US3830922A - Thiopiperidone antiinflammatory agents - Google Patents

Abstract

METHODS AND COMPOSITIONS FOR THE TREATMENT OF INFLAMMATION, PAIN AND FEVER EMPLOYING PIPERIDONES AND THIOPIPERIDONES.

Description

United States Patent 3,830,922 THIOPIPERIDONE ANTIINFLAMMATORY AGENTS Bruce E. Witzel, Westfield, N.J., assignor to Merck & Co., Inc., Rahway, NJ.

No Drawing. Original application May 17, 1971, Ser. No. 144,333, now Patent No. 3,754,088. Divided and this application Nov. 24, 1972, Ser. No. 309,322

Int. Cl. A61k 27/00 US. Cl. 424-267 7 Claims ABSTRACT OF THE DISCLOSURE Methods and compositions for the treatment of inflammation, pain and fever employing piperidones and thiopiperidones.

This is a division of application Ser. No. 144,333 filed May 17, 1971, now Pat. No. 3,754,088 issued Aug. 21, 1973.

This invention relates to a method of treating inflammation in its varying manifestations, utilizing novel antiinflammatory compositions containing piperidones and thiopiperidones. In addition, these novel compositions exhibit potent analgesic and antipyretic activity and, therefore, this invention also relates to analgesic and antipyretic methods and compositions. More particularly, this invention is concerned with compositions containing piperidones and thiopiperidones for use in the treatment of inflammation and associated pain and fever. Furthermore, this invention is directed to analgesic and antipyretic methods for the relief and treatment of pain and fever not symptomatically related to an inflammatory indication and compositions utilized therefor.

The piperidones and thiopiperidones employed in the treatment of a condition symptomatically evidenced by pain, fever and inflammation, either as an essential or concomitant phenomena of the condition are represented by the following formulas:

R5 R3 R5 R3 W and In which R is hydrogen; alkyl (preferably loweralkyl such as methyl, ethyl, propyl, etc. aralkyl (preferably arloweralkyl such as benzyl, phenethyl, phenylhexyl, phenylpropyl, phenylbutyl and substituted derivatives thereof wherein the substituents include halo, amino, alkyl, alkylthio, al kylsulfinyl, alkylsulfonyl, hydroxy, etc. aryl (preferably phenyl) or substituted phenyl (such as tolyl, halophenyl, (haloalkyl)phenyl, aminophenyl, alkylamino and dialkylaminophenyl, (alkylthio)phenyl, alkylsulfinylphenyl, alkylsulfonylphenyl, hydroxyphenyl, anisyl, etc. hydroxyalkyl (preferably hydroxyloweralkyl such as hydroxyethyl, hydroxypropyl, etc. aminoalkyl (preferably aminoloweralkyl such as aminornethyl, aminopropyl, etc. .);dialkylaminoalkyl (preferably diloweralkylamino loweralkyl such as diethylaminoethyl, etc. alkylaminoalkyl (preferably loweralkylaminoloweralkyl); alkylamino (preferably loweralkylamino such as methylamino, ethylamino, etc. carboxyalkyl (preferably carboxyloweralkyl such as carboxymethyl, carboxyethyl, carboxypropyl, etc. .);hal0alkyl (preferably haloloweralkyl such as trifluoromethyl, etc. alkoxyalkyl (preferably loweralkoxy lower alkyl such as methoxymethyl, methoxyethyl, ethoxymethyl, propoxybutyl, etc. acyl, such as acetyl, propionyl, benzoyl, cinnamoyl, etc.

R R R and R are each hydrogen, alkyl (preferably loweralkyl such as methyl, ethyl, propyl, etc.), hydroxy, cyano, halogen (such as fluoro, chloro, *bromo, etc.), haloalkyl (preferably haloloweralkyl such as fiuoromethyl, trichloromethyl, trifluoromethyl, etc.), amino, acylamino (such as acetylamino, propionylamino, benzoylamino, etc.), acyl (such as acetyl, trifluoroacetyl, propionyl, benzoyl, substituted benzoyl, cinnamoyl, nicotinoyl, etc.), carboxy, carboalkoxy (preferably carboloweralkoxy such as carbomethoxy, carboethoxy, etc.), carbamyl, alkylamino (preferably loweralkylamino such as methylamino, ethylamino, etc.), and dialkylamino (preferably diloweralkylamino such a dimethylamino, diethylamino, etc.), alkylmercapto (preferably loweralkylmercapto, such as methylmercapto, etc. alkylsulfinyl (preferably loweralkylsulfinyl, such as methylsulfinyl, etc.), alkyl sulfonyl (preferably loweralkylsulfonyl, such as methylsulfonyl, etc.), alkoxy (preferably loweralkoxy such as metho-Xy, ethoxy, butoxy, etc. hydroxyalkyl (preferably hydroxyloweralkyl such as hydroxymethyl, hydroxyethyl, hydroxybutyl, etc. carboxyalkyl (preferably carboxyloweralkyl such as carboxymethyl, carboxyethyl, carboxypropyl, carboxypentyl, etc. trialkylammonium (a quaternary compound, preferably triloweralkylammonium such as trimethylammonium, dimethylethylammoniurn, tripropylammoniurn, etc. halides, tosylates, etc., carboalkoxyalkyl (preferably carboloweralkoxy loweralkyl such as carbome thoxymethyl, carboethoxypropyl, carbomethoxypentyl, etc. alkoxyalkyl (preferably loweralkoxy loweralkyl such as methoxymethyl, ethoxypropyl, methoxypentyl, ethoxymethyl, etc. aminoalkyl (preferably aminoloweralkyl such as aminomethyl, aminopropyl, aminopentyl, etc. alkylaminoalkyl (preferably loweralkylaminoloweralkyl such as methylaminoethyl, ethylaminopropyl, methylaminopropyl, methylaminopentyl, etc. dialkylaminoalkyl (preferably diloweralkylaminoloweralkyl, dimethylaminoethyl, diethylamino propyl, methylethylaminopentyl, etc. acyloxy (such a acetoxy, propionyloxy, butyroyloxy benzoyloxy, substituted benzoyloxy, nicotinoyloxy, etc. substituted carbamyl (such as monoand dialkyl carbamyl and monoand diarylcarbamyl such as dimethylcarbarnyl, phenylcarbamyl, methylethylcarbamyl, etc.

In its preferred aspects this invention relates to the compounds of formula I wherein R =hydrogen, alkyl, aralkyl, aryl, dialkylaminoalkyl, carboxyalkyl; R =amino, alkylamino, dialkylamino, alkoxy, hydroxy, cyano, halogen, trialkylammonium; R =alkyl, hydrogen, hydroxyalkyl, carboxyalkyl, carboxy, acylamino, haloalkyl, alkylamino, alkylaminoalkyl; R hydrogen, alkyl, dialkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, acyl; R hydrogen, alkyl.

Representative of the compounds included Within the scope of the invention include the following:

4-methyl-2-piperidone 4-ethyl-2-piperidone 4-i-propyl-2-piperidone 4-n-propyl-2-piperidone 4-n-butyl-2-piperidone 4-t-butyl-2-piperidone 3-amino-4-methyl2-piperidone 3-methylamino-4-methyl-2-piperidone 5-dirnethylamino-4-methyl-Z-piperidone 3-dimethylamino-4-11ethyl-2-piperidone 3-dimethylamino-4-ethyl-Z-piperidone 6-ethyl-2-piperidone 3-methoxy-4-methyl-2-piperidone 4-methyl-5-methylmercapto-2-piperidone the E-aminoester or acid. Also, rearrangement of cyclopentanones and their oximes, ammonolysis of the corresponding lactone, and partial reduction of substituted glutarimides are useful procedures for these compounds.

EXAMPLE 1 4-t-Butyl-2-piperidone A mixture of 4-tbutyl-2[1H]-pyridone (3.0 g., 0.02 m.), acetic acid (glacial, 60 ml.) and platinum oxide (0.7 g.) is reacted in a 40 p.s.i. hydrogen atmosphere until hydrogen uptake ceases. The mixture is then filtered, the acetic acid removed in vacuo, toluene (125 ml.) is added, the toluene removed in vacuo, and the residue recrystallized from ether (boiling to ca. 50 ml.) to yield 4-t-butyl- 2-piperidone, m.p. 134136 C.

Representative piperidones prepared from the corresponding pyridones by this procedure include 6-methyl-4- trifluoromethyl-2-piperidone, m.p. 106-111 C.; 4-cyclohexyl 2 piperidone (from 4 phenyl 2 pyridone), mp. 161-162 C.; 3 cyclohexyl 2 piperidone, m.p. 1170-1185 C.; 5 trifluoromethyl 2 piperidone, mp. 136-139 C.; 6 ethyl 4 methyl 2 piperidone, m.p. 7682 C.; 4-ethyl-2-piperidone, m.p. 3745); 6-ethyl-4- methyl 2 piperidone (m.p. 100-103 C.), 4,6-dimethyl- 2-piperidone, m.p. 125126 C.

EXAMPLE 2 4-methyl-2-piperidone and 3-dimethylamino-4-methyl-2- piperidone A mixture of 3 dimethylamine 4 methyl 2 [1H]- pyridone (2.3 g., 0.015 m.), acetic acid (glacial, 60 ml.) and platinum oxide (1.0 g.) is reacted in a 40' p.s.i. hydrogen atmosphere until hydrogen uptake is 12% over theory. The mixture is then filtered, the acetic acid removed in vacuo, the oily residue taken up in chloroform, washed with dilute sodium bicarbonate solution, the chloroform layer dried, filtered and concentrated to 2.6 g. of an oil, which is then chromatographed on a 125 g. silica gel column using a methanol-methylene chloride system (v./v. -3% methanol) to yield 4-methyl-2-piperidone and 3- dimethylamino-4-methyl-2-piperidone. Recrystallization of either from ether yields pure material, m.p. 87-895 and 144.5-146.5 C., respectively.

EXAMPLE 3 3-dimethylamino-4-methyl-Z-piperidone A mixture of 3-bromo-4-methyl-2-piperidone (0.01 m.), 40% aqueous dimethylamine ml.), and dimethylformamide (25 ml.) is heated at 140 C. for 18 hours in a sealed tube. The cooled mixture is concentrated in menu, the residue partitioned between chloroform-dilute sodium bicarbonate solution, the layers separated, the aqueous layer re-extracted with chloroform, and the chloroform extracts combined, dried and concentrated to a residue.

Chromatography of this residue on a silica gel column using a methanol-methylene chloride system (v./v. 0-5% methanol) as eluant yields 3-dimethylamino-4-methyl-2- piperidone.

EXAMPLE 4 4-methy1-3-trimethylammonium-2-piperidone iodide 3-Dimethylamino 4 methyl 2 piperidone is boiled in excess methyliodide, filtered, and the solution boiled down to a small volume and allowed to stand several days. Filtering yields 4-methyl-3-trimethylammonium-2 piperidone iodide.

EXAMPLE 5 4-methyl-S-methylsulfiinyl-2-piperidone To an ice-cooled solution of 4-methyl-5-methylmercapto-Z-piperidone (0.01 m.) in methanol-acetone is added a solution of sodium metaperiodate (0.012 m.) in a minimum of water. The mixture is stirred below C until precipitation of sodium iodate is completed, the iodate removed by filtration, the solvents removed in vacuo (below room temperature), and the residue taken up in chloroform, the chloroform dried, concentrated in vacuo and the material thus obtained chromatographed on a silica gel column using a methanol-methylene chloride system (v./v. O-10% methanol) as eluant to yield 4-methyl-5-methylsulfinyl-2-piperidone.

Use of excess metaperiodate at elevated temperatures or use of hydrogen peroxide in acetic acid, followed by chromatography yields the corresponding sulfone, 4-methyl-5-methylsulfonyl-Z-piperidone.

Use of excess metaperiodate at elevated temperatures or use of hydrogen peroxide in acetic acid, followed by chromatograph yields the corresponding sulfone, 4-methyl-S-methylsulfonyl-2-piperidone.

The piperidones and thiopiperidones of the invention possess a high degree of anti-inflammatory, analgesic and antipyretic activity. They are of value in the treatment of arthritic and dermatological disorders or like conditions responsive to anti-inflammatory drugs. In general they are indicated for a wide variety of conditions where one or more of the symptoms of inflammation, fever and pain are manifested. Included within this category are diseases such as rheumatoid arthritis, osteo arthritis, gout, infectious arthritis and rheumatic fever. As indicated above the compounds utilized in the practice of the invention also possess a useful degree of analgesic and antipyretic activity.

For these purposes the compounds of the invention may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, dogs, cats, etc., the compounds of the invention are effective in the treatment of humans.

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a pharmaceutically elegant and palatable preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, maize starch, or alginic acid; binding agents, for example starch, gelatine or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate above or with a wax may be employed.

Formulations for oral use may also be presented as hard gelatine capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatine capsules wherein the active ingredient is mixed with water or an oil medium, for example arachis oil, peanut oil, liquid parafiin or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturallyoccurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol mono-oleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan mono-oleate. The said aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxy benzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid parafiin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraflin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oils, or a mineral oil, for example liquid paraflin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring'phosphatides, for example soya bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan mono-oleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan mono-oleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or Wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or sus pension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringers solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic monoor diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectibles.

The compounds of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by 8 mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions etc. containing the antiinflammatory agents are employed.

Dosage levels of the order of 20 mg. to 7 grams per day are useful in the treatment of the above indicated conditions. For example, inflammation is effectively treated and anti-pyretic and analgesic activity manifested by the administration from about .3 to 100 milligrams of the compound per kilogram of body weight per day. Advantageously from about 2 mg. to about 50 mg. per kilogram of body weight and especially from about 4 mg. to about 20 mg./ kg. per daily dosage produce highly effective results.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example a formula tion intended for the oral administration of humans may contain from 5 mg. to 5 grams of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about percent of the total composition. Dosage unit forms will generally contain between from about 25 mg. to about 500 mg. of active ingredient.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

The following are illustrative of the techniques that may be employed in the preparation of pharmaceutical formulations to be utilized in the practice of the invention:

EXAMPLE 1 A mixture of 250 parts of 4-methyl-2-piperidone and 25 parts of lactose is granulated with suitable water, and to this is added parts of maize starch. The mass is passed through a 16 mesh screen. The granules are dried at a temperature below 60 C. The dry granules are passed through a 16 mesh screen, and mixed with 3.8 parts of magnesium stearate. They are then compressed into tablets suitable for oral administration.

The 4-methyl-2-piperidone used in the foregoing example may be replaced by 25, 100, 250, or 500 parts of other piperidones or thiopiperidones of this invention to produce tablets suitable for oral administration as an antiinflammatory, antipyretic and/or analgesic according to the method of this invention.

EXAMPLE 2 A mixture of 50 parts of 4-ethyl-2-piperidone, 3 parts of the calcium salt of lignin sulphonic acid, and 237 parts of Water is ball-milled until the size of substantially all of the particles of 4-ethyl-2-piperidone is less than 10 microns. The suspension is diluted with a solution containing 3 parts of sodium carboxymethylcellulose and 0.9 parts of the butyl ester of p-hydroxybenzoic acid in 300 parts of water. There is thus obtained an aqueous suspension suitable for oral administration for therapeutic purposes.

EXAMPLE 3 A mixture of 250 parts of 3-ainino-4-methyl-2-piperidone, 200 parts of maize starch and 30 parts of alginic acid is mixed With a suflicient quantity of 10% aqueous paste of maize starch, and granulated. The granules are dried in a current of warm air and the dry granules are then passed through a l6-mesh screen, mixed with 6 parts of magnesium stearate and compressed into tablet form to obtain tablets suitable for oral administration.

EXAMPLE 4 A mixture of 500 parts 6-ethyl-2-piperidone, 60 parts maize starch and 20'parts of gum acacia is granulated with a sutficient quantity of water. The mass is passed through a 12-mesh screen and the granules are dried in a current of warm air. The dry granules are passed through a 16-mesh screen, mixed with parts of magnesium stearate and compressed into tablet form suitable for oral administration.

EXAMPLE 5 (1) Tablets.--10,000 scored tablets for oral use, each containing 500 mg. of piperidone are prepared from the following ingredients:

Gm. 3-methoxy-4-methyl-2-piperidone 5000 Startch, U.S.P. 350 Talc, U.S.P 250 Calcium stearate 35 Gm. 4-carboxy-2-thiopiperidone 2500 Lactose, U.S.P. 1000 Starch, U.S.P 300 Talc, U.S.P 65 Calcium stearate 25 The powdered thiopiperidone is mixed with the starchlactose mixture followed by the tale and calcium stearate. The final mixture is then encapsulated in the usual manner. Capsules containing 10, 25, 50, and 100 mg. of piperidone are also prepared by substituting 100, 250, 500 and 1000 gm. for 2500 gm. in the above formulation.

(3) Soft elastic capsu1es.--One-piece soft elastic capsules for oral use, each containing 200 mg. of piperidone or thiopiperidone are prepared in the usual manner by first dispersing the powdered active material in sufficient corn oil to render the material capsulatable.

(4) Aqueous suspension-An aqueous suspension for oral use containing in each 5 ml., 1 gram of piperidone is prepared from the following ingredients:

4-hydroxymethyl-2-piperidone gm 2000 Methylparaben, U.S.P. gm.. 7.5 Propylparaben, U.S.P. ..gm 2.5 Saccharin sodium gm 12.5 Glycerin ml 3000 Tragacanth powder gm Orange oil fiavor gm 10 F. D. and C. orange dye gm..- 7.5 Deiomzed water, q.s. to 10,000 mg.

What is claimed is: 1. A method of treating humans and animals exhibiting at least one of the symptoms of pain, fever, and inflam- 10 mation which comprises the administration to said humans and animals of from about 20 mg. to 7 grams of a compound having the formula:

in which R is hydrogen, loweralkyl, hydroxyloweralkyl, haloloweralkyl or loweralkoxyloweralkyl; and

R R R and R are each hydrogen, loweralkyl, hydroxy,

halogen, haloloweralkyl, loweralkoxy, hydroxyloweralkyl or loweralkoxyloweralkyl.

2. The method of Claim 1 wherein R is hydrogen or loweralkyl; R is loweralkoxy, hydroxy or halogen; R is loweralkyl, hydrogen, hydroxyloweralkyl or haloloweralkyl; R is hydrogen or loweralkyl; and R is hydrogen or loweralkyl.

3. The method of Claim 1 wherein the compound is selected from the group consisting of 4-methyl-Z-thiopiperidone, 4-ethyl-2-thiopiperidone, 4-i-propyl-Z-thiopiperidone, 4-n-propyl-Z-thiopiperidone, 4-n-butyl-2-thiopiperidone, 4-t-butyl-2-thiopiperidone, 6-ethyl-Z-thiopiperidone, 3-methoxy-4-methyl-2-thiopiperidone, 3-hydroxy-4-methy1-2-thiopiperidone, 4-hydroxymethy1-2-thiopiperidone, 4-hydroxyethyl-2-thiopiperidone, 3-fluoro-4-methyl-2-thiopiperidone, 3-chloro-4-methyl-2-thiopiperidone, 3-fluoro-4,5-dimethyl-2-thiopiperidone, 1,4-climethyl-Z-thiopiperidone, 4-methoxymethyl-2-thiopiperidone and 1-methyl-5-ethyl-2-thiopiperidone.

4. The method of Claim 1 wherein the compound is 4- methyl-Z-thiopiperidone.

5. The method of Claim 1 wherein the compound is 4- ethyl-Z-thiopiperidone.

6. The method of Claim 1 wherein the compound is 4-ipropyl-Z-thiopiperidone.

7. The method of Claim 1 wherein the compound is 4- n-butyl-Z-thiopiperidone.

OTHER REFERENCES Chemical abstracts :7025g-7026a (1966). Chemical abstracts 67:50082g (1967).

ALBERT T. MEYERS, Primary Examiner L. SCHENKMAN, Assistant Examiner