DE1470215A1 - New heterocyclic compounds and processes for their preparation - Google Patents

Description

fotenl-Anwäil

Dr. V /. Rogue
Dipl.-In ₃ . Peter Wirth

DipUnrj. G. Dc.nnor.berg 1470215

Dr V. ScWoJ-Kowarzik ' Dr. P. Weiniioid

Sandoz AG * Frankfurt a Main Case 1531 Basel ** · S "* ·· * ·« » Sk. 39

New heterocyclic compounds and processes for their Manufacturing

The present invention relates to new heterocyclic compounds, namely thiaxanthene derivatives of the general Formula I, in which R- is chlorine, an alkoxy or alkyl mercapto group n with 1 - 4 carbon atoms each, and P.p one Mean alkyl group with 1-4 carbon atoms, and Ver ' drive to their production.

The method according to the invention is characterized in that that: - ■ -

compounds of the general formula IV, in which R ₁ and R _{2 have the} above meanings, are treated with dehydrating agents and the compounds of the general formula I obtained are optionally converted into their acid addition salts in catfish known per se «

The compounds of general formula I are obtained ™

according to the invention by the thiaxanthenol derivative of .Formula IV with dehydrating agents, such as phosphorus oxychloride, acetic anhydride, polyphosphoric acid, Sulfuric acid, reacts at an elevated temperature. The elimination of water from the thiaxanthenol derivative can also be used advantageously with conc. Hydrochloric acid can be run at room temperature.

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To isolate the end product, the reaction solution, optionally after removing excess dehydrating agent in vacuo, on ice poured, made alkaline with an alkali hydroxide solution, and the thiaxanthene derivative with a with Water immiscible, organic solvent, preferably chloroform, extracted, the end product is isolated and purified by known methods and optionally converted into its acid addition salts.

Compounds of the general formula IV can be obtained be by a thlaxanthone of the general formula II, wherein R, has the above meaning with

an organometallic compound of the general formula III, in which Rp has the above meaning, Me means divalent metal and Hai stands for chlorine, bromine or iodine, converts the reaction product to the Thiaxanthenol derivative of the general formula IV hydrolyzed and optionally converted into its salts.

For example , the compounds of the general formula TV can be obtained as follows *

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.Activated magnesium chips are covered with a anhydrous open-chain or cyclic ether, e.g. tetrahydrofuran, and leaves an N-alkyl-4-halopiperidine drip.

The activation of the magnesium takes place according to known methods, e.g. with iodine, bromine or HgClp. Instead of pure magnesium, a magnesium-copper alloy (according to Gilman) can also be used.

The Orignard solution prepared in this way is then mixed with a thiaxanthone, and the reaction mixture during heated for several hours. The solvent is removed under reduced pressure, and the organometallic Treated complex with aqueous ammonium chloride solution.

The thiaxanthenol derivative IV is after-known metho- " the isolated and cleaned.

The thiaxanthene derivatives prepared according to the invention are viscous or viscous at room temperature

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crystalline bases, resistant to inorganic or organic acids, at room temperature form crystallized salts.

The novel thiaxanthene-A derivatives prepared according to the invention are suitable for use as medicaments because of their excellent pharmacodynamic properties. Above all, they are highly effective Antihistamines / which are particularly well tolerated. They also have anesthesia-potentiating, adrenolytic, sedative and antipyretic effects and can also are used as intermediates in the manufacture of drugs.

According to the invention, suitable starting materials are used of formula II to use those «those in the 3-position a chlorine atom, a lower alkoxy group (e.g. a methoxy, ethoxy, propoxy, isopropoxy, butoxy or isobutoxy group) or a lower alkyl mercapto group (e.g. a methyl, ethyl, propyl, ieopropyl, Butyl or isobutylraercapto group).

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The thiaxanthones used as starting materials are prepared by condensing thiosalicylic acid with halogenobenzenes substituted in the m-position and the reaction product with Sulfuric acid conc. or cyclized with thionyl chloride and aluminum chloride.

In the following examples, which illustrate the implementation of the process, but the invention in should not restrict any V / eise, all temperatures are given in degrees Celsius and have been corrected.

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II

HaI-Me-

III

IV

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Example It> Chlor-9- (N-methyl-piperidylidene-4 '). thiaxanthene

15.27 g ^ -

xanthenol- (9) (Snip. 192-194 °) with j> 8 ccra conc. Hydrochloric acid heated in an oil bath at 95 ° for 1 1/2 hours. After dilution with} 8 ecm of water, it is mixed with conc. Ammonia is added until the phenolphthalein-alkaline reaction is achieved and the crystalline base which has separated out is filtered off. After crystallization from acetone, the pure ^ -Chlor-9- (N-methylpiperidylidene-4 ^f ) -thiar.anthen vom Sm ?. 141-110 °.

Malemate: 8.94 g of the free base and 5 * 32 & Maleic acid are m 80 ecm abs. Dissolved ethanol. The maleate which precipitated in crystalline form on cooling becomes from abs. Recrystallized ethanol. The pure 3-chloro-9- (N-methyl-piperidylidene-4 ') - thiaxanth ^ n-maleate obtained has a melting point of 125-127 ° vesicles, according to Smt. from 120 °. -. The substances used as the starting material are manufactured as follows:

^a ) §zi FrPMPrP ^ PylJr thi psali ογ isäure ^ 2LO0 s thiosaicylic acid, 12.5 S copper br once, 17.5 g potassium iodide and 900 com methyl carbitol (Diaethylene glycol monoaethyIaether) are at 100 ° below

Stir in portions with a total of 269 g potash

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sets and heated to 200 ° with descending cooler. Then for 1 hour 273 & m-Bromchlorbeniol added dropwise (dissolved in 250 cc of methyl carbitol), and boiled for 15 hours at 200 °. The methyl carbitol is then concentrated in vacuo at 150 °, the hot residue is dissolved in 2.0 liters of water, filtered and acidified with hydrochloric acid 1: 1. The precipitated carboxylic acid [S- (m-chlorophenyl) -thiosalicylic acid] is sealed off, dried and recrystallized from glacial acetic acid. M.p .: 192-1 ^ 4 ° C const.)

159 g of S-Cm-chlorophenylJ-thiosalicylic acid .at room temperature with stirring in 320 ecm (59Og) conc. Entered sulfuric acid and heated to 115 ° for 2 hours, then cooled \ ind stirred into 650 ecm of water. It will be abbreviated washed out, dried. Then recrystallized from xylene, then from glacial acetic acid. The 3-chlorothiaxanthone obtained has a constant melting point of 176 ° -178 °.

ο) ^ -Chlor- ^ CN-methyl-piperidyl-J ^) - thiaxanthenol- (9)

In a well-dried. Apparatus are 5 # 91 fe Magnesium shavings covered with tetrahydrofuran and with an iodine crystal and a few drops 909819/1212

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Etched ethylene bromide. Then leave 52.5 6 Add dropwise N-methyl-4-chloropiperidine so that the Reaction always remains in motion. At the same time will the difference between the amount of tetrahydrofuran put in front and yO ecm was added dropwise. After finished The addition is allowed to stir for a further 1 hour at 80 ° oil bath temperature, then adjusted to 45 ° oil bath temperature represents. During one hour, a total of 40.0 g of 3-chlorothiaxanthone are entered in portions, w-> at the internal temperature rises to 50 °. At the end, the oil bath temperature is set to 65 ° for another hour heated. The cooled reaction mixture is poured into a mixture of 32 g of ammonium chloride and 130 g of ice and 130 ecm V / water entered and filtered the excreted substance. After crystallizing twice from acetone, the pure 3-chlorine - ^ - (N-methyl-? Iperidyl-4 ') -thiaxanthenol- (9) from Srap. 192-194 °. Fumarates 3.36 g of the free base and 1.18 g

Fumaric acid are in Ip ecm abs. Dissolved ethanol. BxJira cooling fills the fumarate in crystalline form and becomes from abs. Recrystallized ethanol. The pure 3-chloro-y- (N-methyl-piperidyl-4) -thiaxanthenol- (9) -furaarat obtained has a melting point of 158-160 ° unites, from 145 ·.

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Example 2: ^ -Methoxy-g-CNTmethyl-piperidylidene- V) thiaxanthene

8.0 g of 3-methoxy-9- (N-methyl-piperidyl-V5-thiaxanthenol- (9) with 10.0 ecm of acetic anhydride and 1.0 g of anhydrous sodium acetate for 5 hours. boiled at reflux at 170 ° oil bath temperature. Most of the acetic anhydride is then _ Send distilled off in a partial vacuum, the evaporation residue dissolved in 75 ecm chloroform and concentrated in a mixture of 15 ecm. Caustic soda and 50 ecm Stir in ice water. After the chloroform layer has been separated off, 25 ecm of chloroform are added extracted, washed with 25 ecm of water, dried and concentrated. The evaporation residue is crystallized twice from acetone for further purification, the analytically pure 3-methoxy-S-CN-methyl-piperidylidene-VJ-thiaxanthene from the

M.p. 172-174 ° is obtained.

i '6.0 g of base are dissolved in 50 cc of abs · ethanol and treated with ethanolic hydrogen chloride until acidic to Congo reaction. After good cooling, suction is performed and 25 ecm abs. Ethanol crystallizes. The analytically fine j-methoxy ^ -iN-raethyl-piperidylidene- * ¹ ) -thia xanfchen -chlorhydrat obtained has the mp * 174-176 °

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.Ground the substances used as starting material manufactured as follows:

s - (. ir - «" ethoxyphenyl) thiosalicylic acid

The S- (m-kethoxyphenyl) -thiosalicylic acid is prepared analogously to Example la from 200 g of thiosalicylic acid and 2β7 g of a-broa ^ nisol. M.p. 171-173 °. . ·

b) 3-kethoxythiaxanthone

A mixture of 47.0 g of S - (.- n-methoxyphenyl) thiosalicylic acid, 14.5 cca thionyl chloride, 2.0 cca Dimethylfor .- = a = id as well as 170 ecm nitrobenzene heated with stirring for 2 hours at 60 °. Then v / ground 1/4 hour in portions totaling 25.3 S aluminum chloride entered and then heated to 80 ° for 1 hour. Then slowly 25 cca Hydrochloric acid conc. added dropwise. After adding 50 ecm of water, a total of 300 ecm of chloroform is added extracted and after washing with 100 cca water and drying over potash the chlorofora distilled off. The nitrobenzene is then distilled off in vacuo at a 160 ° oil bath. The concentration residue is crystallized once from xylene and then from benzene. The pure 3-kethoxy-thiaxanthone has the smp '. 133-135 °

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_BA0 ORIGINAL

U70215 ₁₅₅₁

o) 3?

thiajcanthenol- [9) '

From 19.4 g of N-methyl-4-chloropiperidine and 23.4 g of 3-kethoxythiaxanthone (Sn: p. 133-135 °), can receives analytically pure 3-methoxy-9- (Nn: ethyl -piperidyl-4 ^f ) -thiaxanthenol- (9) from STp 172-17 ^ °.

Example 3: 3-Methylr.ercapto-9- (H ~ r, ethyl ~ piperidyllden 4 *) -thlaxanthene

The above compound is obtained by splitting off water from 3-Hethyl3-.ercapto-9- (ii-n: «tnyl-piperidyl-4 ') -thiaxanthenol- (9) in a manner analogous to Example 2

won.

Chlorohydrate ^ ^ »23 g of base are in 15 cca abs. Dissolved ethanol and mixed with methanolic hydrogen chloride until the Congo-acidic reaction occurred. After J ₀ good cooling, suction is carried out and 7 ecm abs.

co ethanol crystallizes. The resulting, analytically pure 3-methylxercapto-9- (ii- = ethyl-piperidylidene- ^ IV) -thiaxahthene chlorohydrate has the sap. 176-173 ·. ro

^ The substances used as starting material are manufactured as follows:

The S-Cm-Kethylcercapto-phenylJ-thiosalicylsäursAD original is prepared in a manner analogous to Example 1a from 200 g of thiosalicylic acid and 290 g of m-bromothioanisole.

U70215

put {Sz ?. 159-161 °) and the 3-methylmercaptothiaxanthone from Sasp. 149-151 °, also in to

Example To analogous way, by intramolecular Ringschltiss obtained from it.

From 19.4 g of N-methyl-4-chloropiperidine and 25.0 g 3-Methyl2: ercapto-thiaxanthone receives nan in an analogous way Way for example ic the analytically pure 3-Methylaercapto ^ -O ^ ethyl-piperidyl-V ) -thiaxanthenol- (9) voa Sz ?. 195-197 °.

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Example 4; ^ -Aethylmeroapto-g-CN-methyl-piperidylidene- '4') -thiaxanthene

19 * 0 g 3-AethylEercapto-9 - (: i-ethyl-piperidyl- ⁱ 0-thiaxanthenol- (9) v; earth with 21.5 cca acetic anhydride and 2 g anhydrous sodium acesate for 5 hours at 170 ° bath temperature under reflux The major part of the acetic anhydride is then distilled off in a partial vacuum, the evaporation residue is dissolved in 150 cca chloroform and stirred into a mixture of 35 cca of concentrated sodium hydroxide solution and 125 cc of sisvane. After the chloroform layer has been separated off, extraction is carried out with 50 cca of chloroform 50 ecm of water washed out, dried and concentrated. The Sindanip residue is crystallized from 90 ecm of absolute ethanol. The pure 3-ethylmercapto-9 - (ji-se thyl -piperidylidene-4) -thiaxanthene has the sap. 138 ° - l4o °.

The substances used as starting materials are manufactured as follows:

a) m-Aethylr.ercapto-crcrcbenzene

m-Aethylcercapto-aniline is diazotrated into the Diazonium salt converted and this according to Sandmeyer in hydrobromic acid solution with copper (i) bromide implemented. The n-ethylniercapto-bromobenzene obtained has a boiling point of 122P-123 ° / 11 mm.

b) S- (3-Ethylr.er cap-to-phenyl) -thiosalipylic acid

200 g of thiosalicylic acid, 12.5 Z of copper bronze, 21.5 S of potassium iodide and 900 ecm of dietethylene glycol xonomethyl ether are added in portions at 100 ° with stirring with a total of 270 g of potassium carbonate and heated to a bath temperature of 200 ° with a descending cooler. Then 310 g of m-ethylmercapto-bromobenzene dissolved in 300 ecm of di-ethylene glycol monomethyl ether are added dropwise over the course of 1 hour and the bath is heated for 15 hours at 200 °

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BATH ORIGINAL

stirs. Then, at a ^{bath temperature of 150 0,} the di-ethylene glycol monomethyl ether is distilled off in vacuo, and the residue is dissolved in 2.0 liters. Dissolve hot water, filter and make 16 % Congo acidic with approx. 500 ecm hydrochloric acid. The precipitated carboxylic acid is suction filtered and 1.5 ltr. Recrystallized ethanol. The pure S- (3-ethylmercapto-phenyl) -thiosalicylic acid has the snip. 142 ° -144 °.

100 g of S'to-Aethylrsercapto-phenyiJ-thiosalicylic acid at room temperature with stirring in 200 ecm (368 g) conc. Sulfuric acid entered ^ heated to 115 ° bath temperature for 2 hours, then cooled and in 2.0 ltr ice water is stirred in. It is sucked off, washed out and dried. The odor is derived from oCO ecm Xylene recrystallized. The pure 3-Aethylssrcaptothiaxanthone shows the Sn: p. 135 ° -l40 °.

thenol- (9)

In a well-dried apparatus, 4.68 g of magnesium shavings are obtained covered with tetrahydrofuran and thylenbrosiid with an iodine crystal and a few drops of ethylene etched. Then can 25.3 g of H-Methy 1-4-chlorpiperidJ.n Add drops in such a way that the reaction always remains in motion. At the same time, the difference between the submitted Amount of tetrahydrofuran to 100 cca added dropwise,! Iach When the addition is complete, 1 hour at a bath temperature of 8 ° C left to stir, then set to 45 ° bath temperature During one hour, a total of 35 * 0 g of 3-Ae thy liner cap-to-thiaxanthon are entered in portions, with the internal temperature rises to 50 °. Too the end will be heated to 65 ° bath temperature for one hour. The cooled down The reaction mixture is poured into a mixture of 25 g of ammonium

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Chloride, 100 g ice and ICO ecm water entered and the precipitated base sows a total of 250 ccc chloroform extracted. After washing out the chloroforal solution cit 100 ecm water, it is dried over potassium carbonate, filtered and concentrated in the partial vacuum. The concentration residue is crystallized from ISO cca ethyl acetate. Da3 pure 3-ethylnerca? Tc-9- (N-cstfcyl-piperidyl- ² i *) -thiaxanthenol- (9) has the S = ?. 131 ° -133 ° and crystallizes with one: Quarterly Krlstallxasser.

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Claims (1)

U70215 Patent claims: 1. New thiaxanthene derivatives of the general formula I, in which R, chlorine, an alkoxy or "alkyl mercapto group each having 1-4 carbon atoms and R ₂ an alkyl group having 1-4 carbon atoms, and their acid addition salts. 2. Process for the preparation of new thiaxanthene derivatives, characterized in that compounds of the general Formula I, wherein R, and Rp are given in claim 1 Have meaning, by splitting off Kasser from compounds of the general formula IV, wherein R. and Rp have the above meaning, represents and the thus obtained If appropriate, compounds are converted into their acid addition salts in a manner known per se. 5. remedies, characterized in that λ partially or entirely from the new Thiaxanthenderivat of the general formula I wherein R ₁ and Rp have the above meanings, is. 37 / srAr The patent attorney: ORIGINAL INSPECTED 909019/1212 ^0R