NO167455B - Intermediates - Google Patents

Description

The present invention relates to intermediate products. These intermediates can be used to prepare dihydropyridines. Dihydropyridines can be used for the treatment of cardiovascular diseases and other diseases where relaxation of smooth muscles is therapeutically important in mammals including humans and pharmaceutical preparations containing said compounds.

The purpose of the invention is to provide compounds which are useful as intermediates for the production of dihydropyridines.

Adalat® (nifedipine) with the formula:

which is described in DE patent no. 1,670,827, is known to have a cerebral vasodilatory effect, an effect against angina pectoris and a blood pressure-lowering effect.

Agents that relax vascular smooth muscles can be used for the treatment of arterial hypertension, since such patients suffer from increased peripheral resistance to blood flow. Compounds that affect the activity of vascular smooth muscle have been used clinically for many years. However, their usefulness has often been limited due to insufficient effectiveness and/or due to adverse effects. Side effects (outside the cardiovascular system) have often been associated with properties of the agent that are not relevant to the relaxing effect on smooth muscles. Sometimes the vasodilators have also exerted a negative effect on the contractility of the heart. •' _/ It seems that the development of specific agents that have a relaxing effect on smooth muscles without adverse effects may offer a therapeutic advantage in arterial hypertension and for the treatment of ischemic heart diseases and for acute heart failure. Furthermore, such agents can also be used in the treatment of other conditions with excessive activation of smooth muscles of the visceral type.

Surprisingly, compounds with the formula have now been found:

wherein R<*> is one or two (same or different) substituents on the phenyl ring selected from the group consisting of NO2. CN, Cl and Br, A-means an alkylene group of 2-5 carbon atoms, R<2> is where B is a linear or branched alkylene group of 2-5 carbon atoms, and R<3> and R<6> mean C^- C^alkylbenzyl or together means morpholino, R<4> is a linear or branched alkyl group of 1-5 carbon atoms, or a linear or branched alkyl group of 1-5 carbon atoms in which the alkyl group carbon chain may be substituted with C^-C^ alkoxy . Linear or branched alkylene groups with 2-5 carbon atoms can be -CH2CH2-, -CH2CH2CH2-. -CH2CH2CH2CH2-, -CH2CH2CH2-

Lower alkyl is an alkyl group with 1-5 carbon atoms, f in e.g. methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, i-butyl, tert-butyl.

Linear or branched alkyl groups with 1-5 carbon atoms; in which the carbon chain is interrupted by an oxygen atom can be

The new compounds are obtained according to methods known per se.

Thus,

a<*>) a compound is reacted with the formula:

wherein R<*> and R<4> have the meanings given above, with a compound of the formula: wherein A and R<2> have the meanings given above, to form a compound of formula I, or a <2>) is reacted with a compound of the formula: in which R<1>, R<2> and A have the meanings indicated above, with a compound of the formula:

wherein R<4> has the meaning indicated above, for the formation of a compound of formula I, or

b<*>) a compound is reacted with the formula:

wherein R<1> is as defined above, with compounds having the formulas: wherein R<2>. R<4> and A have the meanings indicated above, to form a compound of formula I, or b<2>) a compound of formula IV above is reacted, in which R<* >has the meaning indicated above, with compounds of the formulas: in which R<2>, R<4> and A have the meanings indicated above, to form a compound of formula I, or c<*>) a compound of formula II above is reacted, in which R <* >and R<4> have the meanings given above, with a compound of the formula: wherein R<2> and A have the meanings given above, in the presence of ammonia, to form a compound of the formula I , or c<2>) a compound of formula Ilb above, in which R<*>, R<2> and A have the meanings indicated above, is reacted with a compound of the formula:

wherein R<4> is as defined above, in the presence of ammonia, to form a compound of formula I, or

d) a compound of formula IV above, in which R<* >has the meaning indicated above, is reacted with the compounds

with the formula Va and Vb, wherein R<2>, R<4> and A have the meanings indicated above, in the presence of ammonia, to form a compound of formula I, after which, if desired, the compound obtained by means of one of the methods a<*>) - d) is converted into a physiologically acceptable salt thereof, and/or converted into an essentially stereoisomer thereof.

The reactions a<*>) - d) are carried out in the presence or absence of a solvent, preferably in the presence of water or an organic solvent. The reactions are carried out at a temperature of 20-200<*>C.

Depending on the choice of starting materials and method, the new compounds can be present as optical antipodes or racemates, or if they contain at least 2 asymmetric carbon atoms, be present as an isomer mixture (racemate mixture).

The isomer mixtures (racemate mixtures) obtained can, depending on the physico-chemical differences of the components, be separated into the two stereoisomeric (diastereomeric) pure racemates, e.g. by means of chromatography and/or fractional crystallization.

The racemate obtained can be separated according to known methods, e.g. by means of recrystallization from an optically active solvent, by means of microorganisms, by means of chromatography or by a reaction with optically active acids which form salts of the compounds, and separating the salts thus obtained, e.g. by means of the difference in solubility of the diastereomeric salts, from which the antipodes may be liberated by the action of a suitable agent. Suitable usable optically active acids are e.g. The L and D forms of tartaric acid, di-o-tolyl tartaric acid, malic acid, mandelic acid, camphor sulphonic acid or quinic acid. Preferably, the most active of the two antipodes is isolated.

Appropriately, silk starting materials are used to carry out the reaction leading to groups of

end products which are preferably desired and especially to the particularly described and preferred end products.

The starting materials are known or, if they are new, can be obtained according to methods which are known per se.

The present invention also applies to acceptable, non-toxic salts of these basic compounds. Such salts include those obtained from organic and inorganic acids such as e.g. without limitation, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lactic acid, succinic acid, sulfuric acid, malic acid, maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, embonic acid, enanthic acid, or any acid acceptable as an additive additive .

The compounds of formula I are used as intermediates for the production of dihydropyrldines, which e.g. compounds with the formula:

wherein A is a linear or branched alkylene group of 2-5 carbon atoms, and R<1> is one or two (same or different) substituents on the phenyl ring selected from the group consisting of lower alkyl, NO2, CN, Cl or Br, R<4> is a linear or branched alkyl group with 1-5 carbon atoms, or a linear or branched alkyl group with 1-5 carbon atoms, in which alkyl group the carbon chain may be substituted with C1-C4 alkoxy.

Such compounds are previously known as antihypertensive agents. For example, the compound 2,6-dimethyl-4-(2,3-dichloro-phenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-ethyl-5-methyl ester (felodlpine), which is described in US patent No. 4,264,611.

The generally used methods for the preparation of a particular compound of formula Ia above result in the achievement of a mixture of compounds in terms of the substituents on the after-groups. This mixture of symmetrical and slightly asymmetrical substances is very difficult to separate into its various components, and thus results in a very impure preparation.

The intermediate of formula I is highly unsymmetrical and is an organic monofunctional base. By using its properties as an organic base, it can be easily separated from unwanted by-products and then transferred to the pure substance of formula I a. The process results in final products with a very high degree of purity, and especially with a low contamination of closely related dihydropyridine-dicarboxylic acid esters.

The method is characterized by the treatment of a compound of formula I above in a solvent with a Raney catalyst, whereby a compound of formula I a above is obtained.

Suitable solvents are methanol, ethanol, dioxane, tetrahydrofuran, benzene, toluene, acetone, methyl ethyl ketone and ethyl acetate.

Raney nickel and Raney cobalt can be used as Raney catalysts.

The process is conveniently carried out at a temperature of 15-100<*>C.

Example 1 (method b<2>)

Preparation of 2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dlhydro-pyridine-3,5-dicarboxylic acid-3-[2-(2-N,N-dlmethylamlnoethyl-51° iÉ^ YilllllÆS^y reads .

A mixture of 2.9 g of 2,3-dichlorobenzaldehyde, 2.3 g of 3-aminocrotonic acid methyl ester, 4.7 g of acetoacetic acid 2-(2-N,N-dimethylaminoethyltlo)ethyl ester and 125 ml of isopropanol was tllbakelops treated within 1 night. The mixture was then evaporated and to the residue was added with stirring 100 ml of 0.4 M HCl. The mixture was extracted with ether. The aqueous phase was then extracted with methylene chloride. The methylene chloride phase was then shaken with 1 M NaOH. After drying and evaporating the methylene chloride, the title compound was obtained as an oil. 3-H and <13>C-NMR spectra are consistent with the given structure.

Yield: 37*.

Example 2 (method a<2>)

Preparation of 2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid-3-[2-(2-morpholinoethylthio)ethyl]-5-i2l?É52 ^§XSiYlilɧiÉE

A mixture of 12.9 g of 2,3-dichlorobenzylideneacetylacetic acid 2-(2-morpholnoethylthio)ethyl ester and 4.7 g of 3-aminoprotic acid 2-methoxyethyl ester in 50 ml of pyridine was refluxed for 4 hours. The mixture was then evaporated and the residue dissolved in 1100 ml of methylene chloride. The resulting solution was washed twice with 50 mL of 2 M EC1 and then twice with 2 M NaOH. Drying and evaporation of the organic phase gave the title compound as an oil. <*>H— and <*3>C NMR spectra are consistent with the given structure.

Yield: 61*.

The following compounds have also been prepared (see Table I)

<1>H-NMR and <13>C-NMR have been obtained for all compounds 1 table

IN.

Example 3 (new procedure)

Preparation of 2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydro-<ES>^i^i^I^<i>^<l>^<i>^^<r> ^^^<EYl>^<YESl>^<l>^^<Yll>^<I>^^<iYi>^^^<E >1.95 g 2,6-dimethyl-4-(2,3 -dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-[2-(2-N,N-dimethylaminoethylthio)ethyl]-5-methyl ester was dissolved in 150 ml of ethanol. Raney nickel was added and the mixture was refluxed for 10 minutes. The mixture was then filtered and evaporated. To the residue was then added 50 ml of 1M HCl and the mixture was extracted with ether. The ether phase was dried and evaporated. The residue was crystallized from isopropyl ether. the title compound was obtained, melting point: 145°C. 3 H-NMR spectrum was consistent with the given structure.

Dividend; 73*.

Biological tests

The antihypertensive activity of the compounds was tested on conscious, unrestrained, spontaneously hypertensive rats (SHR) of the Okamoto strain. The animals were prepared in advance with the implantation of indwelling catheters in the abdominal aorta via the femoral artery. Mean arterial blood pressure (MABP) and heart rate - were continuously monitored. After a 2 hour control period, the compound to be investigated was administered orally by incubation at 2 hour intervals, suspended in methocel solution (5 ml/kg body weight). The cumulative doses were 1.5 and 25 jjmol/kg body weight. The antihypertensive response, i.e. the BP reduction for each dose, was expressed as a * of the initial control BP level and plotted against the dose on a logarithmic scale. The dose that produced a 20* BP reduction was then determined by interpolation. The results are shown in table 2.

Smooth muscle relaxation specificity was examined as follows: The isolated portal vein preparation from Wistar rats was mounted in an organ bath together with a walking isolated papillary cardiac muscle preparation from the same animal. The integrated contractile activity of the smooth muscle of the portal vein and the peak force amplitude of the papillary myocardial preparation were recorded. The respective activities during a 30 minute control period were set as 100*, and the subsequent activities under the influence of the substance to be examined were expressed in * thereof. The drug was administered at 10-minute intervals, and the capacity for vasodilatation (-log ED50 of the portal vein) and that for myocardial contraction (-log ED50 for papillary muscle) was determined by interpolation from the concentration-effect relationships determined in each experiment. A "separation" value was determined for each compound by averaging the differences between the -log ED 50 values for vasodilation and myocardial depression, respectively, obtained in the experiments. This logarithmic separation value was converted into number format and entered in table 2.

The compounds produced using the intermediates according to the invention were compared with nifedipine [2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3,5-dimethyl ester].

Claims (1)

Intermediate product, characterized in that it has the formula: in which R<1> means one or two substituents, such as halogen, nitro or cyano, A means C2~C5-alkylene, R<2> means where B stands for C2-C5- alkylene, R<3> and R<6> mean C1-C4 alkylbenzyl or together mean morpholino. R<4> means C 1 -C 8 alkyl, which may be substituted by C 1 -C 4 alkoxy, or a salt thereof. 2. Intermediate product according to claim 1, characterized in that it has the formula: where R<2> has the same meaning as in claim 1.