JP2941702B2 - Pharmaceutical composition comprising a lactam derivative that antagonizes the action of 5-HT at the 5-HT3 receptor - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION Field of the Invention The present invention is, lactam derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their medical use.

[0002] In particular, the present invention relates to effective and is a selective antagonist compounds of 5-hydroxytryptamine at 5-HT receptors of the type located at the end of primary afferent nerves (5-HT). This type of receptor is currently 5-HT
_It is called _three receptor and is also present in the central nervous system. 5-HT is widely present in neuronal pathways of the central nervous system, and impairments of these 5-HT-containing pathways are known to alter behavioral patterns such as mood, psychomotor activity, appetite and memory.

[0003] Compounds having antagonist activity at 5-HT ₃ receptor have been disclosed.

[0004] For example, published British Patent No. 2153821A.
Specification and published European Patent Nos. 191562 and 21.
Nos. 9193 and 210840 disclose 3-imidazolylmethyltetrahydrocarbazolones represented by the following general formula and physiologically acceptable salts and solvates thereof.

[0005]

Embedded image [In the above formula, R ¹ is a hydrogen atom or C _1-10 alkyl,
_Represents a group selected from _3-6 alkenyl, C _3-10 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-4 alkyl, phenyl or phenyl C _1-3 alkyl, wherein Q is hydrogen When representing an atom, R ¹ is -CO ₂
R ⁵ , —COR ⁵ , —CONR ⁵ R ⁶ or —SO ₂ R ⁵
Wherein R ⁵ and R ⁶ may be the same or different and each represents a hydrogen atom, a C _1-6 alkyl or C _3-7 cycloalkyl group, or phenyl or phenyl C _1-4 alkyl A phenyl group, in which case the phenyl group is optionally substituted with one or more C _1-4 alkyl, C _1-4 alkoxy or hydroxy groups or halogen atoms, provided that R ¹ is a group —CO ₂ R ⁵ or -SO ₂
When representing the R ^{5 R 5} does not represent a hydrogen atom).

One of the groups represented by R ² , R ³ and R ⁴ is a hydrogen atom or a C _1-6 alkyl, C _3-7 cycloalkyl, C _2-6 alkenyl or phenyl C _1-3 alkyl group. And the other two groups may be the same or different and each represent a hydrogen atom or a C _1-6 alkyl group.

Q represents a hydrogen atom or a halogen atom, a hydroxy, C _1-4 alkoxy, phenyl C _1-3 alkoxy or C _1-6 alkyl group or a group —NR ⁷ R ⁸ or —CONR ⁷ R ⁸ (wherein , R ⁷ and R ⁸ may be the same or different and each is a hydrogen atom or C _1-4
Represents an alkyl or C _3-4 alkenyl group or forms a saturated 5- to 7-membered ring together with the nitrogen atom to which they are attached)]

[0008]

DETAILED DESCRIPTION OF THE INVENTION We have discovered a new class of compounds that are structurally distinct from the foregoing and are effective antagonists of 5-HT action at the 5-HT ₃ receptor.

Compounds The present invention provides a tricyclic lactam of the following general formula (I) and physiologically acceptable salts and solvates thereof.

[0010]

Embedded image

[In the above formula, Im represents an imidazolyl group represented by the following formula.

[0012]

Embedded image

R ¹ is a hydrogen atom or C _1-6 alkyl, C 1
_3-6 alkenyl, C _3-10 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-4 alkyl, phenyl, phenyl C _1-3 alkyl, phenylmethoxymethyl, phenoxyethyl, phenoxymethyl,- CO ₂ R
^{5, -COR 5, -CONR 5 R} 6 or _-SO 2 R
⁵ wherein R ⁵ and R ⁶ may be the same or different and are each hydrogen, C _1-6 alkyl or C _3-7 cycloalkyl or phenyl or phenyl C _{1- 4} alkyl group, in which case the phenyl group optionally contains one or more C _1-4 alkyl,
_1-4 may be substituted with an alkoxy or hydroxy group or a halogen atom, provided that R ¹ is a group —CO ₂ R ⁵
Or it may represent _-SO 2 ^{R 5 R 5} does not represent a hydrogen atom). One of the groups represented by R ² , R ³ and R ⁴
One is a hydrogen atom or C _1-6 alkyl, C _3-7 cycloalkyl, C _3-6 alkenyl, phenyl or phenyl C
_{It is a 1-3} alkyl group, and the other two groups may be the same or different and represent a hydrogen atom or a C _1-6 alkyl group. n represents 2 or 3]

According to one aspect, the present invention relates to a compound of the invention wherein R ¹ is hydrogen or C _1-6 alkyl, C _3-6 alkenyl, C _3-10 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C
A compound of formula (I) is provided which represents a group selected from _1-4 alkyl, phenyl or phenyl C _1-3 alkyl, wherein n and Im are as defined for formula (I).

Suitable physiologically acceptable salts of the compounds of general formula (I) include acid addition salts formed with organic or inorganic acids, for example hydrochlorides, hydrobromides, sulphates, alkyl or Aryl sulfonates (eg methanesulfonate or p-toluenesulfonate), phosphates,
There are acetate, citrate, succinate, tartrate, fumarate and maleate. Examples of solvates include hydrates.

All optical isomers of the compounds of the general formula (I), their mixtures, including racemic mixtures thereof, and all geometric isomers of the compounds of the formula (I) are included in the present invention.

In the general formula (I), the alkyl group means a linear or branched alkyl group, for example, methyl, ethyl, n-
Propyl, prop-2-yl, n-butyl, but-2-
Yl, 2-methylprop-2-yl, n-pentyl, pent-3-yl or n-hexyl. The C _3-6 alkenyl group is, for example, a propenyl or butenyl group.
Whether R ¹ represents a C _3-6 alkenyl or C _3-10 alkynyl group, or R ³ represents a C _3-6 alkenyl group;
Or when R ⁷ or R ⁸ represents a C _3-4 alkenyl group, the double or triple bond must not be adjacent to a nitrogen atom. A phenyl C _1-3 alkyl group is, for example, benzyl,
It is a phenethyl or 3-phenylpropyl group. C _3-7
The cycloalkyl group is, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group.

A preferred class of compounds of formula (I) is R ¹
Is a hydrogen atom or C _1-6 alkyl (eg, methyl, ethyl, n-propyl, prop-2-yl), C _3-4 alkenyl (eg, prop-2-enyl), C _3-4 alkynyl (eg, Prop-2-ynyl), C _5-6 cycloalkyl (eg, cyclopentyl), C _5-6 cycloalkylmethyl (eg, cyclopentylmethyl), phenyl C _1-2 alkyl (eg, benzyl), phenylmethoxymethyl, N , N-diC _1-3 alkylcarboxamide (eg, N, N-dimethylcarboxamide) or C _1-3 alkylsulfonyl (eg, methylsulfonyl).

More preferably, R ¹ is C _1-4 alkyl (eg, methyl or n-propyl), C _3-4 alkynyl (eg, prop-2-ynyl), C _5-6 cycloalkyl (eg, cyclopentyl) , C _5-6 cycloalkylmethyl (eg, cyclopentylmethyl), phenyl C
_{Represents a 1-2} alkyl (eg, benzyl), phenylmethoxymethyl or N, N-diC _1-3 alkylcarboxamide (eg, N, N-dimethylcarboxamide) group.

Another preferred class of compounds of formula (I) is
R ² is a hydrogen atom or C _1-3 alkyl (eg, methyl)
Group, more preferably a hydrogen atom.

Another preferred class of compounds of formula (I) is
R ³ is a hydrogen atom or C _1-3 alkyl (eg, methyl)
Group, more preferably a hydrogen atom.

Another preferred class of compounds of formula (I) is
R ⁴ represents a hydrogen atom or a C _1-3 alkyl (eg, methyl or n-propyl) group. Most preferably, R ⁴ represents a methyl group.

When R ² and R ³ represent a hydrogen atom, R
⁴ is preferably C _1-6 alkyl, C _3-7 cycloalkyl, C _3-6 alkenyl or phenyl C _1-3 alkyl, especially C _1-6 alkyl.

Another preferred class of compounds of formula (I) is
This is the case where n represents 2.

A preferred group of compounds of the formula (I) is that R ¹ is hydrogen or C _1-4 alkyl, C _3-4 alkenyl, C
_3-4 alkynyl, C _5-6 cycloalkyl, C _5-6 cycloalkylmethyl, phenyl C _1-2 alkyl, phenylmethoxymethyl, N, N-di C _1-3 alkyl carboxamide or C _1-3 alkyl sulfonyl group And R ²
Represents a hydrogen atom, and R ³ and R ⁴ each represent a hydrogen atom or a C _1-3 alkyl group.

A particularly preferred group of compounds of formula (I) is
¹ is methyl, n-propyl, prop-2-ynyl, cyclopentyl, cyclopentylmethyl, benzyl or N,
Represents an N-dimethylcarboxamide group, R ² and R ³
, Each represents a hydrogen atom, and R ⁴ represents a methyl group.

A particularly important group of compounds among the above preferred and particularly preferred compounds is when n represents 2.

Preferred compounds of the present invention are as follows. 2,3,4,5-tetrahydro-5-methyl-2
-[(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indol-1-one, 2,3,4,5-tetrahydro-5- (phenylmethyl) -2-[(5-Methyl-1H-imidazole-4-
Yl) methyl] -1H-pyrido [4,3-b] indol-1-one, 5-cyclopentyl-2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazole-
4-yl) methyl] -1H-pyrido [4,3-b] indol-1-one, 2,3,4,5-tetrahydro-2-
[(5-Methyl-1H-imidazol-4-yl) methyl] -5-propyl-1H-pyrido [4,3-b] indol-1-one, 5- (cyclopentylmethyl) -2
3,4,5-tetrahydro-2-[(5-methyl-1H
-Imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indol-1-one, 3,4,5,6-
Tetrahydro-6-methyl-2-[(5-methyl-1H
-Imidazol-4-yl) methyl] azepino [4,3-
b] indol-1 (2H) -one, 2,3,4,5-tetrahydro-N, N-dimethyl-2-[(5-methyl-
1H-imidazol-4-yl) methyl] -1-oxo-
5H-pyrido [4,3-b] indole-5-carboxamide, 2,3,4,5-tetrahydro-2-[(5-
Methyl-1H-imidazol-4-yl) methyl] -5-
(2-Propinyl) -1H-pyrido [4,3-b] indol-1-one and physiologically acceptable salts and solvates thereof.

[0029] 5 by the compounds of the present invention in the utilization / pharmaceutical 5-HT ₃ receptors of the compound
-The effective and selective antagonism of HT is
(entorhinal) in the cortex homogenate 3- (5-methyl-1H-imidazol-4-yl) -1-inhibit binding of [1- (methyl _-t 3)-1H-indol-3-yl] -1-propanone Possible abilities [Natural by G. Kilpatrick et al.
e), 1987, vol. 330, p. 746] and / or their ability to inhibit 5-HT-induced depolarization of isolated rat vagus nerve.

In addition to their activity as effective and selective antagonists of 5-HT at the 5-HT ₃ receptor, certain compounds of the present invention have the advantage of long-acting activity.

Particularly preferred compounds, both in terms of potency and time of action, are 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl) methyl]- 1H-pyrido [4,3-b] indole-
1-one and its physiologically acceptable salts and solvates. Preferred salts of this compound are the hydrochloride and maleate.

Compounds of formula (I) which antagonize the action of 5-HT at the 5-HT ₃ receptor include compounds such as psychiatric disorders (eg, schizophrenia and illness); anxiety; nausea and vomiting, especially cancer. It is useful in treating conditions associated with chemotherapy and radiation therapy. Compounds of formula (I) are useful in treating gastric stasis; dyspepsia, peptic ulcer, reflux esophagitis, bloating and irritable bowel syndrome as well as gastrointestinal dysfunction symptoms;
It is also useful for treating migraine and pain. The compounds of formula (I) are also useful for addiction to drugs and substances of abuse, depression, dementia, and other impaired sensations.

According to another aspect, the invention relates to a psychiatric disorder such as schizophrenia or sickness; anxiety; nausea or vomiting;
Gastrointestinal stagnation; gastrointestinal dysfunction symptoms such as indigestion, reflux esophagitis, peptic ulcer, distension and irritable bowel syndrome; an effective amount of a compound of formula (I) in a human or animal with migraine or pain Alternatively, a therapeutic method comprising administering a physiologically acceptable salt or solvate thereof is provided.

Further, in the present invention, at least one compound selected from the compounds of the formula (I) and their physiologically acceptable salts and solvates (for example, hydrates) for human or veterinary use. Also provided are pharmaceutical compositions containing a compound of the invention and formulated for administration by any convenient route.

[0035] Such compositions are formulated according to conventional methods using one or more physiologically acceptable carriers and / or excipients.

The compounds of the present invention are formulated in a form suitable for oral, buccal, parenteral or enteral administration or for inhalation or insufflation (either via the mouth or nose).

For oral administration, the pharmaceutical composition may contain a binder (eg, pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose),
Fillers (eg, lactose, microcrystalline cellulose or calcium hydrogen phosphate), lubricants (eg, magnesium stearate, talc or silica), disintegrants (eg, potato starch or sodium starch glycolate) or wetting agents (eg, It can be produced in the usual manner with pharmaceutically acceptable excipients such as sodium lauryl sulphate), for example in the form of tablets or capsules. Tablets may be coated according to methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid formulations may include suspending agents (eg, sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifiers (eg, lecithin or gum arabic), non-aqueous vehicles (eg, almond oil, oily esters, ethyl alcohol or fractionation) Vegetable oils) and preservatives (eg, methyl or propyl p-hydroxybenzoate or sorbic acid), together with pharmaceutically acceptable additives, according to conventional methods. The formulation is appropriately buffered,
Flavoring, coloring and sweetening agents may be included.

Formulations for oral administration are suitably formulated to give slow release of the active ingredient.

For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

The compounds of the present invention may also be formulated for parenteral administration by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, eg, in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. . Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

The compounds of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compounds of the present invention may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the present invention may be formulated with suitable polymeric or hydrophobic materials (eg, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, such as sparingly soluble salts. .

For administration by inhalation, the compounds of the present invention may be prepared in a pressurized pack or nebulizer by use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. Expediently in the form of an aerosol spray. In the case of a pressurized aerosol the dosage unit will be determined by providing a valve to eject a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator are formulated by containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.

For nasal administration, the compounds of the invention may be formulated as a solution administered from a suitable metered or unit dose device or as a powder mix with a suitable carrier administered from a suitable injection device.

The compounds of formula (I) can also be administered in combination with other therapeutic agents. For example, the stomach contents stagnant, symptoms of gastrointestinal dysfunction, the treatment of nausea and vomiting, compounds of formula (I) histamine H ₂ receptor antagonists (e.g., ranitidine, sufotidine, 1-methyl-5 - [[3 -[3
-(1-piperidinylmethyl) phenoxy] propyl]
Amino] -1H-1,2,4-triazole-3-methanol, cimetidine, famotidine, nizatidine or loxatidine) or an antisecretory agent such as an H ⁺ K ⁺ ATPase inhibitor (eg omeprazole) .

The proposed dose of a compound of the present invention for human (about 70 kg) administration is 0.001 to 100 mg, preferably 0.00 mg, of active ingredient when expressed as free base weight.
The dose is 1 to 50 mg, more preferably 0.1 to 20 mg / unit dose, for example, administered 1 to 4 times a day. It will be apparent that it is necessary to vary doses routinely depending on the age and symptoms of the patient. The dosage also depends on the route of administration.

Preparation of Compounds The compounds of general formula (I) and their physiologically acceptable salts or solvates are prepared by the general methods outlined below. In the following description, the groups R ¹ , n and Im have the same meanings as in the case of the compound of the general formula (I) unless otherwise indicated.

According to a first general process (A), a compound of general formula (I) is a compound of formula (II):

[0049]

Embedded image Is a compound of the following formula (III): LCH ₂ -Im (III) wherein L is a leaving atom or group, for example, a halogen atom (for example, chlorine, bromine or iodine) or an acyloxy group (for example, trifluoroacetyl Oxy or acetoxy) or a sulfonyloxy group (eg, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy or methanesulfonyloxy)) or a protected derivative thereof, followed by removal of the protecting group if necessary. Manufactured. L is preferably a halogen atom (for example, a chlorine atom).

The reaction may be carried out with an ether (eg, dimethoxyethane, diglyme or tetrahydrofuran), a substituted amide (eg, dimethylformamide or N-methylpyrrolidone), an aromatic hydrocarbon (eg, toluene), a ketone (eg, acetone) or dimethyl. 100 ° C. from ambient temperature in the presence of a base in an inert solvent such as sulfoxide
Performed at temperatures up to. Suitable bases include alkali metal hydrides (eg, sodium hydride), alkali metal carbonates (eg, sodium carbonate), alkali metal amides (eg, sodium amide), alkali metal alkoxides (eg, potassium t-butoxide). Or an alkali metal hydroxide (eg, sodium or potassium hydroxide).

According to another general process (B), a compound of the general formula (I) is converted into another compound of the formula (I) in a conventional manner. Such conventional methods include hydrogenation, alkylation and acylation, but if necessary, protection and deprotection are used.

According to one embodiment of the interconversion process (B), hydrogenation is utilized to convert an alkenyl or alkynyl substituent to an alkyl substituent or an alkynyl to an alkenyl substituent. Hydrogenation is also used to replace a phenylmethoxymethyl group with a hydrogen atom. The hydrogenation according to the general process (B) is carried out according to the customary methods, for example using hydrogen in the presence of a catalyst, as described in EP-A-242 973.

The term "alkylation" in the general process (B) involves the introduction of groups such as cycloalkyl, alkenyl or phenalkyl groups.

Thus, for example, if R ¹ is C _1-6 alkyl, C _3-6 alkenyl, C _3-10 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-4 alkyl, phenyl C _{1- 3} alkyl, phenyl methoxymethyl, formulas representing phenoxyethyl or phenoxymethyl group (I)
Are prepared by alkylating a compound of formula (I) wherein R ¹ represents a hydrogen atom, and wherein R ³ is
Compounds representing _1-6 alkyl, C _3-7 cycloalkyl, C _3-6 alkenyl or phenyl C _1-3 alkyl groups are represented by R ³
Are prepared by alkylating the corresponding compound of the formula (I), which represents a hydrogen atom, using the customary methods as described, for example, in EP-A-2 42973. That is, the reaction is carried out, preferably in the presence of a base, using a suitable alkylating agent of the formula R ⁷ Z, where R ⁷ is the group to be introduced and Z is a leaving atom or group.

According to another embodiment of the general process (B), R ¹ is —CO ₂ R ⁵ , —COR ⁵ , —CONR ⁵ R
Compounds of formula (I) representing ⁶ or —SO ₂ R ⁵ are represented by R ¹
Is a compound of the formula (I) in which represents a hydrogen atom by appropriate acylation or sulfonylation. The acylation / sulfonylation reaction is described, for example, in published European Patent No. 2108.
The reaction is carried out according to a conventional method as described in JP-A No. 40, using an appropriate acylating / sulfonylating agent.

It will be clear that in the above conversion it is necessary or desirable to protect the reactive groups in the molecule of the compound in question in order to avoid undesired side reactions. For example, a nitrogen atom of indole and / or imidazole can be replaced with, for example, arylmethyl (eg, trityl), arylmethoxymethyl (eg, phenylmethoxymethyl), alkyl (eg, t-butyl),
Alkoxymethyl (eg, methoxymethyl), acyl (eg, benzyloxycarbonyl) or sulfonyl (eg, N, N-dimethylaminosulfonyl or p-
(Toluenesulfonyl) group.

According to another general process (C), compounds of general formula (I) are prepared by removing protecting groups from the protected form of a compound of formula (I). Deprotection is described by TW Greene [John Wiley and Sons, 1].
983], “Protective groups in organic synthesis”.
Groups in Organic Synthesis) are performed using a conventional method.

For example, an arylmethoxymethyl N-protecting group is cleaved by hydrogenolysis in the presence of a catalyst (eg, palladium on charcoal). Trityl groups are cleaved by acid hydrolysis (eg, using dilute hydrochloric acid or acetic acid). Alkoxyalkyl groups are removed using a mineral acid (eg, dilute hydrochloric or hydrobromic acid). Acyl groups are removed by hydrolysis under acidic or basic conditions (eg, using hydrogen bromide, dilute hydrochloric acid or sodium hydroxide). Further, sulfonyl groups are removed by hydrolysis of alkali or acid, and N, N-dimethylaminosulfonyl groups are removed by photolysis (eg, from imidazole nitrogen atoms).

The compound of formula (II) is an oxime of formula (IV):

Embedded image (Wherein m represents 1 or 2) or a protected derivative thereof, which is obtained by Beckmann rearrangement. The Beckmann rearrangement is carried out according to a conventional method, for example, in an inert solvent such as an ether (for example, dioxane), an amide (for example, dimethylformamide) or a hydrocarbon (for example, toluene or cyclohexane) under an elevated temperature of, for example, 50 to 120 ° C. Using an acid (eg, polyphosphoric acid or sulfuric acid or a mixture of hydrochloric acid, acetic anhydride and acetic acid). On the other hand, equation (IV)
The hydroxy group of the oxime may be converted to a leaving group such as a chloride (eg, phosphorus pentachloride), a hydrocarbyl sulfonate (eg, mesylate or tosylate) or a trifluoroacetate group (using conventional acylation techniques). Good. Thereafter, in an inert solvent as described above,
For example, by heating at a temperature of 20 to 150 ° C.,
A compound of formula (II) is obtained.

The compound of formula (IV) is a corresponding tricyclic ketone of formula (V):

Embedded image (Wherein m represents 1 or 2) or a protected derivative thereof by a conventional method using hydroxylamine hydrochloride in a solvent such as pyridine.

The compounds of the formula (III) and their protected derivatives are known or, if not, prepared by the methods described, for example, in DE-A-37 40 352.

Compounds of formula (V) may be prepared, for example, by the method of H. Iida et al., Journal of Organic Chemi-stry, 1
980, Vol. 45, page 2938.

When it is desired to isolate a compound of the present invention as a salt, for example, a physiologically acceptable salt,
In a suitable solvent such as an alcohol (eg, ethanol or methanol), an aqueous alcohol (eg, aqueous ethanol), a halogenated hydrocarbon (eg, dichloromethane), an ester (eg, ethyl acetate) or an ether (eg, tetrahydrofuran). The reaction is carried out by reacting a compound of formula (I) in the form of the free base, preferably in an equivalent amount, with the appropriate acid.

Physiologically acceptable salts are also prepared according to the usual methods from other salts of the compounds of the formula (I), including other physiologically acceptable salts.

The individual enantiomers of the compounds of this invention may be obtained by resolution of an enantiomeric mixture (eg, a racemic mixture) using conventional means, such as an optically active resolving acid (eg, EL EL)
liel) “Stereochemistry of carbon compounds” (Stereochemis
try of Carbon Compounds) [McGrough Hill (McGr
ow Hill), 1962] and “Tables of Reagents” by SH Wilen.
solving Agents)).

The above process for preparing the compounds of the present invention can be used to introduce a desired group at any stage in the stepwise formation of a required compound. Obviously, it may be combined with the method. The reaction sequence in a multi-step process should of course be selected such that the reaction conditions applied do not affect the groups in the molecule desired in the final product.

EXPERIMENTAL EXAMPLES The present invention is further illustrated by the following intermediates and examples. All temperatures are in ° C. Thin layer chromatography (TLC) was performed on silica, and flash column chromatography (FCC) was performed on silica (Merck 9385). The solvent system A used in the chromatography is dichloromethane: ethanol:
Represents 0.88 ammonia solution. The organic extract was dried over magnesium sulfate or sodium sulfate as needed. The following abbreviations have been used: DMF-dimethylformamide, THF-tetrahydrofuran, DME-
Dimethoxyethane. ¹ H-NMR spectra were obtained at 250 MHz for dilute solutions in d ₆ -dimethylsulfoxide.

Intermediate 14 4- (chloromethyl) -1- (triphenylmethyl)-
1H-imidazole thionyl chloride (0.82 g) was added at 23 ° to 1- (triphenylmethyl) -1H-imidazole-4-in a mixture of dichloromethane (50 ml) and DMF (1.0 ml).
To a stirred suspension of methanol (1.3 g) was added over 1 minute. The solution thus obtained was stirred for 15 minutes and extracted with an 8% sodium hydrogen carbonate solution (80 ml). The organic phase was washed with water (50ml), dried and evaporated to give an oil which solidified. The solid was slurried in hexane and filtered to give the title compound (1.28
g) was obtained. mp 139-141}.

Intermediate 2 4-Formyl-N, N-dimethyl-5-propyl-1H
-Imidazole -1-sulfonamidodimethylsulfamoyl chloride (0.67 mg) was added under nitrogen to 5-propyl-1H-imidazole-4-carboxaldehyde (8 in dry dichloromethane (10 ml)).
60 mg) and a stirred solution of triethylamine (0.87 ml). The solution was heated at reflux for 24 hours, cooled, poured into water (50ml) and extracted with dichloromethane (3x25ml). The combined dry organic extracts were evaporated to give an oil (1.9 g), which was ethyl acetate:
Purification, eluting with hexane (1: 1) gave the title compound (500 mg). mp57-58 ゜.

Intermediate 3 4- (hydroxymethyl) -N, N-dimethyl-5-p
Ropyr-1H-imidazole-1-sulfonamido sodium borohydride (139 g) was added under nitrogen to 4-formyl-N, N-dimethyl-5-propyl-1H-imidazole-1-in absolute ethanol (5 ml). It was added to a stirred solution of the sulfonamide (450 mg). Three hours later,
The mixture was poured into water (30 ml) and dichloromethane (3 × 1
5 ml). The combined dried organic extracts were evaporated to give a solid (425mg) which was combined with ether (2x1).
0 ml) to give the title compound (350 mg). mp
86-88 °.

Intermediate 4 4- (chloromethyl) -N, N-dimethyl-5-propyl
L -1H-Imidazole-1-sulfonamide A solution of thionyl chloride (0.12 ml) in dry dichloromethane (1.2 ml) was treated under nitrogen with 4- (hydroxymethyl)-in dry dichloromethane (7.5 ml). N, N
-Dimethyl-5-propyl-1H-imidazole-1-
It was added dropwise to a cold (0 °) stirred solution of the sulfonamide (340 mg). After 1.5 hours, the solution was washed with 8% sodium bicarbonate solution (2 × 15 ml) and the aqueous phase was extracted with dichloromethane (2 × 10 ml). The combined organic extracts were washed with water (15ml), dried and evaporated to give the title compound (180mg) as an oil. TLC (ethyl acetate)
Rf 0.68.

Intermediate 5 3,4-dihydro-4-methylcyclopent [b] yne
3,4-dihydro-4-methylcyclopent [b] indole-1 (2H) -one (1.7 g) and hydroxylamine hydrochloride (1.925 g) in dollar-1 (2H) -one oxime pyridine were Heat at 60 ° for 18 hours and cool. The reaction mixture was evaporated under reduced pressure to give a residue, to which 8% sodium bicarbonate (15%
0 ml) was added. Extraction with ethyl acetate (300 ml) resulted in a suspension in the organic layer, which layer and the aggregated solids were separated from the aqueous layer. The aqueous layer was washed with ethyl acetate (250 ml)
Was re-extracted. The combined organic extracts (and suspended solids) were evaporated to a residue and ethanol (150
and a mixture of methanol (150 ml) and cooled to about 50 °. The residue is separated from this solution by FCC
It was adsorbed on silica and applied to an FCC column. Elution with ethyl acetate / 3-10% methanol gave the title compound (1.
69 g) were obtained. mp 219-224 (decomposed).

Intermediate 6 2,3,4,5-tetrahydro-5-methyl-1H-py
Lido [4,3-b] indol-1-one 3,4-dihydro-4-methylcyclopent [b] indol-1 (2H) -one oxime (1.53 g), polyphosphoric acid (40 g) and dioxane (15 ml) ) Was heated at 110-120 ° for 2.2 hours under nitrogen. The reaction mixture was cooled and treated with 2N sodium carbonate solution (11). The suspension was extracted with ethyl acetate (4 × 400 ml) and the combined extracts were dried. Solids (1.43 by evaporation)
g) was obtained, which was recrystallized from ethyl acetate / cyclohexane. This solid was subjected to a system A (20
0: 10: 1) to give a solid (1.26).
g) was obtained, which was recrystallized from ethanol to give the title compound (960 mg). mp 234-238.

[0074]Intermediate 7 3,4,5,6-tetrahydro-6-methylazepino
[4,3-b] indol-1 (2H) -one 1,2,3,9-tetrahi in dioxane (500 ml)
Dro-9-methyl-4H-carbazol-4-oneoxy
(24 g) and polyphosphoric acid (600 g)
Was processed according to the method described for Of organic extract
The solid obtained by evaporation (22 g) was treated with ethyl acetate (3
00 ml) to give a solid (19.2 g).
Was. This is eluted by FCC with system A (200: 8: 1)
And purified to give the title compound (5.5 g). mp
212-215}.

[0075]Intermediate 8 5,6-dihydro-4- (phenylamino) -1 (2
H) -Pyridinone 2,4-dioxopiperidine (1.13 g) and anili
(930 mg) at 120 ° under a nitrogen stream.
Heat for 5 minutes. Triturate the resulting solid with ether,
The crystals were collected by filtration to give the title compound (1.74 g). mp23
5-238 °.

Intermediate 9 2,3,4,5-tetrahydro-1H-pyrido [4,3
-B] 5,6-Dihydro-4- (phenylamino) -1 (2H) -pyridinone (1.5 g) in indol-1-one dry DMF (50 ml)
And a solution of palladium acetate (150 mg) was treated with cupric acetate (3.2 g), and the resulting mixture was treated under nitrogen with 1
Heated at 20-130 ° for 1.5 hours. Then, the mixture was concentrated under reduced pressure to obtain a solid substance.
Milled in l). The acid was decanted and the resulting solid was extracted with ethyl acetate for 18 hours. 2N decanted acid
Basify with sodium hydroxide and add ethyl acetate (3 × 10
0 ml). These organic extracts were combined with the previous ethyl acetate extract and adsorbed on silica. Purification by FCC eluting with system A (100: 8: 1) gave the title compound (874 mg). mp 212-215}.

Intermediate 10 2,3,4,5-tetrahydro-5-[(phenylmeth
Xy) methyl] -1H-pyrido [4,3-b] indole
A solution of 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indol-1-one (1.12 g) in 1 -one dry DMF (60 ml) was treated with sodium hydride (oil Medium 60
% Dispersion; 480 mg) and the resulting mixture was stirred under nitrogen until bubbling ceased. The mixture was then cooled to 0 ° and benzyl (chloromethyl) ether (10 w / v solution in DMF; 0.835 ml) was added over 10 minutes. Stirring was continued for a further 5 minutes, after which water (10 ml) was added. The reaction mixture was concentrated under reduced pressure to give an oil which was dissolved in ethyl acetate (100 ml) and water (3 × 100 ml)
And washed. The organic phase was dried and adsorbed on FCC silica. Purification by FCC, eluting with System A (150: 8: 1), gave the title compound (1.1 g). mp133
-135 °.

Intermediates 11 to 14 were prepared in the same manner as in the case of Intermediate 10, that is, hydrogenation of 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indol-1-one. Prepared by treatment with sodium followed by a suitable alkylating agent. Product isolation and purification were as described for Intermediate 10 unless otherwise indicated.

Intermediate 11 5-ethyl-2,3,4,5-tetrahydro-1H-py
Lido [4,3-b] indol-1-one 2,3,4,5-tetrahydro-1H-pyrido [4,3
-B] Indol-1-one (931 mg) was treated with sodium hydride (60% dispersion in oil; 400 mg), then stirred with ethyl iodide (10% v / v solution in DMF) to give the title Compound (758 mg) was obtained. mp203-
204.5 ゜.

Intermediate 12 2,3,4,5-tetrahydro-5- (1-methylethyl
L) -1H-pyrido [4,3-b] indol-1-one 2,3,4,5-tetrahydro-1H-pyrido [4,3
-B] Indol-1-one (931 mg) was treated with sodium hydride (73% dispersion in oil; 328 mg) and then stirred with 2-bromopropane (615 mg) at room temperature for 72 hours. Purification by FCC eluting with system A (200: 8: 1) gave a foam (324 mg), which was further purified by recrystallization from ethyl acetate: hexane (1: 1). The title compound (294 mg) was obtained. TLC (system A, 100: 8: 1) Rf 0.58.

[0081]Intermediate 13 2,3,4,5-tetrahydro-5- (phenylmethyl
Le) -1H-pyrido [4,3-b] indole-1-one 2,3,4,5-tetrahydro-1H-pyrido [4,3
-B] Hydrogenated indol-1-one (559 mg)
(197% dispersion in oil; 197 mg)
Then, the mixture was stirred with benzyl bromide (513 mg) at room temperature for 30 minutes.
Stirred. Dichloromethane: ethanol (8
Purification eluting with 0: 1) gave the title compound
(347 mg) was obtained. mp209-212}.

Intermediate 14 5- (cyclopentylmethyl) -2,3,4,5-tetra
Lahydro-1H-pyrido [4,3-b] indole-1-
On-2,3,4,5-tetrahydro -1H- pyrido [4,3
-B] Indol-1-one (950 mg) was treated with sodium hydride (60% dispersion in oil; 408 mg) and then stirred with cyclopentyl, methylsulfonate (909 mg) at room temperature for 7 days. The solid obtained by FCC (570 mg) was further purified by slow evaporation from a solution in methanol to give the title compound. mp179
-181 ゜.

Intermediate 15 2,3,4,5-tetrahydro-2-[[5-methyl-
1- (triphenylmethyl) -1H-imidazole-4-
Yl] methyl] -1H-pyrido [4,3-b] indole
A solution of triphenylmethyl chloride (3.36 g) in 1-one dry DMF (40 ml) was added to triethylamine (1.52 g).
g) in dry DMF (50 ml) containing 2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazole-
4-yl] methyl] -1H-pyrido [4,3-b] indol-1-one (2.8 g) was added dropwise to a stirred solution. After the addition was complete, the mixture was stirred overnight. Then the mixture was poured into water (1000 mg) and the resulting suspension was extracted with ethyl acetate (3 × 300 ml). The combined organic extracts were washed with water (2 × 500 ml), dried and concentrated on silica. Elution with FCC with system A (100: 8: 1) gave the title compound (4.3 g). mp235-236
゜.

[0084]Intermediate 16 2,3,4,5-tetrahydro-5-methyl-2-
[[1- (Triphenylmethyl) -1H-imidazole-
4-yl] methyl] -1H-pyrido [4,3-b] in
Dollar-1-on 2,3,4,5-tetrahydro in dry DMF (5 ml)
-5-methyl-1H-pyrido [4,3-b] indole-
1-one (0.3 g) and sodium hydride (80 in oil)
% Dispersion; 0.05 g) until hydrogen evolution ceased.
(About 0.5 hour) and stirred at 50 ° under nitrogen. mixture
The mass was cooled to 40 ° C and dried in dry THF (3 ml).
(Chloromethyl) -1- (triphenylmethyl) -1H
-A solution of imidazole (0.53 g) was added. blend
Was stirred for 2 hours from 40 ° to 23 °, and water (10
0ml) and extracted with dichloromethane (3x100ml)
did. The dried organic phase is evaporated to give a semi-solid, which is
Dichloromethane: ethyl acetate: triethyl by FCC
Purified by elution with amine (50: 50: 1)
I got This is slurried in hexane, filtered and
The title compound (0.37 g) was obtained. mp205-210
゜ (decomposition).

[0085]Example 1 2,3,4,5-tetrahydro-5-methyl-2-
[(5-Methyl-1H-imidazol-4-yl) methyl
Ru] -1H-pyrido [4,3-b] indole-1-one
Maleate 2,3,4,5-tetrahydride in dry DMF (15 ml)
B-5-Methyl-1H-pyrido [4,3-b] indole
-1-one (0.6g) and about 78% hydrogenated sodium in mineral oil
The mixture of the lithium dispersion (0.109 g) stopped generating hydrogen.
The mixture was stirred at 50 ° C under nitrogen for about 1.5 hours. mixture
The mass was cooled to 40 ° and dried in dry THF (15 ml).
(Chloromethyl) -5-methyl-1- (triphenylmeth
Chill) -1H-imisol (1.12 g) solution
Was. The reaction was then incubated at 40 ° for 3 hours and at 20 ° for 16 hours.
Stir for 4 hours and then add 4- (chloro) in dry THF (15 ml).
(Romethyl) -5-methyl-1- (triphenylmethyl)
-1H-imidazole (1.12 g) was added. Got
The mixture was heated at 40 ° for 3 hours, water (20 ml) and acetic acid
(20 ml) and heated at 100 ° for 2 hours. Next
The mixture was concentrated under reduced pressure to about 60 ml with 1M hydrochloric acid (40 ml).
1) and washed with ethyl acetate (3 × 50 ml).
Discard the organic phase and basify the acidic aqueous phase with potassium carbonate (p
H9) and ethyl acetate: ethanol (20: 1, 3 × 1
00 ml). Combine the extracts, dry and evaporate
This gave a brown gum (about 1 g). This rubber-like material
It is adsorbed on silica and the system A (100: 8:
Purify by eluting with 1) to give a light brown solid (0.8 g)
Obtained. mp 238-240 ° (decomposition). Heat this solid
Mixing of ethanol and methanol (1: 1, 100mg)
Dissolved in a solution, ethanolic solution of maleic acid (318 g)
The solution was treated. The resulting solution is concentrated to about 20 ml and dried.
Dilute with dry diethyl ether (about 8 ml) to obtain an off-white solid
The title compound (0.75 g) was precipitated. mp1
60-162 ゜. Analysis found: C, 61.6; H, 5.5; N, 13.6; C₁₇H₁₈N₄O. C₄H₄O₄Calculated as: C, 61.5; H, 5.4; N, 13.8%.

[0086]Example 2 3,4,5,6-tetrahydro-6-methyl-2-
[(5-Methyl-1H-imidazol-4-yl) methyl
Ru] azepino [4,3-b] indol-1 (2H) -o
Nmaleate 3,4,5,6-tetrahydro-6-methylazepino
[4,3-b] indol-1 (2H) -one (0.64
g) with sodium hydride (about 75-80% dispersion in oil;
0.108 g) and then as described in Example 1
4- (chloromethyl) -5-methyl-1- (trife
(Nylmethyl) -1H-imidazole. Next
The reaction mixture was poured into water (300 ml)
(4 × 250 ml). Combined dry organic extraction
The liquid was evaporated to give a semi-solid (about 1.8 g), which was
Purified by FCC eluting with system A (200: 8: 1)
Then, a rubber-like substance (0.7 g) was obtained. This rubbery substance (0.
7 g) in acetic acid, THF and water (1: 1: 1, about 70 ml)
And heated on a steam bath for 1 hour. An example
After treatment as described in 1 above, the rubbery material (0.2
2g), which was analyzed by FCC for system A (200: 8:
Purify by eluting with 1) to give a solid (0.11 g)
Was. A rubbery substance was obtained by maleate formation, which was reduced.
Pressure drying to give a foam, which is mixed with ether and ethanol
Trituration with a mixture of gels (50: 1, approx.
The title compound was obtained as a product. mp132-133}.¹
1 H-NMR showed the presence of 0.39 mol of ethanol.
Was. Moisture content analysis measured value: 0.583% w / w=0.14mol H₂O. Analysis found: C, 61.4; H, 5.7; N, 12.6; C₁₈H₂₀N₄O. C₄H₄O₄. 0.39 EtOH. 0.14H₂Calculated for O: C, 61.4; H, 6.0; N, 12.6%.

Example 3 2,3,4,5-tetrahydro-2-[(5-methyl-
1H-Imidazol-4-yl) methyl] -5-[(Fe
Nylmethoxy) methyl] -1H-pyrido [4,3-b]
Indol-1-one 2,3,4,5-Tetrahydro-5-[(phenylmethoxy) methyl] -1H-pyrido [4,3-b] indol- 1-one in maleic acid dried DME (75 ml) (920 mg) was added under nitrogen to sodium hydride (about 6 in oil).
(0% dispersion; 180 mg) and the reaction mixture was stirred at 60 ° for 6 hours. Next, 4- (chloromethyl) -5-
Methyl-1- (triphenylmethyl) -1H-imidazole (1.11 g) was added and the mixture was stirred at 60 ° overnight. Then acetic acid (10 ml), water (10 ml) and THF
(10 ml) was added and the resulting solution was heated to reflux for 6 hours. After cooling, 2N sodium hydroxide (100 ml) was added and the resulting suspension was dichloromethane (3 × 100 ml)
Extracted. The combined dried organic extracts were adsorbed on FCC silica and eluted with FCC with System A (150: 8: 1) to give the free base of the title compound as a foam (1.08
g) was obtained. A small amount of this compound (200 mg) was dissolved in methanol (30 ml) and the resulting solution was treated with maleic acid (5 ml).
8 mg). The solution was heated for 10 minutes, cooled, and dry ether was added to precipitate the title compound (170 mg). mp165-168}. Water content analysis Found: 0.22% w / w = 0.06mol H 2 O. Analysis Found: C, 64.5; H, 5.6 ; N, 10.7; C 24 H 24 N 4 O. C ₄ H ₄ O ₄ . 0.06H calculated for _{2 O: C, 65.0; H} , 5.5; N, 10.8%.

Examples 4 to 7 were prepared in the same manner as in Example 3.

[0089]Example 4 5-ethyl-2,3,4,5-tetrahydro-2-
[(5-Methyl-1H-imidazol-4-yl) methyl
Ru] -1H-pyrido [4,3-b] indole-1-one
Maleate 5-ethyl-2,3,4,5-tetrahydro-1H-pi
Lido [4,3-b] indol-1-one (500mg)
Treated with sodium hydride (60% dispersion in oil; 138 mg)
And then 4- (chloromethyl) -5-methyl-1
-(Triphenylmethyl) -1H-imidazole (92
7.5 mg) to afford the title compound as a solid.
The released base (320 mg) was obtained. Marked by maleate formation
The title compound (380 mg) was obtained. mp 175.5-177
゜. Analysis found: C, 62.1; H, 5.7; N, 13.0; C₁₈H₂₀N₄OC₄H₄O₄Calculated as: C, 62.2; H, 5.7; N, 13.2%.

Example 5 2,3,4,5-Tetrahydro-5- (1-methylethyl
Ru) -2-[(5-methyl-1H-imidazole-4-i
Ru) methyl] -1H-pyrido [4,3-b] indole-
1 -onemaleate 2,3,4,5-tetrahydro-5- (1-methylethyl) -1H-pyrido [4,3-b] indol-1-one (228 mg) in sodium hydride (in oil) 60% dispersion;
60 mg) and then 4- (chloromethyl) -5
Stirring with -methyl-1- (triphenylmethyl) -1H-imidazole (371 mg) gave the free base of the title compound (180 mg) as a solid. The title compound (172 mg) was obtained by maleate formation. mp203-2
05 ゜. Analysis Found: C, 62.6; H, 6.0 ; N, 12.6; C 19 H 22 N 4 O. Calculated for _{C 4 H 4 O 4: C} , 63.0; H, 6.0; N, 12.8%.

[0091]Example 6 2,3,4,5-tetrahydro-5- (phenylmethyl
Ru) -2-[(5-methyl-1H-imidazole-4-i
Ru) methyl] -1H-pyrido [4,3-b] indole-
1-Onmaleate monohydrate 2,3,4,5-tetrahydro-5- (phenylmethyl
Le) -1H-pyrido [4,3-b] indole-1-one
(960 mg) in sodium hydride (73% dispersion in oil;
132 mg) and then 4- (chloromethyl)-
5-methyl-1- (triphenylmethyl) -1H-imi
Stirred with dazole (1.3 g). Play of the title compound
The released base (571 mg) was converted to the system A (175:
8: 1) to give a solid.
The title compound (420 mg) was obtained by maleate formation.
Was. mp198-200}, TLC (System A, 100:
8: 1) Rf 0.3.

Example 7 5- (cyclopentylmethyl) -2,3,4,5-tetra
Lahydro-2-[(5-methyl-1H-imidazole-4
-Yl) methyl] -1H-pyrido [4,3-b] india
1-one-maleic acid salt 5- (cyclopentylmethyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole-1-
On (200 mg) is treated with sodium hydride (60% dispersion in oil; 60 mg) and then 4- (chloromethyl)
Stirred with -5-methyl-1- (triphenylmethyl) -1H-imidazole (280 mg). The free base of the title compound was obtained by FCC eluting with system A (200: 8: 1) as a solid (96 mg). The formation of the maleate gave the title compound (60 mg). m
p81-83 ゜, TLC (system A, 100: 8: 1) Rf
0.20.

[0093]Example 8 2,3,4,5-tetrahydro-5-methyl-2-
[(5-propyl-1H-imidazol-4-yl) methyl
Ru] -1H-pyrido [4,3-b] indole-1-one
Maleate Sodium hydride (oil 60% dispersion; 25 mg)
Below, 2,3,4,5-tetra in dry DME (5 ml)
Hydro-5-methyl-1H-pyrido [4,3-b] yne
Added to the stirred suspension of dollar-1-one (124 mg). Mixed
The mixture was heated at 50 ° C. for 7 hours and then dried DME (3
ml) 4- (chloromethyl) -N, N-dimethyl-5
-Propyl-1H-imidazole-1-sulfonamide
(165 mg) and stirring at 50 ° for 20 hours
Continued. 2N hydrochloric acid (5 ml) was added and the solution was heated for 6 hours.
Shed. The solution was treated with an 8% sodium hydrogen carbonate solution (50 ml)
And extracted with dichloromethane (3 × 25 ml). Combination
The dried organic extract was evaporated to a solid (200 mg)
And obtained by FCC using the system A (200: 10: 1).
Purified by eluting with the free salt of the title compound as a solid.
(58 mg) was obtained. This is heated in absolute ethanol (5m
l) dissolved in maleic acid in ethanol (0.5 ml)
(21 mg). The solvent was removed under reduced pressure and the residue
Is crystallized from ethanol: ether to give the title compound
(58 mg). mp137-138 ゜. Analysis found: C, 62.7; H, 5.9; N, 12.4; C₁₉H_{twenty two}N₄OC₄H₄O₄Calculated as: C, 63.0; H, 6.0; N, 12.8%.

Example 9 2,3,4,5-tetrahydro-N, N-dimethyl-2
-[(5-Methyl-1H-imidazol-4-yl) methyl
Ru] -1-oxo-5H-pyrido [4,3-b] india
Ole-5-carboxamide maleate 2,3,4,5-tetrahydro-2-[[5-methyl-1- (triphenylmethyl) in dry DMF (25 ml)
-1H-imidazol-4-yl] methyl] -1H-pyrido [4,3-b] indol-1-one (261 mg) was treated with sodium hydride (60% dispersion in oil; 30 mg).
And the mixture was stirred at room temperature under nitrogen for 15 minutes. Then, N, N-dimethylcarbamoyl chloride (D
(1M solution in MF; 1 ml) was added and the solution was allowed to stand for another 15
Stirred for minutes. Water (1 ml) was added carefully, after which the reaction mixture was poured into water (100 ml). The resulting mixture was extracted with ethyl acetate (2 × 50 ml) and the combined organic extracts were washed with water ((2 × 100 ml) and concentrated to give an oil which was water (10 ml). Glacial acetic acid (10 ml) and T
Dissolve in a mixture of HF (10 ml) and heat the solution to reflux for 1.5 hours. After cooling, the solution was washed with 2N sodium hydroxide (1
(00 ml) and the resulting mixture was extracted with ethyl acetate (2 × 75 ml). The combined dried organic extracts were adsorbed on FCC silica and the free base of the title compound (100 mg) was purified by FCC into System A (100: 8:
Elution in 1) gave a solid. This was dissolved in dry methanol (10 ml) and heated with maleic acid (36 mg) on a steam bath for 5 minutes. After cooling,
Dry ether (3 ml) was added and the title compound (105 mg)
Was precipitated. mp 161-163}. Water content analysis Found: 1.85% w / w = 0.49mol H 2 O. Analysis Found: C, 57.8; H, 5.4 ; N, 14.3; C 19 H 21 N 5 O 2. C ₄ H _{4 O.} 0.49H calculated for _{2 O: C, 68.0; H} , 5.5; N, 14.7%.

Examples 10, 11 and 12 were prepared in a manner similar to Example 9 unless otherwise indicated.

Example 10 2,3,4,5-tetrahydro-2-[(5-methyl-
1H-imidazol-4-yl) methyl] -5- (methyl
Sulfonyl) -1H-pyrido [4,3-b] indole-
1-one maleate 2,3,4,5-tetrahydro-2-[[5-methyl-
1- (triphenylmethyl) -1H-imidazole-4-
Yl] methyl] -1H-pyrido [4,3-b] indol-1-one (261 mg) in sodium hydride (60 in oil)
% Dispersion; 30 mg), followed by methanesulfonyl chloride (1 M solution in dry DMF; 1 ml).
Stir for 5 minutes. Deprotection, work-up and purification gave the free base of the title compound (60 mg) as a solid. The title compound (57 mg) was obtained by maleate formation. mp
152-155 °. Analysis Found: C, 53.2; H, 4.7 ; N, 11.7; C 17 H 18 N 4 O 3 S. Calculated for _{C 4 H 4 O 4: C} , 53.2; H, 4.7; N, 11.8%.

Example 11 2,3,4,5-tetrahydro-2-[(5-methyl-
1H-Imidazol-4-yl) methyl] -5- (2-p
Lopinyl) -1H-pyrido [4,3-b] indole-1
- one maleate dry acetone (75 ml) solution of 2,3,4,5-tetrahydro-2 - [[5-methyl-1- (triphenylmethyl)-1H-imidazol-4-yl] methyl] -1H -
Pyrid [4,3-b] indol-1-one (522 mg)
And a suspension of potassium carbonate (276 mg) was treated with propargyl bromide (1 M solution in acetone; 2 ml) and the mixture was heated at reflux overnight. After cooling, excess acetone was removed in vacuo to give an oil which was partitioned between water (100ml) and ethyl acetate (100ml). The aqueous phase was washed with ethyl acetate (50
ml), and the combined organic extracts were concentrated under reduced pressure. Deprotection, work-up and purification gave the free base of the title compound (100 mg) as a solid. The title compound (89 mg) was obtained by maleate formation. mp202-205
゜, TLC (system A, 100: 8: 1) Rf 0.29.

Example 12 2,3,4,5-tetrahydro-2-[(5-methyl-
1H-Imidazol-4-yl) methyl] -5- (2-p
Lopenyl) -1H-pyrido [4,3-b] indole-1
- one maleate 2,3,4,5-tetrahydro-2 - [[5-methyl -
1- (triphenylmethyl) -1H-imidazole-4-
Yl] methyl] -1H-pyrido [4,3-b] indol-1-one (1.0 g) was treated with sodium hydride (60 in oil).
% Dispersion; 114 mg) and then stirred with allyl bromide (460 mg) for 1 hour. Deprotection, workup and purification gave the free base of the title compound (380 mg) as a solid. The title compound (160 mg) was obtained by maleate formation. TLC (system A, 100: 8:
1) Rf 0.3. Analysis Found: C, 63.2; H, 5.5 ; N, 12.5; C 19 H 20 N 4 O. Calculated for _{C 4 H 4 O 4: C} , 63.3; H, 5.5; N, 12.8%.

Example 13 5-Cyclopentyl-2,3,4,5-tetrahydro-
2-[(5-methyl-1H-imidazol-4-yl) me
Chill] -1H-pyrido [4,3-b] indole-1-o
2,3,4,5-tetrahydro-2-[[5-methyl-1- (triphenylmethyl) in anhydrous maleic acid DMF (30 ml)
A solution of -1H-imidazol-4-yl] methyl] -1H-pyrido [4,3-b] indol-1-one (523mg) was treated with sodium hydride (60% dispersion in oil; 46mg).
And stirred under nitrogen at 21 ° for 15 minutes. Then, cyclopentyl bromide (298 mg) was added dropwise, and the mixture was diluted with 1
After stirring for an hour, the mixture was refluxed for 4 hours. Solution 21
２ 2 days, then acetic acid (7ml), water (7ml)
And a mixture of THF (8 ml). The resulting solution was heated at reflux for 4 hours, then basified with 2N sodium hydroxide and extracted with dichloromethane (3 × 25 ml). The combined extracts were washed with water (2 × 50 ml), concentrated in vacuo and purified by FCC, eluting with System A (100: 8: 1) to give the free base of the title compound as a solid (4
2 mg) were obtained. The title compound (3
8 mg). mp180 ° (decomposition), TLC (system A,
100: 8: 1) Rf 0.3.

Example 14 2,3,4,5-Tetrahydro-2-[(5-methyl-
1H-imidazol-4-yl) methyl] -5-propyl
-1H-pyrido [4,3-b] indole-1-onmale
2,3,4,5-tetrahydro in a mixture of in salt ethanol (20ml) and 2N hydrochloric acid (0.5 ml) -2 - [(5-methyl -1H- imidazol-4-yl] methyl] -5-
A solution of (2-propenyl) -1H-pyrido [4,3-b] indol-1-one (248 mg) was added at room temperature and atmospheric pressure to a 10% palladium oxide carbon catalyst pre-reduced (50%).
% Aqueous paste; 50 mg). The mixture was filtered and evaporated under reduced pressure. The residue was basified with 2N sodium hydroxide (10 ml) and dichloromethane (3 × 20)
ml). The combined organic extracts were washed with water (30ml) and evaporated to give the free base of the title compound (258mg) as a solid. The title compound (345 mg) was obtained by maleate formation. TLC (system A, 100: 8:
1) Rf 0.4. Water content analysis Found: 1.13% w / w = 0.28mol H 2 O. Analysis Found: C, 62.1; H, 5.9 ; N, 12.5; C 19 H 22 N 4 O. C ₄ H ₄ O ₄ . 0.28H calculated for _{2 O: C, 62.2; H} , 6.0; N, 12.6%.

Example 15 2,3,4,5-Tetrahydro-2-[(5-methyl-
1H-Imidazol-4-yl) methyl] -1H-pyrido
[4,3-b] Indol-1-one maleate 2,3,3 in ethanol (20 ml) and glacial acetic acid (5 ml)
4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl) methyl] -5- (phenyl (methoxymethyl)]-1H-pyrido [4,3-b] indol-1-one (400 mg) at room temperature under atmospheric pressure,
Hydrogenated overnight with pre-reduced 10% palladium oxide on carbon catalyst (50% aqueous paste; 100 mg). The reaction mixture was filtered and the residue was washed with ethanol (100ml). The filtrate was concentrated under reduced pressure to give an oil, to which 2N sodium hydroxide (50 ml) was added. The resulting suspension was extracted with dichloromethane (2 × 50 ml) and the combined dried organic extracts were evaporated to give a solid. This was purified by FCC eluting with System A (75: 8: 1) to give the free base of the title compound (240 mg) as a solid, which was then dissolved in dry methanol (50 mL). The title compound (261 mg) was obtained by maleate formation. TL
C (System A, 75: 8: 1) Rf 0.2. Analysis Found: C, 60.3; H, 5.2 ; N, 13.8; C 16 H 16 N 4 O. Calculated for _{C 4 H 4 O 4: C} , 60.6; H, 5.1; N, 14.1%.

[0102]Example 16 2,3,4,5-tetrahydro-5-methyl-2-
[(1,5-dimethyl-1H-imidazol-4-yl)
Methyl] -1H-pyrido [4,3-b] indole-1-
Onmaleate Sodium hydroxide (73% dispersion in oil; 40 mg)
2,3,4,5-Tet in dry DMF (3 ml)
Lahydro-5-methyl-2-[(5-methyl-1H-i
Midazol-4-yl) methyl] -1H-pyrido [4,3
-B] To a stirred suspension of indol-1-one (300 mg)
added. After 30 minutes, cool the suspension to 0 ° and add iodine
(0.076 ml) was added dropwise. Bring the mixture to room temperature
Stir for 1.5 hours, then pour into water (30 ml)
Extracted with dichloromethane (3 × 15 ml). Dry together
The organic extract was evaporated to give an oil (about 545 mg)
Was purified by FCC eluting with system A (200: 8: 1).
To give a solid (95 ml). Part of this substance (9
0 mg) was dissolved in absolute ethanol (3 ml).
Treatment with a solution of maleic acid (35 mg) in ethanol (1 ml)
Was. The solvent was removed under reduced pressure, and the residue was dried in ether (3 × 5 m
Trituration in l) afforded the title compound (122 mg). mp1
78-180 °. Analytical Found: C, 62.1; H, 5.7; N, 13.1; C₁₈H₂₀N₄O. C₄H₄O₄Calculated as: C, 62.3; H, 5.7; N, 13.2%.

Example 17 2,3,4,5-tetrahydro-2-[(1H-imida
Sol-4-yl) methyl] -5-methyl-1H-pyrido
[4,3-b] Indol-1-one dimaleate 2,3,4,5-tetrahydro-5-methyl-2-in a mixture of acetic acid, THF and water (1: 1: 1; 10 ml)
[[1- (Triphenylmethyl) -1H-imidazole-
A solution of 4-yl) methyl] -1H-pyrido [4,3-b] indol-1-one (0.22 g) was heated on a steam bath for 30 minutes. The suspension thus obtained was diluted with 1M hydrochloric acid (20 ml) and washed with ethyl acetate (3 × 20 ml). Basify the acidic aqueous phase with solid sodium carbonate,
Extracted with dichloromethane: methanol (9: 1; 3 × 20 ml). The combined dried organic extracts were evaporated to give a foam which was dissolved in methanol (5 ml) and treated with a solution of maleic acid (0.15 g) in methanol (5 ml). Evaporation of the clear solution gave a gum which was triturated with ether to give the title compound (0.17 g) as a solid. mp 117-118}. Analysis Found: C, 56.1; H, 4.3 ; N, 10.5; C 16 H 16 N 4 O. Calculated for _{2C 4 H 4 O 4: C} , 56.2; H, 4.7; N, 10.9%.

[0104]Example 18 2,3,4,5-tetrahydro-5-methyl-2-
[(5-Methyl-1H-imidazol-4-yl) methyl
Ru] -1H-pyrido [4,3-b] indole-1-one
Hydrochloride 2,3,4,5-tetrahydro-5-methyl-2-
[(5-Methyl-1H-imidazol-4-yl) methyl
Ru] -1H-pyrido [4,3-b] indole-1-one
(1.00 g) was suspended in ethanol (40 ml) and concentrated
The acid (1.00 ml) was added. Heat the mixture to 40 °,
Activated carbon (0.25 g) was added. Stir the resulting suspension
And warmed for 5 minutes, then filtered. About 20 ml of filtrate
Evaporated under reduced pressure and cooled to 20 °. Ether (40
ml) with stirring over 5 minutes, and the mixture is
And stored overnight. The resulting precipitate was collected by filtration and washed with ether.
(2 × 10 ml), 2 hours at room temperature, then 70
Dry under reduced pressure at ゜ for 7 hours to give the title compound (0.95 g)
I got mp288-291 ゜. Analysis found: C, 61.4; H, 5.8; N, 16.7; Cl, 10.7;₁₇H₁₈N₄O. Calculated for HCl: C, 61.7; H, 5.8; N, 16.9; Cl, 1
0.7%.

[0105]Example 19 2,3,4,5-tetrahydro-5-methyl-2-
[(5-Methyl-1H-imidazol-4-yl) methyl
Ru] -1H-pyrido [4,3-b] indole-1-one
Sulfate 2,3,4,5-tetrahydro-5-methyl-2-
[(5-Methyl-1H-imidazol-4-yl) methyl
Ru] -1H-pyrido [4,3-b] indole-1-one
(0.81 g) was suspended in absolute ethanol (6 ml), and 5
Heated at 0 ° with concentrated hydrochloric acid (0.15 ml). More eta
Knol (4 ml) was added and the mixture was activated charcoal (0.1 g).
With the mixture. The suspension was then filtered and the collected solid
Was washed with ethanol (about 3 ml). The obtained filtrate is placed in a chamber.
After stirring at room temperature for about 1 hour,
ml) was added slowly and the mixture was stirred for 20 minutes. Precipitate
, And ethanol: t-butyl methyl ether
(1: 1; 6 ml), followed by t-butyl methyl ether
(6 ml), and dried under reduced pressure at 40 ° C for 4 hours.
The compound (0.4 g) was obtained. mp205-209. Analysis found: C, 49.5; H, 5.6; N, 13.5; S, 8.
4; C₁₇H₁₈N₄O. 1.1H₂SO₄Calculated as: C, 49.9; H, 5.4; N, 13.3; S, 8.4.
%.

[0106]Example 20 2,3,4,5-tetrahydro-5-methyl-2-
[(5-Methyl-1H-imidazol-4-yl) methyl
Ru] -1H-pyrido [4,3-b] indole-1-one 2,3,4,5-tetrahydro in dry DME (50 ml)
-5-methyl-1H-pyrido [4,3-b] indole-
A suspension of 1-one (400 mg) was treated with sodium hydride (oil
60% dispersion; 100 mg) and the mixture is treated with nitrogen
The mixture was stirred at 60 ° for 6 hours. 4- (chloromethyl)-
5-methyl-1- (triphenylmethyl) -1H-imi
Dazole (474 mg) was added and the reaction mixture was added under nitrogen.
Stirred at 60 ° overnight. Then 2N hydrochloric acid (10 ml) and
Water (10 ml) was added and the mixture was heated at reflux for 6 hours. cold
After quenching, the mixture was basified with 2N sodium hydroxide and
The resulting mixture was extracted with ethyl acetate (2 × 50 ml).
The combined dried organic extracts are concentrated on FCC silica and
Purified by CC eluting with System A (150: 8: 1)
This gave the title compound (352 mg) as a solid. TL
C (System A, 100: 8: 1) Rf 0.28.¹ H-NMR: δ 2.2 (3H, s), 3.04 (2
H, t), 3.62 (2H, t), 3.72 (3H,
s), 4.53 (2H, s), 7.1-7.28 (2
H, m), 7.43 (1H, s), 7.47-7.55
(1H, dd), 7.94-8.03 (1H, dd).

The following examples show that 2,3,4,5
-Tetrahydro-5-methyl-2-[(5-methyl-1
1 illustrates a pharmaceutical formulation of the present invention containing [H-imidazol-1-yl] methyl] -1H-pyrido [4,3-b] indol-1-one. Physiologically acceptable salts and / or solvates of this compound, as well as other compounds of formula (I) and their physiologically acceptable salts and / or solvates, are formulated in a similar manner.

Tablets for oral administration Tablets are prepared by a conventional method such as direct compression or wet granulation. Tablets may be film-coated with a suitable film-forming substance such as hydroxypropylmethylcellulose using standard techniques. Or,
Tablets may be sugar-coated.

[0109] * Grade suitable for direct compression The active ingredient is sieved through 60 mesh and mixed with calcium hydrogen phosphate, croscarmellose sodium and magnesium stearate. The resulting mix is compressed into tablets on a Manesty F3 tablet press equipped with a 5.5 mm uniform bevel edge punch.

[0110] The active ingredient is sieved through a suitable sieve, mixed with the excipients and compressed with a suitable punch. Other strength tablets are made by varying the ratio of active ingredient to excipients or compressive weight and using an appropriate punch.

[0111] The active ingredient is sieved through a suitable sieve and mixed with lactose, starch and pregelatinized maize starch. Add an appropriate amount of purified water to granulate the powder. After drying, the granules are sieved and mixed with magnesium stearate. The granules are then compressed into 7 mm diameter punch tablets.

Other strength tablets are made by varying the ratio of active ingredient to lactose or compressive weight and using the appropriate punch.

[0113] The active ingredient is passed through a suitable sieve and mixed with mannitol and hydroxypropyl methylcellulose. Add an appropriate amount of purified water and granulate the powder. After drying, the granules are sieved and compressed into tablets with a suitable punch.

Other strength tablets are made by varying the ratio of active ingredient to mannitol or compressive weight and using an appropriate punch.

[0115] * In the form of starch for direct compression The active ingredient is sieved and mixed with excipients. The mix is filled into a size 2 hard gelatin capsule with a suitable machine. Other doses are made by changing the capsule size to the appropriate size, if necessary, and changing the total weight.

Syrup This can be either a product with or without sucrose. A. Sucrose syrup mg / 5 ml dose Active ingredient 0.5 Sucrose BP 2750.0 Glycerin BP 500.0 Buffer Flavor Required amount Colorant Preservative Make up to a total volume of 5.0 ml with purified water BP.

The active ingredient, buffers, flavoring agents, coloring agents and preservatives are dissolved in a portion of the water and glycerin is added. The remaining water is heated to dissolve the sucrose and then cooled. Combine the two solutions, adjust to the required volume, and mix.
The syrup is clarified by filtration.

B. Syrup-free syrup mg / 5 ml Dose Active ingredient 0.5 Hydroxypropyl methylcellulose USP 22.5 (viscous type 4000) Buffering agent Coloring agent Required amount Preservative Sweetener Purified water BP Make up to 5.0 ml with purified water.

The hydroxypropyl methylcellulose is dispersed in hot water, cooled and then mixed with an aqueous solution containing the active ingredient and the other ingredients of the formulation. The resulting solution is adjusted to an appropriate amount and mixed. The syrup is clarified by filtration.

[0120] Sodium chloride is added to adjust the tonicity of the solution to obtain an optimally stable pH and / or to adjust the pH with an acid or alkali to promote active ingredient dissolution. Alternatively, an appropriate buffer may be added.

The solution is prepared, clarified, filled into appropriately sized ampules and sealed by glass melting. The injection is sterilized by heating in one of the acceptable cycles in an autoclave. Alternatively, the solution may be sterilized by filtration and filled into sterile ampoules under aseptic conditions. The solution may be filled under an inert atmosphere of nitrogen or other suitable gas.

Mg pressurized aerosol suspension aerosol mg / measurement per can finely divided active ingredient 0.050 12.0 mg oleic acid BP 0.020 4.80 mg trichlorofluoromethane BP 23.64 5.67 g dichlorodifluoromethane BP 61 .25 14.70 g The active ingredient is comminuted in a liquid energy mill to a fine particle size range. Oleic acid is mixed with trichlorofluoromethane at a temperature of 10-15 ° C and the finely divided drug is mixed into the solution with a high shear mixer. The suspension is metered into an aluminum aerosol can, a suitable metering valve for injecting 85 mg of the suspension is crimped on the can, and dichlorodifluoromethane is pressure-filled from the valve into the can.

Mg of liquid aerosol / measuring amount per active ingredient 0.05 12.0 mg ethanol BP 7.500 1.80 mg trichlorofluoromethane BP 18.875 4.53 g dichlorodifluoromethane BP 48.525 11.65 g olein A suitable surfactant such as acid BP or Span 85 (sorbitan trioleate) may be included.

The active ingredient is dissolved in ethanol, if necessary with oleic acid or a surfactant. The alcohol solution is metered into a suitable aerosol container, and then trichlorofluoromethane. Appropriate metering valves are crimped into the containers and dichlorodifluoromethane is pressure-filled into them from the valves.

[0125] The active ingredient is comminuted in a liquid energy mill to a fine particle size range before mixing with conventional tablet lactose in a high energy mixer. The powder blend is filled into # 3 hard gelatin capsules with a suitable capsule filling machine.
The contents of the cartridge are administered using a powder inhaler.

[0126] The total volume 1.0g in suppository active ingredient 0.5 mg ^* Witepsol (Witepsol) H15. * Witepsol H15 is available from Adeps Solidus Ph. Eur.
Is a monopoly grade.

A suspension of the active ingredient is prepared in dissolved Witepsol and filled into 1 g size suppository molds using a suitable machine.

The effective and selective antagonism of 5-HT at the biologically active 5-HT ₃ receptor by the compounds of the present invention was demonstrated by G. kilpatrick in rat medial entorhinal cortex homogenates.
(G. Kilpatrick) et al., Nature, 1987, 33rd.
0, page 746,
In vitro 3- (5-methyl-1H-imidazole-4)
-Yl) -1- [1- (methyl-t ₃ ) -1H-indol-3-yl] -1-propanone. The experimental result is expressed as a pKi value. Examples 1, 3 to 9, 11, 12, 14,
The pKi values of compounds 15 and 16 are between 9.0 and 10.
5 range.

[0129]

Toxicity of toxic compounds will be assessed by administering them intravenously to mice. Examples 1, 7, 9, 1 of the present invention
Compounds 2, 15, and 16 did not produce adverse effects at a dose of 3 mg / kg.

──────────────────────────────────────────────────続 き Continuation of the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/00 626 A61K 31/00 626H 626N 643 643G 31/435 31/435 31/55 31/55 C07D 487/04 150 C07D 487 / 04 150 // (C07D 487/04 209: 08 223: 10) (72) Inventor Alexander, William, Oxford Hertfordshire, UK, Royston, Green, Drift, 60 (58) Fields studied (Int .Cl. ⁶ , DB name) C07D 471/04 103 A61K 31/435 AAE A61K 31/435 AAH A61K 31/435 AAM A61K 31/435 AAN A61K 31/435 ACL A61K 31/435 AEN A61K 31/55 ACP C07D 487 / 04 150

Claims (8)

(57) [Claims] 1. A neuronal 5-HT comprising, as an active ingredient, at least one compound of the following general formula (I) or a physiologically acceptable salt or solvate thereof. A pharmaceutical composition for the treatment of a condition caused by a dysfunction. Embedded image [In the above formula, Im represents an imidazolyl group of the following formula. Embedded image R ¹ is a hydrogen atom or C _1-6 alkyl, C _3-6 alkenyl, C _3-10 alkynyl, C _3-7 cycloalkyl, C _3-7
Cycloalkyl C _1-4 alkyl, phenyl, phenyl C
_1-3 alkyl, phenyl methoxymethyl, phenoxyethyl, _{^{phenoxymethyl, -CO 2 R 5, -COR 5}} ,
Represents a group selected from —CONR ⁵ R ⁶ or —SO ₂ R ⁵ (where R ⁵ and R ⁶ may be the same or different and each represents a hydrogen atom, C _1-6 alkyl or C
_3-7 cycloalkyl group or phenyl or phenyl C
_{Represents a 1-4} alkyl group, in which case the phenyl group may be optionally substituted by one or more C _1-4 alkyl, C _1-4 alkoxy or hydroxy groups or halogen atoms, provided that R ¹ is a group -CO ₂ R ⁵ or _-SO 2 ^{R 5}
And R ⁵ does not represent a hydrogen atom). R ² ,
One of the groups represented by R ³ and R ⁴ is a hydrogen atom or a C _1-6 alkyl, C _3-7 cycloalkyl, C _3-6 alkenyl, phenyl or phenyl C _1-3 alkyl group, The two groups may be the same or different,
Represents a hydrogen atom or a C _1-6 alkyl group. n is 2 or 3
Represents 2. The treatment for nausea and vomiting, characterized by comprising at least one compound of the following general formula (I) or a physiologically acceptable salt or solvate thereof as an active ingredient. And / or a pharmaceutical composition for promoting gastric emptying. Embedded image [In the above formula, Im represents an imidazolyl group of the following formula. Embedded image R ¹ is a hydrogen atom or C _1-6 alkyl, C _3-6 alkenyl, C _3-10 alkynyl, C _3-7 cycloalkyl, C _3-7
Cycloalkyl C _1-4 alkyl, phenyl, phenyl C
_1-3 alkyl, phenyl methoxymethyl, phenoxyethyl, _{^{phenoxymethyl, -CO 2 R 5, -COR 5}} ,
Represents a group selected from —CONR ⁵ R ⁶ or —SO ₂ R ⁵ (where R ⁵ and R ⁶ may be the same or different and each represents a hydrogen atom, C _1-6 alkyl or C
_3-7 cycloalkyl group or phenyl or phenyl C
_{Represents a 1-4} alkyl group, in which case the phenyl group may be optionally substituted by one or more C _1-4 alkyl, C _1-4 alkoxy or hydroxy groups or halogen atoms, provided that R ¹ is a group -CO ₂ R ⁵ or _-SO 2 ^{R 5}
And R ⁵ does not represent a hydrogen atom). R ² ,
One of the groups represented by R ³ and R ⁴ is a hydrogen atom or a C _1-6 alkyl, C _3-7 cycloalkyl, C _3-6 alkenyl, phenyl or phenyl C _1-3 alkyl group, The two groups may be the same or different,
Represents a hydrogen atom or a C _1-6 alkyl group. n is 2 or 3
Represents 3. An irritable bowel syndrome comprising at least one compound of the following general formula (I) or a physiologically acceptable salt or solvate thereof as an active ingredient: Pharmaceutical composition for treatment. Embedded image [In the above formula, Im represents an imidazolyl group of the following formula. Embedded image R ¹ is a hydrogen atom or C _1-6 alkyl, C _3-6 alkenyl, C _3-10 alkynyl, C _3-7 cycloalkyl, C _3-7
Cycloalkyl C _1-4 alkyl, phenyl, phenyl C
_1-3 alkyl, phenyl methoxymethyl, phenoxyethyl, _{^{phenoxymethyl, -CO 2 R 5, -COR 5}} ,
Represents a group selected from —CONR ⁵ R ⁶ or —SO ₂ R ⁵ (where R ⁵ and R ⁶ may be the same or different and each represents a hydrogen atom, C _1-6 alkyl or C
_3-7 cycloalkyl group or phenyl or phenyl C
_{Represents a 1-4} alkyl group, in which case the phenyl group may be optionally substituted by one or more C _1-4 alkyl, C _1-4 alkoxy or hydroxy groups or halogen atoms, provided that R ¹ is a group -CO ₂ R ⁵ or _-SO 2 ^{R 5}
And R ⁵ does not represent a hydrogen atom). R ² ,
One of the groups represented by R ³ and R ⁴ is a hydrogen atom or a C _1-6 alkyl, C _3-7 cycloalkyl, C _3-6 alkenyl, phenyl or phenyl C _1-3 alkyl group, The two groups may be the same or different,
Represents a hydrogen atom or a C _1-6 alkyl group. n is 2 or 3
Represents 4. A method for treating a psychiatric disorder, characterized by comprising at least one compound of the following general formula (I) or a physiologically acceptable salt or solvate thereof as an active ingredient. Pharmaceutical composition for. Embedded image [In the above formula, Im represents an imidazolyl group of the following formula. Embedded image R ¹ is a hydrogen atom or C _1-6 alkyl, C _3-6 alkenyl, C _3-10 alkynyl, C _3-7 cycloalkyl, C _3-7
Cycloalkyl C _1-4 alkyl, phenyl, phenyl C
_1-3 alkyl, phenyl methoxymethyl, phenoxyethyl, _{^{phenoxymethyl, -CO 2 R 5, -COR 5}} ,
Represents a group selected from —CONR ⁵ R ⁶ or —SO ₂ R ⁵ (where R ⁵ and R ⁶ may be the same or different and each represents a hydrogen atom, C _1-6 alkyl or C
_3-7 cycloalkyl group or phenyl or phenyl C
_{Represents a 1-4} alkyl group, in which case the phenyl group may be optionally substituted by one or more C _1-4 alkyl, C _1-4 alkoxy or hydroxy groups or halogen atoms, provided that R ¹ is a group -CO ₂ R ⁵ or _-SO 2 ^{R 5}
And R ⁵ does not represent a hydrogen atom). R ² ,
One of the groups represented by R ³ and R ⁴ is a hydrogen atom or a C _1-6 alkyl, C _3-7 cycloalkyl, C _3-6 alkenyl, phenyl or phenyl C _1-3 alkyl group, The two groups may be the same or different,
Represents a hydrogen atom or a C _1-6 alkyl group. n is 2 or 3
Represents 5. A method for treating dementia, which comprises as an active ingredient at least one compound of the following general formula (I) or a physiologically acceptable salt or solvate thereof. Pharmaceutical composition. Embedded image [In the above formula, Im represents an imidazolyl group of the following formula. Embedded image R ¹ is a hydrogen atom or C _1-6 alkyl, C _3-6 alkenyl, C _3-10 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-4 alkyl, phenyl, phenyl C _1-3 Alkyl, phenylmethoxymethyl, phenoxyethyl, phenoxymethyl, -CO ₂ R
^{5, -COR 5, -CONR 5 R} 6 or _-SO 2 R
⁵ wherein R ⁵ and R ⁶ may be the same or different and each represents a hydrogen atom, C _{1-6
Represents} an alkyl or C _3-7 cycloalkyl group or a phenyl or phenyl C _1-4 alkyl group, in which case the phenyl group optionally contains one or more C _1-4 alkyl, C _1-4 alkoxy or hydroxy groups or halogen atoms With the proviso that R ¹ is a group-
^R when CO ₂ R ⁵ or represent a _-SO 2 ^{R 5 5} does not represent a hydrogen atom). One of the groups represented by R ² , R ³ and R ⁴ is a hydrogen atom or C _1-6 alkyl,
_{A 3-7} cycloalkyl, C _3-6 alkenyl, phenyl or phenyl C _1-3 alkyl group, and the other two groups may be the same or different and each represent a hydrogen atom or a C _1-6 alkyl group. . n represents 2 or 3] 6. A reflux esophagitis, characterized in that it contains at least one compound of the following general formula (I) or a physiologically acceptable salt or solvate thereof as an active ingredient: Pharmaceutical composition for treatment. Embedded image [In the above formula, Im represents an imidazolyl group of the following formula. Embedded image R ¹ is a hydrogen atom or C _1-6 alkyl, C _3-6 alkenyl, C _3-10 alkynyl, C _3-7 cycloalkyl, C _3-7
Cycloalkyl C _1-4 alkyl, phenyl, phenyl C
_1-3 alkyl, phenyl methoxymethyl, phenoxyethyl, _{^{phenoxymethyl, -CO 2 R 5, -COR 5}} ,
Represents a group selected from —CONR ⁵ R ⁶ or —SO ₂ R ⁵ (where R ⁵ and R ⁶ may be the same or different and each represents a hydrogen atom, C _1-6 alkyl or C
_3-7 cycloalkyl group or phenyl or phenyl C
_{Represents a 1-4} alkyl group, in which case the phenyl group may be optionally substituted by one or more C _1-4 alkyl, C _1-4 alkoxy or hydroxy groups or halogen atoms, provided that R ¹ is a group -CO ₂ R ⁵ or _-SO 2 ^{R 5}
And R ⁵ does not represent a hydrogen atom). R ² ,
One of the groups represented by R ³ and R ⁴ is a hydrogen atom or a C _1-6 alkyl, C _3-7 cycloalkyl, C _3-6 alkenyl, phenyl or phenyl C _1-3 alkyl group, The two groups may be the same or different,
Represents a hydrogen atom or a C _1-6 alkyl group. n is 2 or 3
Represents 7. The pharmaceutical composition according to claim 1, which is in a form suitable for oral or parenteral administration. 8. An active ingredient comprising 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b The pharmaceutical composition according to any one of claims 1 to 7, which is indol-1one or a physiologically acceptable salt or solvate thereof.