WO1996030350A1 - Derives d'amidine - Google Patents

Derives d'amidine Download PDF

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Publication number
WO1996030350A1
WO1996030350A1 PCT/JP1996/000776 JP9600776W WO9630350A1 WO 1996030350 A1 WO1996030350 A1 WO 1996030350A1 JP 9600776 W JP9600776 W JP 9600776W WO 9630350 A1 WO9630350 A1 WO 9630350A1
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WO
WIPO (PCT)
Prior art keywords
compound
salt
formula
defined above
pyridin
Prior art date
Application number
PCT/JP1996/000776
Other languages
English (en)
Inventor
Yousuke Katsura
Shigetaka Nishino
Tetsuo Tomishi
Original Assignee
Fujisawa Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to JP8529162A priority Critical patent/JPH11503121A/ja
Priority to AU50155/96A priority patent/AU5015596A/en
Publication of WO1996030350A1 publication Critical patent/WO1996030350A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/18—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/40—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention relates to amidine derivatives. More particularly, this invention relates to amidine derivatives and pharmaceutically acceptable salts thereof which have pharmacological activities, processes for preparation
  • composition comprising the same and a use of the same.
  • one object of this invention is to provide the new and useful amidine derivatives and pharmaceutically acceptable salts thereof which possess a strong inhibitory activity on the production of nitric oxide.
  • Another object of this invention is to provide process for preparation of the amidine derivatives and salts thereof.
  • a further object of this invention is to provide a pharmaceutical composition comprising said amidine
  • Still further object of this invention is to provide a use of said amidine derivatives or a pharmaceutically
  • NOS-mediated diseases such as adult respiratory distress syndrome, myocarditis, synovitis, septic shock, insulin-dependent diabetes mellitis, ulcerative colitis, cerebral infarction, rheumatoid arthritis,
  • osteoarthritis osteoporosis
  • systemic lupus erythematosis organ transplantation, asthma, pain, ulcer, and the like in human being and animals.
  • amidine derivatives of the present invention are novel and can be represented by the following general formula (I) :
  • R 1 is heterocyclic group
  • X is (CH 2 ) a in which a is 0 or 1, O or S, Y is CH 2 , O, S or N-R 2
  • R 2 is hydrogen or lower al kyl
  • Z is O or H 2 .
  • n 0 or 1.
  • the object compound (I) of the present invention can be prepared by the following processes.
  • R 1 , R 2, X, Y, Z, m and n are each as defined above,
  • R 3 is lower alkylthio or halogen
  • R 4 , R 5 , R 6 and R 7 are each lower alkyl
  • R 8 is acyl
  • R 1 a is heterocyclic group having acylamino
  • R 1 b is heterocyclic group having amino
  • W 1 , W 2 and W 3 are each halogen.
  • the starting compounds can be prepared by the Preparations as mentioned below or by conventional methods.
  • Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.); an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt dicycl
  • carboxylic or sulfonic acid addition salt e.g., formate, acetate, trifluoroacetate, maleate, tartrate, citrate, fumarate, methanesulfonate, benzenesulfonate,
  • toiuenesulfonate etc.
  • a salt with a basic or acidic amino acid e.g., arginine, aspartic acid, glutamic acid, etc.
  • Suitable “lower alkyl” and “lower alkyl moiety” in the terms “lower alkvlthio” may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, hexyl, and the like, and in which more
  • halogen may be chloro, bromo, fluoro and iodo.
  • Suitable "heterocyclic group” may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like.
  • heterocyclic group may be heterocyclic group such as
  • the heterocyclic moiety as stated above may have one to two, same or different, suitable substituent (s) such as lower alkyl as exemplified above, lower alkoxy (e.g. methoxy, etc.), acylamino such as lower alkanoylamino (e.g. acetylamino, etc.), amino, dilower alkylaminomethyl wherein lower alkyl moiety is as exemplified above, halogen as exemplified above, acyl such as lower alkanoyl (e.g. acetyl, etc.) and diaminomethyleneamino.
  • suitable substituent such as lower alkyl as exemplified above, lower alkoxy (e.g. methoxy, etc.), acylamino such as lower alkanoylamino (e.g. acetylamino, etc.), amino, dilower alkylaminomethyl wherein lower alkyl moiety is as exemplified above,
  • acylamino such as lower alkanoylamino (e.g. formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino, isovalerylamino,
  • acylamino such as lower alkanoylamino (e.g. formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino, isovalerylamino,
  • Suitable "heterocyclic group having amino” may include heterocyclic group as mentioned above which is substituted by amino, for example, aminopyrimidinyl, and the like.
  • Suitable “acyl” may include lower alkanoyl such as formyl, acetyl, propionyl, butyryl, isobutyryl, and the like.
  • R 1 is as follows.
  • R 1 is pyridyl having amino, pyridyl having lower
  • imidazolyl imidazolyl having lower alkyl
  • imidazopyridyl which may have one to two substituent(s) selected from the group consisting of lower alkyl, lower alkoxy and halogen.
  • R 1 is 6-amino-2-pyridyl, 6-acetamido-2-pyridyl,
  • the object compound (I) or a salt thereof can be
  • This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethancl, propanol,
  • reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.
  • the compound (VI) or a salt thereof can be prepared by reacting the compound (IV) or a salt thereof with the
  • This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.],
  • the reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.
  • the object compound (I-a) or a salt thereof can be prepared by reacting the compound (VI) or a salt thereof with the compound (VII) or a salt thereof.
  • This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.],
  • the reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.
  • the object compound (I-b) or a salt thereof can be prepared by reacting the compound (IV) or a salt thereof with the compound (VIII) or a salt thereof.
  • This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.],
  • the reaction temperature is not critical, and the reaction is usually carried cut at ambient temperature or under warming or heating.
  • the object compound (I-d) or a salt thereof can be prepared by reacting the compound (I-c) or a salt thereof with the compound (IX) or a salt thereof.
  • the compound (IX) or a salt thereof is used with formalin.
  • the reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform,
  • a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform,
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
  • the reaction may be carried out in the presence of an inorganic or organic base such as an alkali metal
  • bicarbonate tri(lower)alkylamine (e.g. triethylamine, etc.) pyridine, N-(lower)alkylmorphorine,
  • N,N-di(lower)alkylbenzylamine or the like.
  • the reaction may also be carried out in the presence of acetyl chloride.
  • the compound (IX) can be prepared by mixing
  • the object compound (I-f) or a salt thereof can be prepared by subjecting the compound (I-e) or a salt thereof to deacylation.
  • Suitable method for this deacylation reaction may include conventional one such as hydrolysis, reduction, or the like.
  • the hydrolysis is preferably carried out in the presence of a base or an acid.
  • Suitable base may include, for example, an inorganic base such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium, hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g. magnesium
  • alkali metal hydroxide e.g. sodium hydroxide, potassium hydroxide, etc.
  • alkaline earth metal hydroxide e.g. magnesium hydroxide, calcium, hydroxide, etc.
  • alkali metal carbonate e.g. sodium carbonate, potassium carbonate, etc.
  • alkaline earth metal carbonate e.g. magnesium
  • alkali metal bicarbonate e.g. sodium bicarbonate, potassium bicarbonate, etc.
  • alkali metal acetate e.g. sodium acetate, potassium acetate, etc.
  • alkaline earth metal phosphate e.g. magnesium
  • alkali metal hydrogen phosphate e.g. disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.
  • organic base such as tri(lower)alkylamine (e.g. trimethylamine
  • Suitable acid may include an organic acid (e.g. formic acid, acetic acid, propionic acid, etc.) and an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, etc.).
  • organic acid e.g. formic acid, acetic acid, propionic acid, etc.
  • inorganic acid e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, etc.
  • the present hydrolysis is usually carried out in an organic solvent, water or a mixed solvent thereof.
  • the reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.
  • the object compound (I-h) or a salt thereof can be prepared by subjecting the compound (I-g) or a salt thereof to deacylation.
  • reaction can be carried out in substantially the same manner as Process 5, and therefore the reaction mode and reaction conditions [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those as
  • the object compound (I-i) or a salt thereof can be prepared by reacting the compound (X) or a salt thereof with thiourea.
  • This reaction is usually conducted in a conventional solvent which does net adversely influence the reaction such as methyl acetate, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, acetone,
  • alcohol e.g. methanol, ethanol, etc.
  • acetic acid formic acid, etc. or a mixture thereof.
  • the reaction temperature is not critical and the
  • the compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, or the like.
  • the compound (I) and the other compounds may include one or more stereoisomer(s) such as optical isomer(s) and geometrical isomer(s) due to asymmetric carbon atom(s) and double bond(s), and all or such isomers and mixture thereof are included within the scope of this invention.
  • acceptable salt thereof may include a solvate [e.g.,
  • enclosure compound e.g., hydrate, etc.
  • the object compounds (I) and pharmaceutically acceptable salts thereof possess a strong inhibitory activity on the production of nitric oxide (NO).
  • nitric oxide synthase (NOS)-inhibitory activity or a NOS-production inhibitory activity.
  • a crude preparation of NOS obtained from the brains of male SD rats.
  • the whole brain (including cerebellum) was homogenized in 5 volume (W/V) of 50 mM Tris buffer (pH 7.0 at 4°C), centrifuged at 48,000 x g for 20 minutes, the pellet discarded and the supernatant passed through 1/4 volume (V/V) of Dowex AG50WX-8 resin (Na + form), in order to remove of endogenous arginine.
  • the supernatant was collected, the pH adjusted to 7.0 at 22°C and this cytosolic preparation was frozen and stored at -80oC until required. In the binding.
  • each drug was incubated with the brain cytozole (200 ⁇ g protein/tube) in a final volume of 0.15 ml of 50 mM Tris buffer including 10 ⁇ M CaCl 2 and 10 nM 3 [H]Na (Amersham, Amersham, UK). Incubations were performed at 27°C for 90 minutes and were terminated by vacuum filtration over 0.3 % polyethyleneimine pretreated GF/B glass fibre filters which were subsequently washed with 4 ml ⁇ 4 of 4°C distilled water. Non specific binding was defined by use of 100 ⁇ M Na. Data were expressed as inhibition % of specific binding. Test Result
  • the object compounds (I) of the present invention and pharmaceutically acceptable salts thereof are used in a form of the conventional
  • compositions in admixture with a conventional pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration.
  • a conventional pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration.
  • the pharmaceutical preparation may be compounded in a solid form such as granule, capsule, tablet, dragee or suppository, or in a liquid form such as solution, suspension or emulsion for injection, ingestion, eye drops, etc. If needed, there may be included in the above preparation auxiliary substance such as stabilizing agent, wetting or emulsifying agent, buffer or any other commonly used additives.
  • a solid form such as granule, capsule, tablet, dragee or suppository
  • a liquid form such as solution, suspension or emulsion for injection, ingestion, eye drops, etc.
  • auxiliary substance such as stabilizing agent, wetting or emulsifying agent, buffer or any other commonly used additives.
  • the effective ingredient may usually be administered with a unit dose of 0.001 mg/kg to 500 mg/kg, preferably 0.01 mg/kg to 10 mg/kg, 1 to 4 times a day.
  • the above dosage may be increased or decreased according to age, weight and conditions of the patient or the administering method.
  • Benzoyl chloride (1 ml) was added dropwise under reflux to stirred solution of ammonium thiocyanate (0.73 g) in acetone (20 ml). The mixture was stirred under reflux for 15 minutes, and then 2-[2-(4-aminophenyl)ethyl]-3,7-dimethylimidazo[1,2-a]pyridine (2.2 g) in acetone (10 ml) was added dropwise. After the resulting mixture was stirred under reflux for further four hours, concentrated in vacuo and mixed with ethyl acetate (20 ml) and water (50 ml).
  • Triph ⁇ nylphosphine (1.21 g) was added to a solution of p-nitrobenzyl bromide (1.0 g) in N,N-dimethylformamide (10 ml) at room temperature. The mixture was stirred at room temperature for 3.5 hours. 2-Acetylamino-4-formylthiazole (1.18 g) and potassium t-butoxide (620 mg) were added to the reaction mixture and then the mixture was stirred at room temperature for 21 hours. The solvent was removed under reduced pressure. The residue was suspended in toluene (20 ml). The mixture was stirred for 30 minutes at room
  • Phosphorus oxychloride (0.34 ml) was added to a solution of 2-pyrrolidone (0.64 g) in dichloromethane (5 ml) with stirring at ambient temperature. After stirring for three hours, 2-[2-(4-aminophenyl)ethyl]-3,7-dimethylimidazo[1,2-a]-pyridine (1.0 g) and triethylamine (0.53 ml) were added to the solution and the mixture was stirred at ambient temperature for further two hours. The reaction mixture was poured into water (20 ml). The aqueous layer separated was basified with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated in vacuo. The residue was recrystallized from a mixture of dichloromethane and
  • Acetyl chloride (0.39 ml) was added dropwise to a solution of 2-[4-[ 2-(furan-2-yl)ethyl]phenylamino]-2- thiazoline (1.34 g) and pyridine (2.0 ml) in dichloromethane (25 ml) at 0°C. After being stirred for four hours, the mixture was poured into saturated aqueous sodium bicarbonate. The organic layer separated was dried over magnesium sulfate and concentrated in vacuo. The residue, 36% formalin (0.49 ml) and dimethylamine hydrochloride (0.53 g) were dissolved in acetic acid. After being stirred at 80°C for 1.5 hours, the solution was concentrated in vacuo.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé ayant pour formule (I), dans laquelle R1 est un groupe hétérocyclique, X est (CH¿2?)a, a représentant 0, 1, O ou S, Y est CH2, O, S ou N-R?2, R2¿ étant l'hydrogène ou un alkyle inférieur, Z est O ou H¿2?, et m et n sont égaux chacun à 0 ou 1. L'invention concerne aussi des sels de ce composé acceptables en pharmacie, utiles comme médicaments pour le traitement prophylactique et thérapeutique de maladies à médiation par NOS.
PCT/JP1996/000776 1995-03-27 1996-03-26 Derives d'amidine WO1996030350A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP8529162A JPH11503121A (ja) 1995-03-27 1996-03-26 アミジン誘導体
AU50155/96A AU5015596A (en) 1995-03-27 1996-03-26 Amidine derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9506188.3 1995-03-27
GBGB9506188.3A GB9506188D0 (en) 1995-03-27 1995-03-27 Amidine derivatives

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WO1996030350A1 true WO1996030350A1 (fr) 1996-10-03

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AU (1) AU5015596A (fr)
GB (1) GB9506188D0 (fr)
WO (1) WO1996030350A1 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997045417A1 (fr) * 1996-05-25 1997-12-04 Wivenhoe Technology Limited Inhibiteurs de production de cytokines, leurs formulations et leur utilisation dans des medicaments et procedes servant a les identifier
EP0902018A2 (fr) 1997-09-04 1999-03-17 F. Hoffmann-La Roche Ag Dérivés de 2-(arylphényl)amino-imidazoline
FR2780971A1 (fr) * 1998-07-08 2000-01-14 Sod Conseils Rech Applic Nouveaux derives de 2-aminopyridines, leur application en tant que medicaments et compositions pharmaceutiques les contenant
WO2000002860A1 (fr) * 1998-07-08 2000-01-20 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Derives de 2-aminopyridines, leur utilisation en tant que medicaments et compositions pharmaceutiques les contenant
FR2791674A1 (fr) * 1999-04-02 2000-10-06 Sod Conseils Rech Applic Nouveaux derives de 2-aminopyridines, leur utilisation en tant que medicaments et compositions pharmaceutiques les contenant
US6184242B1 (en) 1997-09-04 2001-02-06 Syntex Usa (Llc) 2-(substituted-phenyl)amino-imidazoline derivatives
WO2002040453A1 (fr) * 2000-11-14 2002-05-23 F. Hoffmann-La Roche Ag Derives de 2-phenylaminoimidazoline phenyle cetone substitues utilises comme antagonistes de la prostaglandine i2
WO2004067521A1 (fr) * 2003-01-27 2004-08-12 Astellas Pharma Inc. Derives de thiazole et leur utilisation en tant qu'inhibiteurs de vap-1
WO2005005394A2 (fr) * 2003-07-09 2005-01-20 F.Hoffmann-La Roche Ag Thiophenyl amino imidazolines
WO2006011631A2 (fr) * 2004-07-27 2006-02-02 Astellas Pharma Inc. Derives de thiazole presentant une activite d'inhibition de la vap-1
EP1981343A2 (fr) * 2006-01-17 2008-10-22 Barrier Therapeutics, Inc. Traitement de troubles inflammatoires avec des composes de triazole

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WO2016043260A1 (fr) * 2014-09-19 2016-03-24 塩野義製薬株式会社 Composé d'amidine ou de guanidine cyclique

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WO1997045417A1 (fr) * 1996-05-25 1997-12-04 Wivenhoe Technology Limited Inhibiteurs de production de cytokines, leurs formulations et leur utilisation dans des medicaments et procedes servant a les identifier
US6693200B2 (en) 1997-09-04 2004-02-17 Syntex (U.S.A.) Llc 2-(substituted-phenyl)amino-imidazoline derivatives
US6596876B2 (en) 1997-09-04 2003-07-22 Syntex (U.S.A.) Llc 2-(substituted-phenyl)amino-imidazoline derivatives
EP0902018A2 (fr) 1997-09-04 1999-03-17 F. Hoffmann-La Roche Ag Dérivés de 2-(arylphényl)amino-imidazoline
US7141584B2 (en) 1997-09-04 2006-11-28 Roche Palo Alto Llc 2-(substituted-phenyl)amino-imidazoline derivatives
US6184242B1 (en) 1997-09-04 2001-02-06 Syntex Usa (Llc) 2-(substituted-phenyl)amino-imidazoline derivatives
EP0902018A3 (fr) * 1997-09-04 2001-05-02 F. Hoffmann-La Roche Ag Dérivés de 2-(arylphényl)amino-imidazoline
AU746480B2 (en) * 1997-09-04 2002-05-02 F. Hoffmann-La Roche Ag 2-(arylphenyl)amino-imidazoline derivatives
CN1110484C (zh) * 1997-09-04 2003-06-04 弗·哈夫曼-拉罗切有限公司 2－(芳基苯基)氨基－咪唑啉衍生物
US6472536B1 (en) 1997-09-04 2002-10-29 Syntex (U.S.A.) Llc 2-(substituted-phenyl)amino-imidazoline derivatives
FR2780971A1 (fr) * 1998-07-08 2000-01-14 Sod Conseils Rech Applic Nouveaux derives de 2-aminopyridines, leur application en tant que medicaments et compositions pharmaceutiques les contenant
CZ299818B6 (cs) * 1998-07-08 2008-12-03 Societe De Conseils De Recherches Et D'applications Scientifiques (S. C. R. A. S.) Deriváty 2-aminopyridinu, farmaceutické kompozices jejich obsahem a použití derivátu jako léciva
WO2000002860A1 (fr) * 1998-07-08 2000-01-20 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Derives de 2-aminopyridines, leur utilisation en tant que medicaments et compositions pharmaceutiques les contenant
US6762176B1 (en) 1998-07-08 2004-07-13 Societe De Consells De Recherches Et D'applications Scientifiques (S.C.R.A.S.) 2-aminopyridine derivatives, their use as medicines and pharmaceutical compositions containing them
FR2791674A1 (fr) * 1999-04-02 2000-10-06 Sod Conseils Rech Applic Nouveaux derives de 2-aminopyridines, leur utilisation en tant que medicaments et compositions pharmaceutiques les contenant
WO2002040453A1 (fr) * 2000-11-14 2002-05-23 F. Hoffmann-La Roche Ag Derives de 2-phenylaminoimidazoline phenyle cetone substitues utilises comme antagonistes de la prostaglandine i2
US7442715B2 (en) 2003-01-27 2008-10-28 Astellas Pharma Inc. Thiazole derivatives
US7125901B2 (en) * 2003-01-27 2006-10-24 Astellas Pharma Inc. Thiazole derivatives
WO2004067521A1 (fr) * 2003-01-27 2004-08-12 Astellas Pharma Inc. Derives de thiazole et leur utilisation en tant qu'inhibiteurs de vap-1
WO2005005394A3 (fr) * 2003-07-09 2005-03-31 Hoffmann La Roche Thiophenyl amino imidazolines
WO2005005394A2 (fr) * 2003-07-09 2005-01-20 F.Hoffmann-La Roche Ag Thiophenyl amino imidazolines
WO2006011631A2 (fr) * 2004-07-27 2006-02-02 Astellas Pharma Inc. Derives de thiazole presentant une activite d'inhibition de la vap-1
WO2006011631A3 (fr) * 2004-07-27 2006-04-20 Astellas Pharma Inc Derives de thiazole presentant une activite d'inhibition de la vap-1
EP1981343A2 (fr) * 2006-01-17 2008-10-22 Barrier Therapeutics, Inc. Traitement de troubles inflammatoires avec des composes de triazole
EP1981343A4 (fr) * 2006-01-17 2010-12-15 Stiefel Laboratories Traitement de troubles inflammatoires avec des composes de triazole

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GB9506188D0 (en) 1995-05-17
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