US2941999A - Phenthiazine derivatives - Google Patents

Phenthiazine derivatives Download PDF

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Publication number
US2941999A
US2941999A US633395A US63339557A US2941999A US 2941999 A US2941999 A US 2941999A US 633395 A US633395 A US 633395A US 63339557 A US63339557 A US 63339557A US 2941999 A US2941999 A US 2941999A
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phenthiazine
solution
mixture
methoxycarbonyl
benzene
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Jacob Robert Michel
Robert Jacques Georges
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Rhone Poulenc SA
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Rhone Poulenc SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/18—[b, e]-condensed with two six-membered rings

Definitions

  • N R2 (I) and their salts and their quaternary ammonium derivatives (wherein X represents a sulphur atom or an S0 or SO; group, R represents an alkyl group containing not more than four carbon atoms, R and R are the same or different and either each represents a lower alkyl group or one of R and R represents a hydrogen atom and the other represents a lower alkyl group or R and R together with the adjacent nitrogen atom collectively represent a heterocyclic group such as pyrrolidino, piperidino, morpholino, piperazino or 4-alkylpiperazino, and B represents a straight or branched chain divalent aliphatic hydrocarbon group containing 2 to 5 carbon atoms unsubstituted or substituted by a group wherein A represents a single bond or -CH and R and R are as hereinbefore defined) have useful pharmacological properties.
  • R1 BN/ is (OH:)aN(CHz): or CH:-CHCHr-N(0Hl)a Rn I H;
  • Those derivatives in which the chain B carries another amino group are particularly interesting as spasmolytics and local anaesthetics, and of particular importance are those compounds in which the group B is Compounds of outstanding utility and having the aforesaid chain groupings are: 3-n1ethoxycarbonyl-10-(3-dimethylaminopropyl)phenthiazine, 3-methoxycarbonyl-10- (2-methyl-3-dimethylaminopropyl)phenthiazine, 3-methoxycarbonyl 10 (3 pyrrolidiiiopropyl)phenthiazine, 3- methoxycarbonyl 1O (2 methyl 3 .pyrrolidinopropyl) phenthiazine, 3 ethoxycarbony-l 10 (3 dimethylaminopropyl) phenthiazine, 3 butoxycarbonyl 10 (3 dimethylaminopropyl)phenthiazine, 3 methoxycarbonyll0- (2 diethylaminoethy
  • lower alkyl as used in this specification and in the appended claims means that the alkyl group contains not more than five carbon atoms.
  • the new phenthiazine compounds of the present invention may be prepared in a number of different ways.
  • Hal-B-N R, 111) (where Hal represents a halogen atom and the other symbols are as hereinbefore defined).
  • the reaction may becarried out with or without a $01? vent in the presence or absence of a condensing agent. It is advantageous to operate in an aromatic hydrocarbon solvent (for example, toluene .or xylene) in the presence of a condensing agent, preferably in the form of an alkali metal or derivative thereof (such as, for example, hydride, amide, hydroxide, alcoholate or metal alkyl or ml) and especially metallic. sodium, sodarnide, powdered. sodium or potassium hydroiiide, lithium hydride, sodium tertbutylate, butyllithium. and phenyllithium.
  • the reaction is preferably carried out at the boiling temperature of the.
  • halogenoamine in the form of the free base in solution, for example, with benzene, toluene or xylene, and to add this to.
  • the reaction may also be carried out using a salt of the halogeno'amine but in this case a greater proportion of the condensing agent must clearly be used in order to neutralise the acid of the salt employed.
  • divalent aliphatic hydrocarbon group -B-- is an asymmetric branched chain, such for example, as
  • orn-'em-cn isomerisation can take place during the course of the reaction.
  • This isomerisation is analogous to that which takes place in the preparation of promethazine by the condensation of phenthiazine with a dimethylaminoha-logenopropane [Charpentien C. R. 225, 306 (1947)], which gives with Z-dimethylamino-l-chloropropane or with 1-dimethylamino-Lchloropropane as starting material the same final mixture in which promethazine predominates.
  • the reaction can be etfected with the phenthiazine-lO- carboxylate alone, i.e. without a diluent, 'or'in an inert medium such as liquid parafiin, diphenyl or diphenyl oxide, or in the classical diluents for deoarboxylation, such, forexample, as quinoline or weak bases with a sufliciently high boiling point, or in solution in a chlorinated aromatic compound, such as .o-dichlorobenzene.
  • an isomerisation similar to that hereinbefore described in process (1), takes place when the divalent aliphatic hydrocarbon group B is an asymmetric branched chain and a mixture of isomers is obtained. Separation of the isomers may be effected by, for example, fraction-a1 crystallisation of salts such as the hydrochlorides from a suitable solvent such as alcohol.
  • the phenthiazine-lO-carboxylates employed as starting materials may be. obtained by known methods; For example, they may be prepared by the action of a halide (or an ester). of a 3-alkoxycarbonylphenthiazine 10-carboxylic acid. on the. appropriate aminoalcohol;v or by the action of a, halogenoalkyl ester of such an acid on an appropriate amine.
  • optically active forms include within its scope the racemates as well as the" corresponding optically active isomers of such compounds.
  • the optically active isomers may beobtained by methods (1) and (3) described aboveby commencing with starting materials which are themselves optically active. They may also. be prepared by resolution of the corresponding racemates.
  • the bases of general Formula I are preferably'employed in the form of acid addition salts containing pharmaceutically acceptable anions (such as hydrochlorides and other hydrohalides, 8-chlorotheophyllinates, phosphates, nitrates, sulphates, maleates, fumarates, citrates, tartrates, oxalates, methanesulphonates and ethanedisulphonates) or of quaternary ammonium salts obtained by reaction with organic halides (cg. methyl or ethyl iodide, chloride or bromide or ally l or benzyl chloride or bromide) or other reactive esters.
  • pharmaceutically acceptable anions such as hydrochlorides and other hydrohalides, 8-chlorotheophyllinates, phosphates, nitrates, sulphates, maleates, fumarates, citrates, tartrates, oxalates, methanesulphonates and ethane
  • the melting points are those determined on the Kofier bench.
  • Example I Sodamide 2.25 g.) is added to a boiling solutionof 3-methoxycarbonylphenthiazine (12.85 g.) (Baltzly R., Harfenist M., Webb, F. 1.4-].
  • a xylene solution (186 cc.) containing 3-dimethylamino-1-chloropropane (6.68 g.) is then run in over 20 minutes and heating under reflux is continued for a further 16 hours.
  • the mixture is agitated with 2 N hydrochloric acid (200 cc.) and ether cc.).
  • the ethereal layer is separated and the aqueous layer is extracted with ether (200, 100 and 100 cc. successively).
  • the aqueous layer is separated, treated with 4 N sodium hydroxide cc.) and extracted with ether (200, 100 and 100 cc. successively).
  • the ethereal extracts are combined and dried over potassium carbonate and ether is removed on the water-bath.
  • Example II Sodamide (95 3.06 g.) is added to a boiling solution of 3-methoxycarbonylphenthiazine (20.0 g.) in anhydrous xylene (250 cc.) and the mixture is heated under reflux for 1 hour.
  • a solution of 1-chloro-2-methyl-3-dimethyl aminopropane (10.2 g.) in anhydrous xylene (30 cc.) is then run in over 15 minutes, and heating under reflux is continued for 20 hours. After cooling, the mixture is agitated with water (100 cc.) and 4 N hydrochloric acid (40 cc.).
  • the xylene phase is decanted and the aqueous phase, in which the hydrochloride has crystallised, is diluted with water (1 litre) and made alkaline while. hot with 4 N sodium hydroxide (60 cc.).
  • the base which'precipitates is extracted with ether, the corn:
  • Example III A solution of 3-methoxycarbonyl phenthiazine (15 g.) in anhydrous xylene (200 cc.) is heated to 115 C.; 95 sodamide (2.45 g.) is added and the mixture is heated under reflux for 10 minutes. A solution of 1-chloro-3- pyrrolidinopropane (9.3 g.) in anhydrous xylene (75 cc.) is then added and refluxing is continued for hours. After cooling, the reaction liquors are washed with water (2 x 300 cc.) and the xylene layer is separated, dried over anhydrous potassium carbonate and concentrated to dryness at 100 C. under a pressure of 20 mm. Hg. The residual oil is dissolved in boiling n-heptane (500 cc.) and the solution is cooled to C. and separated from the resin which has precipitated.
  • the heptane solution is passed over a column of alumina (200 g.) for chromatography and is eluted with 10 fractions of n-heptane (250 cc.). The filtrates from the elution are combined and the solvent is evaporated.
  • the purified base (6.4 g.) is converted into an acid oxalate in acetone and, after recrystallisation from methanol, there is obtained 3-methoxycarbonyl-10-(3-pyrrolidinopropyl)phenthiazine acid oxalate (5 g.) as a pale yellow crystalline powder, M.P. 176 C. i
  • Example IV Proceeding as in Example HI but replacing the l-chloro- 3-pyrrolidinopropane by 1-chloro-2-methyl-3-pyrrolidiriopropane (10.2 g.), the residual oil (20 g.) remaining from the evaporation of the xylene is dissolved in a boiling mixture (500 cc.) of equal parts of cyclohexane and petroleum ether (B.P. 35 C. to 50 C.). The solution is cooled to 5 C. and the solid resins which have precipitated are filtered 01f.
  • Example V A solution of 3-ethoxycarbonylphenthiazine (13.6 g.) in anhydrous xylene (200 cc.) is heated to 100 C.; 95% sodamide (2.25 g.) is added and the mixture is heated under reflux for 5 minutes. A solution of l-chloro- B-dimethylaminopropane (6.7 g.) in anhydrous xylene (180 cc.) is then poured in over minutes, and refluxing is continued for 2 hours. After cooling, the reaction mixture is diluted with ether (100 cc.) and shaken with hydrochloric acid (about 0.8 N, 125 cc.).
  • aqueous acid phase is separated, washed with ether (3 x 400 cc.) and made alkaline with 4 N sodium hydroxide solution (30 cc.) and the liberated base is extracted with ether (400 cc.).
  • the ethereal phase is dried over anhydrous carbonate and the solvent is removed at ordinary pressure and then under a pressure of mm. Hg with heating on the water-bath.
  • the residual oil (8.5 g.) is dissolved in a mixture (425 cc.) of cyclohexane and benzene (3:7); the solution is passed over a column of alumina (160 g.) for chroma- 6 tography and the adsorbed product is eluted successively with benzene (1400 cc.) and a mixture (900 cc.) of benzene and ethyl acetate (9:1).
  • the filtrates from the elution are combined, the solvent is evaporated and the purified base obtained is converted into the acid maleate in ethyl acetate.
  • the initial 3-ethoxycarbonylphenthiazine, M.P. 152 C. is prepared by the esterification of phenthiazine-3-carboxylic acid with ethanol in the presence of sulphuric acid.
  • the aqueous acid phase is separated and made alkaline with 4 N sodium hydroxide solution (30 cc.) and the liberated base is extracted with ether (200 cc.).
  • the ethereal phase is dried over anhydrous potassium carbonate and the solvent is removed at ordinary pressure and finally at C. under a pressure of 20 mm. Hg.
  • the residual oil 12 g.) is dissolved in a mixture (600 cc.) of equal parts of cyclohexane and benzene, the solution is passed over a column of alumina (240 g.) for chromatography and the adsorbed product is eluted successively with benzene (1000 cc.), 2% ethyl acetate in benzene (1500 cc.), 5% ethyl acetate in benzene (750 cc.) and 10% ethyl acetate in benzene (500 cc.).
  • the initial 3-butoxycarbonylphenthiazine, M.P. 149 C., is prepared by the esterification of phenthiazine-3- carboxylic acid with n-butanol in the presence of sulphuric acid.
  • Example VII A solution of 3-methoxycarbonylphenthiazine-10-carbonyl chloride (32 g.) in anhydrous toluene 150 cc.) is heated to C. and diethylaminoethanol (23.4 g.) is added over 20 minutes. The mixture is then heated under reflux for 5 hours and, after cooling, is diluted with ether (150 cc.) and agitated with water (150 cc., cc., and 100 cc. successively).
  • the ethereal solution is dried over anhydrous potassium carbonate and the solvent is removed on the water-bath.
  • The. brown residual oil comprising crude Z-diethylaminoethyl-3-methoxycarbonylphenthiazine 10 carboxylate is dissolved in o-dichlorobenzene (220 cc.) and the solution is heated between -170" C. until the evolution of carbon dioxide has ceased, that is for about 1% hours.
  • the mass is treated with ether (530 cc.) and agitated with 3 successive amounts of 0.35 N (approx) hydrochloric acid (total 450 cc.).
  • the aqueous acid phases are combined, washed with ether (200 cc.) and made alkaline with 4 N sodium hydoxide solution (45 cc.) and the liberated base. is extracted with ether (400 cc.) in four lots.
  • the ethereal phase is dried over anhydrous potassium carbonate and the solvent is re moved' on-the Water-bath.
  • the residual oil (22 g.) is dissolved in petroleum ether (250 00., B1. 3550 C.), the solution is passed over a column of alumina (250 g.) for chromatography andthe adsorbed product is eluted successively with petroleum ether, cyclohexane and benzene.
  • the filtrates from the elution are combined and concentrated to dryness and the base thus purified (15.7 g.) is converted into the hydrochloride in acetone by the addition of ethereal hydrogen chloride.
  • the initial 3 methoxycarbonylphenthiazine 10 carbonyl chloride, M,P. 145-147 C., is obtained by the action of phosgene on 3-methoxycarbonylphenthiazine in toluene in the presence of pyridine at room temperature.
  • Example VIII A solution of 3-methoxycarbonylphenthiazine-10-carbonyl chloride (32 g.) in anhydrous toluene (150 cc.) is heated to 90 C.; l-diethylamino-2-propanol (26.2 g.) is run in over 35 minutes and the mixture is then heated for hours under reflux. Proceeding as in Example VII,- there is isolated a brown oil (31.3 g.) comprising crude 3- diethylamino-2-propyl 3-methoxycarbonylphenthiazine-lO-carboxylate, the hydrochloride of which prepared in acetone by the addition of ethereal hydrogen chloride melts at 187190 C.
  • Example VII A solution of the above oil (26.5 g.) in o-dichlorobenzene (140 cc.) is heated between 165-180 C. until the evolution of carbon dioxide ceases, that is for about 1 /2; hours. Proceeding as in Example VII there is obtained a crude base (21.4 g.) which is dissolved in petroleum ether (25 0 cc., B.P. 35-50 C.). tion is passed over a column of alumina (250 g.) for chromatography and the adsorbed product is eluted successively with petroleum ether, cyclohexane and mixtures of cyclohexane and benzene.
  • Example IX A solution of 3-methoxycarbonylphenthiazine-IO-carbonyl chloride g.) in anhydrous toluene (150 Co.) is heated to 90 C.; a solution of 3-(4-methylpiperazinyl) propanol (14.4 g.) in anhydrous toluene (50 cc.) is run in over '15 minutes and the mixture is then heated under reflux for 4 hours.
  • Example VII there is isolated a brown oil g.) comprising crude 3 (4 methylpiperazino)propyl 3 methoxycaronylphenthiazine-10-carboxylate, the dihydrochloride of which, prepared in ethanol by the addition .of ethereal hydrogen chloride, melts at about 235240 C.
  • the brown oil (14 g.) is heated between 170-210 C. until the evolution of carbon dioxide ceases, that is for about 45 minutes.
  • Example VII On cooling and proceeding asin Example VII, there is obtained a thick oil (7 g.) which is dissolved in a mixture (350 cc.) of cyclohexane and benzene (7:3
  • the solution is passedover a column of alumina (140 g.) for chromatography and the adsorbed product is eluted with benzene (10 x 250 cc.) and then twice witha mixture of benzene and ethyl acetate (9:1).
  • methoxycarbonyl 10 (3 a 4' methylpiperazinopropyl)-phenthiazine dihydr ochloride (0.8 g.) as a yellow crystalline powder, M.P. about 215 C.
  • Example X A solution of 3 methoxycarbonylphenthiazine 10 a carbonyl chloride (32 g.) in anhydrous toluene (50 cc.) is heated to C; l:3-bis-dimethylamino-Z-propanol (14.6 g.) is run in over 15 minutes and the mixture is then heated under reflux for 4 hours. Proceeding as in Example VII there is isolated a brown oil (27.6 g.) comprising crude 1:3-bis-dimethylamino-2-propyl 3-methoxycarbonylphenthiazine-10-carboxylate. After purification through the ditartrate prepared in ethanol, there is obtained the purified base (21.7 g.) which crysta1 lises slowly and melts at 102106 C.
  • Example XI Into a solution of ,3-methoxycarbonyl-10-( 3-dimethylaminopropyl)-phenthiazine (5.13 g.) in glacial acetic acid (25 cc.) at 30 C. there is run in over A hour a solution of pure sulphuric acid (2.1 g.) in acetic acid (25 cc.) followed by a solution of 32.6% hydrogen peroxide (3.95 cc.) in acetic acid (6 cc.). The mixture is then heated for 15 hours at 60 C. After cooling, the reaction mixture is poured into iced water (300 cc.) and made alkaline with sodium hydroxide solution (d: 1.33, 115 cc.).
  • the precipitated base is extracted with ethyl acetate (3 x 100 cc.) and the combined organic extracts are dried over anhydrous potassium carbonate and evaporated to dryness on the water-bath.
  • the crude base obtained is. recrystallised from isopropanol. There is thus obtained 3 methoxycarbonyl-9:9-dioxy-10-(3-dimethyk aminopropyl)phenthiazine (2.6 g.) as creamy white crystals, M.P. 116-118 C.
  • Example Xll Preceeding as described in Example XI but commencing with 3 methoxycarbonyl l0 (2 methyl 3 dimethylaminopropyl)phenthiazine (4.98 g.), there is obtained a crude oily base (4.3 g.). This base is dissolved in ethanol (35 cc.) and a 5 N ethereal solution (2.2 cc.) of dry hydrogen chloride is added. There is thus obtained 3 methoxycarbonyl 9:9 dioxy 10 (2 methyl 3 dimethylarninopropyl)phenthiazine hydrochloride (3.9 g.) as white crystals, M.P. about 150 C. with decomposition.
  • R represents an alkyl group containing up to four carbon atoms
  • R and R are selected from the class consisting of methyl and ethyl groups and groups which with the adjacent nitrogen atom collectively represent pyrrolidino, piperidino, morpholino, piperazino and 4- mcthyl piperazino groups
  • B is a member of the class consisting of straight and branched chain divalent saturated aliphatic hydrocarbon groups containing 2 to 5 carbon atoms and acid addition salts thereof formed with pharmaceutically acceptable anions.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
US633395A 1956-01-10 1957-01-10 Phenthiazine derivatives Expired - Lifetime US2941999A (en)

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US (1) US2941999A (enrdf_load_stackoverflow)
BE (1) BE554020A (enrdf_load_stackoverflow)
CH (2) CH355147A (enrdf_load_stackoverflow)
DE (1) DE1059460B (enrdf_load_stackoverflow)
GB (1) GB808239A (enrdf_load_stackoverflow)
NL (1) NL96990C (enrdf_load_stackoverflow)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3435114A (en) * 1965-11-08 1969-03-25 Mead Johnson & Co Topical antihistaminic compositions containing methdilazine sulfoxide
US4705854A (en) * 1984-05-31 1987-11-10 Burroughs Wellcome Co. Phenothiazine compounds

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ206458A (en) * 1982-12-02 1987-07-31 Wellcome Found Phenothiazine derivatives and pharmaceutical compositions
US4634699A (en) * 1983-11-30 1987-01-06 Burroughs Wellcome Co. Branched chain phenothiazine
US4681878A (en) * 1985-07-26 1987-07-21 Burroughs Wellcome Co. Fluoropheno-thiazine and pharmaceutical use

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2789978A (en) * 1954-07-15 1957-04-23 Rath Stephen Dimethylaminopropyl-dipyridothiazane

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE910301C (de) * 1950-12-21 1954-04-29 Rhone Poulenc Sa Verfahren zur Herstellung von neuen Phenthiazinderivaten
CH298685A (fr) * 1951-06-28 1954-05-15 Rhone Poulenc Chemicals Procédé de préparation d'un nouveau dérivé de la phénothiazine.
BE529656A (enrdf_load_stackoverflow) * 1953-04-10

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2789978A (en) * 1954-07-15 1957-04-23 Rath Stephen Dimethylaminopropyl-dipyridothiazane

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3435114A (en) * 1965-11-08 1969-03-25 Mead Johnson & Co Topical antihistaminic compositions containing methdilazine sulfoxide
US4705854A (en) * 1984-05-31 1987-11-10 Burroughs Wellcome Co. Phenothiazine compounds

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GB808239A (en) 1959-01-28
BE554020A (enrdf_load_stackoverflow)
CH355148A (fr) 1961-06-30
DE1059460B (de) 1959-06-18
CH355147A (fr) 1961-06-30
NL96990C (enrdf_load_stackoverflow)

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