DD245195A1 - PROCESS FOR PREPARING NEW 2-POSSIBLE 5-ARYL-3-CYAN-6-METHYL-PYRIDINE - Google Patents

Abstract

The invention relates to a process for preparing new 5-aryl-3-cyano-6-methyl-pyridines substituted in the 2-position by oxaalkylamino or oxaalkoxy groups. The aim of the invention is to produce biologically active 5-aryl-3-cyano-6-methyl-2- (oxaalkylamino) - or 5-aryl-3-cyano-6-methyl-2- (oxaalkoxy) pyridines. This object is achieved in such a way that 5-aryl-3-cyano-2-halo-6-methyl-pyridines substituted by OH or alkoxy primary and secondary alkylamines or morpholine or with polyhydric alcohols or alkoxyalkanols in the presence of bases be implemented. The compounds are possible cardiotonics and vasodilators. Field of application of the invention is the pharmaceutical industry.

Description

Field of application of the invention

The invention relates to a process for the preparation of 5-aryl-3-cyano-6-methyl-pyridines of the formula I.

in which X is hydroxyalkylamino, acyloxyalkylamino, alkoxyalkylamino, morpholino or hydroxyalkoxy, alkoxyalkoxy or

Acyloxyalkoxy and R represents H, 4-methoxy and 3,4-dimethoxy.

The compounds show cardiotonic and vasodilatory effects. The invention is applicable in the pharmaceutical industry.

Characteristic of the known technical solutions

5-Aryl-3-cyano-6-methyl-1,2-dihydro-pyrid-2-ones and their cardiotonic activity are known (GY Lesher et al., US Pat. No. 4,465,686, EP-PS 061774, EP-PS 74091, G Bormann, GB-PS 2070606, BE-PS 896678).

2-Chloro-3-cyano-6-methyl-5-phenylpyridine (M. Julia et al. Bull. Soc. Chim. France 1966, 2387) and 2-amino-3-cyano-6-hexene have been described. methyl-5-phenylpyridine (JL Miesel, U.S. Patent 4,405,552, European Patent No. 60071).

Not yet known sine] 5-aryl-3-cyano-6-methyl-2- (oxaalkylamino) - or 5-aryl-3-cyano-6-methyl-2- (oxaalkoxy) -pyridine. Also not described are 2-chloro-3-cyano-5- (4-methoxyphenyl) -6-methyl-pyridine and 2-chloro-3-cyano-5- (3,4-dimethoxyphenyl) -6- methyl-pyridine.

The inventively prepared 5-aryl-3-cyano-6-methyl-2- (oxaalkylamino) - or 5-aryl-3-cyano-6-methyl-2- (oxaalkoxy) -pyridines have surprisingly good cardiotonic and vasodilatory effects ,

Object of the invention

The invention aims to produce novel biologically active δ-aryl-S-cyano-e-methyl-pyridines.

Explanation of the essence of the invention

The invention has for its object to develop a process for the preparation of new o-aryl-S-cyan-o-methyl-pyridines. The object has been achieved by preparing 5-aryl-3-cyano-6-methyl-2- (oxaalkylamino) - or 5-aryl-3-cyano-6-methyl-2- (oxaalkoxy) -pyridines.

According to the invention, compounds of the formula I in which X can be hydroxyalkylamino, acyloxyalkylamino, aikoxyalkylamino, morpholino, hydroxyalkoxy, alkoxyalkoxy or acyloxyalkoxy and R is H, 5-methoxy and 3,4-dimethoxy are prepared by reacting 5-aryl-3-cyano 2-halo-6-methyl-pyridine

a) with hydroxyalkylamines, alkoxyalkylamines or morpholine in organic solvents, such as alcohols, tertiary amines, pyridine, methylglycol, dimethylformamide, dimethylsulfoxide, acetonitrile, mixtures of these solvents and the oxaalkylamines themselves to the 2-oxaalkylamino compounds

b) with di- or polyhydroxyalkanes or alkoxyalkanols in the presence of bases, for example anhydrous KOH or NaOH, or with the corresponding alkali metal alcoholates in the respective alcohol or in inert organic solvents to the 2-oxaalkoxy compounds

implements. From the 2-hydroxyalkylamino or the 2-hydroxyalkoxy compounds, respectively, with acid anhydrides or with acid halides, advantageously in tertiary amines, such as pyridine or trialkylamines, as solvent, the 2-acyloxyalkylamino or the 2-acyloxyalkoxy-3-cyano-pyridines be won.

The preparation of the 5-aryl-3-cyano-2-halo-6-methyl-pyridines is carried out in principle by known methods by reaction of 5-aryl-3-cyano-6-methyl-1,2-dihydro-pyrid-2 -one with halogenating agents such. B. POCI ₃ , PCI ₃ or PBr ₃ . The 5-aryl-3-cyano-6-methyl-2- (oxaalkylamino) - or 5-aryl-3-cyano-6-methyl-2- (oxaalkoxy) -pyridines can be converted into the corresponding salts with strong acids ,

The free bases and their salts are biologically active. In particular, cardiotonic and vasodilatory effects were found. For example, S-cyano-δ-methyl-morpholino-B-phenyl-pyridine according to i.v. Injection on the anesthetized dog a pronounced and dose-dependent positive inotropic effect and a vasodilatory effect.

The invention will be explained in more detail with reference to exemplary embodiments.

Auführungsbeispiele

Example 1 2-Chloro-3-cyano-5- (4-methoxy-phenyl) -6-methyl-pyridine

24 g of 3-cyano-6-methyl-5- (4-methoxyphenyl) -1,2-dihydro-pyrid-2-one, 10 ml of POCl ₃ and 2.5 ml of dimethylformamide are added 8 h. Boiled under reflux with stirring. After cooling, the black-brown solution is carefully suspended with vigorous stirring in about 11 ice-water, the precipitate is filtered off with suction, washed several times with water and recrystallized from i-propanol. Yield: 21.0 g (81.5% of theory). M .: 136.5-137 ° C

Example 2 2-Chloro-3-cyano-5- (3,4-dimethoxy-phe-nyl) -6-methyl-pyridine

Analogously to Example 1, starting from 27g of 3-cyano-5- (3,4-dimethoxyphenyl) -6-methyl-1,2-dihydro-pyrid-2-one, 10OmI POCl ₃ and 2.5 ml of dimethylformamide.

Yield: 25.5 g (88.5% of theory). M.p .: 161.5-162 ° C

Example 3 3-cyano-2- (2-hydroxyethylamino) -6-methyl-5-phenylpyridine

0.45 g of 2-chloro-3-cyano-6-methyl-5-phenylpyridine are refluxed with 1.2 ml of ethanolamine in 15 ml of ethanol for 12 hours. It is then concentrated under reduced pressure, mixed with water and the precipitate is filtered off with suction. Yield: 0.42 g (83.5% of theory). M .: 113-5.5 ⁰ C

Example 4 3-Cyano-2- (2-hydroxypropylamino) -6-methyl-5-phenyl-pyridine

0.45 g of 2-chloro-3-cy6n-6-methyl-5-phenyl-pyridine are refluxed for 16 hours with 0.75 g of 1-amino-propanol- (2) and 0.5 ml of pyridine in 8 ml of methyl glycol. It is then concentrated under reduced pressure, mixed with water and the precipitate is filtered off with suction.

Yield: 0.43g (80% of theory). Mp .: 134-6.5 ° C

Example 5 S-Cyano-β-SS-hydroxy-propylaminol-e-methyl-S-phenyl-pyridine

0.45 g of 2-chloro-3-cyano-6-methyl-5-phenyl-pyridine are refluxed for 16 hours with 1.5 g of 1-amino-propanol- (3) and 1 ml of pyridine. It is then concentrated under reduced pressure, mixed with water and the precipitate is filtered off with suction. Yield: 0.519 g (95% of theory). M.p .: 107.5-5-9 ⁰ C

Example 6 S-Cyano-e-methyl-a-morpholino-S-phenyl-pyridine

0.45 g of 2-chloro-3-cyano-6-methyl-5-phenyl-pyridine are refluxed with 1 ml of morpholine in 15 ml of ethanol for 8 hours. It is concentrated under reduced pressure, mixed with water and the precipitate is filtered off with suction. · Yield: 0.49 g (88% of theory). M .: 109-13 ⁰ C

Example 7 3-Cyano-5- (4-methoxy-phenyl) -6-methyl-2-morpholino-pyridine

11.4 g of 2-chloro-3-cyano-5- (4-methoxyphenyl) -6-methyl-pyridine are refluxed with 20 ml of morpholine in 100 ml of methylene glycol for 14 hours, treated with charcoal, filtered while hot, in vacuo concentrated and mixed with water. The precipitate is filtered off with suction and washed with water.

Yield: 9.2 g (67% of theory). A sample was recrystallized from i-propanol to give the product was obtained with mp. 72 to 74.5 ⁰ C.

Example 8 3-Cyano-5- (3,4-dimethoxy-phenyl) -6-methyl-2-morpholino-pyridine

6.8 g of 2-chloro-3-cyano-5- (3,4-dimethoxyphenyl) -6-methylpyridine are refluxed with 10 ml of morpholine in 60 ml of methylene glycol for 12 hours. The hot solution is mixed with activated charcoal, filtered, concentrated and treated with water.

The precipitate is filtered off with suction and washed with water.

Yield: 5.6 g (83% of theory). \

A sample was recrystallized from acetonitrile / water to afford the product was obtained with a mp. Of 127 to 8.5 ⁰ C.

Example 9 3-Cyano-2- (2-hydroxyethoxy) -6-methyl-5-phenyl-pyridine

4.6 g of 2-chloro-3-cyano-6-methyl-5-phenyl-pyridine are stirred with 1.2 g of powdered potassium hydroxide in 100 ml of dihydroxyethane at about 100 ° C for 30 min. It is then mixed with water and the solution is neutralized with glacial acetic acid. The precipitate is filtered off and recrystallized from methanol

Yield: 3.4 g (67% of theory), m.p .: 76.5 to 79 ⁰ C.

Example 10 2- (2-Acetoxyethoxy) -3-cyano-6-methyl-5-phenyl-pyridine

2.54 g of 3-cyano-2- (2-hydroxyethoxy) -6-methyl-5-phenyl-pyridine are refluxed with 2 ml of acetic anhydride in 20 ml of pyridine with exclusion of moisture for 1 hour. Subsequently, water is added and the precipitate is filtered off with suction. , '

Yield: 2.8 (95% of theory)

 A sample was recrystallized from methanol to give the product with a mp of 96-98 ° C.

Example 11 Anesthetized dog Lv.

The studies were conducted on bastard dogs in chloralose-urethane anesthesia when premedicated with morphine hydrochloride under spontaneous respiration.

The left ventricular pressure was measured by means of a tip manometer and the arterial pressure was measured via cardiac catheter via the brachial artery (compare K. Femmer et al., Pharmacie 30, 642 [1975]). Under the influence of 5-aryl-3-cyano-6-methyl-2- (oxaalkylamino) - or 5-aryl-3-cyano-6-methyl-2- (oxaalkoxy) -pyridine was a dose-dependent marked increase in contractility of the heart, as well as a significant decrease in total peripheral resistance. Thus, for example, the compound of Example 6 at a dose of 5 mg / kg shows an increase in the contractility parameter dp / dt _max by 56% and the compounds of Examples 7 and 8 show an increase of dp / dt _max at a dose of 10 mg / kg 72 or 84%. For the compounds of Example 4,6 and 8 at the dose of 5 mg / kg as a measure of peripheral vascular effect a reduction of diastolic blood pressure by 22%, 19 and 14% was found.

Example 12 ·

3-cyano-2- (2-methoxy-ethoxy) -6-methyl-5-phenyl-pyridin

1.37 g of 2-chloro-3-cyano-6-methyl-5-phenylpyridine are dissolved in 40 ml of methyl glycol and mixed with 0.34 g of powdered potassium hydroxide. It is heated for 2 hours at reflux, then treated with water and the precipitate filtered off with suction. '· _;

Yield: 1.49 g (92.6% of theory). M .: 92.5-94.5 ° C

Example 13 2- (2-Acetoxy-propylamino) -3-cyano-6-methyl-5-phenyl-pyridine

1.6 g of 3-cyano-2- (2-hydroxy-propylamino) -6-methyl-5-phenyl-pyridine are dissolved in 12 ml of pyridine and refluxed with 1.2 ml of acetic anhydride with exclusion of moisture for 1 hour. Subsequently, water is added and the precipitate is filtered off with suction

Yield: 1.74 g (89.8% of theory). M .: 93.5-95 ⁰ C

Claims (3)

Invention claim: 1. A process for the preparation of new substituted in the 2-position B-aryl-S-cyano-δ-methyl-pyridines of the formula I, in which X is hydroxyalkylamino ^ cyloxyalkylamine, oxyalkoxyalkylamino, morpholino, hydroxyalkoxyjalkoxyalkoxy or acyloxyalkoxy; and R is H, 4-methoxy- and 3,4-dimethoxy, and optionally the corresponding pharmaceutical
Administration form, characterized in that o-aryl-S-cyano ^ -halo-S-methyl-pyridines a) with hydroxyalkylamines, alkoxyalkylamines or morpholine to the 2-oxaalkylamino compounds
or b) with di- or polyhydroxyalkanes or alkoxyalkanols in the presence of bases, such as anhydrous KOH or NaOH, or with the corresponding alkali metal alcoholates in the respective alcohol or in inert organic solvents to the 2-oxaalkoxy compounds c) the 2-hydroxyalkylamino compounds from a) and the 2-hydroxyalkoxy compounds from b) with acid anhydrides or acid halides, preferably in the presence of tertiary amines, to the 2-acyloxyalkylamino or 2-acyloxyalkoxy compounds if appropriate, and the compounds of the formula I are mixed with appropriate pharmaceutical carriers. 2. The method according to item 1, characterized in that the reaction of 5-aryl-3-cyano-2-halo-6-methyl-pyridine with
Oxaalkylamines in organic solvents, preferably pyridine, alcohols, methyl glycol, dimethylformamide,
Dimethyl sulfoxide, acetonitrile or the oxaalkylamine itself is made. 3. The method according to item 1 and 2, characterized in that the compounds of formula I in the form of pharmaceutically
compatible salts, in particular hydrogen halides, sulfates and methosulfates are produced.