CS252490B2 - 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 anthistamine and antiallergic activity and properties which make them suitable for use in pharmaceutical preparations intended for medical use.

U.S. Pat. No. 2,530,451 discloses a group of 9- (dialkylaminoalkyl) phenothiazines with antihistamine activity, the most prominent of which is given the generic name 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 this invention are most structurally similar to the phenothiazine derivatives described in U.S. Patent Nos. 3,112,310, 2,905,668 and 2,789,978 and Messer et al., Arzneim. Forsch, 11j, 1193-169 (1969).

The antihistamines now in use, including diphenylhydramine, feniramine, pyrilamine, promethazine and triprolidine, generally have a potential disadvantage as they all cause sedative effects 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 a good antihistamine effect and are essentially devoid of central nervous system (CNS) side effects and have a significantly lower anticholinergic effect than promethazine.

The present invention provides a process for the preparation of phenothiazines of the general formula I → 4

AND

AND

AND

N / \ ^r 2 ^r 3 where (i)

Rj denotes a divalent aliphatic hydrocarbon group having 1 to 7 carbon atoms or a single bond, β

^R 2 ^{and R} 3 ^{are the} same or different and are each a hydrogen atom, a C 1 -C 4 alkyl group or together with the nitrogen atom form a 4 to 6 membered heterocyclic ring, a hydrogen atom, a halogen atom, a C 1 -C 6 alkoxy group C 4 -C 4 alkyl, C 1 -C 4 alkyl optionally substituted with up to 3 halogen atoms or R znamenáCX vzorceH as defined above,

A denotes a (C 1 -C 4) alkylene group or ANR 1 R 4 forms a group of the formula

and salts, esters and amides thereof, with the exception of the esters and amides of the compounds of formula I wherein R ^ represents a hydrogen atom and R ^ represents a bond at the 2-position of the phenothiazine ring system and represents a hydrogen atom and represents a group of formula ANR2R3 dimethylaminopropyl group and compounds where the group of formula represents ANR2R3 diethylaminoethyl group and R represents a hydrogen atom and a group R ^ CC ^ H = CH ₂ CO ₂ H in the second

Among these compounds of formula I which can be produced according to the invention are preferably those having the general formula II ^R 4 6

R, CO ₂ H (II)

Wherein R 1 and A are as defined in formula (I), or a salt thereof, and an ester or amide thereof.

R 1 may have a straight or branched chain, a saturated or unsaturated hydrocarbon group, or a single bond. Suitably, R ^ represents a C 1-Clov hydrocarbon group or a single bond or comprises at least one double bond. R is preferably a group ~ ^(E ~ 2 ^ N '^ ^{n ce} number 0-3 or CH = CH or -CH (CH ₃₎ (CH _{2) m,} wherein m is 0 or 1, or -C (CH ₃ ) ₂ -, R 4 CC 4 H most preferably represents the group -CH ₂ CO ₃ , H.

R ₂ and R 1 are suitably the same or different and individually represent a methyl or ethyl group or form together with the nitrogen atom to which they are attached a four to six-membered heterocyclic ring, preferably a saturated heterocyclic ring, for example pyrrolidine, piperidine or morpholine.

NH 4 R 3 ^is preferably dimethylamino or ethylamino, most preferably dimethylamino,

R @ 1 is preferably hydrogen, halogen, C1 -C4 alkyl or trifluoromethyl. R ^ is particularly preferably hydrogen, methyl, ethyl, chlorine or fluorine. most preferably denotes a hydrogen atom. 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.

A is suitably an ethylene, n-propyl 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 an intermediate in the preparation of carboxylic compounds of formula (X). Suitable esters include conventional ester groups known to be used to protect carboxyl groups, e.g. (C 1 -C 6) alkyl ester wherein the alkyl group has a straight or branched chain optionally substituted by a halogen atom. C 1 -C 4 alkyl esters are particularly preferred. The compounds of formula I may form either addition salts or 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, the 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 can also be prepared as alkali metal or alkaline earth salts, for example potassium, sodium or calcium salts of 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- [10-2 (2-dimethylaminopropyl) phenothiazin-2-yl] -acrylic 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, [X] -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) phenothaizine, [7-chloro-10 (2-dimethylaminopropyl) -2-phenothiazinyl] acetic acid, [10- (2-dimethylaminoethyl) -7 -methyl-2-phenothiazinyl] acetic acid, [10- (2-dimethylaminoethyl) -7-fluoro-2-phenothiaznyl] acetic acid,

2-C10- (2-dimethylaminopropyl) -2-phenothiazinyl] -2-methylpropionic acid,

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

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

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

Pharmacokinetic studies comparing the relative brain and plasma distribution of the two compounds obtainable 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 for the preparation of the compounds of the formula I according to the invention consists in reacting a compound of the formula V

where

R ₂ , R 8, and A are as defined above and

Rg is a single bond, reacted with malonic acid or an ester thereof to form a compound of formula I wherein Rg is -CH = CH- and the other symbols are as defined above, then optionally converting the compound of formula I to another compound of formula (I) by hydrogenating a double bond in the side chain carboxyl group, and optionally converting the compound to an acid addition salt, carboxylate salt, ester, or amide of a compound of formula (I) or optionally releasing another compound within the scope of compounds of formula (I) .

The reaction of the compound of formula V with malonic acid or an ester thereof is preferably carried out in the presence of a base, preferably pyridine, which can also serve as a solvent at an elevated temperature, i.e. between 20 and 150 ° C, preferably between 80 and 120 Deň: 32 ° C.

The compounds obtainable according to the invention with an antiallergic effect can be used in the same indication as clinically used antiasthmatics, ie to help control the abdominal constriction or bromchospasm characteristic of allergic and induced asthma and the symptoms of bronchoconstriction and bronchospasm resulting in acute or chronic bronchitis. Compounds are believed to inhibit the release of antacoids (ie, histamine, serotonin, and the like) from mast cells and directly inhibit the production of antigen-induced histamine.

They can therefore be classified as mast cell stabilizers with antihistamine activity.

The compounds of the invention with antihistamine activity can be used in the same indication as clinically used antihistamines, namely to alleviate unpleasant symptoms caused by histamine release, nasal congestion and vasomotor rhinitis, and symptomatically affect allergic conditions including nasal allergy, perennial rhinitis, urticaria, urticaria , allergic conjunctivities, soil allergies, serum and drug reactions, insect bites and prickles, and deansitization reactions. The compounds may also be used under conditions responsible for antipruritic activity, including allergic dermatoses, naurodermatitis, 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 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 Compound (B) for a patient is between 0.03 to 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 such as a decongestant, pseudoephedrine, an antitussive such as 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 pareteral, including subcutaneous, intramammary and intravenous administration.

The compositions are preferably in a dosage form and can be prepared by any method known in the art of pharmacy. All methods include the step of mixing the active compound with a carrier which constitutes one or more components. Generally, the 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.

Formulations of the invention suitable for oral use may be administered in separate dosage units such as wafers, capsules, tablets or lozenges, each containing a predetermined amount of the active compound (referred to herein as a compound of Formula I), powder or granules, or suspensions. in an aqueous liquid or 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 compounds. Compressed tablets may be prepared 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 sachazose, to which additional ingredients may be added. Such additives may include thickeners, sugar crystallization inhibiting agents or solubility enhancers of any other ingredient, for example a polyhydric alcohol such as glycerin or sorbitol and suitable preservatives.

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

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

Nasal sprays are purified aqueous solutions of the active compound with protective and isotonic agents. Such formulations are adjusted to a specific pH and isotonic state by compatible and nasal mucomemirates.

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

Topical formulations comprise the active ingredient dissolved or suspended in one or more 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 the 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.

He did

Process for preparing trans-beta- [10- (2-dimethylaminopropyl) phenothiazin-2-yl] acrylic acid

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

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

The oil is a mixture of the desired compound and its 2-bromo-10- (2-dimethylamino-1-methylethyl) phenothiazine isomer and separated as a colorless oil by preparative HPLC on silica gel eluting with ethyl acetate / methylene chloride 4: 1.

Ί

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

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

Using a syringe and nitrogen atmosphere, 20 ml of anhydrous tetrahydrofuran is added to a flask containing 2.8 g of ex-1a. The solution was stirred and cooled with a dry ice bath in acetone and a solution of 5.2 ml of a 1.5 molar solution of n-butyllithium in hexane was added dropwise over 5 minutes. After stirring at -78 ° C for 30 minutes, 0.8 ml of distilled dimethylformamide was added and the reaction mixture was allowed to warm to room temperature over 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.

Compounds ex1b 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 methanol / chloroform (9: 1) indicated the presence of a single substance which is less mobile than the starting material, ie the compound ex 1a.

c) Process for the preparation of trans-beta-Q0- (2-dimethylaminopropyl) phenothiazin-2-yl] acrylic acid (compound A)

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

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

NMR and elemental analysis confirm the assumed structure.

Example2

A process for the preparation of 3- (2-carboxyethyl) -10- (2-dimethylaminopropyl) phenothiazine

A solution of 1 g of [e] -3- (2-carboxyvinnyl) -10- (2-dimethylaminopropyl) phenothiazine hydrochloride in 20 ml of methanol containing 100 mg of 10% palladium on charcoal catalyst is stirred under a hydrogen atmosphere until it is absorbed. completely (9 hours). The catalyst was filtered off and the solvent was evaporated to give saturated carboxylic acid hydrochloride. A small amount of impurities was removed by the extinction according to Example 4, and the ester was chromatographed on a silica column from a 50: 1 mixture of chloroform and methanol and hydrolyzed the pure ester as in Example 5. 3- (2-Carboxyethyl) -10 The (2-dimethylaminopropyl) phenothiazine thus obtained is crystallized from a mixture of ethanol and ether. 170 DEG-173 DEG C. (compound F).

Example 3

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

a) Method for producing [e *] - 4 (or 1) - (2-methoxycarbonylvinyl) -10- (2-dimethylaminopropyl) phenothiazine

5.7 g of 10- (2-dimethylaminopropyl) phenothiazine were treated with butyllithium as in Example 7. To this solution was added sequentially 3.1 ml of dimethylforniamide and allowed to stand at room temperature for 18 hours. The crude was isolated by extraction into ether and used without further purification.

The crude aldehyde is reacted with a phosphonate carbanion prepared from diethylphenylcarbonylmethylphosphonate to give 4 (or 1) - (2-methoxycarbonylvinyl) -10- (2-dimethylaminopropyl) phenothiazines, which is crystallized by ethanol. Melting point: 129-130 ° C.

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

This ester is hydrolyzed as in the example with dilute sodium hydroxide solution to give [E] -4 (or 1) - (2-carboxyvinyl) -10- (2-dimethylaminopropyl) phenothiazines, crystallizing from isopropanol / petroleum ether (b.p. 60-80). ° C) in the form of tiny yellow needles, m.p. 120-125 ° C (compound H).

Example 4

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

A solution of 500 mg of [1- E] -4 (or 1) - (2-methoxycarbonylvinyl) -10- (2-dimethylaminopropyl) phenothiazine in 20 ml of ethyl acetate was stirred under a hydrogen atmosphere in the presence of Raney nickel until hydrogen uptake occurred. The filtered solution was evaporated to give 4- (or 1) - (2-methoxycarbonylethyl) -10- (2-dimethylaminopropyl) phenothiazines which was hydrolyzed in aqueous ethanolic sodium hydroxide solution. The 4 (or 1) - (2-carboxyethyl) -10- (2-dimethylaminopropyl) phenothiazine thus produced crystallizes from isopropyl alcohol in the form of colorless needles. 155-157 ° C (compound I).

Example 5

Process for the preparation of 2- [10- (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 concentrated hydrochloric acid. Compound ex 13a precipitated as a white 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 acid (compounds ex 13b)

The title compound is obtained by nitration of compound ex 13a as described in Example 3a. Ex 13b is a solid having a melting point of 167-171 ° C, whose NMR spectrum is consistent with the structure.

C) A process for the preparation of ethyl E 2- (4-bromo-3-nitrophenyl) -2-methylpropionate J (compounds ex 13c)

This ester gives Compound ex 12b according to Example 8. Compound ex 13c is obtained

Λ has a melting temperature close to room temperature. The NMR spectrum confirms the expected structure.

Substances were used without further purification. j *

d) A process for the preparation of ethyl [2-methyl-2- (3-nitro-4-phenylthiophenyl) propionate J (compound ex 13d).

The synthesis was carried out as in Example 8 using thiophenol and compound ex 13c. The product, compound ex-13d, was obtained in quantitative yield as a very viscous yellow oil which did 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 compounds ex 13d by cyclization and purification to homogeneity by flash 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) Method for the preparation of ethyl [2- / 10- (2-dimethylaminopropyl) -2-phenothiazinyl] -2-methylpropionate] (compounds ex 13f, compounds 0)

This compound is synthesized from compound ex 13e by the alkylation reaction of Example 8. 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 analysis, NMR and mass spectra are consistent with the reported structure.

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

This material was obtained by alkaline hydrolysis (sodium hydroxide) of ex 13f according to Example 9. 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 melting point 192 DEG-196 DEG C. (decomposition), whose NMR and mass spectra as well as elemental (C, H, N) analysis confirm the expected structure.

Example 6

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

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

2.9 g of ethyl [2-methyl-2- (2-phenothiazinyl) propionate obtained as an intermediate in Example 5 are dissolved in 30 ml of dimethylformamide, then 1.13 g of potassium tert-butoxide and 0.2 g of iodide are added. lithium. The mixture was heated at 80 ° C for 30 minutes 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 were added, and after a further 30 min, 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 the methylene chloride yielded 4.3 g of a viscous oil which was flash chromatographed on a silica gel column and eluted with 96: 4 methylene chloride / methanol. 2.8 g of ex 14a are thus obtained in the form of an oil which is homogeneous by thin layer chromatography and whose NMR spectrum is consistent with the proposed structure.

b) Method for producing 2- [10- (3-dimethylaminopropyl) -2-phenothiazinyl] -2-methylpropionic acid (compound Q)

This material was obtained by alkaline hydrolysis, 1N sodium hydroxide, ex 14a according to Example 9. The hydrochloride crystallized from aqueous hydrochloric acid as a hydrate of compound Q.HCl.H2O, mp 128 C (decomposition), mp not reproducible. The elemental (C, H, N), NMR analysis and mass spectrum are consistent with the proposed structure

Example 7

A process for the preparation of 10- (2-dimethylaminopropyl) phenothiazine-4 (or 1) -carboxylic acid

To a stirred solution of 5.7 g of 10- (2-dimethylaminopropyl) phenothiazines in 150 mL of dried ether was added dropwise a 1.55 molar solution of butyllithium in hexane at 20 ° C. The solution was stirred at this temperature for 30 hours, then cooled to -15 ° C and 25 g solid carbon dioxide was added. The mixture was allowed to warm to room temperature and allowed to stand for 16 hours. Water was added to the mixture, the mixture was shaken well and the ether layer separated. Evaporation of the washed and dry extract gave 4.5 g of unreacted starting material.

The aqueous solution was neutralized by addition of 2N hydrochloric acid and evaporation to dryness. The residue is extracted with ethanol and the filtered extract is evaporated to dryness. 2.5 g of the residue are purified by chromatography on a silica gel column using chloroform and methanol as eluent to give 10- (2-dimethylaminopropyl) phenothiazine-4 (or 1) -carboxylic acid, in the form of colorless needles, m.p. 220 DEG-222 DEG C. (decomposition) (from methanol) (combined G).

Example 8

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

(a) Method for producing 4'-bromo-3'-nitrophenylacetic acid (compounds 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 while cooling with water so as to maintain 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 excess 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 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) Process for the preparation of ethyl [1- (4-chlorophenylthio) -3'-nitrophenyl acetate] (compound 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 N 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, m.p. 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 10d)

24.3 g of ex 10c and 46.0 g of triethylphosphite are combined in 200 ml of dried n11

of oxygen-free propylbenzene under nitrogen and heated at reflux for 4 hours. Volatile components are removed at 80 ° C with suction by a water pump. The dark residue was purified by silica gel flash column chromatography 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, ex 10d, is a colorless crystalline solid, m.p. 193-194 ° C, whose NMR spectrum is consistent with the proposed structure. This rearrangement cyclization has been described by Gadogan et al. in J. Chem. Soc. (1970) 2,437.

e) Process for the preparation of ethyl [(7-chloro-10- (2-dimethylaminopropyl) -2-phenothiazinyl / acetate) (compound ex 10e, compound J)

4.1 g of ethyl [(7-chloro-2-phenothiazinyl) acetate] and 1.52 g of potassium tert-butylate were stirred in 30 ml of deoxygenated toluene under nitrogen for 10 minutes with stirring. 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 t-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 is 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 (to litmus with ammonium hydroxide and extracted with chloroform). thin layer chromatography on silica gel, ethanol / ethyl acetate 6: 1.

The oil was fractionated by flash chromatography eluting with ethyl acetate / ethanol (12: 1, 8: 1 and 5: 1). The title compound ex 10e is in the form of an oil. Hydrogen maleate is prepared and crystallized from ethyl acetate, m.p. 158-160 ° C (dec.); whose NMR and elemental (C, H, N) analysis correspond to the increased structure.

b) Method for the preparation of [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 of the solution gave the hydrochloride as a colorless solid, mp 140 ° C (dec.). The melting point (decomposition) is difficult to reproduce, as it depends greatly on the heating rate.

It is ex-10F hydrochloride monohydrate. HCl. H ₂ <3, whose NMR spectrum, elemental (C, H, N) analysis and mass spectrum correspond to the assumed structure.

Example 9

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

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

The compound was prepared as in Example 8 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) Method for producing ethyl [(7-fluoro-2-phenothiazinyl) acetate] (compounds ex 12b)

The compound was prepared from ex 12a by the method of Example 8. The recrystallized product, ex 12b, had a melting point of 167-168 ° C and a NMR spectrum consistent with the indicated structure.

c) Method for producing ethyl [10- (2-diethylaminoethyl) -7-fluoro-2-phenothiazinyl / acetate3 (compound ex 12c) This compound is obtained as an oil from compound ex 12b and 2-diethylaminoethyl chloride by the method of Example 8 and purified by silica gel flash column chromatography eluting with ether. NMR and mass spectra were consistent with the assigned structure.

d) Method for producing [10- (2-dimethylaminoethyl) -7-fluoro-2-phenothiazinyl] acetic 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 crystalline-resistant resin. Therefore, it is purified by high pressure liquid chromatography [on a 10 mm x 50 Spherisorb GP (reverse phase -C ^ g column and Brownlee C ^ g mantle column) eluting with 50% methanol and 0.1% triethylamine to give a neutral compound N which, after recrystallization from ethyl acetate has a melting point of 141-143 [deg.] C. Its elemental (C, N, H) analysis, NMR and mass spectra correspond to the structure considered.

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

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

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

10- (2-dimethylaminopropyl) phenothiazine-3-carboxylic acid (Compound D), m.p. 185-188 ° C, [S] -3- (2-carb ^ox yvinyl) -10- (2-dimethylaminopropyl) phenothiazine (compound Ε), melting point 220 to 225 ° C (decomposition),

3- (2-carboxyethyl-10- (2-dimethylaminopropyl) phenothiazine, m.p. 170-173 ° C, ethyl [7-chloro-10- (2-dimethylaminopropyl) -2-phenothiazinyl] acetate, m.p. 158-160 ° C (decomposition), ethyl [10- (2-dimethylaminoethyl) -7-methyl-2-phenothiazinyl] -acetate (Compound L), in the form of hydrogen maleainam, m.p. 146-148 ° C,

10- (2-dimethylaminoethyl) -7-methyl-2-phenothiazinyl acetic acid (substance Μ), m.p. 127-132 ° C (dec.),

10- (2-diethylaminoethyl) -7-fluoro-2-phenothiazinyl acetic acid (N), m.p. 141-143 ° C, ethyl [2- / 10- (2-dimethylaminopropyl) -2-phenothiazinyl] -2 -methylpropionate] (substance O), oil, ethyl [2-methyl-2- / 10- [3- (N-pyrrolidino) propyl] -2-phenothiazinyl / propionate] (substance R), oil,

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

Example 1 (I I 0

Antihistamine effect

A. Antihistamine activity in vitro

The longitudinal muscle strip was isolated from the intact guinea pig ileum (Hartley, male 250-400 g) and placed in a bath at a load of 300 mg. After one hour equilibration, cumulative concentration-response curves were obtained (Van Rossum, JM, Arch, Int. Pharmacodyn, Ther., 143, 299-330 (1963)) for histamine. After washing, the tissues were incubated for 1 hour with test substance and evaluated. another agonist curve following the effect of histamine concentration on the reaction Shifts to the right of the agonist concentration-response curve produced by the antagonists were used to construct Schild plots (0. Arunlakshana and H. 0. Schild,

Br. J. Pharmacol. 14, 48-58 (1959). Regression of log (dr 1) to log (Β), where dr is an equiactive response in the presence and absence of antagonist, and (B) is the molar concentration of the antagonist, allowed the determination of pA 2, the negative logarithmic concentration of the antagonist. reaction twice to the right.

Tabulkal.

Substance pA ₂

8.9 ^X Promethatin

AND

(B)

C

D

E

F

G

H

AND

J

TO

L

M

N

O

P

Q

WITH

8.2

9.4

8.1

6.2

6.2

5.2

6.8

7.8

7.2

9.0

9.1

8.9 8.6 8.5

8.8 8.7

9.9 ^X R. B, Barlow, Introduction to Chemical Pharmacology, 2nd edition, page 373, edited by Wiley, New York, 1964

B. Antihistamine activity in vivo

Guinea pigs (Hartley, male, 300-350 g) were left without food for 20 hours, then p.o. or i.p. evaluated substances. An hour after administration on an individual basis, guinea pigs were placed in a transparent plastic chamber, which was saturated and continuously supplemented with 0.25% aerosol histamine. Guinea pigs were evaluated for signs of histamine anaphylaxis (for example, cough, sneezing, significant abdominal movements, cyanosis or loss of righting reflex). Under these test conditions, the control animals collapsed for an average of 33 seconds. Εϋ, -θ for histamine protection were calculated using probit analysis. In this test Εϋ ^ θ shows that a single dose perfectly protects 50% of the animals against the effects of histamine during the evaluation period (1 hour post-dose). The proven protection was defined as no histamine in the aerosol chamber (about ten times the time required for the collapse of control animals).

Table II

Substance

Triprolidine

AND

(B)

Results of antihistamine tests

ED ₅₀ / mg / kg, po /

5.77

1.70

0.30 (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, 11 mg / kg p.o. stands for EO pro for 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 naphthylactoid inducer (48/80). One hour prior to exposure, 5 mg / kg i.p. propranolol. The anaphylactoid inducing agent was administered intravenously at 2 mg / kg and the symptoms of respiratory distress were monitored in animals.

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

The above experimental setup does not give a positive result for selective antihistamines. Also, rats do not respond to histamine (i.v.) symptoms of anaphylaxis. Agents that block the use of the effects are usually classified as inhibitors of afylactic mediators or inhibitors of the release of anaphylatic mediators.

Table III

Inhibition of anaphylactoid reaction

Substance

Ketotifen

AND

(B)

C

E

Astemizole

0.87

2.64

0.89 (1.2)

1.43

3.11

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

^xx ED ₅₀ down the road.

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

Example 11

Pharmaceutical forms

Component

Substance of Formula I Water for Injection q.s (A) -injection Amount in ampoule 1.0 mg

1.0 mg

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

(B) -P suppositories

Component Quantity in suppository

Compound of Formula I 1.0 rog

Cocoa butter 2.0 g

TM or Wecobee base q.s.

TM

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

The finely divided active substance was mixed with the melted rosehip base (bud TM cocoa butter or Wecobee to form the desired suppositories. base), the branched suppositories were cast and left cool (C) -Super Component Amount in ml Compound of formula (I) 1.0 mg Ethanol 0.3 mg Sucrose 2.0 mg Metylparaben 0.5 mg Sodium benzoate 0.5 mg Cherry flavor q.s. Dye * q.s. Water q.s. ad 5.0 ml Ethanol, sucrose, benzoate sodium, methylparoben and flavor were combined in 70% total amount of water. Flavor and active the substance was dissolved in the remaining water, then 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, pre- gelatinised 2.5 mg Potato starch 12.0 mg Magnesium stearate 0.5 mg

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

(E) - Waffles

Component Quantity in wafer

Compound of Formula I 1.0 mg

Lactose 440.0 mg

Magnesium stearate 5.0 mg

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

Component

Compound of formula (I) 1 0 mg Pseudoephedrine hydrochloride 60 0 mg Lactose 62 5 mg Potato starch 14 0 mg Magnesium stearate 1 0 mg Gelatine 2 8 mg

(F) -Tablets Quantity per tablet

Tablets were prepared from the above mixture as described in Example 11 (D) above.

AND

Folders

Compound of formula (I) Pseudoephedrine hydrochloride Codeine phosphate Guaifenesin

Metylparaben

Sodium benzoate

Flavor

Dye

Glycerine

Sucrose 2

Purified Water (G) -Sirup Amount in 5 ml 1.0 mg

30.0 mg 10.0 mg

100 mg 0.5 mg 0.5 mg q.s. q.s.

500 mg

00 mg

q.s. ad 5.0 ml

A syrup containing other active ingredients than the compound of Formula I was prepared from the above ingredients in an analogous manner to that described for Example 11 (C) above.

(H) -spray into the nose

Component Quantity per 100.0 ml

Compound of Formula I 1 g

Sodium chloride 0.8 g

Protective substance 0.5 g

Purified water 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 purified water was added to adjust the final volume. to 100.0 ml.

Component (I) -Ophthalmic solution Amount in 100.0 ml Compound of formula (I) 0.1 g Sodium chloride 0.8 g Protective substance 0.5 g Water for injections q.s. 100.0 ml

The preparation was prepared similar to a nasal spray.

Claims (7)

(J) - Local cream Component Quantity per 100.0 ml of the formula 1 0/1 y. Emulsifying wax N.F. 15,0 g Mineral oil 5.0 g SUBJECT OF THE INVENTION A process for the preparation of phenothiazines of the general formula I-Q- ^R ' ^C ° ^2H AND AND AND N z \ R ₂ R 3 wherein represents a divalent aliphatic hydrocarbon group having 1-7 carbon atoms or a single bond, ^R 2 ^{and R} 3 3 ^sou same or different and each is hydrogen, alkyl having 1 to 4 carbon atoms, or together with nitrogen forms a 4-6 membered nitrogen heterocyclic ring, R4 represents a hydrogen atom, a halogen atom, a (C1-C4) alkoxy group, a (C1-C4) alkyl group optionally substituted by up to 3 hologens, or represents a group of the formula R ^C ^H H as defined above, A represents a (C 1 -C 4) alkylene group or ANR 1 R 4 forms a group of the formula -CH or -CH ₂ and salts, esters and amides thereof, with the exception of the esters and amides of the compounds of formula I wherein R 1 represents a hydrogen atom and R 2 represents a bond at the 2-position of the phenothiazine ring system and at the 2-position of the phenothiazine ring and R ₄ is a hydrogen atom and a group of formula ANR 1 R 2 is dimethylaminopropyl and compounds of formula I wherein the group of formula ANR 2 R 2 is diethylaminoethyl and R 4 is hydrogen and R 4 CO 2 H is wherein the compound of formula (V) is in the 2-position R-, C (V) And where R 2, R 6, R 6 and A are as defined above and R @ 1 denotes a single bond, reacted with malonic acid or an ester thereof to give a compound of formula I wherein -CH = CH- and the other symbols are as defined above, then optionally converting a compound of formula I into another compound of formula by hydrogenating a double bond in the side chain carboxy group, and optionally converting the compound obtained to an acid addition salt, carboxylate ester or amide salt of the compound of Formula I, or optionally releasing another compound within the scope of the compounds of Formula I. AND 2. The method of item 1 for the preparation of compounds of formula Ia CH = CHCOOH (Ia) wherein ^R 2a ^{and R} 3a 3 ^are 3 ⁿ 1 to 4 carbon atoms or ^NR 2a ^R 3a or different and each represent a hydrogen atom, the alkyl group together form a 5- to 7-membered heterocyclic ring and A 'represents a straight-chain or branched alkylene group having 1 to 4 carbon atoms, and salts, esters or amides thereof, with the exception of the esters and amides of the compounds of formula (Ia) wherein R R represents a hydrogen atom and R ^ represents a bond at the 2-position of the phenothiazine ring system, with the exception of compounds of formula Ia wherein R₁ represents a bond at position 2 of the phenothiazine ring and R represents a hydrogen atom and a group of formula ANR2R2 is a dimethylaminopropyl group and a compound of formula Ia, wherein the group of formula ^ANR 2 ^R 3 ^{represents-diethylaminoethyl} group, and R @ 1 represents a hydrogen atom and a group of the formula R @ 2 CC @ H represents a group of the formula CH2CO2 H at the 2-position, characterized in that the compound of the formula Va N / \ ^R 2a ^R 2b wherein ^R 2a ^{'and R} 3a ^ ^m * ^ ^v y ^ e defined above, is reacted with malonic acid or its ester to give a compound of formula Ia wherein R₁ represents a group of formula -CH = CH and the other symbols have the meanings given above, then optionally converting a compound of formula Ia to another compound of formula Ia 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 the compound of formula (Ia) or optionally selected from another compound within the scope of the compounds of formula (Ia). 3. A process according to claim 1, wherein the compounds of formula (II) are prepared using appropriate starting materials R ^COjH (II) wherein R @ 1 to R @ ₄ and A are as defined for formula I, or a salt, ester or amide thereof, with the exception of the esters and amides of compounds of formula II wherein R @ 1 is hydrogen; wherein R 1 is a bond, is hydrogen and ANR 2 R 3 is dimethylaminopropyl and compounds of formula (II) wherein CH ₂ , R 2 is hydrogen and ANR ₂ R ₃ is diethylaminomethyl. 4. A process according to claim 1, wherein R 1 is a group of formula (CH ₂ ) _n , n is an integer of 0 to 3, a group of formula CII- CH or CH (CH ^) r ^CH 2 * m ^r O or 1 is -C (O) 2 ^{and the} other symbols are as defined in item 1, except for a compound of formula I wherein m is 1, R 1 is hydrogen and ANR ₂ R ₃ is diethylaminoethyl. 5. Method according to claim 1, characterized in that, using the appropriate starting compounds prepared compound according to any one of claims 1-4, wherein NR ₂ R ₃ represents a dimethylamino group or a diethylamino group, and other symbols are as defined in claim 1, or third 6. The method of item 1, wherein the compounds of any one of items 1 to 5 are prepared using the appropriate starting compounds, wherein R 1 is hydrogen, methyl, chlorine or fluorine, and the other symbols are as defined in item 1. 1, 3 or 4. 7. The process of claim 1, wherein A is an ethylene, n-propyl or isopropylene group, and the other symbols are as defined in claim 1, or 3 to 5.