US3278541A - Di-substituted-n-alkyl piperidines - Google Patents

Di-substituted-n-alkyl piperidines Download PDF

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US3278541A
US3278541A US3278541DA US3278541A US 3278541 A US3278541 A US 3278541A US 3278541D A US3278541D A US 3278541DA US 3278541 A US3278541 A US 3278541A
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • R stands for a hydrocarbon radical having up to carbon atoms and containing one or more double linkages which may be substituted by halogen, amino, or alkyl or alkoxy having up to 3 carbon atoms, R stands for alkyl having up to 4 carbon atoms, and R stands for hydroxy or alkoxy having up to 4 carbon atoms, wherein an amine of the general Formula II:
  • R and R have the meanings given above, is reacted with a carboxylic acid of the general formula R-COOH, in which R has the meaning given above, or a halide, an anhydride, an ester or an azide of said acid, the compounds of the general Formula I being converted into their addition salts with physiologically tolerable acids where such salts are required.
  • carboxylic acids As reactive derivatives of carboxylic acids, the corresponding halides, preferably chlorides and bromides are used, furthermore, for instance, anhydrides, esters or azides.
  • the carboxylic acids referred to may contain one or several double linkages in the molecule. These double linkages may likewise be present in an aromatic ring system.
  • carboxylic acids may be used, for instance: dimethyl-acrylic acid, crotonic acid, a-methyl-crotonic acid, a,,8-dimethyl-crotonic acid, fl-chloro-isocrotonic acid, ,B-ethyl-crotonic acid, a-ethyl-fi-methyl-crotonic acid, sorbic acid, cinnamic acid, benzoic acid and their derivatives, such as salicylic acid, acetyl-salicylic acid, benzoic acids substituted by halogen, amino or alkyl or alkoxy having up to 3 carbon atoms, as well as their diand tetrahydro-derivatives, naphthoic acids, diphenylcarboxylic acids; the use of a,/3-unsaturated carboxylic acids having 4 to 5 carbon atoms, e.g. dimethyl-acrylic acid and benzoic acid, being of particular advantage.
  • the process of the invention is materialized by acylating one of the above-mentioned amines with one of the above-mentoned carboxylic acids or its reactive derivatives.
  • Carboxylic acid halides especially chlorides or bromides are favorably used as starting substances. Acid halides are reacted with the amines at a temperature between 0 and 0, preferably between 0 and 30 C. Acid azides are reacted at O30 C., whereas free acids and acid esters are reacted between 60 and 200 C., the esters preferably at a temperature between and 200 C.
  • the reaction may be carried out with or without the use of solvents.
  • solvents there are suitable, for instance, diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofnrane and dioxane.
  • ketones such as acetone, methyl-ethyl-ketone, hydrocarbons such as petroleum ether, benzene, toluene, xylene, furthermore dimethyl-forrnamide, ethyl acetate or acetonitrile can be used as solvents.
  • the hydrogen halide is liberated and bound by the tertiary amino group in the reaction mixture. If a solvent is used in which the salt thus formed is insoluble or sparingly soluble, the reaction product is in many cases obtained as crystallized hydro-halide of the corresponding basic amide. If necessary, the products may be purified according to the usual methods, for instance by recrystallizing or converting them into the free base and subsequent addition of an appropriate acid.
  • another amine may be used, especially a tertiary amine such as trimethylamine, triet-hylamine, dimethylaniline or pyridine, which, if desired, simultaneously serves as a solvent.
  • a tertiary amine such as trimethylamine, triet-hylamine, dimethylaniline or pyridine
  • an excessive amount of the starting amine or an alkali metal hydroxide, an alikali metal carbonate, an alkaline earth metal hydroxide or an alkaline earth metal carbonate may be used as a hydrogen halide binding agent.
  • the products of the invention are valuable medicatmen-ts. They are well tolerated and show favorable pharmacological properties. They are especially suitable as antitussive agents. Some of them likewise show a sedative efiiciency.
  • German Patent 1,112,514 basic carboxylic acid amides are known which are open-chain compounds analogous to those obtained according to the process of the present invention. It is surprising that the physiological action of the novel compounds differs from that of the known substances.
  • the known 5- methyl-crotonic acid-2- (m-methoxy-phenyl) -2- (tr-dimethylamino-ethyl)-butylamide-hydrochloride (A) shows a strong analgesic and, practically, no antitussive efliciency
  • the compounds prepared according to the process of the present invention for instance 4-(B-methyl-crotonoyl) aminomethyl 4-(m-methoxy-phenyl)-1-methyl-pipractically show no analgesic but a strong antitussive efliciency.
  • a dose of 0.7 mg./ kg. of the products of the invention provokes the same antitussive effect as a dose of 1 mg./ kg. of codein.
  • they show no analgesic effect when given in the above-mentioned doses.
  • the absence of analgesic efiiciency means an advantage for antitussive agents, particularly since the use of substances like codein which show analgesic as well as antitussive activity implies the risk of addiction.
  • the products of the present invention are used as such or in the form of their salts.
  • hydrohalic acids such as hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, amidosulfonic acid and organic acids such as formic acid, acetic acid, malonic acid, succinic acid, lactic acid, maleic acid, pamino-salicylic acid and aceturic acid can be used.
  • the compounds are processed into pharmaceutical preparations by mixing them with physiologically tolerable, usual organic or inorganic, solid or liquid carriers which do not react with the compounds, for instance,
  • EXAMPLE 1 4-benz0yl-amin0methyl-4- (m-methoxy-phenyl) 1-methyl-piperidine-hydrohloride (a) To a solution of 14 grams of benzoyl-chloride in 300 cc. of benzene, a solution of 23.4 grams of l-methyl- 4-aminomethyl-4-(m-methoxy-phenyl) piperidine (boiling point of 144-146 C. under a pressure of 0.1 mm. of mercury) in milliliters of benzene is gradually added while stirring at 20-30 C. Stirring is continued for 30 minutes. The crystalline magma thus formed is filtered with suction, dried and recrystallized from methanol by adding ether.
  • EXAMPLE 2 4-(fl-methyl-crotonoyl) -amin0methyl-4-(m-methoxyphenyl -methyl-piperidine-hydroclzloride 11.9 grams of B-methyl-crotonic acid chloride and 23.4 grams of 1 methyl 4 aminomethyl 4-(m-methoxyphenyl)-piperidine are reacted according to the method described in Example 1(a). 29.5 grams of 4-(/3-methylcrotonoyl) aminmoethyl 4 (m-methoxy-phenyl) 1 methyl-piperidine-hydrochloride are obtained, melting at 149152 C. after recrystallization from acetone.
  • EXAMPLE 3 4-benz0yl-aminomethyl-4-(m-hydr0xy-phenyl)- 1 -methyl-piperidine-hydrochloride 8.3 grams of 1-methyl-4-aminomethyl-4-(m-hydroxyphenyl)-piperidine-dihydrobromide (prepared from 1- methyl 4 aminomethyl-4-(m-methoxy-phenyl)-piperidine by reaction with hydro'bromic acid of 63% strength at 120 C.) are dissolved in 180 cc. of absolute ethanol; 20.2 cc. of 2.15 N-methanolic sodium-methylate solution are added and the solution is concentrated by evaporation.
  • 1-methyl-4-aminomethyl-4-(m-hydroxyphenyl)-piperidine-dihydrobromide prepared from 1- methyl 4 aminomethyl-4-(m-methoxy-phenyl)-piperidine by reaction with hydro'bromic acid of 63% strength at 120 C.
  • EXAMPLE 4 4-(p-eth0xy-benzoyl) -aminomethyl-4-(m-methoxyphenyl) -1-methyl-piperidine-hydrochloride
  • a solution of 23.4 grams of 1-methyl-4-aminomethyl-4-(m-methoxy-phenyl)-piperidine in 300 cc. of benzene heated to the boil a solution of 18.5 grams of pethoxy-benzoyl-chloride in 100 cc. of benzene is gradually added while stirring. After cooling, the reaction product is filtered with suction, washed with ether and recrystallized fIom ethanol. 15.8 grams of 4-(p-ethoxy-benzoyl)- aminomethyl-4 (m-methoxy-phenyl) l-methyl-piperidine-hydrochloride melting at 237239 C. are obtained.
  • R is selected from the group consisting of a hydrocarbon radical, halohydrocarbon, aminohydrocarbon, alkyl and alkoxy hydrocarbon radicals wherein the hydrocarbon portion has at least one double linkage and up to ten carbon atoms and the alkyl and alkoxy portions have up to three carbon atoms, R stands for alkyl having up to four carbon atoms, and R stands for hydroxy or alkoxy having up to four carbon atoms, and addition salts thereof with a physiologically tolerable acid.

Description

nited States Patent 3,278,541 4,4-Dll-SUBSTlTUTED-N-ALKYL PIPERIDINE Karl Schmitt and Ernst Linrlner, Frankfurt am Main, Germany, assignors to Farbwerke Hoechst Aktiengesellschaft vormals Meister Lucius & Briining, Frankfurt am Main, Germany, a corporation of Germany No Drawing. Filed Apr. 30, 1963, Ser. No. 276,982
Claims priority, application Germany, May 5, 19 62,
6 Claims. or. 260294) in which R stands for a hydrocarbon radical having up to carbon atoms and containing one or more double linkages which may be substituted by halogen, amino, or alkyl or alkoxy having up to 3 carbon atoms, R stands for alkyl having up to 4 carbon atoms, and R stands for hydroxy or alkoxy having up to 4 carbon atoms, wherein an amine of the general Formula II:
in which R and R have the meanings given above, is reacted with a carboxylic acid of the general formula R-COOH, in which R has the meaning given above, or a halide, an anhydride, an ester or an azide of said acid, the compounds of the general Formula I being converted into their addition salts with physiologically tolerable acids where such salts are required.
As reactive derivatives of carboxylic acids, the corresponding halides, preferably chlorides and bromides are used, furthermore, for instance, anhydrides, esters or azides. The carboxylic acids referred to may contain one or several double linkages in the molecule. These double linkages may likewise be present in an aromatic ring system. The following carboxylic acids may be used, for instance: dimethyl-acrylic acid, crotonic acid, a-methyl-crotonic acid, a,,8-dimethyl-crotonic acid, fl-chloro-isocrotonic acid, ,B-ethyl-crotonic acid, a-ethyl-fi-methyl-crotonic acid, sorbic acid, cinnamic acid, benzoic acid and their derivatives, such as salicylic acid, acetyl-salicylic acid, benzoic acids substituted by halogen, amino or alkyl or alkoxy having up to 3 carbon atoms, as well as their diand tetrahydro-derivatives, naphthoic acids, diphenylcarboxylic acids; the use of a,/3-unsaturated carboxylic acids having 4 to 5 carbon atoms, e.g. dimethyl-acrylic acid and benzoic acid, being of particular advantage.
3,278,541 Patented Oct. 11, 1966 The above-mentioned carboxylic acids are reacted with the following amines, for instance:
1-methyl-4-aminomethyl-4-(o-, mor p-methoxy-phenyl)-piperidine, 1-methyl-4-aminomethyl-4-(o-, mor pethoxy-phenyl) -piperidine, 1-methyl-4-aminomethyl-4- 0-, mor propoxyor isopropoxy-phenyl)-piperidine, l-methyl-4-aminomethyl-4-(o-, mor p-n-butoxy, sec.butoxyor iso-butyl-phenyl)-piperidine; instead of l-methyl, there may also stand l-ethyl, l-n-propyl, l-isopropyl, l-n-butyl, 1-sec.butyl or l-isobutyl. It is of advantage to use l-methyl-4-aminomethyl-4- (m-methoxy-phenyl) -piperidine.
The process of the invention is materialized by acylating one of the above-mentioned amines with one of the above-mentoned carboxylic acids or its reactive derivatives. Carboxylic acid halides, especially chlorides or bromides are favorably used as starting substances. Acid halides are reacted with the amines at a temperature between 0 and 0, preferably between 0 and 30 C. Acid azides are reacted at O30 C., whereas free acids and acid esters are reacted between 60 and 200 C., the esters preferably at a temperature between and 200 C.
The reaction may be carried out with or without the use of solvents. As solvents there are suitable, for instance, diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofnrane and dioxane. Furthermore, ketones, such as acetone, methyl-ethyl-ketone, hydrocarbons such as petroleum ether, benzene, toluene, xylene, furthermore dimethyl-forrnamide, ethyl acetate or acetonitrile can be used as solvents.
In the course of the reaction of the acid halides with the amines the hydrogen halide is liberated and bound by the tertiary amino group in the reaction mixture. If a solvent is used in which the salt thus formed is insoluble or sparingly soluble, the reaction product is in many cases obtained as crystallized hydro-halide of the corresponding basic amide. If necessary, the products may be purified according to the usual methods, for instance by recrystallizing or converting them into the free base and subsequent addition of an appropriate acid.
For binding the hydrogen halide, another amine may be used, especially a tertiary amine such as trimethylamine, triet-hylamine, dimethylaniline or pyridine, which, if desired, simultaneously serves as a solvent. Furthermore, an excessive amount of the starting amine or an alkali metal hydroxide, an alikali metal carbonate, an alkaline earth metal hydroxide or an alkaline earth metal carbonate may be used as a hydrogen halide binding agent. Finally, it is possible to carry out the reaction in an aqueous suspension in the presence of alkaline or alkaline earth agents. In this case, the reaction products are formed as free bases which, if desired, are converted into the corresponding salts by treatment with physiologically tolerable organic or inorganic acids.
The products of the invention are valuable medicatmen-ts. They are well tolerated and show favorable pharmacological properties. They are especially suitable as antitussive agents. Some of them likewise show a sedative efiiciency.
From German Patent 1,112,514 basic carboxylic acid amides are known which are open-chain compounds analogous to those obtained according to the process of the present invention. It is surprising that the physiological action of the novel compounds differs from that of the known substances. Whereas, for instance, the known 5- methyl-crotonic acid-2- (m-methoxy-phenyl) -2- (tr-dimethylamino-ethyl)-butylamide-hydrochloride (A) shows a strong analgesic and, practically, no antitussive efliciency, the compounds prepared according to the process of the present invention, for instance 4-(B-methyl-crotonoyl) aminomethyl 4-(m-methoxy-phenyl)-1-methyl-pipractically show no analgesic but a strong antitussive efliciency.
The Tables I and II show these effects and, in comparison therewith, the known effects of codein which simultaneously is a strong analgesic and antitussive agent.
(I) Test regarding analgesic cfficiency in mice (according to Wolf, Hardy and Goodell [J. Clin. Invest. 19, (1940), 659] Dose in Compound mg./kg. s.c.
Angalesic elficiency Strong effect.
No efiect.
(II) Test regarding antitussive eflicicncy in cats (according to R. Domenjoz [Naunyn-Schmcidebcrgs Arch. Exp. Pathol. Pharmakol. 215 (1952), 18]
According to the above pharmacological test results, a dose of 0.7 mg./ kg. of the products of the invention provokes the same antitussive effect as a dose of 1 mg./ kg. of codein. In contradistinction to compounds of similar structure, and to codein, they show no analgesic effect when given in the above-mentioned doses. The absence of analgesic efiiciency means an advantage for antitussive agents, particularly since the use of substances like codein which show analgesic as well as antitussive activity implies the risk of addiction.
The products of the present invention are used as such or in the form of their salts. For salt formation, for instance, hydrohalic acids such as hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, amidosulfonic acid and organic acids such as formic acid, acetic acid, malonic acid, succinic acid, lactic acid, maleic acid, pamino-salicylic acid and aceturic acid can be used.
The compounds are processed into pharmaceutical preparations by mixing them with physiologically tolerable, usual organic or inorganic, solid or liquid carriers which do not react with the compounds, for instance,
water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, benzyl alcohol, gum, polyalkylene-glycols, cholesterin. They are used, for example, with or without addition of wetting agents, emulsifiers or stabilizers, as solutions or suspensions, tablets, dragees, in capsules or in the form of suppositories.
As single dose 5 to 50 milligrams are used.
The following examples serve to illustrate the invention but they are not intended to limit it thereto:
EXAMPLE 1 4-benz0yl-amin0methyl-4- (m-methoxy-phenyl) 1-methyl-piperidine-hydrohloride (a) To a solution of 14 grams of benzoyl-chloride in 300 cc. of benzene, a solution of 23.4 grams of l-methyl- 4-aminomethyl-4-(m-methoxy-phenyl) piperidine (boiling point of 144-146 C. under a pressure of 0.1 mm. of mercury) in milliliters of benzene is gradually added while stirring at 20-30 C. Stirring is continued for 30 minutes. The crystalline magma thus formed is filtered with suction, dried and recrystallized from methanol by adding ether. 30.2 grams of 4-benzoyl-aminomethyl-4- (m-methoxy-phenyl)-1-methyl piperidine hydrochloride are obtained which, after drying at 80 C. under a pressure of 20 mm. Hg, melt at 194196 C.
(b) The same compound is obtained, if instead of benzoyl chloride the equivalent amount of benzoic acid anhydride is used and the reaction mixture is heated to the boil for 1 hour. For the conversion into the hydrochloride, the reaction mixture is triturated with dilute sodium hydroxide solution and the benzene layer is neutralized by means of hydrogen chloride after drying by means of anhydrous potassium carbonate.
(0) The same compound is obtained by heating 25 grams of benzoic acid methyl ester, 23.4 grams of 1- methyl-4-aminomethyl-4 (m-methoxy-phenyl) piperidine and 0.2 gram of sodium methylate in an atmosphere of nitrogen for 6 hours to 200 C. The reaction mixture is taken up in hot isopropanol, acidified with isopropanolic hydrochloric acid and after filtration a seed crystal is added. After several recrystallizations, 3.6 grams of the compound melting at 194196 C. are obtained.
(d) The same compound is obtained by adding a solution of 5.5 grams of 1-methyl-4-aminomethyl-4-(mmethoxy-phenyl)-piperidine in 75 cc. of ether to a solution of 3.7 grams of benzazide in 50 cc. of ether, while cooling with ice, and allowing the mixture to stand for some days excluding moisture. The reaction mixture is then triturated several times with dilute sodium carbonate solution. The ether solution is dried with sodium sulfate and acidified by means of methanolic hydrochloric acid, and the salt thus obtained is recrystallized from isopropanol. 1.8 grams of the hydrochloride melting at 194- 196 C. are obtained.
(e) The same compound is obtained by suspending 23.4 grams of 1-methyl-4-aminomethyl-4-(m-methoxyphenyl)-piperidine in 200 cc. of normal sodium hydroxide solution while vigorously stirring, and by gradually adding 15 grams of benzoyl chloride while cooling with ice. The reaction product is taken up in ether and converted as described above into the hydrochloride melting at 194-196 C.
EXAMPLE 2 4-(fl-methyl-crotonoyl) -amin0methyl-4-(m-methoxyphenyl -methyl-piperidine-hydroclzloride 11.9 grams of B-methyl-crotonic acid chloride and 23.4 grams of 1 methyl 4 aminomethyl 4-(m-methoxyphenyl)-piperidine are reacted according to the method described in Example 1(a). 29.5 grams of 4-(/3-methylcrotonoyl) aminmoethyl 4 (m-methoxy-phenyl) 1 methyl-piperidine-hydrochloride are obtained, melting at 149152 C. after recrystallization from acetone.
EXAMPLE 3 4-benz0yl-aminomethyl-4-(m-hydr0xy-phenyl)- 1 -methyl-piperidine-hydrochloride 8.3 grams of 1-methyl-4-aminomethyl-4-(m-hydroxyphenyl)-piperidine-dihydrobromide (prepared from 1- methyl 4 aminomethyl-4-(m-methoxy-phenyl)-piperidine by reaction with hydro'bromic acid of 63% strength at 120 C.) are dissolved in 180 cc. of absolute ethanol; 20.2 cc. of 2.15 N-methanolic sodium-methylate solution are added and the solution is concentrated by evaporation. The free base thus obtained is taken up in benzene, separated from sodium bromide and reacted with 3 grams of benzoyl-chloride. The reaction mixture is stirred for 1 hour at 40 to 60 C. 7 grams of 4-benzoyl-aminomethyl- 4-(m-hydroxy-phenyl)-l-methyl-piperidine hydrochloride are obtained melting at 257 to 260 C, after having been recrystallized from a mixture of methanol and ether.
EXAMPLE 4 4-(p-eth0xy-benzoyl) -aminomethyl-4-(m-methoxyphenyl) -1-methyl-piperidine-hydrochloride To a solution of 23.4 grams of 1-methyl-4-aminomethyl-4-(m-methoxy-phenyl)-piperidine in 300 cc. of benzene heated to the boil, a solution of 18.5 grams of pethoxy-benzoyl-chloride in 100 cc. of benzene is gradually added while stirring. After cooling, the reaction product is filtered with suction, washed with ether and recrystallized fIom ethanol. 15.8 grams of 4-(p-ethoxy-benzoyl)- aminomethyl-4 (m-methoxy-phenyl) l-methyl-piperidine-hydrochloride melting at 237239 C. are obtained.
EXAMPLE 5 4-(2'-ohloro-6'-methyl-benz0yl) -amin0methyl-4- (m-methoxy-phenyl) -1-methyl-piperidine To a solution of 18.9 grams of 2-chloro-6-methylbenzoyl-chloride in 300 cc. of ether, 23.4 grams of 1- methyl-4-aminomethyl-4-(m-methoxy phenyl) piperidine are dropwise added while stirring, the temperature being allowed to reach the boiling point of the solvent. The reaction product is isolated in usual manner. 34.5 grams of 4-(2-chloro-6'-methyl-benzoyl)-aminomethyl- 4-(m-methoxy-phenyl)-1-methyl-piperidine are obtained, showing a melting point of 152-154 C. (from a mixture of methanol and ether).
6 We claim: 1. A compound of the formula in which R is selected from the group consisting of a hydrocarbon radical, halohydrocarbon, aminohydrocarbon, alkyl and alkoxy hydrocarbon radicals wherein the hydrocarbon portion has at least one double linkage and up to ten carbon atoms and the alkyl and alkoxy portions have up to three carbon atoms, R stands for alkyl having up to four carbon atoms, and R stands for hydroxy or alkoxy having up to four carbon atoms, and addition salts thereof with a physiologically tolerable acid.
2. 4-benzoy1aminomethyl 4 (m-methoxyphenyl)-1- methyl-piperidine.
3. 4-(,B-methyl-crotonoylamino-methyl) 4 (m-methoxyphenyl -1-rnethyl-piperidine.
4. 4-benzoylaminomethyl-4 (m-hydroxyphenyl) 1- methyl-piperidine.
5. 4-(p-ethoxybenzoylaminomethyl) 4 (m-methoxyphenyl)-l-rnethyl-piperidine.
6. 4 (2' chloro-6-methyl-benzoylaminomethyl)-4- (m-methoxyphenyl-l-methyl-piperidine.
References Cited by the Examiner UNITED STATES PATENTS 1,794,292 2/1931 H0110 16755 1,915,334 6/1933 Salzberg et al. 260243 2,075,359 3/ 1937 Salzberg et a1. 167-22 2,425,320 8/1947 Hill 252149 2,606,155 8/1952 Hill 252149 3,033,869 5/1962 Giudicelli et al 260294 3,058,986 10/ 1962 Lutz et a1 260294 3,069,317 12/1962 Jensen 16755 ALEX MAZEL, Primary Examiner.
NICHOLAS S. RIZZO, Examiner.
JOSE TOVAR, Assistant Examiner.

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002528503A (en) * 1998-10-30 2002-09-03 メルク エンド カムパニー インコーポレーテッド Heterocyclic potassium channel inhibitors
JP2004526761A (en) * 2001-04-12 2004-09-02 ファーマコピア， インコーポレイテッド Arylpiperidines and biarylpiperidines used as MCH antagonists
JP2005529114A (en) * 2002-04-19 2005-09-29 ブリストル−マイヤーズ　スクイブ　カンパニー Heterocyclic inhibitors of potassium channel function
JP2008526701A (en) * 2004-12-30 2008-07-24 ノバルティス アクチエンゲゼルシャフト Organic compounds

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US1794292A (en) * 1929-02-15 1931-02-24 Eugene J Lorand Remedy for colds and the like
US1915334A (en) * 1930-10-16 1933-06-27 Du Pont Fluosilicate of organic heterocyclic bases and process of making it
US2075359A (en) * 1930-10-16 1937-03-30 Du Pont Insecticide
US2425320A (en) * 1942-10-23 1947-08-12 Koppers Co Inc Cleaning and pickling of metals
US2606155A (en) * 1946-11-26 1952-08-05 Koppers Co Inc Cleaning and pickling composition for metals
US3033869A (en) * 1962-05-08 A-piperidino-a-phenyl-n-cyclohexyl
US3058986A (en) * 1962-10-16 N-ammoalkyl-x-phenyl-x-lower alkyl-z-
US3069317A (en) * 1957-10-07 1962-12-18 Upjohn Co Terpin hydrate suspensions

Patent Citations (8)

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Publication number Priority date Publication date Assignee Title
US3033869A (en) * 1962-05-08 A-piperidino-a-phenyl-n-cyclohexyl
US3058986A (en) * 1962-10-16 N-ammoalkyl-x-phenyl-x-lower alkyl-z-
US1794292A (en) * 1929-02-15 1931-02-24 Eugene J Lorand Remedy for colds and the like
US1915334A (en) * 1930-10-16 1933-06-27 Du Pont Fluosilicate of organic heterocyclic bases and process of making it
US2075359A (en) * 1930-10-16 1937-03-30 Du Pont Insecticide
US2425320A (en) * 1942-10-23 1947-08-12 Koppers Co Inc Cleaning and pickling of metals
US2606155A (en) * 1946-11-26 1952-08-05 Koppers Co Inc Cleaning and pickling composition for metals
US3069317A (en) * 1957-10-07 1962-12-18 Upjohn Co Terpin hydrate suspensions

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002528503A (en) * 1998-10-30 2002-09-03 メルク エンド カムパニー インコーポレーテッド Heterocyclic potassium channel inhibitors
JP4764550B2 (en) * 1998-10-30 2011-09-07 メルク・シャープ・エンド・ドーム・コーポレイション Heterocyclic potassium channel inhibitors
JP2004526761A (en) * 2001-04-12 2004-09-02 ファーマコピア， インコーポレイテッド Arylpiperidines and biarylpiperidines used as MCH antagonists
JP2005529114A (en) * 2002-04-19 2005-09-29 ブリストル−マイヤーズ　スクイブ　カンパニー Heterocyclic inhibitors of potassium channel function
JP4729259B2 (en) * 2002-04-19 2011-07-20 ブリストル−マイヤーズ スクイブ カンパニー Heterocyclic inhibitors of potassium channel function
JP2008526701A (en) * 2004-12-30 2008-07-24 ノバルティス アクチエンゲゼルシャフト Organic compounds

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