CS235347B2 - Method of new aminocompounds production - Google Patents

Description

(54) A method for producing new amino compounds

The present invention relates to a process for the production of novel chemical compounds having an untlhiutamine effect; also mentioned are the intermediates used in their manufacture and the pharmaceutical compositions containing them and used in medicine.

U.S. Patent No. 2,567,245 discloses a family of aliphatic amine-containing pyridyl amines having an antihistamine effect, and specifically discloses 3- (p-bromophenyl) -3- (2-pyridyl) -N, N-dimethylpropylamine and 3- (p-chlorophenyl) -3- (2-pyridyl) -N, N-dimethylpropylamine, hereinafter referred to by their trivial names brompheniramine and chlorpheniramine.

U.S. Patent No. 2,717,023 discloses a class of pyridylpropenylamines with antihistamine activity, the most prominent being a compound called (E) -1- (4-methylleuyxi-1- (2-pyridyl) -3-pyrrolidinono-1-propene), which is disclosed herein Tripolidine has achieved widespread clinical use and is one of the most effective antihistaminic agents available.

Tripolidine is known to be metabolised in humans to (E) -1- (4-carboxyphenyl) -1- (2-pyridyl) -3-pyrrolidino-1-propene which has little or no antihistamine effect.

The antihistaminic agents currently used, including diphenylhydramine, phentramines, pyrilamine, promethazine and triprolidine, generally have the significant disadvantage that they all have a sedative effect or cause drowsiness in some patients.

A new class of compounds having antihistamine activity has now been discovered.

The present invention provides a process for the preparation of compounds of formula (1)

R 1 represents a bivalent aliphatic hydrocarbon group having 1 to 7 carbon atoms or a single bond,

R ₂ and R, which are identical or different, each denote hydrogen, alkyl having 1-4 carbon atoms or form together with the Nitrogen heterocyklicbý ring containing 4-6 members in floe hu

R1 is hydrogen, halogen, hydroxy, cyano, C1-C4 acyloxy, C1-C4 alkoxy or C1-C4 alkyl optionally substituted by 1 to 3 halogen atoms,

X is --N or --CH2 a

A and B are hydrogen or

CA-CB represents a group --C CC or salts, esters or amides thereof.

Among the compounds of formula I, compounds of formula 11 are preferred

R1 to R1, X, A and B are as defined for formula I, or salts, esters or amides thereof.

R 1 may be a straight or branched chain saturated or unsaturated hydrocarbon group or a single bond. Preferably R 1 contains at most one double or triple bond. R preferably represents a group of the formula ⁿ * ^ ^{e CE3} -4 ůlslo 0-7 or a group of formula _{(CH2) a} CH "CH (CH _{2) b»} where a and b are independently 0 if 5 »sum of a and b does not exceed the fifth

Further preferred groups of compounds of formula 1 are those of formula IIIa

^R 4A (IIIa) or Formula IIIb

wherein is a group of formula (CHg) 2, wherein p is an integer from 1 to 7 or a group of formula (CHg) aCH = CH (CHg) _b , wherein a and b are independently 0 to 5 and the sum of a and b does not exceed 5,

R g and R p, which are the same or different, denote hydrogen, lower alkyl of 1 to 4 carbon atoms, or together with nitrogen form a nitrogen-containing heterocyclic ring of 4 to 6 ring members, such as pyrrolidino, piperidino or morpholino and

_And R ^ represents hydrogen or halogen, such as bromo or chloro, lower alkyl having 1 to 4 carbon atoms or lower alkoxy having 1 to 4 carbon atoms, or salts, esters or amides.

Suitably n is 0 to 3 and preferably n is 2. Suitably the sum of a and b does not exceed 2, preferably both a and b being 0.

Suitably, R 8 and R 8 are the same or different and are each methyl or ethyl or together with the nitrogen atom to which they are attached a four to six membered heterocyclic ring, preferably a saturated heterocyclic ring such as pyrrolidine, piperidine or morpholine. Preferably, NR 8 R 6 is pyrrolidino or dimethylamino.

Suitably R @ 1 represents hydrogen, halogen, C1 -C4 alkyl, C1 -C1 alkoxy or trifluoromethyl. Particularly preferably R @ 1 represents hydrogen, methyl, ethyl, trifluoromethyl, aethoxy, bromine, chlorine or fluorine. Preferably R @ 1 denotes methyl, trifluoroethyl, aethoxy, bromine or chlorine. Most preferably, R 1 is methyl.

Preferably, X is a group of formula - B '.

A preferred group of compounds of formula I is represented by formula IV

R 1 and R 2 are as defined above or are salts, esters or amides thereof. Among the compounds of formula (IV), those in which R @ 1 is a single bond (i.e. η ηηδδ 0) are particularly preferred, --CH.dbd.CH-- or --CH2 CH2 -, NR @ 8 R @ 6 is pyrrolidino and R @ 4 is methyl or trifluoromethyl.

Another preferred group of compounds of Formula 1 are compounds of Formula V

where

R1 to R1 are as defined above, or salts, esters or amides thereof. Among the compounds of formula (V), those in which R @ 1 represents a single bond, a group of the formula --CH.dbd.CH-- or --CH.sub.2 CH.sub.2 -, are particularly preferred,

NR 6 R 6 represents dimethylamino and R 6 represents chlorine or bromine.

The amides of the compounds of formula (I) included within the scope of the present invention are amides usually formed from carboxylic acids. Particularly preferred are amides formed from ammonia, primary amides or amino acids such as glycine.

Solvates of the compounds of formula I are also included in the scope of the invention. Preferred solvates include hydrates and C 1 -C 4 alkanolates.

When the compounds of formula I contain a double bond in the side chain terminated by the -NRgRp group, for example, compounds of formula IV, the cell exists in either the trans-isomeric form or forms (relative to the X-containing ring). The compounds of formula (IV) are depicted in the trans-configuration, and these are isomers which in particular have a suitable antihistamine action. Compounds with a cis configuration are particularly useful as intermediates for the production of trans-isomers. The invention also relates to mixtures of isomers. When R ₁ in the -R 5 O 8 H substituent contains a double bond, there are additional isomers of the compounds of formula (I). When the -R 3 COgH group contains a double bond, the preferred isomers are those in. wherein the carboxyl group is in the trans-configuration with respect to the aromatic ring.

Esters and amides of compounds of formula I having an antihistamine activity may also be useful as intermediates for the preparation of carboxy compounds of formula I. Suitable esters include conventional ester groups known to be useful for protecting carboxy groups such as alkyl esters and alkyl esters. The alkyl group has a straight or branched chain and is optionally substituted by halogen. C 1 -C 4 alkyl esters are particularly preferred.

Salts of the compounds of formula (I) may be acid addition salts or salts formed on a carboxylic acid group. Addition salts and acids are preferred, but salts formed on the carboxylic acid group may be particularly suitable for the production of the corresponding carboxy compounds. Preferred are pharmaceutically acceptable eolls.

If the salts of the compounds of formula (I) are to be used in medicine, they should be both pharmacologically and pharmaceutically acceptable. However, not only pharmaceutically acceptable salts can be conventionally used to produce the free active compounds or pharmaceutically acceptable salts thereof, and such eolls are not excluded from the scope of the invention. Pharmacologically and pharmaceutically acceptable acid addition salts include those made from the following acids, but are not exhaustive: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, salicylic acid, p-toluenesulfonic acid, tartaric acid, citric acid , methanesulfonic acid, formic acid, malonic acid, isothionic acid, succinic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. Also, pharmaceutically acceptable salts can be prepared as alkali metal or alkaline earth metal salts, such as sodium, potassium or calcium salts formed on the carboxy group.

Preferred compounds of formula I include:

(E) -3- [6- / 3-Pyrrolidino-1- (4-tolyl) prop-1E-enyl] -2-pyridyl] acrylic acid

3- [6- / 3-pyrrolidino-1- (4-tolyl) prop-, E-enyl] -2-pyridyl] propionic acid, (E) -3- [6- / 3-dimethylamino-1- (4) (E) -3- [6- / 3-pyrrolidino-1- (4-trifluoromethyl-phenyl) -prop-1E-phenyl] -2-pyridyl-tolyl) -prop-1E-enyl / -2-pyridyl] -acrylic acid (E) -3- {6- (3-pyrrolidino-1- (4-methoxyphenyl) prop-1E-enyl) -: 2-pyrridyl] acrylic acid, (E) -3- [6- / 1-phenyl-3-pyrrolidinoprop-1-E-enyl / -2-pyridyl] acrylic acid, (E) -3- [6- / 1- (4-chlorophenyl) -3-pyrrolidinoprop-1E-enyl] -2 6- (3-pyrrolidino-1- (4-tolyl) prop-1E-enyl) pyridine-2-carboxylic acid, (E) -3- [3-pyrrolidino-, - (4-tolyl) -pyridyl] acrylic acid (E) -3-? 3-pyrrolidino-1- (4-tolyl) prop-1-enyl} cinnamic acid, (E) -3-? (E) -3-pyrrolidino- (E) -3-E) -3-dimethylamino-1- (4-tolyl) prop-1-enyl] cinnamic acid, 1- (4-methoxyphenyl) prop -, - enyl] cinnamic acid, (E) - 3- [3- (3-pyrrolidino-1- (4-tolyldprop-1-enyl) -phenyl} propionic acid), 6- [3-dimethylamino-1- (4-tolyl) propyl-2-pyridylcarboxyloyo] u acid,

6- [1- (4-chlorophenyl) -3-dimethylaminopropyl] -2-pyridylcarboxylic acid,

6- [1- (4-chlorophenyl) -3-dimethylaminopropyl] -2-pyridylacrylic acid, or salts, esters or amides thereof.

Pharmacokinetic studies comparing the relative distribution of one of the compounds of the invention and triprolidine in brain and plasma show that, unlike triprolidine, this compound (Compound A - see examples) is difficult to penetrate into rodent brains.

Accordingly, the present invention provides a process for the preparation of a compound of formula (I), which process comprises a compound of formula (X)

where

X 1, H 2, R 1 and R 2 are as defined above and

R y is hydrogen or C 1 -C 4 acyl, or an ester or amide thereof;

RyOH, where

Ry is as defined above, then optionally converting it with formula (1) by a method of formula (XII) well-known to those skilled in the art of formula (I) into another compound by, for example, compounding.

where

X and R ₁ to R have the abovementioned meaning and

CA-CB means a double bond, isomerizes, one or more double bonds are reduced or the ester group is de-esterified.

The cleavage of the compound of formula RyOH from the compounds of formula X is usually carried out in the presence of a strong mineral acid, for example concentrated sulfuric acid, at an elevated temperature, for example between 100 and 200 ° C, suitably 125 to 150 ° C.

Compounds of formula X may be prepared by reacting compounds of formula XXX

R ₄ (XXX) where

X and R8, R1 and R4 are as defined above, with a compound of formula

CH = CHCO;

13 where

R ₃ is an ester or amido group, and carbon dioxide. This reaction is usually carried out in the presence of a catalyst consisting of palladium acetate, triarylphosphine and in the presence of a tertiary amine, a commonly aqueous solution of a tertiary amine, such as N-ethylmorpholine. The compound of formula XXX is usually prepared by reacting a compound of formula XVIII (R ₉ ) ₃ P ⁺ (CH ₂ ) _d CO ₂ R ₆ Hal - or (R ₁₀ ) ₂ PO (CH ₂ ) _d CO ₂ R ₆ (XVIII) where'

Hal is halogen, especially chlorine or bromine,

R1 denotes alkyl of 1 to 4 carbon atoms or phenyl,

R ₁₀ is C 1 -C 4 alkoxy,

R 8 represents an acid, ester or amide group and d is 1 to 6, with an alkyl metal compound such as butyllithium and a reaction with a compound of formula XXI

(XXI) where

R _2, R and R have the meanings given výěe.

The reaction is conveniently carried out at a low temperature, for example between -90 and -30 ° C, usually between -70 and -40 ° C, in an inert solvent such as toluene and under an inert atmosphere.

A compound of formula X can also be prepared by reacting a compound of formula XXII

CHO

CH 2 CH 2 NR 2 R 3 (XXII) wherein

X, Rg, Rj, R ^ and Ry are as defined above, β malonic acid. This reaction is usually carried out in pyridine in the presence of a base, for example piperidine, at an elevated temperature, for example between 50 and 100 ° C. Compounds of formula XXII can be prepared by reacting 2-bromo-6- (1,3-dioxolan-2-yl) benzene with a compound of formula XXI as defined above and then, if necessary, acylating.

For example, 2-Boom-6- (1,3-dioxolan-2-yl) pyridine is conveniently mixed with butyllithium in an inert solvent such as toluene at a low temperature, for example between -80 and -40 ° C, typically between -60 and -70 ° C, under an inert atmosphere, such as nitrogen, before the compound of formula XXI is added. The reaction is usually carried out in an inert solvent such as toluene at a low temperature, for example between -80 and -40 ° C, suitably between -70 and -60 ° C under an inert atmosphere, usually under nitrogen.

The isomerization of the compound of formula XII is conveniently carried out in the presence of an excess of one molar equivalent of a strong acid, suitably a strong mineral acid, for example sulfuric acid, at an elevated temperature, for example between 50 and 160 ° C, usually between 125 and 150 ° C.

The compounds of formula (XII) may be prepared as by-products in the preparation of both compounds of formula (I) and may be obtained from the reaction mixture by conventional separation techniques, for example chromatography, or by utilizing different solubilities of the two isomers in a suitable solvent. For example, it has been found that when a compound of formula (IV) is to be prepared in the free acid form, it is more common to produce the corresponding ester and then saponify it, for example with an alkali metal hydroxide such as sodium hydroxide in a C 1 -C 4 alkanol such as ethanol, to obtain the acid.

The reduction of one or two double bonds, i.e. reduction of the double bond terminating at the -NR 8 R 6 group or reduction of the double bond in the carboxyl side chain, can conveniently be carried out by hydrogenation in the presence of a transition metal catalyst such as platinum on activated carbon. The preparation of esters or amides from the corresponding carboxylic acid and vice versa can be accomplished by methods well known to those skilled in the art.

The starting material of formula (X) has not yet been described and constitutes another important feature of the invention.

The compounds of the present invention can be used for the same indications as triprolidine, namely, symptoms that reduce nasal congestion due to colds and allergic rhinitis, and to control symptoms of allergic conditions, including nasal allergy, persistent rhinitis, urticaria, angioneurotic edema, allergic conjunctivitis, food allergy , drug and serum reactions, insect bites and insect bites, and responses that remove sensitivity.

The compounds may also be used under conditions appropriate to alleviate the effects of the worm, including allergic dermatoses, neurodermatides, anogenital pruritus and pruritus of indeterminate origin, as a result of eczema and for special causes such as chickenpox, photoaensitivity and sunburn. The present invention therefore relates

The present invention also relates to a method of counteracting the internally released hietamine by administering an effective amount of a compound of formula I. Some of the compounds of the present invention have been found to be substantially non-sedative and have little they have no or no antichalergic effects. The amount of active compound required for use under the above conditions varies with the compound selected, the route of administration, the conditions and the mammal being treated and ultimately controlled by the physician. A suitable oral dose of the active compound for mammals is in the range of 0.003 to 1.0 _; mg per kilogram of body weight per day, preferably from 0.04 to 0.24 mg / kg. For example, a typical human dose of Compound A (see Example 1 and Table 1 below) is 0.12 mg / kg body weight, and day.

The desired daily dose is preferably administered in one to six sub-doses administered at appropriate intervals throughout the day as desired. When three sub-doses of a compound of formula I are used, each will be in the range of 0.014 to 0.08 mg / kg body weight, for example a typical additional dose of such a compound for human recipient is between 1 and 20 mg, e.g. mg.

While it is possible for the compound of Formula 1 to be administered alone as a raw chemical, it is preferable to administer the compound of Formula I as a pharmaceutical composition. The present invention also relates to pharmaceutical compositions, both for veterinary and for human medical purposes, which consist of a compound of formula 1 together with one or more pharmaceutically acceptable carriers thereof and optionally some other therapeutic ingredients. For example, the active compound may be formulated with a sympathomimetic agent such as a decongestant pseudoephedrine, a cough agent such as codeine, an analgesic, an anti-inflammatory, an anti-magnesium or an expectroant. The carrier or carriers must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

The compositions include those suitable for oral, rectal, topical, nasal, ocular, or parenteral (including subcutaneous, intramuscular and intravenous) administration.

The compositions may conveniently be administered in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include contacting the active compound with a carrier which constitutes one or more accessory ingredients. Generally, the compositions are prepared by contacting the active ingredient uniformly and thoroughly with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, adjusting the product to the desired compositions.

Compositions of the present invention suitable for oral administration may be presented as discrete units, such as capsules, cachets, tablets or capsules, each containing a predetermined amount of the active compound (defined herein as a compound of formula 1), such as a powder or granules, or suspensions in an aqueous or non-aqueous liquid such as a syrup, elixir, emulsion or beverage.

Tablets may be made by compression or melt, optionally with one or more accessory ingredients. Compressed tablets may be administered by compressing in a suitable machine the active ingredient in free form as a powder or granules, optionally mixed with a binder, disintegrant, lubricant, inert diluent, surfactant or dispersant. Molded tablets, consisting of a mixture of the powdered active compound with a suitable carrier, can be made by melting in a suitable machine.

A syrup may be made by adding the active compound to a concentrated aqueous solution of a sugar, for example a saccharide, to which a minor component or components may also be added. Such minor component (s) may include flavoring agents, sugar crystallization retardants, means to increase the solubility of some other component, such as a polyhydric alcohol such as glycerol or sorbitol, or a suitable preservative.

Compositions for rectal administration may be presented as a suppository with a conventional carrier such as cocoa butter or hydrogenated fats or hydrogenated carboxylic acids.

Compositions suitable for parenteral administration usually include sterile aqueous compositions of the active compound which are preferably isotonic with the blood of the recipient.

Nasal spray formulations include purified aqueous solutions of the active compound with preservatives and isotonic additives. Such compositions are adjusted to pH and isotonic state compatible with the nasal mucous membranes.

Ophthalmic formulations are made by a method similar to nasal sprays except that the pH and isotonic factors are adjusted to eye-fit values.

Topical formulations comprise the active ingredient dissolved or suspended in one or more of the formulations such as mineral oil, petroleum, polyhydric alcohols or other bases used for topical pharmaceutical formulations. The addition of other co-additives listed below may be desirable.

In addition to the above ingredients, the compositions of the invention may further comprise one or more ingredients selected from diluents, buffers, flavoring agents, binders, disintegrants, surfactants, thickeners, lubricants, preservatives (including antioxidants) and the like.

The present invention also relates to the use of compounds of formula I in medicine.

The following examples are intended to illustrate the invention and are not intended to limit the invention. All temperatures are in degrees Celsius.

Example 1

Process for the preparation of (E) -3- [6- (3-pyrrolidino-1- (4-tolyl) prop-1E-enyl) -2-pyrldyl2 acrylic acid

To a solution of 52.14 g of 3,6-dibromopyridine in toluene cooled to -50 ° e, 130 ml of a 1.7011 solution of n-butyllithium in hexane are added and stirred under nitrogen. while temperature was kept at -50 DEG., After stirring for two hours at this temperature -50 ⁰ at the same temperature a solution of 3-pyrrolidino-1- (4-tolyl) -propan-1-one, prepared from 50.72 g of the corresponding hydrochloride and azeotropically dried in 150 ml of toluene. The reaction mixture is stirred at -50 ° for 1.5 hours, then allowed to warm to -30 ° and held at this temperature for 1.5 hours. 300 ml of 2N hydrochloric acid and then 800 ml of water are added to the mixture. The separated aqueous layer was washed with ether and basified with 2N sodium hydroxide solution. The solid was filtered, dried and crystallized twice to give 43.0 g of 1- (4-tolyl) -1-C2- (6-bromo) pyridyl] -3-pyrrolidino-1-propanol, m.p. 124 °.

g of the above carbinol, 12.61 g of ethyl acrylate, 0.518 g of palladium acetate,

1) 55 g of triphenylphosphine and 140 ml of N-ethylmorpholine are mixed and heated to 145 ⁰ with stirring for 5 hours. After cooling, the reaction mixture is poured onto 800 ml of water and the product is extracted with white spirit (b.p. 60-80 °). The extracts were washed with water, dried and evaporated under reduced pressure. Ethyl [(E) -3- [6- [1- (4-tolyl) -1-hydroxy-3-pyrrolidino] -2-pyridyl] acrylate] is obtained as a red gum of 41.6 g.

25.39 g of the above-mentioned carbonol ester are mixed with 50 ml of 90% by weight sulfuric acid and the mixture is heated to 135 ° with stirring for 3 hours. The cooled mixture was then poured into 760 ml of ethanol and the solution was heated at reflux for 1.5 hours. The solution is then evaporated to approximately one third of its volume under reduced pressure and then poured onto 1 liter of ice. The solution was neutralized with a small excess of aqueous ammonia under cooling and the product extracted with ether. The extracts were washed with water, dried and evaporated under reduced pressure. This gives 21.1 g of a red solid which consists of a mixture of streolsomers (E,

E: E, Z = 80: 20) ethyl [1- (6-E 3 -pyrrolldino-1- (4-tolyl) prop-1E, 2-enyl-2-pyridyl) acrylate].

g of the above ester mixture is dissolved in 250 ml of ethanol and 60 ml of 1N sodium hydroxide solution are added. The alcohol is then removed by rotary evaporation under reduced pressure. The residue was neutralized by the addition of 60 ml of 1N aqueous sulfuric acid and the mixture was then evaporated to dryness under reduced pressure.

The residue is extracted three times with 75 ml of hot isopropanol each and the combined extracts are cooled. The resulting crystalline solid was filtered off to give 4.57 g of the title compound. Another 0.625 g portion was obtained by evaporation of the mother liquors. The combined fractions were crystallized from Isopropanol.

Example 2

(E) -3- [6- / 3-Pyrrolidino-1- (4-tolyl) prop-1E-enyl] -2-pyridyl-acrylic acid (Compound A) ml of a 1.65 M solution of butyllithium in hexane was added under nitrogen to a stirred suspension of 19.5 g of 2,6-dibromopyridine in 200 ml of dry ether at -50 °. After 0.75 h a solution of 10 g of 4-tolunitrile in 50 ml of ether was added and stirring was continued at -50 ° h. The mixture was warmed to -30 ⁰ and treated with 200 ml of 2M hydrochloric acid. The precipitated solid was collected, washed with water and recrystallized from aqueous ethanol. The resulting 2-bromo-6- (4-toluoyl) pyridine, weighing 12.2 g, forms colorless needles with a melting point of 97-98 °.

A mixture of 200 g of 2-bromo-6- (4-toluoyl) pyridine, 85 ml of ethylene glycol, 32 g of p-toluenesulfonic acid and 11 ml of benzene is boiled under a Dean-Stark trap until water is separated, which proceeds very slowly (about 20 mL is collected in 16 hours).

The cooled solution was poured onto ice and water containing 100 g of sodium carbonate with stirring. The benzene layer was separated, washed with water, dried over sodium sulfate and evaporated to about 500 ml. Cooling gave 170 g of 2- (6-bromo-2-pyridyl) -2- (4-. Tolyl) -1,3-dioxane (compound 1), m.p. , 4 °. Dilution with petroleum ether to give a second crop of 34 g of the substance ó, m.p.

A solution of 70 g of the above compound (1) in 800 ml of dry toluene is added dropwise over 5 hours to a stirred solution of 200 ml of 1,611 butyllithium in hexane and 200 ml of toluene at -65 to -72 ° under nitrogen. After an additional 30 minutes at -70 °, 40 ml of dry dimethylformamide are added over 35 minutes. Stirring was continued overnight at -70 to -60 °.

400 ml of 2N hydrochloric acid are then added and the temperature is allowed to rise to about -10 DEG. After another 30 minutes, about 90 mL of 2N ammonia was added to adjust the pH to 7-8. The toluene layer was separated and the aqueous phase extracted with ether. The combined organic layers were washed with water and ice, dried over magnesium sulfate and evaporated under reduced pressure at a temperature below 50 °. The resulting aldehyde, i.e. 2- (6-forayl-2-pyridyl) -2- (4-tolyl) -1,3-dioxolane weighing 63.9 g, crystallized at a temperature maintained at 3 °. The substance has a melting point of 52-63

2.5 g of the aldehyde produced as above are dissolved in 100 ml of 1,2-dimethoxyethane and added to a solution of carbanion phosphonate made of 2 g of triethylphosphonoanetate and 0.22 of sodium hydride in the same solvent. The mixture was stirred for 2 hours, diluted with ether (25 ml) and treated with 2M hydrochloric acid (5 ml). The organic phase was separated, washed with water, dried and evaporated. The resulting oil was dissolved in 20 mL of ethanol containing 3 mL of concentrated hydrochloric acid and 3 mL of water. The mixture was then heated on a steam bath for 10 minutes, diluted with ice water, basified with sodium bicarbonate solution and extracted with ether. Evaporation gave (E -> - 3-E6- (4-toluoyl) -2-pyridyl] acrylate (compound 2), which crystallized from cyclohexane to colorless plates with a melting point of 08-1.1 °. have a weight of 1 g.

ml of a 1.6411 solution of butyllithium in hexane was added to the stirred suspension under nitrogen.

7.2 g of triphenyl-2-pyrrolidinoethylphosphonlumbromide in 75 ml of dry toluene. After 0.5 hours, 4.8 g of compound 2 above was added to 50 ml of toluene. The suspension was initially orange, turned dark purple and then slowly turned yellow over 2 hours with heating to 75 °. The cooled solution was diluted with ether (150 ml) and treated with 8 50 B1 211 hydrochloric acid. The aqueous phase was separated, washed with ether and basified with potassium carbonate under ice-cooling and extracted with ether. The mixture of isomeric esters obtained by evaporation is diluted with 100 ml of ethanol containing 20 ml of 1M sodium hydroxide solution and partially evaporated on a steam bath under reduced pressure for 5 minutes. The remaining aqueous solution was neutralized with 20 ml of 0.5 M sulfuric acid and evaporated to dryness. The solid was washed three times with 50 ml of hot iaopropanol each and the extracts were evaporated until crystallization occurred. (E) -3- [6- / 3-Pyrrolidino-1- (4-tolyl) prop-1E-enyl] -2-pyridyl] acrylic acid (Compound A) has a melting point of 222 ° (2a decomposition).

Example 3

Process for preparing ethyl F (E) -3- 6- / 3-pyrrolidino-1- (4 ^i, tolyl) prop-E-enyl / -2-pyridylJakrylátjoxalátu

A solution of 0.5 g of compound A (from Example 2) in 25 ml of ethanol containing 0.5 ml of sulfuric acid was boiled at reflux for 2.5 hours and rapidly evaporated to a volume of 10 ml under reduced pressure. The solution was treated with ice and excess ammonia solution and extracted with ether. Addition of 0.13 g of oxalic acid in 5 ml of ethanol to a dry ether solution gives a precipitate of the oxalate salt, which crystallizes from ethyl acetate as white prisms, m.p. 155-156 °.

Example

Method for isomerization of ethyl E (E) - [6- (3-pyrrolidino-1- (4-tolyl) prop - 2-enyl) -2-pyridyl] acrylate

13.9 g of the above ester are mixed with 28 ml of 90% by weight sulfuric acid and the mixture is heated to 130 DEG C. with stirring for 3 hours. After cooling, the mixture was poured gradually into 300 ml of ethanol with cooling. The solution is then heated at reflux for 1 hour, then evaporated to approximately one third of its volume under reduced pressure and then poured into excess crushed ice. Aqueous ammonia is then added to liberate the free base. It is extracted with 500 ml of ether. The extract is washed twice with 250 ml of water, 100 ml of brine and dried. Filtration and evaporation under reduced pressure gave 11.9 g (85%) of a red solid which was mixed with 50 ml of acetone / tril. Cooling in a refrigerator gave an almost solid which was filtered off and washed with a soft amount of cold acetone / tril. This material, weighing 7.5 grams, is essentially a numbered E, E-ameramer.

The following compounds can also be produced by the process of the invention:

Isomer E of 3- [6- / 3-pyrrolidino-1- (4-tolyl) -prop-1E-enyl (-2-pyridyl) -propionic acid (Compound B), mp 156-157 °.

(E) -3- [6- / 3-dimethylamino-1- (4-tolyl) prop-1E-enyl] -2-pyridyl] acrylic acid, m.p. 222-225 ° (dec.), acid ( E) -3-t6- / 3-pyrrolidino-1- (4-tolyl) prop-1E-enyl / -2-pyridylJakrylová, mp 220 ⁰ (decomp), (E) -3- [6- / 3-pyrrolidino-1- (4-tolyl) prop-1 E-enyl / -2-pyridylacrylic, m.p. 218-2.9 ^° (dec.),

E isomer of 6-β-pyrrolidino-1- (4-tolyl) prop-1E-enyl} pyridine-2-carboxylic acid, m.p. 200-202 °,

Z isomer of 6- [3-pyrrolidino-1- (4-tolyl) prop-1E-enyl] -pyridine-2-carboxylic acid, m.p. 187-189 °, (E) -3-6- (3-pyrrolidino) acid - (4-trifluoromethylphenyl) prop-1E-enyl) -2-pyridylJakrylová, mp 223-225 ⁰ (dec), (E) -3- £ 6- / 3-pyrrolidino-1- (4-methoxyphenyl) prop 1E-enyl) -2-pyridyl] acrylic acid, mp 231-232 ⁰ (dec), (E) -3- [6_ (1-phenyl-3-pyrrolidinoprop-1E-enyl) -2-pyridyl] 180 DEG-182 DEG (dec.), (E) -3- [6- / 3-pyrrolidino-1- (4-tolyl) prop-1E-enyl] -2-pyridyl] acrylaraide oxalate, m.p. mp 198-199 ⁰ (dec), (E) -3-6- / 1- (4-chlorophenyl) -3-pyrrolidinoprop-1E-enyl / = 2-pyridyl] acrylic acid, m.p. 218-220 °, 3- [6- / 3-pyrrolidino-1- (4-tolyl) prop-1E-enyl] -2-pyridyl] prop-2E-enamidoacetic acid, m.p. 257-258 ⁰ (dec.), acid (E) -3- [3-pyrrolidino-1- (4-tolyl) prop-1-enyl] benzoic acid, m.p. 210-215 ⁰ (dec), (E) -3- / X'E) -3-p yrrolidino-1- (4-tolyl) prop-1-enyl / cinnamic acid, melting point, 90 ^° (dec.), (E) -4- [3-pyrrolidino-1- (4-tolyl) prop-1- phenyl] benzooová, mp 235-240 ⁰ (dec), (Z) - <- [3-pyrrolidone »imidazolidin-1- (4-tolyl) prop-l-enyl] benzoic acid, mp 245-250 ⁰ (dec.), (E) -4-1 (R) -3-pyrrolidino-1- (4-tolyl-1- (4-tolyl) prop-1-enyl] cinnamic acid, m.p. 210-220 ⁰ ( dec), (E) -3 - [(Z) -3-pyrrolidino-1- (4-methoxyphenyl) prop-1-enyl] cinnamic acid, mp 215-220 ⁰ (dec), (E) -3-f (E) -3-pyrrolidino-1- (4-methoxyphenyl) prop-1-enyl] cinnamon, m.p. 220-225 ^° (dec.), (E) -3-Γ (E) - 3-pyrrolidino-1- (4-chlorophenyl) -prop-1-enyl] cinnamon, m.p. 193-195 °, (E) -3- (E) -3-pyrrolidino- (4-chlorophenyl) -prop 193-195 °, (E) -3 - [(E) -3-dimethylamino-1- (4-tolyl) prop-1-enyl] cinnamic acid, m.p. 200-205 ° C, acid (E ) -3-t (Z) -3-dimethylamino-1- (4-tolyl) -prop-1-enyl] cinnamon, m.p. 200-205 °, (E) -3- [3- / 3-pyrrolidino acid] -1- (4-tolyl) prop-1-enyl / phenyl] propioaová, mp 138-140 °, _t (Z) -3-Γ3- / 3-pyrrolidino-1- (4-tolyl) prop-1 (E) -3- [6- / 3-pyrrolidino-1- (4-tolyl) prop-1E-enyl-2-pyridyl acrylic acid, 6-phenyl-phenyl] propionic acid, not isolated in pure form [6- / 3-Pyrrolidino-1- (4-tolyl) prop-1Z-enyl] -2-pyridyl] hex-5E-enoic, m.p. 118-121 °, 6- [3-dimethylamino-1 - ( 4-methalfenyl) propyl] -3-pyridinecarboxylic acid, TLC Rf:

0.34 (silica-silica, methanol),

NMR (80 MHz, CDCl 3): δ 2.10-3.0 (m, 13H) includes 2.30 (s, 3H) and 2.77 (a, 6H),

4.47 (broad m, 1H), 4.6 to 5.2 (broad, replaceable), 6.80 to 8.20 (m, 7H),

Analysis for C 18 H 18 O 2 O 6 O.HgO:

calculated: 68.33% C, 7.65% H, 8.85% N, found: 68.16% C, 7.65% H, 8.82% N, acid 6- [1- (4- chlorophenyl) -3-dimethylaminopropyl] -2-pyridinecarboxylate, i

NMR (80 MHz, CDCl 3) δ 2.30 to 2.70 (m, 2H), 2.85 (s, 6H), overlap over 2.70 to 3.15 (m, 2H), 3.83 (broad, exchangeable), 4.40 (broad t, 1H), 6.90-7.45 (m, 5H),

7.68 (dd, 1 H), 8.13 (d, 1 H),

Analysis for C ^ HH, ^ClNNgOg.HHOg:

calculated: 57.54% C, 6.53% H, 7.89% N, 9.99% Cl, found :: 57.68% C, 6.52% H, 7.86% N, 10.10 % Cl, 6- [1- (4-chlorophenyl) -3-dimethylaminopropyl] -2-pyridinecarboxylic acid,

TLC _Rf: 0.24 (silica gel-methanol), (E) -6- [j- (4-chlorophenyl) -3-dimethyÍaminopropyť] 2-pyrldylakrylové, TLC _Rf: 0.40 (silica gel, methanol)

NMR (80 MHz, CDCl ₃ ) δ 2.40 (s, 6H), overlapping of 2.0 to 3.0 (m, 4H), 3.97. (shin t, 1H), 6.65 to 7.70 (m, 9H), 11.5 (wide s, exchangeable), ethyl [(E) -3- [6- / 3-acetoxy-1- (4) -tolyl) prop-1E-anyl / 2-pyridyl] acrylate] and ethyl [(E) -3- [6- / 3-pyrrolidin-1- (4-tolyl) prop-1E-enyl] -2-pyridyl] acrylate].

Antihistamine effect

A. Antihistamine effect in vitro

Isolate the longitudinal muscle from intact guinea pig ileum (Hartley, male 250-400 g) and place in an organic bath under a foam of 300 mg. After one hour of equilibrium, curves corresponding to the total concentration (JM Van Rossum, Arch. Int. Pharmacodyn, Ther. 143, 299-330, 1963) of histamine are obtained. After washing, the tissues are incubated for 1 hour with the test compound and / or a curve corresponding to the secondary histamine concentration is run, shifts to the right of the curve corresponding to the agonist concentration generated by the antagonists are used to construct Schild plots (O. Arunlákéhapa, and W O. Schild, Br. (J. Pharmacel 14 48-58, 1959). The regression of log (dr-1) to log (B), where dr is an equiactive response in the presence or absence of antagonist and Γ · Β] is the molar concentration of antagonist, allows to determine pA ₂ , i.e. negative log concentration of antagonist. corresponds to the curve 2x right.

Table 1

Results of in vitro determination of antihistamine tests

RjCOQ X NR ₂ ^R 3 »4 pA ₂ compound AND (E) -2-CH-CHCO ₂ H - N CH ₃ 8.6 compound (B) -2-CH ₂ CH ₂ CO ₂ H N NR ₂ ^r 3 CH ₃ 9.2 (E) -2-CH-CH-CO ₂ H N NR ₂ ^r 3 Cl 9.0 (E) -2-CH = CHCO ₂ C ₂ H ₅ N nr ₂ r ₃ CH ₃ 7.7 (E) -2-CH = CHCONH ₂ N NR2R3 CH ₃ 8.49 (E) -2-CH-CHCO ₂ H N I ₂ ^R 3 OCH ₃ 8.94 (E) -2-CH-CHCO ₂ H N nr ₂ r ₃ CP ₃ 10.4 (E) -2-CH ₂ CHCNCH ₂ CO ₂ H N nr ₂ r ₃ CH ₃ 6.9 -2-CO ₂ H CH NR ₂ R ₃ ch ₃ 8, ’ compound C (E) -2-CH-CHCO ₂ H N ch ₃ 8.2 -2-CO ₂ H ch ₃ 8.9 compound D (E) -2-CH-CHCO ₂ H CH nh ₂ y ₃ ch ₃ 8.8

B. Antihietamine effect in vivo

Guinea pigs (Hartley, males weighing 300-350 g) are fasted for 20 hours and then administered orally or intraperitoneally with the test compound. One hour after receiving the dose, guinea pigs are placed on individual basis in transparent plastic chambers that are saturated with histamine, which is continuously replenished in gaseous form as 0.25% histamine from an aerosol inhalation device. In guinea pigs, signs of histamine anaphylaxis (for example, cough, sneezing, severe abdominal movements, cyanosis) are recorded. Under test conditions, control animals collapse on average for 23 seconds. The ED 50 for protection against histamine is calculated with probit analysis. In this EOjq test, at a special dose of 50% of the animals, it is shown that it is completely protected against the action of histamine during the test (1 hour post dose). Complete protection is determined as protection against histamine · symptoms for 6 minutes in an aerosol chamber (approximately ten times the collapse time of control animals):

Table 11

Results of in vivo determination of antihistamine tests. Compound

ED ₅₀ (mg / kg, po)

Tripolidin 5.77

A 0.44

B 0.17

C 1.7

D 0.64

In addition to these results, it has been found that Compound A can have a very long antihietamine effect (e.g. 11 mg / kg p.o. is ED 50 for protection for 24 hours).

23534-7

Example 5

Pharmaceutical preparations

Composition A

Injection

Ingredient Quantity per ampoule

Compound of Formula I 1.0 mg

Water for injections up to 1.0 ml

The finely divided active compound is dissolved in water for injection. The solution is filtered and sterilized in an autoclave.

Composition B

Cípky

Component Quantity per suppository

Compound of Formula I 1.0 mg.

Cocoa butter or suppository base nt

Wecobee up to 2.0 g

Note:

Wecobee is a protected designation, it is ό hydrogenated fatty carboxylic acid.

The finely divided active compound is mixed with the molten suppository base (either cocoa butter or Wecobee base), poured into molds and allowed to cool to obtain the desired suppositories.

Composition C

Syrup

Ingredient Quantity per 5 ml

Compound of Wiped Formula I

Ethanol

Sucrose

Methylparaben

Sodium benzoate

Cherry flavor

Dye

Water, 0 mg 0.3 mg 2.0 mg 0.5 mg 0.5 mg as needed to 5.0 ml

Ethanol, sucrose, sodium banzoate, methylparaben and flavor are mixed in 70% of the total amount of water needed for the batch. The dye and the active compound are dissolved in the remaining water, and then the two solutions are mixed and purified by filtration.

Composition D

Tablets

Quantity tab on tablet

Compound of Formula I Lactose

Pregelatinized maize starch

1.0 mg 110.0 mg

2.5 mg

Composition D

Tablets

Component

Quantity on tablet

Potato starch 12.0 mg

Magnesium stearate 0.5 mg

The active compound is ground finely and intimately mixed with powdered excipients, i.e., lactose, corn starch, potato starch and magnesium stearate. The formulation is then compressed into tablets weighing 126 mg.

Composition E

Capsules

Ingredient Quantity per capsule

Compound of Formula I 1.0 mg

Lactose 440.0 mg

Magnesium stearate 5.0 mg

The finely divided active compound is mixed with powdered excipients, i.e. lactose magnesium stearate, and packaged in gelatin capsules.

Composition F

Tablets

Quantity tab on tablet

Compound of Formula I 1.0 mg Pseudosphedrin hydrochloride 60.0 mg Lactose 62.5 mg Potato starch 14.0 mg Magnesium stearate 1.0 mg Gelatine 2.8 mg

Tablets were prepared from the ingredients by the method described in Example 5D above.

Composition G

Syrup

Component Quantity to 5 ml Compound of formula (X) 1.0 mg Pseudoephedrine hydrochloride 30.0 mg Codeine phosphate 10.0 mg Guaifenesin 100 ALIGN! mg Methylparaben 0.5 mg Sodium benzoate 0.5 mg Flavor by po · tře by Dye as required Glycerol 500 mg Sucrose 2 000 mg cleaned water to 5.0 mg

A syrup is prepared from the ingredients listed above by a method similar to that described in Example 5C above.

Means Η

Nasal spray

Component Quantity per 100.0 ml

Compound of formula (I) Sodium chloride Preservative

Water for injections. -.G

0.8 g 0.5 g to 100.0 ml

The preservative is dissolved in hot, purified water and, after cooling to 25-30 ^° , sodium chloride and a compound of formula I are added. The pH is then adjusted to 5.5 to 6.5 and the volume is made up to a final 100 with purified water. 0 ml.

Composition I Eye solution

Component Quantity per 100,0 ml Compound of Formula I 0,1 β Sodium chloride 0.8 g Preservative 0.5 g Water for injections to 100.0 ml

This composition is prepared in a similar manner to a nasal spray.

Prostředek J

Topical cream

Component Quantity per 100.0 ml

Compound of Formula I 0.1 g

Emulsifying Wax, N.P. 15,0 g

Mineral oil 5.0 g

Claims (12)

SUBJECT OF THE INVENTION A process for the preparation of novel amino compounds of formula (I) wherein:. »Í, R. represents a bivalent aliphatic hydrocarbon group and 1 to 7 carbon atoms or a single bond, and Rj, which is identical or different, each denotes hydrogen ₍ alkyl of 1 to 4 carbon atoms, or four together with nitrogen) a nitrogen-containing heterocyclic ring containing from 4 to 6 ring members; R ^ is hydrogen; halogen, hydroxy, cyano, C 1 -C 4 acyloxy, C 1 -C 4 alkoxy or C 1 -C 4 alkyl optionally substituted with 1 to 3 halogen atoms, X is -N = or -CH = a A and B are hydrogen or CA-CB represents a group of formula -C -CC-, or salts, esters or amides thereof, (X) wherein X, R 1, R 8, R 6 and R 6 are as defined above and R y is hydrogen or C 1 -C 4 acyl, or an ester or amide thereof cleaves a compound of formula R? OH where Γγ is as defined above, and then optionally converting the compound of formula I obtained into another compound of formula or into a salt, ether or amide thereof. 2. A process according to claim 1, wherein the compounds of formula (II) are formed from the above compounds wherein R ₁ to R ₄ , X, A and B are as defined above, or a salt, ester or amide thereof. 3. A process according to claim 1 or 2, starting from compounds of the above formulas to form a compound of the formula wherein R1 is a group of formula (CHg) wherein n is an integer from 0 to 7 or a group of formula (CHg). ) _and CH = CH (CHg) _b , where a and b are independently 0 to 6 and the sum of a and b does not exceed 5. 4. A process according to any one of claims 1 to 3, starting from compounds of the above formulas to form the general formula IIIa (IIIa) wherein: R1 represents a group of formula (CHg) _n , where n is an integer from 1 to 7, or represents a group of formula (CHg) _and CH = CH (CHg) _b m where a and b are independently 0 to 5 and the sum of a and b does not exceed 5 , R 8 and R p, which are the same or different, denote hydrogen, lower alkyl of 1 to 4 carbon atoms or together with nitrogen form a nitrogen-containing heterocyclic ring of 4 to 6 ring members such as pyrrolidino, piperidino or morpholino and R @ 1 represents hydrogen or halogen, such as bromine or chlorine, a lower alkyl group having 1 to 4 carbon atoms or a lower alkoxy group having 1 to 4 carbon atoms, or a salt, ester or amide thereof. 5. A process according to any one of Claims 1 to 4, starting from compounds of the above formulas to form a compound of the formula wherein R @ 1 is a group of formula (CH3) g or --CH.dbd.CH--; and Rolid is methyl, trifluoromethyl, methoxy, bromo or chloro. nin 6. A method according to any one of claims 1 to 3, characterized in that starting from sloučevýěe listed formula to a compound of formula IIIb COOH / ^H / ^R CC 2 / ^X CHgěK O>"3 (IIIb) wherein R1 is a group of formula (CHg) _n wherein n is an integer from 1 to 7, or is a group of formula (CHg) _and CH = CH (CHg) _b wherein a and b are independently 0 to 5 and the sum of a and b does not exceed 5, R 8 and R 8, which are the same or different, denote hydrogen, lower alkyl of 1 to 4 carbon atoms or, together with nitrogen, form a nitrogen-containing 4 to 6-membered heterocyclic ring such as pyrrolidino, piperidino or morpholino and R _4A represents hydrogen or halogen, such as bromine or chlorine, a lower alkyl group having 1 to 4 carbon atoms or a lower alkoxy group having 1 to 4 carbon atoms, or a salt, ester or amide thereof. 7. A process according to any one of Claims 1 to 3 and 6, which comprises starting from the compounds of the above formulas to form a compound of the formula wherein R 1 is a group of formula (CH ₂ ) ₂ or -CH = CH- -NR 8 R 6 is pyrrolidino or dimethylamino and R 6 is methyl, trifluoromethyl, methoxy, bromo or chloro. 8. A process according to any one of claims 1 to 7, wherein the compound of the above formulas is formed to form a compound of formula IV wherein: R1 to R1 are as defined above, or a salt, ester or amide thereof. 9. The process of claim 8, wherein the compound of formula IV is a compound of formula IV wherein R 1 is a single bond, -CH = CH- or -CHgCHg-, the -NR 9 R 3 is pyrrolidino and R 1 represents methyl or trifluoromethyl. 10. A process according to any one of claims 1 to 9, starting from compounds of the above formulas to form a compound of the formula wherein CA-CB is a double bond and the -CHgNRgR4 group is in the trans position relative to the X-containing ring. . 11. A process according to any one of Claims 1 to 7, which comprises starting from a combination of the above formulas to form a compound of formula V <Ch-ch ₂ -ch ₂ n / ^R 2 (V) ^R 4 wherein: R1 to R1 are as defined above, or a salt, ester or amide thereof. 12. The process of claim 11, wherein the compound of formula (V) is a compound of formula (V) wherein R 1 is a single bond, -CH = CH- or -CHgCHg-, the -NR 8 R 3 is dimethylamino; R @ 1 represents chlorine or bromine.