HU207318B - Process for producing lactame derivatives and pharmaceutical compositions containing them - Google Patents

Abstract

Imidazolyl pyrido or azepino pyrroloindole or quinoline derivs. of formula (I) or their physiologically acceptable salts or solvates are new. n = 2 or 2; Im = a gp. of formula (II) or (III); one of R1-R3 = H, 1-6C alkyl, 3-7C cycloalkyl, 3-6C alkenyl, phenyl or phenyl 1-3C alkyl and each of the other two gps. = H or 1-6C alkyl; Y = (CH3)m or X(CH2)p; m = 2, 3 or 4; p = 2 or 3; X = O, S or NR4, and is attached to the benzene ring; R4 = 1-6C alkyl. Pref. R1-R3 = H or 1-4C alkyl; or R1-R2 = H; R3 = 1-3C alkyl; Y = (CH2)2 or (CH2)3.

Description

The present invention relates to lactam derivatives and to pharmaceutical compositions containing them.

More particularly, the invention relates to the preparation of compounds which are potent and selective antagonists of 5-hydroxytryptamine (5HT) at 5-HT type receptors located at the terminals of the primary nerve terminals. Receptors of this type are now called 5-HT ₃ receptors and are also present in the central nervous system. 5-HT is widespread in the nervous system in the central nervous system and disorders of 5-HT-containing neurons are known to alter behavioral syndromes such as mood, appetite, memory, and psychomotor activity.

Compounds having antagonistic activity at 5-HT ₃ receptors have been reported previously. For example, German Patent Publication No. 3,740,352 discloses compounds of formula A wherein im is an imidazolyl group of formula (a) or (b) wherein

R 'is hydrogen or C 1 -C 6 alkynyl, C 3 -C 7 alkenyl, C 3 -C 10 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl-C 1 -C 4 alkyl, phenyl or phenyl. C 1 -C 3 alkyl, -CO ₂ R ⁵ , -COR ⁵ , -CONR ⁵ R ⁶ or SO ₂ R ⁵ , wherein

R ⁵ and R ⁶ may be the same or different and are each independently hydrogen, C 1-6 alkyl or C 3-7 cycloalkyl, phenyl or phenyl (C 1-4 alkyl) wherein the phenyl is optionally one or more C 1-4 alkyl -, C 1-4 alkoxy, hydroxy or halogen, provided that R ^{5 is} not hydrogen when R ¹ is -CO ² R ⁵ or -SO ² R ⁵

One of R ² , R ³ and R ⁴ is hydrogen or C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 alkenyl, phenyl or phenyl (C 1 -C 3 alkyl) and the other two they may be the same or different, represent a hydrogen atom or a C 1-6 alkyl group,

Q is hydrogen or halogen or hydroxy, C 1-4 alkoxy, phenyl (C 1-3) alkoxy or C 1-6 alkyl or -NR ⁷ R ⁸ or -CQNR ⁷ R ⁸ where

R ⁷ and R ⁸ may be the same or different and are hydrogen, (C 1 -C 4) alkyl or (C 3 -C 4) alkenyl, or together with the nitrogen to which they are attached,

They form a 5-7 membered saturated ring, n is 1, 2 or 3 and

AB is CH-CH ₂ or C-CH or their physiologically acceptable salts and solvates.

A new class of compounds has been prepared which is structurally different from the above-mentioned compounds and has potent 5-HT antagonist activity.

5-HT ₃ receptors.

Thus, in accordance with the present invention, tetracyclic lactams of formula (I) are prepared wherein n is 2 or 3. Im is a group of formula (c)

Y is - (CH ₂ ) _m -, wherein m is 2, 3 or 4, or

Y is -O (CH ₂ ) _p - where p may be 2 or 3,

Further, physiologically active salts of these compounds were prepared.

Physiologically acceptable salts of the compounds of formula I include acid addition salts with organic or inorganic acids such as hydrochlorides, hydrobromides, sulphates, alkyl or allyl sulphonates such as methanesulphonates or para-toluene sulphonates, phosphates, cis, acetates, fumarates and maleate.

In relation to the compound of formula (I), the alkyl group may be a straight chain branched chain such as methyl, ethyl, propyl, prop-2-yl, butyl, but-2-yl, 2-methylprop-2-yl, pentyl. -, pent-3-yl or hexyl.

Preferred compounds are those compounds of formula I wherein R ³ is C 1-4 alkyl such as methyl. Other preferred compounds are those wherein R ^{3 is C} 1-3 alkyl such as methyl.

Further preferred are compounds of formula I wherein Y is - (CH ₂ ) ₂ -, -) CH ₂ ) ₃ - or -O (CH ₂ ) ₂ -, more preferably - (CH ₂ ) ₂ - or - (CH ₂ ) ₃ -.

Preferred compounds of the present invention are:

5,6,9,10-Tetrahydro-10 - [(5-methyl-1H-imidazol-4-yl) methyl] -4H-pyrido [3 ', 4': 4,5] pyrrole [3,2,1 -ij] quinol η-11 (8H) -one;

4,5,7,8-tetrahydro-9 - [(5-methyl-lH-imidazol-4-yl) methyl] pyrido [4,3-b] pyrrolo [3,2, l-hi] indole 10 (9H) -one; 4,5,7,8,910-Hexahydro-10 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-azepino [4,2-b] pyrrolo [3,2,1-hyindol-11- you; and physiologically acceptable salts thereof.

The potent and selective antagonism of 5-HT is

At the 5-HT ₃ receptors, the compounds of formula (I) can be demonstrated by demonstrating the ability of the compounds to inhibit 3- (5-methyl-1 H -imidazol-4-yl) -1- [1 (methyl ₃ ) Binding of -1H-indol-3-yl] -1-propanone in rat entorhinal cortex homogenate (described by G. Kilpatrick et al., Natura, 1987, 330, 746), and the effect of including measuring the ability to inhibit 5-HT-induced depolarization of an isolated rat nerve preparation.

Compounds of formula I antagonizing the 5-HT ₃ receptor at 5-HT ₃ receptors are useful in the treatment of psychotic disorders such as schizophrenia and mania, as well as anxiety, dizziness and vomiting, particularly associated with cancer chemotherapy and radiotherapy. The compounds of formula (I) may also be used in

Gastrointestinal disorders such as indigestion, peptic ulcer, reflux esophagitis, windpipe, intestinal irritation syndrome, migraine, obesity, and conditions such as lupus and pain. The compounds of formula továbbá are also useful in the treatment of drug and drug addiction, depression, softening of the brain, and other recognition disorders. The compounds of formula (I) or their pharmaceutically acceptable salts can be used to treat the above-listed symptoms in an effective amount.

Thus, the present invention also provides pharmaceutical compositions comprising at least one compound of formula (I), pharmaceutically acceptable salts thereof, which can be administered in a manner known per se in human or veterinary medicine. The formulations may be formulated in known manner using one or more physiologically acceptable carriers and / or excipients. The compounds may be formulated for oral, buccal, parenteral, or rectal administration, or may be formulated for administration by inhalation or insufflation (oral or nasal administration). For oral administration, the pharmaceutical composition may be in the form of tablets or capsules, which may be formulated in known manner using pharmaceutically acceptable substances such as excipients such as pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose, fillers such as lactose, phosphate, a lubricant such as magnesium stearate, talc or silica, a disintegrant such as corn starch or sodium starch, a glycolate or a wetting agent such as sodium lauryl sulfate. The tablets may be coated in a known manner. Liquid preparations for oral administration may take the form of solutions, syrups or suspensions, or they may be presented in a dry form for constitution with water or other suitable vehicle before use. Such liquid compositions may be prepared in a known manner by the addition of pharmaceutically acceptable additives such as suspending agents such as sorbitol syrup, cellulose derivatives or hydrogenated edible fats, emulsifying agents such as lecithin or acacia, anhydrous solvents such as almond oil, vegetable alcohol esters, oils, preservatives such as methyl or propyl parahydroxybenzoates or sorbic acid. The formulations may also contain buffering salts, flavoring, coloring and sweetening agents.

Formulations for oral administration may also be formulated so as to provide a controlled release of the active ingredient.

Formulations suitable for buccal administration may take the form of tablets or lozenges.

Formulations suitable for parenteral administration may be presented as a bolus injection or a continuous infusion. Formulations for injection are prepared in unit dose form, for example, in ampoules or multi-dose containers, and a preservative is added. The compositions may take such forms as suspensions, solutions, or emulsions, in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and / or dispersing agents. The active ingredient may also be in the form of a powder, which may then be mixed with a suitable medium, for example sterile pyrogen-free water, before use.

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

In addition to the formulations described above, the compounds may also be formulated as sustained release formulations. Such sustained release formulations may be administered, for example, subcutaneously or intramuscularly by implantation, i.e., implantation, or by intramuscular injection. For example, suitable polymeric or hydrophobic materials such as a suitable oily emulsion or ion exchange resin or slightly soluble derivatives such as a sparingly soluble salt may be incorporated into the compositions.

For administration by inhalation, the compounds will usually be placed on the market in an aerosol spray under pressure or in an aerosol dispenser using a suitable builder such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. The pressurized aerosol dosage unit is determined using a valve that delivers a metered amount. Capsules, for example, are made from a gelatin capsule inhaler or insufflator, containing a compound of the invention in powder form together with a suitable powder base such as lactose or starch.

For intranasal use, the compounds of the present invention are prepared in the form of a solution for administration in an appropriate metered amount, or in a unit dose device or as a powder mixture, in admixture with a suitable vehicle.

For human medicine, the recommended dose is from 0.001 to 100 mg, preferably 0.01 to 50 mg, of active ingredient per unit weight of 70 kg body weight, expressed as the free base, which may be administered, for example, 1 to 4 times daily. In some cases, the dose may need to be adjusted depending on the age and condition of the patient. The dose may also vary depending on the route of administration.

The physiologically acceptable salts of the compounds of formula (I) may be prepared by the general method outlined below. R ³ , η, Y and lm are as defined above.

In this process, compounds of formula I can be prepared by reacting a compound of formula Π with a compound of formula (TH) or a protected derivative thereof, wherein L is a leaving atom or group such as a halogen such as chlorine, bromine, or an iodine atom or an acyloxy group such as trifluoromethanesulfonyloxy, p-toluenesulfonyloxy or

The methanesulfonyloxy group was removed and the protecting groups removed. Preferably L is halogen, for example chlorine.

The reaction may be carried out in an inert solvent such as ether such as dimethoxyethane, lignin or tetrahydrofuran or a substituted amide such as dimethylformamide or N-methylpyrrolidone in an aromatic hydrocarbon such as toluene, ketone such as acetone or dimethylsulfoxide. At a temperature of about 1 ° C in the presence of a base.

Suitable bases include alkali metal hydrides such as sodium hydride, alkali metal carbonates such as sodium carbonate, alkali metal amides such as sodium amide, alkali metal alkoxide such as potassium t-butoxide or alkali metal hydroxide such as sodium.

For example, compounds of formula (II) may be prepared by cyclizing a compound of formula (IV) or a salt thereof. The cyclization is carried out in an aqueous or anhydrous medium, optionally in the presence of an acid catalyst. When used as an acid catalyst, it may be an inorganic acid such as concentrated sulfuric acid or hydrochloric acid. The acid catalyst can also serve as a solvent. In the anhydrous reaction medium, the acid catalyst may also be a Lewis acid such as eucchloride. The cyclization reaction is preferably carried out at a temperature of 20 to 200 ° C. If an acid catalyst is not used, the cyclization can also be carried out thermally, for example by boiling the mixture in a high boiling organic solvent, e.g. .

Compounds of formula IV may be prepared, for example, by reaction of a compound of formula V or a salt thereof with a compound of formula VI or a protected derivative thereof in a suitable solvent such as an alcohol such as ethanol at a temperature of 20-100 ° C. Compounds of formula (II) may be prepared directly by reacting a compound of formula (V) or a salt thereof with a compound of formula (VI) or a protected derivative thereof, under the conditions described above. Compounds of formula (IV) may be isolated as intermediates in the above reaction. The compounds of formula (ΠΙ) and their protected derivatives are known or may be prepared according to the methods described in German Patent Publication No. 3,740,352, and the compounds of formulas (V) and (VI) may be known or may be prepared in a known manner.

For example, isolation of the desired compounds of Formula I as a physiologically acceptable salt may be accomplished by reacting a compound of Formula I as the free base with a suitable acid such as an equivalent amount of acid in a suitable solvent such as an alcohol such as ethanol or methanol or aqueous alcohol such as aqueous ethanol or a halogenated hydrocarbon such as dichloromethane; or an ester such as ethyl acetate or ether such as tetrahydrofuran.

Physiologically acceptable salts may also be prepared from other salts, for example, physiologically acceptable salts. The preparation is carried out in a known manner.

The invention is illustrated by the following examples of intermediate and finished products. Temperatures are in ° C, TLC analysis on silica, and flash chromatography on Merck 9385 silica. The solvent system A in the chromatography indicates dichloromethane and ethanol and 0.88 ammonia solution. The organic extracts were dried, where indicated, over magnesium sulfate.

1. Intermedier

5,6,9,10-Tetrahydro-4H-pyrido [3 ', 4': 4,5] pyrrolo [3,2,1-ij] -quinolinyl (8H) -one

2-Amino-1,2,3,4-tetrahydroquinoline hemisulfate (500 mg) and 2,4-dioxopiperidine (287 mg) in anhydrous ethanol (20 ml) were kept under nitrogen for 20 hours. The solvent was removed in vacuo to give 700 mg of a gum which was treated with 7 mL of concentrated sulfuric acid for 15 minutes. The resulting solution was neutralized with 200 mL of 8% sodium bicarbonate solution and extracted with dichloromethane (3 x 100 mL). The combined dried organic extracts were evaporated to give 470 mg of a solid which was purified by flash chromatography eluting with solvent system A (400: 10: 1). 230 mg of the title compound are obtained in the form of a solid, m.p. 254-256 ° C.

2. Intermedier

4,5,7,8-Tetrahydro-pyrido [4,3- b] pyrrolo [3,2,1-hi] indol-10 (9H) -one g 1-aminoindoline hydrochloride and 663 mg 2, A solution of 4-dioxopiperidine in 40 ml of anhydrous ethanol was stirred for 48 hours under a stream of nitrogen. The solvent was removed in vacuo and the residue dissolved in diethylene glycol (30 mL). Heat at 200 ° C for 2 hours. The solution was allowed to cool, poured into water (200 mL) and extracted with dichloromethane (3 x 100 mL). The combined dried organic extracts were evaporated to give 2.5 g of an oil which was purified by flash column chromatography on silica gel (Merck 7729). The solvent system was 400: 10: 1 (eluent). 330 mg of the title compound are obtained as a solid. M.p .: 265267 'C.

3. Intermedier

3,4-dihydro-2H-l, 4-benzoxazin-4-amine

A solution of 2.6 g of sodium nitrite cooled to 0 ° C in 12.5 ml of water is added dropwise to 4.9 g of 3,4-dihydro-2H-1,4-benzoxazine in 27.5 ml of water and 9.5 ml of concentrated at 0 ° C in hydrochloric acid. The mixture was stirred at 0-5 ° C for 1.5 h and then extracted with ether (3 x 60 mL). The combined dried organic extracts were evaporated to a solid

This was dissolved in a mixture of 11 ml of acetic acid / 11 ml of water and 27 ml of ethanol and added dropwise to a vigorously stirred suspension of 25 ml of zinc powder in 32 ml of ethanol at 40-50 ° C. After 30 minutes, the mixture was cooled and filtered and the filtrate was evaporated to dryness. The residue was treated with 5N sodium hydroxide solution (300 mL) and extracted with 3 x 100 mL of food. The combined dried organic extracts were evaporated to give an oil (5.3 g) which was purified by flash chromatography eluting with 4: 1 hexane: ethyl acetate. 3.2 g of the title compound are obtained in the form of an oil, which is subjected to TLC eluting with 4: 1 hexane: ethyl acetate. R _f = 0.25.

4. Intermediate 1,2,9,9, 1-Tetrahydropyrrolo [3 ', 4 ³ : 4,5] pyrrolo [1,2,3-de] [1,4] benzoxazin-7 (8H) -one g. A solution of 4-amino-3,4-dihydro-2H-1,4-benzoxazine and 753 mg of 2,4-dioxopiperidine in 40 ml of anhydrous ethanol was stirred under a stream of nitrogen for 1.5 hours. The solvent was removed in vacuo and the residue dissolved in diethylene glycol (30 mL) and heated at 100 ° C for 1 hour and then at 150 ° C for 2 hours. The solution was allowed to cool, poured into water (200 mL) and extracted with dichloromethane (3 x 100 mL). The combined dried organic extracts were concentrated to give about 3 g of a semi-solid which was purified by flash chromatography and eluted with 400: 10: 1 system A. 740 mg of the title compound are obtained in the form of a solid, m.p. 298-300 ° C.

5. Intermedier

3- (2,3-dihydro-lH-indol-l-yl) -2-cyclohexen-l-one

A mixture of 5.39 g of indoline and 5.07 g of cyclohexane-1,3-dione is heated at about 150 ° C for 7 hours. After cooling, the mixture was purified by flash chromatography, eluting with 10: 1 ethyl acetate: methanol, to give 7.30 g of a solid which was recrystallized from 4: 1 ethyl acetate: ether to give 5.08 g of the title compound.

85-86 C.

6. Intermedier

4,5,8,9-tetrahydro-pyrrolo [3,2, l-jk] karbazol10 (7H) -one

2.515 g of 3- (2,3-dihydro-1H-indol-1-yl) -2-cyclohexen-1-one, 4.71 g of copper acetate and 0.20 g of palladium (II) acetate in 40 ml of anhydrous formamide mixture was heated at 135 ° C under a stream of nitrogen for 4 hours. The solvent was then removed in vacuo and the residue suspended in methanol and filtered. The filtrate was concentrated in vacuo and the resulting residue was purified by flash chromatography. Elution with ethyl acetate gave 0.36 g of the title compound as a solid. 20 mg of this are recrystallized from ethyl acetate to give 15 mg of the title compound, m.p.

7. Intermedier

4,5,8,9-Tetrahydro-pyrrolo [3,2, l-jkJ karbazol10 (7H) -one oxime

A mixture of 4,5,8,9-tetrahydropyrrolo [3,2,1-jk] carbazol-10 (7H) -one (364 mg) and hydrochloride (479 mg) in pyridine (50 ml) was heated to 50 ° C for 60 hours, and poured into 100 ml of 2N hydrochloric acid. The resulting precipitate is filtered off, washed with 50 ml of water and dried at 50 ° C in vacuo for 6 hours. 140 mg of the expected product are obtained. The precipitate was filtered off and an additional yield of 104 mg of the filtrate was obtained. M.p. 271-272 ° C.

8. Intermedier

4.5.7.8.9.10- Hexohydro-11H-azepino [4,3-b] pyrrolo [3,2,1-hi] indol-11-one

244 mg of 4,5,8,9-Tetrahydropyrrolo [3,2,1-jk] carbazol-10 (7H) -one oxime are added to 20 ml of polyphosphoric acid at 120 ° C and the mixture is heated to 120 ° C for 1 hour. stir for an hour. After cooling, the mixture was poured into water (150 mL) and extracted with a 10: 1 mixture of dichloromethane and ethanol (4 x 100 mL). The combined dry organic extracts were evaporated in vacuo to give 150 mg of a solid which was purified by flash chromatography eluting with 100: 10: 1 solvent system A. 92 mg of the title compound are obtained, eluted by TLC and 100: 10: 1 solvent system. R _f = 0.47.

Example 1

5.6.9.10- Tetrahydro-10 - [(5-methyl-1H-imidazol-4-yl) methyl] -4H-pyrido [3,4 ': 4,5] pyrrolo [3,2,1-ij] quinoline-11 (8H) -on-maleate mg of sodium hydride in the form of a 60% oil dispersion in oil is added 270 mg of 5,6,9,10-tetrahydro-4H-pyrido [3 ', 4': 4,5] pinolo [3,2,1] -j] quinolin-11 (8H) -one in a stirred suspension of 15 ml of dimethoxyethane and heated at 50 ° C for 6 hours. The mixture was then treated with 522 mg of 4- (chloromethyl) -5-methyl-triphenylmethyl-1H-imidazole and stirred at 50 ° C for 18 hours. Water (3 ml) and acetic acid (3 ml) were added and the solution was heated under reflux for 3 hours. The mixture was poured into 60 mL of 8% sodium bicarbonate solution and extracted with dichloromethane (3 x 30 mL). The combined dried organic extracts were evaporated to give 810 mg of a solid which was purified by flash chromatography eluting with 200: 10: 1 solvent system A. 324 mg of a solid are obtained, which is dissolved and treated with 3 ml of anhydrous ethanol and a solution of 117 mg of maleic acid in 1 ml of anhydrous ethanol. The solvent was removed in vacuo and the residue was triturated with 3 x 5 mL of anhydrous ether. 415 mg of the title compound are obtained. Mp: 146148 'C.

Aqueous analysis found: 0.56% w / w = 0.13 mol water.

Elemental analysis Calc'd C ₉ H2oN ₄ OC ₄ H ₄ 0 _{4 2} 0 .0,13H:

Found: C, 62.8; H, 5.5; N, 12.55;

Calculated: C, 62.9; H, 5.5; N, 12.80.

Example 2

4,5,7,8-Tetrahydro-9 - [(5-methyl-1H-imidazol-4-yl) methyl] pyrido [4,3-b] pyrrolo [3,2,1-hi] indole; 10 mg of 9 (9H) -on-maleate sodium hydride in the form of a 60% oil dispersion are added 300 mg of 4,5,7,8-tetrahydropyrido [4,3-b] pyrrolo [3,2,1-h] indole-10 (9H) ) in anhydrous dimethoxyethane (15 mL) under nitrogen and the mixture was stirred at 60 ° C for 6 h. The mixture was then treated with 634 mg of 4-chloromethyl-5-methyl-1- (triphenylmethyl) -1H-imidazole and stirred for a further 20 hours. Water (3 ml) and acetic acid (3 ml) were added and the solution heated at reflux for 4 hours. The solution was poured into 60 mL of 8% sodium bicarbonate solution and extracted with dichloromethane (3 x 30 mL). The combined dry organic extracts were evaporated to give 935 mg of a solid which was purified by flash chromatography eluting with 200: 10: 1 solvent system A to give 310 mg of a solid. The material was dissolved in 5 ml of anhydrous ethanol and treated with a solution of 118 mg of maleic acid in 2 ml of anhydrous ethanol. The solvent was removed in vacuo and the residue was triturated with anhydrous ether (3 x 10 mL) to give the title compound (413 mg). Mp: 125-128 ° C.

Aqueous analysis, found: 1.79% w / w / 0.43 mol water.

Elemental analysis based on C ₁₈ Hi ₈ N ₄ OC ₄ H ₄ O ₄ .0.43H ₂ O:

Found: C, 61.3; H, 5.4; N, 12.9; Calculated: C, 61.4; H, 5.4; N, 13.0.

Example 3

1.2.9.10- Tetrahydro-8 - [(5-methyl-1H-imidazol-4-yl) methyl] pyrido [3 ', 4': 4,5] pyrrolo [1,2,3] de] [1,4] benzoxazin-7 (8H) -one tnaleát

350 ml of 1,2,4,9,10-tetrahydropyrido [3 ', 4': 4,5] -pinolo [1,2,3-de] [1,4] benzoxazin-7 (8H) -one; mg of 4-chloromethyl-5-methyl-1- (triphenylmethyl) -1H-imidazole

Treated as in Example 2 to give 565 mg of the title compound as a solid, m.p. 149-151 ° C.

Elemental analysis based on the formula C 1 ₈ Hi ₈ N ₄ O ₂ .C ₄ H ₄ O ₄ :

Calculated: C, 60.3; H, 5.1; N, 12.9; Found: C, 60.0; H, 5.1; N, 12.6.

Example 4

4.5.7.8.9.10- Hexahydro-10 - [(5-methyl-1H-imidazol-4-yl) methyl] -HH-azepino [3,4-b] pyrrolo [2,3-b] indo-II-one maleate 4,5,7,8,9,10-hexahydro-11H-azepino [4,3b] pyrrolo [3,2,1-hi] indol-11-one and 159 mg of 4- (chloromethyl) -5- Methyl 1- (triphenylmethyl) -1H-imidazole was treated as in Example 2, except that the eluent was flash chromatographed on a 100: 15: 1 solvent system. 57 mg of the title compound are obtained in the form of a solid, m.p. 173-176 ° C.

Elemental Analysis for: C ₂₃ H ₂₄ N ₄ O ₅ Calculated: C, 63.3; H, 5.5; N, 12.8; Found: C, 63.4; H, 5.8; N, 12.8.

The following examples illustrate the preparation of pharmaceutical compositions. The term active ingredient refers to a compound of formula (I).

Tablets for oral administration

The tablet may be prepared by a conventional method such as direct compression or wet granulation.

The tablet may be coated with a suitable film-forming material, such as hydroxypropylmethylcellulose, by standard technology. Alternatively, tablets may be sugar coated. Other strength tablets may be prepared by varying the ratio of active ingredient to excipients, or by weight of compression and use of a suitable press (compression).

Direct compression tablet mg / tablet

Active ingredient 0.50

Calcium hydrogen phosphate BP * 87.25

Croscarmellose Sodium NF 1.80

Magnesium stearate BP 0.45

Pressing weight 90.00 * suitable grade for direct pressing.

The active ingredient is passed through a 60 mesh screen, mixed with calcium hydrogen phosphate and croscarmellose sodium and magnesium stearate, and the resulting mixture is compressed into tablets using a Manesty F3 tabletting machine with a 5.5 mm flat edge die.

For intravenous administration, injection in mg / ml

Active ingredient 0.05 1.0

Sodium chloride BP as needed

Make up to 1.0 ml with sterile water and make up to 1.0 ml

Sodium chloride may be added to adjust the tone of the solution and adjust the pH to an optimal stability by means of acid or alkali and / or to facilitate dissolution of the active ingredient. Suitable buffer salts may also be used.

The solution is prepared, purified, and filled into ampoules of appropriate size and sealed by melting the glass. The injection is sterilized by heating in an autoclave using appropriate cycles. The solution may also be sterilized by filtration and filled in sterile ampoules under aseptic conditions. The solution may be packaged under an inert nitrogen atmosphere or other suitable gas.

Claims (6)

PATENT CLAIMS A process for the preparation of compounds of formula I wherein n is 2 or 3, EN 207 318 µm is an imidazolyl group of formula (c) wherein Y is -CH 2, where m is 2,3 or 4, or Y is -O (CH ₂ ) _p -, wherein p is 2 or 3, or a physiologically acceptable salt thereof, characterized in that a compound of formula (Π) - wherein n and Y are as defined herein - is a (ΙΠ) alkylation with a protected derivative of the compound of formula (I), wherein lm represents the above leaving L or atom, and then deprotected, and if the compound of formula (I) is in free base form, optionally the base is converted to a salt. A process according to claim 1 for the preparation of compounds of formula I wherein R ³ is C 1 -C 4 alkyl, wherein the appropriate starting materials are used. 3. A process according to claim 1 for the preparation of compounds of formula (I) wherein R ³ is C 1 -C 3 alkyl, wherein the appropriate starting materials are used. 4. A process according to any one of claims 1 to 6 for the preparation of compounds of formula I wherein Y is - (CH ₂ - or - {CH ₂ ) ₃ -, wherein the appropriate starting materials are used. The process of claim 1, 5,6,9,10-tetrahydro-10 - [(5-methyl-1H-imidazol-4-yl) methyl] -4H-pyrido [3 ', 4': 4, 5] pyrrolo [3,2, l-ij] quinolin-ll (8H) -one; 4,5,7,8-Tetrahydro-9 - [(5-methyl-1H-imidazol-4-yl) methyl] pyrido [4,3-b] pyrrolo [3,2,1-hi] indole -10 (9 H) -one; 4,5,7,8,9,10-hexahydro-10 [(5-methyl-lH-imidazol-4-yl) methyl] -l IH-azepino [4,3-b] pyrrolo [3,2, l- hi] indol-llon; or physiologically acceptable salts thereof, wherein the appropriate starting materials are used. 6. A process for the preparation of a pharmaceutical composition comprising mixing the compound of formula (I) or a physiologically acceptable salt thereof according to claim 1, wherein lm, m, Y, R ³ are as defined in claim 1, with a pharmaceutically acceptable carrier. .