CS252466B2

CS252466B2 - Method of phenothiazines production

Info

Publication number: CS252466B2
Application number: CS838972A
Authority: CS
Inventors: Geoffrey Coker; John W Findlay; Harry J Leighton
Original assignee: Wellcome Found
Priority date: 1983-07-12
Filing date: 1983-12-01
Publication date: 1987-09-17
Also published as: GB8318832D0; CS897283A2

Description

252466 2

RjCOjH (I)

wherein the divalent aliphatic hydrocarbon group is 1 or a single bond, up to 7 carbon atoms R 2 and R 8 are the same or different and individually represent a hydrogen atom, a C 1 -C 4 alkyl group or together with the nitrogen atom form a 4 to 6 membered nitrogen ring heterocyclic ring. R5 represents a hydrogen atom, a halogen atom, a (C1-C4) alkoxy group, a (C1-C4) alkyl group optionally substituted with up to 3 halogen atoms, or a group of the formula R5 CO3H as defined above and A represents an alkylene group having 1 to 4 atoms carbon, and their salts, esters and amides, with the exception of the esters and amides of the compounds of formula (I), wherein R 1 represents a bond at the 2-position of the phenothiazine ring system and with the exception of a compound of formula I wherein R 1 represents a bond at the 2-phenothiazine ring position and R 1 is hydrogen and R 2 is hydrogen and R 1 is COOH is C 2 -COOH at the 2-position.

Of these compounds of formula I, those compounds having the general formula XIX are preferred

R1CO2H (XII)

N

Wherein R 1 to R 6 and A are as defined in formula I, or a salt, ester, or amide thereof. R 6 may be straight-chain or branched and may be a saturated or unsaturated hydrocarbon group or a single bond. R @ 1 is suitably a hydrocarbon group having from 1 to 3 carbon atoms or a single bond, R @ 1 preferably contains at least one double bond, R1 is preferably a group of formula (CH2 > n ' where n is an integer from 0 to 3 or a group of formula CH = CH or -CHICH; wherein m is 0 or 1, or a group of formula -CCHCH2 -. R ^C CCH H is most preferably Cinu ^CO COH. And are suitably the same or different, and individually denote a methyl or ethyl group or, together with the nitrogen atom to which they are attached, a four to six membered heterocyclic ring, preferably a saturated heterocyclic ring, for example derived from pyrrolidine, piperidine or morpholine. preferably dimethylamino or diethylamino, most preferably dimethylamino. R5 is preferably hydrogen, halogen, C1 -C4 alkyl or trifluoromethyl. it is particularly preferably hydrogen, methyl or ethyl or chlorine or fluorine. most preferably hydrogen. When R 6 is other than hydrogen, the phenothiazine ring system is attached at the 7 or 8 position and is preferably at the 7 position. A is suitably an ethylene, n-propylene or isopropylene group.

The amides of the compounds of formula I included within the scope of the invention are amides typically 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 alkanollates having 1 to 4 carbon atoms.

The esters and amides of the compounds of formula (I), although possessing some intrinsic antihistamine activity, can be used as intermediates in the preparation of the carboxyl compounds of formula (I). Suitable esters include the usual ester groups known to be used to protect carboxyl groups, e.g. wherein the alkyl group contains 1 to 6 carbon atoms and has a straight or branched chain and is optionally substituted with a halogen atom.

C 1 -C 4 alkyl esters are particularly preferred. Salts of Compound (I) may be either carboxylic acid addition salts or salts. Preferred addition salts, but salts formed at the carboxyl group, may be used in particular to prepare the corresponding carboxylic 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 be advantageously used to prepare the free active compound or a pharmaceutically acceptable salt thereof. All these salts are within the scope of the invention. Such pharmacologically and pharmaceutically acceptable addition salts include those derived from the following acids: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, acid kinalicylic 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.

This list is not exhaustive. Pharmaceutically acceptable salts can also be prepared as alkali metal or alkaline earth metal salts, for example potassium, sodium or calcium salts formed at the carboxyl group.

When compounds of formula I contain a carboxy-terminating double-stranded double bond, they exist either in cis- or trans-isomeric form (s), in relation to the aromatic ring. Included within the scope of this invention are isomers and isomeric mixtures thereof.

When the radical R 1 CC 3 H contains a double bond, preferred isomers are those wherein the carboxyl group is trans to the aromatic ring. Preferred compounds of formula (I) are: trans-beta- [10-2 (2-dimethylaminopropyl) phenothiazin-2-yl] acrylic acid; 2- [10- (2-dimethylaminopropyl) phenothiazin-2-yl] acetic acid; 2- [10- (2-dimethylaminopropyl) phenothiazin-2-yl] propionic acid, 10- (2-Dimethylaminopropyl) phenothiazine-3-carboxylic acid, [e] -3- (2-carboxyvinyl) -10- (2-dimethylaminopropyl) phenothiazine , 3- (2-carboxyethyl) -10- (2-dimethylaminopropyl) phenothiazine, 10- (2-dimethylaminopropyl) phenothiazin-4 (or 1) carboxylic acid, [e] -4 (or 1) - (2-carboxyvinyl) -10 (2-dimethylaminopropyl) phenothiazine, 4- (or 1) - (2-carboxyethyl) -10- (2-dimethylaminopropyl) phenothiazine, [? -Chloro-10 (2-dimethylaminopropyl) -2-phenothiazinyl] acetic acid, 10- (2-dimethylaminoethyl) -7-methyl-2-phenothiazinylacetic acid, [α- (2-dimethylaminoethyl) -7-fluoro-2-phenothiazinyl] acetic acid, 2- (2-dimethylaminopropyl) -2- phenothiazinyl J-2-methylpropionic acid, 2- [10- (3-dimethylaminopropyl) -2-phenothiazine] 2-methylpropionic acid, 2-methyl-2- [10- (3- (N-pyrrolidino) propyl) -2-phenothiazinyl propionic acid and 10- (2-dimethylaminopropyl) phenothiazine-2-carboxylic acid, or salts thereof, esters and amides.

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

It is therefore an object of the present invention to provide a process for the preparation of compounds of formula (I), wherein the compound of formula (III '4', 4 ', 2', 2 ', 2', 2 ') is substituted.

AND

L wherein R 1, R 6 and A are as defined above and L is a leaving group, or an ester thereof, is reacted with an amine of formula 5 252466, wherein r 2 and R 4 are as defined above, and optionally converted to an acid addition salt, a carboxylate salt, an ester or an amide of a compound of formula (I) or, optionally, releasing another compound within the scope of a compound of formula (I).

In a particularly preferred embodiment of the invention, a compound of formula (II) is prepared using the appropriate starting compounds

wherein R 1 to R 4 and A are as defined in 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 5 is a bond and, with the exception of compound of formula (II) where R ^ is water, R znamená is hydrogen and the group ANRRR ^ is dimethylaminopropyl and the compounds of formula II where R znamená is Cl / / R ^ is hydrogen and the group RRR ^ is a dimethylaminoethyl group.

Suitable leaving groups L in the compound of formula (III) are those described by J. March in Adv. Organic Chemistry, 2nd edition, pages 683-895, edited by McGrawHill, New York, 1977. For example, -Br, -Cl, p-toluenesulfonate, methanesulfonate, acyloxy groups (e.g. acetates) and the like.

The reaction may conveniently be carried out in a solvent suitable for such reactions, for example in a polar solvent, for example a C1 -C4 alkanol or a polar aprotic solvent, for example dimethyl sulfoxide, at temperatures between 0 and 180 ° C.

Compounds of formula (III) may be prepared by reacting an ester of the corresponding compound, where L is a hydroxyl group, and an acid or a suitable reactive acid derivative, if desired, followed by removal of the ester function.

Suitable reagents include hydrogen halides, halogenated phosphorus compounds such as phosphorus pentachloride or phosphorus oxychloride, sulfonyl chlorides (e.g. methanesulfonyl chloride, or p-toluenesulfonyl chloride) or acid anhydride (e.g., acetic anhydride).

The reaction is preferably carried out in a suitable solvent under conditions well known in the art, for example in an aprotic solvent, such as an ether, or a halogenated hydrocarbon in the presence of a base, for example a tertiary amine such as trethylamine, and at a usual temperature, for example between 0 and 100 ° C and preferably at room temperature. When used as a base, the excess can be used as a solvent.

Hydroxy compounds can be prepared by reacting phenothiazines unsubstituted at the 10-position, (i.e., Al) with either alkylene oxides such as ethylene (or higher) oxides, or alkanol, 252466 6 which also carries L in the presence of a strong base such as an alkali metal alkoxide, at the usual temperature, for example between 0 and 100 ° C.

The compounds obtainable according to the present invention, with antiallergic activity, can be used in the same indication as the clinically used antiasthmatics, i. to help control bronchoconstriction or bronchospasm characterized by allergic asthma and induced asthma and bronchoconstriction syndromes and bronchospasm resulting from acute or chronic bronchitis. Compounds are believed to inhibit the release of autodescods (ie, histamine, serotonin, etc.) from mast cells and inhibit directly producing antigen-induced histamine.

Thus, they can be classified as mast cell stabilizers with antihistamine activity. The compounds of the invention with antihistamine activity can be used in this indication as a clinically used antihistamine, namely to alleviate unpleasant symptoms caused by histamine release, nasal congestion in the cold and vasomotor rhinitis and to symptomatically affect allergic conditions, including nasal allergies, perennial rhinitis, urticaria, angioneurotic edema, allergic conjunctiva, soil allergy, serum and drug reactions, insect bites and prickles, and desensitization reactions.

The compounds may also be used under conditions responsible for antipruritic activity, including allergic dermatosis, neurodermatitis, anogenital pruritus and non-specific pruritus, for example eczema and the specific case of, for example, chickenpox, photosensitivity and sunburn.

Accordingly, the invention provides a method for the symptomatic treatment of 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 X. Some of the compounds of the invention are substantially free of sedative effects and have little or no anticholinergic activity.

The amount of active compound required to be used in the above seed conditions according to the choice of substance, mode of administration, and condition of the mammal to be treated depends on the physician. A suitable oral dose of the active compound for mammals ranges from 0.003 to 1.0 mg per kg body weight per day; preferably from 0.04 to 0.24 mg / kg. For example, a typical dose of a compound for a patient is between 0.03 to 0.1 mg / kg body weight per day.

F

The desired daily dose is preferably presented from one to six subdeliveries given at appropriate intervals as needed. Where three subdeliveries of general formula I compounds are used, all will preferably range from 0.014 to 0.08 mg / kg body weight; for example, a typical sub-delivery of such a compound to a patient is between 1 and 20 mg, for example 4 or B mg. While it is possible for a compound of Formula I to be administered alone, it is preferred that the compound of Formula X is in the form of a pharmaceutical formulation. The invention also provides pharmaceutical compositions for veterinary and human medicine, which include a compound of formula I together with one or more pharmaceutically acceptable carriers and optionally any other therapeutic ingredient. For example, the active compound can be combined with an agonist, for example, a pseudoephedrine decongestant, an antitussive agent, for example, codeine, an analgesic, an anti-inflammatory drug, an antipyretic, or an expectorant. The carrier (s) must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation. Formulations include those suitable for oral, nasal, ophthalmic or parenteral (including subcutaneous, intramuscular, and intravenous) administration. The formulations are preferably in dosage form and can be prepared by any of the methods well known in the art of pharmacy. All methods include the step of admixing the active compound with a carrier that represents one or more components. 7 252466

In general, the compositions are prepared by uniformly and intimately admixing the active compound with a liquid carrier or a finely divided carrier or both. <. then, if necessary, the product is shaped into the desired formulation. Formulations of the invention suitable for oral use can 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 in a non-aqueous liquid, for example, sugar or honey syrup (elixir), emulsion or droplets.

Tablets may be made by molding or casting, optionally with one or more ingredients. Compressed tablets may be prepared by molding on a suitable machine, with the active compound in free-flowing form, for example as a powder or granules which are optionally admixed with a binder, disintegrant, inert, inert. a diluent, a surfactant or an dispersant. Molded tablets consisting of a powdery active compound with any suitable carrier may be cast on a suitable device.

A syrup may be prepared by adding the active compound to a concentrated aqueous solution of a sugar, such as sucrose, to which additional ingredients may be added. Such additives may include flavoring agents, 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 such as 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 represents purified aqueous solutions 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 nasal spray except that pH and isotonic factors are adapted to the eye.

Topical formulations contain the active ingredient dissolved or suspended in one or more environments, for example mineral oils, kerosene, polyhydric alcohols or other bases. Addition of additional components may be desirable.

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.

Compounds obtainable according to the invention have not yet been used in medicine. The purpose of the following examples is merely to illustrate, not to limit, the invention. All temperatures shown are in degrees Celsius. Example 1

Process for the preparation of trans-beta-Q10- (2-dimethylaminopropyl) phenothiazin-2-ylacrylic acid a) Preparation of 2-bromo-10- (2-dimethylaminopropyl) phenothiazine (ex-1a) 252466 8 5.0 g 2-bromophenothiazine and 2.4 g target. potassium butoxide is mixed in 25 ml of dry oxylene under nitrogen and heated for 10 minutes at 65 ° C. A solution of 2.8 g of 2-dimethylaminopropyl chloride in 2 ml of xylene was added dropwise over 10 minutes. Stirring under nitrogen and heating to 60-70 ° C is continued for 3 hours. The reaction mixture is poured into 100 mL of ethyl acetate and extracted with dilute hydrochloric acid. The acidic extract is basified with excess aqueous ammonia and extracted with methylene chloride, which is dried over magnesium sulfate. and evaporated to give a viscous oil of 6.35 g.

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

The compound ex-1a does not crystallize and no attempt is made to obtain a crystalline salt. The compound is characterized by means of an NMR spectrum which corresponds to the structure indicated and is different from its isomer. b) Preparation of 10- (2-Dimethylaminopropyl) phenothiazin-2-ylcarboxaldehyde (Compound ex 1b) Using a syringe and a nitrogen atmosphere, 20 ml of anhydrous tetrahydrofuran was added to a flask containing 2.8 g of compound. The solution was stirred and cooled in a dry ice bath in acetone and a solution of 5.2 ml of a 1.5 molar solution of N-butyllithium in hexane was added dropwise over 5 minutes. After stirring at -78 ° C for 30 minutes, 0.8 ml of distilled dimethylformamide was added and the reaction mixture was allowed to warm to room temperature for 25 minutes.

It is then poured into dilute hydrochloric acid, washed with benzene and then basified with ammonium hydroxide. The product was extracted with methylene chloride which was dried over magnesium sulfate and evaporated to give a very viscous yellow oil of compound ex-1b. Compound ex-1b did not crystallize and an attempt was made to prepare a crystalline salt. The substance was characterized by NMR spectra, which corresponded to the expected structure. Thin layer chromatography on silica gel in a 9: 1 mixture of chloroform and methanol indicates the presence of a single substance that is less mobile than the starting material, i.e. ex-1a. Method for the preparation of trans-beta- [10- (2-dimethylaminopropyl) phenothiazin-2-yl] acrylic acid (compound A), 2.4 g of compound ex-1b, 1.1 g of malonic acid and 1.120 g of morpholine by dissolution in 8 ml of pyridine and heat in a boiling water bath. Carbon dioxide is immediately released.

After 2 hours, pyridine was evaporated under reduced pressure. The residue was triturated with boiling ethanol (25 mL) to give a yellow solid after cooling and stirring. This was recrystallized from ethanol to give compound A, crystalline, mp 214-218 ° C. Example 2

Process for the preparation of E-3- (2-carboxyvinyl) -10- (2-dimethylaminopropyl) phenothiazine (Compound E) a) Preparation of [d -3- (2-methoxycarbonylvinyl) -10- (2-dimethylaminopropyl) phenothiazine To a stirred solution 4.0 g of 3-bromo-10- (2-dimethylaminopropyl) phenothiazine in a 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 2 hours. One hour later, a solution of 1.7 ml of dimethylformamide in 20 ml of dried ether is added dropwise over one hour. 9 252466

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 is added to a stirred solution of phosphonate carbanion obtained from 2.69 g of diethyl (methoxycarbonylmethylphosphonate) and 385 mg of sodium hydride as an 80% dispersion in oil in 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 and evaporated to give crude [e] -3- (2-dimethylamino-propyl) -10- (2-dimethylamino-propyl) -phenothiazine as a fluorescent yellow oil. b) Method of preparation of [e] -3- (2-carboxyvinyl) -10- (2-dimethylaminopropyl) phenothiazine (Compound E) 4 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 gum. Dissolve the residue in hot 0.4 N hydrochloric acid and add concentrated hydrochloric acid to induce crystallization as orange-colored platelets. Recrystallization from ethanol / ether gave yellow needles of FeJ-3- (2-carboxyvinyl) hydrochloride. 10- (2-dimethylaminopropyl) phenothiazine as hemihydrate, temperature about 170 ° C (decomposition). After drying at 150 DEG C., an anhydrous salt is obtained, m.p. 220 DEG-225 DEG C. (decomposition). Example 3

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

A solution of 1 g of [e] -3- (2-carboxyvinyl) -10- (2-dimethylaminopropyl) phenothiazine hydrochloride in 20 ml of methanol containing 100 mg of 10% palladium on charcoal catalyst is stirred in a hydrogen atmosphere until complete absorption (9 hours).

The catalyst was filtered off and the solvent was evaporated to give saturated carboxylic acid hydrochloride. A small amount of impurities is removed by esterification as described in Example 4 below and chromatography of the ester on a silica column in a 50: 1 mixture of chloroform and methanol and hydrolysis of the pure ester as described in Example 5 below. 3- (2-Carboxyethyl) -10- (2-dimethylaminopropyl) phenothiazine thus obtained was crystallized from a mixture of ethanol and ether. 170 DEG-173 DEG C. (Compound F) is obtained. Example 4

Process for the preparation of 2- [10- (dimethylaminopropyl) phenothiazin-2-yl] propionic acid a) Method for the preparation of 2- [2- (2-dimethylaminopropyl) phenothiazin-2-yl] propionitrile: (ex-3a compounds)

Under nitrogen, a solution of 4.0 g of tosylmethyl isocyanide in 15 ml of dimethyl sulfoxide and 4 ml of tetrahydrofuran was stirred in an ice bath and 5.3 g of potassium tert-butoxide were added. After 5 minutes, 0.68 g of methanol is added. A solution of 3.4 g of 2-acetyl-10- (2-dimethylaminopropyl) phenothiazine in 3 ml of dimethylsulfoxide and 1 ml of tetrahydrofuran was added dropwise over 3 minutes to the reaction mixture. for 20 hours. 252466 10

The reaction mixture was poured into ether and washed with water. The amines are extracted with dilute hydrochloric acid, washed with ether and basified with excess sodium hydroxide. The free amines are then extracted with ether, which is 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 indicates the presence of multiple components. The desired compound ex-3a was separated in pure form by preparative high pressure liquid chromatography on silica gel eluting with a 97: 3 mixture of methylene chloride and methanol. Compound ex-3a is in an oily form and its NMR and IR spectra correspond to the predicted structure. b) Method for the preparation of 2-J1 - (2-dimethylaminopropyl) phenothiazin-2-yl] propionic acid (compound C) Dissolve 1.7 g of ex-3a in 50 ml of 4N hydrochloric acid and reflux for 20 hours. with a reflux condenser. 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 then adjusted by cautious addition of sodium hydroxide (to litmus) to about 10 4, i.e., basic area. The solution was washed with ether and then evaporated to half the original volume. Hydrochloride of compound C precipitates as an oil with excess concentrated hydrochloric acid. The oil was redissolved in water, and again precipitated (again as an oil) with excess hydrochloric acid and then triturated with ether to solidify the oil. The salt was recrystallized from a mixture of methanol and ethyl acetate to give C.HCl.1H2O as colorless crystals, m.p. 156 DEG-162 DEG C. (decomposition) whose elemental analysis (C, Η, N) confirmed the proposed structure. Example 5

Process for preparing 10- (2-dimethylaminopropyl) phenothiazine-3-carboxylic acid To a solution of 2.5 g of 3-bromo-10- (2-dimethylaminopropyl) phenothiazine (prepared similarly to the 2-bromo derivative in Example 1) in dried ether cooled to 0 ° C., a solution of 6.7 ml of 1.55 molar butyllithium in hexane is added dropwise. The solution is stirred at 0 ° C for 1 hour, then cooled to -40 ° C and a significant excess of carbon dioxide is introduced.

The reaction mixture was allowed to warm to room temperature and water was added. After thoroughly stirring, the ether layer was separated and removed, the pH of the aqueous solution was adjusted to 6 by careful addition of 2N hydrochloric acid and the solution was evaporated to dryness.

The residue is boiled with ethanol and the filtered ethanolic solution is evaporated to dryness leaving a semi-solid. Chromatographic separation of the material on a silica gel column with a mixture of chloroform and methanol as eluent gives 1 g of an impure gray colored solid which is further purified as follows via the methyl ester:

A solution of 670 mg of crude acid in 20 ml of methanol and 0.65 ml of concentrated sulfuric acid is refluxed for 3 hours. Most of the methanol was evaporated and water was added. The solution was washed with ether, basified by addition of 2N sodium hydroxide solution, and the separated oil was extracted with ether.

The ethereal solution was washed with water, dried with magnesium sulfate and evaporated to give 570 mg of a yellow viscous oil. This ester is dissolved in a small excess of dilute hydrochloric acid, the solution is evaporated to dryness and the residue is recrystallized from ethanol / ether to give light yellow fine methyl-10- (2-dimethylaminopropyl) -phenothiaziazine-3 hydrochloride. carboxylate. 11 252466

Melting point: 218 DEG C. (decomposition). 584 mg of the previous ester hydrochloride in a mixture of 4 ml of ethanol and 1.77 ml of 2N sodium hydroxide solution were stirred at room temperature for 20 hours. The solution was neutralized by addition of 1 ml of 2N hydrochloric acid and evaporated to dryness. The residue is extracted with hot ethanol and the filtered extract is evaporated to dryness. The resulting solid was recrystallized twice from a mixture of methanol and ethyl acetate to give colorless prisms, m.p. 185-188 ° C, to form 10- (2-dimethylaminopropyl) phenothiazine-3-carboxylic acid (compound D). Example 6

Process for preparing 10- (2-dimethylaminopropyl) phenol-thiazine-4 (or 1) -carboxylic acid To a stirred solution of 5.7 g of 10- (2-dimethylaminopropyl) phenothiazine in 150 ml of dried ether was added 20 ml of 1.55 at a temperature of 20 ° C. molar solution of butyllithium in hexane. The solution is stirred at this temperature for 30 hours, then cooled to -15 ° C and 25 g of solid carbon dioxide are added.

The mixture was allowed to warm to room temperature and allowed to stand for 16 hours. Water was added to the mixture, the mixture was well shaken and the ether layer separated. Evaporation of the washed and dry extract yields 4.5 g of unreacted starting material.

The aqueous solution was neutralized by the addition of 2N hydrochloric acid and evaporated to dryness. The residue was extracted with ethanol and the filtered extract was evaporated to dryness. Purify 2.5 g of the residue by silica gel column chromatography in a chloroform / methanol mixture as eluent to give 10- (2-dimethylaminopropyl) phenothiazine-4 (or 1) -carboxylic acid as colorless needles having a melting point of 220-222. ° C (decomposition) (from methanol) (compound G). Example 7

Process for the preparation of [E-4 (or 1) - (2-carboxyvinyl) -1G, 2-dimethylaminopropyl) phenothiazine a) Process for the preparation of [e] -4 (or 3 (2-methuxycarbonylvinyl) -10- (2-dimethylaminopropyl) phenoxy) thiazine 5.7 g of ΙΟ- (2-dimethylaminopropyl) phenothiazine are reacted with butyllithium under the conditions of Example 6. To the solution obtained, 3.1 ml of dimethylformamide is added in succession and allowed to stand at room temperature for 18 hours. the ether extraction is isolated and used without further purification.

The crude aldehyde is reacted with a phosphonate carbanion prepared from diethylmethoxycarbonylmethylphosphonate as described in Example 2 to give 4 (or 1) - (2-methoxycarbonynyl) -10- (2-dimethylaminopropyl) phenothiazine which crystallizes from ethanol. Melting point: 129-130 ° C. b) Method for the preparation of N-4 (or 1) - (2-carboxyvinyl) -10- (2-dimethylaminopropyl) phenothiazine

This ester is hydrolyzed with a dilute sodium hydroxide solution as described in Example 2 to give? 4 (or 1) - (2-carboxyvinyl) -10- (2-dimethylaminopropyl) phenothiazine, crystallizing from a mixture of isopropyl alcohol with petroleum ether ( boiling point 60-80 ° C) of small yellow needles having a melting point of 120-125 ° C (compound H). 252466 12 Example 8

Process for the preparation of 4- (or 1) - (2-carboxyethyl) -10- (2-dimethylaminopropyl) phenothiazine

A solution of 500 mg of 4H-4 (or 1) - (2-methoxycarbonylvinyl) -10- (2-dimethylaminopropyl) pheno-thiazine in 20 mL of ethyl acetate was stirred under a hydrogen atmosphere in the presence of Raney Nickel leaving hydrogen consumption. The filtered solution was evaporated to give 4 (or 1) - (2-methoxycarbonyl-ethyl) -10- (2-dimethylaminopropyl) phenothiazine which was hydrolyzed in aqueous ethanolic sodium hydroxide solution as described in Example 2.

The 4 (or 1) - (2-carboxyethyl) -10- (2-dimethylamino-propyl) -phenothiazine thus produced crystallizes from isopropyl alcohol as colorless needles. Melting point: 155 DEG-157 DEG C. (compound I). Example 9

Method for the preparation of 1-chloro-10- (2-dimethylaminopropyl) -2-phenothiazinylacetic acid (Compound K) a) Method for the preparation of ethyl N- [7-chloro-10- (2-dimethylaminopropyl) -2-phenothiazinyl] acetate (Compound ex-10e, compound J) 4.1 g of ethyl (7-chloro-2-phenolthiazinyl) acetate, which was prepared, for example, from 4'-bromo-3'-nitrophenylacetic acid by esterification with triethyl orthoformate and the formation of ethyl- [4'-bromo-3'-nitrophenylacetate] with 4-chlorothiophenol and 1.52 g of potassium tert-butoxide are mixed in 30 ml of oxygen-free toluene under nitrogen with stirring for 10 minutes.

To the mixture was added 1.7 g of 2-chloro-1-dimethylaminopropane and the reaction mixture was heated to 80 ° C for 1 hour. A further 1.5 g of potassium tert-butoxide and 1.7 g of 2-chloro-1-dimethylaminopropane are then added and stirring 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, basified with ammonium hydroxide and extracted with chloroform.

After evaporation of the chloroform, 5.85 g of an oil of varying composition is obtained (thin layer chromatography on silica gel, 6: 1 mixture of ethanol with ethyl acetate. The oil is fractionated by flash chromatography eluting with 12: 1, 8: 1 and 5: 1 ethyl acetate: ethanol) .

The title compound is ex-10e as an oil. Hydrogen maleate (and crystallization of ethyl acetate) are prepared, melting point 158-160 ° C (decomposition), whose NMR and elemental (C, N, N) analysis correspond to the proposed structure. b) Method for the preparation of [i-chloro-10- (2-dimethylaminopropyl) -2-phenothiazinyl] acetic acid (compound ex-K)

A solution of 0.4 g of compound ex-10e in 10 ml of concentrated hydrochloric acid and 10 ml of water is heated on a steam bath for 16 hours. Evaporation of the solvent leads to a glass vapor which is dissolved in 2-propanol and decolorized with charcoal. The hydrochloride is recovered by cooling the solution as a colorless solid with a melting point of 140 ° C (decomposition).

The melting temperature (decomposition) is difficult to reproduce because it depends very much on the speed of heating. These are hydrochloride monohydrate, ex-10F.HCl.H2O, whose NMR spectrum, elution (C, Η, N) analysis and mass spectrum correspond to the predicted structure. Example 25

0.5 g of ethyl [10- (2-dimethylaminoethyl) -7-methyl-2-phenothiazinyl) acetate] produced from ethyl [4 '- (4-methylphenylthio) -3'-nitrophenylacetate via ethyl- The methyl 2-phenothiazinyl) acetate salt was dissolved in 14 mL of 3.5 N hydrochloric acid and heated on a steam bath for 10 hours.

After evaporation to dryness, the residue is taken up in 2-propanol and decolorized with charcoal and then evaporated. The residue is triturated with ether to give a solid which is partially purified by dissolution in methanol and addition of ethyl acetate and ether. A yellow powder is obtained whose chromatogram from high pressure liquid chromatography shows considerable contamination. Therefore, they are purified by semi-preparative high pressure liquid chromatography on a 10 mm x 50 cm Spherisorb GPC? G column (reserve phase) and a Brownlee C? G honeycomb 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 solid having a melting point of 127-132 ° C (decomposition) whose NMR spectrum and elemental (C, Η, N) analysis and mass spectrum were sufficient, although one more unidentified contaminant was present according to the NMR analysis by weight. spectra and thin layer chromatography. Example 11

Process for the preparation of J 1 - (2-dimethylaminoethyl) -7-fluoro-2-phenothiazinyl / acetate, prepared from ethyl 1- [4- (4-fluorophenylthio) -3'-nitrophenylacetate via ethyl] -fluoro-2-phenothiazinyl acetate, is suspended in a mixture of 3 ml of dioxane and 6 ml of 1 N sodium hydroxide and the mixture is heated to 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 to give the hydrochloride compound as a crystalline-resistant resinous material.

Therefore, it is purified by high pressure liquid chromatography on 10 mm x 50 cm SpherisorbG. P. (Reverse Phase) C? G Column and Brownlee C? G Column? Eluted with 50% methanol and 0.1% triethylamine. A neutral compound N is obtained which, after recrystallization from ethyl acetate, has a melting point of 141-143 ° C.

Its elementary (C,, N) analysis, NMR and mass spectra correspond to the considered structure. Example 12

Process for preparing 2- [10- (2-dimethylaminopropyl) -2-phenothiazinyl] -2-methylpropionic acid (compound P)

The procedure is as in Example 11, except that ethyl [2- (10-dimethylaminopropyl) -2-phenothiazinyl] -1,2-methylpropionate, made from 2- {2- {10-dimethylaminopropyl} -2-phenothiazinyl} -2- methylpropionate, is used for the alkaline hydrolysis. 4-bromophenyl) -2-methylpropionic acid

acidification, evaporation and digestion with 2-propanol solidified on trituration with ether then recrystallized from methanol / ethyl acetate to give hydrochloride 252466 14 of compound P, mp 192-196 ° C (decomposition), NMR and mass spectrum; as elementary (C, Η, N) analysis confirm the expected structure. Example 13

(compounds ex-14a) 2.9 g of ethyl-2-methyl-2- (S-phenothiazinyl) propionate obtained as an intermediate in Example 12 are dissolved in 30 ml of dimethylformamide, then 1.13 g of potassium tert-butoxide are added and 0 2 g of lithium iodide. This mixture was heated to 80 ° C under nitrogen and then 1.2 g of 3-dimethylaminopropyl chloride, which was freshly released from its hydrochloride, was added.

After heating at 80 ° C for 30 minutes, a further 0.24 g of tert-butoxide potassium and 0.7 g of 3-dimethylaminopropyl chloride are added and after a further 30 minutes 0.34 g of potassium tert-butoxide are added. After a further 30 minutes, the reaction mixture was poured into water and extracted with methylene chloride. After evaporation of methylene chloride, 4.3 g of a viscous oil are obtained, which is flash chromatographed on a silica gel column and eluted with methylene chloride / methanol 96: 4. This gives 2.8 g of ex-14a as an oil which is homogeneous by thin layer chromatography and whose NMR spectrum corresponds to the proposed structure. b) Method for the preparation of 2- [1- (3-dimethylaminopropyl) -2-phenothiazinyl] -2-methylpropionic acid (compound Q)

This material was obtained by alkaline hydrolysis with 1N sodium hydroxide, ex-14, and the procedure described in Example 11. The hydrochloride crystallized from aqueous hydrochloric acid as a hydrate of compound Q.HCl.1 / O, mp 128 ° C (decomposition); the melting point is not reproducible. Elemental (C, Η, N) and NMR analysis as well as mass spectrum are consistent with the proposed structure. Example 14

Process for the preparation of ethyl 2-methyl-2- [10- (3- (N-pyrrolidono) propyl] -2-phenothiazinyl / propionate (compounds R) a) Preparation of ethyl-p-methyl-2- (10-) ( 3-bromopropyl) -2-phenothiazinyl / propionate (compounds ex-15a) 4.7 g of ethyl 2-methyl-2- (2-phenothiazinyl) propionate obtained as an intermediate in Example 12 is dissolved in 25 ml of 1 Of 3-dibromopropane and 1.6 g of potassium tert-butoxide are added.

The mixture was stirred at room temperature under nitrogen for 30 minutes and then heated to 80 ° C. After heating for 30 minutes, an additional 1 g of potassium tert-butoxide is added and the addition is repeated once more after heating for another 30 minutes.

After the last addition, the reaction mixture was heated for an additional hour and then extracted with ether with water. The ether layer was evaporated and the residue was partially purified by silica gel column chromatography, eluting with 20: 1 hexane / ethyl acetate. This yields the target compound (ex-15a) as an oil contaminated with a much faster eluting substance, which was identified by NMR and mass spectra as the olefin formed by the elimination of hydrogen bromide from ex-15a. 15 25246b

The mixture of compound ex-15a and its contaminated soil was purified by NMR and mass spectra consistent with the structure. Since the contaminant is believed to be harmless for the following reaction of 1 y! and the product mixture is used for the next step without further purification. b) Method for the preparation of ethyl-2-methyl-2- [N-73- (h-pyrrolidino) propyl] -2-phenothiazinyl] propionate (Compound R) 0.8 g of ex-35a and 1.7 g of pyrrolidine was dissolved in 5 mL of ethanol and the solution was allowed to stir at room temperature for 5 days. The mixture was then partitioned between ether and dilute hydrochloric acid and the ether extract was washed with additional hydrochloric acid. The combined hydrochloric acid solutions are then basified with excess sodium hydroxide and extracted with methylene chloride.

The methylene chloride solution was dried and evaporated and the residue was chromatographed on a short column with silica gel, eluting with methylene chloride / methanol (94: 6). This gives compound R in the form of a clear viscous oil which is uniform in thin layer chromatography.

Attempts to prepare the crystalline addition salt were unsuccessful, but the substance was characterized by NMR and mass spectra consistent with the proposed structure. Example 16

Antihistamine Activity A. Antihistamine Activity In Vitro: The longitudinal muscle band was isolated from intact and guinea pigs (Hartley, 250-400 g male) and placed in a 300 mg bath. After one-hour equilibration, cumulative concentration-response curves were obtained (Van Rossum. JJ, Arch.Int. Pharmacodyn. Ther. 143, 299-330 (1963)) for histamine.

After washing, the tissues were incubated for 1 hour with the test substance and an additional agonist curve was observed to monitor the effect of histamine concentration on the reaction. Right shifts uu agonist concentration-response curves produced by antagonists were used to construct Schild plots / 0. Arunlakshana and H. 0. Schxld Br. Pharmacol. 14, 48-58 (1959)].

The regression of log (dr-1) to log / B /, where: dr is an equivocal reaction in the presence and absence of an agonist and / B / is the molar concentration of the antagonist, allowed the determination of pAo, ie, a negative log antagonist concentration that shifts the control histamine concentration-reaction curve .vc. times to the right. Substance pA ^

Promethazine 8.9 A 8.2 C 8.1 D 6.2 E 6.2 F 5.2 G 6.8 H 7.8 I 7.2 J 9.0 K 8.8 M 8.9 N 8 , 6 0 8.5 252466 16 Continued Table Substance

P

Q

8.8 8.7 H RB Barlow, Introduction to Chemical Pharmacology, 2nd Edition, p. 373, Ed. Wiley, New York, 1964 B. In vivo Antihistarine Activity: Guinea Pigs (Hartley, 300-350 g were fasted After 20 hours, they were given post or ip evaluation of the substance, one hour after the individual administration, the guinea pigs were housed in a transparent plastic chamber that was saturated and continuously supplemented with 0.25% aerosol histamine.

Guinea pigs have been evaluated for signs of histamine anaphylaxis (e.g., cough, sneezing, significant abdominal movements, cyanosis, or loss of righting reflex). Under these test conditions, the control animals collapsed on average for 33 seconds. EDjq for protection against histamine was calculated by probit analysis. In this test, the .DELTA.q shows that a single dose perfectly protects 50% of the animals against the effects of histamine after evaluation (1 hour post dose). Perfect protection has been defined as no histamine synthesis in the aerosol chamber (about ten times the time required to collapse the control animals).

Table I: Antihistamine test results EDS0 / mg / kg, after, /

Triprolidine 5.77 1.70

In addition to these results, Substance A was found to provide very long-lasting antihistamine activity (e.g., 11 mg / kg post-ED 50 for 24 hours protection).

Method of anaphylactoid evaluation

The Wister rats (180-300 g) were dosed with test substances (µl or po) for 2 hours prior to exposure to anaphylactoid indicator agent (48/80). One hour before exposure, 5 mg / kg ip propranol was administered. Anaphylactoid inducing agent was administered intravenously at 2 mg / kg and symptoms of respiratory problems were observed in animals.

Data were analyzed by probit analysis. The reaction was quatified by evaluating the amount of substance that protected 50% of the animals from death at a given time. The above experimental setup does not provide positive results for selective antihistamines. Also, rats do not respond to histamine (iv) symptoms of anaphylaxis. Agents that block the effects of the agents used are usually classified as inhibitors of anaphylactic mediators or inhibitors of the release of anaphylactic mediators.

Inhibition of anaphylactoid reaction

Substance EDjgX

Ketotifen 0.87

E

Astemizole 2.64 1.43 3.11 1.08 17 252466 Dose of substance (ip) providing 50% protection against 48/80 induced death. The substance was administered 2 hours before the test. Example 17 Dosage Forms

Component

Substance of Formula I

Water for injection qs / A / -injection

Amount in ampoule 1.0 mg1.0 ml

The finely dispersed active and autoclaved. the substance was dissolved in water for injection. The solution was filtered (B-suppositories)

Component

Substance of Formula I

Cocoa butter

TM or Wecobfee base qs

Amount in suppository 1.0 mg2.0 mg

Wecobee

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

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

Component

Compound of Formula I

Ethanol

Sucrose

Methylparaben

Sodium benzoate

Cherry flavor

Dye

Water / C / -Sirup

Amount in ml1,0 mg0,3 mg2,0 mg0,5 mg0,5 mgq.sqsqsad 5,0 ml

Ethanol, sucrose, sodium benzoate, methylparaben and flavor were combined in 70% total water. The flavor and active substance were dissolved in the remaining water, then the solutions were mixed and clarified by filtration. / D / -Tablets

Component Amount in tablet Substance of Formula I 1.0 mg Lactose 110.0 mg Maize starch, pregelatinized 2.5 mg Potato starch 12.0 mg Magnesium stearate 0.5 mg

The active substance was finely dispersed and mixed with powdered lactose, corn starch, potato starch and magnesium stearate. The mixture was then compressed to give a tablet weight of 126 mg. 252466 18

Component Substance of general formula ILactose

Magnesium Stearate / E / -Payments

Wafer amount1 / 0 mg 440.0 mg5.0 mg

The finely dispersed stearic acid was mixed with powdered lactose, corn starch packed into gelatin wafers. / F / ~ Tablets

Component Amount in tablet Substance of Formula I 1.0 mg pseudoephedrine hydrochloride 60.0 mg Lactose, 62.5 mg Potato Starch 14.0 mg Magnesium Stearate 1.0 mg 2.8 mg Gelatin

The tablets were prepared from the above mixture as described previously in Example 17 ZD /. / G / -Sirup

Ingredients Amount in 5 ml Substance of Formula I I, O mg Pseudoephedrine Hydrochloride 30.0 mg Codeine Phosphate 10.0 mg Guaifenesin 100 mg Methylparaben 0.5 mg Sodium Benzoate 0.5 mg Fry qs, Dye qs, Glycerin 500 mg Sucrose 2 000 mg purified water qs ad 5, '

A syrup containing other active ingredients in addition to the compound of Formula I was prepared from the above ingredients in an analogous manner to that described above for Example 17 ZC.

Component Substance of Formula I Sodium ChlorideProtectant Purified Water / H / Spray in the nose

Amount per 100.0 ml 1 9 0.8 g 0.5 g qs 100.0 ml

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

Ingredient Substance of Formula I Sodium ChlorideProtective SubstanceWater for Injection / I / -Pthalmic Solution

Amount in 100.0 ml 0.1 g0.8 g 0.5 g qs 100.0 ml The preparation was prepared similarly to the nose spray.

Claims

19 252466 Ingredient / J / -Local Cream Amount per 100.0 ml Substance of Formula I 0.1 g Emulsifying wax N.F. 15.0 g Mineral oil 5.0 g OBJECT OF THE INVENTION 1. A process for the preparation of phenothiazines of the general formula I wherein R1 is a divalent aliphatic hydrocarbon group having from 1 to 7 carbon atoms or a single bond, R and r3 are the same or different and individually represent a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, or together with the nitrogen atom form a nitrogen ring 4 to 6 membered ring, R 4 represents a hydrogen atom, a halogen atom, an alkoxy group having 1 to 4 carbon atoms C 1 -C 4 alkyl optionally substituted by up to 3 halogen atoms or R 1 C 3 H 2 H is as defined above and A is C 1 -C 4 alkylene. and the salts, esters and amides thereof, with the exception of the esters and amides of the compounds of formula (I) wherein R 1 is hydrogen and R 1 is a bond in the 2-position of the phenothiazine ring system, with the exception of the compound of formula (X) wherein R 1 '. means a bond in the 2-position of the phenothiazine ring and is a hydrogen atom and the group of the formula ANB is R 1 is dimethylaminopropylene and the compounds wherein ANR 1 R 4 is diethylaminoethyl and R 1 is hydrogen and R 4 is C 1 H is C 1 Characterized in that the compound of formula III wherein R 1 -R 1 CO 2 H (III) 1 A 1 R 1 R 2 R 2 and A are as defined above, and L is a displaceable group, or an ester thereof, leaving reacting with an amine of formula 252466 20 hnr2r3, wherein R2 and are as defined above, d optionally converting the compound obtained into an acid addition salt, a carboxylate salt, an ester or an amide of a compound of formula I, or alternatively releasing the compound thereof falling within the scope of the compounds of formula I.

2. A process according to claim 1, wherein the compounds of formula (II) are prepared using the appropriate starting compounds

wherein R ^ až and A A are as defined in formula (I), or a salt, ester or amide thereof, with the exception of esters and amides of compounds of formula (II) wherein R znamená is R a is a bond with the exception of formula (II) where the bond is R 1 is hydrogen and the group ANR 2 R 3 is dimethylaminopropyl and the compounds of formula II wherein CH 2 is hydrogen and the group ANR 1 R 4 is diethylaminoethyl.

3. A process according to claim 1, wherein the compounds of formula (1) or (2) are prepared using the appropriate starting materials, wherein (CH2) n is n is an integer from 0 to 3; CH = CH; Wherein (m) is 0 or 1 or -C (CH 3) 2 and the other symbols are as defined in (1), with the exception of a compound of formula (I) wherein n is 1, R 4 is hydrogen and ANR 2 R 3 is diethylaminoethyl.

4. A process according to claim 1, wherein the compounds of any one of claims 1 to 3 are prepared using the appropriate starting compounds, wherein NR9R8 is dimethylamino or diethylamino and the other symbols are as defined in 1 or 3.

5. A process as claimed in claim 1, wherein the compounds are prepared according to any one of (1), (3) or (4) using a corresponding starting point from 1 to 4, wherein the symbol is hydrogen. point

6. A process according to claim 1, wherein the compounds of any one of claims 1 to 5, wherein A is ethylene, n-propyl or isopropylene, are prepared using the appropriate starting materials and the other symbols are as defined in point 1, or 3 to 5. Severografia, np, MOST Price 2,40 Kčs