DD150461A5 - PROCESS FOR THE PREPARATION OF 2-AMINOALKYL-5-PYRIDINOLENE - Google Patents

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

Berlin, 10. 9. 80 AP C 07 D / 220 844 GZ 57 332 11

Process for the preparation of 2-aminoalkyl-5-pyridinols

Any delivery area of the invention

The invention relates to a process for preparing new aminoalkyl-5-pyridinols *

The invention further relates to pharmaceutical preparations containing these compounds, as well as their therapeutic use as medicaments, for example for the treatment of angina pectoris.

Chara kteri stik of the known technical solutions

According to US Pat. No. 3,952,101, the secondary 2-aminol-hydroxyethyl-5-pyridinols or "cc-aminomethyl-5-hydroxy-2-pyridine-methanols have a direct bronchodilator effect with minimal cardiac stimulation", ie " they have a stronger effect on the smooth musculature of the respiratory organs than on the heart muscle. "

Object of the invention

The aim of the invention is the production of cardioprotective compounds.

Presentation of the essence, of the invention

The invention has for its object to find new compounds with cardioprotective effect and to develop processes for their preparation.

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It has surprisingly been found that omitting the said aliphatic 1-hydroxy or methanolic group, the action of secondary 2-amino-l-hydroxyethyl-5-pyridinolen turns into the opposite. Namely, the cardioactive agents of the present invention having negligible bronchodilator activity are obtained.

According to the invention, new secondary 2-aminoalkyl-5-pyridinols of the general formula I

HO _t R

manufactured,

wherein R is hydrogen or lower alkyl, preferably methyl, m is an integer from 2 to 4, and η is an integer from 1 to 7, and their acid addition salts, in particular therapeutically acceptable acid addition salts.

If R is lower alkyl, preferably methyl, then this group can be in any of the free positions 3, 4 or 6 of the pyridine radical. A lower alkyl radical R is e.g. Methyl, ethyl, n- or isopropyl, n- or isobutyl. However, the symbol R primarily means hydrogen.

The alkylene group C H is preferably 1,2-propylene, but also ethylene, 1,3-propylene, 1,2-, 1,3- or 1,4-butylene.

The lower aliphatic group C EL is preferably lower alkyl, e.g. Methyl, ethyl, n- or i-propyl, n-, iso- or tert .- (butyl, pentyl, hexyl or heptyl); especially for isopropyl.

Said group C H is 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; in particular cyclopropyl or cyclohexyl.

The term "lower" defines in the organic radicals or compounds mentioned above or below those having at most 7, preferably 4, in particular 1 or 2, carbon atoms.

The acid addition salts of the dibasic compounds of formula I are preferably therapeutically acceptable acid addition salts, e.g. those of the acids mentioned below. ,

The compounds of the invention show valuable pharmacological effects, e.g. antihypertensive, but especially cardioprotective, e.g. antiischemic (i.e., antianginal) properties.

These can be used in animal experiments, preferably on mammals,

2.B, rats, cats or dogs, or their isolated organs. The new compounds may be administered enterally or parenterally, preferably orally or intravenously, e.g. by gelatin capsules or in the form of starch-containing suspensions or aqueous solutions. The dose used may range from about 1 to 200 mg / kg / day, preferably about 3 to 30 mg / kg / day in intravenous, or between about 10 and 100 mg / kg / day in peroral administration.

Weak antihypertensive effects can be observed in spontaneously hypertensive rats, or in renal hypertensive dogs. These effects can be registered either by sphygmomanometry on the rat's tail, or directly with a catheter inserted into the femoral artery of a dog, and by a transfer instrument indicating the blood pressure inrnmg.

The cardioprotective effect of the new compounds is similar to that of nitroglycerines, propranolol and / or verapamil. These agents suppress the electrocardiographic (ECG) manifestation (ST-T increase) of myocardial ischemia caused by transient coronary occlusion in anesthetized cats or waking. Dogs, is evoked. A left-sided opening of the thoracic cavity under pentobarbital anesthesia and artificial respiration is first performed on the dogs. The pericardium is opened and a segment of the left coronary artery is exposed. This allows the implantation of an inflatable balloon closure of silicone rubber around the exposed arterial segment. The discharge tube of the closure is passed through the rear of the neck to the shoulder blade and a protective sheath attached. The dogs are allowed to recover in 7 to 10 days, receiving antibiotics during the first four days after surgery. It is then made in the dogs control of the arterial occlusion, but taking no ECG recordings. In the test, the

Occluded at intervals of 5 minutes two to three times for 1-1.5 minutes each and registered the change in the ST segment of the ECG lead II. The average values are calculated before the administration of the active ingredient and, at certain intervals, after the treatment with the active ingredient. The results are expressed as the ratio of values obtained in treated and untreated (control) animals. Permanent coronary occlusion is also performed. Venous blood samples are then collected at 3, 6, and 24 hours post-arterial occlusion for CPK (creatine phospho-kinase) determination. The dogs are then anesthetized, injected with trypan blue dye, ejaculated with an overdose of pentobarbital sodium, and their hearts dissected for evaluation by the necrotic tissue. According to the results obtained, the compounds of the invention cause a significant reduction in the electrical, enzymatic and morphological changes (size of the infarction) caused by coronary occlusion in conscious dogs. The products of the method are therefore valuable cardioprotective, in particular against angina pectoris acting agents. The new compounds can also be used as intermediates for the preparation of other valuable, especially of pharmacologically active preparations.

Preferred compounds are those of the formula I in which R is hydrogen or methyl, m is the integer 2 or 3, and η is an integer from 2 to 6, and their acid addition salts, in particular therapeutically usable acid addition salts.

Particularly noteworthy are compounds of general formula II

0645 - * -

V ^X CH ₂ - iH - NH - C _p

wherein ρ is an integer of 3 to 6, and their acid addition salts, especially therapeutically acceptable acid addition salts.

Preference is further given to compounds of the general formula II in which C is H-propyl, tert-butyl, allyl or cyclopropyl, and their acid addition salts, in particular pharmaceutically usable acid addition salts.

The compounds of the present invention are prepared by methods known per se, e.g. made by that one

a) to a compound of general formula III

Vx ^R

Ii (in),

IM (stiyA.

wherein X represents an alkali metal atom or an alkaline earth metal halogen group, a compound of the general formula IV

™ 1 ^H O ™ O ^{= N} ~ ^C "θτ, -1.1 (IV)

in-1 2m-Z η zn + 1

added and releases the product of general formula I from the resulting metal salt or

b) in a compound of general formula V

i ²

CH, -N-CH,. (V), m 2m η 2n + l '

2 208 44 - * -

wherein each of X and X represents hydrogen or the acyl radical of an aliphatic or aromatic carboxylic acid or sulfonic acid, with the proviso that at least one of these symbols represents an acyl radical, replacing the acyl radical X- and / or X by solvolysis or hydrogenolysis by hydrogen or

c) a Schiff base of the general formula VI

"Vx."

IJ l. (VI)

V ^N C H. (N) C H_.

m 2m-u η 2n + l-v

where one of the symbols u and ν is the number 1 and "~ da" s is zero, reduced or

d) a primary amine of the general formula VII

^H vx ^R

\ A · < ^vii)

^VC m ^H 2rn * ^ 2

condensed with a reactive ester of the alcohol CH " ₊₁ ~ 0H in the presence of a strong base or

e) ·· an amide corresponding to an amine of the general formula I in which a carbon atom adjacent to the secondary amino group has an oxygen atom instead of two hydrogen atoms and, if desired, converts a compound obtained into another compound of the invention, and / or if desired, converting a base obtained into an acid addition salt or a salt obtained into the free base or into another acid addition salt, and / or, if desired, separating a mixture of isomers or racemates obtained into the individual isomers or racemates, and / or if desired, Raeemate splits into the optical antipodes.

The abovementioned metallic substituents X in a starting material of the general formula III are preferably lithium, sodium or halogenated magnesium. In this starting material R is preferably methyl, primarily hydrogen.

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

The conversion of an obtained metal salt of general formula Ia

CH. - N - C _n E m. 2m η 2n + l

wherein all symbols have the meanings given above, into the free compound of formula I is preferably with water or with dilute inorganic or organic acids, e.g. with aqueous acids, such as those enumerated below, preferably at room temperature or below, e.g. at about 0 °, made.

In a starting material of the formula V, wherein the symbols X ₁ and / or X "acylphenylalanine radicals, these are preferably lower alkanoyl or lower alkanesulfonyl, unsubstituted or lower alkylated niederalkoxyliertes and / or halogenated benzoyl, phenyl-lower, benzenesulfonyl or carbobenzyloxy, for example acetyl, propionyl, Phenyl acetyl, methanesulfonyl, benzoyl, p-toluyl, p-anisoyl, m-chlorobenzoyl, benzenesulfonyl, toluenesulfonyl or carbobenzyloxy (benzyloxyformyl).

The replacement of an acyl group X and / or X by hydrogen can be carried out by treatment with solvolysing or hydrogenolysing agents. The solvolysis includes e.g. hydrolysis, alcoholysis or ammonolysis. The hydrolysis of said starting materials of formula V is preferably carried out at elevated temperatures, e.g. at 40 to 120 °, performed. It works in aqueous media, preferably with dilute inorganic or organic acids or bases, e.g. aqueous alkalis or acids, e.g. in the below mentioned. The alcoholysis is preferably carried out 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, e.g. Hydrohalic acids, such as hydrochloric, hydrobromic or sulfuric acid made. The ammonolysis is e.g. by treatment with aqueous ammonia. In the said carbobenzyloxy compounds of the formula V, the carbobenzoxy group can also be hydrogenolytically replaced by hydrogen. One operates according to the methods known from peptide synthesis, e.g. with hydrogen in the presence of noble metal catalysts, e.g. Palladium or platinum catalysts.

In process c) the Schiff's bases of the general formula VI are reduced by conventional methods, either with catalytically activated or nascent hydrogen, such as hydrogen in the presence of palladium, platinum or nickel catalysts, or with electrolytically generated hydrogen. However, reduction can also be achieved 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 amines of general formula VII used as starting materials are preferably reacted with said reactive esters, which are derived from strong inorganic acids, e.g. Halo-

AO

hydrazoic acids such as hydrochloric, hydrobromic, primarily hydriodic or derived from an organic sulfonic acid mentioned above. The strong bases used as condensation agents are preferably tertiary amines, such as tri-lower alkylamines, e.g. Di-isopropyl-ethylamine, or cyclic nitrogen bases, e.g. Pyridine or lutidine. Care must be taken to avoid simultaneous quaternization of the secondary amines of formula I obtained. This can be done e.g. can be achieved by using too large an excess of reactive esters and / or not too high temperatures (above room temperature).

The reduction of amide starting materials of process e) can be carried out in a manner known per se with stronger light metal hydrides, which are mentioned for the reduction of Schiff base VI, preferably with alane in strong bases mentioned, or with alkali metal aluminum hydrides, e.g. Lithium aluminum hydride, lithium or sodium tri-lower alkoxy-aluminum hydride or lithium or sodium bis-alkoxyalkoxy aluminum hydrides, e.g. Lithium tri-tert-butoxy-aluminum hydride or sodium bis (2-methoxyethoxy) -aluminum hydride.

The starting materials are known or, if new, can be prepared by methods known per se, e.g. as illustrated in the examples.

The starting materials of formula III can e.g. by reacting corresponding 2-methyl-5-pyridinols with a lower alkyl-alkali metal compound, e.g. with n-butyllithium. The compounds of formula IV can e.g. by condensation of lower alkanols with corresponding primary amines.

The said acyl derivatives of the formula V can by condensation of a compound of formula

η ι

: η. - NH - χ,

m 2m ι

wherein X and X denote said acyl radicals of aliphatic or aromatic carboxylic or sulfonic acids, with an above-mentioned reactive ester of the alcohol CH ₀ , -0H

η zn + l

become. If necessary, a precursor of the above compound wherein X.sup. Denotes an acyl radical mentioned and X is hydrogen, e.g. be acylated with lower alkanoyl, lower alkanesulfonyl, benzoyl, benzenesulfonyl or benzyloxycarbonyl halides.

The Schiff'sehen bases of the general formula VI used as starting materials can conveniently by condensation of compounds of the general formulas

R.

• ·

N C H_ .., = 0 and H ₀ NC H ₀ . or m 2: ml 2 η 2n + l

VX.

¹ J 1

Y ^x CH ₀ -NH ₀ and 0 = CH ₀ . .. m 2m 2. η 2n (.- 2y

to be obtained. The aldehyde or ketone compounds used as precursors may be similar to the compounds of formula III, i. by condensation of said metal salts of 5-hydroxypikoline with corresponding alkanecarboxamides or nitriles, e.g. Formamide, dimethylacetamide, or propionitrile, and hydrolysis of the condensate 'with water or dilute acids, or hydrogenation to said amines of general formula VII. The latter amines can also be prepared from the aldehydes or ketones mentioned by conversion according to conventional

4h

- ti -

Methods in their oximes and their reduction with catalytically activated hydrogen, preferably with rhodium on alumina, are obtained.

The amide starting materials of process e) can be prepared in the customary manner from the abovementioned primary amines of the formula VII and corresponding halides or anhydrides of acids of the formula

C, H, "". -COOH are produced. On the other hand, these n-1 (2n-2). + L

Starting materials by reaction of 5-Hydroxypyridyl ~ 2-alkansäurehalogeniden or anhydrides with amines of the formula H "N-C H be obtained.

The obtained compounds of the invention can be converted into each other in a manner known per se. Thus, e.g. obtained unsaturated compounds of general formula I, which is the lower alkenyl group C H _. contain, as described for the starting materials of formula VI, are catalytically hydrogenated.

Obtained free compounds can be converted into corresponding: acid addition salts, e.g. using inorganic or organic acids, preferably carboxylic acids or sulfonic acids, which give therapeutically acceptable salts, or with appropriate anion exchangers, and isolation of the desired salt. Obtained acid addition salts can be converted into the corresponding free compounds by treatment with a base, e.g. be converted with a metal hydroxide, ammonia or a Hydroxylionaustauscher. Acids which give therapeutically useful acid addition salts are e.g. inorganic acids such as hydrohalic acids, e.g. Hydrochloric or hydrobromic acid, or sulfuric, phosphoric, nitric or perchloric acid; or organic acids, such as aliphatic or aromatic carboxylic and sulfonic acids, e.g. Ant, vinegar, propion, amber, glycol, milk, apple. Wine, lemon, maleic, hydroxymalein, pyruvic,

ΛΙ

Phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, pamoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethylsulfonic, ethylenesulfonic, benzenesulfonic, halobenzenesulfonic, toluenesulfonic, Naphthalenesulfonic, sufolanilic, cyclohexylsulfamic acid; or the ascorbic acid.

These or other salts, e.g. Picrates, can also be used in the purification of free bases. The bases are converted into their salts, the salts are separated off and the bases are released from the salts. As a result of the close relationship between the new compounds in free form and in the form of their salts, the corresponding salts or free compounds are to be understood as meaningful and appropriate in the preceding and following under free compounds and salts.

Obtained isomer mixtures can be prepared by methods known per se, e.g. by fractional distillation, crystallization and / or chromatography, are separated into the individual isomers. Racemic products may be incorporated into the optical antipodes, e.g. by separating their diastereomeric salts, e.g. by fractional crystallization of the d- or ^-camphorsulfonates or d- or <f-mandelates, preferably such salts of the abovementioned X-esters.

The abovementioned reactions are carried out by methods known per se, in the presence or absence of diluents, preferably in those which are inert towards and dissolve the reagents, catalysts, condensing agents or neutralizing agents, and / or in an inert atmosphere, with cooling Room temperature or at elevated temperatures, carried out at normal or elevated pressure.

The invention also relates to modifications of the present process, according to which an intermediate obtainable at any stage of the process is used as starting material and the remaining process steps are carried out, or the process is stopped at any stage, or after which a starting material is formed under the reaction conditions, or in which a starting material in the form of a salt or a reactive derivative is used. Thus, for example, in the catalytic hydrogenation of carbobenzoxy compounds of the formula V or Schiff's base VI, which have an olefinic C BL _s , radical

n 2n-l

have, the corresponding saturated compounds of the formula I, which contain the radical CH, recovered.

In the process of the present invention, preference is given to using those starting materials which lead to the compounds described above as being particularly valuable, in particular those of the formula II.

The pharmacologically useful compounds of the present invention can be used for the preparation of pharmaceutical preparations containing an effective amount of the active ingredient together or in admixture with excipients suitable for enteral or parenteral administration. Preferably, tablets or gelatin capsules containing the active ingredient together with diluents, e.g. Lactose, dextrose, cane sugar, mannitol, sorbitol, cellulose and / or glycine, and lubricants, e.g. Silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol; Tablets also contain binders, e.g. Magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone and, if desired, disintegrants, eg starches, agar, alginic acid or a salt thereof, enzymes of the binders and / or effervescent mixtures, or adsorption -

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Medium, Colorants, Flavorings and Sweeteners Injectable preparations are preferably isotonic aqueous solutions or suspensions, and suppositories primarily fatliquids or suspensions. The pharmacological preparations may be sterilized and / or adjuvants, e.g. B _e preservatives, stabilizers, wetting agents and / or emulsifiers, solubilisers, salts for regulating the ostnotischen pressure and / or buffers "The present pharmaceutical preparations which, if so, may contain further pharmacologically valuable substances desired to be in a Known manner, z "B * by conventional mixing, granulation or coating methods, prepared and contain from about 1 % to about 75 % _t - in particular from about 10 % to about 50 %, of the active substance"

Finish

The following examples serve to illustrate the invention and should not be construed as its limitation, "temperatures are given in degrees Celsius and the data on parts relate to parts by weight" If not mentioned otherwise, all evaporations are performed under reduced pressure, for _e B " , between about 0.1 and 15 mm Hg. * Azeotropic evaporation is continued with the described solvent until a clear (anhydrous) distillate is achieved. "

IG

example 1

A mixture of 115 g of 2-methyl-5-pyridinol and 1500 ml of tetrahydrofuran is added under stirring in a nitrogen atmosphere with 1350 ml of 1,6-molar n-butyl lithium in hexane (2.1 mol), wherein the temperature between -15 ° and 0 ° stops. The reaction mixture is further stirred for 1 hour at -10 °, then treated with 14 g of isopropyliminoethane in such portions that the temperature remains below 10 °. The mixture is stirred for 1 hour at room temperature, then divided into 2 parts and 1 part in. 750 ml of ice water poured. After shaking thoroughly, the organic layer is separated and the aqueous layer is shaken with the second part of the above mixture, and 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, adjusted to pH 6-6.5 with hydrochloric acid and washed four times with 300 ml of ethyl acetate each time. The aqueous layer is washed with. aqueous sodium hydroxide solution to pH 8.4, saturated with sodium chloride and extracted five times with a total of 2300 ml of ethyl acetate-isopropanol (1: 1). The extract is concentrated, the concentrate is diluted twice with isopropanol and concentrated again to azeotropically remove the water. The 400 ml of the last concentrate are filtered and the filtrate is adjusted to pH 1.5 with hydrogen chloride in ethyl acetate. The resulting precipitate is filtered off, washed with isopropanol and recrystallized from 95% aqueous ethanol. This gives (2-isopropylaminopropyl) -5-pyridinol dihydrochloride, which melts at 210-213 °.

The starting material is freshly prepared as follows: 170.3 ml of isopropylamine are added dropwise. to 112.5 ml of rectified acetaldehyde, with stirring and cooling to -20 to -30 °. The mixture is stirred for 90 minutes at 0 ° and then with 50 g of potassium hydroxide.

Pills added. The mixture is allowed to stand in the cold and separated from the liquefied base by decantation. Another 50 g of potassium hydroxide Täbletten are added twice more and the mixture is finally allowed to stand in the refrigerator overnight. The supernatant product is separated, distilled, and the fraction boiling at 59-62 ° is collected at atmospheric pressure. The isopropyliminoethane is obtained.

Example 2

A mixture of 26.7 g of 2- (2-isopropylaminopropyl) -5-pyridinoldihydrochloride, 200 ml of methylene chloride and 100 ml of saturated aqueous sodium carbonate solution is added dropwise with stirring 16 ml of methanesulfonyl chloride at 0-10 °, the mixture by addition of basic sodium carbonate. The mixture is stirred for a further 30 minutes at a pH of 9.5 to 10, and the amount of saturated aqueous sodium chloride solution corresponding to half of its volume is added. The mixture is separated, the aqueous layer extracted with methylene chloride, the combined organic solutions are washed with saturated aqueous sodium carbonate solution, dried and evaporated. 2- (2-Isopropylaminopropyl) -5-methanesulfonyloxy-pyridine is obtained as an OeI. ,

Dissolve 39.6 g of this oil in 200 ml of isopropanol, add the solution with 11.08 g of v-mandelic acid in 68 ml of anhydrous ethanol and allow the mixture to stand at room temperature for 20 hours. It is filtered, the filtrate concentrated to 75 ml and filtered again. The combined residues are recrystallized from anhydrous ethanol-methanol (20: 3) and then from methanol. The corresponding v mandelate is obtained, which melts at 133.5-134 °.

The combined mother liquors are evaporated and 16 g of the

Residue in the d-mandelate, which melts at 131.5-132 °, converted.

11.9 g of the Λ-mandelate are taken up in a minimal amount of water, the solution basified with saturated aqueous sodium carbonate solution and extracted with methylene chloride. The extract is dried and evaporated to give the free base. This is taken up in 75 ml of dioxane, treated with 62 ml of 1 N aqueous sodium hydroxide solution and the mixture is refluxed for 2 hours with stirring. Concentrate the reaction mixture, adjust the concentrate to pH 8.4 with hydrochloric acid and saturate with sodium chloride. The mixture is extracted with rsop-ropanol-ethyl acetate (1: 1), the extract azeotropically evaporated, 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 resulting precipitate is separated and washed with isopropanol. The levorotatory 2- (2-isopropylaminopropyl) -5-pyridinoldihydrochloride (in. Water) is obtained.

dihydrochloride, which melts at 207-209 °, [α] ⁵ = -11.1

The dextrorotatory antipode is prepared starting from the abovementioned d-mandelate in an analogous manner. F. 209-210 °.

[α] = + 10.0 ° (in water). This compound is pharmacologically less active than the racemic starting material of this compound. Example and the above, left-handed salt.

Example 3

A solution, which is prepared from 6 g of 5-acetoxy-2-pyridylacetone, 100 ml of methanol and 10 ml of isopropylamine is cooled 10 Hinuten to room temperature and at this temperature with stirring, within 20 minutes with 4 g of sodium borohydride added in portions. The reaction mixture is evaporated, the residue taken up in water and the solution washed with chloroform. The aqueous layer

ICi 4 4

is separated, its pH adjusted to S, 4 with hydrochloric acid and saturated with sodium chloride. The mixture is extracted with ethyl acetate-isopropanol (1: 1), the extract is azeotropically evaporated by addition of isopropanol and the residue taken up in isopropanol. The suspension is filtered, the filtrate is concentrated and its pH is adjusted to 1.5 with hydrogen chloride in ethyl acetate. The mixture is kept in the refrigerator overnight, the precipitate separated and washed with isopropanol-ethyl acetate. The 2- (2-isopropylaminopropyl) -5-pyridinol dihydrochloride is obtained, which melts at 207-209 °. The product is identical to that of Example 1.

The starting material is prepared as follows:

A suspension of 32.7 g of 2-methyl-5-pyridinol in 400 ml of tetrahydrofuran is added under stirring in a nitrogen atmosphere and cooling with ice at 10 °, within 1 hour, with 400 ml of 1,6-molar n-butyllithium in hexane , The reaction mixture is then treated with 29 g of dimethylacetamide in 50 ml of tetrahydrofuran over 15 minutes, then stirred for 2 hours at room temperature and poured into 700 ml of water The mixture is shaken thoroughly, the aqueous layer is separated, washed with diethyl ether, acidified with hydrochloric acid and The pH is adjusted to 5 with aqueous sodium bicarbonate solution and, after saturation with sodium chloride, the mixture is extracted with ethyl acetate-isopropanol (1: 1), the extract is azeotroped with benzene and the residue The mixture is stirred for 30 minutes on a steam bath and evaporated, the residue is distilled and the fraction boiling at 13O-138 ° / 0, 9 mmHg is collected to give 5-acetoxy-2-pyridylacetone. Its hydrochloride melts at 69-72 ° and the oxime melts at 149-15O ⁰ ..

XO

Example 4

A suspension of "10.9 g of 2-methyl-5-pyridinol in 200 ml of tetrahydrofuran is added in a nitrogen atmosphere, with stirring at -20 °, with 150 ml of 1.6 molar n-butyllithium in hexane within 30 minutes 25 g of 1-isopropyliminopropane are added over the course of 30 minutes at the stated temperature, the mixture is stirred for 90 minutes and allowed to warm to room temperature, the mixture is poured into 150 ml of water, the organic layer is washed with 50 ml of water and the combined Their pH is first adjusted to 6.8 with hydrochloric acid, the solution is washed once more with ethyl acetate, the pH is increased to 7.5 with aqueous sodium carbonate solution, saturated with sodium chloride and with ethyl acetate The extract is azeotropically evaporated, the residue taken up in ethyl acetate, the solution filtered and washed with chl Hydrogen in isopropanol adjusted to pH 4.5. The 2- (2-isopropylaminobutyl) -5-pyridinol hydrochloride is obtained, which melts at 141-143 °.

The starting material is prepared as follows: With ice-cooling and stirring, 58 g of propionaldehyde are mixed with 59 g of isopropylamine and subsequently with 1 ml of concentrated hydrochloric acid. The reaction mixture is stirred for 2 hours at room temperature, treated with 50 g of potassium hydroxide tablets, stirred for 5 hours, decanted from the aqueous phase, dried with potassium hydroxide and distilled. The fraction boiling at 84-86 ° is collected. The 1-isopropyliminopropane is obtained.

Example 5

A suspension of 9.8 g of 2-methyl-5-pyridinol in 200 ml

is separated, its pH adjusted to 8.4 with hydrochloric acid and saturated with sodium chloride. The mixture is extracted with ethyl acetate-isopropanol (1: 1), the extract is azeotropically evaporated by addition of isopropanol and the residue is taken up in isopropanol. The suspension is filtered, the filtrate is concentrated and its pH is adjusted to 1.5 with hydrogen chloride in ethyl acetate. The mixture is kept in the refrigerator overnight, the precipitate separated and washed with isopropanol-acetic acid 'ethyl ester. The 2- (2-isopropylaminopropyl) -5-pyridinol dihydrochloride is obtained, which melts at 207-209 °. The product is identical to that of Example 1.

The starting material is prepared as follows:

A suspension of 32.7 g of 2-methyl-5-pyridinol in 400 ml of tetrahydrofuran is added under stirring in a nitrogen atmosphere and cooling with ice at 10 °, within 1 hour, with 400 ml of 1,6-molar n-butyllithium in hexane , The reaction mixture is then treated with 29 g of dimethylacetamide in 50 ml of tetrahydrofuran over 15 minutes, then stirred for 2 hours at room temperature and poured into 700 ml of water, shaken thoroughly, the aqueous layer separated, washed with diethyl ether, with hydrochloric acid The pH is adjusted to 5 with aqueous sodium bicarbonate solution and, after saturation with sodium chloride, the mixture is extracted with ethyl acetate-isopropanol (1: 1) The extract is azeotroped with benzene and the residue is taken up in 100 ml The mixture is stirred for 30 minutes on a steam bath and evaporated, the residue is distilled off and the fraction boiling at 13O-138 ° / 0, 9 mmHg is collected to give 5-acetoxy-2-pyridylacetone, the hydrochloride of which melts 69-72 ° and the oxime at 149-150 °.

Example 8

A mixture of 342 g of 2-methyl-5-pyridinol and 4500 ml of tetrahydrofuran is at a temperature between -18 and -10 °, with stirring in a nitrogen atmosphere, with 384.6 g of 1.6-molar n-butyllithium in hexane within 3 hours offset. The mixture is further stirred for one hour at -10 °, then 340 g of isopropyliminoethane are added over 5 minutes and its temperature is allowed to rise to 10 °. The reaction mixture is stirred overnight at room temperature and poured into 4500 ml of cold water. The organic layer is separated and washed with 1200 ml of water. The combined aqueous solutions are washed three times with 900 ml of diethyl ether, acidified to pH 6.0 with 900 ml of concentrated hydrochloric acid and then adjusted to pH 8.0 with 853 g of sodium bicarbonate. The mixture is evaporated at 60 °, the residue suspended in 2400 ml of isopronol at 60 °, the suspension is filtered and the filtrate is evaporated at 60 °. The residue is taken up in 800 ml of water, the mixture is cooled to 10 °, filtered and the filtrate is evaporated at 60 ° again.

Dissolve 232 g of the precipitate in 450 ml of ethanol at 65 °, filtered, the hot solution, the filtrate is cooled to 27 ° and it is added with stirring and cooling to 10 ° with 380 ml of 6-normal hydrochloric acid in ethanol. The suspension is filtered after 18 hours and the residue washed with 50 ml of cold ethanol. Mail receives the 2- (2-isopropylaminopropyl) -5-pyridinol dihydrochloride, which melts at 214-216 °. The product is identical to that of Example 1.

The starting material is prepared as follows: 268.8 g of acetaldehyde are cooled to -25 ° and treated with 357.6 isopropylamine in a nitrogen atmosphere with stirring at this temperature

Λ *

within 2 hours. The mixture is stirred for 2 hours at 0 ° and then sit sit 150 g Kallumhydroxyd tablets. The reaction mixture is allowed to stand for 2 hours, separated from the liquefied base by decantation and treated with a further 150 g of potassium hydroxide. The mixture is allowed to stand for 2 hours at 0 °, poured onto 150 g of potassium hydroxide and the reaction mixture allowed to stand overnight at 10 °. The product floating is separated, distilled at atmospheric pressure and collected at 59-64 ° boiling fraction. The isopropyliminoethane is obtained.

Example 9

A solution of 159 g of 2- (2-isopropylaminopropyl) -5-pyridinol 'dihydrochloride in 1000 ml of water is added with 163 g of sodium bicarbonate and the suspension was evaporated. The residue is suspended in 453 ml of anhydrous ethanol at 60 °, the suspension is filtered, the residue washed three times with 150 ml of anhydrous ethanol and the combined extracts are evaporated. This gives the 2- <2-isopropylaminopropyl) -5-pyridinol, which melts at 135-138 °.

Example 10

A solution of 1.55 g of 5-hydroxy-2-pyridylacetone in 50 ml of methanol is added with stirring at room temperature with 0.61 g of 2-propenylamine, 2 ml of 5.5 normal ethereal hydrogen chloride and 0.5 g of sodium cyanoborohydride in this order added. The mixture is stirred for seven days at room temperature and its pH is then adjusted to 1 by 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 is adjusted to 8 with solid sodium bicarbonate, the mixture is evaporated, the residue is triturated with isopropanol and dissolved in 25 ml of acetone. with 1.28 g of fumaric acid in a minimal amount

hot acetone and the resulting solid material filtered off. This gives the 2- [2- (2-propenylamino) -propyl] -5-pyridinol fumarate, which melts at 194-195 °.

The starting material is prepared as follows:

A mixture of 103.6 g of S-acetoxypyridyl-Z-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 separated. This gives the 5-hydroxy-2-pyridylacetone, which melts at 119-120 °.

Example 11

To a solution of 0.8 g of 5-hydroxy-2-pyridylacetone in 25 ml of methanol is added 0.33 g of cyclopropylamine, 1 ml of 5 normal ethereal hydrogen chloride and 1.16 g of sodium cyanoborohydride in this order, and the mixture is kept at room temperature for 3 days touched. Its pH is then adjusted to 1 with 5 normal ethereal hydrogen chloride and 8 afterwards with solid sodium bicarbonate. The mixture is filtered, evaporated, the residue chromatographed on silica gel and eluted with ethyl acetate-methanol (4: 1) to give 2- (2-cyclopropylaminopropyl) -5-pyridinol. The product is converted according to Example 7 in its Monofumarat, which melts at 161 ° with decomposition.

Example 12

A solution of 1.62 g of 2- (2-aminopropyl) -5-pyridinol hydrochloride in 50 ml of methanol is first treated with 0.83 g of n-hexanal, then 1.75 g of sodium cyanoborohydride, and the mixture is stirred for 3 days at room temperature. rt. Its pH is first adjusted to 1 with 5 normal ethereal hydrogen chloride and then 8 with solid sodium bicarbonate. The mixture is filtered, evaporated

_Λί) 3.5

and the residue triturated with .Isopropaiiol. The oily 2- (2-n-hexylaminopropyl) -5-pyridinol is obtained, which shows peaks in the mass spectrum at 151, 128 and 109 m / e.

The starting material is prepared as follows:

A 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 a minimum amount of ethanol, the solution is filtered and the filtrate is evaporated. The 2- (2-oximino-propyl) -5-pyridinol hydrochloride is obtained, which melts at 141-145 °.

A mixture of 12 g of the latter compound, 500 ml of ammonia-saturated methanol and 2.4 g of rhodium on alumina is hydrogenated at room temperature and atmospheric pressure for 3 weeks. The mixture is filtered and the filtrate is evaporated. The 2- (2-aminopropyl) -5-pyridinol hydrochloride is obtained, which is used without further purification.

A small amount of the latter compound is acidified with fumaric acid and the precipitate recrystallized from ethyl acetate-ethanol. The corresponding fumarate is obtained which melts at 171-176 °.

Example 13

A solution of 0.27 g of 2- (2-aminopropyl) -5-pyridinol dihydrochloride and 0.5 ml of diisopropylethylamine in 0.5 ml of methanol is added with stirring at room temperature with 0.24 g of isopropyl iodide. After 24 hours, the mixture is evaporated and the residue according to Example 9 in the 2- (2-isopropylaminopropyl) -5-pyridinol, which melts at 135-138 °, converted. The two free bases are identical.

The starting material is prepared as follows:

A solution of 0.19 g of 2- (2-aminopropyl) -5-pyridinol hydrochloride in ml of anhydrous ethanol is added with 0.2 ml of ethereal hydrogen chloride and evaporated. This gives 2- (2-aminopropyl) -5-pyridinoldihydrochloride, which melts at 125-128 ° with decomposition.

Example 14

A solution of 0.1 g of 2- (2-acetylamino-propyl) -5-pyridinol in 10 ml of anhydrous tetrahydrofuran is added dropwise with stirring at 0 ° with 1.5 ml of 1 molar solution of alan-triäthylamin in toluene. The mixture is treated after 12 hours with 10 ml of 2 N aqueous sodium hydroxide solution at 0 ° and azeotrcpisch with isopropanol. The residue is taken up in 25 ml of methanol, the pH of the solution is adjusted to 8 with 5 normal ethereal hydrogen chloride, the resulting salts are filtered off and the filtrate is evaporated. The residue is triturated with isopropanol. This gives the 2- (2-ethyl-amino-propyl) -5-pyridinol, which melts at 75-79 °.

The starting material is prepared as follows: A suspension of 1.01 g of 2- (2-aminopropyl) -5-pyridinol hydrochloride in 40 ml of methylene chloride is stirred with stirring at room temperature first with 3.3 ml of fyridine and then with 1.47 g Acetyl chloride added. After 17 hours, the reaction mixture is treated with the same volume of saturated aqueous sodium bicarbonate solution, the organic solution is separated off, dried and concentrated by evaporation. The residue obtained as residue is chromatographed on silica gel and eluted with methanol-ethyl acetate (4: 1). This gives 5-acetoxy-2- (2-aeetylaminopropyl) -pyridine, which shows bands in the IR spectrum at 1578 and 165-8 cm. It is alcoholised as follows: A solution of 240 mg of the latter compound in 5 ml of anhydrous ethanol containing 7.5 mg of anhydrous potassium carbonate is refluxed for 5 hours. The 2- (2-acetylaminopropyl) -5-pyridinol is obtained, which is used without further purification.

i? ·

Example 15

A solution of -0.15 g of dibenzoyl-2- (2-methylaminopropyl) -5-pyridinol in 5 ml of 5N hydrochloric acid is refluxed for 23 hours, cooled, washed twice with 5 ml of diethyl ether and evaporated. The 2- (2-methylaminopropyl) -5-pyridinoline dihydrochloride is obtained, which shows peaks in the mass spectrum at 165, 151, 109 and 58 % .

The starting material is prepared as follows:

A (half 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 solution is stirred for 1 hour at room temperature. The residue is recrystallised from diethyl ether to give dibenzoyl-2- (2-aminopropyl) -5-pyridinol, which melts at 110-112 °.

Dissolve 0.36 g of the latter compound in 1.5 ml of dimethylformamide and add the solution at room temperature to the slurry of 36 mg of sodium hydride in 1 ml of dimethylformamide. The mixture is heated for 15 minutes, allowed to cool to room temperature in one hour and then cooled to 0 °. The mixture is earned with 1 ml of toluene and quickly added with 0.36 g of methyl iodide. The Reaktionsgemiscti is stirred at room temperature for 1 hour and then treated with 20 ml of water. It is extracted twice with 20 ml of diethyl ether and the extracts are evaporated. This gives the oily dibenzoyl-2- (2-tffiethylaminopropyl) -5-pyridinol, which shows a band band at 3.48 ppm in the NMR spectrum.

0.15 g of the latter compound are dissolved in 4 ml of anhydrous methanol in the presence of 0.15 mg of potassium carbonate, under

It

The mixture is stirred at room temperature for 12 hours, partially alcoholised, to give the 2- (N-benzoyl-2-methylaminopropyl) -5-pyridinol. This can replace the above-mentioned dibenzoyl starting material in the acid hydrolysis. '

In an analogous manner, a mixture of 0.1 g of dibenzoyl-2- (2-isopropylaminopropyl) -5-pyridinol and 10 ml of 5N hydrochloric acid is refluxed for 3 days, cooled, filtered, evaporated and the residue triturated with acetone. The 2- (2-isopropylaminopropyl) -5-pyridinol dihydrochloride is obtained, which melts at 199-204 °. The product is identical to that of Examples 1, 3 and 8.

Example 16

A mixture of 0.08 g of 2- (N-carbobenzyloxy-2-methylaminopropyl) -5-p'yridinol and 2.5 ml of 5N hydrochloric acid is boiled under reflux for 23 hours, cooled and extracted with diethyl ether. The extract is dried and evaporated. The 2- (2-methylamino-5-pyridinol) dihydrochloride is obtained which is identical to the product of Example 15.

The starting material is prepared as follows: '.

A 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 solution is added with stirring at room temperature with 1.04 g of benzyloxycarbonyl chloride. After 12 hours, the organic phase is separated, dried, evaporated and the residue recrystallized from diethyl ether-hexane. The bis-carbobenzyloxy-2- (2-aminopropyl) -5-pyridinol, which melts at 63-65 °.

A solution of 0.42 g of the latter compound 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 stirred for one hour

Heated 55 °. The mixture is brought to 25 ° in 4 hours, cooled to 0 °, diluted with 1 ml of toluene and mixed with 0.36 g of methyl iodide '. The mixture is stirred at room temperature for 12 hours and then treated with 10 ml of disodium phosphate buffer. The aqueous phase is extracted twice with 20 ml of diethyl ether, the extract washed with water, dried and evaporated. The BLs-carbobenzyloxy-2- (2-methylaminopropyl) -5-pyridinol and the 2- (N-carbobenzyloxy-2-methylaminopropyl) -5-pyridinol are obtained in approximately equal amounts. This mixture is taken up in ethyl acetate, the solution extracted with 1 N aqueous sodium hydroxide and the aqueous phase separated. Their pH is adjusted to 8 with monosodium phosphate buffer. The mixture is extracted with ethyl acetate, the extract is dried and evaporated. The 2- (N-carbobenzyloxy-2-methylaminopropyl) -5-pyridinol is obtained.

Example 17 -

A mixture of 0.08 g of 2- (N-carbobenzyloxy-2-methylaminopropyl) -5-pyridinol, 5 ml of anhydrous hydrogenated anhydrous ethanol and 0.04 g of palladium on carbon catalyst is stirred for 18 hours at room temperature and atmospheric Hydrogenated pressure. The mixture is filtered, the residue washed with ethanolic hydrogen chloride and the Filtraf evaporated. The 2- (2-methylaminopropyl) -5-pyridinol dihydrochloride is obtained which is identical to the product of Examples 15 and 16.

Example 18

Production of 10'000 tablets containing 100 mg each of the active substance:

ingredients:

2- (2-isopropylaminopropyl) -5-pyridinol dihydrochloride 1000 g lactose 2535 g

Cornstarch 125 g

Polyethylene glycol 6000 '150 g

Talcum powder 150 g

Magnesium stearate 40 g

Purified water q.s.

Procedure: All powdery ingredients are sieved with a sieve of 0.6 mm mesh size. Then the Winkstoff is mixed with lactose, talc, magnesium stearate and half of the starch 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 polyethylene in 260 ml of water. The resulting paste is added to the powders and optionally granulated with the addition of another amount of water. The granules are dried overnight at 35 °, forced through a sieve of 1.2 mm mesh size and pressed into tablets of 10.3 mm diameter having a score line.

Example 19

Preparation of 1000 capsules containing 50 mg each of the active substance: Ingredients:

2- (2-Isopropylaminopropyl) -5-pyridinol monofumarate 50g

Cornstarch 5 g

Milk sugar 143,75 g

Magnesium stearate 1 g

Wetting agent 0.25 g

Method:

All powdery ingredients are sieved with a sieve of 0.6 mm mesh size. Then the active ingredient is first homogenized with magnesium stearate and wetting agent and subsequently with starch and milk sugar in a suitable mixer. Capsules no. 2 are filled with 200 mg of the mixture each with a filling machine.

3λ

Analogously, tablets or capsules containing another compound of the invention, e.g. containing one of the preceding examples, prepared.

Claims (5)

10, 9. 80 AP C 07 D / 220 844 GZ 57 332 11 invention claim 1 * Process for the preparation of new secondary 2-aminoalkyl-5-pyridinols of general formula I. HO R
\ / X (I), ^ 'X ^H 2m ~ ^NH - ^C n ^H 2n _± 1 wherein R is hydrogen or lower alkyl, m is an integer of 2 to 4, and η is an integer of 1 to 7, and their acid addition salts, characterized in that s) to a compound of general formula III XO .R wherein X represents an alkali metal atom or an alkaline earth metal halogen group, a compound of the general formula IV ^C ffl-1 ^H 2m-2- ^N - ^C n ^H 2n + i - < ^IV > added and releases the product of general formula I from the resulting metal salt or £ 0th 9th AP C 07 D / 220 GZ 57 332 b) in a compound of general formula V X.O.R ^C m ^H 2m ~ ^H ~ ^C n ^H 2n + l (V), wherein each of the symbols X ₁ and X "is hydrogen or the al. "W Acyl radical of an aliphatic or aromatic carboxylic acid or sulfonic acid, with the proviso that at least one of these symbols represents an acyl radical, the acyl radical X ₁ and / or X _{2 is} replaced by solvolysis or hydrogenolysis by hydrogen, or c) a Schiff base of the general formula VI HO R Il wherein one of the symbols u and v is the number 1 and the other is zero, reduced or d) a primary amine of the general formula VII HO Hi '^ "X - ^NH 2 10. 9. 80 AP C 07. D / 220 844 GZ 57 332 11 SH With. a reactive ester of the alcohol CH ₁ »0H condensed in the presence of a strong base or"" e) an amide corresponding to an amine of general formula I in which a carbon atom adjacent to the secondary amino group has an oxygen atom instead of two hydrogen atoms and, if desired, converts a compound obtained to another compound of the invention, and / or if desired , converting a base obtained into an acid addition salt or a salt obtained into the free base or into another acid addition salt, and / or, if desired, separating a mixture of isomers or racemates obtained into the individual isomers or racemates, and / or, if desired , racemate splits into the optical antipodes «, 2. The method according to item 1, characterized in that in the reaction a) starting materials of the formula III used in which X is lithium, sodium or halogen magnesium. 3e method according to item 1, characterized in that in the reaction b) the acyl radical X, and / or X ₂ replaced by treatment with solvolysierenden or hydrogenolyzing agents by hydrogen, 4 * Method according to item 1, characterized in that in the reaction c) the reduction is carried out with catalytically activated or nascent hydrogen, or with simple or complex light metal hydrides * 10. 9 "80 AP C 07 D / 220 844 GZ 57 332 II 5 * Process according to item 1, characterized in that in reaction d) those starting materials are used in which the reactive ester is derived from strong inorganic acids or organic sulfonic acids
is, " 6 »Method according to item i, characterized in that in the reaction e) the reduction with a simple
or complex light-weight hydride » 7. The method according to any one of items 1 to 6, characterized in that compounds of the general formula I wherein R is hydrogen or methyl, m is the integer 2 or 3, and η is an integer from 2 to 6, and their acid addition salts » 8 «Method according to one of the items 1 to 6, characterized in that compounds of the general formula II HO ? ^H 3
CH ₂ -CH - NH-Cp wherein p is an integer of 3 to 6, and produces their acid addition salts. 9 «method according to one of the items 1 to 6, characterized in that compounds of the formula II, wherein ^C p ^H 2p + 1-ProPy ¹ 'is tert-butyl, allyl or cyclopropyl, and produces their acid addition salts. 10. 9 · 80 AP C 07 D / 220 844 GZ 57 332 11 1O ₄ , Process according to one of the items 1 to 6, characterized in that 2- (2-isopropylaminopropyl) ~ 5-pyridinol and its acid addition salts are prepared. 11 «A method according to any one of items 1 to 10, characterized in that one isolates the process products obtained in aer form of their levorotatory antipodes"