CH436287A - Process for the preparation of new pharmaceutically active pyridine derivatives - Google Patents

Description

  

  Process for the preparation of new pharmaceutically active pyridine derivatives The present patent relates to a process for the preparation of new pyridine derivatives of the general formula:
EMI0001.0000
    and optionally their salts and the use of these compounds for the preparation of their quaternary ammonium compounds.



  In this formula, R1 and R2 denote alkyl radicals, preferably those which are closed to form a ring which can contain a further heteroatom, in particular oxygen. Alk denotes a straight or branched lower alkylene chain with at most 4 carbon atoms, X denotes sulfur, oxygen or the NH group. Y can be a halogen, preferably in the 3-position, but also a trihalomethyl, e.g. B. a trifluoromethyl, alkyl, preferably methyl, or alkoxy, preferably methoxy group, also the radical -CN, -COORs or -CONR4R5, wherein R3, R4 and R5 can be identical or different udn hydrogen or lower alk are yl groups, mean.



  The compounds mentioned have good pharmacological properties, in particular analgesic and anti-inflammatory effects.



  According to the invention, these compounds are obtained by using a compound of the general formula:
EMI0001.0001
    with a compound of the general formula:
EMI0001.0002
    in which formulas one of the two radicals A and Z is chlorine or bromine and the other radical is the group -XH.



  In the event that A is chlorine or bromine, the reaction is preferably carried out at an elevated temperature and using basic condensation agents, such as potash, sodium ethylate or other basic substances such. B. tertiary amines.



  But if A is the group -XH, the condensation is preferably carried out in the presence of basic substances, such as sodium methylate or sodium amide, at an elevated temperature. The bases obtained can be converted into their salts or quaternary ammonium compounds.



  Example 1 32 parts of morpholinoethyl mercaptan, dissolved in 300 parts of xylene, are mixed with 20 parts of a 50% strength suspension of sodium amide in toluene while boiling under reflux. After the evolution of gas has ceased, 33 parts of 2,3-dichloropyridine, dissolved in 200 parts of xylene, are added dropwise and the mixture is refluxed for 1 hour. After cooling, the batch is decomposed with water, the xylene layer is extracted with dilute hydrochloric acid at a pH of 4 and the acidic aqueous phase is then worked up with sodium hydroxide solution and ether. The ether extract is dried and distilled in vacuo. At 0.5 mm pressure and 164-168 Celsius, 32 g of 2- (morpholinoethylmercapto) -3-chloropyridine pass over.

   The hydrochloric acid salt, precipitated from isopropanol and recrystallized, melts at 181 ° C. Example 2 75 parts of 2-oxy-6-chloropyridine, dissolved in 750 parts of toluene / oigen suspension, are boiled with 43 parts of sodium amide in toluene Reflux added. Then 70 parts of dimethylaminoethyl chloride are added dropwise and the mixture is boiled for a further 3 hours. After working up as in Example 1, 53 parts of 2- (dimethylaminoethoxy) -6-chloropyridine are obtained at boiling point 11: 115-122 C. The hydrochloride melts at 146-148 C.



  Example 3 As in Example 2, but using dimethylaminopropyl chloride, 2- (dimethylaminopropyloxy -) - 6-chloropyridine with a boiling point of 134-138 Celsius is obtained. The hydrochloride melts at 181 to 183 C.



  Example 4 74 parts of 2,6-dichloropyridine and 102 parts of 1-dimethylaminopropylamine 3 are carefully heated on an oil bath. A violent reaction sets in at around 90 ° C. After cooling, it is dissolved in a mixture of water and ether, made alkaline with potash and the ethereal solution is worked up. At bp11: 176 to 182 ° C., 58 g of 2- (dimethylaminopropylamino) - 6-chloropyridine are obtained. The hydrochloride melts at 83-85 C.



  Example 5 As in Example 1, but using 2,6-dichloropyridine instead of 2,3-dichloropyridine, 2- (morpholino-ethyhnercapto) - 6-chloro-pyridine, the hydrochloride of which melts at 163-165 ° C., is obtained. EXAMPLE 6 To a solution of 44 parts of morpholinopropanol in 300 parts of toluene, 24 parts of a 50% strength sodium amide suspension in toluene are added dropwise with refluxing. When the reaction has ended, 45 parts of 2,3-dichloropyridine, dissolved in 200 parts of toluene, are added dropwise. It is then boiled for 2 hours. The reaction mixture is poured into water, the toluene layer is extracted at pH 4 with dilute hydrochloric acid, the acidic aqueous extract is worked up alkaline with ether and distilled.

   At boiling point: 149-151 ° C., 63 g of 2- (morpholinopropyloxy -) - 3- chloropyridine pass over. The hydrochloride is obtained in isopropanol with isopropanolic hydrochloric acid; it melts at 151-162 ° C. Example 7 As in Example 1, but using 2-bromo-3-methyl-pyridine instead of 2,3-dichloropyridine, 2- (morpholinoethyl-mercapto) -3-methyl-pyridine is obtained whose hydrochloride melts at 169-171'C. Example 8 As in Example 6, 2,6-dichloropyridine is used instead of 2,3-dichloropyridine and 2- (morpholinopropyloxy -) - 6-chloropyridine is obtained; the hydrochloride melts at 164-167 C.



  Example 9 As in Example 1, but using piperidinoethyl mercaptan instead of morpholino ethyl mercaptan, 2- (piperidino ethyl mercapto) -3-chloropyridine is obtained. The hydrochloride melts at 181 to 183 C.



  Example 10 38 parts of 2-amino-5-chloropyridine are heated to the boil with 300 parts of toluene. Then 23 parts of a 50% sodium amide-toluene suspension are added dropwise and the mixture is boiled for 1 hour. Then 45 parts of morpholino-ethyl chloride are added, after which the mixture is boiled for another hour. The reaction mixture is then poured into water, the toluene layer is separated off, dried and distilled. At bp1: 164-170 ° C., 46 parts of 2- (morpholinoethylamino) -5-chloropyridine pass over. The dihydrochloride is precipitated in isopropanol; it melts at 223-225 ° C. Example 11 9 parts of sodium are dissolved in 60 parts of morpholinopropanol and 50 parts of xylene.

   Then 57 parts of 6-methoxy-2-chloropyridine are added. After thorough mixing, heating is started slowly. The beginning of the reaction can be observed at an internal temperature of 140.degree. The bath temperature is then kept at 240 ° C. for 1 hour. The batch is then poured into water and worked up with ether. At bp1: 151-163 ° C., 35 parts of 2- (morpholinopropyloxy) - 6-methoxypyridine are obtained. The hydrochloride is precipitated from isopropanol; it melts at 154 to 156 ° C. Example 12 3 parts of sodium are dissolved in 120 parts of ethanol.

   19 parts of morpholinoethyl mercaptan and 18 parts of 2-chloro-3-cyanopyridine are added one after the other. The alcohol is then distilled off and a temperature of 140 ° C. is maintained for 1 hour. After cooling, it is dissolved in ether and water, extracted with dilute hydrochloric acid and the aqueous phase is worked up in an alkaline manner. At b.p. 185-190 C, 23 parts of 2- (morpholinoethylmereapto) -3-cyanopyridine go over. The hydrochloride melts at 197 to 200 C.



  Example 13 6 parts of sodium are dissolved in 250 parts of ethanol. 19 parts of morpholinoethyl mercaptan and 20 parts of 2-chloro-nicotinic acid are added one after the other, the alcohol is distilled off and the residue is heated to 160 ° C. for 1 hour. It is then dissolved in 100 parts of water, 50 parts of 48% strength hydrobromic acid are added, the mixture is heated until the solution is clear and then cooled. 15 parts of 2- (morpholinoethylmercapto) - nicotinic acid hydrobromide with a melting point of 210-213 ° C. are obtained.



  Example 14 2.5 parts of sodium are dissolved in 100 parts of ethanol, then 15 parts of morpholinoethyl mercaptan and 19 parts of 2-chloro-nicotinic acid ethyl ester are added, the alcohol is distilled off and the residue is heated to 150 ° C. for 1 hour. It is then extracted ice-cold with dilute hydrochloric acid and worked up alkaline with ether. The ether residue is 2- (Morpholinoäthyl- mercapto-) - nicotinic acid ethyl ester, the hydrobromide of which melts at 176 ° C.



  Example 15 Analogously to Example 14, using 2-chloronicotinic acid amide, 2- (morpholinoethylmercapto) - nicotinic acid amide is obtained.

 

Claims (1)

PATENT CLAIM I Process for the production of new pharmaceutically active pyridine derivatives of the general formula: EMI0003.0000 where R1 and R2 are alkyl radicals that can be closed to form a ring that may contain a further heteroatom, Alk is a straight or branched alkylene group with at most 4 carbon atoms, X is sulfur, oxygen or the NH group and Y is halogen, alkyl , Trihalomethyl or alkoxy group, also the radical -CN, -COORg or -CONR4R5, in which. R3, R4 and R5 can be the same or different and are hydrogen or lower alkyl groups, are characterized in that a compound of the general formula: EMI0003.0003 with a compound of the general formula: EMI0003.0004 in which formulas one of the two radicals A and Z is chlorine or bromine and the other radical is the group -XH. SUBClaims 1. The method according to claim, characterized in that the bases are converted into their acid addition salts. 2. The method according to claim I, characterized in that R1 and R2 are closed over a ring which contains oxygen as a further heteroatom. PATENT CLAIM II Use of the bases produced according to claim I for the production of their quaternary ammonium compounds.