FI84349B - PROCEDURE FOR THE FRAMEWORK OF PHARMACOLOGICAL PROPERTIES. - Google Patents

Description

1 84349

The present invention relates to a process for the preparation of a pharmacologically valuable compound of formula (I): O R4 R3 --- N N (I) ^ I, Ύ The present invention relates to a process for the preparation of a pharmacologically valuable compound of the formula (I):

R

where

R 1 is a hydrogen atom or a C 1-10 alkyl, C 3-7 cycloalkyl, C 3-6 alkenyl or phenyl-C 1-3 alkyl group, R 2 is a hydrogen atom or a C 1-6 alkyl, C 3-7 cycloalkyl, C 2-6 alkenyl - or a phenyl-C 1-3 alkyl group and r 3 and R 4? which may be the same or different, each represents a hydrogen atom or a C 1-6 alkyl group, and when R 2 is a hydrogen atom or a C 1-6 alkyl group, one of R 3 and R 4 may also be a phenyl-C 1-3 alkyl group; or a physiologically acceptable salt or solvate thereof.

5-hydroxytryptamine, which is endogenously abundant in peripheral nerves and platelets, is known to cause pain in humans by acting specifically on 5HT receptors located at the terminals of primary importing nerves. Compounds that have an antagonistic effect on the neuronal effects of 5HT have been shown to have analgesic activity, for example, they relieve migraine pain. 5HT also causes depolarization of the isolated rat circulatory nerve preparation through the same 5HT receptor mechanism. Inhibition of this effect correlates with analgesic effect in vivo.

2,84349 5-hydroxytryptamine is also widely present in neuronal pathways of the central nervous system, and interference with these 5HT-containing pathways is known to alter behavioral syndromes such as mood, psychomotor activity, appetite, and memory. Because the central nervous system also has the same type of "neuronal" 5HT receptors as the primary import terminals, compounds that antagonize the neuronal effects of 5HT are believed to be useful in treating conditions such as schizophrenia, anxiety, obesity, and mania.

Current treatments for such conditions have a number of disadvantages. For example, known treatments for migraine include the administration of a vaso-constrictor such as ergotamine. This is nonselective and constricts blood vessels throughout the body. Ergotamine 11a is therefore not -1. oi vo 11 u and and potentially dangerous side effects. Migraine can also be treated by administering an analgesic such as aspirin or para-acetamol, usually in combination with an antiemet, when in combination with metac1opramide, but the value of these treatments is only limited.

Similarly, a number of serious side effects, such as extrapyramidal side effects, occur in the current treatments for psychotic diseases such as schizophrenia.

Thus, there is a need for a safe and effective drug for the treatment of conditions associated with disruption of 5HT-containing pathways, such as migraine or psychotic diseases such as schizophrenia. The compound, which is a potent and selective antagonist at "neuronal" 5HT receptors, is believed to fulfill this function.

We have now found a group of 3-imidazolylmethyl-tetrahydrocarbazolones which are potent and selective antagonists at "neuronal" 5HT receptors.

3,84349

In the compound of formula I, it is preferred that when R 1 is a C 3-6 alkenyl group, the double bond need not be adjacent to the nitrogen atom.

In the general formula (I), the alkyl groups of R 1, R 2, R 3 and R 4 may be straight-chain or branched alkyl groups, for example methyl, ethyl, propyl, prop-2-yl, butyl, but-2-yl, 2-methylprop-2-yl, pentyl, pent-3-yl or hexyl.

The alkenyl group may be, for example, a propenyl group.

The phenyl-C 1-3 alkyl group may be, for example, a benzyl, phenethyl or 3-phenylpropyl group.

The cycloalkyl group may be, for example, a cyclopentyl, cyclohexyl or cycloheptyl group.

It should be noted that the carbon atom at the 3-position of the tetrahydrocarbazolone ring is asymmetric and may exist in the R or S configuration. The present invention encompasses both individual isomeric forms of the compounds of formula (I) as well as all mixtures thereof, including racemic mixtures.

Suitable physiologically acceptable salts of the indoles of the general formula (I) include acid addition salts formed with organic or inorganic acids, for example hydrochlorides, hydrobromides, sulphates, phosphates, citrates, fumarates and maleates. The solvates may be, for example, hydrates.

In a preferred group of compounds of general formula (I), R 1 is a hydrogen atom or a C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 alkenyl group.

4,84349

In another preferred group of compounds of general formula (I), one of R 2, R a and R 4 is a C 1-3 alkyl, C 3 -C 6 cycloalkyl or C 3-6 alkenyl group and the other two groups, which may be the same or different, in each case denote a hydrogen atom. or C1--3 a 1 kyy 1 i group.

In another preferred class of compounds of general formula (I), R 1 is a hydrogen atom or a C 1-6 alkyl, C 5-6 cycloalkyl or C 3-4 alkenyl group and either R 2 is a hydrogen atom and R 3 and / or R 4 is a C 1-6 alkyl group or R 2 is A C1-3 alkyl group and both R3 and R4 represent a hydrogen atom.

A particularly preferred class of compounds of the invention can be represented by formula (Ia): jj R4a / Λ Λ A 1 = 1 i Π i \ // N (Ia) • · · · · \\ / \ / \ / I _ • N · R2a i.

Rle wherein R1a is a hydrogen atom or a methyl, ethyl, propyl, prop-2-yl, prop-2-enyl or cyclopentyl group; R3a is a hydrogen atom; and either R 2a is a methyl, ethyl, propyl or prop-2-yl group and R 4a is a hydrogen atom or R 2a is a hydrogen atom and R 4a is a methyl or ethyl group) and their physiologically acceptable salts and solvates (for example hydrates).

Preferred compounds are: 1,2,3,9-tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -9- (prop-2-enyl) -4H-carbazol-4- one; 9-cyclopentyl-l, 2,3,9-tetrahydro-3 - [(2-methyl-lH-imidazol-1-yl) methyl] -4H-carbazol-4-one; and Λ 1,2,3,9-tetrahydro-3- [2-methyl-1H-imidazol-1-yl) methyl] -5,84349- (prop-2-yl) -4H-carbazol-4-one and their physiologically acceptable salts and solvates.

A particularly preferred compound is 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1'-yl) methyl] -1H-carbazol-4-one , which can be represented by the formula (Ib): S „.//x.__/Χ./ΧΓ~i” »> I 11 II I \ // • · · · ·

\\ / \ / \ / I

• N · Me

Me and its physiologically acceptable salts and solvates (e.g. hydrates). The preferred form of this compound is the hydrochloride dihydrate.

It should be noted that the invention also extends to a process for preparing such i.e. physiologically acceptable compounds which are converted in vivo to the parent compound of formula (I).

The compounds of the invention are potent and selective antagonists of the 5HT-induced reactions of the isolated rat circulatory nerve preparation and thus act as potent and selective antagonists of the "neuronal" 5HT receptor type present in primary import nerves.

The compounds of formula I are useful as analgesics, for example in the relief of migraine-related pain, headaches and other forms of pain in which 5HT is an endogenous mediator.

Animal experiments have shown that the compounds of the invention are also useful in the treatment of schizophrenia and other psychotic diseases. It has already been mentioned above that 5-hydroxytryptamine is widely present in neuronal pathways of the central nervous system and interference with these 5HT-containing pathways is known to alter many other behavioral syndromes such as mood, appetite and memory. Because the central nervous system also has the same type of "neuronal" 5HT receptors as the primary import terminals, the compounds of the invention may also be useful in the treatment of conditions such as pain, obesity and mania.

In particular, the previously defined compounds of formula (Ia) have been found to be highly selective and highly potent in their activity. All of them are well absorbed from the gastrointestinal tract and are suitable for oral or reactive administration. The compounds of formula (Ia) do not prolong sleep time pentobarbitone 11a is anesthetized in 11a mice, suggesting that no undesirable interactions occur with the drug metabolizing enzyme. In fact, they have no effect on normal behavior, are non-toxic, and have no adverse effects on intravenous doses of 1 mg / kg in mice ast i.

In addition to the excellent properties of the compounds of formula (Ia), the compounds of formula (Ib) had no inappropriate effects when administered to humans.

Biological values

Antagonism of the 5HT-induced response to the neuronal V-SHT receptor by the compounds of the invention can be investigated by an in vitro method described in Ireland by SJ, Straughan NW and Tyers MB; British Journal of Pharmacology, 7-7, 16P, 1982. the results are expressed as pA2, which are given in the table below 7 84349. The value is defined as the negative logarithm of the molar concentration of the dose required to reduce the 5HT effects to the ED50 effect compared to the ED50 effect without the antagonist.

Compound Rat isolated circulatory nerve

Eg, No. ___1 stepped PÄ2 _________ Sat 8.6 le 8.9

Id 8.0 lg 6.4 3c 8.6 4d 8.7 4e 8.2 4 f 7.7 5 8.5 6 8.7 9 9.1

Equivalent values can also be obtained in vivo by examining the effect of compounds on 5HT-induced Bezold-Jarisch reflexes. The experiment has been described by Collins DP, and Fortune RH, British Journal of Pharmacology 8j0, 570P, 1983. The results are shown in the table below as ED 50 values, which is the dose required to induce 5HT-induced reflexes by 50% (see Fozard JR, and Host M., British Journal of Pharmacology, 7, 520P, 1982).

Compound ED50

Eg, No. (ug / kq) la 7 5 3.2 6 2.5 9 11.6

Toksokologia

The acute toxicity of the compounds has been determined in experiments in which the compound has been administered intravenously at different doses to mice.

s 84349

At a dose of 5.2 mg / kg i.v. less than 50% of the experimental animals survived, and at a dose of 10 mg / kg i.v. more than 50% of the experiments survived with compounds 5, 6 and 9. It can be seen that the ratios of the ED 50 values for inhibition of Bezo1d-Jarisch reflex in the lethal dose are generally about 1000-fold.

A pharmaceutical composition can be prepared containing at least one compound selected from the 3-imidazolylmethyltetrahydrocarbazolone derivatives of general formula (I) and their physiologically acceptable salts and so-called claims, for example hydrates, which is made suitable for human or veterinary medicine and which is formulated as such. that it can be given by any suitable route.

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

The compounds of the invention may thus be formulated for oral, buccal, parenteral or reactive administration or in a form in which they may be administered by inhalation or insufflation (either orally or nasally).

For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binders (for example pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (for example lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (for example magnesium stearate, talc or silica); disintegrants (for example potato starch or sodium starch); or wetting agents (for example sodium hydroxide solution). The tablets may be coated by methods well known in the art 9,84349. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means using pharmaceutically acceptable excipients such as suspending agents or hydrogenated edible fats); emulsifiers (for example lecithin or acacia); anhydrous intermediates (for example almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and obtained igniters (for example methyl or propyl p-hydroxybenzoates or sorbic acid). The preparations may also contain, if necessary, a buffer salt and, without flavoring, coloring and sweetening agents.

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

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

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

10 84349

The compounds of formula I may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., in forms containing 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 a depot preparation. Such long acting formulations may be administered by injection (for example subcutaneously or subcutaneously) or by intramuscular injection. Thus, for example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic substances (for example as an emulsion in an acceptable oil or ion exchange resin, or as sparingly soluble derivatives, for example as a sparingly soluble salt).

For administration by inhalation, the compounds of the invention are conveniently removed from the aerosol spray formulation from pressurized containers or nebulizers using a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable base powder such as lactose or starch.

The proposed dose of the compounds according to the invention for humans (weighing about 70 kg) is 0.05 to 20 mg, preferably 0.1 to 10 mg of active ingredient per unit dose, which can be administered, for example, 1 to 4 times a day. It will be appreciated that the dosage may need to be routinely adjusted depending on the age and weight of the patient and the severity of the condition being treated.

For oral administration, the unit dose preferably contains 0.5 to 10 mg of active ingredient. A unit dose for parenteral administration preferably contains from 01.1 to 10 mg of active ingredient.

Aerosol formulations are best made so that each metered dose, or "push", released from a pressurized aerosol can contains 0.2 to 2 mg of a compound of the invention and that each dose delivered through an insufflator or inhaler capsule or cartridge contains 0.2 to 20 mg of a compound of the invention. The total daily dose administered by inhalation may be between 0.4 and 80 mg. The administration can take place several times a day, for example 2-8 times, in which case, for example, 1, 2 or 3 doses are administered each time.

The compounds of the invention may, if desired, be administered in combination with one or more other therapeutic agents, such as antiemetics.

According to the invention, the compounds of the general formula (I) and their physiologically acceptable salts and solvates or their physiologically acceptable equivalents can be prepared by the following general methods.

In the first general method (A), a compound of general formula (I) or a physiologically acceptable salt or solvate thereof or a physiologically acceptable equivalent thereof can be prepared by subjecting a compound of general formula (II) to 12,84349. • · γ // \ / \ / • · - · · III II I (ίΐ) • · · · "λ / \ / \ / • Ν ·

R1 (wherein R1 · is as defined above and V is a reactive substituent) or a protected derivative thereof for reacting with an imidazole of general formula (III) R3 \ • --- · I-1 UN N fill '\ 1' R2 2 3 4 ( wherein R, r and R are as defined above) or a salt thereof.

Examples of compounds of general formula (II) used as starting materials in process (A) are compounds in which V is a group selected from an alkenyl group = CH 2, or a group of formula CH 2 Z in which Z is an easily displaceable atom or group, such as a halogen atom, for example chlorine or bromine; an acyloxy group such as acetoxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy + 5 6 7 5 or methanesulfonyloxy; the group -NR RRX ", wherein R 1 and R 2, which may be the same or different, are each lower alkyl, for example methyl, aryl, for example phenyl, or aralkyl, for example benzyl, or and R 1 together with the nitrogen atom to which they are attached may form a 5- or 6-membered ring, for example a pyrrolidine ring, and X is an anion such as a halide ion, for example chloride, bromide or iodide, or a group -NR 1 R 2, 13 84349 wherein and means, the same as above, for example -N (CH3) 2.

When V is a group = CH, the process may conveniently be carried out in a suitable solvent, examples being water; esters, for example ethyl acetate; ketones, for example acetone; or methyl isobutyl ketone; amides, for example dimethylformamide; alcohols, for example ethanol; and ethers, for example dioxane or tetrahydrofuran; or mixtures thereof. The process can be carried out, for example, at a temperature of 20 to 100 ° C.

When Y is a group C H Z where Z is a halogen tower or an acyloxy group, the process may conveniently be carried out in a suitable solvent such as an amide, for example dimethylformamide; in alcohol, for example methanol or methylated industrial spirit; or in a haloalkane, for example dichloromethane, and at a temperature of -10 to + 150 ° C, for example 20 to 100 ° C.

A compound of formula (II) wherein Y is a group CH Z, wherein Z is a group -NR R R X? the reaction may conveniently be carried out in a suitable solvent such as water, an amide, for example dimethylformamide; in a ketone, for example acetone; or in an ether, for example dioxane, and at a temperature of 20 to 150 ° C.

The reaction of a compound of formula (II) wherein Y is a group -CH 2, wherein Z is a group -NR R may conveniently be carried out in a suitable solvent such as water or an alcohol, for example methanol, or a mixture thereof and at a temperature of 20 to 150 ° C. C.

In another general method (B), a compound of formula (I) may be prepared by oxidizing a compound of formula (IV): 4 14 84349 Λ / Β.

/ "'Λ / * \ Τ —- I

I I) J \ / (IV) • · · · * / \ / \ / · • γ · r2

R 11 (wherein A is a hydrogen atom or a hydroxyl group and R, R, R 1 and R 2 are as defined above) or a salt or protected derivative thereof.

Oxidation can be performed using conventional methods. The reagents and reaction conditions should be selected so as not to cause oxidation of the indole group. Oxidation is thus best performed using a mild oxidant.

When oxidizing a compound of formula (IV) wherein A is a hydrogen atom, suitable oxidants are, for example, quinones in the presence of water, for example 2,3-dichloro-5,6-dicyano-1,4-benzoquinone or 2,3,5,6-tetrachloro- 1,4-benzoquinone; selenium dioxide; a cerium (IV) oxidant such as cerium ammonium nitrate or a chromium (VI) oxidant, for example a solution of chromic acid in acetone (e.g. Jones reagent) or chromium trioxide in pyridine.

For the oxidation of a compound of formula (IV) wherein A is a hydroxyl group, suitable oxidants are, for example, quinones in the presence of water, for example 2,3-dichloro-5,6-dicyano-1,4-benzoquinone or 2,3,5,6-tetrachloro- 1,4-benzoquinone; ketones, for example acetone, methyl ethyl ketone or cyclohexanone in the presence of a base, for example aluminum t-butoxide; a chromium (VI) oxidant, for example a solution of chromic acid in acetone (e.g. Jones' reagent) or chromium trioxide in pyridine; N-halosuccinimide, for example N-chlorosuccinimide or N-bromosuccinimide; a dialkyl sulfoxide, for example dimethyl sulfoxide in the presence of an activating agent such as N, N'-dicyclohexylcarbodiimide or an acyl halide, for example oxalyl chloride or tosyl chloride; pyridine-rikkitrioksidikomplek-si; or a dehydrogenation catalyst such as copper chromite, zinc oxide, copper or silver.

Suitable solvents may be selected from: ketones, for example acetone or butanone; ethers, for example tetrahydrofuran or dioxane; amides, for example dimethylformamide; alcohols, for example methanol; hydrocarbons, for example benzene or toluene; halogenated hydrocarbons, for example dichloromethane; and water or mixtures thereof.

The process is conveniently carried out at a temperature of -70 to + 50 ° C. It is noteworthy that the choice of oxidant affects the recommended reaction temperature.

In the general process (C), a compound of formula (I) according to the invention or a salt or protected derivative thereof can be converted into another compound of formula (I) by conventional means. Such conventional means include, for example, alkylation at any point in a compound of formula (I) wherein one or more of R and R is a hydrogen atom, and alkylation which may be used, for example, to convert an alkenyl substituent to an alkyl substituent. The term "alkylation" includes the addition of other groups such as cycloalkyl or alkenyl groups. Thus, for example, a compound of formula (I) in which R 1 is a hydrogen atom may be converted into the corresponding compound in which R 1 is a 10 C alkyl, C 1 cycloalkyl, C 1 alkenyl or phenyl-C 1 alkyl group.

The above alkylation reactions may be performed using a suitable alkylating agent selected from compounds of formula RaXa, wherein R is an alkyl, cycloalkyl, acenyl or phenyl-C 1-6 alkyl group and Xa is a leaving group such as a haloene or an acyloxy group such as as defined above in connection with group Z or a sulfate of formula (R) SO 2.

The alkylation reaction is conveniently carried out in an inert organic solvent such as an amide, for example dimethylformamide; in ether, for example tetrahydrofuran; or in an aromatic hydrocarbon, for example toluene, preferably in the presence of a base. Suitable bases are, for example, alkali metal hydrides, such as sodium hydride, alkali metal amides, such as sodium amide, alkali metal carbonates, such as sodium carbonate, or an alkali metal oxide, such as sodium or potassium methoxide, ethoxide or t-butoxide. The reaction may conveniently be carried out at a temperature in the range of -20 to + 100 ° C, preferably 0 to 50 ° C.

The hydrogenation according to the general process (C) can be carried out by conventional methods, for example, using hydrogen in the presence of a noble metal catalyst, for example palladium, Raney nickel, platinum, platinum oxide or radium. The catalyst may be supported on carbon, for example, or a homogeneous catalyst such as tris (triphenylphosphine) rhodium chloride may be used. The hydrogenation is generally carried out in a solvent such as an alcohol, for example ethanol; in an amide, for example dimethyl formamide; in ether, for example dioxane; or in an ester, for example ethyl acetate, and at a temperature in the range of -20 to + 100 ° C, preferably 0 to 50 ° C.

It should be noted that in some of the above reactions, it may be necessary or desirable to protect any sensitive groups in the compound to avoid undesired side reactions. The protecting groups used in the preparation of the compounds of formula (I) are preferably groups which can be easily removed at a suitable stage in the reaction sequence, suitably in the last stage. For example, during the reaction sequences described above, it may be necessary to protect the keto group, for example, as a ketal or thioketal.

The compounds of general formula (I) can thus be prepared by general method (D) in which any protecting groups are removed from the protected form of the compound of formula (1).

Deprotection can be performed by conventional methods, for example, as described in 1 'Protective Groups in Organic Chemistry, ed. JFW McOmie (Plenum Press, 1973). the group may be removed by treatment with a mineral acid such as hydrochloric acid, the iioketal group may be cleaved by treatment with a mercury salt, for example mercuric chloride in a suitable solvent such as ethanol.

The compounds of formula (I) can be converted into physiologically acceptable salts by conventional methods.

Thus, for example, the free base of general formula (I) may be treated with a suitable acid, preferably in an equivalent amount, in a suitable solvent (e.g. aqueous ethanol).

Physiologically acceptable equivalents of a compound of formula (I) may be prepared by conventional methods.

The individual enantiomers of the compounds of the invention may be obtained by resolution of a mixture of enantiomers (e.g. a racemic mixture) using conventional means such as an optically active resolving acid; see, e.g., 'Stereochemistry of Carbon Compounds', E.L. Eliel (McGraw Hill 1962) and 'Tables of Resolving Agents', S.H. Wilen.

Examples of optically active resolving acids that can be used to form salts with racemic compounds include the (R) and (S) forms of organic carboxylic acids and sulfonic acids such as tartaric acid, di-p-toluoyltartaric acid,% 34 349 camphorsulfonic acid and lactic acid.

The resulting mixture of isomeric salts can be separated into, for example, fx-action-crystallized lead stereoisomers and, if desired, the optically active isomer can be converted to the free base.

The methods given above for the preparation of the compounds of the invention can be used as the final major step in the preparation. The same general procedures can be used to attach the desired groups in the intermediate stepwise formation of the required compound. It is noteworthy that these general methods can be combined in different ways in such multi-step methods. The order of the reactions in the multi-step methods should, of course, be chosen so that the reaction conditions do not affect the groups of the molecule desired in the final product.

The starting materials of formula (II) in which Y is a group RCH 4 can be prepared from compounds of formula (II) in which Y is a group CH 2 NR 2 R 2 R 2 X f by reaction with a base in a suitable solvent. Examples of bases are the first 1 hydroxides, for example potassium hydroxide or the age 1 metal carbonates or bicarbonates, for example sodium hydrogen carbonate.

Quaternary salts can be formed from the corresponding tertiary amine by reaction with an alkylating agent such as methyl iodide or dimethyl sulfate, if desired in a suitable solvent, for example dimethylformamide. The tertiary amine can be prepared by subjecting a tetrahydrocarbazolone of general formula (V) * i 84 8449 n

M

• ·, \ '\ \

• * ---- * * IM

'li!' I lV · "* * .V * • 'N · f» 1 to react with formaldehyde and the corresponding secondary amine, if desired in a suitable solvent such as an alcohol, for example ethanol.

Compounds of general formula (V) may be prepared, for example, by the method of H. Il da1n et al., Described by J.Org.Chem. (1980) Vol. 45, no. 15, pages 2938-2942.

The starting materials of general formula (II) in which Y is -CH 2 Z in which L is a halogen atom or an acyloxy group can be prepared from the corresponding hydroxymethyl derivative of general formula (VI) n

M

. , v phf] "

".: vP

? r— * * \, · · * '/ · • N · i <1 which can be obtained by reacting a tetrahydrocarbazolone of general formula (V) with formaldehyde, in a most suitable solvent such as an alcohol, for example ethanol, and most preferably in the presence of a base.

Compounds in which Z is a halogen atom can thus be obtained by reacting a compound of formula (VI) with a halogenating agent such as a phosphorus trihalide, for example phosphorus trichloride.

Compounds in which Z is an acyloxy group may be prepared by reacting a compound of formula (VI) with a suitable acylating agent such as an anhydride or a sulphonyl halide such as a sulphonyl chloride.

Compounds of formula (II) wherein Y is -CH 2 Z, wherein Z is a halogen atom may also be prepared by reacting a compound of formula (II) wherein Y is a group = CH 2 with a suitable hydrogen halide, for example hydrogen chloride, in a suitable solvent. , such as in an ether, for example diethyl ether.

Compounds of general formula (IV) may be prepared by reacting a compound of formula (VII) Λ. · C \\ 7ll // \ J w (VH)

T I! !! I

• · · · W / \ / \ / • N · 1 · (where R 1 - and A have the same meaning as above and Z 1 is an easily substitutable atom or group such as a halogen atom, an acyloxy group or a group -NR 2 R 2 R 2 X ", as defined above in connection with group Z) to react with an imidazole of formula (III) according to method (A).

Compounds of formula (VII) may be prepared by reduction of compounds of formula (II) using 2i 84349 for example 1 of ytuminium hydride or sodium borohydride.

The supernatant of formula (VII) in which A is an export tower can also be prepared by reacting a compound of formula (VJ 1) wherein A is a hydroxyl group with a tosyl halide (e.g. tosyl chloride) followed by reduction of the tosylate obtained. lithium aluminum hydride 11 a.

The compounds of formula (IV) are novel compounds and as such form part of the invention.

The following examples illustrate the invention. Temperatures are in degrees Celsius. The solutions were dried over sodium sulfate and the solids were dried in vacuo over phosphorus pentoxide at 50 ° C overnight. Chromatography was performed on W.C. By the technique described by Still et al. (J. Org. Chem., 1978 4-3, 2923-2925) silicic acid gel 118511.

PREPARATIVE EXAMPLE 1 2,3,4, -Tetrahydro-NNN-trimethyl-4-oxo-1H-carbazole-3-methanaminium judide 3 - [(dimethylamino) methyl] -1,2,3,9-tetrahydro-4H-carbazole A solution of 4-one (0.53 g) in iodomethane (15 ml) was heated at reflux for 5 hours and evaporated to dryness to give the title compound as a white solid (0.84 g), m.p. 202-205 °.

PREPARATIVE EXAMPLE 2 2.3,4,9-Tetrahydro-N, NN-n-tetramethyl-4-oxo-1H-carbazole-3-methanaminium iodide 3 - [(dimethylamino) methyl] -1,2,3,9-tetrahydro-9- A suspension of methyl 22 8 4349 4H-carbazol-4-one (3.80 g) in iodomethane (100 ml) was stirred at reflux for 57 hours. The resulting suspension was concentrated in vacuo to give the title mid. ananeamium iodide as a solid (5.72 g), sup. 192-195 °.

PREPARATIVE 51 EXAMPLE 3 1.2.3.9-Tetrahydro-9-methyl-3-methylene-4H-carbazol-4-amino Preparation of the product (5.0 y) i; in water (20 ml) was treated with 2N sodium carbonate (6.55 ml) and heated for 45 minutes at 35 ° C. The resulting slurry was cooled to 0 ° and the solid was filtered off, washed with water and dried to give the title compound (2.8 g), m.p. 127-9 °.

PREPARATION 5 EXAMPLE 4 2.3.4.9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -1H-carbazole maleate

Sodium borohydride (90 mg) was added under nitrogen to a stirred solution of the product of Example 7 (500 mg) in a mixture of methanol (3 ml) and chloroform (3 ml). Stirring was continued for 48 hours (sodium borohydride (250 mg) was added after 17.75 hours and 42 hours) and then the suspension was partitioned between 2N hydrochloric acid (15 ml) and chloroform (3 x 10 ml). The aqueous layer was basified with solid sodium carbonate, extracted with chloroform (3 x 10 mL) and the combined extracts washed with water (2 x 10 mL) and brine (10 mL), dried and concentrated in vacuo. The remaining foam (557 mg) was subjected to column chromatography with a mixture of dichloromethane, ethanol and 0.88 aqueous ammonia (300: 10: 1) to give a solid (200 mg). This material was dissolved in refluxing absolute ethanol (3 mL) and a solution of maleic acid (80 mg) in refluxing 23,84349 absolute ethanol (1 mL) was added. The hot solution was filtered, stirred and filtered; nne 11 in dry ether (40 ml) to give the title compound (240 mg), m.p. 138.5 to 140 ° C.

PREPARATIVE EXAMPLE 5 2,3,4,4,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -1H-carbazol-4-ol

The product of Example 7 (30.0 g) was added under nitrogen to a stirred suspension of lithium aluminum hydride (7.75 g) in dry tetrahydrofuran (750 ml). The mixture was stirred at reflux for 1 hour and then cooled on ice. The suspension was carefully diluted with aqueous tetrahydrofuran (15% H 2 O; 100 mL) and water (100 mL), concentrated in vacuo, and the residual solid was extracted with dichloromethane (2 x 500 mL). The organic extracts were concentrated in vacuo and the residual solid (16.4 g) was purified by short term flash chromatography on silica (Kieselgel 60; Merck 7747; 500 g). Eluted with a mixture of dichloromethane, ethanol and 0.88 aqueous ammonia (150: 10: 1) to give the title compound as a foam (13.4 g).

TLC. Silica, dichloromethane / ethanol / 0.88 ammonia (150: 10: 1) Rf 0.34 and 0.36 (two pairs of diastereoisomers), detection by UV and iodoplatinic acid.

NMR δ / CDCl 3 + CD 3 OD (1 drop) / 1.6-2.3 and 2.6-3.0 (5H, m), 2.32 and 2.40 (3H, s + s, Me in two different isomers), 3.32 (3H, s, NMe), 3.65-4.3 (2H, m, CHCl 3), 4.75-4.85 (1H, m, CH-OH), 5.8-7.8 (CH, m, aromatic)

Example 1a 1,2,3,9-Tetrahydro-9-methyl-3- (2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride

A solution of the product of Preparation Example 2 (82.0 g) and 2-methylimidazole (5.0 g) in dry dimethylformamide (30 ml) λ 24 84 349 was stirred under nitrogen for 16.75 hours at 95 ° and then allowed to cool. The crystallized solid was filtered off, washed with ice-cold dry dimethylformamide (3 x 2 ml) and dry ether (2 x 10 ml) and then dried. The resulting solid (0.60 g) was suspended in a mixture of absolute ethanol (30 ml) and net ethanolic hydrogen chloride (1 ml) and gently heated to give a solution which was filtered hot. The filtrate was then diluted with dry ether. A solid (0.6 g) precipitated which was recrystallized from absolute ethanol to give the title compound as a solid (0.27 g), m.p. 186-187 °.

Analysis Found: C, 61.9; H, 6.4; N, 11.8.

εΐ8Η19Ν3ϋ'ΗΕ1'Η20 calculated C, 6 2.3; H, 6.1; N, 12,1¾.

The following compounds were prepared by a similar method detailed in Table I.

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2 * 84349 NOTE. 1

Compounds Ie and 1f were prepared in the same experiment and the isomers were separated by short-term chromatography (D.F. Taber, J,

Org. Chem. , 1982, 4-7, 1351) eluting with dichloromethane / ethanol / 0.88 ammonia (300: 10: 1). The following 1 H NMR values were obtained.

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U-5,6,7, B CH, -1 and CH, -2 iene propo- H-2 HJ jb / Ui _._ j H-3_L ponits H "5 le d -DMS0 7.2-8.05 '2 , 91-3.25 1.75-2.3 Å, 47 (dd) 9.20s 7.55s' and ·, ___i_ 4.64 (dd) ____ lf | CDCl3 7.15-8.05 j: 2.6 -3.05 1.75-2.1 4.02 (dd) 8.17s 6.93s + DMSO 4.63 (dd) Ig 7.2-8.05 inter alia 7.61d d6_DMS ° 2.9- 3.3 1.6-2.2 4.42 (dd) and 4.73 (dd) 7> 70 i 27 84349 EXAMPLE 2 1,2,3,9-Tetrahydro-9-methyl; (2-Methyl-1H-imidazol-1-yl) -roethyl] -4H-carbazol-4-one roaleate 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methylimidazol-1-yl) -yl) -methyl-4H-carbazol-4-one (300 mg) was suspended in hot ethanol (5 ml) and treated with maleic acid (116 mg).

The solution was cooled and the white crystalline material was filtered off and dried to give the title compound (300 mg), m.p. 132.3 °.

Example 3a 1,2,3,9-Tetrahydro-3- (1H-imidazol-1-ylmethyl) -4H-carbazol-4-one

A solution of the product of Preparation Example 1 (0.04 g) and imidazole (0.90 g) in dimethylformamide (25 ml) was heated at 105 ° for 6 hours, cooled, added to water (200 ml) and extracted six times with ethyl acetate. The combined extract was washed, dried and evaporated to a solid which was purified 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, m.p. 220-222 °.

TLC silica, dichloromethane / ethanol / Q.88 ammonia (100: 8: 1)

Rf 0.33, detection by UV and iodoplatinic acid.

The following compounds were prepared by a similar method, the details of which are shown in Table II. Salt formation was performed as described in Example 2.

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29 84349

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Example 4 1.2.3.9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one 1.2.3.9-Tetrahydro-3 - [(2- A solution of methyl 1H-imidazol-1-yl) methyl-4H-carbazol-4-one (1.0 g) in dry dimethylformamide (10 ml) was added dropwise to a stirred and ice-cooled suspension containing nitrogen. sodium hydride (80% in oil; 0.11 g) in dry dimethylformamide (3 ml). After 0.5 h, dimethyl sulfate (0.34 mL) was added and the solution was stirred for 4 h at room temperature. The resulting solid was filtered, washed with ice-cold dry dimethylformamide (2 x 5 mL) and dry ether (3 x 15 mL) and dried to give the title compound as a solid (0.25 g), m.p.

* 223-224 ° (decomposes).

30 8 4 3 4 9 TLC silica, chloroform / methanol (93: 7) Rf 0.27, detection with UV and iodoplatinic acid, identical to the product of Example 1a.

The following compounds were prepared by a similar method using a suitable alkylating agent. Details of the method are given in Table III.

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3 ?. 84 349 HUQM. 1

The following 1 H NMR values were obtained.

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Solvent Chemical shifts (6 ppm) and multiples of certain protons ----- 1 I Carbazolone proton _ Imidazo- Imidazole protons 1 / Aromatic and aliphatic methylmethyl H-2 'H-4' and / or t H- 5,6,7,8 ίCH_-1 and CH'-2-propylene-H-5 '| H-3 tones 49 id -DMSO M5 "8" 1 2.9 -3.2 1.9-2.2 6.29 (dd) i 7.55d 16 and "i and 6.68 (dd) 7, 65d -i - 1 ----- / it-, *! 6,26 (dd) 7,42d k jv ™ 50 p2-8'1 · 9-3'3 | -

Example 5 9-Cyclopentyl-1,2,3,9-tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbatolol-4-one maleate 1,2,3,9- A solution of tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one (1.20 g) in dry dimethylformamide (9 ml) was added under nitrogen. under a stirred and ice-cooled suspension of sodium hydride (80% in oil; 0.14 y) in dry dimethylformamide (2 ml) and stirring was continued for 0.25 hours. Bromocyclopentane (0.51 ml) was added and the stirred solution was heated at 100 ° C for 18.5 hours. The solution was allowed to cool and then partitioned between water (100 mL) and ethyl acetate (3 x 70 mL). The combined organic extracts were washed with 2N sodium carbonate (2x50 ml), water (2x50 ml) and brine (50 ml), dried, evaporated to dryness and purified by chromatography eluting with a mixture of dichloromethane, ethanol, 0.88 ammonia (150: 10: 1) to give an oil ( 0.27 g). This oil was dissolved in refluxing absolute ethanol (7 ml) and a solution of maleic acid (0.10 g) in refluxing absolute ethanol (0.5 ml) was added. The hot solution was filtered, stirred and diluted with dry ether (20 mL). The resulting yellow gum was washed with dry ether (7x25 mL) and the combined mother liquors and washes were allowed to stand. The solid crystallized from solution was filtered off, washed with dry ether (3 x 5 ml) and dried to give the title salt as a white crystalline solid (0.058 g), m.p. 104.5 to 106.

Analysis Found: 0.65.95; H, 6.4; N, 8.6.

C22H25N3O, C4H404'0-6H2 calcd c, 65.8; H, 6.4; N, 8,9¾.

Example 6 1.2.3.9-Tetrahydro-3 - [(2-methyl-1H-inudazol-1-yl) methyl] -9- (2-propenyl) -4H-carbazol-4-one maleate 1.2.3.9-Tetrahydro-3-yl A solution of 3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one (1.0 g) in dry dimethylformamide (6 ml) was added to a stirred, ice-cooled suspension of sodium hydride (80% in oil). , 0.12 g) in dry dimethylformamide (2 ml). After 0.25 h, allyl bromide was added, the solution was stirred for 0.25 h at 0 ° t 34 84349 and 20 h at room temperature, then partitioned between water (75 mL) and ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water (2 x 50 mL), brine (50 mL), dried and concentrated in vacuo and purified by chromatography eluting with dichloromethane, ethanol and 0.88 aqueous ammonia (200: 10: 1) to give a solid (0.43 mL). 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. The hot solution was filtered, diluted with dry ether (4 mL) and the crystallized solid was filtered off, washed with dry ether (3 x 5 mL) and dried to give the title compound as a white solid (0.48 g), m.p. 150.5-151 °

Analysis Found: C, 6.3; H, 5.75; N, 9.6.

C 20 H 21 N 3 O, C 4 H 4 O 4 requires C, 66.2; H, 5.8; N, 9,65¾.

Example 7 1.2.3.9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one 3 - [(dimethylamino) methyl] -1,2 A solution of 3,9-tetrahydro-9-methyl-4H-carbazol-4-one hydrochloride (1.7 g) in water (17 ml) was treated with 2-methylimidazole (1.4 g) and then heated to reflux. hours. The cooled mixture was filtered and the residue washed with water (3 x 15 ml) to give the crude product (1.7 g), m.p.

221 to 221.5 °. This material was recrystallized from methanol to give the title compound (1.4 g), m.p. 231-232 °, identical by TLC to the product of Example 4.

Example 8 1.2.3.9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one * 35 84349

A suspension of the product of Preparation Example 3 (0.5 g) and 2-methylimidazole (0.4 g) in water (5 ml) was heated at reflux for 20 hours. The cooled reaction mixture was filtered and the residue was washed with water (3 x 10 ml), dried and recrystallised from methanol (18 ml) to give the title compound (0.3 g), m.p. 232-244 ° (decomposes), identical by TLC to the product of Example 4.

Example 9 [2,9,9-Tetrahydro-9- (1-methylethyl) -3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride

Sodium hydride (80¾ dispersion in oil, 0.208 g) was added to 1,2,3,9-tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4] H-carbazol-4-one. (1.93 g) to a 0 ° solution in dimethylformamide (35 ml) and the resulting suspension was stirred for 0.25 hours at D ° C. 2-Bromopropane (0.78 ml) was then added and stirring was continued at room temperature overnight, then kept at 40 ° for 4 hours.

The reaction mixture was partitioned between sodium carbonate (2 N; 200 mL) and ethyl acetate (2 x 150 mL). The combined organic extracts were washed with water (3 x 75 ml), dried and evaporated in vacuo and the product purified by chromatography eluting with dichloromethane: ammonia (100: 8: 1) to give an oil. This oil was dissolved in ethanol (3 ml), acidified with ethereal hydrogen chloride and diluted with dry ether to give the title compound as a white solid (0.13 g), m.p. 230-232 °.

Analysis Found: 0.65.3; H, 6.6; N, 11.1 ° C 20 H 23 N 3 O * HCl * 0'5H 2 O calculated 0.65.4; H, 6.9; N, 11.45¾ 36 8 4 349

Example 10 1.2.3.9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride dihydrate 1.2.3.9-Tetrahydro-9-yl methyl 3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one (18.3 g) in 90 ml of isopropanol and water (18.3 g). ml) in hot mixture was treated with concentrated hydrochloric acid (6.25 ml). The hot mixture was filtered and the filtrate was diluted with isopropanol (90 ml), stirred for 17 hours at room temperature, cooled to 2 ° and the solid separated by filtration (21.6 g). From a mixture of water (6 ml) and isopropanol (10 ml), a sample (6 g) was recrystallized to give the title compound as a white crystalline substance (6 g), m.p. 178.5 to 179.5 ° C.

Analysis Found: C, 59.45; H, 6.45; N, 11.5.

C 12 H 19 N 3 O · HCl * 2H 2 U calcd for C, 59.1; H, 6.6; N, 11,5¾

Water determination Obtained: 10.23% C H..N 0.HC1.2H 0 calculated 9.85¾.

1O 17 J L

Example 11 1.2.3.9-Tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -9-phenyl-4H-carbazol-4-one maleate i) 3 - [(dimethylamino) methyl] -1,2,3,9-tetrahydro-9-phenyl-4H-carbazol-4-one hydrochloride 1.2.3.9-1-tetrahydro-9-phenyl-4H-carbazol-4-one (3.90 g), dimethylamine hydrochloride (1.50 g ) and a solution of paraformaldehyde (0.60 g) in glacial acetic acid were stirred at reflux under nitrogen for 42 hours, allowed to cool and concentrated in vacuo. The remaining brown gum was stirred with water (50 mL), ethyl acetate (50 mL) and brine (20 mL) for 0.25 h and the resulting solid was filtered off, washed with dry ether (4 x 30 mL) and dried to give the title compound (37 84349). 4.2 g). A portion of this solid (1.0 g) was recrystallized twice from absolute ethanol (10 ml) to give the title compound as a tan powder (0.39 g), m.p. 193-194 ° (dec.) · 1 i) 1,2,3,9-Tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -9-phenyl-4H-carbazol-4-one -Maleate 2-methyl-1H-imidazole (1.4 g) was added under nitrogen to 3 - [(dimethylamino) methyl] -1,2,3,9-tetrahydro-9-phenyl- To a stirred suspension of 4H-carbazole-4-om hydrochloride (2.0 g) in water (20 mL). The mixture was heated at 90 ° for 43 hours and the solvent was decanted off from the tan solid. To this solid was added chloroform, the suspension was filtered through hyflon, the filtrate was dried and concentrated in vacuo. The residual tan foam (2.04 g) was chromatographed eluting with a mixture of dichloromethane, ethanol and 0.88 aqueous ammonia (200: 10: 1) to give a white foam (1.1 g). A solution of this foam in ethanol (3 ml) was treated with maleic acid (0.4 g) in ethanol (1 ml) followed by treatment with dry ether (40 ml) and the resulting gum triturated with dry ether (2 x 40 ml). There was thus obtained the title compound as a cream solid (1.37 g), m.p. 163-166 ° (dec.).

Analysis Found: C, 68.65; N, 5.3; N, 8.7.

C23H21N3O, C4H4O4 Calculated C, 68.8; N, 5.3; N, 8.9. "

Example 12 1.2.3.9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one phosphate (1: 1) 1.2.3.9-Tetrahydro -9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one (0.61 g) was dissolved in phosphoric acid (90%, 0.13 mL) and water. (10 ml) to a hot mixture, filtered through hyflon and allowed to crystallize to give the title compound (0.5 g), m.p. 225 °.

Analysis Found: C, 55.1; H, 5.6; N, 10.55.

C 18 H 19 N 3 Q, H 3 PO 4 calcd C, 55.2; H, 5.7; N, 10.7 ».

Example 13 1.2.3.9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one citrate (2: 1) 1.2.3.9-Tetrahydro -9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbabase-1-4-one (0.89 g) was dissolved in citric acid ( 0.58 g) in a hot solution in ethanol (20 ml) and allowed to crystallize. The resulting crystalline material was recrystallized by dissolving in acetone / water (2: 1, 2 mL) and diluted with acetone (20 mL) to give the title compound (0.6 g), m.p. 162 °.

Example 14 1.2.3.9-Tetrahydro-3 - [(2-propyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride

Iodomethane (0.75 ml) was added to a stirred solution of 3 - [(dimethylamino) methyl] -1,2,3,9-tetrahydro-4H-carbazol-4-one (2.9 g) in dry dimethylamide (30 ml). and the solution was stirred for 30 minutes at room temperature. A solution of 2-propyl-1H-imidazole (2 g) in dimethylformamide (5 ml) was added and the solution was stirred for 2 days at 100 ° C, cooled and partitioned between sodium carbonate (2N, 150 ml) and ethyl acetate (2 x 100 ml). The combined extracts were washed with water (100 ml), dried and evaporated in vacuo.

The residue was purified by flash chromatography eluting with dichloromethane: ethanol: ammonia (400: 30: 3) to give the free base as a solid (1.2 g). 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. The oil crystallized on scratching to 39,84349 to give a solid (0.15 g).

The salt was recrystallized from a mixture of methanol and isopropyl acetate to give the title compound (0.08 g), m.p. 206-208 °.

Analysis Found: 0.65.6; H, 6.8; N, 12.0.

C 19 H 21 N 3 O, HCl · -2H 2 O requires C, 65.7; H, 6.5; N, 12.1 ».

NMR δ (CD 3 SO CD 3) 0.94 (3H, t, CH 2), 1.77 (2H, sex 11 i, CH CH 2 CH 2), 1.9-2.15 and 2.95-3.2 (7H, m), 4.32 and 4.71 (2H, ABX, CHCH N), 7.1-8.0 (6H, aromatic)

Example 15 1.2.3.9-Tetrahydro-3 - [(2-propyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride

A solution of the product of Example 3g (0.03 g in methanol (15 ml)) was hydrogenated at room temperature and pressure with 10-palladium oxy di / carbon (50 x water paste, 0.03 g) for 4 hours (H 2 O The catalyst was filtered off and the filtrate evaporated in vacuo to give an oil which was triturated with ether to give the title compound as a white solid (0.03 g), mp 199-203 °.

Based on TLC and NMR, this material was identical to the product of Example 14.

Example 16 1.2.3.9-Tetrahydro-9-propyl-3 - [(2-propyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride

Sodium hydride (80 ° dispersion in oil) was added under nitrogen to a stirred solution of the product of Example 14 (1.0 g) in dry dimethylformamide (20 ml) and the suspension was stirred at room temperature for 30 minutes. 1-Bromopropane (0.35 ml) was added and the solution was stirred for 20 hours at 40 °. The solution was partitioned between sodium carbonate (2N, 150 ml) and ethyl acetate 84349 tate (2 x 100 mL). The combined extracts were washed with water (100 ml), dried and evaporated in vacuo to give an oil. The residue was purified by column chromatography eluting with dichloromethane: ethanol: ammonia (100: 8: 1) to give the pure free base as an oil. The oil was dissolved in absolute ethanol (5 mL), acidified with ethereal hydrogen chloride and diluted with dry ether (200 mL). The ether was separated from the resulting solution by decantation and replaced with a new portion of dry ether (200 ml). Upon overnight storage at 0 °, an oil crystallized to give the title compound (0.53 g), m.p. 144-147 °.

NMR δ (CD 3 SO CD 3; 0.90 and 0.93 (6H, t + t, 2xMe), 1.65-2.2 and 2.9-3.25 (10H, m), 4.19 (2H, t , CH CH N), 4.32 and 4.71 (2H, ABX, CH 2 Cl 2 N), 7.15-8.1 (6H, m, aromatic)

Analysis Found: C, 66.6; H, 7.7; N, 10.0.

C 22 H 27 N 3 O · HCl · 0'7H 2 O requires C, 66.3; H, 7.4; Nf10,5 ».

Example 17 1,2,5,9-Tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -9-propyl-4H-carbataol-4-one maleate

A solution of the product of Example 6 (0.86 g) in a mixture of absolute ethanol (20 ml) and dry dimethylformamide (5 ml) was hydrogenated at room temperature and pressure with 5 platinum / carbon / (0.1 g, pre-reduced in absolute ethanol (10 ml)). ) / For 1 hour ((^ consumption = 70 ml). The catalyst was filtered off, washed with ethanol and the filtrate was concentrated in vacuo to about 15 ml. The residual solution was stirred, diluted with water (50 ml) and the precipitated solid was filtered off, washed with water (3 x 15 mL) and dried to give a powder (0.73 g).

This material was dissolved in refluxing absolute ethanol (7 ml), filtered and a solution of maleic acid (0.25 g) in refluxing absolute ethanol (1 ml) was added.

41 84349

The stirred solution was diluted with dry ether (50 mL) to give the title compound (0.84 g), mp 150-151 °.

Analysis Found: C 5.8; H, 6.1; N, 9.3.

C20H23N3U'C4H4O4 Calculated C, 65.9; H, 6.2; N, 9,6S.

Example 18 [2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one (i) 3- (chloromethyl) -1 , 2,3,9-tetrahydro-9-methyl-4H-karbat sol-4-one

Ethereal hydrogen chloride (3.0 mL) was added to a stirred, ice-cooled solution of the product of Preparation Example 3 (1.90 g) in chloroform (15 mL), and the resulting suspension was stirred in a sealed vessel for 16.5 hours at room temperature, concentrated in vacuo and the remaining solid ( 2.27 g) was purified by flash chromatography eluting with chloroform. There was thus obtained the title compound (1.75 g), m.p. 109 to 110.5 °.

When an attempt was made to crystallize some of this material from ethyl acetate, partial decomposition occurred.

(ii) 1,2,3,9-tetrahydro-9-methyl-3 - [(2-roethyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one 3- (chloromethyl) -1,2 A solution of 3,9-tetrahydro-9-methyl-4H-carbazol-4-one (0.50 g) and 2-methyl-1H-imidazole (1.60 g) in dry dimethylformamide was stirred under nitrogen for 3.75 hours at 90 ° and then poured into water (25 ml). The suspension was stirred for 1 hour and the solid was filtered off, washed with water (3 x 20 ml) and dried in vacuo at 50 °. This solid (0.53 g) was subjected to column chromatography eluting with a mixture of dichloromethane, ethanol and 0.88 aqueous ammonia (150: 10: 1) to give the title compound (0.45 g), m.p. 228-229 °. By TLC and NMR, this 42 84349 material was identical to the product of Example 7.

Example 19 1.2.3.9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one 2,3-dichloro-5,6-dicyano-1, A solution of 4-benzoquinone (170 mg) in dry tetrahydrofuran (1.5 ml) was added dropwise under nitrogen to a stirred and ice-cooled suspension of the product of Preparative Example 4 (100 ml) in a mixture of tetrahydrofuran (3.5 ml) and water (0.4 ml). The resulting blue solution was stirred for 1.5 hours and then concentrated in vacuo. The residual solid was subjected to column chromatography eluting with a mixture of dichloromethane, ethanol and 0.88 ammonia (150: 10: 1) to give the title compound (45 mg), m.p. 227 to 228.5 °. Based on TLC and NMR, this material was identical to the product of Example 7.

Example 20 1.2.3.9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one 2,3-dichloro-5,6-dicyano-1, A solution of 4-benzoquinone (80 mg) in dry tetrahydrofuran (1.5 ml) was added dropwise under nitrogen to a stirred and ice-cooled suspension of the product of Preparation Example 5 (100 ml) in a mixture of tetrahydrofuran (3.5 ml) and water (0.4 ml). The resulting blue solution was stirred for 1.5 h and then the red suspension was concentrated in vacuo.

The residual solid was subjected to column chromatography eluting with a mixture of dichloromethane, ethanol and 0.88 ammonia (150: 10: 1) to give the title compound as a white solid (0.47 g), m.p. 227.5 to 229 ° C. Based on TLC and NMR, this material was identical to the product of Example 7.

Example 21 3S-1- [2,3-tetrahydro-3 - [(2-methylimidazol-1-yl) methyl] -9-methyl-4H-carbazol-4-one maleate

A solution of the product of Example 7 (0.5 g) in dissolved hot methanol (30 ml) and treated with a hot solution of (+) - di-p-toluoyl-Dv / nitric acid monohydrate (0.7 g) in methanol (10 ml) and the resulting solution was allowed to crystallize overnight to give the desired salt (0.68 g). This salt was dissolved in hot dimethylformamide (DMF, 20 mL), diluted with hot water (10 mL) and allowed to crystallize overnight.

The product was filtered off and dried in vacuo to give about 90? Enantiomerically pure (based on N M R) (+) - di-p-toluoyl-D-tartaric acid salt (0.23 g), m.p. 231-233 °. A sample of this salt (0.15 g) was partitioned between 8% sodium bicarbonate (25 mL) and chloroform (2 x 25 mL). The combined extracts were dried and evaporated in vacuo to give pure free base (0.07 g).

The base was dissolved in methanol (5 ml), acidified with maleic acid (0.03 g) and the salt precipitated by the addition of excess dry ether (80 ml) to give the title compound (0.062 g), m.p. 14 £ -145 °.

TLC silica, dichloromethane / ethanol / 0.88 ammonia (100: 8: 1) Rf 0.3 detection with UV and iodoplatinic acid, identical to the product of Example 7. En The enantiomeric ratio determined by NMR was 93: 7 (S: R). The maleate salt sample did not have any significant optical coating ability in methanol. Turning capacity of the free base from the maleate salt: [α] 25 D - 14 ° (£ 0.19, MeOH).

i + 44 84349

Example 2 2 3R-1,2,3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one maleate

A solution of the product of Example 7 (0.5 g) was dissolved in hot methanol (30 ml) and treated with a hot solution of (-) - di-p-toluoyl-L-tartaric acid monohydrate (0.7 g) in methanol (10 ml) and the resulting solution. was allowed to crystallize overnight to give the desired salt (0.8 g).

This salt was dissolved in hot dimethylformamide (DMF, 20 mL), diluted with hot water (10 mL) and allowed to crystallize for 3 days. The product was filtered off and dried in vacuo to give about 95% enantiomerically pure (by NMR) (-) - di-p-toluoyl-L-tartaric acid salt (0.26 g), m.p.

170-172 °. A sample of the salt (0.2 g) was partitioned between 8% sodium bicarbonate (25 mL) and chloroform (2 x 25 mL). The combined extracts were dried and evaporated in vacuo to give pure free base (0.12 g). The base was dissolved in methanol (5 ml), acidified with maleic acid (0.045 g) and the salt precipitated by the addition of excess dry ether (80 ml) to give the title compound (0.08 g), m.p. 142-145 °.

TLC silica, dichloromethane / ethanol / 0.88 ammonia (100: 8: 1) Rf 0.3, detection with UV and iodoplatinic acid, identical to the product of Example 7. The enantiomeric ratio determined by 1 H NMR was 95: 5. The sample of the maleate salt did not have any significant optical inversion in methanol. Turning capacity of the free base from the maleate salt: [α] D + 16 ° (c 0.34, MeOH).

Claims (5)

A process for the preparation of a pharmacological value compound of formula (I) Wherein R 1 is a hydrogen atom or a C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 alkenyl or phenyl C 1-3 alkyl group, R 2 is a hydrogen atom or a C 1 -6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl or phenyl-C1-3 alkyl group and R3 and R4, which may be the same or different, are each hydrogen atom or a C1-6 alkyl group and where R2 is a hydrogen atom or a C1-6 alkyl group, one of the groups R3 and R4 may also be a phenyl-C1-3 alkyl group; or its physiologically acceptable site or derivative, characterized in that (A) the compound of general formula (II) OJ (II) (where Y is a reactive substituent) or its protected derivative, an imidazoline of general formula (III) (III) HN 2 NV R 1 or its salt; or (B) a compound of formula (IV) Δ N = = R 3 "f", N, IV> ₂ 2 (where A is a hydrogen atom or hydroxyl group) or its salt or protected derivative is oxidized; or (C) a compound of formula (I) or its salt or protected derivative is converted to another compound of formula (I); or (D) removing the protecting group or groups from a protected form of a compound of formula (I); and when a compound of formula (I) is obtained as an enantiomeric mixture, the mixture is separated as necessary to obtain the desired enantiomer; yes / or where the compound of formula (I) is in the form of its free base, if necessary the free base is re-banded into a site. Process according to claim 1, characterized in that 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one is produced. 3.9-tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -9- (prop-2-enyl) -4H-carbazol-4-one; 9-cyclopentyl-1,2,3,9-tetrahydro-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one; 1,2,3,9-tetrahydro-3- [2-methyl-1H-imidazol-1-yl) methyl] -9- (prop-2-yl) -4H-carbazol-4-one or its physiologically acceptable salt or soivat. Process according to Claim 2, characterized in that 1,2,3,9-tetrahydro-9-methyl-3- [(2-methyl-1H-imidazo-1-yl) methyl] -4H-carbazole is prepared. 4-one in the form of a hydrochloride salt. Process according to claim 2, characterized in that hydrochloride dihydrate of 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazo-1-yl) methyl] -4H-hydrochloride is prepared. carbazol-4-one.