CS252489B2 - Method of phenthiazines production - Google Patents

Description

The present invention provides a process for the preparation of phenothiazines of the general formula I, S.

R ₁ CO ₂ H

AND

AND

AND

N / \

1 * 2 ** 3 (I) where

R1 represents a divalent aliphatic hydrocarbon group having 1 to 7 carbon atoms or a single bond,

R j and R j 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 @ 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 @ 5 CC4 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 ₂ or

CH ₂ —WH ₂ )

And the salts of the esters and amides thereof, with the exception of the esters and amides of the compounds of formula (I) wherein R R represents a hydrogen atom and R ^ represents a bond at the 2-position of the phenothiazine ring system; in position 2 of the phenothiazine ring, and R represents a group of formula vodíkuia ANRjRj means dimethylaminoproylovou groups and compounds wherein the group of formula ANRjRj is diethylaminoethyl and R represents a hydrogen atom and a group of formula RjCOjH = CH ₂ CO ₂ H in the second

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

6 r ₁ every ₂ h (li) where

R ₃ to R 6 and A are as defined in formula I, or a salt, ester or amide thereof.

it may have a straight or branched chain, a saturated or unsaturated hydrocarbon group, or it may be a single bond. Suitably, R 1 represents a C 1 -C 3 hydrocarbon group or a single bond or comprises at least one double bond. R is preferably a group ^{11 CE} ^ · number to 3 or CH = CH or -CHťCH ^) _(CH2), wherein m is 0 or 1, a group "C (CH ₂ ^ i ~ · RjCC ^ H is most preferably ~ CH ₂ CO ₉ H.

^R 2 ^{and R} 3 3 ^{are not} appropriate same or different and each represents a methyl or ethyl group or together with the nitrogen atom to which they are attached four-membered to six-membered heterocyclic ring, preferably a saturated heterocyclic ring, e.g., pyrrolidine, piperidine or morpholine ^WR 2 ^R Or a diethylamino group and preferably a dimethylamino group.

R @ 1 is preferably hydrogen, halogen, C1 -C4 alkyl or trifluoromethyl; R @ 3 is preferably methyl, ethyl, chlorine or fluorine. R @ 1 is preferably hydrogen. When R 4 is other than hydrogen it is attached at the 7 or 8 position of the phenothiazine ring system and usually preferably at the 7-position.

A is preferably an ethylene, n-propyl group or iuoioopxcpylanová or Al ^ R _i form a group

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 the amides formed from ammonia. '; _T --imárních amides or amino acids such as glycine.

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

Esters and amides of compounds of formula (I), while 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 useful for protecting carboxyl groups, for example, alkyl having 1 to ^'r' 6 carbon atoms, wherein the alkyl group is a straight or branched chain and is optionally substituted by a halogen atom.

C 1 -C 4 alkyl esters are particularly preferred. The compounds of formula 1 may form either addition salts or salts formed from a carboxyl group. Preferred addition salts, however, salts formed from the carboxyl group can be used, in particular, for example. of the corresponding carboxyl compounds. Pharmaceutically acceptable salts are preferred.

For use in medicine, the salts of the compounds of formula (I) should be pharmacologically pharmaceutically acceptable, but pharmaceutically unacceptable salts may advantageously be used in the preparation of the free active compound or pharmaceutically acceptable salts thereof, and most preferably. excluded from the scope of the invention.

Such acceptable and pharmaceutically acceptable salts include, but are not limited to, those acceptable. They were swept onto them, e-mJ derived from the others. kyr.clina of chlorine ovedlki · '· -' ·· cinemas. Rovai _f luníčná acetic acid, fo; maleic, talic acid, tartaric toluenesulfonic acid, tartaric acid, cirronic acid, acid, methacrylic acid, raric acid, butyric acid, lithium acid -v, acid · jancorcin-6. kyu 11 ^T e ta.i <252489

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 at the carboxyl group.

When the compounds of formula (I) contain a double bond in the side chain terminating the carboxyl group, they exist either in pis 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 ₁ CO ₂ 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-E10-2 (2-dimethylaminopropyl) phenothiazin-2-yl-acrylic acid,

2-Bo ^- (2-dimethylaminopropyl) phenothiazin-2-yl] acetic acid,

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

10- (2-dimethylaminopropyl) phenothiazine-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, [e] -4 (or 1) -2-carboxyvinyl-10 (2-dimethylaminopropyl) phenothiazine,

4- (or 1) -2-carboxyethyl-10- (2-dimethylaminopropyl) phenothiazine, [U-chloro-10 (2-dimethylaminopropyl) -2-phenothiazinyl] acetic acid,

Q10- (2-dimethylaminoethyl) -7-methyl-2-phenothiazinyl] acetic acid, [10- (2-dimethylaminoethyl) -7-fluoro-2-phenothiazinyl] acetic acid,

2- [10- (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-phenothiazine] 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 produced according to the present invention and apromethazine show that, unlike promethazine, these compounds (see examples of compounds A and B) do not readily penetrate the brain of rodents.

The process according to the invention consists in hydrolyzing a compound of the formula VI wherein

AND

AND

Ν / \

(VI),

R ₂ , R 1, R 2 and A are as defined above and denote the group R 1 CN, wherein

R ^ is a divalent hydrocarbon group having 1-7 carbon atoms or a group of the formula _R7-CH = C / Y / H, wherein the divalent hydrocarbon group having 1 to 6 carbon atoms and a single bond,

X is oxygen or sulfur; and

Y is amino, and then optionally converting a 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 to an acid addition salt, carboxylate salt, ester or amide of a compound of formula I or optionally releasing another compound within the scope of compounds of Formula I from such a compound.

The hydrolysis is conveniently carried out by adding a dilute mineral acid such as hydrochloric acid to the compound of formula VI and heating to a higher temperature, for example between 50 and 100 ° C, preferably to 100 ° C. Such hydrolytic reactions of nitrile groups of amide groups with thioamide groups are well known in the art.

Compounds of formula VI wherein Z is R značCN may be prepared by reaction of formula V

R,

R ₂ R 3 where

R ₂ , R 8 / R 6 and A are as defined above.

R @ 1 denotes a single bond or a divalent hydrocarbon group having 1 to 6 carbon atoms as defined above, and

B represents a hydrogen atom or methyl, with a compound of the formula I ₁ ch ₂ n = ch ₂ where

L denotes a sulfonyloxy group, for example a tosyl group, in the presence of a base, for example an alkali metal alkoxide, for example potassium butylate * in an antioxidant solvent, for example, dimethylsulfoxide at a usual temperature, for example -20 to 100 ° C, preferably at 20 ° C.

Compounds of formula VI wherein R 1 -Z represents a group r ₇ -CH = CH / Y / XH in which X represents a sulfur atom and Y is a secondary amino group can be prepared by reacting a compound of formula V wherein R 1 represents a single bond and B denotes a hydrogen atom or a C 1 -C 4 alkyl group with a sulfur and a secondary amine, for example morpholine at an elevated temperature, i.e. 50 to 150 ° C, preferably in an inert atmosphere. Appropriate amides, i.e. compounds wherein X is an oxygen atom, may be prepared by hydrolysis of the appropriate thioamide or nitrile.

The compounds produced according to the invention with antiallergic effect 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 bronohospasm 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.

Compounds of the invention with antihistamine 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, 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 symptomatically treating allergic conditions by administering an effective amount of a compound of Formula I. The invention also provides a method for antagonizing 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. anticholinengiokou efficacy.

The amount of active compound required for use in the above-mentioned conditions varies according to the choice of the substance, the mode of administration and the condition of the mammal to be treated, depending on the judgment of the physician. A suitable oral dosage of the active compound for mammals is 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 (see Example 2 and Table 1) is between 0.03 and 0.1 mg / kg body weight per member.

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 be in the range of 0.014 to 0.08 mg / kg body weight, for example a typical sub-dose of such a compound for a patient is between 1 and 20 mg, e.g. 4 or 8 mg. .

While it is possible for the compound of formula I to be administered alone in the raw material 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 such as a decongestant, pseudoephedrine, an antitussive such as codeine, an analgesic, an anti-inflammatory agent, an antipyretic, or expectants. The carrier or carriers must be pharmaceutically acceptable in terms of compatibility and other ingredients of the formulation.

The compositions include forms suitable for oral, nasal, ophthalmic 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. Generally, formulations are prepared by uniformly and intimately admixing ^one active compound with liquid carriers or finely divided solid carrier or both, and ptoom, if necessary, shaping the product into the desired formulation.

Formulations of the invention suitable for oral use may be administered in discrete 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 aqueous liquid or non-aqueous liquid such as 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 contain flavoring agents, sugar-crystallizing 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 can be prepared in a similar manner to a nasal spray, with the difference that the pH and the isotonic factors are adapted 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 aforementioned 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

A process for the preparation of 2- [10- (2-dimethylaminopropyl) phenothiazin-2-yl] acetic acid

(a) Method of production of 2-acetylphenothiazinethylene ketal (substances ex-2a)

A solution of 100 g of 2-acetylphenothiazine in 50 g of ethylene glycol and 2.0 g of p-toluenesulfonic acid hydrate in 900 ml of benzene was heated to boiling under azeotropic water separation conditions (Dean-Stark trap) for 18 hours.

Thin-layer chromatography on silica gel in hexane / ethyl acetate 4: 1 confirms that most of the starting material has reacted and has been replaced by a higher R? Material. After cooling the reaction mixture, the benzene solution was washed with 1% sodium hydroxide solution, dried with solid potassium carbonate and evaporated to give 115 g of a dark oil which solidified on standing at room temperature to a dark green crystalline solid.

NMR spectra confirm the reported structure. The material was used without further purification.

(b) Method for the preparation of 2-acetyl-10- (2-dimethylaminopropyl) phenothiazine (substances ex-2b)

47.5 g of crude ex-2a and 20.9 g of potassium tert-butylate were mixed in 250 ml of benzene and stirred for 15 minutes under a nitrogen atmosphere. To this was added 23 g of 2-dimethylaminopropyl chloride and the resulting solution was heated to reflux for 75 minutes.

After cooling, the amines were extracted into dilute aqueous hydrochloric acid and the resulting acid solution was heated for 20 minutes in a boiling water bath to hydrolyze the ketal. After cooling, the aqueous solution was washed with ether and then basified with excess sodium hydroxide.

The aqueous amines were then extracted into methylene chloride, which was dried with magnesium sulfate and evaporated to give a red viscous oil consisting of a crude mixture of ex-2b and its isomer, 2-acetyl-10- (2-dimethylamino-1-methylethyl) phenothiazine .

Ex-2b was predominant and was obtained in analytically pure form by formation of hydrogen maleate in a mixture of otetate acetate and niothanol and after 2 recrystallizations from the same solvent had a melting point of 187-19 ° C. NMR and elemental analysis confirmed the reported structure. The isomer was obtained in pure form from the mother liquors by column chromatography of the free amine on silica gel, eluting with a 20: 1 mixture of ethyl acetate and ethanol.

c) Method for producing 2- (10- (2-dimethylaminopropyl) phenothiazin-2-yl) acetic acid (Compound B)

15.4 g of ex-2b, 3.2 g of sulfur and 10 ml of morpholine were mixed and heated to boiling under nitrogen for 5 hours. The hot reaction mixture was then poured into 300 mL of ethyl acetate and 100 mL of ether with stirring, followed by stirring. filtration. A small amount of insoluble material was removed. The amines were extracted into dilute hydrochloric acid.

The aqueous solution was washed with ether and basified with excess sodium hydroxide. The product was extracted into 400 ml of chloroform, which was washed three times with 600 ml of water each time. Evaporation of chloroform gave a viscous red oil weighing 16.4 g; thin layer chromatography on silica gel in methylene chloride / methanol (25: 1) showed the presence of more substances.

The sample was fractionated by high pressure liquid chromatography using two successive silica gel columns, first eluting with methylene chloride / methanol 98: 2 and then methylene chloride / methanol 97: 3.

Evaporation of the main fractions yielded 9.2 g of a viscous orange oil, the NMR spectrum of which indicated that it was an incompletely separated mixture of the expected thiomorpholide and possibly the product of its partial hydrolysis, oxymofrolide.

Since both substances are suitable intermediates for hydrolysis to the desired acid, Compound B, the mixture was not further purified but combined, dissolved in 255 ml of 4N hydrochloric acid and heated to boiling for 6 hours, removing all traces of starting material according to thin-layer chromatograms.

The reaction mixture was evaporated to give a viscous green residue which was dissolved in 70 mL of water and washed with ethyl acetate. The solution was then basified with a slight excess (per litmus) of solid sodium hydroxide and washed with methylene chloride. Partial evaporation of the aqueous solution led to precipitation of the sodium salt of Compound B.

Precipitation was complete by not diluting the aqueous solution with saturated sodium chloride solution. The solid was filtered and recrystallized from water saturated with sodium chloride 4: 1. After filtration and drying under vacuum overnight at 70 ° C, 4.3 g of dry powder was obtained which gave the expected elemental analysis result. Karl Fischer analysis showed that the sodium salt of Compound B contained 5.5 moles of water.

A hydrogen maleate having a melting point of 115-120 [deg.] C. was also prepared, whose NMR and elemental analysis confirmed the reported structure.

Example 2

Process for the preparation of 2-N, O- (2-dimethylaminopropyl) phenothiazin-e-yl] propionic acid

(a) Method for the preparation of 2- [10- (2-dimethylaminopropyl) phenothiazin-4-yl-propionitrile (substances ex-3a)

A solution of 4.0 g of tosylmethylisocyanide in 15 ml of dimethyl sulfoxide and 4 ml of tetrahydrofuran was stirred in an ice bath under nitrogen, and then 5.3 g of potassium tert-butylate were added. After 5 minutes, 0.68 g of methanol was added.

To this reaction solution was added dropwise a solution of ex-2b in 3 ml of dimethylsulfoxide and 1 ml of tetrahydrofuran over 3 minutes. The room temperature was then allowed to set and stirring was continued for 20 hours.

The reaction mixture was poured into ether and washed with water. The amines were extracted into dilute hydrochloric acid, which was washed with ether and basified with excess sodium hydroxide. The free amines were then extracted into ether, dried with magnesium sulfate and evaporated to give 2.5 g of an oily crude product whose thin layer chromatography on silica gel in methylene chloride / methanol 24: 1 showed the presence of multiple components.

The title compound ex-3a was obtained in pure form by preparative high pressure liquid chromatography on silica gel, eluting with a 97: 3 mixture of methylene chloride and ethanol. The substance ex-3a is in an oily form, the NMR and IC of which were consistent with the proposed structure.

b) Method for producing 2- [10- (2-dimethylaminopropyl) phenothiazin-2-yl] propionic acid i (Compound C)

1.7 g of ex-3a was dissolved in 50 ml of 4N hydrochloric acid and heated to reflux for 20 hours. The solution was evaporated under reduced pressure to give a viscous oil, which was then redissolved in 30 ml of water, washed with ether, and the pH was adjusted by cautiously adding sodium hydroxide (litmus) to about 10.9 in the basic region.

The resulting solution was washed with ether and then evaporated to half its original volume. Compound C hydrochloride was prepared as an oil with excess concentrated hydrochloric acid. The oil was redissolved in water and precipitated (again as an oil) with excess hydrogen chloride and then triturated with ether to solidify the oil.

The salt was recrystallized from methanol-ethyl acetate to give C.HCl.H2O, colorless crystals of m.p. 156 DEG-162 DEG C. (decomposition), whose elemental analysis (chn) confirmed the expected structure.

Example 3

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

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) phenothiamine in dried ether at 0 ° C was added dropwise 8.5 ml of a 1.55 M solution of butyllithium in hexane. The resulting yellow solution was stirred at 0 ° C for one hour, and then a solution of 1.7 ml of dimethylformamide in 20 ml of ether was added dropwise over one hour.

The reaction mixture was stirred at room temperature for 3 hours. 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 carbanion obtained from 2.69 g of diethylmethoxycarbonylmethylphosphonate and 385 g of sodium hydride as an 80% dispersion in oil per 30 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, evaporated to give crude (E) -3- (2-dimethylaminopropyl) -10- (2-dimethylaminopropyl) phenothiazines as a fluorescent yellowish oil.

b) Production method of [E] -3- (2-carboxyvinyl) -10- (2-dimethylaminorpopyl) phenothiazines g of this ester were hydrolyzed in a solution of 22 ml of ethanol and 8.8 ml of 2N sodium hydroxide solution at room temperature for 4 hours . The product was isolated by conventional means to give 3 g of crude carboxylic acid as an orange-colored gum. This was dissolved in hot 0.4 N hydrochloric acid and concentrated hydrochloric acid was added to induce crystallization in the form of orange-colored platelets.

Recrystallization from ethanol-ether gave yellow needles of E-3- (3-carboxyvinyl) -10- (2-dimethylaminopropyl) phenothiazines hydrochloride as a hemihydrate, m.p. 170 ° C (dec.). After drying at 150 ° C, an anhydrous salt was obtained which had a melting point of 220-225 ° C (decomposition) (Compound E).

Example 4

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

a) Method for producing (E) -4 (or 2) - (2-methoxycarbonylvinyl) -10- (2-dimethylaminopropyl) -phenothiazine

5.7 g of 10- (2-dimethylaminopropyl) phenothiazines were treated with butyllithium. Dimethylformamide (3.1 ml) was added sequentially and the mixture was allowed to stand at room temperature for 18 hours. The crude aldehyde was isolated by ether extraction and used without further purification.

The crude aldehyde was reacted with a phosphonate carbanion prepared from diethylmethoxycarbonylmethylphosphonate as described in Example 3 to give 4 (or 1) - (2-methoxycarbonylvinyl) -10- (2-dimethylaminopropyl) phenothiazide, which was crystallized from ethanol.

Melting point: 129-130 ° C.

b) Process for the preparation of [? E] -4 (or 1) - (2-carboxyvinyl) -10- (2-dimethylaminorpopyl) phenothiazines

This ester was hydrolyzed with dilute sodium hydroxide solution as described in Example 3 to give E-4 (or 1) - (2-carboxyvinyl) -18- (2-dimethylaminopropyl) phenothiazines, crystallizing from a mixture of isopropyl alcohol and petroleum ether at boiling point. 60-80 ° C, in the form of tiny yellow needles having a melting point of 120-125 ° C (H).

Example 5

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) phenothiazine in 20 mL of ethyl acetate was stirred under an atmosphere of hydrogen in the presence of Raney nickel until hydrogen consumption 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 3.

The 4 (or 1) - (2-carboxyethyl) -10- (2-dimethylaminopropyl) phenothiazine thus obtained crystallized from isopropyl alcohol as colorless needles.

M.p .: 155-157 ° C (Compound I).

Example 6

Method for the preparation of [4- 7-chloro-10- (2-dimethylaminopropyl) -2-phenothiazinyl] acetic acid (substance K)

(a) Method for producing 4'-bromo-3'-nitrophenylacetic acid (substances ex-10a)

20 ml of concentrated nitric acid and 10 ml of concentrated sulfuric acid were mixed, and 21.4 g of 4'-bromophenylacetic acid were added in portions over 20 minutes while cooling with water to maintain the internal temperature between 50 and 55 ° C. The mixture was then heated at 85 ° C for 10 minutes and then poured onto ice and diluted with water.

The resulting yellow solid was filtered off, washed with water, dissolved in a small amount of 2N sodium hydroxide and then reprecipitated by addition of excess concentrated hydrochloric acid. The solid was dried and recrystallized three times from benzene to give 10.2 g of ex-10a, mp 108-113 ° C. NMR analysis confirmed a single isomer of predicted structure.

b) Process for the preparation of ethyl 4'-bromo-3-nitrophenylacetate (substance ex-10b)

Ex-10a was suspended in a mixture of 400 ml of ethanol and 25 ml of triethyl orthoformate and 2 ml of concentrated sulfuric acid and heated to reflux for 3 hours. The solvent was evaporated and the residue was dissolved in ether and washed with water,

5 »sodium hydroxide and saturated with sodium chloride. The ether was evaporated and dried to give 35.1 g of ex-10b as a moving yellow-orange oil whose structure was consistent with NMR.

c) Method for producing ethyl 4- (4-chlorophenylthio) -3'-nitrophenyl acetate (ex-10c substances)

A mixture of 8.6 g of ex-10b, 5.5 g of 4-chlorothiophanol and 6.3 g of sodium carbonate in 75 ml of ethanol was stirred under nitrogen for 5.5 hours. The reaction mixture was poured into 900 ml of ice-cold 5% sodium hydroxide and extracted three times with 100 ml of ether.

The ether extract was washed with 5% sodium hydroxide and then dried over magnesium sulfate and evaporated to give 10.3 g of ex-10c as a yellow oil which solidified to a solid, mp 71-82 ° C, NMR consistent with expected structure. The substance was not further purified.

d) A process for producing ethyl (7-chloro-2-phenothiazinyl) acetate (ex-10d substances).

24.3 g of ex-ΙΟο and 46.0 g of triethylphosphite were combined in 200 ml of oxygen-free n-propylbenzene under reflux and heated at reflux for 4 hours. The volatile components were removed at 80 ° C with suction by a water pump. The dark residue was purified by silica gel column chromatography, eluting with a 6: 1 mixture of hexane and ethyl acetate.

6.1 g of a yellow solid were obtained, which was recrystallized from a 1: 1 mixture of ethanol and ethyl acetate. The product, ex-10d, was a colorless crystalline solid having a melting point of 193-194 ° C, whose NMR was consistent with the proposed structure. This rearrangement-related cyclization was described by Gadogan et al. in J. Chem. Soc. (1970) 2437.

é) Method for the preparation of ethyl [7-chloro-10- (2-dimethylaminopropyl) -2-phenothiazinyl] acetate (compound J)

4.1 g of ex-10d and 1.52 g of potassium butylate were mixed in 30 ml of deoxygenated toluene under nitrogen with stirring for 10 minutes. 1.7 g of 2-chloro-1-dimethylaminopropane was added and the reaction mixture was heated at 80 ° C for 1 hour.

An additional 1.5 g of potassium butylate and 1.7 g of 2-chloro-1-diraethylaminopropane were added and stirring and heating continued for a further 2 hours. The reaction mixture was diluted with 50 mL of toluene and washed with water and saturated with sodium chloride.

The amines were extracted with dilute hydrochloric acid and washed once with toluene, alkali (ammonia) and extracted into chloroform. After evaporation of the chloroform afforded 3 (l ^r> g · oil composition varied according to thin layer chromatography on silica gel and applied syntoniu J el lianol-ethyl] acetate in a ratio of 6: 1.

The oil was chromatographed by column chromatography eluting with ethyl acetate: ethanol (12: 1, 8: 1 and 5: 1). Ex-10e was in the form of an oil. Hydrogen maleate was prepared and crystallized from ethyl acetate, m.p. 158-160 ° C (dec.), Whose NMR and CHN analysis were consistent with the proposed structure.

f) Method for the preparation of [7-Chloro-10- (2-dimethylaminopropyl) -2-phenothiazinyl] acetic acid (ex-K)

A solution of 0.4 g of ex-10e in 10 ml of concentrated hydrochloric acid and 10 ml of water was heated in a water boiling bath for 16 hours. Evaporation of the solvent resulted in a glassy residue which was dissolved in 2-propanols and decolourised with activated carbon. Cooling the solution gave the hydrochloride as a colorless solid, m.p. 140 ° C (dec.).

The melting temperature (decomposition) was difficult to reproduce because it greatly depends on the heating rate. It is the monohydrate ex-lOP.HCl whose NMR elemental analysis and mass spectrum were consistent with the proposed structure.

Example 7

Method for the preparation of Q10- (2-dimethylaminoethyl) -7-methyl-2-phenothiazinyl] acetic acid (substance M)

a) Process for the preparation of ethyl 4 '- (4-methylphenylthio) -3'-nitrophenylacetate (ex-11a)

It was prepared by the method of Example 6 except that 4-methylthiophenol was used instead of 4-chlorothiophenol. The crude ex-11a was a yellow solid, mp 79-82 ° C, NMR spectrum was consistent with the proposed structure. The material was used in the next step without purification.

b) Method for producing ethyl f (7-methyl-2-phenothiazinyl) acetate] (substances ex-11b)

It was synthesized from ex-11a by the method of Example 6d. The same column chromatography and recrystallization were also used. The product, ex-11b, was a crystalline colorless material with a melting point of 189-192 ° C; the NMR spectrum was consistent with the proposed structure.

c) Method for the production of ethyl [10- (2-dimethylaminoethyl) -7-methyl-2-phenothiazinyl / acetate] (substances ex-11c, substances L)

Prepared according to the method of Example 6d using 2-dimethylaminoethyl chloride. The free base was purified by column chromatography eluting with a 1:10 mixture of ethanol and ethyl acetate. The oil obtained was taken up in hydrogen maleate and crystallized from ethyl acetate.

Ex-11c solid hydrogen maleate was obtained, m.p. 146-148 ° C, whose NMR and elemental analysis were consistent with the proposed structure.

d) Process for the preparation of 10 10- (2-dimethylaminoethyl) -7-ethyl-2-phenothiazinyl] acetic acid (substance M)

Ex-11c (0.5 g) was dissolved in 14 ml of 3.5 N hydrochloric acid and heated in a boiling water bath for 10 hours. After evaporation, the residue was taken up in 2-propanol and decolourised with charcoal and then evaporated again. The residue was triturated with ether to give a solid which was partially purified by dissolving in methanol and adding ethyl acetate and ether.

AND

A yellow powder was obtained whose chromatogram from high pressure liquid chromatography showed considerable contamination. It was therefore purified by semi-preparative high pressure liquid chromatography on a [10 mm x 50 µm Spherisorb G.P.C ^ g] column (reverse phase) and a QBrownlee jacketed column eluted with 40% methanol and 0.1% triethylamine and finally 100% methanol 0.1% triethylamine.

127-132 [deg.] C. (decomposition) was obtained, the NMR spectrum and elemental analysis as well as the mass spectrum being sufficient, although one further unidentified impurity was present (NMR and mass spectrum, thin-layer chromatography). .

Example 8

Process for the preparation of [10- (2-dimethylaminomethyl) -7-fluoro-2-phenothiazinyl] acetic acid (N substance)

(a) Method for the preparation of ethyl 4 '- (4-fluorophenylthio) -3'-nitrophenyl acetate (substances ex-12a)

The compound was prepared by the method of Example 6c using 4-fluorothiophenol. The crude product, ex-12a, was a yellow solid, mp 41-48 ° C, whose NMR spectrum confirmed the proposed structure and was used without further purification.

(b) Method for producing ethyl [7-fluoro-2-phenothiazinyl) acetate] (substance ex-12b)

It was prepared from ex-12a according to the method of Example 6d. The recrystallized product, ex-12b, had a melting point of 167-169 ° C and a spectrum consistent with the reported structure.

c)) Method for producing ethyl-10- (2-diethylaminoethyl) -7-fluoro-2-phenothiazinyl) acetate] (substance ex-12c)

This was obtained as an oil from ex-12b and 2-diethylaminoethyl chloride by the method of Example 6d and the product was purified by column chromatography on silica gel, eluting with ether. Both NMR and mass spectra were consistent with the reported structure.

Process for the preparation of [11- (2-dimethylaminoethyl) -7-fluoro-2-phenothiazinyl] acetic acid (N substance)

0.6 g of ex-12o was suspended in a mixture of 3 ml of dioxane and 6 ml of 1N sodium hydroxide and the mixture was heated under reflux for 24 hours. The reaction mixture was evaporated, the residue acidified with 8 ml of 1N hydrochloric acid and evaporated to dryness.

The residue was digested with 30 ml of hot 2-propanol. Filtration and evaporation of the solvent It left the hydrochloride of substance N as a resinous material which resists crystallization. It was therefore purified by high pressure liquid chromatography on a [10 mm of a 50 cm Spherisorb CPC _1g ] (reverse phase) column and a Brown Brownlee C ₁₂ ] mantle column] eluting with 50% methanol and 0.1% triethylamine.

A neutral material was obtained which, after recrystallization from ethyl acetate, had a melting point of 141-143 ° C. Its elemental analysis, NMR and mass spectrum were consistent with the structure considered.

Example 9

Process for the preparation of 2-fl0- (2- ^, dimethylaminopropyl) -2-phenothiazinyl] -2-methylpropionic acid (substance P)

and). Process for preparing 2- (4-bromophenyl) -2-methylpropionic acid (substances ex-13a)

The ethyl ester of the title compound was prepared as described in J. Am. Chem. Soc. 93, 6877-87 (1971). 54.1 g of this ester was heated for 5 hours in a mixture of 50 ml of ethanol,

4 g of sodium hydroxide and 400 ml of water.

The mixture was cooled to room temperature, washed with pentane and then acidified by the addition of 100 mL concentrated hydrochloric acid. This precipitated ex-13a as a colorless powder, mp 121-124 ° C, whose NMR spectrum was consistent with the proposed structure.

b) Method for producing 2- (4-bromo-3-nitrophenyl) -2-methylpropionic acid (substances ex-13b)

It was obtained by nitration of ex-13a as in Example 6a. The compound ex-13b obtained is a solid having a melting point of 167-171 ° C, whose NMR spectrum is consistent with the structure.

(c) Method for the preparation of ethyl (4-bromo-3-nitrophenyl) -2-methylpropionate (substance ex-13c)

This ester was obtained from ex-12b as described in Example 6b. The ex-13c obtained had a melting point near room temperature. The NMR spectrum confirmed the structure and the material was used without further purification.

d) Process for the preparation of ethyl (2-methyl-2- (3-nitrophenylthiophenyl) propionate) (substances ex-13d)

The synthesis was performed according to the method of Example 6c using thiophenol and ex-13c. The product, ex-13d, was obtained in quantitative yield as a very viscous yellow oil which did not solidify. Its thin-layer chromatography was essentially homogeneous and the NMR spectrum was consistent with the structure, so the product was used without further purification.

(e) Method for the preparation of ethyl [2-methyl-2- (2-phenothianisyl) propionate] (substances ex-13e)

This material was prepared from ex-13d by cyclization according to Example 6d and purified (homogeneous) by column chromatography (silica gel, hexane / ethyl acetate 10: 1). The product did not crystallize, but its NMR spectrum was consistent with the reported structure and the material was used without further purification.

f) Method for producing ethyl 2- (10- (2-dimethylaminopropyl) -2-phenothiazinyl) -2-methylpropionate] (substances ex-13f, substances 0)

The ester was obtained from ex-13e by the alkylation reaction of Example 6a. The free base was an oil from which a crystalline salt was prepared and crystallized from a mixture of ethyl acetate and hexane as the hydrogen maleate monohydrate of ex-13f.

The elemental, NMR and mass spectra were consistent with the reported structure.

g) Process for the preparation of 2-η 10 - (2-dimethylaminopropyl) -2-phenothiazinyl] -2-methylpropionic acid (substance P) 7.

This material was obtained by alkaline hydrolysis with sodium hydroxide from ex-13f according to the method of Example 6d. The crude hydrochloride obtained by acidification, evaporation and digestion with 2-propanol solidified after trituration with ether and then recrystallized from a mixture of methanol and ethyl acetate to give P.HCl, m.p. 192-196 ° C (dec.), NMR and mass the spectrum confirmed the predicted structure.

Example 10

Process for the preparation of 2- [10- (3-dimethylaminopropyl) -2-phenothiazinyl] -2-methylpropionic acid (Q)

a) Method for the preparation of ethyl {2- / 10- (3-dimethylaminopropyl) -2-phenothiazinyl) -2-methylpropionate] (substances ex-14a)

2.9 g of ex-13e was dissolved in 30 ml of dimethylformamide, followed by 1.13 g of potassium tert-butylate and 0.2 g of lithium iodide. The mixture was heated under nitrogen at 80 ° C and then 1.2 g of 3-dimethylaminopropylene chloride was added, which was freshly released from its hydrochloride.

After heating at 80 ° C for 30 minutes, an additional 0.24 g of potassium tert-butylate and 0.7 g of 3-dimethylaminopropyl chloride were added, and after another 30 minutes 0.34 g of potassium tert-butylate. After an additional 30 minutes, the reaction mixture was poured into water and extracted with methylene chloride.

Evaporation of methylene chloride yielded 4.3 g of a viscous oil which was chromatographed on a silica gel column and eluted with 96: 4 methylene chloride and methanol.

This gave 2.8 g of ex-14a as an oil which was homogeneous by thin-layer chromatography and its NMR spectrum was consistent with the proposed structure.

b) Method for producing 2- (10-2- (2-dimethylaminopropyl) -2-phenothiazinyl) -2-methylpropionic acid (Compound Q)

This material was obtained by alkaline hydrolysis with 1 N sodium hydroxide ex-14a as described in Example 8d. The hydrochloride crystallized from aqueous hydrogen chloride as a hydrate, Q.HCl-H2O, melting point 128 DEG C. (decomposition), the melting point being not reproducible.

Elemental, NMR analysis and mass spectra were consistent with the proposed structure.

Example 11

A solution of 1 g of [E] -3- (2-carboxyvinyl) -10- (2-dimethylaminopropyl) -phenothiazine hydrochloride in 20 ml of methanol containing 100 mg of 10Ϊ 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 saturated carboxylic acid hydrochloride.

A small amount of impurities was removed by esterification, and the ester was chromatographed on a column of silica (strong) in chloroform / methanol (50: 1) and hydrolyzed the pure ester.

The 3- (2-carboxyethyl-10- (2-dimethylaminopropyl) phenothiazine thus obtained was crystallized from a mixture of ethanol and ether to give a cream colored solid, m.p. 170-173 ° C (compound F).

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

trans-beta-η 10 - (2-dimethylaminopropyl) phenothiazin-2-yl 3 acrylic acid (1), mp 214-218 ° C,

10- (2-dimethylaminopropyl) phenothiazine-3-carboxylic acid (Compound D), m.p. 185-188 ° C (dec.),

3- (2-carboxyethyl) -10- (2-dimethylaminopropyl) phenothiazine, m.p. 170-173 ° C,

10- (2-dimethylaminopropyl) phenothiazine-4- (or 1) -carboxylic acid (compound G), m.p. 220-222 ° C (dec.), Ethyl- [2-methyl-2- / 10- (3- (N-pyrrolidino / propyl) -2-phenothiazinyl / propionate] (R), oil,

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

Example 12

Antihistamine effect

A. Antihistamine activity in vitro

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 one hour equilibration, cumulative concentration-response curves (Van Rossum, J. H., Arch. Int. Pharmacodyn, Ther *, 143 299-330, 1063) to histamine were obtained.

After washing, the tissues were incubated for 1 hour with the substance to be evaluated and another agonist curve for the effect of histamine concentration on the reaction was evaluated. Shifts to the right of the agonist concentration-response curve produced by the antagonists were used to construct Schild plots (O. Arunlakshana and H. O. Schild Br. J. Pharmacol. 14, 48-58, 1959).

Regression of log (dr-1) to log (Β), where dr is an equiactive response in the presence and absence of antagonist and (B) is the molar concentration of antagonist, allowed the determination of pA ₂ , ie negative logarithmic concentration of antagonist that shifts control histamine concentration curve - reaction twice to the right.

Table I

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 WITH 9.9

^X RB Barlow, 1964

Pharmacology, 2nd Edition, p. 373, ed. Wiley,

B. Antihistamine activity in vivo

Guinea pigs (hartley, male, 300-350 g) were left without food for 20 hours, then p.o. or i.p. evaluated substances. An 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, sneezing, significant abdominal movements, cyanosis or loss of righting reflex). Under these test conditions, the control animals collapsed for an average of 33 seconds. Εθ ₅₀ for protection against histamine were calculated using probit analysis.

In this test Εβ ^ θ shows that a single dose perfectly protects 50% of the animals against the effects of histamine for the duration of the assessment (1 hour post-dose). Perfect protection was defined as no histamine symptoms in the aerosol chamber (about ten times the time required for the collapse of control animals).

Table II

Results of antihistamine tests

Fabric ED ₅₀ /mg/kg.po/

Triprolidine 5.77

A 1.70

B 0.3 (4 hours post dose)

In addition to these results, it was found that Compound A could provide very long-lasting antihistaminic activity (e.g. 11 mg / kg represents the ED _5Q for 24 hours protection).

Method of anaphylactoid evaluation

Wister rats (180-300 g) were treated with test substances (i.p. or p.o.) 2 hours prior to exposure to the anaphylactoid indicator (48/80). One hour prior to exposure, 5 mg / kg i.p. peropranol. The anaphylactoid inducing agent was administered intravenously at 2 mg / kg, and the symptoms of respiratory distress were monitored in animals.

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 give a positive result for selective antihistamines. 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 or anaphylactic mediator release inhibitors.

T ab ⁷ u 1 ka III

Inhibition of anaphylactoid reaction

Substance

Ketotifen

AND

(B)

C

E

Astemizole

E ° ^50x

0.87

2.64

0.89 (1.2) ^xxx

1.43

3.11

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

γνγ

EDjjq ρ.ο. on the way

Compound B had 210 mg / kg in _LD5Q rats _. Example 13 (i.p.) and greater than 500 i mg / kg (p.o.) Pharmaceutical forms - (A) -Injection Component Amount in ampoule Compound of formula I 1.0 mg Water for Injection q.a. 1.0 ml The finely divided active substance was dissolved in water for injection. The solution was filtered and autoclaved. (B) -Pipes Component Quantity in suppository Compound of formula I 1.0 mg Cocoa butter 2,0 g TM or Wecobbe base q.s. TM Wecobee is a trade name and is a hydrogenated fatty carboxylic acid. The finely divided active substance was mixed with melted suppository base (either cocoa TM or Wecobee base), the molten suppositories were cast and allowed to cool behind formation of desired suppositories. (C) -Super .Component Amount in ml Compound of formula (I) 1.0 mg Ethanol 0.3 mg Sucrose 2.0 mg Methylparaven 0.5 mg Sodium benzoate 0.5 mg Cherry flavor q.s. Dye q.s. Water q.s. ad 5.0 ml Ethanol, sucrose, sodium benzoate, methylparaven and flavoring were combined in 70% of total amount of water. The flavor and the active ingredient were dissolved in the remainder water, then the solutions were mixed and clarified by filtration. (D) -Tablets , <Folder 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 Component Quantity in tablet Compound of formula (I) 1.0 mg Psendoephedrine 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 13 (D) above. (G) -Super Folders Quantity in 5 ml Compound of formula (I) 1.0 mg pseudoephedrine hydrochloride 30.0 mg Codeine phosphate 10.0 mg Guaifenesin ) .00 mg Methylparaven 0.5 mg Sodium benzoate 0.5 mg Flavor q.s. Dye q.s. Glycerine 500 mg Sucrose 2000 ¹ mg Cleaned water q.s. ad 5.0 mg Syrup containing other active ingredients in addition to the compound of formula I was prepared from above of said components in an analogous manner to that described for Example 13 (C) above. (H) -Spray in the nose ’· Folder Quantity per 100,0 ml Compound of formula (I) 1 g Sodium chloride 0.8 g Protective substance 0.5 g Cleaned water g.s. 100.0 ml The preservative was dissolved in warm purified water and after cooling to 25-25 ° C Sodium chloride and the compound of formula I were added at 30 ° C. The pH was then adjusted to 5.5 to 6.5 and purified water was added to adjust the final volume to 100.0 ml. (I) -Ophthalmic solution Component Amount in 100.0 ml Compound of formula (I) 0.1 g Sodium chloride , 0.8 g Protective substance 0.5 g Water for injections q.s. 100.0 ml

The preparation was prepared similar to a nasal spray.

(J) -Local cream

SDo Quantity per 100.0 ml

0.1 g

Emulsifying wax N.P. 15,0 g

Mineral oil 0,5 g

Claims (7)

SUBJECT OF THE INVENTION A method for producing a phenothiazine of the formula I wherein represents a divalent aliphatic hydrocarbon group having 1-7 carbon atoms or a single bond, R 2 and R 3 are you j n é or different and each is hydrogen, alkyl having 1 to 4 carbon atoms or together forms a nitrogen-containing heterocyclic ring of 4 to 6 members with a nitrogen atom, R 4 represents a hydrogen atom, a halogen atom, a C 1 -C 4 alkoxy group, a C 1 -C 4 alkyl group optionally substituted by 1 to 3 halogen atoms, or a group of the formula R 1 -C 4 H as defined above, represents a C 1 alkylene group up to 4 carbon atoms or ANR 1 R 2 form a group of the formula CH 2 or CH 2 and salts, esters and amides thereof, with the exception of the esters and amides of the compounds of formula I wherein R 1 represents hydrogen and represents a bond at position 2 of the phenothiazine and with the exception of a compound wherein R 1 represents a bond at the 2-position of the phenothiazine ring and R 1 represents a hydrogen atom and a group of formula ANR 2 R 2 represents a dimethylaminopropylene group and compounds wherein a group of formula ANR 2 R 2 represents diethylaminoethyl and R 4 represents a hydrogen atom; a group of formula R ^ CC ^ H = CH 2 CO 2 H in position 2, characterized in that the hydrolysis of a compound of formula VI (VI) wherein R 2 'R 3' R 4 and a its meaning as defined above; and R 2 represents a group R 1 CN, where it represents a divalent hydrocarbon group having 1 to 7 carbon atoms, or a group of the formula Ry-CF 1 = C / Y / XH, where Ry is a divalent hydrocarbon group having 1 to 6 carbon atoms, a single bond, X represents an oxygen atom or a sulfur atom and Y represents an amino group, then optionally converting a compound of formula I into another compound of formula I by hydrogenating a double bond in the side chain carboxy group, and optionally converting the compound to an acid addition salt, carboxylate salt , an ester or an amide of a compound of formula (I), or optionally liberating another compound within the scope of the compounds of formula (I) from such a compound. 2. The process of item 1, for producing a compound of formula Ia B-COOH (Ia), I AND AND N / R 2a R 3a where B represents a straight-chain or branched alkylene group having 1-7 carbon atoms or a group of formula (CH ^) = CH = CH (CH ^); wherein a and b are independently 0 to 5, the sum of a and b not exceeding 5, A * is a linear or branched alkylene group having 1 to 4 carbon atoms and? 2a and? 3a 3 SOU same as or different from each other and each represents hydrogen or alkyl with 1 to 4 carbon atoms or optionally form a heterocyclic ring of 5 to 7 members, and its salt, ester or amide thereof, with the exception of esters and amides of compounds of formula Ia wherein R₁ is hydrogen and R is a bond in position 2 of the phenothiazine ring system and with the exception of the compound of formula Ia wherein R 1 is a bond in position phenothiazine ring and R represents a hydrogen atom, a group of the formula ANR ^ R represents dimethylaminopropyl a group of the a compound of formula Ia, wherein the group of formula ANR 2 R is diethylaminoethyl and R represents a hydrogen atom and a group of formula R ^ CO ^ H represents CH 2 CO 2 H at the 2-position, characterized in that a compound of the formula VIa (VIa), R 2a R 3a is hydrolyzed wherein: E is -C = N or -C-NH 2 a R o, R ~, A 'and B' are as defined above under I and thereafter optionally converting a compound of formula la into another compound of formula Ia hydrogenation of the double bond in the carboxy side chain, and optionally the compound obtained is converted to an acid addition salt with an acid, a carboxylate salt, an ester or an amide of a compound of formula (I), or optionally liberating another compound within the scope of the compounds of formula (I). 3. The method according to claim 1, characterized by using appropriate starting Nin · The osmolality, to prepare a compound of formula II R 4 (II), R1 CO2 H wherein g and and A are as defined for formula I, or a salt, ester or amide thereof, with the exception of the esters and amides of the compounds of formula II wherein R 1 is hydrogen and R 1 is a bond, and with the exception of the compound of formula II wherein R 1 is hydrogen; R @ 5 is hydrogen, and the group of formula ANR @ 1 R @ 1 represents dimethyl 1 aminopropyl CH 2 , represents a hydrogen atom and the group of formula ANR 1, R 3 is diethylaminoethyl. 4. A process according to claim 1, wherein the compounds of formula (CH3) are prepared using the appropriate starting compounds, wherein n is an integer of from 0 to 3, CH = CH or a group of formula CH (CH) (CH ^^, wherein m is 0 or 1 or -C (CH 3) 2, and other symbols are as defined in claim 1, with the exception of compounds of formula I wherein n is 1, R₁ represents a hydrogen hydrogen and a group of formula ANR 2 R 3 represents diethylaminoethyl. 5. Method according to claim 1, characterized in that, using the appropriate starting compounds prepared compound according to any one of claims 1-4, wherein NR 2 R 3 represents dimethylamino or diethylamino, and other symbols are as defined in claim 1, or third 6. A process according to claim 1, wherein the corresponding starting compounds are prepared according to any one of items 1 to 5, wherein R1 is hydrogen, methyl, chlorine or fluorine, and the other symbols are as defined in 1, 3 or 4. 7. A process according to claim 1, wherein A is an ethylene, n-propyl or isopropylene group, and the other symbols are as defined in point 1, using the appropriate starting compounds. or 3 to 5.