CS235350B2 - 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 to the novel intermediates used in their manufacture and to 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 antihistatin effect, and specifically discloses 3- (p-bromophenyl) -3- (2-pyridyl) -N, N-dimethylpropylamine and 3- (p-chlorophenyl) -3- (3-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 of which is 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 antihistainic agents available.

It is known that tripolidine is metabolized in man to (E) -1- (4-carboxyphenyl) -1- (2-pyridyl) -3-pyrrolidino-1-propene which has little or no antihistamine effect.

The antihistamines acting now in use, including diphenylhydrazine, pheniramines, pyrilamine, promethazine and iriprolidine, generally have the significant disadvantage that they all have a sedative effect or develop sleepiness 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)

(I) where

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

R g and R j, which are identical or different, each represent hydrogen, alkyl of 1 to 4 carbon atoms or together with nitrogen form a nitrogen-containing heterocyclic ring containing 4 to 6 ring members,

R ₄ represents hydrogen, halogen, hydroxy, cyano, acyloxy β 1-4 carbon atoms, alkoxy having 1 to 4 carbon atoms or alkyl having 1 to 4 carbon atoms optionally substituted. 1 to 3 halogen atoms,

X is -N = or -GH = a

A and B are hydrogen or

CA-CB is -C =C-, or salts, esters or amides thereof.

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

where

R 1 to R 1, 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. Preferably, R is a group of formula (CHg) _n wherein n is an integer from 0 to 7 or a group of formula (CHg) _and CH = CH (CHg) _b , wherein a and b are independently 0 to 5 and sum. a and b does not exceed 5.

Further preferred groups of compounds of formula I are compounds of formula IIIa or IIIb wherein

R ₁ represents a group of formula (CH ₂ ) _n , wherein n is an integer from 1 to 7 or a group of formula (CH ₃ J 8 CH ₂ H ₂ CH ₃ ) 4, wherein a and b are independently 0 to 5 and

the sum of a and b does not exceed 5,

R ₂ and R, which are identical or different, represent hydrogen, lower alkyl or sl to form together with the nitrogen containing heterocyclic ring having 4 to as pyrrolidino, piperidino or morpholino and

Or hydrogen or halogen, such as bromine or chlorine, lower alkoxy and 1 to 4 carbon atoms, lower alkyl of 1 (IIIa) (IIIb) to 4 carbon atoms, 6 ring members, up 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 1 are the same or different and are each methyl or ethyl, or together with the nitrogen atom to which they are attached a 4- to 6-membered heterocyclic ring, preferably a saturated heterocyclic ring, such as pyrrolidine, piperidine or morpholine. Preferably NR8R1 is pyrrolidino or dimethylamino. ,

Suitably, R ^ represents hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or trifluoromethyl. Particularly preferably R @ 1 represents hydrogen, methyl, ethyl, trifluoromethyl, methoxy, bromine, chlorine or fluorine. Preferably R @ 1 is methyl, trifluoromethyl, methoxy, bromine or chlorine, more preferably R @ 1 is methyl.

Preferably X is --N =.

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

] čde

R1 to R1 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., n is 0), -CH 2 CH or -CH 2 CH 6 -, HR 9 R 1 is pyrrolidino and R 6 is methyl or trifluoromethyl are particularly preferred.

Another preferred group of compounds of formula (I) are those 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 --CH2 CH2 -, NR @ 8 R @ 6 is dimethylamino and B @ 4 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 alcoholates of 1 to 4 carbon atoms.

When the compounds of formula I contain a double bond in the side chain terminated by the -NRgR-j group, for example compounds of formula IV, they exist in either cis- or trans-isomeric form or forms (relative to the ring containing X1). in the trans-configuration, these are isomers which, in particular, have a suitable entihistamine action Compounds and cis-configurations are more particularly suitable as intermediates for the preparation of the tris-isomers The present invention also relates to mixtures of isomers. ₂ Η contains a double bond, there are longer isomers of the compounds of formula I. Both isomers and a mixture of isomers of these compounds are within the scope of the invention.If the group -RjCOgH contains a double bond, preferred isomers are those in which the carboxyl group is in the trans configuration due to the aromatic ring.

Esters and amides of compounds of formula (I) which have an antihistaminic 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 protecting carboxyl 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 thereof. 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.

When used in medicine, the salts of the compounds of formula (I) 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 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, 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 30 L alkali metal or alkaline earth metal 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-1E-enyl] -2-pyridyl] propionic acid, (E) -3- [6- / 3-dimethylamino-4- (4- tolyl) prop-1E-enyl] -2-pyridyl] acrylic acid, (E) -3- [6- (3-pyrrolidino-1- (4-trifluoromethylphenyl) prop-1E-enyl) -2-pyridyl] acrylic acid (E) -3- [6- / 3-pyrrolidino-1- (4-methoxyphenyl) prop-1E-enyl / 2-pyridyl] acrylic acid, (E) -3- [6- / 1-phenyl-3] (E) -3- [6- / 1- (4-chlorophenyl) -3-pyrrolidinoprop-1E-enyl] -2-pyridyl] acrylic acid-pyrrolidinoprop-1-E-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- enyl] benzoic acid, (E) -3- [3-pyrrolidino-1- (4-tolyl) prop-1-enyl] cinnamic acid, (E) -3 - [(E) -3-pyrrolidino-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-tolyl) prop-1-enyl / phenyl] propionic acid,

6- [3-dimethylamino-1- (4-tolyl) propyl] -2-pyridylpropyl acid, 6 - [- (4-chlorophenyl) -3-dimethylaminopropyl] -2-pyridylcarboxylic acid,

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

Pharmacokinetic atudules 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) does not readily penetrate rodent brains.

Accordingly, the present invention provides a process for the preparation of compounds of formula (I), comprising the compound of formula (XI)

(XI)

R ₄ where

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

R 8 is C 1 -C 4 acyloxy, reacted with an amine of formula XX for ₂ h ₃ (XX) where

R ₂ and R ₃ are as defined above, and then optionally converting the resulting compound of formula I into another compound of formula I by methods well known to those skilled in the art, for example by treating a compound of formula XII

where

X and R to R ₄ have the abovementioned meaning and

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

The reaction of a compound of formula XI with an amine of formula XX is conveniently carried out in the presence of a palladium catalyst. The reaction is usually carried out in a polar eprotic solvent such as acetonitrile at an elevated temperature, for example between 20 and 100 ° C, suitably between 30 and 80 ° C, preferably between 50 and 70 ° C. Such a reaction is usually carried out on the ester moiety of the compound of formula XI.

The compound of formula XI can usually be prepared by acylacyl of the corresponding compound wherein R 8 is hydroxy. This reaction is preferably carried out using the appropriate acid anhydride in the presence of a base, for example triethylamine. The use of 4-N, N-dimethylaminopyridine as a catalyst has been found to facilitate this reaction. Suitably, the hydroxy compounds are prepared by reacting a compound of formula IX with a Grignard compound of the formula CH ₂ = CHMgHel wherein:

Hal is a halogen atom such as bromine.

This reaction is carried out under the conditions conventionally used for irrigard reactions, for example in an inert anhydrous solvent such as tetrahydrofuran, and can be advantageously carried out in the presence of zinc chloride, wherein the resulting divinylzinc is further reacted in a sieve.

The isomerization of the compound of formula XII is conveniently carried out in the presence of an excess of one solar equivalent of a strong acid, suitably a strong mineral acid, for example sulfuric acid, from an elevated temperature, for example between 50 and 160 ° C, usually between 25 and 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 free acid compound of formula (IV) is to be prepared, it is more common to produce the corresponding ester and 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., the reduction of the double bond terminating at the -NR 1 R 3 group or the reduction of the double bond in the carboxyl side chain can usually be performed 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 likewise be carried out by methods well known to those skilled in the art.

The starting material of formula (XI) 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 in the symptoms of nasal congestion due to colds and allergic rhinitis and to control symptoms of allergic conditions including nasal allergy, persistent rhinitis, urticaria, angioneurotic edema, elergic conjunctivitis, allergies not food , drug and serum reactions, insect bites and insect bites and susceptibility removal.

The compounds may also be used under conditions appropriate to alleviate the effect of itching including allergic dermatoses, neurodermatides, anogenital itching and itching of indeterminate origin, as a result of eczema due to particular 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 1. This invention also relates to a method of counteracting internally released hietamine by administering an effective amount of a compound of formula I. Some of the compounds of this invention have been found to be substantially sedative free They have little or no enticholinergic 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 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 to Compound A (see Examples 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 for human medical purposes, which consist of a compound of the general formula together with one or more pharmaceutically acceptable carriers therefor and optionally some other therapeutic ingredients. For example, the active compound may be formulated with a sympathomimetic agent, such as a decongestant pseudoephedrine, anti-cough agent, such as analgesic codeine, anti-inflammatory, anti-magnesium, or expectorant. 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 present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, and with a special closure, tablet or cap, each containing a predetermined amount of the active compound (defined herein as a compound of formula X), as a powder or granules. or a suspension in an aqueous or non-aqueous liquid such as a syrup, elixir, emulsion or beverage.

The 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 sugar solution, for example a carbohydrate, to which a minor component or components may also be added. Such a secondary component or components may include flavoring agents, sugar crystallization retarding agents, or a solubility enhancing agent of some other component, such as a polyhydric alcohol, for example glycerol or sorbitol, and a suitable preservative.

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

Compositions suitable for parenteral administration typically 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 and preservative and ionic sessiles. Such compositions ae adjust the 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 the values appropriate 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 include one or more co-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 1 in medicine.

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

He did

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

A mixture of 56 g of 2-bromo-6- (4-tolpoyl) pyridine, 25 ml of ethyl acrylate, 30 ml of triethylamine,

0.4 g of palladium acetate, 0.9 g of triphenylphosphine and 50 ml of acetonitrile was charged to the autoclave and heated with stirring at 150 ⁰ for 6 hours. After cooling, the solid product is decomposed, washed with water and alcohol and recrystallized from alcohol. In a yield of 51 g ae, compound 2 is obtained as colorless prisms, m.p. 110-112 °.

g of triphenyl-2-pyrrolidinoethylphosphonium bromide was suspended in 750 ml of dry toluene under nitrogen, cooled with ice and treated with 100 ml of a 1.6 M solution of butyllithium in hexane over 15 minutes. The bath was removed and stirring was continued for 6 hours. 48 g of ice-cold compound 2 above dissolved in 500 ml of dry toluene are added again to the solution over 30 minutes. The mixture was then heated in a bath at 75 ^{° for} 2 hours. The following day, 500 mL of 2M ice-cold hydrochloric acid was added. The aqueous layer was separated, washed with ether, basified with ice cold ammonium hydroxide and extracted with ether. Drying and evaporation gave 46 g of a mixture of basic esters. Concentrated sulfuric acid (75 ml) was added and the mixture was immersed in a 150 ^° oil bath and stirred for 5 minutes.

After rapid cooling, 500 ml of methanol are carefully added to the mixture. The solution was then boiled at reflux for 1 hour, then evaporated to 200 ml under reduced pressure, poured onto excess ice and basified with ammonium hydroxide. Extraction with ether, drying of the washed extracts and evaporation gave 39 g of a dark oil. To this was added 750 ml of ethanol and 150 ml of 1M sodium hydroxide solution and the mixture was heated on a steam bath under reduced pressure to remove the alcohols as quickly as possible. To the remaining aqueous solution was added 150 ml of 0.5U sulfuric acid and the neutral solution was evaporated to dryness under reduced pressure. The dry residue is extracted four times with 200 ml of hot isopropanol each. Evaporation and cooling by evaporation gave 19 g of (E) -3- [6- (3-pyrrolidino-1 '- (4-tolyl) prop-1E-enyl) -2-pyridyl] acrylic acid, m.p. 220 ⁰ (with decomposition).

Example 2

(E) -3- [3-pyrrolidino-1- (4-tolyl) prop-1-enyl] benzoic acid

To a stirred cold suspension of 17.6 g of triphenyl-2-pyrrolidinylmethylphosphonium 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 at 0 ° for 30 minutes, a solution of 10.16 g of 3-methoxycarbonyl-4'-methylbenzophenone (Smith, J. Amer. Chem. Soo.,

1921, 42 (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. Purification by chromatography on 3-silica gel with a 50: 1 mixture of chloroform and methanol as eluent gave a mixture of (E) - and (Z) -methyl [3- / 3-pyrrolidino-1- (4-tolyl) prop- 1-enyl / beazoate] as a cream colored solid weighing 9.8 g.

A solution of 1.34 g of said ester in 8 ml of ethanol and 3 ml of 2 N sodium hydroxide solution was stirred at room temperature for 3 hours and after addition of 3 ml of 2N 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). (The acid hydrochloride has a melting point of 205-207 °). The ethanol extract was evaporated to dryness and the residue was recrystallized from methanol. There were obtained 285 mg of colorless prisms of (E) -3- [3-pyrrolidino-1- (4-tolyl) prop-1-enyl] benzoic acid, mp 210-215 ⁰ (dec). (The acid hydrochloride has a melting point of 180-182 °.) An additional amount of individual isomers is obtained by suitable recrystallization of the filtrate residues.

Example 3

Process for preparing 4- [3-pyrrolidino-1- (4-tolyl) -pop-1-enyl] cinnamic acid

A mixture of 6.9 g of 4-bromo-4'-methylbenzophenone (Slootmaekers, Roosen and Verhulst, Bull. Soc. Chim. Belges., 1962, 71, 446), 2.65 g of ethyl acrylate, 100 mg of palladium acetate, 225 mg of triphenylphosphine and 2.65 g of triethylamine to 20 ml of acetonitrile is heated in an autoclave unreactive »· zavějící steel under a nitrogen atmosphere at a temperature of 55 ⁰ 5 hours. After cooling, water was added and the precipitated solid was recrystallized from methanol. As a colorless plate, 2.5 g of ethyl (4-toluoyl-enemate) are obtained, m.p. 105.5-106.5 °. An additional amount of the same material (2.45 g) was isolated by evaporation of the mother liquor and chromatographic purification of the residue dissolved in dichloromethane on a silica column.

Reaction of 5.9 g of said ketone, with the phosphorate obtained from 8.8 g of triphenyl-2-pyrrolidinoethylphosphonium bromide under the conditions described in Example 2, gives a crude mixture of 4.3 g of (E) - and (Z) -ethyl [4- / 3-form]. -pyrrolldino-1- (4-tolyl) prop-1-enyl / cinnamate].

A solution of the above crude ester mixture in 43 ml of ethanol and 20 ml of 2N sodium hydroxide solution was stirred at room temperature for 4 hours. After neutralization with 20 ml of 2N hydrochloric acid, the solution was evaporated to dryness and the residue was boiled with ethanol. After removal of the insoluble sodium chloride, the filtrate was evaporated and settled, 1.1 g of crystals of (E) -4 - [(E) -3-pyrrolidino-1- (4-tolyl) prop-1-enyl] cinnamic acid, which crystallized from methanol as small colorless chips, m.p. 225-230 ^° (dec.). [The hydrochloride of this compound has a melting point of about 250 ^° (with decomposition)]. The ethanol mother liquor was evaporated and the residue was chromatographed on a silica column with a 1: 1 mixture of chloroform and methanol. 1.1 g of pure (E) -4 - [(Z) -3-pyrrolidino-1- (4-tolyl) prop-1-enyl] cinnamic acid are obtained, which crystallizes from methanol as colorless prismatic needles, m.p. up to 220 ^° (with decomposition). [Hydrochloride of this compound has a melting point of 230-235 ⁰ (dec)].

Example

Process for the preparation of 3- [3-pyrrolidino-1- (4-ethoxyphenyl) prop-1-enyl] cinnamic acid

Under the conditions described in _; Example 3 reacts 14.6 g of 3-bromo-4'-methoxybenzophenone (Allen, Schumann, Day and Van Campen, J. Amer. Chem. Soc., 1958, 8ff. 591) and 5.3 g of ethyl acrylate to give 5, 6 g of ethyl [3- (4-methoxybenzoyl) cinnamate], m.p. 71-5.5 °.

3.1 g of said ketone are reacted with the hypophosphite obtained from 4.4 g of triphenyl-2-pyrrolidinoethylphosphonium bromide under the conditions described in Example 2. 4.3 g of a crude mixture of (E) - and (Z) -ethyl ethyl [3] are obtained. - [3-pyrrolidino-1- (4-methoxyphenyl) prop-1-enyl] cinnamate].

The crude ester mixture was hydrolyzed with aqueous ethanolic sodium hydroxide solution as described in Example 2 to give a mixture of carboxylic acids. The mixture is separated by repeated crystallization from ether or a mixture of methanol and ether. To afford (E). - 3-C ^(Z) -3-pyi'roiiúino-1- (4-methoxyphenyl) prop-1-enyl] cinnamic malé'bezbarvé as prisms, mp 215-220 ⁰ (for and (E) -3 - [(E) -3-pyrrolidino-1- (4-methoxyphenyl) prop-1-enyl] cinnamic acid, as colorless needles, m.p. 220-225 ^° (dec.).

Example 5

Process for preparing 3- [3-pyrrolidino-1- (4-chlorophenyl) prop-1-enyl] cinnamic acid

5.9 g of 3-bromo-4'-chlorobenzophenone, mp 118-119 ⁰ prepared from 3-bromobenzoyl chloride and excess chlorobenzene in the presence of aluminum chloride by the method of Smith (J. Amer. Chem. Soc. 1921, 43, 1921) and 2.1 g of ethyl acrylate were reacted under the conditions described in Example 3. 4.1 g of ethyl [3- (4-chlorobenzoyl) cinnamate], m.p. 98-99.5 °, were obtained. 2.1 g of this ketone are treated with the hypophosphite obtained from 2.9 g of triphenyl-2-pyrrolidinoethylphosphonium bromide by the method of Example 2. 1.6 g of (E) -α (Z) -foray ethyl [3- / 3- pyrrolidino-1- (4-chlorophenyl) prop-1-enyl / tin-bilate].

The ester mixture is hydrolyzed using an aqueous ethanolic sodium hydroxide solution as described in Example 2. 1.5 g of the resulting carboxylic acid mixture are separated on a silica column in a 1: 1 mixture of chloroform and methanol to give (E) - £ 3- (Z) -3-pyrrolidino-1- (4-chlorophenyl) prop-1-enyl] cinnamic acid, mp 178-181 ⁰ and (E) -3- |] (E) -3-pyrrolidino (1- (4-chlorophenyl) prop-1-enyl) cinnamon, m.p. 193-195 °.

Example 6

Process for preparing 3- [1,3-dimethylamino] -1- (4-tolyl) prop-1-enyl] cinnamic acid

Using the method described in Example 3, 3-bromo-4'-methylbenzophenone (Ipatieff and Priedman,

J. Amer. Chem. Soc., 1939, 61. 684) is converted to ethyl [3- (4-toluoyl) o -namnamate], m.p. 86-87 ^°, and then to the mixture of the (E) - and (Z) -isomers of ethyl [3- / 3-dimethylamino-1- (4-). olyl) prop-1-enyl / cinnamate]. Hydrolysis of this mixture of esters and separation of the carboxylic acid mixture by crystallization gives (E) -3 - [(E) -3-dimethylamino-1- (4-tolyl) prop-1-enyl] cinnamic acid, m.p. 200-205 ° C. and (E) -3-C ( ^z ) -3-dimethylamino-1- (4-tolyl) prop-1-enyl] cinnamic acid, m.p. 200-205 ° C.

Example 7

Process for the preparation of 3- [3- / 3-pyrrolidino-1- (4-tolyl) prop-1-enyl / phenyl] propionic acid

3.0 g of ethyl [3- (4-toluoyl) cinnamate] (Example 6) in a solution of 90 ml of ethyl acetate was shaken with hydrogen in the presence of Raney nickel catalyst until more than 1 molar equivalent of hydrogen was absorbed. After filtering off the catalyst the residue was dissolved in 200 ml of dichloromethane, 14 g mangenanu color, and the mixture stirred ee temperature of 50 ⁰ for 2 hours. The filtered solution was evaporated to give pure ethyl [3- / 3- (4-toluoyl) phenyl] propionate] as a yellow oil. (The moiety hydrolyzed with dilute, dilute, alcoholic sodium hydroxide solution afforded the corresponding kerboxylic acid, m.p. 137-138.5 °).

Using the method described in Example 3, the above keto ester is converted into the (E) - acid via a mixture of ethyl [3- [3- / 3-pyrrolidino-1- (4-tolyl) prop-t-enyl / phenyl] propionate] isomers. 3- [3-pyrrolidino-1- (4-tolyl) prop-1-enyl / phenyl] propionic acid, m.p. 138-140 ^°, and (Z) -3- [3- / 3-pyrrolidino-1- (4) (tolyl) prop-1-enyl / phenyl] -propionic acid, but not isolated in pure form.

Example

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

The cobalt magnesium magnesium bromide is prepared under a nitrogen atmosphere from 5.9 g of vinyl bromide and 1.5 g of magnesium chips in 50 ml of tetrahydrofuran. To this water-cooled solution was added 3.74 g of anhydrous zinc chloride under stirring, and the mixture was stirred under a nitrogen atmosphere for 2 hours at or below room temperature. The resulting solution was decanted from the solids of insoluble inorganic materials and gradually added to an ice-cooled and stirred suspension of 7.38 g of the keto-ester in 50 mL of tetrahydrofuran. The mixture was stirred at room temperature for 44 hours, during which time the reaction proceeded almost quantitatively. While boiling, 50 ml of 2N hydrochloric acid are added successively and the mixture is then poured onto 450 ml of water. The product is extracted with 600 [mu] l of ether, the extract is washed three times with 250 ml of water and then with 100 ml of brine and dried. Filtration and removal of the solid in vacuo gave 8.7 g of ethyl [(E) -3- (6- [1- (g-tolyl) -1-hydroxyprop-2-enyl] -2-pyridyl) acrylate] , such as a light brown oil containing some tetrahydrofuran residue.

To a stirred solution of 8.0 g of the above carbinol in 30 ml of triethylamine was added 0.80 g of 4-N, N-dimethylaminopyridine and then 8 ml. acetic anhydride and the mixture was stirred at room temperature overnight. An additional 4 ml portion of acetic anhydride was then added and the mixture was stirred overnight. After this reaction time, the reaction is again substantially complete. To the mixture was added 30 ml of ice-cold ethanol and stirred at room temperature for 30 minutes. After evaporation under reduced pressure, the residue was dissolved in 250 ml of ether and the solution was washed with 50 ml of water, twice with 50 ml of saturated sodium bicarbonate solution, 50 ml of water and 40 ml of brine and dried. Filtration and evaporation of the solvent under reduced pressure gave 8.4 g of a dark red gum. The crude product was then purified by dry column chromatography (250 g silica) eluting with hexane / ether (3: 2). Combine the appropriate fractions by evaporation under reduced pressure to give the product, which is triturated with hexane. Cooling gives 2.86 g of (31%) ethyl [(E) -3- (6- [1- (4-tolyl) -1-acetylprop-2-enyl) -2-pyridyl) acrylate] as light cream colored solid, m.p. 99 °. The sample was crystallized from hexanes to give white crystals having a melting point of 100 °.

1.825 g of the above acetate are dissolved in 15 ml of acetonitrile and 60 mg of tetrakistriphenylphosphine palladium (0) are added, followed by 25 ml of triphenylphosphine and then 0.50 ml of pyrrolidine. The mixture was then heated to 60-65 ^° under nitrogen with stirring for 2 hours. After cooling, the mixture was poured into 100 ml of water and acidified by addition of 20 ml of 2N aqueous hydrochloric acid and the solution was extracted with 50 ml of ether. The aqueous layer was then neutralized with aqueous ammonia added in a small excess and the product was extracted with ether (100 mL). The extract 13 was washed with 50 ml of water and 25 ml of brine and dried. Filtration and evaporation under reduced pressure gave 1.85 g (98%) of a light brown viscous gum-like product which is a mixture of steroisomers (E, E: E, Z = 58: 42) ethyl [1- / 6- (3- pyrrolidino-1-C4-tolyl) prop-1-enyl / 2-pyridyl acrylate].

This product was stirred with 5 ml of 95% sulfuric acid and heated to 130-135 ^° with stirring for 1 hour. The resulting solution was cooled and poured into 50 mL of ethanol and heated at reflux for 1 hour. The volume is then reduced to about half by evaporation under reduced pressure and then 100 ml of water are added. The solution was neutralized by the addition of aqueous ammonia in a small excess. The product is extracted with 100 ml of ether and the extract is washed with 50 ml of water and dried. Filtration of β by evaporation under reduced pressure yields 1.17 g (63 red acid-like substance, consisting primarily of the Ε, ε-isomer ethyl [] (E) ~ -3- / 6- / 3-pyrrolidino-1- (4-) tolyl) prop-1E-enyl (-2-pyridyl) acrylate].

The 0.75 of the above E, E-ester is hydrolyzed in a conventional manner by serosolution in 15 ml of ethanol, 3 ml of 1N aqueous sodium hydroxide solution are added and the alcohol is then evaporated on a rotary evaporator under reduced pressure. 3 ml of 1N aqueous sulfuric acid are added to the cooled residue and the mixture is evaporated to dryness under reduced pressure. The dry residue is extracted three times with 4 ml of hot isopropanol each and the combined extracts are cooled in a refrigerator. 1123 mg of a white solid is obtained, which is crystallized from 6 ml of isopropanol. 42 mg of crystals of the title compound are obtained.

Example 9

Process for isoraeration of ethyl [(E) -] 6- [3-pyrrolidino-1- (4-tolyl) prop-1-Z-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 from 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 was then added to liberate the free base. This is extracted with 500 ml of ether and the extract is washed twice with 250 ml of water, 100 ml. 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 acetonitrile. Cooling in a refrigerator gave an almost solid which was filtered off and washed with a small amount of cold acetonitrile. This material, weighing 7.5 g, is essentially pure Ε, Ε-isomer.

Example 10

A process for the preparation of 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 diethy.letheru under nitrogen at -70 ⁰ was added dropwise over 1.5 hours, 145 ml of 1.55 M solution of n-butyllithium in hexane. The reaction mixture was briefly warmed to -60 ^° and then recooled 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 over magnesium sulfate and then evaporated to give a solid residue of 55.2 g. The residue was recrystallized from ethyl acetate / hexane 1: 1 to give 41.1 g of α- (6-bromo-2). (pyridyl) -4-methylbenzyl alcohol having a melting point of 79.5 to 80 ^° and forming white crystals.

NMR (80 MHz, CDCl ₃ ) δ 2.32 (s, 34), 4.32 (broad s, 1H) 5.70 (broad s, 1H), 7.05 to 7.57 (a, 7H),

Analysis for C ^ HH ^ Br BrNO:

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

A solution of 41 g of .alpha .- (6-bromo-2-pyridyl) -4-methylbenzyl alcohol in 200 ml of Meinylene Chloride was added to a suspension of 53 g of pyridinium chlorohromate in 200 ml of methylene chloride. The mixture was stirred at room temperature for 6 hours and then 500 mL of ether was added. The solvent was decanted and the residue was washed with four additional 150 ml portions of ether. The combined ethereal solutions are passed over 500 g of flonisil β then evaporated to give 37.7 g of solid which is recrystallized from absolute ethanol. 32.1 g of 2-bromo-6- (4-methylbenzoyl) pyridine, m.p.

NMR (80 MHz, CDCl 3) 62.43 (s, 3H), 7.23-8.10 (m, 7H).

calculated: 56.54% C, 3.65% H, 5.07% N, 28.94% Br, found: 56.52% C, 3.70% H, 5.03% N, 28.97%. 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 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 is decanted and evaporated to give a mixture of isomeric Z and E alkenes in a Z: E ratio of about 55:45. 95: 5.

(Z) -3- (6-bromo-2-pyridinyl) -N _' N-dimethyl-3- (4-methylphenyl) allyl amine,

R ^. (silica gel, methanol): 0.37, ’

NMR (60 MHz, CDCl 3) δ 2.23 (s, 6H), 2.28 (s, 3H), 3.11 (d, 2H), 6.20 (t, 1H), 6.95- 7.5 (a, 7H);

(E) -3- (6-bromo-2-pyridyl) -N, N-dimethyl-3- (4-methylphenyl) allylamine,

R _f (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 (a, 8H).

The E-isomer is again chromatographed (silica gel, ethyl acetate, Prap 500) to give a sample with a melting point of 65-66 °.

Analysis for C ^ HH ^ Br BrNg:

calculated: 61.63% C, 5.78% H, 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) ellylemine in 50 ml of absolute ethanol is hydrogenated on activated carbon provided with 10% platinum for a period of time. 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 performed. 3.8 g of an oil are obtained, which is chromatographed on silica gel using methanol. 0.86 g of 2-bromo-6- [3-dimethylemino-1- (4-methylphanyl) propyl] pyridine is obtained, determined by thin-layer chromatography [TLC].

_Rf: 0.25 (silica - silica, methanol).

NMR (80 MHz, CDCl 3) δ 2.05 to 2.45 (m, 4.15 (broad m, 1H), 7.03 to 7.50 (a, 7W).

H), includes 2.18 (s, 3H) and 2.30 (s, 3H),

Analysis for C ^ HHg ^NN:

calculated: 6.22% C, 6.35% H, -8.41% N, 23.98% Br, found: 61.37% C, 6.37% H, 8.38% N, 23 84% Br.

1.0 ml of a 1.7M solution of n-butyllithium in hexane was added dropwise to the solution with stirring, 0.537 g

Of 2-bromo-6- [3-dimethylamino-1- (4-methylphenyl) propyl] -pyridine in 15 mL of dry tetrahydrofuran cooled to -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 was dissolved in 16.1 ml of 0.1N hydrochloric acid and evaporated to dryness. . 6- [3-Dimethylamino-1- (4-methylphenyl) propyl] -2-pyridinecarboxylic acid was isolated as uonohydrate after silica gel thin 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 (β, 6H),

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

Analysis for CjgHggNgOg.HgO:

H, 7.65; N, 8.85. Found: C, 68.16; H, 7.65; N, 8.82.

They did

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

To a suspension of 330 mg of lithium aluminum hydride in 62 ml of ether was added methyl [3- / 3-pyrrolidino-1- (4-tolyl) prop-1-enyl] benzoate (mixture of isomers E and Z of Example 2) and the mixture was refluxed for 6 hours . Then 0.33 ml of water is added, followed by 0.33 ml of 15% sodium hydroxide solution and finally 1 ml of water. The solid was filtered and washed with ether. The ether filtrate was evaporated to give 4.1 g of an oil which, upon cooling in solution in a mixture of ether and petroleum ether (bp 40-60 °), precipitated 1.43 g of crystals. Recrystallization from petroleum ether (b.p. 60-80 °) affords pure (E) -3- [3-pyrrolidino-1- (4-tolyl) prop-1-enyl] benzyl alcohol as colorless needles, m.p. 96-97. °. The ether petroleum ether filtrate was evaporated and the residue separated by high performance liquid chromatography (silica, dichloromethane / methanol / triethylamine 98.5:

: 1,25: 0,25) to obtain most of the above isomer E as well as (Z) -3- [3-pyrrolidino-1- (4-tolyl) prop-1-enyl] benzyl alcohol, which forms colorless prisms m.p. 67-69 °, petroleum ether (b.p. 60-80 °).

To a stirred solution of 1.1 g of the above (E) -3- [3-pyrrolidino-1- (4-tolyl) prop-1-enyl benzyl alcohol in 75 mL of dichloromethane is added barium manganate (Firouzebadi and Qhadari, Tetrahedron Letters, 1978) 839) and the mixture is maintained at 40 ^° C for 7 hours and then left at room temperature for 16 hours. The solid was filtered off and the filtrate was evaporated. There was obtained 1.09 g of crude (E) -3- [3-pyrrolidino-1- (4-cyclohexyl-prop-1-enyl) -benzaldehyde, which was not further purified. To a stirred suspension of 107 mg of sodium hydride (80% oil suspension) in 3 7 ml of 1,2-dimethoxyethane was added 740 mg of diethyl [methoxycarbonylraathylphosphonate] in 3.7 ml of 1,2-dimethoxyethane, after stirring for 15 minutes, a solution of 1.09 g of the above (S) -aldehyde in 3.7 ml of 1 was added dropwise. , 2-dimethoxyethane, and the mixture was stirred at room temperature for 18 hours.

After the addition of water and acidification with dilute acidified hydrochloric acid, the suspension was washed with ether and the clear aqueous solution was basified with sodium carbonate solution. The precipitated oil was extracted with ether. The washed and dry ether solution was evaporated to give 800 mg of a solid which was dissolved in ethanol and refluxed with 200 mg of Grignard reagent P for one hour. The solvent was evaporated, water and ether were added and the ether extract was washed, dried and evaporated. 620 mg of methyl [(E) -3-pyrrolino-1- (4-tolyl) prop-1-phenyl] clnenate] are obtained, m.p. 102-107.

620 mg of this ester are dissolved in 7 ml of ethanol, 2.85 ml of 2N sodium hydroxide solution are added and the mixture is stirred at room temperature for 4 hours. 2.85 ml of 2N hydrochloric acid are added and the solution is evaporated to dryness. Extraction of the solid residue with ethanol and evaporation of the filtered extract gave 600 mg of a solid which was recrystallized from aqueous Isopropenol. Afford acid (£) -3 - [/ E) -3-pyrrolidino-l- (4-tolyl) prop-l-enyl] cinnamic acid mp 190 ⁰ (from decomposition) as a pale buff colored plate. This compound forms a hydrochloride salt, m.p. 240-245 ⁰ (dec).

Example 1 and d 12

Process for preparing 4- [3-pyrrolidino-, - (4-tolyl) prop-1-enyl] benzoic acid

Under the conditions described in Example 2 and 4-methoxycarbonyl-4'-methylbenzophenone (Smith,

J. Amer. Chem. Soc., 1921 (£ 2, 1921) is reacted with a triphenyl-2-pyrrolidinoethylphosphonium bromide-derived hypophosphite. A mixture of (E) - and (Z) - methyl [4- [3-pyrrolidino-1- (4-tolyl) prop-1-enyl] benzoate] was obtained. After hydrolysis as described in Example 2, the acid mixture is readily separated by crystallization from ethanol. To afford (E) -4- [3-pyrrolidino-1- (4-tolyl) prop-1-enyl] benzoic acid as small colorless prisms, m.p. 235-240 ⁰ (dec) Hydrochloride mp 250 with decomposition) and (Z) -4- [3-pyrrolidino-1- (4-tolyl) prop-1-enyl] benzoic acid, as colorless prisms, m.p. 245 ml to 250 ° (dec.) hydrochloride melting greater than 260 ° (slow decomposition).

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

(E) -3- [6- (3-pyrrolidino-1- (4-tolyl) prop-1E-enyl) -η 2 -pyridyl] acrylic acid (compound A), mp 222 ⁰ (dec.), E isomer of acid 3- [6- / 3-pyrrolidino-1- (4-tolyl) prop-1E-enyl] -2-pyridyl] propionic acid (compound B), m.p. 156-57 °, isomer E of 3- [6- (3-Dimethylamino-1- (4-tolyl) prop-1E-enyl) -2-pyridyl] acrylic, m.p. 222-225 ^° (dec.), (E) -3- [6- / 3-pyrrolidino acid] -1- (4-tolyl) prop-1E-enyl / -2-pyridyl] acrylic acid, mp 218-219 ⁰ (dec)

E isomer of 6- [3-pyrrolidino-1- (4-tolyl) prop-, E-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.

(E) -3- [6- (3-pyrrolidino) - (4-trifluoromethylphenyl) prop-1 E-enyl-2-pyridyl] acrylic acid, m.p. 223-225 ^° (dec.), acid (E) ) -3- [6- / 3-Pyrrolidino-1- (4-methoxy-phenyl) -prop-1E-enyl] -2-pyridyl-acrylic acid, m.p. 231-232 ° (dec.), (E) -3 [6- . (T-phenyl-3-pyrrolidinoprop-1E-enyl) -2-pyridyl] acrylic acid, mp 180-182 ⁰ (dec), (E) -3- [6- / 3-pyrrolidino-1- (4 tolyl) prop-1E-enyl / -2-pyridyl] acrylamide oxalate, m.p. 198-199 ⁰ (dec) ethyl / (E) -3- [6- / 3-pyrrolidino-1- (4 - tolyl) prop-1E-enyl (-2-pyridyl) acrylate] oxalate, m.p. 155-156 °, (E) -3-O - [1- (4-chlorophenyl) -3-pyrrolidinoppop-11] 218-220 °, 3- [6- / 3-pyrrolidino-1- (4-tolyl) prop-1E-enyl] -2-pyridyl] prop-2E- enamidoootic, melting point 257-258 ^° (dec.), (E) -3- [6- / 3-pyrrolidino-1- (4-tolyl) prop-1E-enyl] -2-pyridyl] acrylic acid, 6 - [6- / 3-pyrrolidino-1- (4-tolyl) p 118-121 [deg.], 6- [1- (E-chlorophenyl) -3-dimethylaminopropyl] -2-pyridinecarboxylic acid, m.p.

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 to 7.45 (m, 5H),

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

Analysis for C ^ H ^ gCINgOj · 2H ₂ O:

calculated: 57.54% C, 6.53% .H, 7.89% N, 9.99% Cl, found: 57.68% C, 6.652% H, 7.86% N, 10.10% Cl acid, 6- [l- (4-chlorophenyl) -3-dimethylaminopropyl] -2-pyridinecarboxylic TLC _Rf: 0.24 (silica gel-methanol), (E) -6- [l- (4-chlorophenyl) -3-dimethylaininopropyl] - 2-pyridyl acrylic 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 (W, 1H), 6.65 to 7.70 (m, 9H), 11.5 (wide s, exchangeable), ethyl [(E) -3- 6- / 3-acetoxy-1- (4-tolyl) prop-1E-enyl] -2-pyridyl] acrylate ] and ethyl [(E) -3- [6- (3-pyrrolidine-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 tension of 300 mg. After one hour of equilibrium, curves corresponding to the total histamine concentration were obtained (J.M. Van Rossum, Arch. Int. Pharmacodyn, Ther. 143, 299-330, 1963). After washing, the tissues are incubated for 1 hour 8 with the test compound, followed by a curve corresponding to the secondary histamine concentration. Shifts to the right of the curve corresponding to the agonist concentration generated by the anta235350 gonists are used to construct Shild diagrams (O. Arunlakshana and H. O. Schild, Br. J. Pharmacol. 11, 48-58, 1959). The regression of log (dr-1) to log B, where dr is the aquiactive response in the presence or absence of antagonist and B is the molar concentration of the antagonist, allows to determine pAg, i.e. negative log concentration of tag tagonist. right.

Table I

Results of in vitro determination of antihistamine tests

> R, COQ x nr ₂ y. ^R 4 pA _g Compound AND (E) -2-CH-CHCO ₂ H TO ch ₃ 8.6 Compound (B) -2-CH ₂ CH ₂ CO ₂ H N NR-R, CH, 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-GH = CHCOOH ₂ 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-CHCO ₂ H N NR ₂ R ₃ CP ₃ 10.4 (E) -2-CH = CHCONCH ₂ CO ₂ H N ^NR 2 ^R 3 CH ₃ 6.9 -2-COgH CH nr ₂ r ₃ CH ₃ 8.1 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-OH = CHCO ₂ H CH mr ₂ y ₃ CHj 8.8

B. Antihistamine effect in vivo

Guinea pigs (Hartley, males weighing 300-350 g) are left without food for 20 hours and then given the oral or intraperitoneal test compound. One day 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 an aerosol inhaler. In guinea pigs, signs of histamine anaphylaxis such as cough, sneezing, severe abdominal movements, cyanosis are recorded. Under assay conditions, control animals collapse on average 33 seconds for EDg ₀ for histamine protection calculated from probit analysis. In this ED50 test, at a particular 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 ae is determined to protect against hiatamine 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) Triprolidine 5.77 AND 0.44 (B) 0.17 C 1.7 D 0.64

In addition to these results, it has been found that Compound A may have a very long antihistamine effect (for example, 11 mg / kg p.o. will provide ΕΏ ^ θ for protection for 24 hours).

Example 13

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 autoclaved.

Composition B

Cípky

Component Quantity per suppository

Compound of Formula I 1.0 mg

Cocoa butter or suppository base

Wecobee ™ up to 2.0 g

Note:

Wecobee is a protected designation, a 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

Component Quantity per 5 m Compound of Formula I 1.0 mg Ethanol 0.3 mg Sucrose 2.0 mg Methylperaben 0.5 mg Sodium benzoate 0.5 mg Cherry flavor as required Dye as required Water to 5.0 ml

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.

Environment D

Tablets

Quantity tab on tablet

Compound of formula

Lactose

Pregelatinized maize starch

1.0 mg 110.0 mg 2.5 mg

Component

Quantity on tablet

Potato starch Magnesium stearate

12.0

0.5 mg 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

Component Amount per capsule Compound of Formula I 1.0 mg Lactose 440.0 mg Magnesium stearate 5.0 mg The finely divided active compound is mixes with powder excipients, and magnesium stearate and packed into gelatin capsules. Means P Tablets Component Amount on tablet Compound of Formula I ',O mg Pseudoephedrine hydrochloride 60.0 mg Lactose 62.5 mg Potato starch 14.0 mg Magnesium stearate 1.0 mg gelatine 2.8 mg Tablets are prepared from the ingredients by the method. , which is described in Example 13 Resource 0 Syrup Component ³ Quantity to 5 ml Compound of Formula I 1.0 mg Pseudoephedrine hydrochloride 30.0 mg Codeine phosphate 10.0 mg Guaifenesin , 00 mg Methylparaben 0.5 mg Sodium benzoate 0.5 mg Příchul as required Dye as required Glycerol 500 mg Sucrose 2 000 mg Cleaned water to 5.0 ml · Syrup containing other active ingredients components other than the compound of formula 1 from the ingredients listed above by a similar method, as described in Example 13C Composition H Nasal spray Component Amount to 100.0 ml

Compound of Formula I g

Component

Quantity ng 100.0 ml

Sodium chloride 0.8 g Preservative 0.5. G cleaned water to 100.0 ml The preservative is dissolved in hot purified water and after cooling m Sodium chloride a is added at 25 to 30 ^° C compound of formula I. Value; adjust to 5.5 to 6.5 and volume make up with purified water and the final 100 Means I Eye solution Component Quantity per 100,0 ml Compound of Formula I 0.1 g Sodium chloride 0.8 g Preservative 0.5 g Water for injections and 100.0 ml This preparation is being prepared in a similar way to a nasal spray. Prostředek J Topical cream Component Quantity per 100,0 ml Compound of formula Γ 0.1 g Emulsifying Wax, N.P. 15,0 g Mineral oil 5.0 g

? THE INVENTION OF THE INVENTION

Claims (12)

A process for the preparation of novel amino compounds of formula X R - CO ₂ H / A — c— C — B (I) CH ₂ NR ₂ R _{3 -} 4 where R 1 represents a bivaleat aliphatic hydrocarbon group having 1 to 7 carbon atoms or a single bond, R 8 and R 8, which may be the same or different, each represent hydrogen, alkyl of 1 to 4 carbon atoms or together with nitrogen form a nitrogen-containing heterocyclic ring having 4 to 6 ring members, meaning hydrogen, halogen, hydroxy, cyano, acyloxy and (4) carbon atoms, (C1-C4) alkoxy or (C1-C4) alkyl optionally substituted by (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 the compound of formula XI> (XI) where R 1 and X are as defined above and R 8 is C 1 -C 4 acyloxy, reacted with an amine of formula XX ₂ ( ₃₎ (XX) wherein: R ₂ and R are as defined above, and optionally converting the ee obtained compound of formula I into another compound of formula I or a salt, ester or amide. 2. Method according to claim 1, characterized in that starting from compounds of the above formula to a compound of formula II R @ _{1 CO2} H / A - C - C - B q CH ₂ NR ₂ R 3 (II) r ₄ wherein R1 to R1, X, A and B are as defined above, or a salt, ester or amide thereof. 3. The method according to claim 1 or 2, characterized in that starting from compounds of the above formula to a compound of formula wherein R represents a group of formula _{(CH2) n} where n is an integer of 0-7, 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, starting from compounds of the above formulas to form a compound of formula IIIa (IIIa) wherein: R 1 is a group of formula where n is an integer from 1 to 7, or is a group of formula (ΟΗ ₂ ) ₀ ΟΗ = ΟΗ (ΟΗ ₂ ) ^, where a and b are independently 0 to 5 and the sum of a and b 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 form together with nitrogen a 4-6-membered nitrogen-containing heterooyl ring, such as pyrrolidino, piperidino or morpholino and _And R ^ represents hydrogen or halogen, such as bromo or chloro, lower alkyl group of 8 from 1 to 4 carbon atoms or an lower alkoxy group having 1 to 4 carbon atoms, or its salt, ester or amide. 5. The method according to any of the points! to 4, starting from compounds of the above formulas to form a compound of formula wherein R 1 is a group of formula (CH ₂ ) ₂ or -CH = CH-, the radical -NB 9 R 1 is a pyrrolidino or dimethylamino group and R 1 is methyl , trifluoromethyl, methoxy, bromine or chlorine. 6. 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 IIIb. R ₄ A (Illb) R 1 represents a group of formula (UH ₂ ) _n , where n is an integer from 1 to 7, or represents a group of formula (CH ₂ ) _and CH = CH (CH ₂ ) 4, 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 monfolinol; 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, starting from compounds of the above formulas to form a compound of the formula wherein R 1 is a group of formula (CHg) g or -CH = CH-, the radical -NRgR R 4 is pyrrolidino or dimethylamino and R 4 is methyl, trifluoromethyl, methoxy, bromo or chloro. 8. A method according to any one of claims 1 to 7, which is based on compounds of the above formulas to form a compound of formula IV wherein: R1 to R1 are as defined above, or a salt, ester or amide thereof. 9. A process according to claim 8, starting from compounds of the above formulas to form a compound of formula IV, wherein R1 is a single bond, a group of formula -CH = CH- or -CHgCHg-, the radical -NRgR4. is pyrrolidino and 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 wherein CA-CB is a double bond and the -CHgNRgR4 group is in a trans position relative to the X-containing ring. . 11. A process according to any one of claims 1 to 7, wherein the compounds of the above formulas are formed to form a compound of formula (V) Severography, n. P., MOST Price 2,40 Kčs where R 1 or R 2 are as defined above, or a salt, ester or amide thereof. of 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.dbd.CH-- or --CH.sub.2 CH.sub. and R 6 is chloro or bromo.