MXPA96006531A

MXPA96006531A - Pharmaceutical compounds

Info

Publication number: MXPA96006531A
Application number: MXPA/A/1996/006531A
Authority: MX
Inventors: Thaddeus Gallagher Peter; William Smith Colin; Martin Owton William
Original assignee: Lilly Industries Limited
Priority date: 1995-12-19
Filing date: 1996-12-17
Publication date: 1997-06-01

Abstract

Pharmaceutical compounds of the fórmula (see fórmula) in which R1 and R2 are each hydrogen, C1-4 alkyl, C1-4 alkoxy, HO-C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkylthio, halo or PhCR'R''- where Ph is optionally substituted phenyl and R'and R''are each hydrogen or C1-4 alkyl, or R1 and R2 together with the carbon atom to which they are attached from a C3-6 cycloalkyl group. R3, R4, and R5 are each hydrogen halo, nitro, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkyl -CO-, C1-4 alyl-S(O)m- where m is 0, 1 or 2, R'R''N-SO2-, - COOR, -CONR'R'', -NR'R'', -N(OR')COOR'', -COR', -NHSO2R', where R'and R''are each hydrogen or C1-4 alkyl, and n is 1 to 6, x is oxygen or sulfur.

Description

PHARMACEUTICAL COMPOUNDS The present invention relates to pharmaceutical compounds, their preparation and use.

Indole-2-one-type compounds have been described in the literature and have potential use as analgesics or to treat cognitive disorders or as cholinesterase inhibitors as, for example, in J. Med. Chem. 1991, 34, 827-841, WO 93/12085 and CA 119: 225964t.

The compounds of the invention are of the formula: in which R 1 and R are each hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, HO-C 1-4 alkyl, C 1-4 alkoxy-C 4 alkyl, alkylthio of 1 to 4 carbon atoms, halo, Ph, PhCR'R "- wherein Ph is optionally substituted phenyl and R 'and R" are each hydrogen or alkyl of 1 to REF: 23709 4 carbon atoms, or R1 and R2 together with the carbon atom, to which they are attached form a cycloalkyl group of 3 to 6 carbon atoms, > C = 0, > C = NOR 'wherein R' is hydrogen or alkyl of 1 to 4 carbon atoms.

R 3, R 4 and R 5 are each hydrogen, halo, nitro, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, C 1-4 -alkyl-CO- , C1-4- alkyl-S (0) m- where m is 0, 1 or 2, R'R "NS? 2-, -COOR ', -CONR'R ", -NR'R", -N (OR ') COOR ", -COR', NHS02R ', wherein R' and R" are each hydrogen or alkyl of 1 to 4 carbon atoms, R 6 and R 7 are each hydrogen or alkyl of 1 to 4 carbon atoms and n is 1 to 6, X is oxygen or sulfur, W is where p is 4 to 7, and q and r are each 1 to 3, Y is > CO or -CH (OH) -, Z is optionally substituted phenyl or optionally substituted heteroaryl; and salts and esters of them.

The compounds of the invention are indicated for use in the treatment of disorders of the central nervous system. These are active in tests that indicate serotonergic modulation.

In formula (I) above, an alkyl group of 1 to 4 carbon atoms includes methyl, ethyl, propyl, isopropyl, butyl and tert-butyl and is preferably methyl or ethyl. An alkoxy group of 1 to 4 carbon atoms is one such as an alkyl group linked to a ring via an oxygen atom and a halo atom is preferably chlorine, bromine or fluorine and especially chlorine or fluorine. A substituted phenyl group is phenyl substituted with or more for example one to three, substituents selected from, for example, alkyl of 1 to 4 carbon atoms, especially methyl, alkoxy of 1 to 4 carbon atoms, especially methoxy and ethoxy, hydroxy , nitro, cyano, halo, especially chloro, or fluorine, trihalo ethyl, especially trifluoromethyl, carboxy and C? -4alkoxycarbonyl.

A heteroaryl group may have one or more hetero atoms selected from, for example, oxygen, nitrogen and sulfur and preferably contains from 5 to 10 carbon atoms. Preferably a heteroaryl group contains a hetero atom simple and is of the formula: wherein Q is -O-, -S- or -NR-, and R is hydrogen or alkyl of 1 to 6 carbon atoms. Alternatively, a heteroaryl group may comprise a benzene fused to a ring such as, for example: In addition heteroaryl groups include those of the formula: When n is greater than 1. the values of R and R need not be identical in each repetitive unit of methylene.

Preferred compounds are those that have one or more of the following aspects: (i) X is oxygen (ii) R 1 and R 2 are each hydrogen, alkyl of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms or benzyl, (iii) R 1 and R 2 are both methyl (iv) R 1 is hydrogen and R 2 is methyl 3 4 5 (v) R, R and R are each hydrogen, halo or alkyl of 1 to 4 carbon atoms _ 7 (vi) R and R are both hydrogen (vii) n is 2 (viii) W is (ix) p is 5 And it's > CO (xi) Z is optionally substituted phenyl A preferred group of compounds is that of the formula: and preferably one in which R 1 and R 2 are each hydrogen or alkyl of 1 to 4 carbon atoms, R3 is hydrogen, alkyl of 1 to 4 carbon atoms or halo, n is 2 and R is hydrogen or halo. Preferably the benzoyl substituent is attached to the piperidinyl ring at the 4 position. A particularly preferred group is one in which R and R are both hydrogen and R 3 is hydrogen or fluorine, n is 2 and R 8 is halo, preferably fluorine and salts of the same. It will be appreciated that the compounds of the invention may contain one or more asymmetric carbon atoms which give rise to the isomers. The compounds are normally prepared as racemic mixtures and can conveniently be used as such, but the individual isomers can be isolated, if desired, by conventional techniques. Such racemic mixtures and individual optical isomers form part of the present invention. It is preferred to use an enantio pure form.

It is, of course, possible to prepare salts and esters of the compounds of the invention and such salts and esters are included in the invention. The salts are preferably pharmaceutically acceptable, non-toxic addition salts with appropriate acids, such as those with inorganic acids, eg hydrochloric, hydrobromic, nitric, sulfuric or phosphoric acid, or with organic acids such as organic carboxylic acids, for example, glycolic, maleic, hydroxymalonic, fumaric, alic, tartaric, citric, salicylic, o-acetoxybenzoic, or organic sulfonic, 2-hydroxyethane sulphonic, toluene-p-sulphonic or naphthalene-2-sulfonic.

In addition to the pharmaceutically acceptable salts, other salts are included in the invention. These can serve as intermediates in the purification of compounds or in the preparation of others, for example pharmaceutically acceptable acid addition salts, or are useful for identification, characterization or purification.

The compounds can also be used in ester form, such esters are aliphatic or aromatic. The most preferred esters are alkyl esters derived from alkanols of 1 to 4 carbon atoms, especially methyl and ethyl esters.

The invention also includes a process for producing a compound of the formula (I) above, which comprises reacting a compound of the formula H-W-Y-Z with a compound of the formula: wherein the substituents have the values given above and Q is a leaving group, for example halo, or a mesylate or tosylate. The reaction is preferably carried out in an inert organic solvent, for example methyl isobutyl ketone or acetonitrile and at a temperature between 80 ° C to 110 ° C: The reaction takes place under alkaline conditions by the use of, for example, sodium carbonate or potassium carbonate. The compounds of the formula (III) either are known or can be prepared by methods well known in the art.

In the case of compounds in which W is the compounds can be prepared by reacting a partially protected nitrogen containing a cyclic amine with a phenyl or a carbonyl heteroaryl halide, followed by deprotection to obtain the compounds of the formula: optionally followed by reduction to obtain the compound of the formula (III) in which Y is -CH (OH) -.

The compounds of the formula (IV) are either known or can be prepared by methods well known in the art, such as, for example, by reacting a compound of the formula: with a compound of the formula Q '(CR 6R7) nQ, where Q' is also a departing group.

An alternative route for the compounds of the invention consists of a reverse, analogous condensation of the main components of the molecule as for example, by reacting a compound of the formula (V) above with a compound of the formula Q (CR6R7) n-W-Y-Z Such reagents can be prepared as described above or by analogous methods.

As mentioned above, the compounds of the invention have useful activity in the central nervous system. The compounds are active at the 5-HT? Da receptor of serotonin. Its binding activity has been demonstrated in a test described by Zgombic, J. M. et al., Molecular Pharmacology Vol. 40 1992, pages 1036-1042, and the compounds of the invention as described in the following examples have a Ki of 2 nM to 5000 nM. Some of the compounds, for example, those of the formula (III) also have binding activity at the 5-HT? In addition, the compounds have activity at the 5-HT2A receptors as shown in the test described by Leysen, J. E. et al., Molecular Pharmacology Vol. 21 1981, pages 301-314.

Due to their selective affinity for 5-HT receptors the compounds of the present invention are indicated for use in the treatment of a variety of conditions such as obesity, bulimia, alcoholism, pain, depression, hypertension, aging, memory loss, sexual dysfunction, anxiety, schizophrenia, gastrointestinal disorders, headache, cardiovascular disorders, smoking cessation, drug addiction, emesis, sleep disorders and Alzheimer's disease. The compounds of the invention are effective over a wide range of doses, the actual dose administered is dependent on factors such as the particular compound being used, the condition, type and size of the mammal to be treated. However, the required dose will normally fall within the range of 0.01 to 20 mg / Kg. per day, for example in the treatment of adult humans doses of from 0.5 to 100 mg per day can be used.

The compounds of the invention will normally be administered orally or by injection and for this purpose, the compounds will be commonly used in the form of a pharmaceutical composition. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.

Accordingly, the invention includes a pharmaceutical composition, comprising as active ingredient a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, associated with a pharmaceutically acceptable excipient. In the preparation of the compositions of the invention, the active ingredient will be mixed, generally with a carrier or vehicle, or diluted by a carrier, or encompassed within a carrier, which may be in the form of a capsule, sachet, paper or another container. The excipient may be a solid, semi-solid or liquid material, which acts as an excipient vehicle or medium for the active ingredient. Examples of suitable excipients are lactose, dextrose, sucrose, sprbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, tragacanths, gelatin, syrup, methylcellulose, methyl- and propyl-hydroxybenzoate, talc, magnesium stearate or oil. The compositions of the invention may, if desired, be formulated to provide a rapid, sustained or delayed release of the active ingredient after being administered to the patient.

Depending on the route of administration, the above compositions can be formulated as tablets, capsules or suspensions for oral use or injectable solutions or suspensions for parenteral use or as suppositories. Preferably the compositions are formulated in unit dose form, each dose contains from 0.5 to 100 mg, more generally from 1 to 100 mg of the active ingredient.

The following examples illustrate the invention: EXAMPLE 1 3, 3-Dimethyl-1- (2-hydroxyethyl) -1,3-dihydro-2H-indol-2-one 3, 3-Dimethylindol-1,3-dihydro-2H-indol-2-one (6.3g, 40mmol) was dissolved in dry dimethylformamide under nitrogen at room temperature. Sodium hydride (601 dispersion in mineral oil, 1.8 g, 45 mmol) was added and the mixture was stirred until gas emission ceased. 2- (2-Chloroethoxy) tetrahydro-2H-pyran (7.5g, 42mmol) and sodium iodide (0.6g, 4 mmol) were added and the mixture was heated at 75 ° C for 15 hours. Water was added and the mixture was concentrated under reduced pressure. The residue was extracted into ethyl acetate, washed (x 3) with water, dried (MgSO 4), filtered and concentrated under reduced pressure. The resulting oil was extracted into methanol, para-toluenesulfonic acid (0.75g, 4 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was concentrated under reduced pressure, extracted into ethyl acetate, washed (x3) with aqueous sodium hydrogen carbonate solution, dried (MgSO4), filtered and concentrated under reduced pressure. The resulting oil was purified by chromatography on silica gel, and hexane / ethyl acetate as eluent, to give 3, 3-dimethyl-1- (2-hydroxy-1-ethyl) -indole-2 (3H) -one, which was characterized by H rmn and MS. 1 H NMR (CDC13) d 1.4 (6H s), 3.05 (1H broad), 3.95 (4H s), 6.96 (lH d), 7.04 (1H t), 7.12 (2H m).

The MS shows 206 (MH) at the base of the peak. 3, 3-Dimethyl-1- (2- [4- (4-fluorobenzoyl) -1-piperidinyl] -l-ethyl} -l, 3-dihydro-2H-indol-2-one monohydrochloride: , 3-dimethyl-1- (2-hydroxyethyl) -1,3-dihydro-2H-indol-2-one (2.05 g, 10 mmol) and triethylamine (1.10 g, 10.9 mmol) were dissolved in dichloromethane under nitrogen and cooled to less than 5 ° C in an ice / water bath Methanesulfonyl chloride (1.3g, 11.3mmol) was added and the mixture was stirred for one hour with cooling.The mixture was washed with cold dilute hydrochloric acid, dried (MgSO 4), filtered and concentrated under reduced pressure The resulting oil was dissolved in dry acetonitrile, 4-fluorobenzoylpiperidine para-toluenesulfonate was added (Acros, 2.83g, 11.7mmol), potassium carbonate (3g, 21.7mmol) and potassium iodide (0.15g, 0.9mmol). The mixture was vigorously stirred and heated under gentle reflux for two days. The mixture was poured into chloroform, washed with water, dried (MgSO 4), filtered and concentrated under reduced pressure. The resulting oil was extracted into 5N hydrochloric acid in which a white solid was separated. The solid was recrystallized from ethanol to give 3, 3-dimethyl-1- (2- [4- (4-fluorobenzoyl) -1-piperidinyl] -l-ethyl) -1,3-dihydrohydrochloride. 2H-indol-2-one.

Melting point 236-8 ° C.

EXAMPLE 2 3-Methyl-3-methylthio-l / 3-dihydro-2H-indol-2-one: 1,3-dihydro-2H-indol-2-one (3.3g, 25mmol) and tetramethylethylene diamine (6.4g , 55mmol) were dissolved in freshly distilled tetrahydrofuran under nitrogen and cooled to -75 ° C in an acetone / dry ice bath. N-Butyllithium (2.5M, 22ml, 55mmol) was added and the mixture was stirred at -75 ° C for 30 minutes. Iodomethane (3.57g, 25mmol) was added and the mixture was allowed to warm to -20 ° C, the mixture was re-cooled to -75 ° C, then dimethyl disulfide (2.35g, 25mmol) was added and allowed to The mixture will be heated to room temperature. Water (5 ml) was added and the mixture was concentrated under reduced pressure to a yellow oil. Column chromatography on silica gel (eluent ethyl acetate / hexane) gave 3-methyl-3-methylthis-1, 3-dihydro-2H-indol-2-one as a yellow oil, which solidified on standing.

XH NMR (CDC13) d 1.6K3H s), 1.91 (3H s), 6.96 (1H d), 7.04 (1H t), 7.12 (2H m), 8.05 (1H broad). 1- (2-hydroxyethyl-3-methyl-3-methylthio-l, 3-dihydro-2H-indol-2-one: Prepared from 3-methyl-3-methylthio-l, 3-dihydro-2H- indole-2-one and 2- (2-chloroethoxy) tetrahydro-2H-pyran as described in Example 1.

The MS shows 238 (MH +) at the base of the peak. 1- (2- [4- (4-Fluorobenzoyl) -1-piperidinyl] -1-ethyl.} - 3-methyl-3-methylthio-1,3-dihydro-2H-indo-1-2-one monohydrochloride: Prepared from 1- (2-hydroxy-1-ethyl) -3-methyl-3-methylthio-1,3-dihydro-2H-indol-2-one, via methanesulfonate and 4-fluorobenzoyl piperidine tosylate as was described in Example 1. Melting point 198-201 ° C EXAMPLE 3 1- (2- [4- (4-Fluorobenzoyl) -1-piperidinyl] -1-ethyl.} - 3-methyl-1,3-dihiaro-2H-indol-2-one monohydrochloride: The l-. { 2- [4- (4-fluorobenzoyl) -1-piperidinyl} -l-ethyl} 3-methyl-3-methylthio-l, 3-dihydro-2H-indol-2-one (1.42g, 3.3mmol) was dissolved in ethanol, Raney nickel was added and the mixture was stirred at room temperature until the TLC He indicated that the reaction was over. The mixture was filtered and concentrated under reduced pressure to give the crude product which was purified by column chromatography on silica gel (ethyl acetate / hexane as eluent). The resulting clear oil was dissolved in ethanol, ethanolic HCl was added and the mixture was concentrated under reduced pressure to give a white solid which was recrystallized from 2-propanol to give l- monohydrochloride. { 2- [4- (4-fluorobenzoyl) -1-piperidinyl} -l-ethyl} 3-methyl-l, 3-dihydro-2H-indol-2-one. Melting point 209-211 ° C.

EXAMPLE 4 3-benzyl-3-methylthio-l, 3-dihydro-2H-indol-2-one: 3-phenylmethyl-l, 3-dihydro-2H-indol-2-one (4g, 18.25mmol) (prepared from 1,3-dihydro-2H-indole-2-one and benzaldehyde by the method of Daisley &Walker J. Chem Soc. (C) (1971) page 1373) and tetramethylethylenediamine (4.5g, 38.7mmol) ) were dissolved in freshly distilled tetrahydrofuran under nitrogen and cooled to -75 ° C in an acetone / dry ice bath. N-Butyllithium (2.5M, 20ml, 50mmol) was added and the mixture was stirred at -75 ° C for 30 minutes. Dimethyl disulfide (1.65g, 17.6mmol) was added and the mixture was allowed to warm to room temperature. Water (5 ml) was added and the mixture was concentrated under reduced pressure to a yellow oil. Column chromatography on silica gel (eluent of ethyl acetate / hexane) gave 3-methylthio-3-phenylmethyl-1,3-dihydro-2H-indol-2-one as a yellow oil which solidified on standing.

XH NMR (CDC13) 1.9K3H s), 3.25 (1H d), 3.42 (1H d), 6.76 (1H d), 6.94 (1H t), 7.12 (5H m), 7.20 (1H t), 7.28 (1H t) ) 8.08 (1H broad). 1- (2-hydroxyethyl) -3-methylthio-3-phenylmethyl-l, 3-dihydro-2H-indol-2-one: Prepared from 3-methylthio-3-phenylmethyl-1,3-dihydro-2H- indole-2-one and 2- (2-chloroethoxy) tetrahydro-2H-pyran as described in Example 1.

The MS shows 314 (MH +) at the base of the peak.

Monohydrochloride of l-. { 2- [4- (4-fluorobenzoyl) -1-piperidinyl 1 -1-ethyl} -3-methylthio-3-phenylmethyl-1,3-dihydro-2H-indol-2-one: Prepared from 1- (2-hydroxyethyl) -3-methylthio-3-phenylmethyl-1,3-dihydro-2H -indol-2-one, via the methanesulfonate and the 4-fluorobenzoyl piperidine tosylate as described in Example 1. Melting point of 182-184 ° C.

EXAMPLE 5 Monohydrochloride of l-. { 2- [4- (4-fluorobenzoyl) -1-piperidinyl] -l-ethyl} -3-phenylmethyl-l, 3-dihydro-2H-indol-2-one: Prepared from the Raney nickel reduction of 1-. { 2- [4- (4-fluorobenzoyl) -1-piperidinyl] -l-ethyl} 3-methylthio-3-phenylmethyl-1,3-dihydro-2H-indol-2-one as described in Example 1.

Melting point 213-216 ° C.

EXAMPLE 6 3-Methyl-3-phenylmethyl-l, 3-dihydro-2H-indol-2-one: 3-phenylmethyl-l, 3-dihydro-2H-indol-2-one (prepared from 1,3-dihydro-2H-indole-2-one) (4g, 18.25mmol) and benzaldehyde by Daisley's method & Walker J. Chem Soc. (C) (1971) p. 1373) and tetramethylethylenediamine (4.5g, 38.7mmol) were dissolved in freshly distilled tetrahydrofuran under nitrogen and cooled to -75 ° C in an acetone / dry ice bath. N-Butyllithium (2.5M, 20ml, 50mmol) was added and the mixture was stirred at -75 ° C for 30 minutes. Iodomethane (2.84g, 20mmol) was added and the mixture was allowed to warm to room temperature. Water (5 ml) was added and the mixture was concentrated under reduced pressure to a yellow oil. Column chromatography on silica gel (eluent of ethyl acetate / hexane) gave 3-methyl-3-phenylmethyl-1,3-dihydro-2H-indol-2-one as a yellow oil which solidified on standing.

The MS shows 238 (MH +) at the base of the peak and 255 (M + NH4 +) 3-Benzyl-1- (2-hydroxy-1-ethyl) -3-methylindol-2 (3H) -one: Prepared from 3-benzyl-3-methylindol-2 (3H) -one and 2- (2 -chloroethoxy) tetrahydro-2H-pyran.

The MS shows 282 (MH +) at the base of the peak.

Monohydrochloride of l-. { 2- [4- (4-fluorobenzoyl) -1-piperidinyl] -l-ethyl} -3-methyl-3-phenylmethyl-l, 3-dihydro-2H-indol-2-one: Prepared from 1- (2-hydroxyethyl) -3-methyl-3-phenylmethyl-1,3-dihydro-2H -indol-2-one, via methanesulfonate and 4-fluorobenzoyl piperidine tosylate. Melting point of 204-207 ° C.

EXAMPLE 7 3-Ethyl-1- (2-hydroxyethyl) -3-methyl-1,3-dihydro-2H-indol-2-one: Prepared from 3-ethyl-3-methyl-1,3-dihydro-2H -indol-2-one (prepared by the method of Endler &Becker, Organic Syntheses Coll, Vol. 4 page 657) and 2- (2-chloroethoxy) tetrahydro-2H-pyran.

The MS shows a peak base of 220 (MH). 3-ethyl-l- monohydrochloride. { 2- [4- (4-fluorobenzoyl) -1-piperidinyl] -l-ethyl} -3-methyl-l, 3-dihydro-2H-indol-2-one: Prepared from 3-ethyl-1- (2-hydroxyethyl) -3-methyl-1,3-dihydro-2H-indole-2 -one, via the methanesulfonate and the tosylate of 4-fluorobenzoyl piperidine as described above. Melting point of 210-212 ° C.

EXAMPLE 8 3- (1-Methylethyl) -3-methylthio-l, 3-dihydro-2H-indol-2-one: Prepared from 3- (1-methylethyl) -1, 3-dihydro-2H-indol-2 -one (prepared from 1,3-dihydro-2H-indol-2-one and acetone by the method of Daisley &Walker J. Chem Soc. (C) (1971) page 1373) by the method described above for 3-methylthio-3-phenylmethyl-l, 3-dihydro-2H-indol-2-one.

The MS shows a peak base of 222 (M +) 1- (2-Hydroxyethyl) -3- (1-methylethyl) -3-methylthio-l, 3-dihydro-2H-indol-2-one: Prepared from 3- (1-methylethyl) -3-methylthio-l, 3-dihydro-2H-indol-2-one and 2- (2-chloroethoxy) tetrahydro-2H-pyran.

The MS shows 266 (MH) at the base of the peak. 1- monochlorohydrate. { 2- [4- (4-fluorobenzoyl) -1-piperidinyl] -l-ethyl} -3- (1-Methylethyl) -3-methylthio-l, 3-dihydro-2H-indol-2-one: Prepared from 1- (2-hydroxyethyl) -3- (1-methylethyl) -3-methylthio -l, 3-dihydro-2H-indol-2-one, via methanesulfonate and 4-fluorobenzoyl piperidine tosylate.

Melting point of 150-152 ° C.

EXAMPLE 9 1- monochlorohydrate. { 2- [4- (4-fluorobenzoyl) -1-piperidinyl] -l-ethyl} -3- (1-methylethyl) -1, 3-dihydro-2H-indol-2-one: Prepared from the reduction with Raney nickel of the 1-. { 2- [4- (4-fluorobenzoyl) -1-piperidinyl] -l-ethyl} -3- (1-methyl-ethyl) -3-methylthio-l, 3-dihydro-2H-indol-2-one as described above. Melting point of 207-209 ° C.

EXAMPLE 10 -Bromo-3, 3-dimethyl-l, 3-dihydro-2H-indol-2-one: 3,3-dimethyl-1,3-dihydro-2H-indol-2-one (1.12g, ß. 95mmol) was dissolved in chloroform and stirred at room temperature under nitrogen. Bromine (1.12 g) was added and the mixture was heated under reflux until HBr emission ceased and the bromine color was discharged from the solution. The solution was washed with sodium metabisulfite solution and sodium hydrogen carbonate solution, dried (MgSO 4), filtered and concentrated to dryness under reduced pressure to give 5-bromo-3,3-dimethyl-1,3. -dihydro-2H-indol-2-one as a yellow solid.

XH NMR (CDC13) d 1.39 (6H s), 6.8 (1H d), 7.3 (2H m), 7.9 (1H broad).

-Bromo-3, 3-dimethyl-1- (2-hydroxyethyl) -1,3-dihydro-2H-indol-2-one: Prepared from 5-bromo-3, 3-dimethyl-1, 3 -dihydro-2H-indol-2-one and 2- (2-chloroethoxy) tetrahydro-2H-pyran.

.H NMR (CDCl 3) d 1.39 (6H s), 3.05 (broad 1H), 3.95 (4H s), 6.8 (1H d), 7.3 (2H m). 5-Bromo-3, 3-dimethyl-l-. { 2- [4- (4-fluorobenzoyl) -1-piperidi-nyl] -l-ethyl} -l, 3-dihydro-2H-indo1-2-one: Prepared from 5-bromo-3, 3-dimethyl-1- (2-hydroxyethyl) -1,3-dihydro-2H-indole-2- ona, via methanesulfonate and 4-fluorobenzoylpiperidine tosylate.

Melting point of 208-2 ° C.

EXAMPLE 11 3, 3-dimethyl-5-methanesulfonyl-1,3-dihydro-2H-indol-2-one: 5-bromo-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (2g) , 8.3mmol) was dissolved in tetrahydrofuran freshly distilled with tetramethylethylenediamine (2g, 17.2mmol) and cooled to -75 ° C under nitrogen. N-Butyllithium in hexane (2.5M, 8ml, 20mmol) was added and the mixture was stirred at -75 ° C for 40 minutes. Dimethyl disulfide (lg, 10.0 mmol) was added and the mixture was allowed to warm to room temperature. Water (5 mL) was added and the mixture was concentrated under reduced pressure, the resulting oil was extracted into dichloromethane, washed with dilute hydrochloric acid, dried (MgSOc), filtered and concentrated to dryness under reduced pressure. The resulting oil was extracted into acetic acid, sodium perborate (7g, 45mmol) was added and the mixture was stirred at 50 ° C overnight. The mixture was poured into water and extracted with ethyl acetate. The combined organic phases were washed with 2N sodium hydroxide solution, dried (MgSO 4), filtered and concentrated under reduced pressure. Column chromatography on silica gel (eluent of ethyl acetate / hexane) gave 3,3-dimethyl-5-methanesulfonii-1,3-dihydro-2H-indole-2-opa as a pale yellow solid.

The MS shows 240 (MH +) at the base of the peak and 257 (M + NH4) 3, 3-dimethyl-1- (2-hydroxyethyl) -5-methanesulfonyl-1,3-dihydro-2H-indol-2-one: Prepared from 3, 3-dimethyl-5-methanesulfonyl-1, 3-dihydro-2H-indol-2-one and 2- (2-chloro-ethoxy) tetrahydro-2H-pyran.

XH NMR (CDC13) d 1.4K6H s), 2.5 (1H broad), 3.05 (3H s), 3.95 (4H s), 7.18 (lH d), 7.76 (lH s), 7.84 (lH d). 3, 3-dimethyl-l- monohydrochloride. { 2- [4- (4-fluorobenzoyl) -1-piperidinyl] -l-ethyl} -5-methanesulfonyl-l, 3-dihydro-2H-indol-2-one: Prepared from 3,3-dimethyl-1- (2-hydroxyethyl) -5-methanesulfonyl-1,3-dihydro-2H- indole-2-one, via methanesulfonate and 4-fluorobenzoyl piperidine tosylate.

Melting point of 223-226 ° C.

EXAMPLE 12 3, 3-Dimethyl-5-fluoro-1- (2-hydroxyethyl) -1,3-dihydro-2H-indol-2-one: 5-fluoro-1,3-dihydro-2H-indole-2 -one (2.4g, 15.9mmol) (prepared according to the method of Clarck et al., Synthesis (1991) 871) was dissolved in tetrahydrofuran freshly distilled with tetramethylethylenediamine (3.7g, 31.9mmol) and cooled to -75 ° C. , under nitrogen. N-Butyllithium (2.4 equivalents) was added and the mixture was stirred at -75 ° C for 40 minutes. Iodomethane (9g, 63mmol) was added and the mixture was allowed to warm to room temperature. After two hours of stirring at this temperature, water (5 ml) was added and the mixture was concentrated under reduced pressure, the resulting oil was extracted into dichloromethane, washed with dilute hydrochloric acid, dried (MgSO 4), filtered and it was concentrated to dryness under reduced pressure to give a yellow oil. This oil was dissolved in N-methylpyrrolidone and stirred at room temperature under nitrogen. Sodium hydride (0.625g, 15.6mmol) was added and the mixture was stirred until gas emission ceased. 2- (2-Chloroethoxy) tetrahydro-2H-pyran (2.5g, 15mmol) and sodium iodide (O.lg, O.ßßmmol) were added and the mixture was heated at 75 ° C for 15 hours. Water was added and the mixture was concentrated under reduced pressure. The residue was extracted into ethyl acetate, washed (x 3) with water, dried (MgSO 4), filtered and concentrated under reduced pressure. The resulting oil was extracted in methanol, para-toluenesulfonic acid (O.lg, 0.5mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was concentrated under reduced pressure, extracted into ethyl acetate, washed (x3) with aqueous sodium hydrogen carbonate solution, dried (MgSO4), filtered and concentrated under reduced pressure. The resulting oil was purified by chromatography on silica gel, (eluent of hexane / ethyl acetate) to give 3,3-dimethyl-5-fluoro-1- (2-hydroxyethyl) -1,3-dihydro-2H- Indole-2-one as a yellow oil.

The MS shows 224 (MH +) at the base of the peak and 241 (M + NH4) 3, 3-Dimethyl-5-fluoro-l- monohydrochloride. { 2- [4- (4-Fluoro-benzoyl) -1-piperidinyl] -l-ethyl} -l, 3-dihydro-2H-indol-2-one: Prepared from 3,3-dimethyl-5-fluoro-1- (2-hydroxyethyl) -1,3-dihydro-2H-indole-2- ona via the methanesulfonate and the tosylate of 4-flourobenzoyl piperidine as described above. Melting point of 221-223 ° C.

EXAMPLE 13 5,6-Difluoro-3, 3-dimethyl-1,3-dihydro-2H-indol-2-one: 3,4-difluoroacetonitrile (5g, 32.7mmol) was added dropwise to the fuming nitric acid 90% (25 ml) was stirred and cooled in an ice / water bath. After 15 hours of stirring, the mixture was poured into water, neutralized with sodium bicarbonate and extracted into dichloromethane. The organic phase was dried (MgSO 4), filtered and concentrated under reduced pressure.

The resulting oil was dissolved in a complex of acetic acid in boron trifluoride (30 ml), water (1 ml) was added and the mixture was heated under reflux for three hours. The mixture was poured into water, the pH was adjusted to 4 and the mixture was extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The resulting oily solid was dissolved in acetic acid, powdered iron was added and the mixture was heated under reflux for 1 hour. The mixture was filtered through Celite and concentrated under reduced pressure to a dark oil. Column chromatography on silica gel (chloroform / ethanol as eluent) gave 5,6-difluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one as an orange solid.

X H NMR (CDC13) d 3.48 (2 H s), 6.7 (1 H dd), 7.05 (1 H dd), 8.65 (1 H broad). ,6-Difluoro-3, 3-dimethyl-1- (2-hydroxyethyl) -1,3-dihydro-2H-indol-2-one: Prepared from 5, β-difluoro-3, 3-dimethyl- 1,3-dihydro-2H-indol-2-one.

X H NMR (CDCl 3) d 1.38 (6H s), 3.20 (1 H broad), 3.84 (4H m) 6.7 (1H dd), 7.03 (1H dd). ,6-Difluoro-3, 3-dimethyl-l- monohydrochloride. { 2- [4- (4-fluorobenzoyl) -1-piperidinyl] -l-ethyl} -l, 3-dihydro-2H-indol-2-one: Prepared from 5,6-difluoro-3, 3-dimethyl-1- (2-hydroxyethyl) -1,3-dihydro-2H-indole 2-one, via the methanesulfonate and the 4-fluorobenzoyl piperidine tosylate as described above.

Melting point of 223-225 ° C EXAMPLE 14 3, 3-dimethyl-1- (2-hydroxyethyl) -4-methoxy-1,3-dihydro-2H-indol-2-one: Prepared from 3, 3-dimethyl-4-methoxy-1, - dihydro-2H-indol-2-one (prepared according to the method of Clarck et al., Synthesis (1991) 871).

X H NMR (CDCl 3) d 1.42 (6 H s), 2.8 (1 H broad), 3.75 (4 H m) 3.8 (3 H s), 6.57 (2 H t), 7.06 (1 H dd). 3, 3-dimethyl-l- monohydrochloride. { 2- [4- (4-fluorobenzoyl) -1-piperidinyl] -l-ethyl} -4-methoxy-l, 3-dihydro-2H-indol-2-one: Prepared from 3,3-dimethyl-1- (2-hydroxyethyl) -4-methoxy-1,3-dihydro-2H- indole-2-one, via methanesulfonate and 4-fluorobenzoyl piperidine tosylate.

Melting point of 224-227 ° C.

EXAMPLE 15 1- (2-Hydroxyethyl) -3,3,5-trimethyl-1,3-dihydro-2H-indol-2-one Prepared from 3, 3, 3-trimethyl-1,3-dihydro- 2H-indol-2-one (prepared by the method of Endler &Becker, Organic Syntheses Coil, vol 4, page 657).

The MS shows at the base of peak 220 (MH +) and 237 (M + NH4) Monohydrochloride of l-. { 2- [4- (4-fluorobenzoyl) -1-piperidinyl] -l-ethyl} -3,3, 5-trimethyl-l, 3-dihydro-2H-indo1-2-one Prepared from 1- (2-hydroxyethyl) -3,3,5-trimethyl-1,3-dihydro-2H-indol-2-one via the methanesulfonate and 4-fluorobenzoyl piperidine tosylate.

Melting point of 228-230 ° C.

EXAMPLE 16 -Chloro-3, 3-dimethyl-1- (2-hydroxyethyl) -1,3-dihydro-2H-indol-2-one: Prepared from 5-chloro-3, 3-dimethyl-1, 3 -dihydro-2H-indol-2-one (prepared according to the method of Endler &Becker, Organic Syntheses Coil, vol 4, page 657).

XH NMR (CDC13) d 1.39 (6H s), 3.05 (1H broad), 3.95 (4H s) 6.8 (1H d), 7.3 (2H m).

-Chloro-3, 3-dimethyl-l- monochlorohydrate. { 2- [4- (4-fluorobenzoyl) -l-piperidinyl] -l-ethyl} -l, 3-dihydro-2H-indol-2-one: Prepared from 5-chloro-3, 3-dimethyl-1- (2-hydroxyethyl) -1,3-dihydro-2H-indole-2- ona, via the methanesulfonate and the tosylate of 4-fluorobenzoyl piperidine.

Melting point of 175-17 ° C.

EXAMPLE 17 1- (2-Hydroxyethyl) -3,3,7-trimethyl-1,3-dihydro-2H-indol-2-one Prepared from 3, 3, 7-trimethyl-1,3-dihydro-2H-indol-2-one (prepared by the method of Endler &Becker, Organic Syntheses Coil, vol 4, page 657).

The MS shows 220 (MH +) at the base of the peak and 237 (M + NH4).

Monohydrochloride of l-. { 2- [4- (4-fluorobenzoyl) -1-piperidinyl] -l-ethyl} -3,3, 7-trimethyl-l, 3-dihydro-2H-indol-2-one Prepared from 1- (2-hydroxyethyl) -3,3,7-trimethyl-1,3-dihydro-2H-indol-2-one via the methanesulfonate and 4-fluorobenzoyl piperidine tosylate.

Melting point of 150-152 ° C.

EXAMPLE 18 3, 3-dimethyl-1- (2-hydroxyethyl) -5-methoxy-1,3-dihydro-2H-indol-2-one: Prepared from 3, 3-dimethyl-5-methoxy-1 , 3-dihydro-2H-indol-2-one (prepared by the method of Endler &Becker, Organic Syntheses Coil, vol 4, page 657). 1 H NMR (CDCl 3) d 1.39 (6H s), 3.05 (1H broad), 3.82 (3H s) 3.95 (4H s), 6.8 (1H d), 7.3 (2H m). 3, 3-dimethyl-l- monohydrochloride. { 2- [4- (4-fluorobenzoyl) -1-piperidinyl] -1-ethyl} -5-methoxy-l, 3-dihydro-2H-indo1-2-one: Prepared from 3,3-dimethyl-1- (2-hydroxyethyl) -5-methoxy-1,3-dihydro-2H- indole-2-one, via methanesulfonate and 4-fluorobenzoyl piperidine tosylate. Melting point of 117.5-118 ° C.

EXAMPLE 19 3, 3, 4-trimethyl-1,3-dihydro-2H-indol-2-one and 3,3,6-trimethyl-1,3-dihydro-2H-indol-2-one: Prepared from N-isobutyl-3-methylphenylhydrazide by the method of Endler & Becker; Organic Syntheses Coil. vol. 4 pag. 657 and separated by preparative HPLC. Melting point of 3, 3, 4-trimethyl-1,3-dihydro-2H-indol-2-one 133 ° C. Melting point of 3, 3, 6-trimethyl-1,3-dihydro-2H-indol-2-one 178 ° C 1- (2-Hydroxyethyl) -3,3,4-trimethyl-1,3-dihydro -2H-indol-2-one Prepared from 3, 3, 4-trimethyl-1,3-dihydro-2H-indo-2-one (prepared by the method of Endler &Becker, Organic Syntheses Coil, vol 4, page 657) as described earlier.

The MS shows 220 (MH +) at the base of the peak and 237 (M + NH) Monohydrochloride of l-. { 2- [4- (4-fluorobenzoyl) -1-piperidinyl] -l-ethyl} -3, 3, 4-trimethyl-indole-2 (3H) -one Prepared from 1- (2-hydroxyethyl) -3,3,4-trimethyl-1,3-dihydro-2H-indol-2-one via the methanesulfonate and 4-fluorobenzoyl piperidine tosylate as described above .

Melting point of 211-214 ° C.

EXAMPLE 20 1- (2-Hydroxyethyl) -3,3,6-trimethyl-1,3-dihydro-2H-indol-2-one Prepared from 3, 3, 6-trimethyl-1,3-dihydro-2H-indol-2-one (prepared by the method of Endler &Becker; Syntheses Coil. vol. 4 pag. 657) as described above.

The MS shows 220 (MH +) at the base of the peak and 237 (M + NH4).

Monohydrochloride of l-. { 2- [4- (4-fluorobenzoyl) -1-piperidinyl] -l-ethyl} -3,3,3-trimethyl-1,3-dihydro-2H-indol-2-one: Prepared from 1- (2-hydroxyethyl) -3,3,6-trimethyl-1,3-dihydro- 2H-indol-2-one, via the methanesulfonate and 4-fluorobenzoyl piperidine tosylate as described above.

Melting point of 198. r; -200.5 ° C.

EXAMPLE 21 1- (2-Chloroethyl) -1,3-dihydro-2H-indol-2-one: L- (2-chloro-ethyl) -lH-indole-2,3-dione (5.24g) [C.A. Reg. No. 77218-99-6] was suspended in acetic acid (50 ml) and hydrogenated at 60 p.s.i. at room temperature, in the presence of 70% perchloric acid (0.2 ml) and 5% palladium in carbon (lg) for 24 hours. The clear solution was filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, and chloroform as eluent, to give 1- (2-Chloroethyl) -1,3-dihydro-2H-indol-2-one as a white solid.

Melting point 74 ° C L- Hydrochloride. { 2- [4- (4-fluorobenzoyl) -1-piperidinyl] -1-ethyl} -l, 3-dihydro-2H-indol-2-one: 1- (2-Chloroethyl) -1,3-dihydro-2H-indol-2-one (1.95g) and 4-fluorobenzoyl piperidine for toluenesulfonate (4.1 g) to a solution of sodium carbonate (3.18 g) and water (20 ml). The mixture was stirred mechanically at reflux for 9 hours. The hot solution was cooled (water-ice bath) and the hard solid broke, filtered, washed with water and dried. The solid was purified by chromatography on silica gel and chloroform-1% methanol eluant to give an oil. The pure free base was dissolved in a little chloroform, ethanolic HCl was added, the solution was evaporated to dryness and titrated with ether to give the l- monohydrochloride. { 2- [4- (4-fluorobenzoyl) -1-piperidinyl] -l-ethyl} -l, 3-dihydro-2H-indol-2-one as a white solid.

Melting point 206-213 ° C.

EXAMPLE 22 1- (2-Chloroethyl) -5-fluoro-lH-indol-2,3-dione: The 5-fluoro-lH-indole-2,3-dione (8.92 g) was dissolved in dimethylformamide (60 ml). Sodium hydride (60% dispersion in mineral oil, 3.08g) was added in portions with stirring and cooling (ice-water bath) and the mixture was stirred until gas emission ceased. L-bromo-2-chloroethane was added dropwise (5.4 mi, 9.3 g). The mixture was stirred at room temperature for 24 hours then cooled in water and extracted into chloroform. The combined organic phases were washed with water, dried (MgSO 4), filtered and concentrated under reduced pressure. The resulting oil was purified by chromatography on silica gel, and chloroform as eluent, to give 1- (2-chloroethyl) -5-fluoro-lH-indole-2,3-dione as a red solid. Melting point 103 ° C. 1- (2-Chloroethyl) -1,3-dihydro-5-fluoro-2-oxo-2H-indol-3-spiro-2'-1, 3-dithiane: A solution of l- ( 2-Chloroethyl) -5-fluoro-lH-indol-2,3-dione (2.27g), propandithiol (l.lml) in chloroform to a stirred solution of boron trifluoride etherate (1.2 ml) in acetic acid (2.2 ml) ) and chloroform (10 ml) which was maintained at a gentle reflux during the addition. After a reaction time of 1.5 hours, the mixture was cooled, washed with water and sodium hydrogen carbonate solution, dried (MgSO 4) and filtered through a flash silica pad using chloroform as eluent. The combined fractions were evaporated under reduced pressure and titrated with ether to give l- (2-Chloroethyl) -1,3-dihydro-5-fluoro-2-oxo-2H-indol-3-spiro-2'-1, 3-ditiano. Melting point 122 ° C.

EXAMPLE 23 1- (2-Chloroethyl) -5-fluoro-1,3-dihydro-2H-indol-2-one: 1- (2-Chloroethyl) -1,3-dihydro-5-fluoro-2-oxo -2H-Indole-3-spiro-2'-1, 3-dithiane (2.08 g) was dissolved in a mixture of ethanol (30 ml) and tetrahydrofuran (20 ml). Raney nickel was added and the mixture was heated under reflux with vigorous stirring for 3 hours. The cold solution was filtered, evaporated under reduced pressure and titrated with ether to give 1- (2-chloroethyl) -5-fluoro-1,3-dihydro-2H-indol-2-one as a white solid.

Melting point 127 ° C 1- Hydrochloride. { 2- [4- (4-fluorobenzoyl) -1-piperidinyl] -1-ethyl} -5-fluoro-l, 3-dihydro-2H-indol-2-one: 1- (2-Chloroethyl) -5-fluoro-1,3-dihydro-2H-indol-2-one (0.15g, 0.737mmol), 4-fluorobenzoyl piperidine for toluenesulfonate (0.307g, 0.811mmol) and the Sodium carbonate (0.258g, 2.19 mmol) in water (5 ml) were heated under reflux with magnetic stirring for 16 hours, cold ethyl acetate (10 ml) was added and the mixture was stirred for 2 hours, ethyl acetate separated, the aqueous layer was extracted with more ethyl acetate (2 x 20), combined, dried (MgSO 4), filtered and the solvent was evaporated in vacuo to give a white solid which was purified by gel chromatography. silica eluting with ethyl acetate to give a solid (148 mg). 100 mg of this solid was converted to the hydrochloride with trimethylsilyl chloride (0.033 ml) in methanol (8 ml) to give the l- hydrochloride. { 2- [4- (4-fluorobenzoyl) -1-piperidinyl] -l-ethyl} -5-fluoro-1, 3-dihydro-2H-indol-2-one: Melting point 221-223 ° C, EXAMPLE 24 1- (2-Chloroethyl) -3,3-difluoro-1,3-dihydro-2H-indol-2-one: 1- (2-Chloroethyl) -lH-indole-2,3-dione (l.lg, 5.2 mmol) [C.A. Reg. No. 77218-99-6] was heated at 65 ° C under nitrogen in diethylaminosulfide trifluoride (3 mL). The reaction mixture was poured into water and extracted with chloroform. The organic phase was washed with a sodium hydrogen carbonate solution, dried (MgSO 4) and filtered to give l- (2-chloroethyl) -3,3-difluoro-1,3-dihydro-2H-indole. -2-one as a dark oil. The MS shows 231 and 233 (MH +). 1- (2- [4- (4-Fluorobenzoyl) -1-piperidinyl] -l-ethyl} -3,3-difluoro-1,3-dihydro-2H-indol-2-one monohydrochloride: 1- (2-Chloroethyl) -3,3-difluoro-1,3-dihydro-2H-indol-2-one (0.85g, 3.67mmol), the salt of 4-fluorobenzoyl piperidine for toluenesulfonate (1.4g, 3.68 mmol), potassium carbonate (1.2g, 8.7mmol) and potassium iodide (0, lg, 0.6mmol) were dissolved in N-methyl pyrrolidone and heated with stirring at 85 ° C for 6 hours. The reaction mixture was poured into water and extracted into ethyl acetate, dried (MgSOc), filtered and concentrated under reduced pressure. The resulting oil was purified by chromatography on silica gel, and hexane / ethyl acetate as eluent, to give a yellow oil. The oil was dissolved in ethanol, ethanolic HCl was added and the mixture was concentrated under reduced pressure to give a white solid. This was extracted into hot ethyl acetate and cooled, whereupon a white solid was precipitated, this was collected by filtration to give the l- monohydrochloride. { 2- [4- (4-fluorobenzoyl) -1-piperidinyl] -l-ethyl} -3,3-difluoro-l, 3-dihydro-2H-indol-2-one: Melting point 202-205 ° C.

EXAMPLE 25 1- (2-Chloroethyl) -3,3,5-trifluoro-1,3-dihydro-2H-indol-2-one: Prepared from 1- (2-chloroethyl) -5-fluoro-lH-indole-2,3-dione and diethylaminosulfide trifluoride. The MS shows 249 and 251 (MH +).

Monohydrochloride of l-. { 2- [4- (4-fluorobenzoyl) -1-piperidinyl] -1-ethyl} -3,3,5-trifluoro-l, 3-dihydro-2H-indol-2-one: Prepared from 1- (2-chloroethyl) -3,3,5-trifluoro-1,3-dihydro- 2H-indol-2-one and 4-fluorobenzoyl piperidine.

Melting point 209-212 ° C EXAMPLE 26 1-Acetyl-1, 3-dihydro-2H-indol-2-one: 1,3-Dihydro-2H-indol-2-one (35. ßg 0.268 mmol) was suspended in acetic anhydride (30 ml) and the The mixture was kept under reflux for 20 hours. It was filtered and washed with diethyl ether (50 ml) and dried under vacuum at 80 ° C to give a solid. 3-Spirocyclopropyl-l, 3-dihydro-2H-indo1-2-one: The 1-acetyl-l, 3-dihydro-2H-indol-2-one (15.0g, 85.7mmol) was dissolved in dimethylformamide (180ml) and added to the suspension of sodium hydride (60% in oil dispersion). , 7.2g, 4.32g, 0.18mol) in dimethylformamide (30 ml). After 30 minutes, 1,2-dibromoethane (17.71g, 94.27mmol) was added and the mixture was stirred at room temperature for 20 hours. More sodium hydride (1.4g, 0.84g, 14mmol) was added followed by 1,2-dibromoethane (4g, 21.96mmol) and stirred for 1 hour at room temperature. The solvent was removed in vacuo and the residue was added, treated with water (100 ml), extracted with ethyl acetate (2 × 150 ml), separated and dried (MgSO 4), filtered and concentrated in vacuo to give an oil which was purified by column chromatography on silica elute with ethyl acetate / hexane to give an oil.

H NMR (CDC13) d 1.54 (2H m), 1.78 (2H m), 6.82 (1H d), 7.02 (2H m), 7.22 (lH m), 9.0 (1H broad).

EXAMPLE 27 1- (2-Hydroxyethyl) -3-spirocyclopropyl-1, 3-dihydro-2H-indol-2-one: Prepared from 3-spirocyclopoyl-1,3,3-dihydro-2H-indol-2-one and 2- (2-chloroethoxy) tetrahydro-2H-pyran. 1 H NMR (CDC13) dl.54 (2H m), 1.78 (2H m), 3.85 (4H m) 6.82 (lH d), 7.02 (2H m), 7.22 (1H m). 1- monochlorohydrate. { 2- [4- (4-Fluoro-benzoyl) -1-piperidi-nyl] -l-ethyl} -l, 3-dihydro-3-spiro-l-cyclopropyl-2H-indol-2-one: Prepared from 1- (2-hydroxyethyl) -3-spirocyclopropyl-1,3-dihydro-2H-indole 2-one via methanesulfonate and 4-fluorobenzoylpiperidine tosylate.

Melting point 238-240 ° C EXAMPLE 28 1- (2-Hydroxyethyl) -3-methyl-3-phenyl-1,3-dihydro-2H-indol-2-one: Prepared from 3-methyl-3-phenyl-1,3-dihydro-2H -indol-2-one: (prepared by the method of Endler &Becker, Organic Syntheses Coil, vol 4 page 657) and 2- (2-chloroethoxy) tetrahydro-2H-pyran. 1 H NMR (CDCl 3) d 1.78 (3 H s), 6.82 (1 H d), 7.02 (2 H m), 7.22 (1 H m), 7.3 (5 H m), 9.25 (1 H broad). 1- (2- [4- (4-Fluorobenzoyl) -1-piperidinyl] -l-ethyl} - 3-methyl-3-phenyl-1,3-dihydro-2H-indo-1-2-one monohydrochloride: Prepared from 1- (2-hydroxyethyl) -3-methyl-3-phenyl-1,3-dihydro-2H-indol-2-one, via methanesulfonate and 4-fluorobenzoyl piperidine tosylate.

Melting point 215-216 ° C.

EXAMPLE 29 Monohydrochloride of l-. { 2- [4- (4-fluorobenzoyl) -1-piperidinyl] -l-ethyl} -lH-indol-2, 3-dione: Prepared from 1- (2-chloroethyl) -lH-indole-2, 3-dione and 4-fluorobenzoyl piperidine for toluenesulfonate and potassium carbonate and sodium iodide in N-methylpyrrolidinone. Melting point 230-231 ° C.

EXAMPLE 30 Tablets, each containing 10 mg of the active ingredient, were prepared as follows: Active Ingredient 10 mg Starch 160 mg Microcrystalline Cellulose 10C i mg Polyvinyl pyrrolidone (as 10% solution in water 13 mg Sodium Carboxymethyl Starch 14 mg Magnesium stearate 3 mg Total 300 g The active ingredient, starch and cellulose were completely mixed. The polyvinylpyrrolidone solution was mixed with the resulting powders and passed through a screen. The granules thus produced were dried and passed through a sieve again. The sodium carboxymethyl starch and the magnesium stearate were then added to the granules, which, after mixing, were compressed into a tablet machine to produce tablets each weighing 300 mg.

EXAMPLE 31 Capsules, each containing 20 mg of drug, were prepared as follows: Active Ingredient 20 mg Dry starch 178 mg Magnesium stearate 2 mg Total 200 g The active ingredient, starch and magnesium stearate were passed through a sieve and filled into hard gelatin capsules in amounts of 200 mg. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims

1 . A compound of the formula: characterized because R 1 and R 2 are each hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, HO-C 4 alkyl, C 4 alkoxy-C 4 alkyl, alkylthio of 1 to 4 carbon atoms , halo, Ph, PhCR'R "- wherein Ph is optionally substituted phenyl and R 'and R" are each hydrogen or alkyl of 1 to 4 carbon atoms, or R 1 and R 2 together with the carbon atom, which are bonded form a cycloalkyl group of 3 to 6 carbon atoms, > C = 0, > C = NOR 'wherein R' is hydrogen or alkyl of 1 to 4 carbon atoms. R, R and R are each hydrogen, halo, nitro, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, C1-4 -alkyl-CO-, C? -4-alkyl-S (0) m- where m is 0, 1 or 2, R'R "NS? 2-, -COOR ', -CONR'R ", -NR'R", - (OR ') COOR ", -COR', NHS02R ', where R' and R "are each hydrogen or alkyl of 1 to 4 carbon atoms, 6 1 R and R are each hydrogen or alkyl of 1 to 4 carbon atoms and n is 1 to 6, X is oxygen or sulfur, W is where p is 4 to 7, and q and r are each 1 to 3, And it's > CO or -CH (OH) -, Z is optionally substituted phenyl or optionally substituted heteroaryl; and salts and esters of them.

2. A compound according to claim 1, characterized in that X is oxygen and W is:

3. A compound according to any of claims 1 and 2, characterized in that Z is optionally substituted phenyl.

4. A compound of the formula characterized in that R 1 and R 2 are each hydrogen or alkyl of 1 to 4 carbon atoms, R 3 and R 4 are each hydrogen, alkyl of 1 to 4 carbon atoms or halo, n is 2 and R 8 is hydrogen or halo, and you come out of them.

5. A compound according to claim 1 or a pharmaceutically acceptable salt or an ester thereof for use as a drug.

6. A pharmaceutical formulation characterized in that it comprises a compound according to claim 1 or a pharmaceutically acceptable salt or ester thereof together with a pharmaceutically acceptable carrier or a diluent thereof. SUMMARY OF THE INVENTION A pharmaceutical compound of the formula in which R 1 and R 2 are each hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, HO-C 4 alkyl, C 4 alkoxy C 4 alkyl, alkylthio of 1 to 4 carbon atoms carbon, halo, Ph, PhCR'R "- wherein Ph is optionally substituted phenyl and R 'and R" are each hydrogen or alkyl of 1 to 4 carbon atoms, or R 1 and R 2 together with the carbon atom, to which they are attached form a cycloalkyl group of 3 to 6 carbon atoms, > C = 0, > C = NOR 'wherein R' is hydrogen or alkyl of 1 to 4 carbon atoms. R3, R4 and R5 are each hydrogen, halo, nitro, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, C1-4 -alkyl-CO-, Ci-4alkyl-S (0) m- where m is 0, 1 or 2, R'R "N-S02-, COOR ', -CONR'R", -NR'R ", -N (OR') COOR ", -COR ', NHS02R', wherein R 'and R" are each hydrogen or alkyl of 1 to 4 carbon atoms, 6 7 R and R are each hydrogen or alkyl of 1 to 4 carbon atoms yn is 1 to 6, X is oxygen or sulfur, W is where p is 4 to 7, and q and r are each 1 to 3, Y is > CO or -CH (OH) -, and Z is optionally substituted phenyl or optionally substituted heteroaryl; and salts and esters of them.