CS252488B2 - 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.

US patent specification. 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.

The compounds obtainable by the process of the present invention are most similar in structure 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).

Antihistamines now in use, including diphenylhydramine, pheniramine, pyrilamine, promethazine, and triprolidine generally have a potential disadvantage, since they all cause sedation or drowsiness in some patients. Furthermore, promethazine has a potential anticholinergic effect.

We have now found a new class of compounds with anti-allergic activity in vivo, defined by blockade of anaphylactoid effect. Some of these compounds also have good antihistamine activity, are substantially free of central nervous system (CNS) side effects and appear to be substantially free of 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 formula I r ₁ every ₂ h (i)

N

R 3 R 3 wherein

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

Sj and Kj are the same or different and individually represent a hydrogen atom, a C1-C4 alkyl group or together with the nitrogen atom form a nitrogen-containing heterocyclic ring of 4 to 6 members, denote a hydrogen atom, a halogen atom, a C1-C4 alkoxy group or C1-C4alkyl optionally substituted with up to 3 halogen atoms or R RC CCH as defined above denotes an alkylene group of 1 to 4 carbon atoms or ANRjRj forms a group of the formula

or

and their salts, esters and amides, β except esters and amides of compounds of formula I wherein R ₄ is hydrogen and R ₄ represents a bond at the 2-position of the phenothiazine ring system and with the exception of compounds of formula I wherein R 4 represents a bond at position 2 phenothiazine ring and R represents a hydrogen atom and a group of the formula ANR ₂ R ₃ represents dimethylaminopropylenovou groups and compounds wherein the group of formula ANRjR ^ is diethylaminoethyl and R represents a hydrogen atom and a group of formula R₁-CO ₂ H, = CH ₂ CO ₂ H in position 2,

Among these compounds of formula I obtainable according to the invention, those having the formula II are suitable

R4.6

AND

N r ₂ r ₃ r ^zx _{1 CO2} H (II) wherein when R₁ and A are as defined for formula I, or a salt, ester or amide,

Rj. it may have a straight or branched chain, and denote a saturated or unsaturated hydrocarbon group or a single bond. Optionally, R 1 represents a C 1 -C 3 hydrocarbon group or a single bond or comprises at least one double bond. Preferably R 1 is - (CH ₂ > _n -), wherein n is an integer from 0 to 3 or CH = CH or -CH ₂ CH ₂ - (CH ₂ ) _m -, wherein m is 0 or 1, or -C (CH 2 -, R 3 CO 3) H most preferably denotes the group -CH 3 CO 3 H.

and are suitably the same or different and individually denote 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 pyrrolidine, piperidine or morpholine.

3 ^is preferably dimethylamino or diethylamino, and most preferably dimethylamino.

preferably hydrogen represents 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 and usually preferably at the 7 position.

Suitably, A is an ethylene, n-propylene or isopropylene group, or

ANR 1 R 1 forms 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 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 is a straight or branched chain and is optionally substituted with a halogen atom. C 1 -C 4 alkyl esters are particularly preferred. The compounds of formula I may form either addition salts or salts formed from a carboxyl group. Addition salts are preferred, but salts formed from a carboxyl group can be particularly used 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 a pharmaceutically acceptable salt thereof 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 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 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 ^C ^H 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-Q 0-2- (4-dimethylaminopropyl) phenothiazin-2-ylacrylic acid,

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

Q.0- (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- [1 ^{'_' /} 3- (N-pyrrolidino) propyl / fenothiazinylJ -2-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 invention and promethazine 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 alkylating a compound of formula VII (VII)

AND

H where

R 1 and R 2 are as defined above and

CORg is an ester or amide group, 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 obtained to an acid addition salt, carboxylate salt, ester or amide compound or optionally releasing another compound within the scope of the compounds of formula I,

The alkylation of compounds of formula VII is carried out under conditions well known in the art. Alkylating agent of general formula

LANR ₂ ? ₃ , where

A, and H 3 are as defined above and

L is a substituted group, is reacted with a compound of formula VII in the presence of a base at a conventional temperature, for example between 0 and 150 ° C, in an inert solvent.

Preferably, a strong base such as an alkoxide such as a t-butoxide, a hydride such as sodium hydride or a sodium amide is used. The temperature is preferably between 20 and 90 ° C and the solvent is suitably a hydrocarbon such as toluene, an ether such as tetrahydrofuran or a dipolar aprotic solvent such as dimethylformamide or dimethyl sulfoxide.

Compounds of formula VII can be prepared according to the scheme below.

Scheme .Hal

RgCOR, - (Qj nitration

RgCOR.

Hal

NO, (• thiol ©

RgCOR

P (OE ₊ ) ₃ in (3)

RgCOR ^

r ₄

Explanatory notes:

A nitrating agent, for example HNO 4 and f SO 2, at a temperature of 0 to 100 ° C.

2. A thiol of the formula and a base, for example sodium carbonate in a polar solvent, for example an alcohol such as methanol, at elevated temperatures, for example 50 to 100 ° C, preferably at reflux.

3. 2 moles of compound P (OEt), wherein Et is ethyl, in a high-boiling hydrocarbon, for example n-propylbenzene, at an elevated temperature, for example 125-200 ° C, preferably at reflux.

Reduction of one of the two double bonds, i.e. double bonds in the carboxyl post-chain, can be carried out by hydrogenation in the presence of a transition metal catalyst, for example platinum on carbon. The preparation of esters and amides from the corresponding carboxylic acids and vice versa can be carried out by methods known in the art.

The compounds produced according to the invention with antiallergic effect 1: use in the same indication as clinically used antiasthmatics, i.e. to assist in the contraceptive or bronchospasm characteristic of allergic asthma with induced asthma and the symptoms of bronchoconstriction and bronchospasm resulting in acute or chronic bronchitis. The compounds are believed to inhibit the release of autocoids (ie, histamine, aerotonin, 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 antihistamine activity can be used in the same indication as clinically used antihistamines, namely to alleviate unpleasant symptoms, induced histamine release, nasal congestion and vasomotor rhinitis, and to symptomatically affect allergic conditions including nasal allergy, parenial 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 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 and have little or no anticholinergic efficiency.

The amount of active compound required for use in the above 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 in the range of 0.003 to 1.0 mg per kg body weight per day, preferably 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 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 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 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 decongestant, 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, 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. General formulations are prepared by uniformly and 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.

Preparations podlg. of the invention suitable for oral use may be administered in the form of 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 a suspension in an aqueous liquid or 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 contain thickeners, sugar-crystallization-inhibiting agents, or solubility enhancers of any other component, 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 the nanal mucomembranes.

Ophthalmic preparations can be prepared in a similar manner to a nasal spray except 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 media such as 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 present 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 trans-beta- [10- (2-dimethylaminopropyl) phenothiazin-2-yl] acrylic acid

(a) Method for the preparation of 2-bromo-10- (2-dimethylaminopropyl) phenothiazine (substances ex-1a)

5.0 g of 2-bromophenothiazine and 2.4 g of potassium tert-butylate were combined in 25 ml of dry xylene under nitrogen and heated at 65 ° C for 10 minutes. To this was added dropwise over 10 minutes, a solution of 2.8 g of 2-dimethylaminopropyl chloride in 2 ml of xylene. Stirring under nitrogen and heating to 60-70 ° C were 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 with magnesium sulfate and evaporated to give a viscous oil weighing 6.35g. The oil is a mixture of the desired compound and its 2-bromo-10- (2-dimethylamino-1-methylethyl) phenothiazine isomer from which it was separated as a colorless oil by preparative HPLC on silica gel, eluting with ethyl acetate / methylene chloride (4). : 1.

The compound ex-1a did not crystallize and no attempt was made to obtain a crystalline salt. It was characterized by NMR spectra which corresponded to the reported structure and differed from its isomer.

b) Method for producing 10- (2-dimethylaminopropyl) phenothiazin-2-yl-carboxyaldehyde (substances ex-1b)

Using a syringe and nitrogen atmosphere, a flask containing 2.8 g of ex-l and 20 ml of anhydrous tetrahydrofuran was added to the flask. The solution was stirred and cooled with a dry ice bath in acetone and a solution of 5.2 ml of a 1.5 N solution of n-butyllithium in hexane was added dropwise over five 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 to room temperature over 25 minutes. It was then poured into dilute hydrochloric acid where it was washed with benzene and then basified with ammonium hydroxide. The product was extracted into methylene chloride, which was dried with magnesium sulfate and evaporated to give a very viscous yellow oil of ex-1b. 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 with methanol (9: 1) showed the presence of a single substance which was less mobile than the starting material, ie ex-1a.

c) Process for the preparation of trans-beta-Q10- (2-dimethylaminopropyl) phenothiazin-2-yl] acrylic acid (Compound A)

Ex-1b (2.4 g), malonic acid (1.1 g) and morpholine (0.120 g) were dissolved in 8 ml of pyridine and heated in a boiling water bath. Carbon dioxide was 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 melting at 214-218 ° C.

NMR and elemental analysis confirmed the assumed structure.

Example 2

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

a) Method for the preparation of [e] -3- (2-methoxycarbonylvinyl) -10- (2-dimethylaminopropyl) phenothiazine

To a stirred solution of 4.0 g of 3-bromo-10- (2-dimethylaminopropyl) phenothiazine in dried ether at 0 ° C was added dropwise 8.5 ml of a 1.55 molar 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 dried ether was 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 carbanion obtained from 2.69 g of diethyl [methoxycarbonylmethylphosphate and 385 mg of sodium hydride as an 80% dispersion in oil, in 30 ml of 1. Of 2-dimethyoxyethane 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) Production method 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 room temperature for 4 hours. The product was isolated as described in Example 1 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 [ε] -3- (2-carboxyvinyl) -10- (2-dimethylaminopropyl) phenothiazines hydrochloride as a hemihydrate, m.p. 170 ° C (dec.). After drying at 150 ° C, an anhydrous salt is obtained with a melting point of 220-225 ° C (decomposition).

Example3

Process for the preparation of 3- (2-carboxyethyl) -10- (2-dimethylaminopropyl) phenothiazines

A solution of 1 g of [e] -3- (2-carboxy-vinyl) -10- (2-dimethylaminopropyl) -phenothiazines hydrochloride in 20 ml of methanol containing 100 mg of 10% palladium on charcoal catalyst is stirred under a hydrogen atmosphere until absorption. not complete (9 hours). The catalyst is filtered off and the solvent is evaporated to give the carboxylic acid saturation hydrochloride. A small amount of impurities is removed by esterification and the ester is chromatographed on a silica column in a 5: 1 chloroform / methanol mixture and hydrolyzing the pure ester as as described in Example 2. 3- (2-Carboxyethyl) -10- (2-dimethylaminopropyl) phenothiazine thus obtained is crystallized from a mixture of ethanol and ether. 170 DEG-173 DEG C. (compound Fj.

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-methoxycarbonyl) -10- (2-dimethylaminopropyl) phenothiazines in 20 ml of ethyl acetate was stirred under a hydrogen atmosphere in the presence of Raney nickel until the consumption of hydrogen ceased. The filtered solution is evaporated to give 4 (or 1) - (2-methoxycarbonylethyl) -10- (2-dimethylaminopropyl) phenothiazines which is hydrolyzed in aqueous ethanolic sodium hydroxide solution as described in Example 2. 4 (or or 1) - (2-carboxyethyl) -10- (2-dimethylaminopropyl) phenothiazine crystallizes with isopropyl alcohol in the form of colorless needles. M.p .: 155-157 ° C (compound I).

Example 5

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

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

20 ml of concentrated nitric acid and 20 ml of sulfuric acid are mixed and 21.5 g of 4'-bromophenylacetic acid are added in portions over 20 minutes under cooling with water, maintaining the internal temperature between 50 and 55 ° C. The mixture was then heated at 85 ° C for 10 minutes. The mixture was then poured onto ice and diluted with water. The yellow solid obtained is filtered off, washed with water, dissolved in a small amount of 2N sodium hydroxide and then reprecipitated by addition of an excess of concentrated hydrochloric acid. The solid was dried and recrystallized three times from benzene. 10.2 g of compound ex 10a, m.p. 108 DEG-113 DEG C., is obtained. NMR analysis confirmed a single isomer of the proposed structure.

b) Method for producing ethyl [4'-bromo-3'-nitrophenylacetate] (compounds ex 10b)

Compound ex 10a is 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 dried and evaporated. 35.1 g of ex 10b is obtained in the form of a moving yellow-orange oil, the NMR spectrum of which corresponds to the structure.

c) Method for the preparation of ethyl [4 '- (4-chlorophenylthio) -3'-nitrophenylacetate] (compounds ex 10c)

A mixture of 8.6 g of ex 10b, 5.5 g of 4-chlorothiophenol and 6.3 g of sodium carbonate in 75 ml of ethanol is stirred under nitrogen for 5.5 hours. The reaction mixture is poured onto 900 ml of ice-cold 5% sodium hydroxide and extracted three times with 100 ml of ether each time. The ether phase 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 analysis of the compound was consistent with the proposed structure. The substance is not further cleaned.

d) Method for producing ethyl [(7-chloro-2-phenothiazinyl) acetate] (compounds ex 10x)

24.3 g of ex 10c and 46.0 g of triethylphosphite are combined in 200 ml of dried oxygen-free n-propylbenzene under nitrogen and refluxed for 4 hours. Volatile components are removed at 80 ° C with suction by the rear pump. The dark residue was purified by flash column chromatography on silica gel, eluting with hexane / ethyl acetate 6: 1. 6.1 g of a yellow solid are obtained, which is recrystallized from a 1: 1 mixture of ethanol and ethyl acetate. The product, compound ex-10d, is a colorless crystalline solid having a melting point of 193-194 ° C, whose NMR spectrum is consistent with the proposed structure. This rearrangement cyclization has been described by Cadogan et al. in J. Chem. Soc. (1970) 2,437.

e) Production method of ethyl [(7-chloro-10- (2-dimethylaminopropyl) -2-phenothiazinyl] acetate (compound ex 10e, compound J)

4.1 g of ethyl f (7-chloro-2-phenolthiazinyl) acetate and 1.52 g of potassium tert-butoxide were mixed in 30 ml of deoxygenated toluene under nitrogen with stirring for 10 minutes. 1.7 g of 2-chloro-1-dimethylaminopropane are added and the reaction mixture is heated at 80 ° C for 1 hour. An additional 1.5 g of potassium tert-butoxide and 1.7 g of 2-chloro-1-dimethylaminopropane are then added and stirring and heating is 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 are then extracted with dilute hydrochloric acid, washed once with toluene and basified (to litmus) with ammonium hydroxide and extracted with chloroform. Evaporation of the chloroform gave 5.85 g of a varied oil (silica gel thin layer chromatography, ethanol / ethyl acetate 6: 1). The oil was fractionated by flash chromatography eluting with a 12: 1, 8: 1 and 5: 1 mixture of ethyl acetate and ethanol. The title compound ex 10e is in the form of an oil. Ready! m.p. 158 DEG-160 DEG C. (decomposition), the NMR and elemental (C, N, H) analysis corresponding to m.p. designed structure.

b) Method for producing £7-chloro-10- (2-dimethylaminopropyl) -2-phenothiazinyl] acetic acid (ex-K compounds)

A solution of 0.4 g of ex10e compound in 10 ml of concentrated hydrochloric acid and 10 ml of water was heated on a steam bath for 16 hours. Evaporation of the solvent in addition to the glassy residue, which is dissolved in 2-propanol and decolorized with activated carbon. Cooling the solution gave the hydrochloride as a colorless solid, mp 140 ° C (dec.). The melting point (decomposition) is difficult to reproduce because it depends very much on the heating rate. It is the hydrochloride monohydrate, ex 10F. Whose NMR spectrum, elemental (C, H, N) analysis and mass spectrum were consistent with the proposed structure.

Example 6

Process for the preparation of [10- (2-dimethylaminoethyl) -7-methyl-2-phenothiazinyl] acetic acid (compound M)

a) Process for the preparation of ethyl 4- (4-methylphenylthio) -3'-nitrophenyl acetate] (compounds ex 11a)

The compound was prepared according to the method of Example 5c except 4-methylthiophenol was used instead of 4-chlorothiophenol. Crude ex 11a is a yellow solid, mp 78-82 ° C. The NMR spectrum was consistent with the proposed structure. The material is used in the next step without purification.

b) Method for the preparation of ethyl E - (7-methyl-2-phenothiazinyl) acetate] (compounds ex 11b)

The compound was synthesized from ex 11b by the method of Example 5. The same column chromatography and recrystallization were also used. The product, compound ex 11b, is a crystalline solid, m.p. 189-192 ° C. The NMR spectrum was consistent with the structure shown.

c) Process for the preparation of ethyl E / 10- (2-dimethylaminoethyl) -7-methyl-2-phenothiazinyl / acetate (compounds ex 11c, compound L)

This compound was prepared by the method of Example 5 using 2-dimethylaminoethyl chloride. The free base was purified by flash column chromatography eluting with 1:10 ethanol: ethyl acetate. The oil obtained is converted to hydrogen maleate and crystallized from ethyl acetate. This is a solid, ex 11c-hydrogen maleate having a melting point of 146-148 ° C. The NMR spectrum and elemental analysis correspond to the proposed structure.

d) Method for producing (10- (2-dimethylaminoethyl) -7-methyl-2-phenothiazinyl / acetic acid (compound M)

Dissolve 0.50 g of ex 11c in 14 ml of 3.5 N hydrochloric acid and heat on a steam bath for 10 hours. After evaporation to dryness, the residue is taken up in 2-propanol and decolorized with activated carbon 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. A yellow powder is obtained whose chromatogram from high pressure liquid chromatography shows considerable contamination. Therefore, it is purified by semi-preparative HPLC using a 10 mm x 50 cm Spherisorb G.P.C.g column (reverse phase) and a Brownlee jacketed column], eluted with 40% methanol and 0.1% triethylamine and finally 100% methanol and 0.1% triethylamine.

Thus, the desired compound was obtained as a neutral mass with a melting point of 127-132 ° C (decomposition), whose NMR and elemental analysis as well as the mass spectrum were sufficient, although one further unidentified impurity according to NMR analysis, mass spectrum and thin layer chromatography was present. .

Example 7

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

a) Process for the preparation of ethyl-4- (4-fluorophenylthio) -3'-nitrophenylacetate] (compounds ex 12a)

The compound was prepared as in Example 5 using 4-fluorothiophenol. The crude product, compound ex 12a, is a yellow solid, mp 41-48 ° C, whose NMR spectrum confirms the proposed structure. The material was used without further purification.

b) Process for the preparation of ethyl [7-fluoro-2-phenothiazinyl) acetate (compounds ex 12b)

The compound was prepared from ex 12a by the method of Example 5. The recrystallized product, ex 12b, had a melting point of 167-169 ° C; The NMR spectrum was consistent with the reported structure.

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

This compound was obtained as an oil from ex 12b and 2-diethylaminoethyl chloride by the method of Example 5 and was purified by flash chromatography on silica gel, eluting with ether. NMR and mass spectra were consistent with the assigned structure.

d) Process for the preparation of Q10- (2-diethylaminoethyl) -7-fluoro-2-phenothiazinylacetic acid (compound N)

0.6 g of ex 12c is suspended in a mixture of 3 ml of dioxane and 6 ml of 1N sodium hydroxide and the mixture is 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 is digested with 30 ml of hot 2-propanol. Filtration and evaporation of the solvent affords the hydrochloride of compound N as a gum-resistant resin. Therefore, Spherisorb G.P. is purified by HPLC using 10 mm x 50 cm. (reverse phase) column and Brownlee jacketed column] eluting with 50% methanol and 0.1% triethylamine. A neutral compound of N is obtained which, after recrystallization from ethyl acetate, has a melting point of 141-143 ° C. Its elemental (C, H, N) analysis, NMR and mass spectrum correspond to the structure under consideration.

Example 8

Process for the preparation of 2-Q10- (2-dimethylaminopropyl) -2-phenothiazinyl-2-methylpropionic acid (compound P)

(a) Method for the preparation of 2- (4-bromophenyl) -2-methylpropionic acid (compounds ex 13a)

The ethyl ester of the title compound was prepared as described in J. Am. Chem. Soc. 93,

877-6887 (1971). 54.1 g of this ester are heated for 5 hours in a mixture of 50 ml of ethanol, 40 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 of concentrated hydrochloric acid. Compound ex 13a precipitated as a colorless powder, m.p. 121-124 ° C, whose NMR spectrum was consistent with the proposed structure.

(b) Method for producing 2- (4-bromo-3-nitrophenyl) -2-methylpropionic acids (compounds ex 13b)

The title compound is obtained by nitration of compound ex 13a as described in Example 5 below. The compound ex 13b obtained is a solid, m.p.

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

This ester is obtained from compound ex 12b as described in Example 5. The compound ex 13c obtained has a melting point close to room temperature. The NMR spectrum confirms the expected structure. The material was used without further purification.

d) Process for the preparation of ethyl-L2-methyl-2- (3-nitro-4-phenylthiophenyl) propionate] (compounds ex 13d)

The synthesis was carried out as in Example 5 using thiophenol and compound ex 13c. The product, compound ex 13d, is obtained in quantitative yield as a very viscous yellow oil which does not solidify. Its thin layer chromatography shows a substantially homogeneous substance and the NMR spectrum corresponds to the expected structure, the product is used without further purification.

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

This compound was prepared from ex 13d by cyclization from Example 5 below and purified to homogeneity by thin layer chromatography (silica gel, hexane-ethyl acetate 10: 1). The product does not crystallize, but its NMR spectrum is consistent with the given structure. The material was used without further purification.

f) Process for the preparation of ethyl Q2- [10- (2-dimethylaminopropyl) -2-phenothiazinyl] -2-methylpropionate] (compounds ex 13f, compound 0)

This compound is synthesized from compound ex 13e by the alkylation reaction of Example 5. The free base forms an oil from which a crystalline salt is prepared and crystallized from a mixture of ethyl acetate and hexane as the hydrogen maleate monohydrate of compound ex 13f. Elemental (C, H, N) NMR and mass spectra are consistent with the reported structure.

g) Process for the preparation of 2- [4- 10- (2-dimethylaminopropyl) -2-phenothiazinyl] -2-methylpropionic acid (compound P)

This was obtained by alkaline hydrolysis (sodium hydroxide) of ex 13f as in Example 7. The crude hydrochloride obtained by acidification, evaporation and digestion with 2-propanol solidified upon trituration with ether and then recrystallized from methanol / ethyl acetate to give the hydrochloride of compound P mp 192-196 ° C (dec.), NMR and mass spectra as well as elemental (C, H, N) analysis confirm the ' ¹ ' expected structure.

Example 9

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

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

2.9 g of ex 13e are dissolved in 30 ml of dimethylformamide, then 1.13 g of potassium tert-butoxide and 0.2 g of lithium iodide are added. The mixture was heated to 80 ° C under nitrogen, and then 1.2 g of 3-dimethylaminopropyl chloride, which had been freshly released from its hydrochloride, was added.

After heating at 80 ° C for 30 minutes, an additional 0.24 g of potassium tert-butoxide and 0.7 g of 3-dimethylaminopropyl chloride was added, and after another 30 minutes 0.34 g of potassium tert-butoxide was added. 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 flash chromatographed on a silica gel column eluting with methylene chloride / methanol (96: 4). This afforded 2.8 g of ex 14a as an oil which was homogeneous by thin layer chromatography and whose NMR spectrum was designed.

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

This material was obtained by alkaline hydrolysis, 1N sodium hydroxide, of the compound ex-14a as described in Example 7. The hydrochloride crystallized from aqueous hydrochloric acid as a hydrate of compound Q.HCl.I.sub.2 O, m.p. 128 DEG C. (decomposition), m.p. is not reproducible. Elemental (C, H, N), NMR analysis and mass spectrum were consistent with the proposed structure.

Similarly produced:

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

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

4-3- (2-carboxyvinyl) -10- (2-dimethylaminopropyl) phenothiazine (substance Ε), m.p. 220-225 ° C (decomposition),

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.), [.Alpha.] - 4 (or 1) - (2-carboxyvinyl) -10- (2-dimethylaminopropyl) phenothiazine (compound Η), m.p. 120-125 ° C; ethyl-10 (2-dimethylaminoethyl) -7-methyl-2-phenothiazinyl] acetate (compound L), m.p. up to 148 ° C,

2 - [1θ ^ ^- (2-dimethylaminopropyl) phenothiazine-2-yl] -acetic acid (Compound Β) hydrogen maleate salt m.p. 115-120 ° C, ethyl / 2-methyl-2- 10- / 3- (N (2-dimethylaminopropyl) phenothiazin-2-yl] carboxylic acid, m.p. 257 DEG-261 DEG C. (decomposition).

Example 9

Antihistamine effect

A. Antihistamine activity in vitro

The longitudinal muscle strip was isolated from the intact Hartley guinea pig ileum (male 250-400 g) and placed in a bath at a load of 300 mg. After one hour equilibration, cumulative concentration-response curves were obtained (Van Rossum, J. H., Arch. Int. Pharmacodyn. Ther.,

143, 299-330 (1963) for histamine. After washing, the tissues were incubated for 1 hour with the test substance 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 Schilk plots (O. Arunlakshana and HO Schild Br. J. Pharmacol. 14, 48-58 (1959). Regression of log (drl) to log (Β), where dr is an equivalent reaction in the presence and absence of the antagonist, and (B) is the molar concentration of the antagonist, allowing the pA?

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 O 8.5 P 8.8 Q 8.7 with 9.9

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

New York, 1964

B. Antihistamine activity in vivo

Hartley guinea pigs (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.

ED 50 for histamine protection were calculated using probit analysis, in this assay ED 50 indicates 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

Substance ED40 / mg / kg, p.o.

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 a very long lasting antihistamine effect (for example, 1 mg / kg p.o. indicates 24 hours protection).

Method of anaphylactoid evaluation

Wister rats (180-300 g) were dosed 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. propranolol. The anaphylactoid indicator agent was administered intravenously at 2 mg / kg and the symptoms of respiratory distress were observed 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 provide a positive result for a selective antihist ball. Also, rats do not respond to histamine (i.v.) symptoms of anaphylaxis. Agents that block the effects of the agent are usually clad as inhibitors of anaphylactic mediators or inhibitors of anaphylatic mediator release.

Table III

Inhibition of anaphylactoid reaction

Substance

ED

Ketotifen

AND

(B)

C

E

Astemizole

0.87

2.64

0.89 (1.2) ^XXX 1.43 3.11 1.08 ^x Dose of substance (ip) providing 50I protection against 48/80 induced death. The substance was administered 2 hours before the test.

^xxx ED, _o along the way

Compound B had 210 mg / kg (ip, and greater than 500 mg / kg (po) in LD _5Q rats)

Example 10

(A) -injection

Amount in ampoule

Compound of Formula I 1.0 mg

Water for injection q.s. 1.0 ml

The finely divided active substance was dissolved in water for injection. The solution was filtered and autoclaved.

(B) Suppository Compound Amount of suppository of Formula I 1.0 mg

Cocoa butter 2.0 g

TM or Wecobee base q.s.

Wccobcc

TM

is a trade name and is a hydrogenated fatty carboxylic acid.

The finely divided active ingredient was mixed with the molten suppository base (either TM cocoa butter or Wecobee base), the molten suppositories were cast and allowed to cool to form the desired suppositories.

(C) -Super

Component Quantity in ml

Compound of formula X 1.0 mg Ethanol 0.3 mg Sucrose 2.0 mg Methylparaben 0.5 mg Sodium benzoate 0.5 mg

Component

Amount in ml

Cherry flavor

Dye

Water

q.s.

q.s.

q.s. ad 5.0 ml

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

(D) Tablets

Component

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) -Fees

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

Pseudoephedrine hydrochloride 60.0 mg

Component Quantity in tablet 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 10 above (D) (G) - Syrup

Components Quantity in 5 ml Compound of formula (I) 1.0 mg Pseudoephedrine hydrochloride 30.0 mg Codeine phosphate 10.0 mg Guaifenesin 100 ALIGN! mg Methylparaben 0.5 mg Sodium benzoate 0.5 mg Flavors q.s. Dye q.s, Glycerine 500 mg Sucrose 2 000 mg cleaned water q.s, . ad

A syrup containing active ingredients other than the compound of Formula I was prepared from the above ingredients in a manner analogous to that described for Example 10 (C) above.

(H) -spray into the nose

Component

Quantity per 100,0 ml

Substance of formula I Sodium chloride Protective substance purified water 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

Amount in 100.0 ml

Substance of formula I Sodium chloride Protective agent Water for injections

0.1 g 0.8 g 0.5 g

q.s. 100.0 ml

The preparation was prepared similar to a nasal spray.

(J) - Topical cream

Component Quantity per 100.0 ml

Compound of formula I 0.1 g

Emulsifying wax N, F, 15.0 g

Mineral oil 0,5 g

Claims (6)

A process for the preparation of phenothiazines of the general formula I AND AND AND N r ₂ r ₃ (i) wherein denotes a divalent aliphatic hydrocarbon group having 1 to 7 carbon atoms or a single bond, r ₂ and R 3 are the same or different and individually denote a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or together with an atom nitrogen represents a nitrogen-containing 4 to 6-membered heterocyclic ring, denotes a hydrogen atom, a halogen atom, a C1-C4 alkoxy group, a C1-C4 alkyl group optionally substituted by up to 3 halogen atoms or a radical of the formula R @ 1. H as defined above, denotes an alkylene group having 1 to 4 carbon atoms or ANR ₂ R ₃ forms a group of the formula CH _2, or and their salts, esters and amides, with the exception of esters and amides of compounds of formula I wherein R₁ is hydrogen and is a bond in position 2 of the phenothiazine ring system and with the exception of compounds of formula I wherein R₁ represents a bond in position And the group of formula ANR ₂ R ₃ represents dimethylaminopropyl and compounds wherein the group of formula ANR ₂ R ₃ represents diethylaminoethyl and R 6 represents a hydrogen atom and the group R 6 CO ₂ H represents a group CH ₂ CO ₂ H at the 2-position, characterized in that the compound of formula VII is alkylated AND H where R 1 and R 2 are as defined above and _C or ₆ is an ester or amide group, and then optionally converting a compound of formula I to another compound of formula I by hydrogenating the double bond in the side chain carboxy group, and optionally converting the compound to an addition an acid salt, a carboxylate salt, an ester or an amide of a compound of Formula I, or optionally releasing another compound within the scope of the compounds of Formula I from such a compound. 2. The process according to the compounds of claim 1, characterized in that the corresponding starting compounds of the general formula (II) are used RjCOjH (II) AND N OF\ R ₂ where R 1 to R 2 and A are as defined for formula I, or a salt, ester or amide thereof, with the exception of esters and amides of compounds of formula I wherein R 1 is hydrogen and represents a bond and R ₄ represents a hydrogen atom and the group of the formula ANR 1 R 1 represents a dimethyl aminoproyl group and the compounds of formula I wherein CH 3, R 4 represents a hydrogen atom and the group ANR 1 R 1 represents a diethylaminoethyl group. 3. A process according to claim 1, wherein R 1 is a group of formula ( ^CH 2> n 'n is an integer from 0 to 3, a group of formula CH = CH or CH (CH ₃ ) _m (CH ₂ ) _m , wherein m is 0 or 1, or -C (CH ₃ ) _2, and the other symbols have the meaning given in 1 except for a compound of formula I wherein n is 1 represents a hydrogen atom and a group of the formula ANR 1 R 1 represents a diethylaminoethyl group. 4. Method 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 znaŽí dimethylamino or diethylamino, and other symbols are as defined in claim 1, or third 5. A process according to claim 1, wherein the compounds are prepared according to any one of items 1 to 4, wherein they are hydrogen, methyl, chlorine or fluorine, and the other symbols have the meanings given in 1. 3 or 4. 6. A process according to claim 1 wherein A is an ethylene n-propylene or isopropylene group and the other symbols are as defined in item 1 or 3 using the appropriate starting compounds. to 5.