DE2828358A1 - 2,3-DIHYDRO-1,4-BENZOXATHIINE - Google Patents

Description

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Patent application

Applicant: 3HKLL INl ¹ ERWATIOWALJi RESEARCH MAATSCHAPPIJ BV Carel van Bylandtlaan 30, The Hague, Miederlande

Title: 2,3-Dihydro-1,4-benzoxathiine

6292

2/0988

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1A-51 074

Applicant: Shell Int.

The invention relates to new 2,3-dihydro-1,4-benzoxathiines the formula

0 H

_ C - N - CH ₂ - CH =

(I)

in which η is 0 or 1, R is bonded to a carbon atom in the 6- or 7-position in the molecule and is a halogen atom, a nitro, methylsulfonylamino or trifluoromethyl group, an amino, alkyl or alkoxy group, the last two containing 1 to 6 carbon atoms, with a cycloalkyl group 3 to 6 carbon atoms or a phenyl group.

In these compounds, each alkyl or alkoxy group can be straight or branched chain. Preferably each contains such group no more than 3 carbon atoms. The expression "Halogen atom" denotes a bromine, chlorine, B'luor- or Iodine atom, whereby bromine and chlorine are preferred,

Individual 2,3-dihydro-1,4-benzoxathiines of the general formula I are given in the examples. Other typical compounds of the formula I are those in which η is 1 and R is the following Has meaning:

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Fluorine 6-nitro 6-trifluoromethyl 6-methoxy 6-amino 6-methylsulfonylamino

6-cyclohexyl 6-phenyl 7-methyl 7-nitro 7-amino 7-methylsulfonylamino

The compounds of the formula I according to the invention can be prepared are made by reacting a 2,3-dihydro-1,4-benzoxathiin-2-carboxylate the formula

(II)

in which R and η have the meaning given for formula I.

and R represents an alkyl group with allylamine in the presence

-ι

a solvent. The alkyl group R conveniently contains 1 to 5 carbon atoms and preferably methyl or Ethyl group. Ethanol is the preferred solvent. The reaction can advantageously be carried out under refluxing of the reaction mixture can be carried out. Preferably about a 4 to 6 fold excess of the amine is used. The compounds of formula I can be obtained by evaporation of the solvent and excess amine and application common methods, such as selective extraction, recrystallization and / or chromatography over a dry column.

The compounds of the formula I according to the invention can also be prepared by a process in which a 2,3-di hydro-1,4-benzoxathiine-2-carboxylic acid of the formula

(III)

809882/0 988

in dei 'R and η have the meaning given in formula I, is reacted with thionyl chloride and the resulting acyl chloride is reacted with allylamine in the presence of a Solvent. An excess of thionyl chloride is used, some of which serves as a solvent. Favorably the reaction is carried out with refluxing the mixture. The excess thionyl chloride is then evaporated and the acyl chloride can be isolated. Optionally, the crude product can be treated with excess amine, where necessary, a solvent such as methylene chloride is added to control the reaction and / or ensure that the reaction mixture remains liquid. The compound of formula I can from the reaction mixture, such as As stated above, 2,3-dihydro-1,4-benzoxythiine-2-carboxylates are isolated the B'ormel II can be prepared by reacting an alkyl 2,3-dibromopropionate with a 2-mercaptophenol of the formula

(IV)

in which R and η have the meaning given in formula I in the presence of a base such as potassium carbonate and a solvent, like acetone at or slightly above room temperature. The alkyl group in the 2,3-dibromopropionate desirably contains 1 to 5 carbon atoms and is preferably a methyl or ethyl group.

The 2-mercaptophenols occurring as precursors can be produced are obtained by a) diazotization of the corresponding R-substituted 2-aminophenol, b) treatment of potassium ethylxanthate

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M 358

rait the resulting Uiaζoniumsalζ and c) reduction of the resulting Xanthates with lithium aluminum hydride. Each of these reaction steps can be carried out according to the method as described on page 570 of Djerassie et al., J. Am. Chem. Soc, 77 568-571 (1955). 2-Amino-4 ~ - (trifluoromethyl) phenol were made as follows:

87.6 g of finely powdered sodium hydroxide were in individual portions within 8 hours with stirring to a solution of 164.0 g of 2-nitro-4- (trifluoromethyl) chlorobenzene in 220 ml of dimethyl sulfoxide given at room temperature. The mixture was left to stand overnight and then poured into 1.5 liters of cold water. The resulting mixture was acidified to pH 1 with concentrated hydrochloric acid. An oil resulted which separated and was dissolved in diethyl ether. The solution was over MgSO < dried and freed from the solvent under reduced pressure. The residue was washed with cold sodium hydroxide solution mixed. The mixture was extracted with petroleum ether, which aqueous layer acidified with concentrated hydrochloric acid and the resulting oil separated and dissolved in diethyl ether. The solution was dried over MgSO <and freed from the solvent. Man obtained 2 ~ nitro-4- (trifluoromethyl) phenol (A).

82.2 g of A were dissolved in 300 ml of ethanol. 0.5 g of platinum oxide was added as a catalyst and the mixture under a Hydrogenated under pressure of 450 kPa. The resulting solution was filtered and the filtrate was concentrated. The residue became from water recrystallized. 2-Amino-4- (trifluoro-methyl) phenol was obtained.

These compounds in which R is an amino group can be prepared by hydrogenation of the intermediate Esters in which R is a nitro group. The hydrogenation can be carried out in the usual way, e.g. B. by treating the ester occurring as a precursor in a solution in a solvent such as ethanol · with hydrogen, being a

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Catalyst, such as palladium on carbon, is present.

Such compounds in which R is a methylsulfonylamino group can be prepared by treating the precursor ester in which R is an amino group with methanesulfonyl chloride in a solvent such as methylene chloride and in the presence of a hydrogen halide acceptor such as triethylamine at a low temperature , e.g. B. 0 to 5 ⁰ C.

The 2,3-dihydro-1,4-benzoxathiines of the formula I can be used to direct lipogenesis of warm blooded animals, e.g. B. Domestic animals, zoo animals, herd animals, fur animals, such as B. dogs, cats, Merzen, sheep, goats, pigs, cattle, horses, mules, donkeys and poultry. The effect will obtained by administering an effective amount of one or a mixture of two or more 2,3-dihydro-1,4-benzoxathiines, orally or parenterally. The substances can be used as such or as an active ingredient in a conventional drug administered. The invention therefore also relates to medicaments for inhibiting the lipogenesis of warm-blooded animals, containing a 2,3-dihydro-1,4-benzoxathiin of the formula I, if appropriate together with a pharmacologically acceptable carrier. This is used to inhibit lipogenesis in warm-blooded animals orally or parenterally an effective amount of a 2,3-dihydro-1,4-benzoxathiine of the formula I or an agent containing such a compound. The compounds according to the invention or compositions containing these compounds can be administered orally in any conventional manner, e.g. B. as Solution or suspension by intubation, in the animal's diet, in a food additive or in the form of a preparation specially made for the administration of the drug will. Suitable preparations include solutions, suspensions, dispersions, emulsions, tablets, BoIi, powders, granules, Capsules, syrups and elixirs. For parenteral administration

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they can be in the form of a solution, suspension, dispersion or emulsion. They can be in the form of an implant or another preparation with a delayed release of the active ingredient. Inert pharmacologically acceptable carriers, like water, oils suitable for preservatives, gelatine, lactose, Starch, magnesium stearate, talc or vegetable gurams can be used.

The dose of 2,3-dihydro-1,4-benzoxathiine required to inhibit lipogenesis depends on the particular 2,3-dihydro-1,4-benzoxathiine used and the particular animal being treated. In general, however, satisfactory results are obtained when the 2,3-dihydro-1,4-benzoxathiine is administered in a dose of from about 1 to about 500 mg / kg body weight. The compounds can be administered as a single dose or in a series of doses on the same day or over several days. For each specific animal, special treatment should be given according to individual needs _; the particular 2,3-dihydr0-1,4-benzoxathiine used as the inhibitor and the experience of the person administering the agent or supervising the administration.

The invention is illustrated in more detail by the following examples. In the case of the preparative examples, the identity of the product and the intermediate stage (s) confirmed by appropriate chemical or spectral analyzes.

example 1

2,3-Dihydro-H-allyl-1,4-benzoxathiine-2-carboxamide (1)

To a mixture of 41.6 g of ethyl 2,3-dibromopropionate, 400 ml of dry acetone and 11.1 g of potassium carbonate was added dropwise under stirring at 27 ⁰ C a solution of 19.5 g of o-mercaptophenol in 75 ml of acetone. After the addition was complete, the reaction

809882/0966

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mixture was stirred for 10 min at room temperature and a further 50.9 g of potassium carbonate were added. The reaction mixture was then refluxed for 2 hours and allowed to stand at room temperature overnight. The mixture was filtered and the solid was washed with acetone and the washing liquid was added to the filtrate. The acetone was evaporated, wherein a liquid remaining, the ^"n Hethylenchlorid was added The resulting solution was evaporated washed with water over MgSO, dried and the solvent The resulting liquid was chromatographed on a dry column over silica gel to give a 4..: 16:80 mixture (volume) of tetrahydrofuran, ethyl acetate and hexane (solvent Wr. 2) was used as the solvent to give the ethyl ester of 2,3-dihydro-1,4-benzoxathiin-2-carboxylic acid (1A) as a light yellow Liquid whose boiling point has not been determined.

A solution of 4.5 g of 1A, 3> 4 g of allylamine in 25 ml of ethanol was heated to reflux for 20 h. The solvent and excess Amine was evaporated and the residue chromatographed on a dry column of silica gel, the solvent No. 2 was used as the eluent. Plan received (after extraction and removal of the solvent) 1 as a viscous yellow liquid, the boiling point of which was not determined.

Example 2

6-methyl-2,3-dihydro-H-allyl-1,4-benzoxathiin.-2-carboxamide (2)

A solution of 20.0 g of 4-methyl-2-mercaptophenol in 75 ml of acetone slowly became a mixture of 40.2 g of ethyl 2,3-dibromopropionate with stirring and 10.2 g of potassium carbonate in 400 ml of acetone were added at room temperature. The mixture was 10 min at room temperature stirred and then heated under reflux for 16 h, then filtered and the solids washed with acetone. The acetone filtrate was freed from the solvent, the residue was dissolved in methylene chloride and the solution was

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W2Ä358

wash, dried over MgSO ^ and freed from solvent. The liquid residue was chromatographed over a dry silica gel column with solvent no. 2 as the eluent. The first band (high Rf-V / ert) was collected and washed with diethyl ether extracted. The solvent was evaporated from the extract, the residue dried (vacuum, 24 h) and off Recrystallized hexane. The ethyl ester of 2,3-dihydro-6-methyl-1,4-benzoxathiin-2-carboxylic acid was obtained (2A) as white needles, m.p. 41-43 ° C.

A mixture of 10.4 g of 2A, 15 g of allylamine in 20 ml of ethanol was stirred at room temperature for 24 hours. The solvent was evaporated in vacuo and the residue was recrystallized from hexane. 2 were obtained as a solid, mp. 86-88 ⁰ C.

Example 3

6-chloro-2,3-dihydro-N-allyl-i _? 4-benzoxathiine-2-carboxamide (3)

-2-carboxylic acid-dihydro-1,4-benzoxathiin (3A), mp 64-66 ⁰ C as a solid, obtained from 4 - to in Examples 1 and 2 of the methods described ethyl ester of 6-chloro was - /. -Chlor-2-mercaptophenol.

3A was treated according to the procedure of Examples 1 and 2 with allylamine to give 1 as a solid, mp. 98-100 ⁰ C.

Examples 4 to 6 Attempts to prove the lipoftenesis inhibition;

The effectiveness of the compounds according to the invention was determined by immersing samples of pig fat tissue for a period of time in a liquid medium containing radioactive glucose and the compound of interest and then the lipid of that

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treated Gev / ebe isolated and the uptake of radioactive Carbon determined using scintillation counting techniques. These experiments were carried out on pig fat tissue, as the main site of lipogenesis in pigs the adipose tissue appears to be.

In detail, the experiments were carried out according to the following general Procedure carried out:

150 mg sections of pig adipose tissue were shaken for 2 h in 3 nl Krebs-Ringer bicarbonate solution containing half the normal calcium concentration, 60 / μmol glucose, 0.5 / UCi glucose-U ¹⁴ C and 300 μK insulin and 5 % dimethyl sulfoxide (DMSO) incubated. The compounds to be examined were added as a solution or suspension in DMSO and were present in a concentration of 100 / Ug / ml with the incubation mixture.

The incubation was terminated by adding 0.25 ml of 1 η sulfuric acid. The resulting mixture was extracted with a total of 25 ml of chloroform: methanol (2: 1 by volume). The extracts were washed according to Folch et al. (J. Biol. Chem., 226, 497-509, (1957)), air-dried and placed in a liquid scintillation counter with 15 ml of counting liquid (2 parts of toluene, containing 0.4 % w / v, New England Nuclear Omnifluor and 1 part Triton X-100) counted. The experiments were run in triplicate and were accompanied by comparative experiments in which all ingredients, amounts and conditions were the same with the exception that no test compound was added. From the data obtained, the percent inhibition of lipid synthesis by the test compound was calculated. The values obtained in the experiments are reported in Table I as the percentage inhibition of lipogenesis compared to the results obtained in the comparative experiments in which only the test compound was omitted.

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Table I.

Example Wr. Compound No. Percent Inhibition

4 1 63

5 2 63

6 3 54

SG9882 / O9S6

Claims (8)

Claims in which η is O or 1 and R to a carbon atom in 6-or 7-position of the molecule is bonded and a halogen atom, a nitro, methylsulfonylamino or trifluoromethyl group, an amino, alkyl or alkoxy group, the latter being mentioned both groups contain 1 to 6 carbon atoms, a cycloalkyl group with 3 to 6 carbon atoms or a Means phenyl group. 2. Compounds according to claim 1, characterized in that R is a bromine or fluorine atom. 3. Process for the preparation of the compounds according to claim 1, characterized in that a 2,3-dihydro-1,4-benzoxathiine-2-carboxylate the formula (R) (II) 809882/0966 in which R and η have the meaning given for formula I. -ι
and R is an alkyl group, reacted with allylamine in Presence of a solvent. 4. The method according to claim 3, characterized in that R in formula II contains 1 to 5 carbon atoms, preferably a methyl or ethyl group. ¹ 5. Process for the preparation of the compounds according to claim 1, characterized in that one 2,3-Uihydro-1,4-benzoxathiine-2-carboxylic acid of the formula Il C-OH (III) in which R and η have the meaning given for formula I, reacts with thionyl chloride and the acyl chloride formed reacts with allylamine in the presence of a solvent. 6. The method according to claim 3 to 5, characterized in that R in the formulas II and III is a bromine or Means chlorine atom on a carbon atom in 6-position. 7. The method according to claim 3 to 5, characterized in that R in the formulas II and III is a methyl group in the 6-position. 8. Agent for inhibiting lipogenesis in warm-blooded animals, characterized in that it is used as an active ingredient one or more of the compounds according to claim 1, optionally Contains together with usual carriers and / or auxiliaries. 6292 809882/0966