IE49712B1

IE49712B1 - 2-aminoalkyl-5-pyridinols,process for their manufacture,pharmaceutical preparations containing these compounds and their therapeutic application

Info

Publication number: IE49712B1
Application number: IE899/80A
Authority: IE
Original assignee: Ciba Geigy Ag
Priority date: 1979-05-03
Filing date: 1980-05-02
Publication date: 1985-11-27
Also published as: NO801267L; IE800899L; EP0019739B1; DD150461A5; GB2050380A; DK157540C; IL59978A; ATE8501T1; GB2050380B; GR68206B; JPS55149260A; NO154130B; DE3068577D1; DK193180A; FI70212C; NO154130C; DK157540B; ES491055A0; MA18964A1; PL223984A1

Abstract

There is described a process for preparing an enamine of formula (IX): <IMAGE> where R<2> is a carboxylic acid protecting group and R<3> is the residue of a carboxylic acid derived acyl group and where R<5> and R<6> are the same or different C1-4 alkyl or C1-10 aralkyl groups; or taken together with the adjacent nitrogen atom form a heterocyclic ring containing from 4 to 8 carbon atoms and optionally a further heteroatom selected from oxygen and nitrogen; by reacting a compound of formula (XII): <IMAGE> with an amine of formula HNR<5>R<6>, the reactant of formula (XII) being prepared by reaction of an appropriate enol derivative with a phosphorus reagent. The enamines of formula (IX) are useful in the preparation of 3- hydroxycephalosporins. The compounds of formula (XII) are novel.

Description

Secondary 2-amino-l-hydroxyethyl-5-pyridinols, or a-aminomethyl-5-hydroxy-2-pyridinemethanols...have direct bronchodilator action with minimal cardiac stimulation according to the OS-Patent Mo. 3,952,101, i.e., they have greater activity on respiratory smooth muscle than on cardiac muscle.

Surprisingly, by the omission of said aliphatic 1-hydroxyor methanolic function the contrary is achieved, i.e., cardioactive agents according to this invention are obtained, with negligible bronchodilator action.

The present invention concerns new secondary 2-aminoalkyl-5 pyridinols of the general Formula I HO C H, -NH-C H, . m 2m n 2n+l (I) wherein R is hydrogen or lower alkyl,preferably methyl, m is an integer from 2 to 4 and n is an integer frcm 1 to 7 but n is at least 2 when there are 2n-lft atoms; or of acid addition salts, especially pharmaceutically acceptable acid addition salts thereof, process for their manufacture, pharmaceutical preparations containing these compounds and their therapeutic application. 9 712 In case R stands for lower alkyl, preferably methyl, this group may occupy any of the remaining 3-, 4- or 6-pyridine-positions. A lower alkyl $5 I'tis, for example, methyl, ethyl, n- or isopropyl, n- or isobutyl. The symbol R represents, however, advantageously hydrogen.

The alkylene group caH2m represents preferably 1,2-propylene, but also ethylene, 1,3-propylene, 1,2-, 1,3- or 1,4-butylene.

The lower aliphatic group C H, . is preferably lower alkyl, e.g., methyl, ethyl, n- or i-propyl, η-, i- or t-(butyl, pentyl, hexyl or heptyl); especially i-propyl.

Said group C represents either lower alkenyl, e.g., allyl, methallyl, 2- or 3-(butenyl, pentenyl, hexenyl or heptenyl); or lower cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; especially cyclopropyl or cyclohexyl.

As used above and hereinafter in connection with organic radicals or compounds respectively, the term lower defines such with up to 7, preferably up to 4, and advantageously 1 or 2 carbon atoms.

The acid addition salts of the dibasic compounds of Formula I are preferably derived from the pharmaceutically acceptable acids listed below.

The compounds of the invention exhibit valuable pharmacological effects, for example, antihypertensive, but especially cardioprotective, e.g., antiischemic (i.e., antianginal) properties. This can be demonstrated in animal tests, using preferably mammals, such as rats, cats and dogs, or isolated organs thereof. Said compounds can be administered to them enterally or parenterally, advantageously orally or intravenously, for example within gelatin capsules or in the form of starchy suspensions or aqueous solutions respectively. The 9 7 12 applied dosage may range between about 1 and 200 mg/kg/ day, preferably between about 3 and 30 mg/kg/day i.v. or between about 10 and 100 mg/kg/day p.o.

Slight antihypertensive effects can be observed in spontaneous hypertensive rats or renal hypertensive dogs, either by sphygmomanometry at the rats’ tail, or directly by means of a catheter placed into the dogs' femoral artery and a transducer; whereby the blood pressure is expressed in mm Hg.

The cardioprotective activity of said compounds is similar to that of nitroglycerin, propranolol and/or verapamil, which attenuate the electrocardiographic (ECG) manifestation (ST-T elevation) of myocardial ischemia produced by temporary coronary occlusion in anesthetized cats or conscious dogs. The latter were subjected to a left thoracotomy under pentobarbital anesthesia and artificial respiration. The pericardium was opened and a segment of the left caronary artery was exposed to allow the implantation of a silastic balloon occluder around it, which was adjusted to be blown up and exteriorized through the back of the neck at the shoulder blade and a protective jacket was fitted. The dogs were allowed to recover for 7 to 10 days and antibiotics are given the first four days after surgery. The dogs are then subjected to a priming occlusion during which no ECG-readings are taken. Thereupon 2 to 3 occlusions of 1-1.5 minutes duration are conducted in 5 minute intervals and the change in ST-T segment of the lead II ECG is recorded and averaged before and at designated intervals after drug treatment, and the results are expressed as ratio of treated and untreated (control) response. Also permanent coronary occlusion is performed, venous blood samples are drawn for CPK-determinations 3, 6 and 24 hours after occlusion, whereupon the dogs are anesthetized, injected with Trypan blue dye, sacrificed with an overdose of sodium pentobarbital and the hearts dissected to estimate the necrotic tissue. According to Che results obtained, che compounds of Che invention significantly reduce the 9 712 electrical, enzymatic and morphological changes (infarct size) caused by coronary occlusion in conscious dogs. Therefore, they are useful cardioprotective, especially antianginal agents. Moreover, said compounds are also valuable intermediates in the production of other useful products, especially of pharmacologically active compositions.

Particularly useful are compounds of formula I, wherein R is hydrogen or methyl, m is the integer 2 or 3 and n is an integer from 2 to 6, or an acid addition salt, especially a pharmaceutically acceptable acid addition salt thereof.

Preferred compounds of this invention are those of the general Formula II HQ CH (II) wherein p is an integer from 3 to 6, or an acid addition salt, especially a pharmaceutically acceptable acid addition salt thereof.

Outstanding are those compounds of the general Formula II, wherein C Η, , represents i-propyl, t-butyl, allyl or cyclopropyl, or p 2p+l an acid addition salt, especially a pharmaceutically acceptable acid addition salt thereof.

The compounds of this invention are prepared according to 20 conventional methods, for example by a) adding to a compound of the general Formula III (III) .j 97 12 in which X represents an alkali metal or an alkali earth metalhalogen group, a compound of the general Formula IV C H, ,= N - C H, .. m-1 2m-2 n 2n+l (IV) and liberating the product of the general Formula I from the resulting metal salt or b) replacing an acyl group X^ and/or X^ by hydrogen in a compound of the general Formula V Xl°\ // II 7 I Vx 'C H, -Ν-c H, m 2m n 2n+l (V) in which each of the symbols X^ and X^ represents hydrogen or the acyl 10 radical of an aliphatic or aromatic carboxylic or sulfonic acid, with the proviso, that at least one of these symbols stands for an acyl radical, by solvolysis or hydrogenolysis or c) reducing a Schiff's base of the general Formula VI HO //.

' I β · νχ· (VI) 'C H (N)C H, . m 2m-u n 2n+ I-v in which one of the symbols u and v represents the integer 1 and the other is zero or d) condensing a primary amine of the general Formula VII 9 712 HO vX I v \ΗζΛ (VII) with a reactive ester of the alcohol C H_ -OH in the presence of a n 2n+l strong base or e) reducing an amide corresponding to an amine of the general Formula I, in which amide a carbon atom vicinal to the secondary amino group has an oxygen atom instead of two hydrogen atoms, and, if desired, converting any resulting compound into another compound of the invention, and/or, if desired, converting any resulting base into an acid addition salt thereof, or any resulting salt into the corresponding free base or into another acid addition salt, and/or, if desired, resolving a mixture of isomers or racemates obtained into the single isomers or racemates, and/or, if desired, resolving a racemate obtained, into the optical antipodes.

Said metallic substituent X in a starting material of the general Formula III is preferably lithium, sodium or halomagnesium.

In these starting materials R is preferably methyl, advantageously hydrogen.

The addition reaction of the process a) is carried out under anhydrous conditions, advantageously in polar diluents, such as open or cyclic ethers, e.g. diethyl ether or tetrahydrofuran, and at temperatures below room temperature, e.g. between about 10 and -20°.

The conversion of a resulting metal salt of the general Formula Ia if i • · V X I 'c H. -N-C Η , m 2m n 2n+l (Ia) 9 7 12 in which all the symbols have the meanings given above, into the free compound of the Formula I is advantageously performed with water or with diluted inorganic or organic acids e.g. aqueous acids, e.g. those listed below, preferably at or below room temperature, such as at about 0°.

In a starting material of the Formula V the symbols X^ and/or standing for an acyl radical, are advantageously lower alkanoyl or lower alkanesulfonyl, unsubstituted or lower alkylated, lower alkoxylated and/or halogenated benzoyl, phenyl-lower alkanoyl, benzene10 sulfonyl or carbobenzyloxy, such as acetyl, propionyl, methanesulfonyl, benzoyl, phenyl-acetyl, p-toluyl, p—anisoyl, m-chlorobenzoyl, benzenesulfonyl, tosyl or carbobenzyloxy (benzyloxyformyl).

The replacing of an acyl group X^ and/or X2 by hydrogen may be carried out by treatment with solvolysing or hydrogenolyzing agents Solvolysis encompasses for example the hydrolysis, alcoholysis or ammonolysis. The hydrolysis of said starting compounds of the Formula V is advantageously carried out above room temperature, such as 40-120°, in an aqueous medium, preferably with diluted inorganic or organic acids or bases respectively, e.g. aqueous alkalies or acids, e.g. those listed below. The alcoholysis is preferably performed with lower alkanols, e.g. methanol or ethanol, in the presence of strong inorganic bases, e.g. aqueous alkali metal hydroxides or carbonates or of inorganic acids, such as hydrohalic, e.g. hydrochloric, hydrobromic or sulfuric acid. Ammonolysis is carried out, for example, by treating with aqueous ammonia. In said carbobenzyloxy compounds of the Formula V the carbobenzyloxy group may also be replaced by hydrogen hydrogenolytically, as known per se in the peptide-synthesis, i.e. with hydrogen in the presence of noble metal catalysts, e.g. palladium or platinum.

In the process c) the Schiff's bases of the general Formula VI are conventionally reduced, either with catalytically 9712 activated or nascent hydrogen, such as hydrogen in the presence of palladium, platinum or nickel catalysts, or generated electrolytically; or with simple or complex light metal hydrides, e.g. boranes, alane or alkali metal borohydrides or alkali metal cyanoborohydrides, such as sodium borohydride or sodium cyanoborohydride.

The primary amine starting materials of the process d) having the general Formula VII are preferably condensed with said reactive esters derived from strong inorganic acids, such as hydrohalic, e.g., hydrochloric, hydrobromic or advantageously hydriodic acid, or the organic sulfonic acids mentioned above. Said strong bases utilized are preferably tertiary amines, such as tri-lower alkylamines, e.g., diisopropyl-ethylamine, or cyclic nitrogen bases, such as pyridine or lutidine. Care should be taken to avoid a simultaneous quaeternization of the resulting secondary amines of the Formula I, e.g. by avoiding excessive amounts of said reactive esters and/or temperatures excessively above room temperature.

The reduction of the amide starting materials of the process e) is conventionally carried out with the stronger light metal hydrides mentioned for said Schiff's bases VI, advantageously alane in solution of said strong bases, or alkali metal aluminiunhydrides, e.g. lithium aluminiumhydride, lithium or sodium tri-lower alkoxy aluminiumhydrides or lithium or sodium bis-alkoxyalkoxy aluminiumhydrides, e.g. lithium tri-t-butoxy-aluminiumhydride or sodium bis(2-methoxyethoxy)-aluminiumhydride.

The starting materials are known or, if new, they can be prepared according to known methods, for example as illustrated in the examples herein.

Starting compounds of the Formula III may be prepared e.g. by reacting corresponding 2-methyl-5-pyridinols with a lower alkyl 9 7 1 2 alkali metal compound, for example with n-butyllithium. Compounds of the Formula IV may be obtained e.g. by condensation of lower alkanals with corresponding primary amines.

Said acyl derivatives of the Formula V are prepared by condensing a compound of the Formula Xl°\ J II ' I • 0 V C Η, "NH-X, m 2m 2 wherein X^ and X^ are said acyl radicals of an aliphatic or aromatic carboxylic or sulfonic acid, with a reactive ester of the alcohol C H. -OH, mentioned above. If necessary a precursor in which X, is η 2n+l I said acyl radical and X^ represents hydrogen, may be acylated for example with the use of lower alkanoyl, alkanesulfonyl, benzoyl, benzenesulfonyl or benzyloxycarbonyl halides.

The Schiff's base starting materials of the Formula VI are conveniently obtained by condensing compounds of the general Formulae HO.

/X II / I Vs· Ό H, = 0 and H.N-C H, x1 or m 2m-l 2 n 2n+l HO, II I Vx 'C H -NH and 0 = C H, , ,, m 2m 2 n 2n(-2) and the aldehydic or ketonic pyridine precursors thereof are similarly obtained as the compounds of the Formula III, i.e. by condensing said -hydroxy-picoline alkali metal salts with corresponding alkanoic acid amides or nitriles, e.g. formamide, dimethylacetamide or propionitrile, 9 7 12 and hydrolyzing the condensate with water or diluted acids, or hydrogenating it to said amines of the general Formula VII. The latter compounds may also be obtained from said aldehydes or ketones by converting them conventionally into their oximes, and reducing them with catalytically activated hydrogen, preferably with the use of rhodium on alumina.

The amide starting materials of the process e) are conventionally obtained from said primary amines of the Formula VII and corresponding halides or anhydrides of the acids Cn-lH(2n-2)+lCOOH or from 5-hydroxypyridyl -2-alkanoic acid halides or anhydrides and the amines of the Formula Η,Ν-C Η, , i n 2n+l.

The compounds of the invention so obtained can be converted into each other according to known methods. For example, resulting unsaturated compounds of the general Formula I with C H_ , being Tl ZTt"l lower alkenyl, may be caralytically hydrogenated, e.g., as mentioned for compounds VI.

Any resulting free compound can be converted into a corresponding acid addition salt, for example, by reacting it with an inorganic or organic acid, preferably a pharmaceutically acceptable carboxylic or sulfonic acid, or with a corresponding anion exchange preparation, and isolating the desired salt. An acid addition salt may be converted into the free compound by treatment with a base, e.g., a metal hydroxide, ammonia or a hydroxyl ion exchange preparation. Pharmaceutically acceptable acids are, for example, inorganic acids, such as . hydrohalic, e.g., hydrochloric, hydrobromic, sulfuric, phosphoric, nitric or perchloric acid, or organic acids, e.g., aliphatic or aromatic carboxylic or sulfonic acids, such as formic, acetic, propionic, succinic, glycollic, lactic, malic, tartaric, citric, maleic, hydroxymaleic, pyroracemic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, pawoic, nicotinic, methanesulfonic, 9 7 12 ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, benzenesulfonic, halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilic, cyclohexylsulfamic acid; or ascorbic acid.

These or other salts, for example, the picrates, can also be used for purification of the bases obtained; the bases are converted into salts, the salts are separated and the bases are liberated from the salts. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.

Resulting mixtures of isomers can be separated into the single isomers by methods in themselves known, e.g., by fractional distillation, crystallization and/or chromatography. Racemic products can likewise be resolved into the optical antipodes, for example, by separation of diastereomeric salts thereof, e.g., by the fractional crystallization of d- or ^-camphor sulfonates or d- or ^-mandelates, advantageously those of said X^-esters.

The above reactions are carried out according to standard methods, in the presence or absence of diluents, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing or neutralizing agents and/or inert atmospheres, at low ' temperatures, room temperature or elevated temperatures, at atmospheric or superatmospheric pressure.

The invention also comprises any modification of the above processes, wherein a compound resulting as an intermediate at any stage thereof, is used as starting material and the remaining steps are carried out, or the process is discontinued at any stage thereof, or in which the starting material is formed under the reaction conditions or is used in the form of its salt or reactive derivatives. 9 713 For examplefcatalytic hydrogenations of carbobenzoxy compounds of the Formula V, or Schiff’s bases VI with an olefinic C Η, , radical tl Ztll will yield the corresponding saturated C^H^^^compounds I.

In the process of the invention, those starting materials are advantageously selected which yield the above described preferred embodiments thereof, especially those corresponding to Formula II.

The pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions comprising an effective amount thereof in conjunction or admixture with excipents suitable for either enteral or parenteral application. Preferred are tablets and gelatin capsules comprising the active ingredient together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and/or glycine, and lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also binders, e.g. magnesium aluminium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, if desired, disintegrants, e.g. starches, agar, alginic acid or its salts, enzymes of the hinders or effervescent mixtures and/or adsorbents, colorants, flavors and sweeteners. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. They may also contain other therapeutically valuable substances. Said pharmaceutical compositions are prepared according to conventional mixing, granulating or coating methods respectively and contain about 1 to 75%, preferably about 10 to 50% of the active ingredient.

The following examples, illustrating the invention, are not to be construed as being limitations thereon. Temperatures are given 9 7 12 in degrees Centigrade, and all parts wherever given are parts by weight and, if not otherwise stated, all evaporations are carried out under reduced pressure, e.g., between 0.1 and 15 mmHg. Azeotropic evaporations are performed with so much of the solvents disclosed, until a clear (anhydrous) distillate is obtained.

Example 1 9 712 To the mixture of 115 g of 2-methy1-5-pyridinol and 1,500 ml of tetrahydrofuran, 1,350 ml of 1.6 molar n-butyllithium in hexane (2.1 mol) are added while stirring under nitrogen and keeping the temperature between -15 and O’. Stirring is continued for 1 hour at -10’, whereupon 114 g of isopropyliminoethane are added at such a rate that the temperature remains below 10’. After stirring the resulting mixture for 1 hour at room temperature, it is divided into 2 portions and one thereof poured into 750 ml of ice water. After thoroughly shaking, the organic layer is separated and the aqueous layer shaken with the other of said 2 portions. The combined organic layers are extracted once with 400 ml of water and discarded. All aqueous solutions are combined, washed three times with 300 ml of diethyl ether and acidified with hydrochloric acid to pH»6-6.5 and washed four times with 300 ml each of ethyl acetate. The aqueous layer is basified with aqueous sodium hydroxide to pH"8.4, saturated with sodium chloride and extracted five times with a total of 2,300 ml of ethyl acetateisopropanol (1:1). The extract is concentrated, the concentrate twice diluted with isopropanol and concentrated again in order to remove all water azeotropically. The 400 ml of final concentrate are filtered and the filtrate acidified with hydrogen chloride in ethyl acetate to pH»1.5. The precipitate formed is filtered off, washed with isopropanol and recrystallized from 952 aqueous ethanol, to yield the 2-(2isopropylaminopropyl)-5-pyridinol dihydrochloride melting at 210-213°.

The starting material is freshly prepared as follows: To 112.5 ml of redistilled acetaldehyde, cooled to -20 to -30°, 170.3 ml of isopropylamine are added dropwise while stirring at said temperature. The mixture is stirred for 90 minutes at O’, whereupon 50 g of potassium hydroxide pellets are added. The mixture is allowed to stand in the cold and decanted off from the liquified base. Another 50 g of potassium hydroxide pellets are added twice more and the 9 7 12 mixture is finally allowed to stand overnight in the refrigerator. The supernatant product is separated, distilled and the fraction boiling at 59-62° at atmospheric pressure collected., to yield the isopropyliminoethane.

Example 2 To the mixture of 26.7 g of 2-(2-isopropylaminopropyl)-5pyridinol dihydrochloride, 200 ml of methylene chloride and 100 ml of saturated aqueous sodium carbonate, 16 ml of methanesulfonyl chloride are added dropwise while stirring at 0-10° and adding more sodium carbonate to maintain basicity. Stirring is continued for 30 minutes at pH=9.5-10 and the mixture is combined with half of its volume of saturated aqueous sodium chloride. It is separated, the aqueous layer extracted with methylene chloride, the combined organic solutions washed with saturated aqueous sodium carbonate, dried,and evaporated, to yield the 2-(2-isopropylaminopropyl)-5-methanesulfonyloxypyridine as an oil. 39.6 g thereof are dissolved in 200 ml of isopropanol, the solution combined with that of 11.08 g of -μ-Tnandelic acid in 68 ml of anhydrous ethanol and the mixture is allowed to stand at room temperature for 20 hours. It is filtered, the filtrate concentrated to 75 ml and again filtered. The combined residues are recrystallized from anhydrous ethanol-methanol (20:3) and then from methanol, to yield the corresponding μ-mandelate, melting at 133.5-134°.

The combined mother liquors are evaporated and 16 g of the residue similarly converted into the d-mandelate, melting at 131.5-132°. 11,9 g of the μ-mandelate are taken up in the minimum amount of water, the solution made basic with saturated aqueous sodium carbonate and extracted with methylene chloride. The extract is dried and evaporated, to yield the corresponding free base. It is taken up in 9 712 ml of dioxane, 62 ml of IN aqueous sodium hydroxide are added and the mixture refluxed for 2 hours while stirring. It is concentrated, the concentrate adjusted with hydrochloric acid to pH»8.4 and saturated with sodium chloride. It is extracted with isopropanol-ethyl acetate (1:1),the extract evaporated azeotropically, the residue taken up in isopropanol, the solution filtered, acidified with hydrogen chloride in ethyl acetate and the filtrate allowed to stand for 2 days. The precipitate formed is collected and washed with isopropanol, to yield the levorotatory 2-(2-isopropylaminopropyl)-5-pyridinol dihydrochloride, melting at 207-209°; -11.1° (water).

Analogously the dextrorotatory antipode is obtained from 25 said d-mandelate, m.p. 209-210°; [α]ρ « + 10.0° (water); it is pharmacologically less active than both the racemic starting material of this example and said levorotatory salt.

Example 3 To the solution prepared from 6 g of 5-acetoxy-2-pyridylacetone, 100 ml of methanol and 10 ml of isopropylamine, cooled to room temperature for 10 minutes, 4 g of sodium borohydride are added portionwise during 20 minutes while stirring at room temperature. The mixture is evaporated, the residue taken up in water and the solution washed with chloroform. The aqueous layer is separated, its pH adjusted to 8.4 with hydrochloric acid, and saturated with sodium chloride. It is extracted with ethyl acetate-isopropanol (1:1), the extract evaporated azeotropically with additions of isopropanol and the residue taken up in isopropanol. The suspension is filtered, the filtrate concentrated and its pH adjusted to 1.5 with hydrogen chloride in ethyl acetate. The mixture is refrigerated overnight, the precipitate collected and washed with isopropanol-ethyl acetate, to yield the 2-(2-isopropylaminopropyl)-5-pyridinol dihydrochloride melting at 207-209°; it is identical with that obtained according to Example 1. 9 7 12 The starting material is prepared as follows: To the suspension of 32.7 g of 2-methy1-5-pyridinol in 400 ml of tetrahydrofuran, 400 ml of 1.6 molar n-butyllithium in hexane are added during 1 hour while stirring under nitrogen and cooling with ice to maintain the temperature below 10°. Thereupon 29 g of dimethylacetamide in 50 ml of tetrahydrofuran are added during 15 minutes, the mixture is stirred for 2 hours at room temperature and poured into 700 ml of water. It is thoroughly shaken, the aqueous layer separated, washed with diethyl ether, acidified with hydrochloric acid and again washed with diethyl ether.

Its pH is adjusted to 5.0 with aqueous sodium bicarbonate and after saturation with sodium chloride the mixture is extracted with ethyl acetare-isopropanol (1:1). The extract is evaporated azeotropically with the aid of benzene and the residue is taken up in 100 ml of acetic anhydride. The mixture is stirred for 30 minutes at the steam bath, evaporated, the residue distilled and the fraction boiling at 130-138°/0.9 mmHg collectea, to yield the 5-acatoxy-2-pyridylacetone; its hydrochloride melts at 69-72° and the oxime thereof at 149-150°.

Example 4 To the suspension of 10.9 g of 2-methyl-5-pyridinol in 200 ml of tetrahydrofuran, 150 ml of 1.6 molar n-butyllithium in hexane are added during 30 minutes while stirring under nitrogen at -20°. After one hour 25 g of 1-isopropyliminopropane are added during 30 minutes at said temperature, the mixture is stirred for 90 minutes and allowed to warm to room temperature. It is poured into 150 ml of water, the organic layer washed with 50 ml of water and the combined aqueous solutions washed with diethyl ether. The pH thereof is first adjusted to 6.8 with hydrochloric acid, the solution washed once more with ethyl acetate, its pH raised to 7.5 with aqueous sodium carbonate, saturated with sodium chloride and extracted with ethyl acetateisopropanol (1:1).

The extract is evaporated azeotropically, the residue taken up 9 7 1 a in ethyl acetate, the solution filtered and acidified to pH-4.5 with isopropanolic hydrogen chloride, to yield the 2-(2-isopropylaminobutyl)-5-pyridinol hydrochloride melting at 141-143°.

The starting material is prepared as follows: To 58 g of propionaldehyde 59 g of isopropylamine are added while stirring and cooling with ice, followed by 1 ml of concentrated hydrochloric acid. After stirring for 2 hours at room temperature, g of potassium hydroxide pellets are added, the mixture stirred for 5 hours, decanted from the aqueous phase, redried with potassium hydroxide, distilled and the fraction boiling at 84-86° collected, to yield the 1-isopropyliminopropane.

Example 5 To the suspension of 9.8 g of 2-methyl-5-pyridinol in 200 ml of tetrahydrofuran, 135 ml of 1.6 molar n-butyllithium in hexane are added during 30 minutes while stirring under nitrogen at -20°.

After 3 hours 10 g of t-butyliminoethane are added during 30 minutes at said temperature and the resulting mixture is processed as described in Example 4, except that the final solution is acidified with hydrogen chloride in ethyl acetate, to yield the 2-(2-t-butylaminopropyl)-5-pyridinol dihydrochloride melting at 218-220°.

Example 6 h) Analogous to the methods described in the previous examples, the following compounds are obtained from equivalent amounts of the corresponding starting materials: a) 2-(3-isopropylaminobutyl)-5-pyridinol dihydrochloride, m.p. 274-276°; 2-(2-cyclohexylaminopropyl)-5-pyridinol dihydrochloride, m.p. 232-234°. 9 7 12 Example 7 To the suspension of 116 g of 2-(2-isopropylaminopropyl)-5pyridinol and 310 ml of water, 65 g of fumaric acid are added while stirring at 70° under nitrogen. The resulting clear solution is stirred at 20° overnight, the precipitate formed filtered off and washed times with 15 ml of cold water each. 873 g thereof (from several batches) are dissolved in 2,100 ml of water at 70°, the solution filtered hot and the filtrate stirred at room temperature under nitrogen for 2 days. The resulting suspension is filtered and the residue washed twice with 250 ml of cold water each, to yield the 2-(2-isopropylaminopropyl)-5-pyridinol monofumarate melting at 180-183° with decomposition.

Example 8 To the mixture of 342 g of 2-methyl-5-pyridinol and 4,500 ml of tetrahydrofuran, 384.6 g of 1.6 molar n-butyllithium in hexane are added during 3 hours while stirring under nitrogen and keeping the temperature between -18 and -10°. Stirring is continued for 1 hour at -10°, whereupon 340 g of isopropyliminoethane are added during 5 minutes and the temperature is allowed to raise to 10°. After stirring the resulting mixture overnight at room temperature, it is poured into 4,500 ml of cold water. The organic layer is separated and washed with 1,200 ml of water. The combined aqueous solutions are washed three times with 900 ml of diethyl ether each and acidified with 900 ml of concentrated hydrochloric acid to the pH=6.0, which is re-adjusted to 8.0 with 853 g of sodium bicarbonate.

The mixture is evaporated at 60°, the residue suspended in 2,400 ml of isopropanol at 60°, the suspension filtered and'the filtrate evaporated at 60°. The residue is taken up in 800 ml of water, the mixture cooled to 10°, filtered and the filtrate again evaporated at 60°. 9 7 12 232 g of the precipitate are dissolved in 450 ml of ethanol at 65*, the solution filtered hot, the filtrate cooled to 27* and combined with 380 ml of 6N ethanolic hydrogen chloride while stirring and cooling to 10*. After 18 hours the suspension is filtered and the residue washed with 50 ml of cold-ethanol, to yield the 2-(2-isopropylaminopropyl)-5-pyridinol dihydrochloride melting at 214-216°; it is identical with that of Example 1.

The starting material is prepared as follows: To 268.8 g of acetaldehyde, cooled to -25°, 357.6 g of isopropylamine are added during 2 hours while stirring at said temperature under nitrogen. The mixture is stirred for 2 hours at 0°, whereupon 150 g of potassium hydroxide pellets are added. The mixture is allowed to stand for 2 hours, decanted off from the liquified base and treated with another 150 g of potassium hydroxide. After standing at 0° for 2 hours the mixture is decanted onto 150 g of potassium hydroxide and the reaction mixture is allowed to stand overnight at 10°. The supernatant product is separated, distilled at atmospheric pressure and the fraction boiling at 59-64° collected, to yield the isopropyliminoethane.

Example 9 To the solution of 159 g of 2-(2-isopropylaminopropyl)-5pyridinol dihydrochloride in 1,000 ml of water, 163 g of sodium bicarbonate are added and the suspension evaporated. The residue is suspended in 453 ml of anhydrous ethanol at 60°, the suspension filtered, the residue washed 3 times with 150 ml of anhydrous ethanol each and the combined filtrates are evaporated, to yield the 2-(2isopropylaminopropyl)-5-pyridinol melting at 135-138°. Ο 7 I 2 Example 10 'ί'ί To the solution of 1.55 g of 5-hydroxy-2-pyridylacetone in 50 ml of methanol are consecutively added 0.61 g of 2-propenylamine, ml of 5.5 N ethereal hydrogen chloride and 0.5 g of sodium cyanoborohydride in this order, while stirring at room temperature. The mixture is stirred for seven days at room temperature, whereupon its pH is adjusted to 1 by the careful addition of 2N hydrochloric acid.

The acidic mixture is evaporated, the residue dissolved in 20 ml of water and the pH of the solution adjusted to 8 with solid sodium bicarbonate. It is evaporated, the residue triturated with isopropanol . and dissolved in 25 ml of acetone. The solution is filtered, combined with 1.28 g of fumaric acid in the minimum amount of hot acetone, and · the resulting solid filtered off, to yield the 2-[2-(2-propenylamino)propyl]-5-pyridinol fumarate melting at 194-195°.

The starting material is prepared as follows: The mixture of 103.6 g of 5-acetoxypyridyl-2-acetone, 0.75 g of anhydrous potassium carbonate and 400 ml of anhydrous ethanol is refluxed for 24 hours, filtered, concentrated to 100 ml, the concentrate cooled and the precipitate collected, to yield the -hydroxy-2-pyridylacetone melting at 119-120°.

Example 11 To the solution of 0.8 g of 5-hydroxy-2-pyridylacetone in 25 ml of methanol, 0.33 g of cyclopropylamine, 1 ml of 5N ethereal hydrogen chloride and 1.16 g of sodium cyanoborohydride are added in this order and the mixture is stirred at room temperature for 3 days. The pH thereof is then adjusted to 1 with 5N ethereal hydrogen chloride, and then to 8 with solid sodium bicarbonate. The mixture is filtered, evaporated and the residue chromatographed on silica gel with ethyl acetate-methanol (4:1) as eluant, to yield 2-(2-cyclopropylaminopropyl)-5-pyridinol. It is converted into its monofumarate as shown in Example 7, melting at 161’ with decomposition.

Example 12 To the solution of 1.62 g of 2-(2-aminopropyl)-5-pyridinol hydrochloride in 50 ml of methanol, 0.83 g of n-hexanal are added, followed by 1.75 g of sodium cyanoborohydride, and the mixture is stirred at room temperature for 3 days. The pH therof is first adjusted to 1 by the addition of 5N ethereal hydrogen chloride, and then to 8 by the addition of solid sodium bicarbonate. The mixture is filtered, evaporated and the residue triturated with isopropanol, to yield the oily 2-(2-n-hexylaminopropyl)-5-pyridinol, showing peaks in the massspectrum at 151, 128 and 109 m/e.

The starting material is prepared as follows: The mixture of 8.64 g of 5-hydroxy-2-pyridylacetone, 4.08 g of hydroxylamine hydrochloride and 170 ml of anhydrous ethanol is refluxed for 64 hours and evaporated. The residue is taken up in the minimum amount of ethanol, the solution filtered and the filtrate evaporated, to yield the 2-(2-oximinopropyl)-5-pyridinol hydrochloride melting at 141-145°.

The mixture of 12 g thereof, 500 ml of saturated ammoniacal methanol and 2.4 g of rhodium on alumina is hydrogenated at room temperature and atmospheric pressure for 3 weeks. It is filtered and the filtrate evaporated, to yield the 2-(2-aminopropyl)-5-pyridinol hydrochloride, which is used as such.

A small amount thereof in methanol is acidified with fumaric acid and the precipitate reerystallized from ethyl acetate-ethanol, to yield the corresponding fumarate melting at 171-176°. 9 7 12 Example 13 To the solution of 0.27 g of 2-(2-aminopropyl)-5-pyridinol dihydrochloride and 0.5 ml of di-isopropyl-ethylamine in 0.5 ml of methanol, 0.24 g of isopropyl iodide are added at room temperature while stirring. After 24 hours the mixture is evaporated and the residue converted into the 2-(2-isopropylaminopropyl)-5-pyridinol, melting at 135-138°, as described in Example 9. Both free bases are identical.

The starting material is prepared as follows: The solution of 0.19 g of 2-(2-aminopropyl)-5-pyridinol hydrochloride in 10 ml of anhydrous ethanol is combined with 0.2 ml of 5H ethereal hydrogen chloride and evaporated, to yield the 2-(2-aminopropyl)-5pyridinol dihydrochloride melting at 125-128° with decomposition.

Example 14 To the solution of 0.1 g of 2-(2-acetylaminopropyl)-5pyridinol in 10 ml of anhydrous tetrahydrofuran, 1.5 ml of a 1 molar solution of alanetriethylamine in toluene are added dropwise while stirring at 0°. After 12 hours 10 ml of 2N aqueous sodium hydroxide are added at 0°, and the mixture evaporated azeotropically with 2o isopropanol. The residue is taken up in 25 ml of methanol, the pH of the solution adjusted to 8 with 5N ethereal hydrogen chloride, the resulting salts filtered off, and the filtrate evaporated. The residue is triturated with isopropanol, to yield the 2-(2-ethylaminopropyl)-5-pyridinol melting at 75-79°.

The starting material is prepared as follows: To the suspension of 1.01 g of 2-(2-aminopropyl)-5-pyridinol hydrochloride in 40 ml of methylene chloride, 3.3 ml of pyridine are added, followed by 1.47 g of acetyl chloride while stirring at room temperature 9 712 After 17 hours an equal volume of saturated aqueous sodium bicarbonate is added, the organic layer separated, dried and evaporated. The residual oil is chromatographed on silica, using methanol-ethyl acetate (4:1) as eluant, to yield the 5-acetoxy-2-(2-acetylaminopropyl)pyridine, showing in the IR-spectrum peaks at 1758 and 1658 cm 1.

It may be alcoholysed as follows: The solution of 240 mg thereof in 5 ml of anhydrous ethanol, containing 7.5 mg of anhydrous potassium carbonate, is refluxed for 5 hours and evaporated, to yield the 2-(2acetylaminopropyl)-5-pyridinol, which is used without further purification.

Example 15 The solution of 0.15 g of dibenzoyl-2~(2-methyl-aminopropyl)-5pyridinol in 5 ml of 5N hydrochloric acid is refluxed for 23 hours, cooled, twice washed with 5 ml of diethyl ether and evaporated, to yield the 2-(2-methylaminopropyl)-5-pyridinol dihydrochloride, showing in the mass-spectrum peaks at 165, 151, 109 and 58 m/e.

The staring material is prepared as follows: The mixture of 0.5 g of 2-(2-aminopropyl)-5-pyridinol hydrochloride, 0.85 g of benzoyl chloride, 10 ml of methylene chloride and 10 ml of saturated aqueous sodium bicarbonate is stirred at room temperature for 1 hour. The organic phase is separated, dried, evaporated and the residue recrystallized from diethyl ether to give the dibenzoyl-2-(2aminopropyl)-5-pyridinol melting at 110-112°. 0.36 g thereof are dissolved in 1.5 ml of dimethylformamide and the solution added to a slurry of 36 mg of sodium hydride in 1 ml of 4-imethyl fnrmamide at room temperature. The mixture is heated for 15 minutes, allowed to cool to room temperature during one hour and cooled to 0°. It is diluted with 1 ml of toluene and 0.36 g of methyl iodide are added rapidly. The mixture is stirred at room temperature for 1 hour, whereupon 20 ml of water are added. It is extracted twice with 20 ml of diethyl ether and the extract evaporated, to yield the oily, dibenzoyl-2-(2-methylaminopropyl)-5-pyridinol, showing in the NMR a peak at 3.48 ppm. 9 712 0.15 g thereof may be partially alcoholyzed in 4 ml of anhydrous methanol in the presence of 15 mg of potassium carbonate while stirring at room temperature for 12 hours, to yield the 2-(Nbenzoy1-2-methylaminopropyl)-5-pyridinol, which may replace said dibenzoyl compound in the initial acid hydrolysis.

Similarly, the mixture of 0.1 g of dibenzoyl-2-(2-isopropylaminopropyl)-5-pyridinol and 10 ml of 5N hydrochloric acid may be refluxed for three days, cooled^ filtered, evaporated and the residue triturated with acetone, to yield the 2-(2-isopropylaminopropyl)-510 pyridinol dihydrochloride melting at 199-204°; it is identical with that obtained according to Examples 1, 3 and 8.

Example 16 The mixture of 0.08 g of 2-(N-carbobenzyloxy-2-methylamino- propyl)-5-pyridinol and 2.5 ml of 5N hydrochloric acid is refluxed for 23 hours, cooled and extracted with diethyl ether. The extract is dryed and evaporated, to yield the 2-(2-methylaminopropyl)-5pyridinol dihydrochloride, which is identical with that obtained according to Example 15.

The starting material is prepared as follows: To the solution of 0.5 g of 2-(2-aminopropyl)-5-pyridinol in 10 ml of methylene chloride and 10 ml of saturated aqueous sodium bicarbonate, 1.04 g of benzyl chloroformate are added while stirring at room temperature. After 12 hours the organic phase is separated, dried, evaporated and the residue crystallized from diethyl ether-hexane, to yield the bis-earbobenzyloxy-2-(2-aminopropyl)-5-pyridinol melting at 63-65°.

The solution of 0.42 g thereof in 2 ml of dimethylformamide is added to the slurry of 36 mg of sodium hydride in 1.5 ml of dimethylformamide and the mixture is warmed to 55° for 1 hour. It is 9 712 allowed to cool to 25° for 4 hours, cooled to 0°, diluted with 1 ml of toluene and 0.36 g of methyl iodide are added. The mixture is stirred at room temperature for 12 hours, whereupon 10 ml of disodium phosphate buffer are added. The aqueous phase is extracted twice with ml of diethyl ether, the extract washed with water, dried and evaporated, to yield the bis-carbobenzyloxy-2-(2-methylaminopropyl)-5pyridinol and the 2-(N-carbobenzyloxy-2-methylaminopropyl)-5-pyridinol in approximately equal quantities. Said mixture is taken up in ethyl acetate, the solution extracted with N-aqueous sodium hydroxide and the aqueous layer separated. Its pH is adjusted to 8 with monosodium phosphate buffer, extracted with diethyl ether, the extract dried and evaporated to yield the 2-(N-carbobenzyloxy-2->methylaminopropyl)-5pyridinol.

Example 17 The mixture of 0.08 g of 2-(N-carbobenzyloxy-2-methylaminopropyl)-5-pyridinol, 5 ml of anhydrous ethanol saturated with anhydrous hydrogen chloride and 0.04 g of 102 palladium on charcoal is hydrogenated at room temperature and atmospheric pressure for 18 hours. It is filtered, the residue washed with ethanolic hydrogen chloride and 2o the filtrate evaporated, to yield the 2-(2-methylaminopropyl)-5pyridinol dihydrochloride, which is identical with that of Example 15 and 16.

Example 18 Preparation of 10,000 tablets, each containing 100 mg of the 25 active ingredient: Formula: 2-(2-isopropylaminopropyl)-5-pyridinol dihydrochloride 1,000 g 2,535 g 125 lactose Corn starch 9 7 12 Polyethylene glycol 6,000 150 g Talcum powder 150 g Magnesium stearate 40 g Purified water q.s.

Procedure All powders are passed through a screen with openings of 0.6 nm Then the drug substance, lactose, talcum, magnesium stearate and half of the starch are mixed in a suitable mixer. The other half of the starch is suspended in 65 ml of water and the suspension added to the boiling solution of the polyethylene glycol in 260 ml of water. The paste formed is added to the powders, which are granulated, if necessary, with an additional amount of water. The granulate is dried overnight at 35°, broken on a screen with 1.2 mm openings and · compressed into tablets using concave punches with 10.3 mm diameter, upper bisected.

Example 19 Preparation of 1,000 capsules each containing 50 mg of the active ingredient: Formula: 2-(2-isopropylaminopropyl)-5-pyridinol monofumarate 50.00 g Com starch 5.00 g Lactose 143.75 g Magnesium stearate 1.00 g Surfactant 0.25 g Procedure: ' All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance is mixed first with the magnesium stearate and surfactant, whereupon the starch and lactose are added and mixed until homogeneous. No. 2 capsules are filled with 200 mg 9 712 each, using a filling machine.

Analogously tablets or capsules are prepared, containing another compound of the invention e.g., as illustrated by the previous examples herein.

Claims

1. A compound of Che general Formula I . R HO C H -NH-C H„ , m 2m n 2n+l (X) wherein R is hydrogen or lower alkyl, m is an integer from 2 to 4 and n is an integer from 1 to 7, but n is at least 2 when there are 2n-l H atoms

2. A conpound as claimed in claim 1, wherein R is hydrogen or methyl.

3. A conpound as claimed in claim 1 or claim 2 wherein m is the integer 2 or 3 and n is an integer from 2 to 6.

4. A compound of the general Formula II :h,-ch-nh-c H„ , 2 p 2p+l CH. (II) wherein o is an integer from 3 to 6.

5. C H P 2 P + I A compound of the Formula II shown in claim 4, wherein represents isopropyl or tert.-butyl.

6. A compound of the Formula II shown in claim 4, wherein C Η. , represents isopropyl, tert.-butyl, allyl or cyclopropyl. P 2 p+1

7. 2-(2-Isopropylaminopropyl)-5-pyridinol. 2-(2-Isopropylaminobutyl)-5-pyridinol. 4 9 712

8. 9. 2-(2-tert.-Butylaminopropyl)-5-pyridinol.

9. 10. 2-(3-Xsopropylaminobutyl)-5-pyridinol.

10. 11. 2-(2-Cyclohexylaminopropyl)-5-pyridinol.

11. 12. 2-/2-(2-Propenylamino)-propyl/-5-pyridinol. 5

12. 13. 2-(2-Cyclopropylaminopropyl)-5-pyridinol.

13. 14. 2-(2-n-Hexylaminopropyl)-5-pyridinol.

14. 15. 2-(2-Ethylaminopropyl)-5-pyridinol.

15. 16. 2-(2-Methylaminopropyl-5-pyridinol.

16. 17. A compound as claimed in claim 1 or 2 and being the 10 levorotatory optical antipode thereof.

17. 18. An acid addition salt of a compound as claimed in any one of claims 1 to 18.

18. 19. A therapeutically acceptable acid addition salt of a compound as claimed in any one of claims 1 to 18. 15

19.

20. A pharmaceutical preparation comprising a compound claimed in any one of claims 1 to 17 and 19 in admixture or conjunction with a pharmaceutically suitable carrier. 4 9 7 12

21. Process for the manufacture of new secondary 1-aminoalkyl-5-pyridinols of the general Formula I H0 \/X I L (I) •C -NH-C H_ ., m 2m n 2n+l wherein R is hydrogen or lower alkyl, m is an integer from 5 2 to 4 and n is an integer from 1 to 7 but n is at least 2 when there are 2n-lH atoms; or of acid addition salts thereof, which consists in a) adding to a compound of the general Formula III 10 in which X represents an alkali metal or an alkali earth metal halogen group, a compound of the general Formula IV ,H„ _=N -1 2m-2 C n H 2n+l (IV) and liberating the product of the general Formula I from the resulting metal salt or - 49712 b) replacing an acyl group X^ and/or X 2 by hydrogen in a compound of the general Formula V X i\/Y * Ll 7 I X 2 S C H, -A-C H, Al m 2m n 2n+l (V) in which each of the symbols X^ and Xj represents hydrogen or the acyl radical of an aliphatic or aromatic carboxylic or sulfonic acid, with the proviso, that at least one of these symbols stands for an acyl radical, by solvolysis or hydrogenolysis or c) reducing a Schiff's base of the general Formula VI HO yX (VI) Y \ H, (N)C H . . „ m 2m-u n 2n+ l - v in which one of the symbols u and v represents the integer 1 and the other is zero or d) condensing a primary amine of the general Formula VII vX Η I Y \ H, -NH, m 2m Z (VII) with a reactive ester of the alcohol C H„ ,,-OH in the presence of a n 2n+l 15 strong base or - 49712 e) reducing an amide corresponding to an amine of the general Formula I, in which amide a carbon atom vicinal to the secondary amino group has an oxygen atom instead of two hydrogen atoms, and, if desired, converting any resulting compound into another compound of the invention, 5 and/or, if desired, converting any resulting base into an acid addition salt thereof, or any resulting salt into the corresponding free base or into another acid addition salt, and/or, if desired, resolving a mixture of isomers or racemates obtained into the single isomers or racemates, and/or, if desired, resolving a racemate obtained, IQ into the optical antipodes.

22. The process for the preparation of compounds described in any one of examples 1 to 17,

23. The compounds prepared according to either of claims 21 and 22.