JPS63211279A - Tricyclic ketone - Google Patents

Abstract

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

Description

DETAILED DESCRIPTION OF THE INVENTION BACKGROUND OF THE INVENTION This invention relates to tricyclic ketones, processes for their preparation, pharmaceutical compositions containing them and their therapeutic uses. More particularly, the present invention relates to compounds that act on 5-hydroxytryptamine (5-HT) receptors of the type located on primary afferent nerve terminals.

“onneuronal” type located on the primary afferent nerve
Compounds that have an antagonistic effect on (ncuronal) 5-HT receptors have already been identified as 3rJj.

For example, British Patent No. 2,153,821A and European Patent No. 191,562 contain the following general formula for one tetrahydrocarbazolone.

Here, R1 is a hydrogen atom or C alkyl, -1O C3-7 cycloalkyl, C3-7 cycloalkyl C1
-4 alkyl, C3-6 alkenyl, C3-10 flukynyl, phenyl or phenyl C1-3 alkyl group, and one of the groups represented by R2, R3 and R4 is a hydrogen atom or C1-6 alkyl, C3- 7 cycloalkyl, C2-8 fulkenyl or phenyl C1-
3 alkyl group, and each of the other two groups may be the same or different, and each of the other two groups may be a hydrogen atom or a Cl
-8 represents an alkyl group.

[Detailed description of the invention]

The present inventors have now discovered a new class of compounds that are structurally different from these previously described compounds and that are also able to antagonize the effects of 5-HT on its "ono-neuronal" receptors. .

Compounds Accordingly, in one aspect, the present invention provides tricyclic ketones of the following general formula (1), physiologically acceptable salts and solvates thereof: 1m is an imidazolyl group of the following formula, and Table R is:
Hydrogen atom, or C1-6 alkyl, C alkenyl, C alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-4 alkyl, phenyl, phenyl C1-3
Alkyl, -COR5, -COR5, -CONR5R6
or -8OR5 (here, R and R6 may be the same or different, and each represents a hydrogen atom, a Cl-8 alkyl or a C3-7 cycloalkyl group, or a phenyl or phenyl C1 -4 alkyl group, in which the phenyl group is optionally substituted by one or more 01-4 alkyl, Cl-4 alkoxy or hydroxy groups or halogen atoms, provided that in this case , R represents a group -CO2R or a -3o R5 group, R5 does not represent a hydrogen atom)).

One of the groups represented by R, R and R4 is a hydrogen atom, or C1-6 alkyl, C3-7 cycloalkyl, C3-0 alkenyl, phenyl or phenyl C1-3
In the alkyl group, each of the other two groups may be the same or different and represents a hydrogen atom or a C1-6 alkyl group.

Q is a hydrogen atom, a halogen atom, hydroxy, Cl
-4 alkoxy, phenyl C1-3 alkoxy or C alkyl group or group -NR7R8 or -CONRR (here, R7 and R8 may be the same or different and each represents a hydrogen atom or C alkyl or C3 -4
Together with the alkenyl group or the nitrogen atom to which R and R are bonded, they form a saturated 5- to 7-membered ring. ) n is 1.2 or 3
represents.

AB represents the group CH-CH2 or C-CH.

Suitable physiologically acceptable salts of compounds of general formula (I) include acid addition salts formed with inorganic or organic acids, such as hydrochlorides, hydrobromides, sulfates, alkyl or arylsulfonic acids. salts (e.g. methanesulfonate or para-toluenesulfonate) phosphates, acetates, citrates,
Includes succinate, tartrate, fumarate and maleate.

A solvate is, for example, a hydrate.

It will be understood that when AB represents CI (-CI2), the carbon atom A may be asymmetric and present in the R- or S-configuration.
Depending on the properties of 3, R4 and Q, optical and geometric centers may occur elsewhere in the molecule.

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

With respect to compounds of formula (I), R1, R2, R3, R4,
The alkyl groups represented by R5, R6, R7, R8 and Q may be straight-chain or branched alkyl groups, for example methyl, ethyl, propyl, prob-2-yl, butyl, budo-2-yl or 2-methylprob-2. -yl, which in the case of R1-R6 and Q may be pentyl, bent-3-yl or hexyl. An alkenyl group may be, for example, a propenyl or butenyl group.

An alkynyl group may be, for example, a prob-2-ynyl or an oct-2-ynyl group.

It is understood that when R or R3 represents a C alkenyl group and R7 or R8 represents a C alkenyl group, the double or triple bond will not be adjacent to the nitrogen atom.

A phenyl C alkyl group (such as a phenyl C1-37 rufoxy group or a portion thereof) is, for example, a benzyl, phenethyl, or 3-phenylpropyl group. A cycloalkyl group (such as a cycloalkylalkyl group or a part thereof) is, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclohebutyl group.

When R1 represents a CcycloalkylCl-4alkyl group, the alkyl moiety is, for example, a methyl, ethyl, propyl, prob-2-yl or butyl group. Q is C1-4
When representing an alkoxy group, Q is, for example, a methoxy group. When Q represents a halogen atom as shown in Table 1, Q is, for example, a fluorine, chlorine, or bromine atom. The substituent Q may be in the a, bSc or d position of the indole moiety: ↑ A preferred class of compounds of formula (1) are those in which R1 is a hydrogen atom or C1-3 alkyl (e.g. methyl), C3-4 alkenyl ( (e.g. prob-2-enyl), C3-4 alkynyl (e.g. prob-2-ynyl), C5-6 cycloalkyl (e.g. cyclopentyl), C5-6 cycloalkylmethyl (e.g. cyclopentylmethyl), phenyl Cl-2 alkyl ( (e.g. benzyl), C1-3 alkoxycarbonyl (e.g. methoxycarbonyl), N
, N-diC1-3 alkylcarboxamide (e.g.
N,N-dimethylcarboxamide) or phenylsulfonyl group. More preferably, R1 is a hydrogen atom or C1-3 alkyl (e.g. methyl),
C3-4 fulkenyl (e.g. prob-2-enyl),
C3-4 flukynyl (e.g. prob-2-ynyl),
C5-6 cycloalkylmethyl (e.g. cyclopentylmethyl), phenylC1-2 alkyl (e.g. benzyl), C1-3 alkoxycarbonyl (e.g. methoxycarbonyl), or N,N-diC1-3 alkylcarboxamide (e.g. N , N-dimethylcarboxyamide) group.Most preferably, R1 is a hydrogen atom, or C1-3 alkyl (e.g. methyl), C3
-4Flukenyl (e.g. prob-2-enyl)C3-
4furkynyl (e.g. prob-2-ynyl) C5-8
A cycloalkylmethyl (eg cyclopentylmethyl), phenylCl-2alkyl (eg benzyl) or N,N-diC1-3alkylcarboxamide (eg N,N-dimethylcarboxamide) group.

Another preferred class of compounds of formula (I) are those in which R is a hydrogen atom or a Cl-3 alkyl (eg methyl) group, more preferably a hydrogen atom.

A more preferred class of compounds of formula (1) are those in which R4 represents a hydrogen atom or C1-3 alkyl (methyl group).

Another preferred class of compounds of formula (I) is that Q is a hydrogen atom, a halogen atom (e.g. fluorine), or hydroxy,
C1-3 alkoxy (e.g. methoxy) or C1-3
An alkyl (eg, methyl) group. More preferably Q represents a hydrogen atom, a halogen (eg fluorine) atom or a hydroxy group. Most preferably Q represents a hydrogen atom or a fluorine atom.

When Q represents a substituent other than a hydrogen atom, Q is preferably in the b or 0 position of the indole moiety.

Another preferred class of compounds of formula (1) is that AB is C
It represents H-CH2.

A further preferred class of compounds of formula (I) are those in which n is 2 or 3, particularly preferably 2.

Preferred groups of the compound of formula (1) are those in which R1 is a hydrogen atom or C alkyl, C3-4 alkenyl, C alkynyl, C5
-8 cycloalkylmethyl, phenyl C alkyl, Cl
-3 alkoxylic! -2 represents a carbonyl or N,N-diC1-3 alkylcarboxamide group, R and R3 each represent a hydrogen atom, R represents a hydrogen atom or a C1-3 alkyl group, and Q represents a hydrogen atom or a halogen atom or represents a hydroxy group,
AB represents CH-CH2 or C-CH, and n represents 2 or 3.

A particularly preferred group of compounds of formula CI) are those in which R1 is a hydrogen atom or methyl, prob-2-enyl, prob-2-
inyl, cyclopentylmethyl, benzyl, or N,
N-dimethylcarboxamide group, R2 and R3 each represent a hydrogen atom, R4 represents a methyl group, Q represents a hydrogen atom or a fluorine atom, AB represents CH-CH2, n is 2 or 3.

Among the preferred and particularly preferred groups of compounds mentioned above, a particularly important group of compounds are those in which n is 2.

Preferred compounds according to the invention are those listed below and their physiologically acceptable salts and solvates.

(a) 6-fluoro-1,2,3,9-tetrahydro-9-methyl-3-((5-methyl-IH-imidazol-4-yl)-methyl]-4H-carbazol-4-one, )1.2.3.9-tetrahydro-3-[(5-methyl-IH-imidazol-4-yl)methyl] -4H
-carbazol-4-one, (c) 9-(cyclopentylmethyl)-1,2°3.9-tetrahydro-3-[
(5-methyl-IH-imidazol-4-yl)methyl]
-4H-carbazol-4-one, (d)1,2,3.9-tetrahydro-3-[(5-methyl-IH-imidazol-4-yl)methyl)-9-(
2-propynyl)-4H-carbazol-4-one.

A further preferred compound according to the invention is 6,7°8.9
-tetrahydro-5-methyl-9-((5-methyl-I
H-imidazol-4-yl)methyl2cyclohebut(
b) indole-10 (5H)-one and its physiologically acceptable salts and solvates.

Particularly preferred compounds according to the invention are 1,2°3.9
-tetrahydro-9-methyl-3-[(5-methyl-I
H-imidazol-4-yl)methylgo 4H-carbazol-4-one and its physiologically acceptable salts and solvates (eg hydrates) thereof.

The preferred forms of this compound are the hydrochloride and maleate salts. A particularly preferred form is the hydrochloride-hydrate.

It is understood that the invention also extends to physiologically acceptable equivalents of the compounds of the invention, i.e., physiologically acceptable compounds which are converted in vivo into compounds under formula (1). It is about to be done.

Utilization of Compounds/Pharmaceuticals The compounds of the present invention can be used in isolated rat vagus nerve preparations.
It is a potent and selective antagonist of the HT-evoked response, and therefore the neuronal 5-HT receptor on primary afferents
r type ) as a potent and selective antagonist. This type of receptor is called a 5-HT3 receptor. Such receptors are also present in the central nervous system. 5-HT occurs widely in neuronal pathways of the central nervous system, and disorders of this 5-HT-containing pathway are known to alter behaviors, such as mood, psychomotor activity, appetite, and memory. .

Compounds of formula (I) that antagonize the action of 5-HT on the 5-HT3 receptor are useful for treating psychotic disorders (e.g. schizophrenia,
It is useful in treating conditions such as chronic illness), anxiety, nausea, and vomiting (particularly those associated with cancer treatment or radiation therapy). Compounds of formula (1) are also useful in the treatment of gastric fluid retention and gastrointestinal dysfunction such as occurs in dyspepsia, peptic ulcers, anti-bulbar esophagitis, flatulence and irritable bowel symptoms, migraines and pain. . Compounds of formula (1) may also be used in the treatment of drug or substance dependence of abuse, depression and dementia, and other cognitive disorders.

Unlike current drug treatments for those with the above diseases,
It is believed that the compounds of the invention will not produce undesirable side effects due to their strong selectivity for the 5-HT3 receptor. Thus, for example, neuroleptics may produce extrapyramidal effects, such as tardive motor MI harm, and benzodiazepines may produce drug dependence.

In another aspect, the present invention provides treatment for psychosis, such as schizophrenia or chronic illness, or anxiety disorders, particularly nausea and vomiting associated with cancer chemotherapy or radiotherapy, gastric fluid retention, gastrointestinal dysfunction, such as digestive problems, The present invention provides a treatment method for patients and animals with symptoms of anti-control esophagitis, peptic ulcer, flatulence and irritable bowel syndrome, or migraine or pain, and this treatment method is based on the formula (1).
or a physiologically acceptable salt or solvate thereof.

Therefore, the present invention also provides tricyclic ketone derivatives of general formula (1), physiologically acceptable salts and solvates thereof, such as hydrates, for use in the medical or veterinary field. )
consisting of at least one compound selected from ,
Pharmaceutical compositions are provided that are formulated for administration via a convenient route of administration.

Such compositions will be formulated in conventional manner using one or more physiologically acceptable carriers and/or excipients.

Therefore, this compound of the invention is suitable for oral, buccal use.
cal), for parenteral, rectal, transdermal administration, or
They can be formulated in a form suitable for administration by inhalation or infusion (either through the RL or nose).

For oral administration, the pharmaceutical compositions may be in the form of tablets or capsules, for example, by conventional means using pharmaceutically acceptable excipients. The excipient can be, for example, a binder (such as gelled corn starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose), a filler (such as lactose, microcrystalline cellulose, or calcium hydrogen phosphate), a lubricant (such as magnesium stearate) , talc or silica), tablet disintegrating substances (
For example, potato starch, or sodium starch glycolate) or a humectant (eg, sodium lauryl sulfate). The tablets may be coated by methods known in the art. Solution preparations for oral administration may, for example, be in the form of aqueous solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable carrier before use. . Such solution preparations may contain pharmaceutically acceptable excipients, such as suspending agents (such as sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (such as lecithin or acacia), non-aqueous media (such as almond oil), etc. , fat esters, ethyl alcohol, or fractionated vegetable oils) and preservatives (
eg methyl or propyl-p-hydroxybenzoate or sorbic acid). The preparation may contain buffer salts, flavoring, coloring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated for controlled release of the active compound.

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

The compounds of the invention may be formulated for parenteral administration, eg, by injection by bolus infusion 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 be in the form of suspensions, solutions, or emulsions in oily or aqueous carriers and may include formulation materials such as floating agents.
It may also contain stabilizers and/or dispersants. Alternatively, the active ingredient may be in powder form for constitution with a suitable carrier, eg, sterile pyrogen-free water, before use.

The compounds of the invention may be administered in the form of rectal compositions containing conventional herbal bases, such as cocoa butter and other glycerides, such as herbal medicines or continuous enemas (reLenLoneneIIa).
It may be formulated in the form of

In addition to the formulations previously described, the compounds of the invention may also be formulated as a depot. Such long-acting formulations may be administered by implantation (eg, subcutaneously, intradermally, or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention may be formulated with suitable polymers or hydrophobic substances (e.g. as emulsions in acceptable oils) or ion exchange resins, or as poorly soluble derivatives, e.g. as sparingly soluble salts. It may also be formulated into a formulation.

For administration by inhalation, the compounds of the invention can be administered in a pressurized box or as a powder using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorofluoroethane, carbon dioxide or other suitable gas. From the fogger,
It is conveniently released in the form of an aerosol spray preparation. In the case of pressurized aerosols, the dosage unit amount would be determined by defining a valve to release a predetermined amount.

Capsules or cartridges, eg of gelatin, for use in an inhaler or insufflator may be formulated containing a powder mixture of a compound of the invention and a suitable powder base, eg lactose or starch.

For intranasal administration, the compounds of the invention can be administered in a suitable carrier, either as a solution for administration by means of a suitable metering or single-dose device, or alternatively, with a suitable dispensing device. It may be formulated as a powder containing.

Compounds of formula (1) may be administered in combination with other therapeutic agents. Thus, for example, in the treatment of gastric effusion, gastrointestinal dysfunction syndromes and nausea and vomiting, compounds of formula (1) may be used as secretion inhibitors, such as histamine H2-receptor antagonists (such as ranitidine, sufotidine or locustidine) or H" It may also be administered in combination with K+ adenosine triphosphatase (eg omeprazole).

The recommended dosage of the compounds of the present invention for administration to humans (approximately 70 kg body weight) is 0.5 mg of active ingredient per unit dose. OO, 1-100+ng, e.g. 0.01-
50 mg, more preferably 0.1 to 20 mg, which may be administered, for example, 1 to 4 times a day. The dosage depends on the route of administration and the condition. It will be appreciated that routine variations in dosage may be necessary depending on the age and weight of the patient as well as the severity of the symptoms.

Preparation of Compounds According to yet another aspect of the invention, compounds of general formula (I), and physiologically acceptable salts or solvates thereof, may be prepared by the general methods outlined below. can. In the following, the groups R1, R2, R3, R4, A
s Bs Qs n and 1m are as defined for compounds of general formula (I), unless otherwise stated.

According to the first general method (A), A-B is C-CH
The compound of general formula (I) representing Jj is a compound of formula (II) or a derivative having a protecting group of formula (II) (hereinafter referred to as
It can be prepared by dehydration of a protected form (sometimes referred to as a protected form) and, if necessary, subsequent deprotection.

The dehydration step can be carried out in a conventional manner, for example using an organic or inorganic acid (
p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid or hydrochloric acid) in a suitable solvent, such as an ether (e.g. tetrahydrofuran), an alcohol (
For example, methanol) or glacial acetic acid can be used in the temperature range of 0 to 100°C.

According to an embodiment of this method, a compound of general formula (I), in which AB represents moss C-CH, is a compound of formula (III)
) or its protected form as a compound oHC-Im of formula (IV)
It can be prepared by direct reaction with (IV) or its monoprotector in an inert solvent such as an ether (such as tetrahydrofuran) in the presence of a base such as an alkali metal amide (such as lithium diisopropylamide). Dehydration is then carried out "in situ" using the appropriate conditions described above, followed by any necessary deprotection. The compound of formula (n) may be isolated as an intermediate in a preferred embodiment of step (A).

According to another embodiment of this process, a compound of general formula (1), in which AB represents a group C-CH, is a compound of formula (n
) to a leaving group such as a hydrocarbyl sulfonate (e.g. mesylate or trifluoromethanesulfonate), an ether (e.g. tetrahydrofuran) or an alcohol in the presence of a base (e.g. triethylamine or aqueous sodium hydroxide). (eg methanol) by conversion using conventional methods.

According to another general method (B), a compound of general formula (1) may be converted into another compound of formula (1) using conventional techniques. Such common techniques include hydrogenation,
Alkylation, acylation, and acid-catalyzed cleavage (with protection and deprotection where necessary) are included.

Therefore, according to one embodiment of the conversion step (B), the formula (
I) in which A-B represents the group CH-CH, R is other than a C3-6 alkenyl or C3-1o alkynyl group, and/or Q is other than a benzyloxy group ) is the corresponding compound (here A
-B represents a group C-CH). Hydrogenation may also be used to convert alkenyl or alkynyl substituents to alkyl substituents, or alkynyl groups to alkenyl substituents, or benzyloxy substituents to hydroxy groups.

Hydrogenation according to general method (B) can be carried out using conventional processes, for example using hydrogen in the presence of a noble metal catalyst (eg palladium, Raney nickel, platinum or rhodium). This catalyst may be supported on charcoal or alumina, for example, or a homogeneous catalyst such as tris(triphenylphosphine)rhodium chloride may be used. Hydrogenation is generally carried out in a solvent such as an alcohol (e.g. methanol or ethanol), an ether (e.g. dioxane), a halogenated hydrocarbon (e.g. dichloromethane) or an ester (e.g. ethyl acetate) or a mixture thereof. It will be carried out at a temperature range of 20°C to +100°C, preferably 0 to 50°C.

According to another specific example of this conversion step (B), a compound of formula (1) (wherein R1 is C alkyl, C cycloalkyl, C3-8 alkenyl, C alkynyl, C3-7 cycloalkyl Cl-4 alkyl or phenyl Cl-3 alkyl group) or a compound in which at least one of R and R represents Cl-8 alkyl, C cycloalkyl, C3-6 fluorenyl or phenyl C1-3 alkyl group, or Q is a C
A compound representing a 1-4 alkoxy or phenylCl-3 alkoxy group, or a compound in which R7 and/or R represents a C1-4 alkyl or C3-4 alkenyl group, is represented by the formula (
1) (herein, R, R, R, R and R8
one or more of which represents a hydrogen atom and Q represents a hydroxyl group).

According to general method (B) the term "alkylation".

therefore includes the introduction of other groups, such as cycloalkyl, alkenyl or phenalkyl groups.

The above alkylation reaction can be carried out using a suitable alkylating agent selected from compounds of formula R9Z. Here, R9 of the formula RZ is C-e alkyl, C3-7 cycloalkyl, C3-6 alkenyl"3-10 alkynyl, C3-7 cycloalkyl C1
-4 alkyl or phenylC1-3 alkyl group, Z represents a leaving atom or group, such as a halogen atom (e.g. chlorine, bromine, iodine), acyloxy,! ! (for example trifluoroacetyloxy or acetoxy), or a sulfonyloxy group (for example trifluoromethanesulfonyloxy, p-toluenesulfonyloxy or methanesulfonyloxy). In addition, this alkylation reaction is
It may also be carried out using a sulfuric ester of formula (R)2S04.

The alkylation reaction is conveniently carried out in an inert organic solvent such as a substituted amide (e.g. dimethylformamide), an ether (e.g. tetrahydrofuran) or an aromatic hydrocarbon (e.g. toluene), preferably in the presence of a base. Ru. Suitable bases include, for example, alkali metal hydrides (e.g. sodium hydride), alkali metal amides (e.g. sodium amide, or lithium diisopropylamide), alkali metal carbonates (e.g. sodium carbonate) or alkali metal alkoxides (e.g. sodium or potassium methoxide, ethoxide, or t-butoxide). This reaction can be conveniently carried out at a temperature range of -80 to +100°C, preferably between -80°C and +50°C.

According to another embodiment of general process (B), compounds of formula (I) (wherein R1 represents -CoR5, -COR5, -CONR5R6 or (wherein R1 represents a hydrogen atom) ) can be prepared by acylating this acylation reaction.
This can be carried out according to conventional procedures using suitable acylating agents.

Suitable acylating agents include acyl halides (e.g., acyl chloride, bromide, or iodide, alkylsulfonyl or allylsulfonyl), mixed and symmetric anhydrides (e.g.
Symmetric anhydrides of formula (R5CO) O), lower alkyl haloformates (e.g. lower alkyl chloroformates), sulfonates (e.g. hydrocarbyl sulfonates, e.g. p-1 luenesulfonate), carbamoyl halides (e.g. chlorides of formula R5R6Ncoc1) carbamoyl), carboxylic acid salts and isocyanates (eg, isocyanates of formula R5NGO).

This reaction is conveniently carried out in the presence of a base.

Bases in that case include, for example, metal hydrides (e.g. sodium or potassium hydride), alkali metal carbonates (e.g. sodium or potassium carbonate), alkali metal alkoxides (e.g. potassium tert-butoxide), butyllithium, lithium diisopropylamide. or an organic tertiary amine (eg triethylamine or pyridine).

Suitable solvents that can be used in the acylation of general method (B) include amides (e.g. dimethylformamide or dimethylacetamide), ethers (e.g. tetrahydrofuran or dioxane), halogenated hydrocarbons (e.g. methylene chloride, ), nitriles (
for example acetonitrile) and esters (eg ethyl acetate). The reaction is -10~+150℃
It is convenient to do so.

According to yet another embodiment of general process (B), compounds of formula (I) in which Q is a hydroxyl group may be prepared by acid catalytic decomposition of corresponding compounds in which Q is an alkoxy or benzyloxy group. Can be done. This reaction is
Lewis acids such as boron tribromide or aluminum trichloride may be used in a solvent such as a halogenated hydrocarbon such as dichloromethane. Conveniently, the reaction temperature is in the range -80 to +100<0>C.

According to another general method (C), a compound of general formula (1), in which AB is CM-CH2, is a compound of formula (I
II) or its protected form is a compound of formula (V):
(as described above for Z) in the presence of a base, followed by removal of protecting groups if necessary. Suitable bases include alkali metal hydrides (eg sodium or potassium hydride), alkali metal alkoxides (eg potassium t-butoxide) or alkali metal amides (eg lithium diisopropylamide).

This reaction is performed in an inert solvent such as an ether (e.g.
tetrahydrofuran), substituted amides (e.g. dimethylformamide), or aromatic hydrocarbons (e.g.
It is conveniently carried out in the presence of toluene) at a temperature in the range -80 to +50°C.

According to another general method (D), a compound of general formula (I) in which AB represents CH-CH2 is a compound of formula (Vl): (where A is a hydrogen atom or hydroxy (indicating a group) or a salt or protected form thereof, followed by optionally removing the protecting group.

This oxidation reaction can be carried out using conventional methods and reagents, but reaction conditions should be chosen so as not to result in oxidation of the indole moiety or other functional groups. Therefore, the oxidation is preferably carried out using a mild oxidizing agent.

When oxidizing a compound of formula (Vl) in which A is a hydrogen atom, suitable oxidizing agents include quinones (for example, 2,3-dichloro-5,6-dicyano-1,4 −
Benzoquinone or 2,3゜5.6-tetrachlor-1
, 4-benzoquinone), selenium dioxide, cerium (IV
) oxidizing agents (eg, cerium ammonium nitrate) and chromium (Vl) oxidizing agents (eg, chromic acid in acetone, eg, Jones' reagent, or chromium trioxide in pyridine).

When oxidizing a compound of formula (Vl) in which A is a hydroxy group, suitable oxidizing agents include quinones (e.g. 2,3-dichloro) in the presence of water and a base (e.g. aluminum t-butoxide). -5,6-dicyano-1,
4-benzoquinone or 2, 3. 5.6-tetrachloro-1,4-benzoquinone), ketones (e.g.
acetone, methyl ethyl ketone or cyclohexanone), chromium (Vl) oxidizing agents (e.g. chromic acid in acetone such as Jones' reagent, or chromium dioxide in pyridine), N-halosuccinimides (e.g.
N-chlorosuccinimide), N,N'-dicyclohexylcarbodiimide or dialkyl sulfoxides (e.g. dimethyl sulfoxide) in the presence of an acyl halide (e.g. oxalyl chloride or tosyl chloride), a pyridine-sulfur dioxide complex, and a dehydrogenation catalyst ( (e.g. copper chromite, zinc oxide, copper or silver).

Suitable solvents include ketones (e.g. acetone or butanone), ethers (e.g. tetrahydrofuran or dioxane), amides (e.g. dimethylformamide), alcohols (e.g. methanol),
Hydrocarbons (e.g. benzene or toluene),
These include logenated hydrocarbons (eg dichloromethane) and water and mixtures thereof.

This process is conveniently carried out at temperatures between -70 and +50<0>C. It is understood that the preferred reaction temperature will vary depending on the oxidizing agent chosen.

The compounds of formulas (If) and (V[) are novel compounds and constitute one of the features of the present invention.

According to another general method (E), in a compound of formula (I) A
Those in which -B is CH-CH2 can be produced by cyclizing the compound of formula (■) or a salt or protected form thereof, and then removing the protecting group as necessary.

It is understood that the compound of formula (■) exists in the form of the corresponding enolhydrazone tautomer.

This cyclization can be carried out in an aqueous or non-aqueous medium in the presence of an acid catalyst. When an aqueous medium is employed, this may be water or an aqueous organic solvent such as an aqueous alcohol (e.g. methanol, ethanol or isopropanol) or an aqueous ether (e.g. dioxane or tetrahydrofuran) and mixtures of these solvents, and an acid catalyst. is, for example, an inorganic acid such as concentrated hydrochloric acid or sulfuric acid (in some cases the acid catalyst also serves as the reaction solvent). In a non-aqueous reaction medium, for example in a medium consisting of one or more alcohols or ethers (e.g. those mentioned above), carboxylic acids (e.g. acetic acid) or esters (e.g. ethyl acetate), the acid catalyst is Generally Lewis acids such as boron trifluoride, zinc chloride or magnesium chloride. The cyclization reaction is 20-2
It is convenient to carry out the process at a temperature of 00°C, preferably 50-125°C.

Alternatively, the process can be carried out in the presence of a polyphosphate ester in a reaction medium consisting of one or more organic solvents. In this case, solvents include halogenated hydrocarbons such as chloroform, dichloromethane,
Dichloroethane, dichlorodifluoromethane or mixtures thereof are preferred. Polyphosphate esters are made from phosphorus pentoxide, diethyl ether and chloroform.
RIKO-JENTSφ4ORGANIC SYNTHESIS J
(Pieser and Pieser: Reag.
ents for OrganicSynthesls
, John Viley and 5ons 1967
) is a mixture of esters that can be made according to the method described in ).

According to one specific example of method (E), the compound of general formula (I) is a compound of formula (■): or a salt thereof;
The compound: i- or its protected form can be directly prepared by reacting with i- or its protected form under the appropriate conditions described above, followed by deprotection if necessary. The compound of formula (■) can be isolated as an intermediate in this embodiment.

The protected form of the compound of formula (IX) is, for example, one in which one or both of the carbonyl groups are protected (for example,
as enol ether). 3- of the compound of formula (IX)
When a protected carbonyl group is used, it may be necessary to remove this protecting group in order to allow the reaction with the compound of formula (■) to occur. Deprotection may be carried out by any convenient method as described below. If desired, deprotection may be performed "in situ."

It will be appreciated that in the above conversion reactions it may be necessary or desirable to protect sensitive groups in the molecule of the compound in question. For example, it may be necessary to protect the keto group as, for example, a ketal or thioketal or as an enol ether. The carbazolone and/or imidazole nitrogen atom can be replaced with, for example, arylmethyl (e.g. benzyl or trityl), alkyl (e.g. t-butyl), alkoxymethyl (e.g. methoxymethyl), acyl (e.g. benzyloxycarbonyl) or sulfonyl (e.g. ,N,N
-dimethylaminosulfonyl or p-toluenesulfonyl) groups may also be necessary. If Q represents a hydroxy group, it may be necessary to protect this hydroxy group with an arylmethyl (eg benzyl or trityl) group.

Therefore, according to another general method (F), the general formula (1)
The compound of formula (1) can be prepared by removing the protecting group from the protected form of the compound of formula (1).
cnc:Protective Groups 1n
Or-ganic 5ynthcsis, John W.
It may be carried out by employing the method described in J. Ilcy and 5ons, 1981).

For example, a ketal such as an alkylene ketal group is
It can be removed by treatment with mineral acids such as hydrochloric acid. The thioketal group can be removed by treatment with a mercury salt (eg mercuric chloride) in a suitable solvent such as ethanol. Enol ethers can be hydrolyzed in the presence of aqueous acid (eg dilute sulfuric or hydrochloric acid). Arylmethyl N-protecting groups can be removed by hydrogenolysis in the presence of a catalyst, and trityl groups can be removed by acid hydrolysis (eg, using dilute hydrochloric acid or acetic acid). Alkoxyalkyl groups can be removed using Lewis acids such as boron tribromide. Acyl groups can be removed by hydrolysis under acidic or basic conditions (eg, using hydrogen bromide or sodium hydroxide). Sulfonyl groups can be removed by alkaline hydrolysis. The arylmethyl OH protecting group is
It can be removed under acidic conditions (eg with dilute acetic acid, hydrobromic acid or boron tribromide) or by hydrogenolysis in the presence of a catalyst (eg palladium on charcoal).

A compound of formula (II) can be prepared by inactivating a compound of formula (m) or a protected form thereof with a compound of formula (rV) or a protected form thereof in the presence of a base such as an alkali metal amide (e.g. lithium diisopropylamide). It can be made by condensation in a solvent such as an ether (eg, tetrahydrofuran).

Compounds of formula (III) can be prepared, for example, by Oikawa and Yonemitsu: J, Org, ChcIm, 1977.42.
It can be made by a method similar to that described in No. 1213.

Compounds of formula (IV) can be made, for example, by oxidizing the corresponding hydroxymethylimidazole of formula (XI): HOCH21m (X I ) or its protected form with an oxidizing agent such as manganese dioxide.

Compounds of formula (V) in which L is a halogen atom can be prepared by reacting a compound of formula (XI) or a protected form thereof with a halogenating agent such as thionyl chloride or phosphorus trihalide (e.g. phosphorus trichloride). Obtainable. Compounds of formula (V) in which L is an acyloxy or sulfonyloxy group may be prepared by combining a compound of formula (XI) with a suitable acylating or sulfonylating agent such as an anhydride or a sulfonyl halide (e.g. methanesulfonyl chloride). It can be prepared by reacting in the presence of a base (eg, triethylamine or pyridine) depending on the situation.

Compounds of formula (Vl) can be prepared, for example, by reacting compounds of formula (I) with a suitable reducing agent. Therefore, in the compound of formula (Vl) in which A is a hydrogen atom, the compound of formula (I) may be treated with a hydride reducing agent, e.g.
It can be made by reacting with diisobutylaluminum hydride or sodium borohydride.

When using diisobutylaluminum hydride, an additional hydrogenation step may be necessary.

Hydrogenation can be carried out using a conventional method, for example, the method described in method (B). A compound of formula (Vl) in which A is a hydroxy group can be produced, for example, by reacting a compound of formula (1) with an alkali metal hydride (for example, lithium hydride).

The compound of formula (■) can be prepared, for example, by mixing a compound of formula (■) or a salt thereof with a compound of formula (IX) or a protected form thereof in a suitable solvent such as an alcohol, for example, 20-1
It can be produced by reacting at a temperature of 00°C.

A compound of formula (IX) can be prepared by reacting a compound of formula (V) or a protected form thereof with a suitable 1,3-diketone or a protected form thereof under suitable conditions (such as those described above for process (C)). It can be created by letting

The compounds of formulas (■) and (XI) are known or can be prepared from known compounds by conventional methods.

When it is desired to isolate a compound of the invention in the form of a salt, such as a physiologically acceptable salt, the compound of formula (1) in free base form is combined with a suitable acid (preferably in an equivalent amount) and a suitable acid. The reaction may be carried out in a solvent such as an alcohol (eg ethanol or methanol), an aqueous alcohol (eg aqueous ethanol), an ester (eg ethyl acetate) or an ether (eg tetrahydrofuran).

Physiologically acceptable salts include other salts of the compound of formula (1) (
(including other physiologically acceptable salts) by conventional methods.

The individual enantiomers of the compounds of the invention can be obtained by resolving enantiomeric mixtures (eg, racemic mixtures) in conventional manner, eg, by optically active resolving agents. For example, "Stereochemistry Φ of carbon combinations J (E, 1., E
llel: McGravllllll, 1962) and [Tables of Resolving Agents J
See (S, Il, Wi fen).

Optically active resolving agent acids used to form salts with racemates include the (R) and (S) forms of organic carboxylic and sulfonic acids such as tartaric acid, di-p-toluyltartaric acid, camphorsulfonic acid, and lactic acid. There is. The resulting mixture of isomeric salts can be separated, for example by fractional crystallization into diastereoisomers. The desired optically active isomer can then be converted to the free base, if desired.

The above-described method of making the compounds of the invention can be employed as the final major step in synthetic sea fences. The same general methods can be utilized to introduce desired groups at intermediate steps in the stepwise formation of the desired compound, and these general methods can be used in different embodiments during such multistep processes. It is to be understood that combinations can be made.

Of course, the order of reactions in a multi-step process should be chosen such that the reaction conditions employed do not affect the groups in the molecule that are boxed in the final product.

The following examples are intended to further explain the invention. All temperatures are in °C. Thin layer chromatography (t
, 1. c,) was performed on silica and was performed using flash column chromatography (FCC) and short pass number column chromatography (SPC).
C) was carried out on silica (Merck 9385J and Merck 7747J, respectively). Chromatographic solvent system A was dichloromethane:ethanol 20,
88 ammonia solution. IH-N, m,
r.

Spectra were obtained at 2'50 MHz (integration, multiplicity).

Multiplicity symbols: S-singlet, d-doublet, a-triblet, m-multiplet, b'
~Broad. Organic extracts were dried over magnesium sulfate or sodium sulfate. The following abbreviations are used: THF-tetrahydrofuran, DMF-dimethylformamide IMS-industrial methylated spirit.

Intermediate 1 A solution of triphenylchloromethane (13.1 g) in dry 80 MF (80 ml) was added dropwise over 30 minutes to 4-methyl- in dry DMF (75 ml).
It was added to a stirred solution of 5-imidazole methanol hydrochloride (7.0 g) and triethylamine (9.52 g) at room temperature under nitrogen gas. Stirring continued for 2.5 hours. The suspension was poured onto ice (600ml), stirred for 30 minutes and filtered. The resulting solid (12.Qg) was dissolved in acetone (
2X250ml) crushed twice, the indicated compound (8.4g
) and thin layer chromatography (system A94.5:
5:0, 5) with an Rf value of 0.19.

Intermediate 2 5-Methyl-1-(triphenylmethyl)-IH-imidazole-4-methanol (4.0 g) Manganese dioxide (activated) (40 g) and dioxane (2
The mixture of 25 ml) was stirred at room temperature overnight. The suspension was filtered and the solids were washed with hot chloroform (1 g). The filtrate was collected and dried in vacuo to reduce the solids (4.0
g) was obtained.

This was purified by FCC using chloroform as the eluent to obtain a solid, which was triturated with hexane (approximately 50 ml) to yield the compound in Table 5 (2.99 g, m.p.).

184-188°C (decomposition) was obtained.

Intermediate 3 n-Butyllithium (1.57M, 1.08ml) was added to a solution of diisopropylamine in dry THF (7ml) with stirring at -78°C and stirred for a further 30 minutes at 0°C. The solution was cooled to -78°C and 1,2,3,9-tetrahydro-9-methyl-4H-
Added to carbazol-4-one at -78°C with stirring under nitrogen gas.

After 1 hour at -78°C and a further 1 hour at 0°C, the mixture was cooled to -78°C and treated with intermediate 2 (500mg) in THF (6ml). After 4 hours at -78°C, the mixture was warmed to 23°C and stirred for 14 hours. The resulting solid (evaporated reaction mixture) is -
Cooled to 78°C, treated with THF (10ml) followed by acetic acid (1ml), warmed to 0°C and poured into saturated aqueous sodium bicarbonate (50ml). The mixture was extracted with dichloromethane (2X60ml) and the combined, dry organic extracts were evaporated. The residue was purified by sp using System A (967:30:3) as the eluent.
The indicated compound (280 mg) was purified by m.c. p
.

A temperature of 141-147°C was obtained.

Intermediate 4 3-Fluorophenylhydrazine hydrochloride (9.35 g) in water (100 ml) was treated with 2N sodium hydroxide (29 mD) and the resulting solution was dissolved in water (100 ml) under nitrogen gas. ) in cyclohexane-1,3-
Added to a stirred solution of dione (6.65 g) over 2 hours. The mixture was stirred for 18 hours, the resulting precipitate was filtered and further stirred with water (150 m+1). The solid was filtered again, washed with water (50ml) and dried to give a powder (9.90g). Add this to hexane (2
200 ml), and the solid was collected to give the indicated compound (5.3 g) (a, p, 142-144°C).
I got it.

Intermediate 5 Glacial acetic acid (25 ml), 3-(3-fluorophenylhydrazono)-1-cyclohexen-1-ol (1,
1g) and molten zinc chloride at 100°C for 20 hours.
heated with. The cooled reaction mixture was poured into water (35ml) and extracted with dichloromethane (2X30ml). The combined, dry organic extracts were evaporated to give an oil, which was eluted with ethyl acetate/hexane (3:2) as eluent.
Purification by pcc gave the title compound (0.15 g) as a powder (1.p, 231-233°C).

Intermediate 6 7-fluoro-1 in dry DMF (8 ml),
2°3.9-Tetrahydro-4H-carbazol-4-one (1,0 g) solution was prewashed (hexane, 2x
10ml) Sodium hydride (78% strength dispersion in oil, 175II 1g) in dry DMF (5ml)
) was added dropwise under nitrogen gas to a stirred, water-cooled suspension. Stirring was continued for an additional 1.5 hours at room temperature. The solution was cooled to 0°C, iodomethane (0.35ml) was added dropwise and stirring continued at 0°C for 2 hours. The suspension was poured into 8% aqueous sodium bicarbonate (30ml), extracted with dichloromethane (2X30ml), the combined, dry organic extracts were evaporated and heated to 100°C in vacuo.
The title compound (1.03 g) was dried for 18 hours at s
, p, 174-175°C as a solid.

Intermediate 7 -4-one A solution of triphenylchloromethane (4,2 g) in dry mDMF (40 ml) was dissolved in 1 ml of dry DMF (35 ml).
．． 2. 3. 9-tetrahydro-3-((5-methyl-IH-imidazol-4-yl)methyl-4H-carbazol-4-one (3,5r) and triethylamine (1,75 ml) were added dropwise. After stirring for 4 hours, This mixture was poured into water (300 ml) and dichloromethane (
Extracted with 3X 100ml)'. The combined extracts were washed with water (200 ml), dried and evaporated to dryness to give an oil (approximately 9 g) which was transferred to System A (200:1
The title compound (4,57) was purified by FCC using 0:1) as an eluent.

g) was obtained as a foam with an Rf value of 0.32 (System A 200:10:1) by thin layer chromatography.

Intermediate 8 A solution of thionyl chloride (1,3 ml) in dry dichloromethane (10 ml) was dissolved over 5 minutes in a mixture of dichloromethane (100 ml) and dry DMF (2 ml). Added to a stirred suspension of 1H-imidazole-4-methanol (5.0 g) at 0<0>C. The mixture was stirred at 0°C for 30 min and sequentially 8% sodium bicarbonate (2 x 50 ml), water (50 ml),
ml), dried and evaporated in vacuo at below 40° C. to give an oil (5 g). Add this to ether (10
The resulting solution was filtered through a pad of silica and further eluted with ether (2×100 ml). The combined filtrates were evaporated below 40° C. to give a foam, which was triturated with cold hexane and further filtered to give the title compound (4.2 g) as a solid (IIl ,
p, 133-135°C).

Intermediate 9 n-Butyllithium (1.58M in hexane).

21 ml) of dry THF (
This solution was stirred at 0° C. for 30 minutes. This solution was cooled to -78°C and dried THF (25ml
) in 3-methoxy-2-cyclohexen-1-one (
3.4 g) solution under nitrogen gas while stirring.

After stirring for 1 hour at -78°C and an additional 30 minutes at 0°C, the solution was cooled to -78°C and dried THF (100 ml
) was added dropwise with stirring under nitrogen gas.

The solution was stirred at -78°C for 3 hours, roughly at 0°C for 30 minutes, treated with 8% aqueous sodium bicarbonate (400ml) and extracted with ethyl acetate (2X 300ml). Combine and evaporate the dried organic extracts to an oil (approx.
g) and convert it into system A (967: 30:
3) was purified using 5 pcc as an eluent to obtain the title compound (3.28 g) Cta, p.

145-148°C) was obtained.

Intermediate 10 1. in dry DMF (3 ml). 2. 3. 9-tetrahydro-3-((5-methyl-1-(triphenylmethyl)-1H-imidazol-4-ylcomethyl) -4
H-carbazol-4-one (500 mg) in dry DMF
To a stirred suspension of sodium hydride (73% suspension in oil, 38 mg) in (1 ml) was added dropwise under nitrogen gas. After 20 minutes, benzyl bromide (0.14 ml) was added and the mixture was stirred for 3 hours. Water (50ml) was added and the suspension was extracted with dichloromethane (3X25ml). The combined, dry organic extracts were evaporated to give Ura (approximately 850 mg), which was purified by FCC using ethyl acetate and hexane (4:1) as eluent (ethyl acetate:hexane:triethylamine-79). : 20: 1 column) was purified to obtain the indicated compound (265 mg)
was obtained as a solid at m, p, 78-80°C.

Intermediate 11 Using the process described above for intermediate 10, 1°2,
3. 9-tetrahydro-3-((5-methyl-1-(
triphenylmethyl)-1H-imidazol-4-ylcomethyl]-4H-carbazol-4-one (500a+
g) of sodium hydride (73% suspension in oil, 38 mg
) and further stirred with cyclobenkune methanol (p-toluenesulfonate) (292 mg) for 24 hours. The above treatment and FCC purification yielded the indicated compound (283
a+g) (a+, p.

177-179°C).

Intermediate 12 Propargyl bromide (0,086 ml) was dissolved in acetone (1
1.0ml) 2. 3. 9-tetrahydro-3
-[[5-methyl-1-(triphenylmethyl)-1H
-imidazol-4-yl]-methyl]-4H-carbazol-4-one (500 mg) and potassium carbonate (2
65 mg) and the mixture was heated under nitrogen gas for 6 hours.
Stirred for 0 hours. In addition, propargyl bromide (0,086
m1) was added and the mixture was stirred at room temperature for 24 hours and refluxed for a further 6 hours. Water (50ml) was added and the suspension was extracted with dichloromethane (3X25ml).
The combined dry organic extracts were evaporated to form a gum (65
0ff1g) was obtained, which was mixed with ethyl acetate and hexane (4:
1) was purified by FCC (column prepared with ethyl acetate dioxane: triethylamine 80:19:1) as an eluent, and thin layer chromatography on Sio2 impregnated with Et3N showed an Rf value of 0.30. The compound described as a foam (
95 mg) was obtained.

Intermediate 13 1.2.3.9-tetrahydro-3-CC5-methyl-
IH-imidazol-4-yl)methyl2-9-methyl-
A suspension of 4H-carbazol-4-one (0.5 g) in dry dichloromethane (150 ml) was treated with a solution of diisobutylaluminum hydride (1.0 M in cyclohexane, 6 ml) under nitrogen gas at -57 °C. The mixture was stirred for 4 hours while warming to 5°C. Methanol (5
ml) was added and the mixture was stirred for an additional hour and filtered. The gelatin-like precipitate was further dissolved in dichloromethane (50
ml) and the combined filtrates were evaporated in vacuo. Remove residual oil (approximately 0.55r) from system A
(95:5:0.5) as an eluent to give a solid (1 g).

This solid (175a+g) in ethanol (15ml)
) of reduced 10% palladium on carbon (50% aqueous paste, 20 m
A stirred suspension of g) in ethanol (10 ml) was hydrogenated. The mixture was filtered, evaporated in vacuo and the remaining gum was dissolved in 0.2N hydrochloric acid (20ml) and dichloromethane (2
0 ml, discarded). To make this acidic layer basic, use 2N sodium hydroxide), chloroform (3X20
ml).

° These latter chloroform layers were dried and evaporated in vacuo to give a gum (155s+g), which was dissolved in dichloromethane:methanol (1:1) (15ml), maleic acid (65g+g), methanol (0, 3m
1) Treated with solution. The title compound (176 mg) was concentrated in vacuo to approximately 2 ml and diluted with dry ether.
．． p, 175-179°C (decomposed) as a solid.

Intermediate 14 A solution of triphenylchloromethane (286 mg) in dry DMF (10 ml) was diluted with 1 in dry DMF (20 ml).
．． 2. 3. 9-tetrahydro-9-methyl-3-
((5-Methyl-IH-imidazol-4-yl)methyl) -4H-carbazol-4-one (292 mg) and triethylamine (101 μl) were added dropwise to a stirred solution and the resulting solution was heated at room temperature under nitrogen gas for 3 hours. Stirred for .5 hours.

The reaction mixture was then poured into water (100ml) and the resulting suspension was extracted with dichloromethane (3X50ml). The combined, dry organic extracts were adsorbed onto FCC silica and applied to a column using System A (150:8:
1) was purified by FCC as an eluent to obtain a solid, which was further purified by crystallization with dichloromethane:hegyosan (11) to obtain the title compound (304 mg) (Il, L 193
-195°C) was obtained.

Intermediate 15 Dimethylsulfamoyl chloride (
0.16ml) solution in dry dichloromethane (30ml)
1.2. 3. 9-tetrahydro-9-methyl-
3-((5-methyl-IH-imidazol-4-yl)methyl]-4H-carbazol-4-one (438 mg)
and triethylamine (0.25 ml) and the mixture was heated at reflux for 18 hours. After cooling the reaction mixture, it was adsorbed onto FCC silica and applied to a column.
An oil was obtained with FCC using System A (150:8:1) as eluent. This solidified and was ground to a powder with dry hexane (30ml). This powder was further purified by dissolution in dry dichloromethane (30 ml) and crystallized by the addition of dry hexane (10 ml) to give s, p, 122
The title compound (518 mg) was obtained at -124°C.

Intermediate 16 (4:1) A solution of chloromethyl methyl ether (0.22 ml) in chloroform (10 ml) was dissolved in chloroform (0.5 ml).
ml) in 1. 2. 3. 9-tetrahydro-3
-((5-Methyl-IH-imidazol-4-yl)methyl) -9-methyl-4-carbazol-4-one (0
, 44 g) and triethylamine (0.5 ml) under nitrogen gas. The resulting solution was stirred at 20°C for 2 hours and partitioned into chloroform (25ml) and 2N sodium bicarbonate solution (2x30ml). The dry organic extract was evaporated and the residue (0.45 g) was converted into system A.
Purified by FCC using C200:8:1) as eluent and thin layer chromatography (System A75:8).
:1) as a gum with an Rf value of 0.5, the indicated compound (0,
25g) was obtained. NMR (CDC13) showed the title compounds to be in a 4:1 ratio.

Intermediate 17 Carbobenzoxy chloride (
0.26 ml) solution in chloroform (30 ml)
．． 2,3.9-tetrahydro-3-[(5-methyl-I
H-imidazol-4-yl)methyl]-9-methyl-4
It was added to a stirred solution of H-carbazol-4-one (0.44 g) and triethylamine (0.25 ml) under nitrogen gas. The resulting solution was stirred at 20°C for 2 hours, then mixed with chloroform (25ml) and 2N sodium bicarbonate (2X30ml).
Partition extraction was carried out using 1). The organic extract was dried and evaporated to give a gum (0.8 g), which was combined with System A (200:
8:1) was purified by FCC using an eluent to obtain a solid (0.64 g), which was crystallized from ethanol (3 ml) and subjected to thin layer chromatography (System A200
: 8 : 1) with an Rf value of 0.47 (0
, 62g) was obtained. NMR (CDC13) showed that the title compound was in a ratio of 97:3.

Example 1 1. in glacial acetic acid (100 ml). 2.3. 9-tetrahydro-3-[hydroxy[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-ylcomethyl]-9-methyl-4H-carbazol-4-one (2,
70g) of p-toluenesulfonic acid hydrate (10,80g)
g) and the stirred solution was heated at reflux for 4 hours. The cooled dark solution was evaporated, treated with aqueous saturated sodium bicarbonate (250 ml) and treated with ethyl acetate (4X 250 ml).
m1). The combined, dry organic extracts were evaporated and purified with 5 pcc. System A (978:
Elution at 20:2→945:50:5) gave the free base of the title compound as a tan solid (488 mg). A hot solution of free base (87 mg) in ethanol (approximately 16 ml) was added to ethanol (1 ml).
treated with a hot solution of maleic acid (38a+g) in
Cool, collect precipitate, ffi, 9°205-209
IQ is the compound (81 mg) written in °C.

Analysis values are C, 65.1, H, 5.2.

N, 10.2. 018H17N3”C4H40
The calculated value of 4 is C, 64,9°H, 5,2; N, 10.3
%.

Example 2 Lithium diisopropylamide mono(tetrahydrofuran) (1.5M in cyclohexane, 45ml) was dried with T
1. in HF (500 ml). 2. It was added dropwise under nitrogen gas to a cold (-70°C) solution of 3°9-tetrahydro-4-carbazol-4-one (5.0 g). This solution was stirred at -70°C for 1 hour, and Intermediate 2 (1
0 sr) was added and the mixture was left to reach room temperature for 3 hours. Furthermore, this was cooled to -70℃,
Acetic acid (80 ml) followed by p-)luenesulfonic acid (
51.4 g) was added. The resulting solution was heated at reflux for 20 hours and the solvent was removed in vacuo. The residue was treated with 8% sodium bicarbonate solution (2 g) and extracted with dichloromethane (3×H). The combined, dry organic extracts were evaporated to give a gum (approximately 20.8 g), which was System A (
100:10:1) as eluent,
Thin layer chromatography (system A1002 10:1
) A compound (5.2 g) with an Rf value of 0.35 was obtained.

IH-NMR (d4-methanol) δ2.39 (3H,
s), 3.09 (2H, t), 3.50 (2H, b
rt), 7.15-7.25 (2 ears, 'm),
7.33-7.43 (LH, m), 7.53 (IH
, brs), 7.69 (IH.

s), 8.10-8.18 (1, m).

Example 3 Lithium diisopropylamide mono(tetrahydrofuran) (1.5M in cyclohexane).

3.3 ml) of 7-
A stirred suspension of fluoro-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one (975 ■) was treated with -
Added drop by drop. After 1.5 hours, dry THF (10 ml)
A suspension of Intermediate 2 (1.74 g) was added thereto, and the suspension was stirred at -10°C for 2 hours. The resulting solution is
It was cooled to -70°C and acetic acid (12ml) was added. This solution was heated to -10°C, p-)luenesulfonic acid 1
The hydrate (5.8 g) was added and the solution was stirred at reflux for 20 hours. It was then cooled, evaporated and the residue extracted partitioned between 8% aqueous sodium bicarbonate (100ml) and dichloromethane (70ml). This suspension was filtered, and the resulting solid (1.02 g) was dissolved in methanol (100 ml).
The title compound (366ff1g) with m, p, 290-295°C was obtained.

The analytical values were C, 69.9; H, 5.2°N, 13.2%. Cl8H1BFN30 total 1
J value is C, 69.9, H, 5.2; N, 13.6%
It is.

Example 4 one on n-Butyllithium (1.39M in hexane).

5.0 ml) was added dropwise to a cold (-70°C), stirred solution of diisopropylamine (0.98 ml) in dry THF (10 ml). The solution was stirred at 0°C for 30 min, cooled to -70°C and diluted with
．． Added dropwise under nitrogen gas to a cold (-70<0>C) stirred solution of 2,3.9-tetrahydro-6-methoxy-9-methyl-4H-carbazol-4-one (640a+g).

The resulting solution was then allowed to reach 0°C for 1 hour.

This was further cooled to -70°C and dried THF (10 m
A suspension of intermediate 2 (985 mg) in l) was added dropwise and the stirred mixture was allowed to reach room temperature over a period of 3 hours. It was further cooled to -70°C, and acetic acid (8 ml
) followed by p-toluenesulfonic acid (5.3 g) and heated at reflux for 16 hours. The solvent was removed in vacuo and the residue treated with 8% sodium bicarbonate solution (150ml) and extracted with dichloromethane (4X50ml). The combined, dry organic extracts are evaporated and the gum (approximately 2
g) was purified by FCC using System A (200: 10: 1) as eluent and purified by thin layer chromatography (System A 200: 10: 1) with an Rf value of 0.
24, the title compound (220 mg) was obtained as a solid with m, p, 133-135°C.

Example 5 Lithium diisopropylamide (1 in cyclohexane)
．． 5M, 3. 2 ml) solution in dry THF (30 ml
5-methyl-6,7,8,9-tetrahydrocyclohept (b) indole-10(5dan)-one (0,
96g) under nitrogen gas. The resulting solution was stirred at -70°C for 15 minutes, and then
The mixture was stirred at 0°C for 30 minutes and cooled to -70°C. This was treated with a solution of intermediate 2 (1.6 g') in THF (30 ml). The reaction mixture was further heated to -70°C for 30 minutes.
Stir at 20°C for 1 hour, cool to -70°C, add acetic acid (2
5 ml). The resulting solution was heated in a steam bath for 1 hour, concentrated in vacuo to about 10ml and extracted partitioned between saturated potassium carbonate solution (90ml) and ethyl acetate (3X90ml). The combined, dry organic extracts were evaporated to give the gum (approximately 2 g) and dissolved in THF (100 ml).
of p-toluenesulfonic acid for 3 hours at 100°C.
Treated with hydrate (8.5 g). The resulting solution was concentrated in vacuo to approximately 5 ml and partitioned with ethyl acetate (3×90 ml) and saturated potassium carbonate (90 ml). The combined, dry organic extracts are evaporated to form a gum (approximately 2
g) was obtained and purified by FCC using System A (200:8:1) as eluent to give a gum (approximately 0.7'zr).

This was mixed with 2N hydrochloric acid (30ml) and ethyl acetate (30ml).
It was distributed and extracted. The liquid was carefully decanted and the resulting precipitate was extracted partitioned between saturated potassium carbonate (30ml) and ethyl acetate (3x30ml). The combined organic extracts were evaporated to a solid mass (approximately 260 m
g) was crystallized from absolute ethanol (15 ml) to give the free base of the title compound (0.15 sr). This solid was dissolved in hot ethanol (30 ml) and the ethanol (
treated with a solution of maleic acid (57 mg) in
After cooling, the title compound (90 mg, @, p.

A precipitate of 175-176°C was obtained.

The analytical values were C, 65.2; H, 5.4; N, 9.8%. C19HL9N3”C4H40
The calculated value of 4 is C, 65,5; H, 5,5; N, 10.0
%.

4I6 Elution of the FCC column of Example 5 yielded a semi-solid (approximately 0.4
5g) was also obtained. This was crystallized from absolute ethanol (25 ml) to give the title compound (0.3 g, tp, 230-23
2°C).

The analytical values were C, 74.3; H, 6.3; N, 13.6%. Calculated values for C19H19N30 were C, 74,7; H, 6,3; N, 13.8%.

Example 7 A solution of diisopropylamine (1,54 ml) in dry THF (20 ml) at -78° C. was treated dropwise with n-butyllithium (1.32 M in hexane, 8.3 ml). The mixture was warmed to 0°C and recooled to -78°C. This was dried in -78℃ THF (80m
l) 1. 2. Added over 3 minutes to a stirred suspension of 3.9-tetrahydro-9-methyl-4H-carbazol-4-one (2.0 g). The resulting suspension was further stirred at -78°C for 2 hours and further treated with 1-(triphenylmethyl)-1H-imidazole-4-carboxaldehyde (3.72g). The mixture was stirred for an additional 2 hours while slowly warming to room temperature and then to -78°C.
and quenched with acetic acid (2 ml). Warm the resulting solution to room temperature and add 8% sodium bicarbonate solution (600 ml).
poured into.

The mixture was extracted with dichloromethane (3X150ml) and the combined, dry organic extracts were evaporated to give a foam. Acetic acid (25 ml) and dry THF (150 ml)
A solution of this foam and p-toluenesulfonic acid hydrate in a mixture with ) was heated at reflux for 5 hours. This cooled mixture was carefully combined with 8% sodium bicarbonate solution (650 m
l) and extracted with dichloromethane (3X150ml). The combined dry organic extracts were evaporated to give a solid. This is system A (100: 10:
Purify by FCC using 1) as eluent to obtain a+, p, 22
The title compound (1.42 g) was obtained with a temperature of 5-232°C.

This analysis value is C, 73,3, H, 5,6°N, 14.7
%Met. The calculated value of C17H15N30 is C,73,
6; H, 5,5; N, 15.1%.

Example 8 Acid salt 1.2. in DMF (85 ml). 3.9-tetrahydro-9-methyl-3-((5-methyl-IH-imidazol-4-yl)methylene] -4H-carbazol-4
A solution of -one (3.50 g) was added to a pre-reduced suspension of 10% palladium oxide on carbon in ethanol (50 ml) and hydrogenated at room temperature under atmospheric pressure (270 ml) until no hydrogen uptake occurred.

The catalyst was filtered off, and the filtrate was evaporated and dehydrated. The residue was adsorbed onto 5 pcc silica from methanol (170 ml) and
Applied to FCC column. System A (967: 30
Gradient elution: 3→912:80:8) gave the free base of the title compound (2.32 g) as a solid. A portion of this solid (500+ag) in hot ethanol (15 ml) was treated with a solution of hot maleic acid (224 mg) in ethanol (2 ml), cooled and the precipitate collected, m, p, 130. Thin layer chromatography (System A 200: 10:1) R at 5-137 °C
The title compound (415 mg) having an f value of 0.30 was obtained.

This analysis value is C, 63,2; H, 5,5; N, 9.7
%Met. Cl8H19N30, CHO-0,33H
The calculated values for 20 are C, 63.6; H, 5.7, N, 10.1%. The analysis value of the water contained is 1.55%v/wH20-0.3
It was 3a+ol.

IH-NMR (d6-DMSO) 61.8-1.98
(IH,m), 2.1-2.25 (IH.

m), 2.25 (3H, s), 2.68-2.8
4 (2HSm), 2.85-3.3 (3H.

m), 3.75 (3H, s), 6.0 (2H,
s-maleic acid), 7.18-7.32 (2H, m
) 7.57 (LH, b rd) , 8.03 (
IH.

b r d), 8.88 (IH% s).

Example 9 1,2,3,9-tetrahydro-3-(
(5-Methyl-IH-imidazol-4-yl)-methylene] -4H-carbazol-4-one (5.2 g),
Hydrogenation was carried out over a stirred suspension of reduced 10% palladium oxide on carbon catalyst (50% aqueous paste, 1.Or) in ethanol (30 ml) for 4.5 hours at room temperature and atmospheric pressure. The mixture was filtered and evaporated to give an oil (approximately 5 g), which was purified by FCC using System A (100:10:1) as eluent to obtain the free base of the title compound (
3.96 g) was obtained. Sample from now on (400mg)
was taken, dissolved in ethanol (4 ml), and dissolved in ethanol (
A solution of maleic acid (170+ag) in 1.25 ml) was used. The solvent was removed in vacuo and the residue was triturated in dry ether (5825ml) to give a solid (555a+g
) was obtained. This solid (approximately 500 mg) was dissolved in hot methanol (5 ml) and ethyl acetate (15 ml) was added. The solution was concentrated to a volume of 10ml and allowed to cool.

After 1 hour, the precipitated solid was collected and ta, p, 160
The title compound (314 mg) was obtained at -162°C.

The analysis value of the water contained is 0.36%V/V -0,06i
oI H2O, elemental analysis is C, 63,3; H, 5,3;
N, 10.2%.

The calculated values for C17H17N30.C4H404-0,06H20 are C, 63,6; H, 5,4; N, 10.6%.

Example 10 7-fluoro-1°2 in ethanol (25 ml)
3. 9-tetrahydro-9-methyl-3-[(5-methyl-IH-imidazol-4-yl)methylene] -4
A solution of H-carbazol-4-one (315a+g) was hydrogenated over reduced 10% palladium oxide on carbon catalyst (50% aqueous paste, 300 mg) at atmospheric pressure and room temperature for 2 hours. The mixture was filtered and evaporated to give a foam, which was purified by FCC using System A (912; 80:8) as eluent to give the free base of the title compound (230 mg) as a solid. Obtained. Add this to hot ethanol (30
ml) and treated with a solution of maleic acid (85 mg) in warm ethanol (3 ml). The resulting solution was evaporated and the residual oil was triturated with ether (40 ml) to give 21
A powder of 0 nH was obtained. This was combined with the mother liquors, evaporated, treated with 8% aqueous sodium bicarbonate (25ml) and extracted with ethyl acetate (3x20ml). The combined, dry organic extracts were evaporated to remove the solids, dissolved in hot ethanol (20 ml) and further diluted with ethanol (
diluted with a solution of maleic acid (86 mg) in 3 ml).

The solution was evaporated and the remaining solid was removed with ethanol (5 m
1) to obtain the title compound (202II1 g) with m, p, 153-156°C.

The analytical values were C, 61.6; H, 5.2; N, 9.6%. Cl8H18FN30・C4H
The calculated values of 404 are C, 61,8; H, 5,2; N, 9.
It is 8%.

Example 11 4-one (E)-1,2°3. in absolute ethanol (15 ml).
9-tetrahydro-6-methoxy-9-methyl-3-(
(5-Methyl-IH-imidazol-4-yl)methylene-4H-carbablue-4-one (200 mg) was suspended in absolute ethanol (5 ml) on reduced 10% palladium oxide on carbon catalyst (50% aqueous paste, 100+ ag). Hydrogenation was carried out on the suspension at room temperature and atmospheric pressure. The mixture was filtered and evaporated to give a foam (approximately 200 mg), which was purified by FCC using System A (200:10:1) as eluent and thin layer chromatography (System A 200:10:1). 1) Rfli! ! 0.26
A solid substance (154II, 1 g) of the title compound, m, p, 227-229°C, was obtained.

Example 12 (E)- and (Z) in ethanol (250 ml)
) -6,7,8,9-tetrahydro-5-methyl-9
-[(5-Methyl-IH-imidazol-4-yl)methylenecocyclohept[b] -Indolu 10 (51
()-one (0.4 g) was hydrogenated over 10% palladium oxide on carbon (100 a+g) at room temperature and atmospheric pressure for about 5 hours. The catalyst was filtered off and ethanol (1
00ml). The filtrate was collected and evaporated to obtain gum (0.4 g), which was transferred to system A.
Purification by FCC using (200:8:1) as eluent gave an oil (0.32 g). Add this to absolute ethanol (15 m
l) and treated with a solution of maleic acid (120a+g) in ethanol (5ml). Approximately 5 ml of the generated solution
The title compound (0,41
g) was precipitated.

This analysis value is C, 64.9; H, 6.0; N, 9.8%
Met. The calculated values of C■9H21N30/C4H404 are C, 65,2; H, 6,0, N, 9.9%.

Example 13 1.2.3.9-tetrahydro-9-methyl-3-[(IH-imidazole-4-
yl)methylene] -4H-carbazol-4-one (1
, 37 g) solution on charcoal with 10% palladium oxide catalyst (5
Hydrogenated with 0% aqueous paste, 130a+g) at room temperature and atmospheric pressure. After about 30 minutes, a precipitate was formed, so TH
F (approximately 30 ml) was added to redissolve the precipitate. The mixture was stirred for an additional 4 hours and filtered. The filter was treated with maleic acid (569 mg) and the resulting solution was evaporated to give a solid, which was recrystallized from a mixture of methanol and ethyl acetate to give the title compound (1.35 g ) was obtained.

The analytical values were C, 64.2; H, 5.5; N, 10.6%. C17H17N30・C4H
The calculated value of 404 is C, 63, 8; H, 5, 1N, 10.
It is 6%.

Example 14 Intermediate 7 (500 ml) in dry DMF (3 ml)
g) The solution was added dropwise to a stirred suspension of sodium hydride (52% suspension in oil, 53+ag) in dry DMF (1 ml) under nitrogen gas. After 20 minutes, dimethylcarbamyl chloride (0.11 ml) was added and the mixture was stirred for 2 hours. Water (50ml) was added and the suspension was extracted with dichloromethane (3X25ml). The combined, dry organic extracts were evaporated to an oil (approximately 800 m
g) was obtained, which was mixed with THF (10 ml) and acetic acid (10 ml).
1) and water (10 ml) and refluxed to 1.
It was heated for 5 hours. The mixture was dissolved in saturated potassium carbonate solution (60 m
1) and extracted with dichloromethane (3830 ml). The combined, dry organic extracts were evaporated to give an oil (approximately 800 mg), which was converted into System A (200:10
: Purify by FCC using 1) as eluent to obtain a foam (18
8 mg) was obtained. This was dissolved in ethanol (3 ml) and maleic acid (64+a) in ethanol (0.5 ml) was added.
g) treated with solution. The solvent was removed in vacuo and the residue was triturated with dry ether (5X5ml) and 1. p.

The title compound (195 mg) was obtained at 157-158°C.

This analysis value is C, 61,4; H, 5,7; N, 11.8
%Met. The calculated value of C2oH22N4o2 threat C4H404 is C,61,8°H,5,6,N,12.0%.

Examples 15 and 16 were prepared in the same manner as Example 14.

Example 15 Intermediate 7 (5001 g) was mixed with benzenesulfonyl chloride (0
, 15ml) to give the title compound (215mg), p, 154-156°C.

This analysis value is C, 60,3; H, 4,7; N, 7.5%
Met. The calculated values for C23H21N303S and C4H404 are C, 60,6°H, 4,7, and N, 7.9%.

Example 16 Methyl-1.2,3.4-tetrahydro-3-[(5-
Methyl-IH-imidazol-4-yl)methyl] -4
-oxo-9H-carbazole-9 intermediate 7 (500 m
g) with methyl chloroformate (0.09ml) to give the title compound (1
55+ng) was obtained.

This analysis value is C, 60.8; H, 5.0; N, 9.1%
Met. The calculated values of C19H19N303 and C4H404 are C, 60, 9; H, 5, 1; N, 9. It is 3%.

Example 17 Intermediate 7 (500+ag) in dry DMF (10ml)
The solution was added dropwise to a stirred suspension of sodium hydride (73% suspension in oil, 36 cm) in dry DMF under nitrogen gas and the resulting suspension was stirred for 30 minutes at room temperature. A further solution of allyl bromide (121ag) in dry DMF (1 ml) was added and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (500ml) and dichloromethane (4X
100ml). The combined organic extracts were washed with water (3 x 250 ml), dried and concentrated to give an oil. This was dissolved in a mixture of THF (5 ml), water (5 ml) and acetic acid (5 ml) and heated at reflux for 1.5 hours. After cooling, the solution was basified with 2N sodium bicarbonate solution and extracted with dichloromethane (2X50ml). The combined, dry organic extracts were concentrated to an oil and eluted with system A (150:8+1) while F
Purified by CC to give the free base of the title compound (151a+g
) was obtained as a solid. Add this to dry methanol (20m
1), maleic acid (55 mg) was added and the resulting solution was heated in a steam bath for 10 minutes. The solution was further cooled and ether (10 ml) was added to
The title compound (174 mg) was precipitated at 194-196°C.

This analysis value is C, 65.7; H, 6.0; N, 9.3%
Met. The calculated values of C2oH21N30.C4H404 were C, 66, 1; H, 5, 8; N, 9.65%.

Example 18 Intermediate 7 (750ag) in dry DMF (30ml)
The solution was dissolved in sodium hydride (5 ml) in dry DMF (5 ml).
(73% suspension in oil, 50+ag) under nitrogen gas and the resulting mixture was stirred at room temperature for 30 minutes. Dry DMF (5 ml) width of bromocyclopenkune (22
3g) solution was added and the resulting solution was stirred at room temperature under nitrogen gas for 8 hours and further stirred at 100-110°C for 18 hours. After cooling, the reaction mixture was poured into water (500ml) and the resulting suspension was extracted with dichloromethane (2X500ml).

The combined organic extracts were washed with water (2X500ml), dried and concentrated to give an oil. This was adsorbed onto FCC silica. Fcc using System A (100:8:1) as eluent gave the free base of the title compound (77■) as an oil. This was dissolved in dry methanol (10ml), maleic acid (26ng) was added and the resulting solution was heated in a steam bath for 10 minutes. The solution was cooled, ether (10 ml) was added and m, p
The title compound (82+ng) was obtained at 194-196°C.

Example 19 Phosphate 1, 2. 3. 9-tetrahydro-9-methyl-3
-((IH-imidazol-4-yl)methyl]-4H-
8 lbazol-4-one maleate (600 mg)
% sodium bicarbonate (70ml) and extracted with dichloromethane (3X25ml). The combined, dry organic extracts were evaporated to give a foam (483 ng). This was dissolved in dry DMF (25ml) at 5°C and treated with sodium hydride (73% suspension in oil, 59mg). The mixture was stirred for 20 minutes at 5°C and treated with methyl iodide (0.95ml). The solution was stirred for a further 1 hour and treated with 8% aqueous sodium bicarbonate (10ml). The suspension was diluted with water (120ml) and extracted with dichloromethane (3X40ml). The combined, dry organic extracts were evaporated to give a solid, which was
Purified by CC. System A (100:3:0.3→
wax (4:1) with gradient elution of 100:10:1)
32 mg) was obtained, and this was diluted with 20 m
High performance liquid chromatography (HPLC) at a speed of 1/min.
) (Sphcrisorb 5 s
The product was purified using a column (25 cm x 20 mm) to obtain an oil (1 g of 110I) as the UV active component eluted in the first stage. This oil and maleic acid (44+gg) in ethanol (151)
) was evaporated to dryness, and the title compound (1
54 mg) was obtained.

Example 20 Phosphate Salt The HPLC column of Example 19 was further eluted to give a solid (50 mg). A solution of this solid and maleic acid (20 mg) in ethanol (10 ml) was evaporated to dryness and subjected to thin layer chromatography (System A 100210
:1) Layer with Rf value 0.4, p.

The title compound (70+g) was obtained at 122-125°C.

Example 21 Boron tribromide (dichloromethane width IM, 1.4ml)
in dry dichloromethane (15 ml) at 1°2.3.
9-tetrahydro-6-methoxy-9-methyl-3-(
(5-methyl-IH-imidazol-4-yl)methyl]
-4H-carbazol-4-one (150 mg) cold (
(0°C) dropwise to the stirred solution under nitrogen gas. After 1 hour methanol (10ml) was added and the solution was evaporated. The residue was purified by FCC using System A (100:10:1) as eluent to give a solid (83+gg). This was dissolved in ethanol (approx. 20ml) and treated with a solution of maleic acid (32mg) in ethanol (approx. 2ml). The solvent was removed in vacuo and the residue was triturated with dry ether (3X25 ml) and analyzed by thin layer chromatography (System A 100:10:1) Rf value 0.33.
m, +), the indicated compound at 197-199°C (90+
gg) was obtained.

Example 22 Clobent (b) indole 1 (2H) -one maleate and hemimaleate lithium diisopropylamide (1 in cyclohexane)
．． 5M, 6ml) solution of 3,4-dihydro-4-methyl-cyclobent-(b) in dry THF (90ml)
-1(2)-one (1,5 sr) was added dropwise to a cold (-70<0>C) stirred suspension under nitrogen gas. The resulting solution was stirred at -70°C for 15 minutes and then at 20°C for 30 minutes. The solution was further recooled to -70°C and treated with 4-(chloromethyl)-1-(triphenylmethyl)-1H-imidacyl (3.0g). The mixture was stirred at -70°C for 2 hours and then at 20°C for 2 hours, then quenched with acetic acid (30ml) and water (30ml). The resulting mixture was heated in a steam bath for an additional hour, cooled, and diluted with ethyl acetate (
Partition extraction was performed with 200 mL discarded) and 2N hydrochloric acid (2×100 mL). The acidic aqueous layer was basified (pH
9) and ethyl acetate:ethanol (20:1.3X
150 ml) of the mixture. The combined, dried extract was evaporated to give a foam (approximately 2 g). FC using system A (150:8:1) as the eluent
A solid (0.45 g) was obtained which was triturated with absolute ethanol (5 ml). This solid (0.45g)
was dissolved in hot absolute ethanol (20 ml) and treated with a solution of maleic acid (187 mg) in ethanol (5 ml). The resulting solution was concentrated to about 5 ml and diluted with dry ether (
10 ml) to precipitate a solid (0.6 g:). This was mixed with ethyl acetate:methanol (15:1, about 1
Recrystallize with a mixed solution of 5ml), and IB,p, is 207-
Compound (hemimaleate, 0.2g) at 208°C
) was obtained.

The analytical value of ah water is 0.211% w/w - 0.04 mol
H20° elemental analysis is C, 67, 1; H, 5, 7, N,
It was 12.2%.

C17H17N30-0.5C4H404-0,04H
The calculated values for 20 are C, 67,5; H, 5,7; N, 12.
It is 4%.

The title compound of the second eluate (fully maleate, 0.3
g) was also obtained. This had a -,p, of 143-145°C and an Rf value of 0.26 for thin layer chromatography (system A75:8=1).

Example 23 3-Methoxy-6-((5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl)methyl in a mixture of water (15 ml) and 2N hydrochloric acid (2.7 ml))
A solution of -2-cyclohexen-1-one (1.2 g) was stirred under nitrogen gas for 18 hours. 1-methyl-1-(4-
Fluorophenyl)hydrazine (378 .mu.) was added and the suspension was stirred under nitrogen gas and rapid waves for 2 hours. The cooled mixture was poured into 8% sodium bicarbonate solution (60ml) and extracted with ethyl acetate (2X50ml). The combined, dry organic extracts were evaporated to give an oil (approximately 1.2 g). This was purified with 5 pcc using System A (923:70 near) as the eluent to obtain the free base of the title compound (
240a+g) was obtained as a powder.

This was dissolved in hot ethanol (15ml), a solution of maleic acid (99ng) in hot ethanol (2ml) was added and the resulting solution was evaporated. The solid residue was dissolved in ethanol (6
ml) to obtain the title compound (175a+g) with s, p, 148-150°C.

Analysis content water is 2.17%w/w -0,531101H
200 elemental analysis: C, 60,5; H, 5,2; N, 9.
It was 4%. C17H17N30・C4H404-0
The calculated value of ,53H20 is C,60,5,H,5,3;N
, 9.6%.

Example 24 In the same manner as described in Example 23, 3-methoxy-6-
C(5-methyl-1-(triphenylmethyl)-1H-
Imidazol-4-yl)methyl]-2-cyclohexen-1-one (1,14 g) was reacted with 1-methyl-1-(4-methylphenyl)hydrazine (350 mg). Purification on 5Pcc using System A (934:60:6) as eluent gave the free base of the title compound (350 mg) as a solid. Forming maleate salt, m, p, 150-152 °C title compound (205 mg
) was obtained.

The analytical values were C, 64.8; H, 5.8; N, 9.796. C19H21N20・C4H
The calculated values of 404 are C, 65, 2; H, 6, O; N, 9.
It is 9%.

Example 25 Maleate acetic acid (7ml), water (7ml) and THF (7ml)
1 in the mixture of 2. 3. 9-tetrahydro-3
-[5-methyl-1-(triphenylmethyl)-1dan-
imidazol-4-yl)methyl] -9-(phenylmethyl)-4H-carbazol-4-one maleate (2
40+ng) was heated at reflux for 2 hours. The mixture was poured into saturated potassium carbonate solution (40ml) and extracted with dichloromethane (3X20ml). The combined, dry organic extracts were evaporated to give a solid (256 mg), which was evaporated into 5p with System A (200; 10:1) as eluent.
Purification by cc gave a solid (99a+g). This was dissolved in ethanol (3ml) and treated with a solution of maleic acid (33mg) in ethanol (1ml). The solvent was removed in vacuo and the residue was triturated with dry ether to give m, p,
The title compound (128a+g) was obtained at 142-144°C.

Water content analysis: 0.27%w/vm O, 07molH,O
Met. Elemental analysis: C, 68,7; H, 5,6; N,
It was 8.5%.

The calculated values for CHNOψCHO-0,07H20 are C, 69,1; H, 5,6; N, 8.6%.

Examples 26 and 27 were prepared in the same manner as Example 25 from appropriately tethered intermediates.

Example 26 1, 2. 3. 9-tetrahydro-9-(cyclopentylmethyl)-3-(5-methyl-1-(triphenylmethyl)-1H-imidazol-4-ylcomethyl-4
Deprotection of H-carbazol-4-one (255a+g) gave the free base of the title compound (127 mg).

Due to maleate formation, e+, p, 178-180℃
The title compound (144 mg) was obtained.

Water content analysis: 0.37%v/v=0, IIIo
l H20. Elemental analysis is C,67,3,H,6,
2; N, 8.9%. C23H27N30・C4
H404・0. The calculated value of lH2O is C,67,7,H,
6,6,N, 8.8%.

Example 27 1,2.3.9-tetrahydro-3-[5-methyl-1
-(triphenylmethyl)-1H-imidazol-4-yl)methyl)-9-(2-propynyl)-4-carbazol-4-one (90 mg) and purification by FCC to obtain the free base of the title compound. (30 mg) was obtained. i, p, 189-191 by maleate formation
The title compound (40+ag) was obtained.

Water content analysis: 1.4%w/vmo, 34molH20
-Elemental analysis: C, 65,0; H, 5,4; N, 9.1%
Met. C2oH19N30・CHO・0.34H2
The calculated value of 0.125C2H50H is C165,4;H,
5,5; N, 9.4%.

Example 28 Lithium diisopropylamide (n-butyllithium,
1.55M in hexane (57,3ml) and THF
diisopropylamine (11,64 m
1) in THF (510 ml). 2.
3. A stirred suspension of 9-tetrahydro-9-methyl-4H-urbazol-4-one (15 g) was added under nitrogen gas.
Added dropwise over 15 minutes at 5°C. 45 minutes later,
Intermediate 2 (26.5 g) was added in portions and the resulting solution was stirred at -5 to +5°C for 1.75 hours. This solution was heated at 20°C.
Treated with acetic acid at lower temperature and stirred for 1 hour. Methanesulfonic acid (34ml) was added and the mixture was stirred and heated at reflux for 16 hours. The resulting suspension was cooled to 5°C;
Stir at lower temperature for 1 hour and filter the solids. The product was washed with T)fF (2X50ml) and incubated in vacuo for 55 minutes.
It was dried at 0°C to obtain a solid (28.5 g). This was recrystallized from methanol to give the title compound (17g
) was obtained.

Elemental analysis: C, 54,5, H, 5,3; N, 9.7
At 5%, the calculated value of Cl8H17N30φ1.4CH403S is C,54,7°H,5,35;N,9.9%.

Example 29 Methanol (150 ml) and triethylamine (3,
(E)-1,2,3,9-tetrahydro-9-methyl-3-((5-methyl-IH-imidazol-4-yl)methylenecomethanesulfonate (10 g) in 6 ml)
10% on reduced carbon in methanol (10 ml)
With a suspension of palladium oxide catalyst (1 g of aqueous paste),
Hydrogenation was carried out at room temperature and atmospheric pressure. This mixture was filtered and approx.
The mixture was condensed to 00ml and heated under reflux. Water (50ml)
was added and roughly cooled to 0°C. The resulting solid was filtered, washed with water (approx. 50ml) and dried in vacuo at 50°C to give the title compound (3.80g). IH-
When examined by NMR and thin layer chromatography,
Consistent with that obtained for the product of Example 8.

Example 3 Monohydrate I MS (200ml) of 1. 2. 3. 9-
Tetrahydro-3-((5-methyl-IH-imidazol-4-yl)methyl]-9-methyl-4H-carbazol-4-one (20 g) was heated to boiling and 2N hydrochloric acid (50 ml) was added. The product solution was cooled to 20° C., the product suspension was stirred for 1 hour and further cooled for 2 hours at 4° C. The product was filtered and dried in vacuo at 55° C., m, p,
The title compound (20.8 g) was obtained at 290° C. (decomposed).

Elemental analysis: C162,1:H+6.25;N, 12.0
5; C1, 9, 85%.

The calculated value of CHN 0-HCI-H2O is C,62,5
;H, 6, 4, N, 12. 15; C1, 10, 2
It is 5%.

Example 31 (±) -1,2°3 in warm methanol (30ml)
．． 9-Tetrahydro-9-methyl-3-((5-methyl-IH-imidazol-4-yl)methylgo-4H-rubazol-4-one (500+*g) was dissolved in methanol (10
ml) of (+)-2,3-bis-[[(4-methylphenyl)carbonyl]oxy]butanedioic acid;
This solution was kept at 0°C for 3 days. Further filtration leaves a solid, which is recrystallized from methanol to give ts, p,
The desired salt (195 mg) was obtained at 146-148<0>C.

A portion of this salt (186 mg) was suspended in water (10 ml) and the mixture was extracted with dichloromethane (2x40 ml). The combined, dry organic extracts were evaporated in vacuo,
The title compound (79.2+ng) was obtained: -49.7[deg.]C (C, -0.41%, CHCl3).

Example 32 (±)-1,2,3°9- in warm methanol (30 ml)
Tetrahydro-9-methyl-3-((5-methyl-IH
-imidazol-4-yl)methyl] -4H-carbazol-4-one (500 mg) solution was added to methanol (10
C-)-2,3-bis-[[(4-methylphenyl)carbonyl]oxy]butanedioic acid (690 ig) in ml)
The solution was placed at 0°C for 3H1. This was filtered to leave a solid, which was recrystallized from ethanol to obtain a.

Obtained the desired salt (162 mg) at 9.147-149<0>C. This was dispersed in water (15ml), potassium carbonate solution (Ig in 10ml water) was added and the mixture was extracted with dichloromethane (2X30ml). Dry 6 collected in one
The machine extract was evaporated in vacuo, a+, I), 230-2
32℃, [α 0-48.4℃ (c, -0.44%, C
The title compound (72,5m
g) was obtained.

Example 33 A solution of intermediate 7 (190+ag) in dry DMF (1 ml) was added dropwise under nitrogen gas to a stirred solution of sodium hydride (52% dispersion in oil, 20 mg) in dry DMF (0.4 ml). . 15 minute diameter - domethane (0,027
m1) was added and the mixture was stirred for 1.5 hours. Water (20
ml) and the suspension was dissolved in dichloromethane (3X10ml).
l). The combined, dry organic extracts were evaporated and the oil (approximately 300 mg) was dissolved in THF.
(4 ml) was dissolved in a mixture of acetic acid (4 ml) and water (4 ml) and heated at reflux for 1.5 hours. The mixture was poured into saturated potassium carbonate solution (20ml) and extracted with dichloromethane (3X10ml). The combined, dry organic extracts were evaporated to a semi-solid (approximately 255+l1g)
This was purified with 5 pcc using System A (200:10:1) as the eluent to obtain the title compound (7 gg). The H-NMR and thin layer chromatography results of this material were consistent with those obtained for the product of Example 8.

n-Butyllithium (1.45M in hexane).

2.C17! E11) of diisopropylamine (0,42 ml) in dry THF (20 ml) in a cold (-70 °C)
) was added dropwise to the stirred solution under nitrogen gas. The solution was allowed to reach 0°C for over 30 minutes, cooled to -70°C, and 1,2°3.9-tetrahydro-9-methyl-4H-carbazol-4-one (5
00 mg) under nitrogen gas. Hexamethylphosphoramide (0.44ml)
was added and the mixture was allowed to stand for 1 hour until it reached 0°C.

The solution was cooled to -70°C, a suspension of 4-(chloromethyl)-5-methyl-1-(triphenylmethyl)-1H-imidacyl (936mg) in dry THF (15ml) was added and the mixture was The volume was allowed to stand for 2.5 hours until reaching approximately 20°C. Stir for a further 18 hours, pour into 8% sodium bicarbonate solution (100ml) and dichloromethane (3X
50 ml). The combined and dried organic extracts were evaporated to give a semi-solid, which was diluted with acetic acid (10 ml), water (
10 ml) and THF (10 ml) and heated at reflux for 1.5 hours. This solution was poured into saturated potassium carbonate solution (100 ml) and dichloromethane (3 x 5
0ml). The combined, dry organic extracts were evaporated to give a solid (approximately 1.8 g), and system A
The title compound (1 g at 17°C) was purified using 5 pcc using C200: 10: 1) as an eluent.

The H-NMR and thin layer chromatography results of this material were consistent with those obtained for the product of Example 8.

Example 35 1, 2.3.9-tetrahydro-9-methyl-3-(
(5-methyl-IH-imidazol-4-yl)methyl)
-4H-carbazole maleate (37+wg) 2N'ffi carbonate (10ml) and C1 Rio.

Partition extraction was carried out with form (3×15 ml). The combined, dry organic layers were evaporated to give the free base (26+ng), which was dissolved in 10% aqueous THF (4 ml) under nitrogen gas at -10<0>C. Add dry THF to this stirred solution.
A solution of 2,3-dichloro-5,6-dicia-1,4-penzoquinone (49g+g) in (1,6ml) was added dropwise and the reaction mixture was warmed to 0<0>C over 3 hours. This solution was evaporated in vacuo and system A (9
4,5:5:0.5) as an eluent to obtain the title compound (10o+g) as a solid. IH-NMR and thin layer chromatography of this material is Example 8.
This was consistent with that obtained for the product.

Example 36 3-Methoxy-6-[(5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl)methyl-2
- Cyclohexen-1-one (203 mg) was added to water (5
ml) and 2N hydrochloric acid (0.45 ml) and the resulting solution was stirred at room temperature under nitrogen gas for 18 hours. 1
-Methyl-1-phenylhydrazine (0.05 ml) was added dropwise and stirring continued for 7 hours. Furthermore, 1-methyl-1-phenylhydrazine (0.05ml) was added,
Stirring was continued for 50 hours at room temperature. This suspension was poured into 8% aqueous sodium bicarbonate solution (10 ml) and ethyl acetate (
3×15 ml). The combined, dry organic extracts were evaporated to give an oil (approximately 240 cm) and system A.
(189:10:1) was purified by FCC as an eluent to obtain a solid (1 g of 55Il). A portion of this solid (40 mg) was heated with molten zinc chloride (450 mg) in glacial acetic acid (3 ml) at 85° C. for 5 hours. Cool the mixture and add 2N aqueous sodium hydroxide solution (20 ml
) and extracted with ethyl acetate (3815 ml). The combined dry organic extracts are evaporated to an oil (approximately 20+
ng) and convert it into system A (89: 10.:
1) was purified by FCC using as eluent, and the title compound (5 m
g) was obtained. 1H-NMR and thin layer chromatography results for this material were consistent with those obtained for the product of Example 8.

Example 37 - [(5-Methyl-IH-imidazol-4-yl)glacial acetic acid (5 ml), THF (5 ml) and water (5 ml)
) in a mixture of 1.2,3.9-tetrahydro-9-methyl-3-((5-methyl-(triphenylmethyl)-
1H-imidazol-4-yl]methyl]carbazole-4
-one (268 mg) solution was heated to 100-110<0>C for 8 hours. After cooling, add 2N sodium hydroxide solution (50ml
) and the resulting suspension was dichloromethane (2X50m
l). The combined, dry organic extracts are evaporated to form a foam, which is converted into System A C100:
8: Purification by FCC using 1) as an eluent gave the title compound (114 mg) as a solid. L H of this substance
-NMR and thin layer chromatography were consistent with those obtained for the product of Example 8.

Example 38 N,N,5-)limethyl-4-((2,3°4.9-
Tetrahydro-9-methyl-4-oxo-1-carbazol-3-yl)methyl 1-IH-imidazole-1-
Sulfonamide (400 mg) was heated to 100-110°C.
The time was hot. Work-up and FCC purification as described in Example 32 gave the title compound (261 mg) as a solid.

IH-NMR and thin layer chromatography results for this material were consistent with those obtained for the product of Example 8.

Example 39 A solution of the product from intermediate 16 (0.2 g) in 49% hydrobromic acid (3 ml) was stirred at 20° C. for 30 minutes. Heat this mixture in a steam bath for 30 minutes, gently (
The mixture was refluxed for 1.5 hours (approximately 150°C). Sprinkle the mixture with water (20 m
1) and washed with ethyl acetate (2×20 ml, discarded). The acidic aqueous layer was basified (to pH 9) with potassium carbonate and diluted with ethyl acetate:ethanol (20:1.2X30m
l). The combined dry organic extracts were evaporated to give a solid, which was triturated with dry ether.
The title compound (0.09 g) was obtained as a solid.

IH-NMR and thin layer chromatography results were consistent with those obtained for the product of Example 8.

Example 40 Absolute ethanol (20ml) and 2M hydrochloric acid (10ml)
A mixture of the product from intermediate 17 (0,5 IC) in a mixture of was heated in a steam bath for 1 hour. The resulting solution was concentrated in vacuo to approximately 20ml, diluted with water (40ml) and washed with ethyl acetate (2X40ml, discarded). The acidic aqueous layer was basified (pH 9) with potassium carbonate and extracted with ethyl acetate:ethanol (20:1.2X'50ml). The combined, dry organic extracts were evaporated to give the title compound (0.34 g) as a solid. IH- of this substance
NMR and thin layer chromatography results were consistent with those obtained for the product of Example 8.

The following examples, according to the invention, contain 1, 2 as active ingredients.
．． 3. 9-tetrahydro-9-methyl-3-[(5
-Methyl-IH-imidazol-1-yl)methyl)-4
1 illustrates a pharmaceutical formulation containing H-carbazol-4-one. Physiologically acceptable salts of this compound and/or
or solvates and other compounds of formula (1) and their physiologically acceptable salts and/or solvates can be formulated in a similar manner.

Tablets for oral administration Tablets may be prepared by conventional methods such as conventional tableting or wet granulation.

The tablets may be film-coated with a suitable film-forming substance, eg hydroxypropyl methylcellulose, using standard techniques. Alternatively, tablets may be sugar-coated.

Direct compression tablet Form IIg/tablet Active ingredient 0.50* Calcium hydrogen phosphate BP 87.25 Croscarmellose sodium NF 1.80 Magnesium stearate BP 0.45 Tablet weight
90.00 bottles The active ingredient is passed through a 60 mesh sieve and mixed with calcium hydrogen phosphate, croscarmellose sodium and sodium stearate. The resulting mixture was sized to a diameter of 5.5
The tablets are compressed using a Manesty F 3 tablet machine fitted with a beveled flat edge tablet cutter in mm.

Urushita tablet mg/tablet active ingredient
0.5 compressible sugar NF
64. 5 Magnesium Stearate BP
0.5 tablet weight jl
The 65.0 active acid content is sieved through a suitable sieve, mixed with excipients and compressed into tablets using a suitable die cutter.

Tablets of different strengths are prepared by combining the active ingredient with excipients or tabletting ffi
It can be prepared in different proportions and using a suitable die cutter.

Wet granulation method regular tablet mg/tablet active ingredient
0.5 lactose BP
153. 5 starch BP
30.0 Gelatinized corn starch BP 15.0 Magnesium stearate BP 1.5 Tablet weight
200. The 0 active acids are sieved through a suitable sieve and mixed with the lactose, starch and pre-gelatinized corn starch. Add an appropriate amount of purified water and granulate the powder. After drying, sort the granules,
Mix with magnesium stearate. The granules are compressed into tablets using a die cutter with a diameter of 7 mm.

Tablets of various strengths may be prepared by varying the ratio of active ingredient to lactose or tablet weight and using suitable die cutters.

Sublingual tablet ff1g/tablet Active ingredients 0.5 Mannitol BP 58.5 Hydroxypropyl methylcellulose 5.0 Magnesium stearate BP 1.0 Tablet weight
65.0 Sift the active ingredient through a suitable sieve and combine with the mannitol and hydroxypropyl methylcellulose. Add an appropriate amount of purified water and granulate the powder. After drying, the granules are sorted, mixed and made into tablets using a suitable die cutter.

Tablets of various strengths may be prepared by varying the ratio of active ingredient to mannitol or tablet weight and by appropriate die cutting.

capsule tng/tablet active ingredient
0. 5 starch 1500
98.5 Magnesium Stearate BP
1.0 Filling weight 100
．． 0 directly compressible starch form The active ingredient is sieved and mixed with excipients. The mixture is filled into hard gelatin capsules of size No. 2 using suitable equipment. Various dosage capsules may be prepared with varying fill weights and, if necessary, capsule sizes to suit.

syrup This may be a sucrose-containing or non-sucrose-containing preparation.

A2 Sucrose Syrup mg15ml Dosage Active Ingredients 0. 5 Sucrose BP
275. 0 Glycerin BP
500. 0 Buffer) Fragrance) Coloring agent if necessary) Preservative) Active ingredient, made up to 5.0 ml with purified water BP,
Dissolve buffering agents, fragrances, colorants and preservatives in a small amount of water,
Add glycerin. Heat the remaining water to dissolve the sugar,
Then cool. Combine the two solutions, adjust the volumes, and mix.

Clarify the syrup by filtration.

B. Sucrose-free syrup mg 15ml Dosage Active Ingredients 0.5 Hydroxypropyl Methyl Cellulose USP (Viscous Type 4000) 22.5 Buffers) Flavorings) Colorants) Preservatives if necessary) Sweeteners) Purified Water BP 5 Set the volume to .0ml.

Hydroxypropyl methylcellulose is suspended in hot water, cooled and mixed with an aqueous solution containing the active ingredient and other ingredients of the dosage form. Adjust the volume of the product solution and mix. Clarify the syrup by filtration.

Injection solution for intravenous administration mg/ml Active ingredient 0.05 0.5 Sodium chloride PB If necessary If necessary, use water for injection BP 1. Sodium chloride to 1.0 ml may be added to adjust the osmotic pressure of the solution. Acids or alkalis may be used to adjust the optimum pH for stabilization and/or to promote solubilization of the active ingredient. Alternatively, suitable buffer salts may be used.

The solution is prepared, clarified and filled into appropriately sized ampules sealed with glass melt. Autoclave (autoc+avc) using one of the appropriate cycles
The injection solution is sterilized by heat. Alternatively, the solution may be filter sterilized and filled into sterile ampoules under aseptic conditions. The solution may be charged under an inert atmosphere of nitrogen or other suitable gas.

Active ingredient 0. 050 12. Omg
Oleic acid BP 0.020 4.80 mg Trichlorofluoromethane BP 23.64 5.67 g Dichlorodifluoromethane BP 61.25 14.70° The active ingredient was milled into fine particles (1'lne p
orNcle) size range. Oleic acid was mixed with trichlorofluoromethane at 10°C to 15°C and the refining agent was mixed with a high shear mixer (high 5hea
Mix with the solution using a l1ixer). Weigh this floating liquid into an aluminum aerosol can and obtain 85 mg of floating liquid.
Calibrate the appropriate metering valve on the vehicle to dispense the amount. Dichlorodifluoromethane is pressurized into the can through this valve.

Solution Aerosol Active Ingredients 0. 05 12. Om
g ethanol BP 7.500 1.80 g trichlorofluoro, methane BP 18.875 4.53 g dichlorofluoromethane BP 48.525 11.65 g oleic acid PB with a suitable surfactant, e.g. Span 85
(Span 85) It may be used in addition to (sorbitan trioleate).

The active ingredient is dissolved in ethanol along with oleic acid and surfactant if necessary. This alcohol solution is weighed into a suitable aerosol container, followed by filling with trichlorofluoromethane. Mark the appropriate metering valve on the container and fill the dichlorodifluoromethane under pressure through the valve as well.

Inhalation cartridge sg/cartridge active ingredient (micronized) 0.05 lactose BP
The active ingredient is micronized to fine particle size in a fluid energy mill before being blended with conventional tablet grade lactose in a high-intensity mixer to 25.00 mg. This powder mixture is filled into No. 8 hard gelatin capsules in a suitable encapsulation machine. The contents of the cartridge are administered using a powder inhaler.

Herbal medicine active ingredient 0.5a + g * Wltepsol (Wltepsol) 1.0g at HI3: * Wltepsol H15 is ^ deps 5 olidus Ph.

It is a 1Eur exclusive product.

The i9 solution of active ingredient is prepared in molten Witebusol and filled into 1 g size herbal molds using a suitable machine.

Claims (1)

[Claims] 1. Compounds of general formula (I), physiologically acceptable salts and solvates thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) Here, Im represents the imidazolyl group of the following formula. ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ R^1 is a hydrogen atom, or C_1_-_6 alkyl, C
_3_-_8 alkenyl, C_3_-_1_0 alkynyl, C_3_-_7 cycloalkyl, C_3_-_7 cycloalkylC_1_-_4 alkyl, phenyl, phenylC_1_-_3 alkyl, -CO_2R^5, -C
Represents a group selected from OR^5-CONR^5R^6 or -SO_2R^5. 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 phenylC_1_-_4 alkyl group (herein, the phenyl group is, in some cases, R^1 is -CO_2R^
5 or -SO_2R^5, one or more C_2, provided that R^5 does not represent a hydrogen atom.
One of the groups represented by R^2, R^3 and R^4 (substituted by 1_-_4 alkyl, C_1_-_4 alkoxy or hydroxy group, or halogen atom) is a hydrogen atom, or C_1_-_6 alkyl , C_3
_-_7 cycloalkyl, C_3_-_6 alkenyl,
phenyl or phenyl C_1_-_3 alkyl group, and each of the remaining two groups may be the same or different and represents a hydrogen atom or a C_1_-_6 alkyl group. Q is hydrogen or halogen atom, or hydroxy, C_1
_-_4 alkoxy, phenyl C_1_-_3 alkoxy or C_1_-_6 alkyl group, or -NR^7R^
8 or -CONR^7R^8. R^7 and R^8 may be the same or different and each represents a hydrogen atom, C_1_-_4 alkyl or C_
3_-_4 represents an alkenyl group, or forms a saturated 5- to 7-membered ring together with the nitrogen atom to which they are bonded. n represents 1, 2 or 3. AB represents the group CH-CH_2 or C=CH. 2, R^1 is a hydrogen element, or C_1_-_3 alkyl, C_3_-_4 alkenyl, C_3_-_4 alkynyl, C_5_-_6 cycloalkyl, C_5_-_6 cycloalkylmethyl, phenyl C_1_-_2 alkyl, C_1_-_3 alkoxycarbonyl , ¥N¥, ¥N
The compound according to claim 1, which is a ¥-diC_1_-_3 alkylcarboxamide or phenylsulfonyl group. 3. The compound according to claim 1 or 2, wherein R^2 is a hydrogen atom or a C_1_-_3 alkyl group. 4. The compound according to any one of claims 1 to 3, wherein R^3 is a hydrogen atom or a C_1_-_3 alkyl group. 5. The compound according to any one of claims 1 to 4, wherein R^4 is a hydrogen atom or a C_1_-_3 alkyl group. 6, each of R^2 and R^3 is a hydrogen atom, and R^4
The compound according to claim 1 or 2, wherein is a methyl group. 7, Q is hydrogen atom, halogen atom, or hydroxy, C
Any one of claims 1 to 6, which is a _1_-_3 alkoxy or a C_1_-_3 alkyl group
Compounds described in Section. 8. The compound according to any one of claims 1 to 7, wherein AB is CH-CH_2. 9. The compound according to any one of claims 1 to 8, wherein n is 2 or 3. 10, R^1 is a hydrogen atom or C_1_-_3 alkyl,
C_3_-_4 alkenyl, C_3_-_4 alkynyl, C_5_-_6 cycloalkylmethyl, phenyl C_
1_-_2 alkyl, C_1_-_3 alkoxycarbonyl or \N\, \N\-diC_1_-_3 alkylcarboxamide group, each of R^2 and R^3 is a hydrogen atom, and R^4 is C_1_ -_3 alkyl group, Q is hydrogen or a halogen atom or a hydroxyl group, A-B is CH-CH_2 or C=CH, and further n is 2 or 3, Compounds described. 11, R^1 is a hydrogen atom or methyl, prop-2-enyl, prop-2-ynyl, cyclopentylmethyl, benzyl or \N\,\N\-dimethylcarboxamide group, R^2 and R^3 each is a hydrogen atom, R
^4 is a methyl group, Q is hydrogen or a fluorine atom, A-B is CH-CH_2, and n is 2 or 3
The compound according to claim 1, which is 12. Claim 10 or 1, wherein n is 2.
Compound according to item 1. 13,1,2,3,9-tetrahydro-9-methyl-3
- [(5-Thymel-1\H\-imidazol-4-yl)
methyl]-4\H\-carbazol-4-one and its physiologically acceptable salts and solvates. 14. The compound according to claim 13, which is in the form of a hydrochloride. 15,1,2,3,9-tetrahydro-9-methyl-3
-[(5-methyl-1\H\-imidazol-4-yl)
Methyl]-4\H\-carbazol-4-one hydrochloride monohydrate. 16,6-fluoro-1,2,3,9-tetrahydro-
9-Methyl-3-[(5-methyl-1\H\-imidazol-4-yl)-methyl]-4\H\-carbazol-4
-one, 1,2,3,9-tetrahydro-3-[(5-methyl-
1￥H￥-imidazol-4-yl)methyl]-4￥H￥
-carbazol-4-one, 9-(cyclopentylmethyl)-1,2,3,9-tetrahydro-3-[(5-methyl-1\H\-imidazol-4-yl)methyl]-4\H\ -carbazol-4-one, 1,2,3,9-tetrahydro-3-[(5-methyl-
1\H\-imidazol-4-yl)methyl]-9-(2
-propynyl)-4\H\-carbazol-4-one, 6,7,8,9-tetrahydro-5-methyl-9-[(
5-Methyl-1\H\-imidazol-4-yl)methyl]-cyclohept[b]indole-10(5\H\)-
on, and its physiologically acceptable salts and solvates. 17. A compound of the general formula (I) or its physiological state according to any one of claims 1 to 14, which consists of any of the following steps (A) to (G). A method for producing acceptable salts or solvates thereof. (A) For the preparation of compounds of formula (I) in which A-B is the group C=CH, a compound of formula (II) or a derivative thereof with a protecting group is dehydrogenated, if necessary subsequently present The process of removing the protecting groups. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) (B) Converting a compound of formula (I) into another compound of formula (I) using conventional techniques. (C) For the production of a compound of formula (I) in which A-B is a group CH-CH_2, a compound of formula (III) or a derivative thereof having a protecting group is added to the compound of formula (III), in which L is a leaving atom or group. formula(
V) Reaction with the compound of V) or a derivative thereof having a protecting group in the presence of a base, followed by removing any existing protecting group if necessary. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) LCH_2-Im(V) (D) To produce a compound of formula (I) where A-B is a group CH-CH_2, a compound of formula (VI) And, A
is a hydrogen atom or a hydroxyl group, or a salt thereof or a derivative having a protective group, followed by removing the protective group present if necessary. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (VI) (E) For the production of a compound of formula (I) in which A-B is a group CH-CH_2, a compound of formula (VII) or a salt thereof or a protective group thereof cyclization of the derivative with , followed by removal of any protecting groups present if necessary. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (VII) (F) A process of removing the protecting group from the form of the compound of formula (I) that has a protecting group. (G) when the compound of formula (I) is obtained as a mixture of enantiomers, optionally separating the mixture to obtain the enantiomers; and/or when the compound of formula (I) is in the form of a free base; , optionally converting this free base into a salt. 18. General formula (I) according to claim 1 together with at least one physiologically acceptable carrier or excipient
) or a physiologically acceptable salt thereof or a solvate thereof. 19, Im, R^1, Q and n are defined in claim 1
A compound of general formula (II) as defined in any one of Items 1 to 11. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) 20, A is a hydrogen atom or a hydroxy group, Im, R
^1, Q and n are defined in any one of claims 1 to 11, general formula (VI)
compound. ▲ Includes mathematical formulas, chemical formulas, tables, etc. ▼ (VI) 21. Claims 1 to 11 for use in the treatment of symptoms caused by "neuronal" 5HT dysfunction A compound of general formula (I) or a physiologically acceptable salt thereof or a solvate thereof, as defined in any one of the preceding paragraphs. 22. Compounds of general formula (I) or physiologically acceptable salts thereof as defined in any one of claims 1 to 16 for use in the treatment of anxiety disorders Solvate. 23. Claim 1 for use in the treatment of mental illness
The general formula (
A compound of I) or a physiologically acceptable salt or solvate thereof. 24. As active ingredients, claims 1 to 1
containing at least one compound of general formula (I) or a physiologically acceptable salt thereof or a solvate thereof, as defined in any one of Clause 6, caused by neuronal 5HT dysfunction; Pharmaceutical compositions for the treatment of conditions. 25. As active ingredients, claims 1 to 1
A pharmaceutical composition for the treatment of anxiety disorders, comprising at least one compound of general formula (I) or a physiologically acceptable salt thereof or a solvate thereof, as defined in any one of Section 6. . 26. Claims 1 to 1 as active ingredients
A pharmaceutical composition for the treatment of mental illness, comprising at least one compound of general formula (I) or a physiologically acceptable salt thereof or a solvate thereof, as defined in any one of Clause 6. . 27. As active ingredients, claims 1 to 1
caused by neuronal 5HT dysfunction, comprising at least one compound of general formula (I) or a physiologically acceptable salt thereof or a solvate thereof, as defined in any one of Clause 6. Therapeutic agents for the treatment of symptoms associated with 28. As active ingredients, claims 1 to 1
A therapeutic drug for the treatment of anxiety disorders, comprising at least one compound of general formula (I) or a physiologically acceptable salt thereof or a solvate thereof, as defined in any one of Section 6. . 29. As active ingredients, claims 1 to 1
A therapeutic drug for the treatment of mental illness, comprising at least one compound of general formula (I) or a physiologically acceptable salt or solvate thereof, as defined in any one of Section 6. .