JPS61205276A - Heterocyclic compound - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to heterocyclic compounds, and more particularly to novel substituted benzimidazole derivatives, processes for their production, intermediates useful for their production, pharmaceutical compositions S and S containing them. Concerning its use in therapy.

BACKGROUND OF THE INVENTION Substituted benzimidazole derivatives having the ability to suppress gastric acid secretion are known. For example, British Patent No. 150004
No. 3 and No. 1,525,958 disclose a series of 2-pyridylalkylthio and 2-pyridylalkylsulfinylbenzimidazole derivatives in which the pyridyl group is optionally monosubstituted with an alkyl or 110 group. Furthermore, European Patent Nos. 5129B and 743
41A and t480602A are a series of 2-pyridylalkylsulfinyl and 2-pyridylalkylsulfinyl groups in which the pyridyl group is optionally substituted with 1 to 3 substituents selected from methyl, ethyl, methoxy, ethoxy, methoxyethoxy or ethoxyethoxy. -pyridylalkylthio-benzimidazole derivatives, and GB 2134523 further discloses such compounds in which the pyridyl group is optionally substituted with 1 to 3 substituents. Such compounds add +A to H+- in the gastrointestinal tract.
It is thought that the effect is exerted by inhibiting the TPase enzyme (E. Frenias, T. Bergrind,
Cee Sax, El Org, Be Elanter,
Engineering, E. Nustrand and B. Wallmark, (Felenius, E., Berg
lindh, T., 5achs.

G,, 01ke, L,, Elander, B,,
5jostrand, S.E.

and Wallmark B, ), 1981. Nature 290.159-61).

Additionally, U.S. Pat. No. 4,359,465 discloses certain 2-
The cytoprotective effects of pyridylalkylthio- and 2-pyridylalkylsulfinylbenzimidazole derivatives and their use in the treatment and prevention of gastrointestinal inflammation are disclosed.

DISCLOSURE OF THE INVENTION 2- or 4-pyrimidylalkylsulfinyl (and thio)benzimidazole derivatives in which the pyrimidyl group is optionally directly replaced with a substituted ami7 group suppress gastric acid secretion induced by exogenous and endogenous stimuli. It has been found.

Therefore, in one aspect, the present invention provides the formula (■)
: [In the formula, k1 to R4 are the same or different, and each represents hydrogen, alkyl having 1 to 6 carbon atoms, halogen, trifluoromethyl, alkoxy having 1 to 6 carbon atoms, or 1 to 6 carbon atoms.
alkanoyl, alkoxycarbonyl having 1 to 6 carbon atoms, ethoxy group substituted with 0.3 to 5 fluorine atoms, or 2 and 3 taken together to form a group -〇(C
R2) mO- (in the formula, m is 1 or 2, S and each radical mean hydrogen or fluorine)
is O or 1; EL and 16 are the same or different, and each is hydrogen, alkyl having 1 to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms, or K and 6 are the nitrogen to which they are bonded. together with the atoms form an azetidine, pyrrolidino, piperidino, piperazino, N-alkyl (alkyl having 1 to 4 carbon atoms) piperazino or morpholif group; and one of X and Y is a nitrogen atom and the other is a group CR7 ( In the formula, R7 is hydrogen, carbon number 1
to 6 alkyl or NH2] or a pharmaceutically acceptable salt thereof.

Preferably R1-R4 are all hydrogen. More preferably, R[and K are hydrogen, one of R2 and R3 is hydrogen and the other is halogen, trifluoromethyl, RCF20
．． It is an ethoxy group substituted with 3 to 5 fluorine atoms, an alkoxy group having 1 to 6 carbon atoms, or an alkanoyl group having 1 to 6 carbon atoms. Preferably, R1 and R4 are hydrogen, one of R2 and R3 is hydrogen and the other has 1 carbon number.
-6 alkyl or C1-6 alkoxy; or R1 and 4 are hydrogen, and 2 and 3 are the same or different, respectively, C1-6 alkyl or C1-6 alkoxy or taken together to form the group -0(CR2)mO-1.

Preferably, the ethoxy group substituted with 3 to 5 fluorine atoms is 2,2,2-trifluoroethoxy, 1.1.2
-trifluoroethoxy, 1,2.2-trifluoroethoxy, 1,1,2.2-tetrafluoroethoxy, 1
, 2,2.2-tetrafluoroethoxy and perfluoro,loethoxy.

Preferably, the group -0(CR2)rnO- in which m is 1,
For example, difluoromethylenedioxy (-0CF20-
); preferably methylenedioxy (-ocH2o-)
and preferably a group -0(CR2)mO in which m is 2;
- is ethylenedioxy (-0CH2CH20-)g and trifluoroethylenedioxy (-0CHFCF20-
).

Preferably n is 0. Preferably n is 1.

Preferably, one of [5] and R6 is hydrogen and the other is cycloalkyl having 3 to 6 carbon atoms. Preferably, R5 and R6 are the same or different and each is hydrogen or alkyl having 1 to 6 carbon atoms.

Suitably k and and 6 together with the nitrogen atom to which they are attached form an azetidino group. Preferably, Tao and R6 together with the nitrogen atom to which they are attached represent morpholino, pyrrolidino, piperazine/, N
-Alkyl (alkyl having 1 to 4 carbon atoms) forms 7 piperazino or piperidi groups.

Preferably R7 is Ni2. Preferably, R7 is hydrogen or alkyl having 1 to 6 carbon atoms.

1 to 6 carbon atoms by itself or as part of another group (e.g., C1 to C6 alkokene, C1 to C6 alkoxycarbonyl or C1 to C6 alkanoyl)
The alkyl group of is straight-chain or branched, e.g. methyl,
Ethyl, n-propyl, i-propyl, i-butyl, S
-butyl, n-butyl, n-pentyl, i-pentyl or n-hexyl. Preferably, the number of carbon atoms is 1
The alkyl group in ~6 is methyl or ethyl.

Preferably, the C1-C6 alkoxy group is methoxy or ethoxy.

Preferably, the alkoxycarbonyl group having 1 to 6 carbon atoms is methoxycarbonyl or ethoxycarbonyl.

Preferably, the C1-C6 alkanoyl group is meth/yl or ethanoyl.

A cycloalkyl group having 3 to 6 carbon atoms is cyclopropyl,
cyclobutyl, cyclopentyl and cyclohexyl. Preferably, the C3-C6 cycloalkyl group is cyclopentyl or cyclohexyl.

Examples of compounds of the invention include (1) the formula (I) where x is nitrogen, Y is CR7 and n is 1;
Compounds of I, for example 5-methoxy-2-(4-piperidi7-2-pyrimidinylmethylsulfinyl)-(1H)-benzimidazole, 5-methoxy-2-(4-morpholy/-2-pyrimidinylmethylsulfinyl) -(1H)-benzimidazole, 5-methoxy-2-(4-pyrrolidi/-2-pyrimidinylmethylsulfinyl)-(1H)-benzimidazole, 5-methoxy-2-(4-dimethylamino-2-pyrimidinylmethyl sulfinyl)-(11()-benzimidazole, 5-methoxy-2-(4-piperidino-5-methyl-2
-pyrimidinylmethylsulfinyl)-(1H)-benzimidazole, 5-methoxy-2-(4-piperidino-5-amino-2
-pyrimidinylmethylsulfinyl)-(1H)-benzimidazole, 5-methoxy-2-(4-dimethylamino-5-methyl-2-pyrimidinylmethylsulfinyl)-(1H)-
Benzimidazole, 5-methoxy-2-(4-dimethylamino-5-ami/
-2-pyrimidinylmethylsulfinyl)-(1H)-
Benzimidazole; (II) Formula (where X is CR7, Y is nitrogen and n is 1)
Compounds of II, for example 5-methoxy-2-(5-methyl-6-piperidino-4
-pyrimidinylmethylsulfinyl)-(1H)-benzimidazole, 5-methoxy-2-(5-methyl-6-virolidino 4
-pyrimidinylmethylsulfinyl)-(1H)-benzimidazole, 5-methoxy-2-(5-methyl-6-morpholino-4
-pyrimidinylmethylsulfinyl)-(1H)-benzimidazole, 5-methoxy-2-(5-methyl-6-dimethylamino-4-pyrimidinylmethylsulfinyl)-(11-1
)-benzimidazole, 5-methoxy-2-(6-piperidino-4-pyrimidinylmethylsulfinyl)-(
1) ()-Benzimidazole, 5-methoxy-2-(6-pyrrolidino-4-pyrimidinylmethylsulfinyl)-(1H)-benzimidazole, 5-methoxy-2-(6-dimethylamino-4-pyrimidinylmethylsulfinyl) -(11()-benzimidazole; and ■) Corresponding thioether derivatives of the above compounds, that is, analogous compounds in which n is 0.

Compounds of formula (D) that are n'/JSO are capable of forming pharmaceutically acceptable acid addition salts with appropriate organic or inorganic acids. Pharmaceutically acceptable salts include, for example, reactions with hydrochloric acid, sulfuric acid, sulfonic acid or phosphoric acid; aliphatic, cycloaliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids; methionine, tryptophan, lysine or arginine, etc. It can be formed by

Compounds of formula (I), where n is 1, also form pharmaceutically acceptable acid addition salts, but in aqueous solution, compounds of formula (I) where n is 0,
Less stable than the salts formed from compounds of I).

Compounds of formula (I) where n is 1 will react with a suitable base to form basic salts. Such salts include, for example, the sodium, potassium, lithium, calcium and magnesium salts which can be prepared by known methods; for example, the sodium, potassium and lithium salts can be prepared in aqueous or non-aqueous systems. It can be produced by reacting with sodium oxide, potassium hydroxide or lithium hydroxide, and calcium salts can be produced by reacting the 1-IJium, lithium or potassium salt with calcium chloride in an aqueous or non-aqueous system.

Compounds of formula (I) where n is O may also form basic salts, but such salts are less stable than salts prepared from compounds of formula (I) where n is 1.

Compounds of formula (I) in which n is 1 have a sulfur atom (an asymmetric center) and are therefore optically active compounds. These compounds themselves exist as two optical isomers (enantiomers). Further, compounds of formula (I) in which one or more of 8 at R1- are a branched alkyl group having 3 to 6 carbon atoms (either by itself or as part of another group), Owing to the presence of an alkyl group having 3 to 6 carbon atoms, it may further contain asymmetric centers.Such compounds are
Furthermore, it exists as two (or more) optical isomers.

Both pure enantiomers, racemic mixtures (50% mixtures of each enantiomer), and unequal mixtures of each enantiomer are within the scope of the invention. Furthermore, all possible diastereomeric forms (pure enantiomers and mixtures thereof) are also within the scope of the invention.

In all compounds of the present invention, substituents include 1 and R.
It should be noted that 4 and d as well as R2 and 3 can be considered equivalent in solution at room temperature. This is due to the tautomerism of the benzimidazole nucleus, creating an equilibrium between the two possible forms.

In another aspect, the present invention provides a compound represented by fa1 formula (II): I and formula (■): [wherein k1 to 6, X and Y are as defined above, Ll
and one of L2 is St (and the other is a leaving group that can be replaced by a mercaptan); (h) Formula (IV): 1 to 4 [In the formula, K1- 4 has the same meaning as above] and a compound represented by the formula (■): [wherein K, R, X and Y have the same meaning as above, Xl is C
07H or C8X E and X2 mean halogen or alkoxy having 1 to 4 carbon atoms]; fC1 formula (■): , R9 is hydrogen or a protecting group and M is an alkali metal atom] and a compound represented by the formula (■): [wherein R5, R6, x g and Y are as defined above,
Z means a leaving group]; (d) Formula (■): [In the formula, R1 to R4 have the same meanings as above, R9 is hydrogen, or protecting groups S and Y are leaving groups; means a leaving group] Compounds represented by the formula (■): [wherein R5, R6, X and Y have the same meanings as above, and M' means an alkali metal atom or an equivalent of an alkali metal atom ] The compounds represented by the following are reacted, and then, if desired, (1) the formed compound represented by the formula (I) where n is 0 is oxidized to the compound represented by the formula (I) where n is 1; (11) reducing the formed compound represented by formula (I) where n is 1 to a compound represented by formula (I) where n is 0; (++1+remove any protecting group 9; QVI The present invention provides a method for producing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, which is characterized by forming a pharmaceutically acceptable salt.

Suitable leaving groups L1 that can be directly converted into mercaptans include:
chloro, bromo or iodo, arylsulfonyloxy such as toluenesulfonyloxy,
Examples include alkylsulfonyloxy such as methanesulfonyloxy, alkylmercapto such as methylmercapto, alkylsulfinyl such as methylsulfinyl, and alkylsulfonyl such as methylsulfonyl.

Suitable leaving groups L2 have the same meanings as above, and can also be, for example, acyloxy having 1 to 4 carbon atoms, such as acetoxy, or hydroxy.

Suitable alkali metal atoms M include, for example, lithium, sodium or potassium.

Suitable leaving groups Z include, for example, /thalogen (preferably chloro) ji5 and hydroxy activated, for example by esterification with an aryl or alkanesulfonic acid. Suitable sulfonic acids are obvious to those skilled in the art and include, for example, p-toluenesulfonic acid or methanesulfonic acid.

Suitable leaving groups Y include groups which together with the sulfinyl group to which it is attached form a reactive sulfinic acid derivative, such as alkoxy having 1 to 4 carbon atoms, dialkyl (the number of carbon atoms in alkyl 1-4) Amino and carbon number 1-
No. 4 alkyl mercapto is mentioned.

Suitable groups M' equivalent to metal atoms include, for example, alkaline earth metal atoms (eg, magnesium) substituted with halogen atoms (eg, bromine).

Suitable protecting groups 9 are described, for example, by Protective Groups in Organic Synthesis, T.
Double φGree-7 (”ProtectiveGro
ups in Organic 5 synthesis
'T, W, Greene) 1981 (Reilly (
Wiley)). As can be seen, the group R9 has formulas (■) and (IX)
It must not be cleaved under the reaction conditions of the compound shown. Such groups include, for example, benzyl or trityl groups.

The reaction between the compound of formula (II) where L or S)l and the compound of formula (I[I) where L2 is a leaving group can be carried out under basic conditions in the presence of an inert solvent from room temperature to It can be carried out at temperatures between the reflux temperature of .

Suitable solvents include lower alkanols such as methanol or ethyl alcohol, mixtures of lower alkanols and water, or ethers such as dimethoxyethane or tetrahydrofuran.

Suitable bases are obvious to those skilled in the art and include alkali metal hydroxides such as sodium or potassium hydroxide, alkali metal alkoxides such as potassium [-butoxide],
Examples include alkali metal hydrides such as sodium hydride or potassium hydride, and organic tertiary amines such as triethylamine.

Preferably, the reaction is carried out in sodium hydroxide solution.

The reaction is carried out at room temperature in the presence of ethanol as a solvent.

Obviously, under basic conditions, L2 must be a group other than any hydroxy or acetate, for example halogen, preferably chlorine.

Additionally, the reaction can be carried out under neutral conditions in the presence of an inert solvent at the reflux temperature of the solvent. Suitable solvents include those mentioned above.

Furthermore, when L2 is hydroxy or acyloxy having 1 to 4 carbon atoms such as acetoxy, the reaction can be carried out under acidic conditions. Suitable acidic conditions are known, for example, under reflux in hydrobromic acid, optionally in the presence of acetic acid.

Compound 2 of formula (I[) where Ll is a leaving group and L2 is S
The reaction between compounds of formula (N) where H is H is similar to the reaction between compounds of formula (II) where Ll is SH and compounds of formula (N) where L2 is a leaving group as described above. It can be carried out under sexual conditions.

The reaction between the compound of formula (IV) and the compound of formula (V) can be carried out in a suitable solvent under acidic conditions at room temperature to the reflux temperature of the solvent used.

Suitably, the reaction is carried out in a polar solvent such as a lower alkanol, dimethylsulfoxide, acetone, dimethylformamide or acetonitrile, optionally in the presence of water. Preferably, the reaction is carried out in ethanol.

Suitably the reaction is carried out in the presence of a strong acid such as hydrobromic or hydrochloric acid. Preferably, the reaction is carried out in the presence of hydrochloric acid.

Preferably, the reaction is carried out at the reflux temperature of the solvent.

The reaction between compound 2 of formula (VI) and compound of formula (Va) can be carried out in an inert solvent at room temperature or elevated temperature, depending on the nature of the groups M and Z. Suitable solvents include solvents normally used in the reaction of eluted ions and alkylating agents, such as tetrahydro7ane, diethyl ether, and toluene. Preferably, when M or lithium 2 and Z are chlorine, the reaction is carried out in benzene at reflux temperature.

The reaction between a compound of formula (■) and a compound of formula (IX) can be carried out in an organic solvent such as tetrahydrofuran or diethyl ether under conditions commonly used for organometallic reactions known to those skilled in the art.

The product of the reaction of (al~(C1) has the formula (I
) is a compound. These products can be oxidized to compounds of formula (I) in which n is 1 by reaction with an oxidizing agent. Examples of suitable acids and other agents include nitric acid, hydrogen peroxide, peracids, peracid esters, ozone, dinitrogen tetroxide, iotonbenzene, N-halosuccinamide, 1-chlorobenzotriazole, etc. Perhalates such as sodium perchlorate or perchloric acid [-butyl, diazabicyclo(2,
2,2) Octane bromine complex, sodium metaperiodate, selenium dioxide, manganese dioxide, chromic acid, ceric ammonium nitrate, bromine, chlorine or sulfuryl chloride. A preferred oxidizing agent is m-chloroperbenzoic acid.

The oxidation reaction is carried out under conditions known for the oxidation of thiols to sulfoxides. Preferably, the reaction is carried out in an inert solvent at a temperature between -70°C and the boiling point of the solvent used. Suitable solvents include, for example, benzene,
Included are aromatic or chlorinated hydrocarbons such as toluene, dichloromethane or chloroform, esters such as ethyl acetate, ethers such as dioxane. Preferably, the reaction is carried out in dichloromethane at a temperature between -50<0>C and +20<0>C.

The compounds of formula (I) are obtained either in free base or salt form, depending on the chosen starting materials and reaction conditions. If a free compound is obtained, it can be converted into a salt by conventional methods, for example by dissolving the compound in a suitable solvent and adding the desired acid or base; It can be converted to the free compound by methods, for example, by treatment with a suitable acid or base.

Racemic mixtures may also be produced and they may be prepared by conventional methods, for example by recrystallization from optically active solvents or by the analytical method of Niss-Allenmark, B. Bumgren, Etsch Ballen and P.O. Lagerström. Biochemistry (S, Allenmark, B, B
omgren, i(, Baren and P-,
OLagerstrom in Analytical
Biochemistry), 135°293~
7.1984 by high performance liquid affinity chromatography.

Intermediates 2 of formula (IV) and intermediate benzimidazoles of formulas (II), (VI) and (■) are known or can be prepared analogously to known methods. For example, L
The metal compound of formula (II) in which l is SH has the corresponding formula (t
V) with carbon disulfide in the presence of an alkali metal hydroxide or with potassium ethylxanthate [Organic Synthesis (Org, Syn, )].

30.56) or by reacting with thiophosgene. Compounds of formula (II) in which Ll is a leaving group, e.g.
It can be obtained from the corresponding compound of I). Compounds of formula (II) in which Ll is hydroxy can be prepared by reacting compounds of formula (IV) with phosgene.

The compound of formula (IV) is disclosed in European Patent Application No. 127
763, German Patent Application No. 2848531, Chemical Abstracts (CA), 60,13352h
, 1964 and Liebigs Ann, Chem.

), 730.16-30.1969.

The metal compound of formula (VI) is a compound of formula (II) in which Ll is S)I
Methylation, oxidation and protection of compounds (i.e. group R9
can be manufactured by the introduction of

Compounds of formula (III), (V), (■)8 and (IX) are novel and provide another aspect of the invention.

The compound can be prepared by a method analogous to known methods,
For example, a compound of formula (I[) in which Ll is a leaving group replaceable with a mercaptan and 7 is NR2 is tuit'
is hydrogen and Ll, for example methoxy (ff
The compound of formula (ffl) in which i is a nitro group is obtained by reacting the compound of l) with nitric acid and sulfuric acid. The intermediate nitro derivative formed is reduced to give compounds of formula (I[) in which R7 is N R2 and Ll is methoxy.

For example, deprotection of group L2 with boron tribromide provides compounds of formula (III) which are only hydroxy. The hydroxy group can then be converted to other suitable groups L2 using standard methods, for example, the formula (II
I); or reaction with thionyl chloride gives compounds of formula (■) in which Ll is chlorine; or (u) compounds of formula (■) in which J is hydrogen and Ll is, for example, methoxy. Compounds of formula (III) in which 7 is bromine are obtained by reacting compounds of formula (III) with, for example, bromine. The intermediate formed is reacted with ammonia so that R is SH2 and L2
The desired compound of formula (I[[) is obtained, where is methoxy.

The formed compound of formula (11) is reacted with, for example, boron tribromide to obtain the corresponding compound of formula (■) in which L2 is hydroxy. Then, the base is, for example, (1)
can be prepared from the corresponding compound of formula (I[) where R7 is hydrogen.

Compounds of formula (III) in which i is hydrogen can be produced by methods analogous to known methods. For example, a compound represented by the formula (X) 8 [wherein 8 is a halogen, such as chlorine or bromine, and L means methoxy or hydroxy] and a compound represented by the formula % formula % [wherein k and 16 are the above-mentioned It can be produced by reacting a suitable amine represented by the following formula.

Suitable conditions include heating in an inert solvent such as tetrahydrofuran in the presence of excess amine.

The compound of formula (X) can be formed by a known method, for example, by reacting a corresponding compound in which R8 is hydroxy with, for example, phosphorus oxychloride to form a compound of formula (X) in which R8 is chlorine. It can be manufactured by

Compounds of formula (X) where k8 is hydroxy can be prepared by reaction of a suitable substituted amidine with a suitable substituted β-ketoester. For example, the reaction of methoxyacetamidine hydrochloride and ethyl sodium formylacetate salt gives a compound of formula (X) where X is nitrogen, Y is CH and L2 is methoxy; and formamidine acetate and 3-
The reaction of keto-4-methocybutyric acid ethyl ester yields compounds of formula (X) in which X is CH, Y is nitrogen and L2 is methoxy.

A compound of formula (N) in which L2 is 5H is, for example, Na5
1 (by reacting with L2 is a leaving group, e.g.
It can be produced from a compound of formula (N) which is a halogen.

Compounds of formula (V) can be prepared from corresponding compounds of formula (I[); for example, a compound of formula (V) where xl is cscl can be prepared by combining a compound of formula (ffl) where xl is L2 or SH with thiophosgene. Can be produced by reaction.

The compound of formula (■) is prepared by Roszniki chemistry (Ro
szniki Chem, ), 35 +475,
It can be produced in a manner similar to that described in 1961.

In another aspect, the invention provides compounds of formula (I) for therapeutic use. Compound 2 of formula (I) and its pharmaceutically acceptable salts suppress gastric acid secretion induced by exogenous and endogenous stimuli, and are useful in treating gastrointestinal diseases in mammals, especially humans. Such diseases include
Examples include gastric 2 and duodenal ulcers, 2 and Zollinger-Ellin syndrome.

Furthermore, the compounds of formula (I) may be useful in the treatment of other diseases in which a cytoprotective and/or antisecretory effect is desired, such as gastritis, gastritis-inducing N5AIDs, gastritis associated with a history of chronic and acute alcohol intake, gastric ulcers, Prevention of upper gastrointestinal bleeding in patients with acute upper gastrointestinal bleeding, patients at risk of progression of stress-related lesions of the gastric mucosa, as well as risk factors such as, for example, gastric acidity 2 and volumes associated with pulmonary aspiration. It can be used to reduce force S.

After administration to a mammal, the compound of formula (I) where n is O
It is believed that after conversion to a compound of formula (I) where is 1, it exerts its antisecretory and cytoprotective activity.

Furthermore, the compound of formula (I) where n is 1 is believed to exert its anti-secretory activity after being transformed into other chemically reactive substances under acidic conditions after administration to mammals. Active substances produced from compounds of formula (I) are thus also within the scope of the invention.

For therapeutic use, the compounds of the invention are typically administered in standard pharmaceutical compositions. Therefore, in another aspect, the present invention provides a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. be.

Compound S of formula (I) and its pharmaceutically acceptable salts can be administered by standard methods, such as orally, parenterally, rectally, transdermally, by inhalation or buccal administration.

Compounds of formula (I) and their pharmaceutically acceptable salts which are active when administered orally can be formulated into liquids such as syrups, suspensions or emulsions, tablets, capsules and lozenges. be able to.

Liquid formulations typically include a suspension or solution of the compound or a pharmaceutically acceptable salt thereof in a suitable liquid carrier such as water or a non-aqueous solvent such as ethanol, glycerin, polyethylene glycol, oil, etc. , and a suspending agent, preservative, flavoring agent, or coloring agent.

Compositions in the form of tablets can be prepared using any suitable pharmaceutical carriers commonly used in preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.

Compositions in the form of capsules can be manufactured using conventional encapsulation methods. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into hard gelatin capsules. Alternatively, dispersions or suspensions can be prepared with any suitable pharmaceutical carrier such as aqueous gums, cellulose, silicates or oils and then incorporated into soft gelatin capsules. Fill it.

Compounds of formula (I) in which n is 1 are susceptible to degradation in acidic media and therefore tablets and capsules containing such compounds are preferably provided with an enteric coating or Capsules that are generally acid-resistant are used to protect the compound from acid degradation in the stomach. Alternatively, enteric coatings can be provided by coating pellets containing the active ingredient prior to filling the active ingredient into hard gelatin capsules. Suitable enteric coating materials are known in the pharmaceutical industry and include, for example, shellac or cellulose acetate heptatarate and hydroxypropyl methylcellulose heptatarate natonoanionic film-forming polymers, optionally under the influence of plasticizers.

Other standard techniques for enhancing the stability of such compounds can also be used, as will be apparent to those skilled in the art. The type of such technique depends on the route of administration and includes, for example, the formation of stable complexes with β-cyclodextrin and the like.

Compounds of formula (I) and pharmaceutically acceptable salts thereof that are active when administered parenterally (ie, injection or infusion) can be formulated as solutions or suspensions.

Compositions for parenteral administration consist of a solution or suspension of the active ingredient in a sterile aqueous carrier or parenterally acceptable oil, such as polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or sesame oil. Alternatively, the solution can be lyophilized and then reconstituted with a suitable solvent immediately before administration.

Typical suppository compositions include a compound of formula (I), or a pharmaceutically acceptable salt thereof, which is active when so administered, and a glycol polymer, gelatin, cocoa butter or other low melting point compound. binders and/or lubricants such as vegetable or synthetic waxes or fats.

Typical transdermal formulations consist of a conventional aqueous or non-aqueous vehicle such as a cream, ointment, lotion or paste, or in the form of a plaster, patch or membrane with added drug.

Typical inhalable compositions consist of solutions, suspensions or emulsions which can be administered in the form of an aerosol using conventional propellants such as dichlorodifluoromethane or trichlorofluoromethane.

Preferably, the composition is in unit dosage form.

Each unit dosage form for oral administration preferably contains 1 to 2501R9 (preferably 1 to 15°0 for parenteral administration) of the compound of formula (I) or a pharmaceutical thereof in terms of free base. Contains acceptable salts.

The compounds of the invention are commonly administered to patients in need of treatment for gastrointestinal disorders and other conditions caused by or exacerbated by gastric acidity. The daily dosage range for adult patients is
For example, 1q to 500 in terms of free base, preferably,
Oral dosage of 11yg to 250#, or 11119
-500 mg, preferably 1 to 150 mg, of an intravenous, subcutaneous or intramuscular dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof, administered 1 to 4 times per day. Suitably, the compound is administered for the duration of continued treatment, eg, for one week or more.

In addition, the compounds of the invention may be antacids (e.g. magnesium carbonate or magnesium hydroxide and aluminum hydroxide), non-steroidal anti-inflammatory agents (e.g. indomethacin, aspirin or naproxen), steroids or nitrite scavengers (e.g. ascorbic acid or aminosulfonic acid) or other drugs used for the treatment of gastric ulcers, such as pirenzepine, e.g.
It can also be administered in conjunction with other active ingredients such as prostanoids such as 16-dimethyl I'GE2 or histamine H2-antagonists such as cimetidine.

Example Next, the present invention will be explained in more detail with reference to Examples.

Example 1 Preparation of 5-methoxy-2-(4-piperidino-2-pyrimidinylmethylthio)-(1H)-benzimidazole (1) 57 g of methquinacetamidine hydrochloride and 150 g of ethyl formylacetate sodium salt in 670 ml of water.
．． The mixture of 5,9' was stirred at room temperature for 3 days.

Upon concentration, the solution was made acidic, saturated with sulfur chloride, and extracted with chloroform. After drying over magnesium sulfate, the extract was stripped to a solid and triturated with ether to give 2-methoxymethyl-4-pyrimidone 53.5. Got @. Melting point 125-127°C.

(Ill 2-methoxymethyl-4-pyrimidone 1.7
3y and phosphorus oxychloride 20d under reflux.
Heated for 0 minutes. The mixture was stripped, ice/water was added and the pH was raised to 14 with NaOH. The solution was extracted with chloroform and the extract was dried over magnesium sulfate and stripped to give an oil of 2-methoxymethyl-4-
1.72 g of chloropyrimidine was obtained and used without further purification.

(++++ 6, 1 piperidine in 40 scraps of methylene chloride
7 ml were added dropwise to a solution of 4.711 i of 2-methoxymethyl-4-chloropyrimidine in 49 zl of methylene chloride. After standing overnight at room temperature, the mixture was heated under reflux for 1 hour. After cooling, the solution was washed with water, dried and stripped. The residue was subjected to chromatography (silica gel, chloroform) to obtain an oily product of 2-methoxymethyl-4-
Piperidinopyrimidine 4.49. I got p.

2-methoxymethyl-4-piperidinopyrimidine in 60 d of methylene chloride at 0-5°C under nitrogen atmosphere 3.
35. Boron tribromide 6.11R1 was added dropwise to the stirring solution of @. After another 30 minutes, pour the mixture onto ice and add 1 l of Na.
(The pH was raised to 13 with Obtained. Melting point 92-93°C
.

(v) 2-Hydroxymethyl-4-piperidino-pyrimidine 2 in chloroform 20at cooled in an ice/salt bath.
．． 3.01 ml of thionyl chloride was added dropwise to 66 g of the stirred solution. The mixture was allowed to warm up to room temperature, and then heated for a further 2.5 min.
Stir for hours. The solution was poured onto ice, the pH was raised to ~8 with NaOH, and extracted with chloroform. The extract was dried and slipped with l-IJ to give an unstable oil, 2-chloromethyl-4-piperidinopyrimidine, 2.92. I got @ and used it immediately.

2-chloromethyl-4- in V++ ethanol 40*/
A mixture of 2.89II piperidinopyrimidine and 2.46y 2-mercapto-5-methoxybenzimidazole 2 and IN sodium hydroxide 15R1 was added at room temperature to 16
Stir for hours. After stripping, the residue was washed with water and recrystallized from acetonitrile to 5-methoxy-2-(4-piperidino-2-pyrimidinylmethylthio)'-(11(
)-benzimidazole (3.5 g) was obtained. Melting point 145~
147℃.

Example 2 Preparation of 5-methoxy-2-(4-piperidino-2-pyrimidinylmethylsulfinyl)-(1H)-benzimidazole 5-methoxy-2-[ 4-Piperidino-2-pyrimidinylmethylthio)-(1H)-benzimidazole 3.4
8,9 to a stirred solution of 1.69% m-chloroperbenzoic acid in 25d methylene chloride. A solution of p was added dropwise. After 1.5 hours at -20°C, add an additional 0.3 m-chloroperbenzoic acid.
4, p added. After another 30 minutes, ammonia was passed through the reaction mixture and the precipitated solids were filtered out. Carbonate the F solution.
- Washed with IJum aqueous solution, and backwashed with chloroform. The organic layers were combined, dried over potassium carbonate, stripped, and the residue was purified by column chromatography (silica gel, 2% methanol-ammonia/chloroform) to give an oil of 5-methoxy-2-(4-piperidino- 2-pyrimidinylmethylsulfinyl)-(1
) 3.28 g of 1)-benzimidazole were obtained.

Example 3 5-methoxy-2-(4-piperidino-2-pyrimidinylmethylsulfinyl)-(1H)-benzimidazole calcium salt 2,5H205-methoxy-2-(4
-piperidino-2-pyrimidinylmethylsulfinyl)
~(1H)-benzimidazole 3.28. Partitioned between 20j11 methylene chloride, 20m water and 8.83au IN sodium hydroxide. Separate the organic layer, pass through the aqueous layer and add calcium chloride (6H20,0
, 971i). The precipitate was separated and dried to obtain 1.89 g of the title compound. Melting point 204-206℃
(Disassembly).

Elemental analysis, C36H4oCaN1oO4S2・2.5H
20, the actual value (%l: C, 52, 30; f(,
5,43; N, 16.71; S, 7.71 Theoretical value (%): C, 52,341H, 5,19iN,
16.96 iS, 7.76 Example 4 5-methoxy-2-(4-morpholino-2-pyrimidinylmethylthio)-(1H)-benzimidazole (1) Morpholine 12 in 100 d of tetrahydro7rane
．． 67, p and 2-methoxymethyl-4-chloropi I
J Mijin 7.69. The solution of p was heated under reflux for 1 hour. After cooling, the mixture was treated with 100 R1 of water, the pH was adjusted to 8 with concentrated hydrochloric acid and extracted with chloroform. After drying over potassium carbonate, the extract was stripped and the residue was purified by chromatography (silica gel, chloroform/methanol) to obtain 5.4 g of 2-methoxymethyl-4-morpholinopyrimidine as an oil.

(11) To a stirred solution of 4.991i of 2-methoxymethyl-4-morpholy/pyrimidine in 5°yxe of methylene chloride at −25°C under a nitrogen atmosphere, 1001I of methylene chloride was added.
A solution of 9.02 ml of boron tribromide in Il was added dropwise.

After 15 minutes, the mixture was allowed to warm up to 0-5°C and left at this temperature for 2 hours. After pouring on ice, p)%N
a OH to 14 and the organic layer was separated. The aqueous layer was further extracted with chloroform, and the combined extracts were dried over potassium carbonate and stripped.

Tritrate the residue with Ranithyl to form a crystalline solid of 2-hydroxymethyl-4-morpholinopyrimidine 3.16.
I got a 9. Melting point 76-78°C.

(Ill in 30 d of chloroform cooled in an ice bath (7
) 3.4 d of thionyl chloride was added dropwise to a stirred solution of 2-hydroxymethyl-4-morpholinopyrimidine. The mixture was allowed to warm to room temperature and was left for an additional 165 hours.

The solution was concentrated and ether was added with stirring to give 3.81 g of 2-chloromethyl-4-morpholinopyrimidine hydrochloride as a crystalline solid. Melting point 214-216°C.

θV12-Chloromethyl-4-morpholinopyrimidine
Zine hydrochloride 3.65,9 and 2-mercapto-5
-Methoxybenzimidazole 2.63. Stirred mixture of 5N sodium hydroxide 6,42 yrl
I put it down. Stirring was continued for 1.5 hours and the mixture was heated for an additional 16 hours.
I left it for a while. After stripping, the solid residue is washed with water,
Recrystallized from acetonitrile to give 5-methoxy-2-(4
-morpholino-2-pyrimidinylmethylthio)-(1H
)-benzimidazole 4.09. Got @. Melting point 18
8 to 192°C0 Example 5 Production of 5-methoxy-2-(4-morpholino-2-pyrimidinylmethylsulfinyl)-(11()-benzimidazole In the method of Example 2, 5-methoxy-2-( 4-piperidino-2-pyrimidinylmethylthio) -(L H
)-5-Methogyushi 2- instead of benzimidazole
(4-morpholy/-2-pyrimidinylmethylthio)-(
1H)-benzimidazole 3.53. 5-methoxy-2-(4-morphol/-2-
pyrimidinylmethylsulfinyl)-(1H)-benzimidazole 2.58. I got p. Melting point 154-156
°C (decomposition).

Elemental analysis・017H19N5°35(!l-sheet・Actual value (%): C, 54-851H15,11iN, 18.
64; S, 8.61 theoretical value (%l:c, 54.68 threads H, 5, 13 pickled N, 1
8.76°S, 8.59 Example 6 Production of 5-methoxy-2-(4-pyrrolidino-2-pyrimidinylmethylthio)-(1H)-benzimidazole (1) Method number of Example 1t++++, Using pyrrolidine 8.51d instead of piperidine and other reagents in corresponding molar ratios, the oil was
2-(4-pyrrolidino-2-pyrimidinylmethylthio)
-(1H)-benzimidazole 8.491 was obtained.

(11) Using the method of Example 10V), replacing 2-methoxymethyl-4-piperidinopyrimidine with 2-methoxymethyl-4-pyrrolidinopyrimidine 8.31. Using p,
2-Hydrobovine dimethyl-4-pyrrolidi/pyrimidine 6.72. Recrystallized from ether using other reagents in corresponding molar ratios. I got y. Melting point 114-116°C.

(U++ Example 4 (Jail method (2)
2-hydroxymethyl-4-pyrrolidinopyrimidine 3 instead of hydroxymenal-4-morphol/pyrimidine
, Ogi and using other reagents in corresponding molar ratios, 2-chloromethyl-4-pyrrolidi/pyrimidine hydrochloride 3.72.9 was obtained. Melting point: 186-189°C.

6V) In the method of Example 40Vl, instead of 2-chloromethyl-4-morpholinopyrimidine hydrochloride -2
-Chloromethyl-4-pyrrolidinopyrimidine hydrochloride3.
61. 5-methoxy-2-(4-
pyrrolidi/-2-pyrimidinylmethylthio)-(1)1
)-benzimidazole 4°03Ii was obtained. Melting point 19
9-202℃.

Example 7 Production of 5-methoxy-2-(4-pyrrolidino-2-pyrimidinylmethylsulfinyl)-(11()-benzimidazole) In the method of Example 2, 5-methoxy-2-(4-piperidino-2- pyrimidinylmethylthio)-(1H)-
5-methoxy-2-(4
-pyrrolidino-2-pyrimidinylmethylthionyl 3.92,p and other reagents in corresponding molar ratios, recrystallized from acetonitrile to obtain 5-methoxy-2-(4-pyrrolidino-2-pyrimidinyl). Methylsulfinyl)-(1H)-benzimidazole 2.88p
I got it. Melting point 175-177°C (decomposition).

Elemental analysis・'L7H19N5°254・Calculated value (%
): c, s7. ot if(,5.35;N,19
．． 50; S, 9.0 8 Theoretical value (%): c, 57.12if(, 5.36; N
, 19.59iS, 8.9 7 Example 8 Preparation of 5-methoxy-2-(4-dimethylamino-2-pyrimidinylmethylthio)-(1H)-benzimidazole (1) 2 in 100 d of ethanol cooled in a water bath. - 33% of dimethylamine in 45ffiJ of ethanol to a stirred solution of 7.54g of medoxymethyl-4-chloropyrimidine.
%η ~ solution was added dropwise. The mixture was allowed to warm up to room temperature and left for 16 hours. After stripping, the residue was treated with 100 ml of water and extracted with chloroform. The extract was dried over potassium carbonate and stripped to give 2-methoxymethyl-4-dimethylaminopyrimidine 7.411i as an oil.

(II) In the method of Example 14v), using 2-methoxymethyl-4-dimethylami/pyrimidine 7.2I instead of 2-methoxymethyl-4-piperidinopyrimidine and using other reagents in corresponding molar ratios. and recrystallized from ether to give 2-hydroxymethyl-4-dimethylaminopyrimidine 5.7. I got p. Melting point: 83-84°C.

(Example 4 (In method 2, 2-hydroxymethyl-4-dimethylaminopyrimidine was substituted for 2-hydroxymethyl-4-morpholinopyrimidine.
and other reagents in corresponding molar ratios, recrystallized from ether to give 2-chloromethyl-4-dimethylamide/pyrimidine hydrochloride 7°39.9. Melting point 204~
206℃.

-V) Example 4 In the QVI method, 2-chloromethyl-4-morpholinopyrimidine hydrochloride was replaced with 2-chloromethyl-4-morpholinopyrimidine hydrochloride.
Chloromethyl-4-dimethylaminopyrimidine hydrochloride 3
．． using 7 g and other reagents in corresponding molar ratios,
Recrystallization from ethanol gave 5-methoxy-2-(4-dimethylamino-2-pyrimidinylmethylthio)-(1H
)-benzimidazole 4.41. I got p. Melting point 18
2-183℃.

Example 9 Production of 5-methoxy-2-(4-dimethylamino-2-pyrimidinylmethylsulfinyl)-(1H)-benzimidazole In the method of Example 2, 5-methoxy-2-(4-piperidino-2 -pyrimidinylmethylthio)-(1H)-
5-methoxy-2-(4
-dimethylamino-2-pyrimidinylmethylthio)-(
1H)-benzimidazole 4.25. 5-methoxy-2-(4-dimethylamino-
2.67 g of 2-pyrimidinylmethylsulfinyl)-(1H)-benzimidazole was obtained.

Elemental analysis・015H17N5°252・Actual measurement value (%
l: C, 54,461H, 4,97; N, 21.07
iS, 9.56 Theoretical value (%l: G, 54.36i) 1,5.17iN
, 21.13iS, 9.68 Example 10 ゛5-Methoxy-2-(5-methyl-6-piperidino-4
Preparation of -pyrimidinylmethylthio)-(1H)-benzimidazole (i12-methyl-3-keto-4-methoxybutyric acid ethyl ester 60y and formamidine acetate 39.06
g was dissolved in 150 mZ of methanol, and under an argon atmosphere, 17.42 J of sodium and 22 J of methanol were dissolved.
Treated with sodium methoxide solution prepared from 5d. The mixture was stirred at 50° C. for 23 hours, stripped, water was added, and the temperature was lowered to mid-7 with hydrochloric acid. The solution was extracted with chloroform, the extract was dried over magnesium sulfate,
Stripped and triturated the residue with diethyl ether to give 4-methoxymethyl-5-methyl-6-hydroxypyrimidine 38.72. p, was obtained. Melting point 139
~140℃.

38.40 g of 1if4-methoxymethyl-5-methyl-6-hydroxypyrimidine was stirred with 275 d of phosphorus oxychloride at room temperature for 24 hours. Strip the mixture, add ice/water and add NaOH to pH 11.5.
I raised it to . The solution was extracted with chloroform, the extract was dried over magnesium sulfate, stripped and the oil
-methoxymethyl-5-methyl-6-chloropyrimidine 38.23. p was obtained and solidified by cooling to 5°C. Melting point: 37-38°C. The compound was used without further purification.

(Piperidine 15 in Tetrahydro 7rane 4 Q d
d was added dropwise to a solution of 5 g of 4-methoxymethyl-5-methyl-6-chloropyrimidine in 4 Ostl of tetrahydrofuran. The mixture was heated under reflux for 7 hours and then left at room temperature overnight. filter, strip,
Water was added to the oily residue. Hydrochloric acid was added to lower the pH to 7.5, and the mixture was extracted with chloroform. The extract was dried over potassium carbonate and stripped to give an oil of 4-methquinemethyl-5-methyl-6-piperidinopyrimidine 6.08
, 9 was obtained and solidified by cooling to 5°C. Melting point 45-47
℃.

The compound was used without further purification.

methylene chloride 10 at 0-5°C under dVl nitrogen atmosphere.
25 methylene chloride to a stirred solution of 4-methoxymethyl-5-methyl-6-piperidinopyrimidine 51i in 0 mj
8.9 m of boron tribromide in d was added dropwise. After another 2 hours, the mixture was poured onto ice, Na01-1 was added to raise the pH to 13, and extracted with chloroform. The extract was dried over potassium carbonate, stripped and triturated with diethyl ether to give a crystalline solid of 4-hydroquinemethyl-5-methyl-6-biperidinopyrimidine 3.80.
I got p. Melting point: 79-81°C.

(v) Thiochloride in chloroform 30IILt = /l
/4.5 d of chloroform cooled in an ice-salt bath 30
(7) 4-hydroxymethyl-5-methyl-6 in 11I
-Dropped into a stirred solution of 4.24 g of biperidinopyrimidine. The mixture was allowed to warm up to room temperature and stirred for a further 22 hours. The solution was stripped to a glassy residue and triturated with diethyl ether to give 4-chloromethyl-5-methyl-6-biperidinopyrimidine hydrochloride 5.24. I got p. Melting point: 182-184°C.

v, 1) 4-chloromethyl-5 in ethanol 180d
-Methyl-6-piperidinopyrimidine hydrochloride 4.631
A mixture of 3.181I and 2-mercapto-5-methoxybenzimidazole was heated at 50<0>C for 5 hours.

The solution was stripped to a glassy residue, water was added, NaOH was added to raise the pH to 13, and the solution was extracted with chloroform. The extract was dried over potassium carbonate, stripped to a glassy residue, and crystallized from ethyl acetate to give 5-methoxy-2-(5-methyl-6-piperidino-4
-pyrimidinylmethylthio)-(1H)-benzimidazole 5.6717 was obtained. Melting point 94-96°C.

Example 11 5-methoxy-2-(5-methyl-6-piperidino-4
Preparation of -pyrimidinylmethylsulfinyl)-(1H)-benzimidazole 2.16 m-chloroperbenzoic acid in 4Od methylene chloride
A solution of 5-methoxy-2-(5-methyl-6-
piberidi/-4-pyrimidinylmethylthio)-(11(
)-benzimidazole to a stirred solution of 4.0 g.

After an additional hour at −40° C., ammonia was passed through the reaction mixture and the precipitated solid was discarded. Strip F and triturate the glassy residue with acetonitrile to give 5-methoxy-2-(5-methyl-6-piperidino-4-pyrimidinylmethylsulfinyl)-(1H)-
Benzimidazole 2.66, p was obtained. Melting point 87-8
9℃.

Elemental analysis・As 019H23N5°25°0・5H2°・Calculated value (%): C, 58, 22, H, 5, 87, N
, 17.78BS, 8.43 Theoretical value (%l: C, 57,931H, 6,121J1
7.78;S, 8.14 Example 12 5-methoxy-2-(5-methyl-6-pyrrolidino-4
-pyrimidinylmethylthio)-(1H)-benzimidazole (1) Example 1o (In the method of u+1, using 12.20 mg of pyrrolidine instead of piperidine and using 1,4-dioxane instead of tetrahydrofuran as the solvent, Using other reagents in corresponding molar ratios, the oil was
Pyrimidine 5.52. I got p. The compound was used without further purification.

(11) In the method of Example 10aV), 5.4! i and other reagents in corresponding molar ratios, recrystallized from diethyl ether to give 4-
Hydroxymethyl-5-methyl-6-pyrrolidinopyrimidine 4.11. I got p.

Melting point 112-114°C.

) Example 10 (In the method of Vl, 3.90 g of 4-hydroxymethyl-5-methyl-6-virolidi/pyrimidine was used instead of 4-hydroxymethyl-5-methyl-6-piperidinopyrimidine, and other 4-chloromethyl-5-methyl-6-
Virolidinopyrimidine hydrochloride 4.88. I got p. Melting point 173-175°C.

6Vl Example 1o (4-chloromethyl-5-methyl-6-pyridinopyrimidine hydrochloride 4.80.p instead of 4-chloromethyl-5-methyl-6-piperidinopyrimidine in the method of vD) was recrystallized from acetonitrile using other reagents in corresponding molar ratios
Methoxy-2-(5-methyl-6-pyrrolidino-4-pyrimidinylmethylthio)-(1H)-benzimidazole 5.781i was obtained. Melting point 104-106°C.

Example 13 5-methoxy-2-(5-methyl-6-virolidino 4
-pyrimidinylmethylsulfinyl)-(1H)-benzimidazole In the method of Example 11, 5-methoxy-2-(5-
Using 5-methoxy-2-(5-methyl-6-pyrrolidino-4-pyrimidinylmethylthio)-(1H)-benzimidazole instead of methyl-6-piperidino-4-pyrimidinylmethylthio)-(1H)-benzimidazole, Recrystallization from acetonitrile using other reagents in corresponding molar ratios gave 5-methoxy-2-(5-methyl-6-pyrrolidino-4-pyrimidinylmethylsulfinyl)-(1H)-benzimidazole 3.331 . Melting point 144-146°C (decomposition).

Elemental analysis, Cl8H2□N50□S, actual measured value (%
l: C, 58,14; H, 5,70iN, 18.66
逼S, 8.57 Theoretical value (%l: C, 58,201H, 5,70iN,
8.85iS, 8.63 Example 14 5-methoxy-2-(5-methyl-6-morpholy/-4
Preparation of -pyrimidinylmethylthio)-(1H)-benzimidazole (Example 10) (In the method of n++, 12.9 m/m of morpholine was used instead of piperidine and 1,4-dioxane was used instead of tetrahydro7rane as the solvent. and other reagents in the corresponding molar ratios gave an oil of 4-methobodimethyl-5-methyl-6-morpholinopyrimidine 5.81.p. The compound was used without further purification.

(II) In the method of Example 10QV), 5.77 g of 4-methoxymethyl-5-methyl-6-morpholinopyrimidine was used instead of 4-methoxymethyl-5-methyl-6-piperidinopyrimidine, and other Recrystallization from petroleum ether (40/60) using the reagents in the corresponding molar ratio gave 4-hydroxymethyl-5-methyl-6-morpholinopyrimidine 3.461. Melting point 66-68℃
.

(Ii+1 In method 2 of Example 10(v), 4-hydroxymethyl-5-methyl-6 instead of 4-human a-F dimethyl-5-methyl-6-piperidinopyrimidine)
-morpholinopyrimidine 3.35. Recrystallization from diethyl ether using @ and other reagents in corresponding molar ratios gave 4-chloromethyl-5-methyl-6-morpholinopyrimidine hydrochloride 4.22,9. Melting point 188~
190°C (decomposition).

OVl Example 10 (8 in method V9, 4-chloromethyl-5-methyl-6-morpholinopyrimidine hydrochloride 4.1 instead of 4-chloromethyl-5-methyl-6-piperidinopyrimidine hydrochloride) ?, 9 and other reagents in corresponding molar ratios, recrystallized from ethyl acetate to obtain 5.
-methoxy-2-(5-methyl-6-morpholino-4-
4.51 g of pyrimidinylmethylthio)-(1H)-benzimidazole was obtained. Melting point: 129-131°C.

Example 15 5-methoxy-2-(5-methyl-6-morpholino-4
Preparation of 5-methoxy-2-(5-pyrimidinylmethylsulfinyl)-(1H)-benzimidazole according to the method of Example 11.
5-methoxy-2-(5-methyl-6-morpholino-4-pyrimidinylmethylthio)-(1H)-benzimidazole in place of methyl-6-piperi"cyno-4-pyrimidinylmethylthio)-(1H)-benzimidazole. 5-methoxy-2-(5-methyl-6-monomorpholy/-4-pyrimidinylmethylsulfinyl)-(1H)-benzimidazole 2. 671 was obtained, melting point 176-178°C (decomposition).

Elemental analysis, C engineering 8H2□N5Oa S, actual value (%l:c:, 55.74;) 1.5.40iN, 17
．． 96; S, 8.17 Theoretical value (%): C, 55,801H, 5,46iNt
18.08 iS, 8.28 Example 16 Preparation of 5-methoxy-2-(5-methyl-6-dimethylamino-4-pyrimidinylmethylthio)-(1H)-benzimidazole (1) Example 8 (1) 2, using 5.0y of 4-methoxymethyl-5-methyl-6-chloropyrimidine in place of 2-methoxymethyl-4-chloropyrimidine and using other reagents in the corresponding molar ratios, the oil 4.77 g of 4-methoxymethyl-5-methyl-6-dimethylaminopyrimidine was obtained. The compound was used without further purification.

(11) In the method of Example 10QV), 4.7 g of 4-methoxymethyl-5-methyl-6-dimethylaminopyrimidine was used instead of 4-methoxymethyl-5-methyl-6-piperidinopyrimidine. , and other reagents in corresponding molar ratios, recrystallized from petroleum ether (40/60) to give 4-hydroxymethyl-5-methyl-6-
Dimethylaminopyrimidine 3.52.9 was obtained. Melting point 4
6-48℃.

+nn Example 10 (In the method of Vl, using 4-hydroxymethyl-5-methyl-6-dimethylaminopyrimidine 3.35,9 instead of 4-hydroxymethyl-5-methyl-6-piperidinopyrimidine) , and other reagents in the corresponding molar ratios, and recrystallized from diethyl ether to obtain 4.30 g of 4-chloromethyl-5-methyl-6-cynotylaminopyrimidine hydrochloride. Melting point 176.
~178℃.

OV) In the method of Example 10, 4-chloromethyl-
4- instead of 5-methyl-6-piperidinopyrimidine
Chromatography (silica gel,
chloroform/methanol), 5.28 g of glassy 5-methoxy-2-(5-methyl-6-dimethylami/-4-pyrimidinylmethylthio)-(1)()-benzimidazole was obtained.

Example 17 5-methoxy-2-(5-methyl-6-dimethylamino-4-pyrimidinylmethylsulfinyl)-(1H)-
Production of benzimidazole In the method of Example 11,
5-methoxy-2-(5-methyl-6-piperidino-4
5-methoxy-2-(5-methyl-6-dimethylamino-4-pyrimidinylmethylthio) instead of -pyrimidinylmethylthio)-(11-1)-benzimidazole
-(11-1)-benzimidazole 3.86,9' and other reagents in corresponding molar ratios were recrystallized from acetonitrile and 5-methoxy-2-(5-methyl-6-dimethylamine 7 3.36 g of -4-pyrimidinylmethylsulfinyl)-(1H)-benzimidazole was obtained. Melting point: 141-143°C.

Elemental analysis・As 016H19N5°25・Actual measurement value (%
):C,55,439t(,5,64;N,20.14
iS, 9.25 Theoretical value (%): C, 55, 63;) (, 5, 54; N
, 20.27.

S, 9.28 Example 18 Preparation of 5-methoxy-2-(6-piveridino-4-pyrimidinylmethylthio)-(1H)-benzimidazole+i+Example 1o (in the method of 11, 2-methyl-
3-keto-4-methoxybutyric acid ethyl ester instead of 3-keto-4-methoxybutyric acid ethyl ester 35.75
．． Using F and other reagents in corresponding molar ratios, 4-methoxymethyl-
13.35y of 6-hydroxypyrimidine was obtained. Melting point 1
59-161°C.

(II) In the method of Example 4-methoxymethyl-6-chloropyrimidine 16.77, p was obtained. Melting point 34-36°C. The compound was used without further purification.

(Song Example 10 (In the method of Il+1, 4-methoxymethyl-6-chloropyrimidine 4.0
Using g and other reagents in corresponding molar ratios, the oil 4-methoxymethyl-6-piveridinopyrimidine 4.88,9 was obtained. The compound was used without further purification.

4-methoxymethyl-6-biperidinopyrimidine in place of 4-methoxymethyl-5-methyl-6-piperidinopyrimidine in the method of Example 10 (IV).
Recrystallization from diethyl ether using 70.9 and other reagents in corresponding molar ratios gave 4-hydroxymethyl-6-biperidinopyrimidine 3.67.9. Melting point 70-72°C.

(v) 4-hydroxymethyl-6-biperidinopyrimidine 3 in place of 4-hydroxymethyl-5-methyl-6-piperidinopyrimidine in the process of Example 10M.
．． Recrystallization from diethyl ether using 56.9 and other reagents in corresponding molar ratios gave 4-chloromethyl-6-piveridinopyrimidine hydrochloride 4.55.9. Melting point 187-189°C.

■ In the method of Example 10, 0, 4-chloromethyl-
4-chloromethyl-6-piperidi/pyrimidine hydrochloride instead of 5-methyl-6-piperidinopyrimidine hydrochloride 4.47. Glassy 5-methoxy-2-(
6-piperidino-4-pyrimidinylmethylthio)-(1
H)-benzimidazole 5.72. I got p.

Example 19 Preparation of 5-methoxy-2-(6-piperidino-4-pyrimidinylmethylsulfinyl)-(1H)-benzimidazole Following the method of Example 2, 5-methoxy-2-(5-methyl-6 -piberidino 4-pyrimidine; methylthio)
5-methoxy-2-(6-piperidino-4-pyrimidinylmethylthio)-(1H)-benzimidazole instead of -(1H)-benzimidazole 4.12. 5-methoxy-2-(6-piperidino-
4-Birimidinylmethylsulfinyl)-(1H)-benzimidazole 2.44. ! I got ir. Melting point 98~
101℃.

Elemental analysis, Cl8H2□N502S -0,33E t
As OAc・0.18 H2O, actual value (%): C, 57,44; H, s. 93 iN
, 17.29iS, 7.90 Theoretical value (%): C, 57,471H, 5,99iN,
17°36;S, 7.95 Example 20 Preparation of 5-methoxy-2-(6-pyrrolidino-4-pyrimidinylmethylthio)-(1)1)-benzimidazole (1) Example 18 (in the method of li+1, Using 10.4 m of pyrrolidine instead of piperidine and other reagents in corresponding molar ratios, an oily 4-methoxymethyl-6-pyrrolidinopyrimidine 4.65.9 was obtained.The compound was further purified. It was used without purification.

(11) In the method of Example 10QV), 4.60 g of 4-methoxymethyl-6-pyrrolidinopyrimidine was used instead of 4-methoxymethyl-5-methyl-6-piperidi/pyrimidine, and other reagents were used. Recrystallization from diethyl ether gave 3.84 g of 4-hydroxymethyl-6-virolidi/pyrimidine. Melting point 136-139°C.

(In the method of Example 10(v), 4-hydroxymethyl-6-pyrrolidinopyrimidine was used instead of 4-hydroxymethyl-5-methyl-6-piperidi/pyrimidine, and the other reagents were added in corresponding molar ratios. and recrystallized from diethyl ether to obtain 4.66 g of 4-chloromethyl-6-pyrrolidinopyrimidine hydrochloride. Melting point: 180.
~182°C (decomposed).

In the method of trvr example 10fVi), 4-chloromethyl-6-pyrrolidinopyrimidine hydrochloride is used instead of 4-chloromethyl-5-methyl-6-piperidi/pyrimidine hydrochloride, and other reagents are used according to the The molar ratio was used to obtain 6.41.9 of glassy 5-methoxy-2-(6-pyrrolidino-4-pyrimidinylmethylthio)-CIH)-benzimidazole.

Example 21 Preparation of 5-methoxy-2-(6-pyrrolidino-4-pyrimidinylmethylsulfinyl)-(1H)-benzimidazole Following the method of Example 11, 5-methoxy-2-(5-
5-methoxy-2-(6-pyrrolidino-4-pyrimidinylmethylthio)-(1H)-benzimidazole 460y was used instead of methyl-6-piperidino-4-pyrimidinylmethylthio)-(1H)-benzimidazole, and other Recrystallization from acetonitrile using reagents in corresponding molar ratios gave 5-methoxy2-(6-pyrrolidino-4-pyrimidinylmethylsulfinyl)-(1H)-
2.79 g of benzimidazole was obtained. Melting point 95-97
°C (decomposition).

Elemental analysis, CFH Eng. N502S・0.04CH2C
As 12・0.67H20, actual measured value (%l:c, 55.O1H, 5, 68, N, 18
．． 72°S, 8.54 Theoretical value (%l: C, 54,85; H, 5,52iN,
18.78iS, 8.59 Example 22 Production of 5-methoxy-2-(6-dimethylamino-4-pyrimidinylmethylthio)-(1H)-benzimidazole (1) In the method of Example 8 (1), 2 -4-methoxymethyl-6-chloropyrimidine instead of methoxymethyl-4-chloropyrimidine4. Using Oy and other reagents in corresponding molar ratios, 4-methoxymethyl-6-dimethylaminopyrimidine 4,1y was obtained as a low melting solid. Melting point 42-44°C.

The compound was used without further purification.

(11) In the method of Example 100VI, instead of 4-methoxymethyl-5-methyl-6-piperidi/pyrimidine 4-methoxymethyl-6-dimethylaminopyrimidine 4.06. 3.05 g of 4-hydroxymethyl-6-dimethylaminopyrimidine was recrystallized from diethyl ether using p and other reagents in corresponding molar ratios.
I got it. Melting point: 137-139°C.

(ul) Example 10fV) in which 4-hydroxymethyl-6-dimethylaminopyrimidine 2.95. 4-chloromethyl-6-dimethylami/pyrimidine hydrochloride by recrystallization from diethyl ether using p and other reagents in corresponding molar ratios.
97g was obtained. Melting point 225-226°C.

θ■ Example 10 (in the method of Vll, using 3.90.p of 4-chloromethyl-6-dimethylaminopyrimidine hydrochloride in place of 4-chloromethyl-5-methyl-6-piperidi/pyrimidine, Glassy 5-methoxy-2-(6-dimethylamino-4-pyrimidinylmethylthio)-(1H) was prepared using other reagents in corresponding molar ratios.
-Benzimidazole 5.80. Got @.

Example 23 Preparation of 5-methoxy-2-(6-dimethylamino-4-pyrimidinylmethylsulfinyl)-(1tL)-benzimidazole Following the method of Example 11, 5-methoxy-2-(5-
4.0 g of 5-methoxy-2-(6-dimethylamino-4-pyrimidinylmethylthio)-(1H)-benzimidazole was used instead of methyl-6-piperidino-4-pyrimidinylmethylthio)-(1H)-benzimidazole. , and other reagents in corresponding molar ratios and recrystallized from acetonitrile to give 5-methoxy-2-(6-dimethylamino-4-pyrimidinylmethylsulfinyl)-(
1H)-benzimidazole 3.06. I got p. Melting point 104-106°C.

Elemental analysis, C, 5H, N5025.0.230 (3CN
Measured value (%l:c, 54.45; H, 5,
33iN, 21.51iS, 9.23 Theoretical value (%): C, 54,48;t(, 5,24iN
, 21.50 iS, 9.41 Example 24 Ingredients INfl/Compound represented by tablet formula (I) 100 Mannite 153 Starch
33 Polyvinylpyrrolidone
12 Microcrystalline Cellulose 30 Magnesium Stearate 230 II9 Tablets for oral administration are prepared by combining the above ingredients into 9 MM tablets. If the active ingredient is a compound of formula (I) where n is 1, the tablets are then subjected to enteric coating.

Example 25 Ingredients %wZW formula (I)
Compound represented by: 8゜Microcrystalline cellulose 10Sodium carboxymethylcellulose 2Lactose
8. Pellet formulations for oral administration can be prepared by formulating the ingredients into pellets using standard methods.

If the active ingredient is a compound of formula (I) where n is 1, the pellets are first subjected to enteric coating before being filled into hard gelatin capsules.

Example 26.

Ingredients %w/w Example 1
Compounds of 1 to 5 polypropylene glycol 40 ethanol
10 Water for injection E P 100%w
A parenteral injection is prepared by blending the above-mentioned ingredients into /W.

Then, the solution was sterilized by an appropriate method, and 2d and 5
Fill in ml ampoules and vials.

Example 27 Ingredients %W/y Formula (I)
Salt of the compound represented by 1 to 5 mannitol
Sodium trichloride Sufficient amount of water to reconstitute an isotonic solution Adjusted to 100% w/w A reconstituted lyophilizate for parenteral administration is prepared from the above ingredients.

Sterilize the solution by an appropriate method, and add 15ml of 5me each.
Dispense into vials and lyophilize the solution. The lyophilizate can be reconstituted with a suitable carrier such as water, a buffer solution or a co-solvent mixture.

biological data Suppression of gastric acid secretion is demonstrated by the following test method.

A, ATPase activity induced by stimulation of the compound of formula (I) at a single concentration (l mM) of 1 (+-) on ATPase at pH 6,
1 and pH 7 and 4. Among the compounds represented by formula (I), preferred ones are tested at a certain concentration range,
I Cso values were measured at pH 6.1 and pH 7.4.

(1) Preparation of freeze-dried Kakkojo (+-ATP to H+-
Biochemistry and Bio° by Satsukomani et al.
Physics Actor (Saccomani et a
l.

Biochem, and Biophys, Act
a, ), 465, 311, (1977)
H'',-+ATPase was prepared from freeze-dried gastric sac of porcine gastric fundus mucosa according to the method of .

(IIK+ stimulation (due to ATPase activity).
Aase preparation 3 preparation g protein/d with lQmM
pH 6.1g and pH 7.4i in Pipes/Tris buffer solution
I made a lot of ink.

After 30 minutes at 37°C, the preincubation was diluted 5-fold with assay buffer to initiate the ATPase reaction. The assay conditions were Pipes/Tris 100mM 1MgC.
122mM, 1<CI 10mM, nigericin 5μg/d, Na2A'I''P2rnM,
The pH is 7.0. After 15 minutes of incubation at 37°C, the released non-IJ phosphate was removed and released by Yoda & Hokin (Biochem, Biophys).
, Res, Com, ), 40.880.197
0). Meta nigericin/-
The final concentration was 0.5%, but the enzyme activity was not affected.

The effect of the same concentration of the compound of formula (I) (preincubated with the H4-K+-ATPase preparation at pH 7.4 as before) to cause 100 nmol of inorganic phosphate regeneration was also determined.

The compound of formula (I) was first dissolved in dimethyl sulfoxide, polyethylene glycol (type 400) or Vives/Tris buffer. None of these seven solvents affected K-ATPase activity at the concentrations used.

(Results) The compound of Example 3 was found to inhibit potassium-stimulated H+ATPase at pH 6.1 and 7.4.

B, ## Aminopyrine (AP) accumulation in the wounded calyx gland.Equation of a single concentration (100 μm) on dibutyryl cAMP-stimulated AP metabolism in the intact blue line of rabbits (
The effect of the compound shown in I) was measured. Preferred compounds of formula (I) were tested over a range of concentrations and I Cso values were determined.

(1) Preparation of intact four wires Berghindh et al.
) (7yri・Physiology・Scandinavica (Ac
ta.

Physio, 5cand, ), 96, 150.19
Intact capsular glands were prepared from New Zealand white rabbits according to the method of 76). Gastric mucosal strips were treated with collagenase (100U1 type 1, Sigma) at 37°C for 45 minutes.
Digest for ~60 min, coarse filtration and sedimentation (glands were collected).

(B) Ap accumulation glands and test compounds incubated with 300 μM dibutyryl cAMP for 30 min at 37°C.

Incubation medium NaC4132, 5mM,
1<C15, 4mM, Na) (2PO41, OmM
, Na2t(PO45, OmM, Mg5041.2
mM%CaCl! 2 1.0mM, glucose 11,
1mM, rabbit albumin 2.0■/at, phenol red 10μg/a/.

(14C) 7mi/PiUy approx. 0.3 μM (11
It contained 0mC1/+nmole) and had a pH of 7.4.

After incubation, the glands were centrifuged and the supernatant was removed. The glands were dried, weighed and dissolved in NaOH. Then, Berglindhet et al.
al, ) (Acta, Physiol, 5cand, )
, 97.401.

The AP ratio was calculated using the radioactivity distribution between the lines and the lines according to the method of (1976).

The I Cs o value is the amount of compound required to inhibit histamine-stimulated aminovirine accumulation by 50%.

11 6.15 19 2.64 C, Rat: Before rumen perfusion (gastric acid secretion due to histamine stimulation) Ghosh and 5chi
ld) (British Journal of Pharmacy (Br, J, Pharmacology)
), 13, 54.

Either intraduodenal (i, d) or intravenous (i, ■) administration using a modification of the method described in (1958)
After doing this, the following EDbo values were obtained.

E Ds.

3 i, v, 1.4
9 i, a, 2.4
1a i, d, 2
．． 8 showed no obvious signs of toxicity in any of the above tests.

Special applicant Smith Klein & Frente Laboratories Ltd.

Claims (16)

[Claims] (1) Formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R^1 to R^4 are the same or different, and each represents hydrogen or alkyl having 1 to 6 carbon atoms. , halogen, trifluoromethyl, alkoxy having 1 to 6 carbon atoms, 1 carbon number
~6 alkanoyl or alkoxycarbonyl having 1 to 6 carbon atoms, RCF_2O, ethoxy group substituted with 3 to 5 fluorine atoms, or R^2 and R^3 taken together to form a group -O(CR_2)_mO- (In the formula, m is 1 or 2,
and each radical R means hydrogen or fluorine)
form; n is 0 or 1; R^5 and R^6 are
The same or different, hydrogen, alkyl having 1 to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms, respectively, or R^5 and R^6 together with the nitrogen atom to which they are bonded represent azetidino , pyrrolidino, piperidino,
Piperazino, N-alkyl (alkyl has 1 to 4 carbon atoms)
forming a piperazino or morpholino group; and
One of X and Y is a nitrogen atom, and the other is a group CR^7
(wherein R^7 means hydrogen, alkyl having 1 to 6 carbon atoms, or NH_2)] or a pharmaceutically acceptable salt thereof. (2) The compound according to item (1) above, wherein n is 1. (3) R^5 and R^6 together with the nitrogen atom to which they are bonded form a pyrrolidino, piperidino, piperazino, N-alkyl (alkyl having 1 to 4 carbon atoms) piperazino or morpholino group The compound of item (1) or item (2) above. (4) 5-methoxy-2-(4-piperidino-2-pyrimidinylmethylsulfinyl)-(1H)-benzimidazole, 5-methoxy-2-(4-morpholino-2-pyrimidinylmethylsulfinyl)-(1H)- Benzimidazole, 5-methoxy-2-(4-pyrrolidino-2-pyrimidinylmethylsulfinyl)-(1H)-benzimidazole, 5-methoxy-2-(4-dimethylamino-2-pyrimidinylmethylsulfinyl)-(1H) -benzimidazole, 5-methoxy-2-(4-piperidino-5-methyl-2
-pyrimidinylmethylsulfinyl)-(1H)-benzimidazole, 5-methoxy-2-(4-piperidino-5-amino-2
-pyrimidinylmethylsulfinyl)-(1H)-benzimidazole, 5-methoxy-2-(4-dimethylamino-5-methyl-2-pyrimidinylmethylsulfinyl)-(1H)-
Benzimidazole, 5-methoxy-2-(4-dimethylamino-5-amino-2-pyrimidinylmethylsulfinyl)-(1H)-
Benzimidazole, 5-methoxy-2-(5-methyl-6-piperidino-4
-pyrimidinylmethylsulfinyl)-(1H)-benzimidazole, 5-methoxy-2-(5-methyl-6-pyrrolidino-4
-pyrimidinylmethylsulfinyl)-(1H)-benzimidazole, 5-methoxy-2-(5-methyl-6-morpholino-4
-pyrimidinylmethylsulfinyl)-(1H)-benzimidazole, 5-methoxy-2-(5-methyl-6-dimethylamino-4-pyrimidinylmethylsulfinyl)-(1H)-
Benzimidazole, 5-methoxy-2-(6-piperidino-4-pyrimidinylmethylsulfinyl)-(1H)-benzimidazole, 5-methoxy-2-(6-pyrrolidino-4-pyrimidinylmethylsulfinyl)-(1H)- The compound according to any one of items (1) to (3) above, which is benzimidazole or 5-methoxy-2-(6-dimethylamino-4-pyrimidinylmethylsulfinyl)-(1H)-benzimidazole. (5) A pharmaceutical composition comprising the compound of item (1) above and a pharmaceutically acceptable carrier. (6) A pharmaceutical composition comprising the compound of item (2) above and a pharmaceutically acceptable carrier. (7) The pharmaceutical composition of item (6) above, which is in a dosage form suitable for oral administration. (8) The pharmaceutical composition according to item (7) above, which is provided with an enteric coating. (9) The pharmaceutical composition of item (5) above, which is in a dosage form suitable for intravenous administration. (10) Items (1) to (4) above used as therapeutic agents
A compound represented by formula (I) in any one of the terms. (11) Items (1) to (4) above used for the treatment of gastrointestinal diseases.
) A compound represented by formula (I). (12) (a) Formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) Compounds represented by formula (III): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) [In the formula , R^1 to R^6, X and Y have the same meanings as above,
One of L^1 and L^2 means SH, and the other means a leaving group that can be substituted with mercaptan.] (b) Formula (IV): [In the formula, R^1 ~R^4 has the same meaning as above] Compound and formula (V): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) [In the formula, R^5, R^6, X and Y has the same meaning as above,
X^1 is CO_2H or CSX^2 and X^2 means halogen or alkoxy having 1 to 4 carbon atoms]; (c) Formula (VI): ▲Mathematical formula, chemical formula, table etc.▼(VI) [In the formula, R^1 to R^4 have the same meanings as above, R^9 means hydrogen or a protective group, and M means an alkali metal atom]
Compound and formula (VII) shown by: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (VII) [In the formula, R^5, R^6, X and Y have the same meanings as above,
Z means a leaving group] React the compound represented by; (d) Formula (VIII): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(VIII) [In the formula, R^1 to R^4 has the same meaning as above, R^9 means hydrogen or a protecting group, and Y means a leaving group] Compounds represented by formula (IX): ▲Mathematical formulas, chemical formulas, tables, etc.▼(IX) [In the formula , R^5, R^6, X and Y have the same meanings as above, and M' means an alkali metal atom or an alkali metal atom equivalent], and then, if desired, (i ) oxidize the formed compound of formula (I) where n is 0 to a compound of formula (I) where n is 1; (ii) oxidize the formed compound of formula (I) where n is 1; reducing the compound represented by formula (I) to a compound represented by formula (I) where n is 0; (iii) removing any protecting group R^9; (iv) forming a pharmaceutically acceptable salt. A method for producing the compound according to item (1) above. (13) Formula (III) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) [In the formula, R^5 and R^6 are the same or different,
Respectively, hydrogen, alkyl having 1 to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms, or R^5 and R^6, together with the nitrogen atom to which they are bonded, represent azetidino, pyrrolidino, piperidino, piperazino, N-alkyl (alkyl having 1 to 4 carbon atoms) forms a piperazino or morpholino group; one of X and Y is a nitrogen atom and the other is a group CR^7 (wherein R^7 is hydrogen, carbon number 1 to 6 and L^2 means a leaving group which can be substituted with SH or mercaptan]. (14) Formula (V): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) [In the formula, R^5 and R^6 are the same or different,
Respectively, hydrogen, alkyl having 1 to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms, or R^5 and R^6, together with the nitrogen atom to which they are bonded, represent azetidino, pyrrolidino, piperidino, piperazino, N-alkyl (alkyl having 1 to 4 carbon atoms) forms a piperazino or morpholino group; one of X and Y is a nitrogen atom and the other is a group CR^7 (wherein R^7 is hydrogen, carbon number 1 to 6 means alkyl or NH_2;);X^1 is CO
_2H or CSX^2 and X^2 mean halogen or alkoxy having 1 to 4 carbon atoms] A compound represented by the following. (15) Formula (VII): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(VII) [In the formula, R^5 and R^6 are the same or different,
Respectively, hydrogen, alkyl having 1 to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms, or R^5 and R^6 together with the nitrogen atom to which they are bonded are azetidino, pyrrolidino, piperidino, Piperazino, N-alkyl (alkyl having 1 to 4 carbon atoms) forms a piperazino or morpholino group; one of X and Y is a nitrogen atom and the other is a group CR^7 (wherein R^7 is hydrogen, carbon number 1 ~
6 means an alkyl or NH_2) and Z means a leaving group]. (16) Formula (IX): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IX) [In the formula, R^5 and R^6 are the same or different,
Respectively, hydrogen, alkyl having 1 to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms, or R^5 and R^6 together with the nitrogen atom to which they are bonded are azetidino, pyrrolidino, piperidino, Piperazino, N-alkyl (alkyl having 1 to 4 carbon atoms) forms a piperazino or morpholino group; one of X and Y is a nitrogen atom and the other is a group CR^7 (wherein R^7 is hydrogen, carbon number 1 ~
6 alkyl or NH_2) and M' mean an alkali metal atom or an alkali metal atom equivalent].