GB789703A - New phenthiazine derivatives and processes for their preparation - Google Patents

New phenthiazine derivatives and processes for their preparation

Info

Publication number
GB789703A
GB789703A GB31671/55A GB3167155A GB789703A GB 789703 A GB789703 A GB 789703A GB 31671/55 A GB31671/55 A GB 31671/55A GB 3167155 A GB3167155 A GB 3167155A GB 789703 A GB789703 A GB 789703A
Authority
GB
United Kingdom
Prior art keywords
methyl
phenthiazinyl
methoxy
prepared
dimethylamino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
GB31671/55A
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Rhone Poulenc SA
Original Assignee
Rhone Poulenc SA
Societe des Usines Chimiques Rhone Poulenc SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rhone Poulenc SA, Societe des Usines Chimiques Rhone Poulenc SA filed Critical Rhone Poulenc SA
Publication of GB789703A publication Critical patent/GB789703A/en
Expired legal-status Critical Current

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention comprises the racemic and optically active phenthiazine derivatives of the formula: <FORM:0789703/IV (b)/1> and salts thereof, including their quaternary ammonium derivatives, wherein Y represents a sulphur atom or an > SO2 group, X represents a lower alkyl or lower alkoxy group, containing at most four carbon atoms, preferably in position 3 (Beilstein numbering), R1 is lower alkyl and R2 and R3 both represent lower alkyl groups or one of them represents hydrogen with the other being lower lower alkyl, or R2 and R3 together with the N atom form a mono-nuclear heterocyclic group, e.g. pyrrolidino, piperidino and morpholino. The above compounds are prepared by the following methods: (a) reacting phenthiazine (or its 9; 9 -dioxy derivative) carrying a nuclear X-substituent with a reactive ester Z,CH2,CHR1 CH2,NR2R3 or an acid addition salt thereof, Z being a halogen atom or the residue of a sulphuric or sulphonic ester; (b) condensation of an amine HNR2R3 with a phenthiazine (or 9 : 9-dioxy derivative) carrying a nuclear X-substituent and substituted at position 10 by -CH2,CHR1,CH2Z; (c) alkylation of the corresponding primary or secondary amines, e.g. by methylation with HCHO and hydrogen; (d) reduction of the corresponding compounds wherein the 10-substituent is -CH2 CHR1CONR2R3 or -CH2CHR1CH2N(R2) COR4, (CH2R4 represents R3); (e) reduction in the presence of an amine HNR2R3 of the corresponding phenthiazine derivative wherein the 10-substituent is -CH2CHR1T, (T being -CN or -CHO); (f) cyclization of compounds of the formula: <FORM:0789703/IV (b)/2> in the presence of an alkali condensing agent (e.g. alkali metal hydroxide or carbonate), preferably in a solvent such as dimethyl formamide and in the presence of a dehydrohalogenation catalyst, e.g. copper powder; (g) the dioxophenthiazines are also prepared by oxidation of the corresponding phenthiazines. The optical isomers may be obtained by resolution of the racemates or by synthesis from optically-active starting materials or intermediates. The bases have therapeutic activity and are preferably employed as acid addition or quaternary ammonium salts, e.g. hydrohalides, 8-chlorotheophyllinates, and methiodides. In examples: (1) 3-ethylphenthiazine and sodamide are treated with 1 - dimethylamino - 2 - methyl - 3-chloropropane in xylene to give 3-(31-ethyl-101-phenthiazinyl) - 2 - methyl - 1 - dimethylaminopropane, characterized as the HCl salt; (2) to (7), similarly are prepared the corresponding 31-methyl, 31-methoxy-, 31-n-propyl- and 31-ethoxy derivatives and also 3-(31-ethyl-101-phenthiazinyl) - 2 - ethyl - 1 - dimethylaminopropane, and 3 - (31 - methoxy - 101 - phenthiazinyl) - 2 - methyl - 1 - pyrrolidinopropane; (8) 3 - (31 - methoxy - 101 - phenthiazinyl) - 2-methylpropyl toluene p-sulphonate is autoclaved with ethanol and dimethylamine giving 3 - (31 - methoxy - 101 - phenthiazinyl) 2 - methyl - 1 - dimethylaminopropane, (A); (9) optically active 3-(31-methoxy-101-phenthiazinyl) - 2 - methyl - 1 - aminopropane hydrochloride in methanol and aqueous HCHO is hydrogenated over Pt2O to give laevo-rotatory A; (10) as in (9) using the corresponding optically active 31-ethyl compound characterizing the product as its acid maleate; (11) 3-(31 - methoxy - 101 - phenthiazinyl) - 2 - methyl-1-methylaminopropane is alkylated as in (9) to A; (12) 3-(31-methoxy-101-phenthiazinyl) -2-methyl-1-methyl-formamidopropane is reduced with LiAlH4 in tetrahydrofuran to yield A; (13) as in (12), using optically active starting material; (14) 3 - (31 - methoxy - 101 - phenthiazinyl) - 2 - methyl - N : N - dimethylpropionamide is reduced as in (12) to A, also prepared (15) by hydrogenation over Pd-BaSO4 of 3-(31 - methoxy - 101 - phenthiazinyl) - 2 - methylpropionitrile in methanol containing dimethylamine; (16) oxidation of A in acetic acid containing H2O2 and H2SO4 gives 3-(31-methoxy-91 : 91 - dioxy - 101 - phenthiazinyl) - 2 - methyl-1-dimethylaminopropane, purified via its acid fumarate; (17) to (19) A is converted to its quaternary salt with benzyl bromide, its laevorotatory l-tartrate, and dextro-rotatory d-tartrate from which the optical isomers of the base are isolated; (20) 2-bromo-21-(3-dimethylamino - 2 - methylpropylamino) - 41 - methoxydiphenyl sulphide, dimethylformamide and potassium carbonate and refluxed with copper powder to yield A. The preparation of the following starting materials is described: 1-dimethylamino-2-methyl-3-chloropropane from SOCl2 and 3-dimethylamino - 2 - methylpropan - 1 - ol, itself prepared by reduction of 3-dimethylamino-2-methylpropionaldehyde; 1 - dimethylamino-2-ethyl-3-chloropropane hydrochloride by a similar method; 3-n-propylphenthiazine by Wolff-Kishner reduction of 3-propionylphenthiazine, which is obtained from n-propionyl chloride and 10-acetyl-phenthiazine; 3-ethoxyphenthiazine by cyclization of 3-ethoxydiphenylamine with sulphur; 3 - (31 - methoxy - 101 - phenthiazinyl)-2 - methylpropyl toluene - p - sulphonate by esterification of 3 - (31 - methoxy - 101 - phenthiazinyl) - 2 - methyl - 1 - propanol, prepared by LiAlH4 reduction of methyl 3-(31-methoxy-101 - phenthiazinyl) - 2 - methylpropionate (B), itself obtained from the corresponding nitrile by hydrolysis and treatment with diazomethane; optically active 3-(31-methoxy-101-phenthiazinyl) - 2 - methyl - 1 - aminopropane hydrochloride by LiAlH4 reduction of 3-(31-methoxy - 101 - phenthiazinyl) - 2 - methylpropionitrile, prepared from aqueous ethanolic KCN and 1-(31-methoxy-101-phenthiazinyl)-2-propyl toluene p-sulphonate, which is obtained from 3-methoxyphenthiazine by condensation with L-propylene oxide in presence of lithium, and esterification of the 1-(31-methoxy-101-phenthiazinyl)-isopropanol produced; optically-active 3 - (31 - ethyl - 101 - phenthiazinyl) - 2 - methyl-1-aminopropane is similarly prepared; 3 - (31 - methoxy - 101 - phenthiazinyl) - 2 - methyl-1-methylaminopropane is prepared by hydrolysis of 3 - (31 - methoxy - 101 - phenthiazinyl) - 2 - methyl - 1 - methylformamidopropane, itself prepared from the sodium derivative of 3-methoxyphenthiazine and 1-methylformamido-2-methyl-3-chloropropane, which is obtained from methyl 3-methylamino-2-methylpropionate by reduction with LiAlH4, treatment with formamide, and then SOCl2; optical isomers of methyl-3-methylamino - 2 - methylpropionate are produced by resolution with camphosulphonic acid; 3 - (31 - methoxy - 101 - phenthiazinyl) - 2 - methyl - N : N - dimethylpropionamide is prepared from dimethylamine and B; 2 - bromo-21 - (3 - dimethylamino - 2 - methylpropylamino)-41 - methoxydiphenyl sulphide from 2 - bromo-21 - amino - 41 - methoxydiphenyl sulphide and 3 - dimethylamino - 2 - methyl - 1 - chloropropane in the presence of sodamide. Specifications 608,208, 632,277, 673,005 and 701,741 are referred to.
GB31671/55A 1954-11-08 1955-11-04 New phenthiazine derivatives and processes for their preparation Expired GB789703A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
FR789703X 1954-11-08

Publications (1)

Publication Number Publication Date
GB789703A true GB789703A (en) 1958-01-29

Family

ID=9220219

Family Applications (1)

Application Number Title Priority Date Filing Date
GB31671/55A Expired GB789703A (en) 1954-11-08 1955-11-04 New phenthiazine derivatives and processes for their preparation

Country Status (2)

Country Link
CY (1) CY220A (en)
GB (1) GB789703A (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3063996A (en) * 1959-03-02 1962-11-13 Smith Kline French Lab Substituted piperidinylalkyl phenothiazines
US3240779A (en) * 1958-04-22 1966-03-15 Rhone Poulenc Sa Phenthiazine derivatives

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5377903A (en) * 1994-06-16 1995-01-03 International Paper Company Reduced warp paperboard tray

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3240779A (en) * 1958-04-22 1966-03-15 Rhone Poulenc Sa Phenthiazine derivatives
US3063996A (en) * 1959-03-02 1962-11-13 Smith Kline French Lab Substituted piperidinylalkyl phenothiazines

Also Published As

Publication number Publication date
CY220A (en) 1961-04-14

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