HK1021728B - Pharmaceutical composition containing 4-oxo-butynic acids - Google Patents

Description

Pharmaceutical composition containing 4-oxo-butyric acid

The present invention relates to a pharmaceutical composition containing 4-oxobutanoic acid, which is extremely effective in the treatment of diabetes.

Accordingly, an object of the present invention is a pharmaceutical composition comprising as an active ingredient a compound of formula I:wherein the groups A and B are independently of each other selected from:

-mono-, bi-or tricyclic aryl having 6 to 14 carbon atoms;

-heteroaryl, selected from pyridyl, pyrimidinyl, pyrrolyl, furanyl and thienyl;

-an alkyl group having 1 to 14 carbon atoms;

-cycloalkyl having 5 to 8 carbon atoms;

-a saturated heterocyclic group selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, piperidinyl and pyrrolidinyl;

the groups A and B may carry 1 to 3 substituents selected from: c₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₆-C₁₄Aryl, heteroaryl, the heteroaryl is selected from pyridyl, pyrimidyl, pyrrolyl, furyl and thienyl, (C)₆-C₁₄) Aryl radical (C)₁-C₆) Alkyl, (C)₆-C₁₄) Aryl radical (C)₁-C₆) Alkyl radical (C)₆-C₁₄) Aryl, halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, nitro, amino, carboxy, (C)₁-C₆) Alkoxycarbonyl, carbamoyl, (C)₁-C₆) Alkylsulfonyl, sulfamino, (C)₁-C₆) Alkylsulfonylamino, sulfamoyl or (C)₁-C₆) Alkylcarbonylamino, or two of these substituents together form methylenedioxy.

In a preferred embodiment of the present invention, the composition comprises as active ingredient a compound of formula I wherein a and B are selected from aryl.

The aryl group may be, for example, phenyl, α -naphthyl, β -naphthyl and fluorenyl.

C₁-C₆The alkyl group may be linear or branched. The group may be, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl.

C₁-C₆The alkoxy groups can likewise be straight-chain or branched. The group may be, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutoxy.

Halogen may be selected from fluorine, chlorine, bromine and iodine;

the scope of the present invention includes compositions comprising tautomers, enantiomers, diastereomers and epimers of the compounds of formula I.

The pharmaceutically acceptable salts may be, for example, sodium, potassium, magnesium, calcium, amine (aminesalts) and other salts of the same type (aluminum, iron, bismuth, etc.).

In a preferred embodiment, the composition of the invention comprises a compound selected from the group consisting of:

-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- (. beta. -naphthylmethyl) -4-phenyl-4-oxobutanoic acid

-2-benzyl-4- (. beta. -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-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, and

solvates thereof and salts of these acids with pharmaceutically acceptable bases.

Certain compounds of formulｃA I are known substances (bio-organic chemistry [ Bioorg. chem. ], 14, 148, 1986; Biochemistry [ Biochemistry ], 23, 2083, 1984; journal of the American chemical society [ J.A.C.S ], 100, 7750, 1978; EP-A-310918 and DE-A-3839401).

The present invention also aims at novel compounds of formula I, i.e. compounds of formula (I):

wherein the groups A and B are independently of each other selected from:

-mono-, bi-or tricyclic aromatic groups having 6 to 14 carbon atoms;

-a heteroaryl group selected from pyridyl, pyrimidinyl, pyrrolyl, furanyl and thienyl;

-an alkyl group having 1 to 14 carbon atoms;

-cycloalkyl having 5 to 8 carbon atoms;

-a saturated heterocyclic group selected from tetrahydrofuranyl, tetrahydropyranyl, piperidinyl and pyrrolidinyl;

the groups A and B may carry 1 to 3 substituents selected from: c₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₆-C₁₄An aromatic group; heteroaryl selected from the group consisting of pyridyl, pyrimidinyl, pyrrolyl, furanyl and thienyl; (C)₆-C₁₄) Aryl radical (C)₁-C₆) Alkyl, (C)₆-C₁₄) Aryl radical (C)₁-C₆) Alkyl radical (C)₆-C₁₄) Aryl, halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, nitro, amino, carboxy, (C)₁-C₆) Alkoxycarbonyl, carbamoyl, (C)₁-C₆) Alkylsulfonyl, sulfamino, (C)₁-C₆) Alkylsulfonylamino, sulfamoyl or (C)₁-C₆) Alkylcarbonylamino, or two of said substituents together form methylenedioxy.

With the proviso that compounds of the formula I do not include those in which B is unsubstituted phenyl and A is phenyl, 4-methoxyphenyl, 4-chlorophenyl or cyclohexyl,

as well as solvates thereof and salts of these acids with bases.

The novel compounds include salts of acids with pharmaceutically acceptable bases or salts with other bases which can be used to identify, purify or resolve compounds of formula I.

The compounds of formula I may be prepared according to a malonic acid synthesis comprising reacting a compound of the formula:

wherein X is halogen as defined above and a is as defined above, with a malonic acid derivative of the formula:

wherein R and R' are C₁-C₆Alkyl and B has the above-mentioned meaning,

the reaction is carried out in the presence of an alkali metal hydride or alkoxide, with the aim of forming a compound of formula:

wherein A, B, R and R' have the above definitions; subsequent saponification of the compound of formula IV, for example with a mixture of alkali metal hydroxide, water, tetrahydrofuran and/or ethanol, gives the compound of the formula:

and, thereafter decarboxylating (especially by heating to dryness) the compound of formula V to provide the compound of formula I.

The separation of the enantiomers of the compound of formula (I) is accomplished by: namely, continuous recrystallization of a salt formed by an acid of the formula (I) and an optically active base in a solvent such as acetone, ethyl acetate, isopropyl alcohol, etc.; the optically active acid is then displaced from the salt by a mineral or organic acid according to standard procedures.

The compositions of the present invention are suitable for the treatment of diabetes, particularly non-insulin-dependent diabetes mellitus (insulin-independent), due to the blood glucose lowering efficacy of the compositions at effective doses and their non-toxicity.

The pharmaceutical compositions of the present invention may be administered parenterally, orally, rectally, transmucosally (permucous), or transdermally.

Thus, their pharmaceutical forms are: multiple dose bottled or injectable solutions or suspensions, plain or coated tablets, sugar-coated tablets, wafer capsules, gelatin capsules, pills, cachets, powders, suppositories, rectal capsules, solutions or suspensions in polar solvents for transdermal or transmucosal administration.

Suitable excipients for administration are cellulose derivatives or microcrystalline cellulose, carbonates of alkaline earth metals, magnesium phosphate, starch, modified starches and lactose in solid form.

For rectal administration, the preferred excipient is cocoa butter or a stearate of polyethylene glycol.

For parenteral administration, the media conventionally used are water, aqueous solutions, physiological saline and isotonic solutions.

The dosage employed may vary within wide limits depending on the indication treated, the route of administration and the age and weight of the patient.

The following examples describe the preparation of the compounds of formula I.

Example 1

Preparation of 2-benzyl-4- (4-methoxyphenyl) -4-oxobutanoic acid (product 2)

Preparation of diethyl A-2-benzyl-2- [ 2- (4-methoxyphenyl) -2-oxoethyl ] malonate

A mixture of 24ml of diethyl 2-benzylmalonate, 3g of 80% sodium hydride oil (pre-washed with petroleum ether before use) and 150ml of tetrahydrofuran was heated at 70 ℃ for 1 hour. 24g of 2-bromo-4' -methoxyacetophenone dissolved in 50ml of tetrahydrofuran are added at +5 ℃ over 1 hour. The reaction mixture was poured into 400ml of water at room temperature overnight. After extraction with ethyl acetate, the organic solution was washed with brine, dried over magnesium sulfate and concentrated to dryness under reduced pressure. 40g of crystalline yellow oil are obtained.

m.p. 67 ℃ (hexane)

I.r. (KBr): v CO (acetone) ═ 1671cm^-1(ii) a V CO (ester) 1735cm^-1

¹H NMR(DMSO/TMS)

1.2(6H，t，2CH₃)；3.35(4H，d，2CH₂)；3.8(3H，s，OCH₃)；4.1(4H，q，2OCH₂) (ii) a 7.1(7H, m, aromatic ring H); 7.85(2H, d, aromatic ring H).

Preparation of B-2-benzyl-2- [ 2- (4-methoxyphenyl) -2-oxoethyl ] malonic acid

30g of diethyl 2-benzyl-2- [ 2- (4-methoxyphenyl) -2-oxoethyl ] malonate, 80ml of a 2N aqueous sodium hydroxide solution and 250ml of tetrahydrofuran were mixed under vigorous stirring.

After 5 days at room temperature, the reaction mixture was poured into 1L of ice water. The resulting mixture was washed 2 times with 200ml of ethyl acetate and subsequently acidified with 60ml of 3N aqueous hydrochloric acid under cooling.

The resulting mixture was extracted 3 times with 200ml of ethyl acetate. The organic phase obtained is washed with 100ml of neutral water, 100ml of brine and dried over magnesium sulfate and finally concentrated to dryness under reduced pressure. The greasy yellow solid was recrystallized from acetonitrile to yield 18g of a white solid.

Decomposing at 175 deg.C

I.r. (KBr): v CO (acetone) ═ 1660cm^-1(ii) a V CO (acid) ═ 1749cm^-1

¹H NMR(DMSO/TMS)

3.1(4H，s，2CH₂)；3.8(3H，s，OCH₃) (ii) a 7(7H, m, aromatic ring H); 7.8(2H, d, aromatic ring H); 13.7(m, OH).

Preparation of C-2-benzyl-4- (4-methoxyphenyl) -4-oxobutanoic acid

17g of 2-benzyl-2- [ 2- (4-methoxyphenyl) -2-oxoethyl ] malonic acid are heated with stirring until they melt. When the gas evolution ceased, the heating was stopped and the result cooled to room temperature. The resulting yellow solid was recrystallized from ethyl acetate to give 12g of a white solid.

m.p.＝131℃

I.r. (KBr): v CO (acetone) ═ 1664cm^-1(ii) a V CO (acid) ═ 1729cm^-1

¹H NMR(DMSO/TMS)

3.1(5H，m，CH and 2CH₂)；3.8(3H，s，OCH₃) (ii) a 7.1(7H, m, aromatic ring H); 7.9(2H, d, aromatic ring H); 13.5(m, OH).

Example 2

Preparation of (-) -2-benzyl-4- (4-methoxyphenyl) -4-oxobutanoic acid (product 3)

20g of the acid from example 1 were dissolved in 200ml of hot acetone. 8.12g of S- (-) - α -methylbenzylamine dissolved in 40ml of acetone was added. The mixture was cooled, filtered and a white solid was isolated. Recrystallization was continued in isopropanol until the optical deviation of the salt (polarization) was stabilized to give 7.3g of salt; the product is treated with 100ml of 2N hydrochloric acid and 50ml of diethyl ether with vigorous stirring. After standing the mixture was separated and the acidic aqueous layer was extracted with 50ml of ether. The combined ether solutions were washed 1 time with neutral water and then 1 time with brine. Subsequently, the organic solution was dried over magnesium sulfate and concentrated to dryness at room temperature under reduced pressure. The residual oil was crystallized from pentane to give 5.1g of a white solid. HPLC purity > 95% (. alpha.) at 94 ℃ [. alpha.]²² _D1(c ═ 5, ethyl acetate) 18 °

Example 3

Preparation of (+) -2-benzyl-4- (4-methoxyphenyl) -4-oxobutanoic acid (product 4)

The product of this example was isolated using the same technique as for the isolation of (-) acid, except that R- (+) - α -methylbenzylamine was used to isolate the product as a white solid. m.p. 93 ℃ HPLC 98% [ α%]¹⁹ _D= 17 ° 6(c ═ 5, ethyl acetate)

Example 4

Preparation of 2-benzyl-4- (4-fluorophenyl) -4-oxobutanoic acid (product 5)

Preparation of ethyl A-2-benzyl-2- [ 2- (4-fluorophenyl) -2-oxoethyl ] malonate

Prepared according to the same procedure as in step a of example 1 to give a Copper-yellow (Copper-yellow) oil.

I.R. (film): v CO (acetone) ═ 1687cm^-1(ii) a V CO (ester) 1735cm^-1.

¹H NMR(DMSO/TMS)＝1.25(6H，t，2CH₃)；3.5(4H，d，2CH₂)；4.2(4H，q.2OCH₂) (ii) a 6.8-8(9H, m, aromatic ring H).

Preparation of B-2-benzyl-2- [ 2- (4-fluorophenyl) -2-oxoethyl ] malonic acid

Prepared according to the same procedure as in example 1, step B, to give a white solid.

185-90 deg.C (acetonitrile)

I.R. (KBr): v CO (acetone) ═ 1675cm^-1(ii) a V CO (acid) ═ 1747cm^-1.

¹H NMR(DMSO/TMS)：3.3(4H，d，2CH₂) (ii) a 6.7-8(9H, m, aromatic ring H); 13(m, OH).

Preparation of C-2-benzyl-4- (4-fluorophenyl) -4-oxobutanoic acid

Preparation was carried out following the same procedure as step C of example 1 to give a yellow solid, which was recrystallized from acetonitrile to give the corresponding acid as a white solid.

m.p.＝140℃

I.R. (KBr): v CO (acetone) ═ 1683cm^-1(ii) a V CO (acid) ═ 1708cm^-1.

¹H NMR (DMSO/TMS): 3(5H, m, CH and 2 CH)₂) (ii) a 7-8.1(9H, m, aromatic ring H); 12.2(s, OH).

Example 5

Preparation of (+) -2-benzyl-4- (4-fluorophenyl) -4-oxobutanoic acid (product 6)

Prepared by the same method as example 4. A white solid was obtained. m.p.. 83 ℃ HPLC 99.8% [ α%]²² _D= 9 ° (c ═ 5, ethyl acetate)

Example 6

Preparation of (-) -2-benzyl-4- (4-fluorophenyl) -4-oxobutanoic acid (product 7)

The same procedure as in example 3 was used. A white solid was obtained. m.p. 89 ℃ HPLC 98.5% [ α%]²² _DNot-8 ° 9(c not 10, ethyl acetate)

The properties of the compounds of formula I are set forth in table I below.

TABLE I

TABLE I (continuation)

The results of the pharmacological experiments will be given below. Antidiabetic effect in 1-nOSTZ rat experiments

The anti-diabetic effect of the compounds of formula I is determined in rats by an experimental model of streptozotocin-induced non-insulin dependent diabetes mellitus and by oral administration.

Non-insulin dependent diabetes models were obtained by injecting rats with streptozotocin during the neonatal period (day of birth).

The rats with diabetes are selected to be 8 weeks old.

Animals were allowed to stabilize in the animal house at controlled temperatures of 21-22 ℃ with fixed cycles of light (7.00-19.00) and darkness (19.00-7.00) from the day of birth of the animals to the day of the experiment. Animals were fed on a maintenance diet (maintanance diet) and water and food were ad libitum, but this did not include a 2 hour pre-test fasting period during which no food was provided (post-absorption state).

Rats were dosed orally on days of treatment with test product. Animals 300 μ l blood samples were taken from the tail roots of rats 2 hours after the last product administration and 30 minutes after anaesthesia with sodium pentobarbital (Nembutal ).

Table II gives the main results obtained.

These results indicate that the compounds of formula I have blood glucose lowering efficacy in diabetic animals.

Certain compounds of formula I also have short duration premature insulin secretion.

TABLE II

TABLE II (continuation)2-non-diabetic rat test

On the day of the experiment, the non-diabetic rats were orally administered the product to be tested. Within the first 30 minutes after product administration, 30 μ l blood samples were taken from the tail of the rat.

By way of example, the results obtained with the treatment of product No.5 (200mg/kg oral) are as follows:

time after administration (minutes)	5	10	15	20	30
						Blood sugar%	-4	-11	-25	-31	-35
Insulin blood%	102	94	57	55	52

A decrease in blood glucose was observed and no significant increase and decrease in insulin levels occurred. 3-toxicity test

Products 5 and 6 were administered orally at a dose of 200mg/kg, with no evidence of toxicity. 4-Effect on glucagon secretion

This experiment was performed in vitro with a perfused pancreas from non-diabetic rats, isolated using the technology developed by Assan et al (Nature, 239: 125, 1972) Sussman et al (Diabetes 15: 4661966), and the results show that: the compounds of formula I stimulate glucagon secretion in the absence of glucose but in the presence of arginine in the perfusate. Under the same conditions, sulfonylureas have significant inhibitory effects. However, at high concentrations of glucose, the compounds of formula I do not alter the glucagon inhibitory effect of glucose. The risk of hypoglycemia associated with sulfonylurea therapy is avoided in the treatment of the compounds of formula I.

Claims (4)

1. A pharmaceutical composition comprising as an active ingredient a compound represented by the following formula, or a solvate thereof or a salt of such an acid with a pharmaceutically acceptable base:wherein the groups A and B are independently of one another selected from the following groups:

-mono-, bi-or tricyclic aromatic groups having 6 to 14 carbon atoms;

-a heteroaryl group selected from pyridyl, pyrimidinyl, pyrrolyl, furanyl and thienyl;

-an alkyl group having 1 to 14 carbon atoms;

-cycloalkyl having 5 to 8 carbon atoms;

-a saturated heterocyclic group selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, piperidinyl and pyrrolidinyl;

the groups A and B may carry 1 to 3 substituents selected from: c₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₆-C₁₄An aromatic group; heteroaryl selected from the group consisting of pyridyl, pyrimidinyl, pyrrolyl, furanyl and thienyl; (C)₆-C₁₄) Aryl radical (C)₁-C₆) Alkyl, (C)₆-C₁₄) Aryl radical (C)₁-C₆) Alkyl radical (C)₆-C₁₄) Aryl, halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, nitro, amino, carboxy, (C)₁-C₆) Alkoxycarbonyl, carbamoyl, (C)₁-C₆) Alkylsulfonyl, sulfamino, (C)₁-C₆) Alkylsulfonylamino, sulfamoyl or (C)₁-C₆) An alkylcarbonylamino group; or two of said substituents together form a methylenedioxy group.

2. Pharmaceutical composition according to claim 1, characterized in that it comprises as active principle a compound of formula I in which a and B are chosen from aromatic groups.

3. Pharmaceutical composition according to claim 1, characterized in that it comprises as active principle a compound selected from the following, or their solvates or their salts with pharmaceutically acceptable bases:

-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- (. beta. -naphthylmethyl) -4-phenyl-4-oxobutanoic acid

-2-benzyl-4- (. beta. -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-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.

4. A compound of formula I or a solvate thereof or a salt of such an acid with a base:wherein the groups A and B are independently of each other selected from:

-mono-, bi-or tricyclic aromatic groups having 6 to 14 carbon atoms;

-a heteroaryl group selected from pyridyl, pyrimidinyl, pyrrolyl, furanyl and thienyl;

-an alkyl group having 1 to 14 carbon atoms;

-cycloalkyl having 5 to 8 carbon atoms;

-a saturated heterocyclic group selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, piperidinyl and pyrrolidinyl;

the groups A and B may carry 1 to 3 substituents selected from: c₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₆-C₁₄An aromatic group; heteroaryl selected from the group consisting of pyridyl, pyrimidinyl, pyrrolyl, furanyl and thienyl; (C)₆-C₁₄) Aryl radical (C)₁-C₆) Alkyl, (C)₆-C₁₄) Aryl radical (C)₁-C₆) Alkyl radical (C)₆-C₁₄) Aryl, halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, nitro, amino, carboxy, (C)₁-C₆) Alkoxycarbonyl, carbamoyl, (C)₁-C₆) Alkylsulfonyl, sulfamino, (C)₁-C₆) Alkylsulfonylamino, sulfamoyl or(C₁-C₆) An alkylcarbonylamino group;

or two of said substituents together form a methylenedioxy group;

with the proviso that compounds of the formula I do not include those in which B is unsubstituted phenyl and A is phenyl, 4-methoxyphenyl, 4-chlorophenyl or cyclohexyl.