Process for producing derivatives of phenothiazine or their acid additive salts

专利摘要:
The invention relates to new phenothiazine derivatives of the general formula (I) or an acid addition salt thereof, <IMAGE> wherein R stands for a group of the general formula (IIa), (IIb) or (IIc), <IMAGE> and in these latter formulae X stands for hydrogen, a C1-4 alkyl group, halogen atom or a nitro group and n is equal to 1, 2 or 3, with the proviso that if n is equal to 2 or 3, the X substituents attached to the aromatic ring may be the same or different. The compounds are useful as neuroleptic agents.
公开号:SU925250A3
申请号:SU802903447
申请日:1980-04-04
公开日:1982-04-30
发明作者:Толди Лайош；Тот Иштван；Кирай Илдико；Борши Йожеф
申请人:Эдьт Дьедьсерведьесети Дьяр (Инопредприятие)；
IPC主号:

专利说明:

and evaporated under reduced pressure. On standing, 56.3 g of crystalline product is lost. T. Sh1. 54-6ОС. After recrystallization from one-and-a-half amounts of petroleum ether, pure Z.-dimethylphenoxyisoic acid is obtained, melting oil. However, to obtain an acid haorial, the crude product is also suitable. 30 g of the resulting 3,5-dimeptiphenoxy isobutyric acid are dissolved to 150 MP anhydrous benzene. After the addition of -48 m thionic chloride, the reaction mixture is heated for 3 hours and the spines are heated. ; Benzene and excess thionylchloride are removed under well-controlled pressures and the residue is distilled in vacuo. Obtain 2O g of 3,5-dimethyl chloride | fvnoxy iso-oil KHcnotM. T. Il. 115-119 C at 0,6-O, 8 mm Hg. Art. . Example 2. Preparation of complex 2-trifluorometip-Yu- {3- 14- {2-hydroxyethyp) piperazinyl-1) propnp} feit aa 2 -2, 5-dimethylphenoxy1tzomas NY | Acid di (| 7 marata. Anapogic is given to Example 1; however, instead of 3,5-dimethylphenoxy-iso-butyl chloride. acid, chloride 2,5-amimetyphenoCs of 1-isomeric acid is used. After recrystallization from ethanol, the resulting dihydrate melts at 152154 С. Used as a new 2,6-Sh1metyphenoxyiso butyric acid starting material was prepared in Example 1, but 2,5-dimethylphenol was used instead of 3 | 5-dimethylphenol. T. mp 98-1OO C From the obtained product, chloride 2.5 -leptyphenoxyisobutyric acid b.p. 100108 С pr Oj6-l mmHg Example 3 Preparation of the ester of 2-etil Thrifty {€ z--10- {1- (2-hydroxyethyl) -1 piperaziiil) propyl} feitiazyi NY-.b dimetkpfenoksiizomasl hydrochloric sour. you are difumarata. Example 1 is prepared analogously; however, 2,6-dimethylphenoxyisobutyric acid chloride is used instead of 3,5-dimethylfevoxy isobutyric acid chloride. After recrystallization from a mixture of ethanol and methanol (3; 1), the resulting fumarate melts at 13 ° -13 ° C. , 6-4methylfeiol. Chl RID 2,6-AYmetyphenoxyisobutyric acid is obtained from the crude product as in Example 1, however, after heating to boiling point, benzene and excess thionyl chloride are distilled off under reduced pressure, the residue is dissolved in benzene and benzene is also removed under reduced pressure. The acid chloride obtained in this way, crude in the degree of purity, is subjected to Florida processing. Example 4. Preparation of 2-trifluoromethEn-1O- (3-14- (2-hydroxyethyl) piperazinyl-11 ester) propip phenothiazinefeioxyisomas nsL kvlosh-d fumarate. Example 1 is used, but instead of 3,5-dimethoxy-iso-butyl chloride and I used it, I used instead of 3). phenoxyisobutyric acid. After recrystallization from ethanol, the halfway difumaatar is melted at 152-154 C. I. - Example 5. Preparation of ester 2-tr1formate -1O- {3- 4- (2-) Cree etip) piperazinyl-11 propyphenthiazine -4; chlorophenoxyisobutyric acid difumarate. It is prepared as in Example 1, but instead of the chloride of 3.5-4 Methylphenoxyisobutyric acid, the known chloride 4-chlorophenoxyisobutyric acid is used. After recrystallization from ethanol, the resulting fumarate melts at 164-166 ° C. The base is released from Difumarate according to the method described in Example 1c. T. pl. 54-5bs. Example 6. Preparation of 2-trifluoromethyl-1O- {3- {4- (2-hydroxyethyl) piperazinip-11 propyl) phenythiazine-2, 6-dichlorophenoxyisomatic acid kispotifumarate ester. Proceed in example 1, but in return. 3,5-dimethylphenoxyisobutyric acid chloride is replaced by 2,6-dichlorophenoxy-butyric acid chloride. After recrystallization from ethanol, the preparate difumarate melts at 160-162 0. A new 2,6-dichloroperoxy-isomas oil is used as the starting material | (the brush is prepared as in Example 1, but 2,6-dichlorophenol is used instead of 3,5-dimethylphenol. Made of non-crystalline The product is obtained with 2,6 dichlorophenoxyisobutyric chloride (T. Kip. 120-126 ° C at 1-1.5 mm Hg) Example 7. Preparation of 2-trifluoromethyl-1O ester {3- {4- (2 -oxyethyl) piperazinyl-11 propip phenythasia-2, 3-dichlorophenoxyisobutyl oil NY1 difolate chiols. Proceed in example 1, but 3,5-dimethylphenoxyisome acid is used in a new chloride of 2,3-dichlorophenoxyisobutyric acid. After recrystallization from ethanol, the resulting difumarate melts at 154-156 ° C. The 2,3-dichlorophenoxyisobutyric acid used as the starting material is obtained analogously to the example 1, but instead of 3,5-dimethylphenol, 2,3-d chlorophenol is used, mp 94-96 C. From this product, 2,3-dichlorophenoic isobutyric acid chloride is obtained as in Example 1. T. b. 120-124 ° C at 0.4. 0, 6 mm Hg. st, Example 8. Preparation of 2-trifluoromethyl-10- {3- 4- (2-hydroxyethyl) piperazinyl-1 ester ester phenazaz-4-sh1trophenoxyisobutyric acid-difumarate. It is prepared as in Example 1, but instead of 3,5-dimethylphenoxyisobutyric acid chloride, the well-known 4-nitrophenoxyisobutyric acid chloride is used. After recrystallization from ethanol, the expanded fumarate melts at 170 17 2 ° C. Example 9. Preparation of 2-trifluoromethyl-10-j3-4- (2-hydroxyethyl) piperazinyl-1-propyl ester-1-naphthoxy-isobutyric acid-difumarate ester. It is prepared as in example 1, but instead of 3,5-dimethylphenoxyisobutyric acid chloride, the known chloride is used: 1-naphthoxyisobutyric acid. After recrystallization from ethanol, the resulting fumarate melts at 149-151 ° C. Example 1O. Preparation of 2-trIfluoromethyl-10- (3- 4- {2TT-hydroxyethyl) piperazinyl-1-propyl} phenythazin-2- (6-methoxy-2-naphtyp) propionic acid-difumarate ester. It is prepared as in Example 1, but instead of 3,5-dimethyl-phenoxy-isobutyric acid chloride, the well-known 2- (6-methoxy-2-naphthyl) -propionic acid chloride is used. After recrystallization from ethanol, the resulting fumarate melts at 152-154 ° C. The purified ester base can be obtained analogously to example 1c. Example 11. Preparation of 2-trifluoromethyl-10-3-4- (2-hydroxyethyl) piperazinyl-1-propyl | phenothiazin-4-tert.butylphenoxy-isobutyric acid-difumarate ester. Prepared according to example 1, however, 4-tert.-β-butylphenoxyisobutyric acid chloride is used instead of 3,5-dimethylphenoxyisomasNOIC chloride. After recrystallization from ethanop, the resulting fumarate melts at 160. From 4-tert.-butylphenoxyisomatic acid, yrimer 1, 4-tert.-butylphenoxyisobutyric acid chloride used as the starting material, is obtained with the difference that after heating at boiling point benzene and excess thionyl chloride are distilled off under reduced pressure, the residue is dissolved in benzene and benzene are also removed under reduced pressure. The new fluphenazine esters of the general formula I in accordance with the invention are of a more powerful neuroleptic effect. In other words, such esters have a higher effect compared to the fentiazine structure in terms of decreased motility (SMS), increased effect of anesthesia, suppression of the reflex during expectoration caused by apomorphine, as well as antagonistic and cataleptic action. When determining the degree of inhibition of the conditioned reflex in rats, after 2 weeks (the time period set for this test), the 3,5-dimethylphenoxyisobutyric acid ester and the 2- (6-methoxy-2-naphthyl) -propionic acid ester are superior to the known fluphenazine decanoate, and 4-chlorophenoxyisobutyric acid ester achieves a compound accepted for comparison. The same is found in experiments on dogs. The new ester of the general formula causes for 3 weeks a stronger inhibition of the emetic effect caused by apomorphine compared with the known fluanazine deanate. In addition, the duration of action of new compounds is more than that of the known. The co1Sh of a new ester of general formula 7, mainly fumarate, is able to be well absorbed when administered through the mouth and restore spontaneous locomotor activity and the conditioned defensive (defensive) reflex to the same extent as flufenazine. The cataleptic effect of the inventive novel compounds is also similar to that of phaofenazine. Compounds of general formula 1, even with the administration of 0.6-0.7 times the amount relative to fluphenazine, 9 have the same effect as 1 hour of phenazine. New compounds of phpk itself - trifluoromethyl-10- | 3- 4- (2-hydroxyethyl) pi. nontoxic.pereinip-} propyl) fentiaine avipiruyut 92525OlO carboxylic imcnoToft formula SchA SchV or Shs

权利要求:
Claims (2)
[1]
Invention Formula
. Method for preparing fentiazine derivatives of general formula I
. I / -
fCHjf- N HCHfCHfOR
where R is a group of the formula Pa, c in or L c,
; Oh-oh-he
x;
(iHj o1Po
But
1M
where X and P have the above values, or an ester derivative capable of forming an ester, preferably an acid chloride, and the desired product is isolated in free form or as an acid addition salt. where X is a hydrogen or hlf atom, lower alkyl with 1-4 carbon atoms or a nitro group; P 1 or 2, or their acid additive salts, 35 characterized in that 2 Sources of information taken into account during the examination 1. Mashkovsky M. D. Medicinal sretsgva, M., Metzitsyna, 1978, I, p.55 .
[2]
2. ByullerK., Pearson D. Organic syntheses. M., Mir, 1973, 2, p. 283.

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引用文献:

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JP3932785B2|1999-08-25|2007-06-20|株式会社村田製作所|Method for manufacturing piezoelectric body|

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WO2006058199A1|2004-11-23|2006-06-01|Fazix Corporation|Methods of modulating high-density lipoprotein cholesterol levels and pharmaceutical formulations for the same|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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HU79GO1442A|HU179190B|1979-04-06|1979-04-06|Process for preparing new phenthiazine derivatives|

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