CS235348B2 - Method of new aminocompouds 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 novel intermediates used in their manufacture and pharmaceutical compositions containing them and used in medicine.

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

U.S. Patent No. 2,717,023 discloses a class of pyridylpropenylamines with antihistamine activity, the most prominent being a compound called (E) -1- (4-methylphenyl) -1- (2-pyridyl) -3-pyrrolldino-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) -S-pyrrolidino-1-propene which has little or no antihistamine effect.

The antihistaminic agents used, including diphenylhydramine, pheniramines, pyrilamine, promethazine and tripolidine, 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.

(1)

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 atoms or a single bond,

R 6 and R 6, which may be 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

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

X is -N = or -CH = a

A and B are hydrogen or

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

Among the compounds of formula I, 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 1 may be a straight or branched chain saturated or unsaturated hydrocarbon group or a single bond * Preferably R 1 contains at most one double or triple bond, R 1 preferably represents a group of formula (C ^ n * ^{where n is an} integer from 0 to 7 or a group of formula ( Wherein e and b are independently the numbers 0 to 5 and the sum of a 'and b does not exceed 5.

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

^R 4A (IIIa) or Formula IIIb

where

R 1 represents a group of formula (CH ₂ ) _n , wherein n is an integer of 1 to 17 or a group of formula (CK ₂ ) Cl ₆ 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 with nitrogen form a nitrogen-containing heterocyclic ring of 4 to 6 ring members such as pyrrolidino, piperidino or morpholino and

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

f t

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 are 0.

Suitably, R 1 and R 2 are the same or different and are each methyl or ethyl or form together with the nitrogen atom to which they are attached a four to six membered heterocyclic ring, preferably a saturated heterocyclic ring such as pyrrolidine, piperidine or morpholine. NR @ ₂ R @ ₃ is preferably pyrrolidino or dimethylamino.

Suitably R @ 1 is hydrogen, halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or trifluoromethyl. Particularly preferably R @ 1 represents hydrogen, methyl, ethyl, trifluoromethyl, methoxy, bromine, chlorine or fluorine. Preferably R @ 1 denotes methyl, trifluoromethyl, methoxy, bromine or chlorine. Most preferably, R R 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 are especially preferred those in which R represents a single bond (i.e. n is 0), -CH = CH- or -CHgCHg-, NR ^ R ^ is pyrrolidino and R ₊ is methyl or trifluoromethyl.

Another preferred group of compounds of formula I are compounds of formula V (V) / R 1 CO 3 H 2 A

CH-CH ₂ -CH ₂ N / ^W 2 1 → 4 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 CH2 -, NR @ 8 R @ 6 is dimethylamino and R @ 4 is chloro or bromo are particularly preferred.

The amides of the compounds of formula 1 included within the scope of the present invention are amides usually formed from carboxylic acids. Particularly preferred are amides formed from ammonia, primary amines or amino acids such as glycine.

Solvates of the compounds of Formula 1 are also included within the scope of this invention. Preferred solvates include hydrates and alkanols having 1 to 4 carbon atoms.

When the compounds of formula I contain a double bond in the side chain terminated by -NR 8 R 1, 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 invention also relates to mixtures of isomers. When the S ₁ sub-substituent-R 3 CO 5 H contains a double bond, there are additional isomers of the compounds of formula I. Both isomers and a mixture of isomers of these compounds are within the scope of the invention. When the -R5CO8H 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 of amides of compounds of formula I having 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 suitable 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.

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 benzeneulfonic acid. Also, pharmaceutically acceptable salts can be prepared as alkali metal or alkaline earth metal salts, such as sodium, potassium or calcium salts formed on the carboxy group.

Preferred compounds of formula I include:

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

3- [6- / 3-pyrrolidino-1- (4-tolyl) prop-1E-enyl] -2-pyridyl] propionic acid, (E) -3- 6- / 3-dimethylamino-1- (4-tolyl) (E) -3- [6- (3-pyrrolidino-1- (4-trifluoromethyl-phenyl) -prop-1E-enyl) -2-pyridyl] -acrylic acid, prop-1E-enyl] -2-pyridyl] -acrylic acid,

CE) -3- [6- (3-pyrrolidino-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-enyl] benzoic acid, (E) -3- [3-pyrrolidino-1- (4-tolyl) prop-1-enyl] cinnamic acid, (E) -3-C (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-pyridylcarboxylic acid,

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

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

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

Accordingly, the present invention provides a process for the preparation of compounds of formula (I) by reacting a compound of formula (L)

Y kde

Y is CHO or R ^COOH;

Z, and Zg together represent a group of formula = 0 or one of Z, and Zg is A and the other of these represents a group of formula

-CH-B

AND

H,> ^ 2 ' ^R 3' 4 ' ^A > ® and X are as defined above, with the proviso that when Y represents a group of the formula CHO, Z, and Zg have different meanings from each other, and when Y represents a group RjCOOH, Z , and Zg together form a group = O, with a Wittig reagent suitable for introducing the side chain of the formula -CH = CH (CHg) 2 CORg, wherein b is 0 to 5 and CORg is an acid, ester or amide group as defined above; when Z, and Zg have different meanings from each other, or suitable for introducing a side chain of the formula = CHCH ₂ NR ₂ R ₃ ·, wherein R ₂ and R 6 are as defined above, when Z ₁ and Z ₂ together form = O, and then deprotecting as necessary from the carboxy group to form a compound of formula (I) wherein R 1 is (CH ₂ ) _b CH = CH (CH ₂ ) 4 and is zero and R ₂ , R ₂ R 1, R 2, X, A and B are as defined above when Y in the starting compound of formula L is CHO, or to form compounds of formula 1 wherein CA-CB is a double bond and R 1, R ₂ ,

R p R 6 and X are as defined above when Y in the starting compound of formula L is R, COOH, and then optionally converting the obtained compound of formula I into another compound of formula I by methods well known to those skilled in the art, e.g. The compound of formula (XII)

where

X and 8 to R 6 are as defined above and

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

Thus, in the process of the invention, a compound of formula VIII is reacted

(VIII) where

R ₂ , R p R 6, A e B are as defined above, with a Wittlg reagent suitable for side-chain introduction of -CH 5 Cl 2 CH 2 J 2 CORg, where b is 0 to 5 and CORg is an acid, ester or amide group as defined above; then deprotecting as necessary the carboxy group to form a compound of formula I wherein R 1 is a group of formula (CH ₂ ) _and CH = CH (CH ₂ ) b, and is 0, or an ester, amide or carboxylic acid salt representing the compound of formula IX

R4 r ₁ every ₂ h (ix) where

X, R ₁ and R 6 are as defined above, are reacted with a Wittlg reagent suitable for introducing a side chain with CHCl 2 NR 6 R p where R ₂ and R 6 are as defined above, then removing the carboxy protecting group as necessary to form Compounds of formula 1 wherein CA-CB is a double bond and R 1, H 2, R p, R 6 and X are as defined above.

The reaction is a preliminary Wittig reaction and as such is analogous to those described in Organic Reactions, 14, 270-490 (1965) and Pure and Applied Chemistry, 2>

245-254 (1964). The reaction is conveniently carried out in an anhydrous solvent inert under the reaction conditions used, for example toluene, benzene, tetrahydrofuran, dioxane, glycol ether and C 1 -C 6 alkyl ethers, such as ethyl ether, at a temperature between -80 and 100 ° C. The Wittig reagent is conveniently prepared by treating a strong base phosphonium salt, for example, a C 1 -C 4 alkyl lithium such as butyllithium, or aryllithium, or a metal hydride such as sodium hydride, in a suitable inert solvent such as the one defined above.

The Wittig reagent allowing the introduction of the side chain of formula (ΟΗ ₂ ) _β ΟΗ = ΟΗ (ΟΗ ₂ ) ^, Nde and b are as defined above, is usually produced by reacting a compound of formula (R, _O ) ₂ PO (CH ₂ ) _and CO ₂ R ₆ where

Rg is as defined above,

R ₁₀ is C 1 -C 4 alkoxy and d is 1 to 6, or by reacting a compound of formula (R 9) ₃ P ( ^CH 2) _d CO ₂ R 6 wherein

R 8 and R 8 are as defined above and d is 1 to 6, with a strong base such as sodium hydride in a suitable inert solvent such as tetrahydrofuran or dimethoxyethane at a temperature between 0 and 50 ° C, usually at room temperature.

The reaction between the Wittig reagent and the compound of formula VIII is conveniently provided by adding the compound of formula 7111 to the Wittig reagent at a temperature between 0 and 50 ° C, usually at room temperature.

The compound of formula VIII is conveniently produced by oxidation of the corresponding alcohol, for example by oxidation of barium manganese in a halogenated alkane such as dichloromethane at a temperature that is not extreme, for example between 0 and 75 ° C. The alcohol may be prepared by reduction of the corresponding acid or ester thereof, i.e., a compound of formula I wherein S is (CH3) g. This reduction can conveniently be carried out using a metal hydride such as lithium aluminum hydride in an inert solvent such as an ether, for example diethyl ether, at a temperature between 0 and 75 ° C, suitably in the reflex.

The Wittig reagent to introduce the side chain of formula aCHCHgNRgR ^ ,, R ₂ and R are as defined above, is typically a compound of the formula _{(R) 3} P = CHCH ₂ NR ₂ R ₃ wherein

R ₂ and R have the abovementioned meaning and

R 8 represents a C 1 -C 4 alkyl group or a phenyl group which may be liberated from the corresponding phosphonium salt of formula (R 8) ₃ P ⁺ CH ₂ CH ₂ NR ₃ R ₃ Hal wherein:

Hal means chloride or bromide and

R ₂ and R ₃ are as defined above, with a strong base. The reaction is conveniently carried out in an inert solvent such as toluene or tetrahydrofuran at a temperature of 0 to 50 ° C, usually at room temperature. Suitable strong bases are alkyllithium compounds such as butbyllithium or aryllithium, or metal hydrides such as sodium hydride. It has been found that the use of butyllithium in toluene at room temperature is particularly suitable. Phosphonium salts of general formula (Rg) ₃ P ⁺ CH ₂ CH ₂ NR ₂ R ₃ Hal where

R ₂ , ^H 3> ^H 9 ^{and Hal} have the meanings given above, can be prepared by known methods (see, for example, British Patent No. 1,161,201).

Compounds of formula (IX) wherein R 1 means the group -CH = CH- in the trens position may be prepared by reacting a compound of formula XV ⁿ 4 (XV) wherein

R 6, R 8 and X are as defined above, with an acrylate of formula XVI

CH ₂ - ··· CHCO 3 R 6 (XVI) where

R 8 represents a C 1 -C 4 alkyl group in the presence of a catalyst consisting of palladium acetate, triarylphosphine and a tertiary amine such as triethylamine or tributylamine at elevated temperatures, for example 120 to 180 ° C, usually 140 to 50 ° C. The reaction may optionally be carried out under reduced pressure to achieve the desired temperature range. Optionally, solvents such as acetonitrile may be used and the reactants may be heated together in a sealed pressure vessel (see, for example, R. P. Heck et al., J. Org. Chem. 2 947 (1978)).

Compounds of formula (IX) may also be prepared by reacting a compound of formula (XVII)

where

X and R ^ are as defined above, and ®, 1 ^and 12 12 ', which are the same or different, are each alkyl of 1 to 4 atoms or may together form a cyclic ketal of up to 6 carbon atoms, with malonic acid in the presence of a suitable base , such as pyridine or pyperidine, or with a Wittig reagent produced by treating a phosphonium salt of formula XVIII A (Rg) ₃ P ⁺ (CH ₂ ) _d CO ₂ R ₆ Hal (XVIII A) wherein

R g, R g, and d Hal are as defined above, or a phosphonate of general formula XVIII B (R _{10) 2} PO (CH _{2) d} C0 ₂ Rg (XVIII B) wherein

R 8, R ₁₀ and d are as defined above, in a suitable base in an appropriate solvent.

The ketone of formula (IX) can also be prepared by hydrolyzing the protected ketal under acidic conditions. The double bond in the R group can, if desired, be reduced with hydrogen in the presence of a catalyst such as palladium on activated carbon.

Compounds of formula XVII may be prepared from compounds of formula XV by conversion to ketal, by reaction with a mono- or dihydroxy compound in the presence of an acid catalyst and then by reaction with an alkyl metal compound such as butyllithium and then treatment with dimethylformamide. The reaction is preferably carried out at a low temperature below -60 ° C in a solvent such as toluene.

Compound (XV), on the other hand, can be produced by treating compound (XVIII) (XVIII) wherein:

X is as defined above and

R 8 represents a halogen, such as chlorine or bromine, with an alkyl metal compound, for example butyllithium, in a suitable solvent such as toluene and then reaction with a compound of formula XIX

(XIX) where

R1 is as defined above.

•

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

Compounds of formula (XII) may be prepared as by-products in the preparation of compounds of formula (1) 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 then saponify it with, for example, an alkali metal hydroxide such as sodium hydroxide,

In a C 1 -C 4 alkanol such as ethanol to obtain an acid.

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

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

The compounds of the present invention can be used for the same indications as triprolidine, namely, symptoms that reduce nasal congestion due to colds and allergic rhinitis, and to control symptoms of allergic conditions including nasal allergy, persistent rhinitis, urticaria, angioneuretic edema, allergic conjunctivitis, food allergies , reaction on. drugs g serum, insect bites and insect bites and reactions causing sensitivity 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 and for special 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. This invention also relates to a method of counteracting internally released histamine by administering an effective amount of a compound of formula I. Some of the compounds of this invention effects have little or no anticholinergic 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's judgment. A suitable oral dose of the active compound P Cobbler ^r0 is in the range from 0.003 to 1.0 mg per kilogram body weight and Fr, preferably from 0.04 to 0.24 mg / kg. For example, a typical human dose to 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 1 are used, each will be in the range of 0.014 to 0.08 mg / kg body weight, for example a typical longer dose of such human compound recipient is between 1 and 20 mg, e.g. 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 invention also relates to pharmaceutical compositions, both for veterinary and for 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 sypatomometric agent such as decongestant pseudophedrine, a 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 such; which are 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 or non-aqueous liquid such as a syrup, elixir, emulsion or beverage.

Tablets may be made by compression or melt, optionally with one or more accessory ingredients. The compressed tablets may be compressed on a suitable machine with 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 compound to a concentrated aqueous solution of a sugar, for example a saccharide, to which may also be added a minor component or components. Such minor component (s) 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 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 co-ingredients selected from diluents, buffers, flavoring agents, binders, disintegrants, surfactants, thickeners, preservative lubricants (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.

He did

(E) -3- [6- (3-Pyrrolidino-1- (4-tolyl) prop-1E-enyl-2-pyridyl] acrylic acid (Compound A) ml of a 1.65 M solution of butyllithium in hexane was added under nitrogen to a stirred suspension

19.5 g of 2,6-dibromopyridine in 200 ml of dry ether at -50 °. After 0.75 h a solution of 10 g of 4-tolunitrile in 50 ml of ether was added and stirring was continued at -50 ° C for three 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-toluoyl) pyridine, weighing 12.2 g, forms colorless needles with a melting point of 97-98 °.

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

The cooled solution was poured onto ice and water containing 100 g of sodium carbonate with stirring. The benzene layer was separated, washed with water, dried over sodium sulfate and evaporated to about 500 ml. Cooling gives 170. g of 2- (6-bromo-2-pyridyl) -2- (4-tolyl) -1,3-dioxane (compound 1), m.p. Dilution with petroleum ether gave a second crop (34 g), m.p. 109-112 ° C. The 3 g residue obtained after evaporation is recirculated.

A solution of 70 g of the above compound in 800 ml of dry toluene was added dropwise over 5 hours to a stirred solution of 200 ml of 1.6 M butyllithium in hexane and 200 ml of toluene at -65 to -72 ° under nitrogen. After an additional 30 minutes at -70 °, 40 ml of dry dimethylformamide are added over 35 minutes. Stirring was continued overnight from -70 to -60 °.

Then 400 ml of 2 L hydrochloric acid are added and the temperature is allowed to rise to about -10 °. After another 30 minutes, about 90 mL of 2 N 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) -1,3-dioxolene, weighing 63.9 g, is crystallized at a temperature maintained at 3 °. The substance has a temperature of 52 to 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 ether (25 mL) and treated with 2N hydrochloric acid (5 mL). The organic phases are separated, washed with water, dried and evaporated. The resulting oil was dissolved in 20 mL of ethanol containing 3 mL of concentrated hydrochloric acid and 3 mL of water. The mixture was then heated on a steam bath for 10 minutes, diluted with ice water, basified with sodium bicarbonate solution and extracted with ether. Evaporation gave (E) -3- [6- (4-toluoyl) -2-pyridyl] acrylate (compound 2), which crystallized from cyclohexane to colorless plates, m.p. 108-111 °, weighing 1 βίο ml. A 1.64 M solution of butyllithium in hexane was added to a stirred suspension of 7.2 g of triphenyl-2-pyrrolidinoethylphosphonium bromide in 75 mL of dry toluene under nitrogen. After half an hour, 4.8 g of compound 2 above was added to 50 ml of toluene. The suspension initially orange turned dark purple 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 from 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 1 L of sodium hydroxide solution and partially evaporated on a steam bath under reduced pressure for 5 minutes. The remaining aqueous solution was neutralized with 20 ml of 0.5 M sulfuric acid and evaporated to dryness. The solid residue is extracted three times with 50 ml of hot isopropanol each and the combined extracts are evaporated until crystallization occurs. (E) -3- [6- (Pyrrolidino-1- (4-tolyl) prop-1E-enyl) -2-pyridyl] acrylic acid (compound A) after recrystallization from isopropanol has a melting point of 222 ° (with decomposition).

Example 2

Process for the preparation of 3- [6- / 3-pyrrolidino-1- (4-tolyl) prop-1E-anyl] -2-pyridyl] propionic acid (compound B)

A solution of 3 g of Compound 2 above in 100 ml of alcohol containing 1 g of Raney nickel is stirred under hydrogen at room temperature and 100 kPa pressure until the calculated amount of hydrogen has been absorbed (about 45 minutes). The reduced ester was filtered off, evaporated and purified on a silica gel column using petroleum ether as eluent. Treatment of this ester with the Wittig reagent by the method of Example 1 and then saponification yields a mixture of two isomeric acids which is separated by fractional crystallization from a mixture of ethyl acetate and petroleum ether. The less soluble isomer of 3- [6- (3-pyrrolidino-1- (4-tolyl) prop-1E-enyl) -2-pyridyl] propionic acid (Compound B) has a melting point of 156-157 °.

Example 3

(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-tolyl) 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 are placed in an autoclave and heated to 150 DEG C. with stirring for 6 hours. After cooling, the solid product is decomposed, washed with water and alcohol and recrystallized from alcohol. Yield: 51 g, colorless prisms 2, 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 again added 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. Ethanol (750 ml) and sodium hydroxide solution (150 ml) were added 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 0.5 U 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. Partial evaporation and cooling gave 19 g of (E) -3-C5- [3-pyrrolidino-1- (4-tolyl) prop-1E-enyl] -2-pyridyl acrylic acid, m.p. 220 (dec.) .

Example

Process for preparing 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 U 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 2 L hydrochloric acid and filtered from a small amount of solid 3. The toluene layer was separated and evaporated to give 7 g of an oil. This was heated in a steam bath for 10 minutes with 10 ml of 6 M 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 °. (Treatment 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 affords, after the usual operating procedure, 2.5 g of ethyl [6- (4-tolyl) pyridine-2-carboxylate] (compound 4) as a colorless oil which slowly crystallizes.

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 the ethyl acetate solution of Example 3 results in crystallization of the more soluble Z isomer, m.p. 187 DEG-189 DEG.

EXAMPLE 1 a.d 5 'Process for the preparation of (E) -3- [6-pyrrolidino-1- (4-trifluoromethylphenyl) prop-1E-enyl] -2-pyridyl acrylic acid

2-Bromo-6- (4-trifluoromethylbenzoyl) pyridine, m.p. 66-68 [deg.] (Prepared from 2,6-dibromopyridine and 4-trifluoromethylbenzonitrile by the method of Example 1) was converted to (E) -ethyl- [3] by the method of Example 3 - [6- (4-Trifluoromethylbenzoyl) -2-pyridyl] acrylate] m.p. 129-132 [deg.] C. Further treatment with the Wittig reagent by the method of Example 1 yields (E) -3- [6- (6-) - after saponification and crystallization from isopropanol. (3-pyrrolidino) - (4-trifluoromethylphenyl) prop-1E-enyl) -2-pyridyl] acrylic, m.p. 223-225 ° (dec.).

Example 6

(E) -3- [6- (3-pyrrolidino-1- (4-methoxyphenyl) prop-1E-enyl) -2-pyridyl] acrylic acid

The 4-methoxybenzonitrile was converted by the method of Example 5 to 2-bromo-6- (4-methoxybenzoyl) pyridine having a melting point of 116-118 °, and then to (E) -ethyl-3- [f] - (4-methoxybenzoyl) - 2-pyridyl] acrylate having a melting point of 99-100 ° C and longer to (E) -3- [6- / 3-pyrrolidino-1- (4-methoxyphenyl) prop-1E-enyl) -2-pyridyl] acrylic acid, which isopropanol to form colorless crystals having a melting point of 231-232 ° (with decomposition).

Example 7

(E) -3- [6- (1-phenyl-3-pyrrolidinoprop-1E-enyl) -2-pyridyl] acrylic acid

Using the method of Example 5, benzonitrile was reacted with 2,6-dibromopyridine to give 2-bromo-6-benzoylpyridine, m.p. 56-62 ° C, which was worked up to give (E) -ethyl-3- (6-benzoyl-2-pyridyl). acrylate having a melting point of 34 to 36 °. Treatment with Wittig's reagent then affords (E) -3-Q6- (1-phenyl-3-pyrrolidino-prop-1E-enyl) -2-pyridyl-acrylic acid, which forms white prisms from ethyl acetate, m.p. 180-182 ° ( decomposition).

Example

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

A solution of 0.5 g of compound A (from Example 1) in 25 ml of ethanol containing 0.5 ml of sulfuric acid was boiled at reflux for 2.5 hours and rapidly evaporated to a volume of 10 ml under reduced pressure. The solution was treated with ice and excess ammonia solution and extracted with ether. By adding 0.13 g of oxalic acid in 5 ml of the ethanol oxalate salt, which crystallizes from ethyl acetate as white prisms, m.p. 155-156 °.

Example 9

Process for the preparation of 6- [6- (3-pyrrolidino-1- (4-tolyl) prop-1Z-enyl) -2-pyridyl] hex-5E-enoic acid

12.8 g of 4-carboxybutyltriphenylphosphonium bromide are added under a nitrogen atmosphere to a stirred solution prepared from 30 ml of dimethylsulfoxide and 2.8 g of sodium hydride (50% oily suspension). After 5 minutes, a solution of 9.9 g of 2- (6-formyl-2-pyridyl) -2- (4-tolyl) -1,3-dioxolane in 20 ml of tetrahydrofuran was added and the mixture was stirred at 45 ° time

2.5 hours. The cold mixture was diluted with 100 mL of water, washed with ether, acidified with hydrochloric acid (ice) and extracted with chloroform. The extracts were washed thoroughly with water, dried and evaporated to dryness. 20 g of the resulting oil was heated in 100 ml of ethanol containing 50 ml of 2M hydrochloric acid for 40 minutes. The crude acid obtained by evaporation is esterified with methanol in the presence of sulfuric acid and the ester purified by distillation. Its boiling point is 200 to 210 ° / 27 Pa. Treatment of this ester with the Wittig reagent by the method of Example 1 produces a mixture of acids from which the title compound is isolated by crystallization from ethyl acetate as off-white prisms, m.p. 118-121 °.

He did

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

Treatment of compound 2 in Example 1 with a Wittig reagent obtained from triphenyl dimethylaminoethylphosphonium bromide by the method of Example 1 affords a mixture of isomeric acids which is separated by fractional crystallization from ethyl acetate. The less soluble isomer E of (E) -3r

6- (3-dimethylamino-1- (4-tolyl) prop-1E-enyl) -2-pyridyl acrylic m.p. 222-225 ° (dec.).

They did

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

To a stirred suspension of 50 g of 2,6-dibromopyridine in 500 ml of dry diethyl ether, under a nitrogen atmosphere at -70 DEG, 145 ml of a 1.55 M solution of n-butyllithium in hexane was added dropwise over 1.5 hours. The reaction mixture was briefly warmed to -60 ° and then cooled to -70% again.

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 L of 2.5 K hydrochloric acid. The aqueous layer was separated and extracted three times with ether. The combined extracts were dried (MgSO4) and evaporated to give a solid residue (55.2 g). The residue was recrystallized from ethyl acetate / hexane (1: 1). 41.1 g of N- (6-bromo-2-pyridyl) -4-methylbenzyl alcohol, having a melting point of 79.5 to 80 DEG, is obtained, which forms white crystals.

NMR (80 MHz, CDCl ₃ ) δ2.32 (s, 34), 4.32 (broad s, 1H) 5.70 (broad s, 1HX, 7.05-7.57 (m, 7H)).

H, 4.35; N, 5.04; Br, 28.73. Found: C, 56.15; H, 4.36; % N, 28.63% 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 decented and the residue was washed with four additional 150 ml portions of ether, and the combined ethereal solutions were passed through 500 g of florisil and then evaporated to give 37.7 g of solid which was recrystallized from absolute ethanol to give 32.1 g of 2. -bromo-6- (4-methylbenzoyl) pyridine, m.p. 95-96 °.

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

Analysis for Ο, ₃ Η, θΒΓΝ0:

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; A solution of 30 g of 2-bromo-6- (4-methylbenzoyl) pyridine in 300 ml of dry tetrahydrofuran is added dropwise at room temperature for a further 1 hour. 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 decented 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 HPLC

235348 16 (Waters Prep 500) on silica gel, using a 95: 5 mixture of methylene chloride and methanol.

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

R _f (silica gel, methanol) = 0.37.

NMR (60 MHz, CDCl 3) $ $ 2.23 (s, 6H), 2.28 (s, 3H), 3.11 (d, 2H), 6.20 (t, 1H), 6.95-7 1.5 (m, 7H).

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

R _f (silica gel, methanol): 0.53.

NMR (60 MHz, CDCl ₃ ) 32.23 (s, CH), 2.39 (s, 3H), 2.96 (d, 2H), 6.70-7.33 (m, 8H).

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

Analysis for C ₇ H _LG BrN _2:

calculated: 61.63%, 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) allylamine in 150 ml of absolute ethanol is hydrogenated on activated carbon with 10% platinum reagent. 7 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 with methanol. 0.86 g of 2-bromo-6- [3-dimethylamino-1- (4-methylphenyl) propyl] pyridine is obtained according to thin layer chromatography [TLC], Rf: 0.25 (silica-silica, methanol).

NMR (80 MHz, CDCl 3) δ 2.05-2.45 (m, 13H), includes 2.18 (s, 6H) and 2.30 (s, 3H), 4.15 (broad, 1H), 7.03-7.50 (m, 7H).

Analysis for C 7 ^H 2 BrN _2:

calculated: 6-1.26% 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 1.74 M solution of n-butyllithium in hexane was added dropwise with stirring 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 to temperature -70 ° under 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 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 by thin layer chromatography on silica gel, 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) 4.6-5.2 (broad, exchangeable), 6.80-8.20 (m, 7H).

Analysis for C ^ HggN ^ .HgO:

calculated: 68.33% C, 7.65% H, 8.85% N, found: 68.16% C, 7.65% H, 8.82% N.

Severography, n. P., MOST

Price 2,40 Kčs

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

(E) -3- [6- / 3-pyrrolidino-1- (4-tolyl) prop-1E-enyl] -2-pyridyl] acrylic acid, m.p. 218-219 ° (dec.), (E) - 3- [6- / 3-pyrrolidino-1- (4-tolyl) prop-1E-enyl] -2-pyridyl] acrylamide oxalate, m.p. 198-199 ° (dec.), (E) -3- [ 218 DEG-220 DEG C. 6- [1- (4-Chlorophenyl) -3-pyrrolidino-prop-1E-enyl] -2-pyridyl] acrylic acid, m.p. tolyl) prop-1E-enyl / -2-pyrldyl] prop-2E-enamidoacetic acid, m.p. 257-258 ° (dec., (E) -3- [3-pyrrolidino-1- (4-tolyl) prop- 210 DEG-215 DEG (with decomposition), (E) -3- (E) -pyrrolidino-1- (4-tolyl) prop-1-enyl] cinnamic acid, m.p. 190 DEG (with decomposition) (E) -4- [3-pyrrolidino-1- (4-tolyl) prop-1-enyl] benzoic acid, m.p. 235-240 ° (dec.), (Z) -4- [3- 245 to 250 ° (dec.), (E) -4 - [(Z) -3-pyrrolidino-1- (4-tolyl) -pyrrolidino-1- (4-tolyl) prop-1-enyl] benzoic acid ) prop-1-enyl] cinnamon, 210 DEG-220 DEG (dec.), (E) -3 - [(Z) -3-pyrrolidino-1- (4-methoxyphenyl) -prop-1-enyl] cinnamic acid, melting point 215 DEG-220 DEG, ( (dec), (E) -3 - [(E) -3-pyrrolidino-1- (4-methoxyphenyl) prop-1-enyl] cinnamic acid, m.p. 220-225 ° (dec.), _r acid ( E) -3 - [(Z) -3-pyrrolidino-1- (4-chlorophenyl) prop-1-enyl] cinnamon, m.p. 178-181 °, (E) -3- (E) -3- 193-195 °, pyrrolidino-1- (4-chlorophenyl) prop-1-enyl cinnamic acid, (E) -3 - [(E) -3-diraethylamino-1- (4-tolyl) prop-1-enyl acid 200 DEG-205 DEG C., (E) -3 - [(Z) -3-dimethylamino-1- (4-tolyl) prop-1-enyl] cinnamic acid, melting point 200 DEG-205 DEG.

(E) -3- [3- / 3-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 has been ionized in pure form, (E) -3 - [[6- / 3-pyrrolidino-1- (4-tolyl)] (E) -3- [6- / 3-pyrrolidino-1- (4-tolyl) -prop-1E-enyl] -2-pyridyl] -acrylic acid, prop-1E-enyl / -2-pyridyl Q- (4-chlorophenyl) -3-dimethylaminopropyl-2-pyridinecarboxylic acid,

NMR (80 MHz, CDCl 3) δ 2.30-2.70 (ia, 2H), 2.85 (s, 6H), overlapping over 2.70-3.15 (m, 2H), 3.83 (Broad, exchangeable), 4.40 (broad t, 1H), 6.90-7.45 (m, 5H), 7.68 (dd, 1H), 8.13 (d, 1H),

Analysis for C C proH, gClNjOg. 2 HgO:

calculated: 57.54% C, 6.53% H, 7.89% N, 9.99% Cl, found: 57.68% C, 6.52% H, 7.86% N, 10.10% Cl, 6-1- (4-chlorophenyl) -3-dimethylaminopropyl] -2-pyridinecarboxylic acid, TLC Rf: 0.24 (silica gel, methanol),

235 348 8 (E) -6- [l- (4-chlorophenyl) -3-dimethylaminopropyl] -2-pyridylakrylové, TLC _Rf: 0.40 (silica gel, methanol)

NMR (80 MHz, CDCl 3) δ 2.40 (s, 6H), overlap over 2.0-3.0 (m, 4H), 3.97 (broad t, 1H), 6.65-7.70 (m, 9H), 11.5 (wide s, exchangeable), ethyl [(E) -3- [6- (3-acetoxy-1- (4-tolyl) prop-1E-enyl) -2-pyridyl] acrylate J, ethyl |] (E) -3 - [6- (3-pyrrolidin-1- (4-tolyl) prop-1E-enyl) -2-pyridyl] acrylate].

Example 12

Method Isomerization of ethyl E (E) - [t] - [3-pyrrolidino-1- (4-tolyl) prop-1-Z-enyl] -2-pyridyl | acry fabrics]

13.9 g of the starting ester are mixed with 28 ml of 90% by weight sulfuric acid and the mixture is heated under stirring at 130 ° C for 3 hours. After cooling, the mixture was poured gradually into 300 ml of ethanol under 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 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 substantially pure E, E-isomer.

Antihistamine effect

A. in vitro antihistamine effect

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 concentration (JM van Rossum, Arch. Int. Pharmacejlyn. Ther. IU, 299-330, 1963) of histamine are obtained. After washing, the tissues are incubated for 1 hour with the test compound, followed by a curve corresponding to the secondary histamine concentration. Displacements to the right of the curve corresponding to the agonium concentration; generated by antagonists and ee after reconstitution of Schild diagrams (0. Arunlakehane and HO Shild, Br. J. Fharmacel. 14: 48-58, 1959). Regression of log (dr -1) to log (B), where dr is an occlusive response in the presence or absence of antagonist α. (B) is the molar concentration of the antagonist, allows to determine pA ₂ ; i.e., a negative log of antagonist concentration whose histamine control concentration plots correspond to the 2X right curve.

Tabulkal

Results of in vitro determination of antlhistamine tests

RjCOQ X nr ₂ r ₃ «4 pA ₂ Compound A (E) -2-CH-CHCO ₂ H N ch ₃ 8.6 Compound B -2-CH ₂ CH ₂ CO ₂ H N nr ₉ r ₃ ch ₃ 9.2 (E) -2-CH-CH-CO ₂ H N nr ₂ r ₃ Cl 9.0 (E) -2-CH = CHCO ₂ C ₂ H ₅ N nr ₂ r ₃ ch ₃ 7.7 (E) -2-CH = CHCONH ₂ N 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 cf ₃ 10.4

Table I (continued)

RjCOQ X nr ₂ r ₃ ^R 4 pA ₂ (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-CH = CHCO ₂ 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 individually placed in transparent plastic chambers saturated with histamine, which is continuously replenished in gaseous form as 0.25% histamine from an aerosol inhalation device. In guinea pigs, signs of histamine anaphylaxis (eg cough, sneezing, severe abdominal movements, cyanosis) are recorded.

Under test conditions, control animals collapse on average 33 seconds. for protection against histamine is calculated from probit analysis. This test Εβ ^ θ shows that at a special dose of 50% of the animals it is completely protected against the action of histamine during the test (1 hour

Even after dose). Clamp protection is determined as protection against histamine symptoms for 6 minutes in an aerosol chamber (approximately 10-fold collapse time of control animals).

Table II

Results of in vivo determination of antihistamine tests

Compound ^ED 50 s ^ ^m / Eg, po)

Triprolidine 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 may have a very long antihistamine effect (for example, 11 mg / kg p.o. provides Εβ ^ θ for protection for 24 hours). Example 13

Pharmaceutical preparations

Composition A

Injection

Ingredient Quantity per ampoule

Compound of Formula X Water for Injection, 0 mg to 1.0 mL

The finely divided active compound is dissolved in water for injection. The solution is filtered and autoclaved.

Formulation B suppositories

Component Quantity per suppository

Compound of Formula I 1.0 mg

Cocoa butter or suppository base TM

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 a 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 Amount to 5 ml Compound of Formula I 1.0 mg Ethanol 0.3 mg Sucrose 2,0 mg Methylparaben 0.5 mg Sodium benzoate 0.5 mg Cherry flavor according to needs Dye according to needs Water to 5.0 al

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 1.0 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 g.

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 into gelatin capsules.

Composition F

Tablets

Quantity tab on tablet

Compound of formula (X) Pseudoephedrine hydrochloride Lactose 1.0 mg 60.0 mg 62.5 mg Component Quantity on tablet Potato starch 14.0 mg Magnesium stearate 1.0 mg gelatine 2.8 mg

Tablets are prepared by the fee ingredients according to the method described in Example 3 D above.

Composition G Syrup

Ingredient Quantity per 5 ml

Compound of Formula I 1.0 mg Pseudoephedrine hydrochloride 30.0 mg Codeine phosphate 10.0 mg Guaifenesin 100 ALIGN! mg Methylparaben 0.5 mg Sodium benzoate 0.5 mg Flavor as required Dye as required Glycerol 500 mg Sucrose 2 000 mg cleaned water to 5.0 ml

235348 22

Syrups containing active ingredients other than the compound of formula I are prepared from the ingredients listed above by a method similar to that described in Example 13C above.

Means H Nasal spray

Component Quantity per 100.0 ml

Compound of Formula I Sodium chloride 1 0.8 Preservative 0.5 cleaned water to 100.0

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

Composition I Eye solution

Component Quantity per 100.0 ml

Compound of Formula I 0.1 Sodium chloride 0.8 Preservative 0.5 Water for injections to 100.0

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

Formulation J Topical cream

Component Quantity per 100.0 ml

Compound of Formula I 0.1 g

Emulsifying wax, N. 15.0 g

Mineral oil 5.0 g

Claims (12)

FIELD OF THE INVENTION A process for the preparation of the novel amino compounds of the general formula I (I) wherein R ₁ represents a divalent aliphatic hydrocarbon group having 1-7 carbon atoms or a single bond, R ₂ and R, which are identical or different, each denote a hydrocarbon, alkyl of 1 to 4 carbon atoms or together form a nitrogen containing heterocyclic ring containing 4-6 ring members, R ₄ 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 the formula -C = C-, or a salt, ester or amide thereof, characterized in that a compound of formula L is reacted Y kde X represents a group of formula CHO or R aCOOH and Z, and Zg taken together are = O or one of Z, and Zg is And the second of these symbols marks the group pattern -CH-B ( CH 3 ^NR 6 ^R 6 and ^R 1, ^R 2 ' ^R 3' ^R 4 * ^A 'B ^{r X are} as defined above, provided that if Ϊ represents a group of the formula CHO, Z, and Zg have different meanings from each other and when X is R ^COOH, Z, and Zg together form = O, with a Wittig reagent suitable for introducing the side chain of the formula -CH = CH (CH =) _b CORg, where b is 0-5 and CORg is an acid, ester or amide as defined above when Z and Zg have different meanings from each other or suitable for introducing a side chain of the formula sCHCHgNRgR ^ where Rg and R ^ are as defined above when Z and Zg together form = O, and then deprotecting as necessary from the carboxy group to form a compound of formula I wherein R 1 is a group of formula (CHg) _and CH = CH (CHg) _b , and is zero, Rg, Rj, R X, A, B and B are as defined above when Y in the starting compound of formula (L) is CHO, or to form a compound of formula (I) wherein CA-CB is a double bond and R, R8, R5, R5 and X is as defined above when X in the starting compound of formula L is a group 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. Method according to claim 1, characterized in that starting from compounds of the above formula to a compound of formula II .RlCOjH "/ ^H ACCB - / ^X CH ₂ NR ₂ R ₃ (II) wherein R 1 to R 1, X, A and B are as defined above, or a salt, ester or amide thereof. 3. A process according to claim 1 or 2, wherein the compound of formula (R) is a compound of formula wherein R 1 is a group of formula (CH ₂ ) _n wherein n is an integer from C to 7 or a group of formula ( CH ₂ ) _and CH = CH (CH ₂ ) 2, wherein 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-COOH (IIIa) r ₄ and where R 1 is a group of formula (CH ₂ ) _n , wherein n is an integer from 1 to 7, or is a group of formula (CH ₂ ) _e CH = CH (CH ₂ ) _b , where a and b are independently 0 to 5 and the sum of aeb does not exceed 5 , R ₂ and R, which are identical or different, represent hydrogen, lower alkyl of 1 to 4 carbon atoms or together form a nitrogen containing heterocyclic ring having four to six ring members, such as pyrrolidino, or morpholino, and piperidino3kupinu _And R ^ represents hydrogen or halogen, such as bromo or chloro, lower alkyl having 1 to 4 carbon atoms or lower alkoxy having 1 to 4 carbon atoms, or its salt, ester or amide. 5. A process according to any one of Claims 1 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 ), or -CH = CH _{2 -} , the radical -NR 8 R 3 is and Rolid is methyl, trifluoromethyl, methoxy, bromo or chloro. 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. Rc = COOH H R ₄ A (IIIb) where 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 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 to 6-membered heterocyclic ring such as pyrrolidino, piperidino or morpholino and R ^ 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 as claimed in any one of claims 1 to 3 and 6, which is based on compounds of the above formulas to form compounds of the formula wherein R 1 is a group of formula (CH ₂ > ₂ or -CH = CH-, - NR 6 R 6 is pyrrolidino or dimethylamino and R 6 is methyl, trifluoromethyl, methoxy, bromo or chloro. 8. A process as claimed in any one of claims 1 to 7, which comprises starting from compounds of the above formulas to form a compound of formula (IV): 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 R is a single bond, a group of formula -CH = CH- or -CHgCKg-, the moiety -NiíK K. R 1 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 give a compound of formula V-ch ₂ -ch ₂ n / ^R 2 _R \ _R ^r 3 (O where R 1, R 1 to R 2 are as defined above, or a salt, ester or amide thereof. 12. The process of claim 11, wherein the compound of formula (V) is a compound of formula (V) wherein R @ 1 is a single bond, a group of formula -CH = CH- or -CH ₂ CH ₂ -, an -NR 4 moiety. R1 is dimethylamino and R1 is chloro or bromo.