Carbamate derivatives of 4-amino-3-isoxazolidinones and 3-amino-1-hydroxypyrrolidin-2-ones, a process for their preparation and their use as medicaments

Abstract: The present invention relates to compounds having Formula I depicted below, where R₁ is and R₂ is and to a process for their preparation. The compounds are useful for alleviating various memory dysfunctions characterized by a cholinergic deficit such as Alzheimer's disease.

Description: The present invention relates to carbamate derivatives of 4-amino-3-isoxazolidinones and 3-amino-1-hydroxypyrrolidin-2-ones, a process for their preparation and their use as medicaments. WO-A-8808708 describes certain galanthamine analogs and their preparation and use for the treatment of Alzheimer's disease. EP-A-0253372 describes certain physostigmine analogs and their preparation and use as memory-enhancing and analgesic agents. The present invention provides compounds having Formula I depicted below, where R is R 4 is hydrogen, or phenyl (C 1 -C 6 )alkyl; R 5 is hydrogen or phenyl (C 1 -C 6 )alkyl; X is hydrogen, halogen, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy; R 1 is (C 1 -C 6 )alkyl or phenyl (C 1 -C 6 )alkyl; R 2 is hydrogen or (C 1 -C 6 )alkyl; R 3 is hydrogen, (C 1 -C 6 )alkyl, (up to C 6 )alkenyl, (up to C 6 )alkynyl, phenyl ((C 1 -C 6 )-akyl, formyl, (C 1 -C 6 )alkylcarbonyl, phenyl (C 1 -C 6 )alkylcarbonyl or (C 1 -C 6 )alkoxycarbonyl wherein phenyl in each occurence is optionally substituted with 1, 2 or 3 substituents each of which being independently (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy, halogen, trifluormethyl or nitro; or a pharmaceutically acceptable acid addition salt thereof; which compounds are useful for alleviating various memory dysfunctions characterized by a cholinergic deficit such as Alzheimer's disease. Compounds of Formula I of this invention subsume compounds having Formula IV and VI depicted below. Unless otherwise stated or indicated, the following definitions shall apply throughout the specification and the appended claims. The term (C 1 -C 6 )alkyl shall mean a straight or branched alkyl group having from 1 to 6 carbon atoms. Examples of said (C 1 -C 6 )alkyl include methyl, ethyl, n-propyl, isopropyl, iso-butyl, sec-butyl and straight- and branched-chain pentyl and hexyl. The term halogen shall mean fluoride, chlorine, bromine or iodine. Throughout the specification and the appended claims, a given chemical formula or name shall encompass all geometric, stereo, optical and tautomeric isomers where such isomers exist. The compounds of this invention are prepared by utilizing one or more of the synthetic steps described below. Throughout the description of the synthetic steps, the notations X, R and R 1 -R 5 shall have the respective meanings given above unless otherwise stated or indicated. STEP A A compound of Formula VIII (see for instance, Hamer et al., US-A-4 791 107 as to the synthesis thereof) is hydrolyzed in situ and coupled with a compound of Formula IX, where R is as defined earlier except that neither the substituent R 4 nor R 5 may be hydrogen, to afford a compound of Formula X. This reaction is typically conducted by first allowing compound VIII to react with a strong base such as potassium tertiary butoxide at a temperature of 0° to 25°C and thereafter adding carbonyldiimidazole and compound IX to the reaction mixture and stirring the resultant mixture at a temperature of -30° to +25°C. As to the preparation of the starting compounds of Formula IX where R is the reader is referred, for instance, to EP-A-0,318,091(1989). As to the preparation of the starting compounds of Formula IX, where R is the reader is referred to J. Med. Chem., 13 , 1013 (1970). STEP B A compound of Formula XV obtained from STEP A is allowed te react with 1,4-cyclohexadiene in the presence of palladium on carbon to afford a compound of Formula XVI (hydrogen transfer reaction, See Felix et al., J. Org. Chem., 43 , 4194 (1978)). This reaction is typically conducted in the presence of a suitable solvent such as absolute ethanol at a temperature of 0° to 25°. STEP C A compound of Formula XVII obtained from STEP A is subjected to a hydrogenation reaction conducted in a routine manner known to the art to afford a compound of Formula XVIII The compounds of Formula I of the present invention are useful for the treatment of various memory dysfunctions characterized by a cholinergic deficit such as Alzheimer's disease. The activity to alleviate such memory dysfunctions is manifested by the ability of these compounds to inhibit the enzyme acetylcholinesterase and thereby increase acetylcholine levels in the brain. Cholinesterase Inhibition Assay Cholinesterases are found throughout the body, both in the brain and in serum. However, only brain acetylcholinesterase (AchE) distribution is correlated with central cholinergic innvervation. This same innervation is suggested to be weakened in Alzheimer patients. We have determined in vitro inhibition of acetylcholinesterase activity in rat striatum. In Vitro Inhibition of Acetylcholinesterase Activity in Rat Striatum Acetylcholinesterase (AChE), which is sometimes called true or specific cholinesterase, is found in nerve cells, skeletal muscle, smooth muscle, various glands and red blood cells. AchE may be distinguished from other cholinesterases by substrate and inhibitor specificities and by regional distribution. Its distribution in brain roughly correlates with cholinergic innervation and subfractionation shows the highest level in nerve terminals. It is generally accepted that the physiological role of AchE is the rapid hydrolysis and inactivation of acetylcholine. Inhibitors of AchE show marked cholinomimetic effects in cholinergically-innervated effector organs and have been used therapeutically in the treatment of glaucoma, myasthenia gravis and paralytic ileus. However, recent studies have suggested that AchE inhibitors may also be beneficial in the treatment of Alzheimer's disease. The method described below was used in this invention for assaying cholinesterase activity. This is a modification of the method of Ellman et al., Biochem. Pharmacol. 7 , 88 (1961). Procedure: A. Reagents - 1. 0.05 M Phosphate buffer, ph 7.2 (a) 6.85 g NaH 2 PO 4 •H 2 O/100 ml distilled H 2 O (b) 13.40 g Na 2 HPO 4 •7H 2 O/100 ml distilled H 2 O (c) add (a) to (b) until pH reaches 7.2 (d) Dilute 1:10 2. Substrate in buffer (a) 198 mg acetylthiocholine chloride (10mM) (b) bring to 100 ml with 0.05 M phosphate buffer, pH 7.2 (reagent 1) 3. DTNB in buffer (a) 19.8 mg 5,5-dithiobisnitrobenzoic acid (DTNB) (0.5 mM) (b) bring to 100 ml with 0.05 M phosphate buffer, pH 7.2 (reagent 1) 4. A 2 mM stock solution of the test drug is made up in a suitable solvent and brought to volume with 0.5 mM DTNB (reagent 3). Drugs are serially diluted (1:10) such that the final concentration (in cuvette) is 10 -4 M and screened for activity. If active, IC 50 values are determined from the inhibitory activity of susequent concentrations. B. Tissue Preparation - Male Wistar rats are decapitated, brains rapidly removed, corpora striata dissected free, weighed and homogenized in 19 volumes (approximately 7 mg protein/ml) of 0.05 M phosphate buffer, pH 7.2 using a Potter-Elvehjem homogenizer. A 25 microliter aliquot of the homogenate is added to 1.0 milliter vehicle or various concentrations of the test drug and preincubated for 10 minutes at 37°C. C. Assay - Enzyme activity is measured with the Beckman DU-50 spectrophotometer. This method can be used for IC 50 determinations and for measuring kinetic constants. Instrument Settings Kinetics Soft-Pac Module #598273 (10) Program #6 Kindata: Source - Vis Wavelength - 412 nm Sipper - none Cuvettes - 2 ml cuvettes using auto 6-sampler Blank - 1 for each substrate concentration Interval time - 15 seconds (15 or 30 seconds for kinetics) Total time - 5 minutes (5 or 10 minutes for kinetics) Plot - yes Span - autoscale Slope - increasing Results - yes (gives slope) Factor - 1 Reagents are added to the blank and sample cuvettes as follows: Blank: 0.8 ml Phosphate Buffer/DTNB 0.8 ml Buffer/Substrate Control: 0.8 ml Phosphate Buffer/DTNB/Enzyme 0.8 ml Phosphate Buffer/Substrate Drug: 0.8 ml Phosphate Buffer/DTNB/Drug/Enzyme 0.8 ml Phosphate Buffer/Substrate Blank values are determined for each run to control for non-enzymatic hydrolysis of substrate and these values are automatically substracted by the kindata program available on kinetics soft-pac module. This program also calculates the rate of absorbance change for each cuvette. For IC 50 Determinations: Substrate concentration is 10mM diluted 1:2 in assay yielding final concentration of 5 mM. DTNB concentration is 0.5 mM yielding 0.25 mM final concentration. % Inhibition = slope control - slope drug slope control x 100 IC 50 values are calculated from log-probit analysis. Results of this assay for some of the compounds of this invention and physostigmine (reference compound) are presented in Table 1. Compound IC 50 (µM) (3aS-cis)-1,2,3,3a,8,8a-Hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-yl[2-oxo-1-(phenylmethoxy)-3R-pyrrolidinyl]carbamate 0.067 (3a5-cis)-1,2,3,3a,8,8a-Hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-yl[2-(phenylmethyl)-3-oxo-4R-isoxazolidinyl]carbamate hemihydrate 0.50 (3aS-cis)-1,2,3,3a,8,8a-Hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-yl[2-oxo-1-(hydroxy)-3R-pyrrolidinyl] carbamate, citrate salt 2.31 (Reference Compound) Physostigmine 0.034 This utility is further demonstrated by the ability of these compounds to restore cholinergically deficient memory in the Dark Avoidance Assay described below. Dark Avoidance Assay In this assay mice are tested for their ability to remember an unpleasant stimulus for a period of 24 hours. A mouse is placed in a chamber that contains a dark compartment; a strong incandescent light drives it to the dark compartment, where an electric shock is administered through metal plates on the floor. The animal is removed from the testing apparatus and tested again, 24 hours later, for the ability to remember the electric shock. If scopolamine, an anticholinergic agent that is known to cause memory impairment, is administered before an animal's initial exposure to the text chamber, the animal re-enters the dark compartment shortly after being placed in the test chamber 24 hours later. This effect of scopolamine is blocked by an active test compound, resulting in a greater interval before re-entry into the dark compartment. The results for an active compound are expressed as the percent of a group of animals in which the effect of scopolamine is blocked, as manifested by an increased interval between being placed in the text chamber and re-entering the dark compartment. Results of this assay for some of the compounds of this invention and those for tacrine (reference compound) are presented in Table 2. Compound Dose (mg/kg of body weight, s.c.) % of Animals with Scopolamine Induced Memory Deficit Reversal (3aS-cis)-1,2,3,3a,8,8a-Hexahydro1,3a,8-trimethylpyrrolo[2,3-b]indol-5-yl[2-(phenylmethyl)-3-oxo-4R-isoxazolidinyl]carbamate hemihydrate 0.3 27 (Reference Compound) Tacrine 0.63 13 Effective quantities of the compounds of the invention may be administered to a patient by any of the various methods, for example, orally as in capsule or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions. The free base final products, while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable acid addition salts for purposes of stability, convenience of crystallization, increased solubility. Acids useful for preparing the pharmaceutically acceptable acid addition salts of the invention include inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and perchloric acids, as well as organic acids such as tartaric, citric, acetic, succinic, maleic, fumaric, 2-naphthalenesulfonic and oxalic acids. The active compounds of the present invention may be orally administered, for example, with an inert diluent or with an edible carrier, or they may be enclosed in gelatin capsules, or they may be compressed into tablets. For the purpose of oral therapeutic administration, the active compounds of the invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixiers, suspensions, syrups, wafers, chewing gum. These preparations should contain at least 0.5 % of active compounds, but may be varied depending upon the particular form and may conveniently be between 4 % to 70 % of the weight of the unit. The amount of active compound in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that an oral dosage unit from contains between 1.0 - 300 milligrams of active compound. The tablets, pills, capsules, troches and the like may also contain the following ingredients: a binder such as micro-crystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, cornstarch; a lubricant such as magnesium stearate or Sterotex; a glidant such as colloidal silicon dioxide; and a sweeting agent such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings. Thus, tablets or pills may be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes, coloring and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used. For the purpose of parenteral therapeutic administration, the active compounds of the invention may be incorporated into a solution or suspension. These preparations should contain at least 0.1 % of active compound, but may be varied between 0.5 and 30 % of the weight thereof. The amount of active compound in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present inventions are prepared so that a parenteral dosage unit contains between 0.5 to 100 milligrams of active compound. The solutions or suspensions may also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in disposable syringes or multiple dose vials made of glass or plastic. Examples of the compounds of this invention include: (3aS-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-yl[2-(phenylmethoxy)-3oxo-4R-isoxazolidinyl]carbamate; (3aS-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-yl[2-oxo-1-phenylmethoxy)-3R-pyrrolidinyl]carbamate; (3aS-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-yl[2-oxo-1-(hydroxy)-3R-pyrrolidinyl]carbamate; (3aS-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-yl[2-(phenylmethyl)-3-oxo-4S-isoxazolidinyl]carbamate; (3aS-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-yl[2-oxo-1-(phenylmethoxy)-3S-pyrrolidinyl]carbamate; (3aS-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-yl[2-oxo-1-(hydroxy)-3S-pyrrolidinyl]carbamate; (3aS-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-yl[2-(phenylethyl)-3-oxo-4R-isoxazolidinyl]carbamate; (3aS-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-yl[2-oxo-1-(phenylmethoxy)-3R-pyrrolidinyl]carbamate; (3aS-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrro(o[2,3-b]indol-5-yl[2-(phenylethyl)-3-oxo-4S-isoxazolidinyl]carbamate; (3aS-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-yl[2-oxo-1-(phenylethoxy)-3S-pyrrolidinyl]carbamate; (3aS-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-yl[3-oxo-4R-isoxazolidinyl]carbamate; and (3aS-cis)-1,2,3,3a,8, 8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-yl[3-oxo-4S-isoxazolidinyl]carbamate; The following examples are presented in order to illustrate the present invention. Example 1 (3aS-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-yl[2-(phenylmethyl)-3-oxo-4R-isoxazolidinyl]-carbamate hemihydrate To a reaction system completely free of air and moisture was added physostigmine as the free base (0.55 g) and degassed, anhydrous tetrahydrofuran (THF, 5 ml). The mixture was cooled to 0°C, treated with potassium tert-butoxide (0.22g) and stirred at this temperature for 20 minutes. The temperature was lowered to -30°C, and the mixture was treated with glacial acetic acid (0.10 ml) and carbonyldiimidazole (0.26 g), and held at -30°C for four hours. A solution prepared from 4-amino-2-(phenylmethyl)-3-isoxazolidinone (0.38 g) in THF (2ml) and glacial acetic acid (0.56 ml) was then added, and the stirred mixture allowed to warm to room temperature overnight. The THF was removed on a rotary evaporator and the residue taken up in ethyl acetate (100 ml). the mixture was washed successively with brine (2 x 50 ml), saturated NaHCO 3 (2 x 50 ml) and brine (1 x 50 ml). The organic extracts were dried (Na 2 SO 4 ), filtered and concentrated to a dark amber oil which was purified by preparative HPLC (silica gel) with 5 % methanol in dichloromethane as the loading solvent and eluent. The appropriate fractions were combined and concentrated to a yellow foam (0.40 g) which was pure by TLC (silica gel). Analysis: Calculated for C 24 H 28 N 4 O 4 .½ H 2 O 64.64 %C 6.56 %H 12.58 %N Found 64.94 %C 6.47 %H 12.94 %N Example 2 (3aS-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-yl[2-oxo-1-(phenylmethoxy)-3R-pyrrolidinyl]carbamate A 50 ml three-neck round bottom flask was evacuated and flushed with N 2 to completely exclude air and moisture. Physostigmine (0.64g) was added followed by anhydrous THF (7 ml, freshly degassed). The solution was cooled to -5°C and treated with potassium tert-butoxide (0.287 g) via gooche tube addition. The mixture became bright yellow and was stirred at this temperature for 15 minutes under N 2 . The temperature was lowered to -30°C (dry ice/MeOH bath) and acetic acid (0.13 ml) was added, followed by dry carbonyldiimidazole (0.27 g). The solution became light red to brown in color and was held at this temperature for 3.5 hours. A solution of (3R)-3-amino-1-phenylmethoxypyrrolidin-2-one(0.48 g) in the THF (2 ml) was added via canula along with acetic acid (0.70 ml). The mixture was allowed to gradually warm to room temperature and stirred overnight. The mixture was then cooled with an ice bath and neutralized with saturated aqueous sodium bicarbonate solution. The THF was removed on a rotary evaporator and the residue dissolved in EtOAc. The mixture was extracted twice with brine, dried (Na 2 SO 4 ), filtered and concentrated to an amber oil. The material was purified via preparative HPLC (silica gel column) with 5 % methanol in DCM used as loading solvent and eluant. The appropriate fractions were combined and concentrated to afford 0.27 g of a foam, which was triturated with diethyl ether and hexane to afford a low melting solid, mp 55-65°C. Analysis: Calculated for C 25 H 30 N 4 O 4 66.65 %C 6.71 %H 12.44 %N Found 66.03 %C 6.71 %H 12.28 %N Example 3 (3aS-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-yl[2-oxo-1-(hydroxy)-3R-pyrrolidinyl]carbamate, citrate salt To a solution of (3aS-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-yl[2-oxo-1-(phenylmethoxy)-3R-pyrrolidinyl]carbamate (0.26 g) in absolute ethanol (6 ml) was added 10 % palladium on activated carbon (0.24 g) under a nitrogen atmosphere with stirring. 1,4-Cyclohexadiene(0.90 ml) was added at room temperature and the solution was stirred for 12 hours. Product formation was detected by TLC using a 2 % FeCl 3 (ethanol) stain. The mixture was filtered through Celite® and washed repeatedly with ethanol followed by dichloromethane. The filtrate was concentrated under reduced pressure and purified via flash column chromatography (silica gel) using 30 % methanol in DCM as eluent to afford a tan solid (0.15 g). The material was suspended in dry diethyl ether, and methanol was added dropwise until all material had gone into solution. One equivalent of a 0.1 M solution of citric acid in diethyl ether was added. The salt which precipitated was filtered, and dried under reduced pressure over toluene, m.p. 133°C - 153°C. the material was pure by TLC. Analysis: Calculated for C 24 H 32 N 4 O 11 52.17 %C 5.84 %H 10.14 %N Found 52.05 %C 5.98 %H 10.19 %N

Claims: Claims for the following Contracting States : AT, BE, CH, DE, DK, FR, GB, IE, IT, LI, LU, NL, PT, SE A compound having the formula I, where R is wherein R 4 is hydrogen or phenyl (C 1 -C 6 )alkyl; R 5 is hydrogen or phenyl (C 1 -C 6 )alkyl; X is hydrogen, halogen, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy; R 1 is (C 1 -C 6 )alkyl or phenyl (C 1 -C 6 )alkyl; R 2 is hydrogen or (C 1 -C 6 )alkyl; and R 3 is hydrogen or (C 1 -C 6 )alkyl, (up to C 6 )alkenyl, (up to C 6 )alkynyl, phenyl (C 1 -C 6 )-alkyl, formyl, (C 1 -C 6 )alkylcarbonyl, phenyl (C 1 -C 6 )alkylcarbonyl or (C 1 -C 6 )alkoxycarbonyl; wherein phenyl in each occurence is optionally substituted with 1, 2 or 3 substituents each of which being independently (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy, halogen, trifluormethyl or nitro; or a pharmaceutically acceptable acid addition salt thereof. A compound as defined in claim 1, wherein R 4 is phenyl (C 1 -C 6 )alkyl, R 1 , R 2 and R 3 are (C 1 -C 6 )alkyl and X is hydrogen, wherein phenyl is optionally substituted as defined in claim 1. A compound as defined in claim 2, wherein R 1 , R 2 and R 3 are methyl and X is hydrogen, R 4 is benzyl and R 5 is hydrogen or benzyl. The compound as defined in claim 1, which is (3aS-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-yl[2-oxo-1-(phenylmethoxy)-3R-pyrrolidinyl] or a pharmaceutically acceptable acid addition salt thereof. The compound as defined in claim 1, which is (3aS-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2, 3-b]indol-5-yl[2-(phenylmethyl)-3-oxo-4R-isoxazolidinyl] or a pharmaceutically acceptable acid addition salt thereof. The compound as defined in claim 1, which is (3aS-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-yl[2-oxo-1-(hydroxy)3R-pyrrolidinyl] or a pharmaceutically acceptable acid addition salt thereof. A pharmaceutical composition, which comprises as the active ingredient a compound of the formula I as defined in any one of the preceding claims and a suitable carrier therefor. Use of a compound of the formula I as defined in any one of the preceding claims for the preparation of a medicament having memory dysfunction alleviating activity. A process for the preparation of a compound of the formula I as defined in any one of the preceding claims, comprising hydrolyzing a compound of formula VIII wherein R 1 , R 2 , R 3 and X are as defined in claim 1, and reacting the resultant intermediate with a compound of the formula RNH 2 , where R is as defined in claim 1, in the presence of carbonyldiimidazole. A process as defined in claim 9, comprising reacting a compound of the formula I, wherein R is the group and R 5 is phenyl (C 1 -C 6 )alkyl, where phenyl is optionally substituted as defined in claim 1, with 1,4-cyclohexadiene in the presence of palladium on carbon, to form a compound of the formula I, wherein R is the above indicated group and R 5 is hydrogen. A process as defined in claim 9, comprising hydrogenating a compound of the formula I, wherein R is the group where R 5 is phenyl(C 1 -C 6 )alkyl, where phenyl is optionally substituted as defined in claim 1, to form a compound of the formula I, wherein R is the above indicated group and R 5 is hydrogen. Claims for the following Contracting States : ES, GR A process for the preparation of a compound of the formula I where R is wherein R 4 is hydrogen or phenyl (C 1 -C 6 )alkyl; R 5 is hydrogen or phenyl (C 1 -C 6 )alkyl; X is hydrogen, halogen, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy; R 1 is (C 1 -C 6 )alkyl or phenyl (C 1 -C 6 )alkyl; R 2 is hydrogen or (C 1 -C 6 )alkyl; and R 3 is hydrogen, (C 1 -C 6 )alkyl, (up to C 6 )alkenyl, (up to C 6 )alkynyl, phenyl (C 1 -C 6 )-alkyl, formyl, (C 1 -C 6 )alkylcarbonyl, phenyl (C 1 -C 6 )alkylcarbonyl or (C 1 -C 6 )alkoxycarbonyl; wherein phenyl in each occurence is optionally substituted with 1, 2 or 3 substituents each of which being independently (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy, halogen, trifluormethyl or nitro; or a pharmaceutically acceptable acid addition salt thereof, which comprises a) hydrolyzing a compound of the formula VIII wherein R 1 , R 2 , R 3 and X are as defined in claim 1, and reacting the resultant intermediate with a compound of the formula RNH 2 , where R is as defined above, in the presence of carbonyldiimidazole; b) optionally reacting a compound of the formula I, wherein R is the group where R 5 is phenyl(C 1 -C 6 )alkyl, where phenyl is optionally substituted as defined above, with 1,4-cyclohexadiene in the presence of palladium on carbon, to form a compound of the formula I, wherein R is the above indicated group and R 5 is hydrogen, c) optionally hydrogenating a compound of the formula I, wherein R is the group where R 5 is phenyl(C 1 -C 6 )alkyl, where phenyl is optionally substituted as defined above, to form a compound of the formula I, wherein R is the above indicated group and R 5 is hydrogen. A process as defined in claim 1, wherein R 4 is phenyl(C 1 -C 6 )alkyl, where phenyl is optionally substituted as defined in claim 1, R 1 , R 2 and R 3 are (C 1 -C 6 )alkyl and X is hydrogen. A process as defined in claim 2, wherein R 1 , R 2 and R 3 are methyl, R 4 is benzyl and R 5 is hydrogen or benzyl. The process as defined in claim 1, wherein (3aS-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-yl[2-oxo-1-(phenylmethoxy)-3R-pyrrolidinyl] or a pharmaceutically acceptable acid addition salt thereof is produced. The process as defined in claim 1, wherein (3aS-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-yl[2-(phenylmethyl)-3-oxo-4R-isoxazolidinyl]or a pharmaceutically acceptable acid addition salt thereof is produced. The process as defined in claim 1, wherein (3aS-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-yl[2-oxo-1-(hydroxy)-3R-pyrrolidinyl] or a pharmaceutically acceptable acid addition salt thereof is produced. Process for the manufacture of a medicament for alleviating memory dysfunction characterised in the use, as an essential constituent of said medicament, of a compound of the formula I as defined in claim 1.

Inventors: FLANAGAN DENISE MARY, MARTIN LAWRENCE LEO, FLANAGAN, DENISE MARY, MARTIN, LAWRENCE LEO
Applicants: AVENTIS PHARMA INC, AVENTIS PHARMACEUTICALS INC.
Application year: 1992
Main classification: C07D487
IPC codes: A61K31, C07D223, C07D261, C07D209, C07D307, C07D491, C07D207, C07D487, A61P25