CS235349B2 - Method of new aminocompounds production - Google Patents

Description

The present invention relates to a process for the production of novel chemical compounds having an antihistamine effect. Also disclosed herein are new intermediates used in their manufacture and pharmaceutical compositions containing them and used in medicine.

U.S. Pat. No. 2,567,245 discloses a family of aliphatic amine-containing pyridyl amines having an antihistamine effect, and particularly 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 a β antihistamine action, the most prominent being a compound called (E) -1- (4-methylphenyl) -1- (2-pyridyl) -3-pyrrolidino-1-propene, which is referred to herein by its trivial name tripolidine. 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, pheniramines, 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 (I)

where

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

R ₂ and R 3, which are identical or different, denote! in each case hydrogen, alkyl of 1 to 4 carbon atoms or together with nitrogen form a nitrogen-containing heterocyclic ring containing 4 to 6 ring members,

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

X is -N = or -CH 2 and a

A and B are hydrogen or

CA-CB represents a group of the formula -C = C-, or salts, esters or amides thereof.

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

(II) where

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

R | it 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. Preferably, R is a group of formula (CH ₂ ) _n where n is an integer from 0 to 7 or a group of formula (ΟΗ ₂ ) _β <3Η = ΟΗ (ΟΗ ₂ ) &, where a and b are independently 0 to 5 and the sum of a and b not exceeding.

Other preferred groups of compounds of formula I are those of formula IIIa

or of formula (111b)

where

R 1 represents a group of formula (CH ₂ ) _n,.

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

R ₂ and R 3, which are the same or different, denote hydrogen, lower alkyl of 1 to 4 carbon atoms, or together with nitrogen form a nitrogen-containing 4-6-membered heteroeyl ring, such as pyrrolidino, piperidino or morpholino and

R @ 4 is hydrogen or halogen, such as bromine or chlorine, lower alkyl of 1 to 4 carbon atoms or lower alkoxy of 1 to 4 carbon atoms, or salts, esters and amides thereof.

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 ₂ and R 6 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 heteroeyl ring, such as pyrrolidine, piperidine or morpholine. NR ₂ ^R 3 'is preferably pyrrolidino or dimethylamino.

Suitably R @ 1 is hydrogen, halogen, C1 -C4 alkyl, C1 -C4 alkoxy or trifluoromethyl. Particularly preferably R @ 1 is hydrogen, methyl, ethyl, trifluoromethyl, methoxy, bromochloro or fluoro. Preferably R @ 1 denotes methyl, trifluoromethyl, methoxy, bromine and chlorine. Most preferably, R 1 is methyl.

Preferably X is --N =.

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

where

R1 to R1 are as defined above or are salts, esters or amides thereof. Of the compounds of formula IV, those in which R1 is a single bond (i.e., n is 0), -CH = CH or - are particularly preferred. CH 8 CH 8 -, NR 8 R 6 is pyrrolidino and R 6 is methyl or trifluoromethyl.

Another preferred group of compounds of formula I 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 is a single bond, --CH.dbd.CH-- or --CH.sub.2 CH.sub.3 -, HR @ 8 R @ 6 is dimethylamino and R @ 1 is chloro or bromo are particularly preferred.

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

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

When compounds of formula I contain a double bond in the side chain terminated by -NRgRp, for example, compounds of formula IV, the cells exist in cis- or trans-isomeric form or forms (in relation to the X-containing ring). The compounds of formula (IV) are depicted in the trans-configuration, and these are isomers which primarily have a suitable antihistamine effect. Compounds with a cis configuration are particularly useful as intermediates for the production of trans-isomers. The present invention also relates to mixtures of isomers.

When R 1 in the -R 3 COgH substituent contains a double bond, there are additional isomers of the compound of formula (I). Both isomers and a mixture of isomers of these compounds are within the scope of this invention. When the -R 3 COgH group contains a double bond, preferred isomers are those in which 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 effect 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 the protection of carboxy groups, such as alkyl esters of 1. 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 either acid addition salts or salts formed on the carboxylic acid group. Acid addition salts are preferred, but salts formed on the carboxylic acid group may be particularly suitable for the production of the corresponding carboxy compounds. Pharmaceutically acceptable salts are preferred.

If the salts of the compounds of formula (I) are to be used in medicine, they would be both pharmacologically and pharmaceutically acceptable. However, for the manufacture of free active compounds, or a pharmaceutically acceptable salt thereof, and such salts are not excluded from the scope of the invention. Pharmacologically and pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, ¹ 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 of 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-1E-enyl] -2-pyridyl] propionic acid, (E) -3- [6- / 3-dimethylamino-1- (4-) tolyl) prop-1- (4-tolyl) prop-1E-enyl / -1E-pyridyl] acrylic acid, (E) -3- [b- [3-pyrrolidno-1- (4-trifluoromethyl) prop-1E-] enyl] -2-pyridyl] acrylic acid, (E) -3- [6- / 3-pyrrolidinino-1- (4-methoxyphenyl) prop-1E-enyl] -2-pyridyl] 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-pyridyl] acrylic acid,

6- (3-pyrrolidino-1- (4-tolyl) prop-1E-enyl) -pyridine-2-carboxylic acid, (E) -3- / 3-pyrrolidino-1- (4-tolyl) prop-1- phenyl / benzoic acid, (E) -3- / 3-pyrrolidino-1- (4-tolyl) prop-1-enyl / cinnamic acid, (E) -3 - ^{[(E) -} 3-pyrrolidno-1- ( 4-methoxyphenyl) prop-1-enyl] -cinnamic acid. (E) -3- [(E) -3-dimethylamino-1- (4-tolyl) prop-1-enyl] cinnamic acid, (E) -3- [3- / 3-pyrrolidino-1- (4) 6- [3-dimethylamino-1- (4-tolyl) propyl] -2-pyridylcarboxylic acid-tolyl) prop-1-enyl / phenyl] propionic 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 plasma distribution of one of the compounds of the invention and triprolidine in the brain 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 comprises reacting a compound of formula (VII / ^R 5) < ^X >

CH-CH ₂ -CH ₂ NR ₂ R ₃ (VII) ^R 4 wherein

R _2, R p R p, X, A and B have the meaning indicated and výěe is halogen.

with a lithium alkyl compound containing up to 6 carbon atoms and then treatment with carbon dioxide to give a compound of formula I wherein R 1 is a group of formula (CH ₂ ) q, A and B are hydrogen and R 8, R p and R 6 are X is as defined above, and then optionally converting the compound of formula I obtained into another compound of formula I by methods known to those skilled in the art, for example by reacting a compound of formula XII

where

X and B | to R 6 are as defined above and

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

The reaction of a compound of formula VII with an alkyl lithium followed by treatment with carbon dioxide is conveniently carried out in a solvent inert under the reaction conditions used, for example benzene, toluene or an ether such as tetrahydrofuran, under an inert atmosphere such as nitrogen and at low temperature e.g. and -20 ° C. Suitably, butyllithium is used as the alkyl lithium compound. The reaction is usually carried out in toluene or tetrahydrofuran at a temperature between -80 and -50 ° C under nitrogen.

A compound of formula VII can be produced by reducing a compound of formula XIII (XIII),

where

X and R ₂ to R 8 are as defined above, under conditions that do not attack the R 8 group.

This reduction is conveniently carried out by hydrogenation in the presence of a transition metal catalyst such as platinum on activated carbon.

Compounds of formula XIII can usually be prepared by reacting the appropriate Wittigo v reagent with a compound of formula XIV (XIV)

where '

X, R 6 and R 8 are as defined above.

The Wittig reagent is suitably a compound of the formula (R _{9) 3} P = CHCH ₂ NR ₂ R where

R ₂ and R ₃ have the abovementioned meaning

R 8 represents an alkyl group of β 1 to 4 carbon atoms or a phenyl group which has been liberated from the corresponding phosphonium salt of the general formula (R 8) ₃ P ⁺ CH ₂ CH ₂ III ₂ R ₃ Hal "where

Hal means chloride or bromide and

R 8 and R ₃ are as defined above by treatment with a strong base. Suitable strong bases are C 1 -C 4 alkyl lithium compounds or aryl lithium compounds such as butyllithium, or metal hydrides such as sodium hydride. The reaction is conveniently carried out in an inert solvent, for example an ether, such as tetrahydrofuran, at a temperature which is not extreme, for example at 0 to 50 ° C, but usually at room temperature.

The isomerization of the compound of formula (XIIe) is conveniently carried out in the presence of an excess of one molar equivalent of a strong acid, suitably a strong mineral acid such as sulfuric acid from an elevated temperature such as 50 ° C and 160 ° C, usually between 125 150 ° C.

Compounds of formula (XII) may be prepared as by-products in the preparation of compounds of formula (I) and may be obtained from the reaction mixture by conventional separation techniques, for example chromatography or techniques which utilize 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 saponify it, not to mention an alkyl metal hydroxide such as sodium hydroxide in alkanol and 1 to 4 carbon atoms. ethanol to obtain the acid.

Reduction of one or two double bonds, i.e. reduction of a double bond terminating at the-NR 1 R j group, or reduction of a double bond in the carboxyl side chain can usually be performed by hydrogenation in the presence of a transition metal catalyst, for example platinum on activated carbon. The preparation of esters or amides from the corresponding carboxylic acid and vice versa can likewise be carried out by methods well known to those skilled in the art.

The starting materials of formula (VII), (XIII) and (XIV) have not yet been described and constitute another important feature of the invention. Said compounds of formula (VII), (XIII) and (XIV) are east, whereas a compound of formula (VII) is particularly preferred.

The compounds of the present invention can be used for the same indications as trlprolidine, 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 stings, and responses that cause sensitivity to be removed.

The compounds may also be used under conditions appropriate to alleviate the effect of itching including allergic dermatoses, neurodermatides, anogenitious itching and itching of indeterminate origin, as a result of eczema and for specific causes such as chickenpox, photosensitivity and sunburn. The present invention therefore relates to a method of symptomatically treating allergic conditions by administering an effective amount of a compound of formula I. The present invention also relates to a method of counteracting the internally released histamine by administering an effective amount of a compound of formula I. and have little or no anticholinergic effects. The amount of active compound required for use under the above conditions varies according to the compound selected, the route of administration, the conditions, and the mammal being treated and ultimately controlled by the physician. A suitable oral dosage 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 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 per 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, for example 4 to 8 mg.

While it is possible to administer the compound of formula I 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 human medical purposes, which consist of a compound of formula I 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, an anti-cough agent, such as codeine, an analgesic, anti-inflammatory, anti-magnesium or expectorant agent. 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.

In general, 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 invention suitable for oral administration may be presented as discrete units, such as capsules, wafers with a special cap, tablets or taps, each containing a predetermined amount of the active compound (defined herein as a compound of formula I), such as a powder or granules; suspensions in an aqueous liquid such as a syrup, elixir, emulsion or beverage.

Tablets may be made by compression or melting 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 may 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 retarding agents, or a solubility enhancer of some other component, such as a polyhydric alcohol such as glycerol or sorbitol, and a suitable preservative.

Compositions for rectal administration may be administered as a suppository and a conventional carrier, such as cocoa butter, or hydrogenated fats or hydrogenated aliphatic carboxylic acids.

Compositions suitable for parenteral administration typically include sterile sodium formulations 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.

The ophthalmic compositions are made by a method similar to a nasal spray, except that the pH and isotonic factors are adjusted to values suitable for the eyes.

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 additives listed below may be desirable.

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

This invention also relates to the first use of the 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

(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 to the stirred suspension under nitrogen

19.5 g of 2,6-dibromopyridine in 200 mL of dry ether at -50 ^u. After 0.75 hours a solution of 10 g of 4-tolunitrile in 50 ml of ether was added and stirring was continued at -50 ^° C for 3 hours. The mixture was allowed to warm to -30 ° 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-toluyl) 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, washed with sodium sulfate and evaporated to about 500 ml. Cooling gives 70 g of 2- (6-bromo-2-pyridyl) -2- (4-tolyl) -1,3-dioxane (compound 1), m.p. . Dilution of petroleum ether gives a second yield of 34 g, m.p. The evaporation residue (3 g) was recirculated.

A solution of 70 g of 1 above in 800 mL of dry toluene was added dropwise over 5 hours to a stirred solution of 200 ml of 1, 611 butyllithium in hexane and 200 ml toluene at -70 ⁰ was added over 35 minutes 40 ml of dry dimethylformamide. Stirring was continued overnight at -70 to -60 °.

400 ml of 2 N hydrochloric acid are then added and the temperature is allowed to rise to about -10 °. 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-formyl-2-pyridyl) -2- (4-tolyl) -1,2-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 10 ml of 1,2-dimethoxyethane and added to a solution of carbanion phosphonate made of 2 g of triethylphosphonoacetate and 0.22 g of sodium hydride in the same solvent. The mixture was stirred for 2 hours, diluted with 25 mL of ether and treated with 5 mL of 2M hydrochloric acid. 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. After heating on a steam bath for 0 min, the solution was diluted with ice water, basified with sodium bicarbonate solution and extracted with ether. Evaporation gave (E) -3- [6- (4-toluoyl) -2-pyridyl] acrylate (compound 2), which crystallized from cyclohexane to colorless plates, m.p. 108-1.1 °, weighing 1 g. .

ml of a 1.64 M solution of butyllithium in hexane was added under nitrogen to a stirred suspension of 7.2 g of triphenyl-2-pyrrolidinoethylphosphonium bromide in 75 ml of dry toluene. After 0.5 h

4.6 g of compound 2 above are added to 50 ml of toluene. The suspension initially orange, turned dark purple and then slowly to yellow over 2 hours with heating to 75 °. The cooled solution was diluted with 150 mL of ether and treated with 50 mL of 2M 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 to; 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 residue is extracted three times with 50 ml of hot isopropenol each and the extracts are evaporated until crystallization occurs. (E) -3- [j5- / 3-pyrrolidino-1- (4-tolyl) prop-1E-enyl / -2-pyridylJ acrylic acid (Compound A), after recrystallization from isopropenolu mp 222 ⁰ (dec ).

Example 2

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

A solution of 91 g of 2-bromo-6- (1,3-dioxolan) -2-yl) pyridine in 50 ml of toluene was added under nitrogen to a stirred mixture of 260 ml of 1.6U butyllithium in 1.1 liter of toluene at a temperature between -60 and -70 °. After 2 hours, a solution of 1-pyrrolidino-3- (4-tolyl) propan-3-one, which was made from 85 g of the corresponding hydrochloride and dried, was added in 200 µl of toluene at -70 ^° and the mixture was stirred for an additional 3 hours. at this temperature. The solution was allowed to warm to -20 ^° and treated with 510 mL of 21 L hydrochloric acid. The separated aqueous layer was washed with ether, basified with 10M sodium hydroxide solution from ⁰ e and extracted with toluene.

Evaporation of the extracts to dryness gave 120 g of oil. This was dissolved in 200 ml of 211 hydrochloric acid and heated on a steam bath for 30 minutes. Cooling, alkalization and re-isolation afforded 115 g of 2- (1-hydroxy-3-pyrrolidino-1- (4-tolyl) propyl) pyridine-6-eldehyde as an oil. The crude eldehyde is dissolved in 133 ml of pyridine and treated with 58 g of melonic acid in the presence of 2 ml of piperidine at reflux for 1 hour. After evaporation of the reduced pressure ee, the residue was dissolved in a small volume of glacial acetic acid, diluted with 2 liters of water and stored at 0 ° to crystallize. The solid product is esterified with methenol in the presence of sulfuric acid. 27 g of methyl [(E) -3 * [6- (1-hydroxy-3-pyrrolidino-1- (4-tolyl) propyl) -2-pyrldyl] acrylate] are obtained in the form of a dark oil. A small sample crystallized from petroleum ether as colorless prisms, m.p. 75-77 ° C. A mixture of 25 g of crude ether and 50 ml of concentrated sulfuric acid was heated in an oil bath for 160 ° minutes. Re-isolation and saponification affords (E) -3- [6- (3-pyrrolidino-1- (4-tplyl) prop-1E-enyl) -2-pyridyl] acrylic acid as bleach crystals of m.p. 218 ei 219 ⁰ (with decomposition). Further recrystallization from isopropenol increases the melting point to 222-223 °.

Example 3

Process for the preparation of 6- (3-pyrrolidino-1- (4-tolyl) prop-1E-enyl) pyridine-2-carboxylic acid

A solution of 7 g of compound 1 in 80 ml of dry toluene was added dropwise under nitrogen to a stirred solution of 20 ml of 1.6 M butyllithium in hexane cooled to below -60 °. After 3 hours at this temperature, 25 g of solid carbon dioxide are added to the solution. The mixture was allowed to warm to 10 °, treated with 20 mL of 211 hydrochloric acid and filtered off a small amount of solid. 3 The toluene layer was separated and evaporated to give 7 g of an oil. This was heated on a steam bath for 10 minutes with 10 ml of 6M hydrochloric acid containing just enough alcohol to obtain a clear solution. Cooling and diluting with water gives a gummy solid which crystallizes from water in colorless needles with a melting point of 151-153 °. (Purification of solid 3 with hydrochloric acid gave an additional 0.9 g of the same). Esterification of this acid with ethanol in the presence of sulfuric acid afforded, after a conventional procedure, 2.8 g of ethyl [6- (4-tolyl) pyridine-2-carboxylic acid] (compound 4) as a colorless oil which slowly crystallized.

Treatment of compound 4 with a Wittig reagent obtained from triphenyl-2-pyrrolidinoethylphosphorium bromide by the method of Example 1 yields a mixture of two geometric isomers after saponification, which is separated by extraction from hot ethyl acetate. The insoluble isomer E (title compound) had a melting point of 200-202 ° after crystallization from isopropanol. Cooling of the ethyl acetate solution results in crystallization of the more soluble Z isomers, m.p.

Example

(E) -3-C, 6-pyrrolidino-1- (4-trifluoromethylphenyl) prop-1E-enyl] -2-pyridylacrylic acid

2-Bromo-6- (4-trifluoremthylbenzoyl) pyridine, m.p. 66-68 ⁰ (made from 2,6dibrompyridinu and 4-trifluoromethylbenzonitrile by the method of Example 1) was converted into the (E) ethyl 3- [/ 6- ( 4-trifluoromethylbenzoyl) -2-pyridyl acrylate] m.p. 129-132 °. Further treatment with the Wittig reagent according to the method of Example 1, after saponification and crystallization from isopropanol, affords (E) -3- [6- (3-pyrrolidino) - (4-trifluoromethylphenyl) prop-1E-enyl-2-pyridyl] acrylic acid, m.p. 223 to 225 ⁰ (decomp.).

Example 5

(E) -3- [6- / 1- (4-chlorophenyl) -3-pyrrolidinoprop-1E-enyl] -2-pyridyl] acrylic acid

1- (4-Chlorophenyl) -3-pyrrolidinopropan-1-one was converted by the method of Example 2 to give the title compound, which is white isopropanol crystals having a melting point of 218-220 °.

Example 6

Process for the preparation of (E) -3- [3-pyrrolidino-1- (4-tolyl) prop-1-enyl] benzoic acid

To a stirred cold suspension of 17.6 g of triphenyl-2-pyrrolidinoethylphosphonium bromide in 96 mL of tetrahydrofuran was added portionwise a solution of 28 mL of a 1.6 M solution of butyllithium in hexane while maintaining the temperature at 0 °. After stirring for 30 minutes at 0 ^° C, a solution of 10.16 g of 3-methoxycarbonyl-4-methylbenzophenone (Smith,

J. Amer. Chem. Soc., 1991, 43, 1921) in 50 ml of tetrahydrofuran and allowed to warm to room temperature and then heated to 55 ^° C for 18 hours. Most of the tetrahydrofuran was evaporated under reduced pressure, water and dilute hydrochloric acid were added and the mixture was washed with ether. The clear aqueous solution was basified with 2N sodium carbonate solution and the precipitated oil was extracted with ether, and purified by silica gel column chromatography with chloroform / methanol (50: 1) as eluent to give a mixture of (E) - and (Z) -methyl form [3- (3-pyrrolidino-1- (4-tolyl) -prop-1-phenyl) benzoate as a cream colored solid, 9.8 g.

A solution of 1.34 g of the above ester in 8 ml of ethanol and 3 ml of 2N sodium hydroxide solution was stirred at room temperature for 3 hours and after addition of 3 ml of 3N hydrochloric acid, the solution was evaporated to dryness. The residue is extracted twice with 20 ml of boiling ethanol each time. An insoluble residue remains which is washed with water. There were obtained 300 mg of (Z) -3- [3-pyrrolidino-1- (4-tolyl) prop-1-enyl] benzoic acid, which crystallized from methanol in colorless wires of m.p. 238-240 ⁰ (dec). (Acid hydrochloride, m.p. 205-207 ° C.) The ethanol extract was evaporated to dryness and the residue was recrystallized from methanol. There were obtained 285 mg of colorless prisms of (S) -3- 3-pyrrolidino-l- (4-tolyl) prop-1-enyl-benzoic acid, mp 210-215 ⁰ (dec) / acid hydrochloride has a melting point of 180 to 182 °.) Additional amounts of individual isomers are obtained by suitable recrystallization, by stabilizing the residue and the filtrate.

Example 7

(E) -3-L6- [3-pyrrolidino-1- (4-tolyl) prop-1H-ethyl] -2-pyridyl] acrylic acid

To a solution of 52.14 g of 2,6-dibromopyridine in toluene cooled to -50 ^° , 130 ml of a 1.70 M solution of n-butyllithium in hexane was added under stirring under nitrogen atmosphere, maintaining the temperature at -50 °. After stirring at -50 ^° for 2 hours, 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 toleuene is added at the same temperature at the same temperature. . The reaction mixture was stirred at -50 ^° C for 1.5 hours, then allowed to warm to -30 ^° C and held at this temperature for 1.5 hours. To the mixture was then added 300 mL of 2N hydrochloric acid, followed by 800 mL of water. The separated aqueous layer was washed with ether and basified with 2N sodium hydroxide solution. The solid was filtered off, dried and crystallized twice to give 43.0 g of 1- (4-tolyl) -1- [2- (6-bromo) pyridyl] -3-pyrrolidino-1-propanol at white temperature as white crystals. mp 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 ae mixed and heated to 145 ⁰ with stirring for 5 hours. After cooling, the reaction mixture was poured into 800 l of water and the product was extracted with white spirit (b.p. 60-80 °). The extracts were washed with water, dried and evaporated under reduced pressure. As a red gum weighing under reduced pressure · Ethyl ((E) -3-L6- / 1- (4-tolyl) -1-hydroxy-3-pyrrolidino) is obtained as a red gum weighing 41.6%. -2-pyridyl acrylate;

25.39 g of the aforementioned carbinol ester are mixed with 50 ml of 90% by weight sulfuric acid and the mixture is heated to a temperature of 50%. 135 ⁰ with stirring for 3 hours. The cooled mixture was then poured into 760 ml of ethanol and the solution heated from the reflex 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 extracted with ether. The extracts were washed with water, dried and evaporated under reduced pressure. 21.1 g of a red solid are obtained, consisting of a mixture of stereoisomers (Ε, Ε: EZ = 80: 20) ethyl / (E) -3-E6- / 3-pyrrolidino-1- (4-tolyl) 1-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 herpes were neutralized by the addition of 60 ml of 1N aqueous sulfuric acid and the mixture was then evaporated to dryness; reduced pressure.

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

235349 ¹⁴

Example 8

Process for preparing 6- [3-dimethylamino-1- (4-methylphenyl) propyl] -2-pyridinecarboxylic acid

To a stirred suspension of 50 g of 2,6-dibromopyridine in 500 ml dry diethyl ether under nitrogen at -70 ⁰ was added dropwise over 1.5 hours, 145 ml 1 5511 n-butyllithium in hexane. The reaction mixture was warmed to krétce -60 ⁰ · and again cooled to -70 °. A solution of 26 ml of p-tolualdehyde in 200 ml of ether was added dropwise.

After the addition was complete, the reaction mixture was allowed to warm to room temperature and poured into 1 liter of 2.5N hydrochloric acid. The aqueous layer was separated and extracted three times with ether. The combined extracts were dried (MgSO4) and then evaporated to give a solid residue (55.2 g). The residue was recrystallized from ethyl acetate / hexane (1: 1). To give 41.1 g <*> - (6-bromo-2-pyridyl) -4-methylbenzyl alcohol having a melting point of 79.5 to 80 ^0, and forms white crystals.

NMR (80 MHz, CDCl3) δ2.32 (s, 34), 4.32 (broad s, 1H) 5.70 (broad β, 1H),

7.05-7.57 (·, 7H).

Analysis for gBrNO:>

calculated: 56.13% C, 4.35% H, 5.04 N, 28.73 9 Br, found: 56.15 9 C, 4.36 9 H, 5.00 9 N, 28.63 9 Br.

A solution of 41 g of (X- (6-bromo-2-pyridyl) -4-methylbenzyl alcohol in 200 ml of methylene chloride) was added to a suspension of 53 g of pyridinium chlorochromate in 200 ml of methylene chloride. The solvent was decanted and the residue was washed with four additional 150 ml portions of ether, and the combined ethereal solutions were passed through 500 g of flossilil and then evaporated to give 37.7 g of solid which was recrystallized from absolute ethanol to give 32.1 g. g of 2-bromo-6- (4-methylbenzoyl) pyridine, m.p.

NMR (80 MHz, CDCl 3) δ 2.43 (s, 3H), 7.23 to 8.10 (m, 7H).

Analysis for C ^ HH ^ Br BrNO:

calculated: 54.54 9 C, 3.65 9 H, 5.07 9 N, 28.94 9 Br, found: 56.52 9 C, 3.70 9 H, 5.03 9 N, 28.97 9 Br.

A solution of 71 ml of 1.55 M n-butyllithium in hexane was added dropwise over one hour to a stirred suspension of 45.1 g of (2-dimethylaminoethyl) triphenylphosphonium bromide in 500 ml of dry tetrahydrofuran under nitrogen and thereto was added dropwise over 30 minutes at room temperature. g of 2-bromo-6- (4-methylbenzoyl) pyridine in 300 ml dry tetrahydrofuran. The mixture was refluxed for 2.5 hours, then cooled to room temperature and poured into 1 liter of water. The ether layer was separated and the aqueous phase was extracted with two additional portions of ether. The ether layers were combined, dried with magnesium sulfate and evaporated. An oil is obtained which is thoroughly triturated with 500 ml of hexane. The hexane was decanted and evaporated to give a mixture of isomeric Z and E alkenes in a Z: E ratio of about 55:45. The isomers were separated by preparative high-sensitivity liquid chromatography (Waters Frep 500) on silica gel, using methylene chloride / methanol in a ratio of 95: 5.

(Z) -3- (n-bromo-2-pyridyl) -N, N-dimethyl-3- (4-methylphenyl) allyamine,

R _f (silica gel, methanol) = 0.37.

NMR (60MHz, CDCl ₃ ) 2.23 (s, 6H), 2.28 (s, 3H), 3.11 (d, 2H), 6.20 (t, 1H), 6.95 to 7.5 (m, 7 H).

(E) -3- (6-bromo-2-pyridyl) -, N-dimethyl-3- (4-methylphenyl) allylamine, (silica gel, methanol): 0.53,

NMR (60 MHz, CDCl 3) δ 2.23 (S, 6H), 2.39 (S, 3H), 2.96 (d, 2H), 6.70-7.33 (m, 8H).

The E-isomer is again chromatographed (silica gel, ethyl acetate, Prep 500) β to give a sample with a melting point of 65 to p6 °.

Analysis for C ^ HH ^ gBrNgO:

calculated: 61.63 ° C, 5.78% Η, 8.46% N, 24.13% Br, found: 61.64% C, 5.82% H, 8.42% N, 24.12% Br.

A solution of 4.48 g of E-3- (6-bromo-2-pyridyl) -N, N-dimethyl-3- (4-methylphenyl) allylamine in 150 ml of absolute ethanol was hydrogenated on activated carbon with 10% platinum for 7 hours. days. The reaction mixture was filtered (through Celite) and fresh catalyst was added four times during the reduction. When the starting material is consumed, as determined by thin layer chromatography, filtration and evaporation are carried out. 3.8 g of an oil are obtained, which is chromatographed on silica gel with methanol. There was obtained 0.86 g of 2-bromo-6- [3-dimethylamino-1- (4-methylphenyl) propyl] pyridine, determined by thin layer chromatography [hereinafter TLC], Rf: 0.25 (silica, methanol).

NMR (80 MHz, CDCl 3 δ 2.05-2.45 (m, 13 H), includes 2.18 (s, 3 H - and 2.30 (s, 3 H), 4.15 (broad m, 1 H), 7 0.03 to 7.50 (m, 7H).

Analysis for C, yH ₂₁ BrN ₂ :

calculated: 61.26%, 6.35% Η, 8.41% N, 23.98% Br, found: 61.37% C, 6.37% H, 8.38% N, 23.84% Br.

1.0 ml of a 1.7 M solution of n-butyllithium in hexane is added dropwise to a solution of 0.537 g of 2-bromo-6- [3-dimethylamino-1- (4-methylphenyl) propyl] pyridine in 15 ml of dry tetrahydrofuran cooled with stirring at -70 ^° under a nitrogen atmosphere. After 15 minutes, carbon dioxide gas was bubbled through the solution for several minutes. The reaction mixture was allowed to warm to room temperature and the solvent was removed under reduced pressure. The residue is dissolved in 16.1 ml of 0.1 N hydrochloric acid and the resulting solution is evaporated to dryness. 6- [3-Dimethylamino-1- (4-methylphenyl) propyl] -2-pyridinecarboxylic acid was isolated as the monohydrate after silica gel thick layer chromatography, 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 (s, 6H), 4.47 (broad m, 1H), 4.6 to 5.2 (broad, exchangeable), 6.80 to 8.20 (m, 7H).

Analysis ^c) 8 ^H 22 ^N 2 ° 2 ^H 2 ^0: Calculated: 68.33% C, 7.65% Η, 8.85% N Found: 68.16% C, 7.65% Η , 8.82% N.

Example 9

Process for preparing 6- [1- (4-chlorophenyl) -3-dimethylaminopropyl] -2-pyridinecarboxylic acid

To a stirred solution of 100 g of 2,6-dibromopyridine in 1 liter of dry ether under a nitrogen atmosphere at -70 ^° was added dropwise 270 ml of a 1.7 M n-butyl lithium solution over 2 hours. thia in hexane.

After a further 30 minutes, a solution of 65 g of p-chlorobenzaldehyde was added over 1 hour. in 500 ml dry ether. The reaction mixture was allowed to warm to about 0 ° ^C and then poured onto a liter of 4N aqueous hydrochloric acid. The ether layer was separated and the aqueous layer was extracted with two additional 300 mL portions of ether. The combined ether layers were washed with 500 mL of water, dried over sodium sulfate and evaporated to a syrup. The crude product was chromatographed on silica gel (Waters Prep 500) using methylene chloride. There were obtained 93.8 g of alpha (o-bromo-2-pyridyl) -4-chlorbenzylelkoholu e melting point of 64.5 to 65 '°, E _f TLC: 0.56 (silica gel, hexane: ethyl acetate = 1: 1 ).

NMR (80 MHz, CDCl 3) δ 4.39 (d, 1H), 5.71 (d, 1H), 7.04 to 7.51 (m, 7H).

Analysis for C ₁₂ H ₉ BrClNO:

H, 3.04; N, 4.69. Found: C, 48.32; H, 3.05; N, 4.67.

g of benzhydrol was dissolved in 400 ml of methylene chloride and added with stirring to a suspension of 120 g of pyridinium chlorochromate in 500 ml of methylene chloride. After 22 hours, the solvent was decanted and the resulting slurry was washed four times with 250 ml of ether each time. The combined organic layers were filtered (over 500 g of florisil) and evaporated. 78.6 g of a dusty residue are recrystallized from a mixture of hexane and methylene chloride. There was obtained 71.8 g of 2-bromo-6- (4-chlorobenzoyl) pyridine, m.p. 83.5-84 °. TLC _Rf: 0.48 (silica gel, hexane: ethyl acetate 4: 1).

NMR (80 MHz, 0001?)? 7.26, 8.16 (m, 7H).

Analysis for C, ₂ HyBrClNO:

calculated: 48.60% C, 4.72% H, 2.38% N, 11.96% Cl, 26.95% Br, found: 48.70% C, 4.68% H, 2.44% N, 11.92% Cl, 36.87% Br.

A solution of 60 ml of 1.55 M n-butyllithium in hexane was added dropwise over a period of 45 minutes to a stirred suspension of 38.1 g of (2-dimethylaminoethyl) triphenylphosphonium bromide in 300 ml of dry tetrahydrofuran under a nitrogen atmosphere. After an additional hour at room temperature, a solution of 27.3 g of 2-bromo-6- (4-chlorobenzoyl) pyridine in 200 ml of dry tetrahydrofuran was added dropwise. The mixture was stirred at room temperature for 20 minutes, then refluxed for 80 minutes, cooled to room temperature and poured into 500 ml of water. The ether layer was separated and the aqueous layer was extracted with three additional portions of ether. The ether layers were combined, washed once with water, dried over magnesium sulfate and evaporated. An oil is obtained which is triturated with 500 ml of hexane. The hexane layer was decanted and evaporated to give a crude mixture of isomers of Z and E alkenes which was chromatographed (Waters Prep 500) on silica gel with methylene chloride / methanol (95: 5) to give 7.53 g of isomer E and 15, 19 g isomer, Z. The individual isomers are then re-chromatographed on silica gel with ethyl acetate.

(Z) -2-bromo-6- [J- (4-chlorophenyl) -3-pyridine člimethylaniinoallyl] mp 56-62 ⁰ has Rf 0.41 on silica gel (methanol).

NMR (80 MHz, CDCl ₃ ) 2.25 (s, 6H), 3.11 (d, 2H), 6.26 (t, 1H), 7.04-7.64 (m, 7H). Analysis for C ₁₆ H gBrCINj:

calculated: 54.64% C, 7.97% H, 4.59% N, 10.08% Cl, 22.73% Br, found:% C, 71% C, 7.99% H, 4.56% N, 10.07% Cl, 22.69% Br.

(E) -2-Bromo-6- [1- (4-chlorophenyl) -3-dimethylaminoallyl] -pyridine, m.p. 69-70 ^° , R _f 0.52 on silica gel (methanol).

NMR (80 UR, CDC1,) and 2.22 (s, 6H), 2.94 (d, 2H), 6.76 (dd, 1H), 7.45 7,0'2 _and f (m, 7H ) Analysis for CjgHjgClNg!

calculated: 54.64% C, 7.96% H, 4.59% N, 10.08% Cl, 22.73% Br, found: 54.55% C, 7.99% H, 4.56% N, 10.10% Cl, 22.78% B >

To a solution of 1.1 g of Z-alkene in 7 ml of dry THF stirred under nitrogen at -70 ⁰ was added dropwise over 15 minutes 2.0 ml 1 5M solution of n-hexane butllithia. After an additional 15 minutes at -70 ^° C, the solution was treated with carbon dioxide gas, then the solution was allowed to warm to room temperature and the solvent was evaporated under reduced pressure. The residue is dissolved in 10 ml of water and after introducing 3.1 ml of 1N hydrochloric acid as a gas, the solvent is removed under reduced pressure. Chromatography of the residue (Watera Prap 500) using methylene chloride / methanol 3: 1 gives (Z) -6- [1- (4-chlorophenyl) -3-dimethylaminoallyl] pyridine-2-carboxylic acid, TLC _Rf : 0.26 (silica gel, methylene chloride / methanol 3: 1) ·

NMR (60 MHz, CDCl 3) δ 2.83 (s, 6H), 3.64 (d, 2H), 6.08 (t, 1H), 7.0-8.3 (m, 7H), 8.9 (wide, replaceable).

0.30 g of this compound is reduced in 150 ml of ethanol to 1.9 g of 10% platinum on activated carbon for 72 hours. The catalyst was filtered off through a pad of celite and the filtrate was evaporated to dryness under reduced pressure. The residue is chromatographed on silica gel (Waters Prep 500) in methanol. The product obtained has TLC _Rf: 0.32 on silica gel in methanol. This product was further purified by reversed phase chromatography (C, _g , methanol / water 55:45). 0.14 g of 6- [1- (4-chlorophenyl) -3-dimethylaminopropyl] -2-pyridinecarboxylic acid is thus obtained as a dihydrate (K ¹ : 0.31 perCg with a 55:45 mixture of methanol and water). .

NMR (80 MHz, CDCl 3) δ 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 to 7.45 (m, 5H),

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

Analysis CjyH ^ Ο ClNgOg.2Η _2:

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.

He did

Process for preparing 6- [1- (4-chlorophenyl) -3-dimethylaminopropyl] -2-pyridinecarboxylic acid

Catalytic hydrogenation of either E- or Z-2-bromo-6- [1- (4-chlorophenyl) -3-dimethylaminoallyl] pyridine mentioned above or a mixture of Z and E isomers to 10% platinum activated carbon affords 2-bromo-6- - (4-chlorophenyl) -3-dimethylaminopropyl] pyridine. A typical procedure is given below.

A solution of 2.0 g of E-bromolefin in 150 ml of absolute ethanol was stirred under a hydrogen atmosphere in the presence of 0.86 g of 10% platinum on activated carbon for 48 hours. Filtration (through Celite) and evaporation under reduced pressure gave an oil. which is chromatographed on silica gel (Watera Prep 500) using a 3: 1 mixture of methanol and methylene chloride;

0.66 g of 2-bromo-6- [1- (4-chlorophenyl) -3-dimethylaminopropyl] pyridine is thus obtained in the form of an oil, TLC Rf 0.22 (silica gel, methanol).

NMR (80 MHz, CDCl 3) δ 2.18 (s, 10H), 4.09 (broad m, 1H), 7.0-7.5 (m, 7H).

Analysis for C, gH, gBrCLNg:

calculated: 54.33% C, 5.13% H, 7.92% N, 22.60% Br, 10.02% Cl, found: 54.22% C, 5.17% H, 7.89% N, 22.51% Br, 9.99 Cl.

0.25 g of bromide was dissolved in 5 ml of dry tetrahydrofuran and the solution was cooled to -70 ^° under a nitrogen atmosphere. 0.42 ml of a 1.7 M solution of n-butyllithium in hexane is added over 10 minutes and stirring is continued for a further 15 minutes at -70 °. Carbon dioxide gas was bubbled through the solution, then the reaction mixture was warmed to room temperature and the solvent removed under reduced pressure. The residue was dissolved in 7.1 ml of 0.1N aqueous hydrochloric acid and the solution was dried to dryness under reduced pressure. The resulting foam was chromatographed on silica gel (Waters Prep 500) in methanol.

0.08 g of the carboxylic acid TLC _Rf: 0.24 (silica gel, methanol), k '= 3.1 to C _e in a mixture of methanol: water = 55' · 45 ·

Example 11

Process for the preparation of (E) -6- [1- (4-chlorophenyl) -3-dimethylaminopropyl] -2-pyridylacrylic acid

To a solution of 1.44 g of 2-bromo-6- [1- (4-chlorophenyl) -3-dimethylaminopropyl] pyridine under a nitrogen atmosphere in 50 ml of dry tetrahydrofuran cooled to -70 °, was added, with stirring, 2.4 ml of 1. 7M n-butyllithium hexane. After a further 5 minutes at -70 ^° , 1.5 ml of dry dimethylformamide are added dropwise over 2 minutes. The solution is allowed to warm and then vigorously mixed with 5 ml of water. The solvent was removed under reduced pressure and the residue was dissolved in 50 ml of methylene chloride. The solution is extracted three times with 25 ml of water each time, dried over sodium sulfate and evaporated to give crude 6- [1- (4-chlorophenyl) -3-dimethylaminopropyl] -2-pyridinecarboxaldehyde (formyl proton 10.05, 60 MHz, CDCl3). chromatographed on reverse phase (C 8 waters Prop 500, acetonitrile: water = 60: 40, K ¹ = 6.3, C1G, acetonitrile: water = 70: 30).

Reaction of the aldehyde with the sodium salt (from sodium hydride) of triethylphosphonoacetate in dry toluene under nitrogen and then isolation of the product by ether extraction affords crude ethyl]] 6- [1- (4-chlorophenyl) -3-dimethylaminopropyl] -2-pyridylacrylate (K ¹ = 8.3 on C, ₈ with 70: 30 acetonitrile: water).

NMR (80 MHz, CDCl ₃ ) δ 1.32 (t, 3H), 2.15 (m, 10H), 4.25 (m, 3H), 6.75-7.80 (m, 9H)

The ester was hydrolyzed with 4 equivalents of sodium hydroxide in aqueous methanol. The reaction mixture was neutralized with 1 N aqueous hydrochloric acid and the solvent was evaporated under reduced pressure. The residue was treated with methanol, filtered and the methanol removed under reduced pressure. The crude acid was obtained. Reverse phase chromatography (C, ₈ , 3 mixture of methanol and water, 40:60) affords (E) -6- [1- (4-chlorophenyl) -3-dimethylaminopropyl] -2-pyridylacrylic acid (k '). = 5.7 to _C-8 with a mixture of methanol and water in the ratio 30: 70), TLC _Rf 0.40 (silica, methanol).

NMR (80 MHz, CDCl 3) δ 2.40 (s, 6H), overlap over 2.0 to 3.0 (m, 4H), 3.97 (broad, t, 1H), 6.65 to 7 70 (m, 9H), 11.5 (wide s, exchangeable).

The following compounds of the invention can also be prepared by the method described above:

isomer E of 3- [6- / 3-pyrrolidino-1- (4-tolyl) prop-1E-enyl] -2-pyridyl] propionic acid (compound B), m.p. 156-157 °, isomer E of 3- [6] - (3-dimethylamino-1- (4-tolyl) prop-1E-phenyl) -2-pyridyl] acrylic, m.p. 222-225 ^° (dec.), (E) -3- [6- (3)] 3-pyrrolidno-1- (4-tol'yl) prop-1E-enyl / -2-pyridyl] acrylic acid, m.p. 220 ⁰ (decomp), (E) -3 - [_ 6- / 3-pyrrolidino 1- (4-Methoxy-phenyl) -prop-1E-enyl-2-pyridyl] -acrylic acid, m.p. 231-232 ⁰ (dec.), (E) -3- [6- (1-phenyl-3-pyrrolidinoprop-) - 1E-enyl) -2-pyridyl] acrylic acid, m.p. I80 to 182 ⁰ (decomp), (E) -3- [6- / 3-pyrrolidino-1- (4-tolyl.) -prop-E-enyl / -2-pyridyl] akryinmid-oxalét, mp 198-199 ⁰ (dec)

- ethyl [(E) -3- [6- (3-pyrrolidino-1- (4-tolyl) prop-1E-enyl) -2-pyridyl] acrylate] oxalate, m.p. 155-156 [deg.] C; - / 3-pyrrolidin-1 - (4-tolyl) prop-1E-enyl / -2-pyridyl] -prop-2E-enamidooctová, mp 257-258 ⁰ (dec), (E) -3 - / ( E) -3-pyrrolidino-1- (4-tolyl) prop-1-enyl / cinnamon, m.p. 190 ^° (dec.), (E) -4- / 3-pyrrolidino-1- (4-tolyl) acid ) prop-1-enyl / benEoová, mp 235-240 ⁰ (dec), (Z) -4- / p.yrrolidino 3-1 - (4-tolyl) prop-1 -eny1 / benzoic temperature mp 245-250 ⁰ (dec), (E) -4 - / (Z) pyrrolidine-1- (4-tolyl) prop-1-enyl / cinnamic> mp 210-220 ⁰ dec) acid ( E) -3 - / (Z) -3-pyrrolidino-1- (4-methoxyphenyl) prop-1-phenyl / cinnamic, m.p. 215-230 ° (dec.), (E) -3-] (E) -3-pyrrolidino-1- (4-methoxyphenyl) prop-1-enyl / cinnamon, m.p. 220-225 ^° (dec.), ✓

(E) -3 - / (Z) -3-pyrrolidino-1- (4-chlorophenyl) prop-1-enyl / cinnamic acid, m.p. 178-181 °, (E) -3 - / (E) - 193-195 °, 3-pyrrolidino-1- (4-chlorophenyl) prop-1-enyl / cinnamic acid, (E) -3 - / (E) -3-dimethylamino-1- (4-tolyl) prop (E) -3 - / (Z) -3-dimethylamino-1- (4-tolyl) prop-1-enyl / cinnamic acid, m.p. 200-205 °, (E) -3- [3- [p-pyrrolidino-1- (4-tolyl) prop-1-enyl / phenyl] propionic acid, m.p. 138-140 °, (Z) -3- [3-] -3 -pyrrolidino-1- (4-tolyl) prop-1-enyl / phenyl] propionic acid, which was not isolated in pure form, (E) -3- [6- / 3-pyrrolidino-1- (4-tolyl) prop] 6-6- (3-pyrrolidino-1- (4-tolyl) prop-1Z-enyl) -2-pyridyl] hex-5E-enoic acid, m.p. , 21 °.

ethyl [_ (E) -3- [3-acetoxy-1- (4-tolyl) prop-1E-enyl] -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 (Iartley, male 250-400 g) and place in an organic bath under tension of 300 mg. After one hour of equilibrium, curves corresponding to the total concentration (J; M. Van Roasum, Arch. Int. Rharmacedyn. Ther. 143, 299-330, 1963) of histamine are obtained. After washing, the tissues are incubated for 1 hour with test compound and then a curve corresponding to the secondary histamine concentration is run. Shifts to the right of the curve corresponding to the agonist concentration produced by the antagonists. these are used to construct Schild diagrams (O. Arunlakshana and H. C. Schild, Br.

J. Pharmacol: 14, 48-58 (1959). Regression of log (dr-1) to log (B), where? D is an equiactive response in the presence or absence of antagonist, allows to determine _? that is, the negative log of the antagonist concentration whose histamine control concentration graphs correspond to the 2X right curve.

Table I

Results of in vitro determination of antihistemic tests

RjCOQ X NR ₂ R ₃ ^R 4 pA ₂ compound AND (E) -2-CH-CHCO ₂ H N CH ₃ 8.6 compound (B) -2CH ₂ CH ₂ CO ₂ H N NR ₂ R ₃ CH. 9.2 (E) -2-CH-CH-CO ₂ H if NRgRj Cl 9.0 (E) -2-CH = CH ₂ CO ₂ C ₂ H ₅ N nr ₂ r ₃ ch ₃ 7.7 (E) _-2-chloro-2 GHCONH N ^NR 2 ^R 3 ch ₃ 8.49 (E) -2-CH-CHCO ₂ H N nr ₂ r ₃ och ₃ 8.94 (E) -2-CH = H ₂ GHCO N NRgR ₃ CF ₃ 10.4 (E) -2-CH = GHCONCH ₂ CO ₂ H N NR ₂ R ₃ CH ₃ 6.9 -2-COgH CH NRgRj ch ₃ 8.1 compound C (E) -2-CH = H ₂ GHGO N ch ₃ 8.2 -2-GO ₂ H ch ₃ 8.9 compound D (E) -2-GH = CHGO ₂ H CH NR ₂ R ₃ ch ₃ 8.8

B. Antihistamine 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 saturated with histamine, which is continuously replenished in gaseous form as 0.25% histamine from a non-rosol inhalation device. In guinea pigs, signs of histamine anaphylaxis (such as cough, sneezing, severe abdominal movements, cyano za) have been reported. Under test conditions, control animals collapse on average 33 seconds. The Ed? Q for protection against histamine is calculated from probit analysis. In this ED50 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). Full protection ae is determined to protect against histamine symptoms for 6 minutes in an aerosol chamber (approximately ten times the collapse time of control animals).

Table II

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 antihistamine effect (e.g. 11 mg / kg p.o. is ED 50 for protection for 24 hours).

Example 12

Pharmaceutical Compositions Composition And 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 autoclaved.

Composition B

Cípky

Component Quantity per suppository

Compound of Formula I 1.0 mg

Cocoa butter or Wecobee ' ¹ ''lace base up to 2.0 g

Note:

Wecobee is a protected designation, a hydrogenated fatty acid.

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

Composition G

Syrup

Component

Compound of Formula I

Ethano1

Sucrose

Methylparaben

Sodium benzoate

Cherry flavor

Dye

Water

Amount per 5 ml, 0 mg 0.3 mg 2.0 mg 0.5 mg 0.5 mg up to 5.0 ml as needed

Ethanol, sucrose, sodium benzoate, 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), 0 mg

Lactose 110.0 mg

Pregelatinized maize starch 2.5 mg

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 and magnesium stearate, in gelatin capsules.

Composition F

Tablets

Quantity tab on tablet

Compound of Formula 1 1.0 mg

Pseudoephedrine hydrochloride 60.0 mg

Lactose 62.5 mg

Potato starch 14.0 mg

Magnesium stearate 1.0 mg

Gelatin 2.8 mg

Tablets were prepared from the ingredients by the method described in Example 12D above.

means G

Syrup

Ingredient Quantity per 5 ml

Compound of Formula I 1.0 mg Pseudoephedrine hydrochloride 30.0 mg Codeine phosphate 10.0 mg Guaifenesein 100 mg Methylparaben 0.5 mg Sodium benzoate 0.5 mg Příchul as required Dye as required Glycerol 500 mg Sucrose 2000 mg Cleaned water to 5.0 mg

A syrup containing active ingredients other than the compound of formula (I) is prepared from the ingredients listed above by a method similar to that described in Example 12C above.

Composition H

Nasal spray

Component Quantity per 100.0 ml

Compound of formula I Sodium chloride Preservative Purified water g 0.8 g 0.5 g to 100 ml

The preservative is dissolved in hot purified water and, after cooling to 20-30 ^° , 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.

Means I

Eye solution

Component Quantity per 100.0 ml

Compound of formula (I) Sodium chloride Preservative Water for injections

0.1 & 0.8 g 0.5 g 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 Emulsifying Wax, N.F. Mineral oil

0.1 g ’5.0 g

5.0 g

Claims (12)

SUBJECT OF THE INVENTION 1. A process for the preparation of the novel amino compounds of the formula I ACCB, - ( ^X 1 CH ₂ NR ₂ ^r 3 (I) where R @ 1 represents a bivalent aliphatic hydrocarbon group having 1 to 7 carbon atoms or a single bond; A @ 2 and R @ 2 which are identical or different denote hydrogen, alkyl having 1 to 4 carbon atoms or 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 is a group of formula -C -CC-, or salts, esters or amides thereof, characterized in that a compound of formula VII is reacted wherein: CH — CH ₂ -CH ₂ NR ₂ R ₃ (VII) R ₂ , R p R 6, X, A and B are as defined above and a R 1 represents a halogen atom, a β alkyl compound containing lithium! to 6 carbon atoms and then treated with carbon dioxide to give a compound of formula I wherein R 1 is a group of formula (CH ₂ ) _O , A and B are hydrogen and R ₂ , R 6, R 6 and X are as defined above and then optionally converting the compound of formula I obtained into another compound of formula I or into a salt, ester or amide thereof. 2. A process according to claim 1, which comprises starting from compounds of the above formulas to form a compound of formula II ch ₂ nr ₂ r ₃ (II) / wherein up to R1, 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 formula wherein R 1 is a group of formula (CH ₂ ) _n wherein n is an integer from 0 to 7 or a group of formula (CH ₂ ) _and CH = CH (CH ₂ ) _b , where a and b are independently 0 to 5 and the sum of a and b does not exceed 5. 4. A process according to any one of claims 1 to 3, wherein the compounds of the above formulas are formed to form a compound of formula IIIa. R-ICOOH (IIIa) wherein R ₁ represents a group of formula (CH ₂ ) _n where n is an integer from 1 to 7, or represents a group of formula (CH ₂ ) _and CH = CH (CH ₂ ) _b wherein a and b are independently 0 to 5 and the sum of a and b does not exceed 5, 8 ₂ and 8p 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 is 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 an ester or amide salt thereof. 5. Process according to any one of claims 1 to 4 characterized in that it starts merging nin above formula to give a compound of formula wherein R represents a group of formula (CH _{2) 2} or - CH = CH .. rest - NR 8 R 11 is pyrrolidino or dimethyl amino and R 8 is methyl, trifluoromethyl, methoxy, bromo or chloro. 6. A process according to any one of claims 1 to 3, starting from compounds of the above formulas to form a compound of formula IIIb (IIIb) wherein: R 1 is a group of formula (CH ₂ ) _n where n is an integer from 1 to 7, or is a group of formula (CH ₂ ) _and CH = CH (CH ₂ ) _b wherein a and b are independently 0 to 5 and the sum of a and b does not exceed 5, R ₂ ^{and R} p, which are the same or different, denote hydrogen, lower alkyl of 1 to 4 carbon atoms or together form a nitrogen-containing 4 to 6-membered nitrogen 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 method according to any one of claims to 3 and 6, characterized in that starting from compounds of the above formula to a compound of general formula '. Wherein R is (CH _{2) 2} or CH = -jCH - rest - NR 8 R 6 is pyrrolidino or di-ethylamino 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. R '4 (IV) where R1 to R1 are as defined above, or a salt, ester or amide thereof. 9. A process according to claim 8, wherein the compound of formula IV is a compound of formula IV wherein Rj is a single bond, -CH = CH- or -CHgCHg-, the -MRgRj radical is R, ? is 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 formula I wherein CA-CB is a double bond and the -CHgNRgRj group is in a trans position relative to the X-containing ring. . 11. A process according to any one of claims 1 to 7, starting from compounds of the above formulas to form a compound of formula V (V) 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 (S), wherein R 1 is a single bond, is a group of formula - -, GH = CH - or a - CH 8 CH 8 radical - HR 9 R 6. R 2 is dimethylamino and R 6 is chloro or bromo.