CH579080A5 - N-(Lysergyl)-3-aminopyridines prodn - from lysergic acid reactive derivs and (substd)3-aminopyridines, having CNS and circulatory activities - Google Patents

Abstract

Process for preparing new lysergic acid derivs. of formula (I) comprises reacting reactive functional derivs. of acids (II) with amines (III) in an inert solvent or solvent mixt., then opt. converting (I) to an acid addition salt. (R1 = H or 1-4C alkyl, r2 = 3 pyridyl, opt. substd. one or more times by 1-4C alkyl, 1-4C alkoxy, OH or halo). (I) have specific CNS activity and circulatory activity, and are intermediates for other therapeutically useful cpds.

Description

  

  
 



   The present invention relates to a process for the preparation of new heterocyclic compounds of the formula I (see formula sheet), in which Rl stands for hydrogen or an alkyl group with 1 to 4 carbon atoms and R2 denotes a 3 pyridyl radical, which is optionally substituted one or more times by an alkyl radical with 1 up to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a hydroxyl group or can be substituted by halogen, and their acid addition salts.



     According to the invention, the compounds of the formula I and their acid addition salts are obtained by mixing a reactive, functional derivative of the acid of the formula II in an organic solvent or solvent mixture which is inert under the reaction conditions in the presence of an acid-binding agent with a compound of the formula III, in which R1 and R2 have the above meaning, and the compounds of the formula I thus obtained are optionally subsequently converted into their pharmacologically acceptable salts with acids.



   In the process according to the invention, the reaction product resulting from the reaction of the acid of the formula II with a chlorinating agent, for example thionyl chloride, phosgene, phosphorus oxychloride or oxalyl chloride, and an N-di (lower) alkyl-substituted acid amide of an aliphatic monocarboxylic acid having 1 to 3 carbon atoms is used as a reactive derivative the acid of formula II is used.



  However, other reactive derivatives of the acid of formula II can also be used, e.g. the acid chloride hydrochloride, the acid azide, the addition product with carbodiimide or mixed anhydrides of the acid of the formula II with sulfuric acid or trifluoroacetic acid.



   Suitable inert organic solvents for the condensation reaction according to the invention are, for example, chloroform, methylene chloride, acetonitrile or dimethylformamide, and tertiary amines as acid-binding agents, e.g.



  Pyridine or triethylamine. The reaction is advantageously carried out at temperatures between about -30 to OOC.



   The compounds of the formula III are preferably added as a base, but their salts can also be used. The preferred procedure is to add the acid of the formula II at 30ob to a suspension of dimethylformamide and oxalyl chloride in an inert solvent, preferably acetonitrile. In principle, however, the reaction is independent of the order in which the reagents are added. The mixture is stirred for about 30 minutes at -10 ° C., then cooled to -30 ° C. and a compound of the formula III, dissolved in dimethylformamide, is added with the addition of an acid-binding agent, for example pyridine.



  The reaction mixture is warmed to 0 ° C. and stirred for a further 2 hours.



   A compound of the formula III in the presence of an acid-binding agent such as triethylamine can also be added to the acid chloride hydrochloride of the compound of the formula II in an inert solvent, for example methylene chloride, at 0 ° to 56 ° C.



   To work up the reaction mixture obtained, it is poured onto ice-cold sodium carbonate solution and extracted with methylene chloride. The compounds of the formula I are isolated from the organic phase in a known manner, optionally in the form of their salts.



   The compounds of the formula I prepared according to the invention are substances which are crystalline at room temperature and which form stable salts with inorganic or organic acids which crystallize at room temperature.



   The compounds of the formula I show interesting properties in pharmacological testing, on the basis of which they can be used as medicaments.



   For example, they have a specific effect on the central nervous system and are active in the circulation. In addition, the compounds of the formula I serve as intermediate compounds for the preparation of therapeutically active compounds.



   The new compounds of the formula I or their physiologically tolerable acid addition salts can be used as medicaments alone or in appropriate medicament forms for oral, enteral or parenteral administration.



  In order to produce suitable dosage forms, these are processed with inorganic or organic, pharmacologically indifferent auxiliaries.



   In the following examples, which explain the invention in greater detail but are not intended to limit its scope in any way, all temperatures are given in degrees Celsius.



   If the preparation of the starting compounds is not described, these are known or can be prepared by processes known per se or analogously to processes known per se.
EMI1.1




   example 1
N-lysergyl-3'-aminopyridine
A solution of 8.55 ml (100 mmol) of oxalyl chloride in 60 ml of absolute acetonitrile is slowly added dropwise to 150 ml of absolute dimethylformamide and 300 ml of absolute acetonitrile at -300 with exclusion of moisture and passing over nitrogen. After 5 minutes, 26.8 g (100 mmol) of anhydrous lysergic acid are added at the same temperature with stirring and the mixture is stirred at -10 for 30 minutes. The reaction mixture is then cooled to -300, mixed with 50 ml of absolute pyridine and immediately afterwards with 14.1 g (150 mmol) of 3-aminopyridine, dissolved in 150 ml of absolute dimethylformamide.



   After stirring for 2 hours at 0O, the reaction mixture is poured into one liter of ice-cold 10% sodium carbonate solution and extracted with methylene chloride. After washing with water, the organic phase is dried over sodium sulfate, concentrated and dried at 50 ° in a high vacuum. From the solution of the crude product in acetone, N-lysergyl 31-aminopyridine of melting point 197-1990, [a] D2 = -68 + 2 (c = 0.5 in pyridine) crystallizes.



   Example 2 N-Lysergyl-5'-amino-2'-chloropyridine
To a suspension of 3.25 g (10 mmol) of lysergic acid chloride hydrochloride in 100 ml of abs. Methylene chloride is added dropwise with exclusion of moisture at 0-5O in about 15 minutes, a solution of 1.61 g (12.5 mmol) of 5-amino-2-chloropyridine, 3.5 ml (25 mmol) of triethylamine and 50 ml of abs. Methylene chloride. The reaction mixture is stirred at the same temperature for 40 minutes, then poured onto ice and extracted with methylene chloride and 2N soda solution while cooling with ice.



  The methylene chloride phases are washed with water, dried and evaporated.



   The hydrogen maleate is produced from the raw base in the usual way.



   Hydrogen maleate: from methanol, m.p. 200-2020 (decomp.); [a] Dl = +600 (c = 0.50; 50 percent ethanol).



  The following compounds can also be prepared analogously to Examples 1 and 2: Example Compound, melting point, spec. Rotation 3 N-lysergyl-5 / -amino-205-2080 [a] Dl = +630
2 / -n-butoxypyridine as (decomp.) (C = 0.5; 50 percent.



   Hydrogen maleate from ethanol)
Methanol-acetone $ N-lysergyl-3 / -amino-202-2030 [α] D21 = + 51o 2 /, 6'-dimethoxypyridine (decomp.) (C = 0.5; 50% percent.

 

   as hydrogen maleate ethanol) from methanol-acetone 5 N-lysergyl-5 / - (N-207-2090 [a] 2Dl = -127 "methylamino) -2'- (c = 0.5; pyridine) methoxypyridine as
Base from methanol ether as hydrogen maleate 150-1520 [ct] 2u1 = 660 from acetone ether (c = 0.5; 50 percent.



   Ethanol) 6 N-lysergyl-5 / -amino-2 / - 195-1970 [cr] = -560 methoxypyridine as (c = 0.5; pyridine)
Base from acetone-ether (x 1 mol of water of crystallization) as maleate from methanol decomposition. from 2050 [a12n0 = - 290
Acetone (c = 0.5; pyridine)

 

Claims (1)

PATENT CLAIM Process for the preparation of new heterocyclic compounds of the formula I, EMI2.1 where Rl is hydrogen or an alkyl group having 1 to 4 carbon atoms and R2 is a 3-pyridyl radical which is optionally substituted one or more times by an alkyl radical having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a hydroxyl group or halogen can be, and its acid addition salts, characterized in that a reactive, functional derivative of the acid of the formula II, EMI2.2 in an organic solvent or solvent mixture which is inert under the reaction conditions in the presence of an acid-binding agent with a compound of the formula III, EMI3.1 where Rl and R2 have the above meaning, and the compounds of the formula I thus obtained are optionally subsequently converted into their pharmacologically acceptable salts with acids.