HK1098465B - Use of tricyclic compounds as glycine transport inhibitors - Google Patents

Description

Use of tricyclic compounds as glycine transport inhibitors

The present invention relates to N-heterocyclyl methylbenzamide derivatives, to processes for their preparation and to their use in therapy.

The compounds of the invention correspond to the general formula (I)

Wherein

R represents a hydrogen atom or a vinyl group;

n represents 0 or 1 or 2 when R represents a hydrogen atom, and n represents 1 when R represents a vinyl group;

x represents a group of formula CH or a nitrogen atom when R represents a hydrogen atom, and X represents a group of formula CH when R represents a vinyl group;

R₁represents a linear or branched chain (C) optionally substituted by one or more groups selected from halogen atoms₁-C₆) Alkyl, hydroxy and (C)₁-C₆) Phenyl or naphthyl groups substituted with substituents of alkoxy groups, trifluoromethyl groups, or cyclohexyl groups, or heteroaryl groups selected from thienyl, pyridyl, oxazolyl, furyl, thiazolyl, quinolinyl, and isoquinolinyl groups;

R₂represents a hydrogen atom, or one or more groups selected from a halogen atom and a trifluoromethyl group, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, thienyl, phenoxy, hydroxy, mercapto, thio (C)₁-C₆) Alkyl, cyano or of the formula-NR₄R₅、SO₂NR₄R₅、-SO₂-(C₁-C₆) Alkyl, -SO₂-phenyl, -CONR₄R₅、-COOR₇、-CO-(C₁-C₆) Alkyl, -CO-phenyl, -NHCOR₈、-NHSO₂-(C₁-C₆) Alkyl, -NHSO₂-phenyl and-NHSO₂NR₄R₅Or to the 2-and 3-positions of the phenyl radical₂A substituent of an O-group;

(C₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, -SO₂-(C₁-C₆) Alkyl, -CO- (C)₁-C₆) Alkyl and-NHSO₂-(C₁-C₆) The alkyl group is optionally substituted with one or more R₃Substituted by groups;

phenyl, -SO₂-phenyl, -CO-phenyl and-NHSO₂-phenyl group optionally represented by R₆Substituted by groups;

R₃represents a halogen atom, a phenyl group, or (C)₁-C₆) Alkoxy, -NR₄R₅；

R₄And R₅Independently of one another, represents a hydrogen atom or (C)₁-C₆) Alkyl radicals or R₄And R₅Together with the nitrogen atom to which it is attached form a pyrrolidine, piperidine or morpholine ring;

R₆represents a hydrogen atom, a halogen atom, a trifluoromethyl group, a cyano group, a hydroxyl group, a mercapto group, a (C)₁-C₆) Alkyl radical or (C)₁-C₆) An alkoxy group;

R₇represents a hydrogen atom or optionally one or more R₃Radical substituted (C)₁-C₆) Alkyl radical, or optionally from R₆A phenyl group substituted with a group;

R₈represents optionally one or more R₃Radical substituted (C)₁-C₆) Alkyl radical, or optionally from R₆Radical substituted (C)₁-C₆) An alkoxy group or a phenyl group.

Among the compounds of general formula (I), certain compounds can be distinguished among all the preferred compounds:

group 1: a compound of threo configuration and a compound of general formula (I) wherein n represents 0 or 1;

group 2: group 1 compounds in which X represents a group of formula CH;

group 3: group 2 compounds in which R represents a hydrogen atom in the formula;

group 4: group 3 compounds in which n represents 1 in the formula;

group 5: in the formula R₁A compound of group 4 representing an optionally substituted phenyl group.

The compounds of formula (I) may contain multiple asymmetric centers. They may thus exist in enantiomeric or diastereomeric forms. These enantiomers, diastereomers, and mixtures thereof, including racemic mixtures, are within the scope of the invention.

More particularly, for those compounds of formula (I) in which R ═ H, may be present in the threo ((1S, 2S) and (1R, 2R)) or erythro ((1S, 2R) and (1R, 2S)) diastereoisomeric forms, or in the pure enantiomeric forms or in the form of mixtures of these isomers.

The compounds of formula (I) may exist in the form of base or acid addition salts. Such addition salts are within the scope of the present invention.

These salts are preferably prepared with pharmaceutically acceptable acids, but other useful salts of acids, such as those used for purification and isolation of the compounds of formula (I), are also within the scope of the invention. The compounds of formula (I) may also exist in the form of hydrates or solvates, i.e. in association or combination with one or more molecules of water or solvent. Such hydrates or solvates are also within the scope of the present invention.

The compounds of the invention exhibit specific activity as inhibitors of glyt1 and/or glyt2 of the glycine transporter.

The compounds of formula (I) can be prepared according to the method shown in scheme 1 below.

Scheme 1

According to scheme 1, wherein n, X, R and R₁Diamines of the formula (II) as defined above with activated acids or acid chlorides of the formula (III) (wherein Y represents a nucleophobic group such as a halogen atom, R₂As defined above) are subjected to coupling reactions using methods known to those skilled in the art.

Diamines of the general formula (II) (where R ═ H, n, X and R₁As defined above) can be prepared according to the method shown in the following scheme 2.

Scheme 2

Reacting a ketone of formula (IV) (wherein n, X and R₁As defined above) with benzyloxyhydroxylamine hydrochloride in pyridine to give the oxime of the general formula (V). Both the Z and E forms of the oxime can be isolated according to methods known to those skilled in the art, for example, silica gel column chromatography.

The preferred oxime (V) hydrochloride form Z is then reduced by refluxing with lithium aluminum hydride in tetrahydrofuran to afford the largely threo-form of the diamine of formula (II).

The mixture of two diastereoisomers (threo/erythro) diamine (II) is obtained by reduction of the oxime form E of general formula (V).

The erythro and threo diastereomers may be separated according to methods known to those skilled in the art, for example, silica gel column chromatography.

Another preparation wherein R and R₁The diamine of formula (II) as defined above, n being equal to 1 and X being CH, is prepared as shown in scheme 3 below.

Scheme 3

According to Bull. Soc. Chim. Belg. (106), 1997, 77-84 and Tetrahedron: as described in Asymmetry, (6), 1995, 1699-Aswellia 1702, alcohols of the formula (VI) were converted to amines by the Mitsunobu reaction.

Alternatively, chiral compounds of formula (I) corresponding to the enantiomers (1R, 2R) or (1S, 2S) of the threo diastereomer and the enantiomer (1S, 2R) or (1R, 2S) of the erythro diastereomer can be obtained by separation of the racemic compound on a chiral column by High Performance Liquid Chromatography (HPLC), or from the resulting chiral amine, or by using chiral acids such as tartaric acid, camphorsulfonic acid, dibenzoyltartaric acid, N-acetylleucineResolution of the racemic amine of formula (II) by fractional and preferential recrystallization of diastereomeric salts in alcoholic solvents or by enantioselective synthesis from chiral alcohols of erythro or threo form using a method analogous to that described in scheme 3. Chiral alcohols can be obtained by methods similar to those described in Tetrahedron, (55), 1999, 2795-2810. In which R represents a vinyl group and R₁In the case of representing a quinolinyl group, the diamines of the general formula (II) can be prepared according to scheme 3 using the corresponding commercially available chiral alcohols.

Racemic ketones of formula (IV) can be prepared by deprotonation of an activated complex of a bridged cyclic amine and reaction with an electrophile such as an ester or a Weinreb amide in a manner analogous to that described in chem. Commun., 1999, 1927-1928, or by reaction of an organometallic compound with ethyl 2-quinate in a manner analogous to that described in J.Med. chem., 1980, 180-184, or by oxidation of the corresponding alcohol obtained in a manner analogous to that described in J.org chem., 50, 1985, 29-31 and chem. Comm., 1999, 1927-1929, with an oxidising agent known to those skilled in the art, such as manganese dioxide or oxalyl chloride-dimethyl sulfoxide systems.

The alcohols of the formula (VI) can also be obtained by reduction of the corresponding ketones of the formula (IV) under conditions known to those skilled in the art.

The acids and acid chlorides of formula (III) can be obtained commercially or prepared by analogous methods known to those skilled in the art.

For example, 4-amino-3-chloro-5-trifluoromethylbenzoic acid can be prepared by chlorinating 4-amino-5-trifluoromethylbenzoic acid with sulfuryl chloride in a chlorine-containing solvent such as chloroform, in a manner similar to that described in Arzneim.

2, 6-dichloro-3-trifluoromethylbenzoic acid can be prepared by a process analogous to that described in US 3,823,134.

Benzoic acids derived from sulfonamides can BE prepared analogously to the methods described in patents DE-2436263, BE-620741, DE-1158957, US-3112337, GB-915259, US-3203987, DE-642758, EP-68700, FR-2396757, DE-2734270, and J.pharm.Pharmacol. (1962), 14, 679-.

M-chlorosulphonic acid can be obtained according to a process similar to that described in J.chem.Soc. (C), (1968), 13, and in patents U.S. Pat. No. 2273444, DE-19929076, EP-0556674.

The chlorosulfonation in the ortho or para position can be effected by reacting the diazonium salt with 4-amino-3-chlorobenzoic acid in a manner similar to that described in patent US-3663615.

Sulfonamides are obtained by reacting chlorosulfonated derivatives in the presence of an excess of amine in a solvent such as tetrahydrofuran at room temperature or reflux.

The secondary sulfonamides can BE methylated in analogy to the procedure described in patent BE-620741.

The primary sulfonamide can be reacted with an isocyanate in a solvent such as tetrahydrofuran in the presence of a base such as potassium carbonate.

Certain sulfoxide derivatives of benzoic acid are described in patents DE-2056912, DE-2901170 and US-3953476 or can BE obtained by processes analogous to those described in patents BE-872585 and J.org.chem. (1991), 56(1), 4976-4977.

Benzoic acid derivatives of the general formula (III) (wherein R₂Representing branched alkyl groups) may be prepared in analogy to the methods described in patents US-4879426 and syn.lett. (1996), 473-.

The biphenyl type of benzoic acid derivatives can be prepared according to methods known to those skilled in the art.

Finally, the carbonylated benzoic acids can be synthesized in a manner analogous to that described in patents US-3725417 and GB-913100 and chem.pharm.Bull. (1988), 36(9), 3462-.

The ester or amide may be introduced by direct carbonylation with a strong base at the para position of the acid under the conditions described in Tetrahedron lett, (2000), 41, 3157-3160.

Finally, the cyano derivatives of benzoic acid are obtained by heating halogenated benzoic acids or benzoic esters in a solvent of the tetrahydrofuran type in the presence of potassium cyanide, a catalyst of the tetrakis (triphenylphosphine) palladium type, according to a method similar to that described in J.org.chem. (1967)62, 25, 8634-8639.

Other acids and acid chlorides of formula (III) can be obtained analogously to the methods described in patents EP-0556672, US-3801636 and J.chem.Soc., (1927), 25, chem.pharm.Bull., (1992), 1789-.

The following examples illustrate several methods for the preparation of the compounds of the present invention. Elemental analysis, as well as IR, NMR spectra and chiral column HPLC spectra confirm the structure and enantiomeric purity of the resulting compounds.

The numbers indicated in parentheses in the examples headings correspond to the numbers in column 1 of the later specific tables.

In compound names, the hyphen "-" is a part of a word, and the hyphen "_" is used only as a connection for a line of word-end breaks; if there is no line break, it is cancelled and should not be replaced by normal hyphen and space.

Example 1(Compound No. 3)

threo-2-chloro-N- [ (1-azabicyclo [2.2.2] oct-2-yl) phenylmethyl ] -3-trifluoromethylbenzamide hydrochloride 1: 1

(Z) -1-azabicyclo [2.2.2] oct-2-yl (phenyl) methanone O-benzyl oxime hydrochloride

In a 100ml flask equipped with magnetic stirring, 2.2g (9.35 mmol) of 1-azabicyclo [2.2.2] oct-2-yl (phenyl) methanone (chem. Commun., 1999, 1927-1928) and 3g (18.69 mmol) of benzyloxyhydroxylamine hydrochloride and 50ml of pyridine were added and the mixture was heated under reflux for 20 h.

After the solvent was evaporated under reduced pressure, the residue was diluted with water and chloroform, and the aqueous layer was separated and extracted with chloroform. After washing the combined organic phases, drying over sodium sulfate and evaporation of the solvent under reduced pressure, the residue is purified by column chromatography on silica gel, eluting with a mixture of chloroform and methanol.

0.5g of the component corresponding to (E) -1-azabicyclo [2.2.2] oct-2-yl (phenyl) methanone O-benzyl oxime and 2.25g of the other component corresponding to (Z) -1-azabicyclo [2.2.2] oct-2-yl (phenyl) methanone O-benzyl oxime hydrochloride are obtained, m.p. 195-197 ℃.

1.2. Threo- [ 1-azabicyclo [2.2.2] oct-2-yl (phenyl) methyl ] amine

In a 250ml three-necked flask equipped with magnetic stirring and under nitrogen atmosphere, a suspension of 1.3g (34.32 mmol) of lithium aluminum hydride in 10ml of tetrahydrofuran was placed therein, to which was added 2.2g (6.16 mmol) of (Z) -1-azabicyclo [2.2.2] oct-2-yl (phenyl) methanone O-benzyl oxime hydrochloride in portions and heated under reflux for 2 h.

After cooling, the solution was hydrolyzed by adding 1.3ml of water, 1.3ml of 15% aqueous soda solution and 3.9ml of water at 0 ℃. By usingThe heterogeneous mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was diluted with 1N hydrochloric acid and chloroform. The organic layer was separated and the aqueous layer was basified with ammonia. Extracted 2 times with chloroform. After washing the combined organic phases, drying over sodium sulfate and evaporation of the solvent under reduced pressure, 1.25g of threo- [ 1-azabicyclo [2.2.2] are obtained as an oily, crystallizable threo- [ 1-azabicyclo [2.2.2 ].]Oct-2-yl (phenyl) methyl]Amine, used directly in the next reaction. Melting point: 120 ℃ and 140 ℃.

1.3. threo-2-chloro-N- [ (1-azabicyclo [2.2.2] oct-2-yl) phenylmethyl ] -3-trifluoromethylbenzamide hydrochloride 1: 1

In a 100ml flask equipped with magnetic stirring, 0.51g (2.12 mmol) of 2-chloro-3-trifluoromethylbenzoyl chloride in 5ml of chloroform and 0.29g (2.12 mmol) of potassium carbonate were placed therein at 0 ℃ and 0.42g (1.93 mmol) of threo- [ 1-azabicyclo [2.2.2] oct-2-yl (phenyl) methyl ] amine in 5ml of chloroform was added and the mixture was stirred at room temperature for 6 h.

After hydrolysis with water and dilution with chloroform, the aqueous layer was separated and extracted with chloroform. After washing the combined organic phases, drying over sodium sulfate and evaporation of the solvent under reduced pressure, the residue is purified by column chromatography on silica gel, eluting with a mixture of chloroform and methanol. 0.18g of oily product is obtained.

This product was dissolved in a few ml of propan-2-ol, 6ml of a solution of propan-2-ol in 0.1N hydrochloric acid was added and the mixture was concentrated under reduced pressure to reduce the solvent volume. After trituration, 0.15g of the hydrochloride salt was finally isolated as a solid. Melting point: 257 ℃ C. about.262 ℃.

Example 2(Compound No. 4)

Threo-2, 6-dichloro-N- [ (1-azabicyclo [2.2.2] oct-2-yl) phenylmethyl ] -3-trifluoromethylbenzamide hydrochloride 1: 1

In a 100ml flask equipped with magnetic stirring, 0.36g (1.38 mmol) of 2, 6-dichloro-3-trifluoromethylbenzoic acid, 0.187g (1.38 mmol) of hydroxybenzotriazole, and a solution of 0.264g (1.38 mmol) of 1- [3- (dimethylamino) propyl ] -3-ethylcarbodiimide hydrochloride in 7ml of chloroform were added, and the mixture was stirred at room temperature for 30 minutes.

A solution of 0.3g (1.38 mmol) threo- [ 1-azabicyclo [2.2.2] oct-2-yl (phenyl) methyl ] amine in 5ml of chloroform was added and stirred at room temperature overnight.

After hydrolysis with water and dilution with chloroform, the aqueous layer was separated and extracted with chloroform. After washing the combined organic phases, drying over sodium sulfate and evaporation of the solvent under reduced pressure, the residue is purified by column chromatography on silica gel, eluting with a mixture of chloroform and methanol. 0.37g of oily product is obtained.

This product was dissolved in a few ml of propan-2-ol, 20ml of a solution of propan-2-ol in 0.1N hydrochloric acid was added and the mixture was concentrated under reduced pressure to reduce the solvent volume. After trituration, 0.35g of the hydrochloride salt was finally isolated as a solid. Melting point: 270 ℃ and 273 ℃.

Example 3(Compound N14)

2-chloro-N- (8 α, 9S-cinchona-9-yl) -3-trifluoromethylbenzamide hydrochloride 2: 13.1.8 α, 9S-cinchona-9-amine

In a 100ml three-necked flask equipped with magnetic stirring and under a nitrogen atmosphere, a suspension of 0.74g (2.5 mmol) of 8 α, 9R-cinchonan-9-ol (cinchonidine) and 0.79g (3 mmol) of triphenylphosphine in 15ml of tetrahydrofuran was placed therein, and 3.5ml of a 0.9M solution of hydrazoic acid in benzene (3 mmol) was added. To this solution, 0.55ml (2.75 mmol) of a solution of diisopropylcarbodiimide in 1.5ml of tetrahydrofuran was added dropwise and heated at 40 ℃ for 16 hours.

0.65g (2.5 mmol) triphenylphosphine was added and stirred for 30min, 0.5ml water was added and stirred for a further 6 h.

Hydrolysis with 1N hydrochloric acid and dilution with chloroform. The aqueous layer was basified with ammonia and extracted several times with chloroform. After washing the combined organic phases, drying over sodium sulfate and evaporation of the solvent under reduced pressure, 0.97g of 8 α, 9S-cinchonan-9-amine are obtained as an orange oil, the crude product being used in the next reaction.

3.2.2-chloro-N- (8 α, 9S-Octacan-9-yl) -3-trifluoromethylbenzamide hydrochloride 2: 1

Following the procedure described in example 1.3, 0.360g of oil was obtained from 0.97g (3.3 mmol) of 8 α, 9S-cinchonan-9-amine, 0.84g (3.4 mmol) of 2-chloro-3-trifluoromethylbenzoyl chloride and 0.5g (3.63 mmol) of potassium carbonate and dissolved in 30ml of 1N hydrochloric acid. The aqueous layer was extracted with chloroform, and then the solvent was evaporated under reduced pressure. 0.26g of the hydrochloride salt was obtained as a white solid.

Melting point: 185 ℃ and 205 ℃; [ alpha ] to]_D ²⁵＝-5.4(c＝0.986，MeOH)。

Example 4(Compound N.cndot.17)

2, 6-dichloro-N- [ (1S) - [ (2S) (1-azabicyclo [2.2.2] oct-2-yl) phenylmethyl ] -3- (trifluoromethyl) benzamide hydrochloride 1: 1

4.1(1S) - [ (2S) -1-azabicyclo [2.2.2] oct-2-yl (phenyl) methyl ] amine D-tartrate

9.4g (43.45 mmol) of threo- [ 1-azabicyclo [2.2.2] oct-2-yl (phenyl) methyl ] amine are dissolved in 150ml of ethanol. To this was added 6.52g (43.45 mmol) of D-tartaric acid in 200ml of ethanol. After evaporation of the solvent under reduced pressure, the residue was taken up in 500ml of an ethanol/water (9/1) solution and then heated to dissolve. After 3 consecutive recrystallizations, 5.39g of (1S) - [ (2S) -1-azabicyclo [2.2.2.] oct-2-yl (phenyl) methyl ] amine D-tartrate were obtained.

Melting point: 125 ℃ and 135 ℃.

[α]_D ²⁵＝-46.1(c＝0.616；MeOH)。

4.2.2, 6-dichloro-N- [ (1S) - [ (2S) (1-azabicyclo [2.2.2] oct-2-yl) phenylmethyl ] -3- (trifluoromethyl) benzamide hydrochloride 1: 1

In a 100ml flask equipped with magnetic stirring, a solution of 3.33g (12.02 mmol) of 2, 6-dichloro-3- (trifluoromethyl) benzoyl chloride in 30ml of chloroform and 1.82g (13.22 mmol) of potassium carbonate were added at 0 ℃, a solution of 2.6g (12.02 mmol) of (1S) - [ (2S) -1-azabicyclo [2.2.2.] oct-2-yl (phenyl) methyl ] amine (obtained by basification of the salt described in 4.1 followed by extraction) in 40ml of chloroform was added thereto, and the mixture was stirred at room temperature for 6 h.

After hydrolysis with water and dilution with chloroform, the aqueous layer was separated and extracted with chloroform. After washing the combined organic phases, drying over sodium sulfate and evaporation of the solvent under reduced pressure, the residue is purified by column chromatography on silica gel, eluting with a mixture of chloroform and methanol. 5.4g of oily product are obtained.

The product was dissolved in a few ml of chloroform, 600ml of a hydrochloric acid-saturated ether solution was added, and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate. This gave 4.7g of 2, 6-dichloro-N- [ (1S) - [ (2S) (1-azabicyclo [2.2.2] oct-2-yl) phenylmethyl ] -3- (trifluoromethyl) benzamide hydrochloride.

Melting point: 264 ℃ and 268 ℃.

[α]_D ²⁵＝+61.1°(c＝0.32；MeOH)。

Example 5(Compound N ° 26)

Threo form N- [ 1-azabicyclo [2.2.2] oct-2-yl (4-fluorophenyl) methyl ] -2, 6-dichloro-3- (trifluoromethyl) benzamide hydrochloride 1: 1

5.11-azabicyclo [2.2.2] oct-2-yl (4-fluorophenyl) methanol

In a 100ml three-neck-flask and under argon, 1.11g (10 mmol) of quinuclidine are placed in 40ml of anhydrous tetrahydrofuran at 0 ℃. 1.33ml (10.5 mmol) of boron trifluoride-diethyl ether complex are added dropwise and stirred at 0 ℃ for 30min (solution A). 2.47g (22 mmol) of anhydrous potassium tert-butoxide are placed in parallel in 60ml of anhydrous tetrahydrofuran in a 250ml three-neck-flask and under argon. It was cooled to-70 ℃ and 22ml of a 1 molar solution of sec-butyllithium in cyclohexane/hexane (22 mmol) mixture was added dropwise, maintaining the temperature below-60 ℃ (solution B). After the addition was complete, solution A was introduced into solution B, maintained at a temperature of about-70 ℃ and stirred for 2 h.

In a 50ml three-neck-flask and under argon, 2.36ml (22 mmol) of redistilled 4-fluorobenzaldehyde are placed at-70 ℃ in 20ml of tetrahydrofuran solution. Solution B was introduced and the temperature was maintained to about-70 ℃. The resulting solution was left at-70 ℃ for 30min and the temperature was raised to-20 ℃. Then hydrolyzed with 10% hydrochloric acid solution. After extraction with ether, the aqueous layer was taken again and basified with ammonia. Extraction was performed with chloroform, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography eluting with a mixture of chloroform and methanol. 0.53g of 1-azabicyclo [2.2.2] oct-2-yl (4-fluorophenyl) methanol are obtained as a yellow solid.

Melting point: 69-70 ℃.

5.21-azabicyclo [2.2.2] oct-2-yl (4-fluorophenyl) methanone

In a 250ml three-necked flask and under nitrogen, 1.3ml of dimethyl sulfoxide was placed in 40ml of tetrahydrofuran at-70 ℃, 0.9ml of oxalyl chloride (11 mmol) was added dropwise, and stirred at that temperature for 30 min. A solution of 1g (4.6 mmol) of 1-azabicyclo [2.2.2] oct-2-yl (4-fluorophenyl) methanol in 40ml of tetrahydrofuran is added dropwise. After 30min, 4ml (27.6 mmol) triethylamine were added at-70 ℃. The reaction mixture was then stirred at-70 ℃ for 30min, at 0 ℃ for 30min, then at room temperature for 1 h.

The mixture was poured into an aqueous ammonia solution, followed by extraction with chloroform several times. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a mixture of chloroform and methanol. 1g of 1-azabicyclo [2.2.2] oct-2-yl (4-fluorophenyl) methanone are obtained.

Melting point: 68-69 ℃.

5.3(Z) 1-azabicyclo [2.2.2] oct-yl (4-fluorophenyl) methanone O-benzyl oxime hydrochloride

Following the procedure described in example 1.1, starting from 1.17g (5 mmol) of ketone, the reaction mixture was worked up and the residue obtained was triturated with diethyl ether to give 1.4g of (Z) 1-azabicyclo [2.2.2] oct-yl (4-fluorophenyl) methanone O-benzyl oxime hydrochloride.

Melting point: 202 ℃ and 203 ℃.

5.4 threo-type 1-azabicyclo [2.2.2] oct-yl (4-fluorophenyl) methylamine

Starting from 1.47g (4.54 mmol) of (Z) 1-azabicyclo [2.2.2] oct-yl (4-fluorophenyl) methanone O-benzyl oxime hydrochloride according to the procedure described in 1.2, 1g of threo 1-azabicyclo [2.2.2] oct-yl (4-fluorophenyl) methylamine are obtained (diastereomeric excess, de ═ 90%).

5.5N- [ (S) - (2S) -1-azabicyclo [2.2.2] oct-2-yl (4-fluorophenyl) methyl ] -2, 6-dichloro-3- (trifluoromethyl) benzamide hydrochloride 1: 1

Starting from 0.39g (1.66 mmol) of threo 1-azabicyclo [2.2.2] oct-yl (4-fluorophenyl) methylamine, 0.5g (1.83 mmol) of 2, 6-dichloro-3-trifluoromethylbenzoyl chloride and 0.25g (1.83 mmol) of potassium carbonate, chromatography purification gives 0.79g of threo N- [ 1-azabicyclo [2.2.2] oct-2-yl (4-fluorophenyl) methyl ] -2, 6-dichloro-3- (trifluoromethyl) benzamide as an oil, which is then salified with a solution of hydrogen chloride in diethyl ether according to the procedure described in 1.3.

Melting point: 290 ℃ and 291 ℃.

Other compounds were obtained starting from other functionalized aldehydes following the procedures described in examples 1, 2 and 5.

The following table 1 illustrates the chemical structures of several compounds of the present invention.

In the column "R" -CH ═ CH₂Refers to a vinyl group, in "R₁In column, C₆H₅Means a phenyl group and 4-C₉H₆N denotes a quinolin-4-yl group. In the column "salt" the-refers to the compound in base form, "HCl" refers to the hydrochloride salt, "tfa" refers to the trifluoroacetate salt.

Compounds 14, 19 to 23, 24 are present as solvated hydrochloride or dihydrochloride salts of one or more water molecules (see table).

Compounds 15 and 16 in the table form a pair of enantiomers which can be separated by preparative HPLC and usedAD 20 μm column in isohexane/propan-2-ol 95/5 mixture as well as compounds 17 and 18.

The physical properties, melting points and optical rotations of the compounds are given in table 2. "(d)" means decomposition at the melting point.

TABLE 2

A series of pharmacological tests have been carried out on the compounds of the invention, the results showing their importance as therapeutically active substances.

Glycine conversion in SK-N-MC cells expressing the human native transporter glyt1 Research on transportationIs especially suitable for the treatment of diabetes

In SK-N-MC cells (human neuroepithelial cells) expressing the human native transporter glyt1, by measuring the bound radioactivity in the presence or absence of the test compound¹⁴C]And (4) capturing glycine. Monolayers were incubated for 48h in plates pre-treated with 0.02% fibronectin. On the day of the assay, the culture medium was discarded and the cells were washed with Krebs-HEPES buffer [4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid ] at pH 7.4. After a 10min preincubation at 37 ℃ in the presence of buffer (control) or different concentrations of test compound or 10mM glycine (assay for non-specific capture), 10. mu.M [ alpha ], [ beta ] -glycine was added¹⁴C]Glycine (specific activity 112 mCi/mmol). Incubation was continued at 37 ℃ for 10min and the reaction was stopped by washing 2 times with Krebs-HEPES buffer pH 7.4. After adding 100. mu.l of scintillation fluid and stirring for 1h, the cell-bound radioactivity was determined. Using Microbeta Tri-lux^TMThe counter counts. Effectiveness of Compounds concentration IC of 50% Glycine specific Capture reduced by Compounds₅₀And the concentration was determined from the difference in bound radioactivity between the control and the 10mM glycine containing group.

In this assay, the IC of the most active compounds of the invention₅₀Is 0.001-10 μ M.

Specific results for some compounds are as follows (IC)₅₀Unit μ M):

compound N ° 30.017

Compound N ° 40.004

Compound N ° 140.07

Compound N ° 170.001

Compound N ° 260.07

The compound is used in mouse cortex homogeneous body¹⁴C]In vitro study of Glycine Capture inhibitory Activity

On the day of the experiment, the drug was taken orally (by passage in a mortar at 0.5% Tween/Methocel) at increasing doses^TMGrinding test molecules in distilled water) or intraperitoneally (dissolving test molecules in physiological serum, or by dissolving the molecules in a mortar at 0.5% Tween/Methocel, depending on the solubility of the molecules^TMPrepared by grinding in distilled water) 20-25g OF1 IffaCr é do male mice were dosed with the compound to be studied. Vehicle was administered to the control group. The dose is expressed in mg/kg, and the route of administration and the duration of treatment are determined by the properties of the molecule to be investigated.

At a specific time after dosing, animals were euthanized and the cortex of each animal was either quickly peeled off on ice, weighed and stored at 4 ℃ or frozen at-80 ℃ (in both cases samples were stored for up to 1 day). Each sample was homogenized at 10ml/g tissue in Krebs-HEPES buffer pH 7.4. 20 μ l of each homogenate were incubated at room temperature in the presence of 10 mML-alanine and buffer for 10 min. Nonspecific capture was determined by adding 10mM glycine to the control group. The reaction was stopped by suction filtration and the radioactivity obtained was determined by solid scintillation in Microbeta Tri-lux^TMCounting on a counter.

[¹⁴C]Glycine capture inhibitors will reduce the amount of bound radioligand in each homogenate. Activity of the Compounds from their ED₅₀(inhibited by 50% relative to the control group¹⁴C]Glycine trapped dose).

In this test, the most effective compounds of the invention were administered by intraperitoneal or oral administration of ED₅₀Is 0.1-5 mg/kg.

Study of Glycine transport in mouse spinal cord homogenosomes

The transporter glyt2 p [ c ] in mouse spinal cord homogenates was studied by measuring the bound radioactivity in the presence or absence of the compound under investigation¹⁴C]And (4) capturing glycine.

Animals (OF 1 weighing 20-25g on the day OF the experimentIffa Cr do male mice) were euthanized, the spinal cord of each animal was quickly stripped, weighed, and kept on ice. The samples were homogenized in 25ml/g tissue in Krebs-HEPES buffer [4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid ] pH 7.4. Mu.l of homogenate were preincubated for 10min at 25 ℃ in the presence of pH 7.4Krebs-HEPES buffer and different concentrations of the compound to be investigated or 10mM glycine (to determine non-specific capture). Then adding the alpha-amylase at 25 ℃ within 10min¹⁴C]Glycine (specific activity 112 mCi/mmol) was added to a final concentration of 10 μ M. The reaction was stopped by suction filtration and the radioactivity was measured by solid scintillation in Microbeta Tri-lux^TMCounting on a counter.

Effectiveness of Compounds concentration IC of 50% Glycine specific Capture reduced by Compounds₅₀And the concentration was determined from the difference in bound radioactivity between the control and the 10mM glycine containing group.

In this assay, the IC of the most active compounds of the invention₅₀Is 0.02-10 μ M.

IC of Compound N.cndot.17₅₀It was 0.69. mu.M.

The results of the experiments carried out with the compounds of the general formula (I) according to the invention show that they are inhibitors of the glycine transporter glyt1 (mostly present in the brain) and of the glycine transporter glyt2 (mostly present in the spinal cord).

The compounds of the invention are therefore useful for the preparation of medicaments, in particular for the preparation of medicaments against the glycine transporter glyt1 and/or glyt2 inhibitors.

Thus according to another aspect, the object of the present invention is a medicament comprising a compound of formula (I), or an addition salt thereof with a pharmaceutically acceptable acid, or a hydrate or solvate of the compound of formula (I).

The compounds of the invention are particularly useful in the treatment of behavioral disorders associated with dementia, psychosis, particularly schizophrenia (both deficient and productive) and acute or chronic extrapyramidal symptoms caused by neuroleptics, in the treatment of various forms of anxiety, panic attacks, phobias, obsessive compulsive disorders, in the treatment of various forms of depression, including psychotic depression, in the treatment of disorders arising from alcohol abuse or withdrawal, sexual behavior disorders, eating disorders, and in the treatment of migraine.

In addition, the compounds of the invention are useful for the treatment of painful muscle contractures caused by rheumatism and acute spinal disorders, for the treatment of spastic contractures of the marrow or brain, for the treatment of mild to moderate acute and subacute pain symptoms, for the treatment of intense and/or chronic pain, neuropathic pain and intractable pain, for the treatment of parkinson's disease and neurodegeneration or parkinson's symptoms caused by neuroleptics, for the treatment of primary and secondary generalized epilepsy, partially simple or complex symptoms, mixed and other epileptic syndromes as a supplement or monotherapy to other anti-epileptic treatments, for the treatment of sleep apnea and neuroprotection.

The subject of the invention is also pharmaceutical compositions containing an effective dose of at least one compound of the invention in the form of a pharmaceutically acceptable base or salt or solvate, if appropriate in admixture with one or more conventional excipients.

The excipients are selected according to the pharmaceutical dosage form and the desired mode of administration.

The pharmaceutical compositions of the present invention may also be administered orally, sublingually, subcutaneously, intramuscularly, intravenously, topically, intratracheally, intranasally, transdermally, rectally, intraocularly.

The unit dosage forms for administration can be, for example, tablets, capsules, granules, powders, oral or injectable solutions or suspensions, transdermal patches (ointments), suppositories. For topical administration, ointments, lotions and eye washes may be used.

By way of example, a unit dosage form for administration of a compound of the invention in the form of a tablet may comprise the following ingredients:

compound of the invention 50.0mg

Mannitol 223.75mg

Croscarmellose sodium 6.0mg

Corn starch 15.0mg

Hydroxypropyl-methylcellulose 2.25mg

Magnesium stearate 3.0mg

Depending on the form of the preparation, the unit dosage form is administered so that 0.01 to 20mg of the main active substance per kg of body weight is taken daily.

There may be special cases where higher or lower doses are appropriate doses, and such doses do not depart from the scope of the present invention. According to routine usage, the appropriate dosage for each patient is determined by the physician in light of the mode of administration, body weight, and patient response.

The present invention also relates, according to other aspects thereof, to methods for the treatment of the above-mentioned conditions, comprising administering to a patient an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

Claims (8)

1. A compound corresponding to the general formula (I),

wherein

R represents a hydrogen atom or a vinyl group;

n represents 1;

x represents a group of formula CH when R represents a hydrogen atom or a vinyl group;

R₁represents phenyl optionally substituted by one or more halogen atoms, or R₁Represents a quinolyl group;

R₂represents one or more substituents selected from halogen atoms and trifluoromethyl groups;

said compounds are in the form of the free base or of an addition salt with an acid.

2. The compound of claim 1, characterized in that said compound is in the threo configuration.

3. A compound according to claim 1, characterized in that R represents a hydrogen atom.

4. A compound according to claim 1, characterized in that R₁Represents a phenyl group optionally substituted by one or more halogen atoms.

5. The compound according to claim 1, characterized in that it is selected from:

(1) threo-2-chloro-N- [ (1-azabicyclo (2.2.2) oct-2-yl) -phenylmethyl ] -3-trifluoromethylbenzamide;

(2) threo-2-chloro-N- [ (1-azabicyclo (2.2.2) oct-2-yl) -phenylmethyl ] -3-trifluoromethylbenzamide hydrochloride;

(3) threo-2, 6-dichloro-N- [ (1-azabicyclo (2.2.2) oct-2-yl) -phenylmethyl ] -3-trifluoromethylbenzamide;

(4) threo-2, 6-dichloro-N- [ (1-azabicyclo (2.2.2) oct-2-yl) -phenylmethyl ] -3-trifluoromethylbenzamide hydrochloride;

(5) 2-chloro-N- (8 α, 9 s-octenal-9-yl) -3-trifluoromethyl-benzamide;

(6) 2-chloro-N- (8 α, 9 s-cinchonan-9-yl) -3-trifluoromethyl-benzamide hydrochloride;

(7)2, 6-dichloro-N- [ (1S) - ((2S) (1-azabicyclo (2.2.2) oct-2-yl) -phenylmethyl) ] -3- (trifluoromethyl) benzamide;

(8)2, 6-dichloro-N- [ (1S) - ((2S) (1-azabicyclo (2.2.2) oct-2-yl) -phenylmethyl) ] -3- (trifluoromethyl) benzamide hydrochloride;

(9) threo-N- [ 1-azabicyclo (2.2.2) oct-2-yl (4-fluorophenyl) -methyl ] -2, 6-dichloro-3- (trifluoromethyl) benzamide;

(10) threo-N- [ 1-azabicyclo (2.2.2) oct-2-yl (4-fluorophenyl) -methyl ] -2, 6-dichloro-3- (trifluoromethyl) benzamide hydrochloride.

6. A pharmaceutical composition characterized in that it comprises a compound according to any one of claims 1 to 5 and at least one pharmaceutically acceptable excipient.

7. Use of a compound of formula (I) according to any one of claims 1 to 5 in the manufacture of a medicament for inhibiting glyt 1.

8. Use of a compound of formula (I) according to any one of claims 1 to 5 in the manufacture of a medicament for inhibiting glyt 2.