JPS60214784A - Heterocyclic compound - Google Patents

Abstract

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

Description

BACKGROUND OF THE INVENTION TECHNICAL FIELD The present invention relates to heterocyclic compounds, processes for their preparation, pharmaceuticals containing the core compounds, and medical uses of the compounds. In particular, the present invention relates to a compound consisting of 5-hydroxytryptamine (5HTl).

5HT occurs abundantly endogenously in peripheral nerves and platelets
is known to cause pain in humans by specifically acting on 5HT receptors located at the terminals of the main afferent nerves. Compounds that antagonize the neuronal effects of 5HT are previously known to have analgesic effects, eg, reduce migraine pain. Also 5
HT depolarizes isolated rat vagus nerve preparations by the same 5HT-receptor mechanism, and inhibition of this effect correlates with in vitro analgesic effects.

Additionally, 5HT occurs extensively in neuronal pathways of the central nervous system, and disturbances in these 5HT'i-containing pathways are known to alter behavioral syndromes such as mood, psychomotor activity, appetite, and memory. There is.

Since 5HT-IJ sesotar, the same type of "neuronal unit" present in the main afferent nerve endings, is also present in the central nervous system, compounds that antagonize the effects of 5HT neuronal units may be used to treat schizophrenia and anxiety. It is believed to be useful in the treatment of medical conditions such as cancer, obesity and intestinal disease.

PRIOR ART Current treatments for such conditions have a number of disadvantages. For example, known treatments for migraine include the administration of vasoconstrictors such as Elvitamin, which are non-selective and constrict blood vessels throughout the body. Therefore, Elvitamin has undesirable and potentially dangerous side effects. Migraines may also be treated with analgesics such as aspirin or noguracetamol, usually in combination with antiemetics such as methalopramide, but these treatments are of limited value.

Similarly, current treatments for mental illnesses such as schizophrenia include
There are a number of serious side effects, such as extrapyramidal side effects.

Therefore, 5HTt-
There is a need for safe and effective drugs to treat pathologies involving disorders of the inflammatory pathway.

Compounds that are potent and selective antagonists at the "neuronal" 5HTIJ receptor are believed to accomplish such tasks.

DESCRIPTION OF THE INVENTION Compounds The inventors have discovered that 5 HT of "neurons"
We have discovered a group of 3-imidazolylmethyltetrahydrocarmesolones that are potent and selective in IJ sesotar.

The present invention therefore provides tetrahydrocarbazolones of general formula (1) and physiologically acceptable salts and solvates (eg hydrates).

Here, R1 is a hydrogen atom, C□~1o alkyl, C3N7no7chloroalkyl, C3,6 alkenyl,
Phenylmataha phenyl-cl is a 3-alkyl group. One of the groups represented by R2, R3 and R4 is a hydrogen atom, C0-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl or phenyl-01-
3 alkyl group, and the other two groups can be the same or different, and each has a hydrogen atom or C□~6
represents an alkyl group.

It is understood that when R represents a C3-6 alkenyl group, the double bond cannot be adjacent to any desired atom.

In general formula (1), the alkyl groups represented by R1, R2, R3 and R4 can be linear or branched, such as methyl, ethyl, propyl, pro-2-
yl, butyl, but-2-yl, 2-methyl procy2
-yl, pentyl, bent-3-yl or hexyl.

An alkenyl group can be, for example, a propenyl group.

A phenyl-C1-3 alkyl group can be, for example, a benzyl, phenethyl or 3-phenylpropyl group.

A cycloalkyl group can be, for example, a cyclopentyl, cyclohexyl or cycloalkyl group.

It is understood that the carbon atom in the 3-position of the tetrahydrocarbazolone ring is asymmetric and can exist in the R-configuration IIIt or S-configuration.

The present invention is directed to both the individual isomeric forms of the compounds of formula (1) and to all mixtures thereof, including racemates.

Suitable physiologically acceptable salts of indoles of general formula (1) include acid addition salts formed with organic or inorganic acids, such as hydrochloride, hydrobromide, sulfate, phosphoric acid salt,
Includes citrate, fumarate and maleate. A solvate can be, for example, a hydrate.

A preferred type of compound represented by general formula (1) is R
is a hydrogen atom, a 01-6 alkyl group, a 03-6 cycloalkyl group, or a C3-6 alkenyl group.

Another preferred type of compound represented by general formula (1) is one of the groups represented by R2, R3 and R4.
1-3 alkyl, 03-6 cycloalkyl or C
It is an alkenyl group having 3 to 6 carbon atoms, and the other two groups are the same or different and are hydrogen atoms or C□-3 alkyl groups.

Another preferable vertebrate of the compound represented by the general formula (1) is one in which R is a hydrogen atom or C□-6 alkyl, C5-6
is a cycloalkyl or C3-4 alkenyl group, and R2 is a hydrogen atom, and R4 and/or R4 are an alkyl group of 01-3, or R
is a C1-3 alkyl group, and both R3 and R4 are hydrogen atoms.

A particularly preferred class of compounds according to the invention is of formula (Ia)
and their physiologically acceptable salts and solvates (eg hydrates).

Here, nla represents a hydrogen atom or a group of methyl, ethyl, propyl, phlobu-2-yl, phlobu-2-enyl or cyclopentyl. R represents a hydrogen atom.

R2a is methyl, ethyl, propyl or prop-2-
yl and R4'' represents a hydrogen atom, or R2m represents a hydrogen atom and 14a represents a methyl or ethyl group.

Preferred compounds are as follows.

(a) 1,2,3.9-tetrahydro-3-[: (
2-Methyl-IH-imidazol-l-yl)methyl]-
9-(pro-2-enyl)-4! ! -Cartumazol-
4-one, (b) 9-cyclopentyl-1,2,3,9-tetrahydro-3-((2-methyl-1!!-imidazole-
1-yl)methyl)-4H-carbazol-one, and (iii) 1,2,3.9-tetrahydro-3-[2-methyl-1! ! -imidazol-1-yl)methyl]-9-
(Prop-2-yl)-4H-carbazol-4-one 1
and) their physiologically acceptable salts and solvates.

Particularly preferred compounds are 1, 2 which can be represented by formula (Ib)
,3.9-tetrahydro-9-methyl-3-[(2-methyl-1-imidazol-l-yl)methyl)-4H-
carbazol-4-ones, and their physiologically acceptable salts and solvates (e.g. hydrates). The preferred form of this compound is the hydrochloride dihydrate.

The invention may be extended to other physiologically acceptable equivalents of the compounds according to the invention, i.e. physiologically acceptable compounds which are converted in vitro to frozen compounds of formula (1). be understood.

Drugs The compounds of the present invention can be used in isolated rat vagus nerve preparations (
the rat 1solated vagus ne
is a potent and selective antagonist with respect to the 5HT-induced response of rvepreparation);
Therefore, the 5 HT of the "neuronal units" present in the main afferent nerves
It acts as a potent and selective antagonist of the IJ receptor type.

The compounds of the invention are useful as analgesics, for example, in alleviating pain associated with migraine, headache, and other forms of pain in which 5HT is an endogenous medicinal agent.

The compounds of the present invention have also been found to be useful in the treatment of schizophrenia and other psychoses in animal studies. As mentioned above, 5HT occurs in a wide range of neuronal pathways in the central nervous system, and disorders of these 5HT'i-containing pathways are associated with many other behavioral symptoms such as mood, appetite, and memory.
is known to change. Because the same type of "neuronal" 5HTIJ receptors that are present in the main afferent nerve endings are also present in the central nervous system, the compounds of the invention may also be useful in the treatment of conditions such as anxiety, obesity, and intestinal disease. Can be useful.

In particular, the compounds of formula (Ia) described above have been found to be highly selective in action and highly effective.

The compound is well absorbed from the gastrointestinal tract and is suitable for oral or rectal administration.

The compound of formula (1a) does not prolong the sleeping time of mice anesthetized with bendoparbitone, and does it exhibit undesirable interactions with drug-metabolizing enzymes? Not shown. In fact, this compound has no observed effects on normal behavior, is nontoxic, and exhibits no undesirable effects in mice at doses up to 1 mg/kg intravenously.

In addition to exhibiting the remarkable properties of compounds of formula (Ia), compounds of formula (Ib) did not exhibit any adverse effects when administered to humans.

According to another aspect, the invention provides that 5 of the "neural units"
A method of treating a human or animal with a condition caused by impairment of HT function is provided. Accordingly, a method of treating humans suffering from mental illness, such as migraine or schizophrenia, is therefore provided by the present invention.

Therefore, 3-imidazolylmethyltetrahydrocarbazolone derivatives of general formula (I), physiologically acceptable salts thereof and in a solvent phase, used in pharmaceutical or veterinary medicine and formulated for administration by convenient routes. Pharmaceutical preparations containing at least one selected from (e.g. hydrates)
Provided by the present invention.

Such formulations may be formulated in conventional manner using one or more physiologically acceptable carriers or excipients.

The compounds of the invention may therefore be formulated in a form suitable for oral, buccal, parenteral or rectal administration, or for administration by inhalation or insufflation (via the mouth or nose).

For oral administration: 1 binder (e.g. pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose), filler (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate),
Lubricants (e.g. magnesium stearate, talc or silica), disintegrants (e.g. potato starch or soybean)
The preparation may be in the form of tablets or capsules prepared by conventional methods, for example, with pharmaceutically acceptable excipients such as IJum starch glycolate) or wetting agents (e.g. sodium lauryl sulfate). I can do it. The tablets may be coated by methods well known in the art. Liquid preparations for oral administration can be in the form of, for example, solutions, syrups or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use. Good morning. Such liquid formulations may contain suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia), non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionating agents). It can be prepared by conventional methods using pharmaceutically acceptable additives such as methyl- or propyl-p-hydroxypenzoate or sorbic acid); can. The formulation may also contain buffer salts, flavoring, coloring and sweetening agents as desired.

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

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

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

The compounds of the invention may also be formulated in rectal preparations such as suppositories or retention enemas, which accordingly contain conventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described above, the compounds of the invention may also be formulated as depot preparations. Such long-acting formulations may be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention may be prepared from suitable polymeric or hydrophobic materials (
For example, as an emulsion in an acceptable oil), or using ion exchange resins, or as a sparingly soluble derivative (eg, a sparingly soluble salt).

For administration by inhalation, the compounds according to the invention may be prepared using a suitable propellant such as, for example, dichlorodifluoromethane, trichlorofluoromethane, cuchlortetrafluoroethane, carbon dioxide or other suitable gases. is conveniently supplied in the form of an aerosol spray from a pressurized package or a nebulizer.

In the case of pressurized aerosols, the dosage unit could be determined by providing a pulp that delivers a metered amount. Capsules and cartridges, eg of gelatin, for use in an inhaler or insufflator can be formulated with a suitable powder base, such as lactose or starch, and a powder mixture of the compound of the invention.

The proposed dosage of the compounds of the invention for administration to humans (approximately 70 kg body weight) is, for example, 0.05 to 20 mg, preferably 0.1 mg per unit dose, which can be administered 1 to 4 times a day.
It is the active ingredient of ~lomg. This dosage will depend on the route of administration and the weight of the patient. It is understood that it may be necessary to vary the dosage on a daily basis, based on the age and weight of the patient and the severity of the condition being treated.

For oral administration, the unit dose is preferably between 0.5 and 10
mg of the active ingredient. A unit dose for parenteral administration will preferably contain from 0.1 to 10 mg of the active ingredient.

The aerosol formulation is such that each metered dose delivered from the pressurized aerosol, i.e., the "-times ejection volume" is 0.2
It is preferably set to contain ~2 mg of the compound of the invention. The dose administered via a capsule or cartridge in a syringe or inhaler is between 0.2 and 2
Contains 0 mg of the compound of the invention. Total by inhalation method
The daily dosage will be within the range of 0.4-80 mg. Administration can be several times per day, for example 2 to 8 times, for example 1.2 or 3 doses each time.

If desired, the compounds of the invention can be administered in combination with other therapeutic agents (eg, anti-emetics).

According to another aspect of the invention, compounds of general formula (1) and their physiologically acceptable salts or solvates or physiologically acceptable equivalents are prepared by the general method outlined below. can be manufactured.

According to a first general method (A), compounds of general formula (1) or their physiologically acceptable salts or physiologically acceptable equivalents are converted into compounds of general formula (II) 1 \, R1 is as defined above and Y represents a reactive substituent) or protected derivatives thereof, of the general formula (1), R2, R3 and R4 are as defined above. ) or their salts.

Examples of compounds of formula (II) used as starting materials include those in which Y is (i) an alkenyl group=CH2 or a group 2〇H2z, where 2 is a readily atom such as a halogen atom (e.g. chlorine or bromine). (represents a substitutable atom or group), ←)
Acetoxy, trifluoromethanesulfonyloxy, i
-) an acyloxy group such as luenesulfonyloxy or methanesulfonyloxy, (c) -N+85R6R
In the 7X group, R5, R6 and R7 can be the same or different and represent lower alkyl (e.g. methyl), allyl (e.g. phenyl) or aralkyl (e.g. benzyl), or R5 and R
6 is 5 negative to 6 along with the nitrogen atom to which they are bonded
can form a membered ring (e.g. pyrrolidine ring) and X is a halogen ion (e.g. chlorine, bromine, iodine)
represents an anion such as ), or )-NR5R6
Based on \, R5 and R6 are the same as above, for example -
N(CH3) 2 ).

When Y represents a :=:CH2 group, the process can be conveniently carried out in a suitable solvent. Examples of such solvents include water, esters (e.g. ethyl acetate), ketones (e.g.
(e.g. acetone or methylisobutylketone), amides (e.g. dimethylformamide), alcohols (e.g.
ethanol), and ethers (eg dioxane or tetrahydrofuran), or mixtures thereof. This method can be carried out, for example, at temperatures between +100°C.

When Y represents a CH2z group (2 is a halogen atom or an acyloxy group), amides (e.g. dimethylformamide), alcohols (e.g. methanol or industrial methylated spirit) or talloalkanes (e.g. dichloromethane) The process may be conveniently carried out in a suitable solvent such as 10C to 150C (e.g. 10C to +100C).

The reaction of the compound of formula (...) in the case of representing a YkaCH2z group (con\nizbarN+R5R6R7X- group) is to react with water, amides (e.g. dimelformamide), ketones (
It may be conveniently carried out in a suitable solvent such as eg acetone) or ethers (eg dioxane) and at temperatures from 20 to 150<0>C.

Y car Cl2Z group (ko\Klt-NR"R6 tear, b
) may be conveniently carried out in a suitable solvent such as water or alcohols (e.g. methanol) or mixtures thereof and at a temperature between 150°C and 150°C. .

According to another general method (B), the compound of formula CI) is
by oxidizing a compound of formula (■) in which A represents a hydrogen atom or a hydroxyl group and R1, R2, R3 and R4 are as defined above) or a salt or protected derivative thereof. can be manufactured.

This oxidation method may be carried out using conventional methods, but the reagents and reaction conditions should be chosen so as not to oxidize the indole groups. Therefore, the oxidation method is preferably carried out using a mild oxidizing agent.

When oxidizing a compound of formula (■) where A is a hydrogen atom,
Excessive oxidizing agents include quinones in the presence of water (e.g. 2
．． 3-dichloro-5,6-dicyano-1,4-benzoquinone or 2,3,5,6-tetrachloro-1,4-benzoquinone), selenium dioxide, cerium(IV) oxidizing agent (e.g. ceric ammonium sulfate) or a chromium (Vl) oxidizing agent (such as Jones' reagent, romic acid in acetone or chromium trioxide in pyridine).

When oxidizing a compound of formula (■) in which A is a hydroxyl group, suitable oxidizing agents include quinones (e.g. 2,3-dichloro-5,6-dicyano-1,4-benzoquinone) in the presence of water. or 2,3.5.6-tetrachlor-1,
4-benzoquinone), Kents (e.g. acetone, methyl ethyl ketone or cyclohexanone) in the presence of a base (e.g. aluminum t-butoxide), chromium (
Vl) oxidizing agent (e.g. Jones reagent, romic acid in acetone or chlorine trioxide in pyridine)
, N-halosuccinimides (e.g. N-chlorosuccinimide or N-bromsuccinimide), activating agents (e.g. N,N'-.cyclohexylcarbodiimide or acryl halides such as oxalyl chloride or tosyl chloride) were present. Dialkyl sulfoxides (e.g. dimethyl sulfoxide), pyridine-
Sulfur trioxide complexes, or dehydrogenation catalysts such as copper chromite, zinc oxide, copper or silver are included.

Suitable solvents include ketones (e.g. acetone or butanone), ethers (e.g. tetrahydrofuran or dioxane), amides (e.g. dimethylformamide).
, alcohols (e.g. meketal) 1. Hydrocarbons (e.g. penzey or toluene), halogenated hydrocarbons (
dichloromethane), water, or mixtures thereof.

This process is conveniently carried out at temperatures between -70<0>C and +50<0>C. It will be appreciated that the choice of oxidizing agent will vary the preferred reaction temperature.

By another general method (C), the formula (1) according to the invention
or their salts or protected derivatives can be converted into other compounds of formula (1) employing conventional techniques. Such prior art techniques include alkylation (which can be carried out at any position in the compound of formula (I) where one of R1 and R2 represents a hydrogen atom), and hydrogenation (e.g. alkenyl substituents (which can be employed to convert to alkyl substituents) are included. The term "alkylation" includes the introduction of other groups such as cycloalkyl or alkenyl groups. Therefore, for example, the formula (1
), R1 is C□-1o alkyl, C3,...
, 7 cycloalkyl, C3-6 alkenyl or phenyl-C1-3 alkyl groups.

The above alkylation reaction gives a compound of formula RJL Xa\
in which Ra represents C1-10 alkyl, 03-7 cycloalkyl, C3-6 alkenyl or phenyl-C1-3 alkyl group, and Xa represents a halide or a leaving group such as an acyloxy group as defined above for Y. ) or a sulfate of the formula (Ra)2S04.

This alkylation reaction is conveniently carried out in an inert organic solvent such as amides (e.g. dimethylformamide), ethers (e.g. tetrahydrofuran), or aromatic hydrocarbons (e.g. toluene), preferably in the presence of a base. be done. Suitable bases include, for example, alkali metal hydrides (e.g. sodium hydride), alkali metal amides (e.g. sodium amide), alkali metal carbonates (e.g. sodium carbonate), or alkali metal alkoxides (e.g. sodium or potassium). methoxide, ethoxide or t-methoxide). This reaction is carried out between −+ and +100°C, preferably between θ and 50°C.
It may be conveniently carried out at temperatures in the range of 'C.

Hydrogenation according to general method (C) can be carried out using conventional methods, for example using hydrogen in the presence of noble metal catalysts (eg palladium, Raney nickel, platinum, platinum oxide, rhodium). The catalyst may be supported on charcoal, for example, or a homogeneous catalyst such as tris(triphenylphosphine)rhodium chloride may be used. This hydrogenation is carried out in a solvent such as an alcohol (e.g. ethanol), an amide (e.g. dimethylformamide), an ether (e.g. dioxane), or an ester (e.g. ethyl acetate) and at a temperature of from 1 to 100° C., preferably It will generally be carried out at temperatures ranging from 0 to 50'C.

It should be understood that in some of the above transformations it may be necessary or desirable to protect sensitive groups in the compounds to prevent undesired side reactions.

The protecting group used in the preparation of the compound of formula (1) is preferably a group that can be easily removed at an appropriate step in the reaction sequence, conveniently at the final step. For example, in the above reaction sequence it may be necessary to protect the keto group, eg as a ketal or thioketal.

In this way, compounds of general formula (1) can be prepared by another general method (D) comprising the step of removing the protecting group from the protected form of the compound of formula (1). Removal of protecting groups is carried out according to [Protective Groups in Organic Chemistry J Ed, J, F, W, M
cOmie (Plenum Presa+1973
) can be implemented using conventional techniques such as those described in . That is, ketals such as alkylene ketals may be removed by treatment with a mineral acid such as hydrochloric acid.

The thioketal group may be separated by treatment with a mercuric salt (eg, mercuric chloride) in a suitable solvent such as ethanol.

Compounds of formula (1) can be converted into physiologically acceptable salts according to conventional methods. For example, general formula (1)
The free base of may be treated with a suitable acid (preferably an equivalent amount) in a suitable solvent (eg aqueous ether).

Physiologically acceptable equivalents of compounds of formula (1) can be prepared according to conventional methods.

The individual enantiomers of the compounds of the invention can be obtained by resolving mixtures of enantiomers, eg racemic mixtures, using conventional means such as acids for optically active resolution. For example, E, L.

"Stereochemistry Op Carboncon Ie Unno J" by Eliel (McGraw Hllll 19
62) and S. H. Wilen, Tables of Resilping Agents, all references.

Examples of optically active resolving acids that can be used to form salts with the racemates include organic carboxylic or sulfonic acids such as tartaric acid, p-)luoyltartaric acid, camphorsulfonic acid, and lactic acid. (R) body and (S)
Includes the body. The resulting mixture of isomeric salts can be separated into diastereoisomers, for example by fractional crystallization. If desired, all of the required optically active isomers can be converted to the free base.

The above-described method of producing the compounds of the invention can be employed as the last main step in the production sequence. This general method can be used to introduce desired groups at intermediate stages in the stepwise formation of the required compound. It will be appreciated that these general methods can be combined in various ways in such multi-step processes. The sequence of reactions in the multistep process is such that the reaction conditions employed do not affect the molecular groups desired in the final product.
Naturally, it should be selected.

The starting material of formula (n) in which X represents a CH2 group can be prepared by reacting with a base in a suitable solvent to
The formula representing the group N+R5R6R7 ) Contains IJum).

The quaternary salt may be formed from the corresponding tertiary amine by reaction with an alkylating agent such as methyl iodide or dimethyl sulfate, if preferred in a suitable solvent (e.g. dimethylformamide). can. This tertiary amine can be prepared by reacting a tetrahydrocarbazolone of general formula (V) with formaldehyde and the corresponding tertiary amine in a suitable solvent such as an alcohol (e.g. ethanol) in the desired setting. It can be prepared.

Compounds of general formula (V) are, for example, J, Org, Ch
em.

(1980) Volume 45, No. 15, 2938-2942
It can be manufactured by the method described by 11da et al.

Starting materials of the general formula (II) in which Y is -CH2z and 2 is an acyloxy group spanning a halogen atom can be prepared from the corresponding hydroxymethyl derivatives of the general formula (Vl).

1 This compound (Vl) can be obtained by reacting a tetrahydrocarbazolone of general formula (V) with formaldehyde, preferably in a suitable solvent such as an alcohol (e.g. ethanol) and preferably in the presence of a base. .

Therefore, the compound in which 2 is a halogen atom has the formula (Vl
) can be obtained by reacting the compound with a halogenating agent such as phosphorus trihalide (e.g. phosphorus trichloride).

The compounds in which 2 is an acylox7 group can be prepared by reacting a compound of formula (Vl) with an acylating agent such as an acid anhydride or a sulfonyl halide (eg sulfonyl chloride).

Furthermore, the compound of formula (It) in which Y represents 10H2Zk and 2 is a nitrogen atom, the compound of formula (It) in which Y represents a ) in a suitable solvent such as hydrogen chloride.

The compound of general formula (IV) is a compound of formula (■) where R1 and A are as defined above and
iFi is an easily substitutable atom or group such as a halogen atom, an acyloxy group or a 1N+R5R6R7X- group as defined above in connection with 2) in accordance with the above method (A).
It can be prepared by reacting with the imidazole of formula (1) according to the method of .

Compounds of formula (VII) can be prepared using, for example, lithium aluminum hydride or sodium borohydride.
can be prepared by reducing the compound of

In addition, the compound of formula (■) where A is a hydrogen atom can be obtained by reacting the compound of formula (■) where A is a hydroxyl group with tosyl halide (for example, tosyl chloride), and then using the obtained tosylated product with lithium hydride. It can be prepared by reduction with aluminum.

Compounds of formula (IV) are novel compounds and therefore provide additional features of the present invention.

Experimental Examples The following examples illustrate the invention. Temperature is in °C. In a related note, the solution was dried over Na2SO4 and the solid was vacuum dried over P2O5 at 50 C overnight. Chromatography is w, c
, 5titt et al. (J, Or
g, Chem-t 1978.43+ 2923-2
925)
elgel) 9385.

Preparation 1 Ru-4-oxo-IH-carbazole-3-meta-3-[
A solution of (dimethylamino)methyl)-1,2,3°9-tetrahydro-4H-carbazol-4-one (0,53 g) in iodomethane (15 ml) was heated to reflux for 5 hours and evaporated to dryness to give the title compound. white solid (0.84g
), melting point 202''-205°.

Preparation 2 2.3,4.9-tetrahydro-N,N,N,9-tetra3-[(dimethylamino)methyl)-1,2,3゜9
-tetrahydro-9-methyl-4H-carbazole-4-
A suspension of On (3.80 g) in iodomethane (100 ml) was stirred under reflux for 57 hours. The resulting suspension was concentrated under reduced pressure to obtain the title methanaminium iodide as a solid (5
, 72g), melting point 192°-195°.

Preparation 3 The product from Preparation 2 (5.0 g) was treated with a solution of Q2N sodium carbonate (6.55 ml) in water (20 ml) and warmed to 35° for 45 minutes. Obtained slurry t-0
' and one portion of the solid was taken, washed with water and dried to give the title compound (2.8 g), mp 127-9°;
I got it.

Preparation 4 Sodium borohydride (90 mg) methanol (3 ml) and chloroform (3 ml)
) was added to a stirred solution of the product from Example 7 ('500 mg) in a mixture with ). Stirring was continued for a total of 48 hours (additional sodium borohydride (250 mg) added after 17.75 and 42 hours), and the entire suspension was partitioned between 2N hydrochloric acid (15 ml) and chloroform (3XIO ml). . The aqueous layer was basified with solid sodium carbonate, extracted with chloroform (3XIOml) and the combined extracts were washed with water (2X 100ml) and brine (10ml), dried and concentrated in vacuo. Residual foam (557
mg) k dichloromethane, ethanol and 0.88
The solid (
200 mg) was obtained. This material was dissolved in refluxing absolute ethanol (3 ml) and maleic acid (80 mg)
A refluxing solution of anhydrous ethanol (1 ml) was added. Add hot akP, stir and dilute with dry ether (40 ml) to give the title compound (240 mg), mp 138.5.
°~140° was obtained.

Preparation 5 The product of Example 7 (30.0 g) was added to a stirred solution of lithium aluminum hydride (7.75 g) in dry tetrahydrofuran (750 ml) under a nitrogen atmosphere. The mixture was stirred under reflux for 1 hour, then cooled in water. The suspension was dissolved in aqueous tetrahydrofuran (15% H2O, 100
m1) and water (100 ml), concentrated in vacuo, and the remaining solid was dissolved in dichloromethane (2X
500ml). The organic extract was concentrated in vacuo and the remaining solid (16.4 g) was purified using silica (Kieselgel 60, Merck
kl 7747.500g)
dichloromethane, ethanol and 0.88 aqueous ammonia (1
Purification eluting with a mixture of 50:1O:1) gave the title compound as a foam (13.4g).

TLC, 7 Lika, dichloromethane/ethanol 10.8
8 Ammonia (150:10:1) Rf O,3
4 and 0.36 (two pairs of diastereoisomers), detected U.

■, and iodoplatinic acid.

N, m, r, δ [CDCl3+CD30D (1 drop)]
1.6-2.3 and 2-6 3-0 (5H9m
), 2-32 and 2.40 (3H,s+s, Me in two different isomers), 3.32 (3H,s, NMe
), 3-65 4.3 (2H1m, CHCH2N)
, 4.75-4.85 (IH, m, CH-OH),
6.8-7.8 (CH.

m, aromatic).

Example 1a Product of chloride preparation 2 (2,0 g) and 2-methylimidacyl (5,0 g) in dry dimethylformamide (30 g)
ml) The solution was stirred at 95° under nitrogen atmosphere for 16.75 hours and then allowed to cool. Collect the crystallized solid 'JtP,
Washed with ice-cold dry dimethylformamide (3X 2ml) and dry ether (2XIOml) then dried. The obtained solid (0.60 g) was mixed with anhydrous ethanol and ethanol (
(30 ml) and ethanolic hydrogen chloride (1 ml) and warmed covertly to obtain a solution, which was stirred warm. Next, liquid f was diluted with dry ether to precipitate a solid (0.6 g), which was recrystallized from absolute ethanol to obtain the title compound as a solid (0.2 g).
7g), melting point 186-187°.

Analysis actual values: C: 61.9, H: 6.4, N:
11.8C18H19N306) Calculated values of IC1, H2o c: 62.3, H: 6.1, N: 12.
The following compounds were prepared by procedures similar to those detailed in Table 1.

Example 2 Above 1.2.3.9-tetrahydro-9-methyl-3-[(
2-Methylimidazol-1-yl)methyl-4H-carbazol-4-one (300 mg) was dissolved in hot ethanol (5
ml and maleic acid (116 mg)
Processed with. The solution was cooled and one portion of the white crystalline solid was taken and dried to give the title compound (300 mg), mp 132
．． 3° was obtained.

Example 3a - Product of 1 preparation (0,84g1 and imidazole (0,84g1)
90 g 1 solution in dimethylformamide (25 ml)
Heated to 105° for 6 hours, cooled, added to water (200 ml) and extracted 6 times with ethyl acetate. The combined extracts were washed, dried and evaporated to give a solid and placed on a silica column (Merck 7734) eluting with ethyl acetate/methanol (4:1). Recrystallization twice from ethyl acetate/methanol gave the title compound (0
,095 g) as a crystalline solid, melting point 220-222°.

TLC silica, dichloromethane/ethanol 10.88
Ammonia (100: 8: 1) Rf O,3
3. Detection U, V, and iodoplatinic acid.

The following compounds were prepared by the procedure detailed in Table 1. Salt formation is carried out as described in Example 2. Note to Table 1: Compounds 3e and 3f were prepared in the same experiment and the isomers were preliminarily prepared on Zorbax-8il. 1. c, hexane/ethyl acetate/ethanol 10.88 ammonia (400:100
:100:0.6).

Example 4 1.2,3.9-tetrahydro-9-methyl-3-1,
2,3,9-tetrahydro-3-[(2-methyl-IH
-Imidazol-1-yl)methylcou 4H-carbazol-4-one (1,0 g) in dry dimethylformamide (10 ml J under a total nitrogen atmosphere) and sodium hydride (80% in oil, 0.11 g) in dry dimethylformamide (10 ml J). 5 ml) added to the stirred, water-cooled suspension.0.5
After an hour, dimethylphorphae (<0.34 ml) was added and the solution was stirred at room temperature for 4 hours. The obtained solid substance eF was collected and diluted with ice-cooled dry dimethylformamide (2×5
Washing with m1) and dry ether (3×15 ml) and drying gave the title compound as a solid (0.25 g), mp 223-224° (dec.).

TLe silica, chloroform/methanol (93 near)
, R, 0,27, detected U, V, and iodoplatinic acid, identical to the product of Example 1a.

The following compounds were prepared using a similar procedure as detailed in Table 1 using the appropriate alkylating agent.

Example 5 Maleate 1.2,3.9-tetrahydro-3-((2-methyl-
A solution of IH-imidazol-1-yl)methylcou 4H-carbazol-4-one (1,20 g) in dry dimethylformamide (9 ml) was dissolved in sodium hydride (80% in oil).
, 0.14 g) of dry dimethylformamide (2 ml
) Add to the stirred water-cooled suspension under nitrogen atmosphere and stir K1-0.
．． It lasted 25 hours. Bromocyclopentane (0.51m
1) K was added and the stirred solution was heated to 100° for 18.5 hours. The solution was allowed to cool and then partitioned between water (100ml) and ethyl acetate (3X 70ml). The combined organic extracts were dissolved in 2N sodium carbonate (2X 50ml) and water (
Washed with 2X 50 ml and brine (50 ml), dried, evaporated to dryness and chromatographed in dichloromethane, ethanol, 0.88 ammonia (15
It was purified by elution with a mixture of 0:to:1) to give an oil (
0.27 g) was obtained. This oil was dissolved in refluxing absolute ethanol (7 ml) and maleic acid (0,1
A solution of 0 g) in refluxing absolute ethanol (0.5 ml) was added. The hot solution was filtered 1k, stirred and diluted with dry ether (20ml).

The resulting yellow gum completely dried ether (7 x 25 ml)
and the combined mother liquor and washing solution were allowed to stand.

The solid that crystallized from the solution was collected and dissolved in dry ether (3X
5 ml) and dried to give the title salt as a white crystalline solid (0,058 g l, mp 104.5°-106
°, obtained as.

Analysis actual value C: 65.95, H: 6. Tun N: 8
．． 6C2□H25N30, C4H404,0,6)I
Calculated values of 20: C: 65.8, H: 6.4, N:
8.9 Example 6 1.2,3.9-tetrahydro-3-[(2-methyl-1-imidazol-1-yl)methyl]-4! ! - A solution of carbazol-4-one (1,0 g) in dry dimethylformamide (6 ml) was dissolved in sodium hydride (80 g in oil).
%, 0.12 g) of dry dimethylformamide (2 ml
) was added to the stirred water-cooled suspension.

After 0.25 hours, add allyl bromide and add dissolved water (75 m
Stirred at 0° for 0.25 hours and at room temperature for w hours before partitioning between l) and ethyl acetate (3×50 ml).

The combined organic extracts were washed with water (2×50 ml) and brine (50 ml), dried, evaporated under reduced pressure and chromatographed with a mixture of dichloromethane, ethanol and 0.88 ammonia (200:10:1). Purification was performed to obtain a solid (0.43 g). This solid was dissolved in refluxing absolute ethanol (2 ml) and a solution of maleic acid (0.18 g) in refluxing absolute ethanol (1 ml) was added. Pass the hot solution once,
Diluted with dry ether (4 ml) and collected the crystallized solid kP, washed with dry ether (3 x 5 ml) and dried to give the title compound as a white solid (0.48 gL, mp 150.5°-151°). Obtained.

Analysis actual value C: 66.3, H: 5.75, N
: 9.6C2oH2□N30. Calculated values of C4H404: C: 66.2, H: 5.8, N: 9.6
5%1 3-[(dimethylamino)methyl)-1,2,3゜9-
Tetrahydro-9-methyl-4H-cartumazol-4-
A solution of on hydrochloride (1.7 g) in water (17 ml) was treated with 2-methylimidazole (1.4 g),
It was then heated to reflux for an hour. The cooled mixture was poured and the residue was washed with water (3x15ml) to give the crude product (1.7g), melting point 221-221.5°. This material was recrystallized from methanol to yield the title compound (1,
4g), melting point 231-232°.

Identical to the product of Example 4 by TLC.

Example 8 [(2-Methyl-IH-imidazol-1-yl) Preparation 3
(0,5 g) and 2-methylimidazole (
A suspension of 0.4 g) in water (5 ml) was heated to reflux for an additional period of time. The cooled reaction mixture was poured and the residue was dissolved in water (3X
Washed with methanol (18ml), dried and diluted with methanol (18ml).
Recrystallization from l) gave the title compound (0.3 g), melting point 232-234° (decomposition).

Identical to the product of Example 4 by TLC.

Example 9 Hydrogen ratio sodium (80% oil dispersion, 0°208 g
) to 1.2,3.9-tetrahydro-3-[(
2-methyl-1! ! -imidazol-1-yl)methyl-4■-carbazol-4-one (1,93 g) in DMF
(35ml) was added to the stirred solution and the resulting suspension i was stirred at 0°C for 0.25h. 2-bromopropane (0.78ml) was then added and stirring continued overnight at room temperature and then at 40°C for 4 hours.

The reaction mixture was dissolved in sodium carbonate (2N, 200 ml).
and ethyl acetate (2×150ml). The combined organic extracts were washed with water (3 x 75 ml), dried and evaporated under reduced pressure and the product was chromatographed in dichloromethane:ethanol:ammonia (1
Purification eluting with 00:8:1) gave an oil. This oil was dissolved in ethanol (3 ml and diluted with ether to give the title compound <0.13 g as a white solid),
It was obtained with a melting point of 230-232°.

Analysis actual value C: 65.3, l(: 6.6, N:
11.1C20H23N30, HCl, 0-5H
Calculated values of 20: C: 65.4, H: 6.9, N: 1
1.45% Example 10 Isozolopanol (90ml) and water (18.3ml)
1,2,3,9-tetrahydro-9-methyl-3-C(2-methyl-IH-imidazol-1-yl)methyl)-4H-carbazol-4-one (18,3
g) k Treated with concentrated hydrochloric acid (6.25 ml).

The hot mixture was filtered 1' and the P solution was diluted with isozolo-zonol (
90 ml) and stirred at room temperature for 17 hours.
The mixture was cooled to 50°C and the solid tF was collected (21.6g).

A sample (6 g) was recrystallized from a mixture of icr water (6 ml) and isopronoethanol (LO ml) to give the title compound as a white crystalline solid (6 g), mp 178.5-179.
5°.

Analysis actual value C: 59.45, H: 6.45,
N: 11.5C□2H□9N30, HCl,
Calculated value of 2H20 C: 59.1, H: 6.6
,N: 11.5%Moisture test actual value 10.23CHC□8H□gNao, HCl, 2H20 calculated value 9.85%Example 11 1.213.9-tetrahydro-3-[(2-methyl-
IH-imidazol-1-yl)methyl]-9-phenyl-4H-carbazol-4-one maleate 1.2,3.9-tetrahydro-9-phenyl-4! !
A glacial acetic acid solution of carbazol-4-one (3.90 g), dimethylamine hydrochloride (1.50 g) and paraformaldehyde (0.60 g) was stirred under reflux in a nitrogen atmosphere for 42 hours and allowed to cool. Then, it was concentrated under reduced pressure. The residual brown gum was dissolved in water (50 ml) and ethyl acetate (5 ml).
0 ml) and brine (20 ml) at 0.25 h 1
Stirred for 1JI and the resulting solid was washed in portions with dry ether (4X30ml) and dried to give the title compound (4.2g). Some of this solid matter (
1.0 g) was recrystallized twice from absolute ethanol (10 ml) to give the title compound as a pale brown powder (0.39 g).
, melting point 193°-194° (decomposition).

ChiruIH-imidazol-1-yl)methyl]-leate 2-methyl-1! ! -imidazole (1,4 g) 3-((dimethylamino)methyl) under nitrogen atmosphere
-1,2,3,9-tetrahydro-9-phenyl-4H
-Calhaflu-4-one hydrochloride (2.0g)
of water (20 ml) was added to the stirred suspension. Rotate the mixture at 90°
for 43 hours and the solvent was decanted from the tan solid. Chloroform was added to the solid and the suspension was passed through hyflo.
The P solution was dried and concentrated under reduced pressure. The residual light tan foam (2.04 g) was chromatographed in dichloromethane, ethanol and 0.88 aqueous ammonia (2.04 g).
0: to: 1) to give a white foam (1,
1 g) was obtained.

An ethanol (3 ml) solution of keratin foam was diluted with ethanol (1 ml).
ml) followed by dry ether (40 ml) and the resulting gum was triturated with dry ether (2840 ml) to give the title compound. creamy solids +1.37g),
It was obtained with a melting point of 165-166° (decomposition).

Analysis actual value C: 68.65, H: 5.5, N
: 8.7C23H2□N30. Calculated values of C4H404 C: 68.8, H: 5.3, N: 8.9 Example 1
2 1.2,3.9-tetrahydro-9-methyl-3-[(
2-methyl-1! ! -imidazol-1-yl)methyl]
-4■-Carbazol-4-one (0,61 g) was dissolved in a hot mixture of phosphoric acid (90%, 0.13 ml) and water (loml), filtered through Hyflo and Crystallization gave the title compound (0.5 g), melting point 225°.

Analysis actual value C: 55.1, H: 5.6, N
: 10.55C engineering 8H19N30. Calculated value of H3PO4' C: 55.2, H: 5.7, N: tO
,7%Example 13 1,2,3.9-tetrahydro-9-methyl-3-[(
2-Methyl-1-imidazol-1-yl)methyl]-
4H-carbazol-4-one (0.89 g) was dissolved in a hot solution of citric acid (0.58 g) in ethanol (20 ml) and crystallized. The crystals obtained were dissolved in acetone/water (2: 1.2 ml) and acetone (
Recrystallization by dilution with 20 ml) gave the title compound (0.6 g), melting point 162°1.

Example 14 Iodomethane (0.75ml) k, 3-((dime f
(2,9 g) of dry p.
MF (30 ml) was added to the stirring solution and the solution was stirred at room temperature for a while. A solution of 2-propyl-I II-imidazole (2 g) in DMF (5 ml) was added and the solution was stirred at 100 °C for 2 days, cooled and treated with sodium carbonate < 2 N% 150 ml) and ethyl acetate (
2×100ml). The combined extracts were washed with water (100ml), dried and evaporated under reduced pressure. The residue was purified by column chromatography using dichloromethane:ethanol:ammonia (400:30).
The free base was purified by elution with :3) and the isomorph (1.2 g
) was obtained. A sample (0.2 g) was dissolved in absolute ethanol (5 ml), acidified with ethereal hydrogen chloride and diluted with dry ether (ca. 200 ml) to give an oil. Upon scratching, the kernel oil crystallized to give a solid (0.15 g).

The salt was crystallized from a mixture of methanol and isozolobyl acetate to give the title compound (0.08 g), mp 206
°~208℃,? Obtained.

Analysis actual value C: 65.6, H: 6.8, N
:'12.0C□9H2□N30. HCl0.2H20
Calculated values of C: 65.7, H: 6.5, N:
12.1 chi N, m, rδ (CD3SOCD3) 0.94
(3H,t, CH3), 1.77 (2H9 sextet,
CH2 desired. CHa), 1.9-2.15 and 2.9
5-3.2 (7H, m), 4.32 and 4.71 (
2H, ABX.

C-condescension. N), 7.1-8.0 (6H, aromatic) Example 15 Example 3 g product (0.03 g) in methanol (15 ml
) Dissolved in hydrogen quenched (H2 uptake, 5 ml) over 10% para-Num oxide (50% aqueous paste, 0.03 g) supported on charcoal at room temperature and atmospheric pressure for 4 hours (H2 uptake, 5 ml). , and the e-liquid was evaporated under reduced pressure to obtain an oil. When triturated with ether, the title compound was converted into a white solid (0,0
3g), melting point 199°-203°C.

This material was identified by TLC and NMR as the product of Example 14 (
Of course it was the same.

Example 16 Sodium chloride hydride (80% oil dispersion)? The product of Example 14 (1.0 g) was dissolved in dry DMF (20 m
1) Added to the stirred solution and stirred the suspension for I minutes at room temperature. 1-Bromopropane (0.35ml) was added and the solution was stirred at -40°C for an extended period of time.

The solution was partitioned between sodium carbonate (2NX 150ml) and ethyl acetate (2X 100ml). The sweetened extract was washed with water (100ml), dried and evaporated under reduced pressure to give an oil. The oil was purified by total column chromatography eluting with dichloromethane:ethanol:ammonia (100:8:l) to give the pure free base as an oil.The kernel oil was purified by absolute ethanol (5 ml). ether, acidified with ethereal hydrogen chloride and diluted with dry ether (200 ml). The ether/I/ was decanted from the resulting oil and replaced with another dry ether (200 ml) at 0°C. Upon storage overnight, the oil crystallized to form the title compound (0,5
3g), melting point 144°-147°C.

N, m, r, δ (CD3SOCD3) 0.90 and 0.93 (6H.

t+t, 21M@), 1.65-2.2 and 2.9-
3.25 (IOH.

m), 4.19 (2H,t, Cl2CH2N), 4
．． 32 and 4.71 (2H, ABX, CH2CH
2N), 7.15-8.1 (6H, m, aromatic) Analysis actual value C: 66.6, H: 7.7, N: 1
0.0C22) 127N30. Hcl, 0.7H20
Calculated values of C: 66.3, H: 7.4, N:
10.5% Example 17 Etate Product of Example 6 (0.86 g) in a mixture of absolute ethanol (20 ml) and dry dimethylformamide (5 ml)
) was hydrogenated for 1 hour over 5% platinum on carbon (prereduced in 0.1 g% absolute ethanol (10 ml)) at room temperature and normal pressure (H2 uptake = 7
0ml). The catalyst was filtered and washed with ethanol and concentrated in vacuo to about 15 ml. The residual solution was stirred, diluted with water (50 ml) and the precipitated solid was collected, washed with water (3 x 15 ml) and dried to give a powder (0.73 g).

Dissolve this material in refluxing ethanol (7 ml) and f
A solution of maleic acid (0.25 g) in refluxing absolute ethanol (1 ml) was added. The stirred solution was diluted with total dry ether (50ml) to give the title compound (0.84g
), melting point 150-151°.

Analysis actual value c: 65.8, H: 6.1, N:
9.3c20H23N3°・c4H4°4') Calculated value C
: 65.9, H: 6.2, N: 9.6% Example 1
8 (1) 3-Chloromethyl l-112e3,9-tetrahydro-9-methyl-4I(-carbazol-4-oethyl) Ethereal hydrogen chloride (3,0 ml) was added to the product of Preparation 3 (1,90 g). Chloroform (15 ml) was added to the stirred water-cooled solution and the resulting suspension was stirred in a closed container at room temperature for 16.5 hours, concentrated in vacuo, and the remaining solids (
Purified by k column chromatography eluting with chloroform to give the title compound (1.75 g)
), melting point 109-110.5°.

When attempting to crystallize some of this material from total ethyl acetate, it partially decomposed.

3-(chloromethyl)-1,2,3,9-tetrahydro-9-methyl-4H-carmesol-4-one (0,50
g) and 2-methyl-1! ! -imidazole (1,6
0 g) of dry DMF solution at 90° under nitrogen atmosphere.
．． Stirred for 75 hours then poured into water (25ml). The suspension was stirred for 1 hour and the solid matter was removed and water (
3×20 ml) and dried under vacuum at 50°. Column chromatography of this solid (0.53 g) eluted with a mixture of dichloromethane, ethanol and 0.88 aqueous ammonia (150:10:1) yielded
The title compound (0.45 g), melting point 228-229°, was obtained. This material was found in Example 7 by TLC and NMR.
The product was identical to that of

Example 19 2.3-dichloro-5,6-dicyano-1,4-benzoquinone (170 mg) in dry tetrahydrofuran (1,
5 ml) solution under total nitrogen, tetrahydrofuran (3,
5 m1) and water (0,4 m1) /l! was added dropwise to a stirred, water-cooled suspension of the product of Preparation 4 (100 mg) in solution. The resulting blue solution 1 was stirred for 1.5 hours and then concentrated under reduced pressure. Column chromatography of the residual solids in dichloromethane, ethanol and 0.88 ammonia (1
Elution with a mixture of 50:10:1) gave the title compound (45 mg), mp 227°-228.5°.

This material was identical to the product of Example 7 by TLC and NMR.

Example 2. Addition of 3-dichloro-5,6-dicyano-1,4-benzoquinone (80 mg) to dry tetrahydrofuran (1,5
m1) solution under nitrogen, diluted with tetrahydrofuran (3,5
ml) and water (0.4 ml) was added to a stirred, water-cooled suspension of the product of Preparation 5 (100 mg) in a mixture of ml) and water (0.4 ml). The resulting blue solution was stirred for 1.5 hours, and then the red suspension was concentrated under reduced pressure. Column chromatography of the residual solid, eluting with a mixture of dichloromethane, ethanol and 0.88 ammonia (150:10:1), gave the title compound as an all-white solid (0.47 g), mp 227.5.
°~229°. This material was tested by TLC and N
According to MRK it was identical to the product of Example 7.

Example 21 A solution of the product of Example 7 (0.5 g) in hot methanol (30
ml) and (+)-di-p-toluoyl-
D-Tartaric acid hydrate (0.7 g) in methanol (lOm
l) treatment with hot solution and the resulting solution was crystallized overnight to obtain the desired salt (0.68 g). This salt was dissolved in hot dimethylformamide (DMF, 20ml) and
Diluted with hot water (10ml) and allowed to crystallize overnight. The product kF was collected and dried in vacuo to give an enantiomeric ca.
0% pure (as shown by NMR) (+)-p-)
Luo-D-tartrate (0.23g melting point 231-2
33° was obtained. A sample of this salt (0.15g) t-SS
Sodium bicarbonate (25 ml) and chloroform (2Xδ
ml). The combined extracts were dried and evaporated under reduced pressure to give the pure free base (0.07g).

This basic solution was dissolved in methanol (5 ml), acidified with maleic acid (0,03 g) and the salt precipitated by addition of excess dry ether (80 ml) to give the title compound (0,062 g), mp 142~ 145° was obtained. TLC silica, dichloromethane/ethanol 10.8
8 ammonia (100:8:1) R,0,3, detected U, V, and iodoplatinic acid, same as the product of Example 7.

The enantiomeric ratio is 93 nia (S:R) as determined by HNMR.
Met. The maleate salt sample showed no significant optical rotation in methanol. The free base regenerated from maleate is [α)B5-14(c O,19, MeOH)
I gave k.

Example 22 A solution of the product of Reate Example 7 (0.5 g) was dissolved in hot methanol (30 g).
ml) and (→-p-toluoyl-L
-7 Nisitoric acid-hydrate (0.7 g) in methanol (lO+
nll hot solution and the resulting solution was crystallized overnight to yield the desired salt (0.8 g). The salt was dissolved in hot methylformamide (DMF, 20 ml), diluted with hot water (10 ml) and crystallized over 3 days. The product was collected and dried in vacuo to give approximately 95% enantiomerically pure (as shown by NMR) (→-Jp-)luo-L-tartrate (0.26 g), mp 1
70-172° was obtained. A sample (0.2 g) of this salt was mixed with 8% sodium bicarbonate (25 ml) in chloroform (2X
25 ml). The sweetened extract was dried and evaporated under reduced pressure to give the pure free base (0.12 g). The base was dissolved in total methanol (5 ml), acidified with maleic acid (0,045 g) and the salt precipitated by addition of excess dry ether (80 ml) to give the title compound (0,08 g), mp 142- 145° was obtained.

TLC silica, dichloromethane/ethanol 10.88
Ammonia (100: 8: 1) R, 0, 3,
Detected U, V, and iodoplatinic acid, identical to the product of Example 7.

The enantiomeric ratio was >95:3 as determined by 'HNMR. The maleate salt sample showed no significant optical rotation in methanol. The free base regenerated from maleate is [α)D+16° (!: 0.3 MeOH)
I gave a meeting.

The example below is 1,2,3.9-tetrahydro-9-methyl-3-[(2-methyl-IH-imidazol-1-yl)methyl)-4! ! - Illustrating a pharmaceutical formulation according to the invention comprising carbazol-4-one hydrochloridonihydrate as active ingredient (1.25 g of the hydrochloridoni water dish containing 1.00 g of its free base) It is. Other compounds of the present invention can be incorporated in a similar manner.

Tablets for oral administration Tablets can be manufactured by conventional methods such as direct compression or wet granulation.

Tablets may be film coated with a suitable film forming material such as hydroxysolvyl methylcellulose using standard methods. Alternatively, tablets may be sugar coated.

Direct compression tablet mg/' Active ingredient 4.68828.125 Calcium hydrogen phosphate BP" 83.06 87.75
Croscarmellose 1.8 1.8 (Croscarmellose) Sodium NF Magnesium Stearate BP O, 450, 45 Compressed weight 90.0 118.0 Equal numbers of products suitable for direct compression in a cage All 60 meshes of active ingredients passed through , blended with calcium hydrogen phosphate, croscarmellose sodium and magnesium stearate.

The resulting mix k was compressed into tablets using a Maneity F3 tablet machine fitted with a 5.5 mm flat beveled punch.

Sublingual tablet mg/tablet Live tablet Number of ingredients 2.5 Compressible sugar NF 62.5 Magnesium stearate BP 0.5 Compressed weight @
65.0 The active ingredient is sieved through a suitable St, blended with excipients and compacted using a suitable punch.

Tablets of other strengths may be made by varying the ratio of active ingredient to excipients or compressed salts and using a suitable nocent.

Wet Granulation Active Ingredients 2.5 Lactose BP 151.5 Starch BP 30.0 Pregelatinized Corn Starch BP 15
．． 0 Magnesium stearate BP 1.5 Compressed weight 2
00.0 The active ingredient is sieved through a suitable St- and blended with lactose, starch and pre-gelatinized corn starch. Add appropriate volume of pure water and granulate the powder. After drying, sieve the granules and blend with magnesium stearate. Next, granules? ,7
Compress into tablets using a mm diameter punch.

Tablets of other strengths may be made by varying the active ingredient to lactose ratio or compressed weight and using the appropriate /en.

Active Ingredients 2.5 Mannitol BP 56.5 Hydroxypropyl Methylcellulose 5.0 Magnesium Stearate BP 1.5 Compressed Weight 65.5 The active ingredient is sieved through a suitable sieve and blended with the mannitol and hydroxysolvyl methylcellulose. Add appropriate volume of pure water and granulate the powder. After drying, the granules are screened and blended with magnesium stearate and then compressed into tablets using a suitable punch.

Tablets of other strengths may be made by varying the active ingredient to mannitol ratio or compaction weight and using suitable punches.

Capsule mg/tablet Number of ingredients 2.5 Mukashi Starch 1500 97.0 Magnesium stearate BP 1.0 Filling weight 10
0.0 In the past, the active ingredients were all sieved in directly compressible starch form and blended with excipients.

The mix is filled into size 2 hard Latin capsules using a suitable machine. Other dosages may be produced by varying the fill weight and, if necessary, varying the size of the capsule to suit the overall size.

Syrup This can be either sucrose-containing or sucrose-additive.

A, L Yotate Syrup mg15ml Dosage Active Ingredient Amount Active Ingredient 2.5 Sugar HP 2750.0 Glycerin BP 500.0 Pure Water BP T-Additional 5.0ml Active Ingredient, Buffer, Flavoring, Coloring Agent and preservatives.
Dissolve the amount of gold in water and add glycerin. The remaining amount of water is heated to dissolve the sucrose and then cooled. Combine the two solutions, adjust volume and mix. Clarify by filtering the syrup.

B, L, no sugar additives mg15ml active ingredient 2
．． 5 Hydroxypropyl methylcellulose (viscosity type 40001 22.5 Hydroxypropyl methylcellulose is dispersed in hot water, cooled and then mixed with an aqueous solution containing the active ingredient and other ingredients of the formulation. Volume of solution used) Adjust and mix. Clarify the syrup by filtration.

Injectable injections can be administered by intravenous or subcutaneous routes.

Injection μg 7m 1 Active ingredient 50 800 Add dilute hydrochloric acid BP 9) 13.59) Add L3.5 sodium chloride injection BP to 1ml Dissolve 1ml active ingredient in sodium chloride injection BP for an appropriate customer base. , the pH of the obtained solution was adjusted to pH 3.5 with diluted hydrochloric acid BP,
The solution Sodium Chloride Injection BP is then added to the solution and mixed thoroughly. The solution was filled into 5 ml ampoules of transparent glass of type 1, which were sealed by melting the glass in a headspace F of total air, and then heated at 120° for 15 ml.
Sterilize by autoclaving for at least 1 minute.

Micronized active ingredient 0.250 66mg OL/inic acid B
PO, 0205, 28 mg Dichlorodifluoromethane BP 61.25 14.70 g The active ingredient is micronized to a fine particle size range in a fluid energy mill.

Oleic acid total trichlorofluoromethane and 10-15℃
The atomized agent is blended at a temperature of
mix into the solution. Weigh the suspension into an aluminum aerosol line and fringe a suitable meter/9 lube to the can providing 185 mg of the suspension and add dichlorodifluoromethane into the can with the pulp. Fill under pressure.

Solution aerosol mg/4↑Volume Dosage Active ingredient per can 0.25 30.0 mg Ethanol BP 7.500 1.80 g Trichlorofluoromethane BP 18.875 4.35 g Dichlordifluorometa 7BP 48.525 1i, 65 g A suitable surfactant may also be included, such as Span 85 (sorbitan trioleate), BP oleate.

Discard the active ingredient in ethanol (oleic acid or surface active ingredient).

Weigh the alcohol solution into a suitable aerosol container and then meter out the trichlorofluoromethane. A suitable metered pulp is flanged onto the entire vessel and dichlorodifluoromethane is pressure-filled through the pulp and into the vessel.

Active Ingredient (Micronized) 0.5 Add Lactose BP 25.00 The active ingredient is micronized in a fluid energy mill before blending with regular tablet grade lactose in a high energy mixer. The powder blend is filled into three-quarter hard gelatin capsules in a suitable encapsulation machine. The contents of the cartridge are administered using a powder inhaler.

The antagonism of the responses induced by the bioactive compounds of the present invention at neuronal J, 5HT receptors has been demonstrated by Ireland S,
J., Straugian, D., W., and Tyera.
M, B, :Br1tlsh Journal of
Pharmacology+ 77 +169, 19
It can be measured at 22·g±2 by the method described in 82. The results of this test are shown in the table below as pAZ values. This value is defined as the negative logarithm of the molar concentration of antagonist required to reduce twice the EDso effect of 5HT in the presence of antagonist to the ED5o effect in the absence of antagonist.

1 a 3.6 1 c B, g l d 8.0 1 g 6.4 3 c g, 6 4 d 8.7 4e 8.2 4 f 7.7 5 8.5 6 8.7 9 9. 1 The antagonism of responses induced at neuronal 5HT receptors by compounds of the invention can be assessed in vivo by measuring the effects of the compounds on 5HT induction (the Hart-Jaritzch reflex). This test was performed on Coff1ns D,P.

and Fortune R,H*:'Br1tish
Journal of Pharmacology 8
0.570P, 1983. The results are shown in the table below as F, D5o, which indicates the dose required to suppress the 5HT-induced reflex by 50%.

la 7 53.2 62.5 9 11.6 Toxicity Knowledge of the acute toxicity of these compounds was obtained by intravenously administering various doses to mice.

&yo f1 city a-θ) Lhi 1i moe IO≦↓n divination, Shi pushi enter mI 毫 Tsuru 4 tot Ire compound 1a is 5.
2 mg/kg, and for compounds 5.6 and 9 to mg/kg. ED5o value (p,
o,), the lethal dose is generally found to be 1000 times greater.

Applicant's agent Kiyoshi Inomata

Claims (1)

[Scope of Claims] 1. A heterocyclic compound selected from the group consisting of a compound of the following general formula (1), and physiologically acceptable salts and solvates of the compound. Here, R represents a hydrogen atom, Ci~1omil1oalkylcycloalkyl, C3~6 alkenyl, phenyl or phenyl-01~3alkyl, R2, R3
and one of the groups represented by R4 is a hydrogen atom or C
1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl or phenyl-C1-3 alkyl, and the other two groups can be the same or different, respectively, and hydrogen atoms or C□-6 Represents an alkyl group. The compound according to claim 1, wherein 2.81 represents a hydrogen atom or a C1-6 alkyl, C(4 cycloalkyl or C3-6 alkenyl group). 3, one of the groups represented by R2, R3 and R4 is 01
~3 alkyl, 03-6 cycloalkyl or C3-6
represents an alkenyl group, and the other two groups can be the same or different, and each represents a hydrogen atom or C□
3. A compound according to claim 1 or claim 2, which represents an alkyl group. 4.81 is a hydrogen atom or C□~6 alkyl, C5,6
represents a cycloalkyl or C3-4 alkenyl group,
R2 represents a hydrogen atom and R3 and/or
A compound according to claim 1, wherein 14 represents a C□-3 alkyl group, or R2 represents a C1-3 alkyl group and R3 and R4 both represent a hydrogen atom. 5. Compounds of claim 1 which are compounds of general formula (Ia) and physiologically acceptable salts and solvates of said compounds. Here, R represents a hydrogen atom or a group of methyl, ethyl, propyl, solo-f-2-yl, solo-but-2-endyl or cyclopentyl, and R3a represents a hydrogen atom; B
2 m is methyl, ethyl, propyl or! Roboo 2-
represents a group of yl, and 14a represents a hydrogen atom,
Alternatively, R2a represents a hydrogen atom and R4a represents a methyl or ethyl group. 6.1+2t3t9-tetrahydro-9-methyl-3-
[(2-Methyl IH-imidazol-1-yl)methyl)
-4H-carbazol-4-one, Nara and physiologically acceptable salts and solvates of said compounds. 7.1,2,3.9-tetrahydro-3-[:(2-methyl-IH-imidazol-1-yl)methyl]-9-(
proc2-enyl)-4! ! -carbazol-4-one, 9-cyclopentyl-1,2°3.9-tetrahydro-3-((2-methyl-IH-imidazol-1-yl)
-Methyl]-4H-galpazol-4-one, 1.2,3
．． 9-tetrahydro-3-[2-methyl-1! ! -imidazol-1-yl)methyl)-9-(zolobut-2-yl)-41(-carmesol-4-one, and physiologically acceptable salts and solvates of said compounds. The compound of Item 1. 8. A method for producing a compound of the following general formula (1) or a physiologically acceptable salt or solvate of the compound, which comprises the following steps. represents a hydrogen atom or C1-1o alkyl, and one of the groups represented by R2, B3 and R4 is a hydrogen atom or C0-6 alkyl, C3,...7 cycloalkyl, C2-6 alkenyl or 7 enyl 〇l~3 alkyl, and the other two groups can be the same or different, respectively, and represent a hydrogen atom or a C□~6 alkyl group. (A) General formula (formerly compound 1\ R is as defined above and Y represents a reactive substituent) or a protected derivative of said compound,
R2, R3 and R4 in the imidata of general formula (1)
is as defined above) or a salt of said compound, or (B) reacting the compound of formula (IV) with A represents a hydrogen atom or a hydroxyl group, and R1, R2, R3 and R4 is as defined above) or (C) oxidizing a compound of formula (1) or a salt or protected derivative of said compound as defined above; or, if obtained as a mixture, optionally splitting this mixture to obtain the desired enantiomers, and/or optionally if the compound of formula (1) is the free base. converting the free base into a salt. 9. The process according to claim 8(A), wherein Y represents an alkenyl group =CH2 or a group of the formula CH2z in which 2 is an easily substitutable atom or group. 10. A compound of formula (1) or a salt or protected derivative thereof is subjected to alkylation or hydrogenation to form a compound of formula (1).
Claim 8 (C
) Production method of Q. 11. Comprising at least one compound of the following general formula (I) or a physiologically acceptable salt or solvate of the compound together with at least one physiologically acceptable carrier or excipient. drug. Here, R1 is a hydrogen atom, or C0-1o alkyl,
C3+v7 cycloalkyl, C3,+v6 alkenyl,
represents phenyl or phenyl-C1-3,
One of the groups represented by R2, R3 and R4 is a hydrogen atom or 01-6 alkyl, C3-7 cycloalkyl,
C2-6 alkenyl or phenyl-〇i-3mil3alkyl, and the other two groups each can be the same or different and represent a hydrogen atom or a C□-6 alkyl group.