[go: up one dir, main page]

WO1996030350A1 - Amidine derivatives - Google Patents

Amidine derivatives Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
compound
salt
formula
defined above
pyridin
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP1996/000776
Other languages
French (fr)
Inventor
Yousuke Katsura
Shigetaka Nishino
Tetsuo Tomishi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fujisawa Pharmaceutical Co Ltd
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/en
Priority to AU50155/96A priority patent/AU5015596A/en
Publication of WO1996030350A1 publication Critical patent/WO1996030350A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

A compound of formula (I), wherein R1 is heterocyclic group, X is (CH¿2?)a in which a is 0 or 1, O or S, Y is CH2, O, S or N-R?2¿ in which R2 is hydrogen or lower alkyl, Z is O or H¿2?, and m and n are each 0 or 1, and pharmaceutically acceptable salts thereof, which is useful as a medicament for prophylactic and therapeutic treatment of NOS-mediated diseases.

Description

DESCRIPTION
AMIDINE DERIVATIVES TECHNICAL FIELD :
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
thereof, a pharmaceutical composition comprising the same and a use of the same.
Accordingly, 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
derivatives or a pharmaceutically acceptable salt thereof.
Still further object of this invention is to provide a use of said amidine derivatives or a pharmaceutically
acceptable salt thereof as a medicament for prophylactic and therapeutic treatment of 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.
DISCLOSURE OF INVENTION :
The object amidine derivatives of the present invention are novel and can be represented by the following general formula (I) :
Figure imgf000004_0001
wherein R1 is heterocyclic group,
X is (CH2)a in which a is 0 or 1, O or S, Y is CH2, O, S or N-R2
in which R2 is hydrogen or lower al kyl ,
Z is O or H2, and
m and n are each 0 or 1.
The object compound (I) of the present invention can be prepared by the following processes.
Process 1
Figure imgf000004_0002
Figure imgf000005_0001
Process 2
Figure imgf000005_0002
Figure imgf000005_0003
Figure imgf000006_0001
Process 3
Figure imgf000006_0002
Figure imgf000006_0003
Process 4
Figure imgf000007_0001
Figure imgf000007_0002
Process 5
Figure imgf000007_0003
Figure imgf000008_0001
Process 6
Figure imgf000008_0002
Figure imgf000008_0003
Process 7
Figure imgf000009_0001
Figure imgf000009_0002
wherein R1, R2, X, Y, Z, m and n are each as defined above,
R3 is lower alkylthio or halogen,
R4, R5, R6 and R7 are each lower alkyl,
R8 is acyl,
R1 a is heterocyclic group having acylamino, R1 b is heterocyclic group having amino, and W1, W2 and W3 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
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.).
In the above and subsequent descriptions of the present specification, suitable examples and illustration of the various definitions which the present invention intends to include within the scope thereof are explained in detail as follows. The term "lower" is used to intend a group having 1 to 6, preferably 1 to 4, carbon atom(s), unless otherwise provided.
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
preferable example may be C1-C4 alkyl. Suitable "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.
And, especially preferable heterocyclic group may be heterocyclic group such as
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl,
piperidyl, piperazinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl,
indclinyl, indolizinyl, benzimidazolyl, quinolyl,
isoquinolyl, indazolyl, benzotriazolyl, imidazopyridyl, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1, 2, 5-oxadiazolyl, etc.), etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example,
morpholinyl, sydnonyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example,
thiomorpholinyl, thiazolidinyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s), for example, thienyl, dihydrodithiinyl,
dihydrodithionyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom, for example, furyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, dihydrooxathiinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s), for example, benzothienyl, benzodithiinyl, etc.;
unsaturated condensed heterocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example,
benzoxathiinyl, etc.; and the like.
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 "heterocyclic group having acylamino"
may include heterocyclic group as mentioned above which is substituted by acylamino such as lower alkanoylamino (e.g. formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino, isovalerylamino,
pivaloylamino, hexanoylamino, etc.), for example,
acetamidopyrimidinyl, and the like.
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.
Particularly, the preferred embodiment of R1 is as follows.
R1 is pyridyl having amino, pyridyl having lower
alkanoylamino, pyrimidinyl having amino, pyrimidinyl having lower alkanoylamino, furyl, furyl having
N,N-di(lower)alkylaminomethyl, thiazolyl having
diaminomethyleneamino, thiazolyl having amino, thiazolyl having lower alkanoylamino, pyrrolidinyl, morpholinyl, piperazinyl, piperazinyl having lower alkanoyl,
imidazolyl, imidazolyl having lower alkyl, and
imidazopyridyl which may have one to two substituent(s) selected from the group consisting of lower alkyl, lower alkoxy and halogen.
Furthermore, the preferred embodiment of R1 is as follows. R1 is 6-amino-2-pyridyl, 6-acetamido-2-pyridyl,
2-amino-4-pyrimidinyl, 2-acetamido-4-pyrimidinyl,
2-furyl, 5-dimethylaminomethyl-2-furyl,
2-diaminomethyleneamino-4-thiazolyl, 2-amino-4- thiazolyl, 2-acetamido-4-thiazolyl, 1-pyrrolidinyl, morpholino, 1-piperazinyl, 4-acetyl-1-piperazinyl,
2-imidazolyl, 2-methyl-1-imidazolyl, imidazo[1,2-a]- pyridin-2-yl, 7-methylimidazo[1,2-a]pyridin-2-yl,
7-methoxyimidazo[1,2-a]pyridin-2-yl,
3,7-dimethylimidazo[1,2-a]pyridin-2-yl, and
3-chloro-7-methylimidazo[1,2-a]pyridin-2-yl.
The processes for preparing the object compound (I) of the present invention are explained in detail in the
following.
Process 1
The object compound (I) or a salt thereof can be
prepared by reacting the compound (II) or a salt thereof with the compound (III) 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, ethancl, propanol,
2-methoxyethanol, etc.], tetrahydrofuran, dioxane, dimethyl sulfoxide, N,N-dimethylformamide or a mixture thereof.
The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating. Process 2-(i)
The compound (VI) or a salt thereof can be prepared by reacting the compound (IV) or a salt thereof with the
compound (V) 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.],
tetrahydrofuran, dioxane, dimethyl sulfoxide, N,N- dimethylformamide or a mixture thereof.
The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.
Process 2- (ii)
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.],
tetrahydrofuran, dioxane, dimethyl sulfoxide, N,N-dimethylformamide or a mixture thereof.
The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.
Process 3
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.],
tetrahydrofuran, dioxane, dimethyl sulfoxide, N,N-dimethylformamide or a mixture thereof.
The reaction temperature is not critical, and the reaction is usually carried cut at ambient temperature or under warming or heating.
Process 4
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,
dichloromethane, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, pyridine or any other organic solvent which does not
adversely influence the reaction.
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
di( lower ) al kylamine hydrochloride with formalin.
Process 5
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
carbonate, calcium carbonate, etc.), 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
phosphate, calcium phosphate, etc.), alkali metal hydrogen phosphate (e.g. disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.), or the like, and an organic base such as tri(lower)alkylamine (e.g. trimethylamine,
triethylamine, etc.), picoline, N-methylpyrrolidine,
N-methylmorpholine, 1,5-diazabicyclo[4,3,0]non-5-one,
1,4-diazabicyclo[2,2,2]octane, 1,5-diazabicyclo[5,4,0]-undecene-5 or the like. The hydrolysis using a base is often carried out in water or a hydrophilic organic solvent or a mixed solvent thereof.
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.).
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.
Process 6
The object compound (I-h) or a salt thereof can be prepared by subjecting the compound (I-g) or a salt thereof to deacylation.
The 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
explained in Process 5. Proces s 7
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,
N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, water, alcohol [e.g. methanol, ethanol, etc.] acetic acid, formic acid, etc. or a mixture thereof.
The reaction temperature is not critical and the
reaction is usually conducted unoer cooling to heating. Suitable salts of the object and starting compounds in Processes (1), (2), (3), (4), (5), (6) and (7) can be
referred to the ones as exemplified for the compound (I).
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.
It is to be noted that 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.
The object compound (I) and a pharmaceutically
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).
Accordingly, the object compounds (I) and
pharmaceutically acceptable salts thereof are expected to possess a nitric oxide synthase (NOS)-inhibitory activity or a NOS-production inhibitory activity.
Accordingly, they are useful for prevention and/or treatment of 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 order to illustrate the usefulness of the object compound (I), the pharmacological test data of the
representative compound of the compound (I) are shown in the following.
Test Compound
(a) 2-[4-[2-(7-Methylimidazo[1,2-a]pyridin-2-yl)ethyl]- phenylamino]-2-thiazoline
Test
Binding assay using nitric oxide synthase (NOS) Test Method
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. assay, each drug was incubated with the brain cytozole (200 μg protein/tube) in a final volume of 0.15 ml of 50 mM Tris buffer including 10 μM CaCl2 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 μM Na. Data were expressed as inhibition % of specific binding. Test Result
Figure imgf000020_0001
For therapeutic administration, the object compounds (I) of the present invention and pharmaceutically acceptable salts thereof are used in a form of the conventional
pharmaceutical preparation 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.
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.
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. However, the above dosage may be increased or decreased according to age, weight and conditions of the patient or the administering method. The following Preparations and Examples are given for the purpose of illustrating the present invention in detail.
Preparation 1
A solution of 2-chloromethyl-7-methylimidazo[1,2-a]- pyridine (6.8 g) and sodium 4-nitrophenyl sulfide (6.7 g) in N,N-dimethylformamide (35 ml) was stirred for two hours at ambient temperature. The reaction mixture was poured into water (175 ml) and. the resulting precipitate was collected by filtration. Recrystallization from ethanol afforded
7-methyl-2-(4-nitrophenyl)thiomethylimidazo[1,2-a]pyridine (5.5 g).
mp : 150-151°C
IR (Nujol) : 1575, 1330 cm-1
NMR (DMSO-d6, δ) : 2.32 (3H, s), 4.48 (2H, s),
6.70 (1H, dd, J=2Hz and 7Hz), 7.27 (1H, d, J=2Hz), 7.60 (2H, d, J=9Hz), 7.82 (1H, s), 8.12 (2H, d, J=9Hz), 8.35 (1H, d, J=7Hz) Preparation 2
2-(Diaminomethyleneamino)-4-(4-nitrophenyl)-thiomethylthiazole was prepared from 4-chloromethyl-2- (diaminomethyleneamino)thiazole hydrochloride in a similar manner to that of Preparation 1.
mp : 173-174°C
IR (Nujol) : 3410, 1710, 1665, 1545, 1335 cm-1
NMR (DMSO-d6, δ) : 4.30 (2H, s), 6.65 (1H, s),
6.82 (4H, s), 7.63 (2H, d, J=9Hz), 8.16 (2H, d, J=9Hz)
Preparation 3
A suspension of 2-chloromethyl-7-methylimidazo[1,2-a]-pyridine (4.0 g) and sodium 4-nitrophenyl oxide (4.0 g) in N,N-dimethylformamide (20 ml) was stirred at 60°C for 19 hours. The reaction mixture was poured into water (100 ml) and the resulting precipitate was collected by filtration. Recrystallization from a mixture of methanol - dioxane afforded 7-methyl-2-(4-nitrophenoxy)methylimidazo[1,2-a]-pyridine (2.6 g).
mp : 199-200°C
IR (Nujol) : 1510, 1335 cm-1
NMR (DMSO-d6, δ) : 2.35 (3H, s), 5.35 (2H, s), 6.77
(1H, dd, J=2Hz and 7Hz), 7.28 (2H, d, J=9Hz), 7.32 (1H, d, J=2Hz), 7.93 (1H, s), 8.21 (2H, d, J=9Hz), 8.41 (1H, d, J=7Hz)
Preparation 4
7-Methyl-2-(4-nitrophenoxy)methylimidazo[1,2-a]pyridine (2.5 g) was added portionwise to a stirred mixture of iron powder (2.0 g) and ammonium chloride (0.24 g) in refluxing ethanol (25 ml) and water (2.5 ml). After being stirred for an hour, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was added to saturated aqueous sodium bicarbonate and extracted with
dichloromethane. The extract was dried over anhydrous magnesium sulfate and concentrated in vacuo to afford 2-(4-aminophenoxy)methyl-7-methylimidazo[1,2-a]pyridine (1.4 g). mp : 149-150°C
IR (Nujol) : 3420, 3320, 3200, 3145 cm-1
NMR (DMSO-d6, δ) : 2.33 (3H, s), 4.58 (2H, s),
5.02 (2H, s), 6.51 (2H, d, J=9Hz), 6.70 (1H, dd, J=2Hz and 7Hz), 6.78 (2H, d, J=9Hz), 7.23 (1H, d, J=2Hz), 7.80 (1H, s), 8.36 (1H, d, J=7Hz)
Preparation 5
The following compounds were prepared according to a s imilar manner to that of Preparation 4 .
( 1 ) 2- ( 4-Aminophenyl ) thiomethyl-7-methylimidazo [ 1 , 2-a ] - pyridine mp : 130-133°C
IR (Nujol) : 3450, 3290, 3160, 3135 cm-1
NMR (DMSO-d6, δ) : 2.32 (3H, s), 4.07 (2H, s),
5.00 (2H, br s), 6.55 (2H, d, J=8Hz), 6.68 (1H, dd, J=2Hz and 7Hz), 7.13 (2H, d, J=8Hz), 7.27 (1H, d,
J=2Hz), 7.62 (1H, s), 8.33 (1H, d, J=7Hz)
(2) 4-(4-Aminophenyl)thiomethyl-2-(diaminomethyleneamino)- thiazole
mp : 175-176°C
IR (Nujol) : 3425, 3310, 3110, 1715, 1650 cm-1
NMR (DMSO-d6, δ) : 3.80 (2H, s), 5.17 (2H, br s),
6.28 (1H, s), 6.50 (2H, d, J=8Hz), 6.80 (4H, s), 7.07 (2H, d, J=8Hz)
Preparation 6
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).
The resulting precipitate was collected by filtration and recrystallized from ethanol - n-hexane to afford 1-benzoyl-3-[4-[2-(3,7-dimethylimidazo[1,2-a]pyridin-2-yl)ethyl]phenyl]thiourea (3.0 g).
mp : 171-172ºC
IR (Nujol) : 1665 cm-1
NMR (DMSO-d6, δ) : 2.31 (3H, s), 2.50 (3H, s),
3.07 (4H, s), 7.18 (1H, dd, J=2Hz and 7Hz), 7.25 (1H, d, J=8Hz), 7.51 (1H, d, J=2Hz), 7.59 (5H, s), 7.94 (1H, d, J=8Hz), 8.40 (1H, d, J=7Hz), 11.44 (1H, br s), 12.53 (1H, s) Preparation 7
A mixture of 1-benzoyl-3-[4-[2-(3,7-dimethylimidazo- [1,2-a]pyridin-2-yl)ethyl]phenyl]thiourea (6.3 g) and sodium hydroxide (0.59 g) in methanol (60 ml) was stirred at 60°C for 20 minutes. After concentration, the residue was mixed with water (30 ml) and the resulting precipitate was
collected by filtration and recrystallized from methanol - tetrahydrofuran to afford 4-[2-(3,7-dimethylimidazo[1,2-a]-pyridin-2-yl)ethyl]phenylthiourea (4.45 g).
mp : 194-195°C
IR (Nujol) : 3400, 3265, 3170 cm-1
NMR (DMSO-d6, δ) : 2.25 (3H, s), 2.33 (3H, s),
2.92 (4H, s), 6.68 (1H, dd, J=2Hz and 7Hz), 7.13 (2H, d, J=9Hz), 7.24 (2H, s), 7.29 (2H, d, J=9Hz), 7.31 (1H, d, J=2Hz), 7.98 (1H, d, J=7Hz), 9.56 (1H, s)
Preparation 8
A solution of 4'-nitrophenyl-4-pentanone (6.7 g) and bromine (5.43 g) in methanol (70 ml) was stirred at room temperature for 5 hours. N-acetylthiourea (3.82 g) and potassium carbonate (11.17 g) were added to the reaction mixture. The mixture was heated at 50°C for 4 hours. The solvent was removed under reduced pressure and the residue was dissolved in a mixture of water (100 ml) and
tetrahydrofuran (30 ml). The mixture was extracted with ethyl acetate (120 ml) and the extract was dried over
magnesium sulfate. The solvent was removed under reduced pressure and the residue was chromatographed on a silica gel column eluting with chloroform:methanol = 100:1. The
appropriate fractions was collected to afford 2-acetylamino-4-[3-(4-nitrophenyl)propyl]thiazole (1.0 g).
mp : 147-148°C
IR (Nujol) : 3150, 1640 cm-1
NMR (DMSO-d6, δ) : 1.39-2.04 (2H, m), 2.11 (3H, s), 2 . 61 ( 2H, t , J=7 . 4Hz ) , 2 . 75 ( 2H, t , J=7 . 4Hz ) , 6 . 77 ( 1H, s), 7 . 49 ( 2H, d, J=8 . 7Hz ) , 8 . 16 ( 2H, d,
J=8 . 7Hz), 12 . 04 ( 1H, s ) Preparation 9
Triphεnylphosphine (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
temperature and then the insoluble material was removed by filtration. The solvent was removed under reduced pressure and the residue was chromatographed on a silica gel column eluting with a mixture of ethyl acetate:methanol = 50:1 and then chloroform:methanol = 100:1. The appropriate fractions was collected and the solvent was removed under reduced pressure. Crystallization from diisopropyl ether afford 2-acetylamino-4-((E)-4-nitrophenylvinyl)thiazole (700 mg).
mp : 197-198°C
IR (Nujol) : 3330, 1680, 1670, 1620, 1540 cm-1
NMR (DMSO-d6, δ) : 2.14 (3H, s), 6.60-6.74 (2H, m),
7.16 (1H, s), 7.79 (2H, d, J=8.6Hz), 8.17 (2H, d, J=8.6Hz), 11.94 (1H, br s)
Preparation 10
A mixture of 2-acetylamino-4-((E)-4-nitrophenylvinyl)-thiazole (4.5 g) and palladium on activated carbon (wet) (1.9 g) in methanol (45 ml) and tetrahydrofuran (65 ml) was stirred at room temperature for 8.5 hours under hydrogen stream. The insoluble material was removed by filtration. The solvent was removed under reduced pressure and the residue was chromatographed on a silica gel column eluting with chloroform:methanoI = 50:1. Crystallization from ethyl acetate afford 2-acetylamino-4-[2-(4-aminophenyl)ethyl]- thiazole (2.3 g).
mp : 135-136°C
IR (Nujol) : 3370, 1650 cm-1
NMR (DMSO-d6, δ) : 2.11 (3H, s), 2.76 (4H, br s), 4.83 (2H, s), 6.46 (2H, d, J=8.3Hz), 6.84 (2H, d,
J=8.3Hz), 12.08 (1H, br s)
Example 1
A solution of 2-[2-(3-aminophenyl)ethyl]-3,7-dimethylimidazo[1,2-a]pyridine (1.0 g) and 2-methylthio-2-thiazoline hydriodide (1.1 g) in dimethylsulfoxide (10 ml) was stirred at 100°C for 20 hours. After concentration, the residue was added to saturated aqueous sodium bicarbonate and extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated in vacuo to give a
residue, which was chromatographed on silica gel eluting with chloroform - methanol (100/1). The free base obtained was converted to the difumarate in the usual manner, and the salt was recrystallized from methanol to afford 2-[3-[2-(3,7-dimethylimidazo[1,2-a]pyridin-2-yl)ethyl]phenylamino]-2-thiazoline difumarate (0.64 g).
mp : 157°C (decomp.)
IR (Nujol) : 1690, 1670, 1645 cm-1
NMR (DMSO-d6, δ) : 2.22 (3H, s), 2.42 (3H, s),
2.97 (4H, s), 3.23 (2H, t, J=7Hz), 3.87 (2H, t, J=7Hz), 6.67 (4H, s), 6.82-6.93 (1H, m), 6.95 (1H, dd, J=2Hz and 7Hz), 7.13-7.22 (3H, m), 7.50 (1H, d,
J=2Hz), 8.19 (1H, d, J=7Hz), 10.57 (5H, s)
Example 2
The following compounds were prepared according to a similar manner to that of Example 1. (1) 2-[4-[2-(Imidazo[1,2-a]pyridin-2-yl)ethyl]phenylamino]- 2-thiazoline
mp : 160-161°C
IR (Nujol) : 3280, 3220, 3150, 1625 cm-1
NMR (DMSO-d6, δ) : 2.95 (4H, s), 3.27 (2H, t, J=7Hz), 3.92 (2H, t, J=7Hz), 6.80 (1H, dt, J=2Hz and 7Hz), 7.10 (2H, d, J=8.5Hz), 7.13-7.50 (2H, m), 7.38 (2H, d, J=8.5Hz), 7.63 (1H, s), 8.42 (1H, dd, J=2Hz and 7Hz)
(2) 2-[4-[2-(7-Methylimidazo[1,2-a]pyridin-2- yl)ethyl]phenylamino]-2-thiazoline
mp : 185-136°C
IR (Nujol) : 3240, 3175, 3100, 1630 cm-1
NMR (DMSO-d6, δ) : 2.33 (3H, s), 2.93 (4H, s),
3.28 (2H, t, J=7Hz), 3.93 (2H, t, J=7Hz), 6.67 (1H, dd, J=2Hz and 7Hz), 7.12 (2H, d, J=8Hz), 7.27 (1H, d, J=2Hz), 7.40 (2H, d, J=8Hz), 7.55 (1H, s), 8.33 (1H, d, J=7Hz)
(3) 2-[4-[2-(7-Methoxyimidazo[1,2-a]pyridin-2- yl)ethyl]phenylamino]-2-thiazoline
mp : 180-181°C
IR (Nujol) : 3220, 3165, 3090, 1630 cm-1
NMR (DMSO-d6, δ) : 2.92 (4H, s), 3.28 (2H, t, J=7Hz),
3.32 (3H, s), 3.93 (2H, t, J=7Hz), 6.55 (1H, dd, J=2Hz and 7Hz), 6.88 (1H, d, J=2Hz), 7.13 (2H, d, J=9Hz), 7.41 (2H, d, J=9Hz), 7.47 (1H, s), 8.28 (1H, d, J=7Hz)
(4) 2-[4-[2-(3,7-Dimethylimidazo[1,2-a]pyridin-2- yl)ethyl]phenylamino]-2-thiazoline
mp : 202-203°C
IR (Nujol) : 3240, 3180, 1630 cm-1
NMR (DMSO-d6, δ) : 2.20 (3H, s), 2.33 (3H, s), 2.87 (4H, s), 3.27 (2H, t, J=7Hz), 3.91 (2H, t, J=7Hz), 6.70 (1H, dd, J=1.5Hz and 7Hz), 7.06 (2H, d, J=9Hz), 7.26 (1H, d, J=1.5Hz), 7.36 (2H, d, J=9Hz), 8.03 (1H, d, J=7Hz), 8.78 (1H, br s)
(5) 2-[4-[(7-Methylimidazo[1,2-a]pyridin-2- yl)methoxy]phenylamino]-2-thiazoline
mp : 196-197°C
IR (Nujol) : 1615 cm-1
NMR (DMSO-d6, δ) : 2.33 (3H, s), 3.27 (2H, t, J=7Hz),
3.90 (2H, t, J=7Hz), 5.12 (2H, s), 6.72 (1H, dd, J=1.5Hz and 7Hz), 6.94 (2H, d, J=9Hz), 7.30 (1H, d, J=1.5Hz), 7.38 (2H, d, J=9Hz), 7.85 (1H, s), 8.38 (1H, d, J=7Hz), 8.65 (1H, br s)
(6) 2-[4-[(7-Methylimidazo[1,2-a]pyridin-2- yl)methylthio]phenylamino]-2-thiazoline
mp : 162-163°C
IR (Nujol) : 1625 cm-1
NMR (DMSO-d6, δ) : 2.32 (3H, s), 3.28 (2H, t, J=7Hz),
3.93 (2H, t, J=7Hz), 4.20 (2H, s), 6.67 (1H, dd, J=1.5Hz and 7Hz), 7.25 (1H, d, J=1.5Hz), 7.26 (2H, d, J=9Hz), 7.44 (2H, d, J=9Hz), 7.65 (1H, s), 8.29 (1H, d, J=7Hz)
(7) 2-[4-[2-(3,7-Dimethylimidazo[1,2-a]pyridin-2- yl)ethyl]phenylamino]-2-oxazoline
mp : 206-207°C
IR (Nujol) : 3240, 1675 cm-1
NMR (DMSO-d6, δ) : 2.23 (3H, s), 2.33 (3H, s),
2.88 (4H, s), 3.36-3.45 (2H, m), 3.71-3.88 (2H, m), 6.66 (1H, dd, J=1.5Hz and 7Hz), 6.79 (1H, s), 7.07 (2H, d, J=9Hz), 7.18 (1H, d, J=1.5Hz), 7.39 (2H, d, J=9Hz), 7.97 (1H, d, J=7Hz) (8) 2-[4-[2-(3,7-Dimethylimidazo[1,2-a]pyridin-2-yl)ethyl]- phenylamino]-2-imidazolin-4-one
mp : >250°C
IR (Nujol) : 1680, 1640 cm-1
NMR (DMSO-d6, δ) : 2.24 (3H, s), 2.53 (3H, s),
2.91-3.30 (4H, m), 4.32 (2H, s), 7.19 (1H, dd, J=2Hz and 7Hz), 7.27 (4H, s), 7.49 (1H, d, J=2Hz), 8.13 (1H, d, J=7Hz) (9) 2-[4-[2-(Furan-2-yl)ethyl]phenylamino]-2-thiazoline
IR (Film) : 1635 cm-1
NMR (DMSO-d6, δ) : 2.90 (4H, s), 3.27 (2H, t, J=7Hz), 3.92 (2H, t, J=7Hzi, 6.07 (1H, dd, J=1Hz and 3Hz), 6.33 (1H, dd, J=2Hz and 3Hz), 7.08 (2H, d, J=9Hz), 7.38 (2H, d, J=9Hz), 7.50 (1H, dd, J=1Hz and 2Hz),
8.78 (1H, br s)
(10) 2-[[4-[2-(Diaminomethyleneamino)thiazol-4- yl]methylthio]phenylamino]-2-thiazoline fumarate
mp : 201-202°C
IR (Nujol) : 1670, 1620 cm-1
NMR (DMSO-d6, δ) : 3.30 (2H, t, J=7Hz), 3.95 (2H, t,
J=7Hz), 4.05 (2H, s), 6.62 (2H, s), 7.18-7.62 (9H, m)
(11) 2-[4-[2-(6-Acetamidopyridin-2-yl)ethyl]phenylamino]-2- thiazoline
mp : 168-169°C
IR (Nujol) : 3170, 1700, 1620 cm-1
NMR (DMSO-d6, δ) : 2.12 (3H, s), 2.85-3.15 (4H, m),
3.28 (2H, t, J=7Hz), 3.93 (2H, t, J=7Hz), 6.95 (1H, dd, J=1Hz and 8Hz), 7.08 (2H, d, J=9Hz), 7.39 (2H, d, J=9Hz), 7.67 (1H, t, J=8Hz), 7.95 (1H, dd, J=1Hz and 8Hz), 8.78 (1H, br s), 10.40 (1H, s) (12) 2-[4-[2-(2-Acetamidopyrimidin-4-yl)ethyl]phenylamino]-2- thiazoline
mp : 180-181°C
IR (Nujol) : 1680, 1630 cm-1
NMR (DMSO-d6, δ) : 2.22 (3H, s), 2.93 (4H, s),
3.25 (2H, t, J=7Hz), 3.89 (2H, t, J=7Hz), 6.95 (1H, d, J=5Hz), 7.03 (2H, d, J=8Hz), 7.30 (2H, d,
J=8Hz), 8.41 (1H, d, J=5Hz), 8.70 (1H, br s), 10.2 (1H, br s)
Example 3
A suspension of 2-[4-[2-(7-methylimidazo[1,2-a]pyridin-2-yl)ethyl]phenylamino]-2-thiazoline (0.70 g) and N-chlorosuccinimide (0.29 g) in dichloromethane (10 ml) was stirred at ambient temperature for two hours. After washing with water, the reacting solution was dried over magnesium sulfate and concentrated in vacuo. The residue was
recrystallized from methanol to afford 2-[4-[2-(3-chloro-7-methylimidazo[1,2-a]pyridin-2-yl)ethyl]phenylamino]-2-thiazoline (0.35 g).
mp : 185-186°C
IR (Nujol) : 3260, 3195, 3125, 1635 cm-1
NMR (DMSO-d6, δ) : 2.37 (3H, s), 2.93 (4H, s),
3.26 (2H, t, J=7Hz), 3.90 (2H, t, J=7Hz), 6.83 (1H, dd, J=1.5Hz and 7Hz), 7.00 (2H, d, J=8Hz), 7.27
(2H, d, J=8Hz), 7.30 (1H, d, J=1.5Hz), 8.60 (1H, d, J=7Hz), 8.70 (1H, br s)
Example 4
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
diisopropyl ether to afford 2-[4-[2-(3,7-dimethylimidazo- 11,2-a]pyridin-2-yl)ethyl]phenylamino]-1-pyrroline (0.46 g). mp : 195-196°C
IR (Nujol) : 3300, 1645 cm-1
NMR (DMSO-d6, δ) : 1.62-1.96 (2H, m), 2.20 (3H, s),
2.32 (3H, s), 2.37-2.56 (2H, m), 2.84 (4H, s), 3.55 (2H, t, J=6Hz), 6.66 (1H, dd, J=1Hz and 7Hz), 6.96 (2H, d, J=8Hz), 7.19 (1H, d, J=lHz), 7.39 (2H, d, J=8Hz), 7.97 (1H, d, J=7Hz)
Example 5
A solution of 4-[2-(3,7-dimethylimidazo[1,2-a]pyridin-2-yl)ethyl]phenylthiourea (1.6 g) and methyl iodide (0.31 ml) in methanol (25 ml) was refluxed for two hours. After concentration, ethylenediamine (1 ml) and ethanol (25 ml) were added to the residue and the mixture was refluxed for two hours. The solvent was evaporated in vacuo. The residue was mixed with aqueous potassium carbonate and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated in vacuo to give a residue, which was chromatographed on alumina eluting with chloroform - methanol (20/1) followed by recrystallization for dichloromethane - diisopropyl ether to afford 2-[4-[2-(3,7-dimethylimidazo-[1,2-a]pyridin-2-yl)ethyl]phenylamino]-2-imidazoline
(0.46 g).
mp : 186-187°C
IR (Nujol) : 3425, 1660 cm-1
NMR (DMSO-d6, δ) : 2.27 (3H, s), 2.35 (3H, s),
2.87 (4H, s), 3.33 (4H, s), 5.88 (2H, br s), 6.73 (1H, dd, J=2Hz and 7Hz), 6.91 (2H, d, J=9Hz), 7.06 (2H, d, J=9Hz), 7.25 (1H, d, J=2Hz), 8.04 (1H, d, J=7Hz) Example 6
The following compound was obtained according to a similar manner to that of Example 5.
2-[4-[2-(3,7-Dimethylimidazo[1,2-a]pyridin-2-yl)ethyl]-phenylamino]-1-methyl-2-imidazoline dihydrochloride
mp : 187-188°C
IR (Nujol) : 1640 cm-1
NMR (DMSO-d6, δ) : 2.42 (3H, s), 2.55 (3H, s), 3.13
(3H, s), 3.17 (4H, s), 3.65 (4H, s), 7.32 (4H, s), 7.36 (1H, d, J=7Hz), 7.73 (1H, s), 8.20 (1H, s),
8.61 (1H, d, J=7Hz), 10.33 (1H, s)
Example 7
A solution of 4-[2-(3,7-dimethylimidazo[1,2-a]pyridin-2-yl)ethyl]phenylthiourea (0.62 g) and ethyl chloroacetate
(0.25 g) in N,N-dimethylformamide (10 ml) was stirred at 60°C for 22 hours. After concentration, the residue was mixed with aqueous sodium bicarbonate and extracted with
dichloromethane. The extract was dried over magnesium sulfate and concentrated in vacuo. The residue was
chromatographed on silica gel eluting with chloroform - methanol (20/1) and recrystallized from methanol - tetrahydrofuran to afford 2-[4-[2-(3,7-dimethylimidazo-[1,2-a]pyridin-2-yl)ethyl]phenylamino]-2-thiazolin-4-one (0.27 g).
mp : 257-258°C
IR (Nujol) : 1705, 1630 cm-1
NMR (DMSO-d6, δ) : 2.15 (3H, s), 2.35 (3H, s),
2.92 (4H, s), 3.90 (2H, s), 6.71 (1H, dd, J=2Hz and 7Hz), 7.05-7.67 (6H, m), 7.93 (1H, d, J=7Hz) Example 8
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. The residue was added to saturated aqueous sodium bicarbonate and extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated in vacuo to give a residue, which was chromatographed on silica gel eluting with chloroform - methanol (20/1). The free base obtained was converted to the fumarate in the usual manner, and the salt was recrystallized from ethanol - ether to afford 2-[4-[2-(5-dimethylaminomethylfuran-2-yl)ethyl]phenylamino]-2-thiazoline 3/2
fumarate.
mp : 144-145°C
IR (Nujol) : 1665 cm-1
NMR (DMSO-d6, δ) : 2.43 (6H, s), 2.87 (4H, s),
3.30 (2H, t, J=7Hz), 3.87 (2H, s), 3.93 (2H, t, J=7Hz), 6.04 (1H, d, J=3Hz), 6.38 (1H, d, J=3Hz),
6.61 (3H), 7.10 (2H, d, J=8Hz), 7.38 (2H, d,
J=8Hz), 10.87 (4H, s)
Example 9
A solution of 2-[4-[2-(6-acetamidopyridin-2-yl)ethyl]phenylamino]-2-thiazoline (0.90 g) and concentrated hydrochloride (1.17 ml) in ethanol (18 ml) was refluxed for 7 hours with stirring. After concentration, the residue was added to 20% aqueous potassium carbonate and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated in vacuo. The free base obtained was converted to the dihydrochloride in the usual manner, and the salt was recrystallized from ethanol - diisopropyl ether to afford 2-[4-[2-(6-aminopyridin-2-yl)ethyl]phenylamino]-2- thiazoline (0.71 g).
mp : 215-216°C
IR (Nujol) : 1655, 1630 cm-1
NMR (DMSO-d6, δ) : 3.08 (4H, s), 3.63 (2H, t, J=6Hz), 4.00 (2H, t, J=6Hz), 6.68-7.02 (2H, m), 7.23-7.55 (4H, m), 7.72-8.18 (4H, m)
Example 10
The following compound was prepared according to a similar manner to that of Example 9.
2-[4-[2-(2-Aminopyrimidin-4-yl)ethyl]phenylamino]-2-thiazoline
mp : 218-219°C
IR (Nujol) : 3310, 3120, 1630 cm-1
NMR (DMSO-d-: δ) : 2.79 (4H, s), 3.25 (2H, t, J=7Hz),
3.89 (2H, t, J=7Hz), 6.39 (1H, d, J=5Hz), 6.42 (2H, s), 7.02 (2H, d, J=9Hz), 7.27 (2H, d, J=9Hz), 8.03 (1H, d, J=5Hz), 8.45 (1H, br s) Example 11
A solution of 1-(3-aminophenyl)methylpyrrolidine (0.35 g), 2-methylthio-2-thiazoline (0.27 g) and cone, hydrochloric acid (0.18 ml) in 2-methoxyethanol (5 ml) was stirred at 100°C for 8 hours. After concentration in vacuo, the residue was mixed with 20% aqueous potassium carbonate and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated in vacuo. The free base obtained was converted to dioxalate in a usual manner and the salt was recrystallized from methanol-acetone-diisopropyl ether to afford 2-[3-(pyrrolidin-1-ylmethyl)phenylamino]-2-thiazoline dioxalate (0.48 g).
mp : 195-196°C
IR (Nujol) : 1665, 1610 cm-1
NMR (DMSO-d6, δ) : 1.92 (4H, s), 3.19 (4H, s), 3.31 (2H, t, J=7Hz), 3.89 (2H, t, J=7Hz), 4.26 (2H, s),
7.11 (1H, d, J=7Hz), 7.27-7.34 (2H, m), 7.57 (1H, s)
Example 12
The following compounds were prepared according to a similar manner to that of Example 11.
(1) 2-[4-(Pyrrolidin-1-ylmethyl)phenylamino]-2-thiazoline dioxalate
NMR (DMSO-d6, δ) : 1.92 (4H, s), 3.17 (4H, s), 3.30
(2H, t, J=7.5Hz), 3.94 (2H, t, J=7.5Hz), 4.22 (2H, s), 7.37 (2H, d, J=8.5Hz), 7.48 (2H, d, J=8.5Hz)
(2) 2-[3-(Imidazol-2-ylthiomethyl)phenylamino]-2-thiazoline dihydrochloride
NMR (DMSO-d6, δ) : 3.60 (2H, t, J=7Hz), 3.97 (2H, t,
J=7Hz), 4.71 (2H, s), 7.24-7.45 (4H, m), 7.67 (2H, s) (3) 2-[3-(2-Methylimidazol-1-ylmethyl)phenylamino]-2- thiazoline
mp : 190-191°C
IR (Nujol) : 1620 cm-1
NMR (DMSO-d6, δ) : 2.29 (3H, s), 3.26 (2H, t, J=7Hz), 3.88 (2H, t, J=7Hz), 5.13 (2H, s), 6.70 (1H, d,
J=7.5Hz), 6.92 (1H, s), 7.17-7.25 (3H, m), 7.34 (1H, br s)
(4) 2-[4-[2-(2-Acetylaminothiazol-4-yl)ethyl]phenylamino]-2- thiazoline mp : 215-216°C
IR (Nujol) : 3150, 1675, 1620 cm-1
NMR (DMSO-d6, δ) : 2.11 (3H, s), 2.84 (4H, s), 3.26
(2H, t, J=7.4Hz), 3.91 (2H, br s), 6.71 (1H, s), 7.03-7.07 (2H, m), 7.20-7.60 (3H, m), 12.00-12.50
(1H, m)
Anal. Calcd. for C16H18N4OS2 : C 55.47, H 5.24, N 16.17
Found : C 55.20, H 5.22, N 15.90 (5) 2-[4-[2-(Morpholin-4-yl)ethyl]phenylamino]-2-thiazoline mp : 137-138°C
IR (Nujol) : 3370, 1630, 1590 cm-1
NMR (DMSO-d6, δ) : 2.37-2.46 (6H, m), 2.61-2.68 (2H, m), 3.26 (2H, t, J=7.4Hz), 3.56 (4H, t, J=4.6Hz), 3.90 (2H, br s), 7.07 (2H, d, J=8.4Hz), 7.34 (2H, br s), 9.05 (1H, br)
(6) 2-[4-[2-(4-Acetylpiperazin-1-yl)ethyl]phenylamino]-2- thiazoline
mp : 162-163°C
IR (Nujol) : 3400, 1640, 1620, 1590 cm-1
NMR (DMSO-d6, δ) : 1.98 (3H, si, 2.36-2.44 (6H, m),
2.60-2.75 (2H, m), 3.26 (2H, t, J=7.5Hz), 3.35-3.45 (4H, m), 3.96 (2H, br), 7.07 (2H, d, J=8.4Hz), 7.45 (2H, br), 9.15 (1H, br)
Example 13
A solution of bromine (0.69 g) in acetonitrile (2 ml) was added dropwise to a solution of 2-(3-acetylphenylamino)-2-thiazoline hydrochloride (1.1 g) in methanol (10 ml) - dioxane (10 ml) at ambient temperature. After being stirred for one hour, the mixture was added to a suspension of thiourea (0.33 g) in ethanol (10 ml) and the whole mixture was refluxed for 6 hours. The resulting precipitate was collected by filtration and dissolved with water. The solution was basified with 20% potassium carbonate and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated in vacuo to give a
residue. The free base was converted to dihydrochloride in a usual manner and the salt obtained was recrystallized from acetone-ethyl acetate to afford 2-[3-(2-aminothiazol-4- yl)phenylamino]-2-thiazoline dihydrochloride (0.50 g).
mp : >250°C
IR (Nujol) : 3300, 1625 cm-1
NMR (DMSO-d6, δ) : 3.61 (2H, t, J=7.5Hz), 3.99 (2H, t,
J=7.5Hz), 7.29 (1H, s), 7.34 (1H, d, J=8.5Hz), 7.57 (1H, t, J=8.5Hz), 7.81 (1H, d, J=8.5Hz), 7.82 (1H, s) Example 14
2-[4-[3-(2-Acetylaminothiazol-4-yl)propyl]phenylamino]-2-thiazoline was obtained from 2-acetylamino-4-[3-(4-nitrophenyl)propyl]thiazole according to a similar manner to that of Preparation 10 and then Example 11.
mp : 190-191°C
IR (Nujol) : 3120, 1620, 1600 cm-1
NMR (DMSO-d6, δ) : 1.80-1.93 (2H, m), 2.10 (3H, s),
2.50-2.61 (4H, m), 3.26 (2H, t, J=7.3Hz), 3.90 (2H, br s), 6.74 (1H, s), 7.05 (2H, d, J=8.3Hz), 7.45 (2H, br s), 12.01 (1H, br s)
Anal. Calcd. for C17H20N4OS2 : C 56.64, H 5.59, N 15.54
Found : C 56.54, H 5.79, N 15.24
Example 15
A mixture of 2-[4-[2-(2-acetylaminothiazol-4-yl)ethyl]phenylamino]-2-thiazoline (1.0 g) and 6N
hydrochloric acid (30 ml) was refluxed for 18 hours. The mixture was adjusted to pH 13.0 with potassium hydroxide and then was extracted with a mixture of ethyl acetate (70 ml) and tetrahydrofuran (70 ml). The extract was dried over magnesium sulfate. The solvent was removed under reduced pressure. Recrystallization from a mixture of ethyl acetate and diisopropyl ether afford 2-[4-[2-(2-aminothiazol-4-yl)ethyl]phenylamino]-2-thiazoline (400 mg).
mp : 158-159°C
IR (Nujol) : 3420, 1620 cm-1
NMR (DMSO-d6, δ) : 2.55-2.70 (2H, m), 2.70-2.85 (2H, m), 3.26 (2H, t, J=7.4Hz), 3.92 (2H, br s), 6.09 (1H, s), 6.81 (2H, s), 7.05 (2H, d, J=8.3Hz), 7.35 (2H, br s)
Example 16
2-[4-(2-Piperazin-1-ylethyl)phenylamino]-2-thiazoline was obtained according to a similar manner to that of Example 15.
mp : 105-106°C
IR (Nujol) : 3240, 1630, 1600 cm-1
NMR (DMSO-d6, δ) : 2.32-2.44 (6H, m), 2.59-2.69 (6H, m), 3.26 (2H, t, J=7.2Hz), 3.80-4.00 (2H, m), 7.06 (2H, d, J=8.3Hz), 7.20-7.50 (2H, m)

Claims

C L A I M S
1. A compound of the formula :
Figure imgf000039_0001
wherein R1 is heterocyclic group,
X is (CH2)a in which a is 0 or 1, O or S,
Y is CH2, O, S or N-R2
in which R2 is hydrogen or lower alkyl,
Z is O or H2, and
m and n are each 0 or 1,
and pharmaceutically acceptable salts thereof.
2. A compound of claim 1, wherein
R1 is pyridyl having amino, pyridyl having lower
alkanoylamino, pyrimidinyl having amino,
pyrimidinyl having lower alkanoylamino, furyl, furyl having N,N-di(lower)alkylaminomethyl, thiazolyl having diaminomethyleneamino, thiazolyl having amino, thiazolyl having lower alkanoylamino, pyrrolidinyl, morpholinyl, piperazinyl, piperazinyl having lower alkanoyl, imidazolyl, imidazolyl having lower alkyl, and imidazopyridyl which may have one to two substituent(s) selected from the group consisting of lower alkyl, lower alkoxy and halogen.
3. A compound of claim 2, wherein
R1 is 6-amino-2-pyridyl, 6-acetamido-2-pyridyl,
2-amino-4-pyrimidinyl, 2-acetamido-4-pyrimidinyl, 2-furyl, 5-dimethylaminomethyl-2-furyl,
2-diaminomethyleneamino-4-thiazolyl, 2-amino-4- thiazolyl, 2-acetamido-4-thiazolyl, 1-pyrrolidinyl, morpholino, 1-piperazinyl, 4-acetyl-1-piperazinyl, 2-imidazolyl, 2-methyl-1-imidazolyl, imidazo- [1,2-a]pyridin-2-yl, 7-methylimidazo[1,2-a]pyridin- 2-yl, 7-methoxyimidazo[1,2-a]pyridin-2-yl,
3,7-dimethylimidazo[1,2-a]pyridin-2-yl, and 3-chloro-7-methylimidazo[1,2-a]pyridin-2-yl.
4. A process for preparing a compound of the formula :
Figure imgf000040_0001
wherein R1 is heterocyclic group,
X is (CH2)a in which a is 0 or 1, O or S,
Y is CH2, O, S or N-R2
in which R2 is hydrogen or lower alkyl,
Z is O or H2, and
m and n are each 0 or 1,
or pharmaceutically acceptable salts thereof,
(1) reacting a compound of the formula :
Figure imgf000041_0001
wherein R1, X, m and n are each as defined above, or a salt thereof, with a compound of the formula :
Figure imgf000041_0002
wherein Y and Z are each as defined above, and
R3 is lower alkylthio or halogen,
or a salt thereof, to give a compound of the formula :
Figure imgf000041_0003
wherein R1, X, Y, Z, m and n are each as defined above, or a salt thereof, or
(2) reacting a compound of the formula :
Figure imgf000042_0001
wherein R1, X, m and n are each as defined above, or a salt thereof, with a compound of the formula : R4 - W1 wherein R4 is lower alkyl, and
W1 is halogen,
or a salt thereof, to give a compound of the formula :
Figure imgf000042_0002
wherein R1, R4, X, m and n are each as defined above, or a salt thereof, and continuously reacting it with a compound of the formula :
H2NCH2CH2NHR2 wherein R2 is as defined above,
or a salt thereof, to give a compound of the formula :
Figure imgf000043_0001
wherein R1, R2, X, m and n are each as defined above, or a salt thereof, or
(3) reacting a compound of the formula :
Figure imgf000043_0002
wherein R1, X, m and n are each as defined above, or a salt thereof, with a compound of the formula :
W2CH2COOR5 wherein R5 is lower alkyl, and
W2 is halogen,
or a salt thereof, to give a compound of the formula :
Figure imgf000043_0003
wherein R1, X, m and n are each as defined above, or a salt thereof, or (4) reacting a compound of the formula :
Figure imgf000044_0001
wherein X, Y, Z, m and n are each as defined above, or a salt thereof, with a compound of the formula :
Figure imgf000044_0002
wherein R6 and R7 are each lower alkyl,
or a salt thereof and with formalin, to give a compound of the formula :
Figure imgf000044_0003
wherein R6, R7, X, Y, Z, m and n are each as defined above,
or a salt thereof, or
(5) subjecting a compound of the formula :
Figure imgf000045_0001
wherein X, Y, Z, m and n are each as defined above, and
R1 a is heterocyclic group having acylamino, or a salt thereof, to deacylation, to give a compound of the formula :
Figure imgf000045_0002
wherein X, Y, Z, m and n are each as defined above, and
R1 b is heterocyclic group having amino, or a salt thereof, or
(6) subjecting a compound of the formula :
Figure imgf000046_0001
wherein X, Y, Z, m and n are each as defined above, and
R8 is acyl,
or a salt t thereof, to deacylation, to give a compound of the formula :
Figure imgf000046_0002
wherein X, Y, Z, m and n are each as defined above, or a salt thereof, or
(7) reacting a compound of the formula :
Figure imgf000047_0001
wherein Y and Z are each as defined above, and
W3 is halogen,
or a salt thereof, with thiourea,
to give a compound of the formula :
Figure imgf000047_0002
wherein Y and Z are each as defined above,
or a salt thereof.
5. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or a
pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers.
6. A method for the treatment of ulcer which comprises administering a compound of claim 1 or a
pharmaceutically acceptable salt thereof to human or animals.
7. A use of a compound of claim 1 as a medicament.
8. A use of a compound of claim 1 or a pharmaceutically
acceptable salt thereof as a medicament for prophylactic and therapeutic treatment of NOS-mediated diseases.
PCT/JP1996/000776 1995-03-27 1996-03-26 Amidine derivatives Ceased WO1996030350A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP8529162A JPH11503121A (en) 1995-03-27 1996-03-26 Amidine derivative
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

Publications (1)

Publication Number Publication Date
WO1996030350A1 true WO1996030350A1 (en) 1996-10-03

Family

ID=10771947

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1996/000776 Ceased WO1996030350A1 (en) 1995-03-27 1996-03-26 Amidine derivatives

Country Status (4)

Country Link
JP (1) JPH11503121A (en)
AU (1) AU5015596A (en)
GB (1) GB9506188D0 (en)
WO (1) WO1996030350A1 (en)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997045417A1 (en) * 1996-05-25 1997-12-04 Wivenhoe Technology Limited Cytokine production inhibitors, formulations thereof and their use in medicine, and methods for their identification
EP0902018A2 (en) 1997-09-04 1999-03-17 F. Hoffmann-La Roche Ag 2-(Arylphenyl)amino-imidazoline derivatives
FR2780971A1 (en) * 1998-07-08 2000-01-14 Sod Conseils Rech Applic NOVEL 2-AMINOPYRIDINE DERIVATIVES, THEIR APPLICATION AS MEDICAMENTS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
WO2000002860A1 (en) * 1998-07-08 2000-01-20 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) 2-aminopyridine erivatives, their use as medicines and pharmaceutical compositions containing them
FR2791674A1 (en) * 1999-04-02 2000-10-06 Sod Conseils Rech Applic NOVEL 2-AMINOPYRIDINE DERIVATIVES, THEIR USE AS MEDICAMENTS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
US6184242B1 (en) 1997-09-04 2001-02-06 Syntex Usa (Llc) 2-(substituted-phenyl)amino-imidazoline derivatives
WO2002040453A1 (en) * 2000-11-14 2002-05-23 F. Hoffmann-La Roche Ag Substituted 2-phenylaminoimidazoline phenyl ketone derivatives as ip antagonists
WO2004067521A1 (en) * 2003-01-27 2004-08-12 Astellas Pharma Inc. Thiazole derivatives and their use as vap-1 inhibitors
WO2005005394A3 (en) * 2003-07-09 2005-03-31 Hoffmann La Roche Thiophenylaminoimidazolines as prostaglandin i2 antagonists
WO2006011631A3 (en) * 2004-07-27 2006-04-20 Astellas Pharma Inc Thiazole derivatives having vap-1 inhibitory activity
EP1981343A4 (en) * 2006-01-17 2010-12-15 Stiefel Laboratories Treatment of inflammatory disorders with triazole compounds

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19948434A1 (en) * 1999-10-08 2001-06-07 Gruenenthal Gmbh Substance library containing bicyclic imidazo-5-amines and / or bicyclic imidazo-3-amines
WO2016043260A1 (en) * 2014-09-19 2016-03-24 塩野義製薬株式会社 Cyclic guanidine or amidine compound

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0279398A1 (en) * 1987-02-17 1988-08-24 Merrell Dow Pharmaceuticals Inc. Antifungal 2-anilinothiazolines
US5066664A (en) * 1990-02-28 1991-11-19 Allergan, Inc. 2-(hydroxy-2-alkylphenylamino)-oxazolines and thiazolines as anti-glaucoma and vasoconstrictive agents
WO1994012165A2 (en) * 1992-11-27 1994-06-09 The Wellcome Foundation Limited Enzyme inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0279398A1 (en) * 1987-02-17 1988-08-24 Merrell Dow Pharmaceuticals Inc. Antifungal 2-anilinothiazolines
US5066664A (en) * 1990-02-28 1991-11-19 Allergan, Inc. 2-(hydroxy-2-alkylphenylamino)-oxazolines and thiazolines as anti-glaucoma and vasoconstrictive agents
WO1994012165A2 (en) * 1992-11-27 1994-06-09 The Wellcome Foundation Limited Enzyme inhibitors

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997045417A1 (en) * 1996-05-25 1997-12-04 Wivenhoe Technology Limited Cytokine production inhibitors, formulations thereof and their use in medicine, and methods for their identification
CN1110484C (en) * 1997-09-04 2003-06-04 弗·哈夫曼-拉罗切有限公司 2-(arylphenyl) amino-imidazoline derivatives
US6693200B2 (en) 1997-09-04 2004-02-17 Syntex (U.S.A.) Llc 2-(substituted-phenyl)amino-imidazoline derivatives
US7141584B2 (en) 1997-09-04 2006-11-28 Roche Palo Alto Llc 2-(substituted-phenyl)amino-imidazoline derivatives
EP0902018A2 (en) 1997-09-04 1999-03-17 F. Hoffmann-La Roche Ag 2-(Arylphenyl)amino-imidazoline derivatives
US6184242B1 (en) 1997-09-04 2001-02-06 Syntex Usa (Llc) 2-(substituted-phenyl)amino-imidazoline derivatives
EP0902018A3 (en) * 1997-09-04 2001-05-02 F. Hoffmann-La Roche Ag 2-(Arylphenyl)amino-imidazoline derivatives
AU746480B2 (en) * 1997-09-04 2002-05-02 F. Hoffmann-La Roche Ag 2-(arylphenyl)amino-imidazoline derivatives
US6596876B2 (en) 1997-09-04 2003-07-22 Syntex (U.S.A.) Llc 2-(substituted-phenyl)amino-imidazoline derivatives
US6472536B1 (en) 1997-09-04 2002-10-29 Syntex (U.S.A.) Llc 2-(substituted-phenyl)amino-imidazoline derivatives
WO2000002860A1 (en) * 1998-07-08 2000-01-20 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) 2-aminopyridine erivatives, their use as medicines and pharmaceutical compositions containing them
FR2780971A1 (en) * 1998-07-08 2000-01-14 Sod Conseils Rech Applic NOVEL 2-AMINOPYRIDINE DERIVATIVES, THEIR APPLICATION AS MEDICAMENTS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
CZ299818B6 (en) * 1998-07-08 2008-12-03 Societe De Conseils De Recherches Et D'applications Scientifiques (S. C. R. A. S.) Derivatives of 2-aminopyridines, pharmaceutical composition containing such derivatives and their use as medicaments
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 (en) * 1999-04-02 2000-10-06 Sod Conseils Rech Applic NOVEL 2-AMINOPYRIDINE DERIVATIVES, THEIR USE AS MEDICAMENTS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
WO2002040453A1 (en) * 2000-11-14 2002-05-23 F. Hoffmann-La Roche Ag Substituted 2-phenylaminoimidazoline phenyl ketone derivatives as ip antagonists
RU2284995C2 (en) * 2000-11-14 2006-10-10 Ф.Хоффманн-Ля Рош Аг Substituted derivatives of 2-phenylaminoimidazoline phenylketone as ip antagonists
WO2004067521A1 (en) * 2003-01-27 2004-08-12 Astellas Pharma Inc. Thiazole derivatives and their use as vap-1 inhibitors
US7125901B2 (en) * 2003-01-27 2006-10-24 Astellas Pharma Inc. Thiazole derivatives
US7442715B2 (en) 2003-01-27 2008-10-28 Astellas Pharma Inc. Thiazole derivatives
WO2005005394A3 (en) * 2003-07-09 2005-03-31 Hoffmann La Roche Thiophenylaminoimidazolines as prostaglandin i2 antagonists
WO2006011631A3 (en) * 2004-07-27 2006-04-20 Astellas Pharma Inc Thiazole derivatives having vap-1 inhibitory activity
EP1981343A4 (en) * 2006-01-17 2010-12-15 Stiefel Laboratories Treatment of inflammatory disorders with triazole compounds

Also Published As

Publication number Publication date
AU5015596A (en) 1996-10-16
GB9506188D0 (en) 1995-05-17
JPH11503121A (en) 1999-03-23

Similar Documents

Publication Publication Date Title
JP6726226B2 (en) Heterocyclic amines and uses thereof
AU2003298693B2 (en) Novel chemical compounds
AU2007235237B2 (en) Thiazoles, imidazoles, and pyrazoles useful as inhibitors of protein kinases
DE69430988T2 (en) PYRAZOLOTRIAZINE WITH INTERLEUKIN-1 AND TUMOR NECROSIS FACTOR INHIBITOR EFFECT
CA2167673C (en) Condensed benzazepine derivative and pharmaceutical composition thereof
FI96857C (en) Process for the preparation of a pharmacologically useful thiazole compound
CN106061947B (en) Cyclohexylsulfone RORγ modulator
EP2300466B1 (en) Imidazopyridine and imidazopyrazine compounds useful as kinase inhibitors
JP7688000B2 (en) Spiroquinoxaline derivatives as inhibitors of non-apoptotic regulated cell death
US20060079536A1 (en) Calcium receptor modulating compound and use thereof
US4742057A (en) Antiallergic thiazole compounds
AU6143899A (en) Fused pyridine inhibitors of cgmp phosphodiesterase
WO2005048953A2 (en) Amide derivatives as kinase modulators
NZ563866A (en) Thiazole compounds and methods of use
WO2009010871A2 (en) Pyrazole derivatives as antagonists of adenosine a3 receptor
AU2005264002A1 (en) Imidazole and thiazole derivatives as antiviral agents
WO1996030350A1 (en) Amidine derivatives
AU2013358591A1 (en) Pyrimido [4,5-b]quinoline-4,5 (3H,10H)-diones as nonsense mutation suppressors
WO2016075137A1 (en) Spiropyrazine derivatives as inhibitors of non-apoptotic regulated cell-death
CA3108076A1 (en) Muscarinic acetylcholine m1 receptor antagonists
WO1996030370A2 (en) Thiazole and thiadiazole derivatives, their preparation and pharmaceutical compositions useful in the treatment of thrombocytopenia
WO2018039518A1 (en) Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
CA2950724A1 (en) Naphthyridinedione derivatives
JP2022552158A (en) Indazole carboxamides as kinase inhibitors
CA2012716A1 (en) Thiazole compounds, processes for the preparation thereof and pharmaceutical composition comprising the same

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA CN HU JP KR MX NO NZ US AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
ENP Entry into the national phase

Ref country code: JP

Ref document number: 1996 529162

Kind code of ref document: A

Format of ref document f/p: F

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA