DE3546324A1 - Novel benzoic acid derivatives, and processes for their preparation and their use as medicaments - Google Patents

Abstract

Para-substituted benzoic acid derivatives of the general formula (I) <IMAGE> and their physiologically tolerable salts, in which R<1> can be H, isopropyl or t-butyl, X can be <IMAGE>, R<2> can be -OH or -OR', where R' is a straight-chain, optionally branched, saturated or unsaturated C1- to C3-alkyl radical or an -NHCH2COOH group, have hypolipaemic action. They can be obtained by methods known per se either via corresponding unsaturated keto compounds or saturated hydroxy compounds, it also being possible to hydrolyse the benzoic acid radical which is esterified per se or to convert it into a carboxymethyl amide.

Description

Are used for drug treatment of lipid metabolism disorders Numerous active ingredients have already been introduced into therapy. One of the first representatives from the group of aryloxy-isoalkanoic acids was the CLOFIBRAT. Because of its weak effectiveness a number of derivatives such as e.g. B. ETOFIBRAT or ETOFYLLINCLOFIBRATE as well as structural analogues such as B. BEZAFIBRAT, FENOFIBRAT or GEMFIBROZIL developed, however, in their adverse effects are similar to CLOFIBRAT, suggesting an similar mechanism of action suggests. Known side effects are z. B. gastrointestinal complaints, loss of appetite, nausea, allergies Myositis, myalgia and erectile dysfunction as well as an increase in serum creatinine, Serum urea and the lithogenic index, lowering the alical Phosphatase, an increase in creatinine phosphokinase and stimulation peroxisome formation.

The only way to remedy this previous defect is to find it new active substances possible due to their significantly different structure changed biological properties can be expected.

Surprisingly, it has now been found that benzoic acid derivatives the formula (1) given in claim 1, one opposite BEZAFIBRAT have clearly superior hypolipemic effects. These are parasubstituted phenylpentanol or Phenylpentanonbenzoic acid compounds to one not previously described Structure row can be counted.

Benzoic acids etherified in para-position are also known possess hypolipemic properties. This includes connections which are derived from ethers of glycerol [DE-PS 24 60 689], 1,3-dihydroxy acetones [DE-OS 27 35 856] and other alcohols [DE-OS 33 26 164; U.S. Patent 4,067,892; US Pat. No. 4,154,850]. Because of their ether function changed biological properties will.

The production of these new hypolipemic compounds can be carried out in a manner known per se, one according to the invention applies the method specified in claim 2.

The necessary for the synthesis of the compounds of the invention Starting products can be used, for example, according to the following procedures produce  

By condensation of acetone with aldehydes of the general formula (7) in which R ^{1 has} the meaning given in claim 1, benzal acetones of the general formula (8) are obtained.

A reaction with 4-formylbenzoic acid alkyl ester of the general formula (9) in which R 'has the meaning given in claim 1 leads to 1,4-pentadienones of the general formula (2) in the presence of tris (triphenylphosphine) ruthenium (II) chloride with benzyl alcohol selectively to the compounds of the formula (3) according to the invention let it hydrate.

The compounds of the general formula (10) according to the invention are obtained therefrom by alkaline saponification and subsequent acidification with mineral acid.

Compounds of the general formula (3) can be cold with sodium boranate to give the compounds of the general formula (4) according to the invention reduce, and convert by alkaline saponification and subsequent acidification with mineral acid into the acids of general formula (11) according to the invention.

A reaction with acetyl chloride gives compounds of the general formula (12) which react with thionyl chloride in acid chlorides of the general formula (13) get transferred.

The compounds of the general formula (14) according to the invention are obtained from the acid chlorides of the general formula (13) after reaction with sodium glycinate and subsequent alkaline saponification by acidification with mineral acid

By selective oxidation with dimethyl sulfoxide, compounds of the general formula (4), (11) and (14) are converted into the compounds of the general formula (15) according to the invention. in which R ¹ and R ^{2 have} the meaning given in claim 1.

The superiority of the claimed compounds over the BEZAFIBRAT, which has been introduced into therapy for a long time prove themselves clearly on the basis of the lipid-lowering effect.

The lipid-lowering effect was demonstrated in groups of 10 normolipaemic, male, 200 to 220 g heavy Wistar Rats tested.

The tests were carried out after a 3-week period Training the animals' eating habits. The controlled one Feeding was carried out daily from 10 a.m. to 12 noon. The test substances were applied at 11:00 a.m.

The test compounds were in an aqueous solution of 0.25% agar and 0.84% sodium chloride added and administered orally. After application of 3 × 100 mg / kg over a period of three Blood was taken from the animals for days.

The determination of cholesterol and triglycerides was carried out with Using the "Cobas Bio" centrifugal analyzer from Hoffman-La Roche performed.

Methods:

• a) Cholesterol determination
  CHOD-PAP method; enzymatic color test according to J. Siedel et al
  [J. Clin. Chem. Clin. Biochem. 19, 838 (1981)]
• b) Triglyceride determination
  Enzymatic cleavage of the triglycerides with the help of special lipases with subsequent enzymatic determination of the released glycerol.
  [HU Bergmeyer, "Methods of Enzymatic Analysis", 3rd Edition, Vol. II, Verlag Chemie, Weinheim, 1974, p. 1878],

Table 1

Percentage change in total cholesterol (TC) and triglyderide (TG) levels in rat serum after oral administration of the test substances

For therapeutic use as hypolipemic drugs the new compounds of general formula (1) and their salts preferably administered orally. Usually it is oral daily dose in adults 0.1 to 1 g.

The active ingredients can be used for oral administration in the usual way Galenically administered. As pharmaceutical carriers common auxiliaries such as lactose, sucrose, Mannitol, potato or corn starch, cellulose derivatives or gelatin, optionally with the addition of lubricants, such as. B. Magnesium or calcium stearate, as well as polyethylene glycols.

Preferred forms of administration are hard gelatin capsules as well as closed soft gelatin capsules. The release of the compounds claimed may vary depending on pharmaceutical processing be accelerated or decelerated.

In pure capsules, the pure active ingredient may possibly with a small amount of lubricant. At The pure active ingredient can be packaged in soft gelatin capsules be dissolved or suspended in suitable liquids, e.g. B. in liquid polyethylene glycols or vegetable oils. With appropriate physical properties of the active ingredient becomes processing preferred to granules.

The synthesis of the precursors is carried out according to known Processes as shown below using some examples to be discribed.  

example 1 4- [5- (4'-Isopropylphenyl) -3-oxopentyl] methyl benzoate a) 4- [5- (4'-Isopropylphenyl) -3-oxo-1,4-pentadienyl] methyl benzoate

94.1 g (0.50 mol) of 4'-isopropylbenzalacetone and 91.8 g (0.56 mol) of methyl 4-formylbenzoate are added under Nitrogen dissolved in 500 mL methanol and with stirring within 5 minutes with 45 mL 2 N sodium hydroxide solution. After an hour, another 45 mL of 2N sodium hydroxide solution are added and stir for another three hours. The secluded The product is filtered off with suction, washed neutral with cold methanol and from 675 mL methanol with the addition of 70 mL Recrystallized ethyl acetate. Light yellow crystals from Mp 113-115 ° C. (The melting points were determined using a Kofler Hot stage microscope determined and are not corrected.) Yield 84.9 g (51%)

¹ H-NMR spectrum (CDCl ₃ ):
(Recorded at 60 MHz
The chemical shifts are given in ppm against TMS (δ = 0.o), the relative intensities are enclosed in brackets. s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet.)
1.27 d (6) (C H ₃ ) ₂ CH
2.93 m (1) (CH _{3) 2} C H
3.93 s (3) (C H ₃ O
6.80 to 8.20 m (12) aromatics, 4 = C H -

b) Production of 4- [5- (4'-Isopropylphenyl ′) -3-oxopentyl] methyl benzoate

33.4 g (0.10 mol) of 4- [5- (4'-isopropylphenyl) -3-oxo-1,4-pentadienyl] methyl benzoate are dissolved in 40 mL (0.385 mol) Dissolved benzyl alcohol under nitrogen with 0.20 g (0.2 mmol) Tris (triphenylphosphine) ruthenium (II) chloride added and on Air cooler in a weak nitrogen flow for two hours 190-200 ° C (bath temperature) heated. Then the The resulting benzaldehyde together with the benzyl alcohol still present removed in vacuo and the residue to complete the Reduction again with 30 mL fresh benzyl alcohol and 0.15 g Catalyst for another two hours under nitrogen to 190- 200 ° C (bath temperature) heated. The volatile parts will then removed at 0.1 mbar and 100 ° C (bath temperature) and the red-brown oily residue taken up in dichloromethane. To purification by column chromatography on silica gel with dichloromethane, the solvent is removed in vacuo and the residue distilled at 0.03 mbar and 225 ° C in a Kugelrohr oven. Colorless Oil with a refractive index of n = 1.5445. Yield 11.2 g (33%).

C ₂₂ H ₂₆ O ₃ (338.4)
Mol. Wt .: 338 (determined by mass spectrometry) (by means of electron impact ionization (70 eV))
IR spectrum (film): ν (C = O) 1720, 1710 cm ^-1
1 H-NMR spectrum (CDCl ₃ ):
1.20 s (6) (C H ₃ ) ₂ CH
2.47 to 3.13 m (9) 2 ArC H ₂ CH ₂ and (CH ₃ ) ₂ C H 3.90 s (3) OC H ₃ 6.93 to 8.10 m (8) aromatics

Example 2 4- [5- (4'-Isopropylphenyl) -3-hydroxypentyl] benzoic acid

34.0 g (0.10 mol) of crude 4- [5- (4'-isopropylphenyl) -3-oxopentyl] benzoic acid methyl ester, prepared according to Example 1, are dissolved in 100 ml of ethanol and slowly at 0-10 ° C. with an ice-cold solution of 2.0 g (0.053 mol) of sodium boranate are added to 10 ml of water. After the addition is complete, the cooling is removed and stirring is continued for 2.5 hours at room temperature. Then 13 g of potassium hydroxide are added, the mixture is stirred for a further three hours at room temperature and left to stand overnight. After dilution of the reaction mixture with water, the mixture is extracted twice with ether, the aqueous phase is acidified with concentrated hydrochloric acid and the separated product is taken up in ethyl acetate. It is washed neutral with water, dried over sodium sulfate and the solvent is removed in vacuo. The residue is purified chromatographically on silica gel with CH ₂ Cl ₂ / CH ₃ OH (95/5) and, after the solvent has been stripped off, crystallized from acetonitrile. Colorless crystals with a melting point of 104-106 ° C. Yield 12.7 g (39%).

C ₂₁ H ₂₆ O ₃ (326.4)
Mol.wt .: 326 (determined by mass spectrometry)
IR spectrum (KBr): ν (OH) 3500 to 2400 cm ^-1
ν (C = O) 1865 cm ^{-1 1} H-NMR spectrum (CDCl ₃ ):
1.23 d (6) (C H ₃ ) ₂ ) CH
1.57 to 2.07 m (4) 2 ArCH ₂ C H ₂ 2.50 to 3.03 m (5) 2 ArC H ₂ CH ₂ and (CH ₃ ) ₂ C H 3.67 m (1) C H (OH) 6.67 broad s (2) O H , COO H 7.03 to 8.13 m (8) aromatics

Example 3 4- [5- (4'-tert-butylphenyl) -3-hydroxypentyl] benzoic acid isopropyl ester

34.0 g (0.10 mol of 4- [5- (4'-tert-butylphenyl) -3-hydroxypentyl] benzoic acid, shown analogously to Examples 1 and 2, are refluxed in 300 ml of isopropanol with 5 ml of concentrated sulfuric acid for 20 hours After cooling, the reaction mixture is poured into ice water and shaken twice with dichloromethane. The organic phase is washed neutral with water, then with aqueous sodium hydrogen carbonate solution and finally again with water. After drying over sodium sulfate, the solvent is removed in vacuo and the colorless is cleaned The residue is chromatographed with CH ₂ Cl ₂ / CH ₃ OH (98/2) on silica gel, and after the solvent has been stripped off in vacuo, the residue is crystallized from petroleum ether (40-60 ° C. fraction), colorless crystals with a melting point of 47-48 ° C. Yield 18.4 g (48%)

C ₂₂ H ₃₄ O ₃ (382.5)
Mol.Weight: 382 (determined by mass spectrometry)
IR spectrum (KBr): ν (OH) 3600 to 2800 cm ^-1
ν (C = O) 1720 cm ^{-1 1} H-NMR spectrum (CDCl ₃ ): 1.30 s (C H ₃ ) ₃ C1.33 d (C H ₃ ) ₂ CHO
1.53 to 2.07 m (5) 2 ArCH ₂ C H ₂ and O H (interchangeable with D ₂ O) 2.50 to 3.00 m (4) 2 ArC H ₂ CH ₂ 3.60 m (1) C H (OH) 5.23 m (1 ) (CH ₃ ) ₂ C H O
6.53 to 8.10 m (8) aromatics

Example 4 N-carboxymethyl-4- [5- (4'-tert-butylphenyl) -3-hydroxypentyl] - benzamide a) 4- [5- (4'-tert-Butylphenyl) -3-acetoxypentyl] benzoic acid

34.0 g (0.10 mol) of 4- [5- (4'-tert-butylphenyl) -3-hydroxypentyl] - benzoic acid and 0.30 g (2.2 mmol) of anhydrous zinc chloride suspended in 50 mL anhydrous acetic acid and with 14.3. mL (0.20 mol) acetyl chloride was added, giving a clear solution arises. After stirring for two hours at room temperature, pour the reaction solution in ice water. The secluded The product is taken up in chloroform and washed with water. After drying over sodium sulfate, the solvent removed in vacuo and the colorless, crystallizing crude product used for further implementation without cleaning. Raw yield 38.3 g (100%)

¹ H-NMR spectrum (CDCl ₃ ):
1.30 s (9) (C H ₃ ) ₃ C1.63 to 2.13 m 2 ArCH ₂ C H ₂ and2.0 sC H ₃ CO 2.37 to 2.90 m (4) 2 ArC H ₂ CH ₂ 4.97 m (1) C h (OCOCH ₃ ) 6.83 to 8.10 m (8) Aromat 11.82 wide s (1) COO H b) Production according to the invention of N-carboxymethyl-4- [5- (4'-tert.butylphenyl) -3-hydroxypentyl] benzamide 38.3 g (0.10 mol) of crude 4- [5- (4'-tert-butylphenyl) -3-acetoxypentyl] benzoic acid and 12 ml (0.165 mol) of thionyl chloride in 200 ml of toluene are heated under reflux for 3.5 hours. The solvent and excess thionyl chloride are then distilled off in vacuo and the oily residue is taken up in 250 ml of dry dioxane. This solution is added dropwise with vigorous stirring at 5 to 7 ° C in a solution of 29.5 g (0.39 mol) glycine and 15.6 g (0.39 mol) sodium hydroxide in 350 mL water, then stirred for three hours at room temperature and left overnight. Then add 20 g of sodium hydroxide and stir for a further 3.5 hours at room temperature. The reaction solution is finally diluted with water and, after acidification with concentrated hydrochloric acid, the precipitated end product is taken up in ethyl acetate. After washing the organic phase twice, it is dried over sodium sulfate, the solvent is removed in vacuo and the residue is crystallized from acetonitrile. Colorless crystals with a melting point of 133-135 ° C. Yield 32.3 g (81%) C ₂₄ H ₃₁ NO ₄ (397.5)
Mol. 397 (determined by mass spectrometry)
IR spectrum (KBr) ν (OH) 3600 to 2400 cm ^-1
ν (C = O) 1725 cm ^-1
ν (NH) 3360 cm ^{-1 1} H-NMR spectrum (d ₆ ) -acetone):
1.23 s (9) (C H ₃ ) ₃ C
1.57 to 2.03 m (4) 2 ArCH ₂ C H ₂ 2.50 to 3.03 m (4) 2 ArC H ₂ CH ₂ 3.60 m (1) C H (OH) 4.10 4.20 2 s (2) NC H ₂ 6.47 to 8.17 m (11) Aromat, N H , O H , COO H In a manner analogous to the examples, further compounds of the general formula (1) were prepared and listed with the melting points in the table below. For the sake of completeness, the compounds described in the examples are given again in the following table. Example 5 Medicament containing methyl 4- [5- (4'-isopropylphenyl) -3-oxopentyl] benzoate 400 g of methyl 4- [5- (4'-isopropylphenyl) -3-oxopenthyl] benzoate are mixed with 200 g of polyethylene glycol and according to the shear method filled into one thousand soft gelatin capsules, each containing 400 mg of active ingredient. Example 6 4- [5- (4'-tert-butylphenyl) -3-hydroxypentyl] benzoic acid-containing medicament containing 500 g of 4- [5- (4'-tert-butylphenyl) -3-hydroxypentyl] benzoic acid after fine powdering with talc and calcium stearate, and after thorough mixing, filled into two thousand hard gelatin capsules, so that each capsule contains 250 mg of active ingredient.

Claims (3)

1. Benzoic acid derivatives of the general formula (1) and their physiologically acceptable salts, wherein
R ¹ = H, isopropyl, t-butyl
X = and
R ² = -OH, -OR ', where R' is a straight-chain branched saturated or unsaturated C ₁ to C ₃ alkyl radical or an -NHCH ₂ COOH group. 2. A process for the preparation of benzoic acid derivatives according to claim 1, characterized in that

• a) compounds of the general formula (2) in which R ¹ and R 'have the meaning described in claim 1 with benzyl alcohol in the presence of tris (triphenylphosphine) ruthenium (II) chloride to the claimed compounds of the general formula (3) in which R ¹ and R 'have the meaning described in claim 1, reacted, if appropriate saponified with alkali, liberates the carboxyl compound by addition of mineral acid and, after crystallization, if necessary by addition of bases, produces the corresponding salts.
• b) compounds of the general formula (3) in which R ¹ and R 'have the meaning described in claim 1, with sodium boranate to give the corresponding alcohols of the general formula (4) implemented, wherein R ¹ and R 'have the meaning given above, optionally saponified with alkali, liberates the carboxyl compound by adding mineral acid and, after crystallization, if necessary, by adding bases, the corresponding salts are obtained;
• c) compounds of the general formula (5) in which R ^{1 has} the meaning described in claim 1, Z is a protective group, for. B. represents acetyl and Hal is a halogen atom, preferably chlorine, reacted with sodium glycinate in a manner known per se, then cleaves off the protective group with alkali, releases the carboxyl compound by adding mineral acid and, after crystallization, if appropriate with bases to the corresponding salts;
• d) compounds of the general formula (6) in which R ¹ and R ^{2 have} the meaning described in claim 1, are subjected to oxidation with dimethyl sulfoxide, the oxidation product crystallizes and, if appropriate, the corresponding carboxyl compounds are reacted with bases to give the salts.

3. Medicinal product, characterized by the content of a compound according to claim 1, in addition to pharmaceutically applicable diluents or carriers.