IL30747A - Acylated n-(alkylaminoalkyl)-aminopyridines - Google Patents

Description

BAYER Invention concerns new acyleted The German patent specification describes a process the production of pyridine derivatives having analgesic by acylating of the in which R is a or branched alkylene radical of carbon is a saturated or unsaturated aliphatic hydrocarbon radical of carbon atoms or a lower aralkyl and is hydrogen or a saturated or unsaturated phatic hydrocarbon radical of carbon or together with either or R and the adjacent nitrogen atom may form a or membered heterocyclic The present invention provides new acylated pyridine derivatives having a stronger and better analgesic effect and an advantageous therapeutic as will be shown The invention consists in new acylated of the in which X is a saturated or unsaturated bivalent aliphatic hydrocarbon radical of carbon which is branched once or several times and forms with the nitrogen atom a to membered heterocyclic bearing at least one alkyl with the proviso that the total number of carbon atoms on the heterocyclic ring the alkyl Is from 5 to and is hydrogen or an alkyl or alkenyl group of carbon is reacted an aliphatic acylating agent which contains 1 5 carbon in which formula X has the same meaning as This process is carried out a conventional acylating agents may for saturated or saturated aliphatic carboxylic acid halides or anhydrides or their corresponding mixed used as starting materials which have not been described in the literature can be prepared by known For aminopyridines can be alkylated with corresponding isopropyl halides in the presence of sodium Prom the resultant mixture of the two the desired isomer can be separated by known as by crystallization suitable and the purity can be controlled with the aid of the The isopropyl halides mentioned above are for In known manner by the reaction of propylene oxide with corresponding heterocyclic amines and subsequent halogen of the resultant for with thlonyl the synthesis of the aforesaid can also be carried out by reacting corresponding heterocyclic amines with catalytically reducing the resultant amlnoketones in the presence of and heating the resultant primary with halopyrldlnes in the presence of copper bronze and potassium H CI CO X Suitable heterocyclic amines of the formula X NH in which X has the meaning stated above for the and and and 3 3 j and 2 2 piperidine piperidine The acyl compounds so obtained are oils which be distilled in a vacuum and which form salts with pharmacologically unobjectionable inorganic or organic Suitable acids for hydrochloric sulphuric nitric phosphoric eulphonic acetic succinic glutarlc maleic fumaric tartaric citric mandelic acid and The new compounds are racemates and can therefore be resolved in known manner into their optically active Dosage forms suitable for pharmaceutical application for injectable which can be administered in amounts aminopyridine of 158 mm The starting material is prepared as described in Example 1 by reacting with chloroacetone to form the mm reducing the latter in the presence of and heating the resultant diamine mm with EXAMPLE 3 By the method described in Example 1 there is from g of h pyridine 132 133e mm and g of g of of 162 The starting material is prepared by with chloroacetone to form the mm catalytically reducing the latter in the presence of and heating the resultant diamine mm with EXAMPLE 4 By the method described in Example 1 there is obtained from 33 g of mm and g of propionyl g of of 156 mm The starting material is prepared by reacting jdimeth with chloroacetone to form the aminoketone 92 mm catalytically reducing the latter the presence of and heating the resultant diamine mm with EXAMPLE 5 By the method described in Example 1 there is from g of aminopyrldlne 120 mm and g of propionyl g of of 148 mm The starting material is prepared by reacting with chloroacetone to form the aminoketone mm catalytically reducing the latter in the presence of and heating the resultant diamine 72 mm with EXAMPLE 6 By the method described in Example 1 there is from 29 g of 126 mm and g of propionyl g of of 153 mm The starting material is prepared by reacting with chloroacetone to form the aminoketone mm catalytically reducing the latter in the presence of and heating the resultant diamine 79 mm with EXAMPLE 7 30 g of aminopyridine and 50 ml of acetic acid anhydride are at C for 8 the mixture then concentrated by evaporation in a vacuum and the residue taken up with The base is precipitated from the solution with a hydroxide the product is taken up with ether and dried with potassium After driving off the the mixture is distilled in a vacuum and there are obtained g of aminopyridine of 151 mm EXAMPLE 8 By the method described in Example 7 there from 30 g of and 50 ml of propionic acid g of the aminopyridine of 156 mm Hg described in Example EXAMPLE 9 By the method described in Example 7 there is from 30 g of and 60 g of valerianic acid g of pyridine of 180 mm EXAMPLE 10 By the described in Example 1 there is obtained from 30 g of 149 mm and g of propionyl g of of 164 mm The starting material is prepared by reactin with chloroacetone to form the ketone 93 mm reducing the latter in the presence of and heating the 88 EXAMPLE 11 By the method described 1 there is from 25 g of mm and ICS of 173 mm The starting material is prepared by reacting with chloroacetone to form the aminoketone 101 mm catalytically reducing the latter in the presence of and heating the resultant diamine 94 mm with Ey the method described Example 1 there from 38 g mm and g propionyl g of The starting material is prepared by reacting piperidine with chloroacetone to form catalytically reducing the latter the presence of and heating the resultant diamine 92 with 13 By the method described in Example β are reacted with 9 g propionyl chloride in methylene After removing the solvent in a the crystallised residue is dissolved In After addition of ml there hydrochloride which melt at 170 after from The starting material prepared by reacting with chloroacetone to form the amlnoketone mm catalytically reducing the in the presence of and heatin the resultant diamine 87 mm with Example By the method described Example 1 there from g mm and β propionyl g of 177 mm The Gtarting material is prepared by acylating mm of picre te with reacting the resultant 116 with to piperidine 127 and reducing the latter with lithium aluminium 15 3y the method described in 1 13 there is g 144 and g hydrochloride of 175 recrystallisation from methylene starting material prepared by reacting of picrate 184 with acetone to form the 94 mm catalytically reducing the latter in the presence of and heating the resultant diamine 89 mm with 16 3y the method described in Example 1 there is from 34 g 152 mm and g propionyl 29 g of 160 The starting material ie by reacting by catalytic hydrogenation lutidine by means of a catalyst at C 220 excess pressure and fractional distillation of the resultant isomer mm of picrate with chloroacetone to form the 3ninoketone 33 8 mm catalytically reducing the latter in the presence of and heating the resultant diamine 30 10 mm with Example 17 3y the method i Example 1 there is from g 153 mm and g propionyl g of The starting is prepared by reacting by catalytic hydrogenation of by means of a catalyst at VJ 220 excess pressure and fractional distillation of resultant isomer mixture mm of picrate 118 with chloroacetone to form the 95 mm catalytically reducin the latter in the presence of and heating the resultant diamine 88 mm with Example 18 In the described in Example two diastereomers can be detected by gas For 28 g of the isomer mixture are distributed in Crai apparatus between aqueous methanol ligroin in the proportion 1 1 ml each lower and upper 262 distributive steps and by evaporation of the fractions 45 there are obtained g of a crystallised isomer A which at after recrystallisation from petroleum the fractions 97 262 there are obtained 2 g of isomer B which at 62 after recrystallisation from petroleum The mixed melting point of A and 3 is below Example 19 By the method described in 1 there is from g 2 155 raa and 11 g propionyl g 2 of 163 mm The starting material prepared by reacting 2 by catalytic hydrogenation of by means of a catalyst at excess 60 mm with chloroacetone to form the aminoketone 93 catalytically reducing the latter in the presence of and heating the diamine 36 with 20 By the method described in Example 1 there is from 37 155 mm g propionyl g of 165 ma The starting eaterial is prepared by reacting h with chloroacetone to form th9 aminoketone mm catalytically reducing the latter in the presence of and heating the resultant diamine 32 with By the method described in 1 there is from g 153 mm ε g propionyl g of 1SS The starting material is prepared by reacting to form the ketone 96 catalytically reducing the latter in the presence and heating resultant diamine 83 with Example 22 3y the described in Example 1 there is from g 150 mm and g propionyl g of 170 mm The starting material is prepared by reacting copellidine of hydrochloride with to form the aminoketone 94 nun catalytically reducing the latter in the presence of and heating the resultant diamine 89 mm with Example 23 By the method described Example 1 there ie from g 154 mm and g propionyl g inopyridine of 170 starting material is prepared reacting by catalytic hydrogenation of by means of a cataly t 2 3 220 pressure and fractional distillation of the resultant isomer V7ith chloroacetone to form the 94 mn catalytically reducing the latter the presence of and the resultant 38 with 24 By the laethod described in 1 there is 65 and 13 g propionyl g of 170 starting material is prepared by reacting by catolytic hydrogenation of by means of a catalyst at 220 pressure and fractional distillation of the resultant isomer am with acetone to form the one 91 catalytically reducing the latter in the presence of and heating the resultant diamine 83 with fopogoing intondod not ae limitative ioationo of tho of and which all have aimilar ties and uses 25 By the method described in Example g of aminopyridine mm prepared from of aminopyridine mm and g of propionyl The starting material ie prepared by reacting with chloroacetone to form the amino ketone mm catalytically reducing the latter the presence of and heating the diamine formed mm with Example 26 By the method described in Example g of ne mm is prepared from g of aminopyridine mm and g of propionyl The starting material is prepared by reacting methylpiperidine with chloroacetone to form amino ketone mm catalytically reducing the latter in the presence of and heating the diamine formed mm with Example 27 By the method described in Example g of aminopyridine of mm Hg is prepared from g of and g of propionyl The starting material is prepared by reacting with chloroacetone to form the amino ketone mm catalytically hydrogenating the latter in presence of ammonia and heating the diamine formed mm with In the reaction product two diasteormers can be found by gas separation of the mixture is effected by means of counter current distribution to van in a syatem With constant purity control by gas chromatograph g of Isomer A are obtained from the light phase and g of Isomer B from the heavy 2Q By the method described in Example g of aminopyridine is prepared from g of the Isomer of amlnopy described in Example and g of propionyl According to gas chromatographic and spectroscopic the product still contains about of the Isomer A described in Example Example 29 3y the method described in Example g of aminopyridine of mm Hg is prepared from g mm and g of propionyl The starting material is prepared acyl ting with chloride and reacting the mixture of diasteormeric mm thus with From the mixture of diasteormeric thus an Isomer A of 116 and an Isomer B of can be isolated by fractional Reduction of both with lithium aluminium hydride produces two corresponding isomers A mm and an isomer The latter was present in a very small amount and ascertained by gas chromatography It was found to be homogeneous and different from Example By the method described in Example the reaction of of the Isomer B of described in Example 26 with g of propionyl chloride yields g of an oil which is found to be uniform and according to the and is the Isomer B of Example 31 By the method described in Example g of aminopyridine of mm Hg is prepared from 19 g of and g of propionyl The starting material prepared by acylating with chloride and reacting the mixture of diaateormerio 10 mm thus obtained with From the aiixture of fractionated by crystallization from methyl isobutyl the pure Isomer A of can be From the mother liquors of there can be by recrystallization from an ethyl petroleum ether the Isomer B which has a purity of 88 as determined and appears to be contaminated with Isomer Reduction with hydride affords the corresponding diastereomeric pyridines A and of 5 Kg and Example By the method described g of of is obtained from g of the isomer of Hg described in Example product is pure and spectrum shows it to be a isomers Example By the method described in Example g of pyridine of mm Hg is obtained from g of and g of propionyl material is prepared by hydrogenating under high pressure over in the presence of acylating the obtained with chloride to form mm reacting the latter with to compound and reducing this lithium aluminium 34 3y the method described in Example g of of is prepared by reacting g of mm with g of propionylchloride in a methylene chloride evaporation of the solvent in vacuum and crystallization of the residue from a mixture of methylene chloride and dry The starting material is prepared by acylating with reacting the tetrahydropyridine mm with to form tetrahydropyridine and reducing the latter with lithium Example 35 By the method described Example g of of mm Eg prepared from g of and of propionyl The starting material is prepared by acylating with propionyl reacting the with to form and reducing the latter with lithium aluminium Example 36 the method described in g of yridine of mm is prepared by reacting g of mm and g of propionyl The starting material is prepared by acylating mm Picrate with acid reacting the h lhexahydroazepine mm thus obtained with to form azepine and reducing the latter with lithium aluminium Example 37 By method described in Example g of of mm Hg is obtained from 25 of mm and of propionyl The starting material is prepared by acylating mm picrate with acid reacting the mm thus obtained with to form azepine mm and reducing the latter with lithium aluminium Example 38 By the method described in Example g of of mm Hg is obtained from g of mm and g of propionyl starting material is prepared by subjecting to a rearrangement to form the mm reducing this compound with lithium aluminium acylating of the azepine picrate thereby obtained with acid reacting the mm thus obtained with to form and reducing the latter with lithium aluminium The the method described in Example g of of Hg is obtained from 15 g of mm and 10 g of The starting material is prepared by of acid mm with cobalt and subjecting the lhexamethylene diamine mm to ring closure by catalytic splitting of ammonia with aluminium to form hexahydroazepine mm Hg 163 this latter compound is acylated with the mm is reacted with to form azepine and the latter is reduced with lithium aluminium Example the method described in Example g of of mm Hg is obtained from g of mm and g of propionyl The starting material is prepared by subjecting cyclohexanone mm to a Schmidt rearrangement to form the oxohexahydroazepine mm and reducing the latter with lithium aluminium hydrides the mm thus obtained is aoylated with a acid the mm thus obtained is reacted with to form and the latter is reduced with lithium aluminium 41 By the method described in Example g of of mm Hg mixture of is obtained from g of aminopyridine mm and S propionyl The starting material is prepared by hydrogenating acid dinitrile mm a mixture of with Baney nickel and subjecting the diamine mm to ring closure by catalytic splitting of ammonia with aluminium oxide to form 10 mm this latter compound is aoylated with propionic acid the hexahydroazepine mm is reacted with to form and the latter is reduced with lithium aluminium Example By the method described Example g of aminopyridine of mm Hg is obtained from 15 g of mm and g of propionyl The starting material is prepared by 2 with reacting the mm thus obtained to form piperidine mm and reducing the latter with lithium aluminium 28 Example The analgesic effect of some compounds according to the invention was compared with that of a corresponding known compound which differed from the compounds according to the invention bein unsubstituted in the heterocyclic For comparison the heat radiation test on the rat tail was In the the tail of male rats of to g body weight was irradiated with a focussed heat drug Animals to which no been reacted after an age time of irradiation of seconds by withdrawing the Under the influence of an analgesic dru the reaction time became Compounds which produced a reaction time of 20 seconds were considered analgesically Five animals were used for each dose of analgesic drug and the test period was 90 to 180 The established in these tests indicates 50 the dose at which the reaction time for an average of of the tested animals is prolonged to at least 20 The results of the tests are reported in Table I TABLE 1 Example Configuration R R 10 H 33 H 35 36 38 mixture 31 This Table shows that the dose required for longing the reaction of of the animals to more than 20 seconds much greater for the known compound than for the compounds according to the 32 insufficientOCRQuality

Claims (1)

1. Pyridine compounds of the formula in which X is a saturated or unsaturated bivalent alkylene radical of 5 to 9 carbon atoms which is branched once or several times and forms with the nitrogen atom a to heterocyclic ring bearing at least one alkyl with the proviso that the total number of carbon atoms on the heterocyclic ring and the alkyl is from 5 to and is alkyl or alkenyl of 1 to 4 carbon and tically acceptable salts h 33 Analgesic compositions containing an effective amount of a compound according to any of Claims 1 to 11 in dosage For the Applicants AND PARTNERS insufficientOCRQuality