US2776971A

US2776971A - Chlorophenotffiazinecarboxamides

Info

Publication number: US2776971A
Authority: US
Publication date: 1957-01-08
Anticipated expiration: 1974-01-08

Description

2,776,971 CHLOROPHENOTHIAZINECARBOXAMIDES ohn W. Cusic, Skkie, and Markus Zimmermann, Evanston, Ill., asslgnors, by mesne assignments, to G. D. Searle & Co., Skokie, 111., a corporation of Delaware No Drawing. Application February 14, 1955,

' Serial No. 488,110

9 Claims. (Cl. 260- 243) This invention is concerned with a new group of chlorophenothiazinecarboxamides and, more particularly, with the compounds of the basic structunal formula and the non-toxic salts thereof, wherein X is a halogen atom and preferably chlorine or fluorine, Alk 1s a lower alkylene radical separating the two nitrogen atoms attached thereto by at least two carbon atoms and NRR" is a member of the class consisting of dialkylamlno and nitrogen containing heterocyclic radicals which are attached to the group Alk through a nitrogen in the heterocycle.

In the foregoing structural formula the radical Alk represents a bivalent, saturated, aliphatic hydrocarbon radical derived from a straight or branched-chain hydrocarbon :and which includes radicals such asethylene,

propylene, butylene, amylene, hexylene and polymethylene radicals such as trimethylene, tetramethylene, pentamethylene,rand hexamethylene. The radicals R and R can represent such lower alkyl radicals as methyl, ethyl, straight and branched propyl, butyl, amyl, and hexyl radicals. The radical NRR" can also represent a nitrogen-containing radical such as a piperazino, N-(lower alkyl)piperazino, thiamorpholino, tetrahydroquinolino, and tetrahydroisoquinolino radical, but of special value for the purposes of this invention are heterocyclic radicals in which NR'R" represents pyrrolidino, piperidino, and morpholino radicals. p

p The organic bases of the foregoing type form pharmaceutically acceptable non-toxic salts with a variety of inorganic and strong organic acids including sulfuric, phosphoric, hydrochloric, hydrobromic, sulfamic, citric, ascorbic, and related acids. They also form quaternary ammonium salts with a variety of organic esters of sulfuric, hydrohalic and aromatic sulfonic acids. Among. such esters are methyl chloride and bromide, ethylchloride, propyl chloride, butyl chloride, isobutyl chloride, benzyl chloride and bromide, phenethyl bromide, naphthyl chloride, dimethyl sulfate, diethyl sulfate, methyl benzenesulfonate, ethyl toluenesulfonate, ethylene chlorohydrin, propylene chlorohydrin, allyl bromide, methallyl bromide, and crotyl bromide.

In U. S. Patent No. 2,627,517, issued February 3, 1953, one of us (John W. Cusic) described certain nonhalogenated basically substituted phenothiazineoarbox- :amides. It has now been found that by substitution of a halogen atom in the phenothiazine moiety of these amides there are obtained medicinally valuable products with a pharmacological spectrum of activities ditferent from that shown by the non-halogenated phenothiazinecarboxamides. Specifically, the compounds of this invention have a strong anti-emetic effect, a tranquilizing effect in cases of hyperirritability and of over-stimulation of the ethyl acetate using charcoal decolorization yields N-(y- 2,776,971 Patented Jan. 8 1 957 ice 2 central nervous system. Their eifect is directed specifically to the central nervous system and they do not share the activity of the previously described non-halogenated phenothiazinecarboxamides on the sympathetic nervous system. As an example, they'fail to show the potent inhibiting efiect of the action of acetylcholine on the intestine exhibited by the compounds of U. S. Patent No. 2,627,517.

The invention will be described more fully in conjunction with the following examples. However, it should be understood that these examples are given by way of illustration only and that the invention is not to be construed as limited in spirit or in scope by the details set forth. In these examples temperatures are given uncorrected in degrees centigrade and quantities of materials in parts by weight. i

Example 1 To a mixture of 60 parts of 2-chlorophenothiazine in 500 parts of toluene and 40 parts of vphosgene in parts of toluene, there are added gradually 32 parts of pyridine. After stirring at room temperature for 90 minutes, the temperature is slowly raised to 80 C. When the mixture has regained room temperature, 20 parts of phosgene in 50 parts of toluene are added and then, gradually, 16 parts of pyridine. The mixture is maintained at room temperature for 2 hours, after which it is gradually heated to C. and maintained at that temperature for 2 hours;

The mixture is then poured intoice water. The organic layer is washed repeatedly with Water and then dried over' To this solution of 2-chloro-l()-chloroformylphenothia- V zine there are added 37 parts of N,N-dimethylethylenedi-- amine and the reaction mixture is refluxed for 2 hours.

It is then cooled and extracted with dilute hydrochloricacid. This extract is rendered alkaline by addition of cold aqueous sodium hydroxide solution and extracted withether. The ether extract is dried over anhydrous sodium. sulfate, filtered and evaporated. On repeatedrecrystal-- lization from ethanol and benzene and then from ethanol and ether, the N-(fl-dimethylaminoethyl)-2-chloro-l0-- phenothiazinecarboxamide is obtained in very fine color--- less needles.

Treatment of an ether solution of this base with 1 molecular equivalent of hydrogen chloride in propanol' causes precipitation of a hydrochloride which, recrys tallized from a mixture of ethyl acetate and ethanol using charcoal clarification melts at about ZOO-201 C. This.

salt has the structural formula N o l o 0-Nn on2 21y(om)1 irol Example 2 To a solution of 56 parts of Z-chloro-lO-chloroformylphenothiazine in 990 parts of toluene are added 41 parts of N,N-dimethyltrimethylenediamine and the mixture is refluxed for 2 hours. it is then cooled and extracted with dilute hydrochloric acid. The extract is rendered alkaline with dilute sodium hydroxide solution and the dimethylamiuopropyl) 2 chloro l phenothiazinecarboxamide hydrochloride melting at 176477" C.

Example 3 A mixture of 56 parts of 2-chloro-l0-chloroforrnylphenothiazine and 46 parts of N,N-diethylethylenediamine in 800 parts of butanone is refluxed for 2 hours, concentrated to one-fifth of its original volume, diluted with ether and extracted with dilute hydrochloric acid. This acid extract is rendered alkaline by addition of dilute sodium hydroxide solution and extracted with ether. The ether solution is dried over anhydrous sodium sulfate, filtered and evaporated. The residue is dissolved in dry ethanol and one equivalent of hydrogen chloride in propanol is added. On concentration of the resulting mixture the hydrochloride separates as an oil. Repeated crystallization from acetone and a small amount of ethanol yields the hydrochloride of N-diethylarninoethyl- 2-chloro-l0phenothiazinecarboxamide melting at about ZOO-201 C.

Example 4 To a. solution of 11.9 parts of Z-chloro-l0-chloroformylphenothiazine in 120 parts of butanone are added 10.4 parts of N,N-diethyltrimethylenediarnine and the mixture is heated at reflux for 2 hours. 'It is then poured into ice water and the aqueous solution is washed with ether, rendered alkaline by addition of sodium hydroxide and extracted with ether. The ether extract is dried over anhydrous sodium sulfate, filtered and evaporated. The residue, containing the N(- diethylaminopropyl)-2- chloro-lO-phenothiazinecarboxamide, is taken up in ether and treated with one equivalent of hydrogen chloride in propauol. Recrystallized repeatedly from a mixture of alcohol and acetone using charcoal clarification, the hydrochloride melts at about 184-185" C.

Example 5 in Z-propauol yields a crystalline hydrochloride which,

recrystallized from butanone, melts at about l88-l90 C. The compound has the structural formula Example 6 A solution of 127 parts of 3-chloro-10-chloroformylphenothiazine and 110 parts of N-(fl-aminopropyD-pyrrolidine in 2000 parts of butanone is refluxed for 3 hours, concentrated to about 400 parts, diluted with ether and treated with aqueous hydrochloric acid. The aqueous layer is separated, washed with ether, rendered alkaline by the addition of dilute "sodium hydroxide solution and then extracted with ether. This extractis dried over anhydrous calcium sulfate, filtered and evaporated to yield A the yellowish oily N-(fl-pyrrolidinopropyl)-3chloro-l0- phenothiazinecarboxarnide. It has the structural formula N CHz-OH:

(llO-NEP-C H-O HI'N (3H3 CH2CH:

Example 7 A solution of 78 parts of 2-chloro-10-chloroformylphenothiazine and 33.4 parts of N-(fi-aminoethyumorpholine in 400 parts of butanone is refluxed for an hour and then poured into ice water. The aqueous solution is washed with ether, rendered alkaline with sodium carbonate, and then extracted with ether. This extract is dried over anhydrous potassium carbonate, filtered, treated with one equivalent of gaseous hydrogen chloride in 2-propanol, and evaporated. The residue is dissolved in ethanol, clarified with charcoal and then treated with ethyl acetate and concentrated to yield the hydrochloride of N (p morpholinoethyl) 2 chloro 10 phenothiazinecarboxamide melting at about 192193 C. The compound has the structural formula O 0NH-(CHz): 0

i OKs-C inn Example 8 13 parts of N-phenyl-4-fluoroanthranilic acid are heated to about 270 C. for minutes and then dissolved in ether. The ether solution is washed with 2-N sodium hydroxide and with water and then dried over anhydrous sodium sulfate. After evaporation of the ether the residue is distilled at about 0.05 mm. pressure and 70 C. to yield m-fluorodiphenylamine as a colorless oil. A mixture of 3.7 parts of this oil, 1.3 parts of sulfur and 0.1 part of iodine are heated at 180195 C. for an hour. The residue is sublimed in vacuum and then crystallized repeatedly from ethanol to yield Z-fiuorophenothiazine melting at about ZOO-201 C.

Reaction of this compound with phosgene in toluene by the method of Example 1 yields a toluene solution of 2-fiuoro-10-chloroformylphenothiazine. A solution of 5 3 parts of this compound and 69 parts of N-(6-aminobutyl)- diisopropylamine in 1000 parts of toluene is refluxed for 2 hours. It is then cooled and treated with dilute hydrochloric acid. The aqueous layer is separated, rendered alkaline with dilute sodium hydroxide and extracted with ether. This ether extract is dried over anhydrous sodium sulfate, filtered and evaporated to yield as a residue N (5 diisopropylaminobutyl) 2 fluoro 10 phenothiazinecarboxamide in the form of a yellow resin.

Example 9 By the procedure of the foregoing example 3-fluorophenothiazine is prepared which melts at about 176177 C. Substitution of 58 parts of this compound for the 2-chlorophenothiazine used in Example 1 yields the N (5 dimethylaminoethyl) 3 fluoro 10 phenothiazinecarboxamide in the form of a light orange resin.

What is claimed is:

1. A compound of the structural formula 6 wherein X is a halogen atom of an atomic weight less wherein Alk is a lower alkylene radical separating the than 40, Alk is a lower alkylene radical separating the two nitrogen atoms attached thereto by at least two two nitrogen atoms attached thereto by at least two carbon atoms and n is a positive integer less than 3. carbon atoms and NR'R" is a member of the class con- 7. A compound of the structural formula sisting of di-(lower)alkylamino, pyrrolidino, piperidino 5 and morpholino radicals.

2. A compound of the structural formula S\ v N CH2C z 01 lTT wherein Alk is a lower alkylene radical separating the two nitrogen atoms attached thereto by at least two carbon atoms.

3. A compound of the structural formula I| T CHZ-CHZ *01 o ONHAlk-'N 8. A compound of the structural formula 4. A compound of the structural formula wherein Alk is a lower alkylene radical separatlng the two nitrogen atoms attached thereto by at least two carbon atoms. \N 01 9. A compound of the structural formula CONH(CHz)2N(CH3)z 5. A compound of the structural formula CHa-C n OO-NH-(GH2)e-N(QH3)2 6. A compound of the structural formula References Cited in the file of this patent UNITED STATES PATENTS 2,627,517 Cusic Feb. 3, 1953 \N OH2 CHI 2,645,640 Charpentier July 1953 J0NH N FOREIGN PATENTS 1,060,715 France APL 5, 9

Claims

1. A COMPOUND OF THE STRUCTURAL FORMULA