D E S C R I P T I O N

GUANIDINE DERIVATIVES

TECHNICAL FIELD

This invention relates to new guanidine derivatives. One object of this invention is to provide the new and useful guanidine derivatives and pharmaceutically acceptable salts thereof which possess a strong inhibitory activity on Na ⁺ /H ⁺ exchange in cells.

Another object of this invention is to provide processes for preparation of the guanidine derivatives and salts thereof.

A further object of this invention is to provide a pharmaceutical composition comprising said guanidine derivatives or a pharmaceutically acceptable salt thereof. Still further object of this invention is to provide a use of said guanidine derivatives or a pharmaceutically acceptable salt thereof as a medicament for the treatment and/or prevention of cardiovascular diseases, cerebrovascular diseases, renal diseases, arteriosclerosis, shock and the like in human being and animals.

BACKGROUND ART

Some guanidine derivatives having pharmaceutical activities such as inhibitory activity on Na ⁺ /H ⁺ exchange in cells have been known as described in WO 94/26709.

DISCLOSURE OF INVENTION

The object guanidine derivatives of the present invention are novel and can be represented by the following general formula (I) :

wherein R ¹ is [mono(or di) (lower alkyl)amino] (lower) alkyl which may have hydroxy, pyrrolidinyl which may have lower alkyl, piperidyl which may have lower alkyl, pyrrolidinyl (lower)alkyl which may have lower alkyl, piperidyl (lower) alkyl or morpholinyl(lower)alkyl,

R ² is dihalothienyl or dihalophenyl, and

-A- is -0- or -CH ₂ -.

The object compound (I) of the present invention can be prepared by the following process.

Process (1

(ID or its reactive derivative at the carboxy group, or a salt thereof

derivative oup, of

( I) or a salt thereof

wherein R , R ² and A are each as defined above .

The starting compound can be prepared by the following processes or Preparations mentioned below, or similar manners thereto.

Process (h)

( IV) or a salt thereof

introduction of

© a leaving group

(V) or a salt thereof

ereof

20

(Vila) or a salt thereof

30

elimination of hydroxy protective group

35

(VII) or a salt thereof

P ocess (g)

(VII) or a salt thereof

hereof

(ID or a salt thereof

wherein R ¹ and R ² are each as defined above, R- ³ is protected hydroxy, 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, sulfate, phosphate, etc.); an organic carboxylic or sulfonic acid addition salt (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, isethionate, 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 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 "[mono(or di) (lower alkyl)amino] (lower)alkyl",

"pyrrolidinyl (lower)alkyl", "piperidyl (lower)alkyl" and "morpholinyl (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^ alkyl.

Suitable "halogen moiety" in the term "dihalothienyl" 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 "hydroxy protective group" in the term "protected hydroxy" may include acyl, mono(or di or tri)phenyl(lower)alkyl which may have one or more suitable substituent(s) (e.g., benzyl, 4-methoxybenzyl, trityl, etc.), trisubstituted silyl [e.g., tri (lower)alkylsilyl (e.g., trimethylsilyl, t-butyldimethylsilyl, etc.), etc.], tetrahydropyranyl and the like. Suitable "[mono(or di) (lower alkyl) amino] (lower)- alkyl" may include [methylamino] ethyl, 1- (or 2-)- [ ethylamino]ethyl, 1- (or 2- or 3-) [methylamino]propyl, [ethylamino]methyl, l-(or -2) [ethylamino]ethyl, 1- (or 2- or 3-) [ethylamino]propyl, [propylamino]methyl, l-(or 2-) [propylamino]ethyl, l-(or 2- or 3-) [propylamino]- propyl, [isopropylamino]methyl, 1- (or 2-) [isopropylamino]- ethyl, l-(or 2- or 3-) [isopropylamino]propyl, [butyla ino] ethyl, l-(or 2-) [butylamino]ethyl, l-(or 2- or 3-) [butylamino]propyl, [isobutylamino]methyl, l-(or 2-) [isobutylamino]ethyl, l-(or 2- or 3-)- [isobutyla ino]propyl, [tert-butylamino]methyl, l-(or 2-) [tert-butylamino]ethyl, l-(or 2- or 3-) [tert- butylamino]propyl, [dimethylamino] ethyl, l-(or 2-)- [dimethylamino]ethyl, l-(or 2- or 3-) [dimethylamino]- propyl, l-(or 2- or 3- or 4-) [dimethylamino]butyl,

(1- or 2- or 3- or 4- or 5-) [dimethylamino]pentyl, ^' [diethylamino]methyl, 1- (or 2-) [diethylamino]ethyl, l-(or 2- or 3-) [diethylamino]propyl,

[dipropylamino]methyl, 1- (or 2-) [dipropylamino]ethyl, l-(or 2- or 3-) [dipropylamino]propyl,

[diisopropylamino]methyl, 1- (or 2-) [diisopropylamino]- ethyl, l-(or 2- or 3-) [diisopropylamino]propyl, [dibutylamino] ethyl, 1- (or 2-) [dibutylamino]ethyl, l-(or 2- or 3-) [dibutylamino]propyl, [diisobutylamino]methyl, l-(or 2-) [diisobutylamino]ethyl, l-(or 2- or 3-) [diisobutylamino]propyl, [di (tert- butyl)amino]methyl, l-(or 2-) [di (tert-butyl)amino]ethyl, l-(or 2- or 3-) [di (tert-butyl)amino]propyl, and the like. Suitable "acyl" and "acyl moiety" in the term "acyloxy" may include carbamoyl, aliphatic acyl group, acyl group containing an aromatic ring, which is referred to as aromatic acyl and the like.

Suitable example of said acyl may be illustrated as follows :

Carbamoyl; Thiocarbamoyl; Sulfamoyl;

Aliphatic acyl such as lower or higher alkanoyl (e.g., for yl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc. ) ; lower or higher alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.); lower or higher alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, etc.); trihalo(lower)alkylsulfonyl (e.g.,

trifluoromethylsulfonyl, 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.

The processes for preparing the object and starting compounds of the present invention are explained in detail in the following.

Process fl)

The compound (I) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at

the carboxy group, or a salt thereof with the compound (III) or its reactive derivative at the imino group, or a salt thereof.

Suitable reactive derivative at the imino group of the compound (III) may include a silyl derivative formed by the reaction of the compound (III) with a silyl compound such as bis (trimethylsilyl)acetamide, mono(tri ethylsilyl)acetamide [e.g. N- (trimethylsilyl)- acetamide], bis (trimethylsilyl)urea or the like; a derivative formed by reaction of the compound (III) with phosphorus trichloride or phosgene, and the like.

Suitable reactive derivative at the carboxy group of the compound (II) may include a conventional one such as an acid halide, an acid anhydride, an activated amide, an activated ester, and the like.

Suitable examples of the reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid [e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid halogenated phosphoric acid, etc.], dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid [e.g. methanesulfonic acid, etc.], aliphatic carboxylic acid [e.g. acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.] or aromatic carboxylic acid [e.g. benzoic acid, etc.]; a symmetrical acid anhydride; an activated amide with imidazole, 1-hydroxy-lH-benzotriazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester [e.g. cyanomethyl ester, methyl ester, ethyl ester, methoxymethyl ester,

+ dimethyliminomethyl [ (CH3) ₂ N=CH-]ester, vinyl ester, propargyl ester, 2-trifluoromethylsulfonylaminoethyl ester, 2-trifluoromethylsulfonylaminopropyl ester,

2-methyl-2-trifluoromethylsulfonylaminopropyl ester, p-nitrophenyl ester, 2, -dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, benzothiazolyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.], or an ester with a N-hydroxy compound [e.g. N,N-dimethylhydroxylamine, l-hydroxy-2- (IH)- pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide,

1-hydroxy-lH-benzotriazole, etc.], and the like. These reactive derivatives can optionally be selected from them according to the kind of the compound (II) to be used.

The reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. These conventional solvent may also be used in a mixture with water.

In this reaction, when the compound (II) is used in a free acid form or its salt form, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carboxiimide; N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide; N-ethyl-N'- (3-dimethylaminopropyl)carbodiimide; N,N'-carbonyl-bis(2-methylimidazole) ; pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-l-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride) ; phosphorus trichloride;

thionyl chloride; oxalyl chloride; lower alkyl haloformate [e.g. ethyl chloroformate, isopropyl chloroformate, etc.]; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5- (m-sulfophenyl) isoxazoliu hydroxide intramolecular salt; 1- (p-chlorobenzenesulfonyloxy)-6- chloro-lH-benzotriazole; a combination of N-lower alkylhalopyridinium halide (e.g., l-methyl-2- chloropyridinium iodide, etc.) and tri(lower)alkylamine (e.g. triethylamine, etc.); so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc.; or the like.

The reaction may also 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)alkylmorpholine, N,N- di (lower)alkylbenzylamine, alkali metal lower alkoxide (e.g. sodium methoxide, etc.) or the like.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.

Process (Al-G

The compound (V) or a salt thereof can be prepared by subjecting the compound (IV) or a salt thereof to introduction of a leaving group.

The reaction can be carried out in the manners disclosed in Preparation 2 or similar manners thereto.

Process (A)-© The compound (Vila) or a salt thereof can be prepared by reacting the compound (V) or a salt thereof with the compound (VI) or a salt thereof.

The reaction can be carried out in the manner disclosed in Preparation 3 or similar manners thereto.

13

Process (A) - G)

The compound (VII) or a salt thereof can be prepared by subjecting the compound (Vila) or a salt thereof to elimination reaction of hydroxy protective group. The reaction can be carried out in the manner disclosed in Preparation 3 or similar manners thereto.

Process (B)

The compound (II) or a salt thereof can be prepared by reacting the compound (VII) or a salt thereof with the compound (VIII) or a salt thereof.

The reaction can be carried out in the manner disclosed in Preparation 7 or similar manners thereto.

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. It is further to be noted that isomerization or rearrangement of the object compound (I) may occur due to the effect of the light, acid, base or the like, and the compound obtained as the result of said isomerization or rearrangement is also included within the scope of the present invention.

It is also to be noted that the solvating form of the compound (I) (e.g. hydrate, etc.) and any form of t _h e crystal of the compound (I) are included within the scope of the present invention. Regarding the object compound (I), it is to be understood that they include tautomeric isomers.

That is, a group of the formula :

can be also alternatively represented by its tautomeric formula :

That is, both of the said groups are in the state of equilibrium and such tautomerism can be represented by the following equilibrium.

And it is obvious to any person skilled in the arts that both of the tautomeric isomers are easily convertible reciprocally and are included within the same category of the compound per se. Accordingly, the both of the tautomeric forms of the object compound (I) are clearly included within the scope of the present invention.

In the present specification, the object compound including the group of such tautomeric isomers is represented by using one of the expressions therefor, that is the formula :

only for the convenient sake.

Suitable salts of the object and starting compounds and their reactive derivatives in Processes (1) and (A) -(B) can be referred to the ones as exemplified for the compound (I) .

The new guanidine derivatives (I) and a pharmaceutically acceptable salt thereof of the present invention possess a strong inhibitory activity on Na ⁺ /H ⁺ exchange in cells and therefore are useful as an inhibitor on Na ⁺ /H ⁺ exchange in cells.

Accordingly, the new guanidine derivatives (I) and a pharmaceutically acceptable salt thereof can be used for the expectorant and for the treatment and/or prevention of cardiovascular diseases [e.g. hypertension, angina pectoris, myocardial infarction, heart failure (e.g. congestive heart failure, acute heart failure, cardiac hypertrophy, etc.), arrhythmia (e.g. ischemic arrhythmia, arrhythmia due to myocardial infarction, arrhythmia after PTCA or after thrombolysis, etc.), restenosis after PTCA, etc.], cerebrovascular diseases [e.g. ischemic stroke, hemorrhagic stroke, etc.], renal diseases [e.g. diabetic nephropathy, ischemic acute renal failure, etc.], arteriosclerosis, shock [e.g. hemorrhagic shock, endotoxin shock, etc.] and the like, and can also be used as an agent for ischemic reperfusion injury, myocardial protection, organ protection in organ transplantation, open heart surgery, and the like.

In order to show the utilities of the guanidine derivatives (I) and a pharmaceutically acceptable salt thereof of the present invention, pharmacological test data of the representative compound of the guanidine derivatives (I) are illustrated in the following.

[1] Test Compound

(a) [5- (2,5-Dichlorothiophen-3-yl]-3-[2- (1- methylpyrrolidin-2-yl) ethoxy]benzoyl]- guanidine-dihydrochloride

[2] Inhibitory activity on Na ⁺ /H ⁺ exchange in cells

[i] Test Method

Procedure was carried out according to a similar manner to the method described in Enzymology 173. 777 (1989) .

Cell preparation : One male SD strain rat weighing 250-

300 g was sacrificed with the blow on the head. Then, the thymus was removed into ice-cold NaCl medium (140 mM sodium chloride, 1 mM potassium chloride, 1 mM calcium chloride, 1 mM magnesium chloride, 10 mM glucose and 20 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid

(HEADS) pH 7.3), cut in small fragments, and transferred to glass homogenizer. The cells were dissociated by gentle strokes, and the resulting suspension was filtrated through six layers of surgical gauze and the filtrate was centrifuged at 4°C at 1000 g for 5 minutes. The pellet was resuspended in RPMI 1640 medium (pH 7.3) at room temperature to adjust final cell concentration (1 x IO ⁷ cells/ml) .

Assay : This method detects the swellings that accompanies activation of Na ⁺ /H ⁺ exchanger in cells incubated with sodium propionate. Propionic acid rapidly penetrates through the membrane. Intracellular dissociation brings about cytoplasmic acidification and consequently activation of Na ⁺ /H ⁺ exchanger, which

17 exchange extracellular Na ⁺ for cytoplasmic H ⁺ . The uptake of osmotically obliged water was manifested as cell swelling.

Cell sizing and counting were performed electrically with the Coulter Counter-Channelyzer (AT-II) . 0.1 ml Thymocytes solution were suspended in 20 ml sodium- propionate medium (140 mM sodium propionate, 1 mM potassium chloride, 1 mM calcium chloride, 1 mM magnesium chloride, 10 mM glucose, 20 mM N-2-hydroxyethylpiperazine- N'-2-ethanesulfonic acid (HEPES) PH 6.8) including test compound solved in dimethyl sulfoxide (final concentration of dimethyl sulfoxide was 0.1%). During 4 minutes, increase of cell volume induced by Na ⁺ /H ⁺ exchanger was kept linear, and the time course of swelling was observed each minute after the addition of thymocytes. Rate of Swelling (Δ volume/min.) was measured by using 3-5 concentrations of test compound. Then, apparent Ki value of test compound was calculated by using Line weaver-Burk plot.

[3] Test Result

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, suppository, ointment, or the like. The pharmaceutical composition of this invention can contain various organic or inorganic carrier materials, which are conventionally used for pharmaceutical purpose such as excipient (e.g., sucrose, starch, mannit, sorbit.

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 glycolestarch, sodium bicarbonate, calcium phosphate, calcium citrate, etc.), lubricant (e.g., magnesium stearate, talc, sodium laurylsulfate, etc.), flavoring agent (e.g., citric acid, entol, 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, etc.), base wax (e.g., cacao butter, polyethyleneglycol, white petrolatum, etc.). The effective ingredient may usually be administered with a unit dose of 0.01 mg/kg to 500 mg/kg, 1 to 4 times a day. However, the above dosage may be increased or decreased according to age, weight, conditions of the patient or the administering method.

Preferred embodiments of the object compound (I) are as follows :

R ¹ is [mono(or di) (lower alkyl)amino] (lower)alkyl [more preferably [mono(or di) (C- C^ alkyl)amino] (C _ι _-C ₄ )- alkyl, much more preferably 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, 5-dimethylaminopentyl, 2-diethylaminoethyl or 3-diethylaminopropyl] which may have hydroxy,

lower alkylpyrrolidinyl (more preferably C-^-C^ alkylpyrrolidinyl, much more preferably methyl- pyrrolidinyl, most preferably l-methylpyrrolidin-3- yl) , piperidyl, lower alkylpiperidyl (more preferably ^c l ^-c 4 alkylpiperidyl, much more preferably methylpiperidyl, most preferably l-methylpiperidin-4- yl) , pyrrolidinyl(lower)alkyl [more preferably pyrrolidinyl (C^-C^) alkyl, most preferably 2-pyrrolidinoethyl] which may have lower alkyl (more preferably C-^- ^ alkyl, most preferably methyl), piperidyl (lower)alkyl [more preferably piperidyl- (C -C^alkyl, most preferably 2-piperidinoethyl] or morpholinyl (lower)alkyl [more preferably morpholinyl- ( ^c l~ ^c 4)alkyl, most preferably 2-morpholinoethyl] , R ² is dihalothienyl (more preferably dichlorothienyl, most preferably 2,5-dichlorothiophen-3-yl) or dihalophenyl (more preferably dichlorophenyl, most preferably 2,5- dichlorophenyl) , and

-A- is -0- or -CH ₂ -.

More preferred embodiments of the object compound (I) are as follows :

R ¹ is lower alkylpiperidyl (more preferably C -C alkylpiperidyl, much more preferably methylpiperidyl, most preferably l-methylpiperidin-4-yl) , R^ is dihalothienyl (more preferably dichlorothienyl, most preferably 2, 5-dichlorothiophen-3-yl) or dihalophenyl (more preferably dichlorophenyl, most preferably 2,5-dichlorophenyl) , and -A- is -0-.

The following Preparations and Examples are given for the purpose of illustrating the present invention in more detail.

Preparation 1

To a mixture of methyl 3, 5-dihydroxybenzoate (20 g) and tert-butyldimethylsilyl chloride (21.5 g) in N,N- dimethylformamide (100 ml) was slowly added imidazole (20.2 g) at 20-35°C.' After stirring at room temperature for 4 hours, the reaction mixture was poured into aqueous 5% sodium hydrogen carbonate solution (500 ml) . The product was extracted with ethyl acetate (2 x 400 ml) and the organic layer was washed with water (2 x 200 ml) and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (20:1). The fractions containing the desired product were collected and evaporated to give methyl 3-(tert-butyldimethylsilyloxy)-5- hydroxybenzoate (14.62 g) . mp : 77-79°C IR (Nujol) : 3300, 1710, 1590, 1490, 1350, 1250,

1160 cm ^-1 NMR (DMS0-d ₆ , δ) : 0.19 (6H, s) , 0.95 (9H, s) , 3.62 (3H, s), 6.53 (IH, dd, J=2.3, 2.3Hz), 6.84 (IH, dd,

J=2.3, 2.3Hz), 7.00 (IH, dd, J=2.3, 2.3Hz), 9.82 (IH, s) (+) APCI MASS : 283 [M+H] ⁺

Preparation 2

To a mixture of methyl 3- (tert-butyldimethylsilyloxy) -5- hydroxybenzoate (14.0 g) , 2,6-lutidine (6.93 ml) and 4- (dimethylamino)pyridine (0.93 g) in dichloromethane (280 ml) was added dropwise trifluoromethanesulfonic anhydride (10.01 ml) at -30°C. After stirring at room temperature for 4 hours, saturated ammonium chloride solution (100 ml) was added to the reaction mixture. Two layers were separated and the aqueous layer was extracted with dichloromethane. The organic layer were combined, dried over magnesium sulfate and concentrated under reduced pressure. The residue was

dissolved in ethyl acetate (300 ml) and washed successively with water, 10% hydrochloric acid, saturated sodium hydrogen carbonate aqueous solution and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo to give methyl 3- (tert-butyldimethylsilyloxy)-5- trifluoromethylsulfonyloxybenzoate (20.42 g) . p : 30-32°C

IR (Nujol) : 1730, 1610, 1580, 1320, 1240, 1210 cm ^-1 NMR (DMSO-d ₆ , δ) : 0.24 (6H, s), 0.96 (9H, s) , 3.89 (3H, s), 7.35 (IH, dd, J=2.2, 2.2Hz), 7.46 (IH, dd,

J=2.2, 2.2Hz), 7.57 (IH, dd, J=2.2, 2.2Hz) (+) APCI MASS : 415 [M+H] ⁺

Preparation 3 A mixture of methyl 3- (tert-butyldimethylsilyloxy)-5- trifluoromethylsulfonyloxybenzoate (0.75 g) , 2,5- dichlorothiophen-3-yl-dihydroxyborane (0.50 g) , tetrakis (triphenylphosphine)palladium(0) (0.105 g) , lithium chloride (0.23 g) and 2M sodium carbonate solution (2.54 ml) in 1,2-dimethoxyethane (6 ml) was heated at 85°C and stirred vigorously for 3 hours. After being cooled to room temperature, ethyl acetate (20 ml) and 2M sodium carbonate solution (20 ml) were added to the reaction mixture. Two layers were separated and the organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diethyl ether, collected by filtration and washed with diethyl ether to give methyl 5- (2, 5-dichlorothiophen-3-yl)-3-hydroxybenzoate (0.32 g ⁾ . mp : 183-185°C

IR (Nujol) : 3300, 1700, 1600, 1320, 1200 cm" ¹ NMR (DMS0-d ₆ , δ) : 3.85 (3H, s) , 7.21 (IH, dd, J=1.5, 1.5Hz), 7.38 (IH, dd, J=1.5, 1.5Hz), 7.40 (IH, s) , 7.56 (IH, dd, J=1.5, 1.5Hz), 10.14 (IH, s) (+) APCI MASS : 303 [M+H] ⁺ , 305 [M+H] ⁺

Preparation 4

To a mixture of methyl 5- (2, 5-dichlorothiophen-3-yl)-3- hydroxybenzoate (4.3 g) and triphenylphosphine (5.58 g) in tetrahydrofuran (43 ml) was added dropwise a solution of diethyl azodicarboxylate (3.35 ml) in tetrahydrofuran (11 ml) at room temperature. After 10 minutes, a solution of 2,3- epoxypropanol (1.41 ml) in tetrahydrofuran (43 ml) was added dropwise to the mixture. The reaction mixture was stirred at room temperature overnight and then evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (50:1). The fractions containing the desired product were collected and evaporated in vacuo to give methyl 5- (2, 5-dichloro- thiophen-3-yl) -3- (2,3-epoxypropyloxy)benzoate (2.10 g) . p : 76-78°C

IR ^" (Nujol) : 1710, 1590, 1290, 1230 cm ^-1 NMR (DMS0-d ₆ , δ) : 2.75 (IH, dd, J=5.0, 2.6Hz), 2.87 (IH, dd, J=5.0, 4.4Hz), 3.33-3.40 (IH, m) , 3.88 (3H, s), 3.96 (IH, dd, J=11.4, 6.7Hz), 4.50 (IH, dd, J=11.4, 2.4Hz), 7.43 (IH, dd, J=1.6, 1.6Hz),

7.48 (IH, s), 7.51 (IH, dd, J=1.6, 1.6Hz), 7.76 (IH, dd, J=1.6, 1.6Hz)

Preparation 5 A mixture of methyl 5- (2,5-dichlorothiophen-3-yl)-3- (2,3-epoxypropyloxy)benzoate (0.60 g) and isopropylamine (0.57 ml) in methanol (12 ml) was stirred at 40°C for 4 hours and then the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (10:1).

The fractions containing the desired product were collected and evaporated in vacuo. The residue (0.58 g) was dissolved in ethanol (3 ml) and 4N hydrogen chloride in dioxane (0.693 ml) was added thereto. The mixture was concentrated and crystallized with diethyl ether and the crystalline was

collected by filtration and washed with diethyl ether to give methyl 5- (2,5-dichlorothiophen-3-yl)-3- (2-hydroxy-3- isopropylaminopropyloxy)benzoate-hydrochloride (0.61 g) . mp : 155-157°C IR (Nujol) : 3350 (br) , 1730, 1600, 1350, 1290,

1230 cm ^-1 NMR (DMSO-d ₆ , δ) : 1.27 (6H, d, J=6.5Hz), 2.90-3.30

(3H, m) , 3.88 (3H, s), 4.12-4.28 (3H, m) , 5.92 (IH, d, J=4.9Hz), 7.44 (IH, dd, J=1.6, 1.6Hz), 7.48 (IH, s), 7.52 (IH, dd, J=1.6, 1.6Hz), 7.76 (IH, dd,

J=1.6, 1.6Hz), 8.61 (IH, br s), 8.88 (IH, br s) (+) APCI MASS : 418 [M+H] ⁺ , 420 [M+H] ⁺

Preparation 6 The following compounds were obtained according to a similar manner to that of Preparation 5.

(1) Methyl 5- (2,5-dichlorothiophen-3-yl)-3- (2-hydroxy-3- tert-butylaminopropyloxy)benzoate-hydrochloride mp : 120-123 °C

IR (Nujol) : 1720, 1590, 1290 cm ^-1

NMR (DMS0-d ₆ , δ) : 1.32 (9H, s) , 2.87-3.05 (IH, m) ,

3.05-3.20 (IH, m) , 3.89 (3H, s) , 4.15-4.35 (3H, m) , 5.95 (IH, d, J=4.0Hz), 7.45 (IH, dd, J=1.6, 1.6Hz), 7.50 (IH, s), 7.53 (IH, dd, J=l.6, 1.6Hz), 7.77

(IH, dd, J=1.6, 1.6Hz), 8.56 (IH, br s) , 9.00 (IH, br s) (+) APCI MASS : 432 [M+H] ⁺

(2) Methyl 5- (2, 5-diclorothiophen-3-yl) -3- (3-diethylamino-2- hydroxypropyloxy)benzoate IR (Neat) : 3400 (br) , 1720, 1590 cm ^-1 NMR (DMS0-d ₆ , δ) : 0.94 (6H, t, J=7.0Hz), 2.35-2.60

(6H, m), 3.87 (3H, s) , 3.95-4.08 (IH, m) , 4.10-4.20 (IH, m), 4.82 (IH, d, J=4.4Hz), 7.40 (IH, s) , 1 ΛI

(IH, s), 7.49 (IH, s), 7.72 (IH, s) (+) APCI MASS : 432 [M+H] ⁺ , 434 [M+H] ⁺

Preparation 7 To a mixture of methyl 5- (2,5-dichlorothiophen-3-yl)-3- hydroxybenzoate (0.70 g) and triphenylphosphine (0.67 g) in tetrahydrofuran (7 ml) was added a solution of diethyl azodicarboxylate (0.40 ml) in tetrahydrofuran (1.7 ml) dropwise at 25°C. After being stirred for 10 minutes at room temperature, to the mixture was added a solution of

2-dimethylaminoethanol (0.26 ml) in tetrahydrofuran (7 ml) dropwise at 25°C. The reaction mixture was stirred at room temperature overnight and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (30:1). The fractions containing the desired product were collected and evaporated in vacuo. The residue was dissolved in ethanol, and excess hydrogen chloride in dioxane was added thereto. The mixture was concentrated and triturated with diethyl ether. The crystalline was collected and washed with diethyl ether to give methyl 5- (2, 5-dichlorothiophen-3-yl) -3- (2- dimethylaminomethoxy)benzoate-hydrochloride (0.38 g) . mp : 178-179°C IR (Nujol) : 3350 (br) , 2450, 1730, 1590, 1360, 1290,

1220 cm ^"1

NMR (DMSO-d ₆ , δ) : 2.85 (6H, s), 3.50-3.60 (2H, m) ,

3.89 (3H, s), 4.47-4.57 (2H, m) , 7.45 (IH, s), 7.49 (IH, s), 7.57 (IH, s), 7.80 (IH, s), 10.40 (IH, s) (+) APCI MASS : 374 [M+H] ⁺ , 376 [M+H] ⁺

Preparation 8

The following compounds were obtained according to a similar manner to that of Preparation 7.

( 1 ) Methyl 5- (2 , 5-dichlorothiophen-3-yl ) -3- [2- (pyrrolidin-1 - yl ) ethoxy] benzoate-hydrochloride mp : 142-145°C

IR (Nujol) : 1720, 1600, 1350, 1280 cm ^"1

NMR (DMSO-d ₆ , δ) : 1.85-2.05 (4H, m) , 3.05-3.20 (2H, m) , 3.57-3.67 (4H, m) , 3.89 (3H, s) , 4.49 (2H, t, J=4.8Hz), 7.47 (IH, s) , 7.49 (IH, s), 7.56 (IH, s), 7.80 (IH, s) , 10.81 (IH, br s)

(+) APCI MASS : 400 [M+H] ⁺ , 402 [M+H] ⁺

(2 ) Methyl 5- ( 2 , 5-dichlorothiophen-3-yl ) -3- [2- (piperidin- 1- yl ) ethoxy] benzoate-hydrochloride mp : 193-195°C

IR (Nujol) : 2450, 1730, 1350, 1290, 1220 cm ^"1 NMR (DMS0-d ₆ , δ) : 1.30-1.90 (6H, m) , 2.92-3.12 (2H, m) , 3.42-3.58 (4H, m) , 3.89 (3H, s) , 4.57 (2H, t, J=4.8Hz), 7.47 (IH, s), 7.49 (IH, s), 7.55 (IH, s), 7.80 (IH, s) , 10.83 (IH, br s) (+) APCI MASS : 414 [M+H] ⁺ , 416 [M+H] ⁺

(3) Methyl 5- (2, 5-dichlorothiophen-3-yl) -3- [2- (morpholin-4- yl) ethoxy]benzoate-hydrochloride p : 194-196°C

IR (Nujol) : 2400, 1720, 1600, 1350, 1290 cm ^"1 NMR (DMSO-d ₆ , δ) : 3.15-3.30 (2H, m) , 3.45-3.65 (4H, m), 3.78-3.98 (4H, m) , 3.89 (3H, s) , 4.59 (2H, t, J=4.8Hz), 7.46 (IH, s) , 7.48 (IH, s) , 7.56 (IH, s), 7.80 (IH, s) , 11.50 (IH, br s) (+) APCI MASS : 416 [M+H] ⁺ , 418 [M+H] ⁺

(4) Methyl 5- (2, 5-dichlorothiophen-3-yl) -3- (3- diethylaminopropoxy) benzoate-hydrochloride mp : 153-155°C

IR (Nujol) : 2450, 1720, 1290, 1190 cm ^"1 NMR (DMSO-d ₆ , δ) : 1.24 (6H, t, J=7.2Hz), 2.10-2.28

(2H, m) , 3.08-3.28 (6H, m) , 3.88 (3H, s), 4.21 (2H, t, J=5.9Hz), 7.42 (IH, s), 7.49 (IH, s), 7.50 (IH, s), 7.76 (IH, s), 10.43 (IH, s) (+) APCI MASS : 416 [M+H] ⁺ , 418 [M+H] ⁺

(5) Methyl 5- (2, 5-dichlorothiophen-3-yl) -3- [2- (1- methylpyrrolidin-2-yl) ethoxy]benzoate IR (Neat) : 1720, 1590, 1430, 1350, 1290, 1220 cm ^-1 NMR (DMSO-d ₆ , δ) : 1.45-1.75 (4H, ) , 1.83-2.23 (4H, m) , 2.23 (3H, s) , 2.90-3.00 (IH, m) , 3.87 (3H, s),

4.05-4.20 (2H, ) , 7.36 (IH, s), 7.45 (IH, s) , 7.46 (IH, s), 7.72 (IH, s) (+) APCI MASS : 414 [M+H] ⁺ , 416 [M+H] ⁺

(6) Methyl 5- (2, 5-dichlorothiophen-3-yl) -3- ti¬ methylpyrrolidin-3-yloxy)benzoate IR (Neat) : 1720, 1590, 1280 cm ^_1 NMR (DMSO-d ₆ , δ) : 1.75-1.92 (IH, m) , 2.26 (3H, s) ,

2.25-2.42 (2H, m) , 2.60-2.85 (3H, m) , 3.87 (3H, s) , 4.95-5.05 (IH, m) , 7.32 (IH, dd, J=1.4, 1.4Hz),

7.39 (IH, dd, J=1.4, 1.4Hz), 7.45 (IH, s) , 7.71 (IH, dd, J=1.4, 1.4Hz) (+) APCI MASS : 386 [M+H] ⁺ , 388 [M+H] ⁺

(7) Methyl 5- (2, 5-dichlorothiophen-3-yl) -3- (1- methylpiperidin-4-yloxy)benzoate IR (Neat) : 1720, 1590 cm ^-1 NMR (DMSO-d ₆ , δ) : 1.57-1.73 (2H, m) , 1.83-2.01 (2H, ) , 2.10-2.27 (2H, m) , 2.18 (3H, s), 2.50-2.68 (2H, m) , 3.87 (3H, s) , 4.47-4.60 (IH, m) , 7.39 (IH, dd,

J=1.4, 1.4Hz), 7.45 (IH, s), 7.47 (IH, dd, J=1.4, 1.4Hz), 7.71 (IH, dd, J=1.4, 1.4Hz) (+) APCI MASS : 400 [M+H] ⁺ , 402 [M+H] ⁺

(8) Methyl 5- (2, 5-dichlorothiophen-3-yl) -3- (2-

diethylaminoethoxy) benzoate-hydrochloride mp : 163-165°C

IR (Nujol) : 1720, 1590, 1290, 1240 cm ^"1

NMR (DMS0-d ₆ , δ) : 1.27 (6H, t, J=7.2Hz), 3.15-3.30

(4H, m) , 3.48-3.60 (2H, m) , 3.89 (3H, s), 4.51 (2H, t, J=4.8Hz), 7.48 (IH, dd, J=1.4, 1.4Hz), 7.49 (IH, s), 7.55 (IH, dd, J=1.4, 1.4Hz), 7.81 (IH, dd, J=1.4, 1.4Hz), 10.46 (IH, br s)

(+) APCI MASS : 402 [M+H] ⁺ , 404 [M+H] ⁺

(9) Methyl 5- (2,5-dichlorothiophen-3-yl)-3- (3- dimethylaminopropoxy)benzoate-hydrochloride mp : 168-171°C

IR (Nujol) : 1720, 1285, 1230, 1065, 760 cm ^-1 NMR (DMSO-d ₆ , δ) : 2.1-2.3 (2H, m) , 2.76 (3H, s), 2.79

(3H, s), 3.15-3.35 (2H, m) , 3.88 (3H, s), 4.21 (2H, t, J=6.0Hz), 7.41 (IH, s), 7.50 (2H, s) , 7.75 (IH, s) , 10.88 (IH, br s) (+) APCI MASS : 388 [M+H] ⁺ , 390 [M+H] ⁺

Example i

To a solution of guanidine-hydrochloride (0.41 g) in N,N-dimethylformamide (1 ml) was added sodium methoxide (28% in methanol, 0.77 ml) under nitrogen atmosphere. After being stirred for 10 minutes at room temperature, to the mixture was added a solution of methyl 5- (2, 5-dichlorothiophen-3-yl)- 3- (2-dimethylaminoethoxy)benzoate (0.35 g) in N,N- dimethylformamide (2 ml) . After being stirred for 7 hours at room temperature, the solvent was removed under reduced pressure. The residue was dissolved in a mixture of ethyl acetate (30 ml), tetrahydrofuran (30 ml) and water (30 ml). Two layers were separated and the organic layer was successively washed with water and brine, dried over sodium sulfate and evaporated in vacuo. The residue was triturated with diethyl ether and collected by filtration. The

crystalline was dissolved in ethanol and excess hydrogenchloride in dioxane was added thereto. The resultant precipitates were collected and was recrystallized from ethanol and water to give [5- (2, 5-dichlorothiophen-3-yl) -3- (2-dimethylaminoethoxy)benzoyl] guanidine-dihydrochloride (0.19 g) . mp : 197-199°C

IR (Nujol) : 3350 (br) , 1710, 1280, 1230 cm ^"1 NMR (DMSO-d ₆ , δ) : 2.86 (6H, s) , 3.54-3.64 (2H, m) , 4.52-4.62 (2H, m) , 7.57 (IH, s), 7.64 (IH, s), 7.88

(IH, s), 7.97 (IH, s), 8.67 (2H, br s) , 8.88 (2H, br s), 10.50 (IH, br s), 12.48 (IH, s) (+) APCI MASS : 401 [M+H] ⁺ , 403 [M+H] ⁺

Example 2

The following compounds were obtained according to a similar manner to that of Example 1.

(1 ) [5- (2, 5-Dichlorothioρhen-3-yl) -3- (2-hydroxy-3-isopropyl- aminopropyloxy)benzoyl] guanidine-dihydrochloride mp : 133-135°C

IR (Nujol) : 3300, 3150, 1700, 1590, 1290, 1240 cm ^"1 NMR (DMS0-d ₆ , δ) : 1.27 (6H, d, J=6.4Hz) , 2.95-3.08 (IH, m) , 3.08-3.28 (IH, m) , 3.30-3.45 (IH, ) , 4.18-4.35 (3H, m) , 5.92-5.98 (IH, m) , 7.53 (IH, s),

7.64 (IH, s), 7.80 (IH, s), 7.94 (IH, s) , 8.60 (IH, br s), 8.67 (2H, br s) , 8.86 (2H, br s), 8.90 (IH, br s) , 12.38 (IH, s) (+) APCI MASS : 445 [M+H] ⁺ , 447 [M+H] ⁺

(2) [5- (2, 5-Dichlorothiophen-3-yl) -3- [2- (pyrrolidin-1- yl) ethoxy]benzoyl] guanidine-dihydrochloride mp : 193-195°C

IR (Nujol) : 3350, 3150, 1680, 1570, 1280 cm ^"1 NMR (DMS0-d ₆ , δ) : 1.85-2.10 (4H, ) , 3.04-3.24 (2H,

29 m) , 3.55-3.70 (4H, m) , 4.57 (2H, t, J=4.8Hz), 7.58 (IH, s), 7.63 (IH, s), 7.89 (IH, S), 7.97 (IH, s), 8.67 (2H, br s) , 8.88 (2H, br s), 10.82 (IH, br s), 12.48 (IH, s) (+) APCI MASS : 427 [M+H] ⁺ , 429 [M+H] ⁺

(3) [5- (2, 5-Dichlorothiophen-3-yl) -3- [2- (piperidin-1- yl) ethoxy]benzoyl] guanidine-dihydrochloride mp : 175-178°C IR (Nujol) : 3300 (br) , 1700, 1600, 1280, 1230 cm ^"1 NMR (DMSO-d ₆ , δ) : 1.32-1.88 (6H, m) , 2.95-3.12 (2H, m) , 3.50-3.65 (4H, m) , 4.61 (2H, t, J=4.8Hz), 7.56 (IH, s), 7.62 (IH, s), 7.88 (IH, s), 7.95 (IH, s), 8.64 (2H, br s) , 8.86 (2H, br s) , 10.34 (IH, br s) , 12.45 (IH, s)

(+) APCI MASS : 441 [M+H] ⁺ , 443 [M+H] ⁺

(4) [5- (2, 5-Dichlorothiophen-3-yl) -3- [2- (morpholin-4- yl) ethoxy]benzoyl]guanidine-dihydrochloride p : 200-202°C

IR (Nujol) : 3200 (br) , 1700, 1560, 1200, 1240 cm ^"1 NMR (DMS0-d ₆ , δ) : 3.10-3.28 (2H, m) , 3.48-3.68 (4H, m) , 3.78-4.02 (4H, m) , 4.60-4.70 (2H, m) , 7.57 (IH, s), 7.62 (IH, s), 7.89 (IH, s), 7.96 (IH, s) , 8.66 (2H, br s), 8.87 (2H, br s), 11.19 (IH, br s) ,

12.44 (IH, s) (+) APCI MASS : 443 [M+H] ⁺ , 445 [M+H] ⁺

(5) [5- (2, 5-Dichlorothiophen-3-yl) -3- (3- diethyla inopropoxy)benzoyl] guanidine-dihydrochloride mp : 148-150°C

IR (Nujol) : 1700, 1550, 1300, 1220 cm ^"1 NMR (DMSO-d ₆ , δ) : 1.24 (6H, t, J=7.2Hz), 2.10-2.30

(2H, m) , 3.08-3.30 (6H, m) , 4.29 (2H, t, J=6.0Hz), 7.51 (IH, s), 7.62 (IH, s) , 7.81 (IH, s) , 7.93 (IH,

s), 8.66 (2H, br s) , 8.87 (2H, br s), 10.30 (IH, br s), 12.40 (IH, s) (+) APCI MASS : 443 [M+H] ⁺ , 445 [M+H] ⁺

(6) [5- (2, 5-Dichlorothiophen-3-yl)-3- [2- (1-methylpyrrolidin- 2-yl) ethoxy]benzoyl] guanidine-dihydrochloride mp : 174-177°C

IR (Nujol) : 3350 (br) , 1690, 1590, 1290, 1220 cm ^"1

NMR (DMSO-d ₆ , δ) : 1.68-2.48 (6H, m) , 2.82 (3H, s), 3.00-3.20 (IH, m) , 3.40-3.62 (2H, m) , 4.22-4.40

(2H, m) , 7.50 (IH, s) , 7.62 (IH, s) , 7.84 (IH, s), 7.92 (IH, s), 8.66 (2H, br s), 8.89 (2H, br s), 10.68 (IH, br s) , 12.43 (IH, s) (+) APCI MASS : 441 [M+H] ⁺ , 443 [M+H] ⁺

(7) [5- (2, 5-Dichlorothiophen-3-yl) -3- (2-hydroxy-3-tert- butylaminopropyloxy) benzoyl] guanidine-dihydrochloride mp : 95-100°C

IR (Nujol) : 3150 (br) , 1700, 1680, 1280, 1220 cm ^"1 NMR (DMSO-d ₆ , δ) : 1.33 (9H, s) , 2.85-3.05 (IH, m) ,

3.10-3.30 (IH, m) , 4.20-4.35 (3H, ) , 7.54 (IH, s), 7.66 (IH, s), 7.81 (IH, s), 7.95 (IH, s) , 8.50-8.80 (IH, m) , 8.71 (2H, br s) , 8.88 (2H, br s) , 8.80- 9.10 (IH, m) , 12.40 (IH, s) (+) APCI MASS : 459 [M+H] ⁺ , 461 [M+H] ⁺

(8) [5- (2, 5-Dichlorothiophen-3-yl) -3- (2-hydroxy-3- isopropylaminopropyloxy) benzoyl] guanidine bis (trifluoroacetate) mp : 60-65°C

NMR (DMSO-d ₆ , δ) : 1.26 (6H, d, J=6.4Hz) , 2.80-3.45

(3H, m) , 4.15-4.30 (3H, m) , 5.96 (IH, br s) , 7.52 (IH, s) , 7.58 (IH, s) , 7.71 (IH, s), 7.87 (IH, s), 8.50 (IH, br s), 8.65 (IH, br s), 8.73 (4H, br s) , 12.15 (IH, s)

(+) APCI MASS : 445 [M+H] ⁺ , 447 [M+H] ⁺

(9) [5- (2, 5-Dichlorothiophen-3-yl) -3- (3-diethylamino-2- hydroxypropyloxy) benzoyl] guanidine-dihydrochloride mp : 126-128°C

IR (Nujol) : 3300 (br) , 1700, 1590, 1290 cm ^"1

NMR (DMSO-d ₆ , δ) : 1.24 (6H, t, J=7.1Hz), 3.10-3.38

(6H, m) , 4.18-4.28 (2H, m) , 4.30-4.45 (IH, m) , 6.01 (IH, d, J=4.4Hz), 7.53 (IH, s), 7.63 (IH, s), 7.81 (IH, s), 7.94 (IH, s) , 8.63 (2H, br s), 8.85 (2H, br s), 9.60 (IH, br s) , 12.38 (IH, s) (+) APCI MASS : 459 [M+H] ⁺ , 461 [M+H] ⁺

(10) [5- (2, 5-Dichlorothiophen-3-yl) -3- (l-methylpyrrolidin-3- yloxy)benzoyl] guanidine-dihydrochloride mp : 210-212°C

IR (Nujol) : 3300, 1690, 1600, 1280, 1230 cm ^"1 NMR (DMSO-d ₆ , δ) : 2.10-2.75 (2H, m) , 2.88 (3H, s) ,

3.10-4.00 (4H, m) , 5.40-5.50 (IH, m) , 7.53 (IH, s), 7.63 (IH, s), 7.84 (IH, s) , 7.97 (IH, s), 8.66 (2H, br s), 8.88 (2H, br s), 10.87 (IH, br s) , 12.45 (IH, s) (+) APCI MASS : 413 [M+H] ⁺ , 415 [M+H] ⁺

(11) [5- (2, 5-Dichlorothiophen-3-yl) -3- (l-methylpiperidin-4- yloxy)benzoyl]guanidine-dihydrochloride mp : 245-247°C

IR (Nujol) : 3300, 1700, 1590, 1290 cm ^"1 NMR (DMSO-d ₆ , δ) : 1.83-2.22 (4H, m) , 2.77 (3H, s) , 3.05-3.57 (4H, m) , 5.00-5.10 (IH, m) , 7.50 (IH, s),

7.61 (IH, s), 7.93 (IH, s) , 7.98 (IH, s), 8.66 (2H, br s), 8.90 (2H, br s) , 10.74 (IH, br s), 12.42 (IH, s) (+) APCI MASS : 427 [M+H] ⁺ , 429 [M+H] ⁺

(12) [5- (2, 5-Dichlorothiophen-3-yl) -3- (2- diethylaminoethoxy) benzoyl] guanidine-dihydrochloride mp : 189-190°C

IR (Nujol) : 3350, 1700, 1580, 1290, 1240 cm ^"1 NMR (DMS0-d ₆ , δ) : 1.26 (6H, t, J=7.1Hz), 3.15-3.35

(4H, m) , 3.55-3.65 (2H, m) , 4.55-4.65 (2H, m) , 7.55 (IH, s), 7.63 (IH, s), 7.89 (IH, s) , 7.96 (IH, s) , 8.66 (2H, br s) , 8.88 (2H, br s), 10.32 (IH, br s), 12.47 (IH, s) (+) APCI MASS : 429 [M+H] ⁺ , 431 [M+H] ⁺

(13) [5- (2, 5-Dichlorothiophen-3-yl) -3- (3- dimethylaminopropoxy) benzoyl] guanidine-dihydrochloride mp : 174-178°C IR (Nujol) : 1695, 1290, 720 cm ^"1

NMR (DMS0-d ₆ , δ) : 2.1-2.3 (2H, m) , 2.78 (3H, s), 2.80 (3H, s), 3.1-3.3 (2H, m) , 4.27 (2H, t, J=5.7Hz), 7.50 (IH, s), 7.64 (IH, s), 7.81 (IH, s), 7.93 (IH, s), 8.70 (2H, s), 8.90 (2H, s), 10.50 (IH, br) , 12.44 (IH, s)

(+) APCI MASS : 415 [M+H] ⁺ , 417 [M+H] ⁺

Preparation 9

The following compound was obtained according to a similar manner to that of Preparation 3.

Methyl 5- (2, 5-dichlorophenyl) -3-hydroxybenzoate mp : 167-169°C

IR (Nujol) : 3300, 1700, 1600, 1330, 1200 cm ^"1 NMR (DMSO-d ₆ , δ) : 3.85 (3H, s), 7.08 (IH, dd, J=2.0, 2.0Hz), 7.40-7.45 (2H, m) , 7.46-7.58 (2H, ) , 7.61 (IH, dd, J=6.3, 2.9Hz), 10.10 (IH, s) (+) APCI MASS : 297, 299 [M+H] ⁺

Preparation 10

The following compounds were obtained according to a similar manner to that of Preparation 4.

(1) Methyl 5- (2, 5-dichlorophenyl) -3- (2-dimethylaminoethoxy) - benzoate hydrochloride p : 203-205°C

IR (Nujol) : 2450, 1730, 1340, 1230 cm ^"1

NMR (DMS0-d ₆ , δ) : 2.85 (6H, s), 3.53 (2H, t,

J=5.0Hz), 3.88 (3H, s), 4.50 (2H, t, J=5.0Hz), 7.40 (IH, dd, J=2.0, 2.0Hz), 7.50-7.70 (5H, m) , 10.56

(IH, br s) (+) APCI MASS : 368, 370 [M+H] ⁺

(2) Methyl 5- (2, 5-dichlorophenyl) -3- (3- dimethylaminopropoxy)benzoate hydrochloride mp : 195-197°C

IR (Nujol) : 2600, 1720, 1340, 1230 cm ^"1 NMR (DMSO-d ₆ , δ) : 2.12-2.28 (2H, m) , 2.78 (6H, s),

3.23 (2H, t, J=7.6Hz), 3.88 (3H, s) , 4.20 (2H, t, J=6.0Hz), 7.31 (IH, dd, J=1.6, 1.6Hz), 7.50-7.66

(5H, m) , 10.58 (IH, br s) (+) APCI MASS : 382, 384 [M+H] ⁺

Preparation 11 The following compounds were obtained according to a similar manner to that of Preparation 7.

(1) Methyl 3- (l-tert-butyloxycarbonylpiperidin-4-yloxy) -5- (2, 5-dichlorothiophen-3-yl) benzoate IR (Nujol) : 3400 (br) , 1700, 1590, 1280, 1230,

1170 cm ^"1 NMR (DMSO-d ₆ , δ) : 1.41 (9H, s) , 1.48-1.68 (2H, ) , 1.85-2.03 (2H, m) , 3.15-3.35 (2H, m) , 3.62-3.78 (2H, m), 3.87 (3H, s) , 4.70-4.85 (IH, m) , 7.44 (IH, dd, J=1.4, 1.4Hz), 7.48 (IH, s) , 7.50 (IH, dd,

J=1 . 4 , 1 . 4Hz ) , 7 . 72 ( IH, dd, J=1 . 4 , 1 . 4Hz ) ( + ) APCI MASS : 386 , 388 [M-Boc+H ] +

(2 ) Methyl 3- [2- (N-tert-butyloxycarbonyl-N-methylammo) - ethoxy] -5- ( 2 , 5-dιchlorothιophen-3-yl ) benzoate

IR (Neat) : 1720, 1690, 1590, 1290, 1230 cm ^"1 NMR (DMSO-d ₆ , δ) : 1.35 (9H, s) , 2.88 (3H, s), 3.56 (2H, t, J=5.5Hz), 3.87 (3H, s), 4.22 (2H, t, J=5.5Hz), 7.41 (IH, s), 7.47 (IH, s) , 7.48 (IH, s) , 7.74 (IH, s)

(+) APCI MASS : 360, 362 [M-Boc+H] ⁺

(3) Methyl 3- [3- (N-tert-butyloxycarbonylamino)propoxy] -5-

(2, 5-dιchlorothιophen-3-yl)benzoate IR (Neat) : 3350, 1720, 1590 cm ^"1

NMR (DMSO-d ₆ , δ) : 1.37 (9H, s), 1.86 (2H, tt, J=6.3, 6.5Hz), 3.06-3.16 (2H, m) , 3.88 (3H, s) , 4.09 (2H, t, J=6.3Hz), 6.85-6.95 (IH, m) , 7.37 (IH, dd, J=1.4, 1.4Hz), 7.44 (IH, s), 7.47 (IH, dd, J=1.4, 1.4Hz), 7.73 (IH, dd, J=1.4, 1.4Hz)

(+) APCI MASS : 360, 362 [M-Boc+H] ⁺

Preparation 12

To a solution of methyl 3- [3- (N-tert-butyloxycarbonyl- ammo)propoxy] -5- (2, 5-dιchlorothιophen-3-yl)benzoate (0.70 g) in N,N-dιmethylformamide (7 ml) was added 60o sodium hydride (0.091 g) slowly at room temperature. Methyl iodide (0.29 ml) was added dropwise to the mixture and the reaction mixture was stirred at 50°C overnight. After cooling, water and ethyl acetate were added to the reaction mixture. Two layers were separated and the organic layer was washed with water (twice) and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on aluminum oxide eluting with a mixture of toluene and ethyl acetate (50:1) to afford methyl

3- _[3 -( _N -tert-butyloxycarbonyl-N-methylamino)propoxy]-5- (2, 5- dichlorothiophen-3-yl)benzoate (0.46 g) . IR (Neat) : 1720, 1590 cm ^"1

NMR (DMS0-d ₆ , δ) : 1.34 (9H, s), 1.94 (2H, tt, J=6.5, 6.1Hz), 2.79 (3H, s) , 3.35 (2H, t, J=6.5Hz), 3-.87 (3H, s), 4.08 (2H, t, J=6.1Hz), 7.38 (IH, dd, J=1.4, 1.4Hz), 7.45 (IH, s), 7.46 (IH, dd, J=1.4, 1.4Hz), 7.73 (IH, dd, J=1.4, 1.4Hz) (+) APCI MASS : 374 [M+H-Boc] ⁺

P eparation 13

To a mixture of methyl 5- (2, 5-dichlorothiophen-3-yl) -3- hydroxybenzoate (0.80 g) in methylethylketone (8 ml) was added powdered potassium carbonate (0.36 g) and 1,4- dibro obutane (0.95 ml) . The mixture was heated to reflux for 6 hours and then cooled to room temperature. Insoluble matter was filtered off and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with toluene to afford methyl 5- (2,5- dichlorothiophen-3-yl)-3- (4-bromobutoxy) enzoate (0.87 g) as an oil.

IR (Neat) : 1720, 1590, 1350, 1290, 1230 cm ^"1

NMR (DMSO-d _β , δ) : 1.80-2.08 (4H, m) , 3.63 (2H, t,

J=6.4Hz), 3.87 (3H, s), 4.13 (2H, t, J=6.2Hz), 7.39 (IH, dd, J=1.4, 1.4Hz), 7.47 (IH, s), 7.48 (IH, dd,

J=1.4, 1.4Hz), 7.74 (IH, dd, J=1.4, 1.4Hz) (+) APCI MASS : 437, 439, 441 [M+H] ⁺

Preparation 14 The following compound was obtained according to a similar manner to that of Preparation 13.

Methyl 5- (2, 5-dichlorophenyl) -3- (4-bromobutoxy)benzoate IR (Nujol) : 1720, 1590, 1430, 1330 cm ^"1 NMR (DMSO-d ₆ , δ) : 1.78-2.06 (4H, ) , 3.62 (2H, t,

J=6.4Hz), 3.87 (3H, s), 4.13 (2H, t, J=6.0Hz), 7.29 (IH, dd, J=1.6, 1.6Hz), 7.48-7.64 (5H, m) (+) APCI MASS : 431, 433, 435 [M+H] ⁺

Preparation 15

To a mixture of methyl 5-(2, 5-dichlorothiophen-3-yl) -3- (4-bromobutoxy)benzoate (0.80 g) in tetrahydrofuran (4 ml) was added 50% aqueous dimethylamine solution (4 ml) . After being stirred at room temperature for 2 hours, the reaction mixture was poured into water. The product was extracted with ethyl acetate and the organic layer was washed with water and brine, dried over sodium sulfate and evaporated in vacuo. The residue (0.71 g) was dissolved in ethanol (7 ml) and 4N hydrogenchloride in dioxane (0.66 ml) was added to the solution. Diethyl ether (10 ml) was added to the mixture and the crystalline was collected by filtration, washed with diethyl ether to give methyl 5- (2, 5-dichlorothiophen-3-yl) -3- (4-dimethylaminobutoxy)benzoate hydrochloride (0.46 g) . mp : 170-171°C IR (Nujol) : 2600, 1730, 1350, 1290 cm ^-1

NMR (DMSO-d ₆ , δ) : 1.75-1.92 (4H, m) , 2.74 (6H, s),

3.07-3.15 (2H, m) , 3.88 (3H, s), 4.10-4.18 (2H, m) , 7.40 (IH, dd, J=1.4, 1.4Hz), 7.47 (IH, s), 7.49 (IH, dd, J=1.4, 1.4Hz), 7.74 (IH, dd, J=1.4, 1.4Hz) , 10.31 (IH, br s)

(+) APCI MASS : 402, 404 [M+H] ⁺

Preparation 16

The following compound was obtained according to a similar manner to that of Preparation 15.

Methyl 5- (2,5-dichlorophenyl) -3- (4- dimethylaminobutoxy)benzoate hydrochloride mp : 204-205°C IR (Nujol) : 2600, 1720, 1340, 1230 cm ^"1

NMR (DMSO-d ₆ , δ) : 1.78-1.90 (4H, m) , 2.73 (6H, s), 3.05-3.18 (2H, m) , 3.87 (3H, s), 4.13 (2H, t, J=5.5Hz), 7.30 (IH, dd, J=1.6, 1.6Hz), 7.49-7.61 (4H, m) , 7.64 (IH, d, J=8.4Hz), 10.54 (IH, br s) (+) APCI MASS : 396, 398 [M+H] ⁺

Preparation 17

To a suspension of 2-dimethylaminoethyltriphenyl- phosphonium bromide (19.16 g) in tetrahydrofuran (100 ml) was added dropwise n-butyl lithium (27.4 ml) at -78°C under nitrogen atmosphere. After being stirred for 30 minutes at the same temperature, to the reaction mixture was added dropwise methyl 3-benzyloxy-5-formylbenzoate (10.0 g) in tetrahydrofuran (50 ml) and the whole was being allowed to the ambient temperature, stirred for 2.5 hours. The mixture was poured into a mixture of ethyl acetate (100 ml) and water (100 ml) and adjusted to pH 10.0 with 10% hydrochloric acid. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (400 ml) eluting with a mixture of chloroform and methanol (20:1). The fractions containing the desired product were collected and evaporated in vacuo. The residue was dissolved in methanol (90 ml) . 10% Palladium-carbon (1.2 g, 50% wet) was added to this solution and the mixture was subjected to catalytic reduction at ambient temperature under atmospheric pressure for 2 hours. - The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel (400 ml) eluting with a mixture of chloroform, methanol and triethylamine

(100:10:1). The fractions containing the product were collected and evaporated in vacuo to afford methyl 5- (3- dimethylaminopropyl)-3-hydroxybenzoate (1.60 g) . IR (Film) : 1720, 1585, 1135, 820, 765 cm ^"1 NMR (DMSO-d ₆ , δ) : 1.55-1.80 (2H, m) , 2.20 (2H, t,

J=6.9Hz), 2.56 (2H, t, J=7.3Hz), 3.81 (3H, s), 6.86 (IH, s), 7.17 (IH, s), 7.23 (IH, s), 9.69 (IH, br s) (+) APCI MASS : 238 [M+H] ⁺

Preparation 18

The following compound was obtained according to a similar manner to that of Preparation 17.

Methyl 5- (5-dimethylaminopentyl) -3-hydroxybenzoate IR (Film) : 1710, 1150, 1105, 870, 765 cm ^"1 NMR (DMSO-d ₆ , δ) : 1.1-1.4 (2H, m) , 1.45-1.61 (4H, m) , 2.49 (6H, s), 2.45-2.75 (4H, m) , 3.81 (3H, s), 6.87 (IH, s), 7.18 (IH, s), 7.23 (IH, s) , 9.76 (IH, br s)

(+) APCI MASS : 266 [M+H] ⁺

Preparation 19

To a solution of methyl 5- (3-dimethylaminopropyl) -3- hydroxybenzoate (1.28 g) and triethylamine (0.38 ml) in 1, 2-dichloroethane (20 ml) was added dropwise trifluoromethanesulfonic anhydride (1.1 ml) at -10°C. The reaction mixture was stirred at room temperature for 3 hours. 10% Sodium carbonate aqueous solution was added to the reaction mixture and the aqueous layer was extracted with chloroform (50 ml) . The combined organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give methyl 5- (3-dimethylaminopropyl) -3- trifluoromethylsulfonyloxybenzoate (1.63 g) . IR (Film) : 1720, 1420, 1140, 820, 765 cm ^"1

NMR (DMSO-d ₆ , δ) : 1.60-1.80 (2H, m) , 2.15 (6H, s),

2.20 (2H, t, J=6.9Hz), 2.75 (2H, t, J=7.4Hz), 3.89 (3H, s), 7.69 (IH, s), 7.76 (IH, s) , 7.92 (IH, s) (+) APCI MASS : 370 [M+H] ⁺

Preparation 20

The following compound was obtained according to a similar manner to that of Preparation 19.

Methyl 5- (5-dimethylaminopentyl) -3- trifluoromethylsulfonyloxybenzoate

IR (Film) : 1725, 1585, 1135, 820 cm ^"1 NMR (DMS0-d ₆ , δ) : 1.1-1.5 (4H, m) , 1.5-1.7 (2H, m) , 2.11 (6H, s), 2.19 (2H, t, J=7.3Hz), 2.74 (2H, t, J=7.4Hz), 3.89 (3H, s) , 7.69 (IH, s) , 7.76 (IH, s) ,

7.91 (IH, s) (+) APCI MASS : 398 [M+H] ⁺

Preparation 21 A mixture of methyl 5- (3-dimethylaminopropyl) -3- trifluoro ethylsulfonyloxybenzoate (1.0 g) , (2,5- dichlorothiophen-3-yl)dihydroxyborane (0.64 g) , tetrakis (triphenylphosphine)palladium(O) (0.1 g) and triethylamine (0.75 g) in N,N-dimethylformamide (10 ml) was heated at 90°C for 4.5 hours under nitrogen atmosphere.

After evaporating the solvent, the residue was dissolved in a mixture of ethyl acetate (50 ml) and water (50 ml) . The organic layer was successively washed with 10% sodium carbonate aqueous solution and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel (100 ml) eluting with a mixture of chloroform and methanol (20:1). The fractions containing the desired product were collected and evaporated in vacuo to afford methyl 3- (2, 5-dichlorothiophen-3-yl)-5- (3- dimethylaminopropyl)benzoate (0.65 g) .

IR (Film) : 1725, 1140, 1030, 820 cm ^"1

NMR (DMSO-d ₆ , δ) : 1.65-1.82 (2H, m) , 2.15 (6H, s) , 2.2- 2.35 (2H, m) , 2.65-2.8 (2H, m) , 3.87 (3H, s), 7.46 (IH, s), 7.69 (IH, s) , 7.83 (IH, s) , 7.97 (IH, s)

Preparation 22

The following compounds were obtained according to a similar manner to that of Preparation 21.

(1) Methyl 3- (2, 5-dichlorophenyl) -5- (5-dimethylaminopentyl) - benzoate

IR (Film) : 1720, 1095, 810, 765 cm ^"1 NMR (DMS0-d ₆ , δ) : 1.2-1.55 (4H, m) , 1.55-1.75 (2H, ) , 2.13 (6H, s) , 2.22 (2H, t, J=6.8Hz), 2.72 (2H, t, J=7.3Hz), 3.87 (3H, s), 7.45-7.65 (4H, m) , 7.81-

7.85 (2H, m) (+) APCI MASS : 394 [M+H] ⁺ , 396 [M+H] ⁺

(2) Methyl 3- (2, 5-dichlorophenyl) -5- (3-dimethylaminopropyl) - benzoate

IR (Film) : 1720, 1585, 1140, 820 cm ^"1

NMR (DMSO-d ₆ , δ) : 1.7-1.95 (2H, m) , 2.18 (6H, s),

2.2-2.35 (2H, m) , 2.70-2.85 (2H, m) , 3.87 (3H, s), 7.4-8.0 (6H, m)

Example 3

The following compounds were obtained according to a similar manner to that of Example 1.

(1) [5- (2, 5-Dichlorophenyl) -3- (2-dimethylaminoethoxy) - benzoyl] guanidine dihydrochloride mp : 170-173A

IR (Nujol) : 3300, 1690, 1600, 1310, 1230 cm ^"1 NMR (DMSO-d ₆ , δ) : 2.86 (6H, s), 3.56 (2H, t, J=5.0Hz), 4.58 (2H, t, J=5.0Hz), 7.45 (IH, s), 7.54

(IH, dd, J=8.0, 2.4Hz), 7.62-7.68 (2H, m) , 7.81 (IH, s), 7.95 (IH, s), 8.67 (2H, br s), 8.85 (2H, br s), 10.60 (IH, br s), 12.45 (IH, br s) (+) APCI MASS : 395, 397 [M+H] ⁺

(2) [5- (2, 5-Dichlorophenyl) -3- (3-dimethylaminopropoxy) - benzoyl] guanidine dihydrochloride mp : 216-218°C

IR (Nujol) : 3300, 2650, 1700, 1580, 1310, 1230 cm ^"1 NMR (DMSO-d ₆ , δ) : 2.12-2.28 (2H, m) , 2.78 (6H, s),

3.24 (2H, t, J=7.3Hz), 4.28 (2H, t, J=6.0Hz), 7.37 (IH, s), 7.53 (IH, dd, J=8.6, 2.4Hz) , 7.62-7.67 (2H, m) , 7.78 (IH, s) , 7.88 (IH, s), 8.71 (2H, br s), 8.87 (2H, br s), 10.60 (IH, br s) , 12.41 (IH, br s)

(+) APCI MASS : 409, 411 [M+H] ⁺

(3) [5- (2, 5-Dichlorophenyl) -3- (4-dimethylaminobutoxy) - benzoyl] guanidine dihydrochloride mp : 141 - 143 °C

IR (Nujol) : 3300, 1700, 1310, 1230 cm ^"1

NMR (DMS0-d ₆ , δ) : 1.78-1.92 (4H, m) , 2.74 (6H, s),

3.08-3.20 (2H, m) , 4.18-4.28 (2H, m) , 7.36 (IH, dd, J=1.6, 1.6Hz) , 7.53 (IH, dd, J=8.6, 2.5Hz) , 7.62- 7.67 (2H, m) , 7.74 (IH, s) , 7.89 (IH, s) , 8.70 (2H, br s), 8.89 (2H, br s), 10.42 (IH, br s), 12.39 (IH, s) (+) APCI MASS : 423, 425 [M+H] ⁺

(4) [5-(2,5-Dichlorothiophen-3-yl)-3-(4- dimethylaminobutoxy)benzoyl] guanidine dihydrochloride mp : 135-137°C

IR (Nujol) : 3350, 1700, 1600, 1340, 1280 cm ^"1 NMR (DMSO-d ₆ , δ) : 1.78-1.92 (4H, m) , 2.75 (6H, s) , 3.07-3.22 (2H, m) , 4.15-4.25 (2H, m) , 7.48 (IH, s) ,

7.62 (IH, s), 7.83 (IH, s) , 7.91 (IH, s) , 8.71 (2H, br s), 8.92 (2H, br s), 10.45 (IH, br s), 12.44 (IH, s) (+) APCI MASS : 429, 431 [M+H] ⁺

(5) [5- (2, 5-Dichlorothiophen-3-yl) -3- (piperidin-4- yloxy) benzoyl] guanidine dihydrochloride mp : 221-223°C

IR (Nujol) : 1690, 1550, 1290, 1270, 1230 cm ^"1 NMR (DMSO-d ₆ , δ) : 1.85-2.03 (2H, ) , 2.13-2.30 (2H, m) , 3.10-3.45 (4H, m) , 4.92-5.05 (IH, m) , 7.53 (IH, s) , 7.59 (IH, s), 7.91 (IH, s), 7.95 (IH, s) , 8.64 (2H, br s), 8.90 (2H, br s) , 9.02 (2H, br s), 12.40 (IH, s) (+) APCI MASS : 413, 415 [M+H] ⁺

(6) [5- (2, 5-Dichlorothiophen-3-yl) -3- (2-methylaminoethoxy) - benzoyl] guanidine dihydrochloride mp : 260-261°C IR (Nujol) : 3250, 1690, 1600, 1570, 1290, 1230 cm ^"1 NMR (DMSO-d ₆ , δ) : 2.64 (3H, s) , 3.30-3.45 (2H, m) ,

4.47 (2H, t, J=4.9Hz), 7.57 (IH, s), 7.65 (IH, s), 7.83 (IH, s) , 7.98 (IH, s), 8.67 (2H, br s), 8.87 (2H, br s) , 9.10 (2H, br s) , 12.49 (IH, s) (+) APCI MASS : 387, 389 [M+H] ⁺

(7) [5- (2, 5-Dichlorothiophen-3-yl) -3- (3-methylaminopropoxy) - benzoyl] guanidine dihydrochloride mp : 233-234°C IR (Nujol) : 3300, 1680, 1290, 1230 cm ^"1

NMR (DMSO-d ₆ , δ) : 2.10-2.20 (2H, m) , 2.57 (3H, s) ,

3.01-3.18 (2H, m) , 4.28 (2H, t, J=6.0Hz), 7.51 (IH, s) , 7.63 (IH, s), 7.80 (IH, s) , 7.94 (IH, s), 8.68 (2H, br s) , 8.89 (4H, br s) , 12.42 (IH, s) (+) APCI MASS : 401, 403 [M+H] ⁺

(8) [5- (2, 5-Dichlorophenyl) -3- (5-dimethylaminopentyl) - benzoyl] guanidine dihydrochloride mp : 122-125°C IR (Nujol) : 1710, 1310, 1260, 1230, 1100, 875 cm ^"1

NMR (DMSO-d ₆ , δ) : 1.25-1.50 (2H, m) , 1.55-1.80 (4H, ) , 2.72 (6H, s), 2.60-2.85 (2H, m) , 2.90-3.15 (2H, ) , 7.49-7.70 (4H, m) , 8.01 (IH, s), 8.19 (IH, s), 8.71 (2H, br s) , 8.90 (2H, br s), 10.40 (IH, br s), 12.40 (IH, s)

(+) APCI MASS : 421 [M+H] ⁺ , 423 [M+H] ⁺

(9) [3- (2, 5-Dichlorophenyl) -5- (3-dimethylaminopropyl) - benzoyl]guanidine dihydrochloride mp : 160-162°C (fuse)

IR (Nujol) : 1705, 1260, 1230, 1100, 750 cm ^'1 NMR (DMSO-d ₆ , δ) : 2.0-2.3 (2H, m) , 2.76 (6H, s),

2.7-2.9 (2H, m) , 3.0-3.2 (2H, m) , 7.5-7.75 (4H, m) , 8.03 (IH, s), 8.22 (IH, s) , 8.70 (2H, br s), 8.89 (2H, br s) , 10.50 (IH, br s) , 12.46 (IH, s)

(+) APCI MASS : 393 [M+H] ⁺ , 395 [M+H] ⁺

(10) [3- (2, 5-Dichlorothiophen-3-yl) -5- (3- dimethyla inopropyl)benzoyl]guanidine dihydrochloride mp : 252-254A (dec.)

IR (Nujol) : 3350, 1695, 1280, 1225, 1035, 750 cm ^"1 NMR (DMSO-d ₆ , δ) : 2.0-2.25 (2H, m) , 2.74 (6H, s),

2.70-2.90 (2H, ) , 3.0-3.2 (2H, m) , 7.62 (IH, s) , 7.83 (IH, s), 8.16 (2H, s) , 8.69 (2H, br s) , 8.90 (2H, br s) , 10.50 (IH, br s) , 12.49 (IH, s)

(+) APCI MASS : 399 [M+H] ⁺ , 401 [M+H] ⁺