CS252491B2 - Method of phenthiazines production - Google Patents

Description

The present invention relates to a process for the preparation of novel phenothiazine compounds. The chemical compounds which can be produced according to the invention have antihistaminic and antiallergic activity and properties which make them suitable for use in pharmaceutical preparations intended for medical use.

U.S. Pat. No. 2,530,451 discloses a group of 9- (dialkylaminoalkyl) phenothiazines with antihistamine activity, the most prominent of which is referred to by the generic name as promethazine, i.e. 10- (2-dimethylaminopropyl) phenothiazine. Promethazine has proven itself in clinical use as a tranquilizer and antihistamine.

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The compounds obtainable by the process of the present invention are most structurally similar to the phenothiazine derivatives described in U.S. Patent Nos. 3,112,310, 2,905,668 and 2,789,978 and Messer et al., Arzneim. Forsch, 19, 1193-11198 (1969).

The antihistamines now in use, including diphenylhydrazine, pheniramine, pyrilamine, prothazine and triprolidine generally have a potential disadvantage since they all induce sedation or drowsiness in some patients. Furthermore, promethazine has a potential anticholinergic effect.

We have now found a new class of compounds and in vivo antiallergic activity defined by the blockade of anaphylactoid effect. Some of these compounds also have a good antihistamine effect and are essentially devoid of central nervous system (CNS) side effects and have a significantly lower anticholinergic effect than promethazine.

The present invention provides a process for the preparation of phenothiazines of the general formula X r ₁ every ₂ h (I) wherein

R ₂ R ₃

R represents a group of the formula -CH = CH (CH ₂ ) _{f and} - in which b represents an integer from 0 to 5,

R ₂ and R ₂ are the same or different and are each a hydrogen atom, a C 1 -C 4 alkyl group or, together with the nitrogen atom, form a nitrogen-containing 4 to 6 membered heterocyclic ring,

R ₄ is hydrogen, halogen, C 1 -C 4 alkoxy, C 1 -C 4 alkyl optionally substituted with 1 to 3 halogen atoms or R ₄ CO ₂ H as defined above,

A represents a (C 1 -C 4) alkylene group or ANR 1 R 6 form a group of the formula

or salts, esters and amides thereof, with the exception of the esters and amides of compounds of formula I wherein R ₄ is hydrogen and K i is a bond at the 2-position of the phenothiazone ring system and with the exception of a compound wherein R 4 is a bond at the 2-position of the phenothiazine ring; ₄ is hydrogen and ANR ₂ R ₃ is dimethylaminopropyl and compounds wherein ANR ₂ R ₃ is diethylaminoethyl and R ₄ is hydrogen and R ₄ CO ₂ H is CH ₂ CO ₂ H position 2.

Of these compounds of formula I obtainable according to the invention, those having formula II are preferred

(II) where

R 1 to R ₄ and A are as defined in formula I, or a salt, ester or amide thereof.

it may have a straight or branched chain, and in each case denotes an unsaturated hydrocarbon group. R ₄ is preferably a group of formula -CH = CH-.

R ₂ and are suitably the same or different and individually represent a methyl or ethyl group or form together with the nitrogen atom to which they are attached a four to six membered heterocyclic ring, preferably a saturated heterocyclic ring, for example derived from pyrrolidine, piperidine or morpholine.

is preferably dimethylamino or diethylamino, most preferably dimethylamino.

preferably represents a hydrogen atom, a halogen atom, a C1-C4 alkyl group or a trifluoromethyl group. R ₄ is particularly preferably hydrogen, methyl, ethyl, chlorine or fluorine. Most preferably R @ 1 is hydrogen. When R 6 is other than hydrogen, it is attached at the 7 or 8 position of the phenothiazine ring system, preferably at the 7 position.

A is preferably an ethylene, n-propylene or isopropylene group or ANR ₂ ^R 3 preferably forms a group of formula ^CK 2

The amides of the compounds of formula I included within the scope of the invention are amides usually formed from carboxylic acids. Particularly suitable are amides formed from ammonia, primary amides or amino acids, for example glycine.

Also included within the scope of this invention are solvates of the compounds of Formula I. Preferred solvates include hydrates and alkanolates having 1 to 4 carbon atoms in the alkanolate moiety.

Esters and amides of compounds of formula I, although having some intrinsic antihistamine activity, may be used as intermediates in the preparation of carboxylic compounds of formula I. Suitable esters include conventional ester groups known to be used to protect carboxyl groups, e.g. alkyl esters of 1 to 6 carbon atoms, wherein the alkyl group has a straight or branched chain and is substituted by a halogen atom. C 1 -C 4 alkyl esters are particularly preferred. The compounds of formula I may form either addition salts or formed from a carboxyl group. Addition salts are preferred, but salts formed at the carboxyl group can be used particularly in the preparation of the corresponding carboxyl compounds. Pharmaceutically acceptable salts are preferred.

For use in medicine, salts of the compounds of Formula I should be pharmacologically and pharmaceutically acceptable, but pharmaceutically unacceptable salts may be advantageously used in the preparation of the free active compound or its pharmaceutically acceptable salts and are not excluded from the scope of the invention. Such pharmacologically and pharmaceutically acceptable addition salts include, but are not limited to, salts derived from the following acids: 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. Pharmaceutically acceptable salts may also be prepared as alkali metal or alkaline earth salts, for example, potassium, sodium or calcium salts formed on the carboxyl group.

When the compounds of formula I contain a double bond in the carboxyl-terminated side chain, they exist either in cis- or trans-isomeric forms (relative to the aromatic ring). Isomers and isomeric mixtures of these compounds are included within the scope of this invention. When R 2 CO 4 H contains a double bond preferred isomers are those wherein the carboxyl group is in the trans position to the aromatic ring.

Preferred compounds of formula I are:

trans-beta- [10-2- (2-dimethylaminopropyl) phenothiazin-2-yl] acrylic acid,

2- [10- (2-dimethylaminopropyl) phenothiazin-2-yl] acetic acid,

2- [10- (2-dimethylaminopropyl) phenothiazin-2-yl] propionic acid,

10- (2-dimethylaminopropyl) -enothiazine-3-carboxylic acid, [e] -3 (2-carboxyvinyl) -10- (2-dimethylaminopropyl) phenothiazine,

3- (2-carboxyethyl) -10- (2-dimethylaminopropyl) phenothiazine,

10- (2-dimethylaminopropyl) phenothiazine-4 (or 1) carboxylic acid, (iE-4 (or 1) - (2-carboxylovinyl) -10 (2-dimethylaminopropyl) phenothiazine,

4- (or 1) - (2-carboxyethyl) -10- (2-dimethylaminopropyl) phenothiazine, [7-chloro-10 (2-dimethylaminopropyl) -8-phenethiazinyl] acetic acid, βθ- (2-dimethylaminoethyl) -7 -methyl-β-phenothiazinyl-acetic acid, [10- (2-dimethylamino-ethyl) -7-fluoro-2-phenothiazinyl] -acetic acid,

2- [JO- (2-dimethylaminopropyl) -2-phenothiazinyl] -2-methylpropionic acid,

2- [10- (3-dimethylaminopropyl) -2-phenothiazinyl] -2-methylpropionic acid,

2-methyl-2- [10- [3- (N-pyrrolidino) propyl] -2-phenothiazinyl] propionic acid,

10- (2-dimethylaminopropyl) phenothiazine-2-carboxylic acid, or salts, esters and amides thereof.

Pharmacokinetic studies comparing the relative brain and plasma distribution of the two compounds of the invention and prometanin show that, unlike promethazine, these compounds (see examples of compounds A and B) do not readily penetrate the brain of rodents.

The process for the preparation of the compounds of the formula (V) of the formula (X) according to the invention consists in:

AND

AND

AND

N / \

R ₂ ^r 3 (v) where

R ₂ , R ₃ < R ₄ and A are as defined above for compounds of formula (R ₈ ) ₂ POCH (CH ₂ ) _b CO ₂ R g and of formula (R ₉ ) ₃ PCH (CH ₂ > _b CO ₂ R ₆ in which samples

R 8 represents a C 1 -C 4 alkyl group #

R 8 represents a C 1 -C 4 alkyl group or a phenyl group, b is as defined above for a

CORg is an acid, ester or amide group as defined above, followed, if desired, by deprotection, and then optionally converting the resulting compound of formula I to another compound of formula I by hydrogenating a double bond in the side chain carboxy group, and optionally converting the compound obtained to an acid addition salt, a carboxylate salt, an ester or an amide of a compound of Formula 1, or optionally releasing another compound within the scope of the compounds of Formula I from such a compound.

This meaning is allowed to react with the Wittig reagent selected

The Wittig reagent is prepared by reacting a compound of the formula ^{< R} 8'2 ^{PO (CH} 2> d ^CO 2 ^R 6 'where

Rg is as defined above,

R 8 is C 1 -C 4 alkoxy; and d is 1 to 6, or with a compound of formula (R ₉ ) ₃ P (CH 2) _d CO ₂ R ₆ , wherein:

Rg is as defined above,

R 8 represents an alkyl group having 1 to 6 carbon atoms or a phenyl group and d is 1 to 6, with a strong base, for example sodium hydride in an inert solvent, for example tetrahydrofuran or dimethoxyethane, at 0 to 50 ° C, preferably at room temperature.

The reaction between the Wittig reagent and the compound of formula V is preferably carried out by adding the compound of formula V to the Wittig reagent at a temperature between 0 and 50 ° C, preferably at room temperature.

The compounds produced according to the invention with antiallergic activity can be used in the same indication as clinically used antiasthmatics, ie to help control bronchoconstriction or bronchospasm characteristic of allergic asthma and induced asthma and symptoms of bronchoconstriction and bronchospasm resulting in acute or chronic bronchitis. Compounds are believed to inhibit the release of autocoids (ie, histamine, serotonin, and the like) from mast cells and directly inhibit the production of antigen-induced histamine. They can therefore be classified as mast cell stabilizers with antihistamine activity.

The compounds of the invention with anthistamine activity can be used in the same indication as clinically used antihistamines, namely to alleviate unpleasant symptoms caused by histamine release, nasal congestion and vasomotor rhinitis, and symptomatically affect allergic conditions including nasal allergy, pereneal rhinitis, urticaria, urticaria , allergic conjunctivities, soil allergies, serum and drug reactions, insect bites and stings and desensitization reactions. The compounds may also be used under conditions responsible for antipruritic activity, including allergic dermatoses, neurodermatitis, anogenital pruritus and pruritus of non-specific origin, for example eczema and a specific case of for example chickenpox, photosensitivity and sunburn. Accordingly, the invention provides a method of symptomatic treatment of allergic conditions by administering an effective amount of a compound of Formula I. The invention also provides a method for astagonism of endogenously released histamine by administering an effective amount of a compound of Formula I. Some of the compounds of the invention are substantially devoid of sedative effects. efficiency.

The amount of active compound required for use in the above conditions varies according to the drug, the route of administration, and the condition of the mammal to be treated, depending on the judgment of the physician. A suitable oral dosage of active compound for mammals ranges from 0.003 to 1.0 mg per kg body weight per day, preferably from 0.04 to 0.24 mg / kg. For example, a typical dose of Compound (B) for a patient is between 0.03 and 0.1 mg / kg body weight per day.

The desired daily dose is preferably divided into one to six sub-doses administered at appropriate intervals as desired. Where three sub-doses of the compounds of formula I are used, all will preferably range from 0.014 to 0.08 mg / kg

body weight? for example, a typical sub-dose of such a compound for a patient is between and 20 mg, for example 4 or 8 mg.

While it is possible for the compound of formula I to be administered alone in crude form, it is preferred that the compound of formula I be in the form of a pharmaceutical composition. The invention also makes it possible to manufacture pharmaceutical preparations for veterinary and human medicine, which comprises a compound of formula I together with one or more pharmaceutically acceptable carriers and optionally any other therapeutic ingredient. For example, the active compound may be combined with a sympathomimetic agent, for example, a decontestant, pseudoephedrine, an antitussive, for example, codeine, an analgesic, an anti-inflammatory agent, an antipyretic, or expectorants. The carrier or carriers must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation.

The compositions include forms suitable for oral, nasal, ephthalmic or parenteral, including subcutaneous, intramuscular and intravenous administration.

The compositions are preferably in a dosage form and can be prepared by any method known in the art of pharmacy. All methods include the step of mixing the active compound with a carrier which constitutes one or more components. In general, the formulations are prepared by uniformly intimately mixing the active compound with a liquid carrier or finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

Formulations of the invention suitable for oral use may be administered in separate dosage units, such as wafers, capsules, tablets or lozenges, each containing a predetermined amount of the active compound (referred to herein as a compound of formula I), as a powder or granules, or suspension. in an aqueous liquid or in a non-aqueous liquid, for example, sugar or honey syrup (elixir), emulsion or drops. Tablets may be made by compression or molding, optionally with one or more ingredients. Compressed tablets may be made by compression on a suitable machine, with the active compound in a free-flowing form, for example as a powder or granules, optionally mixed with a binder, disintegrant, lubricant, inert diluent, surfactant or dispersing agent. Molded tablets consisting of a powdered active compound with any suitable carrier may be cast on a suitable machine.

A syrup may be prepared by adding the active compound to a concentrated aqueous solution of a sugar, for example sucrose, to which additional ingredients may be added. Such additives may include thickeners, sugar crystallization inhibiting agents or solubility enhancers of any other ingredient, for example a polyhydric alcohol such as glycerin or sorbitol, and suitable preservatives.

Formulations suitable for rectal administration may be in the form of suppositories with a conventional carrier, for example cocoa butter or hydrogenated fats or hydrogenated fatty carboxylic acids.

Formulations suitable for parenteral administration comprise a sterile aqueous preparation of the active compound, which is preferably isotonic with the blood of the recipient.

Nasal spray is a purified aqueous solution of the active compound with protective and isotonic agents. Such formulations are adjusted to a certain pH and isotonic state compatible with nasal mucomembranes.

Ophthalmic formulations may be prepared in a similar manner to a nasal spray, except that the pH and the isotonic factors adjust to the eye.

Topical formulations comprise the active ingredient dissolved or suspended in one or more of the compositions, for example, mineral oil, kerosene, polyhydroxy alcohols or other bases used for topical pharmaceutical formulations. It may be desirable to add additional components.

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

The present invention also provides a first use of the compounds of Formula I in medicine.

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

Example 1

Process for the preparation of [e] 3- (2-carboxyvinyl) -10- (2-dimethylaminopropyl) phenothiazines (Compound E)

a) Method for producing [e] -3- (2-methoxycarbonylvinyl) -10- (2-dimethylaminopropyl) phenothiazines

To a stirred solution of 4.0 g of 3-bromo-10- (2-dimethylaminopropyl) phenothiazines in v-dried ether at 0 ° C was added dropwise 8.5 ml of a 1.55 molar solution of butilithium in ram. at 0 [deg.] C. for one hour and then a solution of 1.7 ml of dimethylformamide in 20 ml of dried ether is added dropwise over one hour. The reaction mixture was stirred at room temperature for 3 hours and then shaken with water and ether. The washed and dried ethereal solution was evaporated to give the crude aldehyde as a yellow oil.

A solution of 4.0 g of this crude aldehyde in 20 ml of 1,2-dimethoxyethane was added to a stirred solution of the phosphonate carbonion obtained from 2.69 g of dimethyl 4-methoxycarbonylmethylphosphonate and 385 mg of sodium hydride as an 80% dispersion in oil, in 30 ml. ml of 1,2-dimethoxyethane at room temperature. The reaction mixture was evaporated to dryness after 4 hours and water and ether were added. The ether phase was separated, washed, dried and evaporated to give crude [E -3- (2-dimethylaminopropyl) -10- (2-dimethylaminopropyl) phenothiazines as a fluorescent yellow oil.

b) Method for the preparation of [E] -3- (2-carboxyvinyl) -10- (2-dimethylaminopropyl) phenothiazines (compound E) g of this ester are hydrolyzed in a solution of 22 ml of ethanol and 8.8 ml of 2N sodium hydroxide solution at at room temperature for 4 hours. The product was isolated as described in Example 5 below to give 3 g of crude carboxylic acid as an orange-colored gum. This was dissolved in hot 0.4 N hydrochloric acid and added concentrated hydrochloric acid to induce crystallization in the form of orange-colored platelets. Recrystallization from ethanol / ether gave yellow needles of [beta] -3- (2-carboxyvinyl) -10- (2-dimethylaminopropyl) phenothiazines hydrochloride as a hemihydrate, m.p. 170 [deg.] C. (dec.). After drying at 150 ° C, an anhydrous salt is obtained with a melting point of 220-225 ° C (decomposition).

Example 2

Process for preparing 3- (2-carboxyethyl) -10- (2-dimethylaminopropyl) phenothiazines

A solution of 1 g of [e] -3- (2-carboxyvinyl) -10- (2-dimethylaminopropyl) phenothiazines hydrochloride in 20 ml of methanol containing 100 mg of 10% palladium on activated carbon catalyst is stirred under a hydrogen atmosphere until it is absorbed. not complete (9 hours). The catalyst was filtered off and the solvent was evaporated to give the saturated carboxylic acid hydrochloride. A small amount of impurities was removed by esterification and the ester was chromatographed on a column of silica (silica) in a 50: 1 mixture of chloroform and methanol and hydrolysis of the pure ester. The 3- (2-Carboxyethyl) -10- (2-dimethylaminopropyl) phenothiazine thus obtained is crystallized from a mixture of ethanol and ether. 170 DEG-173 DEG C. (compound F).

Example 3

Process for the preparation of [E] -4 (or 1) - (2-carboxyvinyl) -10- (2-dimethylamiriopropyl) phenothiazone

a) Method for producing [e] -4 (or i) - (2-methoxycarbonylvinyl) -10- (2-dimethylaminopropyl) phenothiazines

5.7 g of 10- (2-dimethylaminopropyl) phenothiazine were treated with butyllithium under the conditions described in Example 6 below. 3.1 ml of diemethylformamide were added sequentially and the mixture was allowed to stand at room temperature for 18 hours. The crude aldehyde was isolated by extraction into ether and used without further purification.

The crude aldehyde is reacted with a phosphonate carbanion prepared from diethyl [methoxycarbonylmethylphosphonate] as described in Example 1 to give 4 (or 1) - (2-methoxycarbonylvinyl) -10- (2-dimethylaminopropyl) phenothiazines, which crystallizes from ethanol. Melting point: 129-130 ° C.

b) Method for producing E-4 (or 1) - (2-carboxyvinyl) -10- (2-dimethylaminopropyl) phenothiazines

This ester is hydrolyzed with dilute sodium hydroxide solution as described in Example 1 to give [E] -4 (or 1) - (2-carbonyl) -1- (2-dimethylaminopropyl-phenothiazine), Crystallization from isopropanol / petroleum ether (b.p. 60-80 ° C) as tiny yellow needles, m.p. 120-125 ° C (Compound H).

Example 4

Process for preparing 4 (or 1) - (2-carboxyethyl) -10- (2-dimethylaminopropyl) phenothiazines

A solution of 500 mg of [E] -4 (or 1) - (2-methoxycarbonylvinyl) -10- (2-dimethylaminopropyl) phenothiazines in 20 ml of ethyl acetate was stirred under a hydrogen atmosphere in the presence of Raey nickel until the consumption of hydrogen ceased. The filtered solution was evaporated to give 4 (or 1) - (2-methoxycarbonylethyl) -10- (2-dimethylaminopropyl) phenothiazines, which was subjected to hydrolysis in aqueous ethanolic sodium hydroxide solution as described in Example 1. Thus produced 4 ( or 1) - (2-carboxyethyl) -10- (2-dimethylaminopropyl) phenothiazine crystallizes from isopropyl alcohol as colorless needles. M.p .: 155-157 ° C (compound I).

Example 5

A process for the preparation of 2-bromo-10- (2-methylaminopropyl) -phenothiazines (compounds ex-1a) i.

5.0 g of 2-bromophenothiazine and 2.4 g of potassium t-butoxide are combined in 25 ml of dry xylene under nitrogen and heated at 65 DEG C. for 10 minutes. A solution of 2.8 g of 2-dimethylaminopropyl chloride in 2 ml of xylene is added dropwise over 10 minutes. Stirring under nitrogen and heating to 60-70 ° C was continued for 3 hours. The reaction mixture was poured into 100 mL of ethyl acetate and extracted with dilute hydrochloric acid. The acidic extract was basified with excess aqueous ammonia and extracted with methylene chloride which was dried over magnesium sulfate and evaporated to give a viscous oil weighing 6.35 g.

The oil is a mixture of the desired compound and its isomer of 2-bromo-10- (2-dimethylamino-1-methyl-ethyl) -phenothiazines, from which it is separated as a colorless oil by preparative high pressure liquid chromatography on a silica gel column, eluting with ethyl acetate / methylene chloride 4: 1 dimension.

The compound ex-1a does not crystallize and no attempt was made to obtain a crystalline salt. The compound is characterized by NMR spectrum which corresponds to the reported structure and differs from its isomer.

b) Method for producing 10- (2-dimethylaminopropyl) phenothiazin-2-yl-carboxaldehyde (compounds ex 1b)

Using a syringe and nitrogen atmosphere, add to a flask containing 2.8 g ex 1a and 20 ml anhydrous tetrahydrofuran. The solution was stirred and cooled with a dry ice bath in acetone and a solution of 5.2 ml of a 1.5 molar solution of n-butyllithium in hexane was added dropwise over 5 minutes. After stirring at -78 ° C for 30 minutes, 0.8 ml of distilled dimethylformamide was added and the reaction mixture was allowed to warm slowly to room temperature over 25 minutes. It is then poured into dilute hydrochloric acid, washed with benzene and then basified with ammonia. The product was extracted with methylene chloride, which was dried over magnesium sulfate and evaporated to give a very viscous yellow oil of compound ex 1b. Compound ex 1b did not crystallize and no attempt was made to prepare a crystalline salt.

The substance was characterized by NMR spectra which corresponded to the assumed structure. Thin layer chromatography on silica gel in chloroform / methanol (9: 1) shows the presence of a single substance which is less mobile than the starting material, ie the compound ex 1a.

c) A method for producing trans-beta- [10- (2-dimethylaminopropyl) phenothiazin-2-yl] acrylic acid (compound A)

2.4 g of compound ex-1b, 1.1 g of malonic acid and 0.120 g of morpholine are dissolved in 8 ml of pyridine and heated in a boiling water bath. Carbon dioxide is released immediately.

After 2 hours, pyridine was evaporated under reduced pressure. The residue was triturated with 25 ml of boiling ethanol after cooling and stirring to give a yellow solid. This was recrystallized from ethanol to give Compound A as a crystalline mass, m.p. 214-218 ° C.

NMR and analysis confirm the assumed structure.

Example 6

Process for preparing 10- (2-dimethylaminoproeyl) phenothiazine-4 (or 1) -carboxylic acid

To a stirred solution of 5.7 g of 10- [2-dimethylaminopropyl-phenothiazine in 150 ml of dried ether was added dropwise a solution of 1.55 molar butyllithium in hexane at 20 ° C. The solution is allowed to stand at this temperature for 30 hours, then cooled to -15 ° C and nq of carbon dioxide is added. The mixture was allowed to warm to room temperature and allowed to stand for 16 hours. Water was added to the mixture, the mixture was shaken well and the ether layer separated. Evaporation '. The washed and dry extracts yielded 4.5 g of unreacted starting material. The aqueous solution was neutralized by addition of 2N hydrochloric acid and evaporated to dryness. The residue was extracted with ethanol and the filtered extract was evaporated to dryness. 2.5 g of the residue are purified by chromatography on a silica column. A mixture of chloroform and methanol as eluent to give 10- (2-dimethylaminopropyl) -thenothiazine-4 (or 1) -carboxylic acid in the form of colorless needles, m.p. 220-222 ° C. (decomposition) (from methanol) (compound G).

Other compounds of formula I may be prepared in a similar manner:

2- [10- (2-dimethylaminopropyl) phenothiazin-2-yl] acetic acid, (substance Β), in the form of hydrogen maleate, m.p. 115-120 ° C,

2- [10- (2-dimethylaminopropyl) phenothiazin-2-yl] propionic acid (Compound C), m.p. 156-162 ° C (dec.),

0- (2-dimethylaminopropyl) tert-azine-3-carboxylic acid (Compound D), m.p. ^18-58 ° C;

3- (2-carpoxyethyl) -1- (2-dimethylamino-propyl) phenothiazine, m.p. 170-173 ° C,

4- (or 1) - (2-carboxyethyl) -10- (2-dimethylaminopropyl) phenothiazine (Compound I), m.p. 35-55 ° C, 7-chloro-10- (2-dimethylaminopropyl) - 2-Phenothiazinyl] acetic acid (eluent), melting point 108 DEG -13 DEG C., ethyl [7-chloro-10- (2-dimethoxylaminopropyl) -2-phenothiaminyl] acetate, m.p.

358-160 ° C (decomposition), ethyl [10- (2-dimethylaminoethyl) -7-methyl-2-phenothiazinyl acetate (compound L), in the form of hydrogen maleate, has a melting point of 146-148 ° C; (dimethylaminoethyl) -7-methyl-2-phenothiazinyl] acetic acid (substance Μ), m.p. 127-132 ° C (decomposition),

141-143 ° C, Ethyl-2- (10- (2-dimethylaminopropyl) -2-phenothiazinyl) -2- (2-diethylaminoethyl) -7-fluoro-2-phenothiazinyl] acetic acid (N); - methyl propionate (substance O), oil,

2- [10- (2-dimethylaminopropyl) -2-phenothiazinyl} -2-methylpropionic acid (P), m.p. 192-196 ° C (dec.),

2- [10- (2-dimethylaminopropyl) -2-phenothiazinyl] -2-methylpropionic acid (Q), m.p. 128 ° C (dec.), Ethyl-2-methyl-2- [10- / 3- (N -pyrrolidino) propyl [-2-phenothiazinyl] propionate] (R substance), oil,

10- (2-dimethylaminopropyl) phenothiazin-2-yl-carboxylic acid (Compound S), m.p. 257-261 ° C (dec.).

Example 7

Antihistamine effect

A. In vitro antihistamine activity c

The longitudinal muscle strip was isolated from the intact guinea pig ileum (Hartley, male 250-400 g) and placed in a bath at a load of 300 mg. After a one hour equilibration, the concentration curves obtained kumultitivní-response (Van Roseum J. Μ., Arch. Int. Pharmacodyn. Ther., 143, 299-330 (1963) to histamine. Following washing, the tissues were incubated _for% hour rating substance The shifts to the right of the aginist concentration-response curve produced by the antogonists were used to construct Schild plots (O. Arunlaksbana and HO Schild Br. J. Pharmacol. 14, 48-58 (1959)). The regression of log (dr-1) to log (Β), where dr is an equiactive response in the presence and absence of an anagonist and (B) is the molar concentration of the antagonist, allowed the determination of pA ^, ie negative logarithmic concentration of the antagonist concentration-response curve twice to the right.

Table AND Substance pA ₂ Promethazine 8.9 ' AND 8.2 (B) 9.4 C 8.1 D 6.2 E 6.2 F 5.2 G 6.8 H 7.8 AND 7.2 J 9.0 TO 8.8 L 9.1 M 8.9 N 8.6 0 8.5 P 8.8 Q 8.7 S, 9.9

^X RB Barlow, Introduction to Chemical Pharmacology, 2nd edition, p. 373, eds.

Wiley, New York 1964

B. Antihistamine activity in vivo

Guinea pigs (Hartley, male, 300-350 g) were left without food for 20 hours, after which they were administered either after or ip of the test substance. One hour after administration on an individual basis, guinea pigs were placed in a transparent plastic chamber, which was saturated and continuously supplemented with 0.25% aerosol histamine. Guinea pigs were evaluated for signs of histamine anaphylaxis (for example, cough, breathing, marked abdominal movements, cyanosis, or loss of righting reflex). Under these test conditions, the control animals collapsed for an average of 33 seconds. Εϋ, -θ for histamine protection were calculated using probit analysis. In this test the ED ^ _Q indicates that a single dose completely protected 50% of animals against the effects of histamine for evaluation (1 hour after dosing). Perfect protection was defined as proper histamine symptoms in the aerosol chamber (about ten times the time required for the collapse of control animals).

Table II

Results of antihistamine tests

Substance ED ^ Q / mg / kg, p.o /

Tripolidine, 5.77

A 1.70

B 0.3 (4 hours post dose)

In addition to these results, it was found that substance A could provide a very long lasting antihistamine effect (for example, 11 mg / kg p.o. indicates Εϋ ^ θ for 24 hours protection).

Method of anaphylactoid evaluation e

Wistor rats (180-300 g) were dosed with test substances (i.p. or p.o.) hours prior to exposure to the anaphylactoid indicator (4-8 / 80). One hour prior to exposure, 5 mg / kg i.p. propranolol. The anaphylactoid inducing agent was administered intravenously at 2 mg / kg and the animals were observed for symptoms of respiratory distress.

The results were analyzed by probit analysis. The reaction was quantified by assessing the amount of substance that protected 50% of the animals from death at any given time.

The above experimental setup does not provide a positive result for the selective antihistatic agent. Also, rats do not respond to histamine (i.v.) symptoms of anaphylaxis. Agents that block the effects of the agent are usually classified as anaphylactic mediator inhibitors.

Table III

Inhibition of anaphylactoid reaction

Substance

Ketotifen

AND

(B)

C

E

Astemizole ^ED 50

0.87

2.64

0.89 (1.2) ³

1.43

3.11

1.08 ^X Dose of substance (ip) providing 50% protection against 48/80 induced death. The substance was administered 2 hours before the test.

^xx ED, on the way

Compound B had a rat LD _5Q 210 mg / kg (ip) and greater than 500 mg / kg (po).

Example 8

(A) -injection

Component

Compound of formula I

Water for injection q.s.

The finely divided active substance was filtered and autoclaved.

(B) -Pipes

Component

Compound of formula I

Cocoa butter TM or Wecobee base q.s.

Wecobee ™ is a trade name and acts

The finely divided active ingredient was TM cocoa butter or Wecobee base) to form the desired suppositories.

Amount in ampoule 1,0 mg

1.0 mg t

dissolved in water for injection. The solution was

Amount in suppository 1.0 mg 2.0 mg with hydrogenated fatty carboxylic acid.

mixed with the molten suppository base (either the suppositories were cast and allowed to cool)

Severography, n. P., MOST

Price 2,40 Kčs

 (C> -Super

Component Amount in ml Compound of formula (I) 1.0 mg Ethanol 0.3 mg Sucrose 2.0 mg Metylparaven 0.5 mg Sodium benzoate 0.5 mg Cherry flavor q.s. Dye q.s. Water q.s. ad 5,0 ni

Ethanol, sucrose, sodium benzoate, methyl paraben and flavor were combined in 70% total water. The flavor and the active substance were dissolved in the remaining water, then the solutions were mixed and exhausted by filtration.

(D) -Tablets

Components Quantity in tablet

Compound of formula (I) 1.0 mg Lactose 110.0 mg Corn starch, pregelatinised 2.5 mg Potato starch 12.0 mg Magnesium stearate 0.5 mg

The active ingredient was finely divided and mixed with powdered lactose, corn starch, potato starch and magnesium stearate. The mixture was then compressed to give tablets weighing 126 mg.

(E) - Waffles

Component Quantity in wafer

Compound of Formula I 1.0 mg

Lactose 440.0 mg

Magnesium stearate 5.0 mg

The finely divided active ingredient was mixed with powdered lactose, corn starch and stearic acid and packaged in gelatin wafers.

(F) -Tablets

Quantity in tablet

Component

Compound of formula (I) 1.0 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 were prepared from the above mixture as described in Example 8 (D) above.

Component

Compound of formula (I) Pseudoephedrine hydrochloride Codeine phosphate Guaifenesin

Metylparaben

Sodium benzoate

Flavor

Dye

Glycerine

Sucrose

Purified Water (G) -Sirup

Quantity in 5 ml

1.0 mg 30.0 mg 10.0 mg 100 mg 0.5 mg 0.5 mg

q ·. s.

00 mg 2000 mg

q.s. ad 5.0 ml

A syrup containing other active ingredients than the compound of formula (I) was prepared from the above ingredients in an analogous manner to that described for Example 8 (C) above.

Component

Compound of formula (I) Sodium chloride Protective substance Purified water (H) nose spray

Quantity per 100.0 ml 1 g

0.8 g 0.5 g

q.s. 100.0 ml

The preservative was dissolved in warm purified water, and after cooling to 25-30 ° C, sodium chloride and a compound of formula I were added. The pH was then adjusted to 5.5 to 6.5 and the purified water was added to adjust the final volume. to 100.0 ml.

(I) -Ophthalmic solution

Component Compound of formula (I) Sodium chloride Protective substance Water for injections Amount in 100.0 ml 0.1 g 0.8 g 0.5 g q.s. 100.0 ml The preparation was ready like a nose spray. (J) -Local cream Component Quantity per 100,0 ml Compound of formula (I) 0.1 g Emulsifying wax N.F. 15,0 g Mineral oil 5.0 g OBJECTIVES

A process for the preparation of phenothiazine of the general formula I

Claims (5)

A process for the preparation of a phenothiazine of the formula I wherein ^R 2 ^R 3 represents a group of the formula -CH = CH wherein b represents an integer from 0 to 5 R ₃ and R ₃ are the same or different and are each hydrogen, C 1 -C 4 alkyl, or together with the nitrogen atom form a 4-6 membered nitrogen heterocyclic ring, R @ 1 represents a hydrogen atom, a halogen atom, a C1 -C4 alkoxy group, a C1 -C4 alkyl group optionally substituted by 1 to 3 halogen atoms, or a radical of the formula R @ 1 --C @ 4 H as defined above, A represents a (C 1 -C 4) alkylene group or ANR 2 R 3 forms a group of the formula - CH or or salts, esters and amides thereof, with the exception of the esters and amides of the compounds of formula I wherein R kde represents a hydrogen atom and represents a bond at the 2-position of the phenothiazine ring systemer and ring and R represents a hydrogen atom and a group of formula ANR2R3 is a dimethylaminopropyl group, and compounds of formula I wherein a group of the formula ANR ₂ R ₂ is a diethylaminoethyl group and represents a hydrogen atom and a group R ^ CC ^ H represents a group of formula Cl-CO? H in a position characterized in that the compound of formula V (V) wherein R _2> R, R4 and A have the above meanings, is reacted with a Wittig reagent selected from the group consisting of compounds of the formula (Rg) ₂ POCH (CH _{2) b} CO ₂ R _6, and the general formula (R _{9) 3} PCH (CH ₂ ) _b CO ₂ R ₆ , in which formulas _R² represents an alkyl group having 1 to 4 carbon atoms, for R 8 is C 1 -C 4 alkyl or phenyl, b is as defined above for a CORg denotes an ester or amide group as defined above, followed, if desired, by deprotection, and then optionally converting the resulting compound of formula I to another compound of formula I by hydrogenating a double bond in the side chain herbox group, and optionally converting the compound obtained to an acid addition salt, a carboxylate salt, an ester or an amide of a compound of formula 1, or optionally releasing another compound from the compound of formula I from such a compound. 2. A process according to claim 1, wherein the compounds of formula (II) are prepared using the appropriate starting compounds wherein (II) R @ 1 and A are as defined for formula I, or a salt, ester or amide thereof, with the exception of the esters and amides of compounds of formula II wherein R @ 1 is hydrogen and R @ 1 is a bond; R 2 is a bond, R 2 is a hydrogen atom, and the group of formula ANR ₂ R ₃ is dimethylaminopropyl and compounds of formula II wherein R 2 is CH ₂ , R 4 is a hydrogen atom and the group of formula ANR ₂ R ₃ is diethylaminomethyl. 3. Process according to claim 1, characterized in that, using the appropriate starting compounds prepared compound according to any one of claims 1-3, wherein NR ₂ R represents dimethylamino group or diethylamino group, and other symbols are as defined in claim 1, or third 4. Method according to claim 1, characterized in that, using the appropriate starting compounds prepared compound according to any one of claims 1-4, wherein R is hydrogen, / ⁴ by a methyl group, a chlorine or fluorine and the other symbols are as defined in point 1, 3 or 4. 5. A process according to claim 1, wherein the appropriate starting compounds are prepared according to any one of items 1 to 3, wherein A is an ethylene, n-propyl or isopropylene group and the other symbols have the meaning given in item 1 or 3 to 5.