Patent Publication Number: US-3879551-A

Title: Phenthiazine derivatives in pharmaceutical compositions

Description:
1111. 3,879,55 1451 Apr.` 22,1197  
 1075.976 111965,11101`n11. .;1.v 26o/:13  
 PHENTHiA&#39;zlNgRI&#39;vAT/ES &#39;Pl&#39;j&#39;ihzp derivatiyes of theformula:  
 Int. CI.....  
 U.s.`fc1;...;...;....1.....;; A24/247;&#39;26o/247141&#34; Mosher 3.1941733 7/1965 Yale 26o/2` &#39;3,350,268 l0/I967 Yale ..260/2` Primary Emminr-Stanlejy J. Friedman An&#39;omey. Agent, or F ifm-Stevens. Davis, Miller &amp;  
 ABSTRACT 1 y y k&#39;,&#39;11 I1`11 1 111611127/00` --whe&#39;em R represents a&#34; al l l en) o&#39; d Vmld Search ..1 26o/243A; 4241247 liscrs. y  
  3 Claims. No Drawings This applicationfisa continuatoniapplication of our copendng application Ser. No; 49,192 now abandoned which itself is a continuation-in-partof ourcopendin g application Ser, No. 7 l7 ,0l2 ledfMaL 28. .1968.  
 This invention-relates&#39;to newfther&#39;apeutically useful 1 t `ihcfcordingtda furtherlfeatureof the invention. thi -Yl0V phenthiazne derivatives of formula larejprepared bj phenthiazine derivatives;toprocesses for&#39;their preparation and pharr&#39;nceutical&#39;compositions containing According-ftp ythe:l prcsent&#39;iinven&#39;tion. there are&#39;provided the new p formula:  
 wherein&#39; R.representsastiaighrr.baneheajiiikymke- 25 phonylox&#39;yfor toluene-pfsulphonyloxy residue)A with a defined.  
 When the symbol Xiepresentsa halogen atom.&#34;in  
 purticularchlorine. or an&#39;. imidazolyl` alkanoyloxy, alkenoyloxy or alkynoyloxyI group,A it is advantageous to carry out the process in an inertorganicsolvent (for ex# t ample benzene, toluene,` or chloroform and y&#39;preferably at thevb&#39;oiling point ofthsolvent employed inlthelabsence or presence of an inorganicl &#39;or :organic acidbinding agent.  
 enthi&#39;au&#39;zine..o&#39;fzthef&#39;4 ,Y &#39;aceordmggto theforegoing processesmaygbepurie `by,physical methods such&#39;as&#39;distillation.-fcrystallisatic presnis&#39;neaad@indium formula Ref-,CO-&#39;O Ofi-l- Rbeinglas hereinbefo re V y andjranquillsershey have given good results as sul 1 if &#34;T theproces&#39;s henthiazinederivatives A of the &#39;general n 2 t When the symbol X represents the hydroxy group the process is generally carried out in an inert organii solvent in thepresence of either a strong acid or a Lewis acid or of dieyclohexylcarbodiimide. V  
  I Whenjthe symbol Xrepresents anfalkox&#39;y group. thi processis generallycar&#39;ried outin an&#39;inert organic sol ventsuch` as toluene&#39;and the alcohol formed is remove( byaicotropiedistillation. l.  
  which comprises rcacting aphenthiazine o l yla&#39;lkalijinetai sul; or in acia&#39;nf the formula R-Cof-oi ablyfat&#39;th-elbilingpointofthe solventiemployed. j  
  orchrornatogr`aphy.`f or b&#39;yfchemical methods. such z the formationofsalts.: crystallisationfof the 4salts&#39;and di f&#39;o&#39;rnposition of them in anallaIinemedium; ln the sa I hemi4a11mfhlomthejnaiq-leofihe &#39;nippf the sali -fii&#39;nmaterial.&#39;the only&#39;f&#39;requirement being that the sa V.must.be&#39;jwellfdefined&#39;and readily crystallisable..  
 5o f acids l&#39;onthe new Y&#39;plien&#39;tltiziiief dertvativesin appr which may-.have a straightor `branched hydroeariponi;55`  
 k p rtat v entsifAs organic solvents theremay be use forfe VrnpleQalcoholsQethersl&#39;keitones or chlornat| liydi&#34; A arbons; 1 &#34;l`he&#39;salt which `ist&#39;ornied `is precipitate &#39;if ncessaryiaiter&#39;eoneentratin&#39;lotf&#39;its solution( and parated byltration ofdecantation.  
  The phe&#39;nthiazine derivatiifes of the present inventi interesting pharmacodyn&#39;aineproperties; they a &#39;veiy*&#39;acti&#39;vel as long-aeting &#39;rieuiio&#39;lepticsg antiemeti -in physiological experiments withanimals at doses 0.005 to 1.0 mgl/kg. of animal weight by subcutaneo olf-intramuscular administration. For example. t compounds of formula l have been found to have a pi 5 longed antagonistic; effect against ernesis caused apornbrphine in the&#39;dog. A subcutaneous dosage of o of thenewgcornpounds (as the free base) of 0.05 to rng.lkg`.reduces the number of vom its caused by subc 3,879,551 3 4 tuneous administration of 0.1 mg./kg. of apomorphine dimethylsulphamoyl-l0-{3-[4(2 r t l by 50 percent for from 10 to 50 days. The compounds lauroyloxyethyl)piperidinolpropyl} phenthiazineoxaof formulal have shown no toxic effects ut dosages at lute (13.1 gil.&#39; melting at about 130C. is obtained. t  
 least ushigh us 0.8 mgJkg. Preferred compounds ure Luuroyl chloride employed as starting material (b.p. 3-dmethylsulphumoyl-l0-{3-[4-(2- 5 l l0Cl2mm.l &#39;lg) is prepared according to H. Richet. pulmtoyloxyethyl)ppcrdinolpropy-phenthinzine. BulLSoc. ChimpFr.. (19461` 52. 3-dimethylsulphamoyl.10-{3[.4f(2undecl0&#39; I f l enoyloxycthyl)pperdino]propyl} phenthiuzine` 3- .gggmrevf phent&#39;hiaiine&#39;MJS hydroxyethyl)piperidinolpropy phenthiazine (3.3 g) t a concentration of 0.25 to l percent by weight.- and.  
 ` if necessary. subsequently sterilizing the solution obtained by filtration through a bacteriological filter.  
 The following Examples illustrate the preparation of pharmaceutical compositions according to the invention.  
 ` EXAMPLE xvm lauroylox&#39;yethyl)piperidino]propyl} phenthiazine oxalate (|70 mg.) is treated at ambient temperature with a mixture of a l&#39;percent aqueous solution of sodium bicarbonate&#39;( &#39;l lOcc.) and diethyl ether (50 cc.). After dissolution` the ethereal phase is decanted, washed with distilled water (2 X 50 cc.) until neutral. and then is reacted withjfl 2.2idimethylhexadecanoyl chloride44 (2.l3g`.)` in toluene (&#39;30 cc&#39;:.)`.1l &#39;The-:crude.&#39;productfis chromatographed through a column (115cm. in diarrie-V ter) of neutral alumina (40-g.)tan`d elut` ed with a mix-r f ture oflcyelohe&#39;xane and-ethyl ace&#39;t ate 8-2 by volume) The base&#34;`obtained afterchromatographyf(4.70 g..)&#39;lis dissolvedin refluxing ethyl)acetate-(125cc.) .and .then  
  2,Z-Dimethylhexadecanoyl *chloride ispreparedgby the dimethylhexadecanoie acid:  
  2.2Dimethylhe&#39;xadecanoic acid l&#39; isi-prepared Iaccording to Buu-Hoi et col|., Z-`Physiol.. Chem. 279` A84 Thefpresent inventionV includes within itsscope phari&#39; tained.  
 dried over anhydrous magnesium sulphate. After concentration&#39;undergreduced pre ssure&#34;(20&#39;mm. Hg.)` the residue |50 nig.) isdisslved in ses&#39;ame oil( l5 cc.) at 40C.`Aft er &#39;cooling to ambient temperaturelfa clear yellow&#39;v solution` containing l percent of 3- dimethylsulphanioyl-l0-{3[ 4-( 2 lauroyloxyfethyl)piperidinolpropyll phenthiazine is obenoyloxyethyl)pipcridino]propyl}phenthia2ine (2.5 g.)  
  is&#39;dis&#39;sfolved at 40C &#39;in neutraliser! sesame oil (|00 cc.) with&#39;jagitati&#39;on.;&#39;After&#39;cooling, the yellow solution ob- ,.tainedjisfilteredthrough a bacteriological filter under afnitrogen`pressureeof2-kgJcm The filtered solution c. ofsolution per ampoule. The filled ampoules are sealed undernitrogen.  
 .v ,.&#34;Theresultingampoules each contain |00 mg. of acmaceutical compositionscontaining. as active ingredi-V ent. atleast one of thephenthiazinederivatives of formula `l in association withajpharmaceutical carrier, or coating. The invention includes&#39;espccially such preparations made up for parenteral` inparticular intramus- Y as acttveingredient,a therapeutically acttve&#39;amount of a phenthiazine derivative of the formula:  
 cular or subcutaneous;administration(4 Y Preparations for parenteral administration `include sterile non-aqueous&#39;solutions&#39;.Examples 4of suitable non-aqueoussolvents are injectable vegetable oils, suchlas sesame oil or&#34; olive oil.` and injectablev organic esters such as ethyl oleate&#39;.;.|`he preparations maybe stcrilised by.for,example, filtration through abacteria` retaining filter, by incorporation inthe compositions of stc&#39;rilisingagcnts. by irradiatiomor by heating.) The percentage of active ingredient in the compositions of the inventlon may bc `vut-led. it&#39;belng necessary that |t should constitute u proportion auch vtltata sultable dosage shall be-obtained. The dosage depends `on the desired therapeutic&#39;effectand on the durationof the treatment. ln humanftherapy the composition should generally be administered so as to give an adult between 5 and |00 mg. ofactive substance at the rate of one intramuscular injection every-2 to&#39;4 weeks.;  
 Because of the prolonged anti-emetic effectl of the new phenthiazine derivatives mentioned above. it is often desirable to administer the compounds by intra- Y muscular or subcutaneous injection as depot preparations. Such preparations may be made by conventional methods, e.g., by dissolving the new bases vof formula l in an injectable water-insoluble vegetable oil,` e.g.` in  
 fusing pa|mito loxyethyl)piperidinolpropyphenthiazine. E mp. 6| -62C., ampoules are obtained each containing tiveprfoduct readyfor intramuscular administration.  
 &#39; ExAMPLE&#39;xx&#39; fproceefdingas described( in Example XIX but |00 mg. of active product.  
 We claim:&#39; L Apharmaceutical composition which comprises` sozidca) 2 Lgs-Oe&#39; (cszi-o-coat maceutical carrier.  
  2. composition according to claim l in the form o1 a solutionofthe phenthiazine derivative in an injecta- :ble wateiffinsoluble vegetable oil.  
  3; l&#39;l`he&#34;&#34;cor npositionlaccording to claim 1 comprising at least one phenthiazine&#39; selected from the group con `sistin&#39;g ofzv t Ill-dimethylsulphamo l-lO- {3-[4(2-lauroyloxyethyl) piperidinolpropyl phenthiazine` 3dimethylsulphamoyl-l0-{3f[4(2-undec-l0&#39;enoyloityethyl)Lpiperidino]propyl}phenthiazine` and, 3-dimethylsulphamoyll 0- {3-l 4( 2palmitoyloxye thyl)piperidino]propyl} phenthiazine.  
  Umm@ STATES MTENT om@ @ERTHCATE QBRECTUN Patent No, 3,879,551 Dated April 22, 1975 Inventor(s) Jean-Claude Ren Georges BLONDEL et al It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:  
  In the heading, for vthe residence of che second inventor (Fouch) read -Bourg1aReine-.  
  In the Foreign Application Priority Data, for the second item read --April 6, 19&#39;70 Sweden 4156/68 (filed March 28, 1968, as amended April 6, 1970) gned and @als time A ttes t.&#39;  
 RUTH C. MASON C. MARSHALL DANN .&#39;1Itest1`ng Officer (&#39;mnmissnmr u l&#39;lalents und Trademarks