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WO1993001812A1 - S-(3-(4(5))-imidazolyl)propyl)isothiourea as selective trhistomine h3 receptor antagonist - Google Patents

S-(3-(4(5))-imidazolyl)propyl)isothiourea as selective trhistomine h3 receptor antagonist Download PDF

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Publication number
WO1993001812A1
WO1993001812A1 PCT/GB1992/001299 GB9201299W WO9301812A1 WO 1993001812 A1 WO1993001812 A1 WO 1993001812A1 GB 9201299 W GB9201299 W GB 9201299W WO 9301812 A1 WO9301812 A1 WO 9301812A1
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Prior art keywords
isothiourea
histamine
imidazolyl
propyl
pharmaceutically acceptable
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PCT/GB1992/001299
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French (fr)
Inventor
William Howson
Original Assignee
Smithkline Beecham Plc
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Filing date
Publication date
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to EP92915736A priority Critical patent/EP0595910A1/en
Priority to JP5502676A priority patent/JPH06509109A/en
Publication of WO1993001812A1 publication Critical patent/WO1993001812A1/en

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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to pharmaceutical compositions comprising an imidazole derivative, their use in the manufacture of medicaments having histamine ⁇ -antagonist activity and a method of blocking histamine ⁇ -receptors by administering them.
  • Histamine a physiologically active compound endogenous in mammals, exerts its action by interacting with certain sites called receptors.
  • One type of receptor is known as a histamine H-j_-receptor (Ash and Schild, Brit. J. Pharmac. Chemother. 22.427 (1966)) and the actions of histamine mediated through these receptors are blocked by H- j _- antagonists such as mepyramine.
  • a second type of receptor is known as the histamine H2 ⁇ receptor (Black et al., Nature 1972, 236, 385) which is not blocked by mepyramine but by H2 ⁇ antagonists such as burimamide or cimetidine.
  • histamine H3 ⁇ receptor A third type of receptor known as the histamine H3 ⁇ receptor has more recently been identified (e.g. Arrang et al.. Nature 1987, 327 , 117 and Van der erf et al., (1989) Trends Pharmacol. Sci. 10, 159) which is stimulated by ⁇ -agonists such as (R)- ⁇ —methylhistamine and blocked by ⁇ -antagonists such as thioperamide.
  • ⁇ -agonists such as (R)- ⁇ —methylhistamine
  • ⁇ -antagonists such as thioperamide
  • US-A-3759944 discloses isothiourea derivatives which are described as acting at histamine receptors other than the H ⁇ -receptor and are of utility in inhibiting certain actions of histamine which are not inhibited by H ⁇ -antagonists such as the inhibition of histamine-stimulated secretion of gastric acid.
  • a particular isothiourea described is S-[3- (4 (5)-imidazolyDpropyl]isothiourea dihydrobromide. This compound is also disclosed in Eur. J. ed. Chem.-Chim. Ther., 21(4), 305-9 (1986) wherein it is described as being a weak partial H ⁇ -agonist and a weak ⁇ -agonist. It has now been discovered that the above named imidazole compound is a highly potent selective histamine H3- antagonist.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and S-[3-(4(5)-imidazolyDpropyl]- isothiourea or a pharmaceutically acceptable salt thereof in an amount sufficient to block selectively histamine H3- receptors.
  • the present invention provides the use of S-[3-(4 (5)-imidazolyDpropyl]isothiourea or a pharmaceutically acceptable salt thereof in the manufacture of a medicament having histamine H ⁇ -antagonist activity.
  • this invention provides a method of blocking histamine ⁇ -receptors in a host in need thereof which comprises administering an effective amount to block said receptors of S-[3-(4(5)-imidazolyDpropyl]isothiourea or a pharmaceutically acceptable salt thereof.
  • Pharmaceutically acceptable salts include those formed with hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, citric, maleic, lactic, ascorbic, fumaric, oxalic, methanesulphonic and ethanesulphonic acids.
  • S-[3-(4(5)-imidazolyDpropyl]isothiourea and its pharmaceutically acceptable salts can be administered in standard manner for example orally, sublingually, parenterally, transdermally, rectally, via inhalation or via buccal administration.
  • S-[3-(4 (5)-imidazolyDpropyl]isothiourea and its pharmaceutically acceptable salts which are active when given orally or via buccal administration can be formulated appropriately in dosage forms such as liquids, syrups, tablets, capsules and lozenges.
  • An oral liquid formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, glycerine or water with a flavouring or colouring agent.
  • composition is in the form of a tablet
  • any pharmaceutical carrier routinely used for preparing solid formulations can be used.
  • examples of such carriers include magnesium stearate, starch, celluloses, lactose and sucrose.
  • any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
  • composition is in the form of a soft gelatin shell capsule
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions can be considered, for example aqueous gums, celluloses, silicates or oils and are incorporated in a soft gelatin capsule shell.
  • Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil or solubilising agent, for example polyethylene glycol, polyvinyl-pyrrolidone, 2-pyrrolidone, cyclodextrin, lecithin, arachis oil, or sesame oil.
  • a parenterally acceptable oil or solubilising agent for example polyethylene glycol, polyvinyl-pyrrolidone, 2-pyrrolidone, cyclodextrin, lecithin, arachis oil, or sesame oil.
  • a typical suppository formulation comprises S-[3-(4(5)- imidazolyDpropyl]isothiourea or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogues.
  • a binding and/or lubricating agent for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogues.
  • Typical transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example - A -
  • a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
  • compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane, or are in the form of a powder for insufflation.
  • a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane
  • the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer to himself a single dose.
  • Each dosage unit for oral administration contains suitably from 0.1 mg to 50 mg, and preferably from 1 mg to 25 mg, and each dosage unit for parenteral administration contains suitably from 0.1 mg to 25 mg, of S-[3-(4(5)- imidazolyDpropyl]isothiourea or a pharmaceutically acceptable salt thereof calculated as the free base.
  • the daily dosage regimen for oral administration is suitably about 0.1 mg to 200 mg, preferably 1 mg to 100 mg, of S-[3-(4(5)-imidazolyDpropyl]isothiourea or a pharmaceutically acceptable salt thereof calculated as the free base.
  • the daily dosage regimen for parenteral administration is suitably about 0.1 mg to 100 mg, for example about 1 mg to 40 mg, of S-[3-(4(5)-imidazolyl)- propyl]isothiourea or a pharmaceutically acceptable salt thereof calculated as the free base.
  • the active ingredient may be administered as required for example from 1 to 4 times a day or by infusion.
  • inhalation dosages are controlled by a valve, are administered as required and for an adult are conveniently in the range 0.1- 5.0 mg of S-[3-(4(5)-imidazolyDpropyl]isothiourea or a pharmaceutically acceptable salt thereof.
  • the compounds of this invention may be co-administered with other pharmaceutically active compounds, for example in combination, concurrently or sequentially.
  • the compounds ' of this invention and the other active compound or compounds are formulated in a pharmaceutical composition.
  • diazepam may be included in pharmaceutical compositions comprising S-[3-(4 (5)-imidazolyDpropyl]- isothiourea.
  • the histamine H3 ⁇ antagonist activity of S-[3-(4(5)- imidazolyDpropyl]isothiourea was assessed by a method similar to that described by Trazoakowski (1987) , J. Pharmacol. Exp. Ther., 243. 874-880.
  • Inhibition of the electrically evoked twitch responses of the guinea-pig ileum by histamine ⁇ -receptor agonists was studied by addition of graded concentrations of (R)- ⁇ methyl-histamine (in volumes of 25 ⁇ l or 79 ⁇ l) to the organ bath in a sequential manner. Each concentration of agonist was washed out of the bath when the response had reached equilibrium. A four minute period was allowed between each addition of the compound. In the antagonist studies a ten minute period was used for the antagonist equilibration time. Antagonist activity was quantified by the ability of the compound to block the inhibitory effect of (R)- ⁇ -methylhistamine on the twitch response.
  • S-[3-(4(5)-imidazolyl)- propyl]isothiourea is a highly potent selective histamine H3- antagonist, being about 1000 times more potent at the histamine ⁇ -receptor than at either the histamine H ⁇ - or H2- receptor.
  • Antagonists of the histamine ⁇ -receptor are believed to stimulate the synthesis and release of neurotransmitters such as histamine and are therefore likely to increase neurotransmitter release in the digestive tract and in the nervous,- cardiovascular and immune systems. They are likely to have a psychotropic action and have utility in cognitive disorders including the treatment of Alzheimer's disease and age-associated memory impairment.
  • a pharmaceutical composition for oral administration is prepared containing:
  • ingredients A substituted lactose or microcrystalline cellose for dibasic calcium phosphate dihydrate if desired
  • B added the ingredients B to the dried granules and compressing the mixture into tablets containing 10 mg, 25 mg or 50 mg of the free base.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Use of an isothiourea derivative as a histamine H3-antagonist.

Description

S-(3-(4(5))-IMIDAZOLYL)PROPYL)ISOTHIOUREA AS SELECTIVE TRHISTOMINE H_ RECEPTOR ANTAGONIST
The present invention relates to pharmaceutical compositions comprising an imidazole derivative, their use in the manufacture of medicaments having histamine ^-antagonist activity and a method of blocking histamine ^-receptors by administering them.
Histamine, a physiologically active compound endogenous in mammals, exerts its action by interacting with certain sites called receptors. One type of receptor is known as a histamine H-j_-receptor (Ash and Schild, Brit. J. Pharmac. Chemother. 22.427 (1966)) and the actions of histamine mediated through these receptors are blocked by H-j_- antagonists such as mepyramine. A second type of receptor is known as the histamine H2~receptor (Black et al., Nature 1972, 236, 385) which is not blocked by mepyramine but by H2~ antagonists such as burimamide or cimetidine. A third type of receptor known as the histamine H3~receptor has more recently been identified (e.g. Arrang et al.. Nature 1987, 327 , 117 and Van der erf et al., (1989) Trends Pharmacol. Sci. 10, 159) which is stimulated by ^-agonists such as (R)- α—methylhistamine and blocked by ^-antagonists such as thioperamide.
US-A-3759944 discloses isothiourea derivatives which are described as acting at histamine receptors other than the H^-receptor and are of utility in inhibiting certain actions of histamine which are not inhibited by H^-antagonists such as the inhibition of histamine-stimulated secretion of gastric acid. A particular isothiourea described is S-[3- (4 (5)-imidazolyDpropyl]isothiourea dihydrobromide. This compound is also disclosed in Eur. J. ed. Chem.-Chim. Ther., 21(4), 305-9 (1986) wherein it is described as being a weak partial H^-agonist and a weak ^-agonist. It has now been discovered that the above named imidazole compound is a highly potent selective histamine H3- antagonist.
Accordingly the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and S-[3-(4(5)-imidazolyDpropyl]- isothiourea or a pharmaceutically acceptable salt thereof in an amount sufficient to block selectively histamine H3- receptors.
In another aspect the present invention provides the use of S-[3-(4 (5)-imidazolyDpropyl]isothiourea or a pharmaceutically acceptable salt thereof in the manufacture of a medicament having histamine Hβ-antagonist activity.
In a further aspect this invention provides a method of blocking histamine ^-receptors in a host in need thereof which comprises administering an effective amount to block said receptors of S-[3-(4(5)-imidazolyDpropyl]isothiourea or a pharmaceutically acceptable salt thereof.
Pharmaceutically acceptable salts include those formed with hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, citric, maleic, lactic, ascorbic, fumaric, oxalic, methanesulphonic and ethanesulphonic acids.
In order to use S-[3-(4 (5)-imidazolyDpropyl]- isothiourea or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
S-[3-(4(5)-imidazolyDpropyl]isothiourea and its pharmaceutically acceptable salts can be administered in standard manner for example orally, sublingually, parenterally, transdermally, rectally, via inhalation or via buccal administration. S-[3-(4 (5)-imidazolyDpropyl]isothiourea and its pharmaceutically acceptable salts which are active when given orally or via buccal administration can be formulated appropriately in dosage forms such as liquids, syrups, tablets, capsules and lozenges. An oral liquid formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, glycerine or water with a flavouring or colouring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations can be used. Examples of such carriers include magnesium stearate, starch, celluloses, lactose and sucrose. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
Where the composition is in the form of a soft gelatin shell capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions can be considered, for example aqueous gums, celluloses, silicates or oils and are incorporated in a soft gelatin capsule shell.
Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil or solubilising agent, for example polyethylene glycol, polyvinyl-pyrrolidone, 2-pyrrolidone, cyclodextrin, lecithin, arachis oil, or sesame oil.
A typical suppository formulation comprises S-[3-(4(5)- imidazolyDpropyl]isothiourea or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogues.
Typical transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example - A -
a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane, or are in the form of a powder for insufflation.
Preferably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer to himself a single dose.
Each dosage unit for oral administration contains suitably from 0.1 mg to 50 mg, and preferably from 1 mg to 25 mg, and each dosage unit for parenteral administration contains suitably from 0.1 mg to 25 mg, of S-[3-(4(5)- imidazolyDpropyl]isothiourea or a pharmaceutically acceptable salt thereof calculated as the free base.
The daily dosage regimen for oral administration is suitably about 0.1 mg to 200 mg, preferably 1 mg to 100 mg, of S-[3-(4(5)-imidazolyDpropyl]isothiourea or a pharmaceutically acceptable salt thereof calculated as the free base. The daily dosage regimen for parenteral administration is suitably about 0.1 mg to 100 mg, for example about 1 mg to 40 mg, of S-[3-(4(5)-imidazolyl)- propyl]isothiourea or a pharmaceutically acceptable salt thereof calculated as the free base. The active ingredient may be administered as required for example from 1 to 4 times a day or by infusion. For administration by inhalation dosages are controlled by a valve, are administered as required and for an adult are conveniently in the range 0.1- 5.0 mg of S-[3-(4(5)-imidazolyDpropyl]isothiourea or a pharmaceutically acceptable salt thereof.
The compounds of this invention may be co-administered with other pharmaceutically active compounds, for example in combination, concurrently or sequentially. Conveniently the compounds 'of this invention and the other active compound or compounds are formulated in a pharmaceutical composition. For example diazepam may be included in pharmaceutical compositions comprising S-[3-(4 (5)-imidazolyDpropyl]- isothiourea.
The histamine H3~antagonist activity of S-[3-(4(5)- imidazolyDpropyl]isothiourea was assessed by a method similar to that described by Trzeciakowski (1987) , J. Pharmacol. Exp. Ther., 243. 874-880. Inhibition of the electrically evoked twitch responses of the guinea-pig ileum by histamine ^-receptor agonists was studied by addition of graded concentrations of (R)-αmethyl-histamine (in volumes of 25 μl or 79 μl) to the organ bath in a sequential manner. Each concentration of agonist was washed out of the bath when the response had reached equilibrium. A four minute period was allowed between each addition of the compound. In the antagonist studies a ten minute period was used for the antagonist equilibration time. Antagonist activity was quantified by the ability of the compound to block the inhibitory effect of (R)-α-methylhistamine on the twitch response.
The concentration of compound which caused 50% antagonism of the inhibitory effect of (R)-α-methylhistamine on the twitch response is given as the IC5- (nM) . The following results were obtained:
Figure imgf000007_0001
The activity of S-[3-(4(5)-imidazolyl)propyl]- isothiourea at the histamine H-_- or H2-receptor was assessed substantially as described by Parsons et al., Agents and Actions, 1976, 2(1), 31. Concentrations up to 10~5 M had no agonist or antagonist activity at histamine H-j_- and H2~ receptors.
The above results indicate that S-[3-(4(5)-imidazolyl)- propyl]isothiourea is a highly potent selective histamine H3- antagonist, being about 1000 times more potent at the histamine ^-receptor than at either the histamine H^- or H2- receptor.
Antagonists of the histamine ^-receptor are believed to stimulate the synthesis and release of neurotransmitters such as histamine and are therefore likely to increase neurotransmitter release in the digestive tract and in the nervous,- cardiovascular and immune systems. They are likely to have a psychotropic action and have utility in cognitive disorders including the treatment of Alzheimer's disease and age-associated memory impairment.
The following example serves to illustrate a pharmaceutical composition of this invention.
Example 1
A pharmaceutical composition for oral administration is prepared containing:
% by weight
S-[3-(4 (5)-imidazolyDpropyl]isothiourea 55 Dibasic calcium phosphate dihydrate 20 Approved colouring agent 0.5
Polyvinylpyrrolidone 4.0
% by weight
Microcrystalline Cellulose Maize Starch 8.0
B Sodium glycollate 4.0 Magnesium Stearate 0.5
by mixing together the ingredients A (substituting lactose or microcrystalline cellose for dibasic calcium phosphate dihydrate if desired) , adding a concentrated solution of polyvinylpyrrolidone and granulating, drying and screening the dried granules; adding the ingredients B to the dried granules and compressing the mixture into tablets containing 10 mg, 25 mg or 50 mg of the free base.

Claims

Claims
1. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and S-[3-(4(5)- imidazolyl)propyl]isothiourea or a pharmaceutically acceptable salt thereof in an amount sufficient to block selectively histamine ^-receptors.
2. A pharmaceutical composition according to claim 1 adapted for oral administration wherein each dosage unit comprises from 0.1 mg to 50 mg of S-[3-(4(5)-imidazolyl)- propyl]isothiourea.
3. A pharmaceutical composition according to claim 1 adapted for parenteral administration wherein each dosage unit comprises from 0.1 mg to 25 mg of S-[3-(4(5)- imidazolyl)propyl]isothiourea.
4. The use of S-[3-(4(5)-imidazolyl)propyl]- isothiourea or a pharmaceutically acceptable salt thereof in the manufacture of a medicament having histamine H3- antagonist activity.
5. A method of blocking histamine ^-receptors in a host in need thereof which comprises administering an effective amount to block said receptors of S-[3-(4(5)- imidazolyl)propyl]isothiourea or a pharmaceutically acceptable salt thereof.
PCT/GB1992/001299 1991-07-20 1992-07-16 S-(3-(4(5))-imidazolyl)propyl)isothiourea as selective trhistomine h3 receptor antagonist WO1993001812A1 (en)

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EP92915736A EP0595910A1 (en) 1991-07-20 1992-07-16 S-(3-(4(5))-imidazolyl)propyl)isothiourea as selective trhistomine h3 receptor antagonist
JP5502676A JPH06509109A (en) 1991-07-20 1992-07-16 S-(3-(4(5))-imidazolyl)propyl)isothiourea as a selective trystomine H3 receptor antagonist

Applications Claiming Priority (2)

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GB919115740A GB9115740D0 (en) 1991-07-20 1991-07-20 Medicaments
GB9115740.4 1991-07-20

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Cited By (21)

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US5578616A (en) * 1993-11-15 1996-11-26 Schering Corporation Phenyl-alkyl-imidazoles
US6133291A (en) * 1998-10-16 2000-10-17 Schering Corporation N-(imidazolylalkyl)substituted cyclic amines as histamine-H3 agonists or antagonists
US6211182B1 (en) 1999-03-08 2001-04-03 Schering Corporation Imidazole compounds substituted with a six or seven membered heterocyclic ring containing two nitrogen atoms
US6290986B1 (en) 1996-10-24 2001-09-18 Pharmaceutical Applications Associates, Llc Method and composition for transdermal administration of pharmacologic agents
US6407132B1 (en) 1997-07-25 2002-06-18 James Black Foundation Limited Substituted imidazole derivatives and their use as histamine H3 receptor ligands
US6479074B2 (en) 1996-10-24 2002-11-12 Pharmaceutical Applications Associates Llc Methods and transdermal compositions for pain relief
US6506756B2 (en) 2000-09-20 2003-01-14 Schering Corporation Substituted imidazoles as dual histamine H1 and H3 agonists or antagonists
US6518287B2 (en) 2000-09-20 2003-02-11 Schering Corporation Substituted imidazoles as dual histamine H1 and H3 agonists or antagonists
US6528522B2 (en) 2000-09-20 2003-03-04 Schering Corporation Substituted imidazoles as dual histamine H1 and H3 agonists or antagonists
US6572880B2 (en) 1996-10-24 2003-06-03 Pharmaceutical Applications Associates Llc Methods and transdermal compositions for pain relief
US6762186B2 (en) 2000-09-20 2004-07-13 Schering Corporation Substituted imidazoles as dual histamine H1 and H3 agonists or antagonists
WO2004098591A3 (en) * 2003-05-05 2005-03-31 Probiodrug Ag Inhibitors of glutaminyl cyclase and their use in the treatment of neurological diseases
WO2005041922A2 (en) * 2003-10-24 2005-05-12 Glaxo Group Limited Composition
US6906081B2 (en) 2001-02-08 2005-06-14 Schering Corporation Use of dual H3/M2 antagonists in the treatment of cognition deficit disorders
US7109347B2 (en) 2001-06-27 2006-09-19 Probiodrug Ag Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents
US7144856B2 (en) 2001-09-06 2006-12-05 Probiodrug Ag Inhibitors of dipeptidyl peptidase I
US7304086B2 (en) 2004-02-05 2007-12-04 Probiodrug Ag Inhibitors of glutaminyl cyclase
US7335645B2 (en) 1999-08-24 2008-02-26 Probiodrug Ag Effectors of dipeptidyl peptidase IV for topical use
US7381537B2 (en) 2003-05-05 2008-06-03 Probiodrug Ag Use of inhibitors of glutaminyl cyclases for treatment and prevention of disease
US7462599B2 (en) 2003-10-15 2008-12-09 Probiodrug Ag Use of effectors of glutaminyl and glutamate cyclases
US20160022751A1 (en) * 2014-07-23 2016-01-28 Gangneung-Wonju National University Industry Academy Cooperation Group Novel composition for treating alzheimer's disease and improving cognitive function of alzheimer's patients

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EP0420396A2 (en) * 1989-07-25 1991-04-03 Smith Kline & French Laboratories Limited Imidazole derivatives as histamine H3-agonists

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US3759944A (en) * 1970-10-14 1973-09-18 Smith Kline French Lab Isothioureas and their derivatives
EP0197840A1 (en) * 1985-03-26 1986-10-15 Institut National De La Sante Et De La Recherche Medicale (Inserm) (Imidazolyl-4) piperidines, their preparation and their therapeutical use
EP0420396A2 (en) * 1989-07-25 1991-04-03 Smith Kline & French Laboratories Limited Imidazole derivatives as histamine H3-agonists

Non-Patent Citations (1)

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Title
Agents and Actions, vol. 18, nos. 1/2, 1986, Birkhäuser Verlag, (Basel, DE), G.J. STERK et al.: "The influence of guanidino and isothiourea groups in histaminergic compounds on H2-activity", pages 137-140, see whole document, especially page 138, last paragraph *

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5578616A (en) * 1993-11-15 1996-11-26 Schering Corporation Phenyl-alkyl-imidazoles
US6572880B2 (en) 1996-10-24 2003-06-03 Pharmaceutical Applications Associates Llc Methods and transdermal compositions for pain relief
US6290986B1 (en) 1996-10-24 2001-09-18 Pharmaceutical Applications Associates, Llc Method and composition for transdermal administration of pharmacologic agents
US6479074B2 (en) 1996-10-24 2002-11-12 Pharmaceutical Applications Associates Llc Methods and transdermal compositions for pain relief
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GB9115740D0 (en) 1991-09-04
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EP0595910A1 (en) 1994-05-11

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