JP3387066B2 - Anti-ulcer agent containing pyrrolopyridazine compound - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention has an excellent gastric acid secretion inhibitory action and gastric mucosa protective action and an excellent antibacterial action against Helicobacter pylori , and is a drug (particularly, a preventive or therapeutic agent for ulcer disease). The present invention relates to an optically active pyrrolopyridazine compound or a pharmacologically acceptable salt thereof, or a medicament containing them as an active ingredient (particularly, a preventive or therapeutic agent for ulcer disease).

[0002]

2. Description of the Related Art Peptic ulcer is said to occur when the balance between attacking factors and defense factors against the gastric mucosa is lost. Suppressing the secretion of gastric acid, which is an attacking factor, prevents and treats ulcers. Useful for. So far, as a drug effective in suppressing the secretion of gastric acid, anticholinergics,
Histamine H2 receptor antagonists such as cimetidine and proton pump inhibitors such as omeprazole are widely used clinically. However, although the above-mentioned drugs have an excellent therapeutic effect on ulcers, recurrence of ulcers after discontinuation of use is a serious problem. Recently, a relationship between ulcer recurrence and Helicobacter pylori has been pointed out, and treatment with a combination of a gastric acid secretion inhibitor and an antibiotic has been attempted.

Therefore, a compound that strongly suppresses gastric acid secretion, which is an attacking factor, has a gastric mucosal protective action, and has an antibacterial action against Helicobacter pylori , is an excellent prophylactic or therapeutic agent for ulcerative diseases. Expected as an agent

Several pyrrolopyridazine derivatives are known as compounds having a gastric acid secretion inhibitory action and a gastric mucosa protective action (for example, WO 91/17164, WO 92/06979, WO 93/08).
190 etc.), or Helicobacter pylori ( Helicobacte
A pyrrolopyridazine derivative having an antibacterial action against r pylori ) is also known (for example, JP-A-7-247).
No. 285).

[0005]

DISCLOSURE OF THE INVENTION The present inventors strongly suppress the gastric acid secretion which is an attacking factor, protect the gastric mucosa, and further, Helicobacter pylori
As a result of years of intensive research on the synthesis of pyrrolopyridazine derivatives and their pharmacological activity, aiming at the development of an anti-ulcer agent having an excellent antibacterial action against chlorophyll, it has a certain optically active trans-alkylcyclopropylmethyl group. The pyrrolopyridazine derivative has a strong gastric acid secretion inhibitory effect and gastric mucosal protection effect, as well as an excellent antibacterial effect against Helicobacter pylori , and further has superior properties as a drug as compared with the corresponding racemate. The present invention has been completed by finding out that

The present invention provides an optically active pyrrolopyridazine compound or a pharmacologically acceptable salt thereof, or a drug containing them as an active ingredient (particularly, a preventive or therapeutic agent for ulcer disease).

[0007]

The optically active pyrrolopyridazine compounds of the present invention have the general formula

[0008]

[Chemical 2]

[0009]

In the above formula, R ¹ represents a C ₁ -C ₆ alkyl group, R ² and R ³ are the same or different and represent a C ₁ -C ₆ alkyl group, and R ⁴ is C _1-. C ₆ alkyl, halogeno C ₁
-C ₆ alkyl, C ₁ -C ₆ alkoxy, halogeno C ₁ -C
₆ represents a C ₆ -C ₁₀ aryl group which may be substituted with a substituent selected from the group consisting of ₆ alkoxy and halogen,
A represents an imino group, an oxygen atom or a sulfur atom.

In the above general formula (I), R¹, R²as well as
R³C₁-C₆Alkyl group, R^FourC included in₁-C₆Al
Kill or R^FourHalogeno C included in₁-C₆Alkyl, C₁
-C ₆Alkoxy or halogeno C₁-C₆Alkoxy
C₁-C₆Alkyl moieties are, for example, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, s-bu
May be a tyl, t-butyl, pentyl or hexyl group,
Preferably C₁-C_FourAn alkyl group, and more preferably,
A methyl or ethyl group, most preferably a methyl group
is there.

The halogen atom contained in R ⁴ is, for example,
It may be a fluorine, chlorine, bromine or iodine atom, preferably a fluorine, chlorine or bromine atom, more preferably a fluorine or chlorine atom.

The C ₆ -C ₁₀ aryl group of R ⁴ can be, for example, a phenyl or naphthyl group, and is preferably a phenyl group.

The number of substituents of the substituted aryl group is, for example, 1 to 5, preferably 1 to 3, more preferably 1 to 2 and particularly preferably. Is
It is one.

C optionally substituted with a substituent selected from the group consisting of C ₁ -C ₆ alkyl, halogeno C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogeno C ₁ -C ₆ alkoxy and halogen. _{The 6-} C ₁₀ aryl group is preferably phenyl, methylphenyl, trifluoromethylphenyl,
Methoxyphenyl, trifluoromethoxyphenyl, difluoromethoxyphenyl, fluorophenyl, chlorophenyl, bromophenyl, difluorophenyl, chlorofluorophenyl, dichlorophenyl, trifluorophenyl, trichlorophenyl, naphthyl, methylnaphthyl, methoxynaphthyl, fluoronaphthyl, chloronaphthyl or A bromonaphthyl group, more preferably phenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-difluoromethoxyphenyl, 2
-, 3- or 4-fluorophenyl, 2-, 3- or 4-chlorophenyl, 4-bromophenyl, 2,
4- or 2,6-difluorophenyl, 4-chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl, 2,4- or 2,6-dichlorophenyl,
A 2,4,6-trifluorophenyl or 2,4,6-trichlorophenyl group, and even more preferably 4-fluorophenyl, 4-chlorophenyl, 2,4-difluorophenyl, 4-chloro-2- Fluorophenyl, 2
It is a -chloro-4-fluorophenyl or 2,4-dichlorophenyl group, and most preferably a 4-fluorophenyl or 4-chlorophenyl group.

A is preferably an oxygen or sulfur atom, and more preferably an oxygen atom.

The pharmacologically acceptable salt of the compound (I) of the present invention is an acid addition salt, for example, hydrofluoride salt, hydrochloride salt, hydrobromide salt, hydroiodide salt and the like. Hydrohalide; nitrate; perchlorate; sulfate; phosphate; carbonate; methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, pentafluoroethanesulfonate, propanesulfonate, 1 to 6 carbon atoms that may be substituted with a fluorine atom, such as butane sulfonate, pentane sulfonate, and hexane sulfonate
Alkyl sulfonates; benzene sulfonates, p
-Aryl sulfonates having 6 to 10 carbon atoms such as toluene sulfonate; acetate, propionate, butyrate, benzoate, fumarate, maleate, succinate, citrate, Carboxylates such as tartrate, oxalate, malonate; or amino acid salts such as glutamate, aspartate, preferably hydrochloride, sulfate or carboxylate, and Preferred is the hydrochloride salt. Further, the compound (I) of the present invention or a salt thereof is
It can exist as a hydrate and the present invention also includes those hydrates.

In the compound having the general formula (I), preferably, (1) a compound in which R ¹ is a C ₁ -C ₄ alkyl group, (2) a compound in which R ¹ is a methyl group, (3 ) R ² and R ³ are the same or different and are C ₁ -C ₄ alkyl groups, (4) R ² and R ³ are the same and are methyl groups, (5) R ⁴ is C ₁ -C ₄ alkyl, halogeno C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogeno C ₁
A compound which is a phenyl group substituted with 1 to 3 substituents selected from the group consisting of -C ₄ alkoxy, fluorine, chlorine and bromine; (6) R ⁴ is methyl, trifluoromethyl, methoxy, tri A compound which is a phenyl group substituted with 1 to 3 substituents selected from the group consisting of fluoromethoxy, difluoromethoxy, fluorine, chlorine and bromine, (7) R ⁴ is selected from the group consisting of fluorine and chlorine A compound which is a phenyl group in which 1 or 2 substituents selected from the group consisting of 2-, 4- and 6-positions are substituted with 1 or 2 substituents (8) R ⁴ is fluorine And a compound having 1 or 2 substituents selected from the group consisting of chlorine and a phenyl group substituted at the 4-position or 2,4-position, (9) A is an oxygen atom or a sulfur atom A compound,
(10) A compound in which A is an oxygen atom can be mentioned.

Further, the above (1)-(2), (3)-
In the groups of (4), (5)-(8) or (9)-(10), the more suitable the compound, the more preferable the compound is [the same applies to the following groups (11)-(14). . ], R ¹ from the group (1)-(2), R ² and R ³ from the group (3)-(4), R ⁴ from the group (5)-(8), and A from the group ( Compounds each obtained from 9) to (10) and obtained by arbitrarily combining these are also preferable,
For example, the following can be mentioned.

(11) R ¹ is a C ₁ -C ₄ alkyl group, R ² and R ³ are the same or different and are a C ₁ -C ₄ alkyl group, and R ⁴ is a C ₁ -C ₄ alkyl, halogeno C ₁ −
C ₄ alkyl, C ₁ -C ₄ alkoxy, halogeno C ₁ -C ₄
A compound which is a phenyl group substituted with 1 to 3 substituents selected from the group consisting of alkoxy, fluorine, chlorine and bromine, and A is an oxygen atom or a sulfur atom, (1
2) R ¹ is a methyl group, R ² and R ³ are the same,
A methyl group, wherein R ⁴ is selected from the group consisting of methyl, trifluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, fluorine, chlorine and bromine 1
A phenyl group substituted with 3 to 3 substituents,
Is an oxygen atom or a sulfur atom, (13) R ¹
Is a methyl group, R ² and R ³ are the same and are a methyl group, and R ⁴ is 1 or 2 substituents selected from the group consisting of fluorine and chlorine, And a compound in which 1 or 2 substituents selected from the group consisting of 6-position are substituted phenyl groups, and A is an oxygen atom, (14) R
¹ is a methyl group, R ² and R ³ are the same and are methyl groups, and R ⁴ is 1 or 2 substituents selected from the group consisting of fluorine and chlorine, and is at the 4-position or 2-position. A compound in which the 4-position is a phenyl group in which the substitution position is substituted, and A is an oxygen atom.

Specific examples of suitable compounds in formula (I) include the compounds shown in Table 1 below.

[0022]

[Chemical 3]

[0023]

Table 1 Table 1 Exemplified compounds Exemplified Compound No. A R ⁴ 1 O Ph 2 O 2-FPh 3 O 3-FPh 4 O 4-FPh 5 O 2,4-diFPh 6 O 2,6-diFPh 7 O 2,4,6-triFPh 8 O 2-ClPh 9 O 4-ClPh 10 O 2,4-diClPh 11 O 2,4,6-triClPh 12 O 4-MePh 13 O 4-CF ₃ Ph 14 O 4-OMePh 15 O 4-OCHF ₂ Ph 16 O 2-Cl-6-FPh 17 O 2-Cl-4-FPh 18 O 4-Cl-2-FPh 19 S Ph 20 S 2-FPh 21 S 4-FPh 22 S 2,4-diFPh 23 S 2, 4,6-triFPh 24 S 4-ClPh 25 S 2,4-diClPh 26 S 2,4,6-triClPh 27 S 4-CF ₃ Ph 28 S 2-Cl-4-FPh 29 S 4-Cl-2- FPh 30 NH Ph 31 NH 4-FPh 32 NH 2,4-diFPh 33 NH 2,4,6-triFPh 34 NH 4-ClPh 35 NH 2,4-diClPh 36 NH 4-CF ₃ Ph 37 NH 2-Cl- 4-FPh 38 NH 4-Cl-2-FPh 39 O 4-OCF ₃ Ph 40 O 3-ClPh 41 O 4-BrPh 42 O 2,6-diClPh 43 S 4-OCF ₃ Ph 44 S 4-OCHF ₂ Ph 45 S 3-FPh 46 S 2-ClPh 47 S 4-BrPh 48 S 2,6-diFPh 49 S 2,6-diClPh 50 NH 4-OCF ₃ Ph 51 NH 2-FPh 52 NH 2-ClPh 53 NH 2, 6-diFPh 54 NH 2,6-diClPh 55 NH 2,4,6-triClPh In the above table, the abbreviations represent the following groups. Me ... Methyl Ph ... Phenyl.

In Table 1 above, preferably, Exemplified Compound Nos. 1, 2, 4, 5, 7, 9, 10, 11, 13, 1
7, 18, 19, 21, 22, 23, 24, 25, 2
8, 29, 30, 31, 32, 34, 37 or 38 compounds, more preferably, Exemplified Compound Nos. 1, 4,
5, 7, 9, 10, 17, 18, 21, 22, 24, 2
5, 31, 32 or 34, even more preferably, the compound of Exemplified Compound Nos. 4, 5, 9, 10, 21, 22 or 24, and particularly preferably, the compound No. 4:
7- (4-Fluorobenzyloxy) -2,3-dimethyl-1-[(1S, 2S) -2-methylcyclopropylmethyl] pyrrolo [2,3-d] pyridazine, Compound No. 5: 7- (2 , 4-difluorobenzyloxy) -2,
3-Dimethyl-1-[(1S, 2S) -2-methylcyclopropylmethyl] pyrrolo [2,3-d] pyridazine or Compound No. 9: 7- (4-chlorobenzyloxy)-
It is a compound of 2,3-dimethyl-1-[(1S, 2S) -2-methylcyclopropylmethyl] pyrrolo [2,3-d] pyridazine.

[0025]

BEST MODE FOR CARRYING OUT THE INVENTION The pyrrolopyridazine derivative of the present invention can be easily produced by the method described below.

[0026]

[Chemical 4]

In the above formula, R¹, R², R³, R^FourAnd A is
R has the same meaning as above^FiveIs C₁-C ₆Archi
R group⁶Represents a hydrogen atom or a formyl group,
X is a halogen atom (preferably chloro, bromo or iodo).
Atom) or methanesulfonyloxy, ethanesulfo
Nyloxy, butanesulfonyloxy, benzenesulfo
Nyloxy, toluenesulfonyloxy, naphthalene
C such as a sulfonyl group₁-C₆Alkane or C
₆-C_TenArylsulfonyloxy group (preferably, meta
Sulfonyloxy, ethanesulfonyloxy, benze
Sulfonyloxy or p-toluenesulfonyloxy
Group), Y is a halogen atom (preferably chloro,
Bromo or iodo atom).

The first step is a step of producing a compound having the general formula (IV), which is carried out in the presence of a base in an inert solvent in the presence of a base and a compound having the general formula (III). When R ⁶ is a hydrogen atom,
This is accomplished by further formylating the resulting compound.

The base used in the reaction of compound (II) and compound (III) is, for example, an alkali metal hydride such as lithium hydride, sodium hydride, potassium hydride; lithium amide, sodium amide, potassium amide. Alkali metal amides such as; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate;
Alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, potassium t-butoxide; or triethylamine, tributylamine, diisopropylethylamine, N-ethylmorpholine, pyridine, picoline, 4- (N, N-dimethylamino). ) Pyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane ( DABCO), an organic amine such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), preferably an alkali metal hydride (especially sodium hydride) or an alkali metal alkoxide ( In particular, potassium t-butoxide).

The inert solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and for example, hexane, heptane, ligroin, and aliphatic hydrocarbons such as petroleum ether. Aromatic hydrocarbons such as benzene, toluene, xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane , Ethers such as diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone; formamide, dimethylformamide, dimethylacetamide, N Sulfoxides such as dimethyl sulfoxide; methyl-2-pyrrolidone, amides such as hexamethylphosphoric triamide sulfolane;
Alternatively, it may be a mixed solvent thereof, and preferably ethers (particularly tetrahydrofuran or dioxane).

The reaction temperature is usually 0 ° C. to 250 ° C. (preferably room temperature to 150 ° C.), and the time required for the reaction varies depending on the reaction temperature and the like, but 1 minute to 50 hours (preferably 10 minutes to 30 hours).

In order to effectively carry out this reaction, quaternary ammonium salts such as benzyltrimethylammonium chloride, tetrabutylammonium chloride and tetrabutylammonium bromide; or 18-crown-6, dibenzo-18- Crowns such as Crown-6 can also be added.

When R ⁶ is a hydrogen atom, the reaction to formylate the compound obtained by the reaction of compound (II) and compound (III) is carried out by reacting the corresponding compound in the presence or absence of an inert solvent. It is performed by reacting with Beers-Smeier reagent.

Beer Smeyer used (Vilsmeie
r) Reagents are known, for example, halogenating agents-dimethylformamides such as phosphorus oxychloride-dimethylformamide, phosphorus oxybromide-dimethylformamide, oxalyl chloride-dimethylformamide,
Preferred is phosphorus oxychloride-dimethylformamide.

The inert solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, Chloroform,
Halogenated hydrocarbons such as carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; or amides such as dimethylformamide Get, preferably,
Halogenated hydrocarbons (especially methylene chloride, chloroform or dichloroethane).

The reaction temperature is usually from -20 ° C to 150 ° C.
(Preferably 0 ° C. to 100 ° C.), and the time required for the reaction varies depending on the reaction temperature and the like, but is 15 minutes to 1
It is 2 hours (preferably 30 minutes to 5 hours).

The second step is a step of producing a compound having the general formula (V), which comprises reacting the compound (IV) in an inert solvent.
It is achieved by reacting with hydrazine or a hydrate thereof.

The inert solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and examples thereof include diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether. Ethers such as; alcohols such as methanol, ethanol, propanol and isopropanol; aromatic hydrocarbons such as benzene, toluene and xylene; carboxylic acids such as acetic acid and propionic acid; formamide, dimethylformamide, dimethylacetamide, N
-Methyl-2-pyrrolidone, amides such as hexamethylphosphorotriamide; amines such as triethylamine, pyridine; water; or a mixed solvent thereof, preferably alcohols (particularly ethanol) or Carboxylic acids (particularly acetic acid).

The reaction temperature is usually from -50 ° C to 150 ° C.
(Preferably −10 ° C. to 120 ° C.), and the time required for the reaction is 10 minutes to 12 hours (preferably 30 minutes to 5 hours), depending on the reaction temperature and the like.

The third step is a step for producing a compound having the general formula (VI), which is accomplished by reacting the compound (V) with a halogenating agent in the presence or absence of an inert solvent. .

The halogenating agent used can be, for example, phosphorus oxychloride, phosphorus oxybromide, thionyl chloride, thionyl bromide, oxalyl chloride, phosphorus pentachloride or phosphorus pentabromide, preferably oxy-. Phosphorus chloride or thionyl chloride, which can also be used in large excess also as a solvent.

The inert solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, Chloroform,
Halogenated hydrocarbons such as carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; dimethylformamide, dimethylacetamide, N-methyl- 2-
It may be an amide such as pyrrolidone; or a sulfoxide such as dimethylsulfoxide, preferably halogenated hydrocarbons, especially methylene chloride or dichloroethane.

The reaction temperature is usually 0 ° C. to 150 ° C. (preferably room temperature to 120 ° C.), and the time required for the reaction varies depending on the reaction temperature and the like, but it is 30 minutes to 12 hours (preferably 1 hour to 6 hours).

In order to effectively carry out this reaction, organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-ethylmorpholine, pyridine, picoline and 4- (N, N-dimethylamino) pyridine are used. Can also be added.

The fourth step is a step for producing the target compound (I), which is carried out in the presence of a base in an inert solvent in the presence of a base (V).
This is achieved by reacting I) with a compound having the general formula (VII), and this step is performed in the same manner as the above-mentioned first step.

In each step described above, the target compound of each reaction is collected from the reaction mixture according to a conventional method.
For example, when an insoluble matter is present, it is appropriately filtered off and the solvent is distilled off, or after the solvent is distilled off, water is added to the residue and the mixture is extracted with a suitable water-immiscible solvent. After drying over anhydrous magnesium sulfate or the like, the target compound can be separated by distilling off the solvent. If necessary, it can be purified by a conventional method, for example, recrystallization, column chromatography and the like.

In the first step, instead of the optically active starting compound (III) (1S, 2S-form), the corresponding racemic mixture (IIIa, 1S, 2S-form and 1R, 2R-form) is mixed. )

[0048]

[Chemical 5]

The corresponding racemic compound (compounds (I), (IV), (V)) obtained by carrying out a similar reaction using
Alternatively, a desired optically active compound (1S, 2S) can also be obtained by optically resolving a racemic compound corresponding to (VI).
-Body) can be manufactured. As a method of optical resolution, an ordinary method, for example, a column chromatography method using an optical resolution column, a preferential crystallization method, a method of resolution with a diastereomeric salt, or the like can be appropriately selected and performed.

Furthermore, the compound (I) can be prepared according to a conventional method.
It can be converted into a pharmacologically acceptable salt by treating with an acid. For example, in an inert solvent (preferably ethers such as diethyl ether, tetrahydrofuran, dioxane; alcohols such as methanol, ethanol, propanol; or halogenated hydrocarbons such as methylene chloride, chloroform), The desired salt can be obtained by reacting with the acid used for 5 minutes to 1 hour at room temperature and distilling off the solvent.

Starting compounds (II), (III) and (IIIa) are
A known method or a known method (for example, JP-A-7-2472).
No. 85, Monatschefte fur Chemi
e (1973), 104 , 925, J. Am. Chem. S
oc. , Perkin. Trans. II (197
9) Manufactured in accordance with 287).

The compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof has an excellent gastric acid secretion inhibitory action and gastric mucosal protective action and an excellent antibacterial action against Helicobacter pylori. In addition, since it has excellent properties as a drug, it is a drug for warm-blooded animals (especially humans), especially peptic ulcer, acute or chronic gastric ulcer, gastritis, reflux esophagitis, gastroesophageal reflex disease, digestion Agents for preventing or treating ulcerative diseases such as poor, gastric hyperacidity, and Solinger-Ellison syndrome (particularly therapeutic agents) or Helicobacter pylori ( Helicoba
cter pylori ) infectious disease preventive or therapeutic agent (especially,
It is useful as a therapeutic agent.

When the compound (I) of the present invention and a pharmacologically acceptable salt thereof are used as a medicine, especially as a prophylactic or therapeutic agent for the above-mentioned diseases, they can be used per se or an appropriate pharmacologically acceptable one. , Excipients, diluents, etc.,
Orally by tablets, capsules, granules, powders or syrups, or parenterally by injections (preferably,
Can be administered orally). These formulations
Excipients (eg lactose, sucrose, glucose, mannitol,
Sugar derivatives such as sorbit; corn starch,
Starch derivatives such as potato starch, α-starch, dextrin, carboxymethyl starch; cellulose derivatives such as crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally crosslinked carboxymethylcellulose sodium; Gum arabic; dextran; pullulan; light anhydrous silicic acid, synthetic aluminum silicates, silicate derivatives such as magnesium aluminometasilicate, phosphate derivatives such as calcium phosphate, carbonate derivatives such as calcium carbonate, calcium sulfate Sulfate derivatives, etc.), binders (for example, the aforementioned excipients; gelatin;
Polyvinylpyrrolidone; polyethylene glycol etc.),
Disintegrants (for example, the above-mentioned excipients; chemically modified starches such as croscarmellose sodium, carboxymethyl starch sodium, cellulose derivatives; cross-linked polyvinylpyrrolidone, etc.), lubricants (for example, talc;
Stearic acid; Metal stearates such as calcium stearate and magnesium stearate; Colloidal silica; Luxs such as bee gum and gallow; Boric acid;
Glycols; carboxylic acids such as fumaric acid and adipic acid; sodium carboxylic acid salts such as sodium benzoate; sulfuric acid salts such as sodium sulfate; leucine; lauryl sulfate salts such as sodium lauryl sulfate and magnesium lauryl sulfate; anhydrous Silicic acids, silicic acids such as hydrated silicic acid; starch derivatives in the above-mentioned excipients), stabilizers (for example, parahydroxybenzoic acid esters such as methylparaben, propylparaben; chlorobutanol, benzyl alcohol, phenylethyl) Alcohols such as alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal;
Additives such as acetic anhydride; sorbic acid, etc.), flavoring agents (eg, commonly used sweeteners, acidulants, flavors, etc.), diluents, injectable solvents (eg, water, ethanol, glycerin, etc.) Is manufactured by a known method. The amount used depends on symptoms, age, etc., but in the case of oral administration,
Lower limit 1 mg per day (preferably 5 mg), upper limit 1
000 mg (preferably 500 mg), in the case of intravenous administration, the daily lower limit of 0.1 mg (preferably 1 mg)
mg), the upper limit of 500 mg (preferably 300 mg) is preferably administered to an adult 1 to 6 times per day depending on the symptoms.

Next, the present invention will be described in more detail by showing Examples, Test Examples and Formulation Examples, but the present invention is not limited thereto.

[0055]

EXAMPLES Example 1 7- (4-Fluorobenzyloxy) -2,3-dimethyl-1
-[(1S, 2S) -2-Methylcyclopropylmethyl] pyrrolo [2,3-d] pyridazine (a) 3-formyl-4,5-dimethyl-1-[(1S, 2S)-
Methyl 2-methylcyclopropylmethyl] pyrrole-2-carboxylate Methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate 5.79 g (31.9 mmol) and 0.41 g of 18-crown-6
To a solution of (1.55 mmol) in tetrahydrofuran (130 ml) was added potassium t-butoxide (3.94 g, 35.1 mmol), and the mixture was stirred at room temperature for 1 hour. Then, at 50 ° C., (1S, 2
S) -2-Methylcyclopropylmethyl bromide 5.71 g (3
(8.3 mmol) was added dropwise over 30 minutes, and then 3 under reflux.
Heated for hours. After that, 0.36 g of potassium t-butoxide (3.
(22 mmol) and (1S, 2S) -2-methylcyclopropylmethyl bromide (0.48 g, 3.21 mmol) were added, and the mixture was further heated for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water and saturated brine successively, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (8.26 g, 100%) as a pale-brown oil.

Mass spectrum (CI, m / z): 250
(M ⁺⁺ 1).

NMR spectrum (CDCl ₃ , δppm): 0.25 (d
t; J = 8Hz, 5Hz, 1H), 0.48 (dt; J = 8Hz, 5Hz, 1H), 0.71-0.80 (m,
1H), 0.82-0.89 (m, 1H), 1.00 (d; J = 6Hz, 3H), 2.20 (s, 3H),
2.26 (s, 3H), 3.89 (s, 3H), 4.25 (d; J = 7Hz, 2H), 10.43 (s, 1
H).

Optical rotation: [α] _D ²⁰ = + 17.6 ° (C = 1.02, EtO
H).

(B) 2,3-Dimethyl-1-[(1S, 2S)
2-Methylcyclopropylmethyl] -6,7-dihydropyrrolo [2,3-d] pyridazin-7-one 3-formyl-4,5-dimethyl-1-[(1S, 2S) -2-
To a solution of 7.96 g (31.9 mmol) of methyl methylcyclopropylmethyl] pyrrole-2-carboxylate in acetic acid (38 ml) was added 1.92 g (38.4 mmol) of hydrazine monohydrate at room temperature,
The mixture was stirred at 90 ° C for 1 hour. After completion of the reaction, the reaction solution was cooled to room temperature and poured into ice water. The crude crystals produced are collected by filtration,
After washing with water, it was dissolved in a chloroform / methanol (= 9/1) solution. The organic layer was separated, washed with saturated saline,
The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Toluene / hexane was added to the concentrated liquid, and the precipitated crystals were collected by filtration,
7.02 g (95.0%) of the title compound was obtained as pale yellowish white powder crystals.

Mass spectrum (CI, m / z): 232
(M ⁺⁺ 1).

NMR spectrum (CDCl ₃ , δppm): 0.22 (d
t; J = 8Hz, 5Hz, 1H), 0.64 (dt, J = 8Hz, 5Hz, 1H), 0.86-0.95
(m, 2H), 0.98 (d; J = 5Hz, 3H), 2.21 (s, 3H), 2.35 (s, 3H), 4.44
(d; J = 7Hz, 2H), 8.05 (s, 1H), 9.97 (s, 1H).

Optical rotation: [α] _D ²⁰ = + 11.2 ° (C = 0.50, EtO
H).

(C) 7-chloro-2,3-dimethyl-1-
[(1S, 2S) -2-Methylcyclopropylmethyl] pyrrolo [2,3-d] pyridazine 2,3-dimethyl-1-[(1S, 2S) -2-methylcyclopropylmethyl] -6,7- 55 ml (590 mmol) of phosphorus oxychloride was added to 6.95 g (30.1 mmol) of dihydropyrrolo [2,3-d] pyridazin-7-one, and the mixture was heated and stirred at 90 ° C. for 3.5 hours. After completion of the reaction, the reaction solution was cooled to room temperature and added dropwise to ice water. This aqueous solution was neutralized with a 5N aqueous sodium hydroxide solution and extracted with methylene chloride. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Hexane was added to the concentrate, and the precipitated crystals were collected by filtration to give the title compound (6.90 g, 92.0%) as pale-yellow powder crystals.

Mass spectrum (CI, m / z): 250
(M ⁺⁺ 1).

NMR spectrum (CDCl ₃ , δppm): 0.29 (d
t; J = 8Hz, 5Hz, 1H), 0.54 (dt; J = 8Hz, 5Hz, 1H), 0.73-1.02 (m,
5H), 2.30 (s, 3H), 2.43 (s, 3H), 4.44 (d; J = 6Hz, 2H), 9.15 (s,
1H).

Optical rotation: [α] _D ²⁰ = + 12.3 ° (C = 1.01, EtO
H).

(D) 7- (4-fluorobenzyloxy)
-2,3-Dimethyl-1-[(1S, 2S) -2-methylcyclopropylmethyl] pyrrolo [2,3-d] pyridazine Sodium hydride (0.26 g, 10.8 mmol) in tetrahydrofuran (6 ml) was added with p- Fluorobenzyl alcohol 1.45 g
A solution of (11.5 mmol) in tetrahydrofuran (2 ml) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. Then 7-chloro-2,
A solution of 2.50 g (10.0 mmol) of 3-dimethyl-1-[(1S, 2S) -2-methylcyclopropylmethyl] pyrrolo [2,3-d] pyridazine in tetrahydrofuran (13 ml) was added dropwise at room temperature, and the mixture was refluxed. Heated for 3 hours. After completion of the reaction, the reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, hexane was added to the obtained concentrated liquid, and the precipitated crystals were collected by filtration to give crude crystals. The crude crystals were recrystallized from ethyl acetate / hexane to give the title compound (2.25 g, 66.4%) as pale brown crystals.

Melting point: 114-115 ° C.

Mass spectrum (CI, m / z): 340
(M ⁺⁺ 1).

NMR spectrum (CDCl ₃ , δppm): 0.14 (d
t; J = 8Hz, 5Hz, 1H), 0.39 (dt; J = 8Hz, 5Hz, 1H), 0.59-0.65 (m,
1H), 0.76-0.85 (m, 1H), 0.89 (d; J = 6Hz, 3H), 2.26 (s, 3H), 2.
36 (s, 3H), 4.13 (dd; J = 15Hz, 7Hz, 1H), 4.27 (dd; J = 15Hz, 6H
z, 1H), 5.63 (d; J = 12Hz, 1H), 5.68 (d; J = 12Hz, 1H), 7.05-7.1
2 (m, 2H), 7.47-7.52 (m, 2H), 8.96 (s, 1H).

Optical rotation: [α] _D ²⁰ = + 17.9 (C = 0.50, EtO
H). Example 2 3-formyl-4,5-dimethyl-1-[(1S, 2S) -2-
Methyl Cyclopropylmethyl] pyrrole-2-carboxylate Methyl (a) 4,5-dimethyl-1-[(E) -2-methylcyclopropylmethyl] pyrrole-2-carboxylate Methyl 4,5-dimethylpyrrole-2 -Methyl carboxylate 25.02g
18.33 g (164 mmol) of potassium t-butoxide was added to a solution of (163 mmol) and 3.19 g (12.1 mmol) of 18-crown-6 in tetrahydrofuran (150 ml), and the mixture was stirred at room temperature for 1 hour. Next, 12.70 g (85.2 mmol) of (E) -2-methylcyclopropylmethyl bromide (racemate) was added, and the mixture was heated under reflux for 7 hours. After completion of the reaction, the reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate.
After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography (solvent: toluene) to give the title compound (racemic compound) 1
Obtained 3.50 g (71.6%) as a brown oil.

Mass spectrum (CI, m / z): 222 (M
⁺ +1).

NMR spectrum (CDCl ₃ , δppm): 0.20 (d
t; J = 8Hz, 5Hz, 1H), 0.48 (dt; J = 8Hz, 5Hz, 1H), 0.67-0.93 (m,
2H), 0.98 (d; J = 6Hz, 3H), 2.01 (s, 3H), 2.18 (s, 3H), 3.76 (s,
3H), 4.21 (d; J = 7Hz, 2H), 6.76 (s, 1H).

(B) 4,5-Dimethyl-1-[(1S, 2
S) -2-Methylcyclopropylmethyl] pyrrole-2-carboxylate methyl (E) -4,5-dimethyl-1- (2-methylcyclopropylmethyl) pyrrole-2-carboxylate methyl 10.00 g under the following conditions The product was subjected to high performance liquid chromatography to give 3.33 g of the title compound [(S, S) form] and its antipode [(R, R) form] 3.97 g, respectively.

Separation Conditions Column: CHIRALCEL OJ (50Φ * 500 mm, manufactured by Daicel Chemical) Solvent: hexane / 2-propanol (1000/1) Flow rate: 25 ml / min Title compound [(S, S) body] Mass spectrum (CI, m / z): 222 (M ⁺⁺ 1).

NMR spectrum (CDCl ₃ , δppm): 0.20 (d
t; J = 8Hz, 5Hz, 1H), 0.48 (dt; J = 8Hz, 5Hz, 1H), 0.66-0.80 (m,
1H), 0.82-0.91 (m, 1H), 0.98 (d; J = 6Hz, 3H), 2.01 (s, 3H), 2.
18 (s, 3H), 3.76 (s, 3H), 4.21 (d; J = 7Hz, 2H), 6.76 (s, 1H).

Optical rotation: [α] _D ²⁰ = + 17.6 ° (C = 1.00, EtO
H). Enantiomer [(R, R) body] Mass spectrum (CI, m / z): 222 (M ⁺ +1).

NMR spectrum (CDCl ₃ , δppm): 0.20 (d
t; J = 8Hz, 5Hz, 1H), 0.48 (dt; J = 8Hz, 5Hz, 1H), 0.66-0.80 (m,
1H), 0.82-0.91 (m, 1H), 0.98 (d; J = 6Hz, 3H), 2.01 (s, 3H),
2.18 (s, 3H), 3.77 (s, 3H), 4.21 (d; J = 7Hz, 2H), 6.76 (s, 1
H).

Optical rotation: [α] _D ²⁰ = -17.0 ° (C = 1.01, EtO
H).

(C) 3-formyl-4,5-dimethyl-1-
[(1S, 2S) -2-Methylcyclopropylmethyl] pyrrole-2-carboxylic acid methyl dimethylformamide 1.10 g (15.0 mmol) in toluene (2 ml) solution was added 2.15 g (14.0 mmol) phosphorus oxychloride. The mixture was stirred at room temperature for 30 minutes. Then 4, 5
Methyl 2-dimethyl-1-[(1S, 2S) -2-methylcyclopropylmethyl] pyrrole-2-carboxylate 2.21 g (10.0
Toluene (6 ml) solution was added and heated at 80 ° C. for 10 hours. After the reaction was completed, the reaction solution was poured into water,
After neutralizing with a saturated aqueous solution of sodium hydrogen carbonate, the layers are separated,
The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (solvent: ethyl acetate / hexane = 10/1) to obtain 1.95 g (78.2%) of the title compound as a pale yellow oily substance. Example 3 7- (4-Fluorobenzyloxy) -2,3-dimethyl-1
-[(1S, 2S) -2-Methylcyclopropylmethyl] pyrrolo [2,3-d] pyridazine (a) 7- (4-fluorobenzyloxy) -1-[(E)
-2-Methylcyclopropylmethyl] -2,3-dimethylpyrrolo [2,3-d] pyridazine (racemic) (1S, 2S)-
The reaction was performed in the same manner as in Example 1 except that (E) -2-methylcyclopropylmethyl bromide (racemate) was used instead of 2-methylcyclopropylmethyl bromide, and the title compound was obtained in a yield of 56%. .

Melting point: 120-122 ° C.

Mass spectrum (CI, m / z): 340
(M ⁺⁺ 1).

NMR spectrum (CDCl ₃ , δppm): 0.14 (d
t; J = 8Hz, 5Hz, 1H), 0.39 (dt; J = 8Hz, 5Hz, 1H), 0.59-0.65 (m,
1H), 0.76-0.85 (m, 1H), 0.89 (d; J = 6Hz, 3H), 2.26 (s, 3H), 2.
36 (s, 3H), 4.13 (dd; J = 15Hz, 7Hz, 1H), 4.27 (dd; J = 15Hz, 6H
z, 1H), 5.63 (d; J = 12Hz, 1H), 5.68 (d; J = 12Hz, 1H), 7.05-7.1
2 (m, 2H), 7.47-7.52 (m, 2H), 8.96 (s, 1H).

(B) 7- (4-fluorobenzyloxy)
-2,3-Dimethyl-1-[(1S, 2S) -2-methylcyclopropylmethyl] pyrrolo [2,3-d] pyridazine 7- (4-fluorobenzyloxy) -1-[(E) -2 -Methylcyclopropylmethyl] -2,3-dimethylpyrrolo
25.00 g of [2,3-d] pyridazine (racemic form) was subjected to high performance liquid chromatography under the following conditions and recrystallized from ethyl acetate to give 8.54 g of the title compound [(S, S) form] and its pair. 7.60 g of a palm body [(R, R) body] was obtained.

Separation conditions Column: CHIRALCEL OJ (50Φ * 500mm, made by Daicel) Solvent: Hexane / Ethanol (90/10) Flow rate: 25 ml / min Title compound [(S, S) form] Melting point: 114-115 [deg.] C.

Mass spectrum (CI, m / z): 340
(M ⁺⁺ 1).

NMR spectrum (CDCl ₃ , δppm): 0.14 (d
t; J = 8Hz, 5Hz, 1H), 0.39 (dt; J = 8Hz, 5Hz, 1H), 0.59-0.65 (m,
1H), 0.76-0.85 (m, 1H), 0.89 (d; J = 6Hz, 3H), 2.26 (s, 3H), 2.
36 (s, 3H), 4.13 (dd; J = 15Hz, 7Hz, 1H), 4.27 (dd; J = 15Hz, 6H
z, 1H), 5.63 (d; J = 12Hz, 1H), 5.68 (d; J = 12.2Hz, 1H), 7.05-
7.12 (m, 2H), 7.47-7.52 (m, 2H), 8.96 (s, 1H).

Optical rotation: [α] _D ²⁰ = + 19.0 ° (C = 0.99, MeO
H). Enantiomer [(R, R) body] Melting point: 114-115 ° C.

Mass spectrum (CI, m / z): 340
(M ⁺⁺ 1).

NMR spectrum (CDCl ₃ , δppm): 0.15 (d
t; J = 8Hz, 5Hz, 1H), 0.39 (dt; J = 8Hz, 5Hz, 1H), 0.58-0.66 (m,
1H), 0.78-0.85 (m, 1H), 0.89 (d; J = 6Hz, 3H), 2.26 (s, 3H), 2.
37 (s, 3H), 4.13 (dd; J = 15Hz, 7Hz, 1H), 4.27 (dd; J = 15Hz, 6H
z, 1H), 5.63 (d; J = 12Hz, 1H), 5.68 (d; J = 12Hz, 1H), 7.06-7.1
1 (m, 2H), 7.49-7.52 (m, 2H), 8.97 (s, 1H).

Optical rotation: [α] _D ²⁰ = -18.8 ° (C = 0.98, MeO
H). Test Example 1 Proton / potassium-adenosine triphosphatase (H ⁺ · K ⁺ -ATPase) activity test Method of Sachs et al. [J. Bio. ， Che
m. , 251 , 7690 (1976)], and a microsomal fraction prepared by homogenizing the gastric mucosal layer of fresh pig and performing density gradient ultra high-speed centrifugation was used as a proton / potassium-adenosine triphosphatase preparation. Converted to protein concentration, 70 mM Tris-HCl buffer containing 30-80 μg / ml enzyme preparation (magnesium chloride 5 mM, potassium chloride 20 mM, pH = 6.85)
To 0.75 ml, 10 μl of a test compound solution dissolved in dimethyl sulfoxide was added, and the mixture was shaken at 37 ° C. for 200 times.
Incubated for 45 minutes at times / minute. 8 mM adenosine triphosphate disodium salt solution 0.25
The enzymatic reaction was started by adding ml. Enzyme reaction for 20 minutes, 10% trichloroacetic acid-activated carbon (10
The reaction was stopped by adding 1 ml of a 0 mg solution. After centrifuging the reaction solution (4 ° C., 3000 rpm, 15 minutes), the inorganic phosphoric acid produced by hydrolysis of adenosine triphosphate in the supernatant was analyzed by the method of Yoda et al. [Biochem. Biophys. Res. Comm
un. , 40 , 880 (1970)].
Further, the amount of inorganic phosphoric acid in the reaction solution in the absence of potassium chloride was also measured in the same manner, and the proton / potassium-adenosine triphosphatase activity was measured by subtracting it from the amount of inorganic phosphoric acid in the presence of potassium chloride. The inhibition rate (%) was determined from the control activity value and the activity value at each concentration of the test compound, and the 50% inhibitory concentration (IC ₅₀ μg) for proton / potassium-adenosine triphosphatase was determined.
/ Ml) was determined. As a result, the compound of Example 1
It showed excellent activity with C ₅₀ <0.1 μg / ml. Antibacterial activity Antibacterial Evaluation of Test Example 2 Helicobacter pylori, Helicobacter pylori (Helicobacter
pylori ) 9470, 9472 and 9474 strains,
MIC of the compound of the present invention against Helicobacter pylori
(Minimum Inhibitory Concentration).

4 Helicobacter pylori on plate
Cultured for a day. Brain heart infusion agar (manufactured by Difco) was dissolved in a specified amount of distilled water in the medium,
After sterilization by an autoclave, horse blood (manufactured by Nippon Biological Materials Co., Ltd.) was dispensed to 7% and solidified.

Helicobacter pylori, which had been cultured at 37 ° C. for 4 days under microaerobic conditions, had a bacterial load of about 10 ⁸ in physiological saline.
Suspension was performed so as to have CFU / ml. The suspension was diluted 100-fold, and about 10 μl thereof was inoculated on the medium for measuring MIC. As the medium for MIC measurement, the medium having the same composition as the medium for preculture was used. The compound of the present invention was dissolved in dimethylsulfoxide (DMSO), and a 2-fold dilution series solution with sterile distilled water was mixed with the medium at a ratio of 1:99, and the mixture was solidified on a petri dish to give a medium for MIC measurement. Helicobacter pylori was incubated at 37 ° C under microaerobic conditions in the same manner as in the preculture.
Were cultured for 3 days. After the completion of the culture, the growth of the bacteria in the inoculated portion was visually observed, and the minimum concentration of the compound of the present invention in which no growth of the bacteria was observed was defined as MIC (μg / ml). As a result, the compound of Example 1 had a MIC <12.5 μg /
ml) showed excellent antibacterial activity. Test Example 3 Gastric Acid Secretion Inhibitory Action A group of 3 to 5 rats was fasted overnight, and under ether anesthesia, a midline abdominal incision was made and the pylorus was ligated. The stomach and duodenum were returned to their original positions in the body, and the abdominal incision was closed. A certain amount of test compound was suspended in an aqueous solution of 0.5% carboxymethyl cellulose sodium salt and 0.4% Tween 80 (polysorbate 80), and the suspension was orally administered to rats. As a control, 0.5% carboxymethylcellulose sodium salt and 0.4% Tween 80 (polysorbate 80) aqueous solution (suspension solvent) were orally administered to rats. Four hours after the administration of the test compound or the suspension solvent, carbon dioxide gas was inhaled by the rat, the rat was euthanized, the abdomen was incised, and the stomach was excised. The stomach contents were collected in a glass graduated centrifuge tube and then centrifuged to measure the volume of supernatant (ml) and the volume of sediment (ml). Those with a volume of sediment of 0.5 ml or more were excluded from the data as feces. Take 100 μl of the supernatant in a test tube and add 4 m of distilled water.
1, 0.01 N sodium hydroxide and pH = 7.
Titrated to 0. As a standard acid concentration solution, 100 μl of 0.1 N hydrochloric acid to which 4 ml of distilled water was added was titrated simultaneously. Gastric acid concentration (mEq / l), gastric acid excretion (AO, μ
Eq / hr) and the inhibition rate (%) were calculated according to the following formulas.

Gastric acid concentration (mEq / l) = A / B X
100 A: amount of sodium hydroxide required for titration of 100 μl of supernatant (ml) B: amount of sodium hydroxide required for titration of 100 μl of 0.1 N hydrochloric acid (ml) gastric acid excretion (AO, μEq / hr) = gastric juice Amount of supernatant (m
l) X gastric acid concentration (mEq / l) / 4 inhibition rate (%) = (C−D) / C X 100 C: AO (μEq / hr) of suspension solvent administration group D: AO of test compound administration group (ΜEq / hr) Each dose (0.3 mg / kg, 1 mg / kg, 3 mg /
50% inhibitory dose (ID ₅₀ mg / kg) was determined from the dose-inhibition rate line obtained by subtracting the inhibitory rates at 10 mg / kg and 10 mg / kg) by the least squares method for the logarithmic dose, and is shown in Table 2 below.

[0095]

[Table 2] Table 2 Gastric acid secretion inhibitory effect Test compound 50% gastric acid secretion inhibitory dose (ID ₅₀ mg / kg) Compound of Example 1 0.52 Compound A 1.64 Compound A: 1: 1 mixture of the compound of Example 1 and its enantiomer (racemate: Example 5 of JP-A-7-247285
Compound of 7) From the results of Table 2, it was found that the compound of Example 1 exhibited about 3 times stronger effect than the racemic body with respect to the gastric acid secretion inhibitory action.

Formulation Example 1 Tablets Compound of Example 1 30.0 mg Lactose 144.0 Corn starch 25.0 Magnesium stearate 1.0 200.0 mg The powders of the above formulation were mixed and tableted with a tableting machine. One tablet is 200 mg. This tablet can be sugar-coated or coated as required.

[0097]

INDUSTRIAL APPLICABILITY The compound having the general formula (I) or a pharmacologically acceptable salt thereof of the present invention has an excellent gastric acid secretion inhibitory action and gastric mucosa protective action, and an excellent antibacterial action against Helicobacter pylori. In addition, since it has excellent properties as a medicine, it is a medicine for warm-blooded animals (especially humans), particularly peptic ulcer, acute or chronic gastric ulcer, gastritis, reflux esophagitis, gastroesophageal reflex disease. , dyspepsia, gastric hyperacidity, prophylactic or therapeutic agent for ulcerative diseases such as Zollinger-Ellison syndrome (especially, therapeutic agents) or Helicobacter pylori (Helicobact
er pylori ) is useful as a preventive or therapeutic agent (in particular, a therapeutic agent) for infectious diseases.

─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Keiji Matsunobu 5 1978, Koujigushi, Ube City, Yamaguchi Prefecture 5 1978, Ube Institute of Industrial Science, Ube Research Institute (72) Hiroshi Fujiwara 5 1978, Kogushi, Ube, Yamaguchi Prefecture Part Kosan Co., Ltd. Ube Laboratory (72) Inventor Keiichi Ito 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (58) Fields investigated (Int.Cl. ⁷ , DB name) A61K 31/5025 C07D 487/04 140 CA (STN) REGISTRY (STN)

Claims (12)

(57) [Claims] 1. A general formula: [In the formula, R ¹ represents a C ₁ -C ₆ alkyl group, and R ² and R 6
³ are the same or different and each represents a C ₁ -C ₆ alkyl group,
R ⁴ may be substituted with a substituent selected from the group consisting of C ₁ -C ₆ alkyl, halogeno C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogeno C ₁ -C ₆ alkoxy and halogen. shows the C ₆ -C ₁₀ aryl group, a is shows an imino group, an oxygen atom or a sulfur atom. ] The anti-ulcer agent containing the optically active pyrrolo pyridazine compound or its pharmacologically acceptable salt which has these as an active ingredient. 2. An anti-ulcer agent containing an optically active pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof as an active ingredient according to claim ₁ , wherein R ¹ is a C ₁ -C ₄ alkyl group. 3. An anti-ulcer agent containing an optically active pyrrolopyridazine compound or a pharmacologically acceptable salt thereof as an active ingredient according to claim 1, wherein R ¹ is a methyl group. 4. R ² and R ³ are the same or different and are C _1-.
An anti-ulcer agent containing a C ₄ alkyl group as an active ingredient, which is an optically active pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1. 5. An anti-ulcer agent containing the optically active pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof as an active ingredient according to claim 1, wherein R ² and R ³ are the same and are methyl groups. . 6. R ⁴ is C ₁ -C ₄ alkyl, halogeno C _1-
C ₄ alkyl, C ₁ -C ₄ alkoxy, halogeno C ₁ -C ₄
6. The optically active pyrrolopyridazine compound or a pharmacologically acceptable thereof according to claim 1, which is a phenyl group substituted with 1 to 3 substituents selected from the group consisting of alkoxy, fluorine, chlorine and bromine. An anti-ulcer agent containing salt as an active ingredient. 7. R ⁴ is methyl, trifluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy,
1 to 3 selected from the group consisting of fluorine, chlorine and bromine
6. An anti-ulcer agent containing as an active ingredient an optically active pyrrolopyridazine compound or a pharmacologically acceptable salt thereof according to claim 1, which is a phenyl group substituted with one substituent. 8. R ⁴ is one or two substituents selected from the group consisting of fluorine and chlorine, 2-position, 1-substituted-position of 2 is selected from the group consisting of 4- and 6-position An anti-ulcer agent containing as an active ingredient the optically active pyrrolopyridazine compound or a pharmacologically acceptable salt thereof according to claim 1, which is a substituted phenyl group. 9. A phenyl group in which R ⁴ is substituted with 1 or 2 substituents selected from the group consisting of fluorine and chlorine at the 4-position or 2,4-position. 7. An anti-ulcer agent containing the optically active pyrrolopyridazine compound or the pharmaceutically acceptable salt thereof according to any one of to 5 as an active ingredient. 10. An anti-ulcer agent containing an optically active pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof as an active ingredient according to any one of claims 1 to 9, wherein A is an oxygen atom or a sulfur atom. 11. An anti-ulcer agent containing an optically active pyrrolopyridazine compound or a pharmaceutically acceptable salt thereof as an active ingredient according to claim 1, wherein A is an oxygen atom. 12. 7- (4-Fluorobenzyloxy)-
2,3-Dimethyl-1-[(1S, 2S) -2-methylcyclopropylmethyl] pyrrolo [2,3-d] pyridazine, 7- (2,4-difluorobenzyloxy) -2,3-
Dimethyl-1-[(1S, 2S) -2-methylcyclopropylmethyl] pyrrolo [2,3-d] pyridazine and 7
-(4-chlorobenzyloxy) -2,3-dimethyl-
An optically active pyrrolopyridazine compound selected from the group consisting of 1-[(1S, 2S) -2-methylcyclopropylmethyl] pyrrolo [2,3-d] pyridazine or a pharmaceutically acceptable salt thereof as an active ingredient Anti-ulcer agent contained.