Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2003-01-07
2004-07-06
Shah, Mukund J. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
active
06759534
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for preparing sulfonyl pyridazinone aldose reductase inhibitors. The present invention also relates to novel intermediates used in the process to prepare those aldose reductase inhibitors. Accordingly, the compounds prepared by the process of this invention lower sorbitol levels and, thus, lower fructose levels and have utility in the treatment and/or prevention of diabetic complications such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic microangiopathy and diabetic macroangiopathy in mammals.
BACKGROUND OF THE INVENTION
The enzyme aldose reductase is involved in regulating the reduction of aldoses, such as glucose and galactose, to their corresponding polyols, such as sorbitol and galactitol. Sulfonyl pyridazinone compounds of Formula I of this invention, prodrugs of such compounds and pharmaceutically acceptable salts of such compounds and prodrugs, are useful as aldose reductase inhibitors in the treatment and prevention of diabetic complications of humans and other mammals associated with increased polyol levels in certain tissues (e.g., nerve, kidney, lens and retina tissue) of affected humans and other mammals.
Commonly assigned U.S. Provisional Patent Application No. 60/280,051, which is incorporated herein by reference, discloses compounds of the formula
wherein A, R
1
, R
2
and R
3
are defined as set forth therein.
SUMMARY OF THE INVENTION
This invention is directed to a process for preparing a compound of the formula
wherein R
1
and R
2
are each independently hydrogen or methyl; and R
3
, R
4
, R
5
and R
6
are each independently H, halo, formyl, (C
1
-C
6
)alkyl optionally substituted with up to three fluoro, (C
1
-C
6
)alkoxy optionally substituted with up to three fluoro, (C
1
-C
6
)alkoxycarbonyl, (C
1
-C
6
)alkylenyloxycarbonyl, (C
1
-C
4
)alkoxy-(C
1
-C
4
)alkyl, (C
1
-C
4
)alkylcarbonylamido, (C
3
-C
7
)cycloalkylcarbonylamido, phenylcarbonylamido, benzyl, phenyl or naphthyl, wherein said benzyl, phenyl and naphthyl are optionally independently with up to two substituents independently selected from halo, (C
1
-C
6
)alkyl optionally substituted with up to three fluoro, (C
1
-C
6
)alkoxy optionally substituted with up to three fluoro and (C
1
-C
4
)alkoxy-(C
1
-C
4
)alkyl;
comprising the consecutive steps of:
(a) reacting a compound of the formula
wherein R
3
, R
4
, R
5
and R
6
are each independently defined as set forth above, with an organolithium compound in the presence of a sulfur source in a first reaction inert solvent to form the reactive intermediate
(b) reacting said reactive intermediate IIa with a compound of the formula
to form a compound of the formula
(c) reacting said compound of the formula IV with an alkaline (C
1
-C
2
)alkoxide in a (C
1
-C
2
)alkanol to form an ether compound of the formula
wherein Alk is (C
1
-C
2
)alkyl;
(d) reacting said compound of the formula V with a mineral acid to form a compound of the formula
(e) oxidizing said compound of the formula VI in a second reaction inert solvent to form a compound of the formula I.
In a preferred process of this invention, step (c) and step (d) are performed together in situ. In a further preferred process of this invention, in step (a) said organolithium compound is n-butyllithium, said first reaction inert solvent is tetrahydrofuran and said sulfur source is S
8
; in step (c) said alkaline (C
1
-C
2
)alkoxide is sodium methoxide and said (C
1
-C
2
)alkanol is methanol; and in step (d) said compound of formula VI is oxidized with urea-hydrogen peroxide in the presence of trifluoroacetic anhydride and said second reaction inert solvent is tetrahydrofuran.
In a still further preferred process of this invention, R
3
, R
4
, R
5
and R
6
are each independently hydrogen, methyl, methoxy, chloro, fluoro, ethyl, 4-fluorophenyl, trifluoromethyl, isopropyl or phenyl. In a still further preferred process of this invention, R
1
, R
2
, R
4
and R
5
are each hydrogen; R
3
is 3-methyl and R
6
is 5-chloro.
This invention is also directed to compounds of the formula
and pharmaceutically acceptable salts thereof, wherein R
1
and R
2
are each independently hydrogen or methyl; and R
3
, R
4
, R
5
and R
6
are each independently H, halo, formyl, (C
1
-C
6
)alkyl optionally substituted with up to three fluoro, (C
1
-C
6
)alkoxy optionally substituted with up to three fluoro, (C
1
-C
6
)alkoxycarbonyl, (C
1
-C
6
)alkylenyloxycarbonyl, (C
1
-C
4
)alkoxy-(C
1
-C
4
)alkyl, (C
1
-C
4
)alkylcarbonylamido, (C
3
-C
7
)cycloalkylcarbonylamido, phenylcarbonylamido, benzyl, phenyl or naphthyl, wherein said benzyl, phenyl and naphthyl are optionally independently with up to two substituents independently selected from halo, (C
1
-C
6
)alkyl optionally substituted with up to three fluoro, (C
1
-C
6
)alkoxy optionally substituted with up to three fluoro and (C
1
-C
4
)alkoxy-(C
1
-C
4
)alkyl.
A preferred group of compounds of formula IV of this invention are those compounds, designated as Group A, and pharmaceutically acceptable salts thereof, wherein R
3
, R
4
, R
5
and R
6
are each independently hydrogen, methyl, methoxy, chloro, fluoro, ethyl, 4-fluorophenyl, trifluoromethyl, isopropyl or phenyl.
A preferred compound of this invention is the compound wherein R
1
, R
2
, R
4
and R
5
are each hydrogen; R
3
is 3-methyl and R
6
is 5-chloro, having the structure
This invention is also directed to a process for preparing a compound of the formula IV above wherein R
1
and R
2
are each independently hydrogen or methyl; R
3
, R
4
, R
5
and R
6
are each independently H, halo, formyl, (C
1
-C
6
)alkyl optionally substituted with up to three fluoro, (C
1
-C
6
)alkoxy optionally substituted with up to three fluoro, (C
1
-C
6
)alkoxycarbonyl, (C
1
-C
6
)alkylenyloxycarbonyl, (C
1
-C
4
)alkoxy-(C
1
-C
4
)alkyl, (C
1
-C
4
)alkylcarbonylamido, (C
3
-C
7
)cycloalkylcarbonylamido, phenylcarbonylamido, benzyl, phenyl or naphthyl, wherein said benzyl, phenyl and naphthyl are optionally independently with up to two substituents independently selected from halo, (C
1
-C
6
)alkyl optionally substituted with up to three fluoro, (C
1
-C
6
)alkoxy optionally substituted with up to three fluoro and (C
1
-C
4
)alkoxy-(C
1
-C
4
)alkyl;
comprising the consecutive steps of:
(a) reacting a compound of the formula II wherein R
3
, R
4
, R
5
and R
6
are each independently defined as set forth above with an organolithium compound in the presence of a sulfur source in a reaction inert solvent to form a reactive intermediate of the formula IIa; and
(b) reacting said reactive intermediate IIa with a compound of the formula III to form a compound of the formula IV.
In that process, it is preferred that said organolithium compound is n-butyllithium, said reaction inert solvent is tetrahydrofuran and said sulfur source is S
8
. It is particularly preferred that R
3
, R
4
, R
5
and R
6
are each independently hydrogen, methyl, methoxy, chloro, fluoro, ethyl, 4-fluorophenyl, trifluoromethyl, isopropyl or phenyl. It is still further preferred that R
1
, R
2
, R
4
and R
4
are each hydrogen; R
3
is 3-methyl and R
6
is 5-chloro.
This invention is also directed to a process for preparing the compound of the formula
comprising the consecutive steps of:
(a) reacting the compound of the formula
with n-butyllithium in the presence of S
8
in tetrahydrofuran to form the reactive intermediate
(b) reacting said reactive intermediate XIIa with the compound of the formula
to form the compound of the formula
(c) reacting said compound of the formula XIV with sodium methoxide in methanol to form the compound of the formula
(d) reacting said compound of the formula XV with concentrated hydrochloric acid to form the compound of the formula
(e) oxidizing said compound of the formula XVI with hydrogen peroxide-urea complex in the presence of trifluoroacetic anhydride in tetrahydrofuran to form the compound of the formula XI. It is particularly preferred that step (c) and step (d) are performed in situ.
The subje
Benson Gregg C.
Goddard Carl J.
McKenzie Thomas
Pfizer Inc.
Richardson Peter C.
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