NL8000826A - NEW NICOTINIC ACID DERIVATIVES AND METHOD FOR THE PREPARATION THEREOF - Google Patents

Description

N / 29496-Kp / vdM * ^ - 1 -

New nicotinic acid derivatives and method for their preparation.

The invention relates to new nicotinic acid derivatives, as well as a process for their preparation. The present new nicotinic acid derivatives are pharmaceutically active compounds. Furthermore, the invention includes the pharmaceutically compatible salts of the present novel nicotinic acid derivatives with organic or inorganic acids.

The arteriosclerosis is known to be caused by the deposition of lipids in the aorta, coronary, cerebral and peripheral arteries, with the result that there is an increased risk of thrombosis or arterial blockage.

Depending on the nature of the elevated plasma protein level, the elevation of the cholesterol or triglyceride level is obvious. In this context, a cholesterol level of 200-300 mg / 100 ml serum and a triglyceride level of 4ΞΙ 5 66 mg / 100 ml serum can be considered too high.

The best known two active substances used hitherto for the treatment of hyperlipidemia are the ethyl ester of 2- (p-chlorophenoxy) isobutyric acid, known as clofibrate and their salts, as well as nicotinic acids, which act in various ways. act on the serum lipid. While in animal experiments doses of 30-500 mg / kg body weight of these substances mainly cause a decrease in the cholesterol level - in addition to a small decrease in the free fatty acid -, 3-pyridylcarbinol as well as nicotinic acid and its salts already appear at a lower dose of 0.5-30 mg / kg body weight cause a sharp drop in free fatty acids.

Neither substance has a significant influence on the decrease in triglyceride. In addition, due to its unpleasant and known side effects (blood rises to the head, headache, nausea and vomiting), nicotinic acid is of limited application, so that therapy often has to be stopped early.

In addition, it is known that although clofibrate causes triglyceride (TG) and pre- (5-lipoprotein to drop to 50% below baseline, this does not apply to cholesterol to the extent of 8000826-2. % of cases, the cholesterol (CH) in the S and α-lipoproteins even increases, while nicotinic acid and its derivatives work predominantly at elevated cholesterol levels and free fatty acids and, on the other hand, only decrease secondary via inhibition of tissue lipolysis, the endogenous resynthesis of the triglyceride (treatises of the Deutschen Gesellschaft for internal medicine, 82, Congress, held in Wiesbaden from April 25-29, 1976, part I, JF Bergmann, Publisher Munich).

In addition, from French patent 69 75, the 3-pyridylcarbinol ester of clofibric acid is known as an active lipid and cholesterol level-lowering component. However, this compound, which is used in particular in the form of nicotinate, is useful only in small doses in view of the high content of pyridine components and the associated side effects, and therefore of little therapeutic benefit.

In summary, the said substances have the property of significantly lowering only one of the lipid components, eg, the triglyceride, while the other lipid components are not, or only slightly, therapeutically affected. This only takes place by using a higher dose.

Those skilled in the art have therefore endeavored to find other compounds which have a lipid lowering action on various lipid components without increasing the dosage.

The new compounds of claim 1 of formula 1 surprisingly meet these requirements. The present compounds have a strong action both at elevated serum triglyceride and cholesterol levels.

Compared to nicotinic acid and the ethyl ester of the 2- (p-chlorophenoxy) isobutyric acid, the dosages are incomparably lower, so the risk of side effects is minimized.

The new compounds are solids.

The preparation of the new compounds will now be explained in more detail.

8000826 - 3 -

EXAMPLE I

Preparation of p-cyclohexylphenyl nicotinate.

17.6 g (100 mmol.) Of cyclohexylphenol and 19 g (106 mmol.) Of nicotinic acid chloride hydrochloride were added to 250 ml of dry pyridine, and the mixture was stored at 40 ° C for 4 hours. The mixture was then cooled in an ice bath, followed by portionwise addition of water. After adding 10 ml of water, a clear solution was obtained. Water was further added to this solution until a strong cloudiness occurred (50 ml). After long stirring, the product crystallized out in the ice bath. The precipitate formed was filtered off with suction, washed with pyridine-free water and finally dried. A second fraction was obtained from the filtrate by adding more water (60 ml).

15 Yield: 70% of the theory. Melting point: 103 ° C.

Analysis: calculated: C 76.86; H 6.76; N 4.98 found: C 76.83; H 6.76; N 5.05.

EXAMPLE II

Preparation of p- (1-adamantylphenyl) nicotinate.

11.4 g (50 mmol.) Of p-1-adamantylphenol and 10 g (56 mmol.) Of nicotinic acid chloride hydrochloride were transferred to 150 ml of dry pyridine and the resulting mixture was stored at 45 ° C for 48 hours. By adding 40 ml of water, the product was obtained in the form of crystals by stirring in an ice bath. Then the crystals were separated, washed with water and finally dried.

Yield: 78% of the theory. M.p .: 199 ° C.

Analysis: Calculated: C, 79.27; H 6.90; N 4.20 found: C 78.01; H 6.82; N 4.50.

EXAMPLE III

Preparation of 2- (p-chlorophenoxy) -isobutyric acid-p- (1-adamantylacetyl) -phenyl ester.

6.75 g (25 mmol.) Of p- (1-adamantylacetyl) phenol and 6 g (25.7 mmol.) Of 2- (p-chlorophenoxy) isobutyric chloride were transferred to 60 ml of dry pyridine, after which the resulting mixture was stored at 40 ° C for 20 hours. A crystalline product was obtained by adding 8000 ml of water to 8000826-4. The crystals were filtered off, washed with water and finally dried.

Yield: 77% of the theory. M.p .: 114 ° C.

5 Analysis:

Calculated: C 72.03; H 6.64 found: C 72.12; H 6.61.

EXAMPLE IV

Preparation of p-cyclododecylphenyl nicotinate.

8g (30.8mmol) p-cyclododecylphenol and 5.9g (33.2mmol) nictonic acid chloride hydrochloride were transferred into 140ml dry pyridine and the resulting mixture was stored at 30 ° C for 15 hours. Then 42 ml of water was slowly added dropwise, after which the mixture was cooled to 0 ° C. The crystals obtained were filtered off, washed with pyridine-free water and finally dried.

Yield: 85% of the theory. M.p .: 98 ° C. Analysis: calculated: C 78.91; H, 8.50, found: C, 79.01; H 8.54.

EXAMPLE V

Preparation of p- (cyclohexyl acetyl) phenyl nicotinate. 11 g (50 mmol.) Of p-cyclohexyl acetylphenol and 9.6 g (54 mmol.) Of nicotinic acid chloride hydrochloride were transferred to 160 ml of dry pyridine and the resulting mixture was stirred at 40 ° C for 8 hours. Water was then added dropwise (66 ml) until the solution became cloudy, after which the solution was transferred to an ice bath. The crystallized product is filtered off, washed with pyridine-free water and dried.

Yield: 55% of the theory. Mp .: 103 ° C. Analysis:

Calculated: C 74.30; H 6.50 found: C 74.07; H 6.51.

EXAMPLE VI

Preparation of o-cyclohexylphenylnicotinate hydrochloride ♦

15 g (85 mmol.) Of o-cyclohexylphenol and 16.5 8000826 «Τ '- * - 5 - g (93 mmol.) Of nicotinic chloride hydrochloride were transferred to 200 ml of dry pyridine, and the resulting mixture was stirred at 30 ° C for 24 hours. was stirred. After cooling, the crystallized pyridine hydrochloride was filtered off and 300 ml of water was added to the filtrate. The crude product deposited therein was washed twice with 200 ml of water, then taken up in alcohol and finally transferred to a rotary evaporator. The residual viscous oil was dissolved in 500 ml of dry ether and then hydrochlorinated with HCl gas.

The resulting mixture was then filtered off, washed with ether and finally dried.

Yield: 52% of the theory. M.p .: 151-152 ° C.

Analysis:

Calculated: C 68.03; H 6.29; Cl, 11.18. Found: C, 68.11; H 6.30; Cl 11.20.

EXAMPLE VII

Preparation of 5,6,7,8-Tetrahydro-1-naphthylnicotinate.

7 g (47 mmol) of 5,6,7,8-tetrahydro-1-20 naphthol and 9 g (50 mmol) of nicotinic chloride hydrochloride were mixed with 130 ml of dry pyridine, which mixture was stirred at 30 ° C for 24 hours . After cooling, the pyridine hydrochloride precipitated, which was then filtered off. Then the filtrate was mixed with 200 ml of water. The precipitated crude product was washed twice with 200 ml of water and then recrystallized from methanol.

Yield: 65% of the theory. Mp .: 86 ° C.

Analysis:

Calculated: C 75.88; H 5.93. Found: C 75.81; H 6.07.

«8 0 o: 3 2 β 35 - 6 -

Toxicity tests:

TABLE A

human connection. 0 ^ dose of therap.

, R R R mulch „. .5 no. (Mg /] cg) per deg mdex (mg) 2 cyclohexyl H pyridinoyl- (3) 2200 300 0.1 1 1-adamantyl H pyridinoyl- (3) 3200 300 0.039 10 2-p-chlorophenoxyisobutyric acid ethyl ester 1500 1500 1.0 (standard) nicotinic acid (standard) 4000 3000 0.75

As follows from table A, the toxicity values lie in a comparable range, with the result that very good values are obtained for the therapeutic index.

Demonstration of operation:

Tests were done on female Wistar rats. The rats were fed a special high fat diet for 3 weeks. From the beginning of the second week, half of the rats were treated with a dose of 100 mg / kg body weight. A blood test was performed 18 hours after the last dose after the third week of the animals comparing the concentrations of triglycerides and cholesterol with the values obtained in the 25 untreated rats. The enzymatic test according to Boehringer was used as the test method for the determination of the cholesterol and the triglyceride. According to Table B, a very significant decrease occurred for both parameters. On the other hand, the administration of clofibrate and nicotinic acid in separate form gave a much lower result, which can also be derived from table B.

8 0 0 0 8 2 £ - 7 - TABLE · Β, ,, ,, Chol Triglyceride Compound 1 2 3 Reduction No.

in% in% 5 1 1-adamantyl H pyridinoyl- (3) 28 47 2 cyclohexyl H pyridinoyl- (3) 45 19 4 cumyl H pyridinoyl- (3) 24 1 7 p-chloro. nf, H pyridinoyl- (3) 29 benzoyl 10 8 1-adamantyl-2-methyl-2- (p-acetyl H chlorophenoxyl) 27 35 propionyl nicotinic acid (100 mg / kg) 7 1- (p-chloro-phenoxyiso- (100 mg / kg) - 8 butyric acid

According to the invention these are new compounds of formula 1 of the formula sheet, in which RA = a) the group of formula 2 of the formula sheet, wherein n = 3-12 m = 0.1 z = 0.1 b) the group of formula 3 of the formula sheet, wherein m = 0.1 25 z = 0.1 c) cumyl d) p-chlorobenzoyl e) 1-piperidinyl f) 2-pyrimidinyl 2 30 g) hydrogen, where R is equal to cycloalkyl or cycloalkylene (-CH 2 -), <5 μ n R = - a) (-CH 2 -) / where n = 0 or 4 b) halogen 8000826 rc) C 1 -C 6 alkyl or cycloalkyl d) methoxy e ethoxy f) trifluoromethyl 5 g) nitro h) hydrogen 3 and R = a) the group of formula 4 of the formula sheet b) 2-methyl-2- (p-chlorophenoxy) -propionyl and their pharmaceutically acceptable salts of organic or inorganic acids.

The invention further relates to a process for the preparation of compounds according to claim 1, characterized in that according to a per se known esterification, e.g. 1 mol. nicotinic acid chloride is reacted with 1 mole. starting phenol in the presence of at least 1 mole. of an acid-binding agent, e.g. pyridine. Hereby compounds according to claim 1 are formed which can then be combined with conventional pharmaceutical auxiliaries.

The compounds according to the invention can be processed into medicines which, in addition to the active substance, contain a carrier or a diluent. They can be administered orally or parenterally.

Solid preparations for oral administration are capsules, tablets, pills, powders or granules. In such solid dosage forms, the active ingredient is combined with at least one inert diluent, eg sugar, lactose or starch. Furthermore, other substances, such as lubricants or buffering substances, may be present. The tablets and pills can be coated with a soluble in the intestine. Liquids for oral administration are emulsions, solutions or suspensions, which may contain the commonly used diluents, eg water. Moreover, such liquids may also contain wetting agents, emulsifying agents and suspending agents, but also sweeteners, flavors and fragrances.

Preparations for parenteral administration include sterile, aqueous or non-aqueous solutions, suspensions or emulsions. The 8000826 - 8 substances known for these purposes can be used as a carrier.

The dosage of the active substances in the medicine may vary depending on the dosage form and the treatment.

5 8000826

Claims (10)

1. Compounds of formula 1 of the formula sheet, wherein R1 = a) the group of formula 2 of the formula sheet, wherein n = 3-12 5 m = 0.1 z = 0.1 b) the group of formula 3 of the formula sheet, in which m = 0.1 z = 0.1 10 c) cumyl d) p-chlorobenzoyl e) 1-piperidinyl f) 2-pyrimidinyl 2 g) hydrogen, in case R cycloalkyl or cycloalkylene (-CH- -) 2. n is R = a) ("CH2 ~ ^ n" where; * - nn is 0 or 4 b) halogen c) C 1 -C 6 alkyl or cycloalkyl d) methoxy 20 e) ethoxy f) trifluoromethyl g) nitro h) hydrogen 3 and R = a) the group of formula 4 of the formula sheet, b) 2-methyl-2- (p-chlorophenoxy) -propionyl as well as their pharmaceutically acceptable salts of organic or inorganic acids. The compound of claim 1, wherein the compound is cyclohexylphenyl nicotinate or an acid addition salt thereof. The compound of claim 1, wherein the compound is cyclohexylphenyl nicotinate. The compound of claim 1, wherein the compound is cyclohexylphenyl nicotinate hydrochloride. The compound of claim 1, wherein the compound is cyclododecylphenyl nicotinate. The compound of claim 1, wherein the compound is 5,6,7,8-tetrahydro-1-naphthylnicotinate. 8000825 - 11 - The compound of claim 1, wherein the compound is (1-adamantylphenyl) nicotinate. The compound of claim 1, wherein the compound is (cyclohexyl acetyl) phenyl nicotinate. The compound of claim 1, wherein the compound is 2- (chlorophenoxy) isobutyric acid (1-adamantylacetyl) phenyl ester. 10. Process for the preparation of the compounds according to claims 4-9, characterized in that the compounds follow a per se known esterification of eg 1 mol. nicotinic acid halide with 1 mol. starting phenol in the presence of at least 1 mole. of an acid-binding agent, e.g. pyridine. 15 8 0 0 0 8 2 6 Frankfurt / Main, Federal Republic of Germany. FORMAT SHEET R2 R1—— O - R3 ft) / ch- (ch2) - \ cyz- ^ ch2 ^ - (-? Tg) 8 0 0 0 8 2 6