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WO1996005187A1 - (4-(3-aminomethylphenyl)thiazol-2-yl)-guanidines as h2-receptor antagonists - Google Patents

(4-(3-aminomethylphenyl)thiazol-2-yl)-guanidines as h2-receptor antagonists Download PDF

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Publication number
WO1996005187A1
WO1996005187A1 PCT/JP1995/001596 JP9501596W WO9605187A1 WO 1996005187 A1 WO1996005187 A1 WO 1996005187A1 JP 9501596 W JP9501596 W JP 9501596W WO 9605187 A1 WO9605187 A1 WO 9605187A1
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Prior art keywords
alkyl
compound
phenyl
alkoxy
salt
Prior art date
Application number
PCT/JP1995/001596
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French (fr)
Inventor
Yousuke Katsura
Tetsuo Tomishi
Shigetaka Nishino
Mitsuko Ohno
Original Assignee
Fujisawa Pharmaceutical Co., Ltd.
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Publication date
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to JP8507193A priority Critical patent/JP2000504305A/en
Priority to AU31929/95A priority patent/AU3192995A/en
Publication of WO1996005187A1 publication Critical patent/WO1996005187A1/en

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    • 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
    • C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to NEW COMPOUNDS and pharmaceutically acceptable salts thereof which are useful as a medicament.
  • This invention relates to new compounds and pharmaceutically acceptable salts thereof.
  • One object of this invention is to provide new thiazole derivatives and pharmaceutically acceptable salts thereof which possess antiulcer activity, r ⁇ -receptor antagonism and antimicrobial activity against pathogenic microorganisms such as Helicobacter pylori.
  • Another object of this invention is to provide processes for the preparation of said thiazole derivatives and salt thereof.
  • a further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said thiazole derivatives of pharmaceutically acceptable salts thereof.
  • Still further object of this invention is to provide a method for the prophylactic or therapeutic treatment of ulcer in human being or animals.
  • the thiazole derivatives of this invention are new and can be represented by the following general formula (I) :
  • R 1 is lower alkoxy, lower alkoxy(lower) alkyl, cyano (lower)alkyl, phenyl, phenyl (lower)alkyl,
  • R is hydrogen, lower alkanoyl or carbamoyl.
  • the object compound (I) or a salt thereof can be prepared by processes as illustrated in the following reaction schemes.
  • R and R 2 are each as defined above, R 3 is lower alkyl, and X is a leaving group.
  • 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, hydriodide, sulfate, phosphate, etc.) ; an organic carboxylic or sulfonic acid addition salt (e.g., formate, acetate, trifluor
  • lower is used to intend a group having 1 to 6 carbon atom(s), unless otherwise provided.
  • lower alkyl and “lower alkyl moiety” in the terms “lower alkoxy (lower) alkyl", “cyano (lower) alkyl”, “phenyl (lower) alkyl”, “ [2- (lower) alkoxyphenyl] (lower) - alkyl”, “diphenyl (lower) alkyl”, “phenoxy(lower) alkyl”, “phenyl (lower) alkoxy(lower) alkyl”,
  • cyclo (lower) alkenyl (lower) alkyl 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 C -C ⁇ alkyl.
  • lower alkoxy and “lower alkoxy moiety” in the terms” lower alkoxy (lower) alkyl", “ [2- (lower) alkoxyphenyl] (lower) alkyl” and
  • phenyl (lower) alkoxy (lower) alkyl may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like.
  • Suitable "cyclo (lower) alkenyl moiety" in the term “cyclo (lower) alkenyl (lower) alkyl” may include cyclohexenyl, cyclohexadienyl and the like.
  • Suitable "halogen” may include fluorine, bromine, chlorine and iodine.
  • Suitable “leaving group” may include acid residue, lower alkoxy as exemplified above, and the like.
  • Suitable "acid residue” may include halogen as exemplified above, acyloxy and the like.
  • Suitable “protected amino” may include acylamino or an amino group substituted by a conventional protecting group such as mono (or di or tri) aryl (lower) alkyl, for example, mono (or di or tri)phenyl (lower) alkyl (e.g., benzyl, trityl, etc. ) or the like.
  • a conventional protecting group such as mono (or di or tri) aryl (lower) alkyl, for example, mono (or di or tri)phenyl (lower) alkyl (e.g., benzyl, trityl, etc. ) or the like.
  • acyl and “acyl moiety” in the terms “acylammo” and “acyloxy” may include carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, w ⁇ ich is referred to as aromatic acyl, or heterocyclic ring, which is referred to as heterocyclic acyl.
  • Suitable example of said acyl may be illustrated as follows :
  • Aliphatic acyl such as lower or higher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2, 2-d ⁇ methylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyi, etc.
  • alkanoyl e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2, 2-d ⁇ methylpropanoyl
  • lower or higher alkoxycarbonyl e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.
  • lower or higher alkylsulfonyl e.g., methylsulfonyl, ethylsulfonyl, etc.
  • lower or higher alkoxysulfonyl e.g., methoxysulfonyl, ethoxysulfonyl, etc.
  • cyclo (lower) alkylcarbonyl e.g., cyclopentylcarbonyl, cyclohexylcarbonyl, etc.
  • Aromatic acyl such as aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.); ar (lower) alkanoyl [e.g., phenyl (lower) alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpent
  • heterocyclic acyl such as heterocycliccarbonyl; heterocyclic(lower)alkanoyl (e.g., heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl, heterocyclichexanoyl, etc.); heterocyclic (lower) alkenoyl (e.g., heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl, etc.); heterocyclicglyoxyloyl; or the like; in which suitable "heterocyclic moiety" in the terms "heterocycliccarbonyl", “heterocyclic(lower) alkanoyl", heterocyclic(lower) alkeno
  • 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, pyrrolmyl, lmidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1, 2, -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, pyrrolidiny
  • Suitable "lower alkanoyl” may include for yl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2- dimethylpropanoyl, hexanoyl and the like.
  • object compound (I) may include one or more stereoisomer (s) due to asymmetric carbon atom(s) and double bond(s) and all such isomers and mixture thereof are included within the scope of this invention.
  • the tautomeric forms of the object compound (I) are clearly included within the scope of the present invention.
  • the object and starting compounds including the group of such tautomeric isomers are represented by using one of the expressions therefor, that is the formula :
  • the 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 solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N, -dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N, -dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • the reaction temperature is not critical and the reaction is usually carried out under warming to heating.
  • the starting compound when in liquid, it can be used also as a solvent.
  • the compound (I) 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 solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • the reaction temperature is not critical and the reaction is usually carried out under warming to heating.
  • the reaction may be also carried out in the presence of an inorganic or an organic base such as an alkali metal (e.g., sodium, potassium, etc.), an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), an alkali metal hydrogencarbonate (e.g., sodium hydrogencarbonate, potassium hydrogencarbonate, etc.j, alkali metal carbonate (e.g.
  • an alkali metal e.g., sodium, potassium, etc.
  • an alkali metal hydroxide e.g., sodium hydroxide, potassium hydroxide, etc.
  • an alkali metal hydrogencarbonate e.g., sodium hydrogencarbonate, potassium hydrogencarbonate, etc.j
  • alkali metal carbonate e.g.
  • alkali metal hydride e.g., sodium hydride, etc.
  • alkali metal (lower) alkoxide e.g. sodium methoxide, sodium ethoxide, etc.
  • pyridme lutidine, picoline, dimethylaminopyridine, N- (lower) alkylmorpholme, N,N- di (lower) alkylbenzylamme, N,N-di (lower) alkylaniline or the like.
  • the new thiazole derivatives (I) and pharmaceutically acceptable salts thereof possess antiulcer activity, H 2 ⁇ receptor antagonism, and especially antimicrobial activity against pathogenic microorganisms such as Helicobacter pylori, and are useful for a prophylactic or therapeutic treatment of gastritis, ulcer (e.g. gastric ulcer, duodenal ulcer, anastomotic ulcer, etc.), Zollmger-Ellison Syndrome, reflux esophagitis, upper gastrointestinal bleeding, and the like.
  • Test A H 2 -receptor antagonism in isolated guinea-pig atrium
  • the atrial strip isolated from guinea-pig was suspended under an initial tension 0.3 to 0.6 g in an organ bath containing Tyrode solution at 30°C, aerated 95% 0 2 -
  • the beating rate and amplitude of contraction of the atrium were recorded by means of a transducer and a polygraph. Histamine (1 x 10 ⁇ 6 g/ml) was added to the bathing fluid and the increase in beating rate after dosing was measured. Addition of test compound (1 x 10 -6 g/ml) was made 30 minutes after washing out histamine. Inhibitory effect of test compound was calculated by comparing histamine-induced increases in beating rate before and 30 minutes after dosing with the test compound.
  • Test B in vitro Antimicrobial Activities
  • Incubation was carried out in an atmosphere of 10 r a co 2 .
  • MIC was read after incubation as the lowest Test compound concentration that inhibited macroscopic colonial growth. The data shown below are mean MIC against clinical isolated.
  • the object compound (I) or its pharmaceutically acceptable salts can usually be administered to mammals including human being in the form of a conventional pharmaceutical composition such as oral dosage form (e.g., capsule, micro-capsule, tablet, granule, powder, troche, syrup, aerosol, inhalation, suspension, emulsion, etc.), injection dosage form or suppository, or the like.
  • oral dosage form e.g., capsule, micro-capsule, tablet, granule, powder, troche, syrup, aerosol, inhalation, suspension, emulsion, etc.
  • injection dosage form or suppository or the like.
  • the pharmaceutical composition of this invention can contain various organic or inorganic carrier materials, which are conventional used for pharmaceutical purpose, such as excipient (e.g. sucrose, starch, mannit, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, etc.), binding agent (e.g. cellulose, methyl cellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose, starch, etc.), disintegrator (e.g.
  • excipient e.g. sucrose, starch, mannit, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, etc.
  • binding agent e.g. cellulose, methyl cellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose, starch, etc.
  • disintegrator e.g
  • starch carboxymethyl cellulose, calcium salt of carboxymethyl cellulose, hydroxypropylstarch, sodium glycole-starch, sodium bicarbonate, calcium phosphate, calcium citrate, etc.), lubricant (e.g. magnesium stearate, talc, sodium laurylsulfate, etc.), flavoring agent (e.g. citric acid, menthol, glycine, orange powders, etc.), preservative (e.g. sodium benzoate, sodium bisulfite, methylparaben, propylparaben, etc.), stabilizer (e.g. citric acid, sodium citrate, acetic acid, etc.), suspending agent (e.g.
  • methyl cellulose methyl cellulose, polyvinylpyrrolidone, aluminum stearate, etc.
  • dispersing agent e.g. water
  • aqueous diluting agent e.g. water
  • base wax e.g. cacao butter, polyethyleneglycol, white petrolatum, etc.
  • the dosage of the compound (I) will vary depending upon the age and condition of the patient, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg,
  • 100 mg, 250 mg, 500 mg and 1000 mg of the compound (I) may be effective for treating ulcer.
  • amounts between 0.1 g/body and about 1,000 mg/body may be administered per day.
  • Preferred embodiments of the object compound (I) are as follows.
  • R 1 is lower alkoxy, ethoxy(lower) alkyl, cyano (lower) alkyl, phenyl, phenyl (lower) alkyl,
  • Example 7 A solution of 3- (acetylaminomethyl) acetophenone (700 mg) and bromine (610 mg) in dioxane (10 ml) was stirred at room temperature for 5 hours. Methanol (20 ml), [ (phenylamino) (aminomethylene] thiourea (700 mg) and potassium carbonate (l.llg) were added to the reaction mixture. The mixture was heated at 55°C for 2 hours. The solvent was removed under reduced pressureand the residue was dissolved in a mixtue of water (60 ml) and tetrahydrofuran (40 ml) . The mixture was adjusted to pH 10 with 30% potassium carbonate solution and then was. extracted with ethyl acetate (150 ml) .

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Abstract

New compounds of formula (I), wherein R1 is lower alkoxy, lower alkoxy(lower)alkyl, cyano(lower)alkyl, phenyl, phenyl(lower)alkyl, [2-(lower)alkoxyphenyl] (lower)alkyl, diphenyl(lower)alkyl, phenoxy(lower)alkyl, phenyl(lower)alkoxy(lower)alkyl, cyclo(lower)alkenyl(lower)alkyl, protected amino(lower)alkyl or adamantyloxy(lower)alkyl, and R2 is hydrogen, lower alkanoyl or carbamoyl, and a pharmaceutically acceptable salt thereof which are useful as a medicament.

Description

(4-(3-AMIN0METHYLPHENYL)THIAZ0L-2-YL)-GUANIDINES AS
H2-RECEPT0R ANTIGONISTS
TECHNICAL FIELD
This invention relates to NEW COMPOUNDS and pharmaceutically acceptable salts thereof which are useful as a medicament.
BACKGROUND ART
Some thiazole derivatives have been known as described, for example, in EP 0 545 376 Al .
DISCLOSURE OF INVENTION This invention relates to new compounds and pharmaceutically acceptable salts thereof.
One object of this invention is to provide new thiazole derivatives and pharmaceutically acceptable salts thereof which possess antiulcer activity, r^-receptor antagonism and antimicrobial activity against pathogenic microorganisms such as Helicobacter pylori.
Another object of this invention is to provide processes for the preparation of said thiazole derivatives and salt thereof. A further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said thiazole derivatives of pharmaceutically acceptable salts thereof.
Still further object of this invention is to provide a method for the prophylactic or therapeutic treatment of ulcer in human being or animals.
The thiazole derivatives of this invention are new and can be represented by the following general formula (I) :
Figure imgf000004_0001
wherein R1 is lower alkoxy, lower alkoxy(lower) alkyl, cyano (lower)alkyl, phenyl, phenyl (lower)alkyl,
[2- (lower) alkoxyphenyl] (lower) alkyl, diphenyl (lower) alkyl, phenoxy(lower) alkyl, phenyl (lower) alkoxy(lower) alkyl, cyclo (lower) alkenyl (lower) alkyl, protected amino (lower) alkyl or adamantyloxy(lower) alkyl, and o
R is hydrogen, lower alkanoyl or carbamoyl.
The object compound (I) or a salt thereof can be prepared by processes as illustrated in the following reaction schemes.
Process m
Figure imgf000004_0002
(ID or a salt thereof hereof
Figure imgf000005_0001
Figure imgf000005_0002
(I) or a salt thereof
Process (?'
Figure imgf000005_0003
:ιv) or a salt thereof
eof
Figure imgf000005_0004
(I) or a salt thereof
wherein R and R2 are each as defined above, R3 is lower alkyl, and X is a leaving group.
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, hydriodide, sulfate, phosphate, etc.) ; an organic carboxylic or sulfonic acid addition salt (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, 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 - r> - in detail as follows.
The term "lower" is used to intend a group having 1 to 6 carbon atom(s), unless otherwise provided.
The term "higher" is used to intend a group having 7 to 20 carbon atoms, unless otherwise provided.
Suitable "lower alkyl" and "lower alkyl moiety" in the terms "lower alkoxy (lower) alkyl", "cyano (lower) alkyl", "phenyl (lower) alkyl", " [2- (lower) alkoxyphenyl] (lower) - alkyl", "diphenyl (lower) alkyl", "phenoxy(lower) alkyl", "phenyl (lower) alkoxy(lower) alkyl",
"cyclo (lower) alkenyl (lower) alkyl", "protected amino (lower) alkyl" and "adamantyloxy (lower) alkyl" 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 C -C^ alkyl.
Suitable "lower alkoxy" and "lower alkoxy moiety" in the terms" lower alkoxy (lower) alkyl", " [2- (lower) alkoxyphenyl] (lower) alkyl" and
"phenyl (lower) alkoxy (lower) alkyl" may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like.
Suitable "cyclo (lower) alkenyl moiety" in the term "cyclo (lower) alkenyl (lower) alkyl" may include cyclohexenyl, cyclohexadienyl and the like.
Suitable "halogen" may include fluorine, bromine, chlorine and iodine.
Suitable "leaving group" may include acid residue, lower alkoxy as exemplified above, and the like.
Suitable "acid residue" may include halogen as exemplified above, acyloxy and the like.
Suitable "protected amino" may include acylamino or an amino group substituted by a conventional protecting group such as mono (or di or tri) aryl (lower) alkyl, for example, mono (or di or tri)phenyl (lower) alkyl (e.g., benzyl, trityl, etc. ) or the like.
Suitable "acyl" and "acyl moiety" in the terms "acylammo" and "acyloxy" may include carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, wπich is referred to as aromatic acyl, or heterocyclic ring, which is referred to as heterocyclic acyl.
Suitable example of said acyl may be illustrated as follows :
Carbamoyl; Thiocarbamoyl;
Aliphatic acyl such as lower or higher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2, 2-dιmethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyi, etc. ) ; lower or higher alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc. ) ; lower or higher alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, etc.); lower or higher alkoxysulfonyl (e.g., methoxysulfonyl, ethoxysulfonyl, etc.); cyclo (lower) alkylcarbonyl (e.g., cyclopentylcarbonyl, cyclohexylcarbonyl, etc.); or the like; Aromatic acyl such as aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.); ar (lower) alkanoyl [e.g., phenyl (lower) alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl, etc.), naphthyl (lower) alkanoyl (e.g., naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.), etc.]; ar(lower)alkenoyl [e.g., phenyl (lower) alkenoyl (e.g., phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, etc.), naphthyl (lower) alkenoyl (e.g., naphthylpropenoyl, naphthylbutenoyl, etc.), etc.]; ar (lower) alkoxycarbonyl [e.g., phenyl (lower) alkoxycarbonyl (e.g., benzyloxycarbonyl, etc.), etc.],* aryloxycarbonyl (e.g., phenoxycarbonyl, naphthyloxycarbonyl, etc.); aryloxy(lower) alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl, etc.); arylglyoxyloyl (e.g., phenylglyoxyloyl, naphthylglyoxyloyl, etc. ) ; arylsulfonyl (e.g., phenylsulfonyl, p-tolylsulfonyl, etc.); or the like; Heterocyclic acyl such as heterocycliccarbonyl; heterocyclic(lower)alkanoyl (e.g., heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl, heterocyclichexanoyl, etc.); heterocyclic (lower) alkenoyl (e.g., heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl, etc.); heterocyclicglyoxyloyl; or the like; in which suitable "heterocyclic moiety" in the terms "heterocycliccarbonyl", "heterocyclic(lower) alkanoyl", heterocyclic(lower) alkenoyl" and "heterocyclicglyoxyloyl" ad mentioned above means, in more detail, 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, pyrrolmyl, lmidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1, 2, -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, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6- me bered) 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, -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, 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. Suitable "lower alkanoyl" may include for yl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2- dimethylpropanoyl, hexanoyl and the like.
It is to be noted that the object compound (I) may include one or more stereoisomer (s) due to asymmetric carbon atom(s) and double bond(s) and all such isomers and mixture thereof are included within the scope of this invention.
Regarding the object compound (I), it is to be understood that they include tautomeric isomers.
That is, a group of the formula
Figure imgf000012_0001
can be also alternatively represented by its two tautomeric formulas :
Figure imgf000012_0002
That is, the said three groups are in the state of equilibrium and such tautomerism can be represented by the l-' following equilibrium.
Figure imgf000012_0003
And it is obvious to be any person skilled in the arts that the tautomeric isomers are easily convertible 5 reciprocally and are included within the same category of the compound per se.
Accordingly, the tautomeric forms of the object compound (I) are clearly included within the scope of the present invention. 0 In the present specification, the object and starting compounds including the group of such tautomeric isomers are represented by using one of the expressions therefor, that is the formula :
5
Figure imgf000013_0001
only for the convenient sake.
The processes for preparing the object compound is explained in detail in the following.
Process (1)
The 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 solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N, -dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under warming to heating.
When the starting compound is in liquid, it can be used also as a solvent.
Process (2)
The compound (I) 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 solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof. The reaction temperature is not critical and the reaction is usually carried out under warming to heating. The reaction may be also carried out in the presence of an inorganic or an organic base such as an alkali metal (e.g., sodium, potassium, etc.), an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), an alkali metal hydrogencarbonate (e.g., sodium hydrogencarbonate, potassium hydrogencarbonate, etc.j, alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), tri (lower) alkylamme (e.g., trimethylamme, triethylamine, diisopropylethylamme, etc.) , alkali metal hydride (e.g., sodium hydride, etc.), alkali metal (lower) alkoxide (e.g. sodium methoxide, sodium ethoxide, etc.), pyridme, lutidine, picoline, dimethylaminopyridine, N- (lower) alkylmorpholme, N,N- di (lower) alkylbenzylamme, N,N-di (lower) alkylaniline or the like.
When the base and/or the stating compound are in liquid, they can be used also as a solvent. The new thiazole derivatives (I) and pharmaceutically acceptable salts thereof possess antiulcer activity, H2~ receptor antagonism, and especially antimicrobial activity against pathogenic microorganisms such as Helicobacter pylori, and are useful for a prophylactic or therapeutic treatment of gastritis, ulcer (e.g. gastric ulcer, duodenal ulcer, anastomotic ulcer, etc.), Zollmger-Ellison Syndrome, reflux esophagitis, upper gastrointestinal bleeding, and the like.
In order to illustrate the usefulness of the object compound (I), the pharmacological test data of some representative compounds of the compound (I) are shown in the following.
Tes t compound ( a ) 4- ( 3-Acetylammomethylphenyl ) -2- [ ( ammo ) [ 2- ( 1- cyclohexen-1-yl) ethylamino]methyleneamino]thiazole
(b) 4- (3-Acetylaminomethylphenyl)-2- [ (amino) [2- (2- methoxyphenyl) ethylamino]methyleneamino] thiazole
Test A (H2-receptor antagonism in isolated guinea-pig atrium) :
Test Method The atrial strip isolated from guinea-pig was suspended under an initial tension 0.3 to 0.6 g in an organ bath containing Tyrode solution at 30°C, aerated 95% 02 -
Figure imgf000015_0001
The beating rate and amplitude of contraction of the atrium were recorded by means of a transducer and a polygraph. Histamine (1 x 10~6 g/ml) was added to the bathing fluid and the increase in beating rate after dosing was measured. Addition of test compound (1 x 10-6 g/ml) was made 30 minutes after washing out histamine. Inhibitory effect of test compound was calculated by comparing histamine-induced increases in beating rate before and 30 minutes after dosing with the test compound.
Test Result
Test Compound inhibition (%)
(a) 100
Test B (in vitro Antimicrobial Activities) Test Method
In vitro antimicrobial activity was determined by the agar dilution method. Test strain was precultured in
Brucella Agar with 3 ϊ horse serum and 2% starch at 37°C for
-7 3 days, and 10 cfu/ml were inoculated with a multipoint replicater onto Brucella agar plus 7% horse blood plate containing serial 2-fold dilutions of Test compound and incubated at 37°C for 3 days.
Incubation was carried out in an atmosphere of 10ra co2.
MIC was read after incubation as the lowest Test compound concentration that inhibited macroscopic colonial growth. The data shown below are mean MIC against clinical isolated.
Test Result
M.I,C* (μg/ml!
Test Compound
Test Strain
(b)
Helico bacter
0.0125 pylori 8007
The object compound (I) or its pharmaceutically acceptable salts can usually be administered to mammals including human being in the form of a conventional pharmaceutical composition such as oral dosage form (e.g., capsule, micro-capsule, tablet, granule, powder, troche, syrup, aerosol, inhalation, suspension, emulsion, etc.), injection dosage form or suppository, or the like.
The pharmaceutical composition of this invention can contain various organic or inorganic carrier materials, which are conventional used for pharmaceutical purpose, such as excipient (e.g. sucrose, starch, mannit, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, etc.), binding agent (e.g. cellulose, methyl cellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose, starch, etc.), disintegrator (e.g. starch, carboxymethyl cellulose, calcium salt of carboxymethyl cellulose, hydroxypropylstarch, sodium glycole-starch, sodium bicarbonate, calcium phosphate, calcium citrate, etc.), lubricant (e.g. magnesium stearate, talc, sodium laurylsulfate, etc.), flavoring agent (e.g. citric acid, menthol, glycine, orange powders, etc.), preservative (e.g. sodium benzoate, sodium bisulfite, methylparaben, propylparaben, etc.), stabilizer (e.g. citric acid, sodium citrate, acetic acid, etc.), suspending agent (e.g. methyl cellulose, polyvinylpyrrolidone, aluminum stearate, etc.), dispersing agent, aqueous diluting agent (e.g. water), base wax (e.g. cacao butter, polyethyleneglycol, white petrolatum, etc.).
While the dosage of the compound (I) will vary depending upon the age and condition of the patient, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg,
100 mg, 250 mg, 500 mg and 1000 mg of the compound (I) may be effective for treating ulcer. In general, amounts between 0.1 g/body and about 1,000 mg/body may be administered per day.
Preferred embodiments of the object compound (I) are as follows.
R1 is lower alkoxy, ethoxy(lower) alkyl, cyano (lower) alkyl, phenyl, phenyl (lower) alkyl,
(2-methoxyphenyl) (lower)alkyl (more preferably 2-
(2-methoxyphenyl)ethyl) ) , diphenyl (lower) alkyl, phenoxy(lower) alkyl, phenyl (lower)alkoxy(lower)alkyl, cyclo (lower) alkenyl (lower) alkyl, acylamino (lower) alkyl [more preferably carbamoylamino(lower) alkyl, or aroylamino (lower) alkyl (more preferably benzoyla ino (lower) alkyl) ] or adamantyloxy(lower)alkyl, and R2 is hydrogen, lower alkanoyl (more preferably acetyl) or carbamoyl.
The following Examples are given for the purpose of illustrating the present invention in more detail.
Example 1
A suspension of 4- (3-acetylaminomethylphenyl) -2- (2- methyl-1-isothioureido) thiazole hydriodide (3.0 g) and 2- phenoxyethylamine (5.0 g) in ethanol (100 ml) was refluxed for 38 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 adjusted to pH 10 with 30° potassium carbonate solution and then was extracted with ethyl acetate (200 ml) . The extract was dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column eluting with a mixture of chloroform:methanol = 20:1. Recrystallization from a mixture of ethyl acetate and methanol afforded 4- (3- acetylaminomethylphenyl) -2- [ (amino) (2- phenoxyethylamino)methyleneamino] thiazole (0.46 g) . mp : 164-165°C
IR (Nujol) : 3450, 3300, 1660, 1630, 1600 cm"1 NMR (DMS0-d6, δ) : 1.88 (3H, s), 3.59 (2H, t,
J=5.5Hz), 4.10 (2H, t, J=5.5Hz), 4.27 (2H, d, J=5.8Hz), 6.91-7.02 (3H, m) , 7.12-7.18 (2H, m) , 7.22-7.35 (3H, m) , 7.55 (2H, br s), 7.66-7.70 (2H, m) , 8.35 (1H, t, J=5.8Hz) Elemental Analysis Calcd. for C2 K23N502S :
C 61.59, H 5.66, N 17.10 Found : C 61.30, H 5.65, N 16.80
Exampl 2 The following compounds were obtained according to a similar manner to that of Example 1.
(1) 4- (3-Acetylaminomethylphenyl) -2- [ (amino) (2- ethoxyethylamino)methyleneamino] thiazole p : 123-125°C
IR (Nujol) : 3470, 3300, 1650, 1590 cm"1 NMR (DMSO-d6, δ) : 1.13 (3H, t, J=7.0Hz), 1.89 (3H, s), 3.33-3.54 (6H, m) , 4.28 (2H, d, J=5.8Hz), 7.13-7.17 (2H, m) , 7.29-7.41 (3H, m) , 7.65-7.80 (2H, m) , 8.36 (1H, t, J=5.8Hz)
Elemental Analysis Calcd. for C-^H^Nc^S :
C 56.49, H 6.41, N 19.38 Found : C 56.78, H 6.55, N 19.07
(2) 4- (3-Acetylaminomethylphenyl)-2-[ (amino) [2- (2- methoxyphenyl) ethylamino] ethyleneamino] thiazole p : 155-156°C
IR (Nujol) : 3310, 3280, 1620 cm"1
NMR (DMSO-d6, δ) : 1.88 (3H, s), 2.77-2.85 (2H, t, J=7.0Hz), 3.37-3.43 (2H, ) , 3.80 (3H, s) , 4.28
(2H, d, J=5.8Hz), 6.84-6.99 (2H, ) , 7.14-7.24 (4H, m) , 7.32 (1H, t, J=7.6Hz), 7.44 (2H, br s), 7.63-7.68 (2H, m) , 8.36 (1H, t, J=5.8Hz)
Elemental Analysis Calcd. for C22H25N5°2S : C 62.39, H 5.95, N 16.54
Found : C 62.39, H 6.07, N 16.35
(3) 4- (3-Acetylaminomethylphenyl) -2- [ (amino) [2-(l- cyclohexen-1-yl) ethylamino]methyleneamino] thiazole mp : 136-137°C
IR (Nujol) : 3330, 1660, 1600 cm"1
NMR (DMS0-d6, δ) : 1.40-1.65 (4H, m) , 1.88 (3H, s), 1.90-2.00 (4H, m) , 2.08-2.18 (2H, m) , 3.26-3.31 (2H, m) , 4.28 (2H, d, J=5.8Hz), 5.46(1H, br s), 7.13-7.17 (2H, m) , 7.33 (1H, t, J=7.7Hz), 7.40 (2H, br s) , 7.66-7.70 (2H, m) , 8.36 (1H, t, J=5.8Hz) Elemental Analysis Calcd. for C21H 7N5OS :
C 63.45, H 6.85, N 17.62 Found : C 63.43, H 6.83, N 17.36
(4) 4- (3-Acetylaminomethylphenyl) -2- [ (amino) (3,3- diphenylpropylamino) methyleneamino] thiazole mp : 162-163°C IR (Nujol) : 3400, 3230, 1640, 1600 cm"1
NMR (DMSO-d6, δ) : 1.88 (3H, s), 2.20-2.40 (2H, m) , 3.00-3.20 (2H, m) , 4.06 (1H, t, J=7.7Hz) , 4.26 (2H, d, J=5.8Hz) , 7.13-7.36 (14H, m) , 7.47 (2H, br s), 7.66-7.69 (2H, m) , 8.35 (1H, t, J=5.8Hz)
(5) 4- (3-Acetylaminomethylphenyl) -2- [ (amino) (2- cyanoethylamino)methyleneamino] thiazole mp : 150-151 °C
IR (Nujol) : 3250, 3100, 2230, 1640 cm"1 NMR (DMS0-d6, δ) : 1.89 (3H, s), 2.76 (2H, t,
J=6.3Hz), 3.41-3.50 (2H, m) , 4.29 (2H, d, J=5.9Hz) , 7.16 (1H, d, J=7.6Hz) , 7.21 (1H, s) , 7.34 (1H, t, J=7.6Hz), 7.69-7.72 (4H, m) , 8.36 (1H, t, J=5.9Hz)
(6) 4- (3-Acetylaminomethylphenyl) -2- [ (amino) [2-(l- adamantyloxy) ethylamino]methyleneamino] thiazole p : 85-89°C (dec.)
IR (Nujol) : 3270, 1640 cm"1 NMR (DMSO-d6, δ) : 1.57 (6H, br s) , 1.70 (6H, br s) ,
1.89 (3H, s) , 2.09 (3H, br s) , 3.29-3.34 (2H, m) , 3.46-3.50 (2H, m) , 4.29 (2H, d, J=5.8Hz) , 7.15- 7.17 (2H, m) , 7.32 (1H, t, J=7.8Hz) , 7.41 (2H, br s), 7.69-7.70 (2H, m) , 8.37 (1H, t, J=5.8Hz) (7) 4- (Acetylaminomethylphenyl) -2- [ (amino) (2- phenylpropylamino) ethyleneamino] thiazole mp : 68-70°C
IR (Nujol) : 3270, 1610 cm"1 NMR (DMSO-d6, δ) : 1.25 (3H, d, J=6.9Hz), 1.88 (3H, s), 2.95-3.06 (1H, m) , 3.39-3.42 (2H, m) , 4.28 (2H, d, J=5.8Hz), 7.13-7.36 (10H, m) , 7.60-7.68 (2H, m) , 8.37 (1H, t, J=5.8Hz)
(8) 4- (3-Acetylaminomethylphenyl) -2- [ (amino) (2- phenylethylamino)methyleneamino] thiazole mp : 118-119°C
IR (Nujol) : 3450, 3270, 1650, 1590 cm"1 NMR (DMSO-d6, δ) : 1.88 (3H, s) , 2.83 (2H, t, J=7.3Hz), 3.40-3.50 (2H, m) , 4.28 (2H, d,
J=5.9Hz), 7.14-7.36 (8H, ) , 7.47 (2H, br s) , 7.63-7.69 (2H, m) , 8.35 (1H, t, J=5.9Hz) Elemental Analysis Calcd. for C21H21N5θS :
C 64.10, H 5.89, N 17.80 Found : C 63.88, H 5.94, N 17.56
(9) 4- (3-Acetylaminomethylphenyl) -2-
[ (amino) (benzylamino)methyleneamino] thiazole mp : 124-125°C IR (Nujol) : 3450, 3320, 1630 cm"1
NMR (DMSO-d6, δ) : 1.88 (3H, s), 4.27 (2H, d,
J=5.8Hz), 4.44 (2H, d, J=5.8Hz), 7.13-7.16 (2H, m) , 7.27-7.37 (6H, m) , 7.56 (2H, br s), 7.62-7.67 (2H, m) , 8.35 (1H, t, J=5.8Hz)
(10) 4- (•3-Acetylaminomethylphenyl) -2- [ (amino) (3- phenylpropylamino) methyleneamino] thiazole mp : 135-136°C
IR (Nujol) : 3450, 3300, 1640, 1580 cm"1 NMR (DMSO-d6, δ) : 1.79-1.88 (5H, m) , 2.66 (2H, t, J=7.3Hz), 3.16-3.25 (2H, m) , 4.27 (2H, d, J=5.8Hz), 7.14-7.36 (8H, m) , 7.46 (2H, br s), 7.67-7.70 (2H, m) , 8.34 (1H, t, J=5.8Hz) Elemental Analysis Calcd. for C22H25N50S : C 64.84, H 6.18, N 17.18
Found : C 64.61, H 6.19, N 16.97
Example 3
A suspension of 4- (3-acetylaminomethylphenyl) -2- (2- methyl-1-isothioureido) thiazole hydriodide (5.2 g) and 2- (2-methoxyphenyl) ethylamine (7.0 ml) in methylene chloride (100 ml) was refluxed for 40 hours. The solvent was removed under reduced pressure and the residue was dissolved in a mixture of water (100 ml) and tetrahydrofuran (20 ml) . The mixture was adjusted to pH 9 with 30°o potassium carbonate solution and then was extracted with ethyl acetate (150 ml) . The extract was dried over magnesium sulfate and then the solvent was removed under reduced pressure. The residue was chromatographed on silica gel column eluting with a mixtue of ethyl acetate:methanol = 100:1. The appropriate fraction was collected and the solvent was removed under reduced pressure. The residue was crystallized from ethyl acetate. Recrystallization from a mixture of ethanol and diisopropyl ether afforded 4- (3-acetylaminomethylphenyl) -2- [ (amino) [2- (2-methoxyphenyl) ethylamino]methyleneamino] - thiazole (1.6 g) . mp : 155-156°C
IR (Nujol) : 3310, 3280, 1620 cm"1 NMR (DMSO-d6, δ) : 1.88 (3H, s), 2.77-2.85 (2H, t,
J=7.0Hz), 3.37-3.43 (2H, m) , 3.80 (3H, s), 4.28 (2H, d, J=5.8Hz), 6.84-6.99 (2H, m) , 7.14-7.24 (4H, m) , 7.32 (1H, t, J=7.6Hz), 7.44 (2H, br s), 7.63-7.68 (2H, m) , 8.36 (1H, t, J=5.8Hz) Elemental Analysis Calcd. for C22H25N5°2S : C 62.39, H 5.95, N 16.54 Found : C 62.39, H 6.07, N 16.35
At the same time, by this reaction the following compound was obtained as by-product.
4- (3-Acetylaminomethylphenyl) -2- [3- (2- (2- methoxyphenyl) ethyl) ureido] thiazole mp : 145-146°C IR (Nujol) : 3340, 3240, 1670, 1630 cm"1
NMR (DMSO-d6, δ) : 1.88 (3H, s), 2.76 (2H, t,
J=7.0Hz), 3.34-3.45 (2H, m) , 3.79 (3H, s) , 4.28 (2H, d, J=5.8Hz), 6.46 (1H, t , J=4.6Hz), 6.89 (1H, t, J=7.3Hz), 6.97 (1H, d, J=7.6Hz), 7.15- 7.25 (3H, m) , 7.35 (1H, t, J=7.6Hz), 7.40 (1H, s), 7.69-7.73 (2H, m) , 8.36 (1H, t, J=5.8Hz), 10.60 (1H, s)
Elemental Analysis Calcd. for C22 H24N4°3S :
C 62.24, H 5.70, N 13.20 Found : C 62.44, H 5.66, N 13.20
Example 4
The following compound (Compound A) and by-product (Compound B) were obtained according to a similar manner to that of Example 3.
Compound A :
4- (3-Acetylaminomethylphenyl) -2- [ (amino) (2- benzoylaminoethylamino)methyleneamino] thiazole p : 126-127°C
IR (Nujol) : 3300, 1640 cm"1
NMR (DMSO-d6, δ) : 1.88 (3H, s), 3.42 (4H, br s), 4.28 (2H, d, J=5.8Hz), 7.12-7.17 (2H, m) , 7.31 (1H, t, J=7.9Hz), 7.44-7.52 (3H, m) , 7.50-7.70 (4H, m) , 7.84-7.88 (2H, m) , 8.37 (1H, t, J=5.8Hz), 8.62 (1H, t, J=5.8Hz)
Compound B :
4- (3-Acetylaminomethylphenyl) -2- [ (imidazolidin-2- ylidene) amino] thiazole mp : 228-229°C IR (Nujol) : 3300, 1640 cm-1
NMR (DMSO-d6) : 1.89 (3H, s), 3.59 (4H, s), 4.30 (2H, d, J=5.9Hz), 7.13-7.18 (2H, m) , 7.33 (1H, t, J=8.0Hz), 7.66 (2H, br s), 7.77-7.81 (2H, m) ,
8.37 (1H, t, J=5.9Hz)
Example 5
A suspension of N- (2-benzyloxyethyl)phthalimide (7.5 g) and hydrazine hydrate (1.33 g) in ethanol (100 ml) was refluxed for 2 hours. 4- (3-acetylaminomethylphenyl) -2- (2- methyl-1-isothioureido) thiazole hydriodide (3.0 g) was added to the reaction ixtur and then the mixtue was efluxed for 24 hours. The solvent was removed under reduced pressure and the residue was dissolved in a mixtue of water (100 ml) and tetrahydrofuran (40 ml) . The mixtue was adjusted to pH 10 with 30% potassium carbonate solution and then was extracted with ethyl acetate (150 ml) . The extract was dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel column eluting with a mixtue of chloroform:methanol = 50:1. Recrystallization from a mixture of ethanol and diisopropyl ether afforded 4- (3- acetylaminomethylphenyl) -2- [ (amino) (2- benzyloxyethylamino)methyleneamino] thiazole (0.48 g) . mp : 143-144°C
IR (Nujol) : 3480, 3290, 1650, 1590 cm"1 NMR (DMSO-d6, δ) : 1.88 (3H, s), 3.41-3.44 (2H, m) , 3.57 (2H, t, J=4.8Hz), 4.28 (2H, d, J=5.8Hz), 4.54 (2H, s), 7.12-7.16 (2H, m) , 7.25-7.36 (8H, m) , 7.42 (2H, br s), 7.68-7.72 (2H, m) , 8.36 (1H, t, J=5.8Hz) Elemental Analysis Calcd. for C22H25N5°2S :
C 62.39, H 5.95, N 16.54 Found : C 62.20, H 5.94, N 16.34
Example 6
The following compound was obtained according to a similar manner to that of Example 5.
4- (3-Acetylaminomethylphenyl) -2- [ (amino) (2- uureidoethyla ino)methyleneamino] thiazole mp : 167-168°C
IR (Nujol) : 3290, 3160, 1660, 1610 cm-1 NMR (DMSO-d6, δ) : 1.89 (3H, s), 3.12-3.23 (4H, m) ,
4.29 (2H, d, J=5.9Hz), 5.56 (2H, s) , 6.10 (1H, t, J=5.3Hz), 7.14-7.17 (2H, m) , 7.34 (1H, t, J=7.7Hz), 7.63-7.70 (4H, m) , 8.37 (1H, t, J=5.9Hz) Elemental Analysis Calcd. for C16H21N-70 S :
C 51.18, H 5.64, N 26.11 Found : C 51.45, H 5.69, N 26.09
Example 7 A solution of 3- (acetylaminomethyl) acetophenone (700 mg) and bromine (610 mg) in dioxane (10 ml) was stirred at room temperature for 5 hours. Methanol (20 ml), [ (phenylamino) (aminomethylene] thiourea (700 mg) and potassium carbonate (l.llg) were added to the reaction mixture. The mixture was heated at 55°C for 2 hours. The solvent was removed under reduced pressureand the residue was dissolved in a mixtue of water (60 ml) and tetrahydrofuran (40 ml) . The mixture was adjusted to pH 10 with 30% potassium carbonate solution and then was. extracted with ethyl acetate (150 ml) . The extract was dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was crystallized from ethyl acetate. Recrystallization from a mixtue of ethanol and water afforded 4- (3-acetylaminomethylphenyl) -2- [ (amino) (phenylamino)methyleneamino] thiazole (450 mg) . mp : 185-186°C
IR (Nujol) : 3420, 3290, 1650 cm"1 NMR (DMSO-d6, δ) : 1.89 (3H, s), 4.30 (2H, d,
J=5.8Hz), 7.011 (1H, t, J=7.3Hz), 7.18 (1H, d, J=7.8Hz), 7.27-7.40 (5H, m) , 7.52 (2H, d,
J=7.6Hz), 7.72-7.76 (2H, m) , 7.86 (2H, br s), 8.38 (1H, t, J=5.8Hz), 8.90 (1H, br s) Elemental Analysis Calcd. for C-^gH^gN^OS :
C 62.44, H 5.24, N 19.16 Found : C 62.45, H 5.28, N 19.01
Example 8
The following compound was obtained according to a similar manner to that of Example 7.
4- (3-Acetylaminomethylphenyl) -2- [ (amino) (ethoxyamino)methyleneamino] thiazole hydrochloride mp : 115-117°C
IR (Nujol) : 3250, 1660, 1620 cm"1 NMR (DMSO-d6, δ) : 1.29 (3H, t, J=7.0Hz), 1.90 (3H, s), 4.00 (2H, q, J=7.0Hz), 4.30 (2H, d, J=5.9Hz), 7.25 (1H, d, J=7.7Hz), 7.40 (1H, t, J=7.7Hz), 7.69 (1H, s), 7.76-7.79 (2H, m) , 8.44 (1H, t, J=5.9Hz)
Example 9
A mixture of 4- (3-acetylaminomethylphenyl) -2- [ (amino) [2- (1-adamantyloxy) ethylamino]methyleneamino] - thiazole (500 mg) and 4N hydrogen chloride-dioxane (7 ml) in methanol (10 ml) was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure and the residue was crystallized frm a mixture of methanol and diisopropyl ether. Recrystallization from a mixture of ethanol and diisopropyl ether afforded 4- ( 3- acetylaminomethylphenyl)-2- [ (amino) [2- (1-adamantyloxy) - ethylamino] ethyleneamino]thiazole hydrochloride (320 mg) . mp : 133-135°C
IR (Nujol) : 3270, 1680, 1640 cm"1
NMR (DMSO-d6, δ) : 1.50-1.53 (6H, m) , 1.62-1.66 (6H, m) , 1.89 (3H, s), 2.04 (3H, br s) , 3.45-3.65 (4H, m) , 4.31 (2H, d, J=5.7Hz), 7.25 (1H, d, J=7.8Hz), 7.39 (1H, t, J=7.8Hz), 7.73-7.82 (3H, m) , 8.44 (1H, t, J=5.7Hz), 8.56 (2H, br s)
Example 10
A suspension of 4- (3-acetylaminomethylphenyl)-2- [ (amino) [2- (2-methoxyphenyl) ethylamino]methyleneamino]- thiazole (600 mg) and cone-hydrochloric acid (5 ml) in ethanol (50 ml) was refluxed for 4 days. After cooling, the resulting precipitate was collected by filtration to afford 4- (3-aminomethylphenyl)-2-[ (amino) [2- (2- methoxyphenyl) ethylamino]methyleneamino]thiazole dihydrochloride (500 mg) . mp : 157-159°C (dec.) IR (Nujol) : 3310, 1670, 1600 cm"1
NMR (DMSO-d6, δ) : 2.92 (2H, t, J=6.6Hz), 3.60-3.70 (2H, m) , 3.75 (3H, s) , 4.06 (2H, q, J=5.6Hz), 6.83-6.97 (2H, ) , 7.16-7.28 (2H, m) , 7.45-7.48 (2H, m) , 7.74 (2H, br s), 8.07 (1H, s), 8.56 (4H, br s)
Example 11
A suspension of 4- (3-aminomethylphenyl)-2- [ (amino) [2- (2-methoxyphenyl)ethylamino]methyleneamino]thiazole dihydrochloride (450 mg) and potassium isocyanate (100 mg) in water (10 ml) was stirred at room temperature for 8 hours. The mixture was adjusted to pH 10 with 30% potassium carbonate solution. The resulting precipitate was collected by filtration. Recrystallization from a mixture of ethanol and water afforded 2- [(amino) [2- (2- methoxyphenyl) ethylamino]methyleneamino] -4- (3- ureidomethylphenyl) thiazole (220 mg) . p : 167-168°C
IR (Nujol) : 3350, 1660, 1620 cm"1 NMR (DMSO-d6, δ) : 2.83 (2H, t, J=7.4Hz), 3.39-3.50
(2H, m) , 3.79 (3H, s) , 4.21 (2H, d, J=5.9Hz), 5.54 (2H, s), 6.44 (1H, d, J=5.9Hz), 6.87 (1H, t, J=7.5Hz), 6.9 (1H, d, J=8.0Hz), 7.17-77.22 (4H, m) , 7.33 (1H, t, J=7.6Hz), 7.61-7.75 (4H, m)
Example 12
The following compound was obtained according to a similar manner to that of Example 7.
4- (3-Acetylaminomethylphenyl) -2- [ (amino) [2- (2- methoxyphenyl) ethylamino]methyleneamino] thiazole mp : 155-156°C
IR (Nujol) : 3310, 3280, 1620 cm"1
NMR (DMSO-d6, δ) : 1.88 (3H, s) , 2.77-2.85 (2H, t, J=7.0Hz), 3.37-3.43 (2H, ) , 3.80 (3H, s), 4.28
(2H, d, J=5.8Hz), 6.84-6.99 (2H, m) , 7.14-7.24 (4H, m) , 7.32 (1H, t, J=7.6Hz), 7.44 (2H, br s), 7.63-7.68 (2H, m) , 8.36 (1H, t, J=5.8Hz) Elemental Analysis Calcd. for C22H25N5O2S : C 62.39, H 5.95, N 16.54
Found : C 62.39, H 6.07, N 16.35

Claims

C L A I M S
1. A compound of the formula
Figure imgf000029_0001
wherein R1 is lower alkoxy, lower alkoxy(lower) alkyl, cyano(lower)alkyl, phenyl, phenyl (lower)alkyl,
[2- (lower)alkoxyphenyl] (lower)alkyl, diphenyl (lower)alkyl, phenoxy(lower)alkyl, phenyl (lower) alkoxy(lower)alkyl, cyclo (lower)alkenyl (lower) alkyl, protected amino (lower)alkyl or adamantyloxy(lower) alkyl, and R^ is hydrogen, lower alkanoyl or carbamoyl, and a pharmaceutically acceptable salt thereof.
A compound of claim 1, wherein
R1 is lower alkoxy, ethoxy(lower)alkyl, cyano(lower)alkyl, phenyl, phenyl (lower)alkyl,
(2-methoxyphenyl) (lower)alkyl [2-
(lower) alkoxyphenyl] (lower) alkyl, diphenyl (lower)alkyl, phenoxy(lower) alkyl, phenyl (lower) alkoxy(lower) alkyl, cyclo (lower) alkenyl (lower) alkyl, acylamino (lower) alkyl or adamantyloxy(lower) alkyl, and R is hydrogen, acetyl or carbamoyl.
A compound of claim 2, wherein
R1 is lower alkoxy, ethoxy(lower)alkyl, cyano (lower) alkyl, phenyl, phenyl (lower) alkyl, 2- [2- (lower) alkoxyphenyl] (lower) alkyl, diphenyl (lower) alkyl, phenoxy(lower) alkyl, phenyl (lower)alkoxy(lower)alkyl, 5 cyclo (lower) alkenyl (lower) alkyl, carbamoyl mino (lower) alkyl, aroylamino (lower) alkyl or adamantyloxy(lower) alkyl.
j_0 4. A compound of claim 3, wherein
R1 is lower alkoxy, ethoxy(lower) alkyl, cyano (lower) alkyl, phenyl, phenyl (lower)alkyl,
[2- (lower)alkoxyphenyl] (lower) alkyl, diphenyl (lower)alkyl, phenoxy(lower)alkyl, 15 phenyl (lower) alkoxy(lower) alkyl, cyclo (lower)alkenyl (lower) alkyl, carbamoylamino(lower) alkyl, benzoylamino(lower)alkyl or adamantyloxy(lower)alkyl.
20
5. A compound of claim 4, wherein
R R11 iiss [[22-- ((lloowwer)alkoxyphenyl] (lower) alkyl and R2 is acetyl.
25 6. A process for preparing a compound of the formula
Figure imgf000030_0001
1 wherein R is lower alkoxy, lower alkoxy(lower) alkyl, cyano (lower) alkyl, phenyl, phenyl (lower)alkyl, 35 [2- (lower)alkoxyphenyl] (lower)alkyl, diphenyl (lower) alkyl, phenoxy(lower) alkyl, phenyl (lower) alkoxy(lower)alkyl, cyclo(lower)alkenyl (lower)alkyl, protected amino(lower)alkyl or adamantyloxy(lower) alkyl, and R is hydrogen, lower alkanoyl or carbamoyl, or a salt thereof which comprises
(1) reacting a compound of the formula
Figure imgf000031_0001
wherein R2 is as defined above, and R is lower alkyl, or a salt thereof with a compound of the formula
R1 - NH-
wherein R1 is as defined above, or a salt thereof to give a compound of the formula
Figure imgf000031_0002
wherein R and R^ are each as defined above, or a salt thereof. or
(2) reacting a compound of the formula
Figure imgf000032_0001
wherein R2 is as defined above, and
X is a leaving group, or a salt thereof with a compound of the formula
RX-HN
\
C=N-C-NH-
/
H2N
wherein R1 is as defined above, or a salt thereof to give a compound of the formula
Figure imgf000032_0002
wherein Rι and R^? are each as defined above, or a salt thereof.
7. 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.
8. A use of a compound of claim 1 or a pharmaceutically acceptable salt thereof as antiulcer agent, antimicrobial agent or H2 _receptor antagonist.
9. A method for the prophylactic or therapeutic treatment of ulcer which comprises administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to human or animals.
10. A process for preparing a pharmaceutical composition which comprises admixing a compound of claim 1 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.
PCT/JP1995/001596 1994-08-15 1995-08-09 (4-(3-aminomethylphenyl)thiazol-2-yl)-guanidines as h2-receptor antagonists WO1996005187A1 (en)

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AU31929/95A AU3192995A (en) 1994-08-15 1995-08-09 (4-(3-aminomethylphenyl)thiazol-2-yl)-guanidines as h2-receptor antagonists

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WO1998050373A1 (en) * 1997-05-06 1998-11-12 Bayer Aktiengesellschaft Substituted aminothiazoles and the use thereof as active antimicrobial substances
WO2005082871A3 (en) * 2004-02-19 2005-11-10 Abbott Gmbh & Co Kg Guanidine compounds, and use thereof as binding partners for 5-ht5 receptors

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JPS59225172A (en) * 1983-06-03 1984-12-18 Yamanouchi Pharmaceut Co Ltd Novel guanidinothiazole derivative and its preparation
EP0545376A1 (en) * 1991-12-06 1993-06-09 Fujisawa Pharmaceutical Co., Ltd. Guanidino thiazoles and their use as H2-receptor antagonist

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EP0003640A2 (en) * 1978-01-18 1979-08-22 Imperial Chemical Industries Plc Antisecretory guanidine derivatives, processes for their manufacture and pharmaceutical compositions containing them
JPS59225172A (en) * 1983-06-03 1984-12-18 Yamanouchi Pharmaceut Co Ltd Novel guanidinothiazole derivative and its preparation
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998050373A1 (en) * 1997-05-06 1998-11-12 Bayer Aktiengesellschaft Substituted aminothiazoles and the use thereof as active antimicrobial substances
WO2005082871A3 (en) * 2004-02-19 2005-11-10 Abbott Gmbh & Co Kg Guanidine compounds, and use thereof as binding partners for 5-ht5 receptors
EP2366392A1 (en) 2004-02-19 2011-09-21 Abbott GmbH & Co. KG Guanidine compounds and use of same as binding partners for 5-HT5 receptors
EP2366697A1 (en) 2004-02-19 2011-09-21 Abbott GmbH & Co. KG Guanidine compounds and use of same as binding partners for 5-HT5 receptors
EP2380885A1 (en) * 2004-02-19 2011-10-26 Abbott GmbH & Co. KG Guanidine compounds and use of same as binding partners for 5-HT5 receptors
US8431604B2 (en) 2004-02-19 2013-04-30 Abbott Gmbh & Co. Kg Guanidine compounds, and use thereof as binding partners for 5-HT5 receptors
US8481576B2 (en) 2004-02-19 2013-07-09 Abbott Gmbh & Co. Kg Guanidine compounds, and use thereof as binding partners for 5-HT5 receptors
US9475782B2 (en) 2004-02-19 2016-10-25 AbbVie Deutschland GmbH & Co. KG Guanidine compounds, and use thereof as binding partners for 5-HT5 receptors

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