DK152360B - ANALOGY PROCEDURE FOR PREPARING NICOTIC ACID DERIVATIVES - Google Patents

Description

The present invention relates to an analogous process for the preparation of novel, pharmaceutically active compounds or salts thereof with organic or inorganic acids, namely nicotinic acid derivatives of the general formula I

wherein R represents hydrogen, C Cg. cycloalkyl, (C ^ -j cycloalkylmethyl, (C ^ _ ^ cycloalkyl) carbonyl, (Cg ^-cycloalkylacetyl, cumyl, 2β-chlorobenzoyl, 1-piperidinyl or 2-pyrimidinyl, and R represents hydrogen, so that the alkylene group together with the phenyl ring forms a tetral ring, halogen, alkyl of 1-6 carbon atoms or cycloalkyl, however, R can only represent hydrogen when 2 R represents cycloalkyl or - ( And R cannot be hydrogen when R is cyclohexyl, or pharmaceutically tolerable acid addition salts thereof, which is characterized by performing an esterification wherein 1 mole of nicotinic acid halide is reacted with 1 mole of starting phenol. wherein R and R are as defined above in the presence of at least 1 mole of an acid binding agent such as pyridine.

As is well known, atherosclerosis is associated with an increase in lipids in the aorta, in the coronary and cerebral and peripheral arteries, leading to increased risk of thrombosis or arterial constipation. Depending on the nature of the increased plasma protein level, elevation of cholesterol or triglyceride levels predominates. Here, a cholesterol role of more than 200 - 300 mg / 100 ml of serum and a triglyceride level of 45 - 66 mg / 100 ml of serum are greatly elevated.

The two known and previously used active ingredient classes for the treatment of hyperlipidemia are the ethyl ester of 2- (p-chlorophenoxy) isobutyric acid, known by the name "Clofibrate", and its salts and nicotinic acid, which act differently on the serum lipids. While doses of 30-500 mg / kg body weight for experimental animals primarily cause a lowering of cholesterol levels - in addition to a slight decrease in free fatty acids - 3-pyridylcarbinol and nicotinic acid and salts thereof already produce at lower doses of between 0.5 and 30 mg / kg body weight a sharp decrease in the free fatty acids. However, neither of the two substances exerts any significant effect on the lowering of the triglycerides. In addition, the nicotinic acid is only limited in use due to the unpleasant and known side effects of this compound (rise in the head, headache, nausea and vomiting), so that therapy often has to be interrupted prematurely.

Furthermore, it is known that although the triglycerides (TG) and pre-β-Π-pop proteins can be lowered to less than 50% of the starting value by clofibrate, this does not hold to the same extent for cholesterol. For approx. In about 20% of cases, there is even a further increase in the cholesterol content (CH) of the f $ and α-lipoproteins. Nicotinic acid and its derivatives, on the other hand, work predominantly at elevated cholesterol levels. levels and free fatty acids, but only secondarily, via an inhibition of tissue lipolysis, reduces the endogenous resynthesis of triglycerides (cf. Verlag Miinchen).

Further, from French Patent Specification No. 69 75, the 3-pyridylcarbinol ester of clofibrinic acid is known as the effective lipid and cholesterol lowering component. However, this compound, which is mainly used in the form of nicotinate, can only be used in low doses, due to the high proportion of pyridine component and the resulting side effects and thus is only a little therapeutically usable.

All of the active substances mentioned can only lower one of the lipid components, e.g. the triglyceride, significantly, while the other lipid components are not or only slightly affected therapeutically. This is successful only at higher dosage.

Therefore, there is a need in the art to find additional compounds which, without dose increase, have a lipid lowering effect on several lipid components.

Surprisingly, the need is met by the present compounds of general formula I. The novel compounds have potent effects at least against elevated serum triglyceride and cholesterol levels. Compared to nicotinic acid and the ethyl ester of 2- (p-chlorophenoxy) isobutyric acid, the dosages are significantly lower, so that the possibility of side effects is reduced to a minimum.

The novel compounds are solids.

The process of the invention for the preparation of compounds of formula I is carried out e.g. in the presence of pyridine.

An example of a β-cycloalkyl group is 1-adamantyl, i.e. R may have the formula b)

b) where m represents 0 or 1 and where z represents 0 or 1.

The present compounds of formula I may be formulated into pharmaceutical compositions containing the active substance together with a carrier or diluent. They can be administered orally and parenterally.

The process according to the invention is further illustrated by the following examples: EXAMPLE 1

Preparation of p- (1-adamantylphenyl) nicotinate.

11.4 g (50 ml) of p-1-adamantylphenol and 10 g (56 millimole) of nicotinic acid chloride hydrochloride are poured into 150 ml of dry pyridine and kept at 45 ° C for 48 hours. 40 ml of water is added and stirred in an ice bath to precipitate, suction, wash with water and dry. Yield 78% of theory. Melting point 199 ° C.

Analysis:

Calculated: C 79.27 H 6.90 N 4.20

Found: C 78.01 H 6.82 N 4.50.

EXAMPLE 2

Preparation of β-cyclododecylphenyl nicotinate.

8 g (30.8 millimoles) of p-cyclododecylphenol and 5.9 g (33.2 millimoles) of nicotinic acid chloride hydrochloride are poured into 140 ml of dry pyridine and kept at 30 ° C for 15 hours. Water (42 ml) is slowly added dropwise and cooled to 0 ° C. The precipitated crystal porridge is extracted, washed pyridine-free with water and dried. Yield 85% of theory. Melting point 98 ° C.

Analysis:

Calculated: C 78.91 H 8.50

Found: C 79.01 H 8.54.

EXAMPLE 3

Preparation of p- (cyclohexylacetyl) phenyl nicotinate.

11 g (50 millimoles of p-cyclohexylacetylphenol and 9.6 g (54 millimoles) of nicotinic acid chloride hydrochloride are taken up in 160 ml of dry pyridine and stirred for 8 hours at 40 ° C. 66 ml of water are added until the solution becomes cloudy and set in The crystallized product is filtered off with suction, washed with water and dried, yield 55% of theory, m.p. 103 ° C.

Analysis:

Calculated: C 74.30 H 6.50 Found: C 74.07 H 6.51.

EXAMPLE 4

Preparation of o-cyclohexylphenyl nicotinate hydrochloride.

15 g (85 millimoles) o-cyclohexylphenol and 16.5 g (93 millimoles) nicotinic acid chloride hydrochloride are taken up in 200 ml of dry pyridine and stirred at 30 ° C for 24 hours. After cooling, the precipitated pyridine hydrochloride is extracted and 300 ml of water are added to the filtrate. The precipitated crude product is washed twice with 200 ml of water, taken up in alcohol and evaporated on a rotary evaporator. The viscous oil obtained as the residue is dissolved in 500 ml of dry ether and hydrochlorinated with HCl gas. The product is filtered off, washed with ether and dried. Yield 52% of theory. Melting point 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 5

Preparation of 5,6,7,8-tetrahydro-1-naphthyl nicotinate.

7 g (47 millimoles) of 5,6,7,8-tetrahydro-1-naphtol and 9 g (50 millimoles) of nicotinic acid chloride hydrochloride are mixed with 130 ml of dry pyridine and stirred for 24 hours at 30 ° C. After cooling, precipitated pyridine hydrochloride is aspirated and the filtrate is mixed with 300 ml of water. The precipitated crude product is washed with 2 portions of water each 200 ml and recrystallized from methanol. Yield 65% of theory. Melting point 86 ° C.

Analysis:

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

Toxicity studies.

Table I

1 2

Compound RR LD 2 q Humando Therapeutic No. (mg / kg) Seration / Index Mouse Day (mg) 1 1-ada- H 3200 300 0.093 mantyl 2-p-chlorophenoxyisobutyric acid 1500 1500 1.0 ethyl ester (standard) nicotinic acid ( default) 4000 3000 0.75

As shown in Table I, the toxicity figures are in a comparable range, whereas the compounds of the present invention have a very advantageous therapeutic index.

Detection of effect.

Wistar female rats have been tested. The rats were given a strong high fat diet for 3 weeks. From the beginning of week 2, half of the rats were treated with a dose of 100 mg / kg body weight (for compounds 6 and 9, however, only at 25 mg / kg). After the third week and 18 hours after the last dose, a blood sample was taken from the animals and the concentrations of triglycerides and cholesterol were compared with the values of untreated rats. As a test method to determine the cholesterol and triglycerides was used

Boehringer's enzymatic test. The results are given in Table II below, which shows that significant reductions occurred in one or both parameters. By contrast, administration of clofibrate and nicotinic acid individually showed much poorer results, as also shown in Table II.

Table II

1 2

Combine RR Dose, Choleste Triglyceride Mg / kg Role Reduction No. Tion,%% 1 1-adamantyl H 100 28 47 4 cumyl H 100 24 1 7 p-chlorobenzene Η 100 29 zoyl 6 H 2-cyclohexyl 25 18 16 7 'H - (CH 2) 4- 100 22 18 9 cyclohexyl 2-tert. butyl 25 9 8 nicotinic acid 100 7 2- (p-chloro-100 - 8 phenoxyisobutyric acid ethyl ester

Solid compositions for oral administration are capsules, tablets, pills, powders and granules. In such solid preparations, the active substance is mixed with at least one inert diluent such as cane sugar, lactose or starch. As additional substances, lubricants or buffers may be present. Tablets and pills may be provided with a coating that is soluble in the intestine.

Liquids for oral administration are emulsions, solutions or suspensions containing commonly used inert diluents such as water. Furthermore, such liquid agents may also contain

Claims (6)

1. Analogous Process for the Preparation of Nicotine Syndication Companies of General Formula I Wherein R represents hydrogen, C1-cycloalkyl, (C1-6-cycloalkyl) methyl, (C1-6 -cycloalkyl-orebonyl, (C1-6-cycloalkyl) acetyl, cumyl, p-chlorobenzoyl, T-piperidinyl or 2-pyrimidinyl, and R represents hydrogen, so that the alkylene group together with the phenyl ring forms a tetral ring, halogen, alkyl of 1-6 carbon atoms or cycloalkyl, however, R can only represent hydrogen when Process according to claim 1, characterized in that a compound is prepared wherein C C ^ ^-cycloalkyl is 1-adamantyl. 2. R represents cycloalkyl or - (Ch 2 -) 2 - and R cannot be hydrogen when R is cyclohexyl, or pharmaceutically tolerable acid addition salts thereof, characterized in that an esterification is carried out where 1 in moles of nicotinic acid halide is reacted with 1 mole of starting phenol, wherein R 2 and R are as defined above, in the presence of 1 mole of an acid binding agent. Process according to claim 1, characterized in that cyclododecylphenyl nicotinate is produced. Process according to claim 1, characterized in that 5,6,7,8-tetrahydro-1-naphthyl nicotinate is prepared. Process according to claim 1, characterized in that p- (1-adamantylphenyl-dinicotinate) is prepared. Process according to claim 1, characterized in that p- (cyclohexylacetyl) phenylnicotinate is prepared.