Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
  • C07D213/40—Acylated substituent nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
  • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom

Definitions

• This invention relates to pharmaceutical preparations having adrenocortical inhibitory properties and to a method of producing anti-adrenal activity in animals.
• the pharmaceutical preparations and method of this invention can be used whenever it is desired to suppress adrenal glandular function, thereby inhibiting the synthesis of adrenal steroids in order to, for example, reduce hypertension, edema or hyperglycemia.
• compositions of this invention are unique in that they selectively block the production of adrenal steroids while being free of estrogenic activity.
• Anti-adrenal activity has not been disclosed for compounds of the chemical class described hereinafter.
• compositions are rapidly absorbed, particularly from the gastro-intestinal tract after oral administration, with remarkably low toxicity within the close ranges set forth hereinafter.
• compositions of this invention are in dosage unit form and comprise a nontoxic pharmaceutical carrier and a substituted aliphatic amine which has the following structural formula:
• Y and Y are phenyl, naphthyl, cycloalkyl from to 8 carbon atoms, pyridyl, or derivatives of phenyl, naph thyl, or pyridyl having substituents selected from the group consisting of amino, alkylamino having up to 4 carbon atoms, dialkylamino having up to 8 carbon atoms, benzylamino, acylamino having up to 3 carbon atoms, halogen, such as chloro, tr'ifluoromethyl, hydroxy, mercapto, lower alkyl having up to 3 carbon atoms, lower alkoxy having up to 3 carbon atoms, lower alkylthio having up to 3 carbon atoms, lower alkylsulfinyl having up to 3 carbon atoms, lower alkylsulfonyl having up to 3 carbon atoms, lower acyl having up to 3 carbon atoms, trifluoromethylthio, trifluoro
• X is amino or ANRR, wherein A is an alkylene linkage of from 1 to 4 carbon atoms which may be straight or branched, and R and R are lower alkyl having up to 3 carbon atoms, lower acyl having up to 3 carbon atoms, or hydrogen;
• R is hydrogen, alkyl to 7 carbon atoms, phenyl or benzyl
• n is an integer one or zero.
• substituted aliphatic amines are those represented by the above structure in which n is zero, Y and Y are phenyl, R is hydrogen or alkyl to 7 carbon atoms, and X is ANRR, with A, R and R as defined above, and depicted by Formula II below:
• Z and Z represent amino, alkylamino having up to 4 carbon atoms, dialkylamino having up to 8 carbon atoms, lower alkyl having up to 3 carbon atoms, hydroxy, lower alkoxy having up to 3 carbon atoms, mercapto, lower alkylthio having up to 3 carbon atoms, lower alkylsulfinyl having up to 3 carbon atoms, lower alkylsulfonyl having up to 3 carbon atoms, lower acyl having up to 3 carbon atoms, bromine, chlorine, fluorine, trifluoromethyl, trifluoromethylthio, trifluoromethylsulfonyl, tri fluoromethoxy or hydrogen.
• the compounds of Formula II are advantageous as compounds which inhibit the synthesis of important adrenal corticosteroids.
• these are:
• 2,2-diphenylethylamine Z-(p-aminophenyl)-2-phenethylamine; 2-phenyl-2-(p-trifluoromethylphenyl) ethylamine; 2-phenyl-2-p-methylthiophenylethylamine; 2-p-methylsulfonylphenyl-Z-phenylethylamine; and 2- (p-aminophenyl) -2-phenylpropylamine.
• Certain other compounds of Formula II are preferred, where selective suppression of the particularly important corticosteroid, aldosterone, is desired. Exemplary of these are:
• compositions of this inven tion in dosage unit form comprise a nontoxic pharmaceutical carrier and one of the above-described anti-adrenal compounds, or one of its acceptable acid addition salts.
• substituted aliphatic amine compounds of this invention may have asymmetric carbon atoms, forming optically active dand l-compounds.
• the connotation of the general formulas presented herein is intended to include the separated a. or 1 optical isomers, as well as racemic mixtures of these isomers.
• the isomers may be separated for individual use by resolution methods known to the art, such as frac' tional crystallization of the l-tartrate salts of the diamines.
• resolution methods known to the art, such as frac' tional crystallization of the l-tartrate salts of the diamines.
• a synthesis starting with an optically active side chain may yield the desired optical isomer.
• a wide variety of chemical methods can be employed to reduce these oximes to the monoand di-amines. Treating of these amines with alkylating agents and acylating agents leads to the aryl substituted amines, or the amino hydrogen substituted amines of this invention.
• This intermediate is vigorously reduced using hydrogen and Raney nickel in methanol, to yield the desired substituted l-aryl- 2-arylpropylamine.
• the pyridyl congeners of the diarylalkylamine compounds are prepared by alkylating suitably substituted arylacetonitriles with halopyridines in the presence of a strong base such as sodamide or sodium hydride.
• the cycloalkyl congeners of the diaryl alkylamino compounds are prepared from appropriately substituted phenylacylnitrile by treatment with a cycloalkanone, such as cyclohexanine.
• a cycloalkanone such as cyclohexanine.
• the resulting intermediate, a cycloalkylidene, substituted phenyl acylnitrile, is catalytically reduced, yielding the corresponding substituted phenylcycloalkyl alkylamine.
• diarylalkylamines of Formula I may be obtained from the corresponding diarylalkanoic acid amides by reduction with lithium aluminum hydride.
• Exemplary syntheses are set forth in the examples.
• a nontoxic pharmaceutically acceptable organic or inorganic acid addition salt of the base may be used instead of the base.
• the hydrochloride salt is used.
• other salts such as those derived from sulfuric, nitric, phosphoric, citric, acetic, lactic, mandelic, salicylic, phthalic, fumaric, maleic, tartaric, hydrobromic, benzoic and like nontoxic acids may be used.
• the salts are best prepared by reacting the free base with a stoichiometric amount of the desired organic or inorganic acid in a suitable solvent, such as ethyl acetate-ether solution, ethanol, acetone, water or various combinations of solvents.
• the quaternary ammonium salts may be employed.
• the pharmaceutical carrier employed may be, for example, either a solid or liquid.
• solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
• liquid carriers are syrup, peanut oil, olive oil, water and the like.
• the carrier or diluent include any time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
• a wide variety of pharmaceutical forms can be employed.
• a solid carrier the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
• the amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 1 g.
• a liquid carrier the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, ampul or liquid suspension.
• the method in accordance with this invention comprises administering internally to an animal organism a compound as represented by the above formula, or a nontoxic addition salt thereof, usually combined with a pharmaceutical carrier, for example, any of the above compositions in an amount sufficient to produce anti-adrenal activity.
• the active medicament preferably will be, typically per unit of hydrochloride salt, in an amount of from about 5 mg. to about 800 mg. and advantageously from about 100 mg. to about 500 mg.
• the unit dosage will contain from about 20 mg. to about 600 mg.
• the administration may be parenterally or orally, the latter being the preferable route of administration.
• Advantageously equal doses will be administered two to twelve times daily.
• the daily dosage regimen will be from 0.05 g.
• the preparations can also be given per se, or as an additive to the feed or drinking matter of animals.
• EXAMPLE 1 Preparation of 2-phenyl-2- (p-aminophenyl)-ethyl amine
• a suitable reaction vessel is charged with 111 g. of phenylcyanomethylene quinone oxime, a solution of 20 g. of potassium hydroxide (assay in 400 ml. of methanol, two teaspoons of Raney nickel catalyst No. 28, and hydrogen under an initial pressure of about 1180 lbs. per square inch.
• the vessel is rocked and slowly heated to about 80 C., maintaining that temperature for about three hours. During the heating process, additional hydrogen is charged to the vessel so as to maintain a hydrogen pressure of about 800 lbs. per square inch as a minimum.
• reaction mixture is cooled, filtered and 1500 ml. of water are added with stirring to the filtrate.
• the phenyl-(3-methoxy 4' aminophenyl)-acetonitrile which settles to the bottom of the mixture is removed, Washed with water and after drying, melts at about 53 C. yield).
• An autoclave is charged with 10 g. of phenyl-(3'- methoxy-4'-aminophenyl)-acetonitrile, 100 ml. of methanol, 2 g. of a slurry of Raney nickel in water, 20 g. of ammonia and hydrogen under pressure of 1000 lbs. per square inch.
• the reaction vessel is heated with shaking to C., maintaining that temperature for two hours. After cooling and releasing the pressure, the contents are filtered. Upon removing the methanol and ammonia, and purifying the compound, there is isolated 2-phenyl-2-(3- rnethoxy-4'-aminophenyl)-ethyl amine.
• the dihydrochloride, M.P. 213-215 C. is formed by dissolving the diamine in ether and treating the solution with an excess of dry hydrogen chloride.
• the reduction is completed at 55 C. and 1000 p.s.i. of hydrogen.
• the bomb is opened and the contents are filtered.
• the filter cake is washed withmethanol and the combined filtrates are evaporated to produce an oil.
• the oil is dissolved in ethyl acetate and saturated with hydrogens chloride gas.
• the resulting solid dihydrochloride is filtered and dissolved in water.
• the aqueous solution is extracted several times with ether.
• the aqueous layer is made alkaline and extracted with ethyl acetate.
• the combined organic phases are washed with water, dried over magnesium sulfate and concentrated.
• the concentrate is saturated with hydrogen chloride; the solid formed is filtered and suspended in hot l-butanol.
• the butanol is cooled and the pale yellow solid is filtered and recrystallized from methanol-ethyl acetate (yield 22 g.), M.P. 293-295" C. dec.
• This material in 150 ml. of tetrahydrofuran is reduced at 8095 C. in the presence of Raney nickel under 1000 p.s.i. of hydrogen.
• the catalyst is removed and the solvent is evaporated.
• the residue is dissolved in 35% aqueous acetic acid and extracted with ether.
• the aqueous phase is made basic and extracted with methylene chloride.
• the organic solutions are dried and evaporated to produce a clear oil.
• the oil is triturated with petroleum ether to give crystals which are recrystallized from benzene-petroleum ether.
• the yield of 2-(p-N-carbethoxyaminophenyl)- 2-phenylethylamine, melting at 96-985 C. was 6.5 g.
• the filtrates are concentrated to an oil which distills at l60-170 C. at 1 mm. of Hg.
• the pale yellow oily distillate is dissolved in ether and saturated with hydrogen chloride.
• the salt is filtered, washed with ethyl acetate, and recrystallized from methanol-ethyl acetate twice to give 2 g. of the dihydrochloride, M.P. 254256 C. dec.
• the aqueous mixture is extracted with benzene, the combined benzene phases are washed with 10% sodium hydroxide until alkaline and then are extracted thoroughly with dilute hydrochloric acid. The acidic washes are thoroughly extracted with ether to produce a clear yellow aqueous phase. This aqueous phase is basified with 10% sodium hydroxide and the resulting solid extracted into methylene chloride. Removal of the solvent leaves a solid residue which is recrystallized from ethanol to give 5 .5 g. of crystalline (p-dimethylaminophenyl) phenylacetonitrile, M.P. IOU-102 C.
• a 15 g. sample of the cyano tertiary amine is reduced in methanol containing ammonia at room temperature in the presence of Raney nickel at 1000 p.s.i. of hydrogen.
• the catalyst is removed and the solvent is distilled to give an oil which is dissolved in ether.
• the ether is washed with dilute hydrochloric acid, the acid washes are combined, made basic, and extracted with ether.
• the ether is dried and evaporated.
• the distillate crystallizes on standing and Weighs 9.5 g., M.P. 72'74 C.
• a portion is converted to the tartrate salt, M.P. 241 C. dec. (CH OH).
• the above amide is hydrolyzed by refluxing in 10% sulfuric acid. After neutralization and extraction the diamine is converted to the dihydrochloride, M.P. 280 281.5 C. after recrystallization from methanolethyl acetate.
• EXAMPLE 8 Preparation of 2-(4-amino-3,5-xylyl)-2-phenylethylamine hemifumarate Twenty-seven g. of 3,5-dimethyl 4 oxo-a-phenyl-2, S-cyclohexadiene-A, a-acetonitrile oxime (prepared as described by Davis, Pizzini and Bara, loc. cit.) is reduced with zinc amalgam to the aminonitrile as in Example 2, M.P. 1141l6 C.
• High pressure hydrogenation reduced both the N-oxide and the nitrile to the desired amino compound which is isolated and purified as the hemifumarate.
• EXAMPLE 19 Preparation of 2-(p-methylthiophenyl)-2-pheny1- ethylamine hydrochloride
• EXAMPLE 20 Preparation of 2-(p-methylsulfinylphenyl) -2-phenylethylamine hydrochloride 3-(p-methylthiophenyl)-3-phenylpropionic acid from the previous example, is oxidized with an equimolar quantity of peracetic acid in excess acetic acid.
• the crude 3-(p-methylsulfinylphenyl)-3-phenylpropionic acid is isolated by diluting the acetic acid solution with several volumes of water.
• the sulfoxide is filtered, washed with water and dried.
• the dry sulfoxide is subjected to the conditions of the Curtius reaction as in the previous example, and the amine sulfoxide is isolated and purified as the hydrochloride.
• EXAMPLE 21 Preparation of '2- (p-methylsulfonylphenyl -2-phenylethylamine hydrochloride 3-(p-methylsulfonylphenyl)-3-phenylpropionic acid is prepared from the corresponding p-methylthio acid (Example 19) by oxidation with excess peracetic acid. The sulfone acid is converted to the amine as in Example 19. The HCl salt has a M.P. of 2l2214 C. after recrystallization from methanol-ether.
• EXAMPLE 24 Preparation of 2-(p-n-butylaminophenyl)- 2-phenylethylamine hemifumarate (p n Butyrylaminophenyl) phenylacetonitrile, M.P. 112-113 C. is prepared in the manner shown in Example 23 and converted to 2-(p-n-butylaminophenyl)-2-phenylethylamine, as exemplified in that example. The hemifumarate recrystallizes from methanol-ether melted at 178-18l C.
• EXAMPLE 26 Preparation of 3-(p-dimethylaminophenyl)- 2-phenylpropylamine Seven g. of potassium hydroxide is dissolved in 50 ml. of methanol; to this solution 25 g. (.25 mole) of phenylacetonitrile is added. This solution is then added to a solution of 25 g. (.167 mole) of p-dimethylaminobenzaldehyde in 75 ml. of methanol. This mixture is heated to 50 C. for approximately one hour and then allowed to sit at room temperature. A yellow-green precipitate, 3-(p-dimethylaminophenyl)-2-phenyl I acrylonitrile, M.P. 134-137 C., is obtained in 93.47% yield.
• EXAMPLE 27 Preparation of 3-(p-dimethylaminophenyD- Z-(p-methoxyphenyl)-propylamine
• 25 g. (.167 mole) of p-dimethylaminobenzaldehyde is condensed with 25 g. (.17 mole) of p-methoxyphenylacetonitrile, using potassium hydroxide as a catalyst, the only difference is that the mixture was heated to 50 C. for 6 hrs.
• a yellowgreen precipitate, 3-(p-dimethylaminophenyl)-2-(p-methoxyphenyl) acrylonitrile, M.P. 149151 C. is obtained in 75.40% yield.
• EXAMPLE 28 Preparation of 3-(n-aminophenyl)- 2-phenylpropylamine Thirty-four g. (.226 mole) of m-nitrobenzaldehyde is poured into a solution of 23 g. (.197 mole) of phenylacetonitrile in 600 ml. of methanol; this is followed by the addition of 10 ml. of diethylamine. The reaction mixture is kept between 4050 C. for one hour, and then allowed to stand at room temperature. A silver-green precipitate, 3-(m-nitrophenyl)-2-phenyl acrylonitrile, is obtained in 96% yield.
• a mixture of 12.1 g. (0.034 mole) of 11a above, 200 ml. of ethanol and 12 ml. of 85% hydrazine is stirred and heated to reflux. Solution is effected after a short period of refluxing, followed almost immediately by the formation of a dense precipitate. Enough water is added to dissolve the precipitate, and stirring and refluxing are continued for 1 hr. The solution is stirred an additional hour at room temperature and diluted with water. The alcohol is removed and the aqueous residue is extracted with ether. The ether extracts are washed with Water until neutral and dried.
• EXAMPLE 31 Preparation of Z-(p-aminophenyl)-2-phenylhexylamine
• the n-butyl analog of the compound of Example 30 is prepared in an analogous manner thereto, with substitution of butyl iodide for methyl iodide.
• the hydrochloride salt of the hexylnitrile melts at 190193 C. (ethyl acetate).
• the dihydrochloride salt of the desired product has an M.P. of 272273 C. dec. (ethanol-ether).
• EXAMPLE 32 Preparation of 2-(p-aminophenyl)-2,3-diphenylpr0pylamine hemihydrate
• the benzyl analog of the compound of Example 30 is prepared in a similar manner thereto, with substitution of benzyl halide for methyl iodide.
• the hydrochloride salt of the triphenylnitrile melts at 167168 C.
• the dihydrochloride salt of the desired product has an M.P. of 339- 340 C. dec. (methanol-ethyl acetate).
• EXAMPLE 34 Preparation of 2-cyclohexyl-2-(p-methoxyphenyl) ethylamine
• One hundred and forty-seven g. of p-methoxy phenylacetonitrile is condensed with 100 g. of cyclohexanone in a solution composed of 65 g. of potassium hydroxide in 500 ml. of methanol.
• the resulting solution is refluxed for 1 hr.
• the product, tx-cyclohexyldiene-panethoxyphenylacetonitrile is a white solid, M.P. 54-56 C.
• sucrose, calcium sulfate and d-2-(p-aminophenyl)- 2-phenylethyla'mine hydrochloride are thoroughly mixed and granulated with hot gelatin solution.
• the wetted mass is passed through a #6 mesh screen directly onto drying trays.
• the granules are dried at 120 F. and passed through a #20 mesh screen, mixed with the starch, talc and stearic acid, passed through a #60 mesh, and compressed into tablets.
• One tablet is administered two to twelve times a day.
• EXAMPLE 37 Preparation of 3,3-diphenylpropylamine hydrochloride A mixture of 23 g. (0.1 mole) of diphenylpropionic acid and 48 g. (0.4 mole) of thionyl chloride is refluxed for 2 hrs. The excess thiouyl chloride is removed and the residue is evaporated again with benzene. The residue is dissolved in a small volume of benzene and added with stirring to 100 ml. of concentrated aqueous ammonia. The precipitated 3,3-diphenylpropionamide is cooled, filtered, washed with water, and recrystallized from ethanol to give 78% of product M.P. 125-127 C.
• a solution of 14 g. (0.06 mole) of the above amide in 100 ml. of dry tetrahydroturan is added dropwise to a stirred suspension of 11.7 g. (0.31 mole) of lithium aluminum hydride in 200 ml. of dry ether.
• the mixture is refluxed for 6 hrs. after the addition is completed, and then is stirred overnight at room temperature.
• the complex is decomposed by the sequential addition of 11.7 ml. of water, 11.7 ml. of 10% sodium hydroxide, and ml. of water followed by stirring for 45 min.
• the granular precipitate is filtered and the filter cake is resuspended in either, stirred, and refiltered.
• the combined filtrates are dried (Na SO and evaporated.
• the residual oil weighs 13 g. It is dissolved in ether and saturated with hydrogen chloride to precipitate the hydrochloride.
• the salt is recrystallized from ethanolether to give 15.5 g. (60/) of the pure salt, M.P. 217- 218 C.
• EXAMPLE 38 A preparation of 4,4-diphenylbutylamine hydrochloride Ingredients: Amounts (mg) 2-(p aminophenyl) 2 phenylethylamine hydrochloride Lactose 14 The above ingredients are screened through a #40 mesh screen, mixed well and filled into a #1 hard gelatin capsule. One capsule is administered two to twelve times daily.
• EXAMPLE 40 Ingredients: Amounts (mg) 2 (p aminophenyl) 2 phenylethylamine hydrochloride 100.00 Magnesium stearate 5 .00 Lactose 400.00
• the above ingredients are screened through a #40 mesh screen, mixed well and filled into a #0 hard gelatin capsule.
• One capsule is administered two to twelve times a day.
• EXAMPLE 41 Ingredients: Amounts (mg) I 2-(3' methoxy 4 aminophenyl)-Z-phenylethylamine 25.00 Calcium sulfate dihydrate 125.00 Sucrose 25.00 Starch 15.00 Talc 5.00 Stearic acid 3.00
• sucrose, calcium sulfate and 2-(3-methoxy-4- aminophenyl)-2-phenylethylamine are thoroughly mixed and granulated with hot 10% gelatin solution.
• the wetted mass is passed through a #6 mesh screen directly onto drying trays.
• the granules are dried at F. and passed through a #20 mesh screen.
• These granules are then mixed with the starch, talc and stearic acid, passed through a #60 mesh screen and compressed into tablets.
• EXAMPLE 42 Ingredients: Amounts (mg) 2-(p-aminophenyl)-2-phenylethylamine 150.00 Peanut oil 200.00
• the ingredients are mixed to a thick slurry and filled into a soft gelatin capsule.
• One capsule is administered two to twelve times a day.
• sustained time release compositions which provide a substantially uniform dosage over an extended period of time, thus permitting reduction of the number of unit doses to be taken daily.
• sucrose, calcium sulfate and 2-(p-aminophenyl)- 2-phenylethylamine hydrochloride are thoroughly mixed and granulated with hot 10% gelatin solution.
• the wetted mass is passed through a #6 mesh screen directly onto drying trays.
• the granules are dried at 120 F. and passed through a #20 mesh screen, mixed with the starch, talc and stearic acid, passed through a #60 mesh, and compressed into tablets.
• One tablet is administered two to twelve times a day.
• the method of producing anti-adrenal activity which comprises internally administering to an animal organism requiring suppression of adrenal glandular function a daily dosage regimen from about 0.05 g. to about 16 g. of a compound selected from the group consisting of a tree base and its nontoxic, pharmaceutically acceptable acid additon salt thereof, said free base having the NRR' in which:
• A is an alkylene linkage of from 1 to 4 carbon atoms
• R is hydrogen or acetyl
• R is hydrogen
• R" is hydrogen or alkyl to 7 carbon atoms
• Z is in the para position and represents amino, alkylamino having up to 4 carbon atoms, dialkylamino having up to 8 carbon atoms, acetamido, methyl, chloro, trifluoromethyl, hydroxy, mercapto, methylthio, methylsulfinyl, methylsulfonyl, or hydrogen;
• Z is hydrogen or, when Z is methyl, Z is methyl in the para position.
• the method of producing anti-adrenal activity which comprises internally administering to an animal organism requiring suppression of adrenal glandular function a daily dosage regimen from about 0.05 to about 16 g. of a compound selected from the group consisting of a free base and its nontoxic, pharmaceutically acceptable acid addition salt thereof, said free base having the formula according to claim 1 wherein R, R, R" and Z are hydrogen, Z is p-amino, and A is methylene.
• the method of producing anti-aldosterone activity which comprises internally administering to an animal organism requiring suppression of adrenal glandular function a daily dosage regimen from about 0.05 to about 16 16 g. of a compound selected from the group consisting of a free base and its nontoxic, pharmaceutically acceptable acid addition salt thereof, said free base having the formula according to claim 1 wherein R, R and Z are hydrogen, R" is methyl, Z' is p-amino, and A is methylene.
• the method of producing anti-adrenal activity which comprises internally administering to an animal organism requiring suppression of adrenal glandular function a daily dosage regimen from about 0.05 to about 16 g. of a compound selected from the group consisting of a free base and its nontoxic, pharmaceutically acceptable acid addition salt thereof, said free base having the formula according to claim 1 wherein R, R, R", Z and Z' are hydrogen, A is methylene.

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• 1965
  • 1965-09-29 NL NL6512616A patent/NL6512616A/xx unknown
• 1966
  • 1966-03-01 US US530806A patent/US3510560A/en not_active Expired - Lifetime

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