text:
Xanthene and thioxanthene derivatives
The present invention relates to novel thioxanthene and xanthene derivatives which have useful pharmacodynamic activity, such as neuroleptic activity and antiemetic activity, methods for the preparation of said derivatives, pharmaceutical compositions containing same, and a method for the treatment of psychic disorders by administering a therapeutically active amount of one of said derivatives to a living animal body, including human beings.The new compounds of the present invention corresponds to the Formula I: ##STR1## wherein X is a halogen atom, an alkyl group with from one to four carbon atoms inclusive, an alkyloxy group with from one to four carbon atoms inclusive, a methylthio group, a methylsulphonyl group, a dimethylsulfamoyl group, a trifluoromethyl group or an acetyl group;Y is hydrogen, fluorine or a methyl group;Z is oxygen or sulphur;n is an integer from zero to three inclusive, andR is a cycloalkyl group with from four to six carbon atoms inclusive in the ring substituted with from one to four substituents selected from optionally esterified hydroxy- or hydroxymethyl groups, methyl groups, amino groups, acetamido groups, mesylamino groups or oxo groups, a five- or six-membered saturated heterocyclic ring having one or two heteroatoms selected from oxygen and nitrogen atoms and being optionally substituted with an optionally esterified hydroxy group or oxo group, any esterified hydroxy group present being an ester of an aliphatic carboxylic acid having from ten to twentytwo carbon atoms inclusive, as well as their non-toxic pharmaceutically acceptable acid addition salts.
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In the past, several drugs having a tricyclic structure have been found useful in the treatment of severe psychotic disorders, especially of the schizophrenic type. Some of these drugs are thioxanthenes which are substituted in the 2-position of one of the benzene rings, and some of the most active are described in U.S. Pat. No. 3,116,291. Recently some thioxanthenes having a fluoro atom in the 6-position have been described, for example in U.S. Pat. No. 4,042,695 as having neuroleptic properties of the same level as the known thioxanthene-neuroleptics but a much lower level of pharmacological effects associated with extrapyrimidal symptoms. Further, some piperidylidene-thioxanthene derivatives having almost no extrapyrimidal side effects have been described in Belgian Pat. No. 835,224. However, the said known thioxanthene compounds which have the lowest extrapyrimidal side effects also have relatively short-acting neuroleptic effects.SUMMARY OF THE INVENTION
According to the present invention it has now surprisingly been found that the compounds of Formula I as well as their non-toxic acid addition salts have both strong and very long-lasting neuroleptic effects and, at the same time, a pharmacological profile which indicates relatively low extrapyrimidal side effects when they are evaluated according to standard reliable published test methods. They also have a low acute toxicity compared with related thioxanthene derivatives, which makes the therapeutic index favorable. Moreover, they have moderately strong anticholinergic effects, and comparatively low undesired sedative effect.
This invention also includes pharmaceutically acceptable salts of the compounds of Formula I formed with non-toxic organic acids. Such salts are easily prepared by methods known to the art. The base is reacted with either the calculated amount of organic or inorganic acid in an aqueous miscible solvent, such as acetone or ethanol, with isolation of the salt by concentration and cooling or an excess of the acid in aqueous immiscible solvent, such as ethyl ether or chloroform, with the desired salt separating directly. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, embonic, succinic, oxalic, bis methylene-salicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-amino-benzoic, glutamic, benzene sulfonic and theophylline acetic acids as well as the 8-halotheophyllines, for example 8-bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. Of course, these salts may also be prepared by the classical method of double decomposition of appropriate salts, which is wellknown to the art.
The compounds of Formula I may exist in form of isomers of the cis-trans type, and the present invention comprises the single isomers as well as mixtures of the isomers. The novel xanthene and thioxanthene derivatives of the invention may be administered both orally and parenterally, for example in the form of tablets, capsules, powders, syrups, suppositories or solutions or suspensions for injection.
The invention moreover relates to a method for the preparation of the novel compounds of Formula I, which comprises (a) reacting a compound of the following formula: ##STR2## wherein X, Y and Z are as defined above with a reactive ester of a compound of the formula
wherein n and R are as above defined and any hydroxy or amino group present is protected by esterification, or
(b) reducing a compound of the formula: ##STR3## wherein Y and Z are as defined above, R.sub.1 is as R except that it has no oxo-group and any hydroxy group is protected, X.sub.1 is a halogen atom, an alkyl group with from one to four carbon atoms inclusive, an alkyloxy group with from one to four carbon atoms inclusive, a methylmercapto group or a trifluoromethyl group; and "m" is an integer from zero to two, with lithium aluminium hydride, or
(c) reducing a compound of the formula: ##STR4## wherein X.sub.1, Z and Y are as defined above, and U is --COOH or --OOC.phenyl with lithium aluminium hydride in order to obtain a compound of the formula: ##STR5## wherein X.sub.1, Z and Y are as defined above and U.sub.1 is --CH.sub.2 OH or --OH respectively, or
(d) reducing a compound of the formula: ##STR6## wherein X.sub.1 and Y are as defined above with lithium aluminium hydride in order to obtain a compound of the formula: ##STR7## or
(g) oxidizing a compound of the formula: ##STR8## wherein X.sub.1, Z, Y and n are as defined above, by means of a ketone in the presence of an aluminum alkoxide, in order to obtain a compound of Formula I, wherein R is a cyclohexanone group, whereupon the compound of Formula I obtained is isolated, and any hydroxy group present optionally esterified with a reactive derivative of an aliphatic carboxylic acid having from ten to twenty-two carbon atoms inclusive and, if desired, acetylating or mesylating any amino group present in wellknown manner, as the free base or a non-toxic acid addition salt thereof.
Several of the intermediates of Formula II and all the intermediates of Formula III-VII are novel compounds and fall within the scope of the present invention.
The intermediates of Formula II may conveniently be prepared according to the following reaction scheme: ##STR9## except that X may not be an acetyl group.
When preparing compounds of Formula II wherein X is acetyl they may conveniently be prepared as described in Belgian Pat. No. 558,171 according to the following scheme ##STR10## the further processing being as described above.
The intermediates of Formula III may conveniently be prepared in the following way:
II+Cl OC (HC.sub.2).sub.m.R.sub.1 .fwdarw. III
any protecting group being removed before reduction with lithium aluminum hydride.
Any other obvious chemically equivalent method for the preparation of the amides of Formula III may of course be used.
The intermediates of Formula III may also be prepared in the following way: ##STR11##
The intermediates of Formula IV may according to the invention be prepared by a reductive alkylation of compounds of Formula II with compounds of the formula: ##STR12## wherein U is as defined above by means of sodium cyanoboron hydride (NaCNBH.sub.3).
The intermediates of Formula V, where --COOH is in ortoposition, may according to the invention be prepared by reacting a compound of Formula II with 1,2-cyclohexanedicaboxylic acid anhydride.
Some of the xanthones and thioxanthones used as starting materials for the preparation of the intermediates of Formula II are known substances, the preparation of which is described for example in U.S. Pat. Nos. 3,116,291 and 4,042,695 and Belgian Pat. No. 558,171. Others are new but they are prepared by methods known in the art for the preparation of similar substances.
In method (a) the reactive esters of the compounds of formula HO.(CH.sub.2).sub.n.R may according to the invention conveniently be esters of hydrogen halide, such as hydrogen chloride or hydrogen bromide, or esters of organic sulphonic acids, such as methane sulphonic acid, ethane sulphonic acid, p-toluene sulphonic acid or the like. Otherwise, the reaction (a) is a wellknown reaction type, which is normally carried out in inert organic solvents and under basic conditions in order to neutralize the acid formed by the reaction.
The reductions according to methods (b), (c) or (e) may according to the invention conveniently be carried out by lithium aluminium hydride or similar reducing agents which will not at the same time reduce the double bond between the thiaxanthene and piperidine rings.
The oxidation according to method (g) of the invention is a socalled Oppenauer Oxidation and may according to the invention be carried out in the presence of an excess of a ketone (preferably cyclohexanone or acetone), in the presence of an aluminium alkoxide (preferably aluminiumisopropoxide).
The optional esterification of any hydroxy group or groups present in the compound of Formula I may according to the invention conveniently be carried out by a reactive derivative of the carboxylic acid having from ten to twenty-two carbon atoms inclusive, such as an acid chloride or anhydride. As carboxylic acids may be mentioned decanoic acid, palmitic acid and behenic acid.
The optional acetylation or mesylation of any amono group present in a compound of Formula I may be carried out in conventional manner by treatment with acetic anhydride, acetylchloride or mesylchloride.
The methods of the invention shall in the following be illustrated by some examples which may not be construed as limiting:EXAMPLE 1 Preparation of the starting compounds of Formula II: 4-(2-trifluoromethyl-6-fluoro-9-hydroxy-9-thioxanthenyl)-1-methyl piperidine.
In a 3 liter three necked flask equipped with stirrer, reflux condenser and separatory funnel were placed 60 grams of magnesium filings, 1.5 liter of dry tetrahydrofuran and a few crystals of iodine, whereupon 1 milliliter of ethylene bromide was added and the mixture warmed until the reaction starts. After the reaction has been completed 300 grams of freshly distilled 4-chloro-1-methylpiperidine were added while stirring at a rate which makes the reaction mixture boil by the heat of reaction. After the addition has been completed the reaction mixture was heated under reflux for three hours. Thereafter the reaction mixture was cooled in an ice bath and 430 grams of 2-trifluoro-acetyl -6-fluoro-9-thioxanthone (preparation described in U.S. Pat. No. 4,042,695) were added portion-wise while stirring and keeping the temperature at 10-20 degrees Centigrade. Thereafter the reaction mixture was stirred without cooling for 30 minutes. The dark coloured reaction mixture was poured onto crushed ice, acetic acid was added until the magnesium hydroxide precipitated had been dissolved, and the aqueous phase washed with 4 liters of ether. The organic phase was extracted twice with 1 liter of 10% acetic acid. The combined aqueous phase was made basic with aqueous ammonia and the base which separated out was extracted with ether. The ether extract was dried over anhydrous potassiumcarbonate, treated with active carbon and evaporated to a volume of about one liter. By cooling and standing 385 grams of 4-(2-trifluoromethyl-6-fluoro-9-hydroxy-9-thioxanthenyl)-1-methyl-piperidi ne were obtained as white crystals which melted at 250-255 degrees Centigrade.
In corresponding manner the xanthenols and thioxanthenols of this formula were prepared:
______________________________________ ##STR13## MP in degrees X Y Z Centigrade ______________________________________ 2-CF.sub.3 H S 240-242 2-Cl H S 200-205 2-Cl F S 225-230 2-SCH.sub.3 H S 190-195 2-SCH.sub.3 F S 180-189 3-F H S 195-198 3-F F S 210-211 2-CH.sub.3 F S 200-220 2-F CH.sub.3 S 178-180 2-SO.sub.2 N(CH.sub.3).sub.2 F S 210-220 2-SO.sub.2 CH.sub.3 H S 252-260 2-OCH.sub.3 F S 183-185 2-CF.sub.3 CH.sub.3 S 235-238 ##STR14## H S 206-208 2-OCH.sub.3 H S 175-177 2-SCH.sub.3 F O 164-166 2-Cl H O 205-210 ______________________________________ 4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)-1-methyl-piperidine.
100 grams of 4-(2-trifluoromethyl-6-fluoro-9-hydroxy-9-thioxanthenyl)-1-methyl piperidine were disssolved in a mixture of 500 milliliters of glacial acetic acid and 300 milliliters of concentrated hydrochloric acid. The reaction mixture was heated under reflux for 21/2 hour, whereupon the major part of the acid mixture was distilled off and the residue poured into ice water. The aqueous solution was made basic with aqueous ammonia and extracted with ether. The ether phase was dried over anhydrous potassium carbonate, treated with active carbon and evaporated to about 300 milliliters. Upon cooling and standing 76 grams of 4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)-1-methyl-piperidine were obtained as white crystals which melted at 100-102 degrees Centigrade.
In corresponding manner were prepared the compounds of the following formula:
______________________________________ ##STR15## MP in degrees X Y Z Centigrade ______________________________________ 2-CF.sub.3 H S 100-102 2-Cl H S Oil 2-Cl F S 130-132 2-SCH.sub.3 H S 104-106 2-SCH.sub.3 F S 114-117 3-F H S 115-117 3-F F S 138-140 2-CH.sub.3 F S 90-92 2-F CH.sub.3 S 93-96 2-SO.sub.2 N(CH.sub.3).sub.2 F S 160-162 2-SO.sub.2 CH.sub.3 H S 162-166 2-OCH.sub.3 F S 125-127 2-CF.sub.3 CH.sub.3 S 157-160 2-COCH.sub.3 H S 125-127 2-OCH.sub.3 H S 102-104 2-SCH.sub.3 F O 134-136 2-Cl H O Oil ______________________________________
The compound 4-(2-acetyl-9-thioxanthenylidene)-1-methylpiperidine, was prepared in the following way:
140 grams of the ethylene glycal ketal of 2-acetyl-9-(1-methyl-4-piperidyl)-9-thioxanthenol (MP 206-208 degrees Centigrade) were heated for two hours under reflux with a mixture of 1500 milliliters of propionic acid and 100 grams of 2-sulfobenzoic acid anhydride. Thereafter the mixture was evaporated in vacuum, the residue dissolved in water and made alkaline. The base which separated out was extracted with ether, the ether phase dried over anhydrous potassium carbonate and evaporated until beginning crystallization. The crystals were sucked off and dried. - 50 grams of 4-(2-acetyl-9-thioxanthenylidene)-1-methyl-piperidine were obtained melting at 125-127 degrees Centigrade.1-(2,2,2-trichloroethoxycarbonyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanth enylidene)piperidine
A mixture of 150 grams of 4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)-1-methylpiperidine, 100 grams of the 2,2,2-trichloroethylester of chloroformic acid and 1 liter of dry benzene were heated under reflux for 16 hours. After cooling the benzene solution was washed with dilute hydrochloric acid and dilute sodium hydroxide solution, dried over anhydrous potassium carbonate, filtered and evaporated in vacuum. Thereby somewhat impure 1-(2,2,2-trichloroethoxycarbonyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxant henylidene)piperidine was obtained as an yellow oil which was used in the next step without further purification. Yield: 219 grams.4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)-piperidine
The oil from the previous step was dissolved in 2.5 liters of 90% aqueous acetic acid; the solution was cooled to below 10 degrees Centrigrade and while stirring were added 290 grams of zink which just before had been washed with dilute hydrochloric acid, dilute sodium hydroxide solution, water, ethanol and ether. The temperature rises by the heat of reaction to 15-20 degrees Centrigrade. After 15 minutes the ice bath was removed and the stirring continued for further 3 hours. During this stage the temperature rised to 25-30 degrees Centigrade.
Thereafter the reaction mixture was filtered, washed with 90% aqueous acetic acid, evaporated in vacuum; water was added to the residue and aqueous ammonia added until basic reaction. The base which separated out was extracted with ether, the ether extract dried over anhydrous potassium carbonate and filtered. After evaporation the residue was crystalllized from ether-petroleum ether (1:1). 116 grams of 4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)-piperidine were obtained as white crystals which melted at 125-130 degrees Centigrade.
In corresponding manner were prepared the following starting materials of Formula II
______________________________________ ##STR16## II X Y Z MP in degrees Centigrade ______________________________________ 2-CF.sub.3 H S 116-118 2-Cl H S 137-140 2-Cl F S 135-136 2-S . CH.sub.3 H S 130-131 2-S . CH.sub.3 F S 128-132 3-F H S 126-128 3-F F S 148-150 2-CH.sub.3 F S 122-126 2-F CH.sub.3 S 125-127 2-SO.sub.2 N(CH.sub.3).sub.2 F S 196-198 2-SO.sub.2 CH.sub.3 H S 140-180 (amorph.) 2-OCH.sub.3 F S 130-135 2-CF.sub.3 CH.sub.3 S 135-137 2-CO . CH.sub.3 H S 115-117 2-OCH.sub.3 H S 122-124 2-S . CH.sub.3 F O 118-128 2-Cl H O 140-145 ______________________________________EXAMPLE 2 (Method b)) 1-(Trans-4-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxa nthenylidene)piperidine
In a separatory funnel were placed a solution of 23 grams of 4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine in 100 milliliters of toluene and a solution of 15 grams of potassium carbonate in 100 milliliters of ice water, whereupon trans-4-acetoxycyclohexanecarbonyl chloride prepared from 13 grams of corresponding acid (Helv.Chim.Acta 27, 793-800, 1944) was added and the mixture was shaken for 5 minutes. The aqueous phase was separated and discarded and the organic layer washed with dilute hydrochloric acid, dried over anhydrous potassium carbonate, filtered and evaporated in vacuum. The residue which consisted of somewhat impure 1-(trans-4-acetoxycyclohexanecarbonyl)-4-(2-trifluoromethyl-6-fluoro-9-thi oxanthenylidene)piperidine was used without further purification in the reduction process and was dissolved in dry ether and added dropwise to a solution of 4 grams of lithiumaluminium hydride in dry ether. The reaction mixture was heated under reflux for 3 hours. Water was added with caution until the precipitate clotted. The ether phase was decanted, the precipitate washed thoroughly with ether, and the combined etherphases dried over anhydrous potassium carbonate, treated with active carbon and filtered. The major part of the ether was distilled off and 100 milliliters of petroleum ether were added. Upon cooling and standing 21 grams of 1-(trans-4-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxa nthenylidene)-piperidine were obtained as a white crystalline substance melting at 144-146 degrees Centigrade.
In corresponding manner was prepared:
1-(trans-4-hydroxycyclohexylmethyl)-4-(2-chloro-9-thioxanthenylidene)-piper idine, MP: 185-190 degrees Centigrade.
1-(trans-2-hydroxycyclohexylmethyl)-4-(2-chloro-9-thioxanthenylidene) piperidine, MP: 96-103 degrees Centigrade.
1-(cis-4-hydroxymethylcyclohexylmethyl)-4-(2-chloro-9-thioxanthenylidene)-p iperidine, MP: 85-90 degrees Centigrade.
1-(5-hydroxy-1,3-dioxan-2-yl)methyl-4-(2-chloro-9-thioxanthenylidene)-piper idine, MP: 160-162 degrees Centigrade.
1-(3,4-dihydroxycyclohexylmethyl)-4-(2-chloro-9-thioxanthenylidene)-piperid ine, MP: 173-180 degrees Centigrade.
1-(trans-3-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxan thenylidene)-piperidine oxalate, MP: 155-157 degrees Centigrade.
1-(4-hydroxy-4-methylcyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thio xanthenylidene)-piperidine, MP: 80-90 degrees Centigrade.
1-(cis-2-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanth enylidene)-piperidine, MP: 85-90 degrees Centigrade.
1-(3-trans-4-cis-dihydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9 -thioxanthenylidene)-piperidine, amorphous substance.
1-(trans-4-hydroxycyclohexylmethyl)-4-(2-methylthio-6-fluoro-9-thioxantheny lidene)-piperidine, MP: 138-144 degrees Centigrade.
1-(trans-4-hydroxycyclohexylmethyl)-4-(2-methylthio-9-thioxanthenylidene)-p iperidine, hydrochloride. MP: 285-287 degrees Centigrade.
1-(trans-4-hydroxycyclohexylmethyl)-4-(2-chloro-6-fluoro-9-thioxanthenylide ne)-piperidine, MP: 178-180 degrees Centigrade.
1-(3-trans-4-cis-dihydroxycyclohexylmethyl)-4-(2-chloro-6-fluoro-9-thioxant henylidene)-piperidine, MP: 110-120 degrees Centigrade.
1-(trans-4-hydroxycyclohexylmethyl)-4-(3,6-di-fluoro-9-thioxanthenylidene)- piperidine, MP: 154-156 degrees Centigrade.
1-(trans-4-hydroxycyclohexylmethyl)-4-(2-fluoro-6-methyl-9-thioxanthenylide ne)-piperidine, MP: 158-162 degrees Centigrade.
1-(trans-4-hydroxycyclohexylmethyl)-4-(2-methyl-6-fluoro-9-thioxanthenylide ne)-piperidine, MP: 181-185 degrees Centigrade.
1-(5-hydroxy-1,3-dioxan-2-yl)methyl-4-(2-trifluoromethyl-6-fluoro-9-thioxan thenylidene)-piperidine, MP: 138-140 degrees Centigrade.
1-(5-hydroxy-1,3-dioxan-2-yl)methyl-4-(2-methylthio-6-fluoro-9-thioxantheny lidene)-piperidine, MP: 129-131 degrees Centigrade.
1-(trans-4-hydroxycyclohexylmethyl)-4-(2-methoxy-6-fluoro-9-thioxanthenylid ene)-piperidine, MP: 138-142 degrees Centigrade.
1-(trans-4-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-methyl-9-thioxan thenylidene)-piperidine, MP: 145-147 degrees Centigrade.EXAMPLE 3 1-(Cis-4-hydroxycyclohexylmethyl)-4-(2-chloro-9-thioxanthenylidene)-piperid ine (Method (a))
The starting material, cis-(1-mesyloxymethyl-4-hydroxy)cyclohexane, was prepared in the following way:
24 Grams of cis-4-hydroxycyclohexanemethanol were dissolved in a mixture of 70 milliliters of dry pyridine and 100 milliliters of chloroform. At a temperature of -20 degrees Centigrade were added 23 grams of mesyl chloride dropwise while stirring. The mixture was kept at -10 to -20 degrees Centigrade for 2 hours while stirring, whereupon the mixture was left standing over night at room temperature. The reaction mixture was then poured into ice-water, the chloroform layer was separated off and washed with dilute hydrochloric acid. The chloroform phase was then dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was distilled in vacuum and 30 grams of cis-(1-mesyloxymethyl-4-hydroxy)cyclohexane were obtained as an oil boiling at 120-125 degrees Centigrade/1 mm Hg.
A mixture of 6 grams of 4-(2-chloro-9-thioxanthenylidene)piperidine, 4 grams of cis-(1-mesyloxymethyl-4-hydroxy)cyclohexane, 1.5 grams of finely crushed potassium carbonate and 25 milliliters of methylisobutylketone was heated under reflux for 5 hours while stirring. After cooling were added 200 milliliters of ether, and the organic phase was extracted with 5% aqueous methane sulphonic acid. The aqueous phase was made alkaline with aqueous ammonia, and the base which precipitated was extracted with ether. The etherphase was dried over anhydrous potassium carbonate, treated with active carbon and evaporated. The residue was crystallized from cyclohexane. Yield: 1.5 grams of 1-(cis-4-hydroxycyclohexylmethyl)-4-(2-chloro-9-thioxanthenylidene)piperid ine, which melted at 100-103 degrees Centigrade.
In corresponding manner were prepared:
1-(2-(2-Oxazolidinone-3-yl)ethyl)-4-(2-chloro-9-thioxanthenylidene)piperidi ne, HCl. MP: 250-252 degrees Centigrade.
1-(5-hydroxy-1,3-dioxan-2-yl)methyl-4-(2-chloro-9-thioxanthenylidene)piperi dine. MP: 160-162 degrees Centigrade.
1-(3-trans-4-cis-dihydroxycyclohexylmethyl)-4-(2-chloro-9-thioxanthenyliden e)piperidine. MP: 173-180 degrees Centigrade.
1-(trans-4-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxan thenylidene)piperidine. MP: 144-146 degrees Centigrade.
1-(cis-4-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanth enylidene)piperidine. MP: 149-152 degrees Centigrade.
1-(trans-3-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxan thenylidene)piperidine oxalate. MP: 155-157 degrees Centigrade.
1-(4-hydroxy-4-methylcyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thio xanthenylidene)piperidine. MP: 80-90 degrees Centigrade.
1-(2-cis-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanth enylidene)piperidine. MP: 85-90 degrees Centigrade.
1-(3-Trans-4-cis-dihydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9 -thioxanthenylidene)piperidine. Amorphous substance.
1-(1,3-Dioxan-4-ylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenyliden e)piperidine. MP: 151-153 degrees Centigrade.
1-(4-tetrahydropyranylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenyl idene)piperidine oxalate. MP: 138-140 degrees Centigrade.
1-(Trans-4-hydroxycyclohexylmethyl)-4-(2-methylthio-6-fluoro-9-thioxantheny lidene)piperidine. MP: 138-144 degrees Centigrade.
1-(Trans-4-hydroxycyclohexylmethyl)-4-(2-methylthio-9-thioxanthenylidene)pi peridine, HCl. MP: 285-287 degrees Centigrade.
1-(Trans-4-hydroxycyclohexylmethyl)-4-(2-chloro-6-fluoro-9-thioxanthenylide ne)piperidine. MP: 178-180 degrees Centigrade.
1-(2-(2-Oxazolidinon-3-yl)ethyl)-4-(2-chloro-6-fluoro-9-thioxanthenylidene) piperidine, HCl. MP: 248-250 degrees Centigrade.
1-(3-Trans-4-cis-dihydroxycyclohexylmethyl)-4-(2-chloro-6-fluoro-9-thioxant henylidene)piperidine. MP: 110-120 degrees Centigrade.
1-(Trans-4-hydroxycyclohexylmethyl)-4-(3,6-difluoro-9-thioxanthenylidene)-p iperidine. MP: 154-156 degrees Centigrade.
1-(2-Oxazolidinon-3-yl)ethyl)-4-(2-fluoro-6-methyl-9-thioxanthenylidene)-pi peridine, HCl. MP: 243-246 degrees Centigrade.
1-(Trans-4-hydroxycyclohexylmethyl)-4-(2-fluoro-6-methyl-9-thioxanthenylide ne)-piperidine. MP: 158-162 degrees Centigrade.
1-(2-(2-Oxazolidinon-3-yl)ethyl)-4-(2-methyl-6-fluoro-9-thioxanthenylidene) -piperidine, HCl. MP: 252-254 degrees Centigrade.
1-(Trans-4-hydroxycyclohexylmethyl)-4-(2-methyl-6-fluoro-9-thioxanthenylide ne)-piperidine. MP: 181-185 degrees Centigrade.
1-(Trans-4-hydroxycyclohexylmethyl)-4-(2-bromo-6-fluoro-9-thioxanthenyliden e)-piperidine.
1-(4-hydroxymethylcyclohexyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenyl idene)piperidine. MP: 196-199 degrees Centigrade.
1-(4-hydroxycyclohexyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene) piperidine, HCl. MP: 208-211 degrees Centigrade.
1-(2-Dioxolylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)pip eridine. MP: 137-139 degrees Centigrade.
1-Morpholinoethyl-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperi dine, 2HCl. MP: 300-305 degrees Centigrade.
1-(Cis-2-hydroxymethylcyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thi oxanthenylidene)piperidine. MP: 85-100 degrees Centigrade.
1-(3-Tetrahydrofurylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylid ene)piperidine oxalate. MP: 191-192 degrees Centigrade.
1-(2-(Cis-4-hydroxycyclohexyl)ethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxa nthenylidene)piperidine maleate. MP: 147-150 degrees Centigrade.
1-(1-Methyl-4-piperidylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxantheny lidene)piperidine, 2HCl. MP: 322-324 degrees Centigrade.
1-(3-Trans-4-cis-dihydroxycyclohexylmethyl)-4-(2-bromo-9-thioxanthenylidene )piperidine oxalate. MP: 184-188 degrees Centigrade.
1-(Trans-4-hydroxycyclohexylmethyl)-4-(2-dimethylsulfamoyl-6-fluoro-9-thiox anthenylidene)piperidine, MP: 110-120 degrees Centigrade (amorph.)
1-(Trans-4-hydroxycyclohexylmethyl)-4-(2-methylsulfonyl-9-thioxanthenyliden e)piperidine, MP: 70-85 degrees Centigrade (amorph.)
1-(Trans-4-hydroxycyclohexylmethyl)-4-(2-acetyl-9-thioxanthenylidene)piperi dine oxalate hydrate, MP: 140-210 degrees Centigrade.
1-(2-(2-Imidazolidone-1-yl)ethyl)-4-(2-chloro-9-thioxanthenylidene)piperidi ne, MP: 205-206 degrees Centigrade.
1-(2-(2-Imidazolidone-1-yl)ethyl-4-(2-methylthio-6-fluoro-9-thioxanthenylid ene)piperidine monohydrate, MP: 126-132 degrees Centigrade.
1-(1,3,4,5-tetrahydroxycyclohexylmethyl)-4-(2-methylthio-6-fluoro-9-thioxan thenylidene)piperidine, MP: 90-100 degrees Centigrade (amorph.)
1-(Trans-4-hydroxycyclohexylmethyl)-4-(2-methylthio-6-fluoro-9-xanthenylide ne)piperidine hydrate, MP: 122-126 degrees Centigrade.
1-(Trans-4-hydroxycyclohexylmethyl)-4-(2-chloro-9-xanthenylidene)piperidineEXAMPLE 4 1-(Cis-4-hydroxycyclohexylethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthe nylidene)-piperidine and maleate (Method b)
7.3 Grams of 4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine were dissolved in 50 milliliters of dry methylene chloride. Then 3.8 grams of cis-4-hydroxycyclohexane acetic cid (J.Am.Ch.Soc. 70, pg. 1898-99 (1948)) and 5 grams of dicyclohexylcarbodiimide were added. The mixture was heated at temperatures from 22 to 30 degrees Centigrade during which the dicyclohexylurea formed separated out and was then left standing overnight. The precipitate was filtered from the solution which was then evaporated, and the residue was dissolved in ether. The solution was washed with dilute hydrochloric acid, dried over anhydrous potassium carbonate, filtered and evaporated. The residue, which was an oil, wad dried by evaporation in vacuum with toluene and consisted of somewhat impure 1-(cis-4-hydroxycyclohexylmethylcarbonyl)-4-(2-trifluoromethyl-6-fluoro-9- thioxanthenylidene)piperidine which was used without further purification in the next step. The oil was dissolved in dry ether, and 2 grams of lithium aluminum hydride were added in small portions. The mixture was heated under reflux for one hour. Then water was added dropwise until the precipitate formed clotted. The ether phase was decanted, the precipitate washed thoroughly with ether, the combined ether phases were dried over anhydrous potassium carbonate and treated with active carbon and filtered. The ether was evaporated, and 1-(cis-4-hydroxycyclohexylethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanth enylidene)piperidine was obtained as a yellow oil.
Following solution in acetone and addition of maleic acid 8 grams of the maleate were obtained as white crystals which melted at 147-150 degrees Centigrade.
In corresponding manner were prepared:
1-(3-Trans-4-cis-dihydroxycyclohexylmethyl)-4-(2-methoxy-9-thioxanthenylide ne)piperidine oxalate. MP: 235-236 degrees Centigrade.
1-(3,4,5-Cis-trihydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro9-thi oxanthenylidene)piperidine oxalate. MP: 172-175 degrees Centigrade.
1-(3,4,5-Cis-trihydroxycyclohexylmethyl)-4-(2-methylthio-6-fluoro-9-thioxan thenylidene)piperidine hydrate. MP: 115-120 degrees Centigrade.
1-(3-Trans-4-cis-dihydroxycyclohexylmethyl)-4-(2-chloro-9-xanthenylidene)pi peridine.EXAMPLE 5 1-(Trans-4-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxan thenylidene)piperidine
The starting material, 1-(4-cyclohexanone-carbonyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenyl idene)piperidine, was obtained in the following way:
25 Grams of 4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine were dissolved in 200 milliliters of dry methylene chloride. To this solution were added 12 grams of 4-cyclohexanone carboxylic acid and 16 grams of dicyclohexylcarbodiimide, whereby temperature in the reaction rose from 20 to 32 degrees Centigrade under simultaneous separation of dicyclohexylurea. The resulting mixture was then treated in the same manner as described in Example 4. The resulting 1-(4-cyclohexanonecarbonyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenyli dene)-piperidine was obtained by crystallization from isopropyl ether and melted at 165-179 degrees Centigrade. Yield: 15 grams.
5 Grams of this amide were dissolved in dry ether and reduced with one gram of lithium aluminum hydride as described in Example 2, and the reaction mixture worked up as described there. 3.5 Grams of 1-(trans-4-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxa nthenylidene)piperidine were obtained as a white crystalline substance which melted at 144-146 degrees Centigrade.EXAMPLE 6 1-(4-Hydroxy-4-methylcyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thio xanthenylidene)piperidine (Method d)
14 Grams of 1-(4-cyclohexanonecarbonyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenyli dene)-piperidine, obtained as described in Example 5, were dissolved in a mixture of 50 milliliters of dry tetrahydrofuran and 150 milliliters of dry ether. At 5-10 degrees Centigrade was added dropwise and while stirring a solution of methyl magnesium iodide in ether prepared from 6 grams of methyl iodide. Thereafter the reaction mixture was poured unto crushed ice, and the magnesium hydroxide which precipitated was dissolved by addition of dilute hydrochloric acid. The ether phase was washed once with dilute hydrochloric acid, dried over anhydrous potassium carbonate, filtered and evaporated. The resulting oil was reduced with 3 grams of lithium aluminium hydride without further purification as described in Example 2. The base formed by the reduction was purified by solution in 5% aqueous methane sulphonic acid, the solution washed with ether and the base precipitated with dilute aqueous ammonia. The base was extracted with ether, the ether phase dried over anhydrous potassium carbonate, treated with active carbon and evaporated, finally in vacuum. 12 Grams of 1-(4-hydroxy-4-methylcyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thi oxanthenylidene)piperidine were thereby obtained as an almost white amorphous substance which melted at 80-90 degrees Centigrade.EXAMPLE 7 1-(4-Hydroxymethylcyclohexyl)-4-(2-trifluoromethyl-9-thioxanthenylidene)-pi peridine (Method d)
The starting material, the methyl ester of 1-(4-carboxycyclohexyl)-4-(2-trifluoromethyl-9-thioxanthenylidene)piperidi ne, was obtained in the following way:
11.6 Grams of 4-(2-trifluoromethyl-9-thioxanthenylidene)piperidine were dissolved in 30 milliliters of dry methanol, and to the solution were added 5.5 grams of 4-cyclohexanonecarboxylic acid and 1.5 grams of sodium cyano borohydride, whereupon the mixture was left standing overnight. The amino acid formed was esterified by addition of a mixture of 200 milliliters of dry methanol and 20 milliliters of concentrated sulphuric acid and heating for 3 hours under reflux. The mixture was poured into ice-water, aqueous ammonia added to alkaline reaction and extracted with ether. The ether-solution contained the methyl ester of 1-(4-carboxycyclohexyl)-4-(2-trifluoromethyl-9-thioxanthenylidene)piperidi ne formed and was reduced after drying without further purification using 1.5 grams of lithium aluminium hydride. The reaction mixture was worked up as described in Example 2, and 5.5 grams of 1-(4-hydroxymethylcyclohexyl)-4-(2-trifluoromethyl-9-thioxanthenylidene)pi peridine were obtained by crystallization from ether as white crystals which melted at 193-197 degrees Centigrade.EXAMPLE 8 1-(4 -Hydroxycyclohexyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)-pi peridine and its hydrochloride
In the same manner as described in Example 7 a mixture of 2.2 grams of 4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine and 8.5 grams of benzoyloxycyclohexanone in 30 milliliters of dry methanol adjusted to pH 5 were reduced with 1.5 grams of sodium cyanoborohydride and the resulting 1-(4-benzoyloxy cyclohexyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)-piperidine reduced with lithium aluminium hydride as described in Example 2.
8.4 Grams of the hydrochloride of 1-(4-hydroxycyclohexyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene )-piperidine were obtained as white crystals which melted at 208-211 degrees Centigrade.EXAMPLE 9 1-(Cis-2-hydroxymethylcyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thi oxanthenylidene)piperidine and its oxalate
A mixture of 7.3 grams of 4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine, 3.3 grams of cis-hexahydrophthalic acid anhydride and 30 milliliters of toluene was heated under reflux for 5 hours. After cooling 200 milliliters of dry ether were added and the mixture reduced with 2 grams of lithium aluminium hydride in the same manner as described in Example 2.
7.8 Grams of the oxalate of 1-(cis-2-hydroxymethylcyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-th ioxanthenylidene)piperidine were obtained by drystallization from acetone as white crystals which melted at 155-156 degrees Centigrade.EXAMPLE 10 The decanoic acid ester of 1-(trans-4-hydroxycyclohexylmethyl)-4-(2-chloro-9-thioxanthenylidene)-pipe ridine
6 Grams of 1-(trans-4-hydroxycyclohexylmethyl)-4-(2-chloro-9-thioxanthenylidene)-pipe ridine were dissolved in 50 milliliters of dry pyridine. 4 Grams of decanoylchloride were added and the mixture left standing for 18 hours at room temperature. The mixture was poured into 1 liter of water and extracted with 100 milliliters of isopropyl ether. The etherphase was washed with water, dried over anhydrous potassium carbonate, filtered and evaporated to about 15 milliliters. By addition of petroleum ether and cooling 8 grams of the decanoic acid ester of 1-(trans-4-hydroxycyclohexylmethyl)-4-(2-chloro-9-thioxanthenylidene)-pipe ridine were obtained as a white crystalline substance which melted at 100-108 degrees Centigrade.
In the same manner was prepared:
The decanoic acid ester of 1-(trans-4-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxa nthenylidene)-piperidine. Melting point of the hydrochloride: 210-212 degrees Centigrade.
The palmitic acid ester of 1-(trans-4-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-8-thioxa nthenylidene)-piperidine.
The behenic acid ester of 1-(trans-4-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxa nthenylidene)-piperidine.EXAMPLE 11 1-(4-Oxocyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenyliden e)piperidine and its hydrochloride
A mixture of 13 grams of 1-(trans-4-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxa nthenylidene)piperidine, 80 milliliters of cyclohexanone, 300 milliliters of dry toluene and 4 grams of aluminiumisopropoxide was heated to boiling, and in the course of one hour 200 milliliters of liquid were distilled off. The reaction mixture was cooled, water was added and the aluminium hydroxide which precipitated was sucked off. The organic layer was extracted with dilute hydrochloric acid, the acid solution made alkaline and extracted with ether. The ether phase was dried over anhydrous potassium carbonate and evaporated, the residue was dissolved in acetone, and by addition of dry hydrogen chloride in ether the hydrochloride 1-(4-oxocyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylide ne)piperidine was obtained as white crystals which melted at 232-235 degrees Centigrade. Yield: 4.5 grams.EXAMPLE 12 1-(Trans-4-aminocyclohexylmethyl)-4-(2-chloro-9-thioxanthenylidene)piperidi ne and its acetylderivative and mesylderivative
4-(2-Chloro-9-thioxanthenylidene)piperidine was reacted with trans-4-(2,2,2-trichloroethoxycarbonylamino)cyclohexanecarbonyl chloride as described in Example 2 (Method b). 1-(Trans-4-(2,2,2-trichloroethoxycarbonylamine)cyclohexanecarbonyl)-4-(2-c hloro-9-thioxanthenylidene)piperidine was thereby obtained as a yellow oil.
The yellow oil was reduced with activated zink in acetic acid according to the procedure described for 4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine in Example 1. 1-(Trans-4-aminocyclohexylcarbonyl)-4-(2-chloro-9-thioxanthenylidene)pi peridine was thereby obtained as a white crystalline substance melting at 230-260 degrees Centigrade after recrystallization from toluene.
This substance was then reduced with lithium aluminium hydride as described in example using dry tetrahydrofuran instead of ether. 1-(Trans-4-aminocyclohexylmethyl)-4-(2-chloro-9-thioxanthenylidene)piperid ine was thus obtained as a white crystalline substance melting at 128-135 degrees Centigrade.
The starting material, trans-4-(2,2,2-trichloroethoxycarbonylamino)cyclohexanecarbonyl chloride, was prepared from trans-4-aminocyclohexane carboxylic acid by a Schotten-Baumann reaction with the 2,2,2-trichloroethylester of chloroformic acid followed by reflux for three hours with 50% excess of thionyl chloride. It was obtained as a yellow oil.
In corresponding manner was prepared:
1-(Trans-4-aminocyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanth enylidene)piperidine. MP: 100-102 degrees Centigrade.
The acetyl derivative of the last mentioned amine was prepared to conventional manner by treatment of the amine with acetic anhydride in toluene and melted at 215-217 degrees Centigrade.
The corresponding mesyl derivative was prepared by dissolving 6 grams of the amine in 50 milliliters of dichloromethane, adding a solution of 30 grams of potassiumcarbonate in 100 milliliters of water, and, while stirring vigorously, adding dropwise at zero degrees Centigrade 10 grams of mesyl chloride. The organic phase was dried over anhydrous potassium carbonate and filtered.
By addition of ether 3 grams of the mesylderivative were obtained, melting at 170-180 degrees Centigrade.
The novel xanthones and thioxanthones used as starting materials for the preparation of the compounds of Formula II were prepared as follows:2-Methylthio-6-fluoro-9-thioxanthone 375 Grams of 2-(p-methylthiophenylthio)-4-fluoro-benzoic acid (Collec.Czech.Chem.Commun. 40, pg. 3523 (1975)) were heated with 2.7 kilograms of polyphosphoric acid while stirring for 3 hours at 140 degrees Centigrade. The mixture was cooled to 110 degrees Centigrade and poured into ice-water. The precipitate was sucked off, suspended in aqueous ammonia and sucked off again. After recrystallization from pyridine 200 grams of 2-methylthio-6-fluoro-9-thioxanthone was obtained as a yellow crystalline substance which melted at 135-138 degrees Centigrade. 2-Methyl-6-fluoro-9-thioxanthone
A mixture of 110 grams of 2-bromo-4-fluoro-benzoic acid, 63 grams of 4-methylthiophenol, 100 grams of potassium carbonate, 250 milliliters of dimethylformamide, 2 grams of active copper and 1 gram of cuproiodide was heated while stirring under reflux for 16 hours. The mixture was poured into water, undissolved substance sucked off and the resulting solution made acid with hydrochloric acid. The precipitate was sucked off and dissolved in ether. The ether solution was dried over anhydrous magnesium sulphate, treated with active carbon and most of the ether evaporated. By addition of petroleum ether and cooling 81 grams of 2-(4-methylphenylthio)-4-fluorobenzoic acid were obtained as white crystals which melted at 190-200 degrees Centigrade.
This acid was heated at 50-60 degrees Centigrade with 650 milliliters concentrated sulphuric acid while stirring, whereupon the mixture was poured unto crushed ice. The precipitate was sucked off, suspended in aqueous ammonia and sucked off again. After recrystallization from ethanol 41 grams of 2-methyl-6-fluoro-9-thioxanthone were obtained as pale yellow crystals which melted at 159-165 degrees Centigrade.2-Fluoro-6-methyl-9-thioxanthone
A mixture of 80 grams of 2-bromo-4-methylbenzonitrile, 52 grams of 4-fluorothiophenol, 56 grams of potassium carbonate, 200 milliliters of dimethylformamide and 1 grams of active copper was heated while stirring. At 90 degrees Centigrade a reaction started resulting in rise of temperature and separation of potassium bromide. The mixture was heated under reflux for one hour, cooled and poured into water. The precipitate was sucked off and dissolved in ether. The ether solution was washed with dilute sodium hydroxide solution, dried over anhydrous magnesium sulphate, treated with active carbon and the ether evaporated. The residue was recrystallized from ethanol, and 93 grams of 2-(4-fluorophenylthio)-4-methylbenzonitrile were obtained as white crystals which melted at 93-96 degrees Centigrade.
This nitrile was heated under reflux for 16 hours with a solution of 85 grams of potassium hydroxide in 600 milliliters of 80% ethanol. The mixture was poured into water and made acid with hydrochloric acid. 96 Grams of 2-(4-fluorophenylthio)-4-methylbenzoic acid crystallized thereby as a white crystalline substance which melted at 185-193 degrees Centigrade.
By treatment with concentrated sulphuric acid as described in the previous example, 58 grams of 2-fluoro-6-methyl-9-thioxanthone were obtained after recrystallization from ethanol as yellow crystals which melted at 166-170 degrees Centigrade.2-Methoxy-6-fluoro-9-thioxanthone
This substance is prepared as described for 2-methyl-6-fluoro-9-thioxanthene, and the intermediate 2-(p-methoxyphenylthio)-4-fluoro-benzoic acid melts at 195-204 degrees Centigrade.
This substance yields by heating with polyphosphoric acid, as described above for 2-methylthio-6-fluoro-9-thioxanthone, 2-methoxy-6-fluoro-9-thioxanthone, which melts at 170-174 degrees Centigrade.2-Trifluoromethyl-6-methyl-9-thioxanthone
A mixture of 40 grams of sodium hydroxide, 1 liter of ethanol and 124 grams of m-thiocresol was stirred until the sodium hydroxide was dissolved.
206 Grams of 2-chloro-5-trifluoromethylbenzonitrile were then added while stirring and under reflux. The mixture was then heated under reflux for two hours. After cooling 100 grams of potassium hydroxide were added and the mixture heated under reflux overnight. The mixture was then diluted with 3 liters of water and made acid with hydrochloric acid. The precipitate was filtered off and consisted of 2-(3-methylphenylthio)-5-trifluoromethylbenzoic acid. Yield: 240 grams.
This was then treated with sulphuric acid as described for 2-methyl-6-fluoro-9-thioxanthone. The resulting substance consisted mainly of 2-trifluoro-6-methyl-9-thioxanthone with some 2-trifluoromethyl-8-methyl-9-thioxanthone. When boiling this mixture with acetone the more soluble 8-methyl-compound will go into solution. The remaining 2-trifluoromethyl-6-methyl-9-thioxanthone was obtained as a yellow crystalline substance, which melts at 174-178 degrees Centrigrade. Yield: 80 grams.2-Methylthio-6-fluoro-9-xanthone
A mixture of 36.8 grams of 5-methylthio salicylic acid, 38 grams of 3-bromofluorobenzene, 32 grams of anhydrous potassium carbonate and 3 grams of copper powder in 100 milliliters of dimethylformamide was heated to boiling, and 25 milliliters of liquid were distilled off until the temperature in the mixture reached 150 degrees Centigrade. 35 Grams of 3-bromofluorobenzene were then added, and the mixture was refluxed overnight. 200 Milliliters of water were added, and the warm reaction mixture was filtered with charcoal. The filtrate was extracted once with diethylether and made acid with 6 N hydrochloric acid. The precipitate was sucked off and taken up in 500 milliliters of diethylether, dried over anhydrous magnesium sulphate and concentrated. The crystals were sucked off and dried. 26 Grams of 2-(3-fluoro-phenoxy)-5-methylthio-benzoic acid melting at 137-140 degrees Centigrade were obtained.
The 26 grams of this acid were added to 225 grams of polyphosphoric acid while stirring and the mixture heated on a steam bath for three hours. The reaction mixture was poured onto ice, filtered and taken up in 250 milliliters of methylene chloride. The organic phase was washed with 25% aqueous ammonia and water, dried over anhydrous magnesium sulphate and evaporated to give 20 grams of a mixture of 6- and 8-fluoro-2-methylthio-9-xanthones.
Three recrystallizations from 16 milliliters of pyridine yielded 6 grams of pure 2-methylthio-6-fluoro-9-xanthone which melted at 113-116 degrees Centigrade.
The pharmacological testing of the novel xanthones and thioxanthenes of Formula I consisted of standard and reliable tests.
There the results with salts were compared with the results obtained with the free base it was found that the effect was the same as that obtained with the equivalent amount of free base.
The tests may be described as follows:Methylphenidate antagonism (ED50 mg/kg i.p.)
Perspex observation cages without bottom and lid, consisting of 5 sections each measuring 12.times.25.times.30 cm. White corrugated paper. Mice, male, 18-25 g.Dosage and procedure
The test substance is given i.p. in the doses 0, 1/8, 1/32 and 1/128 of the determined "i.p. LD50". 3.times.2 mice are used for each dose level. Two or 24 hours after injection of test substance, methylphenidate, 60 mg/kg, is injected s.c. After administration of methylphenidate the mice are placed in the observation cages, 2 in each cage, where they remain for exactly 1 hour. The cages are placed on corrugated paper, the corrugations facing upwards. It is examined whether the mice have been biting the corrugated paper or not. If not, the substance has had an antagonistic effect. If one or more of the control pairs have not been biting, the test has to be repeated on a new set of mice.
The result is stated in fractions: 0/3, 1/3, 2/3, and 3/3 where 0, 1, 2 and 3 are the number of pairs which have not been biting on receipt of the dose in question.
The results are calculated as the dose (ED.sub.50), which causes antagonism in 50% of the test animals.Amphetamine antagonism (ED.sub.50 mg/kg i.p.)
Perspex observation cages without bottom and lid, consisting of 5 sections each measuring 12.times.25.times.30 cm. White corrugated paper. Rats, male, 230-270 g.Dosage and procedure
The test substance is given i.p. in a reasonable dose based on the determined LD.sub.50. Two or 24 hours later an intravenous injection of amphetamine sulphate 13.6 mg/kg (10 mg/kg amphetamine base) is given, after which the rats are placed individually in the cages. The cages are placed on white corrugated paper. Five rats are used for each dose level. Observations are made after 55 minutes and 65 minutes--observation time: 1 minute. The animals are observed for stereotypy (movements of the head, compulsive gnawing). If no stereotypy is demonstrated the substance has had an antagonistic effect. If the compound has full antagonistic effect another group of rats is used at a lower dose. If the compound shows no effect a higher dose is used. The results is stated as fractions: 0/5, 1/5, 2/5, 3/5, 4/5 and 5/5, where 0, 1, 2, 3, 4 and 5 indicate the number of rats which have not shown stereotypy at the dose in question. The results are calculated as ED.sub.50 in mg/kg.Catalepsy wire mesh, rat, max. (ED.sub.50 mg/kg s.c.)
A vertical wire netting (50 cm.times.49 cm). The meshes (openings) of the netting are square (1 cm.times.1 cm). The wire diameter is 2 mm. Stop watch. Rats, male, 180-200 g.Dosage and procedure
The animals are labeled and used in groups of five. The test substance is injected subcutaneously (s.c.) (5 ml/kg) at 4 dose levels selected from the fixed dose scale.
The animals are placed in the middle of the vertical wire netting 60, 120, 180, 240, 300 and 360 minutes after injection of the test compound. The animals are considered cataleptic when they remain immobile during a period of 15 seconds. This cataleptic reaction is designated +. If the rats are "atonic" and passively slide down the wire mesh they are considered not cataleptic. If the animals climb up and down the wire mesh they are nor cataleptic. In both situations the designation--is used.
The results are recorded in fractions: 0/5, 1/5, 2/5, 3/5, 4/5 and 5/5, where 0, 1, 2, 3, 4 and 5 are the number of rats with designation+at the time where the dose in question possessed the strongest effect within the first 6 hours.
The compounds tested will appear from the following table:
TABLE 1 __________________________________________________________________________ Code Number X Y n R Z __________________________________________________________________________ Lu 14-047 2-Cl H 1 ##STR17## S Lu 15-014 2-Cl H 1 ##STR18## S Lu 14-106 2-Cl H 2 ##STR19## S Lu 14-140 2-Cl H 1 ##STR20## S Lu 15-041 2-Cl H 1 ##STR21## S Lu 13-135 2-CF.sub.3 F 1 ##STR22## S Lu 15-013 2-CF.sub.3 F 1 ##STR23## S Lu 15-030 2-CF.sub.3 F 1 ##STR24## S Lu 15-048 2-CF.sub.3 F 1 ##STR25## S Lu 15-038 2-CF.sub.3 F 1 ##STR26## S Lu 15-052 2-CF.sub.3 F 1 ##STR27## S Lu 14-130 2-CF.sub.3 F 1 ##STR28## S Lu 15-131 2-CF.sub.3 F 1 ##STR29## S Lu 14-116 2-SCH.sub.3 F 1 ##STR30## S Lu 15-019 2-SCH.sub.3 H 1 ##STR31## S Lu 14-114 2-Cl F 1 ##STR32## S Lu 14-117 2-Cl F 2 ##STR33## S Lu 15-070 2-Cl F 1 ##STR34## S Lu 15-062 3-F F 1 ##STR35## S Lu 14-062 2-F CH.sub.3 2 ##STR36## S Lu 14-090 2-F CH.sub.3 1 ##STR37## S Lu 14-070 2-CH.sub.3 F 2 ##STR38## S Lu 14-082 2-CH.sub.3 F 1 ##STR39## S Lu 16-107 2-SO.sub.2 N(CH.sub.3).sub.2 F 1 ##STR40## S Lu 16-066 2-SO.sub.2 CH.sub.3 H 1 ##STR41## S Lu 16-052 2-OCH.sub.3 F 1 ##STR42## S Lu 16-014 2-CF.sub.3 CH.sub.3 1 ##STR43## S Lu 15-121 2-CF.sub.3 F 1 ##STR44## S Lu 16-105 2-Cl H 2 ##STR45## S Lu 16-104 2-CF.sub.3 F 2 ##STR46## S Lu 15-089 2-CF.sub.3 F 1 ##STR47## S Lu 15-119 2-SCH.sub.3 F 1 ##STR48## O Lu 16-088 2-CF.sub.3 F 1 ##STR49## S Lu 16-042 2-CF.sub.3 F 1 ##STR50## S Lu 16-081 2-Cl H 1 ##STR51## S Lu 16-043 2-CF.sub.3 F 1 ##STR52## S Lu 16-049 2-CF.sub.3 F 1 ##STR53## S __________________________________________________________________________
As reference substances were used the following neuroleptic drugs designated by their INN-names (International Nonproprietary Names): flupentixol, clopenthixol, chlorprothixene, fluphenazine, chlorpromazine, haloperidol and clozapine. Moreover the cis- (z)-isomer of 2-trifluoromethyl-6-fluoro-9-(3-(4-(2-hydroxyethyl)-1-piperidyl)propyliden e)-thioxanthene; INN-name; piflutixol.
TABLE 2 __________________________________________________________________________ Methylphenidate antagon Amphetamine Remarks Substance 2 h 24 h antagon Catalepsy Duration __________________________________________________________________________ Lu 14-047 0.59 >20 0.32 3.5 short acting, strong Lu 15-014 0.20 >10 2.5 " Lu 14-106 0.51 >40 1.0 6.6 " Lu 14-140 0.77 >40 " Lu 15-041 0.62 3.6 <0.31 moderately long acting, strong Lu 13-135 0.32 0.19 0.32 0.4 very long acting, strong Lu 15-013 0.63 0.10 0.76 1.2 long acting, strong Lu 15-030 0.28 0.05 0.88 0.39 long acting, very strong Lu 15-048 1.30 0.13 <0.31 long acting, strong Lu 15-138 1.30 0.15 1.7 " Lu 15-052 0.32 0.06 0.9 0.026 " Lu 14-130 0.77 0.70 0.62 2.8 long acting, moderately strong Lu 15-031 0.52 0.55 1.3 " Lu 14-116 0.44 0.38 0.28 0.58 long acting, strong Lu 15-019 0.77 >40 0.59 0.60 short acting, moderately strong Lu 14-114 0.1 6.6 0.35 short acting, strong Lu 14-117 0.21 29 0.34 1.0 " Lu 15-070 0.51 0.5 moderately long acting, moderately strong Lu 15-062 0.77 >10 0.85 short acting, moderately strong Lu 14-062 0.51 >40 " Lu 14-090 1.25 32 " Lu 14-070 0.32 >40 1.3 1.8 " Lu 14-082 0.79 >10 " Lu 16-107 1.9 0.76 0.28 long acting, moderately strong Lu 16-066 0.73 >10 0.25 short acting, moderately strong Lu 16-052 0.31 29 0.56 0.23 " Lu 16-014 0.31 1.9 1.0 0.97 long acting moderately strong Lu 15-121 2.2 0.31 10.0 >10 long acting, strong, weak catalep. Lu 16-105 0.16 28 1.2 0.38 short acting, strong Lu 16-104 0.06 1.5 0.15 0.11 relatively short acting, strong Lu 15-089 0.32 0.32 1.8 2.7 relatively short acting, moderately strong Lu 15-119 0.09 0.11 0.56 0.08 very strong, long acting. Lu 16-088 0.77 0.06 0.30 p.o. 0.81 strong, long acting Lu 16-042 1.2 0.17 2.5 p.o. 3.3 " Lu 16-081 0.5 .about.10 moderately strong, short acting. Lu 16-043 >10 0.42 >20 relatively strong, long acting Lu 16-049 1.0 0.49 2.5 p.o. 1.7 p.o. moderately strong, long acting. flupentixol 0.20 >20 0.69 0.25 short acting, strong clopenthixol 1.20 0.77 0.95 short acting, moderately strong chlorprothixene 0.71 >20 6.1 4.0 " fluphenazine 0.04 3.6 0.08 0.099 short acting, very strong chlorpromazine 4.0 20 7.1 5.6 short acting, moderately strong haloperidol 0.06 0.14 0.21 short acting, very strong clozapine >160 >40 85 short acting, weak piflutixol 0.03 0.03 0.05 48-72h LD.sub.50 p.o. in male rats after 1 week 1.5mg/kg __________________________________________________________________________
From Table 2 it appears that among the compounds having a substituent in the 2-position and a fluorine atom or methyl group at position 6 one finds the most long acting and also strongest acting.
On the other hand, they also show a comparatively high cataleptic activity, which indicates extrapyrimidal symptoms. The compounds wherein Y is hydrogen are as general rule rather short acting but, on the other hand, they often show a more favourable ration between the cataleptic activity and the methylphenidate antagonism.
Among the compounds wherein R is a cyclohexyl group having from one to three hydroxyl groups one finds some of the most promising compounds. Especially remarkable are Lu 13-135, Lu 15-030, Lu 15-052 and Lu 15-119 in that they are very strong and long acting but they also have a cataleptic activity. Interesting is Lu 15-121 in that it seems to be strong, long acting and at the same time having no cataleptic activity.
When comparing the most long acting and strongest of the compounds of Formula I with piflutixol, which is the most patent and at the same time the most long acting neuroleptic so far known, it has been found that they cause much less sedation. Moreover, they have much stronger anticholinergic effects than the compounds known from U.S. Pat. No. 4,042,695, and this is considered an indication of a lower degree of undesired extrapyrimidal side effects.
The acute toxicity, as measured by LD.sub.50 in male rats following peroral administration, is much lower for Lu 13-135 when compared with piflutixol one week after administration. The figure for Lu 13-135 is > 60 mg/kg against 1.5 mg/kg for piflutixol. The considerably greater toxicity of piflutixol being attributed mainly to the aforementioned very strong sedative effects.
The compounds of Formula I and the non-toxic acid addition salts thereof may be administered to animals such as dogs, cats, horses sheeps or the like, including human beings, both orally and parenterally, and may be used for example in the form of tablets, capsules, powders, syrups or in the form of the usual sterile solutions for injection. Results upon administration to human beings have been very gratifying.
Most conveniently the compounds of Formula I are administered orally in unit dosage form such as tablets or capsules, each dosage unit containing a non-toxic acid addition salt of one of the said compounds in an amount of from about 0.05 to about 50 mg, most preferably, however, from about 1 to 10 mg, calculated as the free amine, the total daily dosage usually ranging from about 0.5 to about 300 mg. The exact individual dosages as well as daily dosages in a particular case will, of course, be determined according to established medical principles under the direction of a physician.
When preparing tablets, the active ingredient is for the most part mixed with ordinary tablet adjuvants such as corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, or the like.
When the compound of Formula I is an ester, perferably a decanoic acid ester, palmitic acid ester or a behenic acid ester, the composition may advantageously be an oily solution for injection, and such solutions often have a very prolonged effect when compared with the corresponding unesterified compound.
Typical examples of formulas for composition containing 1-(trans-4-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxa nthenyliden)-piperidine (called Lu 13-135 for short) as the active ingredient are as follows:
(1) Tablets containing 0.1 milligram of Lu 13-135 calculated as the free base:
Lu 13-135: 0.1 mg
lactose: 37 mg
potato starch: 74 mg
gelatine: 2 mg
talcum: 8 mg
(2) Solution for injection containing per ml:
Lu 13-135: 0.2 mg
sodium chloride: 9.0 mg
sterile water ad: 1 ml
(3) Syrup containing per milliliter:
Lu 13-135: 0.2 mg
methyl-paraben: 1.0 mg
propyl-paraben: 0.1 mg
saccharose: 400 mg
water: ad: 1 ml
(4) Capsules containing per capsule:
Lu 13-135: 1 mg
lactose: 40 mg
magnesium stearate: 0.5 mg
Any other pharmaceutical tableting adjuvants may be used provided that they are compatible with the active ingredient, and additional compositions and dosage forms may be similar to those presently used for neuroleptics, such as thiothixene, clopenthixol or flupenthixol. Also combinations of the compounds of Formula I as well as their non-toxic acid salts with other active ingredients, especially other neuroleptics, thymoleptics, tranquilizers or the like, fall within the scope of the present invention.
As previously stated, when isolating the compounds of Formula I in the form of an acid addition salt the acid is preferably selected so as to contain an anion which is non-toxic and pharmacologically acceptable, at least in usual therapeutic doses. Representative salts which are included in this preferred group are the hydrochlorides, hydrobromides, sulphates, acetates, phosphates, nitrates, methanesulphonates, ethane-sulphonates, lactates, citrates, tartrates or bitartrates, embonates and maleates of the amines of Formula I. Other acids are likewise suitable and may be employed if desired. For example; fumaric, benzoic, ascorbic, succinic, salicylic, bismethylenesalicylic, propionic, gluconic, malic, malonic, mandelic, cannamic, citraconic, stearic, palmitic, itaconic, glycolic, benzenesulphonic, and sulphamic acids may also be employed as acid addition saltforming acids.
When it is desired to isolate a compound of the invention in the form of the free base, this may be done according to conventional procedure as by dissolving the isolated or unisolated salt in the water, treating with a suitable alkaline material, extracting the liberated free base with a suitable organic solvent drying the extract and evaporating to dryness or fractionally distilling to effect isolation of the free basic amine.
The invention also comprises a method for the alleviation, palliation, mitigation or inhibition of the manifestations of certain physiological-psychological abnormalies of animals by administering to a living animal body, including human beings, an adequate quantity of a compound of Formula I or a non-toxic acid addition salt thereof. An adequate quantity would be from about 0.001 mg to about 1 mg per kg of body weight in each unit dosage, and from about 0.003 milligrams to about 3 milligrams/kg of body weight per day.
It is to be understood that the invention is not limited to the exact details of operation or exact compound or compositions shown and described, as obvious medifications and equivalents will be apparent to one skilled in the art.
1. A compound of the formula: ##STR54## wherein X.sub.1, Y, Z, m and R.sub.1 are defined as follows: X.sub.1 is a halogen atom, an alkyl group with one to four carbon atoms inclusive, an alkoxy group with one to four carbon atoms inclusive, a methylmercapto group, or a trifluoromethyl group;
- Y is hydrogen, fluorine, or a methyl group;
- Z is oxygen or sulphur;
- m is zero or an integer from one to two, inclusive; and
- R.sub.1 is a cycloalkyl group with four to six carbon atoms inclusive in the ring, which is substituted with one to four substituents selected from the group consisting of: amino; acetamino; mesylamino; and protected hydroxy- or protected hydroxymethyl, any such protected hydroxy or hydroxymethyl group present being protected by esterification into an ester of an aliphatic carboxylic acid having ten to twenty-two carbon atoms inclusive; and, when a previously-named substituent is present, also methyl.
2. A compound of the formula: ##STR55## wherein X.sub.1, Y, Z, m and R.sub.1 are defined as follows: X.sub.1 is a halogen atom, an alkyl group with one to four carbon atoms inclusive, an alkoxy group with one to four carbon atoms inclusive, a methylmercapto group, or a trifluoromethyl group;
- Y is hydrogen, fluorine, or a methyl group;
- Z is oxygen or sulphur;
- m is zero or an integer from one to two, inclusive; and
- R.sub.1 is a cycloalkyl group with four to six carbon atoms inclusive in the ring, which is substituted with one to four substituents selected from the group consising of: amino; acetamino; and mesylamino; protected hydroxy- or protected hydroxymethyl and, when a previously-named substituent is present, also methyl; a five- or six-membered saturated heterocyclic ring having one or two hetero-atoms selected from oxygen and nitrogen atoms and being optionally substituted with a protected hydroxy group; any such protected hydroxy or hydroxymethyl group present being protected by esterification into an ester of an aliphatic carboxylic acid having ten to twenty-two carbon atoms inclusive.
3. A compound of claim 1 which is 1-(Trans-4-acetoxycyclohexanecarbonyl)-4-(2-trifluoromethyl-6-fluoro-9-thi oxanthenylidene)piperidine.
Type: Grant
Filed: Dec 21, 1979
Date of Patent: Jun 23, 1981
Assignee: Kefalas A/S (Copenhagen-Valby)
Inventors: Niels Lassen (Gentofte), Klaus P. Bogeso (Lyngby), Peter B. Hansen (Allerod), Jorn L. M. Buus (Bj verskov), Allan J. Bigler (Copenhagen)
Primary Examiner: Richard A. Schwartz
Attorney: Gordon W. Hueschen
Application Number: 6/106,353
International Classification: C07D40904;


text:
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"We see this as a counter-proposal by the coalition of which we are a part - the Strait of Hormuz coalition. We cannot work in two coalitions. We are already entering one, "the Foreign Minister said.
Earlier, Iranian Foreign Minister Mohammad Javad Zarif at a working breakfast for journalists on the eve of the UN General Assembly said that Iran had proposed the creation of a security coalition in the Persian Gulf under the auspices of the UN, which would include Iraq, Saudi Arabia, Bahrain, the United Arab Emirates, Qatar, Oman and Kuwait.
Also, Iranian leader Hassan Rouhani announced his intention to submit to the UN a project to ensure the security of the Persian and Oman gulfs, as well as the Strait of Hormuz.


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Everything Parents Need to Know About Nintendo's Amiibo ToysPosted by Andrew Hayward | Tips for Parents | 11 Comments
If your kids are enraptured by Skylanders or Disney Infinity—and/or are huge fans of everything Nintendo—then you may be eyeing a new set of interactive figurines as stocking stuffers this holiday season.
Amiibo is Nintendo's answer to the immense popularity of those other games, but unlike those toy-centric forebears, the figurines of iconic characters like Mario, Link, and Peach aren't tied to a single game or series. Furthermore, while they may look similar on the surface, the Amiibo figures aren't currently used to bring playable characters into games. In Skylanders and Disney Infinity, you pop a figurine on the portal and that character appears in the game and is fully playable. With Amiibo, the experience is a little different, giving you access to bonus content and extra computer-controlled characters, rather than playable ones. Read More


text:
Discussion Starter • #1 •
So, maybe not the best idea, but with multiple drivers, I'm swapping my F350 to a C6. It has 628hp, locked f/r, 4.10's, aggressive 36x14.50's, 1.96:1 low range, ~6000lbs. What should I do to help it hold up? Local transmission guy, with good reputation, advises 3500 stall converter, and a manual valve body. Should I go with a low gear kit, low drag, change the planetary to E4OD? Not much experience here.


text:
Forex Daily Outlook – October 30, 2018
The Euro drifted slightly lower during Monday's session because of the political turmoil in Germany emanating from the recent elections. In the short term, the pair is likely to be in sell on rallies strategy and there is a strong resistance above between the 1.1450 and 1.15 level. The market needs to stabilize a bit first in order to rally higher and 1.13 level underneath should be a stringent support. …Read More
The British Pound initially tried to rally higher, but because of the weak sentiment in the market it failed and was mostly sideways. The pair is getting strong support at the 61.8 per cent in Fibonacci scale and also the previous downtrend line. If the pair breaks below the 1.2750 level, then it will break further down and probably reach down to the 1.25 level. …Read More
The AUD was mostly sideways during the yesterday's session holding above the 0.7050 level. The 50 Day EMA is proving to be a major resistance line and the market will continue to struggle overall. Once the market breaks below the 0.70 level, then it can easily go down to the 0.68 level next or below. At present, both technical and fundamental aspect of the pair is weak and will continue to be in the same line for the next few weeks. …Read More
The USD rallied against the JPY to kick-start the week and also the market is holding 100 EMA as strong support. If the pair breaks above the 112.50 level, then it could easily reach towards the 113 level and above but the area around is significantly resistive. The pair is highly sensitive to the global stock market and will take cues from S&P500 to chart out the future momentum. …Read More


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Lorene Wilson was born January 15, 1928 in Lookeba, Oklahoma to Walter Thrasher and Mary (Von Allman)
Thrasher. She passed away Wednesday, September 25, 2019 in Oklahoma City, Oklahoma, at the age of 91. Lorene grew up in Lookeba and graduated from Lookeba High School. She married Rube Wilson on December 27, 1946 in Anadarko, Oklahoma. Lorene lived in the Lookeba area her entire life. She enjoyed canning, quilting, and sewing. Lorene was a member of the Binger Church of Christ since 1978.
Survivors include, 2 sons; Jerry Wilson of Binger, OK, and Danny Wilson and wife Linda of Lookeba, OK, grandchildren; Cristi Williams and husband Michael, Galyn Wilson and wife Vivian and Jeff Wilson,
siblings; Bobby Warren of Binger, OK, Lonnie Warren of Lookeba, OK and Janice Elliott of Binger, OK as well as numerous nieces, nephews, other relatives and friends.
Lorene was preceded in death by her parents; Walter and Mary, husband; Rube Wilson, daughter; Carolyn Kay Wilson and siblings; Geneva Stevens, Jimmy Warren, and Larry Warren.
Services: Tuesday, 10 AM, October 1, 2019, Church of Christ, Binger, OK
Officiating: Mr. Jeff Dodgen
Burial: Murray Cemetery, Binger, OK services under the direction of Turner Funeral Home, Hinton, Oklahoma. Condolences may be sent to the family at firstname.lastname@example.com, or you can find us on facebook.com (Turner Funeral Homes).
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How to Make Big Money in GTA 5 Stock Market (PS4 and Xbox One)
Has senseless slaughter lost its charm? Tired of earning cash the old-fashioned way? Here's how to cash in on the Los Santos stock market and get rich in GTA 5! Like a billion dollars rich! How to make money in GTA 5 by playing the stock market.
What are the Strongest, Most Competitive Pokemon That'll Help You Build the Best Team?
Catch 'em all? Sure! But when it really comes down to it, the question always goes back to, "What are the best Pokemon?"
What are the Top 10 Best Neutral Cards to Craft in Hearthstone?
Alternatively: 'Top 10 Cards Worth Crafting' or 'Top 10 Cards You Probably Shouldn't Disenchant'.
How to Get a Shiny Pokemon In Pokemon X and Y
Want a team bursting with shiny Pokemon? Here are three ways to make it happen!
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Farmers body plans to defy ban on GM brinjal, cotton
NEW DELHI: In a "pro-GM seed" protest, the Shetkari Sanghatana plans to defy the ban on transgenic crops by planting GM brinjal andherbicide
tolerant (HT) cotton at Akot inMaharashtra
'sAkola district
on June 10 despite the varieties lacking clearance for cultivation.
The organised protests come soon after Haryana government last month uprooted genetically modified (GM) brinjal plants from a farm in Fatehabad district. In doing so, the Shetkari Sanghatana seems to be reflecting a view among many farmers that transgenic crops, with greater protection against pests, could improve yields and reduce costs.
Fatehabad farm in Haryana
The seeds from an undetected larger supply chain of (GM) brinjal, which surfaced in Haryana, may reach Akot where farmers, demanding access to transgenic varieties, have decided to plant it while publicly defying the ban.
Asked whether the environment ministry is aware of any such move by the farmers organisation, joint secretary Richa Sharma said, "No such report has come to the ministry so far".
On a question whether the ministry has written to the state governments concerned for taking actions against those who may defy the ban and plant GM seeds/seedlings of these crops, she said, "The ministry has recently written to state governments, requesting that the State Biotech Coordination Committees, headed by chief secretaries, should take action under Environment Protection Act 1986 and Rules made thereunder, if instances of illegal cultivation ofgenetically modified crops
is reported."
Fatehabad farm in Haryana
Though commercial cultivation of another variety of genetically modified cotton (Bt cotton
) is allowed in India, the HT cotton variety is banned in absence of permission from the genetic engineering appraisal committee (GEAC).
The government had imposed a moratorium on commercial release of Bt brinjal in 2010 when Jairam Ramesh was the environment and forests minister. The ban continued after NDA assumed office with Sangh affiliate Swadeshi Jagran Manch joining hands with activists to oppose GM food crops.
Asked how farmers will procure seeds of the banned GM brinjal, Ajit Narde, chief of the technology cell of the Shetkari Sanghatana, told TOI on Friday that there were many farmers in Punjab and Haryana who had planted this banned variety. He claimed that farmers who benefited from GM brinjal would assemble at Akot in response to a call given by farmer leader Lalit Patil Bahale.
Will it not be an illegal act as cultivation of GM variety of crops is not allowed in India unless approved by GEAC and cleared by the government? Narde said, "There is no other way to tell the government about the farmers' wish, those who really want to go for such beneficial GM varieties - be it Bt brinjal or HT cotton. After all, there are many reports which suggest cultivation of HT cotton by hundreds of farmers in Andhra Pradesh, Telangana and Maharashtra."
Amid threat of such defiance by farmers who called it a 'civil disobedience' agitation to lift the ban on GM crops, another group of farmers who are opposed to transgenic variety on Friday wrote to the GEAC, asking its immediate intervention so that such illegal activity can be stopped.
The group, Coalition for GM-Free India, demanded that the regulator must work with state governments to conduct nationwide investigation to locate illegal GM brinjal cultivation in farms and track supply chain of banned transgenic seeds even as the Haryana government claimed it to be limited to only one farm in Fatehabad.
"It's a usual practice. They would first contaminate (by cultivating GM varities) and then ask for regularisation. It (extent of cultivation and contamination) may come to the stage where there is no way you can control it. So, the government may eventually find itself in a situation to better regularise and regulate it than to enforce a ban," Rajesh Krishnan of the Coalition told TOI.
Referring to farmers' June 10 plan, Krishnan in his letter to the GEAC chairperson, A K Jain, said, "This requires an emergency response from you with a directive to all state government and farmers that any such action will constitute criminal breach of the GMO biosafety law and will be confronted with police action/fines/arrest as appropriate."
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Amid reports of illegal sowing of unapproved varieties of genetically modified (GM) crops by 'pro-GM' farmers at Akot in Maharashtra's Akola district on June 10, the Centre has written to the state government asking for detailed investigation and verification of facts on the ground. Reacting to a formal complaint in this regard, the Union environment ministry - a nodal ministry of the central regulator, Genetic Engineering Appraisal Committee (GEAC) - on June 12 (Wednesday) also asked the Maharashtra government for taking action against all those who might have taken steps to defy ban on transgenic crops in the state. <br/>The Maharashtra government is expected to submit a "detailed report on action taken" to the Centre at the earliest.Vishwa Mohan


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Andy Rubin shares next Essential Phone w/ wild form factor [Gallery]
Last month, Essential confirmed that its second device is "in testing" as some specs emerged. CEO Andy Rubin today shared some wild images of a very narrow candy bar-style touchscreen prototype that could be the next Essential Phone.
The post Andy Rubin shares next Essential Phone w/ wild form factor [Gallery] appeared first on 9to5Google.
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U.S., Allies At Odds Over Aid to Yugoslavia / EU wants to send $5 million in heating oil to opposition cities
1999-10-11 04:00:00 PDT Washington -- With winter fast approaching, the United States and its allies are deeply divided over whether to increase the isolation of Yugoslavia and its leader, Slobodan Milosevic, or to offer some aid to ease the hardship of the people in the hope of encouraging a more vital opposition.
On the eve of a meeting yesterday of the European Union's 15 foreign ministers in Luxembourg, the Clinton administration has outlined its strong opposition to plans by the group to provide heating oil and other aid to certain Yugoslav cities controlled by opposition parties, American and European officials said.
Under the program, the European Union would initially supply two cities with about $5 million in heating oil to help cope with shortages caused by destruction of Yugoslavia's petroleum refineries during NATO's air war over Kosovo. That aid would be the first part of a broader package that would eventually include food, medicine and even small-scale public works projects.
But American officials have said they fear that the assistance could shore up Milosevic by alleviating public discontent, which they hope could lead to protests in Yugoslavia, early elections, or even Milosevic's ouster or resignation.
The dispute over providing aid highlights the difficult situation facing the United States in the wake of NATO's air war over Kosovo last spring, which left Milosevic politically battered but still clinging to power.
While the United States has said it supports aid to relieve the suffering of ordinary people in Yugoslavia, it has ruled out any aid for reconstruction in the nation as long as Milosevic remains in power.
Since the war ended, Yugoslavia has remained under strict sanctions that prohibit trade, even as millions of dollars of aid has poured into Kosovo.
In a report on September 20, the U.N. Office for the Coordination of Humanitarian Affairs says that as winter sets in, Serbia faces severe shortages of electricity, heating oil and coal. Electricity supplies, it warned, could fall 40 to 50 percent below its requirements as winter progresses.
The European Union has been trying to tailor a relief program that would not directly support Milosevic, who has been charged with war crimes by the international tribunal in The Hague. During a meeting last month, the group's humanitarian office pledged roughly $40 million in aid.
European officials said they planned to provide aid only if they could guarantee that it would not end up in the hands of Milosevic's government. The $5 million worth of heating oil being considered under the initial plan would, for example, go to two cities in southeastern Serbia -- Nis and Pirot -- which are governed by opponents of Milosevic's ruling Socialist Party.