Quinoline-4-carbonylguanidine derivatives, process for producing the same and pharmaceutical preparations containing the compounds
BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     The present invention relates to novel quinoline-4-carbonylguanidine derivatives or pharmaceutically acceptable salts thereof. More specifically, the present invention relates to an agent which contains the above-mentioned compounds and which is particularly useful as an inhibitor of an Na +  /H +   exchanger (hereinafter referred to as &#34;NHE&#34;) for treating or preventing hypertension, arrhythmia, myocardial infarction, angina pectoris, arteriosclerosis, diabetic complication, fibrosis of lung, liver, kidney and the like, cell growth of vascular smooth muscle, cardiac muscle, prostate and the like, and cancers, a protective solution of internal organs cut from the body for transplantation or internal organs transplanted, and a diagnostic agent. 
     2. Description of the Related Art 
     It has been known that when the pH in cells changes, the activity of enzymes or ion channels in cells also changes, which greatly influences physiological functions of the cells. Accordingly, a mechanism of regulating an intracellular pH has been long studied, and the presence of various ion exchangers that contribute to maintenance of homeostasis of an intracellular pH in cells has been clarified. NHE is one of these systems, and a variety of physiological functions such as regulation of a pH in cells, cell volumes, cell growth and the like have become known. In recent years, it has become clear through experiments that hormones, growth factors and intracellular acidosis activate NHE and result in a cytoplasmic alkalinization [Cir. Res., 57, 773-788 (1985)]. These NHE activators attract attention as factors that cause various diseases, and studies for clarifying the relationship between enhanced NHE activity and these diseases are now assiduously being conducted. With respect to study reports concerning NHE, there are general reports, such as Cir. Res., 57, 773-788 (1985) and Hypertension Hypertension, 21, 607-617 (1993). 
     Recently, it has been reported that NHE is activated in myocardial ischemia and reperfusion [Cir. Res., 66, 1156-1159 (1990)], and that inhibition of NHE is effective for preventing disorders caused by myocardial ischemia and the consequential arrhythmia [Cir. Res.,73, 269-275, (1993)]. Accordingly, the NHE inhibitor is useful for preventing or treating angina pectoris and myocardial infarction, ischemic arrhythmia, reperfusion arrhythmia, organ disorders following ischemia and reperfusion, cerebral ischemic disorders, cerebral apoplexy and ischemic diseases of limbs and peripheral organs. Further, it is useful as an agent for myocardial protection and organ protection under anoxic condition and reperfusion state in surgical operation or transplantation of internal organs, or as an ingredient of a protective solution for treating or preventing disorders of internal organs cut from the body for transplantation or internal organs transplanted. 
     The relationship between NHE activity and hypertension has attracted attention so far. Recently, hyperfunction of NHE has been observed in cells such as platelets, erythrocytes, leukocytes and the like of patients suffering from essential hypertension [Hypertension, 21, 607-617 (1993)], and the relationship between NHE and hypertension has been clarified. 
     Further, it has been reported that in many cells, NHE participates in cell growth through inclusion of Na +   into cells and intracellular alkalinization, and that amiloride having NHE inhibitory activity suppresses cardiac hypertrophy [Circulation, 86 ( Suppl. I) I -177 (1992)]. That is, it is suggested that the NHE inhibitor is useful as an agent for preventing or treating diseases caused by excessive cell growth with an enhanced NHE activity, such as arteriosclerosis, vascular restenosis after percutaneous transluminal coronary angioplasty (PTCA) associated with a proliferation of vascular smooth muscle cells, rheumatoid arthritis with a proliferation of synovial cells, renal glomerulosclerosis with a proliferation of mesangial cells, pulmonary, hepatic and renal fibrosis with a proliferation of fiblobrasts, diabetic complication caused by vascularization, cardiac hypertrophy, prostatic hypertrophy and the like, and cancers [Cir. Res., 57, 773-788 (1985), Proc. Natl. Acad. Sci. USA., 86, 4525-4529 (1989), and Cir. Res., 73, 269-275 (1993)]. 
     Still further, the relationship between activation of NHE and inflammation has been reported [Am. J. Physiol., 267, C1623-C1632 (1994)], and the NHE inhibitor is useful as an agent for treating or preventing diseases caused by infiltration of leukocytes associated with enhanced NHE activity, such as inflammation. 
     As stated above, it has been known that NHE activity is enhanced in various states of NHE. The NHE activity can easily be measured by using a strong NHE inhibitor to easily obtainable cells such as platelets, erythrocytes and leukocytes. That is, the NHE inhibitor is also useful as a diagnostic agent for hypertension, diseases caused by cell growth, diabetes and the like. 
     Amiloride derivatives containing a guanidinocarbonyl group have been used in animal tests as an NHE inhibitor so far. It has been reported that these compounds suppress simultaneously Na +   (sodium ion) channels and an Na +  /Ca +   (sodium ion/calcium ion) exchanger in concentrations in which they suppress NHE, and with respect to the NHE inhibitory activity, IC 50  (50% inhibitory concentration) is approximately 100 μM which is not satisfactory [J. Membrane, Biol., 105, 1-21 (1988)]. The above-mentioned amiloride derivatives and benzoylguanidine derivatives [JP A 3-106858 (Family: EP416499), and the like; hereinafter &#34;JP A&#34; means Publication of Japanese Patent Application] which are monocyclic compounds have been known as an NHE inhibitor. On the other hand, isoquinoline derivatives [JP A 6-211799 (Family: EP590455)], indole derivatives [JP A 7-10839 (Family: EP622356)] and quinoline derivatives (EP682017) have been known as compounds having a fused ring. The quinoline derivatives described in EP682017 are compounds containing a guanidinocarbonyl group in the 3-position. With respect to the NHE inhibitory activity, IC 50  is several micromoles, and it is not satisfactory. 
     The present invention is to provide compounds which have strong NHE inhibitory activity and which are useful as an agent for preventing or treating various diseases caused by hyperfunction of NHE and as a diagnostic agent. 
     SUMMARY OF THE INVENTION 
     The present inventors have assiduously conducted investigations to solve the above-mentioned problems, and have consequently found that quinoline-4-carbonylguanidine derivatives having a phenyl group in the 2-position have strong NHE inhibitory activity. This finding has led to the completion of the present invention. That is, the present invention relates to: 
     [1] A quinoline-4-carbonylguanidine derivative represented by formula (1) ##STR2## wherein 
     R 1 , R 2 , R 3  and R 4  are the same or different and each represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, a halogen atom, a nitro group, an amino group, a hydroxyl group, an alkyloxy group having from 1 to 6 carbon atoms, an alkyloxy group having from 1 to 6 carbon atoms and containing a terminal alkyloxy group having from 1 to 6 carbon atoms, an alkylsulfonylamino group having from 1 to 6 carbon atoms, or an alkanoylamino group having from 2 to 6 carbon atoms, 
     X 1 , X 2 , X 3 , X 4  and X 5  are the same or different and each represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, a halogen atom, a nitro group, an amino group, a hydroxyl group, a trifluoromethyl group, an alkyloxy group having from 1 to 6 carbon atoms, an alkyloxy group having from 1 to 6 carbon atoms and containing a terminal alkyloxy group having from 1 to 6 carbon atoms, or a trifluoromethoxy group, and 
     Y represents a hydrogen atom, or an alkyl group having from 1 to 6 carbon atoms, 
     or a pharmaceutically acceptable salt thereof. 
     [2] The quinoline-4-carbonylguanidine derivative or the pharmaceutically acceptable salt thereof as mentioned in [1], wherein one or two of R 1 , R 2 , R 3  and R 4  represent an alkyloxy group having from 1 to 6 carbon atoms. 
     [3] The quinoline-4-carbonylguanidine derivative or the pharmaceutically acceptable salt thereof as mentioned in [1], wherein X 1  represents a methyl group. 
     [4] The quinoline-4-carbonylguanidine derivative or the pharmaceutically acceptable salt thereof as mentioned in [2], wherein X 1  represents a methyl group. 
     [5] A process for producing the quinoline-4-carbonylguanidine derivative of [1], [2], [3] or [4], which comprises reacting a quinoline-4-carboxylic acid derivative represented by formula (2) ##STR3## 
     wherein 
     L represents a hydroxyl group, or a leaving group that can easily be substituted by means of a nucleophilic reagent, and 
     R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , X 4 , X 5  and Y are as defined in formula (1) 
     with guanidine. 
     [6] A pharmaceutical composition containing as an active ingredient the quinoline-4-carbonylguanidine derivative or the pharmaceutically acceptable salt thereof as mentioned in [1], [2], [3] or [4]. 
     [7] A Na +  /H +   exchanger inhibitor containing as an active ingredient the quinoline-4-carbonylguanidine derivative or the pharmaceutically acceptable salt thereof as mentioned in [1], [2], [3] or [4]. 
     [8] An agent for treating or preventing hypertension, the agent containing as an active ingredient the quinoline-4-carbonylguanidine derivative or the pharmaceutically acceptable salt thereof as mentioned in [1], [2], [3] or [4]. 
     [9] An agent for treating or preventing arrhythmia, the agent containing as an active ingredient the quinoline-4-carbonylguanidine derivative or the pharmaceutically acceptable salt thereof as mentioned in [1], [2], [3] or [4]. 
     [10] An agent for treating or preventing angina pectoris, reperfusion arrhythmia and myocardial infarction caused by ischemia, ischemic arrhythmia, organ disorders caused by ischemia and reperfusion, cerebral ischemic disorders, cerebral apoplexy and ischemic diseases of limbs and peripheral organs, the agent containing as an active ingredient the quinoline-4-carbonylguanidine derivative or the pharmaceutically acceptable salt thereof as mentioned in [1], [2], [3] or [4]. 
     [11] An agent for treating or preventing diseases caused by cell proliferation or hypertrophy, the agent containing as an active ingredient the quinoline-4-carbonylguanidine derivative or the pharmaceutically acceptable salt thereof as mentioned in [1], [2], [3] or [4]. 
     [12] An agent for treating or preventing organ disorders caused by ischemia in a surgical operation or transplantation of internal organs, the agent containing as an active ingredient the quinoline-4-carbonylguanidine derivative or the pharmaceutically acceptable salt thereof as mentioned in [1], [2], [3] or [4]. 
     [13] An agent for treating or preventing diseases caused by infiltration of leukocytes, the agent containing as an active ingredient the quinoline-4-carbonylguanidine derivative or the pharmaceutically acceptable salt thereof as mentioned in [1], [2], [3] or [4]. 
     [14] A protective solution internal organs cut from the body for transplantation or internal organs transplanted, the protective solution containing as an active ingredient the quinoline-4-carbonylguanidine derivative or the pharmaceutically acceptable salt thereof as mentioned in [1], [2], [3] or [4]. 
     [15] An agent for diagnosis of hypertension, diseases caused by cell growth and diabetes through inhibition of a Na +  /H +   exchanger, said agent containing as an active ingredient the quinoline-4-carbonylguanidine derivative or the pharmaceutically acceptable salt thereof as mentioned in [1], [2], [3] or [4]. 
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The present invention will be described in detail below. 
     R 1  , R 2 , R 3  and R 4  in formula (1) are explained hereinafter. The alkyl group having from 1 to 6 carbon atoms, as represented by R 1 , R 2 , R 3  and R 4 , is a linear, branched or cyclic alkyl group having from to 6 carbon atoms. Examples of the alkyl group include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, 2-methylpropyl, 1-methylpropyl, tert-butyl, 2-methylbutyl, 1-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 1,2,2-trimethylpropyl, 1,1-dimethylbutyl, 1,1,2-trimethylpropyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups. 
     Examples of the halogen atom include iodine, bromine, chlorine and fluorine atoms. 
     The alkyloxy group having from 1 to 6 carbon atoms is a linear, branched or cyclic alkyloxy group having from 1 to 6 carbon atoms. Examples of the alkyloxy group include methoxy, ethoxy, n-propyloxy, n-butyloxy, n-pentyloxy, n-hexyloxy, isopropyloxy, 2-methylpropyloxy, 1-methylpropyloxy, tert-butyloxy, 2-methylbutyloxy, 1-methylbutyloxy, 1,2-dimethylpropyloxy, 1,1-dimethylpropyloxy, 2,2-dimethylpropyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, 1,2,2-trimethylpropyloxy, 1,1-dimethylbutyloxy, 1,1,2-trimethylpropyloxy, 2,2-dimethylbutyloxy, 1,3-dimethylbutyloxy, 2,3-dimethylbutyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy groups. 
     The alkyloxy group having from 1 to 6 carbon atoms and containing a terminal alkyloxy group having from 1 to 6 carbon atoms include methoxymethyloxy, ethoxymethyloxy, n-propyloxyethyloxy, isopropyloxypropyloxy, cyclopropyloxybutyloxy, n-butyloxypentyloxy, tert-butyloxyhexyloxy, 2-methylpropyloxymethyloxy, 1-methyloxyethyloxy, n-pentyloxypropyloxy, cyclopentyloxymethyloxy, n-hexyloxybutyloxy and cyclohexyloxypentyloxy groups. 
     Examples of the alkylsulfonylamino group having from 1 to 6 carbon atoms include methanesulfonylamino, ethanesulfonylamino, n-propanesulfonylamino, n-butanesulfonylamino, n-pentanesulfonylamino, n-hexanesulfonylamino, isopropanesulfonylamino, 2-methylpropanesulfonylamino, 1-methylpropanesulfonylamino, tert-butanesulfonylamino, 3-methylbutanesulfonylamino, 2-methylbutanesulfonylamino, 1-methylbutanesulfonylamino, 1,2-dimethylpropanesulfonylamino, 1,1-dimethylpropanesulfonylamino, 2,2-dimethylpropanesulfonylamino, 4-methylpentanesulfonylamino, 3-methylpentanesulfonylamino, 2-methylpentanesulfonylamino, 1-methylpentanesulfonylamino, 1,2,2-trimethylpropanesulfonylamino, 1,1-dimethylbutanesulfonylamino, 1,1,2-trimethylpropanesulfonylamino, 2,2-dimethylbutanesulfonylamino, 1,3-dimethylbutanesulfonylamino, 2,3-dimethylbutanesulfonylamino, cyclopropanesulfonylamino, cyclobutanesulfonylamino, cyclopentanesulfonylamino and cyclohexanesulfonylamino groups. 
     Examples of the alkanoylamino group having from 2 to 6 carbon atoms include acetylamino, propionylamino, butyrylamino, valerylamino, hexanoylamino, isobutyrylamino, isovalerylamino, pivaloylamino and cyclopentylcarbonylamino groups. 
     One or two of R 1 , R 2 , R 3  and R 4  are preferably an alkyloxy group having from 1 to 6 carbon atoms. 
     X 1 , X 2 , X 3 , X 4  and X 5  in formula (1) are explained hereinafter. The alkyl group having from 1 to 6 carbon atoms, as represented by X 1 , X 2 , X 3 , X 4  and X 5 , is a linear, branched or cyclic alkyl group having from 1 to 6 carbon atoms. Examples of the alkyl group include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, 2-methylpropyl, 1-methylpropyl, tert-butyl, 2-methylbutyl, 1-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 1,2,2-trimethylpropyl, 1,1-dimethylbutyl, 1,1,2-trimethylpropyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups. 
     Examples of the halogen atom include iodine, bromine, chlorine and fluorine atoms. 
     The alkyloxy group having from 1 to 6 carbon atoms is a linear, branched or cyclic alkyloxy group having from 1 to 6 carbon atoms. Examples of the alkyloxy group include methoxy, ethoxy, n-propyloxy, n-butyloxy, n-pentyloxy, n-hexyloxy, isopropyloxy, 2-methylpropyloxy, 1-methylpropyloxy, tert-butyloxy, 2-methylbutyloxy, 1-methylbutyloxy, 1,2-dimethylpropyloxy, 1,1-dimethylpropyloxy, 2,2-dimethylpropyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, 1,2,2-trimethylpropyloxy, 1,1-dimethylbutyloxy, 1,1,2-trimethylpropyloxy, 2,2-dimethylbutyloxy, 1,3-dimethylbutyloxy, 2,3-dimethylbutyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy groups. 
     The alkyloxy group having from 1 to 6 carbon atoms and containing a terminal alkyloxy group having from 1 to 6 carbon atoms include methoxymethyloxy, ethoxymethyloxy, n-propyloxyethyloxy, isopropyloxypropyloxy, cyclopropyloxybutyloxy, n-butyloxypentyloxy, tert-butyloxyhexyloxy, 2-methylpropyloxymethyloxy, 1-methyloxyethyloxy, n-pentyloxypropyloxy, cyclopentyloxymethyloxy, n-hexyloxybutyloxy and cyclohexyloxypentyloxy groups. 
     X 1  is preferably a methyl group. 
     In formula (1), the alkyl group having from 1 to 6 carbon atoms is a linear, branched or cyclic alkyl group having from 1 to 6 carbon atoms. Examples of the alkyl group include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, 2-methylpropyl, 1-methylpropyl, tert-butyl, 2-methylbutyl, 1-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 1,2,2-trimethylpropyl, 1,1-dimethylbutyl, 1,1,2-trimethylpropyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups. 
     When R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , X 4 , X 5  or Y contains an asymmetric carbon atom in formula (1), the compounds of formula (1) in the present invention include optically active compounds. 
     The compounds of formula (1) can be formed into pharmaceutically acceptable salts as required. Examples of the salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid or organic acids such as formic acid, acetic acid, fumaric acid, citric acid, maleic acid, oxalic acid, malic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid. 
     A process for producing the compounds of the present invention will be described in detail below. 
     The compounds of the present invention can be produced by mixing quinoline-4-carboxylic acid derivatives represented by formula (2) ##STR4## 
     wherein 
     L represents a hydroxyl group or a leaving group that can easily be substituted by means of a nucleophilic reagent, 
     and 
     R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , X 4 , X 5  and Y are as defined in formula (1) 
     with guanidine in the absence of a solvent or dissolving or suspending the same in an appropriate solvent or dispersing agent, and reacting the mixture. The ratio of the compounds of formula (2) and guanidine is not particularly limited. The molar ratio of the former: the latter is usually between 1:1 and 1:20, preferably between 1:3 and 1:10. The compounds obtained by this reaction can be purified by an ordinary method such as recrystallization, silica-gel column chromatography or the like. 
     The reaction will be explained when L is a hydroxyl group and when L is a group other than a hydroxyl group. 
     (1) L is a hydroxyl group: 
     A condensation agent can be used in the reaction. Appropriate examples of the solvent or the dispersing agent used in this reaction include benzene, toluene, xylene, 1,4-dioxane, dimethylformamide (hereinafter referred to as &#34;DMF&#34;), tetrahydrofuran (hereinafter referred to as &#34;THF&#34;), ethyl ether, 1,2-dimethoxyethane, dimethylsulfoxide (hereinafter referred to as &#34;DMSO&#34;), chloroform, dichloromethane, and 1,2-dichloroethane. 
     Examples of the condensation agent which can be used in the reaction include 1,1&#39;-carbonyldiimidazole [H. A. Staab, Angew. Chem. Int. Ed. Engl., 1, 351-367, (1962)], dicyclohexylcarbodiimide (hereinafter referred to as &#34;DCC&#34;), 1-ethyl-3-(3&#39;-dimethylaminopropyl)carbodiimide, and diphenylphosphorylazide. 
     The reaction is conducted at a temperature ranging from -20° C. to a reflux temperature of the reaction mixture, for example, from -10° to 150° C., preferably from room temperature to 100° C. The reaction time varies with conditions, and it is between approximately 1 and 48 hours. 
     (2) L is a group other than a hydroxyl group: 
     The active compounds of the quinoline-4-carboxylic acid derivatives represented by formula (2) include acid halides (L=halogen), acid anhydrides (especially mixed acid anhydrides--L=alkoxycarbonyloxy), and carboxylate esters. These can easily be formed from carboxylic acids (L=OH) of formula (2) by a known method. 
     As an acid halide, carbonyl chloride can be formed from a carboxylic acid using a chlorination agent such as thionyl chloride, oxalyl chloride, phosphorus pentachloride or the like. 
     An acid anhydride can be formed from a carboxylic acid using monoalkyl carbonate such as ethyl chlorocarbonate and base such as triethylamine. 
     As a carboxylate ester, a methyl ester can be formed by, for example, treating a carboxylic acid with a hydrogen chloride gas in methanol, and p-nitrophenyl ester which is an active ester can be formed by treating p-nitrophenol with DCC. 
     Appropriate examples of the solvent or the dispersing agent which is used in the reaction of the carboxylic acid active compounds and guanidine include methyl ethyl ketone, 1,4-dioxane, DMF, THF, ethyl ether, 1,2-dimethoxyethane, dimethyl sulfoxide, benzene, xylene, toluene, chloroform, dichloromethane, 1,2-dichloroethane, and pyridine. Alcohols such as methanol, ethanol and isopropanol can be used as required. 
     The reaction of the quinoline-4-carboxylic acid active compounds and guanidine is conducted at a temperature ranging from -20° C. to a reflux temperature of the reaction mixture, for example, from -10° to 150° C., preferably from 0° to 100° C. The reaction time varies with conditions. It is between approximately 1 and 48 hours. Examples of the base that accelerates this reaction include organic bases such as pyridine, dimethylaminopyridine, triethylamine, and diisopropylethylamine; and inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, and potassium hydroxide. 
     When the quinoline-4-carboxylic acid (L=OH) of formula (2) contains an active group such as a hydroxyl group or an amino group, the active group is protected in advance with a protective group, and deprotection is conducted after the production of quinoline-4-carbonylguanidine by the above-mentioned process, whereby the final quinoline-4-carbonylguanidine derivatives of formula (1) can be obtained. At this time, the protection and the deprotection can be conducted by a known method [for example, T. W. Green: Protective Groups in Organic Synthesis, John Wiley &amp; Sons (1981)]. 
     When the quinoline-4-carbonylguanidine derivatives of formula (1) contain an amino group, these compounds can be produced by reducing quinoline-4-carbonylguanidine derivatives containing a nitro group in a known manner. The reduction is conducted under acidic conditions using a metal such as iron, zinc or the like, or through catalytic hydrogenation in the presence of a catalyst such as palladium on activated carbon (hereinafter referred to as &#34;Pd/C&#34;). 
     A method of producing quinoline-4-carboxylic acid (L=OH) of formula (2) is described in, for example, G. Jones, The Chemistry of Heterocyclic Compounds, vol. 32, Quinolines Part I, John Wiley &amp; Sons. It can be produced by the method of Doebner [Ber., 20, 277 (1887), etc.] or the method of Pfitzinger [J. Prakt. Chem., 33, 100 (1866), etc.]. In the method of Doebner, the reaction of aniline derivatives, benzaldehyde derivatives and pyruvic acid is conducted. In the method Pfitzinger, acetophenone is reacted with isatin derivatives. A method of producing isatin derivatives is described in, for example, F. D. Popp, The Chemistry of Isatin, Adv. Heterocycl. Chem., 18, 1-58 (1975). 
     The compounds of formula (1) in the present invention is used in a pharmaceutical composition which is effective as an agent for treating or preventing hypertension and arrhythmia caused by activation of NHE, diseases following ischemia which is a primary or secondary cause, diseases caused by cell proliferation or hypertrophy, and diseases caused by infiltration of leukocytes. 
     Acute or chronic diseases caused by ischemia against which the compounds of the present invention are effective are, for example, angina pectoris, myocardial infarction, ischemic arrhythmia, reperfusion arrhythmia, organ disorders following ischemia and reperfusion, cerebral ischemic disorders, cerebral apoplexy, and ischemic diseases of limbs and peripheral internal organs. The compounds of the present invention can be used as an agent for treating or preventing organ disorders caused by ischemia and reperfusion in surgical operation or transplantation of internal organs, or as an agent for preventing or treating disorders of internal organs cut from the body for transplantation or internal organs transplanted. 
     Diseases caused by cell proliferation or hypertrophy against which the compounds of the present invention are effective are, for example, arteriosclerosis, vascular restenosis caused by proliferation of a vascular smooth muscle after percutaneous transluminal coronary angioplasty (PTCA), rheumatoid arthritis caused by growth of synovial cells, diabetic complication caused by vascularization, renal glomerulosclerosis caused by growth of mesangial cells, fibrosis of lung, liver, kidney and the like caused by growth of fibroblasts, cardiac hypertrophy, prostatic hypertrophy and cancers. 
     Diseases caused by infiltration of leukocytes associated with enhanced NHE activity against which the compounds of the present invention are effective are inflammation and the like. 
     As mentioned above, it is known that NHE activity is enhanced in various diseased states. 
     The NHE activity can easily be measured by using the compounds of the present invention being strong NHE inhibitors in cells such as platelets, erythrocytes and leukocytes which are easily obtainable. That is, the compounds of the present invention can be used as a diagnostic agent for hypertension, diseases caused by cell growth, diabetes and the like. 
     Specific examples of the compounds represented by formula (1) in the present invention are shown below. However, the present invention is not limited thereto. 
     1. 2-phenylquinoline-4-carbonylguanidine 
     2. 2-(2&#39;-methylphenyl)quinoline-4-carbonylguanidine 
     3. 2-(2&#39;-ethylphenyl)quinoline-4-carbonylguanidine 
     4. 2-(2&#39;-n-propylphenyl)quinoline-4-carbonylguanidine 
     5. 2-(2&#39;-isopropylphenyl)quinoline-4-carbonylguanidine 
     6. 2-(2&#39;-n-butylphenyl)quinoline-4-carbonylguanidine 
     7. 2-(2&#39;-cyclobutylphenyl)quinoline-4-carbonylguanidine 
     8. 2-{2&#39;-(2-methylpropyl)phenyl)}quinoline-4-carbonylguanidine 
     9. 2-{2&#39;-(1-methylpropyl)phenyl}quinoline-4-carbonylguanidine 
     10. 2-{2&#39;-(1,1-dimethylpropyl)phenyl}quinoline-4-carbonylguanidine 
     11. 2-{2&#39;-(1,2-dimethylpropyl)phenyl}quinoline-4-carbonylguanidine 
     12. 2-{2&#39;-(2,2-dimethylpropyl)phenyl}quinoline-4-carbonylguanidine 
     13. 2-(2&#39;-n-pentylphenyl)quinoline-4-carbonylguanidine 
     14. 2-(2&#39;-cyclopentylphenyl)quinoline-4-carbonylguanidine 
     15. 2-{2&#39;-(1-methylbutyl)phenyl}quinoline-4-carbonylguanidine 
     16. 2-(2&#39;-n-hexylphenyl)quinoline-4-carbonylguanidine 
     17. 2-{2&#39;-(3-methylpentyl)}phenylquinoline-4-carbonylguanidine 
     18. 2-{2&#39;-(1,3-dimethylbutyl)phenyl}quinoline-4-carbonylguanidine 
     19. 2-(3&#39;-methylphenyl)quinoline-4-carbonylguanidine 
     20. 2-(3&#39;-cyclopropylphenyl)quinoline-4-carbonylguanidine 
     21. 2-(3&#39;-isopropylphenyl)quinoline-4-carbonylguanidine 
     22. 2-{3&#39;-(3-methylbutyl)phenyl}quinoline-4-carbonylguanidine 
     23. 2-(3&#39;-cyclohexylphenyl)quinoline-4-carbonylguanidine 
     24. 2-{3&#39;-(2-methylpentyl)phenyl}quinoline-4-carbonylguanidine 
     25. 2-{3&#39;-(1,2,2-trimethylpropyl)phenyl}quinoline-4-carbonylguanidine 
     26. 2-{3&#39;-(1,1,2-trimethylpropyl)phenyl}quinoline-4-carbonylguanidine 
     27. 2-{3&#39;-(1,1-dimethylbutyl)phenyl}quinoline-4-carbonylguanidine 
     28. 2-(4&#39;-methylphenyl)quinoline-4-carbonylguanidine 
     29. 2-(4&#39;-tert-butylphenyl)quinoline-4-carbonylguanidine 
     30. 2-{4&#39;-(2-methylbutyl)phenyl)}quinoline-4-carbonylguanidine 
     31. 2-{4&#39;-(2,2-dimethylbutyl)phenyl)}quinoline-4-carbonylguanidine 
     32. 2-{4&#39;-(2,3-dimethylbutyl)phenyl)}quinoline-4-carbonylguanidine 
     33. 2-{4&#39;-(4-methylpentyl)phenyl)}quinoline-4-carbonylguanidine 
     34. 2-{4&#39;-(1-methylpentyl)phenyl)}quinoline-4-carbonylguanidine 
     35. 2-(2&#39;,3&#39;-dimethylphenyl)quinoline-4-carbonylguanidine 
     36. 2-(2&#39;,4&#39;-dimethylphenyl)quinoline-4-carbonylguanidine 
     37. 2-(2&#39;,5&#39;-dimethylphenyl)quinoline-4-carbonylguanidine 
     38. 2-(2&#39;,6&#39;-dimethylphenyl)quinoline-4-carbonylguanidine 
     39. 2-(3&#39;,4&#39;-dimethylphenyl)quinoline-4-carbonylguanidine 
     40. 2-(3&#39;,5&#39;-dimethylphenyl)quinoline-4-carbonylguanidine 
     41. 2-(2&#39;,4&#39;,6&#39;-trimethylphenyl)quinoline-4-carbonylguanidine 
     42. 2-(2&#39;-chlorophenyl)quinoline-4-carbonylguanidine 
     43. 2-(3&#39;-chlorophenyl)quinoline-4-carbonylguanidine 
     44. 2-(4&#39;-bromophenyl)quinoline-4-carbonylguanidine 
     45. 2-(4&#39;-iodophenyl)quinoline-4-carbonylguanidine 
     46. 2-(3&#39;-fluorophenyl)quinoline-4-carbonylguanidine 
     47. 2-(4&#39;-fluorophenyl)quinoline-4-carbonylguanidine 
     48. 2-(2&#39;-nitrophenyl)quinoline-4-carbonylguanidine 
     49. 2-(3&#39;-nitrophenyl)quinoline-4-carbonylguanidine 
     50. 2-(4&#39;-nitrophenyl)quinoline-4-carbonylguanidine 
     51. 2-(2&#39;-aminophenyl)quinoline-4-carbonylguanidine 
     52. 2-(3&#39;-aminophenyl)quinoline-4-carbonylguanidine 
     53. 2-(4&#39;-aminophenyl)quinoline-4-carbonylguanidine 
     54. 2-(2&#39;-hydroxyphenyl)quinoline-4-carbonylguanidine 
     55. 2-(3&#39;-hydroxyphenyl)quinoline-4-carbonylguanidine 
     56. 2-(4&#39;-hydroxyphenyl)quinoline-4-carbonylguanidine 
     57. 2-(2&#39;-trifluoromethylphenyl)quinoline-4-carbonylguanidine 
     58. 2-(3&#39;-trifluoromethylphenyl)quinoline-4-carbonylguanidine 
     59. 2-(4&#39;-trifluoromethylphenyl)quinoline-4-carbonylguanidine 
     60. 2-(2&#39;-trifluoromethoxyphenyl)quinoline-4-carbonylguanidine 
     61. 2-(3&#39;-trifluoromethoxyphenyl)quinoline-4-carbonylguanidine 
     62. 2-(4&#39;-trifluoromethoxyphenyl)quinoline-4-carbonylguanidine 
     63. 2-(2&#39;-methoxyphenyl)quinoline-4-carbonylguanidine 
     64. 2-(3&#39;-methoxyphenyl)quinoline-4-carbonylguanidine 
     65. 2-(4&#39;-methoxyphenyl)quinoline-4-carbonylguanidine 
     66. 2-(2&#39;-ethoxyphenyl)quinoline-4-carbonylguanidine 
     67. 2-(2&#39;-n-propyloxyphenyl)quinoline-4-carbonylguanidine 
     68. 2-(2&#39;-isopropyloxyphenyl)quinoline-4-carbonylguanidine 
     69. 2-(2&#39;-n-butyloxyphenyl)quinoline-4-carbonylguanidine 
     70. 2-(2&#39;-cyclobutyloxyphenyl)quinoline-4-carbonylguanidine 
     71. 2-{2&#39;-(2-methylpropyloxy)phenyl)}quinoline-4-carbonylguanidine 
     72. 2-{2&#39;-(1-methylpropyloxy)phenyl)}quinoline-4-carbonylguanidine 
     73. 2-{2&#39;-(1,1-dimethylpropyloxy)phenyl)}quinoline-4-carbonylguanidlne 
     74. 2-{2&#39;-(1,2-dimethylpropyloxy)phenyl)}quinoline-4-carbonylguanidine 
     75. 2-{2&#39;-(2,2-dimethylpropyloxy)phenyl)}quinoline-4-carbonylguanidine 
     76. 2-(2&#39;-n-pentyloxyphenyi)quinoline-4-carbonylguanidine 
     77. 2-(2&#39;-cyclopentyloxyphenyl)quinoline-4-carbonylguanidine 
     78. 2-{2&#39;-(1-methylbutyloxy)phenyl)}quinoline-4-carbonylguanidine 
     79. 2-(2&#39;-n-hexyloxyphenyl)quinoline-4-carbonylguanidine 
     80. 2-{2&#39;-(3-methylpentyloxy)phenyl}quinoline-4-carbonylguanidine 
     81. 2-{2&#39;-(1,3-dimethylbutyloxy)phenyl}quinoline-4-carbonylguanidine 
     82. 2-(3&#39;-cyclopropyloxyphenyl)quinoline-4-carbonylguanidine 
     83. 2-(3&#39;-isopropyloxyphenyl)quinoline-4-carbonylguanidine 
     84. 2-(3&#39;-tert-butyloxyphenyl)quinoline-4-carbonylguanidine 
     85. 2-{3&#39;-(3-methylbutyloxy)phenyl}quinoline-4-carbonylguanidine 
     86. 2-(3&#39;-cyclohexyloxyphenyl)quinoline-4-carbonylguanidine 
     87. 2-{3&#39;-(2-methylpentyloxy)phenyl}quinoline-4-carbonylguanidine 
     88. 2-{3&#39;-(1,2,2-trimethylpropyloxy)phenyl}quinoline-4-carbonylguanidine 
     89. 2-{3&#39;-(1,1,2-trimethylpropyloxy)phenyl}quinoline-4-carbonylguanidine 
     90. 2-{3&#39;-(1,1-dimethylbutyloxy)phenyl}quinoline-4-carbonylguanidine 
     91. 2-{4&#39;-(2-methylbutyloxy)phenyl}quinoline-4-carbonylguanidine 
     92. 2-{4&#39;-(2,2-dimethylbutyloxy)phenyl}quinoline-4-carbonylguanidine 
     93. 2-{4&#39;-(2,3-dimethylbutyloxy)phenyl}quinoline-4-carbonylguanidine 
     94. 2-{4&#39;-(4-methylpentyloxy)phenyl}quinoline-4-carbonylguanidine 
     95. 2-{4&#39;-(1-methylpentyloxy)phenyl}quinoline-4-carbonylguanidine 
     96. 2-(2&#39;,3&#39;-dimethoxyphenyl)quinoline-4-carbonylguanidine 
     97. 2-(2&#39;,4&#39;-dimethoxyphenyl)quinoline-4-carbonylguanidine 
     98. 2-(2&#39;,5&#39;-dimethoxyphenyl)quinoline-4-carbonylguanidine 
     99. 2-(2&#39;,6&#39;-dimethoxyphenyl)quinoline-4-carbonylguanidine 
     100. 2-(3&#39;,4&#39;-dimethoxyphenyl)quinoline-4-carbonylguanidine 
     101. 2-(3&#39;,5&#39;-dimethoxyphenyl)quinoline-4-carbonylguanidine 
     102. 2-(2&#39;-methoxymethyloxyphenyl)quinoline-4-carbonylguanidine 
     103. 2-(3&#39;-ethoxymethyloxyphenyl)quinoline-4-carbonylguanidine 
     104. 2-(4&#39;-n-propyloxyethyloxyphenyl)quinoline-4-carbonylguanidine 
     105. 2-(2&#39;-isopropyloxypropyloxyphenyl)quinoline-4-carbonylguanidine 
     106. 2-(3&#39;-cyclopropyloxybutyloxyphenyl)quinoline-4-carbonylguanidine 
     107. 2-(4&#39;-n-butyloxypentyloxyphenyl)quinoline-4-carbonylguanidine 
     108. 2-(2&#39;-tert-butyloxyhexyloxyphenyl)quinoline-4-carbonylguanidine 
     109. 2-(3&#39;-(2-methylpropyloxymethyloxy)phenyl)quinoline-4-carbonylguanidine 
     110. 2-{4&#39;-(1-methylpropyloxyethyloxy)phenyl)}quinoline-4-carbonylguanidine 
     111. 2-(2&#39;-n-pentyloxypropyloxyphenyl)quinoline-4-carbonylguanidine 
     112. 2-(3&#39;-cyclopentyloxymethyloxyphenyl)quinoline-4-carbonylguanidine 
     113. 2-(4&#39;-n-hexyloxypentyloxyphenyl)quinoline-4-carbonylguanidine 
     114. 2-phenyl-3-methylquinoline-4-carbonylguanidine 
     115. 2-(2&#39;-methylphenyl)-3-methylquinoline-4-carbonylguanidine 
     116. 2-phenyl-3-ethylquinoline-4-carbonylguanidine 
     117. 2-(2&#39;-methylphenyl)-3-ethylquinoline-4-carbonylguanidine 
     118. 2-phenyl-3-n-propylquinoline-4-carbonylguanidine 
     119. 2-(2&#39;-methylphenyl)-3-n-propylquinoline-4-carbonylguanidine 
     120. 2-phenyl-3-isopropylquinoline-4-carbonylguanidine 
     121. 2-(2&#39;-methylphenyl)-3-isopropylquinoline-4-carbonylguanidine 
     122. 2-phenyl-3-cyclopropylquinoline-4-carbonylguanidine 
     123. 2-phenyl-3-n-butylquinoline-4-carbonylguanidine 
     124. 2-phenyl-3-tert-butylquinoline-4-carbonylguanidine 
     125. 2-phenyl-3-(2-methylpropyl)quinoline-4-carbonylguanidine 
     126. 2-phenyl-3-(1-methylpropyl)quinoline-4-carbonylguanidine 
     127. 2-phenyl-3-cyclobutylquinoline-4-carbonylguanidine 
     128. 2-phenyl-3-n-pentylquinoline-4-carbonylguanidine 
     129. 2-phenyl-3-(2-methylbutyl)quinoline-4-carbonylguanidine 
     130. 2-phenyl-3-(1-methylbutyl)quinoline-4-carbonylguanidine 
     131. 2-phenyl-3-(1,2-dimethylpropyl)quinoline-4-carbonylguanidine 
     132. 2-phenyl-3-(1,1-dimethylpropyl)quinoline-4-carbonylguanidine 
     133. 2-phenyl-3-(2,2-dimethylpropyl)quinoline-4-carbonylguanidine 
     134. 2-phenyl-3-cyclopentylquinoline-4-carbonylguanidine 
     135. 2-phenyl-3-n-hexylquinoline-4-carbonylguanidine 
     136. 2-phenyl-3-(4-methylpentyl)quinoline-4-carbonylguanidine 
     137. 2-phenyl-3-(3-methylpentyl)quinoline-4-carbonylguanidine 
     138. 2-phenyl-3-(2-methylpentyl)quinoline-4-carbonylguanidine 
     139. 2-phenyl-3-(1-methylpentyl)quinoline-4-carbonylguanidine 
     140. 2-phenyl-3-(1,2,2-trimethylpropyl)quinoline-4-carbonylguanidine 
     141. 2-phenyl-3-(1,1-dimethylbutyl)quinoline-4-carbonylguanidine 
     142. 2-phenyl-3-(1,1,2-trimethylpropyl)quinoline-4-carbonylguanidine 
     143. 2-phenyl-3-(2,2-dimethylbutyl)quinoline-4-carbonylguanidine 
     144. 2-phenyl-3-(1,3-dimethylbutyl)quinoline-4-carbonylguanidine 
     145. 2-phenyl-3-(2,3-dimethylbutyl)quinoline-4-carbonylguanidine 
     146. 2-phenyl-3-cyclohexylquinoline-4-carbonylguanidine 
     147. 2-phenyl-5-methylquinoline-4-carbonylguanidine 
     148. 2-phenyl-6-methylquinoline-4-carbonylguanidine 
     149. 2-phenyl-7-methylquinoline-4-carbonylguanidine 
     150. 2-phenyl-8-methylquinoline-4-carbonylguanidine 
     151. 2-(2&#39;-methylphenyl)-5-methylquinoline-4-carbonylguanidine 
     152. 2-phenyl-6-ethylquinoline-4-carbonylguanidine 
     153. 2-phenyl-7-n-propylquinoline-4-carbonylguanidine 
     154. 2-phenyl-6-isopropylquinoline-4-carbonylguanidine 
     155. 2-phenyl-5-n-butylquinoline-4-carbonylguanidine 
     156. 2-phenyl-6-tert-butylquinoline-4-carbonylguanidine 
     157. 2-phenyl-7-(2-methylpropyl)quinoline-4-carbonylguanidine 
     158. 2-phenyl-8-(1-methylpropyl)quinoline-4-carbonylguanidine 
     159. 2-phenyl-5-cyclobutylquinoline-4-carbonylguanidine 
     160. 2-phenyl-6-n-pentylquinoline-4-carbonylguanidine 
     161. 2-phenyl-7-(2-methylbutyl)quinoline-4-carbonylguanidine 
     162. 2-phenyl-8-(1-methylbutyl)quinoline-4-carbonylguanidine 
     163. 2-phenyl-5-(1,2-dimethylpropyl)quinoline-4-carbonylguanidine 
     164. 2-phenyl-6-(1,1-dimethylpropyl)quinoline-4-carbonylguanidine 
     165. 2-phenyl-7-(2,2-dimethylpropyl)quinoline-4-carbonylguanidine 
     166. 2-phenyl-7-cyclopentylquinoline-4-carbonylguanidine 
     167. 2-phenyl-8-n-hexylquinoline-4-carbonylguanidine 
     168. 2-phenyl-5-(4-methylpentyl)quinoline-4-carbonylguanidine 
     169. 2-phenyl-6-(3-methylpentyl)quinoline-4-carbonylguanidine 
     170. 2-phenyl-7-(2-methylpentyl)quinoline-4-carbonylguanidine 
     171. 2-phenyl-8-(1-methylpentyl)quinoline-4-carbonylguanidine 
     172. 2-phenyl-5-(1,2,2-trimethylpropyl)quinoline-4-carbonylguanidine 
     173. 2-phenyl-6-(1,1-dimethylbutyl)quinoline-4-carbonylguanidine 
     174. 2-phenyl-7-(1,1,2-trimethylpropyl)quinoline-4-carbonylguanidine 
     175. 2-phenyl-8-(2,2-dimethylbutyl)quinoline-4-carbonylguanidine 
     176. 2-phenyl-5-(1,3-dimethylbutyl)quinoline-4-carbonylguanidine 
     177. 2-phenyl-6-(2,3-dimethylbutyl)quinoline-4-carbonylguanidine 
     178. 2-phenyl-7-cyclohexylquinoline-4-carbonylguanidine 
     179. 2-phenyl-5-fluoroquinoline-4-carbonylguanidine 
     180. 2-phenyl-5-chloroquinoline-4-carbonylguanidine 
     181. 2-(2&#39;-methylphenyl)-5-fluoroquinoline-4-carbonylguanidine 
     182. 2-(2&#39;-methylphenyl)-5-chloroquinoline-4-carbonylguanidine 
     183. 2-(2&#39;-methylphenyl)-5-bromoquinoline-4-carbonylguanidine 
     184. 2-(2&#39;-methylphenyl)-5-iodoquinoline-4-carbonylguanidine 
     185. 2-phenyl-6-fluoroquinoline-4-carbonylguanidine 
     186. 2-phenyl-6-chloroquinoline-4-carbonylguanidine 
     187. 2-phenyl-6-iodoquinoline-4-carbonylguanidine 
     188. 2-phenyl-7-bromoquinoline-4-carbonylguanidine 
     189. 2-phenyl-7-chloroquinoline-4-carbonylguanidine 
     190. 2-phenyl-8-chloroquinoline-4-carbonylguanidine 
     191. 2-phenyl-8-iodoquinoline-4-carbonylguanidine 
     192. 2-phenyl-5-nitroquinoline-4-carbonylguanidine 
     193. 2-phenyl-6-nitroquinoline-4-carbonylguanidine 
     194. 2-phenyl-7-nitroquinoline-4-carbonylguanidine 
     195. 2-phenyl-8-nitroquinoline-4-carbonylguanidine 
     196. 2-phenyl-5-aminoquinoline-4-carbonylguanidine 
     197. 2-phenyl-6-aminoquinoline-4-carbonylguanidine 
     198. 2-phenyl-7-aminoquinoline-4-carbonylguanidine 
     199. 2-phenyl-8-aminoquinoline-4-carbonylguanidine 
     200. 2-phenyl-5-hydroxyquinoline-4-carbonylguanidine 
     201. 2-phenyl-6-hydroxyquinoline-4-carbonylguanidine 
     202. 2-phenyl-7-hydroxyquinoline-4-carbonylguanidine 
     203. 2-phenyl-8-hydroxyquinoline-4-carbonylguanidine 
     204. 2-(2&#39;-methylphenyl)-5-hydroxyquinoline-4-carbonylguanidine 
     205. 2-(2&#39;-methylphenyl)-6-hydroxyquinoline-4-carbonylguanidine 
     206. 2-(2&#39;-methylphenyl)-7-hydroxyquinoline-4-carbonylguanidine 
     207. 2-(2&#39;-methylphenyl)-8-hydroxyquinoline-4-carbonylguanidine 
     208. 2-(2&#39;-methylphenyl)-5,6-dihydroxyquinoline-4-carbonylguanidine 
     209. 2-(2&#39;-methylphenyl)-5,7-dihydroxyquinoline-4-carbonylguanidine 
     210. 2-(2&#39;-methylphenyl)-5,8-dihydroxyquinoline-4-carbonylguanidine 
     211. 2-(2&#39;-methylphenyl)-6,7-dihydroxyquinoline-4-carbonylguanidine 
     212. 2-(2&#39;-methylphenyl)-6,8-dihydroxyquinoline-4-carbonylguanidine 
     213. 2-(2&#39;-methylphenyl)-7,8-dihydroxyquinoline-4-carbonylguanidine 
     214. 2-phenyl-5-methoxyquinoline-4-carbonylguanidine 
     215. 2-phenyl-6-methoxyquinoline-4-carbonylguanidine 
     216. 2-phenyl-7-methoxyquinoline-4-carbonylguanidine 
     217. 2-phenyl-8-methoxyquinoline-4-carbonylguanidine 
     218. 2-phenyl-5,6-dimethoxyquinoline-4-carbonylguanidine 
     219. 2-phenyl-5,7-dimethoxyquinoline-4-carbonylguanidine 
     220. 2-phenyl-5,8-dimethoxyquinoline-4-carbonylguanidine 
     221. 2-phenyl-6,7-dimethoxyquinoline-4-carbonylguanidine 
     222. 2-phenyl-6,8-dimethoxyquinoline-4-carbonylguanidine 
     223. 2-phenyl-7,8-dimethoxyquinoline-4-carbonylguanidine 
     224. 2-phenyl-5,6,7-trimethoxyquinoline-4-carbonylguanidine 
     225. 2-phenyl-5,6,8-trimethoxyquinoline-4-carbonylguanidine 
     226. 2-phenyl-5,7,8-trimethoxyquinoline-4-carbonylguanidine 
     227. 2-phenyl-6,7,8-trimethoxyquinoline-4-carbonylguanidine 
     228. 2-phenyl-5,6,7,8-tetramethoxyquinoline-4-carbonylguanidine 
     229. 2-(2&#39;-methylphenyl)-5-methoxyquinoline-4-carbonylguanidine 
     230. 2-(2&#39;-methylphenyl)-6-methoxyquinoline-4-carbonylguanidine 
     231. 2-(2&#39;-methylphenyl)-7-methoxyquinoline-4-carbonylguanidine 
     232. 2-(2&#39;-methylphenyl)-8-methoxyquinoline-4-carbonylguanidine 
     233. 2-(2&#39;-methylphenyl)-5,6-dimethoxyquinoline-4-carbonylguanidine 
     234. 2-(2&#39;-methylphenyl)-5,7-dimethoxyquinoline-4-carbonylguanidine 
     235. 2-(2&#39;-methylphenyl)-5,8-dimethoxyquinoline-4-carbonylguanidine 
     236. 2-(2&#39;-methylphenyl)-6,7-dimethoxyquinoline-4-carbonylguanidine 
     237. 2-(2&#39;-methylphenyl)-6,8-dimethoxyquinoline-4-carbonylguanidine 
     238. 2-(2&#39;-methylphenyl)-7,8-dimethoxyquinoline-4-carbonylguanidine 
     239. 2-(2&#39;-methylphenyl)-5,6,7-trimethoxyquinoline-4-carbonylguanidine 
     240. 2-(2&#39;-methylphenyl)-5,6,8-trimethoxyquinoline-4-carbonylguanidine 
     241. 2-(2&#39;-methylphenyl)-5,7,8-trimethoxyquinoline-4-carbonylguanidine 
     242. 2-(2&#39;-methylphenyl)-6,7,8-trimethoxyquinoline-4-carbonylguanidine 
     243. 2-(2&#39;-methylphenyl)-5,6,7,8-tetramethoxyquinoline-4-carbonylguanidine 
     244. 2-phenyl-5-ethoxyquinoline-4-carbonylguanidine 
     245. 2-phenyl-6-ethoxyquinoline-4-carbonylguanidine 
     246. 2-phenyl-7-ethoxyquinoline-4-carbonylguanidine 
     247. 2-phenyl-8-ethoxyquinoline-4-carbonylguanidine 
     248. 2-(2&#39;-methylphenyl)-5-ethoxyquinoline-4-carbonylguanidine 
     249. 2-(2&#39;-methylphenyl)-6-ethoxyquinoline-4-carbonylguanidine 
     250. 2-(2&#39;-methylphenyl)-7-ethoxyquinoline-4-carbonylguanidine 
     251. 2-(2&#39;-methylphenyl)-8-ethoxyquinoline-4-carbonylguanidine 
     252. 2-(2&#39;-methylphenyl)-5-n-propyloxyquinoline-4-carbonylguanidine 
     253. 2-(2&#39;-methylphenyl)-6-isopropyloxyquinoline-4-carbonylguanidine 
     254. 2-(2&#39;-methylphenyl)-7-cyclopropyloxyquinoline-4-carbonylguanidine 
     255. 2-(2&#39;-methylphenyl)-8-n-butyloxyquinoline-4-carbonylguanidine 
     256. 2-(2&#39;-methylphenyl)-5-tert-butyloxyquinoline-4-carbonylguanidine 
     257. 2-(2&#39;-methylphenyl)-6-cyclobutyloxyquinoline-4-carbonylguanidine 
     258. 2-(2&#39;-methylphenyl)-7-(2-methylpropyloxy)quinoline-4-carbonylguanidine 
     259. 2-(2&#39;-methylphenyl)-8-(1-methylpropyloxy)quinoline-4-carbonylguanidine 
     260. 2-(2&#39;-methylphenyl)-5-n-pentyloxyquinoline-4-carbonylguanidine 
     261. 2-(2&#39;-methylphenyl)-6-cyclopentyloxyquinoline-4-carbonylguanidine 
     262. 2-(2&#39;-methylphenyl)-7-(2-methylbutyloxy)quinoline-4-carbonylguanidine 
     263. 2-(2&#39;-methylphenyl)-8-(1-methylbutyloxy)quinoline-4-carbonylguanidine 
     264. 2-(2&#39;-methylphenyl)-5-(1,2-dimethylpropyloxy)quinoline-4-carbonylguanidine 
     265. 2-(2&#39;-methylphenyl)-6-(1,1-dimethylpropyloxy)quinoline-4-carbonylguanidine 
     266. 2-(2&#39;-methylphenyl)-7-(2,2-dimethylpropyloxy)quinoline-4-carbonylguanidine 
     267. 2-(2&#39;-methylphenyl)-8-n-pentyloxyquinoline-4-carbonylguanidine 
     268. 2-(2&#39;-methylphenyl)-5-cyclopentyloxyquinoline-4-carbonylguanidine 
     269. 2-(2&#39;-methylphenyl)-6-(4-methylpentyloxy)quinoline-4-carbonylguanidine 
     270. 2-(2&#39;-methylphenyl)-7-(3-methylpentyloxy)quinoline-4-carbonylguanidine 
     271. 2-(2&#39;-methylphenyl)-8-(2-methylpentyloxy)quinoline-4-carbonylguanidine 
     272. 2-(2&#39;-methylphenyl)-5-(1-methylpentyloxy)quinoline-4-carbonylguanidine 
     273. 2-(2&#39;-methylphenyl)-6-(1,2,2-trimethylpropyloxy)quinoline-4-carbonylguanidine 
     274. 2-(2&#39;-methylphenyl)-7-(1,1-dimethylbutyloxy)quinoline-4-carbonylguanidine 
     275. 2-(2&#39;-methylphenyl)-8-(1,1,2-trimethylpropyloxy)quinoline-4-carbonylguanidine 
     276. 2-(2&#39;-methylphenyl)-5-(2,2-dimethylbutyloxy)quinoline-4-carbonylguanidine 
     277. 2-(2&#39;-methylphenyl)-6-(2,3-dimethylbutyloxy)quinoline-4-carbonylguanidine 
     278. 2-(2&#39;-methylphenyl)-5-methoxymethyloxyquinoline-4-carbonylguanidine 
     279. 2-phenyl-8-methoxyethyloxyquinoline-4-carbonylguanidine 
     280. 2-(2&#39;-methylphenyl)-6-ethoxymethyloxyquinoline-4-carbonylguanidine 
     281. 2-(2&#39;-methylphenyl)-7-methoxymethyloxyquinoline-4-carbonylguanidine 
     282. 2-(2&#39;-methylphenyl)-7-n-propyloxyethyloxyquinoline-4-carbonylguanidine 
     283. 2-(2&#39;-methylphenyl)-8-isopropyloxypropyloxyquinoline-4-carbonylguanidine 
     284. 2-(2&#39;-methylphenyl)-5-cyclopropyloxybutyloxyquinoline-4-carbonylguanidine 
     285. 2-(2&#39;-methylphenyl)-6-n-butyloxypentyloxyquinoline-4-carbonylguanidine 
     286. 2-(2&#39;-methylphenyl)-7-tert-butyloxyhexyloxyquinoline-4-carbonylguanidine 
     287. 2-(2&#39;-methylphenyl)-8-(2-methylpropyloxymethyloxy)quinoline-4-carbonylguanidine 
     288. 2-(2&#39;-methylphenyl)-5-(1-methylpropyloxyethyloxy)quinoline-4-carbonylguanidine 
     289. 2-(2&#39;-methylphenyl)-6-n-pentyloxypropyloxyquinoline-4-carbonylguanidine 
     290. 2-(2&#39;-methylphenyl)-7-cyclopentyloxymethyloxyquinoline-4-carbonylguanidine 
     291. 2-(2&#39;-methylphenyl)-8-n-hexyloxypentyloxyquinoline-4-carbonylguanidine 
     292. 2-phenyl-5-methanesulfonylaminoquinoline-4-carbonylguanidine 
     293. 2-phenyl-6-methanesulfonylaminoquinoline-4-carbonylguanidine 
     294. 2-phenyl-7-methanesulfonylaminoquinoline-4-carbonylguanidine 
     295. 2-phenyl-8-methanesulfonylaminoquinoline-4-carbonylguanidine 
     296. 2-(2&#39;-methylphenyl)-5-methanesulfonylaminoquinoline-4-carbonylguanidine 
     297. 2-(2&#39;-methylphenyl)-6-methanesulfonylaminoquinoline-4-carbonylguanidine 
     298. 2-(2&#39;-methylphenyl)-7-methanesulfonylaminoquinoline-4-carbonylguanidine 
     299. 2-(2&#39;-methylphenyl)-8-methanesulfonylaminoquinoline-4-carbonylguanidine 
     300. 2-phenyl-5-ethanesulfonylaminoquinoline-4-carbonylguanidine 
     301. 2-phenyl-6-ethanesulfonylaminoquinoline-4-carbonylguanidine 
     302. 2-phenyl-7-n-propanesulfonylaminoquinoline-4-carbonylguanidine 
     303. 2-phenyl-8-isopropanesulfonylaminoquinoline-4-carbonylguanidine 
     304. 2-phenyl-5-n-butanesulfonylaminoquinoline-4-carbonylguanidine 
     305. 2-phenyl-6-tert-butanesulfonylaminoquinoline-4-carbonylguanidine 
     306. 2-phenyl-7-(2-methylpropanesulfonylamino)quinoline-4-carbonylguanidine 
     307. 2-phenyl-8-(1-methylpropanesulfonylamino)quinoline-4-carbonylguanidine 
     308. 2-phenyl-5-cyclobutanesulfonylaminoquinoline-4-carbonylguanidine 
     309. 2-phenyl-6-n-pentanesulfonylaminoquinoline-4-carbonylguanidine 
     310. 2-phenyl-7-cyclopentanesulfonylaminoquinoline-4-carbonylguanidine 
     311. 2-phenyl-8-n-hexanesulfonylaminoquinoline-4-carbonylguanidine 
     312. 2-phenyl-5-cyclohexanesulfonylaminoquinoline-4-carbonylguanidine 
     313. 2-phenyl-5-acetylaminoquinoline-4-carbonylguanidine 
     314. 2-phenyl-6-acetylaminoquinoline-4-carbonylguanidine 
     315. 2-phenyl-7-acetylaminoquinoline-4-carbonylguanidine 
     316. 2-phenyl-8-acetylaminoquinoline-4-carbonylguanidine 
     317. 2-(2&#39;-methylphenyl)-5-acetylaminoquinoline-4-carbonylguanidine 
     318. 2-(2&#39;-methylphenyl)-6-acetylaminoquinoline-4-carbonylguanidine 
     319. 2-(2&#39;-methylphenyl)-7-acetylaminoquinoline-4-carbonylguanidine 
     320. 2-(2&#39;-methylphenyl)-8-acetylaminoquinoline-4-carbonylguanidine 
     321. 2-phenyl-5-propionylaminoquinoline-4-carbonylguanidine 
     322. 2-phenyl-6-butyrylaminoquinoline-4-carbonylguanidine 
     323. 2-phenyl-7-valerylaminoquinoline-4-carbonylguanidine 
     324. 2-phenyl-8-hexanoylaminoquinoline-4-carbonylguanidine 
     325. 2-phenyl-5-isobutyrylaminoquinoline-4-carbonylguanidine 
     326. 2-phenyl-6-isovalerylaminoquinoline-4-carbonylguanidine 
     327. 2-phenyl-7-pivaloylaminoquinoline-4-carbonylguanidine 
     328. 2-phenyl-8-cyclopentylcarbonylaminoquinoline-4-carbonylguanidine 
     329. 2-(2&#39;-methylphenyl)-5-methoxy-6-methylquinoline-4-carbonylguanidine 
     330. 2-(2&#39;-methylphenyl)-5-methoxy-7-methylquinoline-4-carbonylguanidine 
     331. 2-(2&#39;-methylphenyl)-5-methoxy-8-methylquinoline-4-carbonylguanidine 
     332. 2-(2&#39;-methylphenyl)-5-methyl-8-methoxyquinoline-4-carbonylguanidine 
     333. 2-(2&#39;-methylphenyl)-6-methyl-8-methoxyquinoline-4-carbonylguanidine 
     334. 2-(2&#39;-methylphenyl)-7-methyl-8-methoxyquinoline-4-carbonylguanidine 
     335. 2-(2&#39;-methylphenyl)-5-methoxy-6-fluoroquinoline-4-carbonylguanidine 
     336. 2-(2&#39;-methylphenyl)-5-methoxy-7-chloroquinoline-4-carbonylguanidine 
     337. 2-(2&#39;-methylphenyl)-5-methoxy-8-bromoquinoline-4-carbonylguanidine 
     338. 2-(2&#39;-methylphenyl)-5-methoxy-8-iodoquinoline-4-carbonylguanidine 
     339. 2-(2&#39;-methylphenyl)-5-fluoro-8-methoxyquinoline-4-carbonylguanidine 
     340. 2-(2&#39;-methylphenyl)-5-chloro-8-methoxyquinoline-4-carbonylguanidine 
     341. 2-(2&#39;-methylphenyl)-5-iodo-8-methoxyquinoline-4-carbonylguanidine 
     342. 2-(2&#39;-methylphenyl)-5-bromo-8-methoxyquinoline-4-carbonylguanidine 
     343. 2-phenyl-6-chloro-8-methylquinoline-4-carbonylguanidine 
     344. 2-phenyl-5-methoxy-8-methanesulfonylaminoquinoline-4-carbonylguanidine 
     345. 2-phenyl-5-methanesulfonylamino-8-methoxyquinoline4-carbonylguanidine 
     346. 2-(2&#39;-methylphenyl)-5-methoxy-8-methanesulfonylaminoquinoline-4-carbonylguanidine 
     347. 2-(2&#39;-methylphenyl)-5-methanesulfonylamino-8-methoxyquinoline-4-carbonylguanidine 
     348. 2-phenyl-3-methyl-5,7-dimethoxyquinoline-4-carbonylguanidine 
     349. 2-phenyl-3-methyl-5,8-dimethoxyquinoline-4-carbonylguanidine 
     350. 2-(2&#39;-methylphenyl)-3-methyl-5,7-dimethoxyquinoline-4-carbonylguanidine 
     351. 2-(2&#39;-methylphenyl)-3-methyl-5,8-dimethoxyquinoline-4-carbonylguanidine 
     When the compounds of formula (1) and pharmaceutically acceptable salts thereof in the present invention are used as an agent for treating or preventing hypertension, arrhythmia, diseases owing to ischemia which is a primary or secondary cause and diseases caused by cell growth and organic hyperplasia or hypertrophy (all of these result from activation of NHE), the above-mentioned compounds and salts can be administered either orally or parenterally. The form thereof varies with the properties of the compounds of the present invention which are used as an active ingredient. 
     The preparations of these compounds can be obtained by a known method. These preparations can take various forms depending on therapeutic purposes. Typical forms are solids, solutions, suppositories and the like. More specifically, the solids are tablets, pills, powders, granules and capsules. The solutions are injections, suspensions, syrups and emulsions. 
     When tablets are prepared, it is possible to use various carriers which have been well known in this field so far. Examples of the carriers include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid; binders such as water, ethanol, propanol, simple syrup, liquid glucose, starch solution, gelatin solution, shellac solution, methyl cellulose solution, hydroxypropyl cellulose solution, polyvinyl pyrrolidone solution, and carboxymethyl cellulose solution; disintegrants such as dry starch, sodium alginate, agar powder, sodium hydrogencarbonate, calcium carbonate, polyoxyethylenesorbitan fatty acid esters, sodium laurylsulfate, stearic acid glyceride, starch, and lactose; disintegration suppressants such as sucrose, stearic acid, cocoa butter, and hydrogenated oil; absorption accelerators such as quaternary ammonium base, and sodium laurylsulfate; wetting agents such as glycerin, and starch; adsorbents such as starch, lactose, kaolin, bentonire, colloidal silicic acid, crystalline cellulose, and light silicic anhydride; and lubricants such as talc, stearate salt, boric acid powder, and polyethylene glycol. 
     Further, in the case of tablets, coated tablets can be formed as required. Examples of the coated tablets include sugar-coated tablets, gelatin-coated tablets, enteric coated tablets, and film-coated tablets. Two-layered tablets and multi-layered tablets are also available. 
     In the case of pills, a carrier which is known in this field can be used. Examples of the carrier include excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc; binders such as gum arabic, tragacanth powder, and gelatin; and disintegrants such as carmellose calcium, and agar. 
     In the case of capsules, usually, the active ingredient compound is mixed with the above-mentioned carrier, and the mixture is filled in a hard gelatin capsule, a soft capsule or the like. 
     In the case of injections, a known diluent is used in forming a solution, an emulsion or a suspension. Examples of the diluent include water, ethanol, macrogel, propylene glycol, ethoxyisostearyl alcohol, polyoxyisostearyl alcohol, polyoxyethylenesorbitan fatty acid esters, cottonseed oil, corn oil, peanut oil, olive oil and the like. Further, a suspension is prepared in the presence of an appropriate surfactant by adding water to the compound of the present invention, or an emulsion is formed using a surfactant such as polyoxyethylene-hardened castor oil (HCO-60), Polysorbate 80 or polyethylene glycol. Sodium chloride, glucose or glycerin may be contained in pharmaceutical preparations, or an ordinary dissolution aid, buffer or analgesic may be added thereto. 
     In the case of suppositories, a known carrier can be used. Examples of the carrier include polyethylene glycol, cocoa butter, higher alcohol, higher alcohol esters, gelatin, and semi-synthetic glyceride. 
     Besides, a colorant, a preservative, a flavor, a seasoning, a sweetener and the like can be contained in pharmaceutical preparations. 
     A method of administering the pharmaceutical preparations of the present invention is not particularly limited, and it depends on the age, sex and other conditions of patients, and stages of diseases. For example, tablets, pills, solutions, suspensions, emulsions, powders, granules, syrups and capsules are administered orally. Injections are administered intravenously either singly or in combination with an ordinary aid such as glucose, amino acids or the like. Further, injections are administered intramuscularly, subcutaneously or intraperitoneally as required. Suppositories are administered intrarectally. 
     The dose of these pharmaceutical preparations in the present invention is approximately selected depending on usage, the age, sex and other conditions of patients, and stages of diseases. The dose of the active ingredient compound for adults is preferably between approximately 0.001 and 1,000 mg. The amount of the active ingredient compound in the preparation in administration unit form is preferably between approximately 0.001 and 1,000 mg. 
     The present invention will be illustrated specifically by referring to the following Production Reference Examples, Examples, Preparation Examples and Test Examples. However, the present invention is not limited thereto. 
     EXAMPLES 
     Reference Example 1 
     Synthesis of 2-(4&#39;-methylphenyl)quinoline-4-carboxylic Acid 
     Ten milliliters (2.2N) of a sodium hydroxide aqueous solution was added dropwise to an ethanol (20 ml) suspension containing 1.47 g of isatin and 2.67 ml of 4-methylacetophenone at room temperature, and the reaction mixture was then heat-refluxed for 5.5 hours. The resulting reaction mixture was allowed to cool, and then acidified with 2N sulfuric acid to obtain an orange-colored precipitate. This precipitate was collected by filtration, and dried to form 2.34 g of the above-mentioned compound. 
       1  H-NMR(DHSO-d -   6 ), δ: 2.55(s, 3H), 7.32-7.40(m, 3H), 7.66-7.71(m, 1H), 7.86(d, 1H). 8.15(d, 1H), 8.21(d, 1H), 8.43(s, 1H), 8.64(d, 2H) 
     Reference Example 2 
     Synthesis of 2-(3&#39;-methylphenyl)quinoline-4-carboxylic Acid 
     The above-mentioned compound (0.62 g) was formed from 1.47 g of isatin and 2.68 g of 3-methylacetophenone in the same manner as in Reference Example 1. 
       1  H-NMR(DMSO-d 6 ), δ: 2.46(s, 3H), 7.34(d, 1H), 7.47(t. 1H), 7.70(t, 1H), 7.86(t, 1H), 8.13(m, 3H), 8.46(s, 1H), 8.66(d, 1H) 
     Reference Example 3 
     Synthesis of 2- (2&#39;-methylphenyl)quinoline-4-carboxylic Acid 
     The above-mentioned compound (0.89 g) was formed from 1.47 g of isatin and 2.68 g of 2-methylacetophenone in the same manner as in Reference Example 1. 
       1  H-NMR(DMSO-d 6 ), δ: 2.42(s, 3H), 7.39(m, 3H), 7.55(m, 1H), 7.74(t, 1H), 7.87(t, 1H), 8.05(s, 1H), 8.14(d, 1H), 8.74(d, 1H) 
     Reference Example 4 
     Synthesis of 2-(2&#39;,4&#39;-dimethylphenyl)quinoline-4-carboxylic Acid 
     The above-mentioned compound (1.00 g) was formed from 1.47 g of isatin and 2.96 g of 2,4-dimethylacetophenone in the same manner as in Reference Example 1. 
       1  H-NMR(DNSO-d 6 ), δ: 2.37(s, 3H), 2.40(s, 3H), 7.17(d, 2H), 7.40(d, 1H), 7.72(t, 1H), 7.85(t, 1H), 8.02(s, 1H). 8.12(d, 1H), 8.72(d, 1H) 
     Reference Example 5 
     Synthesis of 2-(3&#39;,4&#39;-dimethylphenyl)quinoline-4-carboxylic Acid 
     The above-mentioned compound (4.35 g) was formed from 2.0 g of isatin and 4.0 g of 3,4-dimethylacetophenone in the same manner as in Reference Example 1. 
       1  H-NMR(DMSO-d 6 ), δ: 2.32(s, 3H), 2.37(s, 3H),7.33(d, 1H), 7.64-7.68(m, 1H), 7.70-7.86(m, 1H), 8.00-8.17(m, 3H), 8.43(s, 1H), 8.65(d, 1H) 
     Reference Example 6 
     Synthesis of 2-(2&#39;,4&#39;,6&#39;-trimethylphenyl)quinoline-4-carboxylic Acid 
     The above-mentioned compound (0.16 g) was formed from 2.21 g of isatin and 4.87 g of 2,4,6-trimethylacetophenone in the same manner as in Reference Example 1. 
       1  H-NMR(DMSO-d 6 ), δ: 1.98(s, 6H), 2.32(s, 3H), 6.99(s, 2H), 7.75(t, 1H), 7.78(s, 1H), 7.86(t, 1H), 8.11(d, 1H), 8.75(d, 1H) m.p. 240° C. (decomp.) 
     Reference Example 7 
     Synthesis of 2-(4&#39;-tert-butylphenyl)quinoline-4-carboxylic Acid 
     The above-mentioned compound (0.70 g) was formed from 1.47 g of isatin and 3.60 g of 4-tert-butylacetophenone in the same manner as in Reference Example 1. 
       1  H-NMR(DMSO-d 6 ), δ: 1.37(s, 9H), 7.55(m, 3H), 7.76(t, 1H), 8.12(d, 2H), 8.27(d, 1H), 8.46(s, 1H), 8.82(d, 1H) 
     Reference Example 8 
     Synthesis of 2-(3&#39;-trifluoromethylphenyl)quinoline-4-carboxylic Acid 
     The above-mentioned compound (1.89 g) was formed from 1.47 g of isatin and 3.76 g of 3-trifluoromethylacetophenone in the same manner as in Reference Example 1. 
       1  H-NMR(DMSO-d 6 ), δ: 7.75-7.92(m, 4H), 8.24(d, 1H), 8.60(s, 1H), 8.65(m, 3H) 
     Reference Example 9 
     Synthesis of 2-(2&#39;-trifluoromethylphenyl)quinoline-4-carboxylic Acid 
     The above-mentioned compound (2.85 g) was formed from 1.90 g of isatin and 5.0 g of 2-trifluoromethylacetophenone the same manner as in Reference Example 1. 
       1  H-NMR(DMSO-d 6 ), δ: 7.76(m, 2H), 7.78(s, 1H), 7.79(s, 1H), 7.90(m, 2H), 8.03(s, 1H), 8.14(d, 1H) 
     Reference Example 10 
     Synthesis of 2-(4&#39;-bromophenyl)quinoline-4-carboxylic Acid 
     The above-mentioned compound (3.00 g) was formed from 1.47 g of isatin and 3.98 g of 4-bromoacetophenone in the same manner as in Reference Example 1. 
       1  H-NMR(DMSO-d 6 ), δ: 7.73-7.84(m, 4H), 8.17(d, 1H), 8.28(d, 2H), 8.47(s, 1H), 8.65(d, 1H) 
     Reference Example 11 
     Synthesis of 2-(4&#39;-fluorophenyl)quinoline-4-carboxylic Acid 
     The above-mentioned compound (2.21 g) was formed from 1.47 g of isatin and 2.76 g of 4-fluoroacetophenone in the same manner as in Reference Example 1. 
       1  H-NMR(DMSO-d 6 ), δ: 7.31-7.44(m, 2H), 7.68-7.74(m, 1H), 7.83-7.93(m, 1H), 8.16(d, 1H), 8.35-8.40(m, 2H), 8.47(s, 1H), 8.64(d, 1H) 
     Reference Example 12 
     Synthesis of 2-(2&#39;-chlorophenyl)quinoline-4-carboxylic Acid 
     The above-mentioned compound (0.90 g) was formed from 1.47 g of isatin and 3.1 g of 2-chloroacetophenone in the same manner as in Reference Example 1. 
       1  H-NMR(DMSO-d 6 ), δ: 7.12(t, 1H), 7.21(d, 1H), 7.48(t, 1H), 7.81(t, 1H), 7.78(m, 2H), 7.99(d, 1H), 8.08(s, 1H), 8.74(d, 1H) 
     Reference Example 13 
     Synthesis of 2-(4&#39;-methoxyphenyl)quinoline-4-carboxylic Acid 
     The above-mentioned compound (1.54 g) was formed from 1.47 g of isatin and 3.0 g of 4-methoxyacetophenone in the same manner as in Reference Example 1. 
       1  H-NMR(DMSO-d 6 ), δ: 3.86(s, 3H), 7.13(d, 2H), 7.62-7.68(m, 1H), 7.79-7.85(m, 1H), 7.94(d, 1H), 8.27(d, 2H), 8.39(s, 1H), 8.61(d, 1H) 
     Reference Example 14 
     Synthesis of 2-(2&#39;-methoxyphenyl)quinoline-4-carboxylic Acid 
     The above-mentioned compound (0.91 g) was formed from 1.47 g of isatin and 3.0 g of 2-methoxyacetophenone in the same manner as in Reference Example 1. 
       1  H-NMR(DMSO-d 6 ), δ:3.89(s, 3H), 7.14(t, 1H), 7.22(d, 1H), 7.50(t, 1H), 7.72(t, 1H), 7.85(m, 2H), 8.13(d, 1H), 8.33(s, 1H), 8.92(d, 1H) 
     Reference Example 15 
     Synthesis of 2-(2&#39;,6&#39;-dimethoxyphenyl)quinoline-4-carboxylic Acid 
     The above-mentioned compound (0.59 g) was formed from 1.50 g of isatin and 3.68 g of 2,6-dimethoxyacetophenone in the same manner as in Reference Example 1. 
       1  H-NMR(DMSO-d 6 ), δ: 3.64(s, 6H), 6.76(s, 1H), 6.80(s, 1H), 7.40(t, 1H), 7.46(s, 1H), 7.55(t, 1H), 7.69(t, 1H), 7.95(d, 1H), 8.75(d, 1H) 
     Reference Example 16 
     Synthesis of 2-(4&#39;-trifluoromethoxyphenyl)quinoline-4-carboxylic Acid 
     The above-mentioned compound (2.27 g) was formed from 1.47 g of isatin and 4.08 g of 4-trifluoromethoxyacetophenone in the same manner as in Reference Example 1. 
       1  H-NMR(DMSO-d 6 ), δ: 7.55(d, 2H), 7.72(t, 1H), 7.87(t, 1H), 8.19(d, 1H), 8.41(d, 2H), 8.49(s, 1H), 8.68(d, 1H) 
     Reference Example 17 
     Synthesis of 2-phenyl-3-methylquinoline-4-carboxylic Acid 
     Ten milliliters (2N) of a sodium hydroxide aqueous solution was added dropwise to an ethanol (20 ml) suspension containing 1.47 g of isatin and 2.68 g of propiophenone at room temperature, and the reaction mixture was then heat-refluxed for 26 hours. The resulting reaction mixture was allowed to cool, and then concentrated under reduced pressure. Ice water was added to the residue, and the mixture was extracted with ethyl ether. The aqueous layer was acidified with dilute hydrochloric acid. The precipitate was collected by filtration, and dried to form 1.47 g of the above-mentioned compound. 
       1  H-NMR(DMSO-d 6 ), δ: 2.39(s, 3H), 7.53-7.70(m, 6H), 7.71-7.83(m, 2H), 8.05(d, 1 g) 
     Reference Example 18 
     Synthesis of 2-phenyl-6-fluoroquinoline-4-carboxylic Acid 
     The above-mentioned compound (1.58 g) was formed from 1.65 g of 5-fluoroisatin and 2.40 g of acetophenone in the same manner as in Reference Example 1. 
       1  H-NMR(DMSO-d 6 ), δ: 7.55(m, 3H), 7.80(m, 1H), 8.26(m, 1H), 8.48(m, 1H), 8.50(m, 1H), 8.56(s, 1H) 
     Reference Example 19 
     Synthesis of 2-phenyl-6-iodoquinoline-4-carboxylic Acid 
     The above-mentioned compound (2.01 g) was formed from 2.73 g of 5-iodoisatin and 2.40 g of acetophenone in the same manner as in Reference Example 1. 
       1  H-NMR(DMSO-d 6 ), δ:7.57(m, 3H), 7.92(d, 1H), 8.12(m, 1H), 8.28(m, 2H), 8.51(s, 1H), 9.15(s, 1H) 
     Reference Example 20 
     Synthesis of 2-phenyl-5-chloroquinoline-4-carboxylic Acid 
     The above-mentioned compound (0.42 g) was formed from 0.70 g of 4-chloroisatin prepared by a known method [A. E. Senear, J. Am. Chem. Soc., 68, 2695-2697 (1946)] and 0.82 ml of acetophenone in the same manner as in Reference Example 1. 
       1  H-NMR(DMSO-d 6 ), δ: 7.52-7.62(m, 3H), 7.81-7.86(m, 2H), 8.16(dd, 1H), 8.26(s, 1H), 8.33-8.37(m, 2H) 
     Reference Example 21 
     Synthesis of 2-phenyl-6-chloroquinoline-4-carboxylic Acid 
     The above-mentioned compound (1.72 g) was formed from 1.47 g of 5-chloroisatin and 3.10 g of acetophenone in the same manner as in Reference Example 1. 
       1  H-NNR(DMSO-d 6 ), δ: 7.61(s, 1H), 7.64(s, 1H), 7.71(t, 1H), 7.86(t, 1H), 8.16(t, 1H), 8.35(s, 1H), 8.36(s, 1H), 8.47(s, 1H),8.67(d, 1H) 
     Reference Example 22 
     Synthesis of 2-phenyl-7-chloroquinoline-4-carboxylic Acid 
     The above-mentioned compound (1.26 g) was formed from 1.0 g of 6-chloroisatin prepared by a known method (A. E. Senear, J. Am. Chem. Soc., 68, 2695-2697 (1946)] and 1.3 ml of acetophenone in the same manner as in Reference Example 1. 
       1  H-NMR(DNSO-d 6 ), δ: 7.53-7.64(m, 3H), 7.74(dd, 1H), 8.21-8.30(m, 3H), 8.49(s, 1H), 8.73(d. 1H) 
     Reference Example 23 
     Synthesis of 2-phenyl-6-chloro-8-methylquinoline-4-carboxylic Acid 
     The above-mentioned compound (1.03 g) was formed from 1.95 g of 5-chloro-7-methylisatin and 2.40 g of acetophenone in the same manner as in Reference Example 1. 
       1  H-NMR(DMSO-d 6 ), δ: 2.53(s, 3H), 7.55(m, 3H), 7.65(d, 1H), 8.03(d, 1H), 8.25(d, 2H), 8.35(s, 1H), 8.46(s, 1H) 
     Reference Example 24 
     Synthesis of 2-phenyl-6-methylquinoline-4-carboxylic Acid 
     Benzaldehyde (2.12 g) and 2.14 g of p-toluidine were dissolved in 50 ml of ethanol, and 1.76 g of pyruvic acid were added thereto dropwise. The reaction mixture was then heat-refluxed for 6 hours. The resulting reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was dissolved in a 1N sodium hydroxide aqueous solution. This aqueous solution was extracted with ethyl ether, and the aqueous layer was acidified with dilute hydrochloric acid. The precipitate was collected by filtration, and dried to form 0.51 g of the above-mentioned compound. 
       1  H-NMR(DMSO-d 6 ), δ: 2.54(s.3H), 7.54(a, 3H), 7.69(d,1H), 8.05(d, 1H), 8.26(d, 2H), 8.37(s, 1H), 8.44(s, 1H) 
     Reference Example 25 
     Synthesis of 2-(3&#39;-nitrophenyl)quinoline-4-carboxylic Acid 
     The above-mentioned compound (0.75 g) was formed from 6.86 g of 3-nitrobenzaldehyde, 4.9 g of aniline and 2.0 g of pyruvic acid in the same manner as in Reference Example 24. 
       1  H-NMR(DMSO-d 6 ), δ: 7.25-7.36(m, 1H), 7.85-7.91(m, 2H), 8.20-8.31(m, 1H), 8.37-8.40(m, 1H), 8.60(s, 1H), 8.69(d, 1H), 8.76(d, 1H), 9.10-9.12(m, 1H) 
     Reference Example 26 
     Synthesis of 2-(2&#39;-isopropylphenyl)quinoline-4-carboxylic Acid 
     The above-mentioned compound (1.48 g) was formed from 1.4 g of 2-isopropylbenzaldehyde prepared by a known method [Chem. Pharm. Bull., 35, 1953-1968 (1987)], 0.88 g of aniline and 0.83 g of pyruvic acid in the same manner as in Reference Example 24. 
       1  H-NMR(DMSO-d 6 ), δ: 1.18(d,6H), 3.16-3.21(m, 1H), 7.32-7.53(m,4H), 7.71(t, 1H), 7.84(t, 1H), 7.92(s, 1H), 8.10(d, 1H), 8.73(d, 1H) 
     Reference Example 27 
     Synthesis of 2-phenyl-7-methylquinoline-4-carboxylic Acid 
     The above-mentioned compound (1.30 g) was formed from 4.0 g of benzaldehyde, 4.0 g of m-toluidine and 3.28 g of pyruvic acid in the same manner as in Reference Example 24. 
       1  H-NMR(DMSO-d 6 ), δ: 2.56(s,3H), 7.52-7.61(m, 4H), 7.97(s, 1H), 8.25(d, 1H), 8.36(s, 1H), 8.56(d, 1H) 
     m.p. 233°-237° C. 
     Reference Example 28 
     Synthesis of 2-phenyl-8-methylquinoline-4-carboxylic Acid 
     The above-mentioned compound (1.74 g) was formed from 3.96 g of benzaldehyde, 4.0 g of o-toluidine and 3.28 g of pyruvic acid in the same manner as in Reference Example 24. 
       1  H-NMR(DMSO-d 6 ), δ: 2.85(s, 3H), 7.50-7.62(m, 4H), 7.71(d, 1H), 8.33-8.36(m,2H), 8.47 (d, 2H) 
     Reference Example 29 
     Synthesis of 2-phenyl-6-isopropylquinoline-4-carboxylic Acid 
     The above-mentioned compound (1.23 g) was formed from 1.59 g of benzaldehyde, 1.35 g of 4-isopropylaniline and 1.32 g of pyruvic acid in the same manner as in Reference Example 24. 
       1  H-NMR(DNSO-d 6 ), δ: 1.26(d,6H), 2.96-3.03(m, 1H), 7.36-7.65(m, 4H), 8.10-8.18(m, 3H), 8.44(s, 1H), 8.64(s, 1H) 
     Reference Example 30 
     Synthesis of 2-phenyl-8-chloroquinoline-4-carboxylic Acid 
     The above-mentioned compound (0.48 g) was formed from 2.12 g of benzaldehyde, 2.60 g of 2-chloroaniline and 1.80 g of pyruvic acid in the same manner as in Reference Example 24. 
       1  H-NMR(DMSO-d 6 ), δ: 7.47-7.78(m, 4H), 8.06(d, 1H), 8.32(d,2H), 8.57(s, 1H), 8.64(d, 1H) 
     Reference Example 31 
     Synthesis of 2-phenyl-6-methoxyquinoline-4-carboxylic Acid 
     The above-mentioned compound (0.63 g) was formed from 3.3 g of benzaldehyde, 3.83 g of p-anisidine and 2.37 g of pyruvic acid in the same manner as in Reference Example 24. 
       1  H-NMR(DMSO-d 6 ), δ: 3.93(s, 3H), 7.50-7.60(m, 4H), 8.08-8.15(m, 2H), 8.24(d, 2H), 8.46(s, 1H) 
     Reference Example 32 
     Synthesis of 2-phenyl-7-methoxyquinoline-4-carboxylic Acid 
     The above-mentioned compound (2.82 g) was formed from 5.31 g of benzaldehyde, 6.16 g of m-anisidine and 4.40 g of pyruvic acid in the same manner as in Reference Example 24. 
       1  H-NMR(DMSO-d 6 ), δ: 3.98(s, 3H), 7.37(d, 1H), 7.58(m, 4H), 8.27(m, 3H), 8.57(d, 1H) 
     Reference Example 33 
     Synthesis of 2-phenyl-8-methoxyquinoline-4-carboxylic Acid 
     The above-mentioned compound (2.45 g) was formed from 3.47 g of benzaldehyde, 4.03 g of o-anisidine and 2.90 g of pyruvic acid in the same manner as in Reference Example 24. 
       1  H-NMR(DHSO-d 6 ), δ: 4.04(s, 3H), 7.30(d, 1H), 7.53-7.66(m, 4H), 8.14(d, 1H), 8.28(d, 2H), 8.44 (s, 1H) 
     Reference Example 34 
     Synthesis of 2-phenyl-5,7-dimethoxyquinoline-4-carboxylic Acid 
     The above-mentioned compound (0.93 g) was formed from 1.06 g of benzaldehyde, 1.68 g of 3,5-dimethoxyaniline and 0.90 g of pyruvic acid in the same manner as in Reference Example 24. 
       1  H-NMR(dMSO-d 6 ), δ: 3.91(s, 3H), 3.95(s, 3H), 6.73(s, 1H), 7.12(s, 1H), 7.54(m, 3H), 7.83(s, 1H), 8.29(m, 2H) m.p. 240°-240.5° C. (decomp.) 
     Reference Example 35 
     Synthesis of 2-(2&#39;-methylphenyl)-5,7-dimethoxyquinoline-4-carboxylic Acid 
     The above-mentioned compound (0.86 g) was formed from 3.60 g of o-tolualdehyde, 4.60 g of 3,5-dimethoxyaniline and 2.64 g of pyruvic acid in the same manner as in Reference Example 24. 
       1  H-NMR(DMSO-d 6 ), δ: 2.35(s, 3H), 3.83(s, 3H),3.89(s, 3H), 6.58(s, 1H), 6.95(s, 1H), 7.01(s, 1H), 7.30(m, 3H), 7.40(d, 1H) 
     Reference Example 36 
     Synthesis of 2-phenyl-6,7-dimethoxyquinoline-4-carboxylic Acid 
     The above-mentioned compound (1.58 g) was formed from 3.18 g of o-benzaldehyde, 4.60 g of 3,4-dimethoxyaniline and 2.64 g of pyruvic acid in the same manner as in Reference Example 24. 
       1  H-NNR(DMSO-d 6 ), δ: 3.96(s, 3H), 4.01(s, 3H), 7.53(m, 4H), 8.15(s, 1H), 8.20(s, 1H), 8.25(s, 1H), 8.33(s, 1H) 
     Reference Example 37 
     Synthesis of 2-(2&#39;-methylphenyl )-6,7-dimethoxyquinoline-4-carboxylic Acid 
     The above-mentioned compound (3.15 g) was formed from 2.40 g of o-tolualdehyde, 3.00 g of 3,4-dimethoxyaniline and 1.70 g pyruvic acid in the same manner as in Reference Example 24. 
       1  H-NMR(DMSO-d 6 ), δ: 2.39(s, 3H), 3.95(s, 3H), 3.9.7(s, 3H), 7.17-7.20(m, 1H), 7.33-7.38(m, 2H), 7.48-7.51(m, 2H), 7.88(s, 1H), 8.20(s, 1H) 
     Reference Example 38 
     Synthesis of 2-phenyl-6,8-dimethoxyquinoline-4-carboxylic Acid 
     The above-mentioned compound (0.89 g) was formed from 2.12 g of benzaldehyde, 3.06 g of 2,4-dimethoxyaniline and 1.76 g of pyruvic acid in the same manner as in Reference Example 24. 
       1  H-NMR(DMSO-d 6 ), δ: 3.85(s,3H), 3.98(s, 3H), 6.82(s, 1H), 7.48(m, 3H), 7.83(s, 1H), 8.19(d, 2H), 8.30(s, 1H) 
     Reference Example 39 
     Synthesis of 2-(2&#39;-methylphenyl)-6,8-dimethoxyquinoline-4-carboxylic Acid 
     The above-mentioned compound (1.69 g) was formed from 2.40 g of o-tolualdehyde, 3.06 g of 2,4-dimethoxyaniline and 1.76 g of pyruvic acid in the same manner as in Reference Example 24. 
       1  H-NMR(DMSO-d 6 ), δ: 2.39(s, 3H), 3.92(s, 3H), 3.97(s, 3H), 6.93(d, 1H), 7,36(m, 3H), 7.49(m, 1H), 7.73(d, 1H), 8.03(s, 1H) 
     Reference Example 40 
     Synthesis of 2-(2&#39;-methylphenyl)-5,8-dimethoxyquinoline-4-carboxylic Acid 
     The above-mentioned compound (3.44 g) was formed from 3.60 g of o-tolualdehyde, 4.60 g of 2,5-dimethoxyaniline and 2.64 g of pyruvic acid in the same manner as in Reference Example 24. 
       1  H-NMR(DMSO-d 6 ), δ: 2.34(s, 3H), 3.79(s, 3H), 3.89(s, 3H), 6.86(d, 1H), 7.06(d, 1H), 7.25(s, 1H), 7.31(m, 4H) 
     m.p. 234°-235° C. (decomp.) 
     Reference Example 41 
     Synthesis of 2-(2&#39;-methylphenyl)-7,8-dimethoxyquinoline-4-carboxylic Acid 
     The above-mentioned compound (2.25 g) was formed from 2.30 g of o-tolualdehyde, 2.90 g of 2,3-dimethoxyaniline and 1.66 g of pyruvic acid in the same manner as in Reference Example 24. 
       1  H-NMR(DMSO-d 6 ), δ: 2.44(s, 3H), 3.95(s, 3H), 4.00(s,3H), 7.13-7.16(m, 1H), 7.33-7.45(m, 2H), 7.54-7.57(m, 1H), 7.66(d, 1H), 7.88(s, 1H), 8.46(d, 1H) 
     Reference Example 42 
     Synthesis of 2-phenyl-8-methoxyethyloxyquinoline-4-carboxylic Acid 
     The above-mentioned compound (1.40 g) was formed from 1.14 g of benzaldehyde, 1.80 g of 2-methoxyethytoxyaniline and 0.95 g of pyruvic acid in the same manner as in Reference Example 24. 
       1  H-NMR(DMSO-d 6 ), δ: 3.52(s, 3H), 3.87(t, 2H), 4.38(t, 2H),7.30(d, 1H), 7.49-7.60(m, 4H), 8:17(d, 1H), 8.29(d, 2H), 8.42(s, 1H) 
     m.p. 128°-133° C. 
     Reference Example 43 
     Synthesis of 2-(2&#39;-methylphenyl)-7-methoxymethyloxyquinoline-4-carboxylic Acid 
     The above-mentioned compound (1.26 g) was formed from 2.74 g of o-tolualdehyde, 3.50 g of 3-methoxymethyloxyanitine and 2.00 g of pyruvic acid in the same manner as in Reference Example 24. 
       1  H-NMR(DMSO-d 6 ), δ: 2.40(s, 3H), 3.41(s, 3H), 5.41(s, 2H), 7.34-7.63(m, 6H), 7.88(s, 1H), 8.68(d, 1H) 
     Reference Example 44 
     Synthesis of ethyl 2-phenyl-8-nitroquinoline-4-carboxylate 
     Benzaldehyde (19.5 g), 25.6 g of 2-nitroaniline and 16.2 g of pyruvic acid were mixed, and 10.4 ml of conc. sulfuric acid were added thereto dropwise at room temperature. After the mixture was stirred for 30 minutes, chloroform, water and aqueous ammonia were added to the reaction mixture, and the aqueous layer was extracted. This aqueous layer was acidified with conc. hydrochloric acid to obtain 25.0 g of crude 2-phenyl-8-nitroquinone-4-carboxylic acid as a dark red semi-solid. This semi-solid was dissolved in 300 ml of ethanol, and 37 ml of conc. sulfuric acid were added thereto. The mixture was heat-refluxed for 6 hours. After the reaction mixture was cooled to room temperature, the precipitate formed was collected by filtration, and recrystallized from methyl ethyl ketone to form 2.50 g of the above-mentioned compound. 
       1  H-NMR(DMSO-d 6 ), δ: 1.46(t, 3H), 4.51(q, 2H), 7.56-7.65(m, 3H), 7.83-7.89(t, 1H), 8.23-8.28(m, 2H), 8.35(d, 1H), 8.64(s, 1H), 8.81(d, 1H) 
     m.p. 138°-140° C. 
     Reference Example 45 
     Synthesis of 2-phenyl-8-nitroquinone-4-carboxylic Acid 
     Ethyl 2-phenyl-8-nitroquinone-4-carboxylic acid (1.09 g) formed in Reference Example 44 was suspended in 8 ml of ethanol, and 1.2M (6 ml) of a sodium hydroxide aqueous solution was added thereto at room temperature. The mixture was then stirred at approximately 40° C. for 2 hours. The reaction mixture was cooled with ice, and neutralized with dilute hydrochloric acid. The crystals precipitated were collected by filtration, washed with water, and dried to obtain 0.97 g of the above-mentioned compound. 
       1  H-NMR(DMSO-d 6 ), δ: 7.60(m, 3H), 7.86(t, 1H), 8.28(m, 2H), 8.38(d, 1H), 8.66(s, 1H), 8.91(d, 1H) 
     Reference Example 46 
     Synthesis of ethyl 2-phenyl-8-aminoquinoline-4-carboxylate 
     Ethyl 2-phenyl-8-nitroquinone-4-carboxylate (2.0 g) formed in Reference Example 44 was hydrogenated in DMF in the presence of Pd/C in a usual manner to obtain 1.70 g of the above-mentioned compound. 
       1  H-NNR(DMSO-d 6 ), δ: 1.43(t, 3H), 4.50(q, 2H), 6.96(d, 1H), 7.36(t, 1H), 7.51-7.62(m, 4H), 8.27-8.37(m 3H) 
     m.p. 66°-69° C. 
     Reference Example 47 
     Synthesis of ethyl 2-phenyl-8-acetylaminoquinoline-4-carboxylate 
     Ethyl 2-phenyl-8-aminoquinoline-4-carboxylate (0.82 g) formed in Reference Example 46 was acetylated in a usual manner to obtain 0.75 g of the above-mentioned compound. 
       1  H-NMR(DMSO-d 6 ), δ: 1.44(t, 3H), 2.35(s, 3H), 4.50(q, 2H), 7.63(m, 4H), 8.12(d, 1H), 8.44(m, 2H), 8.52(s, H), 8.66(d, 1H), 10.12(s, H) 
     m.p. 141.5°-142° C. 
     Reference Example 48 
     Synthesis of 2-phenyl-8-acetylaminoquinoline-4-carboxylic Acid 
     Ethyl 2-phenyl-8-acetylaminoquinoline-4-carboxylate (0.67 g) formed in Reference Example 47 was suspended in 6 ml of methanol, and 4 ml (1.1M) of a sodium hydroxide aqueous solution were added thereto at room temperature. The mixture was then stirred at approximately 40° C. for 1 hour. The reaction mixture was cooled with ice, and neutralized with dilute hydrochloric acid. The precipitate was collected by filtration, and dried to obtain 0.46 g of the above-mentioned compound. 
       1  H-NMR(DMSO-d 6 ), δ: 2.35(s, 3H), 7.54-7.68(m, 4H), 8.27(d, 1H), 8.39(dd, 2H), 8.52(s, 1H), 8.65(d, 1H), 10.13(s, 1H) 
     m.p. 254°-255° C. (decomp.) 
     Reference Example 49 
     Synthesis of ethyl 2-phenyl-8-methanesulfonylaminoquinoline-4-carboxylate 
     Ethyl 2-phenyl-8-aminoquinoline-4-carboxylate (1.02 g) formed in Reference Example 46 was methanesulfonylated in a usual manner to obtain 1.16 g of the above-mentioned compound. 
       1  H-NMR(DMSO-d 6 ), δ: 1.44(t, 3H), 3.17(s, 3H), 4.51(q, 2H), 7.63(m, 4H), 7.72(t, 1H), 7.83(d, 1H), 8.44(s, 1H), 8.46(s, 1H), 8.54(s, 1H), 9.63(s, 1H) 
     m.p. 145.5°-146.2° C. 
     Reference Example 50 
     Synthesis of 2-phenyl-8-methanesulfonylaminoquinoline-4-carboxylate 
     Ethyl 2-phenyl-8-methanesulfonylaminoquinoline-4-carboxylate (0.99 g) obtained in Reference Example 49 was hydrolyzed in the same manner as in Reference Example 48 to form 0.38 g of the above-mentioned compound. 
       1  H-NMR(DMSO-d 6 ), δ: 3.17(s,3H), 7.53-7.72(m, 4H), 7.82(d, 1H), 8.37(d, 1H), 8.45(d, 2H), 8.53(s, 1H), 9.61(s, 1H) 
     m.p. 263°-264° C. (decomp.) 
     Reference Example 51 
     Synthesis of 2-(2&#39;-methoxymethyloxyphenyl)quinoline-4-carboxylic Acid 
     The above-mentioned compound (1.53 g) was formed from 1.47 g of isatin and 3.64 g of 2-methoxymethyloxyacetophenone in the same manner as in Reference Example 1. 
       1  H-NMR(DMSO-d 6 ), δ: 3.58(s, 3H), 5.64(s, 2H), 7.05(m, 2H), 7.51 (d, 1H), 7.60(t, 1H), 7.79(t, 1H), 7.91(m, 1h), 8.20(d, 2H), 8.70(s, 1H) 
     EXAMPLE 1 
     Synthesis of 2-phenylquinoline-4-carbonylguanidine 
     [A] 2-Phenyl-4-quinolinecarboxylic acid (1.99 g) and 1.43 g of 1,1&#39;-carbonyldiimidazole were added to 20 ml of anhydrous DMF, and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. 
     [B] A mixture of 4.60 g of guanidine hydrochloride and 2.90 g of sodium methoxide was stirred in 30 ml of anhydrous methanol at room temperature for 1 hour. Then, the reaction mixture was filtered in a nitrogen stream, and the crystals were washed with methanol. The filtrate was concentrated to dryness under reduced pressure, and anhydrous benzene was added to the residue. The mixture was reconcentrated, and then dried under reduced pressure. 
     [C] The solution obtained in [A] was added to the dry guanidine obtained in [B] under a nitrogen atmosphere while being cooled with ice, and the mixture was stirred at room temperature for 12 hours. Subsequently, the reaction solution was concentrated under reduced pressure, and ice water was added to the residue. The mixture was further stirred for 30 minutes. The precipitate was collected by filtration, and the crystals were washed with water and then with a small amount of ethyl ether. The crystals were further washed with 10 ml of ethanol, and dried to obtain 1.85 g of the above-mentioned compound. m.p. 268° C. (decomp.) 
     EXAMPLE 2 
     Synthesis of 2-(4&#39;-methylphenyl)quinoline-4-carbonylguanidine 
     The above-mentioned compound (1.35 g) was formed as a white crystal in the same manner as in Example 1 using 2.0 g of 2-(4&#39;-methylphenyl)quinoline-4-carboxylic acid obtained in Reference Example 1 as a starting material. m.p. 244.3°-244.5° C. 
     EXAMPLE 3 
     Synthesis of 2-(3&#39;-methylphenyl)quinoline-4-carbonylguanidine 
     The above-mentioned compound (0.60 g) was formed in the same manner as in Example 1 using 0.53 g of 2-(3&#39;-methylphenyl)quinoline-4-carboxylic acid obtained in Reference Example 2 as a starting material. m.p. 248° C. (decomp.) 
     EXAMPLE 4 
     Synthesis of 2-(2&#39;-methylphenyl)quinoline-4-carbonylguanidine 
     The above-mentioned compound (0.75 g) was formed in the same manner as in Example 1 using 0.79 g of 2-(2&#39;-methylphenyl)quinoline-4-carboxylic acid obtained in Reference Example 3 as a starting material. m.p. 257.5°-258.5° C. (decomp.) 
     EXAMPLE 5 
     Synthesis of 2-(2&#39;-isopropylphenyl)quinoline-4-carbonylguanidine 
     The above-mentioned compound (1.17 g) was formed as a brown crystal in the same manner as in Example 1 using 1.46 g of 2-(2&#39;-isopropylphenyl)quinoline-4-carboxylic acid obtained in Reference Example 26 as a starting material. m.p. 224°-230° C. 
     EXAMPLE 6 
     Synthesis of 2-(2&#39;,4&#39;-dimethylphenyl)quinoline-4-carbonylguanidine 
     The above-mentioned compound (1.06 g) was formed as a brown crystal in the same manner as in Example 1 using 0.96 g of 2-(2&#39;,4&#39;-dimethylphenyl)quinoline-4-carboxylic acid obtained in Reference Example 4 as a starting material. m.p. 226°-233° C. (decomp.) 
     EXAMPLE 7 
     Synthesis of 2-(3&#39;,4&#39;-dimethylphenyl)quinoline-4-carbonylguanidine 
     The above-mentioned compound (2.82 g) was formed as a white crystal in the same manner as in Example 1 using 3.3 g of 2-(3&#39;,4&#39;-dimethylphenyl)quinoline-4-carboxylic acid obtained in Reference Example 5 as a starting material. m.p. 240°-243° C. (decomp.) 
     EXAMPLE 8 
     Synthesis of 2-(2&#39;,4&#39;,6&#39;-trimethylphenyl)quinoline-4-carbonylguanidine 
     The above-mentioned compound (0.15 g) was formed in the same manner as in Example 1 using 0.14 g of 2-(2&#39;,4&#39;,6&#39;-trimethylphenyl)quinoline-4-carboxylic acid obtained in Reference Example 6 as a starting material. m.p. 247°-250° C. (decomp.) 
     EXAMPLE 9 
     Synthesis of 2-(4&#39;-tert-butylphenyl)quinoline-4-carbonylguanidine 
     The above-mentioned compound (0.69 g) was formed in the same manner as in Example 1 using 0.61 g of 2&#39;-(4&#39;-tert-butylphenyl)quinoline-4-carboxylic acid obtained in Reference Example 7 as a starting material. m.p. 272° C. (decomp.) 
     EXAMPLE 10 
     Synthesis of 2-(3&#39;-trifluoromethylphenyl)quinoline-4-carbonylguanidine 
     The above-mentioned compound (1.30 g) was formed in the same manner as in Example 1 using 1.59 g of 2-(3&#39;-trifluoromethylphenyl)quinoline-4-carboxylic acid obtained in Reference Example 8 as a starting material. m.p. 263° C. (decomp.) 
     EXAMPLE 11 
     Synthesis of 2-(2&#39;-trifluoromethylphenyl)quinoline-4-carbonylguanidine 
     The above-mentioned compound (1.23 g) was formed in the same manner as in Example 1 using 1.59 g of 2-(2&#39;-trifluoromethylphenyl)quinoline-4-carboxylic acid obtained in Reference Example 9 as a starting material. m.p. 251°-252° C. (decomp.) 
     EXAMPLE 12 
     Synthesis of 2-(4&#39;-bromophenyl)quinoline-4-carbonylguanidine 
     The above-mentioned compound (1.40 g) was formed in the same manner as in Example 1 using 2.70 g of 2-(4&#39;-bromophenyl)quinoline-4-carboxylic acid obtained in Reference Example 10 as a starting material. m.p. 243°-244° C. (decomp.) 
     EXAMPLE 13 
     Synthesis of 2-(4&#39;-fluorophenyl)quinoline-4-carbonylguanidine 
     The above-mentioned compound (1.28 g) was formed as a white crystal in the same manner as in Example 1 using 1.70 g of 2-(4&#39;-fluorophenyl)quinoline-4-carboxylic acid obtained in Reference Example 11 as a starting material. m.p. 238°-241° C. (decomp.) 
     EXAMPLE 14 
     Synthesis of 2-(2&#39;-chlorophenyl)quinoline-4-carbonylguanidine 
     The above-mentioned compound (0.25 g) was formed in the same manner as in Example 1 using 0.83 g of 2-(2&#39;-chlorophenyl)quinoline-4-carboxylic acid obtained in Reference Example 12 as a starting material. m.p. 250°-250.5° C. (decomp.) 
     EXAMPLE 15 
     Synthesis of 2-(4&#39;-methoxyphenyl)quinolinecarbonylguanidine 
     The above-mentioned compound (1.20 g) was formed as a white crystal in the same manner as in Example 1 using 1.54 g of 2-(4&#39;-methoxyphenyl)quinoline-4-carboxylic acid obtained in Reference Example 13 as a starting material. m.p. 244.3°-244.7° C. (decomp.) 
     EXAMPLE 16 
     Synthesis of 2-(2&#39;-methoxyphenyl)quinoline-4-carbonylguanidine 
     The above-mentioned compound (0.41 g) was formed in the same manner as in Example 1 using 0.87 g of 2-(2&#39;-methoxyphenyl)quinoline-4-carboxylic acid obtained in Reference Example 14 as a starting material. m.p. 254°-256.5° C. (decomp.) 
     EXAMPLE 17 
     Synthesis of 2-(2&#39;,6&#39;-dimethoxyphenyl)quinoline-4-carbonylguanidine 
     The above-mentioned compound (20 mg) was formed in the same manner as in Example 1 using 0.52 g of 2-(2&#39;,6&#39;-dimethoxyphenyl)quinoline-4-carboxylic acid obtained in Reference Example 15 as a starting material. m.p. 258° C. (decomp.) 
     EXAMPLE 18 
     Synthesis of 2-(4&#39;-trifluoromethoxyphenyl)quinoline-4-carbonylguanidine 
     The above-mentioned compound (1.88 g) was formed in the same manner as in Example 1 using 1.67 g of 2-(4&#39;-trifluoromethoxyphenyl)quinoline-4-carboxylic acid obtained in Reference Example 16 as a starting material. m.p. 243° C. (decomp.) 
     EXAMPLE 19 
     Synthesis of 2-(3&#39;-nitrophenyl)quinoline-4-carbonylguanidine 
     The above-mentioned compound (0.76 g) was formed as a brown crystal in the same manner as in Example 1 using 0.75 g of 2-(3&#39;-nitrophenyl)quinoline-4-carboxylic acid obtained in Reference Example 25 as a starting material. m.p. 184°-190° C. 
     EXAMPLE 20 
     Synthesis of 2-(3&#39;-aminophenyl )quinoline-4-carbonylguanidine 
     2-(3&#39;-Nitrophenyl)quinoline-4-carbonylguanidine (0.40 g) formed in Example 19 was dissolved in 40 ml of methanol, and hydrogenated under normal pressure for 5.5 hours in the presence of 0.3 g of Pd/C (purity 10%). The catalyst was filtered off from the reaction solution, and the filtrate was concentrated to obtain 0.45 g of the above-mentioned compound as a brown crystal. m.p. 209°-210° C. 
     EXAMPLE 21 
     Synthesis of 2-phenyl-3-methylquinoline-4-carbonylguanidine 
     The above-mentioned compound (1.06 g) was formed in the same manner as in Example 1 using 1.05 g of 2-phenyl-3-methylquinoline-4-carboxylic acid obtained in Reference Example 17 as a starting material. m.p. 270° C. or higher 
     EXAMPLE 22 
     Synthesis of 2-phenyl-6-methylquinoline-4-carbonylguanidine 
     The above-mentioned compound (0.52 g) was formed in the same manner as in Example 1 using 0.50 g of 2-phenyl-6-methylquinoline-4-carboxylic acid obtained in Reference Example 24 as a starting material. m.p. 276.5° C. 
     EXAMPLE 23 
     Synthesis of 2-phenyl-7-methylquinoline-4-carbonylguanidine 
     The above-mentioned compound (0.86 g) was formed as a pale red crystal in the same manner as in Example 1 using 0.92 g of 2-phenyl-7-methylquinoline-4-carboxylic acid obtained in Reference Example 27 as a starting material. m.p. 250° C. or higher. 
     EXAMPLE 24 
     Synthesis of 2-phenyl-8-methylquinoline-4-carbonylguanidine 
     The above-mentioned compound (1.50 g) was formed in the same manner as in Example 1 using 1.32 g of 2-phenyl-8-methylquinoline-4-carboxylic acid obtained in Reference Example 28 as a starting material. m.p. 221° C. (decomp.) 
     EXAMPLE 25 
     Synthesis of 2-phenyl-6-isopropylquinoline-4-carbonylguanidine 
     The above-mentioned compound (0.33 g) was formed in the same manner as in Example 1 using 0.98 g of 2-phenyl-6-isopropylquinoline-4-carboxylic acid obtained in Reference Example 29 as a starting material. m.p. 254.5°-255° C. (decomp.) 
     EXAMPLE 26 
     Synthesis of2-phenyl-6-fluoroquinoline-4-carbonylguanidine 
     The above-mentioned compound (0.54 g) was formed in the same manner as in Example 1 using 1.07 g of 2-phenyl-6-fluoroquinoline-4-carboxylic acid obtained in Reference Example 18 as a starting material. m.p. 258° C. (decomp.) 
     EXAMPLE 27 
     Synthesis of 2-phenyl-6-iodoquinoline-4-carbonylguanidine 
     The above-mentioned compound (1.20 g) was formed in the same manner as in Example 1 using 1.13 g of 2-phenyl-6-iodoquinoline-4-carboxylic acid obtained in Reference Example 19 as a starting material. m.p. 270° C. or higher 
     EXAMPLE 28 
     Synthesis of 2-phenyl-5-chloroquinoline-4-carbonylguanidine 
     The above-mentioned compound (0.41 g) was formed as a brown crystal in the same manner as in Example 1 using 0.42 g of 2-phenyl-5-chloroquinoline-4-carboxylic acid obtained in Reference Example 20 as a starting material. m.p. 229°-234° C. 
     EXAMPLE 29 
     Synthesis of 2-phenyl-6-chloroquinoline-4-carbonylguanidine 
     The above-mentioned compound (1.07 g) was formed as a brown crystal in the same manner as in Example 1 using 1.0 g of 2-phenyl-6-chloroquinoline-4-carboxylic acid obtained in Reference Example 21 as a starting material. m.p. 250° C. or higher 
     EXAMPLE 30 
     Synthesis of 2-phenyl-7-chloroquinoline-4-carbonylguanidine 
     The above-mentioned compound (1.12 g) was formed as a brown crystal in the same manner as in Example 1 using 1.0 g of 2-phenyl-7-chloroquinoline-4-carboxylic acid obtained in Reference Example 22 as a starting material. m.p. 229°-231° C. 
     EXAMPLE 31 
     Synthesis of 2-phenyl-8-chloroquinoline-4-carbonylguanidine 
     The above-mentioned compound (0.11 g) was formed in the same manner as in Example 1 using 0.40 g of 2-phenyl-8-chloroquinoline-4-carboxylic acid obtained in Reference Example 30 as a starting material. m.p. 220° C. (decomp.) 
     EXAMPLE 32 
     Synthesis of 2-phenyl-6-chloro-8-methylquinoline-4-carbonylguanidine 
     The above-mentioned compound (1.00 g) was formed in the same manner as in Example 1 using 0.89 g of 2-phenyl-6-chloro-8-methylquinoline-4-carboxylic acid obtained in Reference Example 23 as a starting material. m.p. 159°-160° C. (decomp.) 
     EXAMPLE 33 
     Synthesis of 2-phenyl-6-methoxyquinoline-4-carbonylguanidine 
     The above-mentioned compound (0.68 g) was formed as a white crystal in the same manner as in Example 1 using 0.63 g of 2-phenyl-6-methoxyquinoline-4-carboxylic acid obtained in Reference Example 31 as a starting material. m.p. 250°-251° C. 
     EXAMPLE 34 
     Synthesis of 2-phenyl-7-methoxyquinoline-4-carbonylguanidine 
     The above-mentioned compound (1.60 g) was formed in the same manner as in Example 1 using 1.40 g of 2-phenyl-7-methoxyquinoline-4-carboxylic acid obtained in Reference Example 32 as a starting material. m.p. 263.5°-264° C. 
     EXAMPLE 35 
     Synthesis of 2-phenyl-8-methoxyquinoline-4-carbonylguanidine 
     (Method 1) 
     The above-mentioned compound (2.40 g) was formed as a white crystal in the same manner as in Example 1 using 2.17 g of 2-phenyl-8-methoxyquinoline-4-carboxylic acid obtained in Reference Example 33 as a starting material. 
     (Method 2) 
     An anhydrous THF (50 ml) solution containing 4.0 g of methyl 2-phenyl-8-methoxyquinoline-4-carboxylate formed from 2-phenyl-8-methoxyquinoline-4-carboxylic acid in a usual manner was added to guanidine formed from 6.50 g of guanidine hydrochloride in the same manner as in [C] of Example 1 at room temperature. Subsequently, the mixture was heat-refluxed for 3 hours, and cooled to room temperature. The reaction mixture was then concentrated under reduced pressure, and ice water was added to the residue. The precipitate formed was collected by filtration, washed with ethyl ether, and dried to obtain 3.59 of the above-mentioned compound as a white crystal. m.p. 232°-235° C. (decomp.) 
     EXAMPLE 36 
     Synthesis of 2-phenyl-5,7-dimethoxyquinoline-4-carbonylguanidine 
     The above-mentioned compound (0.16 g) was formed in the same manner as in Example 1 using 0.77 g of 2-phenyl-5,7-dimethoxyquinoline-4-carboxylic acid obtained in Reference Example 34 as a starting material. m.p. 273.5° C. (decomp.) 
     EXAMPLE 37 
     Synthesis of 2-(2&#39;-methylphenyl)-5,7-dimethoxyquinone-4-carbonylguanidine 
     2-(2&#39;-Methylphenyl)-5,7-dimethoxyquinoline-4-carboxylic acid (0.80 g) formed in Reference Example 35 was suspended in 20 ml of benzene, and 1.76 g of thionyl chloride were added thereto. The mixture was heat-refluxed for 3 hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Benzene was added to the residue, and the resulting mixture was concentrated, and then dissolved in 5 ml of DMF. Guanidine formed from 0.71 g of guanidine hydrochloride was suspended in 10 ml of DMF in the same manner as in [C] of Example 1, and the above-mentioned DMF solution was added thereto dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 hour, and then concentrated. Ice water was added to the residue, and the precipitate was collected by filtration to obtain crystals. The crystals were further purified through silica-gel column chromatography (mixture of methanol and chloroform at a ratio of 1:10) to form 0.29 g of the above-mentioned compound. m.p. 262°-262.5° C. (decomp.) 
     EXAMPLE 38 
     Synthesis of 2-phenyl-6,7-dimethoxyquinoline-4-carbonylguanidine 
     The above-mentioned compound (1.70 g) was formed in the same manner as in Example 1 using 1.60 g of 2-phenyl-6,7-dimethoxyquinoline-4-carboxylic acid obtained in Reference Example 36 as a starting material. m.p. 245° C. (decomp.) 
     EXAMPLE 39 
     Synthesis of 2-(2&#39;-methylphenyl)-6,7-dimethoxyquinoline-4-carbonylguanidine 
     The above-mentioned compound (1.08 g) was formed as a white crystal in the same manner as in Example 1 using 2.57 g of 2-(2&#39;-methylphenyl)-6,7-dimethoxyquinoline-4-carboxylic acid obtained in Reference Example 37 as a starting material. m.p. 234°-235° C. 
     EXAMPLE 40 
     Synthesis of 2-phenyl-6,8-dimethoxyquinoline-4-carbonylguanidine 
     The above-mentioned compound (0.21 g) was formed in the same manner as in Example 1 using 0.80 g of 2-phenyl-6,8-dimethoxyquinoline-4-carboxylic acid obtained in Reference Example 38 as a starting material. m.p. 256° C. (decomp.) 
     EXAMPLE 41 
     Synthesis of 2-(2&#39;-methylphenyl)-6,8-dimethoxyquinoline-4-carbonylguanidine 
     The above-mentioned compound (1.11 g) was formed in the same manner as in Example 1 using 1.29 g of 2-(2&#39;-methylphenyl)-6,8-dimethoxyquinoline-4-carboxylic acid obtained in Reference Example 39 as a starting material. m.p. 227°-229° C. (decomp.) 
     EXAMPLE 42 
     Synthesis of 2-(2&#39;-methylphenyl)-5,8-dimethoxyquinoline-4-carbonylguanidine 
     The above-mentioned compound (0.44 g) was formed in the same manner as in Example 1 using 0.49 g of 2-(2&#39;-methylphenyl)-5,8-dimethoxyquinoline-4-carboxylic acid obtained in Reference Example 40 as a starting material. m.p. 241° C. 
     EXAMPLE 43 
     Synthesis of 2-(2&#39;-methylphenyl)-7,8-dimethoxyquinoline-4-carbonylguanidine 
     The above-mentioned compound (1.56 g) was formed as a yellow crystal in the same manner as in Example 1 using 2.20 g of 2-(2&#39;-methylphenyl)-7,8-dimethoxyquinoline-4-carboxylic acid obtained in Reference Example 41 as a starting material. m.p. 238°14 239° C. 
     EXAMPLE 44 
     Synthesis of 2-phenyl-8-methoxyethyloxyquinoline-4-carbonylguanidine 
     The above-mentioned compound (1.00 g) was formed as a brown crystal in the same manner as in Example 1 using 1.30 g of 2-phenyl-8-methoxyethyloxyquinoline-4-carboxylic acid obtained in Reference Example 42 as a starting material. m.p. 218°-220° C. 
     EXAMPLE 45 
     Synthesis of 2-(2&#39;-methylphenyl)-7-methoxymethyloxyquinoline-4-carbonylguanidine 
     The above-mentioned compound (1.30 g) was formed as a brown crystal in the same manner as in Example 1 using 1.20 g of 2-(2&#39;-methylphenyl)-7-methoxymethyloxyquinoline-4-carboxylic acid obtained in Reference Example 43 as a starting material. m.p. 186°-190° C. 
     EXAMPLE 46 
     Synthesis of 2-(2&#39;-methylphenyl)-7-hydroxyquinoline-4-carbonylguanidine 
     2-(2&#39;-Methylphenyl)-7-methoxymethyloxyquinoline-4-carbonylguanidine (0.9 g) formed in Example 45 was heat-stirred in 20 ml (0.5M) of an isopropyl alcohol solution of hydrochloric acid at approximately 60° C. for 3.5 hours. The reaction mixture was allowed to cool, then neutralized with a 5% sodium hydroxide aqueous solution, and concentrated. The residue was filtered, and the crystals obtained were washed with water, and dried to obtain 0.40 g of the above-mentioned compound as a brown crystal. m.p. 202°-208° C. 
     EXAMPLE 47 
     Synthesis of 2-phenyl-8-nitroquinoline-4-carbonylguanidine 
     The above-mentioned compound (1.07 g) was formed in the same manner as in Example 1 using 0.88 g of 2-phenyl-8-nitroquinoline-4-carboxylic acid obtained in Reference Example 45 as a starting material. m.p. 236°-236.5° C. (decomp.) 
     EXAMPLE 48 
     Synthesis of 2-phenyl-8-aminoquinoline-4-carbonylguanidine 
     The above-mentioned compound (0.23 g) was formed by hydrogenating 2-phenyl-8-nitroquinoline-4-carbonylguanidine obtained in Example 47 as a starting material under normal pressure in the same manner as in Example 20. m.p. 199°-200.5° C. (decomp.) 
     EXAMPLE 49 
     Synthesis of 2-phenyl-8-acetylaminoquinoline-4-carbonylguanidine 
     The above-mentioned compound (0.26 g) was formed in the same manner as in Example 1 using 0.31 g of 2-phenyl-8-acetylaminoquinoline-4-carboxylic acid obtained in Reference Example 48 as a starting material. m.p. 246°-246.5° C. (decomp.) 
     EXAMPLE 50 
     Synthesis of 2-phenyl-8-methanesulfonylaminoquinoline-4-carbonylguanidine 
     The above-mentioned compound (0.33 g) was formed in the same manner as in Example 1 using 0.31 g of 2-phenyl-8-methanesulfonylaminoquinoline-4-carboxylic acid obtained in Reference Example 50 as a starting material. m.p. 255.5°-256.0° C. (decomp.) 
     EXAMPLE 51 
     Synthesis of 2-(2&#39;-methoxymethytoxyphenyl)quinoline-4-carbonyiguanidine 
     The above-mentioned compound (0.93 g) was formed in the same manner as in Example 1 using 1.43 g 2-(2&#39;-methoxymethyloxyphenyl)quinoline-4-carboxylic acid obtained in Reference Example 51 as a starting material. m.p. 219°-220° C. (decomp.) 
     EXAMPLE 52 
     Synthesis of 2-(2&#39;-hydroxyphenyl)quinoline-4-carbonylguanidine hydrochloride 
     2-(2&#39;-Methoxymethyloxyphenyl)quinoline-4-carbonylguanidine (0.51 g) formed in Example 51 was stirred in 24 ml (5M) of an isopropyl alcohol solution of hydrochloric acid at 70° C. for 3 hours. The reaction mixture was cooled with ice, and the precipitate was collected by filtration, and dried to obtain 0.50 g of the above-mentioned compound. m.p. 270° C. or higher 
     EXAMPLE 53 
     Synthesis of 2-phenylquinoline-4-carbonylguanidine Hydrochloride 
     2-Phenylquinoline-4-carbonylguanidine (1.08 g) formed in Example 1 was suspended in 10 ml of ethanol, and 6 ml (1N) of an ethanol solution of hydrochloric acid were added thereto dropwise at room temperature. Thirty minutes later, ethyl ether was added to the reaction solution, and the crystals were collected by filtration, and dried to obtain 1.12 g of the above-mentioned compound. m.p. 278°-279° C. (decomp.) 
     EXAMPLE 54 
     Synthesis of 2-(2&#39;-isopropylphenyl)quinoline-4-carbonylguanidine methanesulfonate 
     2-(2&#39;-Isopropylphenyl)quinoline-4-carbonylguanidine (1.1 g) formed in Example 5 was suspended in 25 ml of ethanol, and 7.5 ml (1M) of an ethanol solution of methanesulfonic acid were added thereto dropwise while being cooled with ice. Ten minutes later, ethyl ether was added thereto, and the crystals precipitated were collected by filtration, and dried to obtain 1.10 g of the above-mentioned compound as a white crystal. m.p. 146°-154° C. 
     The compounds formed in Examples 1 to 51 were converted into hydrochlorides in the same manner as in Example 53 or into methanesulfonates in the same manner as in Example 54. 
     The analytical data of the compounds formed in Examples 1 to 52 are shown in Table 1. 
     
                                           TABLE 1                                 
__________________________________________________________________________
Example No.                                                               
        NMR (Solvent); δppm                                         
                              IR (KBr, cm.sup.-1)                         
__________________________________________________________________________
1       (DMSO-d.sub.6); 7.48-7.61(m, 3H), 7.76(t, 1H),                    
                              3377, 1593, 1524,                           
        8.09(d, 1H), 8.25-8.33(m, 3H), 8.30 (s, 1H),                      
                              1380, 1314, 771                             
        8.64(d, lH)                                                       
2       (DMSO-d.sub.6); 2.40(s, 3H), 7.37(d, 2H), 7.53-                   
                              3378, 1585, 1530,                           
        7.59(m, 1H), 7.72-7.78(m, 1H), 8.06(d, 1H),                       
                              1381, 1316, 819,                            
        8.17(d, 2H), 8.26(s, 1H), 8.60(d, 1H)                             
                              798, 760                                    
3       (DMSO-d.sub.6); 2.38(s, 3H), 7.32(d, 1H), 7.45                    
                              3366, 1578, 1522,                           
        (t, 1H), 7.56(t, 1H), 7.75(t, 1H), 7.99-8.09                      
                              1457, 1376, 1314                            
        (m, 3H), 8.28 (s, 1H), 8.63(d, 1H)                                
4       (DMSO-d.sub.6); 2.38(s, 3H), 7.36(m, 3H), 7.50                    
                              3449, 1654, 1608,                           
        (m, 1H), 7.62(t, 1H), 7.79(t, 1H), 7.90(s,                        
                              1523, 1457, 1374,                           
        1H), 8.05(d, 1H), 8.74(d, 1H)                                     
                              1308, 769                                   
5       (DMSO-d.sub.6); 1.17(d, 6H), 3.11-3.24(m, 1H),                    
                              3449, 1654, 1609,                           
        7.31-7.78(m, 6H), 7.83(s, 1H), 8.02(d, 1H),                       
                              1523, 1375, 1306,                           
        8.30(s, 4H), 8.75(d, 1H)                                          
                              1063, 811, 763                              
6       (DMSO-d.sub.6); 2.37(s, 6H), 7.16(d, 2H), 7.39                    
                              3447, 2975, 1649,                           
        (d, 1H), 7.60(t, 1H), 7.76(t, 1H), 7.84(s,                        
                              1578, 1517, 1365,                           
        1H), 8.04(d, 1H), 8.27(s, 4H), 8.68(d, 1H)                        
                              1303, 1091, 1050,                           
                              897, 882, 810, 767                          
7       (DMSO-d.sub.6); 2.31(s, 3H), 2.36 (s, 3H), 7.31                   
                              3376, 1584, 1541,                           
        (d, 1H), 7.55(t, 1H), 7.70-7.76(m, 1H), 7.96-                     
                              1457, 1374, 758                             
        8.07(m, 2H), 8.25(s, 1H), 8.31(s, 4H), 8.60                       
        (d, 1H)                                                           
8       (DMSO-d.sub.6); 1.95(s, 6H), 2.31(s, 3H), 6.98                    
                              3422, 1637, 1578,                           
        (s, 2H), 7.48-7.64(m, 2H), 7.76(t, 1H),                           
                              1560, 1522, 1457                            
        8.02(d, 1H), 8.26(s, 4H), 8.72(d, 1H)                             
9       (DMSO-d.sub.6); 1.35(s, 9H), 7.57(d, 3H), 7.74                    
                              3447, 2963, 1610,                           
        (t, 1H), 8.06(d, 1H), 8.18(d, 2H), 8.25(s,                        
                              1523, 1377, 1314,                           
        1H) , 8.60-8.63 (m, 1H)                                           
                              766                                         
10      (DMSO-d.sub.6); 7.65(t, 1H), 7.82(m, 3H), 8.16                    
                              3368, 1583, 1523,                           
        (d, 1H), 8.36 (s, 1H), 8.57 (m, 3H)                               
                              1437, 1384, 1341,                           
                              1233, 1168, 1126,                           
                              1073, 888, 800, 758                         
                              698                                         
11      (DMSO-d.sub.6); 7.70 (m, 4H), 7.85 (m, 2H), 7.92                  
                              3422, 1617, 1522,                           
        (d, 1H), 8.06(d, 1H), 8.69(d, 1H)                                 
                              1375, 1316, 1174,                           
                              1128, 771                                   
12      (DMSO-d.sub.6); 6.96(br s, 1H), 7.60(m, 1H),                      
                              3371, 1584, 1529,                           
        7.76(d, 2H), 8.08(d, 1H), 8.24(d, 2H), 8.29                       
                              1399, 1378, 1312,                           
        (s, 1H), 8.61(d, 2H)  1076, 1009, 759                             
13      DMSO-d.sub.6); 7.38(t, 2H), 7.58-7.62(m, 1H),                     
                              3394, 1579, 1517,                           
        7.74-7.80(m, 1H), 8.08(d, 1H), 8.25-8.34                          
                              1382, 1315, 1234,                           
        (m, 3H), 8.60(d, 1H)  841, 812, 760                               
14      (DMSO-d.sub.6); 7.12(t, 1H), 7.19(d, 1H), 7.47                    
                              3445, 1602, 1525,                           
        (t, 1H), 7.57(d.1H).7.75(m, 2H), 8.05(d,                          
                              1460, 1375, 1312,                           
        1H), 8.12(s, 1H), 8.31(s, 4H), 8.65(d, 1H)                        
                              1247, 1025, 759                             
15      (DMSO-d.sub.6); 3.86(s, 3H), 7.12(d, 2H), 7.53-                   
                              3367, 1585, 1522,                           
        7.59(m, lH), 7.72-7.78(m, lH), 8.06(d, 1H),                       
                              1380, 1180, 1027,                           
        8.20(s, 1H), 8.22(d, 2H), 8.55(d, 1H)                             
                              833, 800, 759                               
16      (DMSO-d.sub.6); 3.54(s, 3H), 7.12(t, 1H), 7.20                    
                              3855, 1602, 1524,                           
        (d, 1H), 7.49(t, 1H), 7.59(t, 1H), 7.76(m,                        
                              1459, 1374, 1312,                           
        2H), 8.06(d, 1H), 8.10(s, 1H), 8.63(d, 1H)                        
                              1247, 1025, 758                             
17      (DMSO-d.sub.6); 2.39(s, 6H), 3.71(s, 6H), 6.85                    
                              3380, 3108, 1722,                           
The     (s, 1H), 6.88(s, 1H), 7.51(t, 1H), 7.86(t,                        
                              1598, 1234, 1112,                           
2CH.sub.3 SO.sub.3 H                                                      
        (s, 1H), 6.88(s, 1H), 7.51(t, 1H), 7.86(t,                        
                              1043, 785                                   
salt was                                                                  
        1H), 7.88(s, 1H), 7.97(t, 1H), 8.18(d, 1H),                       
measured.                                                                 
        8.30(d, 1H)                                                       
18      (DMSO-d.sub.6); 7.58(m, 3H), 7.79(t, 1H), 8.10                    
                              3381, 1585, 1522,                           
        (d, 1H), 8.31(s, 1H), 8.38(d, 2H), 8.63(d,                        
                              1378, 1258                                  
        1H)                                                               
19      (DMSO-d.sub.6); 7.61-7.64(m, lH), 7.81-7.90                       
                              3374, 1653, 1526,                           
        (m, 2H), 8.13(d, 1H), 8.31(s, 4H), 8.34-8.40                      
                              1349, 809, 696                              
        (m, 2H), 8.63-8.73(m, 2H), 9.07-9.08(m, 1H)                       
20      (DMSO-d.sub.6); 6.68-6.71(m, lH), 7.14-7.36(m,                    
                              3378, 1583, 1380,                           
        2H), 7.51-7.58(m, 2H), 7.71-7.76(m, lH),                          
                              882                                         
        8.03 (d, 1H), 8.18 (s, 1H), 8.31 (s, 4H), 8.63                    
        (d, 1H)                                                           
21      (DMSO-d.sub.6); 2.30(s, 3H), 7.52(m, 6H), 7.65                    
                              3855, 3056, 1671,                           
        (m, 1H), 7.90(m, 2H)  1560, 1396, 1334,                           
                              767                                         
22      (DMSO-d.sub.6); 3.32(s, 3H), 7.51(m, 4H), 7.99                    
                              3369, 1654, 1541,                           
        (d, 1H), 8.25(m, 3H), 8.39(s, 1H)                                 
                              1508, 1457, 1378,                           
                              1318                                        
23      (DMSO-d.sub.6); 7.43-7.61(m, 4H), 7.90(s, lH),                    
                              3376, 1655, 1592,                           
        8.19-8.23(m, 3fl), 8.50(d, 1H)                                    
                              1524, 1457, 1375,                           
                              1316, 1069, 886,                            
                              826, 769, 701, 669                          
24      (DMSO-d.sub.6); 2.83(s, 3H), 7.57(m, 5H), 8.27                    
                              3451, 3365, 1656,                           
        (m, 3H), 8.39 (d, 1H) 1587, 1559, 1523,                           
                              1373, 1317, 763                             
25      (DMSO-d.sub.6); 1.32(d, 6H), 3.12(m, 1H), 7.56                    
                              3455, 3326, 2962,                           
        (m, 3H), 7.72(m, 1H ), 8.01 (d, 1H), 8.25(m,                      
                              1653, 1602, 1518,                           
        2H), 8.27(s, 1H), 8.45(m, 1H)                                     
                              1372, 1315, 769,                            
                              705                                         
26      (DMSO-d.sub.6); 7.58(m, 3H), 7.71(m, 1H), 8.17                    
                              3381, 1577, 1552,                           
        (m, 1H), 8.26(d, 2H), 8.48(s, 1H), 8.59(m,                        
                              1363, 1318, 1236,                           
        1H                    835, 703                                    
27      (DMSO-d.sub.6); 7.57(m, 2H), 7.90(d, 1H), 8.03                    
                              3375, 1595, 1541,                           
        (m, 1H), 8.22 (s, 1H), 8.25 (m, 2H), 8.35 (s,                     
                              1457, 1390, 1317                            
        1H).9.08(m, 1H)                                                   
28      (DMSO-d.sub.6); 7.53-7.76(m, 6H), 7.92(s, 1H),                    
                              3448, 1654, 1596,                           
        8.06 (d, 1H), 8.30(s, 4H), 8.30-8.36 (m, 1H)                      
                              1522, 1457, 1362,                           
                              1311, 1197, 1071,                           
                              777, 698                                    
29      (DMSO-d.sub.6);7.50-7.62(m, 3H), 7.76-7.80(m,                     
                              3378, 1590, 1530,                           
        1H), 8.12(d, 1H), 8.25(d, 2H), 8.43(s, 1H),                       
                              1492, 1453, 1397,                           
        8.80(s, 1H)           1378, 1317, 1065,                           
                              887, 826, 758, 702                          
30      (DMSO-d.sub.6); 7.52-7.63(m, 4H), 8.12(s, 1H),                    
                              3376, 1600, 1523,                           
        8.24-8.31 (m, 2H), 8.31(s, 4H), 8.36(s, 4H),                      
                              1374, 1316, 1083,                           
        8.75(d, 1H)           908, 829, 767                               
31      (DMSO-d.sub.6); 7.56(m, 4H), 7.95(d, 1H), 8.35                    
                              3453, 1599, 1521,                           
        (m, 3H), 8.58(d, 1H)  1374, 1314, 1063,                           
                              824, 750, 699                               
32      (DMSO-d.sub.6); 2.83(s, 3H), 7.59(m, 2H), 7.65                    
                              3386, 1579, 1522,                           
        (m, 1H ), 8.21(s, 1H), 8.29(m, 2H), 8.37(s,                       
                              1452, 1375, 1320,                           
        1H), 8.53(m, 1H)      884, 767, 706                               
33      (DMSO-d.sub.6); 3.91(s, 3H), 7.40-7.58 (m, 4H),                   
                              3322, 1655, 1624,                           
        8.01(d, 1H), 8.19-8.27(m, 3H), 8.35(s, 1H),                       
                              1578, 1523, 1355,                           
        8.30(s, 4H)           1314, 1229, 831                             
34      (DMSO-d.sub.6); 3.96(s, 3H), 7.27(d, 1H), 7.58                    
                              3370, 1619, 1518,                           
        (m, 4H), 8.14(s, 1H), 8.23(d, 2H), 8.53(d,                        
                              1376, 1315                                  
        1H)                                                               
35      (DMSO-d.sub.6); 4.02(s, 3H), 7.19(d.1H), 7.44-                    
                              3380, 1662, 1608,                           
        7.58(m, 4H), 8.09(d, 1H), 8.23-8.30(m, 3H),                       
                              1526, 1364, 1316,                           
        8.37(s, 4H)           1262, 754                                   
36      (DMSO-d.sub.6); 3.81(s, 3H), 3.93(s, 3H), 6.60                    
                              3373, 1620, 1599,                           
        (s, 1H), 7.06(s, 1H), 7.41 (m, 3H), 7.52(s,                       
                              1518, 1371, 1314,                           
        1H), 8.22(d, 2H)      1254, 1209, 1167,                           
                              1141                                        
37      (DMSO-d.sub.6); 2.35(s, 3H), 3.81(s, 3H), 3.90                    
                              3448, 1619, 1519,                           
        (s, 3H), 6.63(d, 1H) 7.00(d, 1H), 7.04(s,                         
                              1457, 1367, 1308,                           
        1H), 7.33(m, 4H)      1252, 1209, 1143                            
38      (DMSO-d.sub.6); 3.98(s, 3H), 4.04(s, 3H), 7.46-                   
                              3855, 1637, 1508,                           
        7.57(m, 4H), 8.19-8.28(m, 4H)                                     
                              1375, 1250                                  
39      (DMSO-d.sub.6); 2.37(s, 3H), 3.92(s, 3H), 3.94                    
                              3442, 1654, 1508,                           
        (s, 3H), 7.27-7.46 (m, 5H), 7.85 (s, 1H), 8.36                    
                              1357, 1249, 1162,                           
        (s, 1H)               1043, 858, 764                              
40      (DMSO-d.sub.6); 3.93(s, 3H), 3.99(s, 3H), 6.85                    
                              3450, 1619, 1522,                           
        (d, 1H), 7.45-7.59(3m, H), 7.72(d, 1H), 8.18-                     
                              1363, 1324, 1217,                           
        8.23(m, 2H), 8.28(s, 1H)                                          
                              1155, 768                                   
41      (DMSO-d.sub.6); 2.35(s, 3H), 3.88(s, 3H), 3.94                    
                              3422, 1619, 1523,                           
        (s, 3H), 6.83 (d, 1H), 7.28-7.44 (m, 4H), 7.80                    
                              1457, 1374, 1216,                           
        (d, 1H), 7.9 1 (s, 1H)                                            
                              1155, 755                                   
42      (DMSO-d.sub.6); 2.35(s, 3H), 3.79(s, 3H), 3.90                    
                              3444, 1614, 1526,                           
        (s, 3H), 6.92(d, 1H), 7.11(d, 1H), 7.25(s,                        
                              1470, 1367, 1311,                           
        1H), 7.37(m, 4H), 8.37(s, 4H)                                     
                              1261, 1105, 761                             
43      (DMSO-d.sub.6); 2.41(s, 3H), 3.94(s, 3H), 3.98                    
                              3446, 1653, 1605,                           
        (s, 3H), 7.34-7.36(m, 3H), 7.48-7.54(m, 2H)                       
                              1513, 1459, 1355,                           
        7.73(s, 1H), 8.45(d, lH)                                          
                              1306, 1268, 1105,                           
                              740                                         
44      (DMSO-d.sub.6); 3.41(s, 3H), 3.75(t, 2H), 4.26                    
                              3448, 1655, 1606,                           
        (t, 2H), 7.13(d, 1H), 7.29-7.54(m, 4H), 7.98                      
                              1534, 1458, 1372,                           
        (d, 1H), 8.01-8.27(m, 3H)                                         
                              1318, 1262, 1100,                           
                              824, 756, 703                               
45      (DMSO-d.sub.6); 2.37(s, 3H), 3.44(s, 3H), 5.38                    
                              3424, 1594, 1515,                           
        (s, 2H), 7.30-7.63 (m, 6H), 7.76 (s, 1H), 8.31                    
                              1377, 1311, 1149,                           
        (s, 4H), 8.70(d, 1H)  1081, 1067, 992,                            
                              832, 770, 750, 661                          
46      (DMSO-d.sub.6); 2.38(s, 3H), 7.18-7.50(m, 6H),                    
                              3383, 2975, 1622,                           
        7.67(s, 1H), 8.53(d, lH)                                          
                              1522, 1457, 1387,                           
                              1231, 1090, 882,                            
                              746                                         
47      (DMSO-d.sub.6); 7.61(m, 3H), 7.75(t, 1H), 8.28                    
                              3398, 1671, 1589,                           
        (m, 3H), 8.53(s, 1H), 8.97(d, 1H)                                 
                              1527, 1355, 1314,                           
                              765                                         
48      (D.sub.2 O); 6.88(d, 1H), 7.27(t, 1H), 7.55 (m,                   
                              3367, 1616, 1522,                           
        3H), 7.63 ( d, 1H), 8.17(s, 1H), 8.31(d, 2H)                      
                              1466, 1376, 1323,                           
                              766                                         
49      (DMSO-d.sub.6); 3.34(s, 3H), 7.58(m, 4H), 7.75                    
                              3409, 1606, 1555,                           
        (d, 1H), 8.36(m, 3H), 9.50(s, 1H)                                 
                              1528, 1465, 1376,                           
                              1319, 1150                                  
50      (DMSO-d.sub.6); 2.34(s, 3H), 7.60(m, 4H), 8.23                    
                              3340, 1670, 1586,                           
        (d, 1H), 8.32(s, 1H), 8.40(m, 2H), 8.59(d,                        
                              1531, 1374, 1324,                           
        1H)                   765, 693                                    
51      (DMSO-d.sub.6); 3.34(s, 3H), 5.27(s, 2H), 7.18                    
                              3449, 1603, 1524,                           
        (t, 1H), 7.29(d, 1H), 7.45(t, 1H), 7.60(t,                        
                              1376, 1310, 990,                            
        1H), 7.73-7.81(m, 2H), 8.08(d, 1H), 8.20(s,                       
                              764                                         
        1H), 8.70(d, 1H)                                                  
52      (DMSO-d.sub.6); 7.03-7.09(m, 2H), 7.44-7.50(m,                    
                              3375, 2854, 1717,                           
The HCl 1H), 7.77-7.82(m, 1H), 7.93-7.99(m, 1H),                          
                              1607, 1571, 1508,                           
salt was                                                                  
        8.21-8.33(m, 3H), 8.74(s, 1H)                                     
                              1237, 768                                   
measured.                                                                 
__________________________________________________________________________
 
    
     Preparation Example 1 
     Oral Agent Containing 2-phenyl-8-methoxyquinoline-4-carbonylguanidine (Example 35) Methanesulfonate as an Active Ingredient 
     Ninety grams of the compound of the present invention were mixed with 40 g of lactose. The mixture was sieved through a No. 60 screen, and was wet-granulated with an alcohol solution containing 15 g of polyvinyl pyrrolidone. Then, 30 g of corn starch were added thereto, and these were mixed until uniform particles were formed. The mixture was passed through a No. 10 screen, placed on a tray, and dried in an oven of 60° C. for 12 hours. The thus-dried particles were sieved through a No. 16 screen, and mixed with 3 g of magnesium stearate. The mixture was formed into tablets 7 mm in diameter by means of a tablet making machine through compression. The tablets were treated with varnish, and talc was spread. Then, moisture absorption was prevented, and an undercoat layer was coated around the cores. Varnish coating was conducted for internal use. In order to make the tablets completely smooth, an undercoat layer and a smooth coating were further applied thereto. The thus-coated tablets were dried, and then polished to form uniform glossy tablets. 
     Preparation Example 2 
     Oral Agent Containing 2-(2&#39;-methylphenyl)-5,7-dimethoxyquinoline-4-carbonylguanidine (Example 37) Methanesulfonate as an Active Ingredient 
     A tablet was prepared from 80 g of the compound of the present invention, 40 g of lactose, 13 g of polyvinyl pyrrolidone, 30 g of corn starch and 3 g of magnesium stearate in the same manner as in Preparation Example 1. 
     Preparation Example 3 
     Injection Containing 2-(2&#39;-methylphenyl)-5,8-dimethoxyquinoline-4-carbonylguanidine (Example 42) Methanesulfonate as an Active Ingredient 
     The compound (0.5 g) of the present invention was taken up, and dissolved in 10 ml of a 0.9% physiological saline solution. The mixture was sterilized through filtration, and poured into a 10-milliliter ampoule to form an injection. 
     Preparation Example 4 
     Injection containing 2-phenyl-5,7-dimethoxyquinoline-4-carbonylguanidine (Example 36) Hydrochloride as an Active Ingredient 
     An injection was prepared from 0.3 g of the compound of the present invention and 10 ml of a 0.9% physiological saline solution in the same manner as in Preparation Example 3. 
     Test Example 1 
     NHE Inhibitory Activity 
     The NHE inhibitory activity was measured by the following method using a pH in cells as an index. 
     [Method of measuring a pH in cells] 
     A rat mesenteric artery was isolated, and was loaded with a pH-sensitive dye BCECF. Subsequently, the tissue segments were mounted in a bath of an intracellular ion concentration measurement device (CAF-110, manufactured by Japan Spectral Co., Ltd.). The pH in cells was measured in terms of a ratio of fluorescent intensities through 2-wavelength excitation of 495 nm (pH-sensitive wavelength)/450 nm (pH-non-sensitive wavelength). 
     [Measurement of the NHE activity] 
     The pH in cells was shifted into acid through pretreatment with 20 mM ammonium chloride to activate NHE. At this time, when Na +   ions were absent in an external solution, the intracellular acidosis was maintained. When Na +   ions were present in an external solution, the pH in cells was recovered to a control value. This recovery of the pH in cells was ascribable to the activation of NHE. The NHE inhibitory activity of the medication was examined depending on whether or not this recovery was suppressed. The percent NHE inhibition was calculated from a change in pH (ΔpH) measured by the above-mentioned method using the following formula. 
     Percent NHE inhibition (%)={1-ΔpH (in the presence of a medication)/ΔpH (in the absence of a medication)}×100 
     This test was conducted by the method of C. D. Foster et al. [Am. J. Physiol., 262, 31, H1651-H1655 (1992)]. For comparison, the test was conducted with respect to guanidinocarbonylisoquinoline derivatives described in JP A 6-211799 (Family: EP590455). The results of the measurements are shown in Table 2. 
     
                       TABLE 2                                                     
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Inhibitory effect on NHE activity                                         
                         Percent                                          
                         NHE                                              
                         inhibition                                       
                         (%) Conc.                                        
                         (μM)                                          
Example No.: Test Compound 0.1    1                                       
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2-(2&#39;-methylphenyl)-4-guadininocarbonyl-1(2H)-                            
isoquinoline hydrochloride (control compound)                             
1:  2-phenylquinoline-4-carbonylguanidine                                 
                               5.2    52.8                                
    hydrochloride                                                         
2:  2-(4&#39;-methylphenyl)quinoline-4-                                       
                               10.6   41.4                                
    carbonylguanidine hydrochloride                                       
3:  2-(3&#39;-methylphenyl)quinoline-4-                                       
                               21.2   59.8                                
    carbonylguanidine hydrochloride                                       
4:  2-(2&#39;-methylphenyl)quinoline-4-                                       
                               49.2   65.6                                
    carbonylguanidine hydrochloride                                       
5:  2-(2&#39;-isopropylphenyl)quinoline-4-                                    
                               29.3   42.3                                
    carbonylguanidine methanesulfonate                                    
6:  2-(2&#39;,4&#39;-dimethylphenyl)quinoline-4-                                  
                               36.4   55.3                                
    carbonylguanidine methanesulfonate                                    
7:  2-(3&#39;,4&#39;-dimethylphenyl)quinoline-4-                                  
                               33.1   38.8                                
    carbonylguanidine methanesulfonate                                    
8:  2-(2&#39;,4&#39;,6&#39;-trimethylphenyl)quinoline-4-                              
                               23.7   36.3                                
    carbonylguanidine methanesulfonate                                    
11: 2-(2&#39;-trifluoromethylphenyl)quinoline-4-                              
                               22.7   46.1                                
    carbonylguanidine methanesulfonate                                    
13: 2-(4&#39;-fluorophenyl)quinoline-4-                                       
                               14.4   39.8                                
    carbonylguanidine hydrochloride                                       
14: 2-(2&#39;-chlorophenyl)quinoline-4-                                       
                               28.8   34.3                                
    carbonylguanidine methanesulfonate                                    
19: 2-(3&#39;-nitrophenyl)quinoline-4-                                        
                               22.3   35.6                                
    carbonylguanidine hydrochloride                                       
20: 2-(3&#39;-aminophenyl)quinoline-4-                                        
                               36.2   42.2                                
    carbonylguanidine hydrochloride                                       
21: 2-phenyl-3-methylquinoline-4-                                         
                               1.5    45.0                                
    carbonylguanidine methanesulfonate                                    
22: 2-phenyl-6-methylquinoline-4-                                         
                               28.9   57.9                                
    carbonylguanidine methanesulfonate                                    
23: 2-phenyl-7-methylquinoline-4-                                         
                               2.8    49.8                                
    carbonylguanidine methanesulfonate                                    
24: 2-phenyl-8-methylquinoline-4-                                         
                               8.1    50.0                                
    carbonylguanidine methanesulfonate                                    
28: 2-phenyl-5-chloroquinoline-4-                                         
                               33.7   63.3                                
    carbonylguanidine methanesulfonate                                    
29: 2-phenyl-6-chloroquinoline-4-                                         
                               0      38.6                                
    carbonylguanidine methanesulfonate                                    
31: 2-phenyl-8-chloroquinoline-4-                                         
                               12.0   57.0                                
    carbonylguanidine methanesulfonate                                    
32: 2-phenyl-6-chloro-8-methylquinoline-4-                                
                               28.6   35.7                                
    carbonylguanidine hydrochloride                                       
34: 2-phenyl-7-methoxyquinoline-4-                                        
                               29.8   53.0                                
    carbonylguanidine methanesulfonate                                    
35: 2-phenyl-8-methoxyquinoline-4-                                        
                               47.4   63.6                                
    carbonylguanidine methanesulfonate                                    
36: 2-phenyl-5,7-dimethoxyquinoline-4-                                    
                               53.2   69.9                                
    carbonylguanidine hydrochloride                                       
37: 2-(2&#39;-methylphenyl)-5,7-dimethoxyquinoline-                           
                               70.8   84.2                                
    4-carbonylguanidine methanesulfonate                                  
39: 2-(2&#39;-methylphenyl)-6,7-dimethoxyquinoline-                           
                               3.4    41.5                                
    4-carbonylguanidine methanesulfonate                                  
40: 2-phenyl-6,8-dimethoxyquinoline-4-                                    
                               18.3   31.0                                
    carbonylguanidine methanesulfonate                                    
42: 2-(2&#39;-methylphenyl)-5,8-dimethoxyquinoline-                           
                               72.7   89.1                                
    4-carbonylguanidine methanesulfonate                                  
43: 2-(2&#39;-methylphenyl)-7,8-dimethoxyquinoline-                           
                               28.0   37.6                                
    4-carbonylguanidine methanesulfonate                                  
44: 2-phenyl-8-methoxyethyloxyquinoline-4-                                
                               28.4   62.9                                
    carbonylguanidine methanesulfonate                                    
45: 2-(2&#39;-methylphenyl)-7-methoxymethyloxyquino-                          
                               35.0   46.5                                
    line-4-carbonylguanidine methanesulfonate                             
46: 2-(2&#39;-methylphenyl)-7-hydroxyquinoline-4-                             
                               39.3   48.8                                
    carbonylguanidine methanesulfonate                                    
48: 2-phenyl-8-aminoquinoline-4-                                          
                               30.6   41.7                                
    carbonylguanidine methanesulfonate                                    
49: 2-phenyl-8-acetylaminoquinoline-4-                                    
                               20.8   51.2                                
    carbonylguanidine methanesulfonate                                    
50: 2-phenyl-8-methanesulfonylaminoquinoline-4-                           
                               46.2   66.2                                
    carbonylguanidine methanesulfonate                                    
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     Test Example 2 
     Effect on Ischemic Arrhythmia in the Rat 
     A rat was anesthetized with pentobarbital, and the left chest was opened under artificial respiration. Then, the left coronary artery was ligated for 30 minutes. The effect of the test compound on ischemic arrhythmia was examined. The test agent was administered intravenously (i.v.) five minutes before the ligation. The arrhythmias were evaluated according to the guidelines of the Lambeth conventions [Cardiovasc. Res., 22, 447-455 (1988)]. The test compounds, the number of examples and the number of rats in which the arrhythmia occurred are shown in Table 3. 
     
                       TABLE 3                                                     
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Effect on ischemic arrhythmia (i.v.)                                      
                              Incidence                                   
                     Number   of                                          
                     of       arrhythmia                                  
Example No.: Test Compound                                                
                     examples VT      VF                                  
______________________________________                                    
physiological saline (control)                                            
                      11       5/5    4/5                                 
36: 2-phenyl-5,7-dimethoxyquinoline-4-                                    
                          4        2/4  0/4                               
    carbonylguanidine hydrochloride (1                                    
    mg/kg)                                                                
37: 2-(2&#39;-methylphenyl)-5,7-                                              
                          5        3/5  0/5                               
    dimethoxyquinoline-4-                                                 
    carbonylguanidine methanesulfonate                                    
    (1 mg/kg)                                                             
42: 2-(2&#39;-methylphenyl)-5,8-                                              
                          4        2/4  0/4                               
    dimethoxyquinoline-4-                                                 
    carbonylguanidine methanesulfonate                                    
    (1 mg/kg)                                                             
______________________________________                                    
 VT: ventricular tachycardia                                              
 VF: ventricular fibrillation                                             
 
    
     Test Example 3 
     Toxicity Test 
     The test compound was administered to a ddy-strain male mouse, and the toxicity was examined. The test compound was administered intravenously (i.v.) in a dose of 100 mg/kg, and the toxicity was evaluated in terms of mortality of mice after 24 hours of the administration (number of specimens: one group consisting of 3 mice). The results are shown in Table 4. 
     
                       TABLE 4                                                     
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Result of toxicity test                                                   
                      Mortality (%)                                       
Example No.: Test Compound                                                
                      100 mg/kg (i.v.)                                    
______________________________________                                    
42: 2-(2&#39;-methylphenyl)-5,8-                                              
                      0                                                   
dimethoxyquinoline-4-                                                     
carbonylguanidine methanesulfonate                                        
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     As mentioned above, the compounds of the present invention have a strong inhibitory effect on NHE activity, and these compounds are quite useful as an agent for preventing or treating diseases caused by enhanced NHE activity, such as hypertension, arrhythmia, myocardial infarction, angina pectoris, arteriosclerosis, diabetic complication, cancers, fibrosis, cardiac hypertrophy, prostatic hypertrophy and the like. Further, these compounds are useful as an ingredient of a protective solution of internal organs cut from the body for transplantation or internal organs transplanted and as a diagnostic agent for diseases in which NHE activity is enhanced.