US3684803A - 1,4,4-substituted piperidine derivatives - Google Patents

Abstract

1-Substituted 4-alkanoylmethyl-4-carboalkoxy-piperidine derivatives and their pharmaceutically acceptable acid addition salts are prepared by various methods. These compounds have antitussive and analgesic activity and are the active ingredients of pharmaceutical compostions, which can be used for the treatment and amelioration of tussive irritation and pain of various origin. A typical embodiment is 1-(3-phenylpropyl)-4-acetonylisonipecotinic acid ethyl ester.

Description

United States Patent [151 3,64,803 Kuhnis et a]. [451 Aug. 15, 1972 1,4,4-SUBSTITUTED PIPERIDINE [56] 7 References Cited DERIVATIVES UNITED STATES PATENTS [72] Inventors: Hans Herbert Kuhnis, Basel; Ulrich Renner, Riehen both of Switzerland KUhnlS t al [73] Assignee: gilia-Geigy Corporation, Ardsley, Primary Examiner HemyR Giles Assistant Examiner-G. Thomas Todd [22] Filed: March 1, 1971 21 Appl. No.: 119,857 [571 T A l-Substituted 4-alkanoylmethyl-4-carboalkoxy- Relaed Apphcauon Dim piperidine derivativesand their pharmaceutically ac- Continuation of ugceptable acid addition salts are prepared by various 1968, abandoned. methods. These compounds have anti-tussive and analgesic activity and are the active ingredients of [30] Forelgn Apphcanfm Pnomy Data pharmaceutical compostions, which can be used for A g- 11,1967 swltlerland the treatment and amelioration of tussive irritation and pain of various origin. A typical embodiment is l- [52] US. Cl ..260/240 K, 260/293.81, 260/293.88, (3 phenylpmpyl) 4 acetonyl isonipecotinic acid ethyl 424/267 ten [51 Int. Cl. ..C07d 29/24 [58] Field of Search ..260/240 K, 293.81, 293.88 10 Claims, No Drawings 1,4,4-SUBSTITUTED PIPERIDINE DERIVATIVES This application is a continuation of Ser. No. 750,015, filed Aug. 5, 1968, now abandoned.

DETAILED DESCRIPTION The present invention concerns piperidine derivatives having valuable pharmacological properties, processes for the production of these compounds, methods of producing an antitussive and analgesic effect as well as pharmaceutical compositions containing said compounds.

In particular, the present invention pertains to compounds of formula I COOR'I wherein R is alkyl having at most nine carbon atoms, phenylalkyl having at most carbon atoms, the phenyl group of which can be unsubstituted or substituted by nitro, amino, halogen up to the atomic number 35, alkoxy or 3,4-methylenedioxy and in which the phenyl group instead of being bound directly to the alkyl group can also be bound by way of oxygen, carbonyl, hydroxy-methylene, imino, alkanoyloxymethylene with at most four carbon atoms, alkanoylimino with at most three carbon atoms or vinylene;

R is alkyl having at most 2 carbon atoms; and

R is hydrogen or methyl; v as well as to the pharrnaceutically acceptable acid addition salts thereof.

These compounds exhibit valuable pharmacological properties, in particular anti-tussive activity combined with a favorable therapeutic index. Compounds of formula I, except when R is alkyl, additionally exhibit analgesic activity of average intensity which can be detected by the prevention of pain reactions caused by inflammation or heat. The application of these compounds does not give rise to any habituation or addiction effects.

In the compounds of the general formula I and in the apertaining starting materials mentioned below, R is embodied, e.g. by alkyl groups, such as the methyl-, ethyl, n-propylisopropyl-, n-butyl-, isobutyl-, n-heptyl-, n-octyl-, or n-nonyl-group, by the benzyl group, the p-fluorobenzyl, the nitro-, the amino-, p-methoxy-, p-ethoxy-, p-isopropoxy-, 3,4-dimethoxy-, 3,4,5- trimethoxyor 3,4-methylenedioxybenzyl group, the phenylethyl-, 3-phenylpropyl-, 4-phenylbutyl-, 2- phenoxyethyl-, 3-phenoxypropyl-, 4-phenoxybutyl-, phenacyl-, 2-benzylethyl-, 3-benzoylpropyl-, 2hydroxy-2-phenylethyl-, 3-hydroxy-3-phenyl-propyl-, 4- hydroxy-4-phenylbutyl-, 2-acetoxy-phenylethyl-, 2-

' propionoxy-2-phenylethyl-, 3-acetoxy-3-phenylpropylwherein R and R have the meanings given in formula I, is

reacted with a reactive ester of a compound of formula III R OH III. wherein R has the meaning given in formula I and, if desired, the compound obtained of the formula I is converted into an addition salt with an inorganic or organic acid. The reaction is performed at room temperature or moderately raised temperature in a suitable organic solvent such as ethanol, acetone, diethyl ketone or dimethyl formamide. If desired, the reaction is accelerated by the addition of acid binding agents such as potassium carbonate, and/or of catalysts such as potassium iodide. Suitable reactive esters of compounds of the formula III are, in particular, hydrohalic acid esters such as bromides, chlorides and iodides, also arene sulphonic acid esters, e.g. p-toluene sulphonic acid esters. The starting materials of formula II, however, are new compounds the production of which will be described below.

According to a second process, compounds of formula I and their acid addition salts are produced by treating a, compound of formula IV wherein R R and R have the meanings given in formula l, with an aqueous mineral acid containing mercury ions at room temperature to moderately raised temperature and, if desired, converting the compound obtained of formula I into an addition salt with an inorganic or organic acid. For example, 5-84 percent ((N-m-methoxyphenylsulphuric acid is suitable as aqueous mineral acid. The lower the reaction temperature is, the higher the acid concentration; on using 84 percent sulphuric acid, the

reaction is preferably performed at room temperature, with 5-10 percent sulphuric acid, it is performed at 50-60.

The compounds of formula IV required as starting materials for this process are also new. The production thereof will be described after the third process for the production of compounds of formula I.

A third process for the production of compounds of the formula I and their acid addition salts consists in reacting, in an inert organic solvent, an isonipecotinic acid ester corresponding to formula V X o-o-Ri 0 1120 CH; B l H, CH2

wherein X represents an alkali metal ion, particularly a lithium ion,

R represents a group corresponding to the definition of R with the exception of those groups which contain a carbonyl, hydroxyrnethylene or imino group, and

R has the meaning given in formula I,

with a reactive ester of a compound of formula VI wherein R and R represent hydrogen or lower alkyl groups and R has the meaning given in formula I, liberating a compound of formula I from the ketal thereof first obtained, optionally while simultaneously converting an alkylenedioxymethylene group contained in R, into the carbonyl group and, if desired, converting the compound obtained of formula I into an addition salt with an inorganic or organic acid.

As reactive esters of alkyl-substituted l,3-dioxolan- Z-methanols of formula VI, in particular their halides such as bromides, iodides and chlorides, also alkane and arene sulphonic acid esters such as methane sulphonic acid esters or p-toluene sulphonic acid esters are used.

A suitable reaction medium for the main reaction is, e.g. a mixture of abs. diethyl ether or tetrahydrofuran with 1,2-dimethoxyethane (ethylene glycol dimethyl ether). The alkali metal compounds of formula V are produced in situ from other suitable alkali metal compounds. Triphenylmethyl lithium, which is particularly suitable, is preferably also formed in situ from another organic lithium compound such as phenyl lithium by, e.g. adding a solution of triphenylmethane in 1,2- dimethoxyethane to the phenyl lithium, which has been produced in the known way, in diethyl ether. As the triphenylmethyl lithium produces intensively colored solutions, its formation as well as the amount consumed thereof can easily be followed by the isonipecotinic acid ester subsequently added. Instead of triphenylmethyl lithium, also, e.g., triphenylmethyl sodium or potassium can be used. The steps in the processes according to the invention are generally slightly exothermic and can be performed at room temperature or at a slightly raised temperature. The reaction mixture must also be cooled if necessary, depending on the starting materials and amounts used thereof.

The subsequent liberation of the compound I can be performed, e.g. by acid hydrolysis such as the treatment of the corresponding products of the main reaction with dilute, e.g., 6N, aqueous hydrochloric acid at room temperature to the boiling temperature of the acid, or by transketalization e.g. the reaction with acetone in the presence of a catalyst such as p-toluene sulphonic acid, at room temperature or moderately raised temperature.

A number of 1-substituted isonipecotinic acid alkyl esters, which form the basis of the alkali metal compounds of formula V, is known and others can be produced analogously in a simple manner. For example, such starting materials are obtained by quatemization of low isonicotinic acid alkyl esters with halogen compounds of formula VII R I-Ial VII. wherein Hal represents chlorine, bromine or iodine, and R, has the meaning given in formula V, followed by catalytic hydrogenation, e.g. in the presence of rhodiumaluminum oxide catalysts. More generally useful, i.e. also for starting materials wherein R is an aliphatically unsaturated group, is the reaction of a low isonipecotinic acid alkyl ester with a halide of formula VII or with a corresponding methane or p toluene sulphonic acid ester.

Starting materials for the second process mentioned which contain a radical R, as l-substituent, can be produced analogously to the main'reaction of the previ ous process by reacting alkali metal compounds of formula V with a reactive ester of optionally methyl-substituted 2-propinol of formula VIII R C C-CI-b-OI-I VIII. wherein R, has the meaning given in formula I. The same compounds, and also those having a l-substituent corresponding to the broader definition of R are obtained by analogously reacting an alkali metal compound of a lower-benzyl-oxycarbonylisonipecotinic acid alkyl ester with a reactive ester of a compound of formula VIII, splitting off the benzyloxycarbonyl group of the l -benzyloxycarbonyl-4-( 2-alkinyl)- isonipecotinic acid alkyl ester obtained, e.g. with hydrogen bromide in glacial acetic acid, and reacting the 4-(2-alkinyl)-isonipecotinic -alkinyl)- isonipecotinic acid alkyl ester formed with a reactive ester of a compound of formula III analogously to the first process mentioned for the production of compounds of formula I.

Certain starting materials of formula II for the first process for the production of compounds of formula I are obtained, e.g. by hydration of the lower 4-(2-alkinyl)-isonipecotinic acid alkyl esters mentioned above analogously to the second process mentioned for the production of compounds of the formula I. The same starting materials of formula II can also be produced by reaction of alkali metal compounds of lower benzyloxycarbonylisonipecotinic acid alkyl esters with reactive esters of compounds of formula VI followed by liberation of the keto group and splitting off of the benzyloxycarbonyl group as in the processes already mentioned, optionally in the same step. Further possibilities for the production of compounds of formulas II and IV are given following the next process.

Compounds of formula I and their acid addition salts are produced according to a fourth process by alcoholysing a compound of formula IX wherein R and R have the meaning given in formula I, in the known way and, if desired, converting the compound obtained of formula I into an addition salt with an inorganic or organic acid. The alcoholysis is performed by the action, simultaneously or one after the other, of a mineral acid, a lower alkanol and, optionally, water. For example, the nitriles of formula IX are refluxed in lower alkanols in the presence of a concentrated mineral acid, particularly sulphuric acid, for several hours. According to another embodiment of the process, a nitrile of formula IX is reacted in the cold with hydrogen chloride, the imide chloridehydrochloride formed is reacted with a lower anhydrous alkanol to form the corresponding imidoalkyl ester hydrochloride and the latter is decomposed with water to form the alkyl ester of formula I or its hydrochloride.

The nitriles of formula IX required as starting materials for this process are produced in their turn, e.g., starting from isonipecotamide. This is first reacted with a halogen compound of formula VII to form the corresponding l-substituted isonipecotamide and the latter is converted into the corresponding nitrile, e.g. by boiling with thionyl chloride in benzene or chloroform. The alkali metal compounds of the l-substituted isonipecotonitriles so obtained can be reacted with reactive esters of compounds of formula VI or VIII analogously to the alkali metal compounds of formula V. The reaction products directly obtained are finally subjected to ketal splitting or hydration. Nitriles of formula IX having other l-substituents corresponding to the definition of R are obtained by reacting an alkali metal compound of l-benzyl-oxycarbonyL isonipecotonitrile with a reactive ester of a compound of formula VI or VIII splitting off the benzyloxycarbon yl group by means of hydrogen bromide in glacial acetic acid either before or after the ketal splitting or hydration or splitting it off hydrogenolytically before the ketal splitting, and then reacting the 4-(2-oxoalkyl)-isonipecotonitrile obtained with a reactive ester of a compound of formula III analogously to the process first mentioned for the production of compounds of formula I. However, if the 4-(2-oxoalkyl)- isnopecotonitriles still unsubstituted in the l-position mentioned above are subjected to alcoholysis, then compounds of formula II are obtained. i.e. starting materials for the first process mentioned for the production of compounds of formula I, while starting materials of formula IV for the second production process are obtained if the reaction products of the alkali metal compounds of l-substituted isonipecotonitriles mentioned above are subjected to alcoholysis with reactive esters of compounds of formula VII instead of being hydrated.

If desired, the piperidine derivatives of formula I obtained by the processes according to the invention are then converted into their addition salts with inorganic and organic acids in the usual way. For example, the acid desired as salt component or a solution thereof is added to a solution of a piperidine derivative of formula I in an organic solvent such as diethyl ether, methanol or ethanol, and the salt which precipitates either direct or after addition of a second organic liquid, e.g. diethyl ether to methanol, is isolated.

For use as active substances for medicaments, pharmaceutically acceptable acid addition salts can be used instead of free bases, i.e. salts with those acids the anions of which have no pharmacological action or which in themselves have a desired pharmacological action. In addition, it is of advantage if the salts to be used as active substances crystallize well and are not or are only slightly hygroscopic. Hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, 3- hydroxyethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid, embonic acid or 1,5- naphthalene disulphonic acid, for example, can be used for salt formation with piperidine derivatives of formula I.

The anti-tussive activity of the compounds of the invention are illustratively demonstrated in cats according to the method of R. Domenjoz, Arch. exper. Path. Pharmakol. 2l5, l9-24 (1952) and in guinea pigs according to the method of H. Friebel et al., Arch exper. Path. Pharmakol. 224, 384-400 (1955). The latter method is used in a slightly modified form wherein cough is produced in guinea pigs by exposing the animals in a Plexi Glas chamber to a stream of a constant mixture of so zCO zair (20 ml:l.5 liter:l0.5 liter per minute). The beginning of the cough is determined by inspection. Thus it is shown that e.g. l-(3-phenylpropyl)-4-acetonyl-isonipecotinic acid ethyl ester and 1-methyl-4-acetonyl-isonipecotinic acid ethylester administered intravenously in amounts of from about 0.3 to about 2 mg/kg and orally in amounts of from about 38 to about 70 mg/ kg show a very strong anti-tussive effect.

The analgesic activity of the compounds of formula I* are illustratively demonstrated in rats in the gonarthritis test according to the method of G. Wilhelstrated in'mice according to the method of Friebel et al., Arch. exp. Path. Pharmakol. 226, 551 (1955) (tail flick test) as well as to the method of A. D. Wolfe et al., J. Pharmacol. Exptl. Therap. 80, 300 (1944) (hot-plate test). In these two tests pain is produced by heat. Thus it is shown that l(3-phenylpropyl)-4-acetonylisonipecotinic acid ethyl ester and 1-( 3-phenyl-3- propionoxypropyl)-4-acetonyl-isonipecotinic acid ethyl ester administered orally in amounts of from about 30 mg/kg to about 100 mg/kg have a significant analgesic effect.

The toxicity of the compounds of fonnula l is of favorable low order.

For their intended use the compounds of the invention are administered in amounts depending on the spe cies, age and weight of the subject under treatment as well as on the particular conditions to be treated and the mode of administration. Generally the daily dosages of the free bases or of the pharmaceutically acceptable acid addition salts thereof vary between 5 and 600 mg for mammals.

Suitable dosage units such as dragees (sugar coated tablets), capsules, tablets, suppositories or ampoules, preferably contain 5-200 mg of a piperidine derivative of formula I or of a pharmaceutically acceptable salt thereof.

Dosage units for oral administration preferably contain between 1 percent and 90 percent of a piperidine derivative of formula I or of a pharmaceutically acceptable salt thereof as active substance. They are produced by combining the active substance with, e.g., solid, pulverulent carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, maize starch or arnylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or gelatine, optionally with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols, to form tablets or dragee cores. The latter are coated, e. g. with concentrated sugar solutions which can also contain, e.g. gum arabic, talcum and/or titanium dioxide,

or with a lacquer dissolved in easily volatile organic solvents or mixtures of solvents. Dyestuffs can be added to these coatings, e.g. to distinguish between varying dosages of active substance. Other suitable dosage units for oral administration are hard gelatine capsules and also soft, closed capsules made of gelatine and a softener such as glycerin. The former preferably contain the active substance as a granulate in admixture with lubricants such' as talcum or magnesium stearate and, optionally, stabilizers such as sodium metabisulphite or ascorbic acid. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids such as liquid polyethylene glycols to which stabilizers can also be added.

Also, particularly for the treatment of coughs, e.g. lozenges as well as forms not made up into single dosages can be used for oral administration, e.g. cough syrups or drops prepared with the usual auxiliaries.

Dosage units for rectal administration are, e.g. suppositories which consist of a combination of a piperidine derivative of formula I or a suitable salt thereof with a neutral fatty foundation, or also gelatine rectal capsules which contain a combination of the active substance with polyethylene glycols.

Ampoules for parenteral, particularly intramuscular, also intravenous, administration preferably contain a water soluble salt of a piperidine derivative of formula I as active substance in a concentration of, preferably, 0.5-5 percent, in aqueous solution, optionally together with suitable stabilizers and buffer substances.

The following examples illustrate the production of the compounds of formula I and of pharmaceutical compositions but in no way limit the scope of the invention. The temperatures are given in degrees Centigrade.

EXAMPLE 1 i. 2.13 g of 4-acetonyl isonipecotinic acid ethyl ester, 3 g of 2-phenylethyl bromide, 6 g of sodium carbonate and 0.2 g of potassium iodide in 50 ml of acetone are refluxed for 16 hours. The reaction mixture is then filtered, the residue is washed with acetone, the filtrate is concentrated and the residue is distilled under high vacuum. The l-(2-phenylethyl)-4-acetonyl isonipecotinic acid ethyl ester boils at l40-l46/0.08 Torr. The hydrochloride prepared with ethereal hydrogen chloride solution melts at l99'200.

The following compounds are obtained in an analogous manner:

ii. l-methyl-4-acetonyl-isonipecotinic acid methyl ester, B.P. l34136/l2 Torr, citrate M.P. l77l78 (produced with citric acid in acetone, recrystallized from methanol dimethylformamide);

iii. l-methyl-4-acetonyl isonipecotinic acid ethyl ester, B.P. -l36/l2 Torr, citrate M.P. l72l73;

iv. l-ethyl-4-acetonyl-isonipectonic acid ethyl ester, B.P. l38-l5lll2 Torr, hydrochloride, M.P. l77-l78;

v. l-n-heptyl-4-acetonyl isonipecotinic acid ethyl ester, B.P. 170-l90/0.05 Torr (air bath), fumarate M.P. l08l 10;

l-( 3-phenylpropyl)-4-acetonyl isonipecotinic acid ethyl ester B.P. l50-l64/0.0l Torr, hydrochloride M.P.

vii. l-n-octyl-4-acetonyl isonipecotinic acid ethyl ester, B.P. l23-l25/0.02 Torr, hydrochloride M.P. l08-l 1 1;

viii. l-benzyl-4-acetonyl isonipecotinic acid ethyl ester, B.P. l43l52/0.06 Torr, hydrochloride M.P. l83-l84;

ix. l-(4-phenylbutyl)-4-acetonyl isonipecotinic acid ethyl ester, B.P. l70l95/0.1 Torr, hydrochloride M.P. l92l93;

x. l-( 2-phenoxyethyl)-4-acetonyl isonipecotinic acid ethyl ester, B.P. l72l 79/0.1 Torr, hydrochloride M.P. l64l 65;

xi. l-cinnamyl-4-acetonyl isonipecotinic acid ethyl ester, B.P. l70-l75/0.0l Torr, hydrochloride M.P. l66l68;

xii. l-n-nonyl-4-acetonyl isonipecotinic acid ethyl ester, fumarate M.P. l04-l06;

xiii. 1-[2 (N-phenyl-proprionamide)-ethyl]-4-acetonyl isonipecotinic acid ethyl ester, fumarate M.P. l09-1l0;

xiv. l-[2-anilinoethyl1-4-acetonyl isonipecotinic acid ethyl ester, fumarate M.P. 134l 37;

xv. 1-(3-hydroxy-3-phenylpropyl)-4-acetonyl isonipecotinic acid ethyl ester, fumarate, M.P. 133l35;

xvi. l 3-propionoxy-3-phenylpropyl)-4-acetonyl isonipecotinic acid ethyl ester, fumarate, M.P. 120;

xvii.

ethyl ester, fumarate, M.P. l39-l42;

xviii. l-( 3-acetoxy-3-phenylpropyl )-4-acetonyl isonipecotinic acid ethyl ester, fumarate M.P. l32l33;

xix. l-[Z-(N-phenyl-acetamido)-ethyl]-4-acetonyl isonipecotinic acid ethyl ester, hydrochloride, M P. 8l82;

xx. l-[2-(4-methoxyphenyl)-ethyl]-4-acetonyl isonipecotinic acid ethyl ester, fumarate M.P. l39140;

xxi. 1-[3-(4-nitrophenyl)-propyl]-4-acetonyl isonipecotinic acid ethyl ester, fumarate M.P. 208209;

xxii. l-[3(4-aminophenyl)-propyl]-4-acetonyl isonipecotinic acid ethyl ester, B.P. 0.0l Torr, 180-l90;

xxiii. l 2-(4-chlorophenyl)-ethyl]-4-acetonyl isonipecotinic acid ethyl ester, fumarate, M.P. 158160; and

xxiv. 1 3-( 4-methoxyphenyl )-propyl -4-acetonyl isonipecotinic acid ethyl ester, fumarate, M.P. 128-130. I

The 4-acetonyl isonipecotinic acid ethyl ester required as starting material is produced as follows:

(a) 22.8 g of bromobenzene in 180 ml of abs. ether are placed in a 750 ml four-necked flask and, while stirring under an atmosphere of nitrogen, 3.03 g of lithium wire, which has been cut into small pieces and washed with petroleum ether, are added, whereupon the ether begins to boil. After the reaction has subsided, the mixture is refluxed for another 2 is hours. 35.4 g of triphenylmethane in 150 ml of abs. 1,2-dimethoxyethane are added all at once to the solution of phenyl lithium obtained, whereupon, due to the formation .of the triphenylmethyl lithium, the solution becomes deep red colored and gently boils. After stirring for 20 minutes at room temperature, 42.3 g of l-benzyloxycarbonyl isonipecotinic acid ethyl ester, (produced by reaction of isonipecotinic acid ethyl ester with chloroformic acid benzyl ester in the presence of 1N sodium bicarbonate solution), in 50 ml of abs. ether are added at 28. The solution loses its deep red color and the temperature slightly rises. It is stirred for 10 minutes at room temperature and then 18 g of propargyl bromide (3-bromopropine) in 50 ml of abs. ether are added all at once. The mixture is stirred for 2 A hours at room temperature whereupon it turns yellowish and lithium bromide precipitates. 40 ml of water are then added to the reaction mixture which is then evaporated almost to dryness in a rotary evaporator. The residue is taken up in 500 ml of ether and extracted three times with 2N hydrochloric acid. The ether solution is dried and concentrated and the residue is left to stand overnight whereupon the triphenyl-methane crystallizes out. The whole mixture is then suspended in cold methanol, the triphenylmethane is filtered off under suction, the filtrate is concentrated and the residue is distilled under high l-(2-benzoylethyl)-4-acetonyl isonipecotinic vacuum. The l-benzyloxycarbonyl-4-(2-propionyl)- isonipecotinic acid ethyl ester passes over at l-l92 /0.07 Torr.

(b) 8 g of l-benzyloxycarbonyl-4-(2-propinyl)- isonipecotinic acid ethyl ester and 40 ml of a 25-30 percent solution of hydrogen bromide in glacial acetic acid and 9 ml of abs. ether are stirred for 2 hours in a round flask by means of a magnetic stirrer. The initial strong development of carbon. dioxide gradually diminishes. The reaction solution is then evaporated in a rotary evaporator and the residue is taken up in 6N hydrochloric acid. The hydrochloric acid is extracted with ether, then made alkaline with concentrated ammonia while cooling well and extracted with chloroform. Thechloroform solution is dried, concentrated and the resultant 4-(2-propinyl)-isonipecotinic acid ethyl ester is further reacted immediately.

Other low alkyl esters of 4-(2-propinyl)- isonipecotinic acid can also be produced analogously to (a) and (b). (c) The crude 4-( 2-propinyl)-isonipecotinic acid ethyl ester is hydrated at 60 analogously to example 2 by heating for 3 hours with 10 times the amount of 1N sulphuric acid which contains 1 percent of mercury- (II) sulphate, and the 4-acetonyl isonipecotinic acid ethyl ester formed is isolated analogously to example 2 and is further reacted as crude product.

EXAMPLE 2.

i. 15.7 g of l-(3-phenylpropyl)-4-(2-propinyl)- isonipecotinic acid ethyl ester, ml of 1N sulphuric acid and 1.5 g of mercury-(II) sulphate are heated for 3 hours while stirring at 60-70. The suspension is then filtered, the filtrate is made alkaline with concentrated aqueous ammonia solution while cooling and extracted twice with chloroform. The combined chloroform solutions are washed with sodium chloride solution, dried and evaporated and the residue is distilled under high vacuum. The l-( 3-phenylpropyl)4-acetonylisonipecotinic acid ethyl. ester boils at l50l64/0.0l Torr. The hydrochloride is produced therefrom with ethereal hydrogen chloride solution and it is recrystaliized from acetone, M.P.

The following compounds are produced in an analogous way:

ii. l-methyl-4-acetonyl isonipecotinic acid methyl ester, B.P. l34-136/l2 Torr, citrate M.P. l77-l78 (produced withcitric acid in acetone, recrystallized from methanol/dimethyl formamide);

iii. l-methyl-4-acet0nyl isonipecotinic acid ethyl ester, Bl. l30-l36/12 Torr, citrate M.P.

iv. l-ethyl-4-acetonyl isonipecotinic acid ethyl ester, HP. l38-l5l/l2 Torr, hydrochloride M.P. l77-l78;

v. l-n-heptyl-4-acet0nyl isonipecotinic acid ethyl ester, B.P. l70-l90/0.05 Torr (airbath), fumarate M.P. l08l l0;

l B-phenylpropyl )-4-acetonyl acid ethyl ester, B.P. hydrochloride M.P. 165; vii. Ln-octyl-4-acetonyl isonipecotinic acid ethyl ester, BJP. l23l25/0.02 Torr, hydrochloride vi. isonipecotinic viii. l-benzyl-4-acetonyl isonipecotinic acid ethyl ester, B.P. l43-l52/0.06 Torr, hydrochloride M.P. 183l84;

ix. 1-(4-phenylbutyl)-4-acet0nyl isonipecotinic acid ethyl ester, B.P. 170 1 95/O.l Torr, hydrochloride M.P. l92193;

x. 1-(2-phenoxyethyl)-4-acetonyl isonipecotinic acid ethyl ester, B.P. l 72179/0. 1 Torr, hydrochloride M.P. 164-l 65;

xi. l-cinnamyl-4-acetonyl isonipecotinic acid methyl ester, B.P. 170-175/0.0l Torr, hydrochloride M.P. 166168;

xii. 1-n-nonyl-4-acetonyl isonipecotinic acid ethyl ester, fumarate M.P. 104-106;

xiii. 1-( 2-anilinoethyl)-4-acetonyl isonipecotinic ethyl ester, M.P. 134137; xiv. 1-( 2-benzoylethyl)-4-acetonyl isonipecotinic acid ethyl ester, M.P. l39-l42;

xv. l-[2-(N-phenyl-propionamido)ethyl]-4-acetonyl isonipecotinic acid ethyl ester, fumarate M.P. 1091l0;

xvi. 1-(3-hydroxy-3-phenylpropyl)-4-acetonyl isonipecotinic acid ethyl ester, fumarate, M.P. l33135;

xvii. l-(3-propionoxy-3-phenylpropyl)-4-acetonyl isonipecotinic acid ethyl ester, fumarate, M.P. 120;

xviii. l 3-acetoxy-3-phenylpropyl )-4-acetonyl isonipecotinic acid ethyl ester, fumarate M.P. 132-133;

xix. 1-[2-(N-phenyl-acetamido)-ethyl]-4-acetonyl isonipecotinic acid ethyl ester, hydrochloride, M.P. 81-82;

xx. l-[2-(4-methoxyphenyl)-ethyl]-4-acetonyl isonipecotinic acid ethyl ester, fumarate M.P. l39140;

xxi. l-[3-(4-nitrophenyl)-propyl]-4-acetonyl isonipecotinic acid ethyl ester, fumarate M.P. 208-209;

xxii. l-[ 3-(4-aminophenyl )-propyl -4-acetonyl isonipecotinic acid ethyl ester, B.P. 180l90 /0.0l Torr;

xxiii. l 2-( 4-chlorophenyl )-ethyl]-4-acetonyl isonipecotinic acid ethyl ester, fumarate, M.P. l 58-l 60; and

xxiv. 1-[ 3-( 4-methoxyphenyl )-propyl -4-acetonyl isonipecotinic acid ethyl ester, fumarate M.P.

The l-substituted 4-( 2-propinyl)-isonipecotinic acid alkyl esters required as starting materials for the production of the above compounds can be produced, eg as follows:

(a) 20 g of isonicotinic acid ethyl ester and 75.5 g of 3- phenylpropyl bromide in 100 ml of diethylketone are refluxed for 5 hours. The diethylketone is then evaporated under vacuum, the residue is dissolved in water and the aqueous solution is extracted three times with ether. On evaporating the aqueous solution under vacuum and, finally, high vacuum, the ethyl ester of 4- carboxyl-1-(3-phenylpropyl)-pyridinium bromide remains.

(b) 24.1 g of the above quaternary salt in 200 ml of ethanol are hydrogenated at room temperature and 3-4 atm. pressure in the presence of rhodium/aluminium oxide catalyst (5 percent Rh). The catalyst is then filtered off and the filtrate is concentrated. The residue is covered with chloroform and made alkaline with concentrated sodium hydroxide solution. The chloroform is removed and the aqueous phase is exhaustively extracted with chloroform. The combined chloroform solutions are washed with saturated sodium chloride solution, dried and concentrated and the residue is distilled under high vacuum. The l-(3-phenyl propyl)- isonipecotinic acid ethyl ester boils at l30-l32/0.08 Torr.

The following compounds are obtained analogously to (a) and (b) (quaternization being performed in each case in the alkanol used as ester component): l-methyl isonipecotinic acid methyl ester, B.P. 7 375 1 2 Torr; l-methyl isonipecotinic acid ethyl ester, B.P.'7880 ll Torr; l-ethyl isonipecotinic acid ethyl ester, B.P. l00-l07 1 2 Torr; v l-n-heptyl isonipecotinic acid ethyl ester, B.P. 120/0.0l Torr; l-n-octyl isonipecotinic acid ethyl ester, B.P. 130-l 35 /0.l Torr; l-benzyl isonipecotinic acid ethyl ester, B.P. ll0-155 /0.2 Torr; l-(Z-phenylethyl)-isonipecotinic acid ethyl ester, B.P. l40 -l46/0.08 Torr; 1-(4-phenylbutyl)-isonipecotinic acid ethyl ester, B.P. 142l53/0.0l Torr; l-(2-phenoxyethyl)-isonipecotinic acid ethyl ester, B.P. l43148/0.03 Torr; l-cinnamyl isonipecotinic acid ethyl ester, B.P. l50160/0.0l Torr; ln-propyl isonipecotinic acid ethyl ester, B.P. l07-l l 0/0.5 Torr; l-n-nonyl isonipecotinic acid ethyl ester, B.P. l50-16 0/0.00l Torr; l-(3-phenylpropyl)-isonipecotinic acid methyl ester, B.P. l15-1l8/0.0l Torr; l-(2-phenylpropyl)-isonipecotinic acid ethyl ester, B.P. l30145/0.0l Torr;

l 2-( N-phenyl-propionamido)-ethyl ]-isonipecotinic acid ethyl ester, B.P. l-2 l 6/0.0l Torr;

(c) 11 g of bromobenzene in ml of abs. ether are placed in a 350 ml four-necked flask and, while stirring under an atmosphere of nitrogen, 0.98 g of lithium wire, which has been cut into small pieces and washed with petroleum ether, are added, whereupon the ether begins to boil. After the reaction has subsided, the mixture is refluxed for another 2 1% hours. 17.1 g of triphenylmethane in 80 ml of abs. 1,2-dimethoxyethane are added all at once at 30 to the solution of phenyl lithium obtained. Due to the formation of thetn'phenyl lithium, the solution becomes dark red colored and gently boils. After stirring for 20 minutes at room temperature, 18.3 g of l-(S-phehylpropyl)-isonipecotinic acid ethyl ester in 20 ml of abs. ether are added at 28 whereupon the solution loses its dark red color and the temperature rises slightly. The solution is stirred for 10 minutes at room temperature and then 8 g of propargyl bromide (3-bromopropine) in 20 ml of abs. ether are added all at once. The mixture is stirred for 2 k hours at room temperature whereupon it turns yellowish and lithium bromide precipitates. 10 ml of water are then added to the reaction mixture which is then evaporated in a rotary evaporator. Methylene chloride is added to the residue and the methylene chloride solution is extracted four times with 6N hydrochloric acid. The acid extracts are made alkaline and extracted exhaustively with chloroform. The chloroform extracts are dried and concentrated. The residue is taken up in ether, the ether solution is dried and concentrated and the residue is distilled. The 1-(3-phenyl-propyl)-4-(2- propinyl)-isonipecotinic acid ethyl ester boils at 170l72/0.05 Torr. The oil is dissolved in ether and 95 percent of the theoretical amount of fumaric acid is added. The fumarate is filtered off under suction and recrystallized from isopropanol. The l-(3-phenylpropyl)-4-(2-propinyl)-isonipecotinic acid ethyl ester fumarate melts at 153.

The following compounds are produced analogously:

l-methyl-4-(2-propinyl)-isonipecotinic acid methyl ester, B.P. l-l02/l2 Torr, citrate M.P. l67-l68;

1-methyl-4-(2-propinyl)-isonipecotinic acid ethyl ester, B.P. ll2l35 Torr, citrate M.P. l69l70;

1-ethyl-4-(2-propinyl)-isonipecotinic acid ethyl ester, B.P. l l71l9/l2 Torr; l-n-heptyl-4-(2-propinyl)-isonipecotinic acid ethyl ester, B.P. 130-135/0.0l Torr, fumarate ll8l2 l-n-octyl-4-(2-propinyl)-isonipecotinic acid ethyl ester, B.P. 128-l35/0.02 Torr, fumarate M.P. 119-120;

l-benzyl-4-(2-propinyl)-isonipecotinic acid ethyl ester, B.P. l3ll59/0.05 Torr, fumarate M.P. l57l58;

l-( 2-phenylethyl )-4-( 2-propinyl )-isonipecotinic acid ethyl ester, B.P. l39-143/0.08 Torr, hydrochloride M. P. 2 l 2-2 1 3;

l-( 4-phenylbutyl )-4-( 2-propinyl )-isonipecotinic acid ethyl ester, B.P. l65-l85/0.0l Torr, fumarate M.P. ll7l 18;

l 2-phenoxyethyl )-4-( 2-propinyl )-isonipecotinic acid ethyl ester, B.P. l68l69/l Torr, fumarate M.P. l38-139;

l-cinnamyl4-(2-propinyl)-isonipecotinic acid ethyl ester, B.P. l70-178/0.02 Torr, fumarate 164-16 l-n-propyl-4-(2-propinyl)-isonipecotinic acid ethyl ester, B.P. 1l2-1l4/2 Torr, hydrochloride M.P. l68-l69; l-n-nonyl-4-(2-propinyl)-isonipecotinic acid ethyl ester;

1 3=phenylpropyl )-4-( Z-propinyl )-isonipecotinic acid methyl ester, B.P. 134-l39/0.0l Torr, fumarate M.P. l53-l54;

l-(2-phenylpropyl)-4-(2-propinyl)-isonipecotinic acid ethyl ester;

1 [2-(N-phenyl-propionamido)-ethyl]-4-(2-propinyl)-isonipecotinic acid ethyl ester.

((1) l g of 1-[3-(4-nitrophenyl)-propyl]-4-(2-propinyl) isonipecotinic acid ethyl ester is dissolved in glacial acetic acid while stirring at 50. A solution of 3.5 ml of conc. hydrochloric acid and 2.5 g of tin chloride is then added drop-wise over a period of .2 minutes and heated over 30 minutes to 90. It is then cooled, adjusted to p 3.5 with 2 ml conc. sodium hydroxide solution,

separate from the sediment, and washed well with water. The acid solution is made alkaline with cone.

ammonia and extracted with ether. The ethereal solution is dried and evaporated. The l-[3-(4-aminophenyl)-propyl]-4-(2-propinyl)-isonipecotinic acid ethyl ester is distilled in a bulb-tube at ELP. l-l under 0.01 Torr.

EXAMPLE 3 0.64 g of lithium and 7.4 g of bromobenzene in 32 ml of abs. ether are retracted in a 350 ml sulfonating flask while stirring and under nitrogen, and subsequently refluxed for two hours. 1 1.4 g of 'triphenylmethane in 65 ml of dimethoxyethane are then added at 30 and stirred for a further 30 minutes, whereby a red solution is obtained. 6.5 g of l-(3-phenylpropyl)-isonipecotinic acid ethyl ester in 32 ml of abs. ether are then added dropwise with 7 minutes stirring at 30. 8.5 g of 2- methyl-2-bromomethyl-1,3-dioxolane in 13.5 ml of abs. ether are subsequently added so that refluxing occurs. The solution is refluxed for 2. hours, decomposed with 30 ml of water, the ether phase separated off, the aqueous phase extracted twice with ether and the combined ether extracts evaporated in vacuum. The residue is dissolved in alcohol with warming. On cooling, the triphenylmethane crystallizes out, is filtered off, washed with alcohol and the filtrate evaporated. The residue is taken up in 6N hydrochloric acid and heated for 4 hours at 70. Thesolution is cooled, made alkaline withammonia, and extractedexhaustively with ether, dried and evaporated. The residue is distilled in a bulb tube at B.P. -180 and 0.01 Torr, the hydrochloride being produced from that in the normal manner. The l-(3-phenylpropyl)-4-acetonyl isonipecotinic acid ethyl ester hydrochloride melts at and is identical to a sample produced in another way.

EXAMPLE 4 (a) 5.5 g of bromobenzene in 50 ml of abs. ether are placed in a 200 ml four-necked flask and, while stirring under an atmosphere of nitrogen, 0.49 g of lithium wire, which has been cut into small pieces and washed with petroleum ether, are added, whereupon the ether commences to boil. After the reaction has subsided, the mixture is refluxed for a further 2 k hours. 7.6 g of triphenylmethane in 25 ml of abs. l,2-dimethoxyethane are added all at once to the obtained solution of phenyllithium, whereupon, due to the formation of triphenylmethyl lithium, the solution turns deep red and gently boils. After 20 minutes stirring at room temperature, 6.4g of l-(2-phenylethyl)-isonipecotonitrile in 5 ml of abs. ether are added at 28. The solution loses its deep red color with a slight increase in temperature occurring. It is stirred for 10 minutes at room temperature and then mixed all at once with 4.0 g of propargyl bromide (3-bromopropine) in 20 ml of abs. ether. The mixture is stirred for 2 7% hours at room temperature, whereby it turns yellowish and lithium bromide precipitates. The reaction mixture is then mixed with 20 ml of water and evaporated in a rotary evaporator. Ether is added to the residue and the obtained ether solution, is extracted four times with dilute hydrochloric acid. The acid extracts are made alkaline and exhaustively extracted with chloroform, the chloroform extracts being dried and evaporated. The residue is taken up in ether, the ether solution dried and evaporated and the residue distilled. The 1-(2-phenylethyl)-4-(2-propinyl)-isonipecotonitrile passes over at 14l170/0.05 Torr. (b) 12.6 g of l-(2-phenylethyl)-4-(2-propinyl)- isonipecotonitrile with 150 ml of 1N sulphuric acid and 1.5 g of mercury(l1)-sulphate are heated while stirring for 3 hours at 6070. The suspension is then filtered, the filtrate made alkaline with concentrated aqueous ammonia solution while cooling and extracted twice with chloroform. The combined chloroform solutions are washed with sodium chloride solution, dried and evaporated, and the residue distilled in high vacuum. The l-(2-phenylethyl)-4-acetonyl isonipecotonitrile boils at 140l50/0.01 Torr.

(c) 2.7 g of l-(2-phenylethyl)-4-acetonyl isonipecotonitrile with 10 ml abs. ethanol and 2.3 ml of conc. sulphuric acid are refluxed for 11 hours. The reaction mixture is then made alkaline with conc. ammonia while cooling and is extracted with chloroform. The extract is dried, the chloroform evaporated and the residue distilled. The l-( 2-phenylethyl)-4-acetonyl isonipecotinic acid ethyl ester boils at 140l56/0.07 Torr. The hydrochloride produced with ethereal hydrochloric acid has a MP. of l99200.

EXAMPLE 5 1,000 g of active substance, e. g. 1-( 2-anilinoethyl)-4- acetonyl-isonipecotinic acid ethyl ester hydrochloride, 550 g of lactose and 292.0 g of potato starch are mixed, the mixture is moistened with an alcoholic solution of 8.0 g of gelatine and granulated through a sieve. The granulate is dried and carefully mixed with 60.0 g of potato starch, 60.0 g of talcum, 10.0 g of magnesium stearate and g of highly dispersed silicon dioxide. The mixture is pressed into 10,000 tablets each weighing 200 mg and containing 100 mg of active substance, which can be grooved for better adaption of the dosage.

EXAMPLE 6 From 500 g of active substance, e.g. 1-(3-phenylpropyl)-4-acetonyl-isonipecotinic acid ethyl ester hydrochloride, 175.9 g of lactose and the alcoholic solution of 10 g of stearic acid is produced a granulate which is dried, and carefully mixed with 56.6 g of highly dispersed silicon dioxide, 165.0 g of talcum, 20.0 g of potato starch and 2.5 g of magnesium stearate. The

mixture is pressed into 10,000 drage cores. These arethen coated with a concentrated syrup made from 502.28 g of crystallized saccharose, 6.0 g of shellac, 10.0 g of gum arabic, 1.5 g of titanium dioxide and 0.220 g of dyestuff, and dried. The dragees obtained each weigh 145 mg and contain 50 mg of active substance.

EXAMPLE 7 A cough syrup containing 0.5 percent active substance is prepared as follows: 1.5 liters of glycerin, 42 g of p-hydroxy-benzoic acid methyl ester, 18 g of phydroxybenzoic acid n-propyl ester and, while slightly warming, 50 g of l-benzyl-4-acetonyl isonipecotinic acid ethyl ester hydrochloride are dissolved in 3 liters of distilled water. 4 liters of percent sorbitol solution, 1,000 g of crystallized saccharose, 350 g of glucose and a flavoring, e.g. 250 g of Orange Peel Soluble Fluid produced by Eli Lilly & Co., Indianapolis, or 5 g of natural lemon flavoring and 5 g of Halb and l-lalb essence both produced by Haarmann and Reimer, Holzminden, Germany, are added. The solution obtained is filtered and the filtrate is made up to 10 liters with distilled water.

EXAMPLE 9 A cough syrup containing 0.25 percent of active substance is produced as follows: 25 g of l-methyl-4-acetonyl isonipecotinic acid ethyl ester hydrochloride is dissolved by warrning in a mixture of 2.5 liters of water and 0.5 liters of 96 percent ethanol. Also, a syrup is made from 30 liters of water, 1 liter of 70 percent sorbitol solution, 3,000 g of crystallized saccharose, 42 g of p-hydroxybenzoic acid methyl ester and 18 g of phydroxybenzoic acid n-propyl ester, and this syrup is carefully mixed with the solution of active substance. After the addition of flavorings, e.g. those mentioned under (d) and, if necessary, filtration, the syrup obtained is made up to 10 liters with distilled water.

EXAMPLE 10 For the treatment of coughs, drops containing 2.5 percent of active substance are prepared by dissolving 250 g of l-n-heptyl-4-acetonyl isonipecotinic acid ethyl ester hydrochloride and 30 g of sodium cyclamate in a mixture of 4 liters of 96 percent ethanol and 1 liter of propylene glycol. Also, 3.5 liters of 70 percent sorbitol solution are mixed with 1 liter of water and this mixture is added to the above solution of active substance. A flavoring, e.g. 5 g of coughdrop aroma or 30 g of grapefruit essence, both produced by Haarrnann and Reimer, Holzminden, Germany, is added, the whole is well mixed, filtered and made up to 10 liters with distilled water.

EXAMPLE 11 A mass for suppositories is made from 7.5 g of 1-(2- phenoxyethyl)-4-acetonyl isonipecotinic acid ethyl ester hydrochloride and 161.0 g of Adeps solidus and 100 suppositories are filled therewith. Each contains mg of active substance.

EXAMPLE l2 2 g of l-(3-hydroxy-3-phenylpropyl)-4-acetonyl isonipecotinic acid ethyl ester hydrochloride and 2.2 g of glycerin are dissolved in distilled water up to ml and the solution is filled into 100 ampoules. Each contains 1 ml and 20 mg of active substance.

What is claimed is:

1. A compound of the formula:

ornooog, /COOCH;OH3

6. A compound according to claim 1 wherein said compound is l-(2-benzoylethyl)-4-acetonylisonipecotinic acid ethyl ester.

7. A compound according to claim 1 wherein said compound is l-(3-hydroxy-3-phenylpropyl)-4-acetonyl-isonipecotinic acid ethyl ester.

8. A compound according to claim 1 wherein said compound is l-(3-propionoxy-3-phenylpropyl)-4- acetonyl-isonipecotinic acid ethyl ester.

9. A compound according to claim 1 wherein said compound is l-(3-acetoxy-3-phenylpropyl)-4-acetonyl-isonipecotinic acid ethyl ester.

10. A compound according to claim 1 wherein said compound is l-methyl 4-acetonyl-isonipecotinic acid ethyl ester.

Claims (9)

1. 2. A compound according to claim 1 wherein said compound is 1-(3-phenylpropyl)-4-acetonyl-isonipecotinic acid ethyl ester.
2. 3. A compound according to claim 1 wherein said compound is 1-(2-phenoxyethyl)-4-acetonyl-isonipecotinic acid ethyl ester.
3. 4. A compound according to claim 1 wherein said compound is 1-cinnamyl-4-acetonyl-isonipecotinic acid ethyl ester.
4. 5. A compound according to claim 1 wherein said compound is 1-(2-anilinoethyl)-4-acetonyl-isonipecotinic acid ethyl ester.
5. 6. A compound according to claim 1 wherein said compound is 1-(2-benzoylethyl)-4-acetonyl-isonipecotinic acid ethyl ester.
6. 7. A compound according to claim 1 wherein said compound is 1-(3-hydroxy-3-phenylpropyl)-4-acetonyl-isonipecotinic acid ethyl ester.
7. 8. A compound according to claim 1 wherein said compound is 1-(3-propionoxy-3-phenylpropyl)-4-acetonyl-isonipecotinic acid ethyl ester.
8. 9. A compound according to claim 1 wherein said compound is 1-(3-acetoxy-3-phenylpropyl)-4-acetonyl-isonipecotinic acid ethyl ester.
9. 10. A compound according to claim 1 wherein said compound is 1-methyl-4-acetonyl-isonipecotinic acid ethyl ester.