Title of Invention

PHARMACEUTICAL COMPOSITION CONTAINING 4-OXOBUTANOIC ACIDS

Abstract The present invention relates to a pharmaceutical composition comprising, as active principle, a compound of formula: in which the groups A and B are chosen, independently of each other, from: - a mono-, bi- or tricyclic aryl group having from 6 to 14 carbon atoms; - a heteroaromatic group chosen from pyridyl, pyrimidyl, pyrrolyl, furyl and thienyl groups; - an alkyl group having from 1 to 14 carbon atoms; - a cycloalkyl group having from 5 to 8 carbon atoms; - a saturated heterocyclic group chosen from tetrahydrofuryl, tetrahydropyranyl, piperidyl and pyrrolidinyl groups; to its solvate or to a salt of this acid with a pharmaceutically acceptable base.
Full Text The present invention relates to pharmaceutical
compositions containing 4-oxobutanoic acids, which are
useful in particular in the treatment of diabetes.
The subject of the present invention is thus
pharmaceutical compositions comprising, as active
principle, a compound of formula:
in which the groups A and B are chosen, independently
of each other, from:
- a mono-, bi- or tricyclic aryl group having
from 6 to 14 carbon atoms;
- a heteroaromatic group chosen from pyridyl,
pyrimidyl, pyrrolyl,. furyl and thienyl groups;
- an alkyl group having from 1 to 14 carbon
atoms;
- a cycloalkyl group having from 5 to 8 carbon
atoms;
- a saturated heterocyclic group chosen from
tetrahydrofuryl, tetrahydropyranyl, piperidyl and
pyrrolidinyl groups;
it being possible for the groups A and B to
bear 1 to 3 substituents chosen from a Cj-Cj alkyl
group, Ca-C4 alkoxy group, Cs-Clt aryl group, a
heteroaryl group chosen from pyridyl, pyrimidyl,
pyrrolyl, furyl and thienyl, a (C6 - C14)aryl (C^-Cg) alkyl
group, a (C6 - C14) aryl (cx - Ct) alkyl (C6 - C14) aryl group,
halogen, a trifluoromethyl, trifluoromethoxy, cyano,
hydroxyl, nitro, amino, carboxyl, {Cx-Ce)alkoxycarbonyl,
carbamoyl, (C^-C,) alkyl sulphonyl, sulphoamino, (Cj,-
CJalkylsulphonylamino, sulphamoyl or (C^-
CJalkylcarbonylamino group,
or two of the substituents forming a
methylenedioxy group, its solvate or a salt of this
acid with a pharmaceutically acceptable base.
In a preferred embodiment of the invention, the
compositions comprise, as active principles, a compound
of formula I in which A and B are chosen from aryl
groups.
Examples of aryl groups which may be mentioned
are phenyl, a-naphthyl, (J-naphthyl and fluor^nyl
groups.
The Cj-C, alkyl groups may be linear or
branched. Examples which may be mentioned are methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl
and pentyl groups.
The Cx-Cs alkoxy groups may similarly be linear
or branched.
Examples which may be mentioned are methoxy,
ethoxy, propoxy, isopropoxy, butoxy, and isobutjpxy
groups.
The halogens may be chosen from fluorine,
chlorine, bromine and iodine.
The present invention encompasses compositions
which contain the tautomeric forms, the enantiomers,
the diastereoisomers and the epimers of the compounds
of formula I.
Examples of pharmaceutically acceptable salts
which may be mentioned are the sodium salts, potassium
•alts/ magnesium salts, calcium salts, amine salts and
other salts of the same type (aluminium, iron, bismuth,
etc.) .
In a preferred embodiment, the compositions
according to the invention comprise a compound chosen
from:
- 2-benzyl-4-(4-methoxyphenyl)-4-oxobutanoic acid
- 2-benzyl-4-(4-fluorophenyl)-4-oxobutanoic acid
- 2-cyclohexylmethyl-4-(4-methoxyphenyl)-4-oxobutanoic
acid
- 2-benzyl-4-phenyl-4-oxobutanoic acid
- 2-(0-naphthylmethyl)-4-phenyl-4-oxobutanoic acid
- 2-benzyl-4-((5-naphthyl)-4-oxobutanoic acid
- 2-[(4-chlorophenyl)methyl]-4-(4-methoxyphenyl)-4-oxo-
butanoic acid
- 2-benzyl-4-(4-methylphenyl)-4-oxobutanoic acid
- 4-(4-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-4-oxo-
butanoic acid
- 2-benzyl-4- (3,4-methylenedioxyphenyl) -4-oxobutanoic
acid
- 2-benzyl-4-cyclohexyl-4-oxobutanoic acid
- 4-phenyl-2- {(2-tetrahydrofuryl)methyl]-4-oxobutanoic
acid,
the solvates and the salts of these acids with
pharmaceutically acceptable bases.
Certain compounds of. formula I are _ known
(Bioorg. Chem. 14_,__14J,/„_.1&».$;l JLiochemist£y,_23^_2JU.3,
1984/ J.A.C.S. 100, 7750, 1978j.,,,ES-Ar31Q£l&J&nd
DE-A-3 839 401)
The subject of the present invention is also
the novel compounds of formula I, that is to say the
compounds of formula:
vs. COOH
o S
in which the groups A and B are chosen,
independently of each other/ from:
- a mono-, bi- or tricyclic aryl group having
from 6 to 14 carbon atoms;
- a heteroaromatic group chosen from pyridyl,
pyrimidyl, pyrrolyl, furyl and thienyl groups;
- an alkyl group having from l to 14 carbon
atoms;
- a cycloalkyl group having from 5 to 8 carbon
atoms;
- a saturated heterocyclic group chosen from
tetrahydrofuryl, tetrahydropyrranyl, piperidyl and
pyrrolidinyl groups;
it being possible for the groups A and B to
bear 1 to 3 substituents chosen from a C^Cj alkyl
group, q-Cg alkoxy group, C heteroaryl group chosen from pyridyl, pyrimidyl,
pyrrolyl, furyl and thienyl, a (Qt-Cl4) aryl (Cx-Cs) alkyl
group, a (C«-C14) aryl (Cj-Cj) alkyl (Ce-C14) aryl group,
halogen, a trifluoromethyl, trifluoromethoxy, cyano,
hydroxyl, nitro, amino, carboxyl, (C^CgJalkoxycarbonyl,
carbamoyl, (Ci-CJ alkylsulphonyl, sulphoamino, (Cx-
Cs)alkylsulphonylamino, sulphamoyl or (Ci-
C6)alkylcarbonylamino group,
or two of the substituents forming a
mfethylenedioxy group,
with the exclusion of the compounds of formula
I in which B is an unsubstituted phenyl group and A is
a phenyl, 4-methoxyphenyl, 4-chlorophenyl or cyclohexyl
group/
their solvates and the salts of these acids
with bases.
The novel compounds include the salts of jthe
acids with pharmaceutically acceptable bases or other
bases which give salts which may serve to identify,
purify or resolve the compounds of formula I.
The compounds of formula I may be prepared
according to a malonic synthesis which consists in
reacting a compound of formula:
A-C^X
J (id
in which X is a halogen as defined above and A
has the meaning given above,
with a malonic derivative of formula:
COOR
1 B (HI)
R'OOC N/*
in which R and R' are C^-Cg alkyl groups and B
has the meaning given above,
in the presence of an alkali metal hydride or
an alkali metal alkoxide, in order to form a compound
of formula:
A ^ COOR
V/NL-COOR'
:TX 1IV)
in which A, B, R and R' have the meaning given
above, and then in saponifying the compound of formula
IV, for example with a mixture of alkaline hydroxide,
water, tetrahydrofuran and/or ethanol, in order to form
a compound of formula:
The dosage may vary within a wide range
depending on the therapeutic indication and the route
of administration, as well as on the age and weight of
the patient.
The examples which follow illustrate the
preparation of the compounds of formula I.
BffffflPlf Ji
Preparation of 2-benzyl-4- (4-methoxyphenyl) -
4-oxobutanoic acid (product No. 2)
A - Preparation of diethyl 2-benzyl-
2- [2- (4-methoxyphenyl) -2-oxoethyl]propanedioate
A mixture of 24 ml of diethyl 2-benzylmalonate,
3 g of 80% sodium hydride in oil (washed beforehand
with petroleum ether) and 150 ml of tetrahydrofuran is
heated at 70°C for 1 hour. 24 g of 2-bromo-4' -methoxy-
acetophenone dissolved in 50 ml of tetrahydrofuran are
added, at +5°C, over 1 hour. After one night at room
temperature, the reaction mixture is poured into 400 ml
of water. After extraction with ethyl acetate, the
organic solution is washed with brine, dried over
magnesium sulphate and concentrated to dryness under
reduced pressure. 40 g of a yellow oil which
crystallizes are obtained.
m.p. - 67°c (hexane)
I.R. (KBr) : v CO (ketone) = 1671 cm"1; v CO
(ester) » 1735 cm"1
XH NMR (DMSO/TMS)
1.2 (6H, t, 2CH3) ; 3.35 (4H, d, 2CH2) ; 3.8 (3H,
s, OCH,) ; 4.1 (4H, q. 20CHa) ; 7.1 (7H, m, aromatic H) ;
7.85 (2H, d, aromatic H).
B - Preparation of 2-ben«yl-2-[2-(4-aethoxy-
phenyl)-2-oxoethylJpropanedioic acid
30 g of diethyl 2-benzyl-2-[2- (4-
methoxyphenyl)-2-oxo-ethyl]propanedioate, 80 ml of
aqueous 2N sodium hydroxide and 250 ml of
tetrahydrofuran are mixed together with vigorous
stirring.
After 5 days at room temperature, the reaction
mixture is poured onto 1 litre of ice-water. The
mixture is washed twice with 200 ml of ethyl acetate
and is then acidified, while cold, with 60 ml of
aqueous 3N hydrochloric acid-
The mixture is extracted with 3 times 200 ml of
ethyl acetate- The organic phase is washed with 100 ml
of neutral water, 100 ml of brine and then dried oyer
magnesium sulphate and, finally, concentrated to
dryness under reduced pressure. The greasy yellow solid
is recryatallized from acetonitrile. 18 g of a white
solid are obtained.
m.p. - 175°C, decomp.
I.R. (KBr) : v CO (ketone) = 1660 cm"1; v CO
(acid) - 1749 cm"1
lH NMR (DMSO/TMS)
3.1 (4H, s, 2CH,) ; 3.8 (3H, s, 0CHa) ; 7 (7H,! m,
aromatic H); 7.8 (2H, d, aromatic H); 13.7 (m, OH)
C - Preparation of 2-benzyl-4-(4-methoxy-
phenyl)-4-oxobutanoic acid
17 g of 2-benzyl-2-[2-(4-methoxyphenyl)-2-oxo-
ethyl]propanedioic acid are heated with 6tirring until
they melt. When the evolution of gas has ceased, the
heating is stopped and the material is cooled to room
temperature. The yellow solid is recrystallized from
ethyl acetate. 12 g of a white solid are obtained.
m.p. - 131°C
I.R. (KBr): v CO (ketone) = 1664 cm"1; v CO
(acid) ¦ 1729 cm"1
XH NMR (DMSO/TMS)
3.1 (5H, m, CH and 2CH2) ; 3.8 (3H, s, OCH3) ; 7.1
(7H, m, aromatic H); 7.9 (2H, d, aromatic H); 13.5 i (m,
OH) .
EXAMPLE 2
Preparation of (-)-2-benzyl-4-(4-methoxy-
phenyl)-4-oxobutanoie acid (product No. 3)
20 g of the acid obtained in Example 1 are
. dissolved in 200 ml of warm acetone. 8.12 g of S-(-)-
a-methylbenzylamine dissolved in 40 ml of acetone are
added. The mixture is cooled and the white solid is
filtered off and drained. After successive
recrystallization from isopropanol until the optical
deviation of the salt is stable, 7.3 g of a salt are
obtained, which product is treated with 100 ml of 2N
hydrochloric acid and 50 ml of ethyl ether with
yigorous stirring. The mixture is separated after
settling has taken place and the acidic aqueous phase
is extracted again with 50 ml of ethyl ether. Tha
combined ether solutions are washed once with neutral
water and then once with brine. The organic solution is
then dried over magnesium sulphate and concentrated to
dryness under reduced pressure at room temperature. The
residual oil crystallizes from pentane. 5.1 g of a
white solid are obtained.
m.p. - 94°C
HPLC purity > 95%;
[a]"D - -18°1 (c - 5, EtOAc).
EXAMPLE 3
Preparation of (+) -2-benzyl-4- (4-methoxy-
phenyl)-4-oxobutanoic acid (product No. 4)
The technique is the same as that used to
separate the (-) acid, except that R-(+)-o-methyl-
benzylamine is used here. A white solid is obtained.
m.p. - 93°C;
HPLC * 98%;
[a]19D « +17°6 (c - 5, EtOAc) .
EXAMPLE 4
Preparation of 2-benzyl-4-(4-fluorophenyl)-
4-oxobutanoic acid (product No. 5)
A - Preparation of diethyl 2-benzyl-2-[2-
(4-fruorophenyl)-2-oxoetbyl]propanedioate
The process is performed in the same way as in
Example 1, stage A. A copper-yellow oil is obtained.:
I.R. (film): v CO (ketone) = 1687 cm"1; v CO
(ester) = 1735 cm*1.
lH NMR (DMSO/TMS) - 1.25 (6H, t, 2CH3) ; 3.5 (4H,
d, 20^); 4.2 (4H, q. 20CH2) ; 6.8-8 (9H, m, aromatic H) .
B - Preparation of 2-benzyl-2-[2-(4-fluoro-
phenyl) - 2 - oxoethyl] propanedioic aoid
The process is performed in the same way as in
Example 1, stage B. A white solid is obtained.
m.p. ¦ 185-90°C (acetonitrile)
I.R. (KBr) : v CO (ketone) = 1675 cm-1; v CO
(acid) - 1747 cm"1.
XH NMR (DMSO/TMS): 3.3 (4H, d, 2CH,) ; 6.7-8 (9H,
m, aromatic H)/ 13 (m, OH).
C - Preparation of 2-benzyl-4- (4-fluorophenyl) -
4-oxobutanoic acid
The process is performed in the same way as in
Example 1, stage C. A yellow solid is obtained/ which
is recrystallized from acetonitrile. The white solid
thus obtained corresponds to the acid.
m.p. « 140°C
I.R. (KBr): v CO (ketone) = 1683 cm'1; v CO
(acid) - 1708 cm'1.
*H NMR (DMSO/TMS): 3 (5H, m, CH and 2CH2) ; 7-8.1
(9H, m, aromatic H); 12.2 (s, OH).
EXAMPLE 5
Preparation of (+)-2-beazyl-4-(4-fluorophenyl)-
4-oxobutanoic acid (product No. 6)
The same method is used as in Example 4. A
white solid is obtained,
m.p. = 88°C;
HPLC - 99.8*;
[Ccj"D « +9°9 (C - 5, EtOAc)
EXAMPLE 6
Preparation of (-)-2-benzyl-4-(4-fluorophenyl)-
4-oxobutanoic acid (product No* 7)
The same method as in Example 3 is used. A
white solid is obtained.
m.p. = 89°C;
HPLC = 98.5%;
[a]M0 - -8*9 (c - 10, EtAOc) .
The characteristics of the compounds of formula
I are collated in Table I below. -?
Results of the pharmacological studies will be given
below.
f
\ 1 - Study of the antidiabetic activity in nOSTZ
rats
\ The antidiabetic activity of the compounds of
,;formula I was determined orally on an experimental
model of insulin-independent diabetes induced in rats
by streptozocin.
The model of insulin-independent diabetes; is
obtained in rats by neonatal injection (on the day of
birth) of streptozocin.
The diabetic rats used are 8 weeks old.
Stabling of the animals is carried out, from
the day of their birth to the day of the experiment; in
an animal house at a controlled temperature of 21 to
22°C, and subjected to a fixed cycle of light (from
7.00 h to 19.00 h) and of darkness (from 19.00 h to
7.00 h). Their feeding consisted of a maintenance diet;
water and food were supplied *ad libitum", with } the
exception of the 2-hour fasting period preceding!'the
tests, during which the food is removed (postabsorptive
state).
The rats are treated orally during the day with
the test product. 2 hours after the final
administration of the product and 30 minutes after
anaesthetizing the animals with pentobarbital sodium
(Nembutal®) , a 300 /il blood sample is taken from the
end of the tail.
Table II collates the main results obtained:
These results show the efficacy of , the
compounds of formula I for decreasing glycaemia in; the
diabetic animals.
Certain compounds of formula I also have a
precocious insulin-secretory effect of short duration.
2 - Study in non-diabetic rate
On the day of the experiment, non-diabetic fats
are treated orally with the test product. 300 fil blood
samples are taken from the end of the rats' tails in
the first 30 minutes following administration of -the
product.
By way of example, the results obtained with
product No. 5 (200 mg/kg p.o.) will be given.

A reduction in the glycaemia is observed,
without observing any significant increase in the level
of insulin, but rather a decrease in this level.
3 - Test of toxicity
Products Nos. 5 and 6 administered orally at a
dose of 200 mg/kg induced no sign of toxicity.
4 - Action on the secretion of glucagon
Experiments carried out in vitro on infused
pancreas from non-diabetic rats, isolated according to
466,
1966) modified by Assan et al., (Nature 239: 125, 1972)
showed that in the absence of glucose, in the infusion
medium, as well as in the presence of arginine, the
secretion of glucagon was stimulated by the compounds
of formula I. Under the same conditions, sulphonylureas
have a pronounced inhibitory effect. Nevertheless, in
the presence of a high glucose concentration, the
compounds of formula I do not modify the inhibition of
the secretion of glucagon by glucose. The risk's of
hypoglycaemia associated with the treatment : - with
sulphonylureas will thus be avoided during treatments
with the compounds of formula I.
We Claim:
1. Pharmaceutical composition comprising,
as active principle, a compound chosen from the group:
- 2-benzyl-4-(4-methoxyphenyl)-4-oxobutanoic acid
*- 2-benzyl-4-(4-fluorophenyl)-4-oxobutanoic acid
! - 2-cyclohexylmethyl-4-(4-methoxyphenyl)-4-oxobutanoic acid
- 2-benzyl-4-phenyl-4-oxobutanoic acid
- 2-(ß-naphthylmethyl)-4-phenyl-4-oxobutanoic acid
- 2-benzyl-4-(ß-naphthyl)-4-oxobutanoic acid
- 2- [(4-chlorophenyl)methyl)-4-(4-methoxyphenyl)-4-oxobutanoic acid
- 2-benzyl-4-(4-methylphenyl)-4-oxobutanoic acid
- 4-(4-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-4-oxobutanoicacid
- 2-benzyl-4-(3,4-methylenedioxyphenyl)-4-oxobutanoic acid
- 2-benzyl-4-cyclohexyl-4-oxobutanoic acid
- 4-phenyl-2-[(2-tetrahydrofuryl)methyl]-4-oxobutanoic acid
the solvates and the salts of these acids with pharmaceutically acceptable
bases.
2. Compounds selected from the group:
- 2-benzyl-4-(4-methoxyphenyl)-4-oxobutanoic acid
- 2-benzyl-4-(4-fluorophenyl)-4-oxobutanoic acid
- 2-cyclohexylmethyl-4-(4-methoxyphenyl)-4-oxobutanoic acid
- 2-benzyl-4-phenyl-4-oxobutanoic acid
- 2-(ß-naphthylmethyl)-4-phenyl-4-oxobutanoic acid
- 2-benzyl-4-(ß-naphthyl)-4-oxobutanoic acid
- 2- [(4-chlorophenyl)methyl)-4-(4-methoxyphenyl)-4-oxobutanoic acid
- 2-ben2yl-4-(4-methylphenyl)-4-oxobutanoic acid
- 4-(4-fluorophenyl)-2- [(4-methoxyphenyl)methyl] -4-oxobutanoic acid
- 2-benzyl-4-(3,4-methylenedioxyphenyl)-4-oxobutanoic acid
- 2-benzyl-4-cyclohexyl-4-oxobutanoic acid
- 4-phenyl-2-[(2-tetrahydrofuryl)methyl]-4-oxobutanoic acid
their solvates and the salts of these acids with bases.


The present invention relates to a pharmaceutical composition comprising,
as active principle, a compound of formula:

in which the groups A and B are chosen, independently of each other, from:
- a mono-, bi- or tricyclic aryl group having from 6 to 14 carbon atoms;
- a heteroaromatic group chosen from pyridyl, pyrimidyl, pyrrolyl, furyl
and thienyl groups;
- an alkyl group having from 1 to 14 carbon atoms;
- a cycloalkyl group having from 5 to 8 carbon atoms;
- a saturated heterocyclic group chosen from tetrahydrofuryl,
tetrahydropyranyl, piperidyl and pyrrolidinyl groups;
to its solvate or to a salt of this acid with a pharmaceutically acceptable base.

Documents:

1449-cal-1997-abstract.pdf

1449-cal-1997-claims.pdf

1449-cal-1997-correspondence-1.1.pdf

1449-cal-1997-correspondence.pdf

1449-cal-1997-description (complete).pdf

1449-cal-1997-examination report-1.1.pdf

1449-cal-1997-examination report.pdf

1449-cal-1997-form 1.pdf

1449-cal-1997-form 18-1.1.pdf

1449-cal-1997-form 18.pdf

1449-cal-1997-form 2.pdf

1449-cal-1997-form 3-1.1.pdf

1449-cal-1997-form 3.pdf

1449-cal-1997-form 5.pdf

1449-cal-1997-form 6.pdf

1449-cal-1997-gpa-1.1.pdf

1449-cal-1997-gpa.pdf

1449-cal-1997-granted-abstract-1.2.pdf

1449-cal-1997-granted-abstract1.1.pdf

1449-cal-1997-granted-claims-1.1.pdf

1449-cal-1997-granted-claims.pdf

1449-cal-1997-granted-correspondence.pdf

1449-cal-1997-granted-description (complete)-1.1.pdf

1449-cal-1997-granted-description (complete).pdf

1449-cal-1997-granted-examination report.pdf

1449-cal-1997-granted-form 1-1.1.pdf

1449-cal-1997-granted-form 1.pdf

1449-cal-1997-granted-form 18.pdf

1449-cal-1997-granted-form 2-1.1.pdf

1449-cal-1997-granted-form 2.pdf

1449-cal-1997-granted-form 5.pdf

1449-cal-1997-granted-letter patent.pdf

1449-cal-1997-granted-reply to examination report.pdf

1449-cal-1997-granted-specification-1.1.pdf

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1449-cal-1997-others-1.1.pdf

1449-cal-1997-others.pdf

1449-cal-1997-reply to examination report-1.1.pdf

1449-cal-1997-reply to examination report.pdf

1449-cal-1997-specification.pdf

1449-cal-1997-translated copy of priority document.pdf


Patent Number 244524
Indian Patent Application Number 1449/CAL/1997
PG Journal Number 50/2010
Publication Date 10-Dec-2010
Grant Date 09-Dec-2010
Date of Filing 05-Aug-1997
Name of Patentee MERCK PATENT GESELLSCHAFT MIT RESCHRANKTER HAFTUNG
Applicant Address DARMSTADT, FRANKFURTER STRASSE 250
Inventors:
# Inventor's Name Inventor's Address
1 MR. PHILIPPE MAYZERAY C/P. MERCK KGAA, 64271 DARMSTADT
2 MR. GERARD MOINET 15, RUE LAMARTINE 91400
3 MICHELINE KERGOAT MELLE 5, VILLA DES BOIS 91440 BURES SUR YVETTE
4 MR. DIDIER MESANGEAU 5, RUE AUGUSTE RENOIR 77380 COMBS LA VILLE
5 LILIANE DOARE MME 33 AVENUE MARMONT 91170 VIRY CHATILLON
PCT International Classification Number C07D 317/60
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 FR 9610254 1996-08-16 France