FI70212C - ANALOGIFICATION OF THERAPEUTIC ACTIVATION OF THERAPEUTIC ACTIVATED 2-AMINOLALKYL-5-PYRIDINOLER - 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

r, ADVERTISEMENT1 N n n 19 UTLÄGGNINGSSKRIFT f V Z \ Z

• ~ (45) p "0 * '·' 7 'Λ -:“ · 7

v 'Γ ·' ^ - -1 '· 1 ί V. 10 CO 10nG

(51) Kv.lk.7int.Cl.4 C 07 D 213/65 FINLAND — FINLAND (^ 1) Patent application - Patentansökning 801 41 1 (22) Filing date - Ansökningsdag 3 0.04 .8 0 (23) Starting date - Giltighetsdag ^ qq / j gg (41) Become public - Blivlt offentlig g ^ ^ gg

National Board of Patents and Registration Date of publication and publication. -

Patent and Registration Office V 'Ansökan utlagd och utl.skriften publicerad 28.02.86 (32) (33) (31) Privilege claimed - Begärd priority g ^ g ^ yg USA (US) 35668 (71) Ciba-Geigy AG, 4002 Basel , Switzerland-Schweiz (CH) (72) Renat Herbert Mizzoni, Prescott, Arizona, USA (74) Oy Jalo Ant-Wuorinen Ab (54) Analog method for the preparation of new therapeutically active 2-aminoalkyl-5-pyridinols - Analogiförfarande according to U.S. Pat. No. 3,952,101, secondary 2-amino-1-hydroxyethyl-5-pyridinols or "α-arylmethyl-5-hydroxy-2-pyridinemimethones have a direct an dilating effect with minimal cardiac acceleration ", in other words," they have a stronger effect on the smooth muscles of the respiratory system than on the heart muscle ".

It has surprisingly been found that by removing said aliphatic 1-hydroxy or methanol groups, the effect is reversed. Namely, the cardiac agents according to the present invention having a non-bronchodilator effect are obtained.

The present invention therefore relates to novel secondary 2-aminoalkyl-5-pyridinols of general formula I

HV \ \ A α) · VCH, -NH-R m 2m 1 7021 2 JOBBa CH „represents a straight or branched alkylene group containing 2- * J carbon atoms And R ^ represents a straight or branched chain containing 1-7 carbon atoms an alkyl group, an alkylene group having 2 to 7 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms. And their acid addition salts and optically active antlers, especially therapeutically useful acid addition salts, methods for their preparation, pharmaceutical preparations containing these compounds, and their therapeutic use.

The alkylene group C H_ preferably denotes 1,2-propylene, but also m 2m ethylene, 1,3-propylene, 1,2-, 1,3- or tert-butylene.

The alkyl group R 1 preferably denotes methyl, ethyl, n- or i-propyl, n-, iso- or tert- (butyl, pentyl, heyl or heptyl), in particular ieopropyl.

The alkenyl group R 1 denotes, for example, allyl, methallyl, 2- or 3- (butenyl, pentenyl, hexenyl or heptenyl). The cycloalkyl group R 1 denotes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, in particular cyclopropyl or cyclohexyl.

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

The acid addition salts of the dibasic compounds of formula 1 are preferably therapeutically useful acid addition salts, for example the salts of the aforementioned acids.

The compounds according to the invention have valuable pharmacological effects, for example antihypertensive, but in particular cardio-protective, for example anticoagulant (bo. Antianginal) properties.

The properties can be demonstrated in animal experiments, in particular in mammals, for example rats, cats or dogs, or in their isolated organs. The novel compounds can be administered enterally or parenterally, preferably orally or intravenously, for example in the form of gelatin capsules or suspensions containing starch. *. * '-7 .:. *. *., '♦ »·'; . ,. . . ^. . * ,. * * .. *. i t · ... ^ 7021 in 2 forms, for example as aqueous solutions. The dose used may be 7 to 200 mg / kg / day, preferably about 3 to 30 mg / kg / day administered intravenously or about 10 to 100 mg / kg / day orally.

Mild antihypertensive effects may be observed in spontaneously hypertensive rats or in renally hypertensive dogs. These effects can be recorded either by measuring the pulse pressure from the rat tail or by using a catheter inserted into the dog's femoral artery and a measuring device that gives blood pressure in millimeters of mercury.

The cardioprotective effect of the new compounds is similar to that of nitroglycerol, propranolol and / or verapamil. This substance reduces the appearance of electrocardiography (ECG) of myocardial anemia (ST-T elevation) caused by transient coronary thrombosis in anesthetized cats or awake dogs. Dogs are subjected to anterior left thoracic opening in pentobarbita lineage and artificial respiration. The pericardium is opened and part of the left coronary artery is exposed. It allows a balloon choke made of silicon call to be placed around the exposed arterial part. The choke outlet pipe is placed behind the neck on the shoulder and a protective sheath is attached. Dogs are allowed to recover for 7-10 days, during which time they receive antibiotics during the first b days after surgery. The dogs are then tested for an arterial thrombus, but no ECG is taken. In the experiment, the arteries are occluded two or three times every 5 minutes, each time for 1-1.3 minutes, and the change in the ST-T segment of ECG lead II is recorded. The averages before administration of the active ingredient and after treatment with the active ingredient are calculated at certain time intervals. The results are expressed as the ratios of the values obtained with treated animals and untreated (control) animals. Permanent coronary artery constriction is also performed. Venous blood samples are then taken 3i 6 and 2b hours after arterial constriction to determine CPK values (creatine phosphokinase). Dogs are then anesthetized, injected with trypan blue dye, anesthetized with an overdose of pentobarbital sodium, and the heart is excised to determine necrotic tissue. According to the results obtained, the compounds of the invention cause a significant reduction in electrical, enzymatic and morphological changes (infarct intensity) which were triggered in awake dogs by coronary artery constriction. The process products are therefore valuable substances that are cardio-protective, especially against Angina pectoris.

i 7021 2

In addition, the new compounds can be used as intermediates for the preparation of other valuable preparations, in particular pharmacologically active preparations.

Most preferred are compounds of formula I wherein m is an integer of 2 or 3 and their acid addition salts, especially therapeutically useful acid addition salts.

Particularly preferred are compounds of general formula II

HO

N / \ 5! ch3 (II), V * XCH2- <1H-NH-R1 wherein is as defined above, and their acid addition salts, in particular the therapeutically useful acid addition salts.

Further preferred are compounds of general formula II wherein isopropyl, tert-butyl, allyl or cyclopropyl and their acid addition salts, in particular pharmaceutically acceptable acid addition salts.

The compounds of this process are prepared by methods known per se, for example by a) adding a compound of the general formula III X0 \ Π ί (III),

V * NCH2X

wherein X represents an alkali metal atom or an alkaline earth metal halogen group, is attached to the general formula IV

VlH2m-2 = N-R1 (IV) 5 7021 2 and the product of general formula I are liberated from the metal salt obtained or

b) in a compound of general formula V

Xl \! i i <v>.

V \ H, -1 \ a 2m 1 wherein each of the symbols and represents hydrogen or an acyl radical of an aliphatic or aromatic carboxylic acid or sulfonic acid such that at least one of the symbols represents an acyl radical, the acyl radical X1 and / or X2 is replaced by hydrogen by solvolysis or hydrogenation or c) a Schiff's base of formula VI or Via,

H0 \ A

5 i (vr), VNC H, - N-R.

m 2m-l 1 or ° \ A IJ j V · “Ϊ (VU) · in which the thigh has only 1 carbon atom less than R, is reduced or d) the primary amine of general formula VII HV \ H ί (VII) V \ B2rn-m 2 is condensed with a reactive ester of the alcohol R 1 -OH in the presence of a strong base 6 or 7 0 2 2 e) reduction of an amide corresponding to an amine of general formula I having two hydrogen atoms on the carbon atom adjacent to the secondary amino group and converting the resulting compound to another the compound and / or the base obtained is converted, if desired, into an acid addition salt or the salt obtained into the free base or another acid addition salt, and / or the resulting mixture of isomers or racemates is separated into individual isomers or racemates, if desired, and / or cleaved into optical antipodes if desired.

Said metallic substituents X in the starting material of general formula III are preferably lithium, sodium, or halogenmagnesium. In these starting materials, R is preferably methyl, primarily hydrogen.

The addition reaction according to process a) is carried out under anhydrous conditions, preferably in polar solvents, for example open-chain or cyclic ethers, such as diethyl ether or tetrahydrofuran, and at a temperature lower than room temperature, for example at 10 to -20 ° C.

XO of the obtained metal salt of general formula Ia.

\ / V

li IX (Ia) * \ * NCH „- N- R m 2m 1 wherein all symbols have the meanings given above, the conversion to the free compound of formula I is preferably carried out with water or dilute inorganic or organic acids, for example aqueous acids such as those listed below, preferably at room temperature or below, for example at about 0 ° C.

In the starting materials of the formula V in which X 1 and / or X 1 denote an acyl radical, the radicals are preferably lower alkanoyl or lower alkanesulfonyl, unsubstituted or lower alkylylated, lower alkoxylated and / or halogenated benzenyl, acetylsulfonyl, acetylsulphenyl, carbenyl, acetylbenzene, , benzoyl, p-toluyl, p-anisoyl, m-chlorobenzoyl, benzenesulfonyl, toluenesulfonyl or carbobenzyloxy (benzyloxyformyl).

7021 2

Replacement of the acyl group and / or X 1 with hydrogen can be accomplished by treatment with solvolizing or hydrogenating agents. Solvolysis comprises, for example, hydrolysis, alcoholysis or ammonolysis. The hydrolysis of said starting materials of the formula V is preferably carried out at an elevated temperature, for example at -10 ° C to 120 ° C. Work in aqueous media, preferably dilute inorganic or organic acids or bases, for example aqueous alkalis or acids, for example those mentioned below. The alcoholysis is preferably carried out with lower alkanols, for example methanol or ethanol in the presence of strong inorganic bases, for example aqueous alkali metal hydroxides or carbonates or inorganic acids, for example hydrohalic acids, such as hydrochloric acid, hydrobromic acid or sulfuric acid. Ammonolysis is performed, for example, by treatment with aqueous ammonia. In said carbobenzyloxy compounds of formula V, the carbobenzyloxy group can also be hydrogenolytically replaced by hydrogen. Work is carried out by methods known from peptide synthesis, for example hydrogen in the presence of a noble metal catalyst, for example a palladium or platinum catalyst.

In process c) the compounds of general formula VI are reduced

Schiff bases by conventional methods with either catalytically activated or generated hydrogen, such as hydrogen in the presence of a palladium, platinum or nickel catalyst, or electrolytically generated hydrogen. The reduction can also be carried out with simple or complex light metal hydrides, for example boranes, alanines or alkali metal borohydrides or alkali metal cyanoborohydrides, such as sodium borohydride or sodium cyanoborohydride.

The primary amines of the general formula VII used as starting materials are preferably condensed with said reactive esters derived from strong inorganic acids, for example hydrohalic acids, such as hydrochloric, hydrobromic, in particular hydroiodic acid or the abovementioned organic sulfonic acids. The strong bases used as condensing agents used are preferably tertiary amines, such as trialkylalkylamines, for example diisopropylethylamine, or cyclic nitrogen bases, for example pyridine or lutidine. It must then be borne in mind that the simultaneous quaternization of the obtained secondary amines of the formula I is avoided. This can be achieved, for example, by not using too much reactive ester and / or by avoiding excessively high temperatures (above 8, 70212 ° C).

The reduction of the amide starting materials according to process e) can be carried out in a manner known per se with stronger light metal hydrides suitable for the reduction of the Schiff's base, preferably alanine, in said strong bases or alkali metal aluminum trioxide or sodium trioxide or sodium aluminum hydride, for example lithium aluminum hydride, lithium or sodium alkoxyaluminum hydride, for example lithium tritert-butoxyaluminum hydride or sodium bis- (2-methoxyethoxy) aluminum hydride.

The starting materials are known, or when they are new, they can be prepared in a manner known per se, such as those described in the examples.

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

Said acyl derivatives of the formula V can be prepared by condensing a compound of the formula • ACmH2in - NH - X2 wherein X1 and denote said acyl radicals of aliphatic or aromatic carboxylic or sulfonic acids, with the above-mentioned reactive ester of the alcohol R -OH. In case it is necessary, the precursor of the above compounds in which X 1 represents said acyl radical and X 1 is hydrogen can be acylated with, for example, lower alkanoyl, lower alkanesulfonyl, benzoyl, benzenesulfonyl or benzyloxycarbonyl halides.

Schiff's bases of general formula VI used as starting materials can be conveniently obtained by condensing compounds of the following general formulas tl 7021 2 9

HO

n i or HO.

N / * • ·

Il 1 * »" \ H2, fNII2 J »0 = *;

The aldehyde or ketone compounds used as precursors can be prepared in the same way as the compounds of formula III, i.e. by condensing said metal salts of 5-hydroxypicoline with the corresponding alkane carboxylic acid amides or nitriles, for example formamide, dimethylacetamide or propionitrile or with dilute acids, or by hydrogenation to said amines of general formula VII. The latter amines can be obtained from said aldehydes or ketones by converting them into their oximes by customary methods and reducing the oximes with catalytically activated hydrogen, preferably rhodium or alumina.

The amide starting materials of process e) can be prepared conventionally from primary amines of the formula VII and the corresponding halides or anhydrides of the acids of the formula R 1 -COOH. On the other hand, these starting materials can be obtained by reacting 5-hydroxypyridyl-2-alkanoic acid halides or anhydrides with amines of the formula H-N-Rj.

The compounds obtained according to the invention can be converted into one another in a manner known per se. Thus, for example, the obtained unsaturated compounds of the general formula I which contain a lower alkenyl group R 1 can be catalytically hydrogenated as described for the starting materials of the formula VI.

The free compounds obtained can be converted into the corresponding acid addition salts, for example by using inorganic or organic acids, preferably carboxylic acids and M sulfonic acids, which give therapeutically useful salts or by using the corresponding anion exchangers and isolating the desired salt. The resulting acid addition salts can be converted into the corresponding free compounds by treatment with a base such as a metal hydroxide, ammonia or hydroxyl ion exchanger. Acids which give therapeutically useful acid addition salts are, for example, inorganic acids, such as hydrohalic acids, for example hydrochloric or hydrobromic acid, or sulfuric, phosphoric, nitric or perchloric acid, or organic acids, such as aliphatic or aromatic carboxylic acids. . sulfonic acid and, for example, formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, maleic, hydroxymalein, fire grape, phenylacetic, benzoic, β-aminobenzoic acid. , anthranilic, *) - hydroxybenzoic, salicylic, pamoic, nicotine, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, benzenesulfonic, halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic, sulfonylsulfonyl, sulfanilyl, sulfanilyl ascorbic acid.

These or other salts, for example picrates, can also be used to purify the free bases. The bases are converted to their salts, the salts are separated and the bases are liberated from the salts. Since the new compounds in the free form and in the form of their salts are very similar, the free compounds and salts referred to above and below are at the same time and expediently also the corresponding salts or free compounds.

The resulting mixtures of isomers can be separated into the individual isomers by means known per se, for example by fractional distillation, crystallization and / or chromatography. Racemic products can be separated into optical antipodes, for example, by separation of their diastereomeric salts, for example by fractional crystallization of the salts of the d- or β-camphorsulfonate or the d- or ε-mandelate, preferably of the abovementioned β-esters.

The above reactions are carried out in a manner known per se, in the presence or absence of diluents, preferably those which are inert to and soluble in the reagents, catalysts, condensing agents or neutralizing agents, and / or in an inert atmosphere, under cooling or at room temperature. temperature, normal or elevated pressure.

The invention also encompasses modifications of this process using intermediates contained in any step of the process starting from

II

7021 2 as starting materials and the remaining process steps are carried out or the process is stopped at any stage or according to which the starting material is formed under reaction conditions or where the starting material is used in the form of a salt or a reactive derivative. Thus, the catalytic hydrogenation of carbobenzoxy compounds of formula V or Schiff's bases of formula VI having an olefin residue r affords the corresponding saturated compounds of formula I containing the residue r. The processes of this invention preferably use starting materials which lead to compounds of formula II particularly valuable at the beginning. under.

The pharmacologically useful compounds of this invention can be used in the preparation of pharmaceutical preparations containing an effective amount of the active ingredient together or in admixture with carriers suitable for enteral or parenteral administration. Preferably tablets or gelatin capsules are used which, in addition to the active ingredient, contain a diluent, for example lactose, dextrose, cane sugar, mannitol, sorbitol, cellulose and / or glycine and lubricants, for example silica, talc, stearic acid or its salts, such as magnesium or calcium wherein the tablets also contain a binder, for example Mg-Al silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone and, if desired, a wetting agent, for example starch, agar or agar, algin, effervescent or absorbent, coloring, flavoring and sweetening agents. Formulations suitable for injection are preferably isotonic aqueous solutions or suspensions, and suppositories are primarily fat emulsions or suspensions. The pharmacological preparations can be sterilized and / or contain auxiliaries, for example preservatives, stabilizers, wetting and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. These pharmaceutical preparations, which may contain other pharmacologically valuable substances if desired, are prepared in a manner known per se, for example by customary mixing, granulating or granulating methods, and contain from about 5% to about 75%, in particular from about 10% to about 50%, of active ingredient.

The following examples illustrate the invention without limiting it in any way. Temperatures are given in degrees Celsius and parts in parts by weight.

Unless otherwise stated, the solvent is evaporated under reduced pressure, for example at a pressure of about 0.1 to 15 mm Hg. The azeotropic 7021 2 evaporation is continued with the solvent described until a clear (anhydrous) distillate is obtained.

Example 1

To a mixture of 115 g of 2-methyl-5-pyridinol and 1500 ml of tetrahydrofuran are added, with stirring under a nitrogen atmosphere, 1350 ml of 1,6 molar n-butyllithium in hexane (2.1 mol), keeping the temperature between - 15 ° - 0 °. The reaction mixture is further stirred for 1 hour at -10 °, then 11 * g of isopropyliminoethane are added in such portions that the temperature remains below 10 °. The mixture is stirred for one hour at room temperature, then divided into two portions and the other portion is poured into 750 ml of ice water. After thorough shaking, the organic layer is separated and the water layer is shaken with another part of the above mixture. The combined organic phases are extracted once with 100 ml of water and discarded. All aqueous solutions are combined, washed three times with 300 ml of diethyl ether, the pH is adjusted to 6-6.5 with hydrochloric acid and washed four times, in each case with 300 ml of ethyl acetate. The aqueous layer is adjusted to pH 8 with aqueous sodium hydroxide solution, saturated with sodium chloride and extracted five times with acetic acid ethyl ester-isopropanol solution (1: 1) using a total of 2300 ml. The extract is concentrated, the concentrate is diluted twice with isopropanol to azeotropically remove water and reconcentrated. 400 ml of the last concentrate are filtered off and the pH of the filtrate is adjusted to 1.5 with hydrogen chloride in ethyl acetate. The precipitate obtained is filtered off, washed with isopropanol and recrystallized from 95% aqueous ethanol. (2-Isopropylaminopropyl) -pyridinol dihydrochloride is obtained, melting at 210-213 °.

The starting material is prepared fresh as follows: 170.3 ml of isopropylamine are added dropwise to 112.5 ml of purified acetaldehyde with stirring and cooling at -20 ° to -30 °. The mixture is stirred for 90 minutes at 0 ° and then 50 g of potassium hydroxide tablets are placed there. The mixture is left to stand in the cold and separated by decantation from the liquid base. 50 g of potassium hydroxide tablets are added twice more and then the mixture is allowed to stand in the refrigerator overnight. The product floating above is separated, distilled and recovered as a boiling product at 59-62 ° and atmospheric pressure. Isopropyliminoethane is obtained.

Il 13

Example 2 70212

To a mixture of 26.7 g of 2- (2-isopropylaminopropyl) -5-pyridinol dihydrochloride, 200 ml of methylene chloride and 100 ml of saturated aqueous sodium carbonate solution is added, with stirring and dropwise, 16 ml of methanesulfonyl chloride at 0-10 °, keeping the mixture basic by addition. further sodium carbonate. The mixture is further stirred for 30 minutes at pH 9.5-10 and half the volume of saturated aqueous sodium chloride solution is added. The mixture components are separated, the aqueous layer is 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 oil.

39.6 g of this oil are dissolved in 200 ml of isopropanol, 11.08 g of 1-mandelic acid in 68 ml of anhydrous ethanol are added to the solution, and the mixture is allowed to stand for 20 hours at room temperature. The mixture is filtered, the aliquot is concentrated to 75 ml and filtered again. The combined residues are recrystallized from anhydrous ethanol-methanol (20: 3) and then methanol. The corresponding 1-mandelate is obtained, melting at 133.5-13 °.

The combined mother liquors are evaporated off and the residue, 16 g, is converted into d-mandelate, melting at 131.5-132 °.

11.9 g of 1-mandelate are dissolved in a minimum amount of water, basified with saturated aqueous sodium carbonate solution and extracted with methylene chloride. The extract is dried and evaporated to give the free base. It is dissolved in 75 ml of dioxane, 62 ml of 1N aqueous sodium hydroxide solution are added and the mixture is boiled for two hours with stirring and refluxing. The reaction mixture is concentrated, the pH of the concentrate is adjusted to 8 with hydrochloric acid and saturated with sodium chloride. The mixture is extracted with isopropanol-acetic acid ethyl ester (1: 1), the extract is azeotroped, the residue is dissolved in isopropanol, the solution is filtered, acidified with hydrochloric acid in acetic acid-ethyl ester and the filtrate is allowed to stand for 2 days. The resulting precipitate is separated and washed with isopropanol. Left-turning 2- (2-isopropylaminopropyl) -5-pyridinol dihydrochloride is obtained, melting at 207-209 °. = -11.1 ° (in water).

The dextrorotatory antipode is further prepared from the above-mentioned d-mandelate in an analogous manner. Its melting point is 209-210 °.

2 S o ptjy - +10.0 (in water). The compound is less pharmacologically active than the racemic starting material of this example and said levorotatory salt.

Example 5 7021 2

A solution of 6 g of 5-acetoxy-2-pyridylacetone, 100 ml of methanol and 10 ml of isopropylamine is cooled for 10 minutes at room temperature and at this temperature g of sodium borohydride are added portionwise over 20 minutes with stirring. The reaction mixture is evaporated, the residue is dissolved in water and the solution is washed with chloroform. The aqueous layer is separated, adjusted to pH 8.3 with hydrochloric acid and saturated with sodium chloride. The mixture is extracted with acetic acid-ethyl ester-isopropanol (1: 1), the extract is azeotroped with isopropanol and the residue is dissolved in isopropanol. The suspension is filtered, the filtrate is concentrated and the pH is adjusted to 1.5 with hydrogen chloride in ethyl acetate. The mixture is kept in a refrigerator overnight, the precipitate is separated and washed with isopropanol-acetic acid ethyl ester. 2- (2-Isopropylaminopropyl) -5-pyridinol dihydrochloride is obtained, melting at 207-209 °. The product is identical to that obtained in Example 1.

The starting material is prepared as follows:

To a suspension of 52.7 g of 2-methyl-5-pyridinol in 00100 ml of tetrahydrofuran is added, with stirring under a nitrogen atmosphere, cooling on ice below 10 °, within 1 hour ^00 ml of 1.6 molar n-butyllithium in hexane. To the reaction mixture is then added 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 washed again with diethyl ether. The pH of the mixture is adjusted to 5 with aqueous sodium hydrogencarbonate 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 dissolved in 100 ml of acetic anhydride. The mixture is stirred and evaporated for 30 minutes in a steam bath. The residue is distilled and the fraction boiling at 130-138 ° / 0.9 mm Hg is collected. 5-Acetoxy-2-pyridylacetone is obtained. Its hydrochloride melts at 69-72 ° and its oxime at 1-9-1503.

Example * +

To a suspension of 10.9 g of 2-methyl-5-pyridinol in 200 ml of tetrahydrofuran is added under stirring under a nitrogen atmosphere and at -20 °

II

15 7021 2 150 ml of 1.6 molar n-butyllithium in hexane over 30 minutes. After 1 hour, 25 g of 1-isopropyliminopropane are added over 30 minutes at said 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 aqueous solutions are washed with diethyl ether. The aqueous solutions are first adjusted to pH 6.8 with hydrochloric acid, washed once more with ethyl acetate, adjusted to pH 7.5 with aqueous sodium carbonate solution, saturated with sodium chloride and extracted with ethyl acetate-isopropanol (1: 1). The extract is azeotroped, the residue is dissolved in ethyl acetate, the solution is filtered and its pH is adjusted to 4.5 with hydrochloric acid in isopropanol. 2- (2-Isopropylaminobutyl) -5-pyridinol hydrochloride is obtained, melting at 141-143 °.

The starting material is prepared as follows: Under ice-cooling and stirring, 59 g of isopropylamine are added to 58 g of propionaldehyde, followed by 1 ml of concentrated hydrochloric acid. The reaction mixture is stirred for 2 hours at room temperature, 50 g of potassium hydroxide tablets are added, stirred for 5 hours, decanted from the aqueous phase, dried over potassium hydroxide and distilled. The fraction boiling at 84-86 ° is collected. 1-Isopropylimino-propane is obtained.

Example 5

A suspension of 918 g of 2-methyl-5-pyridinol in 200 ml of tetrahydrofuran is stirred under a nitrogen atmosphere at -20 [deg.] C. and 735 [mu] l of 1.6 molar n-butyllithium in hexane are added over 30 minutes. After 3 hours, 10 g of tert-butyliminoethane are added to the mixture at said temperature over a period of 30 minutes. The resulting mixture is treated as described in Example 4, except that the last solution is extracted with hydrogen chloride in ethyl acetate. 2- (2-tert-butylaminopropyl) -5-pyridinol dihydrochloride is obtained, melting at 218-220 °.

Example 6

In the same manner as in the methods described in the previous examples, the following compounds are prepared starting from equivalent amounts of starting materials: ie 7021 2 a) 2- (3-isopropylaminobutyl) -5-pyridinol dihydrochloride, m.p. 27 ^ -276 °; b) 2- (2-cyclohexylaminopropyl) -5-pyridinol dihydrochloride, m.p. 232-233 ° * +.

Example 7

To a suspension of 116 g of 2- (2-isopropylaminopropyl) -5-pyridinol in 310 ml of water is added 65 g of fumaric acid under stirring at 70 ° under a nitrogen atmosphere. The resulting clear solution is stirred overnight at 20 °, the precipitate obtained is filtered off and washed three times with cold water, 15 ml each time. 873 g of this precipitate (obtained in several portions) are dissolved in 2100 ml of water at 70 °, the hot solution is filtered and the filtrate is stirred for two days under a nitrogen atmosphere at room temperature. The suspension obtained is filtered and the residue is washed twice with 250 ml of cold water each time. 2- (2-Isopropylaminopropyl) -5-pyridinol monofumarate is obtained, which melts at 18 DEG-1830 when decomposed.

Example 8

To a mixture of 3 * ~ 2 g of 2-methyl-5-pyridinol and * + 500 ml of tetrahydrofuran is added, at a temperature of -18 to -10 ° with stirring under a nitrogen atmosphere, 38 * +, 6 g of 1.6 molar n -butyllithium in hexane over 3 hours. The mixture is further stirred for one hour at -10 °, then 3 * + 0 g of isopropylaminoethane are added over five minutes and the temperature is allowed to rise to 10 °. The reaction mixture is stirred overnight at room temperature and poured into * + 500 ml of cold water. The organic layer is separated and washed with 1200 ml of water. The combined aqueous solutions are washed three times, each time with 900 ml of diethyl ether, acidified with 900 ml of concentrated hydrochloric acid to pH 6.0 and then the pH is adjusted to 8.0 with 853 g of sodium hydrogen carbonate. The mixture is evaporated at 60 °, the residue is suspended at 60 ° in 2 * + 00 ml of isopropanol, the suspension is filtered and the filtrate is evaporated off at 60 °. The residue is dissolved in 800 ml of water, the mixture is cooled to 10 °, filtered and the filtrate is evaporated again at 60 °.

232 g of precipitate are dissolved in * + 50 ml of ethanol at 65 °, the hot solution is filtered, the filtrate is cooled to 27 ° 'and added with stirring and cooling to 10 ° in 380 ml of 6N hydrochloric acid in ethanol. After 18 hours, the suspension is filtered and the residue is washed with 50 ml of 177021 2 cold ethanol. 2- (2-Isopropylaminopropyl) -5-pyridinol dihydrochloride is obtained, melting at 214-216 °. The product is identical to that obtained in Example 1.

The starting material is prepared as follows: 268.8 g of acetaldehyde are cooled to -25 ° and added under a nitrogen atmosphere, with stirring at this temperature, with 357 g of isopropylamine over two hours. The mixture is stirred for 2 hours at 0 and then 150 g of potassium hydroxide tablets are added. The reaction mixture is allowed to stand for 2 hours, separated from the liquid base by decane and further treated with 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 is allowed to stand overnight at 10 °. The product floating on the reaction mixture is separated, distilled at atmospheric pressure and the fraction boiling at 59-64 ° is collected. Isopropyliminoethane is obtained.

Example 9

To a solution of 159 g of 2- (2-isopropylaminopropyl) -5-pyridinol dihydrochloride in 1000 ml of water is added 163 g of sodium hydrogen carbonate and the suspension is evaporated. The residue is suspended at 60 [deg.] C. in 453 ml of anhydrous ethanol, the suspension is filtered, the residue is washed three times with 150 ml of anhydrous ethanol each time and the combined extracts are evaporated. 2- (2-Isopropylaminopropyl) -5-pyridinol is obtained, melting at 135-138 °.

Example 10

To a stirred solution of 1.55 g of 5-hydroxy-2-pyridylacetone in 50 ml of methanol at room temperature are added 0.61 g of 2-propenylamine, 2 ml of 5.5 N ethereal hydrogen chloride and 0.5 g of sodium cyanoborohydride. in this order. The mixture is stirred for 7 days at room temperature and then the pH is adjusted to 1 by careful addition of 2N hydrochloric acid. The acidic mixture is evaporated, the residue is dissolved in 20 ml of water and the pH of the solution is adjusted to 8 with solid sodium hydrogen carbonate. The mixture is evaporated, the residue is triturated with isopropanol and dissolved in 25 ml of acetone. The solution is filtered, 1.28 g of fumaric acid are added to a minimum of hot acetone, and the solid obtained is filtered off. 2- [2- (2-propenylamino) propyl] -5-pyridinol fumarate is obtained, melting at 19 DEG-195 DEG.

The starting material is prepared as follows:

A mixture of 103.6 g of 5-acetoxypyridyl-2-acetone, 0.75 g of anhydrous potassium carbonate and A-00 ml of anhydrous ethanol is refluxed for 2 hours, filtered, concentrated to 100 ml, the concentrate is cooled and the precipitate is precipitated. separated. 5-Hydroxy-2-pyridylacetone is obtained, melting at 119-120 °.

Example 11

To a solution of 0.8 g of 5-hydroxy-2-pyridylacetone in 25 ml of methanol are added 0.33 g of cyclopropylamine, 1 ml of 5N ethereal hydrogen chloride and 1.16 g of sodium cyanoborohydride, respectively, and the mixture is stirred for 3 days at room temperature. . Its pH is then adjusted to 1 with 5N ethereal hydrogen chloride and then to 8 with solid sodium bicarbonate. The mixture is filtered, evaporated, the residue is chromatographed on silica gel and eluted with ethyl acetate-methanol (^: 1). 2- (2-cyclopropylaminopropyl) -5-pyridinol is obtained. The product is converted as described in Example 7 to its monofumarate, which melted on decomposition at 16 °.

Example 12

To a solution of 62 g of 2- (2-aminopropyl) -5-pyridinol hydrochloride in 50 ml of methanol is first added 0.83 g of n-hexanal, then 1.75 g of sodium cyanoborohydride and the mixture is stirred for 3 days at room temperature. temperature. Its pH is first adjusted to 1 with 5N ethereal hydrogen chloride and then to 8 with solid sodium bicarbonate. The mixture is filtered and evaporated and the residue is triturated with isopropanol. An oily 2- (2-n-hexylaminopropyl) -5-pyridinol having peaks in the mass spectrum at 151-128 and 109 m / e is obtained.

The starting material is prepared as follows:

A mixture of 8.6 g of 5-hydroxy-2-pyridylacetone, 1.08 g of hydroxylaminohydrochloride and 170 ml of anhydrous ethanol is refluxed for 6 hours and evaporated. The residue is dissolved in a minimum

II

19 7021 2 ethanol, the solution is filtered and the filtrate is evaporated. 2- (2-Oximino-propyl) -5-pyridinol hydrochloride is obtained, melting at 1-1-1.5 °.

A mixture of 12 g of the latter compound, 500 ml of methanol saturated with ammonia and 2.1 kg of rhodium with alumina is hydrogenated for 3 weeks at room temperature and atmospheric pressure. The mixture is filtered and the filtrate is evaporated. 2- (2-Aminopropyl) -5-pyridinol hydrochloride is obtained which can be used without further purification.

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

Example 13

To 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 0.2 kg of isopropyl iodide. After 2 h, the mixture is evaporated and the residue is converted according to Example 9 into 2- (2-isopropylaminopropyl) -5-pyridinol, melting at 135-138 °. Both free bases are identical.

The starting material is prepared as follows:

To a solution of 0.19 g of 2- (2-aminopropyl) -5-pyridinol hydrochloride in 10 ml of anhydrous ethanol is added 0.2 ml of ethereal hydrogen chloride and evaporated. 2- (2-Aminopropyl) -5-pyridinol hydrochloride is obtained, melting at 125-128 ° on decomposition.

Example 14

To a solution of 0.1 g of 2- (2-acetylaminopropyl) -5-pyridinol in 10 ml of anhydrous tetrahydrofuran is added dropwise, with stirring at 0 °, 1.5 ml of a 1 molar solution of alanine-triethylamine. toluene. After 12 hours, 10 ml of 2N aqueous sodium hydroxide solution are added at 0 [deg.] C. and the mixture is azeotroped with isopropanol. The residue is dissolved in 25 ml of methanol, the pH of the solution is adjusted to 8 with 5N ethereal hydrogen chloride, the salts obtained are filtered off and the filtrate is evaporated off. The residue is triturated with isopropanol. 2- (2-ethylaminopropyl) -5-pyridinol is obtained, melting at 75-79 °.

20 7021 2 The starting material is prepared as follows:

To a suspension of 1.01 g of 2- (2-aminopropyl) -5-pyridinol hydrochloride in 00 ml of methylene chloride is first added, with stirring at room temperature, 3.3 ml of pyridine and then 1.7 g of acetyl chloride.

After 17 hours, the same volume of saturated aqueous sodium hydrogencarbonate solution is added to the reaction mixture, the organic solution is separated, dried and evaporated. The residual oil is chromatographed on silica gel, eluting with methanol-ethyl acetate to give 5-acetoxy-2- (2-acetylaminopropyl) pyridine, which has lines at 1578 and 1658 cm in the IR spectrum. It is alcoholized as follows: A solution of 2 + + 0 mg of the latter compound in 5 ml of anhydrous ethanol containing 7.5 mg of anhydrous potassium carbonate is refluxed for 5 hours. 2- (2-Acetylaminopropyl) -5-pyridinol is obtained, which is used without further purification.

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. 2- (2-Methylaminopropyl) -5-pyridinol dihydrochloride with peaks at 165, 151, 109 and 58 m / e in the mass spectrum is obtained.

The starting material is prepared as follows:

A 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 hydrogencarbonate solution is stirred for one hour at room temperature. The organic phase is separated, dried and evaporated. The residue is recrystallized from diethyl ether. Dibenzoyl-2- (2-aminopropyl) -5-pyridinol is obtained, melting 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 a slurry of 36 mg of sodium hydride in 1 ml of dimethylformamide. The mixture is heated for 15 minutes, allowed to cool for one hour at room temperature and then cooled to 0 °. The mixture is diluted with 1 ml of toluene and 0.36 g of methyl iodide is added rapidly. The reaction mixture is stirred for one hour at room temperature and then 20 ml of water are added. It is extracted twice with 20 ml of diethyl ether and the extracts are evaporated.

7021 2

An oily dibenzoyl-2- (2-methylaminopropyl) -5-pyridinol is obtained which has a band at 31-8 ppm in the NMR spectrum.

0.15 g of the latter compound can be partially alcoholized in 1 ml of anhydrous methanol in the presence of 0.15 mg of potassium carbonate with stirring for 12 hours at room temperature to give 2- (N-benzoyl-2-methylaminopropyl) -5-pyridinol. This can replace the above-mentioned dibenzoyl starting material in acid hydrolysis.

In a similar manner, a mixture of 0.1 g of dibenzoyl-2- (2-isopropylaminopropyl) -5-pyridinol and 10 ml of 5N hydrochloric acid is refluxed for three days, cooled, filtered, evaporated and the residue is triturated with acetone. 2- (2-Isopropylaminopropyl) -5-pyridinol dihydrochloride is obtained, melting at 199-20 ° C. The product is identical to that obtained in Examples 1, 3 and 8.

Example 16

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

The starting material is prepared as follows:

To 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 hydrogencarbonate solution is added, with stirring at room temperature, 1.0 g of benzyloxycarbonyl chloride. After 12 hours, the organic phase is separated, dried, evaporated and the residue is recrystallized from diethyl ether-hexane. Bis-carbobenzyloxy-2- (2-aminopropyl) -5-pyridinol is obtained, melting at 63-65 °.

A solution of 0.2 g of the latter compound in 2 ml of dimethylformamide is added to a slurry of 36 mg of sodium hydride in 1.5 ml of dimethylformamide and the mixture is heated at 55 ° for one hour. The mixture is kept at 25 [deg.] C. for one hour, cooled to 0 [deg.] C., diluted with 1 ml of toluene and 0.36 g of methyl iodide are added. The mixture is stirred for 12 hours at room temperature and then 10 ml of disodium phosphate buffer are added. The aqueous phase is extracted twice with 20 ml of diethyl ether, the extract is washed with water, dried and evaporated. Bis-7021 2 carbobenzyloxy-2- (2-methylaminopropyl) -5-pyridinol and 2- (N-carbobenzyloxy-2-methylaminopropyl) -5-pyridinol are obtained in approximately the same amount both. This mixture is dissolved in ethyl acetate, the solution is extracted with 1N aqueous sodium hydroxide solution and the aqueous phase is separated. The pH is adjusted to 8 with monosodium phosphate buffer. The mixture is extracted with ethyl acetate, the extract is dried and evaporated. 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 ethanol saturated with anhydrous hydrogen chloride and 0.0 g of palladium-on-carbon catalyst is hydrogenated for 18 hours at room temperature. , and at atmospheric pressure. The mixture is filtered, the residue is washed with ethanol-hydrogen chloride and the filtrate is evaporated. 2- (2-methylaminopropyl) -5-pyridinol dihydrochloride identical to the products of Examples 15 and 16 is obtained.

Claims (1)

? · 3 · · '· ··: · .. Claim: 7021 2 Analogous process for the preparation of new therapeutically active secondary 2-aminoalkyl-5-pyridinols of the general formula 1 and their acid addition salts and optically active antlododle H \ A Il \ (I), \ H. -NH-R. m 2m 1 In the formula CH represents a straight or branched alkylene group having 2 to 1 carbon atoms and a straight or branched alkyl group having 1 to 7 carbon atoms, an alkenyl group having 2 to 7 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms, characterized in that a) to the compound of general formula III XV \ ii ΐ (m), V \ h2x if X represents an alkali metal atom or an alkaline earth metal halogen group is added a compound of general formula IV * "Λ <IV) and a product of general formula I is liberated from the metal salt obtained, or b) in a compound of general formula V xi \ ASJ r <V> »NK \ H -Ä-R m 2m I in which each of the symbols Xj and X? represents hydrogen or an acyl radical of an aliphatic or aromatic carboxylic acid or sulfonic acid such that 2H 7021 2 at least one of these symbols represents an acyl radical, the acyl radical X 1 and / or x 2 is replaced by hydrogen by solvolysis or hydrogenation, or c) in general Schiff's base of formula VI or Via H0 \ / \ |] I (VI), \ tr C H,. - N-R. m 2m-l 1 or • · Il I ^ \ H2m'N R'i (in which formulas Re has only one hydrogen atom less than R, is reduced or d) primary amine of general formula VII HOx /% l] j (VII) N / XC H -NH_ m 2 m 2 is condensed with a reactive ester of the alcohol R 1 -OH in the presence of a strong base or e) an amide corresponding to an amine of general formula I having an oxygen atom in place of two hydrogen atoms adjacent to the secondary amino group is reduced and obtained is converted to another compound of the invention if desired and / or the resulting base is converted to an acid addition salt if desired or the resulting salt is converted to a free base or another acid addition salt and / or the resulting mixture of isomers or racemates is separated into individual isomers or racemates if desired and / or the resulting racemate is separated . 25 Patent claims: 7021 2 Analogs of the invention for the preparation of therapeutically active 2-aminoalkyl-5-pyridinolers according to the formula I, the same addition additions and optically active antipoders HO · ν \ / ^ Il Ϊ (I). V C H, -NH-R. m 2m 1 i vilken formel CH betecnar en rak eller grenad alkylengrupp med 2-U m 2m kolatomer och R , kännetecknat därav, att a) vid en förening med den allmänna formuleln III X0 \ Γ. j (III), V NCH2X and an X-bonded alkali metal or alkali metal halide group, derived from the compounds of formula IV CH = NR, (IV) m-1 2m-2 1 and products of the compounds of formula I in the case of a metal salt, or b) i en förening med den allmänna formuleln V Xl ° \ 5 i? m, V ”Nc H -Ä-R m 2m 1 i vilken vardera av symbolerna och X ^ betecknar väte eller en acylradical av en aliphatisk ell aromatiak carboxylylra ell sulfonosrara, varvid ät-minstone den ena avea deasa aymboler betecknar en acylradical, acylradicalen