mammalian subject, which comprises administering to a mammal
in need of such treatment an effective amount of a compound
of claim 1.
13. A process for the preparation of a compound of the
formula
<IMG> I
wherein
X is CH2, CH2CH2, -CH(CH3), or <IMG>;
Y=O or S;
R1 is benzothiazol-2-yl optionally substituted with one
or two substitutents that are independently selected from
fluorine, chlorine, bromine, methyl, and trifluoromethyl;
R2 and R3 are independently selected from hydrogen, (C1-
C4) alkyl, fluorine, chlorine, bromine, and trifluoromethyl
or R2 and R3 taken together with the carbons to which they
are attached form a group W, wherein W is
<IMG> or <IMG>
wherein p is 1 or 2 and U1 and U2 are independently CH2,
O or S with the proviso that both U1 and U2 are not O or S;
R4 is hydrogen or a prodrug group;
comprising:

. -31-
(a) alkylating a compound of the formula
<IMG> II
wherein R2, and R3 are as defined above and R4 is C1-
alkyl with an alkylating agent of the formula L-X-R1 wherein
L is a leaving group such as chloro or bromo and X and R1 are
as defined above in the presence of a base to obtain a
compound of the formula
<IMG> III
wherein R1 is CN or optionally substituted
benzothiazole; R2 and R3 are as defined above, R4 is C1-C4
alkyl, X is CH2, CH2CH2 or -CH(CH3); and
(b) hydrolyzing the compound of formula III with a
strong acid or aqueous base, to form a compound of Formula
I wherein R4 is hydrogen, and if desired, converting a
compound of Formula I so formed to a pharmaceutically
acceptable salt or prodrug thereof; or
(c) cyclocondensing a compound of the formula III
above wherein R1 is CN; R2 and R3 are as defined above and R4
is C1-C4 alkyl, X is CH2, CH2CH2 or -CH(CH3) with substituted
2-aminobenzenethiol and acid addition salts in the presence
of a polar solvent; and
(d) hydrolyzing the resulting compound of (c) in
accordance with step (b) above, to form a compound of
formula I wherein R4 is hydrogen, and if desired, converting

-32-
the compound of Formula I so formed to a pharamaceutically
acceptable salt or prodrug thereof; or
(e) cyclocondensing a compound of the formula III
above wherein
R1 is CN, <IMG>, R2 and R3 are as defined above and R4
is C1-C4 alkyl and X is CH2, CH2CH2,CH(CH3) with a compound of
the formula
<IMG>
wherein A is F, Cl, Br or I in a polar solvent in the
presence of hydrogen sulfide; and
f. hydrolyzing the resulting compound in accordance
with step (b) above to form a compound of Formula I wherein
R4 is hydrogen, and if desired, converting the compound of
Formula I so formed to a pharmaceutically acceptable salt or
prodrug thereof.
14. A process according to claim 13 wherein X is CH2,
R4 is hydrogen and R2 and R3 are each hydrogen or methyl or R2
is hydrogen and R3 is methyl or R2 and R3 taken together form
a cyclohexyl ring or a cyclopentyl ring.
15. A process according to claim 13 wherein said
compound is selected from the group consisting of:
3,4-Dihydro-4-oxo-5,6-dimethyl-3-[(5,7-difluoro-2-
benzothiazolyl)methyl]-1-pyridazineacetic acid;
3,4-Dihydro-4-oxo-5,6-dimethyl-3-[(5-trifluoromethyl)-
2-benzothiazolyl)methyl]-1-pyridazineacetic acid;
3,4-Dihydro-4-oxo-5,6-cyclohexano-3-[(5,7-difluoro-2-
benzothiazolyl)methyl]-1-pyridazineacetic acid;
3 , 4 - D i h y d r o - 4 - o x o -5 , 6 - c y c lo h e x a n o -3 -
[[5(trifluoromethy1)-2-benzothiazolyl]methyl]-1-
pyridazineacetic acid;

3, 4 -Dihydro-4-oxo-3[(5,7-difluoro-2-
benzothiazolyl)methyl]-1-pyridazineacetic acid;
3,4-Dihydro-4-oxo-6-[[5-trifluoromethyl)-2-
benzothiazolyl]methyl]-1-pyridazineacetic acid;
3,4 -Dihydro-4-oxo-6-methyl-3-[[5-trifluoromethyl]-2-
benzothiazolyl]methyl]-1-pyridazineacetic acid;
3,4-Dihydro-4-oxo-5,6-cyclopentano-3-[[5(trifluoro-
methyl)-2-benzothiazolyl]methyl]-l-pyridazineacetic acid;
3,4-Dihydro-4-oxo-5,6-cyclohexano-3-[(5,7-dichloro-2-
benzothiazolyl)methyl]-1-pyridazineacetic acid; and
3,4-Dihydro-4-oxo-5,6-dimethyl-3-[(5,7-dichloro-2-
benzothiazolyl)methyl]-1-pyridazineacetic acid .
16. A process for the preparation of a compound of the
formula
<IMG>
wherein
R5 is hydrogen or XR1 wherein
X is CH2, CH2CH2, -CH(CH3), -CH2-<IMG>-NH or -CH2-<IMG>-NH; and
R1 is benzothiazol-2-yl optionally substituted with one
or two substitutents that are independently selected from
fluorine, chlorine, bromine, methyl, and trifluoromethyl;
R2 and R3 are independently selected from hydrogen, (C1-
C4) alkyl, fluorine, chlorine, bromine, and trifluoromethyl
or R2 and R3 taken together with the carbons to which they
are attached form a group W, wherein W is

-34-
<IMG>
or <IMG>
wherein p is 1 or 2 and U1 and U2 are independently CH2,
O or S with the proviso that both U1 and U2 are not O or S;
and R4 is (C1-C4)alkyl comprising:
reacting a compound of the formula
<IMG>
lll
wherein
X is <IMG>-NH with phosphorous pentasulfide in the
presence of an aromatic hydrocarbon solvent.
17. A process according to claim 16 wherein R2 and R3
are each methyl, R1 is -C(CH3)3 and R5 is hydrogen.
18. A process according to claim 16 wherein R2 and R3
taken together form a cyclohexyl ring, R4 is ethyl and R5 is
hydrogen.
19. A process according to claim 16 wherein R2 and R3
are each methyl, R5 is XR1 wherein X is CH2, and R4 is
-C(CH3)3.
20. A process according to claim 16 wherein R2 and R3
taken together form a cyclohexyl ring, R5 is XR1 wherein X is
CH2, and R4 is ethyl.
21. A compound of the formula

-35-
<IMG>
wherein
X is CH2, CH2CH2, -CH(CH3), or -CH2-<IMG>-NH;
Y=O or S;
R1 is an optionally substituted group selected from
benzoxazol-2-yl, benzofuran-2-yl, benzothiophen-2-yl,
thiazolopyridin-2-yl, oxazolopyridin-2-yl, 3-phenyl 1,2,4-
oxadiazol-5-yl, and 5-phenyl-1,2,4-oxadiazol-3-yl wherein
said substituted groups are substituted with one or two
substitutents that are independently selected from fluorine,
chlorine, bromine, methyl, and trifluoromethyl;
R2 and R3 are independently selected from hydrogen, (C1-
C4) alkyl, fluorine, chlorine, bromine, and trifluoromethyl
or R2 and R3 taken together with the carbons to which they
are attached form a group W, wherein W is
<IMG> or <IMG>
wherein p is 1 or 2 and U1 and U2 are independently CH2,
O or S with the proviso that both U1 and U2 are not O or S;
R4 is hydrogen or a prodrug group;
or a pharmaceutically acceptable salt thereof.
22. A compound of the formula

-36-
<IMG>
wherein
R5 is hydrogen or XR1 wherein
X is CH2, CH,CH2 -CH(CH3), -CH2-<IMG>-NH or -CH2-<IMG>-NH; and
R1 is CN, <IMG> or an optionally substituted group
selected from benzoxazol-2-yl, benzofuran-2-yl,
benzothiophen-2-yl, thiazolopyridin-2-yl, oxazolopyridin-2-
yl, 3-phenyl 1,2,4-oxadiazol-5-yl, and 5-phenyl-1,2,4-
oxadiazol-3-yl wherein said substituted groups are
substituted with one or two substitutents that are
independently selected from fluorine, chlorine, bromine,
methyl, and trifluoromethyl;
R2 and R3 are independently selected from hydrogen, (C1-
C4) alkyl, fluorine, chlorine, bromine, and trifluoromethyl
or R2 and R3 taken together with the carbons to which they
are attached form a group W, wherein W is
<IMG> or <IMG>
wherein p is 1 or 2 and U1 and U2 are independently CH2,
O or S with the proviso that both U1 and U2 are not O or S;
and R4 is (C1-C4) alkyl.
23. A compound according to Claim 21 wherein R1 is
optionally substituted benzoxazol-2-yl or 3-phenyl-1,2,4-
oxadiazol-5-yl.

-37-
24. A compound according to claim 21 wherein X is CH2,
R1 is optionally substituted benzoxazol-2-yl, or 3-phenyl-
1,2,4-oxadiazol-5-yl, R2 and R3 are each methyl, and R4 is
hydrogen.
25. A compound according to claim 21 selected from the
group consisting of:
3,4-Dihydro-4-oxo-5,6-dimethyl-3-[[(2-fluoro-4-
bromo)benzyl]-1-pyridazineacetic acid;
3,4-Dihydro-4-oxo-5,6-cyclohexano-3-[(2-fluoro-4-
bromo)benzyl]-1-pyridazineacetic acid;
3,4-Dihydro-4-oxo-5,6-dimethyl-3-[(5-bromo-2-
benzoxazolyl)methyl]-1-pyridazineacetic acid; and
3,4-Dihydro-4-oxo-5,6-dimethyl-3-[[3-(2,3-
difluorophenyl)-1,2,4-oxadiazol-5-yl]-methyl]-1-
pyridazineacetic acid.
26. A process for the preparation of a compound of the
formula
<IMG> I
wherein
X is CH2, CH2CH2, -CH(CH3), or -CH2-<IMG>-NH;
Y=O or S;
R1 is an optionally substituted group selected from
benzoxazol-2-yl, benzofuran-2-yl, benzothiophen-2-yl,
thiazolopyridin-2-yl, oxazolopyridin-2-yl, 3-phenyl 1,2,4-
oxadiazol-5-yl, and 5-phenyl-1,2,4-oxadiazol-3-yl wherein
said substituted groups are substituted with one or two
substitutents that are independently selected from fluorine,
chlorine, bromine, methyl, and trifluoromethyl;

-38-
R2 and R3 are independently selected from hydrogen, (C1-
C4) alkyl, fluorine, chlorine, bromine, and trifluoromethyl
or R2 and R3 taken together with the carbons to which they
are attached form a group W, wherein W is
<IMG> or <IMG>
wherein p is 1 or 2 and U1 and U2 are independently CH2,
O or S with the proviso that both U1 and u2 are not O or S;
R1 is hydrogen or a prodrug group;
comprising:
(a) alkylating a compound of the formula
<IMG> II
wherein R2, and R3 are as defined above and R4 is C1-C4
alkyl with an alkylating agent of the formula L-X-R1 wherein
L is a leaving group such as chloro or bromo and X and R1 are
as defined above in the presence of a base to obtain a
compound of the formula
<IMG> III
wherein R1 is CN or optionally substituted
benzothiazole; R2 and R3 are as defined above, R4 is C1-C4
alkyl, X is CH2, CH2CH2 or -CH(CH3); and

-39-
(b) hydrolyzing the. compound of formula III with a
strong acid or aqueous base, to form a compound of Formula
I wherein R4 is hydrogen, and if desired, converting a
compound of Formula I so formed to a pharmaceutically
acceptable salt or prodrug thereof; or
(c) cyclocondensing a compound of the formula III
above wherein R1 is CN; R2 and R3 are as defined above and R4
is C1-C4 alkyl, X is CH2, CH2CH2 or -CH(CH3) with substituted
2-aminobenzenethiol and acid addition salts in the presence
of a polar solvent; and
(d) hydrolyzing the resulting compound of (c) in
accordance with step (b) above, to form a compound of
formula I wherein R4 is hydrogen, and if desired, converting
the compound of Formula I so formed to a pharamaceutically
acceptable salt or prodrug thereof; or
(e) cyclocondensing a compound of the formula III
above wherein
R1 is CN, <IMG> , R2 and R3 are as defined above and R4
is C1-C4 alkyl and X is CH2, CH2CH2,CH(CH3) with a compound of
the formula
<IMG>
wherein A is F, Cl, Br or I in a polar solvent in the
presence of hydrogen sulfide; and
f. hydrolyzing the resulting compound in accordance
with step (b) above to form a compound of Formula I wherein
R4 is hydrogen, and if desired, converting the compound of
Formula I so formed to a pharmaceutically acceptable salt or
prodrug thereof.
27. A process according to Claim 26 wherein R1 is
optionally substituted benzoxazol-2-yl or 3-phenyl-1,2,4-
oxadiazol-5-yl.

-40-
28. A process according to claim 26 wherein X is CH2,
R1 is optionaiLy substituted benzoxazol-2-yl, or 3-phenyl-
1,2,4-oxadiazol-5-yl, R2 and R3 are each methyl, and R4 is
hydrogen.
29. A process according to claim 26 wherein said
compound is selected from the group consisting of:
3,4-Dihydro-4-oxo-5,6-dimethyl-3-[[(2-fluoro-4-
bromo)benzyl]-1-pyridazineacetic acid;
3,4-Dihydro-4-oxo-5,6-cyclohexano-3-[(2-fluoro-4-
bromo)benzyl]-1-pyridazineacetic acid;
3,4-Dihydro-4-oxo-5,6-dimethyl-3-[(5-bromo-2-
benzoxazolyl)methyl]-1-pyridazineacetic acid; and
3,4-Dihydro-4-oxo-5,6-dimethyl-3-[[3-(2,3-
difluorophenyl)-1,2,4-oxadiazol-5-yl]-methyl]-1-
pyridazineacetic acid.
30. A process for the preparation of a compound of the
formula
<IMG>
wherein
R5 is hydrogen or XR1 wherein
X is CH2, CH2CH2, -CH(CH3), -CH2-<IMG>-NH or -CH2-<IMG>-NH; and
R1 is CN, <IMG> or an optionally substituted group
selected from benzoxazol-2-yl, benzofuran-2-yl,
benzothiophen-2-yl, thiazolopyridin-2-yl, oxazolopyridin-2-
yl, 3-phenyl 1,2,4-oxadiazol-5-yl, and 5-phenyl-1,2,4-
oxadiazol-3-yl wherein said substituted groups are
substituted with one or two substitutents that are

-41-
independently selected from fluorine, chlorine, bromine,
methyl, and trifluoromethyl;
R2 and R3 are independently selected from hydrogen, (C1-
C4) alkyl, fluorine, chlorine, bromine, and trifluoromethyl
or R2 and R3 taken together with the carbons to which they
are attached form a group W, wherein W is
<IMG> or <IMG>
wherein p is 1 or 2 and U1 and U2 are independently CH2,
O or S with the proviso that both U1 and U2 are not O or S;
and R4 is (C1-C4)alkyl comprising:
reacting a compound of the formula
<IMG> III
wherein
X is <IMG> with phosphorous pentasulfide in the
presence of an aromatic hydrocarbon solvent.

Description

:
-`~N092/17446'~l O 7 1 0 ~ PCT/US92tO1603
5PYRIDAZINONE ACETIC ACIDS
-Backaround of the Invention
This invention relates to novel pyridazinone acetic
acids and derivatives thereof which are aldose reductase
inhibitors and which are useful in the treatment of csrtain
- lO chronic complications arising from diabetes mellitus, such
as diabetic cataracts, retinopathy, nephropathy and
neuropathy. These compounds can also be used as
hypouricemic agents, useful for lowering blood uric acid
levels. The invention further relates to novel
pharmaceutical compositions containing such compounds and to
a method of using these compounds. ~ ,
In the past, various attempts have been made to obtain
more effective oral anti-diabetic agents. U.S. Patent No.
;~ 3,821,383 discloses aldose reductase inhibitors like l,3-
dioxo-lH-benz-[d,e]-isoquinoline-2-(3H)-acetic acid and
derivatives thereof to be useful for the treatment of ;
c~ronic complications of diabetes. U.S. Patent 4,226,875
teaches the use of spiro-oxazolidinediones for treating ~ -
complications of diabetes as aldose reductase inhibitors.
25 Such aldose reductase inhibitors function by inhibiting the
activity of the enzyme aldose reductase, which is primarily
responsible for regulating the reduction of aldoses, such as
glucose and galactose, to the corresponding polyols, such as
sorbitol and galactitol, in humans and other animals. In
3~0 this way, unwanted accumulations of galactitol in the lens
of galactosemic subjects and of sorbitol in the lens,
peripheral nerves and kidneys of various diabetic subjects
are prevented or reduced. Accordingly, such compounds are
of therapeutic value as aldose reductase inhibitors for
controlling certain chronic diabetic complications,
including those of an ocular nature, since it is known in
;~ the art that the presence of polyols in the lens of the eye
; leads to cataract formation, with a concomitant loss o~ lens
clarity.
French Patent Publication No. 2647676 relates to
pyridazinone derivatives having substituted benzyl side
. :
... ' .
' ,.
c ,~,,"",,j,,.., ,,.",, ,, ,,; ~

210710~
WO92/17~6 PCT/US92/01603 ~~
-2-
chains and benzothiazole side chàins which are described as
being inhibitors of aldose reductase.
U.S. Patent 4,251,528 disclos~s aromatic car~ocyclic
oxophthalazinyl acetic ~-ld~ ~2v~,.g aldose ~eductase
inhibiting properties. The patent mentions that 2-(2-pyrid-
2-ylethyl)-3,4-dihydro-a-o~ophthal~7ln-l-ylacetic acid does
not inhibit aldose reductas2. X2t2.0cyclic oxophthalazinyl
acetic acids and thei ethyl est2rs ~aving an sfIect on the
blood clotting system are discl~sed in Chemical A~stracts
1970, 73, 77173y.
U.S. Patent No. ~,939,1i~0 is diroctod to heterocyclic
oxophthalazinyl ac~tic ~ci~s.
U. S. Patent No. 4,868,301 ls dirocted to processes and
intermediates for the preparation of o~ophthalazinyl acetic
acids having benzothiazole or oiher heterocyclic side
chains.
U. S. Patent No. 4,996,204 is directed to
Pyridopyridazinone acetic acids.
European Patent Publication No. 0,397,350 is directed
to a process and intermediates for the preparation of
oxophthalazinyl acids and analogs thereof.
International Application No. PC~/US89105637 relates to
substituted oxophthalazinyl acetic acids and analogs
thereof.
25Summarv of the Invention
-.
The present invention relates to a compound of the
formula
CH2C 02R4 . .,
;: ~ 30 N
R /~f X~
~ .

`^`WO92/17446 2 1 0 7 1 0 ~ PCT/US92/01603
wherein
Y , .
X is CH~, CH2CH2, -C~(CH3) or -CH2-C-NH; -
Y = o or S; -
R1 is an optionally substituted group selected from
phenyl, benzothiazol-2-yl, benzoxazol-2-yl, ~enzofuran-2-yl,
benzothiophen-2-yl, thiazolopyridin-2-yl, oxazolopy idin-2-
yl, 3-phenyl l,2,4-oxadiazol-5-yl, and 5-phenyl-l,2,4-
oxadiazol-3-yl wherein said substituted groups are
substituted with one or two substituents th2_ ar~
independently selected from fluorine, chlorine, bromine,
methyl, methylthio, methoxy, hydroxy and trifluoromethyl;
R2 and R3 are independently selected from hyd~ogen,
15 fluorine, chlorine, bromine, (C~-C4)alkyl, (Cl-C4)alkylthio, ;~
(Cl-C4)alkoxy and trifluoromethyl or R2 and R3 taken together
with the carbons to which they are attached form a group W,
wherein W is ~-
(ch2)p\ ~ or ~ ~ ~ ~
wherein p is l or 2 and U~ and u2 are independently CH2,
25 O or S with the proviso that both U1 and u2 are not O or S; ~ -
R4 is hydrogen, or a prodrug group;
or a pharmaceutically acceptable salt thereof.
~-The present invention also relates to the
-pharmaceutically acceptable salts of the compounds of
formula I. Such pharmaceutically acceptable salts include
sodium, potassium, calcium and ammonium and those derived
from lower alkylamines (e.g. ethylamine), lower
alkanolamines (e.g. triethanolamine) and meglumine.
~Specific preferred compounds of the invention are:
- 35 3,4-Dihydro-4-oxo-5,6-dimethyl-3-[(5,7 difluoro-2-
benzothiazolyl)methyl]-l-pyridazineacetic acid;

21071~
WO92tl7446 PCT/US92/01603 ~~
3,4-Dihydro-4-oxo-5,6-dimethyl-3-[(5-trifluoromethyl)-
2-benzothiazoly)methyl]-l-py~idazin~2cet1c acid; :~ .
3,4-Dihydro-4-oxo-5,6-di~L~yl-3-~[(2-fluoro-4-
bromo)benzyl]-l-pyrida ineac~ti~ acid;
3,4-Dihydro-4-oxo-5,6-cyclohexano-3[t5,7-difluoro-2-
benzothiazolyl)methyl]-l-pv-lda~in~ac~Llc acid;
3,4-Dihydro-4-oxo-~,6-cyrlohexano-3-[[5(trilluoro-
methyl)-2-benzothiazolyl]methyl]-l-~vridazineacetic acid;~:
3~4-Dihydro-4-o~o-5~ 5-C~y5~ oh~ no-3- [ ( ~-fluoro-4-
bromo)benzyl]-l-pyrida in~ac__ic z~
3,4-Dihydro-4-oxo-,-[(5,7-dl.luo.o-2-~nzo~hi -
zolyl)methyl]-l-pyridazineacelicaci~;
3,4-Dihydro-4-oxo-[[5-(t-ifluoromethyl)-2-b2nzo-
thiazolyl~methyl]-l-pyridazineacetic acid; ,
3,4-Dihydro-4-oxo-6-methyl-3-~[5-trifluoromethyl]-2- - .
benzothiazolyl)methyl]-l-pyridazineacetic acid; ;
3,4-Dihydro-4-oxo-5,6-cyclopentano-3-[~5-(tri-
fluoromethyl)-2-benzothiazolyl]methyl~-l-pyridazineacetic
acid;
3,4-Dihydro-4-oxo-5,6-dimethyl-3-[(5-bromo-2-benzoxa- - .
zolyl)methyl]-l-pyridazineacetic acid; :
3,4-Dihydro-4-oxo-S,6-dimethyl-3-[~3-(2~3-difluoro-
phenyl)-1,`2,4-oxadiazol-5-yl~-methyl]-l-pyridazineacetic r~ . ,
acid; and
3,4-Dihydro-4-oxo-5,6-cyclohexano-3-[(5~7-dichloro-2
benzothiazolyl)methyl]-l-pyridazineacetic acid;
3,4-D-ihydro-4-oxo-5,6-dimethyl-3-[(5,7-dichloro-2-
benzothiazolyl?methyll-l-pyridazineacetic acid.
.The present invention also relates to compounds which
are useful as intermediates for preparing the compounds of
formula I having the general formula:
: i

2tO7~ 0~
` WO 92/17446 PCI'/US92/01603
. . ,:
-5- ;
CH2Co2R4 ::
R3 l ~ :
\ ~ ~N : ::
R 2J~l/ R 5
wherein
R5 is hydrogen or XRI wherein : ~
0 S ,. '
X is CH2, CH2CH2, -CHtCH3), -C~2-C-NH or -CH2-C-Nn; and :: .
s
Rl is CN, c~ or an optionally substituted group
:: : '
selected from phenyl, benzothiazol-2-yl, benzoxazol-2-yl, :
benzofuran-2-yl, benzothiophen-2-yl, thiazolopyridin-2-yl,
oxazolopyridin-2-yl, 3-phenyl 1,2,4-oxadiazol-5-yl, and 5- ~ -
phenyl-1,2,4-oxadiazol-3-yl wherein said substituted groups
are substituted with one or two substitutents that are .
:; independently selected from fluorine, chlorine, ~romine,
methyl, and trifluoromethyl;
R2 and ~3 are indepe~dently selected from hydrogenr (c,-
C4) alkyI, fluorine, chlorine, bromine, and trifluoromethyl :
- or R2 and R3 taken together with the carbons to which they
are attached form a group W, wherein W is
/ Ul
: ~ ~c~2)p ~ or ~ ~ ~
.....
~- 30 wherein p is 1 or 2 and U~ and u2 are independently CH2,
~; - O or S with the proviso that both Ul and U2 are not O or S;
: and R4 is (C,-C4) alkyl.
The present invention also relates to a pharmaceutical .
composition for inhibition of aldose reductase activity .
comprising a compound of formula I or a pharmaceutically
.

wog~ ~67lCil PCT/US92/01603
--6--
acceptable salt thereof in an amount effective in the
inhibition of aldose reducLasP ~c ivity, n admixtur~ with
a pharmaceutically acceptable car.ier. Specific and
preferred compositions con_ain t:~ spe_l ~ aild preLo~r-d
compounds of formula I as described above.
The 3resent invention furth~ a.~ o a method ~I
treating a diabetic host such as an anim~l or a human for
diabetes-associated com~lica;ions w;nich comprises
administering to the host an eI~'C~i'te ~elln~ of ~ compo-~ind
of formula I or a pharmac~u-'- c~ ac_ea.a~ sal~ .~e:^e~L.
Specific and preferraid ~etho~s com3~i~e ~d~inis~2ri~g
specific and preferred compounds of ~ ^...ula I as described
above.
The present invention further relates to a
pharmaceutical composition which can be used for lowering
blood uric acid levels in mammals, e.g., humans comprising
a compound of formula I or a pharmaceutically acceptable
salt thereof in an amount effective for lowering blood uric
acid levels in a admixture with a pharmaceutically
acceptable carrier.
The present invention also relates to a method of
lowering blood uric acid levels in a ma~malian subject which
comprises administering to a mammal in need or such
treatment an effective amount of a compound of formula I or
a pharmaceutically acceptable szlt thereof. Specific and
preferred methods comprise administering specific and
preferred compounds of formula I as described above.
Detailed Description of the I~vention
Unless otherwise indicated, the term "alkyl," as used
herein, includes linear branched and cyclic groups as well
as groups having both linear and cyclic or branched and
cyclic portions.
The term "prodrug" as used in the definition of R4
denotes a group that is converted in vivo resulting in
replacement by hydrogen. Such groups are generally known in
the art and include ester forming groups, to form an ester
prodrug, such as benzyloxy, di (Cl-C4) al~yl amino ethyloxy,
-, . . : .. . ~ , .; .; .: :: .

21Q7~0~
~ 092/17446 PCT/US92/Ot603
. .
-7- ~
acetoxymethyl, pivaloyloxymethyl, phthalidoyl, ethoxy ~ :
carbonyloxyethyl, 5-methyl-2-oxo-1,3-dioxol-4-yl methyl, and
(Cl-C4) alkoxy optionally substituted by N-morpholino and
amide-forming groups such as di (Cl-C4) alkylamino.
The compounds of the present invention are prepared as :
outlined in the following reaction scheme.
' -~
. , ":.
'
; ' ''.'.' ~:
: '
'
~ . ~

WO 92/17446 2 1 n 7 1 0 4 PCI~IJS92/01603 '-
`
N O
Z~C / ~ '' "'
O
~ ': .
2: _ ~ . .
X " Z ...
' o X ~ N
Z--Z ~ Z--= ,
~ r-~, Z~u ~, ~
~; ~ Z
m ~ .
~`' ' . , Z o~
o~ N U
.~ o U o /
~ ~~ '~
. , . ~ ~ l ~ l l
O U N
1 _ U :.",~
~ ~I =
~ ~ . m
~ ~ . ::.
- ~ \F ~ " ~ \F ~D
J

WO92/17~6 ~107t O4 PCT/US92/01603
_g_
Anhydrides of formula 1,4 and 8 are either commercially
available or may be prepared according to standard
procedures. The compounds of formula 2 wherein R3 is ethyl
or t-butyl are prepared by reacting the compounds 1 with (t-
butoxycarbonylmethylene)triphenylphosphorane or (car-
bothoxym_thylene)triphenylphosphorane, respectively, in the
Wittig reaction described in Tetrahedron Letters 1965,
2537.
The compounds of formula 5 may also be prepared by the
lo same procedure.
~he compounds of formula 9 are obtained using stand2r~
Reformatsky reaction conditions with zinc or zinc-copper
couple or using a variety of well-known modifications of the
Reformatsky reaction (see, for example, Tetrahedron Letters,
15 1984, 2569). Suitable solvents for the conversion of 8 to
9 include aromatic hydrocarbons (e.g., benzene) and dialkyl
ethers and cyclic ethers (e.g., tetrahydrofuran). The
temperature is preferably maintained at about 35C to about
100C, more preferably at reflux.
A compound of the formula 6 is prepared by standard
allylic bromination using N-bromosuccinic in refluxing
carbon tetrachloride.
The compounds of formula 3 are prepared by reacting the
compounds of formula 2, 6 or 9 with anhydrous or aqueous
hydrazine in an alcoholic solvent (e.g., ethanol) at a
temperature of about 20C to about 80C, preferably about
60C. Thus the temperature may be room temperature or the
reflux temperature of the solvent.
The compounds of formula 13 are obtained on reacting
compounds of formula 3 with L-X-RI wherein L is chloro or
bromo. The process is generally carried out in a polar
solvent such as an alkanol having one to four carbon atoms
(e.g. methanol or ethanol), dimethylformamide or
dimethylsulfoxide, in the presence of a base. Suitable
bases are alkali metal hydrides or alkoxides of one to four
carbon atoms, such as sodium or potassium hydride, methoxide
or ethoxide. When a hydride is used, a non-aqueous solvent

- 21071~
W092/17446 PCT/US92tO1603 ~- -
- --10--
such as dimethylformamide is required. The reaction is run
at room temperature, or at higher temper7tures (a~out 1~0C) ~-
to accelerate the process.
~he compounds of ~ormula 11 wherein Rl is ~h-n~1 Yi
hydroxy groups are prepared by demethylating the
corresponding methoxy groups. Demethylation is ~f--.~c_2 ~ ~7
refluxing hydrobromic acid or ~orontribromide in methylene
chloride at a temperature between about -70C and abcut 0C.
The preferred temperature is betw2en about -~0C and 2~0Ut
10 0C.
The compounds of formula 11 whPr2in X is CY,2, -HlCH,~ o.
-CH(CH3) and R' is optionàlly substituted ~en~otai~ole a _
also prepared via the compounds OI Iormula 13. The
compounds of formula 13 wherein X is CH2, CH2CH2, or -CH(CH3)
and Rl is CN are prepared by reacting compounds of formula 3
with L~-X-RI (wherein Ll is Cl or Br) in the presence of a
base. Suitable bases are alkali metal hydrides or alkoxides
of one to four carbon atoms. Suitable solvents for the
reaction include non-aqueous solvents such as
dimethylformamide and dimethylsulfoxide. The compounds of
formula 13 wherein Rl is CN are reacted with acid addition
salts of 2-aminobenzenethiols or aminopyridinethiols (e.a.,
hydrochlorides) in Cl to C4 alkanols at a temperature from
about 80C to reflux temperature of the solvent to obtain
compounds of the formula 11 wherein Rl is optionally
substituted benzothiazole. ~hese procedures are also
applicable to the preparation of compounds wherein R~ is
thiazolopyridine.
The compounds of formula 11 wherein R~ is 5 or 7
monosubstituted or 5,7-disubstituted benzothiazole with
substituents selected from fluorine, chlorine, bromine and
trifluoromethyl are also prepared via compounds of the
/5
formula 13 wherein R~ is CN or C/ . The compounds of
NH2
formula 13 (wherein X is CH2, CH2CH2, CH(CH3), Rl is CN or

W092/17446 2 1 0 7 1 0 ~ P~T/~S92/01603
c~\~ ) are reacted with a compound of formula 14 where A is
NH2
F, Cl, Br or I in the presence of hydrogen sulfide.
Generally, the reaction is conducted in a polar solvent.
Suitable solvents include sulfolane, pyridine and N-methyl
pyrrolidone. The preferred solvent is dimethylformamide.
The reaction temperature is yenerally between about 110C
and about 180C, preferably the reflux temperature of the
solvent. The compound of formula 13 wherPin R' is CN is
reacted with the compound of formula 14 in the presence of
lo a tertiary amine. Suitable tertiary amines are tri-(c~
C~j)alkylamines, e.g. triethylamine. These procedures are
also applicable to the preparation of compounds wherein Rl is
thiazolopyridine. The compound of the formula 13 wherein X
is CH2, CH2CH2, or CH(CH3) and Rl is ~ may be prepared by
lS reacting a compound of the formula 13 wherein X is CH2, CH2CH2
or CH(CH3) and Rl is CN with hydrogen sulfide in the presence
of tertiary amines such as tri (C2-C6) alkyl amines, e.g.
triethylamine, in the presence-of a solvent such as pyridine
or dimethylformamide. Preferably, the reaction is conducted
in dimethylformamide. Generally, the reaction is conducted
at temperatures between about ambient temperature
generally, about 25C) and about 100C. Preferably, the
reaction temperature is between abo`ut 40 and about 60C.
S ;
Il ' :.
Compounds of formula 11 wherein X is -C-NH- are -
prepared by reacting compounds of formula 11 wherein X is -
:: ...
0
I~ . .
-C-NH with phosphorous pentasulfide in aromatic hydrocarbon
solvents such as benzene, toluene or xylenes. The reaction
is run at between room temperature and 100C, preferably at
35 between 40-60C. ~; -

~ l U i l U ~
WO92/17446 PCT/US92/01603
The compounds of formula ll may be hydrolyzed to obtain
compounds of formula 12. ~he hydrolysis is carrl~d ou~
the presence of concentrated su~furic 2cld 3_
trifluoroac~tic acid when R~ is t-~utyl a~ abou oo^ L~
temperature. When R4 is methyl or ethyl, the hydrolysis
proceeds at conventional temp2r2Lures and in the p-~s2nse 3-^
acid or base such as mineral acid, for example nydroc`nloric
acid, or an alkali metal hydroxide such as sodium o
potassium hydroxide.
Unless otherwise indica.ed, th2 ~-_ssu~
foregoing reac.ions are no- c.itical. f-ens_~lly, _h_
reaction pressu-res will be in ,he range o^ a~ou_ o.,
atmospheres, preferably ambient pressure (abou~ on~
atmosphere).
The pharmaceutically acceptable salts or compounds or
the formula I may be formed with pharmaceutically acceptabie ~;~
cations by conventional methods. Thus, these salts may be
readily prepared by treating the compound of formula I with
an aqueous solution of the desired pharmaceutically
acceptable cation and evaporating the resulting solution to
dryness, preferably under reduced pressure. Alternatively,
a lower alXyl alcohol solution of the compound of formula I
may be mixed with an alkoxide of the desired metal and the
solution subsequently evaporated to dryness. Suitable
pharmaceutically acceptable cations for this purpose
include, but are not limited to, alkali metal cations such
as potassium and sodium, ammonium or water-soluble amine
addition salts such as N-methylglucamine(meglumine), the
lower alkanolammonium and other base salts with organic
amines which are pharmaceut^ically acceptable, and alkaline
earth metal cations such as calcium and magnesium.
The compounds of formula I and the pharmaceutically
acceptable salts thereof ~hereinafter, also referred to as
the active compounds) are useful as inhibitors of the enzyme
aldose reductase in the treatment of chronic complications
; of diabetes, such as diabetic cataracts, retinopathy
nephropathy and neuropathy. The active compounds can also

--~092/17~6 2 1 Q 7 ~ ~ 4 PCT/US92/01603
-13-
be used for lowering blood uric acid levels in mammals, e.g.
humans. Uric acid containing deposits (also known as
trophi) rPsulting from unphysiologically elevated plasma
uric acld levels tend to occur in various tissues throughout
the body, leading to the disease condition ~nown as gout and
gouty arthritis. Uric acid containing deposits in such
conditions may occur in cartilage, bone, bursae, tendons,
connective tissue overlying bony prominences, as well as,
subcutaneously and in the area of kidney. Elevated blood
uric acid l~vels also occur in number of other disease
conditions including myeloid leukemia, myeloid dysplasia,
pernicious anemia, psoriasis, diabetes mellitus and renal
disease. As used in the claims and specification hereof,
treatment is meant to include both the prevention and
alleviation of such conditions. The active compounds may be
administered to a subject in need of treatment by a variety
of conventional routes of administration, including orally,
parenterally and topically. In general, these compounds
will be administered orally or parenterally at dosages
between about 2 and lO0 mg/kg body weight of the subject to
be treated per day, preferably from 5 to 50 mg/kg per day.
However, some variation in dosage will necessarily occur
depending on the condition of the subject being treated.
The person responsible for administration will, in any
event, determine the appropriate does for the individual
subject.
The active compounds may be administered alone or in
combination with pharmaceutically acceptable carriers, in
either single or multiple doses. Suitable pharmaceutical
carriers include inert solid diluents or fillers, sterile
aqueous solution and various organic solvents. The
pharmaceutical compositions formed by combining the active
compounds and the pharmaceutically acceptable carriers are
then readily administered in a variety of dosage forms such
as tablets, powders, lozenges, syrups, injectable solutions
and the like. These pharmaceutical compositions can, if
desired, contain additional ingredients such as flavorings,

210710~
W092/17~6 PCT/US92/01603
binders, excipients and the like. Thus, for purposes of
oral administration, tablets containing various excipients
such as iodium citrate, calcium carbonate and calcium
phosphate may be employed along with various disintegran~
such as starch, alginic acid and certain complex silicates,
together with binding agents such as polyvinylpyrrolidonQ,
sucrose, gelatin and acacia. Additionally, lubricating
agents such as magnesium stearate, sodium lauryl sulfate and
talc are often useful for tabletting purposes. Solid
compositions of a similar type may 27 SO bQ Qmp7 o~er7 ~S . ~,
fillers in soft and hard fillQd gelatin capsules. ?rQrorrQ~
materials for this include lactose or milk sugar and h gh
molecular weight polyethylene glycols. When aqueous
suspensions or elixirs are desired for oral administration,
the essential active ingredient therein may be combined with
various sweetening or flavoring agents, coloring matter or
dyes and, if desired, emulsifying or suspending agents,
together with diluents such as water, ethanol, propylene
glycol, glycerin and combinations thereof.
For parenteral administration, solutions of an active
compound in sesame or peanut oil, aqueous propylene glycol,
or in sterile aqueous solution may be employed. Such
aqueous solutions should be suitably buffered if necessary
and the liquid diluent first rendered isotonic with
sufficient saline or glucose. These aqueous solutions are
especially suitable for intravenous, intramuscular,
subcutaneous and intraperitoneal administration. In this
connection, the sterile aqueous media employed are all
readily available by standard techniques known to those
skilled in the art.
~ he active compounds may not only be advantageously
employed for the preparation of aqueous pharmaceutical
compositions for parenteral administration, as described
above, but also for the preparation of pharmaceutical .
compositions suitable for use as ophthalmic solutions. Such
ophthalmic solutions are of principal interest for the
treatment of diabetic cataracts by topical administration
.' ' " .' . . " '. ' ' . ' ' ' 1 ' . , . . ; ' ' ' . ~ . '. ' . :, ' ' `,` ; ' .'` . ' ' ' ' ' ~' ' , .

: : `
-- WO92/17446 2 i 0 71 0 ~ PCT/US92/01603
-lS-
and the treatment of such conditions in this manner is a
preferred ~mbodiment of the present invention. Thus, for
the treatment of diabetic cataracts the active compounds of
this in~ention are administ~red to the eye of an ophthalmic
preparàtion prepared in accordance with conventional
pharmaceutical practic~, see for example "Remington~s
Pharmaceutical sciences~ 15th Edition, pa~es 1488 to 1501
(Mack Publishing co., Easton, Pa). The ophthalmic
prepara~lon will contain an active compound in a
concent.ation from about 3.01 to about 1% ~y weight,
preferably Crom about 0.05 to about 0.5~ in a
pharmaceutically acceptable solution, suspension or
ointment. Some variation in concentration will necessarily
occur, depending on the particular compound employed, the
condition of the subject to be treated and the like, and the
person responsible for treatment will determine the most
suitable concentration for the individual subject. The
ophthalmic preparation will preferably be in the form of a
sterile aqueous solution containing, if desired, additional
ingredients, for example preservatives, buffers, tonicity
agents, antioxidants and stabilizers, nonionic wetting or
clarifying agents, viscosity-increàsing agents and the like.
Suitable preservatives include benzalkonium chloride,
benzothonium chloride, chlorobutanol, thimerosal and the
like. Suitable buffers include boric acid, sodium and
potassium~bicarbonate, sodium and potassium borate, sodium
, and potassium carbonate, sodium acetate, sodium biphosphate
and the like, in amounts sufficient to maintain the pH at
between about 6 to 8, preferably between about 7 and 7.5.
Suitable tonicity agents are dextran 40, dextran 70,
dextrose, glycerin, potassium chloride, propylene glycol,
sodium chloride, and the like, such that the sodium chloride
equivalent of the ophthalmic solution is in the range 0.9
plus or minus 0.2%. Suitable antioxidants and stabilizers
include sodium bisuIfite, sodium metabisulfite, sodium
- thiosulfite, thiourea and the like. Suitable wetting and
clarifying agents include polysorbate 80, polysorbate 20,

21071~4
W092/17~6 PCT/US92/01603
-16-
poloxamer 282 and tyloxapol. Suitable viscosity-increasing
agents include dextran 40, dextran 70, gelatin, glycerin,
hydroxyethylcellulose, hydromethylpropylcellulose, lanolin,
methylcellulose, petrolatum, polyethylene glycol, polyvinyl
alcohol, polyvinylpyrrolidone, carboxymethylcellulose and
the li~e. The ophthalmic preparation will be administered
topically to the eye of the subject in need of treatment by
conventional methods, for example in the form of drops or ~y
bathing the ey~ in the ophthalmic solution.
The activity of the compounds of the present inv~n~
as agents for the control of chronic diabetic complications
may be detérmined ~y a number of standard biological or
pharmacological tests. Suitable tests include (l) measuring
their ability to inhibit the enzyme activity of isolated
aldose reductase; (2) measuring their ability to reduce or
inhibit sorbitol accumulation in the sciatic nerve and lens
of acutely streptozotocinized, i.e. diabetic, rats; (3)
measuring their ability to reverse already-elevated sorbitol
levels in the sciatic nerve and lens of chronic
streptozotocin-induced diabetic rats; (4) measuring their
ability to prevent or inhibit galactitol formation in the
lens of acutely -galactosemic rats; (5) measuring their
ability to delay cataract formation and reduce the severity
of lens opacities in chronic galactosemic rats; (6)
2S measuring their ability to prevent sorbitol accumulation and
cataract formation in isolated rat lens incubated with
glucose; and (7) measuring their ability to reduce already
elevated sorbitol levels in isolated rat lens incubated with
glucose.
30 ~ The present invention is illustrated by the following
- examples. It will be understood, however, that the
invention is not limited to the specific details of these
examples. In the examples, melting points are uncorrected.
:~ :
'

~` WO92/17~6 2 J. 0 7 1 ~ 4 PCT/US92/01603
-17-
Example 1
t-~utvl 3 4-dihvdro-4-oxo-5.6-dimethvl-3-~r5-ttri-
fluoromethyl)-2-benzothiazolyl]methyl~-1-pyridazine-1-
vlacetate
A. 3-oxo-4 5-dimethylfuran-1-ylidene acetic acid t-
butyl ester
A solution of 2,3-dimethylmaleic anhydride (6.3 g, 50
mmol) and (t-butoxycarbonylmethylene) triphenylphosphorane
(20.7 g, 55 mmol) in methylene chloride (200 mL) was
re'^lu~ed -o 16 hours. The solution was evaporated to
dryn~ss and the residue was purified by flash chromatography
on siiica gel using a 9:1 mixture of methylene chloride and
ethyl acetate to obtain 3-oxo-4,4-dimethylfuran-1-ylidene
acetic acid t-butyl ester (yield: 6.5 g; 60%).
B. t-butvl 5.6-dimethvl-4-oxo-pyridazine-1-vlacetate
A mixture of the tile compound of Example lA (1.3 g, 4
mmol), ethanol (5 mL) and hydrazine hydrate (3.9 mL, 8 mmol)
was stirred at room temperature for 1 hour. The reaction
mixture was diluted with water (2 mL) and acidified with
acetic acid (4 mL). The precipitated solid was collected,
washed with water and then air-dried to obtain the title
compound (yield: 1.3-g; 92~).
C. t-butyl 3.4-dihydro-4-oxo-5.6-dimethyl-3- r r 5-rtri-
fluoromethvl)-2-benzothiazolyl]methyl~-1-pyridazine-1-
ylacetate
To a solution of the title compound of Example lB (476mg, 2 mmol) in dimethylformamide (4 mL) was added potassium
t-butoxide (236 mg, 2.1 mmol) and stirred for 30 minutes at
room temperature. 2-Chloromethyl-5-trifluoromethylbenzo-
thiazole (554 mg, 2.2 mmol) was added to the reactionmixture and stirring continued for another 3 hours. The
reaction was quenched with water (20 mL), acidified to pH by
addition of sufficient dilute hydrochloric acid and
extracted with ethyl acetate. The ethyl acetate layer was
collected, evaporated to dryness and the residue was
chromatographed over silica gel. Elution with a 9:1 mixture
of methylene chloride and ethyl acetate gave the title

2~071~
W092/l7~6 PCT/US92/01603
-18-
compound (yield: 490 mg; 54%). tH NMR (CDCl3, 250 MHz)
1.45(s, 9H), 2.1(s, 3H), 2.2(s, 3H), 3.6(s, 2H), 5.7(s, 2H),
7.5(d, J=8 Hz, lH), 7.9(m, lH), 8.25(d, J= 8Hz, lH).
Example 2
t-butyl 3.4-dihydro-4-oxo-5,6-dimethyl-3- r L4-bromo-2-
fluoro!benzvl-l ~yridazine-1-ylacetate.
The title compound was prepared according to the
procedure set forth in Example lC (yield: 87%). lH NMR
(CDCl3 250 ~Hz~ 1.45 (s, 9H), 2.08(s, 3H), 2.15 (s, 3H),
3.5~' ~s, 2H), 5-.3 (s, 2H), 7.2 (~, 3H).
Exam~le 3
3 4-dihvdro-4-oxo-5.6-dimethyl-3-~[5-~trifluoromethv~-
2-benzothiazolYllmethyll-1-~yridazine acetic acid
The title compound of Example 1 (450 mg, 1 mmol) was
added to concentrated sulfuric acid (2 mL) and stirred at
room temperature for 30 minutes. The reaction was quenched
with ice-water (20 mL) and the resulting solid was
collected. The solid was crystallized from benzene to
provide the title compound (yield: 270 mg; 68~), m.p.
174C.
Exam~le 4
- 3.4-dihydro-4-oxo-5 6-dimethyl-3- r ( 4-bromo-2-
fluoro)benzyl)-1-pyridazine acetic acid
The title compound of Example 2 (740 mg, 1.74 mmol) was
added to trifluoroacetic acid (2 mL) and stirred at room
temperature for 30 min. The reaction was quenched with ice-
water (15 mL) and the precipitated solid was collected, air-
dried and crystallized from benzene to obtain the title
compound (yield: 115 mg; 33%), m.p. 162C.
ExamPle S
3-oxo-4 5-dihydrofuran-1-ylac~tic acid t-butvl ester
The title compound was prepared according to Example lA
starting from succinic anhydride in place of 2,3-
dimethylmaleic anhydride (1.98 g, 20 mmol); IH NMR (CDCl3,
35 300 MHz) ~ 1.5 (s, 9H), 2.72 (m, 2H), 3.35 (m, 2H), 5.62 (m,
lH). ;~
.'

WO92/17446 210 710 ~ PCT/US92/01603
-19-
Exam~le 6
5-bromo-3-oxo-4 5-dihvdrofuran-1-~laceticacid t-butvl
ester
A mixture of the title compound of Example 5 N-
bromosuccinimide (1.96 g, 11 mmol) and carbon tetrachloride(25 mL) was refluxed under a W lamp for 4 hours. The
reaction was cooled, excess carbon tetrachloride was
evaporated and the residue was chromatographed on silica
gel. Elution with a 1:1 mixture of methylene chloride and
n-hexane gave the title compound (yield, 2.1.g; 76%), IH NMR
(CDCl3, 300 MHz) ~ 1.5 (s,9H), 3.1 (m, lH), 3.4 (m, lH), 5.6
(s, lH), 5.8 (m, lH).
Exam~le 7
4-oxo-3-H-pYridazine-l-vlidene acetic acid t-butvl
ester
To a solution of the title compound of Example 6 (2.77
g, 10 mmol) in ethanol (10 mL) was added hydrazine hydrate
(1 mL, 20 mmol) and then stirred at room temperature for 16
h. Excess ethanol was evaporated and the concentrate was
extracted with ethyl acetate (15 mL). The organic extract
was washed with water, collected and evaporated to dryness.
The residue was chromatographed over silica gel. Elution
with a 1:1 mixture of methylene chloride and ethyl acetate
gave the title compound (yield, 1.03 g; 49~), m.p. 135C.
Exam~le 8
t-butvl-1 3-dihvdro-1-hvdroxy-3-oxo-5-methvl-1-isofuran
acetate
To a solution of citraconic anhydride (11.2 g, 0.1 mol)
in tetrahydrofuran (50 mL) was added zinc-copper couple
(15.0 g, 0.15 mol). Then t-butyl bromoacetate (23.4 g, 0.12
mol) was added slowly and then refluxed for 3 hours. The
reaction was cooled, filtered and the filtrate was
concentrated under vacuum. The residue was partitioned
between 6N hydrochloric acid (20 mL) and ethyl acetate (250
mL). The organic extract was collected and evaporated to
dryness. The residue was chromatographed over silica gel.
Elution with a 1:1 mixture of methylene chloride and ethyl
. _ .... ., ... . . ~ . .... .

~ ~ u ~ s
WO92/17~6 PCT/US92/01603
-20-
acetate gave the title compound (yield, 6.2; 27%), 1H NMR
(300 MHz, CDCl3) ~ 1.45 (s,9H), 2.05 (~,3H), 5.85 (s,lH).
Example 9
t-butyl 5-methyl-4-oxo-eyridazine-1-ylacetate
The title compound of Example 8 was dissolved in
ethanol (20 mL) and hydrazine hydrate (0.6 g, 12 mmol) was
added to the solution. After stirring for 4 h at room
temperature, the solution was concentrated by removing
excess ethanol and the concentrate was triturated with lN
hydrochloric acid (10 mL). The resulting solid was
collected, air-dried and crystallized from ethanol to obtain
the title compound (yield, 0.58 g; 24~), m.p. 114-116~C.
Example 10
(E) and rz~ 3-oxo-4 5-cvclohexanofuran-1-ylideneacetic
acid t-butyl ester
The title compound was prepared in 46% yield (11.1 g)
according to Example lA, starting from 3,4,5,6-
tetrahydrophthalic anhydride in place of 2,3-dimethylmaleic
anhydride (15.2 g, 0.1 mol). This mixture of E and Z
isomers was chromatographed over silica gel and eluted with
a 9l mixture of methylene chloride and ethyl acetate. The
less polar E isomer was eluted first. The more polar Z
isomer was obtained from later fractions.
Example 11
t-butvl 3.4-dihydro-4-oxo-5.6-cyclohexano~vridazine-1-
Ylacetate
A mixture of ~E) and (Z) 3-oxo-4,5-cyclohexanofuran-1-
ylideneacetic acid t-butyl ester (5.0 g, 20 mmol) (The title
compound of Example 10) was dissolved in ethanol (20 mL) and
to the solution was added hydrazine hydrate (2.5 g, 50
mmol). This was refluxed for 4 h and then evaporated to a
gummy residue. This was triturated with lN hydrochloric
acid (10 mL) to obtain the title compound as a white solid
(yield, 2.18 g; 44%), m.p. 179-181C.
.: :, , , . ~ : .. . . . , : . . .
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WO92/17446 2 1 0 7 1 0 ~ PCT/US92/01~3
-21-
Exam~le 12
t-Butyl 3.4-dihydro-4-oxo-5 6-diméthYl-3-cYanomethYl-l-
phthalazineacetate
To a solution of the title compound of Example lB t7.05
g, 29.6 mmol) in DMF (65 ml) was added potassium tert-
bitoxide (3.65g, 32.5 mmol) and stirred at ambient
temperature for 30 min. Bromoacetonitrile (4.26 g, 35.5
mmol) was added to it and stirring was continued for another
1.5 h. The reaction was quenched with water (200 mL),
acidified to pH 2 by addition of sufficient dilute
hydrochloric acid and the resulting solid was collected.
The solid was air-dried and then crystallized from a 3:1
mixture of cyclohexane and methylene chloride (6.26g, 76%);
mp, 120-123C.
ExamDle 13
Ethvl 3 4-dihYdro-4-oxo-5.6-cyclohexano-3-cYnanomethYl-
.-phthalazineacetate
The title compound (liquid) was prepared according to
Example 12, but starting from ethyl 5,6-cyclohexano-1-
phthalazineacetate (yield, 58%); ~HNMR (CDCl3, 300 MHz) ~1.25 (t,J=Hz, 3H), 1.8 (m,4H), 2.4 (m,2H), 2.6 (m, 2H), 4.1
(q, J~8 Hz, 2H), 5.0 (s, 2H).
Additional compounds prepared in accordance with the
present invention are shown in ~ables 1-3. Tables 1-3
include melting point or NMR spectrum for the compounds
; described. ;
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