GB2132194A - Phenothiazines - Google Patents

Abstract

Compounds of the formula (I): <IMAGE> or salts, esters or amides, thereof, wherein R1 is a C1-7 bivalent hydrocarbon group or a single bond; R2 and R3 are the same or different and are each hydrogen, C1-4 alkyl or taken together with the nitrogen comprise a nitrogen-containing heterocyclic ring having four to six ring members; R4 is hydrogen, halogen, C1-4 alkoxy, C1-4 alkyl optionally substituted by one to three halogen atoms; or a group R1 CO2H as hereinbefore defined and A is C1-4 alkylene or ANR2R3 forms a group <IMAGE> exhibit anti-allergic and anti-histaminic activity.

Description

SPECIFICATION Phenothiazine compounds The present invention relates to new chemical compounds exhibiting anti-histamine and antiallergic activity, to processes for preparing them, to novel intermediates involved in their preparation, to pharmaceutical compositions containing them and to their use in medicine.

US Patent No. 2530451 discloses a group of 9-(dialkylaminoalkyl)phenothiazines with antihistamine activity, the most outstanding of which is the compound named and hereinafter referred to by its generic name, promethazine (1 0-(2-dimethylaminopropyl)phenothiazine). Promethazine has gained a fair degree of clinical acceptance as a tranquilliser and as an antihistamine.

The antihistamines now in use, including diphenylhydramine, the pheniramines, pyrilamine, promethazine and triprolidine have one potential disadvantage in common; they all cause sedation or drowsiness in some patients. Promethazine also has the additional disadvantage that it has potent anticholinergic activity.

A novel group of compounds having antiallergic activity in-vivo as defined by blockade of anaphylactoid activity has now been discovered. Some of these compounds also have good antihistamine activity and appear to be substantially free of CNS side-effects and to possess markedly less anticholinergic activity than promethazine.

Accordingly this invention provides a compound of the formula (I).

or a salt, ester or amide thereof; wherein R1 is a C,~7 bivalent aliphatic hydrocarbon group or a single bond; R2 and R3 are the same or different and are each hydrogen, C14 alkyl or taken together with the nitrogen comprise a nitrogen-containing heterocyclic ring having four to six ring members.

R4 is hydrogen, halogen, C14 alkoxy C14 alkyl optionally substituted by one to three halogen atoms; or a group R1 CO2H as hereinbefore defined; and A is C -4 alkylene or ANR2R3 forms a group

Of the compounds of formula (I) those of formula (II) are preferred.

or a salt, ester or amide thereof; wherein R1 to R4 and A are as defined in relation to formula (I).

R1 may be a straight or branched chain, saturated or unsaturated hydrocarbon group or a single bond. Suitably R, is a Its hydrocarbon group or a single bond. Suitably R, contains at the most one double bond. Preferably R, is a group (CH2)n wherein n is an integer 0 to 3, or group CH = CH or a group -CH(CH3)(CH2)m- where m is 0 or 1, or a group -C(CH3)2-. Most preferably R,C02H is a group CH2CO2H.

Suitably R2 and R3 are the same or different and each is methyl or ethyl or taken together with the nitrogen atom to which they are attached form a four to six membered heterocyclic ring, preferably a saturated heterocyclic ring such as pyrrolidine, piperidine or morpholine.

NR2R3 is most suitably a dimethylamino group, or a diethylamino group.

Suitably R4 is hydrogen, halogen, C, 4alkyl, or trifluoromethyl. Most suitably R4 is hydrogen, methyl, ethyl, chloro or fluoro. Preferably R4 is hydrogen. When R4 is other than hydrogen it is attached to the 7- or 8-position of the phenothiazine ring system and conveniently suitably at the 7-position.

Suitably A is an ethylene or n-or iso-propylene group or ANR2R3 forms a group

Amides of the compounds of the formula (I) included within the scope of the invention are amides conventionally formed from carboxylic acids. Amides formed from ammonia, primary amines or amino acids, such as glycine, are particularly suitable.

Solvates of the compounds of the formula (I) are also included within the scope of the present invention. Preferred solvates include hydrates and C14 alkanolates.

Esters and amides of the compounds of the formula (I) whilst having antihistamine activity in their own right may also be useful intermediates in the preparation of the carboxy compounds of the formula (I). Suitable esters include conventional ester groups known to be useful for protecting carboxylic acid groups such as C,-6 alkyl esters wherein the alkyl group is straight or branched chain and is optionally substituted by halogen. Alkyl esters (C1 -4) are particularly preferred. Salts of the compounds of formula (I) may be either acid addition salts or salts formed with the carboxylic acid group. Acid addition salts are preferred but salts formed from the carboxylic acid group may be particularly useful in preparing the corresponding carboxy compound. Pharmaceutically acceptable salts are preferred.

When used in medicine, the salts of the compound of formula (I) should be both pharmacologically and pharmaceutically accepable, but non pharmaceutically acceptable salts may conveninently be used to prepare the free active compound or pharmaceutically acceptable salts thereof and are not excluded from the scope of this invention. Such pharmacologically and pharmaceutically accepable acid addition salts include, but are not limited to, those prepared from the following acids: hydrochloric, sulphuric, nitric, phosphoric, maieic, salicyclic, toluene-psulphonic, tartaric, citric, methanesulphonic, formic, malonic, isothionic, succinic, napthalene-2sulphonic and benzenesulphonic. Also, pharmaceutically acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group.

When the compounds of formula (I) contain a double bond in the side chain terminating in the carboxylic acid group, they exist in either the cis or trans isomeric form(s) (in relation to the aromatic ring). Both isomers and the isomeric mixture of these compounds are included within the scope of the present invention. When R,CO2H contains a double bond, the preferred isomers are those wherein the carboxylic acid group is trans to the aromatic ring.

Preferred compounds of the formula (I) include: trans-fl-Li O-2(-dimethylaminopropyl)phenothiazin-2-yl]acrylic acid 2-( 1 0-(2-dimethylaminopropyl)phenothiazin-2-yl]acetic acid 2-[ 1 0-(2-dimethylaminopropyl)phenothiazin-2-yl]propionic acid 1 0-(2-Dimethylaminopropyl)henothiazine-3-carboxylic acid E-3-(2-Carboxyvinyl)- 1 0-(2-dimethylaminopropyl)phenothiazine 3-(2-Carboxyethyl)- 1 0-(2-dimethylaminopropyl)-phenothiazine 1 0-(2-Dimethylaminopropyl)phenothiazine-4(or 1 )-carboxylic acid (9-4(or 1 )-(2-Carboxyvinyl)- 1 0-(2-d imethylaminopropyl)phenothiazine 4-(or 1 )-(2-Carboxyethyl) 1 0-(2-d i methylaminopropyl)phenothiazine L7-Chlorn- 1 0-(2-dimethylaminoprnpyl)-2-phenothiazinyllacetic acid (1 0-(2-Dimethylaminoethyl)-7-methyl-2-phenothiazinly]acetic acid [1 0-(2-Dimethylami noethyl)-7-fluoro-2-phenothiazinyl]acetic acid 2-[1 0-(2-Dimethylaminoprnpyl)-2-phenothiazinylj-2-methylprnpionic acid 2-El 0-(3-dimethylaminoprnpyl)-2-phenothiazinyli-2-methylprnpionic acid 2-Methyl-2-[1 0-E3-(N-pyrrolidino)prnpyl]-2-phenothiazinyl]prnpionic acid.

1 0-(2-Dimethylaminopropyl)phenothiazine-2-carboxylic acid or salts, esters or amides thereof, Pharmacokinetic studies comparing the relative distribution in brain and plasma of two of the compounds of this invention and promethazine indicate that, unlike promethazine, these compounds (Compounds A and B see examples) do not readily penetrate the brains of rodents.

The present invention also provides analogy methods for preparing compounds of formula (I), for example: a) When it is required to prepare a compound of the formula (I) wherein ANR2R3 is not

The reaction of a compound of the formula (III)

or an ester thereof with an amine HNR2R3 wherein A and R, to R4 are as hereinbefore defined and L is a leaving group; b) When it is required to prepare a compound of the formula (I) wherein R, is (CH2)0 (i) the reaction of a compound of the formula (IV):

wherein R2, R3, R4 and A are as hereinbefore defined and R6 is a hydrogen or halogen atom, with a C,~6 alkyl lithium compound followed by treatment with carbon dioxide; (ii) the oxidation of a compound of the formula (V)::

wherein R2, R3, R4, and A are as hereinbefore defined, R, is a single bond and B is hydrogen; c) When it is required to prepare a compound of the formula (I) wherein R1 is (CH2)a CH = CH(CH2)b) and a is 0 and b is 0 to 5 the reaction of a compound of the formula (V) as hereinbefore defined, with a Wittig reagent suitable for attaching the side chain CH = CH( CH2)bCOR6, wherein COR6 is an acid, ester or amide group as herein before defined, followed by deprotection of the carboxy group if desired; d) When it is required to prepare a compound of the formula (I) wherein R, is CH = CH, the reaction of a compound of the formula (V) as hereinbefore defined, with malonic acid or a malonic acid ester; e) the hydrolysis of a compound of the formula (Vl)::

wherein R2 to R4 and A are hereinbefore defined and R, Z is a group R, CN wherein R, is a C17 bivalent hydrocarbon group, or a group R7 - CH = C(Y)XH wherein R7 is a C1 -6 bivalent hydrocarbon group or a single bond, X is oxygen or sulphur and Y is a secondary amino group; f) the alkylation of a compound for the formula (VII):

wherein R, and R4 are as hereinbefore defined, COR6 is an ester or amide group and thereafter, optionally converting one compound of the formula (I) to another compound of the formula (I) by methods well known to those skilled in the art, for exmaple the reduction of one or more double bonds or de-esterification of an ester group or hydrolysis of an amide.

The analogy methods are carried out suitably in the following manner: a) Suitable leaving group L in the compounds of the formula (III) are those as defined by J.

March, Advanced Organic Chemistry, 2nd ed., pages 683 and 895, McGraw Hill, New York, 1977, e.g. -Br, -Cl, toluene suphonate, methane sulphonate, acyloxy (such as acetate), etc.

This reaction will normally be carried out in a solvent suitable for carrying out such displacement reactions, for example a polar solvent, such as a C14 alkanol or a polar aprotic solvent such as DMSO, at a temperature between 0 and 1 80 C.

The compounds of the formula (III) may be prepared by the reaction of an ester of the corresponding compound where L is a hydroxy group with an acid or a suitable reactive acid derivative, followed by removal of the ester function if desired. Suitable reactants include hydrogen halides, halogenated phosphorus compounds such as phosphorus pentachloride or phosphorus oxychloride, a suitable sulphonyl chloride (such as methane sulphonyl chloride or ptoluene sulphonyl chloride) or an acid anhydride, such as acetic anhydride.The reaction will conveniently be carried out in a suitable solvent under conditions well known to those skilled in the art, for example a non-protic solvent such as an ether or a halogenated hydrocarbon, in the presence of a base such as a tertiary amine (for example triethylamine) at a non-extreme temperature, for example between 0" and 1 00 C and conveniently at room temperature. When a tertiary amine is used as a base, an excess of this may be used as the solvent.

The hydroxy compounds may be prepared by reacting phenothiazines unsubstituted at the 10position (i.e. by the group AL) with either alkylene oxides such as ethylene (or higher) oxide, or with an alkanol which also bears a leaving group, in the presence of a strong base, such as an alkali alcoholate, at a non-extreme temperature, for example between 0" and 1 00 C.

b)(i) The reaction of a compound of the formula (IV) with alkyl lithium followed by treatment with carbon dioxide is suitably carried out in a solvent inert under the reaction conditions utilised, for example benzene, toluene or an ether such as tetrahydrofuran, under an inert atmosphere, such as nitrogen, and at a low temperature, for example - 80"C and - 20"C. R5 is preferably bromine or iodine. The alkyl lithium compound is suitably butyl lithium. The reaction is conveniently caried out in toluene or tetrahydrofuran at a temperature between - 80"C and - 50"C under nitrogen.The compound of the formula (IV) may be prepared by the reaction of a compound of the formula (VIII);

wherein R4 is as hereinbefore defined with a compound LANR2R3 wherein A, R2, R3 and L are as herein before defined. This reaction is suitably carried out in the presence of a base, such as an alkali metal alkoxide, for example potassium butoxide, in an inert solvent, for example xylene, at an elavated temperature i.e. between 20 and 1 50 C and conveniently between 50 and 80"C.

(ii) The compound of formula (V) is suitably prepared by oxidation of the corresponding alcohol under conditions that will not lead to oxidation of the components of the phenothiazine ring, for example by oxidation with silver carbonate on diatomaceous earth in an inert hydrocarbon solvent, such as benzene at a non-extreme temperature, for example between 0 and 1 00 C, conveniently under reflux. The alcohol may be prepared by reduction of the corresponding acid or its ester, i.e. a compound of the formula (I) wherein R is (CH2)0. This reduction may suitably be carried out using a metal hydride, such as lithium aluminium hydride, in an inert solvent, such as an ether, for example diethyl ether, at between 0 and 75"C and suitably under reflux.

This reaction is a conventional Wittig reaction and, as such, is analogous to those described in Organic Reactions, 14, 270-490 (1965) and Pure and Applied Chemistry, 9, 245-254 (1964). The reaction is suitably carried out in an anhydrous solvent inert under the reaction conditions utilised, for example toluene, benzene, tetrahydrofuran, dioxan, glycol ethers and C16 alkyl ethers such as ethyl ether, at a temperature between - 80"C and 100"C. The Wittig reagent will normally be prepared by treatment of a phosphonium salt with a strong base, for example a C1 -4 alkyl or aryl lithium compound such as butyl lithium, or a metal hydride, such as sodium hydride in a suitable inert solvent, such as those specified above.

The Wittig reagent in reaction (c) is conveniently prepared by reacting a compound of the formula (R8)2 PO.(CH2)dCO2R6, wherein R6 is as hereinbefore defined, R6 is a C,~4 alkoxy group and d is 1 to 6, or a compound of the formula (Rg)3P(CH2)dCO2R6 wherein R6 is as hereinbefore defined R9 is C14 alkyl or phenyl and d is 1 to 6 with a strong base, such as sodium hydride in a suitable inert solvent, such as tetrahydrofuran or dimethoxyethane at a temperature between 0 and 50"C, conveniently at room temperature.

The reaction between the Wittig reagent and compound of the formula (V) is conveniently carried out by adding the compound of the formula (V) to the Wittig reagent at a temperature of between 0" and 50"C and conveniently at room temperature.

d). The reaction of a compound of the formula (V) with malonic acid or an ester thereof is suitably carried out in the presence of a base, conveniently pyridine, which can also act as solvent at an elevated temperature i.e. between 20 and 1 50 C and conveniently between 80 and 120"C.

e). The hydrolysis of a compound of the formula (VI) is suitably carried out by the addition of a dilute mineral acid, for example hydrochloric acid and heating at an elevated temperature, for example between 50 and 100"C and conveniently at 1 00 C. Such hydrolysis reactions of nitrile groups, amide and thioamide groups are well known to those skilled in the art.The compounds of the formula (VI) wherein R1 Z is a group R1 CN may be prepared by the reaction of a compound of the formula (V) wherein B is a hydrogen or methyl and R1 is a single bond or a C1 -6 bivalent hydrocarbon group as hereinbefore defined, with a compound L1CH2N = wherein L, is a sulphonyloxy group, for example tosyl in the presence of a base, for example an alkali metal alkoxide such as potassium butoxide, in an aprotic solvent such as dimethyl sulphoxide, at a non-extreme temperature, for example - 20" to 1 00 C and conveniently 20"C. The compounds of the formula (Vl) wherein R1 Z is a group R7-CH = C(Y)XH wherein X is a sulphur and Y is a secondary amino group may be prepared by the reaction of a compound of the.

formula (V) wherein R1 is a single bond and B is hydrogen or C14 alkyl with sulphur and a secondary amine, such as morpholine, at an elevated temperature, i.e. 50 to 1 50 C, preferably in an inert atmosphere. The corresponding amides (i.e. those compounds wherein X is oxygen may be prepared by hydrolysis of the corresponding thioamide or nitrile.

f). The alkylation of a compound of the formula (VII) is carried out under conditions well known to those skilled in the art of such reactions. The alkylating agent LANR2R3 (wherein L, A, R2 and R3 are as hereinbefore defined), is reacted with the compound of the formula (VII) in the presence of a base at a non-extreme temperature, for example between 0" and 1 50 C in an inert solvent.

A strong base is conveniently utilised such as t-butoxide, a hydride such as sodium hydride or sodamide. The temperature is conviently between 20 and 90"C and the solvent is suitably a hydrocarbon, such as tetrahydrofurans, or a dipolar apretic solvent, such as dimethylformamide or dimethylsulphoxide.

The compounds of the formula (VII) may be prepared as described in Scheme 1 attached hereto.

The reduction of one to two double bonds, i.e. the reduction of the double bond in the carboxy side chain may conveniently be carried out by hydrogenation in the presence of a transition metal catalyst, for example platinum on charcoal. The preparation of esters or amides from the corresponding carboxylic acid, and vice versa, may similarly be carried out by methods well known to those skilled in the art.

Those intermediates that are novel form an important aspect of the present invention.

The compounds of this invention having antiallergic activity may be used for the same indications as clinically used antiasthmatic compounds, namely to help to control bronchoconstriction or brochospasm characteristic of allergic asthma and exercise induced asthma and the symptoms of bronchoconstriction and bronchospasm resulting from acute or chronic bronchitis.

The compounds are believed to inhibit the release of autacoids (i.e. histamine, serotonin and the like) from mast cells and to inhibit directly the antigen-induced production of histamine. Thus, they may be classified as mast cell stabilizers with anthistaminic action.

The compounds of this invention having antihistamine activity may be used for the same indications as clinically used antihistamines, namely to relieve detrimental symptons (caused by histamine release) of nasal stuffiness due to colds and vasomotor rhinitis and for the symptomatic control of allergic conditions including nasal allergy perrenial rhinitis, urticaria, angioneurotic oedema, allergic conjunctivitis, food allergy drug and serum reactions, insect bites and stings and desensitizing reactions. The compound may also be used in conditions responsive to its antipruritic activity including allergic dermatoses, neurodermatitis, anogenital pruritis, and pruritis of non-specific origin such as eczema, and of specific cause such as chickenpox, photosensitivity and sunburn.The present invention therefore provides a method for the symptomatic treatment of allergic conditions by the administration of an effective amount of a compound of the formula (I). The present invention also provides a method for the antagonism of endogenously released histamine by the administration of an effective amount of a compound of the formula (I). Some of the compounds of the present invention have been found to be substantially free from sedative effects and to have little or no anticholinergic effects.

The amount of active compound required for use in the above conditions will vary with the compound chosen, the route of administration and the condition and mammal undergoing treatment, and is ultimately at the discretion of the physician. A suitable oral dose of the active compound for a mammal is in the range of from 0.003 to 1.0 mg per kilogram body weight per day; preferably from 0.04 to 0.24 mg/kg. For example a typical dose for a human recipient of compound (B) (see example 2 and Table 1 hereafter) is between 0.03 and 0.1 mg/kg body weight per day.

The desired daily dose is preferably presented as from one to six sub-doses administered at appropriate intervals through the day as needed. Where three subdoses of compounds of formula (I) are employed, each will preferably lie in the range of from 0.014 to 0.08 mg/kg body weight; for example, a typical sub-dose of such a compound for a human recipient is between 1 and 20 mg, for example 4 or 8 mg.

Whilst it is possible for a compound of the formula (I) to be administered alone as the raw chemical, it is preferable to present the compound of formula (I) as a pharmaceutical formulation. Thus, the present invention also provides pharmaceutical formulations, both for veterinary and for human medical use, which comprise a compound of the formula (I) together with one or more pharmaceutically acceptable carriers thereof and optionally any other therapeutic ingredients. For example, the active compound may be formulated with a sympathomimetic agent such as the decongestant pseudoephedrine, an antitussive such as codeine, an analgesic, an antiinflammatory, 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 and not deleterious to the recipient thereof.

The formulations include those suitable for oral, rectal, topical, nasal, ophthalmic or parenteral (including subcutaneous, intramuscular and intravenous) administration.

The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active compound into association with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier or a finely divided solid carrier or both and then, if necessary, shaping the product into desired formulations.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of the active compound (defined herein as a compound of formula (I)); as a powder or granules; or a suspension in an aqueous liquid or nonaqueous liquid such as a syrup, and elixir, an emulsion or a draught. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, with the active compound being in a free-flowing form such as a powder or granules which is optionally mixed with a binder, disintegrant, lubricant, inert diluent, surface active agent or dispersing agent.Molded tablets comprised of a mixture of the powdered active compound with any suitable carrier may be made by molding in a suitable machine.

A syrup may be made by adding the active compound to a concentrated, aqueous solution of a sugar for example sucrose to which may also be added any accessory ingredient(s). Such accessory ingredient(s) may include flavourings, an agent to retard crystallization of the sugar or an agent to increase the solubility of any other ingredient, such as a polyhydric alcohol, for example glycerol or sorbitol, and suitable preservatives.

Formulations for rectal administration may be presented as a suppository with a usual carrier such as cocoa butter, or hydrogenated fats or hydrogenated fatty carboxylic acids.

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

Nasal spray formulations comprise purified aqueous solutions of the active compound with preservative agents and isotonic agents. Such formulations are adjusted to a pH and isotonic state compatible with the nasal mucous membranes.

Ophthalmic formulations are prepared by a similar method to nasal spray except that the pH and isotonic factors are adjusted to match that of the eye.

Topical formulations comprise the active compound dissolved or suspended in one or more media such as mineral oil, petroleum, polyhydroxy alcohols or other bases used for topical pharmaceutical formulations. The addition of other accessory ingredients, vide infra, may be desirable.

In addition to the aforementioned ingredients, the formulations of this invention may further include one or more accessory ingredient(s) selected from diluents, buffers, flavouring agents, binders, disintegrants, surface active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.

The present invention also provides the first use of the compounds of the formula (I) in medicine.

The following Examples are provided by the way of illustration of the present invention and should in no way be construed as a limitation therof. All temperatures indicated are in degrees Celsius.

Example 1: Trans-ss-[1 ()-(2-Dim'ethylaminopropyl)phenoThiazin-ylJacryllc acid a) 2-Bromo- 1 O-(2-dimethylaminopropyl)phenothiazine (Compound ex- 1 a) 2-Bromophenothiazine (5.0 9) and potassium t-butoxide (2.4 g) were combined in 25 ml dry xylene and stirred under nitrogen and heated at 65"C for 10 minutes. To this was added a solution of 2-dimethylaminopropyl chloride (2.8 g) in xylene (2 ml) dropwise over 10 minutes.

Stirring under nitrogen and heating at 60-70" were continued for 3 hours. The reaction was poured into ethyl acetate (100 ml) and extracted with dilute HCI. The acid extract was basified with excess aqueous ammonia and extracted with CH2CI2, which was dried (MgSO4) and evaporated, leaving a viscous oil (6.35 g). The oil was a mixture of the title compound and its isomer 2-Bromo- 1 0-(2-dimethylamino- 1 -methylethyl)phenothiazine, from which it was separated as a viscous colourless oil by preparative HPLC on a silica column, eluting with EtOAc/CH2CI2 (4:1).

Compound ex-1a did not crystallize and no attempt was made to obtain a crystal salt. It was characterized by its nmr spectrum, which was consistent with its indicated structure and different from that of its isomer.

b) 1 O-(2-Dimethylaminopropyl)phenothiazin-2-yl-carboxaldehyde (Compound ex 1 b) Using syringes and a nitrogen atmosphere THF (20 ml) was added to a flask containing compound ex la (2.8 g). The solution was stirred and cooled in a dry ice/acetone bath, and nbutyl lithium (5.2 ml of a 1.5M solution in hexane) was added dropwise over five minutes. After stirring at - 78"C for 30 minutes, distilled DMF (0.8 ml) was added and the reaction was allowed to warm slowly (over 25 minutes) to ambient temperature. It was then poured onto cold dilute HCI which was washed with benzene and then basified with NH4OH. The produce was extracted into CH2CI2 which was dried (MgSO4) and evaporated, leaving 2.5 9 of very viscous yellow oil, compound ex-lb.

Compound ex-1 b did not crystallize and no attempt was made to obtain crystalline salts. It was characterized by its nmr and ir spectra, which were consistent with the structure indicated.

The tic showed a single component silica (CHCl3/MeOH, 9:1) which was slightly less mobile than starting material (compound ex-la).

c) trans-fl-fl O-(2-Dimethylaminopropyl)phenothiazin-2-yijacrylic acid (Compound A) Compound ex-lb(2.4 g), malonic acid (1.1 g), and morpholine (0.120 g) were dissolved in pyridine (8 ml) and heated on steam. Carbon dioxide gas evolved briskly at first. After 2 hours, the pyridine was evaporated at reduced pressure. The residue was triturated with boiling EtOH (25 ml), which poduced a yellow solid upon cooling and stirring. This was recrystallized from EtOH, yielding Compound A, yellow crystalline solid, mp214-8 . The nmr and CHN analysis were consistent with the structure indicated.

Example 2: 2-[1 0-(2-Dimethylaminopropyl)phenothiazin-2-yl]acetic acid a) 2-acetylphenothiazine ethylene ketal[Compound ex-2a) Under nitrogen a solution of 2-acetylphenothiazine (1009), ethylene glycol (50 g), and ptoluenesulfonic acid hydrate (2.0 9) in benzene (900 ml) was refluxed under a water separator (Dean-Stark trap) for 1 8 hours. Analysis by tic (silica gel, hexane/EtOAc 4:1) confirmed that almost all the starting compound was consumed and replaced by one with a higher Rf value (ex4). After cooling, the benzene solution was washed with 1% NaOH solution, dried over solid K2CO3, and evaporated, leaving 11 5 g of dark oil which froze to a dark green crystalline solid upon standing at ambient temperature.The nmr was consistent with the assigned structure. It was not purified further but was carried on to the next step.

b) 2-Acetyl- 1 O-(2-Dimethylaminopropyl)phenothiazine (Compound ex-2b) Crude compound ex-2a (47.5 g) and potassium t-butoxide (20.9 g) were combined in benzene (250 ml) and stirred under nitrogen for 1 5 minutes. To this was added 2-dimethylaminoisopropyl chloride (23 9), and the resulting solution was heated at reflux for 75 minutes. After cooling the amines were extracted into dilute aqueous HCI, and the resulting acid solution was heated for 20 minutes on steam to hydrolyze the ketal. After cooling the aqueous solution was washed with ether and then basified with excess NaOH.The free amines were then extracted into CH2CI2, which was dried (MgSO) and evaporated to leave a red viscous oil which consisted of a crude mixture of compound ex-2b and its isomer, 2-acetyl-1 0-(2-dimethylamino-1-methyl- ethyl)phenothiazine. Compound ex-4 is predominant and was obtained analytically pure by formation of the hydrogen maleate salt in EtOAc/MeOH and two recrystallizations from the same solvent, mp 187-91". The nmr and CHN analysis were consistent with the structure indicated. The isomer was obtained pure from the mother liquors by column chromatography of the free amine on silica gel, eluting with EtOAc/EtOH(20:1).

C) 2-[ 1 O-(2-Dimeth 2-fl O-(2-Dimethylaminopropyl)phenothiazin-2-yljacetic acid (Compound B Compound ex-2b (15.4 9), sulfur (3.2 9) and morpholine (10 ml) were combined and heated at reflux under nitrogen for 5 hours. The warm reaction was then poured into EtOAc (300 ml) plus ether (100 ml), which was stirred and filtered. A small amount of insoluble material was discarded. The amines were extracted into dilute HCI (400 ml H20 plus 1 6 ml conc. HCI). The aqueous solution was washed with ether and then basified with excess NaOH. The product was extracted into CHCI3 (400 ml), which was washed with H20 (3 X 600 ml). Evaporation of the CHCl3 solution produced a viscous red oil (16.4 g) whose tic (silica gel, CH2CI2/MeOH, 25:1) indicated many components present.The sample was fractionated by preparative HPLC, using two silica columns in sequence, eluting with CH2CI2/MeOH (98:2), then switching to CH2CI2/MeOH (97:3). The main fractions, after evaporation, yielded a total of 9.2 g of viscous orange oils, whose nmr's and tlc's indicated that they were imperfectly separated mixtures of the expected thiomorpholide and (apparently) its partial hydrolysis product, the oxymorpholide.

Since both were satisfactory intermediates for hydrolysis to the desired acid, compound B, they were not purified further but were combined, dissolved in 4N HCI (225 ml) and refluxed 6 hours, which removed all trace of starting materials from the talc.

The reaction was evaporated to a viscous green residue, which was dissolved in H20 (70 ml) and washed with EtOAc. The solution was then basified with a slight excess (litmus) of solid NaOH, and washed with CH2CI2. Partial evaporation of the aqueous solution gave precipitation of the Na salt of compound B. The precipitation was increased by dilution with an equal volume of saturated NaCI solution. The resulting solid was filtered and recrystallized from H2O/sat NaCI (4:1). The product after filtration and vacuum drying at 70"C overnight, was 4.3 9 of dry powder, which gave correct CHN analysis and Karl Fischer analysis for Compound B, Na salt, with 5.5 moles H20 included.

A hydrogen maleate salt was also prepared from this, mp 115-120 , whose nmr and elemental analysis were correct for the structure indicated.

Example 3: 2-fl O-(2-Dimethylaminopropyl)phenothiazin-2-yljpropionic acid a) 2-fl O-(2-Dimethylaminopropyl)phenothiazin-2-yljpropionirile Compound ex-3a.

Under nitrogen a solution of tosylmethyl isocyanide (4.0 9) in DMSO (15 ml) and THF (4 ml) was stirred in an ice bath, and potassium t-butoxide (5.3 9) was added. After five minutes 0.68 g of mthanol was added. To this was then added dropwise over three minutes a solution of compound ex-2b (3.4 9) in DMSO (3 ml) and THF (1 ml). It was allowed to warm to ambient temperature and was stirred for 20 hours. The reaction was poured into ether and washed with H2O. The amines were extracted into dilute HCI, which was washed with ether and then basified with excess NaOH. The free amines were then extracted into ether, which was dried (MgSO4) and evaporated, leaving the crude product as an oil (2.5 g) whose tic (silica, CH2CI2/MeOH, 24:1) showed multiple components.The desired component, compound ex-3a, was separated cleanly by preparative HPLC on silica, eluting with CH2CI2/MeOH (97:3). Compound ex-3a was an oil and was identified by its ir and nmr spectra, which were consistent with the structure assigned.

b) 2-fl O-(2-Dimethylaminopropyl)phenothiazin-2-yljpropionic acid Compound C) Compound ex-3a (1.7 9) was dissolved in 4N HCI (50 ml) and heted at reflux for 20 hours.

The solution was evaporated at reduced pressure to a viscous oil which was then redissolved in H20 (30 ml), washed with ether, and then brought to a basic pH (1, 10, litmus) by careful addition of NaOH. The resulting solution was washed with ether and then evaporated to about half the original volume. The HCI salt of compound Cwas precipitated as an oil by addition of excess concentrated HCI. This oil was redissolved in H20, reprecipitated (again as an oil) with excess HCI, and then rubbed with ether, which caused the oil to solidify. This salt was recrystallized from MeOH/EtOAc to yield C.HCl.H2O, colourless crystals, mp 1 56-62'C (dec.), whose elemental analysis (CHN) was correct for the formula assigned.

Example 4: 1 O-(2-Dimethylaminopropyl)phenothiazine-3-carboxylic acid To a solution of 3-bromo-1 0-(2-dimethylaminopropyl)phenothiazine (2.59) (prepared in a similar manner to the 2-bromo compound in Example 1) in dry ether, cooled at 0 C, was added dropwise a solution of butyl lithium in hexane (6.7ml of 1.55M solution). The solution was stirred at O"C for 1 hour, then cooled to - 40"C and a large excess of solid carbon dioxide was added. The mixture was allowed to come to room temperature and water was added. After thorough mixing, the ether layer was separated and discarded, the aqueous solution was brought to pH6 by careful addition of 2N-hydrochloric acid, and then evaporated to dryness.

The residue was boiled with ethanol and the filtered ethanol solution was evaporated to dryness to leave a semi-solid mass. Chromatographic separation of the material on a column of silica with mixtures of chloroform and methanol as eluant gave the impure carboxylic acid as a greycoloured solid (19.) which was further purified by way of its methyl ester, as follows.

A solution of the crude acid (670mg) in methanol (20 ml) and concentrated sulphuric acid (0.65ml) was refluxed for 3 hours. Most of the methanol was evaporated and water was added.

The solution was washed with ether, basified with 2N-sodium hydroxide solution and the pecipitated oil was extracted into ether. The ether solution was washed with water, dried(MgSO4) and evaporated to leave yellow viscous oil (570mug). This ester was dissolved in a small excess of dilute hydrochloric acid, the solution was evaporated to dryness, and the residue was recrystallised from a mixture of ethanol and ether to give fine pale yellow needles of methyl 1 0-(2-dimethylaminopropyl)phenothiazine-3-carboxylate hydrochloride, m.p. 218 C(decomp).

The foregoing ester hydrochloride (584mg) in a mixture of ethanol (4ml) and 2 sodium hydroxide solution (1.77ml) was stirred at room temperature for 20 hours. The solution was neutralised by addition of 2Khydrochloride acid (1 ml) and evaporated to dryness. The residue was extracted with hot ethanol and the filtered extract was evaporated to dryness. The residual solid was-recrystallised twice from methanol-ethyl acetate to give small colourless prisms, m.p.

185-188"C, of I O-(2-dimethylaminopropyl)phenothiazine-3-carboxylic acid (Compound D).

Example 5: E-3-(2-Carboxyvinyl)- 1 O-(2-dimethylaminopropyl)-phenothiazine a) (E)-3-(2-methoxycarbonylvinyl)- 1 O-(2-dimethylaminopropyl)phenothiazine.

To a stirred solution of 3-bromo-1 O-(2-dimethylaminopropyl)phenothiazine (4.0g) in dry ether at O"C was added dropwise a solution of butyl lithium (8.5ml of 1.55M solution in hexane). The resulting yellow solution was stirred at O"C for one hour and then treated dropwise, during 1 hour, with a solution of dimethylformamide (1.7ml) in dry ether (20ml). The reaction mixture was stirred at room temperature for 3 hours, then shaken with water and ether. The washed and dried ethereal solution was evaporated to leave the crude aldehyde as a yellow oil.

A solution of this crude aldehyde (4.09) in dry 1,2-dimethoxyethane (20ml) was added to a stirred solution of the phosphonate carbanion produced from diethyl methoxycarbonylmethylphosphonate (2.699) and sodium hydride (385mg of 80% dispersion in oil) in 1,2-dimethoxyethane (30ml) at room temperature. After 4 hours' stirring the reaction mixture was evaporated in vacuo and water and ether were added. The ethereal phase was separated, washed, dried and evaporated to leave crude (E)-3-(2-methoxycarbonylvinyl)-1 O-(2-dimethylaminopropyl)phenothiazine as a fluorescent yellow oil.

b) E-3-(2-carboxyvinyl)- I O-(2-dimeth ylamin oprop yl)phenothiazine This ester (49) was hydrolysed in a solution of ethanol (22ml) and 2 sodium hydroxide solution (8.8ml) at room temperature for 4 hours. The product was isolated as described in Example 1 to give the crude carboxylic acid as an orange-coloured gum (3.09). This was dissolved in warm 0.4Khydrochloric acid and concentrated hydrochloric acid was added to induce crystallisation of orange-coloured plates. Recrystallisation from a mixture of ethanol and ether gave small yellow needles of E-3-(2-carboxyvinyl)-1 0-(2-dimethylaminopropyl)-phenothiazine hydrochoridehemihydrate, m.p. ca 170"C (efferv).After drying at 150"C, the anhydrous salt had m.p. 220-225"C (decomp.) (Compound E).

Example 6: 3-(2-carboxyethyl)- 1 O-(2-dimethylaminopropyl)phenothiazine A solution of E-3-(2-carboxyvinyl)-1 0-(2-dimethylaminopropyl)phenothiazine hydrochloride (Example 4)(19) in methanol (20ml) containing 10% palladium-on-charcoal catalyst (100mg) was stirred in an atmosphere of hydrogen until uptake was complete (9 hours). The catalyst was removed by filtration and the solvent was evaporated to leave the hydrochloride of the saturated carboxylic acid. It was freed from a small impurity by esterification as described in Example 3, chromatography of the ester on a column of silica in chloroform-methanol (50:1), and hydrolysis of the pure ester as described in Example 4.The 3-(2-carboxyethyl)-1 0-(2-dimethlaminopropyl)phenothiazine so obtained crystallised from an ethanol-ether mixture as a cream-coloured solid, m.p. 1 70-1 73'C (Compound F).

Example 7: 1 O-(2-Dimethylaminopropyl)phenothiazine-4(or 1)-carboxylic acid To a stirred solution of 1 O-(2-Dimethylaminopropyl)phenothiazine(5.7g.) in dry ether (1 50ml) was added dropwise at 20"C a solution of butyl lithium (20 ml of 1 .55M solution in hexane).

The solution was stirred at this temprature for 30 hours, then cooled to - 1 5'C and solid carbon dioxide (ca 259) was added. The mixture was allowed to come to room temperature and left to stand for 1 6 hours. Water was added, the mixture was well shaken and the ethereal layer was separated. Evaporation of the washed and dried extract yielded unchanged starting material (4.59.). The aqueous solution was neutralised by addition of 2Shydrochloric acid and evaporated to dryness. The residue was extracted with ethanol and the filtered extract was evaporated to dryness.The residue (2.5g.) was purified by chromatography on a column of silica with chloroform-methanol mixtures as eluants to give 1 0-(2-dimethylaminopropyl)phenothi- azine-4(or 1)-carboxylic acid, as colourless needles, m.p. 220-222"C (decomp.) (from methanol) (Compound G).

Example 8: (E)-4(or l)-(2-carboxyvinyl)- 1 O-(2-dimethylaminopropyl)phenothiazine a) (E)-4(or 1 )-(2-methoxycarbonylvinyl)-1 O-(2-dimethylaminopropyl)-phenothiazine 1 0-(2-Dimethy- laminopropyl)phenothiazine (5.79.) was treated with butyl lithium under the conditions described in Example 7. To the resulting solution was added gradually dimethylformamide (3.1 ml) and the mixture was allowed to stand at room temperature for 1 8 hours. The crude aldehyde was isolated by ether extraction and used without further purification.

The crude aldehyde was treated with the phosphonate carbanion derived from diethyl methoxycarbonylmethylphosphonate as described in Example 5 to give 4 (or 1)-(2-methoxycar- bonylvinyl)-1 O-(2-dimethlaminopropyl)phenothiazine which was crystallised from ethanol, mp 129-130 C.

(b) E-4(or 1 )-(2-carboxyvinyl)-1 O-(2-dimethylaminopropyl)-phenothiazine. This ester was hydrolysed with dilute NaOH solution as described in Example 5 to give E-4 (or 1 )-(2-carboxyvinyl)- l0-(2-dimethylaminopropyl)phenothiazine, crystallising from isopropanol-light petroleum (b.p.

60-80"C) as small yellow needles, m.p. 120-125"C (Compound H).

Example 9: 4-(or 1)-(2-carboxyethyl)- 1 O-(2-dimethylaminopropyl)-phenothiazine A solution of ( (E)-4(or 1 1)-(2-methoxycarbonylvinyl)- 10-(2-dimethylaminopropyl)-phenothiazine (500 mg) in ethyl acetate (20 ml) was stirred in an atmosphere of hydrogen in the presence of Raney nickel catalyst until no more hydrogen was absorbed. The filtered solution was evaporated to give 4 (or 1 )-(2-methoxycarbonylethyl)- 1 O-(2-dimethylaminopropyl)phenothiazine which was subjected to hydrolysis in aqueous-ethanolic sodium hydroxide solution as described in Example 5. The 4 (or 1 )-(2-carboxyethyl)-1 O-(2-dimethylaminopropyl)phenothiazine so producted crystallised from isopropanol in colourless needles, m.p. 1 55-1 57'C (Compound I).

Example 10: f7-Chloro- 1 O-(2-dimethylaminopropyl)-2-phenothiazinyljacetic acid Compound K a) 4'-Bromo-3'-nitrophenylacetic acid (Compound ex- 1 Oa) Concentrated HNO3 (20 ml) and H2SO4 (20 ml) were mixed and 4'-bromophenylacetic acid (21.59) was added to the stirred solution in portions over 20 minutes with water cooling such that the internal temperature was maintained in the 50-55" range. The mixture was then heated for 10 minutes at 85 . the mixture was then poured onto ice and diluted with H20. The resulting yellow solid was filtered, washed with H20, dissolved in a small excess of 2N NaOH, and then reprecipitated, by addition of excess concentrated HCI.The solid was dried and recrystallised three times from benzene, yielding compound ex-lOa (10.29), mp. mp. 108-113'.

NMR analysis was consistent with a single isomer of the structure indicated.

b) Ethyl-4'-bromo-3'-nitrophenylacetate (compound ex 10b) Compound ex- 10a was suspended in a solution of ethanol (400 ml), triethylothoformate (25 ml) and concentrated H2SO4 (2 ml) and heated at reflux for 3 hours. The solvent was evaporated and the residue was dissolved in ether and washed sequentially with H20, 5% NaOH, and saturated NaCI. The ether was dried and evaporated, leaving compound ex-10b (35.1 g), a mobile yellow-orange oil whose nmr was consistent with the structure indicated.

c) Ethyl-4'-(4-chlorophenylthio)-3'-nitrophenylacetate (Compound ex- 1 Oc) A mixture of compound ex-10b (8.6 9), 4-chlorothiophenol (5.5 9) and Na2CO3 (6.39) in ethanol (75 ml) was stirred under nitrogen at reflux for 5+ hours. It was poured into ice-cold 5% NaOH (900 ml) and extracted with ether (3 X 100 ml). The ether was washed with 5% NaOH and then dried (MgSO4) and evaporated, leaving compound ex-10c(10.3 g) as a yellow oil which froze to a solid (m.p. 71-82"), whose nmr was consistent with the structure indicated. It was not purified further.

d) Ethyl-(7-chloro-2-phenothiazinyl)acetate (Compound ex 10 d) Compound ex-10c (24.3 9) and triethyl phosphite (46.0 9, were combined in dried and deoxygenated n-propylbenzene (200 ml) and refluxed under N2 for 4 hours. The volatile components were removed on the H20 aspirator at 80 . The dark residual oil was purified by flash column chromatography on silica, eluting with hexane (ethyl acetate (6:1). This yielded 6.1 g of a yellow solid which was recrystallized from ethanol/ethyl acetate (1:1). The product, compound ex-lOdwas a colourless solid (m.p. 193-4 ) whose nmr was consistent with the proposed structure. This cyclization/rearrangement reaction has been described by Cadogan, et al., J. Chem. Soc(1970) 2437.

e) Ethyl-[7-chloro- 1 O-(2-dimethylaminopropyl)-2-phenothiazinyljacetate (Compound ex- 1 Oe)(Compound J) Compound ex-10d(4.1 g) and potassium t-butoxide (1.52 9) were combined in dry deoxygenated toluene (30 ml) and stirred under N2 for 10 minutes. 2-Chloror-1-dimethylaminopropane (1.7 9) was added, and the reaction was heated ay 80 for 1 hour. A further 1.5g potassium t-butoxide and 1.79 2-chloro-1-dimethylaminopropane were added and stirring and heating were continued for 2 hours. The reaction was diluted with toluene (50 ml) and washed with H20 and saturated NaCI. The amines were then extracted into dilute HCI, which was washed once with toluene, basified (litmus, conc NH4OH), and extracted with CHCI3.Evaporation of the CHCl3 yielded 5.85 g of an oil with numerous components (silica talc, EtOH/EtOAc 6:1). This oil was fractionated by silica flash-column chromatography, eluting with EtOAc/EtOH (progressively 12:1, 8:1, 5:1). The title compound ex-10e (1.0 9) was an oil. A hydrogen maleate salt was made and crystallized from ethyl acetate, mp 158-160" (dec), whose nmr and CHN analyses were consistent with the structure indicated.

f) [7-Chloro- 1 O-(2-dimethylaminopropyl)-2-phenothiazinyl]acetic acid (Compound ex-K) A solution of compound ex- 1Oe (0.4 9) in conc. HCI (10 ml) and H20 (10 ml) was heated on steam for 1 6 hours. Evporation of the solvent left a glassy residue which was dissolved in 2propanol and decolourised (charcoal). Cooling the solution yielded the HCI addition salt as a nearly colourless solid, mp 140 (dec). The melting (decomposition) point was difficult to reproduce, as it depended strongly on the rate of heating. The compound was a monohydrate, ex-1 OF. HCI. H20, whose CHN, nmr and mass spectral analyses, were correct for this formula and structure.

Example 11: [1 O-(2-Dimethylaminoethyl)- 7-methyl-2-phenothiazinyl]acetic acid. Compound M a) Ethyl 4'-(4-methylphenylthio)-3'-nitrophenyl acetate Compound ex- 1 la This was made by the method of Example 10c, except that 4-methylthiophenol was employed instead of 4-chlorothiophenol. The crude product compound ex-1 1 a, was a yellow solid mp 78-82", whose nmr spectrum was consistent with the proposed structure. It was taken for the next step without further purification.

b) Ethyl (7-methyl-2-phenothiazinyl)acetate. Compound ex-1 11 b This was synthesized from compound ex-1 la by the method of Example 10d. The column chromatography and recrystallization were also the same. The product, compound ex-1 1b, was a crystalline solid, mp. 189-192", whose nmr was consistent with the indicated structure.

c) Ethyl[10-(2-dimethylaminoethyl)-7-methyl-2-phenothiazinyl]acetate. Compound ex- 11 c. (Compound L).

This was prepared by the procedure of Example 1 or, using 2-dimethylaminoethyl chloride.

The free base was purified by flash column chromatography, eluting with EtOH/EtOAc (1:10).

The oil was converted to a hydrogen maleate salt and crystallized from EtOAc. This was a solid, compound ex-1 1c hydrogen maleate, mp 146-148", whose nmr spectrum and elemental analysis were consistent with the structure indicated.

d) [1 O-(2-Dimethylaminoethyl)- 7-methyl-2-phenothiazinyl]acetic acid. (Compound M) Compound ex-1 1c(O.5O g) was dissolved in 3.5 N HCI (14 ml) and heated on steam for 10 hours. After evaporation to dryness the residue was taken into 2-propanol and decolourized (charcoal) and then re-evaporated. The residue was rubbed with ether until a solid formed, which was partly purified by solution in methanol and addition of ethyl acetate and ether. This produced a yellow powder whose HPLC chromatogram indicated significant contamination.

Therefore it was purified by semi-preparative HPLC on a 10 mm by 50 cm. Spherisorb G.P. Ca8 column, with a Brownlee C16 guard column eluting with 40% MeOH + 0.1 % triethylamine and finally 100% MeOH + 0.1 % triethylamine. This yielded the title compound as a neutral solid, mp 127-132 (dec), whose nmr and CHN analysis and mass spectum were satifactory although at least one unidentified contaminant was still apparent (talc, nmr. and mass spectrum).

Example 12: [1 O-(2-Dimethylaminoethyl)- 7-fluoro-2-phenothiazinyl]acetic acid. (Compound N a) Ethyl 4'-(4-fluorophenylthio)-3'-nitrophenyl acetate. Compound ex 1 2a This was made by the method of example 1 or, using 4-fluorothiophenol. The crude product, compound ex-12a, was a yellow solid mp 41-48" whose nmr was consistent with the structure indicated and was used without further purification.

b) Ethyl (7-fluoro-2-phenothiazinyl)acetate. Compound ex 12b This was synthesized from compound ex-12a by the method of example 1O-d. The recrystallised product, compound ex-12b, mp 167-169", had an nmr consistent with the structure indicated.

c) Ethyl [10-(2-dieth ylaminoeth)-7-(2-diethylaminoethyl)-7-fluoro-2-phenothiazinyljacetate. Compound ex- 1 2c.

This compound was obtained as an oil by synthesis from compound ex-12b and 2diethylaminoethyl chloride by the method of example 1 Od and purified by flash column chromatography on silica eluting with ether. Its nmr and mass spectrum were consistent with the structure indicated.

d) [10-(2-diethylaminothyl)-7-fluoro-2-phenothiazinyl]acetic acid. Compound N Compound ex-12c (0.6 9) was suspended in a mixture of dioxane (3 ml) and 1N NaOH (6 ml) and the mixture was heated are reflux for 24 hours. This was evaporated, acidified with 1 N HCI (8 ml), and evaporated to dryness. The residue was digested with hot 2prnpanoI (30 ml).

Filtration and evaporation of solvent yielded the HCI salt of compound N as a resinous mass which failed to crystallize. It was therefore purified by HPLC using a 10mm X 10 cm Spherisorb G.P. (reverse-phase) C,8 column and a Brownlee C,8 guard column, eluting with 50% MeOH plus 0.1 % triethylamine. This yielded neutral compound N as a solid which, after recrystallization from ethyl acetate had mp = 141-143". Its CHN analysis, nmr, and mass spectrum were consistent with the structure indicated.

Example 1 3: 2-[1 O-(2-Dimethylaminopropyl)-2-phenothiazin ylj-2-methylpropionic acid Compound P a) 2-(4-Bromophenyl)-2-methylpropionic acid. Compound ex 1 3a The ethyl ester of the title compound had been prepared by the method described in J. Am.

Chem. Soc, 93, 6877-87 (1971). This ester (54.1g) was refluxed in a solution of ethanol (50 ml) and NaOH (40 9, in H20 (400 ml) for 5 hours. The mixture was cooled to ambient temperature, washed with pentane and then acidified with concentrated HCI (100 ml). This precipitated compound ex-13a as a white powder, mp 121-124", whose nmr was consistent with the structure indicated.

b) 2-(4-Bromo-3-nitropheyl)-2-methylpropionic acid. Compound ex- 1 3b This was obtained by nitration of compound ex 13a by the method of example 10a. The resulting compound ex-l3bwas a solid, mp. 167-71', whose nmr was consistent with the structure indicated.

c) Ethyl 2-(4-bromo-3-nitrophenyl)-2-methyl propionate. Compound ex- 1 3c.

This ester was obtained from compound ex-12b by the method described in example 10b.

The resulting compound ex-13cwas a solid which melted just above room temperature. Its nmr was consistent with the structure indicated, and it was used without further purification d) Ethyl 2-methyl-2-(3-nitro-4-phenylthiophenyl)propionate. Compound ex- 1 3d.

This synthesis was performed by the method of Example 10c using thiophenol and compound ex-13c. The product, compound ex-13d, was obtained in quantitative yield as a very viscous yellow oil which failed to solidify. Its tic was essentially homogeneous and its nmr was consistent with the structure indicated, so it was used without further purification.

e) Ethyl 2-methyl-2-(2-phenothiazinyl)propionate Compound ex- 1 3e This compound was made from compound ex-13d by the cyclization method of Example 1 Od and purified to apparent homogeneity (tlc, silica, hexane/ethyl acetate 10:1) by flash column chromatography. It did not crystallize, but its nmr was consistent with the structure indicated, and it was used without further purification f) Ethyl 2-[1 0-(2-dimethylaminopropyl)-2-methylpropionate. Compound ex- 1 3f. Compound 0.

This compound was synthesized from compound ex-13e by the alkylation reaction of Example 10e. The free base was an oil from which a crystalline salt was made and crystallized from ethylacetate/hexane, compound ex- 13F hydrogen maleate. H2O, mp 107-110'. Its CHN, nmr, and mass spectral analyses were consistent with the structure indicated g) 2-[1 O-(2-Dimeth ylamin opropyl)-2-ph en othiazin yl] 2-methylpropionic acid Compound P.

This was synthesized by base (NaOH) hydrolysis of compound ex-13f by the method of Example 12d. The crude HCI salt obtained after acidification, evaporation, and 2-propanol digestion was successfully solidified by rubbing with ether and then was recrystallised from methanol/ethyl acetate to yield compound P HCI mp 192-196" (dec), whose CHN, nmr, and mass spectral analyses were consistent with the indicated structure.

Example 14: 2-[1 O-(3-Dimethylaminopropyl)-2-phenothiazinylj-2-methylpropionic acid Compound. 0.

a) Ethyl 2-fl O-(3-dimethylaminopropyl)-2-phenothiazinylj-2-methylpropionate. Compound ex 14a.

Compound ex-13e (2.9 g) was dissolved in dry dimethylformamide (30 ml), followed by KOBut (1.13 g) and Lil (0.20 g). This was heated to 80 under N2, and 3-dimethylaminopropyl chloride (1.2 g, freshly released from its HCI salt) was added. After heating at 80 for 30 minutes another 0.24 g of KOBut and 0.7g 3-dimethylaminopropyl chloride were added followed 30 minutes later by a final 0.34 g of KOBut. After 30 more minutes the reaction was poured into water and extracted with CH2CI2. Upon evaporation the CH2CI2 yielded 4.3g of viscous oil which was flash-chromatographed on silica eluting with CH2CI2/MeOH, 96:4. This produced 2.8 g of compound ex-14a as an oil which was apparently homogeneous by tic and whose nmr spectrum was consistent with the structure indicated.

b) 2-[10(3-dimethylaminopropyl)-2-phenothiazinyl-2-methylpropionic acid Compound O This compound was prepared by base (1 N NaOH), hydrolysis of compound ex-14a by the method of Example 12d. The HCI salt crystallized from aqeous HCI as a hydrate, compound Q HCI. H2O, mp 128 (dec; the melting point was not reproducible, as it depended strongly on the rate of heating). The CHN, nmr and mass spectral analyses were consistent with the structure and formula indicated.

Example 15: Ethyl 2-methyl-2-f 1 O-f3-(N-pyrrolidino)propylj-2-phenothiazinyljpropionate. Compound R a) Ethyl 2-methyl-2-f 1 O-(3-bromopropyl)-2-phenothiazinyljpropionate. Compound ex- 1 5a Compound ex-13e(4.7g) was dissolved in 1,3-dibromopropane (25ml) and KOBut (1.6g) was added. The mixture was stirred at ambient temperature under N2 for 30 minutes and then was heated to 80 . After heating 30 minutes a further 1 .Og KOBut was added, and this addition was repeated one more time after heating another 30 minutes.After the last addition the reaction was heated another hour and then extracted between ether and H2O. The ether layer was evaporated and the residue was partially purified by column chromatography on silica gel, eluting with hexane/ethyl acetate (20:1). This yielded the target (compound (ex-15a)as an oil contaminated by a substantial amount of a faster-eluting compound, which was identified by nmr and mass spectrum as the olefin formed by elimination of HBr from Compound ex-15a. The mixture of compound ex 15a and its contaminant was characterised by its nmr and mass spectrum which were consistent with the structure indicated. Since the contaminant was expected to be innocuous in the subsequent reaction, the product mixture was taken for the next step without further purification.

b) Ethyl 2-methyl-2-[1 O-[3-(N-pyrrolidino)-propyl]-2-phenothia yl]propionate. Compound R.

Compound ex-15a (0.8g) and pyrrolidine (1.7g) were dissolved in ethanol (5ml), and the solution was allowed to stand at ambient temperature for 5 days. The mixture was then extracted between ether and dilute HCI and the ether was washed with more HCI. The combined HC1 solutions were then treated with excess NaOH and extracted with CH2CI2. The CH2CI2 was dried and evaporated and the residue was chromatographed on a short silica column, eluting with CH2CI2/MeOH (94:6). This produced Compound R as a clear viscous oil which was homogeneous by talc. Attempts to make a crystalline addition salt were unsuccessful, but the compound was characterized by its nmr and mass spectra, which were consistent with the structure indicated.

Example 16: O-(2-Dimethylaminopropyl)phenothiazin-2-yl-carboxylic acid (Compound S) A silver oxide suspension was prepared by dissolving silver nitrate (357 mg) in H20 (1.0 ml) and adding this to 1.00 g of Na OH solution (4.20 molal). To the resulting suspension was added ethanol (2 ml) and 10-(2-dimethylaminopropyl)phenothiazin-2-yl-carboxyaldehyde (300 mg). This suspension was stirred at ambient temperature for 10 minutes and then at 60 for 10 minutes. The warm suspension was filtered and the filtrate was partially evaporated, which caused precipitation of the sodium salt of the desired carboxylic acid. This was collected and converted to its HCI addition salt with excess conc HCI.The HCI salt was dissolved in ethanol from which it crystallized, yielding Compound S hydrochlorides as a solid m.p. 257-261" (dec).

Its mass spectrum and elemental analysis were consistent with the structure indicated.

Example 17: Antihistamine Activity A. In vitro antihistamine activity: The longitudinal muscle was isolated from the intact ileum of guinea-pigs (Hartley, male 250-400g) and placed in an organ bath under 300 mg tension.

After one hour of equilibration, cumulative concentration-response curves (Van Rossum, J.M., Arch. Int. Pharmacodyn. Ther. 143, 299-330, 1963) to histamine were obtained. Following washing, the tissues were incubated for one hour with the test compound and then a second histamine concentration-response curve was run. Shifts to the right of the agonist concentrationresponse curve produced by the antagonists were used to construct Schild plots (Arunlakshana, 0. and Schild, H.O., Br. J. Pharmacol. 14, 48-58 1959).Regression of Log (drug) on Log [B], where dr is an equiactive response in the presence and absence of antagonist and [B] is the molar concentration of antagonist, allowed and estimate of pA2, i.e. the negative log of the concentration of antagonist which shifts the control histamine concentration response curve 2X to the right.

Compound PA2 Promethazine 8.9* A 8.2 B 9.4 C 8.1 D 6.2 E 6.2 F 5.2 G 6.8 H 7.8 7.2 J 9.0 K 8.8 L 9.1 M 8.9 N 8.6 0 8.5 P 8.8 Q 8.7 S 9.0 *R.B. Barlow, Introduction to Chemical Pharmacology, 2nd ed, p 363, Wiley, New York, 1964.

B. In vivo Antihistaminic Activity: Guinea pigs (Hartley, male, 300-350 g) were fasted for 20 hours and then dosed p.o. or i.p. with the test compound. One hour after dosing, on an individual basis, the guinea pigs were placed in a clear plastic chamber which was saturated and continually gassed with 0.25% histamine from an aerosol nebulizer. The guinea pigs were monitored for signs of histamine anaphylaxis (e.g. cough, sneeze, strong abdominal movements, cyanoses or loss of righting). Under the rest conditions, control animals collapsed on average within 33 seconds. ED50,s for protection against histamine were calculated by probit analysis. In this test the ED50 indicates that at that particular dose 50% of the animals were completely protected against histamine challenge at the time of testing (1 hour post-dosing).Complete protection was defined as no histamine symptoms for six minutes in the aerosol chamber (approximately 10 x the collapse time of the control animals).

Table I: Results of Antihistamine Assays Compound ED50(mg/kg, p.o.) Tripolidine 5.77 A 1.7 B 0.3 (4 hours post dosing) In addition to these results, it was found that Compound A could provide very long durations of antihistaminic activity (e.g. 11 mg/kg p.o. is the ED50 for 24 hours protection).

Anaphylactoid Testing Procedure Non-fasted, Wister rats (180-3009) were dosed with the test compound, (i.p. or p.o.) 2 hours before compound 48/80 challenge. One hour prior to challenge, 5 mg/kg i.p. of propranolol was administered. The anaphylactoid inducing agent, compound 48/80, was given intravenously at 2 mg/kg and the animals were monitored for symptoms of respiratory distress.

Data were analyzed by Probit determinations. the response was quantitated by determining the dose of test compound which protected 50% of the animals from death at a given time point.

The above experimental design does not give positive results for selective antihistamines. Also rats do not respond to histamine (i.v.) with symptoms of anaphylaxis. Agents which block the effects of compound 48/80 are commonly classified as inhibitors of anaphylactic mediators or inhibitors of the release of anaphylic mediators.

Inhibition of Compound 48/80 Induced Anaphylactoid Reaction Compound ED50.

Ketotifen 0.87 A 2.64 B 0.89(1.2)" C 1.43 E 3.11 Astemizole 1.08 *Dose of compound (i p.) providing 50% protection against death induced by compound 48/80. Compound was administered 2 hrs. prior to test.

**ED60 by p.o. route.

Compound B (example 2) had an approximate LD50 in rats of 210 mg/Kg (i.p.) and greater than 500 mg/Kg (p.o) Example 18: Formulations (A)-Injection Ingredient Amount per ampoule Compound of formula (I) 1.0 mg Water for Injections, q.s. 1.0 mL The finely ground active compound was dissolved in the water for Injections. The solution was filtered and sterilized by autoclaving.

(B)-Suppository Ingredient Amount per suppository Compound of Formula (I) 1.0 mg Cocoa Butter, 2.0 g or Wecobee TM Base q.s.

Wecobee is a trademark and is a hydrogenated fatty carboxylic acid.

The finely ground active compound was mixed with the melted suppository base (either Cocoa Butter or Wecobee TM base), poured into moulds and allowed to cool to afford the desired suppositories.

(C)-Syrup Ingredient Amount Per mL Compound of Formula (I) 1.0 mg Ethanol 0.3 mg Sucrose 2.0 mg Methylparaben 0.5 mg Sodium Benzoate 0.5 mg Cherry Flavour q.s.

Colouring q.s.

Water q.s. to 5.0 mL Ethanol, sucrose, sodium benzoate, methylparaben, and flavouring were combined in 70% of the total batch quantity of water. Colouring and the active compound were dissolved in the remaining water, then the two solutions were mixed and clarified by filtration.

(D)-Tablet Ingredient Amount per Tablet Compound of Formula (1) 1.0 mg Lactose 110.Omg Corn Starch, Pregelatinized 2.5 mg Potato Tarch 12.0 mg Magnsium stearate 0.5 mg The active compound was finely ground and intimately mixed with the powdered excipients lactose, corn starch, potato starch and magnesium stearate. The formulation was then compressed to afford a tablet weighing 1 26 mg.

(E)-Capsule Ingredient Amount per Capsule Compound of Formula (I) 1.0 mg Lactose 440.0 mg Magnesium Stearate 5.0 mg The finely ground active compound was mixed with the powdered excipients lactose, corn starch and stearic acid and packed into gelatin capsules.

(F)-Capsule Ingredient Amount per Tablet Compound of Formula (I) 1.0 mg Pseudoephedrine HCI 60.0 mg Lactose 62.5 mg Potato Starch 14.0 mg Magnesium Stearate 1.0 mg Gelatin 2.8 mg A tablet was prepared from the above formulation by the method previously described in Example 11(D).

(G)-Syrup Ingredient Amount per 5 mL Compound of Formula (I) 1.0 mg Pseudoephedrine HCI 30.0 mg Codeine Phosphate 10.0 mg Guaifensin 100 mg Methylparaben 0.5 mg Sodium benzoate 0.5 mg Flavour q.s.

Colour q.s.

Glycerol 500 mg Sucrose 2000 mg Purified Water q.s. to 5.0 mL A syrup containing other active ingredients in addition to a compound of formula (I) was prepared from the above ingredients by an analogous method to that described for Example 11 (C) above.

(H)-Nasal Spray Ingredient Amount per 100.0 mL Compound of Formula (I) 1 g Sodium Chloride 0.8 g Preservative 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 the sodium chloride and the compound of formula (I) were added. The pH was then adjusted to 5.5-6.5 and purified water was added to bring the final volume to 100.0 mL.

(I)-Ophthalmic Solution Ingredient Amount per 100.0 mL Compound of Formula (I) O.lg Sodium Chloride 0.8 g Preservative 0.5 g Water for Injection q.s. 100.0 mL This formulation was prepared in a similar way to the nasal spray.

(J)-Topical Cream Ingredient Amount per 100.0 mL Compound of Formula (I) 0.1 g Emulsifying Wax, N.F. 1 5.0 g Mineral Oil 5.0 g Scheme 1

1. intrating agent, e.g. HNO3/H2SO4 at temperature of 0"-100"C conveniently 60"C.

2.

thiol

and base, e.g. sodium carbonate in a polar solvent such as an alcohol, e.g. methanol or ethanol at an elevated temperature, e.g. 50"-100"C conveniently at reflux.

3. 2 moles of P(OEt)3 in a high boiling hydrocarbon, for example n-propylbenzene at an elevated temperature, e.g. 1 25 -200 C conveniently at reflux.

Claims (34)

1. A compound of the formula (I).

or a salt, ester or amide thereof; wherein R1 is a C17 bivalent aliphatic hydrocarbon group or a single bond; R2 and R3 are the same or different and are each hydrogen, C14 alkyl or taken together with the nitrogen comprise a nitrogen-containing heterocyclic ring having four to six ring members; R4 is hydrogen, halogen, C14 alkoxy, C14 alkyl optionally substituted by one to three halogen atoms; or a group R, CO2H as hereinbefore defined; and A is C14 alkylene or ANR2R3 forms a group -CH2- or

2. A compound according to claim 1 of the formula (all):

or a salt, ester or amide thereof; wherein R1 to R4 and A are as defined in relation to formula (I).

3. A compound according to either claim 1 or 2 wherein R1 is a group (CH2)n wherein n is an integer 0 to 3, or a group CH = CH or a group CH(CH3)(CH2)m where m is O or 1 or a group -C(CH3)2.

4. A compound according to claim 3 wherein NR2R3 is a dimethylamino or diethylamino group.

5. A compound according to claim 4 wherein R4 is hydrogen, methyl, chloro or fluoro.

6. A compound according claim 5 wherein A is an ethylene or n- or iso-propylene group.

7. A compound of the formula (I) selected from: trans-ss-[1 0-2(2-dimethylaminopropyl)phenothiazin-2-yl]acrylic acid 2-[1 O-(2-dimethylaminopropyl)phenothiazin-2-yl]acetic acid 2-[1 0-(2-dimethylaminopropyl)phenothiazin-2-yl]propionic acid 10-(2-Dimethylaminopropyl)phenothiazine-3-carboxylic acid E-3-(2-Carboxyvi nyl)- 1 0-(2-d i methylaminopropyl)phenothiazine 3-(2-Carboxyethyl)-1 O-(2-dimethylaminopropyl)phenothiazine 1 0-(2-Dimethylaminopropylphenothiazine-4(or 1 )-carboxylic acid (E)-4(or I )-(2-Carboxyvinyl)-1 0-(2-dimethlaminopropyl)phenothiazine 4-(or 1 )-(2-Carboxyethyl)- 1 0-(2-d imethylaminopropyl)phenothiazine [7-Chloro- 1 0-(2-dimethylaminopropyl)-2-phenothiazinyl]acetic acid [1 O-(2-Dimethylaminoethyl)-7-methyl-2-phenothiazinyl]acetic acid (1 0-(2-Dimethylam i noethyl)-7-fluoro-2-phenothiazinylzacetic acid 2-( 1 O-(2-Dimethylaminopropyl)-2-phenothiazinyl]-2-methylpropionic acid 2-[ 1 0-(3-dimethylaminopropyl)-2-phenothiazinyl]2-methylpropionic acid 2-Methyl-2-[ 1 0-(3-(N-pyrrolidino)propyl]-2-phenothiazinyl]propionic acid 1 0-(2-Dimethylaminopropyl)phenothiazine-2-carboxylic acid or a salt, ester or amide thereof,

8. An analogy method for preparing compounds of the formula (I) according to claim 1, which comprises: a) When it is required to prepare a compound of the formula (I) where ANR2R3 is not CH2.The reaction of a compound of the formula (III)

or an ester thereof with an amine HNR2R3 wherein A and R1 to R4 are as hereinbefore defined and L is a leaving group; b) When it is required to prepare a compound of the formula (I) where R1 is (CH2)0 (i) the reaction of a compound of the formula (IV):

wherein R2, R3, R4 and A are as hereinbefore defined and R5 is a hydrogen or halogen atom, with a C16 alkyl lithium compound followed by treatment with carbon dioxide; (ii) the oxidation of a compound of the formula (V)::

wherein R2, R3, R4, and A are as hereinbefore defined, R1 is a single bond and B is hydrogen; c) When it is required to prepare a compound of the formula (I) wherein R1 is (CH2)a CH = CH(CH2)b) and a is 0 and b is O to 5 the reaction of a compound of the formula (V) as hereinbefore defined, with a Wittig reagent suitable for attaching the side chain CH = CH (CH2)bCOR6, wherein COR6 is an acid, ester or amide group as hereinbefore defined, followed by deprotection of the carboxy group if desired; d) When it is required to prepare a compound of the formula (I) wherein R1 is CH = CH, the reaction of a compound of the formula (V) as hereinbefore defined, with malonic acid or a malonic acid ester; e) the hydrolysis of a compound of the formula (VI)::

wherein R2 to R4 and A are as hereinbefore defined and R1 Z is a group R1 CN wherein R1 is a C17 bivalent hydrocarbon group, or a group R7-CH = C(Y)XH wherein R7 is a C16 bivalent hydrocarbon group or a single bond, X is oxygen or sulphur and Y is an amino group; f) the alkylation of a compound of the formula (VII): wherein R1 and R4 are as hereinbefore defined, COR6 is an ester or amide group; and thereafter, optionally converting one compound of the formula (I) to another compound of the formula (I) by methods well known to those skilled in the art, for example the reduction of one or more double bonds or de-esterification of.

an ester group or hydrolysis of an amide.

9. Novel chemical intermediates of the formula (III), (V), (Vl) and (VII).

10. A method of relieving the detrimental effects of histamine in a mammal comprising administering to said mammal an effective amount of a compound of formula (I) as described in claim 1.

11. A method of claim 10 wherein the mammal is human.

1 2. A method of claim 10 wherein a compound of formula (I) is selected from: trans--[ 1 O-2(2-dimethylaminopropyl)phenothiazin-2-yI]acrylic acid 2-[1 O-(2-dimethylaminopropyl)phenothiazin-2-yI]acetic acid 2-[1 0-(2-dimethylaminopropyl)phenothiazin-2-yl]propionic acid 1 0-(2-Dimethylaminopropyl)phenothiazine-3-carboxylic acid E-3-(2-Carboxyvinyl)-1 0-(2-dimethylaminopropyl)phenothiazine 3-(2-Carboxyethyl)-1 0-(2-dimethylaminopropyl)phenothiazine 1 0-(2-Dimethylaminopropyl)phenothiazine-4(or 1 )-carboxylic acid (E)-4(or 1 )-(2-Carboxyvinyl)- 1 O-(2-dimethylaminopropyl)phenothiazine 4-(or 1)-(2-Carboxyethyl)- O-(2-dimethylaminopropyl)phenothiazine [7-Chloro-1 0-(2-dimethylaminopropyl)-2-phenothiazinyl]acetic acid fizz inoethyl)-7-methyl-2-phenothiazinyl]acetic acid [10-(2-Dimethylaminoethyl)-7-fluoro-2-phenothiazinyl]acetic acid 2-[1 O-(2-Dimethylaminopropyl)-2-phenothiazinyl]-2-methylpropionic acid 2-Li O-(3-dimethylaminoprnpyl)-2-phenothiazinyl]2-methylprnpionic acid 2-Methyl-2-[i 0-[3-(N-pyrrolidono)-propyl]propionic acid 1 O-(2-Dimethylaminopropyl)phenothiazine-2-carboxylic acid or a salt, ester or amid thereof.

1 3. A method of cliam 10 wherein the compound of formula (I) is administered as hydrochloride salt.

1 4. A method of claim 10 wherein the compound of formula (I) is administered as the sodium salt.

15. A method of claim 10 wherein the compound of formula (I) is administered as the ethyl ester.

1 6. A method or relieving in a mammal the detrimental symptoms caused by histamine release comprising administering to said mammal the compound of formula (I) as described in claim 1.

1 7. A method of claim 16 wherein the mammal is a human.

1 8. A method of claim 1 6 wherein a detrimental symptom is nasal allergy.

1 9. A method of claim 1 6 wherein a detrimental symptom is perennial rhinitis.

20. A method of claim 1 6 wherein a detrimental symptom is urticaria.

21. A method of claim 1 6 wherein a detrimental symptom is antioneurotic oedema.

22. A method of claim 1 6 wherein a detrimental symptom is allergic conjectivitis.

23. A method of claim 1 6 wherein a detrimental symptom is food allergy.

24. A method of claim 1 6 wherein a detrimental symptom is drug and serum reactions.

25. A method of claim 1 6 wherein a detrimental symptom is insect bites and stings.

26. A method of claim 1 6 wherein a detrimental symptom is desensitising reactions.

27. A pharmaceutical composition comprising a compound of formula (I) as described in claim "1.

28. A pharmaceutical composition as claimed in claim 27 in unit dosage form.

29. A pharmaceutical composition as claimed in claim 28 characterized by being in the form of a tablet, syrup, suppository or sterile aqueous preparation.

30. A pharmaceutical compositions as claimed in claim 27 wherein the compound of formula (I) as defined in claim 1 is combined with a therapeutic ingredient.

31. A pharmaceutical composition as claimed in claim 27 in which the compound of formula (I) is selected from: trans-fl-[1 0-2(2-dimethylaminoprnpyl)phenothiazin-2-yl]acrylic acid 2-[ 1 O-(2-di methylaminopropyl phenothiazin-2-yl]acetic acid 2-Li O-(2-dimethylaminopropyl)phenothiazin-2-yljpropionic acid 1 O-(2-Dimethylaminopropyl)phenothiazine-3-carboxylic acid E-3-(2-Carboxyvinyl)- 1 O-(2-d imethylaminopropyl)phenothiazine 3-(2-Carboxyethyl)- 1 O-(2-dimethylami nopropyl)phenothiazine 1 O-(2-Dimethylaminopropyl)phenothiazine-4(or 1)-carboxylic acid (E)-4(or 1 )-(2-Carboxyvinyl)-1 O-(2-dimethylaminopropyl)phenothiazine 4-(or 1 )-(2-Carboxyethyl)- 1 O-(2-d imethlaminopropyl)phenothiazine [7-Chioro- I O-(2-dimethylam inopropyl)-2-phenothiazinyl]acetic acid Li O-(2-Dimethylaminoethyl)-7-methyl-2-phenothiazinyl]acetic acid [10-(2-Dimethylaminoethyl)-7-fluoro-2-phenothiazinyl]acetic acid 2-Li O-(2-Dimethylaminopropyl)-2-phenothiazinyl]-2-methylpropionic acid 2-Li 0-(3-dimethylaminopropyl)-2-phenothiazinyl]2-methylpropionic acid 2-Methyl-2-[1 O-[3-(N-pyrrolidino)propyl]propionic acid 10-(2-Dimethylaminopropyl)phenothiazine-2-carboxylic acid or a salt, ester or amide thereof.

32. A pharmaceutical composition of claim 28 in which the unit dosage form comprises 0.25 mg to 20 mg of a compound of formula (I).

33. A pharmaceutical composition as claimed in claim 27 together with one or more pharmaceutically acceptable carriers thereof.

34. A pharmaceutical composition as claimed in claim 27 together with other therapeutic ingredinets.