NO139519B - CARRYING DEVICE FOR HANDLING ROLLED UP MATERIAL, SUCH AS EX. PAPER ROLLS AND THE LIKE - Google Patents

Description

Process for the preparation of therapeutically active phenthiazine derivatives.

The present invention relates to a

method for the preparation of therapeutically active phenthiazine derivatives.

During the last 15 years are extended

research and experimental work has become

performed in the area of N-substituted phenthiazine derivatives and certain of these compounds are

have been found to possess valuable therapeutic properties. Some are useful primarily because of their

outstanding antihistamine activity, others

because of their calming effect and

their effectiveness as anti-shock agents, and

still others are e.g. effective means for

control and reduction of motion sickness.

It has nevertheless been shown that of it

very large number of possible N-substituted

phenothiazine compounds that have been proposed

or tried by different researchers, has

only relatively few types have been used in

human and veterinary medicine, and that both

the nature and degree of applicable effect

can be radically changed even by appearances

small changes in chemical structure.

It is an aim of the present invention to provide hitherto unknown phenthiazine derivatives which possess unexpected

pharmacological properties of a nature which

it will later be explained in detail and

a degree of activity that could not have been

predicted from the knowledge of their chem

structure in accordance with the general formula:

where X means a hydrogen or halogen atom or an alkyl, alkoxy, acyl, alkoxycarbonyl, alkylthio, alkanesulfonyl, dimethylsulfamoyl, cyano or trifluoromethyl group, R means a hydrogen atom or a methyl group, and n is 1, 2 or 3 and their acid addition and quaternary ammonium salts. The compounds according to the general formula I, where R is a methyl group, have an asymmetric carbon atom and can therefore exist in optically active forms. The invention includes within its scope the production of racemates as well as corresponding optically active isomers of such compounds.

In the present description and subsequent claims, the alkyl, alkoxy, acyl and alkane groups referred to contain no more than 4 carbon atoms.

According to the present invention, the phenthiazine derivatives of formula I are prepared by a method which consists in reacting a phenthiazine compound of the general formula: with a piperidine compound of the general formula: where Z means the acid residue of a reactive ester, such as a halogen atom or a sulfuric acid or sulphonic acid ester residue, e.g. the methanesulfonyloxy or toluene-p-sulfonyloxy group, and the other symbols are as defined above.

The reaction can be carried out by heating the components at a temperature of between 30° and 120° C, preferably in an inert solvent, such as an aromatic hydrocarbon, e.g. benzene or toluene, or an alcohol (eg ethanol), if desired in the presence of a condensing agent which acts as an acid acceptor, such as an alkali metal carbonate or a tertiary amine (eg triethylamine or pyridine). An excess of the piperidine compound can also be used as a condensing agent.

Optically active products can be obtained by starting with starting materials of formula II which are themselves optically active. They can also be produced by optical cleavage of the corresponding racemates.

The phenthiazine derivatives of general formula I can be converted into acid addition and quaternary ammonium salts in a manner known per se. The acid addition salts can be obtained by the action of acids on the phenthiazine bases in suitable solvents. Organic solvents can then be used, e.g. alcohols or ethers. Water can advantageously be used as an inorganic solvent. The salt that is formed settles to the bottom, if necessary after concentration of the solution, and is separated by filtration or decantation. The quaternary ammonium salts can be obtained by the action of esters on the phenthiazine bases, preferably in an organic solvent at room temperature or more rapidly by gentle heating.

The phenthiazine derivatives according to formula I can be purified by physical methods such as des-

tillation, crystallization or chromatography, or by chemical methods such as the formation of salts, crystallization of the salts and their cleavage in an alkaline medium. In carrying out the aforementioned chemical methods, the nature of the anion in the salt is immaterial. The only requirement is that the salt must be well defined and easily crystallizable.

The new phenthiazine compounds obtained by the method according to the present invention possess valuable pharmacodynamic properties. They are active on the central nervous system and are particularly excellent antiemetics. They also have a strong degree of analgesic effect: Compounds of outstanding utility in the aforementioned respect are: 3-methoxy-10-(3-4'^hydroxy-4'-p-hydroxyethyl-r-piperidyl-2-methylpropyl)- phenthiazine, 3-methoxy-10-(3-4'-hydroxy-4'-hydroxymethyl-1'-piperidyl-2-methylpropyl)phenthiazine, 3-trifluoromethyl-10-(3-4'-hydroxy.-4'- hydroxymethyl-1'-piperidylpropyl)phenthiazine, 3-cyano-10-(3-4-hydroxy-4'-hydroxymethyl-1'-piperidylpropyl)phenthiazine, 3-methylthio-10-(3-4'-hydroxy-4 '-hydroxymethyl-1'-piperidyl-2-methylpropyl) f enthiazine, 3-chloro-10-(3-4'-hydroxy-4'-hydroxymethyl- 1 '-piperidylpropyl) f enthiazine, and 3-dimethylsulfamoyl-10- (3-4'-hydroxy-4'-hydroxymethyl-1'-piperidylpropyl)f enthiazine.

Phenthiazine compounds corresponding to the general formula:

has been investigated with regard to anti-emetic effect using the test method described below.

Try:

Variable doses of the phenthiazine derivative under study were administered orally to dogs, and 90 minutes after the administration of the compound, 0.1 mg/kg apomorphine was injected subcutaneously. The dose (in mg/kg) which reduces the number of vomiting compared to the control animals by 50% (ED-0) was determined.

The results of the tests are given in the following table in which each product is [identified by reference to the formula an-I given above.

The compounds A—G are products obtained by the method according to the present invention, and the compounds H, I and J are previously known substances of a closely related nature in which the piperidyl residue in the above formula is unsubstituted in the 4-position or substituted there with a hydroxy or hydroxymethyl group .

The results obtained by the aforementioned test clearly show that the compounds in which the piperidyl residue in the formula carries both a hydroxy and a hydroxyalkyl substituent in the 4-position, i.e. the compounds are new products as described in the present patent, are — in any case except from one — more effective as antiemetics than for previously known compounds which have either no substituent or a hydroxy or hydroxyalkyl substituent in the aforementioned position in the piperidyl residue. In reality, four of the products according to the present claim, namely C, D, E and G, are twice as effective as antiemetics compared to previously known products, namely H, I and J.

For therapeutic purposes, the bases of general formula I are used as such or in the form of non-toxic acid addition salts, e.g. salts containing anions which are relatively harmless to the animal organism in therapeutic doses of the salts (such as hydrochlorides and other hydrohalides, phosphates, nitrates, sulphates, acetates, propionates, succinates, benzoates, fumarates, maleates, tartrates, met -hanesulfonates, ethanedisulfonates, chlorotheophyllines, theophylline acetates, salicylates, phenylphthalinates and methylene bis-|3-hydroxynaphtholates), so that the beneficial physiological properties present in the bases are not destroyed by side effects attributable to the anions. However, they can also be used in the form of non-toxic quaternary ammonium salts obtained by reaction with organic halides (e.g. methyl, ethyl, allyl or benzyl chloride, -bromide or -iodide) or other reactive esters, e.g. e.g. methyl or ethyl sulfates, benzene sulfonate or toluene p-sulfonate. The phenthiazine derivatives according to the invention can also serve as intermediates for the preparation of other therapeutically valuable compounds.

The following examples illustrate the invention.

Example I.

A solution of 3-methoxy-10-(3-methanesulfonyloxy-2-methylpropyl)-phenthiazine (13.3 g) and 4-hydroxy-4-(2-hydroxyethyl)-piperidine (10.15 g) in anhydrous benzene ( 100 cc.) is heated under reflux for 6 hours. After cooling, the reaction medium is extracted by stirring with n hydrochloric acid (100 cc). The aqueous acid phase is separated, made alkaline by the addition of sodium hydroxy solution (d = 1.33;

15 cc) and the free base is extracted with

anesthetic pure ether. The organic solution is dried over anhydrous potassium carbonate and the solvent is removed in the water bath under a pressure of approx. 20 mm Hg. 3-Methoxy-10-(3-4'-hydroxy-4'-|3-hydroxyethyl-1'-piperidyl-2-methylpropyl)-phenthiazine (11.0 g) is obtained which, after recrystallization from acetonitrile, is a creamy white crystalline powder, m.p. 90-92° C.

Starting 4-hydroxy-4-(2-hydroxyethyl)-piperidine (m.p. 79—80° C) is obtained by debenzylation in methanol in the presence of palladium charcoal at 70° C under a pressure of 100 kg/cm<2> of hydrogen, of l-benzyl-4-hydroxy-4-

(2-hydroxyethyl)piperidine, prepared myself according to Grob and Brenneisen, Heiv. 41, 1184

(1958).

Example II.

A solution of 3-methoxy-10-(3-methanesulfonyloxy-2-methylpropyl)-phenthiazine (19 g) and 4-hydroxy-4-hydroxy-methyl-piperidine (13.1 g) in anhydrous benzene (100 cc) is heated under reflux for 7 hours. After cooling, the reaction medium is washed with N sodium hydroxide solution (120 cc). The organic layer is separated and then extracted by stirring with N hydrochloric acid (150 cc). The aqueous acid phase is separated, made alkaline by the addition of sodium hydroxide solution (d = 133; 20 cc) and the free base is extracted with anesthetic pure ether. The organic solution is dried over anhydrous potassium carbonate and the solvent is removed on the water bath under a pressure of approx. 20 mm Hg. 3-Methoxy-10-(3-4'-hydroxy-4'-hydroxymethyl-1'-piperidyl-2-methylpropyl)phenthiazine (15.2 g) is obtained which, after recrystallization from acetonitrile, is a creamy white product, m.p. 133-134° C.

Starting 4-hydroxy-4-hydroxymethyl-piperidine (m.p. 126—128° C) is obtained by debenzylation in methanol in the presence of palladium charcoal at 100° C under a pressure of 100 kg/cm<2> hydrogen, of l-benzyl- 4-hydroxy-4-hydroxymethylpiperidine

(m.p. 82° C, b.p. 130—160° C/0.6 mm Hg.), itself prepared by reduction with lithium aluminum hydride in ether of 1-benzyl-4-hydroxy-4-ethoxycarbonylpiperidine. 1-benzyl-4-hydroxy-4-ethoxycarbonylpiperidine

(b.p. 135-148° C/0.6 mm Hg) is obtained by saponification, followed by esterification of 1-benzyl-4-hydroxy-4-cyanopiperidine (b.p. 95-97° C), itself prepared by the action of dilute hydrochloric acid on an aqueous solution of l-benzylpiperid-4-one and potassium cyanide.

Example III.

A solution of 3-trifluoromethyl-10-(3-chloropropyl)-phenthiazine (17.2 g) and 4-hydroxy-4-hydroxymethylpiperidine (7.2 g) in anhydrous ethanol (250 cc) is heated for 18 hours under reflux in presence of powdered anhydrous sodium carbonate (5.3 g). Additional sodium carbonate (2.65 g) is added and heating is continued for 8 hours. After a final addition of sodium carbonate (2.65 g), the reaction is completed by heating for 16 hours under reflux. Ethanol is removed under reduced pressure (approx. 20 ml Hg.) and the residue is taken up in distilled water (250 cc) and extracted with ether (450 cc). The ethereal phase is extracted with 0.12 N hydrochloric acid (1150 cc). The aqueous phase is separated, made alkaline with sodium hydroxide solution (d = 1.33; 20 cc) and the free base is extracted with ether. The organic solution is dried over anhydrous potassium carbonate and concentrated to dryness under reduced pressure (about 15 mm Hg). 3-Trifluoro-methyl-10-(3-4'-hydroxy-4'-hydroxy-methyl-r-piperidylpropyl)phenthiazine (15.2 g) is then obtained which, after two successive recrystallizations from acetonitrile, is a white crystalline powder, m.p. 122— 124° C.

4-hydroxy-4-hydroxymethylpiperidine (m.p. 126-128° C) is prepared from 1-benzyl-piperid-4-one via the following compounds:

l-benzyl-4-hydroxy-4-cyanopiperidine (m.p. 95—97° C), l-benzyl-4-hydroxy-4-ethoxycarbonyl- piperidine (b.p. 135—148° C/0.5 mm Hg),

and 1-benzyl-4-hydroxy-4-hydroxymethyl-piperidine (m.p. 81-82°C).

Example IV.

Proceeding as in Example III, but starting with 3-cyano-10-(3-chloro-propyl)phenthiazine (15 g), 4-hydroxy-4-hydroxymethylpiperidine (7.2 g), ethanol ( 250 cc) and sodium carbonate (total 10.6 g) and isolate the crude base as in example III, but replace the ether with ethyl acetate, 3-cyano-10-(3-4'-hydroxy-4'-hydroxy-methyl- 1'-piperidylpropyl) f enthiazine (18 g), which, after recrystallization from ethanol and then from acetonitrile, is a yellow crystalline powder, m.p. 134-135° C.

Example V.

A solution of 3-methylthio-10-(3-methanesulfonyloxy-2-methylpropyl)-phenthiazine (15.1 g) and 4-hydroxy-4-hydroxymethylpiperidine (10 g) in anhydrous toluene (150 cc) is heated under reflux for 18 hours. After cooling, distilled water (200 cc) is added and the organic phase is decanted and extracted with hydrochloric acid (150 cc). The aqueous phase is separated and made alkaline with sodium hydroxide solution (d = 1.33; 25 cc). The free base is extracted with ether, the organic phase is dried over anhydrous potassium carbonate and concentrated to dryness under reduced pressure (approx. 15 mm Hg.). 3-methylthio-10-(3-4'-hydroxy-4'-hydroxymethyl-1'-piperidyl-2-methylpropyl)phenthiazine (6 g) is obtained,

as after two successive recrystallizations

from acetonitrile, is a creamy white cryst

powder, s.p. 133-135° C.

Example VI.

By proceeding as in example III, but

starting with 3-chloro-10-(3-methanesulfonyloxypropyl)phenthiazine (18.5 g), 4-hydroxy-4-hydroxymethylpiperidine (7.2 g),

ethanol (250 cc) and sodium carbonate (total

10.6 g) and isolate the crude base as in example III, but replacing the ether with ethyl acetate, an oil is obtained which dissolves in benzene (250 cc). The solution is filtered through a column of chromatographic aluminum oxide (250 g) and eluted with benzene

followed by ethyl acetate containing 5 percent.

methanol. 3-chloro-10-(3-4'-hydroxy-4'-hydroxymethyl-1'-piperidylpropyl)-phenthiazine (7.3 g) is obtained in the form of a yellow

oil. The acidic fumarate prepared in ethyl acetate and recrystallized from methylethyl ketone melts at 136-139°C.

Example VII.

By proceeding as in example II, but

starting with 3-dimethylsulfamoyl-10-(3-chloropropyl)phenthiazine (19.1 g), 4-hydroxy-4-hydroxymethylpiperidine (7.2 g),

ethanol (250 cc) and sodium carbonate (total

10.6 g) and isolate the base as in example III,

but replace the ether with ethyl acetate which

extraction solvent and sodium hydroxide with sodium carbonate to release

base, 3-dimethylsulfamoyl-10-(3-4'-hydroxy-4'-hydroxymethyl-1'-piperidylpropyl)phenthiazine (13 g) is obtained as a yellow oil,

whose hydrochloride, prepared in ethanol and recrystallized from methanol, melts with

216-220°C.

Claims (1)

Method of manufacture of therapeutically active phenthiazine derivatives of the general formula where X means a hydrogen or halogen atom, or an alkyl, alkoxy, acyl, alkoxycarbonyl, alkylthio, or alkane sulfonyl group, the alkyl, alkoxy, acyl and alkane groups not containing more than 4 carbon atoms, or a dimethylsulfamoyl, cyano or trifluoromethyl group, R means a hydrogen atom or a methyl group, and n is 1, 2 or 3, and their acid addition and quaternary ammonium salts, characterized in that a phenthiazine compound of the general formula where Z is the acid residue of a reactive ester, and R and X are as defined above, is reacted with the piperidine compound of the general formula where n is as defined above, and if desired, conversion of such an obtained phenthiazine base into an acid addition or quaternary ammonium salt.