US3862946A - N-benzyl-N-{8 2-phenyl-2-(4-phenyl-1-piperidyl)ethyl{9 {0 propionamide para-chlorobenzene sulfonate - Google Patents

N-benzyl-N-{8 2-phenyl-2-(4-phenyl-1-piperidyl)ethyl{9 {0 propionamide para-chlorobenzene sulfonate Download PDF

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US3862946A
US3862946A US363425A US36342573A US3862946A US 3862946 A US3862946 A US 3862946A US 363425 A US363425 A US 363425A US 36342573 A US36342573 A US 36342573A US 3862946 A US3862946 A US 3862946A
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phenyl
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • C07D211/10—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 radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—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 radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom

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  • the therapeutic regimen devised by Dole et al. involves stabilization of narcotic addiets by the oral administration of a narcotic substitute so that the euphoric effects of even high doses of intravenously administered narcotics are obviated.
  • Oral administration of the narcotic substitute is of central importance to maintenance therapy because the psychological extremes which characterize effects of repeated intravenously administered narcotics are eliminated. Oral ingestion of the narcotic substitute also facilitates supervision of administration, thus minimizing the possibility of illicit redistribution of the substitute.
  • methadone hydrochloride The narcotic substitute most frequently utilized in maintenance therapy is methadone hydrochloride (hereinafter referred to as methadone").
  • methadone is methadone hydrochloride
  • This invention provides a possible candidate for the suppression of withdrawal effects of narcotics and for the maintenance therapy of addiction which is effective only upon oral administration.
  • methadone is chemically unrelated to N-benzyl-N- 5 [2-phenyl-2-(4-phenyl-l-piperidyl)- ethyllpropionamide p-chloro-benzene-sulfonate (hereinafter designated as TR 2923).
  • Strycker (US. Pat. No. 3,518,274 [l970]) disclosed certain congeners of TR 2923 which are reported as analgetics. Although these congeners are chemically similar to TR 2923, they do not exhibit the unexpected properties of TR 2923 in suppressing narcotic withdrawal symptoms or utility in maintenance treatment of narcotic addiction.
  • TR 2923 which is germane to its utility is :its virtual insolubility in water (less than 0.05%).
  • Example 1 of the Description of Preferred Embodiments section of this specification delineates the total synthesis of TR 2923, which is a modification of the method disclosed by W. G. Strycker in US. Pat. No. 3,518,274 (issued June 30, 1970).
  • the following sequence of reactions represents a compendium of this synthesis:
  • TR 2923 In contrast to its congeners, TR 2923, when administered orally, exhibits unexpected utility in suppression of narcotic withdrawal (or abstinence) symptoms and in model maintenance therapy of narcotic addicted experimental animals.
  • Example 2 of the Description of Preferred Embodiments section of this specification outlines detailedresults of the comparable effectiveness of TR 2923 to the reference drug methadone in suppressing naloxone-precipitated abstinence symptoms in narcotic addicted rats.
  • Example 2 also demonstrates the utility of TR 2923 as a possible alternate to methadone in the maintenance therapy of narcotic addiction.
  • the term maintenance therapy refers to the therapeutic concept and regimen developed by Dole and co-workers (see references cited in Field of the Invention, supra).
  • TR 2923 is effective when orally administered; unlike methadone, however, TR 2923 cannot be administered intravenously because of its insoluble character.
  • TR 2923 possesses the additional advantage that it cannot be abused by intravenous self-administration to obtain potentiated effects.
  • TR 2923 was suspended in (W/V) mucilage of acacia. Alternately it can be mixed with a chocolate paste, or with othe preparations for oral ingestion.
  • N-Benzyl-a-Chlorophenylacetamide A benzene solution of a-chlorophenylacetyl chloride (113.5 g, 0.6 mole) was slowly added to an ice-cold, stirred solution of benzylamine (64.4 g, 0.6 mole) in 650 ml of benzene and 200 ml of 20% NaOH. This mixture was stirred in the cold for an additional hour and subsequently filtered. The solid obtained from the concentration of the filtrate was recrystallized from an aqueous methyl alcohol: yield, g; m.p. 96.597.0.
  • Example 2 Comparative Effectiveness of Orally Administered Doses of N-Benzyl-N-[2-Phenyl-2-(4-Phenyl-1-Piperidyl)- Ethyl] Propionamide Para-Chlorobenzenesulfonate (TR 2923) and Methadone in suppressing Narcotic Withdrawal Effects and in Maintenance Therapy of Morphine Addicted Rats It has been demonstrated that narcotic addiction quickly can be induced in the rat by continuous exposure to morphine (Greenbach, Fed.
  • Abstinence effects or withdrawal symptoms in morphine addicted rats include diarrhea. irritability to handling. chewing, withdrawal jumping, and teeth chattering.
  • a rapid test for the action of drugs on addiction in the rat, utilized in this Example involves induction of addiction with a single subcutaneous dose of 150 mg/kg of morphine in a sustained release suspension and, 24 hours later, precipitation of withdrawal effects by administration of a subcutaneous dose of naloxone of 1.0 mg/kg (H. O. J. Collier, et al., Nature: 237, 220 [1972].
  • varying doses of either drug were orally administered to the rats.
  • Methadone HCl or TR 2923 was administered orally in distilled water or a suspension of 20% W/v mucilage of acacia, respectively.
  • Tables 1 and I1 summarize the results of suppression by oral methadone HCI or TR 2923 of naloxone precipitated morphine withdrawal symptoms in the morphine addicted rat.
  • the numerator represents the number of rats in which a given symptom was observed while the denominator denotes the population of rats involved.
  • Naloxone was given at 1 mg base/kg S.C.
  • EXAMPLE 3 Suppression of Heroin-Seeking Behavior by TR 2923 in Heroin-Addicted Rats Heroin dependence was induced in two female Wistar rats by the method described by Collier (Endeavor, 31: 123 H9721): In the latter procedure the rats were prepared with an indwelling intravenous cannula connected to an infusion pump which was activated by a lever in the wall of a cage containing the rats. By pressing the lever, the rats self-injected the heroin.
  • the rats had reached a stable level of selfadministration of heroin over a 2 week period (0.25 mg/kg infusion of heroin at a rate of 0.1 ml/l sec.). During this period the rats were fed chocolate paste (3 g/rat) daily at noon. Food pellets were also available ad lib.
  • TR 2923 in chocolate paste in three dose levels: 10, 40, and 80 mg/kg. and each treatment day was separated by 2 days during which chocolate paste alone was available. Over the 24 hour period following administration of TR 2923 orally, self-administration of heroin was reduced. A dose of 10 mg/kg of TR 2923 reduced self-administration of heroin by 37.5%; doses of 40 mg/kg and mg/kg reduced self-administration of heroin by 64.3% and 81.1%, respectively. During the period 20-24 hours after oral administration of 80 mg/kg of TR 2923, one animal began selfadministration of heroin at a rate equivalent to that prior to oral treatment. This relapse did not occur until the 28-30 hour period in the other animal. Behavioral effects after administration of TR 2923 in both rats were similar to those seen after heroin.

Abstract

N-benzyl-N-(2-phenyl-2-(4-phenyl-1-piperidyl)ethyl) propionamide p-chlorobenzenesulfonate has effectiveness comparable to methadone in suppressing narcotic withdrawal symptoms and in maintenance therapy of narcotic addicted laboratory mammals.

Description

United States Patent 1 1 Havera N-BENZYL-N-[2-PHENYL-2-(4-PHENYL-l- PIPERIDYUETHYL] PROPIONAMIDE PARA-CHLOROBENZENE SULFONATE [75] Inventor: Herbert John Havera, Edwardsburg,
Mich.
[73] Assignee: Miles Laboratories, Inc., Elkhart,
Ind.
[22] Filed: May 24, 1973 21 Appl. No.: 363,425
[51] Int. Cl C07d 29/30 [58] Field of Search 260/293.76, DIG. 13
[56] References Cited UNITED STATES PATENTS 3,518,274 6/1970 Strycker 260/293.76
l l Jan. 28, 1975 Primary ExaminerHenry R. Jiles Assistant Examiner-S. D. Winters Attorney, Agent, or Firm-Myron B. Sokolowski; Louis E. Davidson; Joseph C. Schwalbach [57] ABSTRACT 1 Claim, N0 Drawings BACKGROUND OF THE lNVENTlON 1. Field of the lnvention Treatment of narcotic addiction currently involves two overlapping aspects and objectives: withdrawal of the narcotic and rehabilitation of the addict. in the case of opioid dependence, specifically heroin or morphine addiction, the treatment of withdrawal symptoms and rehabilitation merge in the concept of maintenance therapy.
Maintenance therapy is a relatively new approach to narcotic addiction pioneered predominantly by Dole and co-workers (Arch. lnt. Med. I18: 304 [1966]; J. Am. Med. Assn., 206: 2708 [i968]; and New Engl. J. Med, 280: 1372 {l969]). The therapeutic regimen devised by Dole et al. involves stabilization of narcotic addiets by the oral administration of a narcotic substitute so that the euphoric effects of even high doses of intravenously administered narcotics are obviated. Oral administration of the narcotic substitute is of central importance to maintenance therapy because the psychological extremes which characterize effects of repeated intravenously administered narcotics are eliminated. Oral ingestion of the narcotic substitute also facilitates supervision of administration, thus minimizing the possibility of illicit redistribution of the substitute.
The narcotic substitute most frequently utilized in maintenance therapy is methadone hydrochloride (hereinafter referred to as methadone"). Although the use of methadone as a narcotic substitute in maintenance therapy has been relatively successful, it is po' tentially subject to abuse if administered intravenously to obtain potentiated narcotic effects.
This invention provides a possible candidate for the suppression of withdrawal effects of narcotics and for the maintenance therapy of addiction which is effective only upon oral administration.
2. Description of the Prior Art Bochmuhl et al. reported the synthesis and structure of methadone, 6-dimethy|amino-4,4-diphenyl-3- 2 heptanone (Ann, 56]: 52 [1948]). As is evident from its structure,
methadone is chemically unrelated to N-benzyl-N- 5 [2-phenyl-2-(4-phenyl-l-piperidyl)- ethyllpropionamide p-chloro-benzene-sulfonate (hereinafter designated as TR 2923).
Strycker (US. Pat. No. 3,518,274 [l970]) disclosed certain congeners of TR 2923 which are reported as analgetics. Although these congeners are chemically similar to TR 2923, they do not exhibit the unexpected properties of TR 2923 in suppressing narcotic withdrawal symptoms or utility in maintenance treatment of narcotic addiction.
I SUMMARY OF THE INVENTION One of the physical chemical properties of TR 2923 which is germane to its utility is :its virtual insolubility in water (less than 0.05%).
Example 1 of the Description of Preferred Embodiments section of this specification delineates the total synthesis of TR 2923, which is a modification of the method disclosed by W. G. Strycker in US. Pat. No. 3,518,274 (issued June 30, 1970). For purposes of this section, the following sequence of reactions represents a compendium of this synthesis:
DM F
LiAlH THF hen
zene
In contrast to its congeners, TR 2923, when administered orally, exhibits unexpected utility in suppression of narcotic withdrawal (or abstinence) symptoms and in model maintenance therapy of narcotic addicted experimental animals. Example 2 of the Description of Preferred Embodiments section of this specification outlines detailedresults of the comparable effectiveness of TR 2923 to the reference drug methadone in suppressing naloxone-precipitated abstinence symptoms in narcotic addicted rats. Example 2 also demonstrates the utility of TR 2923 as a possible alternate to methadone in the maintenance therapy of narcotic addiction. For purposes of definition, the term maintenance therapy refers to the therapeutic concept and regimen developed by Dole and co-workers (see references cited in Field of the Invention, supra).
Like methadone, TR 2923 is effective when orally administered; unlike methadone, however, TR 2923 cannot be administered intravenously because of its insoluble character. As a potential alternate to methadone in maintenance treatment of narcotic addicts, TR 2923 possesses the additional advantage that it cannot be abused by intravenous self-administration to obtain potentiated effects. In Example 2 TR 2923 was suspended in (W/V) mucilage of acacia. Alternately it can be mixed with a chocolate paste, or with othe preparations for oral ingestion.
This invention, accordingly, has the following objects:
l. to provide a compound which suppresses narcotic withdrawal symptoms in narcotic addiction; 5
2. to prepare a compound which is a potential alternate to methadone in maintenance therapy of narcotic addiction; and
. ioc n cu HCH2-CH-N 3. to furnish a compound which has the above objects and which additionally can be administered only orally.
DESCRIPTION OF THE PREFERRED EMBODlMENTS EXAMPLE 1 Synthesis of N-Benzyl-N-[ 2-Phenyl-2-(4-Phenyll -Piperidyl) EthyllPropionamide Para-Chlorobenzenesulfonate.
A. N-Benzyl-a-Chlorophenylacetamide A benzene solution of a-chlorophenylacetyl chloride (113.5 g, 0.6 mole) was slowly added to an ice-cold, stirred solution of benzylamine (64.4 g, 0.6 mole) in 650 ml of benzene and 200 ml of 20% NaOH. This mixture was stirred in the cold for an additional hour and subsequently filtered. The solid obtained from the concentration of the filtrate was recrystallized from an aqueous methyl alcohol: yield, g; m.p. 96.597.0.
Analysis: Calculated: C H ClNO: N, 5.39. Found: N, 5.28.
B.- N-Benzyl-2-Phenyl-2-(4-Phenyl-l-Piperidyl) Acetamide.
A mixture of N-benzyl-a-chlorophenylacetamide (62 g, 0.239 mole), 4-phenylpiperidine (38.5 g, 0.239 mole), sodium carbonate (28.6 g, 0.27 mole) and 350 ml of dimethylformamide was heated under reflux with stirring for 20 hours. The mixture was filtered. The filtrate was diluted with methyl alcohol and water, then cooled. The solid that formed was collected and dried: yield, 73.2 g; m.p. l33l34.
Analysis: Calculated C,,,H,,,N,0= N, 7.29. Found: N, 7.42.
C. N-[2-Phenyl-2-(4-Phenyl-l-Piperidyl)Ethyl] Benzylamine.
A tetrahydrofuran (THF) solution of N-benzyl-Z- phenyl-2-(4-phenyl- I -piperidyl)acetarnide (73 g, 0. l 9 mole) was slowly added to a stirred suspension of LiAlH 11 g, 0.285 mole) in 150 ml of THF and the mixture was heated under reflux for 16 hours. The cooled mixture was reacted with l 1 ml of water in 100 ml of THF (dropwise) followed by 11 ml of 20% NaOH, and 33 ml of water. The mixture was filtered and the filtrate was concentrated and distilled: b.p.. 210-218; yield, 46 g.
Analysis: Calculated C 11 N N, 7.56. Found: N, 7.54.
D. N-Benzyl-N-[2-Phenyl-2-(4-Phenyl-l-Piperidyl) EthyllPropionamide.
To 48 g (0.13 mole) of N-[2-phenyl-2-(4-phenyl-lpiperidyl)ethyl]benzylamide in 150 ml of dry benzene was added 17.0 g (0.13 mole) of propionic anhydride. The reaction mixture was heated at reflux for 2 hours. The solution was treated with 200 ml of NaOH and then washed with water. The organic layer was dried over MgSO and concentrated in vacuo giving an oil which was used without an further purification in the preparation of the p-chlorobenzenesulfonate.
E. N-Benzyl-N-[2-Phenyl-2-(4-Phenyll -Piperidyl Ethyl]Propionamide p-Chlorobenzenesulfonate.
To 1.5 g (0.0035 mole) of N-benzyl-N-[2-phenyl-2- (4-phenyl-l-piperidyl)ethyl]propionamide was added 0.7 g (0.0035 mole) of p-chlorobenzenesulfonic acid in 10 ml of CH OH. Upon addition of ether a solid formed. The solid was recrystallized from methyl alcohol and ether: yield, 1.2 g, m.p. 155-l57, solubility 5.2 lO' in water.
Analysis: Calculated C l-l ClN O S: C, 67.89; H, 6.35; N, 4.52. Found: C, 68.39; H, 6.47; N, 4.28.
Example 2 Comparative Effectiveness of Orally Administered Doses of N-Benzyl-N-[2-Phenyl-2-(4-Phenyl-1-Piperidyl)- Ethyl] Propionamide Para-Chlorobenzenesulfonate (TR 2923) and Methadone in suppressing Narcotic Withdrawal Effects and in Maintenance Therapy of Morphine Addicted Rats It has been demonstrated that narcotic addiction quickly can be induced in the rat by continuous exposure to morphine (Greenbach, Fed. Proc., 28: 262 [1969]), and that the degree of this addiction can be assessed by the intensity of abstinence symptoms or by the dose of naloxone required to precipitate such symptoms (Way et al.. Science. 162: 1290 [1968]). Abstinence effects or withdrawal symptoms in morphine addicted rats include diarrhea. irritability to handling. chewing, withdrawal jumping, and teeth chattering. A rapid test for the action of drugs on addiction in the rat, utilized in this Example, involves induction of addiction with a single subcutaneous dose of 150 mg/kg of morphine in a sustained release suspension and, 24 hours later, precipitation of withdrawal effects by administration of a subcutaneous dose of naloxone of 1.0 mg/kg (H. O. J. Collier, et al., Nature: 237, 220 [1972]. To compare the effects of TR 2923 and methadone in naloxone precipitated withdrawal symptoms, varying doses of either drug were orally administered to the rats.
Methadone HCl or TR 2923 was administered orally in distilled water or a suspension of 20% W/v mucilage of acacia, respectively.
Tables 1 and I1 summarize the results of suppression by oral methadone HCI or TR 2923 of naloxone precipitated morphine withdrawal symptoms in the morphine addicted rat. The numerator represents the number of rats in which a given symptom was observed while the denominator denotes the population of rats involved.
TABLE 1 Drug Treatment Dose in mg No. of Deaths lncidence of Withdrawal Effect 1 h Prior to Base/kg Prior to in Morphine-Dependent Rats Naloxone P.O. Naloxone Diarrhea lrritability Chewing by 30 Min. to Handling Distilled 0/6 6/6 4/6 6/6 water Methadone H5 3/4 2/4 l/4* HCI 80 H6 0/5" 0/5 1/5* 160 4/5 0/1 0/1 0/1 Acacia 0/8 7/8 7/8 4/8 TR 2923 40 0/8 7/8 7/8 3/8 80 H6 5/5 3/5 2/5 160 N8 5/7 ll? 2]? Naloxone wan given at l mg hate/kg St. indicates significant (P 0.05) suppression of withdrawal effect compared to controls.
TABLE 11 Drug Dose in No. of Percentage Incidence of Withdrawal Effect Treatment mg base/kg Deaths in Morphine-Dependent Rats l h Prior P.O. Prior to to Naloxone Naloxone Jumping Diarrhea lrritability Chewing Teeth by 15 Min. to touch to handling Chattering Distilled 0/9 78 78 44 100 100 100 water Methadone 40 0/10 30 0* 0* 40* 40* HCl A 160 5/10 0* 0* 0 20* 40* 0* Acacia 0/12 83 100 8 100 100 TR 2923 40 2/9 78 78 ll 78 100 100 Indicates significant (P 0.0S) suppression of withdrawal effect compared to controls.
Naloxone was given at 1 mg base/kg S.C.
EXAMPLE 3 Suppression of Heroin-Seeking Behavior by TR 2923 in Heroin-Addicted Rats Heroin dependence was induced in two female Wistar rats by the method described by Collier (Endeavor, 31: 123 H9721): In the latter procedure the rats were prepared with an indwelling intravenous cannula connected to an infusion pump which was activated by a lever in the wall of a cage containing the rats. By pressing the lever, the rats self-injected the heroin.
The rats had reached a stable level of selfadministration of heroin over a 2 week period (0.25 mg/kg infusion of heroin at a rate of 0.1 ml/l sec.). During this period the rats were fed chocolate paste (3 g/rat) daily at noon. Food pellets were also available ad lib.
Once the rats became dependent on heroin, they were offered TR 2923 in chocolate paste in three dose levels: 10, 40, and 80 mg/kg. and each treatment day was separated by 2 days during which chocolate paste alone was available. Over the 24 hour period following administration of TR 2923 orally, self-administration of heroin was reduced. A dose of 10 mg/kg of TR 2923 reduced self-administration of heroin by 37.5%; doses of 40 mg/kg and mg/kg reduced self-administration of heroin by 64.3% and 81.1%, respectively. During the period 20-24 hours after oral administration of 80 mg/kg of TR 2923, one animal began selfadministration of heroin at a rate equivalent to that prior to oral treatment. This relapse did not occur until the 28-30 hour period in the other animal. Behavioral effects after administration of TR 2923 in both rats were similar to those seen after heroin.
What is claimed is:
1. N-benzyl-N-[2-phenyl-2-(4-phenyl-l-piperidyl) ethyl]propionamide p-chlorobenzenesulfonate.
US363425A 1973-05-24 1973-05-24 N-benzyl-N-{8 2-phenyl-2-(4-phenyl-1-piperidyl)ethyl{9 {0 propionamide para-chlorobenzene sulfonate Expired - Lifetime US3862946A (en)

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US457456A US3906100A (en) 1973-05-24 1974-04-03 N-benzyl-N-{8 2-phenyl-2-(4-phenyl-1-piperidyl)-ethyl{9 -propionamide para-chlorobenzene sulfonate

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5403595A (en) * 1991-05-07 1995-04-04 Dynagen, Inc. Controlled, sustained release delivery system for smoking cessation
US5486362A (en) * 1991-05-07 1996-01-23 Dynagen, Inc. Controlled, sustained release delivery system for treating drug dependency
WO1996008480A1 (en) * 1994-09-17 1996-03-21 Boehringer Ingelheim Kg Neurokinin antagonists
WO1996032386A1 (en) * 1995-04-14 1996-10-17 Boehringer Ingelheim Kg Aryl glycinamide derivatives, methods of producing these substances and pharmaceutical compositions containing such compounds
US5708006A (en) * 1994-09-17 1998-01-13 Boehringer Ingelheim Kg Neurokinin antagonists
US5710169A (en) * 1994-10-25 1998-01-20 Zeneca Limited Therapeutic heterocycles
US5710155A (en) * 1995-04-14 1998-01-20 Boehringer Ingelheim Kg Arylglycinamide derivatives, processes for the manufacture thereof and pharmaceutical compositions containing these compounds
US5780051A (en) * 1992-04-02 1998-07-14 Dynagen, Inc. Methods and articles of manufacture for nicotine cessation and monitoring nicotine use
US5998444A (en) * 1995-10-24 1999-12-07 Zeneca Ltd. Piperidinyl compounds as NK1 or NK2 antagonists
US6413959B1 (en) 1995-04-14 2002-07-02 Boehringer Ingelheim Kg Method of treating depression with arylglycinamide derivatives

Citations (1)

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US3518274A (en) * 1967-10-09 1970-06-30 Miles Lab Phenyl substituted n-(2-aminoethyl)-n-benzylamides

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3518274A (en) * 1967-10-09 1970-06-30 Miles Lab Phenyl substituted n-(2-aminoethyl)-n-benzylamides

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5403595A (en) * 1991-05-07 1995-04-04 Dynagen, Inc. Controlled, sustained release delivery system for smoking cessation
US5486362A (en) * 1991-05-07 1996-01-23 Dynagen, Inc. Controlled, sustained release delivery system for treating drug dependency
US5780051A (en) * 1992-04-02 1998-07-14 Dynagen, Inc. Methods and articles of manufacture for nicotine cessation and monitoring nicotine use
US5696123A (en) * 1994-09-17 1997-12-09 Boehringer Ingelheim Kg Neurokinin antagonists
US5985881A (en) * 1994-09-17 1999-11-16 Boehringer Ingelheim Kg Neurokinin antagonists
US5708006A (en) * 1994-09-17 1998-01-13 Boehringer Ingelheim Kg Neurokinin antagonists
WO1996008480A1 (en) * 1994-09-17 1996-03-21 Boehringer Ingelheim Kg Neurokinin antagonists
US5710169A (en) * 1994-10-25 1998-01-20 Zeneca Limited Therapeutic heterocycles
US6147083A (en) * 1994-10-25 2000-11-14 Zeneca Limited Azospiro compounds as NK1 or NK2 antagonists
US6251909B1 (en) 1995-04-14 2001-06-26 Boehringer Ingelheim Kg Arylglycinamide derivatives, methods of producing these substances and pharmaceutical compositions containing such compounds
US6124296A (en) * 1995-04-14 2000-09-26 Boehringer Ingelheim Kg Arylglycinamide derivatives, methods of producing these substances and pharmaceutical compositions containing such compounds
US5710155A (en) * 1995-04-14 1998-01-20 Boehringer Ingelheim Kg Arylglycinamide derivatives, processes for the manufacture thereof and pharmaceutical compositions containing these compounds
WO1996032386A1 (en) * 1995-04-14 1996-10-17 Boehringer Ingelheim Kg Aryl glycinamide derivatives, methods of producing these substances and pharmaceutical compositions containing such compounds
US6294556B1 (en) 1995-04-14 2001-09-25 Boehringer Ingelheim Kg Arylglycinamide derivatives, methods of producing these substances and pharmaceutical compositions containing such compounds
US6303601B2 (en) 1995-04-14 2001-10-16 Boehringer Ingelheim Kg Arylgycinamide derivatives, methods of producing these substances and pharmaceutical compositions containing such compounds
US6413959B1 (en) 1995-04-14 2002-07-02 Boehringer Ingelheim Kg Method of treating depression with arylglycinamide derivatives
CZ296778B6 (en) * 1995-04-14 2006-06-14 Boehringer Ingelheim Kg Aryl glycinamide derivatives, methods of producing these substances and pharmaceutical compositions containing such compounds
US5998444A (en) * 1995-10-24 1999-12-07 Zeneca Ltd. Piperidinyl compounds as NK1 or NK2 antagonists

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