US2899431A - Unsaturated-plperazino-alkyl- - Google Patents

Unsaturated-plperazino-alkyl- Download PDF

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US2899431A
US2899431A US2899431DA US2899431A US 2899431 A US2899431 A US 2899431A US 2899431D A US2899431D A US 2899431DA US 2899431 A US2899431 A US 2899431A
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piperazine
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ether
phenothiazyl
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/44—Constructional features of apparatus for radiation diagnosis
    • A61B6/4429—Constructional features of apparatus for radiation diagnosis related to the mounting of source units and detector units
    • A61B6/447—Constructional features of apparatus for radiation diagnosis related to the mounting of source units and detector units the source unit or the detector unit being mounted to counterpoise or springs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients

Definitions

  • the preferred compounds of the invention are PHENQTHIAZINES effective in a dose range of 10 to 250 mg. daily, the aver- Margaret H. Sherlock, Bloomfield, -N.J., assignor to age dose being 9 e emesis, Schering Corporation, Bloomfield, N.J.,.a corporation 5 the compounds of this invention exert adepressant effect of New Jersey at doses of 10 to '15 mg. daily No Drawing. Application September 18,1956 It has been found that, unlike most of the neuropsy- Serial No.
  • the .preferred compounds .of 3 Claims, (CL 260.443) this invention show few untoward side effects.
  • the undesirable side effects which are minimized by the This invention relates to a new group of chemical comuse of the compounds of the present invention are dry pounds which possess important therapeutic properties mouth, mydriasis, fall in blood pressure, and tachycardia. and to processes for their manufacture.
  • preferred compounds of the general formula have X representing a'halogen group such as chlorine; A represents S; Y represents an alkylene group containing 3 carbon X atoms and R representsan unsaturated alkyl group. Increasing the number of carbon atoms in Y from 3 to 5 N provides for a decrease in tranquillizing effect, but on the v other hand, the compounds having a longer alkylene chain exhibit more advantageous properties as anti-microbial agents.
  • compounds of the general forwherein A is a member of the group consisting of S, 50 mula are insoluble in aqueous media, they'are preferably and S0 X is a member of the'group consisting of H, administered in the form of soluble non-toxic acid addihalogen, lower alkoxy and lower alkyl;
  • Y is an alkylene tion salts such as dihydrochloride, dimaleate, ditartrate, radical of from 2 to 5 carbon atoms;
  • R represents hydrodicitrate and the like.
  • the compounds are preferably adgen or lower alkyl and R" represents an unsaturated hyministered orally in tablets or elixirs in conjunction with drocarbon chain having 3 to 5 carbon atoms.
  • Typical exsuitable carriers and other types of pharmaceutical dosage amples of the group represented by R" are allyl, vpropunits which lend themselves to such administration.
  • argyl, 2-butenyl, Z-methylallyl and Z-methylbutenyl certain instances where parenteral administration is indi- I have found that the compounds of the general forcated, the compound in the form of a non-toxic acid addimula possesscertain important physiological properties 40 tion salt is prepared in sterile solutions or suspensions.
  • Those compounds possessing anti-microbial properties are These compounds manifest themselves by exerting a-calmpreferably administered topically or locally in the form of ing and a quieting effect, thereby lending themselves to creams, salves and the like application to neuropsychiatric patients in particular.
  • the compounds of my lnventlon may be prepared ac- Thus, in their ability to calm mentally disturbed pacording to a variety-of synthetic steps.
  • the condensation may be carried out in the ditions, environmental pressure, premenstrual tension, presence of a condensing agent such as 'sodamlde, potasdysmenorrhea, and menopause.
  • a condensing agent such as 'sodamlde, potasdysmenorrhea, and menopause.
  • the compounds of the invention are effective in doses ranging upwards of my invention may be prepared according to the folfrom mg. daily, the average daily clinical dose being lowing equation wherein Phz stands for a 10-phenoth1azyl 200 to 250 mg. depending upon the syndrome. For the group.
  • H-N N-C O 002E PhzH Brain-2301 Phz(CH:)aC1 PhZ(CH:)sN NOOOCzH;
  • the compounds of the general formula wherein A represents S or S0 may be prepared by utilizing the appropriate oxygenated phenothiazine as starting material.
  • Compounds of my invention, wherein A of the general formula represents a SO group are prepared by oxidation of the corresponding compounds wherein A is S, by means of hydrogen peroxide.
  • oxygenation may be carried out at any stage, I prefer to oxidize at an intermediary stage before the piperazino moiety is incorporated into the molecule.
  • EXAMPLE 1 1-allyl-4- ['y-(2-chloro-10-phenothiazyl) propyl] piperazine
  • a mixture of g. of lO-(y-chloropropyl)-2-chloro phenothiazine and 18 g. of l-allylpiperazine is stirred and heated on a steam bath for 18 hours.
  • the reaction mixture is diluted with Water, the oil which separates is extracted with ether.
  • the ether extracts are extracted with dilute hydrochloric acid.
  • the aqueous acid solution is made alkaline with sodium hydroxide solution and the resultant mixture extracted 'with ether.
  • the ether extracts are dried and concentrated to a residue yielding the free base of this example.
  • a mixture of 17.5 g. of l-propargyl-piperazine, 33 g. of lo-(v-chloropropyl)-2-chlorophenothiazine and 14 g. of anhydrous sodium carbonate is stirred and heated on a steam bath for 20 hours.
  • the mixture is diluted with water and the oil which separates is extracted with ether.
  • the combined ether extracts are extracted with dilute hydrochloric acid.
  • the acid solution is made alkaline with sodium hydroxide solution and the resultant mixture is extracted with ether.
  • the ether extracts are dried, concentrated and the residue is converted to the dihydrochloric salt as described in Example 1; M.P. 211212. Analysis indicates that the salt crystallizes with 0.5 mole of water of crystallization.
  • a solution of 40 g. of the crotonyl derivative obtained above in 200 ml. of anhydrous ether is added to a suspension of 8 g. of lithium aluminum hydride in 600 ml. of anhydrous ether.
  • the reaction mixture is stirred and refluxed for 10 hours and the excess hydride is destroyed by adding a minimum quantity of water.
  • the lithium and aluminum hydroxides so formed are removed by filtration and the ether solution is concentrated to a residue which is purified by distillation; B.P. 272276/ 1.5 mm.
  • a mixture of 31 g. of lO-(y-chloropropyl)-2-chlorophenothiazine and 28 g. of l-(2-methylallyl)-piperazine are stirred and heated on a steam bath for 18 hours.
  • the reaction mixture is processed according to the analogous procedure of Example 1, yielding the free base of this example; B.P. 261-264/ 0.5 mm.
  • the free base so obtained is converted to its dihydrochloride with ethanolic hydrogen chloride as heretofore described, M.P. 238439.
  • the requisite intermediate l-(3-methy1-2-butenyl)piperazine is prepared according to the analogous proce dure of Example 4 whereupon l-carbethoxypiperazine is alkylated with 1-chloro-3-methyl-butene-2 in the presence of sodium bicarbonate with hydrolysis of the carbethoxy group occurring in the presence of hydrochloric acid; B.P. 110ll2/5 mm.
  • EXAMPLE 6 1 -ally-4- fi- (2-chl0ro-1 O-phenothiazyl) -ethyl] -piperazz n'e
  • EXAMPLE 7 1-allyl4- ['y- (Z-fluoro-l O-phenothiazyl -pr0pyll piperazine
  • the requisite intermediate, 10-('y-chloropropyD-Lfluorophenothiazine is prepared as follows:
  • a mixture of 15 grams of l-allylpiperazine and 15 grams of crude IO-(y-chloropropyl)-2-fluor0phenothiazinc is heated on a steam bath for 18 hours.
  • the mixture is diluted with 200 ml. of water and extracted with ether.
  • the ether solution is extracted with dilute hydrochloric acid.
  • the aqueous acid solution is made alkaline with sodium hydroxide and the oil which separates is extracted with ether.
  • the ether extracts are dried, concentrated and the residue so obtained is converted to a dihydrochloride according to the procedure described in Example 1.
  • EXAMPLE 9 1 (2-butenyl) -4- -(2-meth0xy-1 O-phenothiazyl) propyl] -piperazine
  • the requisite intermediate Z-methoxy-lO-(q-chloropropyD-phenothiazine is prepared by substitulting an equivalent quantity of Z-methoxyphenothiazine .for the 2- fiuorophenothiazine in Example 7.
  • Reaction of the intermediate so obtained with l-crotonyl-piperazine followed by reduction with lithium aluminum hydride as described in Example 3 yields the compound of this example.
  • Purification is preferably eifected by conversion to the dihydrochloride salt, followed by recrystallization.
  • EXAMPLE 10 1 -(2-methylallyl) -3-['y-(3-chl0r0-1 O-phenothiazyl) propyl] -piperazine
  • 3-chloro-l0-(y-chloropropyl')-phenothiazine is prepared by reacting 3-chlorophenothiazine with l-br0mo-3-chloropropane as analogously described in Example 7.
  • Reaction of the intermediate so obtained with l-(Z-methylallyl)-piperazine according to the procedure described in'Exarnple 4 yields the free base of this example.
  • the requisite intermediate 10- 'y-chloropropyl) -pheno- 'thiazine dioxide is prepared by the alkylation of 23 g. of phenothiazine dioxide with sodamide (from 2.5 g. of
  • EXAMPLE 13 1-allyl-4- y-(2-chloro-5-oxid0-JO-phenothiazyl)- propylJ-piperazine
  • the requisite intermediate Z-chloro-S-oxido-lO-(ychloropropyl)-phenothiazine is prepared by adding 125 ml. of 25% aqueous hydrogen peroxide to a stirred and warmed solution of 34 g. of 2-chloro-10-(y-chloro propyl)-phenothiazine in 1300 ml. of alcohol.
  • the reaction mixture is allowed to stand two days and then poured into water containing a small quantity of hydrochloric acid.
  • A is a member of the group consisting of S, SO, and S0
  • X is a member of the group consisting of H, halogen, lower alkoxy, lower 'alkyl
  • Y is an alkylene radical having 2 to 5 carbon atoms
  • Z is a member of the group consisting of H and lower alkyl and R is an unsaturated aliphatic hydrocarbon radical having less than six carbon atoms.
  • X is a halogen atom
  • Y is an alkylene group having 2 to 5 carbon atoms
  • R is an unsaturated aliphatic hydrocarbon radical having less than six carbon atoms.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Medical Informatics (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biophysics (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • High Energy & Nuclear Physics (AREA)
  • Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Optics & Photonics (AREA)
  • Epidemiology (AREA)
  • Radiology & Medical Imaging (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Molecular Biology (AREA)
  • Surgery (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
US2899431D 1955-03-19 Unsaturated-plperazino-alkyl- Expired - Lifetime US2899431A (en)

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US (1) US2899431A (de)
BE (1) BE553467A (de)
CH (1) CH341268A (de)
CY (1) CY258A (de)
DE (1) DE1151509B (de)
GB (1) GB833473A (de)
MY (1) MY6300023A (de)
NL (1) NL95713C (de)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3227708A (en) * 1957-09-11 1966-01-04 Olin Mathieson Trifluoromethyl phenothiazines

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3194733A (en) * 1961-04-26 1965-07-13 Olin Mathicson Chemical Corp Phenothiazine compositions and method of treating mental disorders
US3394131A (en) * 1961-04-26 1968-07-23 Squibb & Sons Inc Acid esters of phenothiazine
CN105153062A (zh) * 2015-10-10 2015-12-16 江苏宝众宝达药业有限公司 一种氟奋乃静盐酸盐的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2766235A (en) * 1956-06-21 1956-10-09 John W Cusic N-(beta-acetoxyethyl)-n'-(chlorophenothiazinepropyl) piperazine
US2787617A (en) * 1955-09-20 1957-04-02 Searle & Co Derivatives of oxopiperazinoalkylhalophenothiazines

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2694705A (en) * 1954-11-16 Nx c c ox a a
GB666457A (en) * 1948-10-30 1952-02-13 Henri Morren Carbonyl chlorides and monocarboxyamides of piperazine and process for the preparation thereof
CH298685A (fr) * 1951-06-28 1954-05-15 Rhone Poulenc Chemicals Procédé de préparation d'un nouveau dérivé de la phénothiazine.

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2787617A (en) * 1955-09-20 1957-04-02 Searle & Co Derivatives of oxopiperazinoalkylhalophenothiazines
US2766235A (en) * 1956-06-21 1956-10-09 John W Cusic N-(beta-acetoxyethyl)-n'-(chlorophenothiazinepropyl) piperazine

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3227708A (en) * 1957-09-11 1966-01-04 Olin Mathieson Trifluoromethyl phenothiazines

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GB833473A (de)
CY258A (en) 1963-04-18
MY6300023A (en) 1963-12-31
NL95713C (de)
DE1151509B (de) 1963-07-18
CH341268A (de) 1959-09-30

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