MXPA98000718A - Derivatives of 2- (4-substitute) -bencilamino-2-methyl-propanam - Google Patents

Abstract

New compounds of 2- (4-substituted) -benzylamino-2-methyl-propanamides are described, having activity in the central nervous system, of general formula (I) wherein: n is zero, 1, 2 or 3; X is -O-, -S-, -CH2-or-NH-, each of R and R1 is independently hydrogen, C1-C6 alkyl, halogen, hydroxy, C1-C4 alkoxytriflumethyl, each of R2, R3 and R4 is independently hydrogen, or C3-C7 C1-C6cycloalkyl, and the pharmaceutically acceptable salts thereof;

Description

The present invention relates to novel 2- (4-substituted) -benzylamino-2-methyl-propanamides, to their use as therapeutic agents, to a process for their preparation and to pharmaceutical compositions containing them. WO 90/14334 presents active N-phenylalkyl-substituted a-amino carboxamide derivatives on the CNS. It has been discovered that the novel derivatives of 2- (4-substituted) -benzylamino-2-methyl-propanamides, as defined herein, have valuable biological properties, in particular as an antiepileptic agent, anti-Parkinson, neuroprotective, antidepressant, antispastic and / or hypnotic. The present invention provides new compounds of general formula (I) where: n is zero, 1, 2 or 3; REP: 26626 X is -O-, -S-, -CH2- or -NH-; each of R and R. is independently hydrogen, C? -C6 alkyl, halogen, hydroxy, C: -C4 alkoxy or trifluoromethyl; each of R2, R3 and R4 is independently hydrogen, or C?-C6 alkyl or d-C ^ cycloalkyl; and their pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts with inorganic acids, e.g. ex. hydrochloric, hydrobromic, sulfuric and phosphoric, or organic acids, p. ex. acetic, propionic, lactic, oxalic, malic, maleic, tartaric, citric, benzoic, mandelic, salicylic, C1-C4 alkylsulfonic and fumaric. The compounds of the formula (I), their pharmaceutically acceptable salts, can also form pharmaceutically acceptable solvates, such as mono- or tri-hydrates, which are also the object of the present invention. The alkyl and alkoxy groups can be branched or straight groups. A C6-C6 alkyl group is preferably a C1-C4 alkyl group, in particular methyl, ethyl, n- and isopropyl, n-, iso-, sec and tere-butyl, more preferably methyl or ethyl.

Representative examples of C -C alkoxy groups include methoxy or ethoxy. A halogen atom is p. ex. chlorine, fluoro, or bromine.

A C3-C7 cycloalkyl group is, for example, a cyclopropyl, cyclohexyl or cycloheptyl group, in particular cyclopropyl. The present invention includes within its scope all possible isomers of the compounds of formula (I) and mixtures thereof, as well as the pharmaceutically acceptable metabolites and bioprecursors (also called pro-drugs) of the compounds of formula (I) Preferred compounds of the invention are the compounds of formula (I), wherein n is 1 or 2; X is -0-, -S- or -NH-; R is hydrogen; Ri is hydrogen or halogen; each of R 2, R 3 and R 4 is independently hydrogen or C 1 -C 4 alkyl; and their pharmaceutically acceptable salts. The most preferred compounds of the invention are the compounds of formula (I), wherein n is 1; X is -0-, -S- or -NH-; R is hydrogen or halogen; R, R2 / R3 and R are hydrogen; and their pharmaceutically acceptable salts. As examples of specific compounds of the invention we have: 2- [4- (3-fluorobenzyloxy) benzylamino] -2-methyl-propanamide; 2- [4- (3-chlorobenzyloxy) benzylamino] -2-methyl-propanamide; 2- [4- (4-chlorobenzyloxy) benzylamino] -2-methyl-propanamide; 2- [4- (3-bromobenzyloxy) benzylamino] -2-methyl-propanamide; 2- [4- (4-fluorobenzyloxy) benzylamino] -2-methyl-propanamide; 2- (4- (2-fluorobenzyloxy) benzylamino] -2-methyl-propanamide; 2- [4- (3-fluorobenzylamino) benzylamino] -2-methyl-propanamide; 2- [4- (benzylsulfanyl) benzylamino] -2-methyl-propanamide; 2- [4- (3-Fluorobenzyloxy) benzylmethylamino] -2-methyl-propanamide; 2- . { [4- (3-fluorobenzyloxy) benzyl] -amino} -2-methyl-N-methyl-propanamide; 2- . { [.- (3-Chlorobenzyloxy) benzyl] methylamino} -2-methyl-propanamide; and 2-. { [4- (3-bromobenzyloxy) benzyl] methylamino} -2-methylpropanamide, as the case may be, as an individual isomer (S) or (R) or a mixture thereof, and pharmaceutically acceptable salts thereof.

The compounds of the invention and their salts can be obtained by a process comprising: a) reaction of a compound of formula (II) where n, R, Ri and X are as previously defined, with a compound of formula (III) where R and R4 are as previously defined, thereby obtaining a compound of formula (I) wherein R2 is hydrogen; or b) reacting a compound of formula (IV) where R, Ri, R3 R4 n and X are as previously defined, with a compound of formula (V) or (VI) R'2W (V) R "; CHO (VI) where W is a halogen atom, R '; is a C] -Ch alkyl, and R "2 is hydrogen or C1-C5 alkyl, thereby obtaining a compound of the invention wherein R2 is C-C alkyl, and, if desired, converting a compound of the invention in another compound of the invention and / or, if desired, converting a compound of the invention to a pharmaceutically acceptable salt and / or, if desired, converting a salt to a free compound All of the procedures described above are analogues and can be carried out according to methods well known in organic chemistry.

A compound of formula (IV) is a compound of formula (I) wherein R 2 is hydrogen. The reaction of a compound of formula (II) with a compound of formula (III) to give a compound of formula (I) or (IV) is a reductive amination reaction which can be carried out according to well-known methods. According to a preferred embodiment of the invention, it can be carried out under a nitrogen atmosphere, in a suitable organic solvent, such as alcohol, e.g. ex. a lower alkanol, in particular methanol, or in acetonitrile, at a temperature comprised between 0 C and 40 ° C, in the presence of a reducing agent, sodium cyanoborohydride being the most appropriate. Occasionally, molecular sieves may be added to the reaction mixture to facilitate the reaction. In a compound of formula (V), the halogen W is preferably iodine. The alkylation reaction of a compound of formula (IV) with a compound of formula (V) can be carried out in a suitable organic solvent, such as an alcohol, e.g. ex. methanol, ethanol or acetonitrile, in the presence of a suitable reducing agent, such as sodium cyanoborohydride at a temperature of 0 ° C to 50 ° C.

The alkylation reaction of a compound of formula (IV) with an aldehyde of formula (VI) can be carried out in a suitable organic solvent, such as alcohol, e.g. ex. methanol, ethanol or acetonitrile in the presence of a suitable reducing agent, such as sodium cyanoborohydride, at a temperature between OC and 30 C. A compound of the invention can be converted, as indicated above, into another compound of the invention, by known methods. Process variant b) above can be considered an example of the optional conversion of a compound of the invention into another compound of the invention. The optional salification of a compound of the invention as well as the conversion of a salt into the free compound can also be carried out by conventional methods. The compounds of formula (II), (III), (V) and (VI) are known compounds or can be obtained in known manner.

When groups in the compounds of the present invention and in their intermediates find groups that require protection before being subjected to the reactions illustrated above, they can be protected before the reaction and then deprotected according to methods well known in organic chemistry.

PHARMACOLOGY The compounds of the invention are active in the central nervous system (CNS) and can be used in therapy, for example as antiepileptics, in the treatment of Parkinson's disease and as neuroprotective agents, e.g. ex. for the prevention or treatment of neuronal losses associated with apoplexy, hypoxia, ischemia, CNS trauma, hypoglycemia or surgery and in the treatment or prevention of neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, Down syndrome, Huntington's disease , dementia caused by the acquired immunodeficiency syndrome (AIDS), dementia due to infarction and infections or inflammations of the brain; they can also be used as antidepressant, hypnotic and antispastic agents and in the treatment of eye damage and retinopathies. The activity on the CNS of the compounds of the invention was evaluated on the basis of pharmacological methods, such as, for example, the antagonism of convulsions and mortality induced by the intravenous injection of bicuculline in mice (Antiepileptic Drugs, DM Woodbury et al., Eds., 2nd ed., Raven Press, New York, 1982), or the antagonism of maximal attacks by electroshock (MES) (Woodbury, LA and Davenport, V.D., Arch. mt. Phar acodyn. Ther. 92; 97-104, 1952). The following table summarizes the activity data obtained by MES test on a representative group of compounds of the invention compared to the respective 2-demethyl related compounds known from WO 90/14334. The symbol * identifies the 2-demet compounds known from WO 90/14334. ED50 means effective dose in 50% of the treated animals after per os administration (po). Table 1 Composite Structure MES-ED > , (code (po) mg / kg Internal) where the internal code: 10 15 20 25 1 or FCE 29088A means 2- (4- (3-fluorobenzyloxy) benzylamino) -2-methyl-propanamide, methanesulfonate; FCE 26743A * means (S) -2- (4- (3-fluorobenzyloxy) benzylamino) propanamide, methanesulfonate; FCE 29482A means 2- (4-benzylsulfanyl) benzylamino) -2-methyl-propanamide, methanesulfonate; FCE 26727A * means (S) -2- (4-benzylsulfanyl) benzylamino) propanamide, methanesulfonate; FCE 29484A means 2- (4- (2-fluorobenzyloxy) benzylamino) -2-methyl-propanamide, methanesulfonate; FCE 26742A * means (S) -2- (4- (2-fluorobenz? Lox) benzylamino) propanamide, methanesulfonate; FCE 29644A means 2- (4- (3-chlorobenzyloxy) benzylamino) -2-methyl-propanamide, methanesulfonate; FCE 26193A * means (S) -2- (4- (3-chlorobenzyloxy) benzylamino) propanamide, methanesulfonate; FCE 29645A means 2- (4- (4-fluorobenzyloxy) benzylamino) -2-methy1-propanamide, methanesulfonate; FCE 26998A * means (S) -2- (4- (4-fluorobenzyloxy) benzylamino) propanamide, methanesulfonate; FCE 29647A means 2- (4- (3-fluorobenzyloxy) benzylamino) -2-methy1-N-methylpropanamide, methanesulfonate; FCE 28657A * means (S) -2- (4- (3-fluorobenzyloxy) benzylamino) -N-methylpropanamide, methanesulfonate. n The data of the comparative activity test indicated in the preceding table show that the new compounds of the present invention are between 2 and 4 times more active than the closely related compounds of the prior art. In accordance with the present invention, a patient is treated by a method comprising administering to the patient an effective amount of one of the compounds of the invention. In this way the present compounds can be used to treat disorders of the central nervous system, for example epilepsy or Parkinson's disease; or as neuroprotective, anti-depressant, hypnotic or antispastic agents. The condition of a patient can therefore be improved. The compounds of the invention can be administered in a variety of dosage forms, e.g. ex. oral, in the form of tablets, capsules, tablets coated with sugar or film, liquid solutions or suspensions; rectally, as suppositories; parenteral, p. ex. in intramuscular form, or by injection or intravenous infusion. The dosage depends on the age, weight, conditions of the patient and route of administration; for example, the dose adopted for oral administration to adult humans, p. ex. in the case of the representative compound of 1 * The invention 2- [4- (3-fluorobenzyloxy) benzylamino] -2-methyl-propanamide can be comprised between 1 and 500 mg per dose between 1 and 5 times per day. The invention includes pharmaceutical compositions comprising a compound of the invention, as an active ingredient, in association with a pharmaceutically acceptable excipient (which can be a carrier or a diluent). The pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in pharmaceutically suitable form. For example, solid oral forms may contain, in addition to the active compound, diluents, e.g. and? . lactose, detritus, sucrose, cellulose, corn starch or potato starch; lubricants, p. ex. silica, talc, stearic acid, magnesium stearate or calcium, and / or polyethylene glycols; binding agents, p. ex. starches, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disaggregating agents, p. ex. a starch, alginic acid, alginates or sodium starch glycolate; effervescent mixtures; colorants; sweeteners; wetting agents such as lecithin, polysorbates, lauryl sulfates; and, in general, non-toxic and pharmacologically inactive substances roasted in pharmaceutical formulations. Said preparations 1t Pharmaceutical preparations can be manufactured in known manner, for example by mixing, granulating, tabletting, coating with sugar or films. The liquid dispersion for oral administration may be p. ex. syrups, emulsions and suspensions. The syrups can contain as carrier, e.g. ex. , sucrose or sucrose with glycerin and / or mannitol and / or sorbitol.

The suspension and the emulsion may contain as a carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. The suspension or solutions for intramuscular injections may contain, in addition to the active compound, a pharmaceutically acceptable carrier, e.g. e. sterile water, olive oil, ethyl oleate, glycols, p. ex. propylene glycol, and, if desired, an appropriate amount of lidocaine hydrochloride. The solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or they may preferably be in the form of sterile, aqueous, isotonic saline solutions. The suppositories may contain, in addition to the active compound, a pharmaceutically acceptable carrier, e.g. ex. cocoa butter, polyethylene glycol, a polyoxyethylene fatty acid ester or lecithin surfactant. The following examples illustrate but do not limit the invention.

Example 1 2- [4- (3-Fluorobenzyloxy) benzylamino] -2-methyl-propanamide, methanesulfonate (FCE 29088A) To a solution of 2-amino-2-methylpropanamide hydrochloride, (7.01 g, 0.051 mol ) in anhydrous methanol (160 ml), under stirring and nitrogen, 7.0 g of 3A molecular sieves were added and then, in a single portion, NaBH, CN (2.31 q, 0.037 mol), at 10 minutes, 10.6 g (0.046 mol) of 4- (3-fluorobenzyloxy) benzaldehyde was added in 140 ml of anhydrous methanol. After 24 hours the reaction was completed, the mixture was filtered, the solution was evaporated to give a residue which was directly subjected to flash chromatography on silica gel (eluent: CHC1, 98: CH3OH 2: 30% NH4OH 0.15) obtaining a white solid (6.2 9, 43%). The free base thus obtained was treated with a stoichiometric amount of methanesulfonic acid to yield the title compound (mp 209-213 ° C).

Analogously, the following products can be obtained, starting from the corresponding aldehyde and the appropriate amide: 2- [4- (3-chlorobenzyloxy) benzylamino] -2-methyl-propanamide, methanesulfonate, m.p. 202-206 ° C (FCE 29644A); 2- [4- (3-bromobenzyloxy) benzylamino] -2-methyl-propanamide, methanesulfonate, m.p. 197-202, JC (FCE 29494A); 2- [4- (4-fluorobenzyloxy) benzylamino] -2-methyl-propanamide, methanesulfonate, p.p. 233C (FCE 29645A); 2- [4- (2-fluorobenzyloxy) benzylamino] -2-methyl-propanamide, methanesulfonate, m.p. 215-220 ° C (FCE 29484A); 2- [4- (3-Fluorobenzylamino) benzylamino] -2-methyl-propanamide, dihydrochloride, m.p. 165 ° ca. (dec.) (FCE 29822A); 2- [(4-benzylsulfanyl) benzylamino] -2-methyl-propanamide, methanesulfonate, m.p. 214-215 ° C (FCE 29482A); 2- [4- (3 ~ Fluorobenzyloxy) benzylamino] -2-methyl-N-methyl-propanamide, methanesulfonate, m.p. 213-218 ° C (FCE 29647A) and 2- [4- (4-chlorobenzyloxy) benzylamino] -2-methyl-propanamide, m.p. 226-227 ° C (FCE 29485A).

Example 2 2-. { [4- (3-fluorobenzyloxy) -cyc] methylamino} -2-methy1-propanamide (FCE 29486).

Dissolve 1 g (0.00316 mol) of 2- [(4- (3-fluorobenzyloxy) benzylamino] -2-methyl-propanamide in acetonitrile (50 ml) under a stream of nitrogen, add 3 to this mixture, 16 ml (0.0389 mol) of 37% formaldehyde and 0.29 g (0.00460 mol) of sodium cyanoborohydride at room temperature After 20 minutes, glacial acetic acid is added to neutralize the solution. The mixture is stirred for 40 minutes and evaporated to dryness, 40 ml of 2N KOH are added to the residue, After extracting with ethyl acetate, washing with N / 2 KOH and then with water and brine, the organic layer is dried in Na2SO, it is then filtered and evaporated to obtain a residue which is subjected to flash chromatography on silica gel (eluent: CHC13200: CH3OH 3: 30% NH4OH 0.2) obtaining 0.75 (72%) of a white solid (mp 121 -123 ° C.) Similarly, the following products can be prepared starting from the corresponding secondary amine: 2- { [4- (3-chlorobenzyloxy) encyl] tilamino.} -2-methy1-propanamide; and 2-. { [4- (3-bromobenzyloxy) benzyl] methylamino} -2-methy1-propanamide. 1Q Example 3 With the usual methods of the pharmaceutical technique, capsules with the following composition can be prepared: 2- [4- (3-Fluorobenzyloxy) benzylamino] -2-methyl-propanamide, methanesulfonate 50 mg Talc 2 mg Corn starch 2 mg Microcrystalline cellulose 6 mg Magnesium stearate 1 mg

Claims (10)

1. A compound of general formula (I) where: n is zero, 1, 2 or 3; X is -O-, -S-, -CH2- or -NH-; each of R and Ri is independently hydrogen, alkyl? -C5 'halogen, hydroxy, C1-C alkoxy or trifluoromethyl; each of R 2, R 3 and R is independently hydrogen, C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl; or a pharmaceutically acceptable salt thereof.

2. A compound of formula (I), according to claim 1, characterized in that: n is 1 or 2; X is -0-, -S- or -NH-; R is hydrogen; Ri is hydrogen or halogen; each of R 2, Ri and R 4 is independently hydrogen or C 1 -C 4 alkyl; or a pharmaceutically acceptable salt thereof.

3. A compound of formula (I), according to claim 1, characterized in that: n is 1, X is -0-, -S- or -NH-; Ri is hydrogen or halogen; R, R2, R3 and R4 are hydrogen; or a pharmaceutically acceptable salt thereof.

4. A compound selected from the group consisting of: 2- [4- (3-fluorobenzyloxy) benzylamino] -2-methyl-propanamide; 2- [4- (3-chlorobenzyloxy) benzylamino] -2-methyl-propanamide; 2- [4- (4-chlorobenzyloxy) benzylamino] -2-methyl-propanamide; 2- [4- (3-bromobenzyloxy) benzylamino] -2-methyl-propanamide; 2- [4- (4-fluorobenzyloxy) benzylamino] -2-methyl-propanamide; 2- [4- (2-fluorobenzyloxy) benzylamino] -2-methyl-propanamide; 2- [4- (3-Fluorobenzylamino) benzylamino] -2-methyl-propanamide; 2- [4- (benzylsulfanyl) benzylamino] -2-methyl-propanamide; 2- [4- (3-Fluorobenzyloxy) benzylmethylamino] -2-methyl-propanamide; 2-. { [4- (3-fluorobenzyloxy) benzyl] -amino} -2-methy1-N-methyl-propanamide; 2-. { [4- (3-chlorobenzyloxy) benzyl] methylamino) -2-methyl-propanamide; and 2-. { [4- (3-bromobenzyloxy) benzyl] methylamino} -2-methylpropanamide, as the case may be, as an individual isomer (S) or (R) or a mixture thereof, or a pharmaceutically acceptable salt thereof.

5. A process for the preparation of a compound of formula (I), according to the definition of claim 1, or a pharmaceutically acceptable salt thereof, said process is characterized in that it comprises: a) reaction of a compound of formula (II) ?3 where n, R, Ri and X are as previously defined, with a compound of formula (III) wherein R3 and R4 are as defined in claim 1, thereby obtaining a compound of formula (I) wherein R_ is hydrogen; or b) reacting a compound of formula (IV) (IV) where R, Ri, R3, R4, n and X are as defined in claim 1, with a compound of formula (V) or (VI) R'2W (V) R ": CH0 (VI) where W is a halogen atom, R'j is a C -C alkyl, and R "2 is hydrogen or Ci-C alkyl, thus obtaining a compound of the invention wherein R2 is C.C.C. alkyl.; and, if desired, converting a compound of the invention to another compound of the invention and / or, if desired, converting a compound of the invention to a pharmaceutically acceptable salt and / or, if desired, converting a salt into a free compound

6. A pharmaceutical composition characterized in that it contains a suitable carrier and / or diluent and, as active ingredient, a compound of formula (I), according to the definition of claim 1, or a pharmaceutically acceptable salt thereof.

7. A compound of formula (I), according to the definition of claim 1, or a pharmaceutically acceptable salt thereof, for use as an active therapeutic substance.

8. A compound of formula (I), according to the definition of claim 1, or a pharmaceutically acceptable salt thereof, for use as an antiepileptic agent, in the treatment of Parkinson's disease, a neuroprotective agent, and for the treatment and prevention of neurodegenerative diseases.

9. A compound of formula (I), according to the definition of claim 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of ocular damage and retinopathies.

10. A compound of formula (I), according to the definition of claim 1, or a pharmaceutically acceptable salt thereof, for use as an atidepressant, hypnotic or antispastic agent.