EP0971929A1

EP0971929A1 - 2,3-DIHYDROFURO 3,2-$i(b)]PYRIDIN, PREPARATION AND APPLICATION THEREOF IN THERAPY

Info

Publication number: EP0971929A1
Application number: EP98914931A
Authority: EP
Inventors: Alistair Lochead; Samir Jegham; Frédéric Galli; Thierry Gallet
Original assignee: Sanofi Synthelabo SA
Current assignee: Sanofi Aventis France
Priority date: 1997-03-20
Filing date: 1998-03-17
Publication date: 2000-01-19
Also published as: WO1998042713A1; FR2761072B1; AU6924298A; FR2761072A1; NO994527L; EE9900414A; BR9808346A; AR012097A1; ZA982365B; JP2001518099A; NO994527D0; HUP0002335A2; HUP0002335A3; KR20000076282A; CN1251105A; US6143761A; PL335759A1; TR199902115T2; IL131254A0; BG103684A

Abstract

The invention concerns compounds of general formula (I) in which R1 represents a hydrogen atom, a (C1-C6)alkyl group or a phenyl(C1-C4)alkyl group; R2 represents a hydrogen atom of a (C1-C6)alkyl group; and R3, R4 and R5 represent each, independently of one another, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxy, (C1-C6)alkyl or (C1-C6)alkoxy group. The results of biological assays carried out on said compounds show that they are powerful and selective cholinergic ligands for nicotinic receptors. These results suggest that the compounds can be used for treating or preventing disorders related to the dysfunction of nicotinic receptors, in particular in the central nervous system or the gastro-intestinal system.

Description

2, 3 -dihydrofuro [3, 2 -b] pyridine derivatives, their preparation and their therapeutic use.

The present application relates to compounds corresponding to the general formula (I)

in which

R- _L represents a hydrogen atom, a group (C ₁ -C ₆ ) alkyl or a phenyl group (C _x -C ₄ ) alkyl optionally substituted, R ₂ represents a hydrogen atom or a group (Ci-Cg ) alkyl, and

R ₃ , R ₄ and R ₅ each represent, independently of one another, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxy, (Cx-Cg) alkyl or (C- _L - Cg) alkoxy.

The two carbon atoms by which the pyrrolidine ring and the furo [3, 2 -jb] pyridine ring are linked are asymmetric; a compound according to the invention can therefore exist in the form of a pure optical isomer (R, R), (R, S), (S, R) or (S, S) or a mixture of such isomers.

A compound according to the invention can also exist in the form of a free base or an addition salt with an acid.

Compounds of interest are those in which R _x and R ₂ each represent a hydrogen atom or an alkyl group, preferably a methyl group, and R ₃ , R ₄ and R ₅ each represent a hydrogen or halogen atom , preferably chlorine, or a (C- _L -C ^ alkyl, preferably methyl, or (C ₁ -C ₄ ) alkoxy, preferably methoxy group. Diagram

In accordance with the invention, the compounds of general formula (I) can be prepared by a process illustrated by the scheme above.

First reacting a 2-halopyridin-3-ol of general formula (II), in which R ₃ , R ₄ and R ₅ are as defined above and X represents a halogen atom, with 1,1-dimethylethyl 2-ethynylpyrrolidine-1-carboxylate of formula (III), under the conditions of a Castro-Stephens reaction, as described in J. Org. Chem. (1966) 31 4071, or else in the presence of copper (I), as described in Synthesis (1986) 749-751, to obtain the cyclized derivative of general formula (IV). For certain compounds, all the substituents R ₃ , R ₄ and R ₅ cannot be present from the start of the synthesis; in these cases, their introduction can be done from the compound of general formula (IV), in which R ₃ , R ₄ and R ₅ each represent a hydrogen atom, according to any known method, for example that described in J. Net. Chem. (1996) 33 1051-1056, optionally after activation of the nitrogen of the pyridine ring by formation of the corresponding N-oxide. Then the nitrogen of the pyrrolidine cycle is deprotected to obtain the compound of general formula (V). The latter is subjected to catalytic hydrogenation to obtain the compound of general formula (VI) and finally, and if desired, a nitrogen alkylation of the pyrrolidine ring is carried out by any known method, for example methylation according to the method Eschweiler-Clarke (formaldehyde and formic acid) or by a reductive amination in the presence of an aldehyde and sodium cyanoborohydride, or alternatively an acylation, to form an amide, followed by a reduction in the presence of a reducing agent such than 1 double hydride of lithium and aluminum.

The 2-halogenpyridin-3-ols are commercially available or can be prepared according to any method known to those skilled in the art.

The (S) - and (R) -2-ethynylpyrrolidine-l-carboxylate of 1,1-dimethylethyl can be prepared from proline (S) or (j) by the method of Corey-Fuchs, described in Tetrahedron Letters (1990) 31 (28) 3957-3960.

The examples which follow illustrate the preparation of some compounds of the invention. Elementary microanalyses, and IR and RMΝ spectra. confirm the struc- tures of the compounds obtained.

The numbers indicated in parentheses in the titles of the examples correspond to those of the 1st column of table 1 given below. cut at the end of the line; it must be deleted in the absence of a break, and must not be replaced either by a normal dash or by a space.

Example 1 (Compounds No. 1 and 2).

Diastereoisomers of (2 S) -2-pyrrolidin-2-yl-2, 3 -dihydro_ furo [3,2 -jfc>] pyridine.

1.1. (S) -2-Furo [3, 2-Jb] pyridin-2-ylpyrrolidine-1-carboxylate of 1, 1-dimethylethyl. In a three-necked 100 ml flask, 2.0 g (10.24 moles) of 1,1-dimethylethyl and 2.26-carboxylate (S) -2-ethynyl-1-pyrrolidine_ are dissolved under an argon atmosphere. g (10.24 mmol) of 2-iodopyridin-3 -ol in 50 ml of pyridine. 0.88 g are added

(6.15 mmol) of copper oxide (I) and the medium is heated to reflux for 24 h.

The solution is filtered on. paper and the solvent is evaporated off under reduced pressure. The residue is purified by chromatography on silica gel, eluting with a 60/40 then 50/50 mixture of cyclohexane and ethyl acetate. 2.43 g of product are thus obtained in the form of a thick oil. [α] _D ° = -102.6 ° (c = 1, CHCl ₃ ).

1.2. (S) -2-pyrrolidin-2-ylfuro [3, 2-Jb] _ pyridine dihydrochloride. In a 100 ml flask, 2.25 g (7.80 mmol) of (S) -2-furo [3, 2-jb] pyridin-2-ylpyrrolidine-l-carboxylate of 1, 1-dimethylethyl are dissolved in 20 ml of dichloromethane and 17.8 ml (0.156 mol) of trifluoroacetic acid are added. There is a release of gas. After 24 hours of stirring, the solvent is evaporated, the residue is taken up in water and the solution obtained is made alkaline by addition of a concentrated aqueous sodium hydroxide solution. Extraction is carried out with dichloromethane to obtain the crude product in the form of an oil, which is purified by chromatography on silica gel, eluting with a 95/5 / 0.5 mixture of dichloromethane, ethanol and ammonia, to obtain the pure product. in basic form. The hydrochloride is formed by addition of hydrochloric acid in ethanol.

1.35 g of product are thus obtained. Melting point: 174-175 °. [α] ξ, ° = -9 ° (c = 1, CH ₃ OH). 1.3. Diastereoisomers of (2 S) -2-pyrrolidin-2-yl-2, 3-dihydrofuro [3,2 -b] pyridine. 6.0 g (22.97 mmol) of (S) -2-pyrrolidin-2-ylfuro [3, 2 -b] pyridine dihydrochloride are introduced into 400 ml of ethanol into a three-necked flask of 1 liter. 3 g of 10% palladium on charcoal are added and catalytic hydrogenation is carried out for 10 h.

The catalyst is removed by filtration, the solvent is evaporated off under reduced pressure and the reaction products are purified by chromatography on silica gel, eluting with a 96/4 / 0.4 mixture of dichloromethane, ethanol and ammonia. 0.22 g of the least polar diastereoisomer (compound No. 1) is thus obtained in the form of the base. Melting point: 79-81 ° C, [α] ² _Ό ° = + 63.7 ° (c = l, CHC1 ₃ ), and 1.2 g of the most polar diastereoisomer (compound No. 2) in the form of based. This is dissolved in ethanol and treated with a solution of hydrochloric acid in ethanol to obtain, after crystallization from butanone, 1.56 g of product in the form of dihydrochloride. Melting point: 171-173 °, [α] ^ = -75.9 ° (c = 1, CH ₃ OH).

Example 2 (Compound No. 6).

(-) - (2S) -2- (1-methylpyrrolidin-2-yl) -2, 3-dihydro_ furo [3,2 -jb] pyridine tartrate.

0.6 g (2.19 mmol) of the most polar diastereomer of (2S) - 2-pyrrolidin-2-yl-2, 3-dihydrofuro [3, 2-b] is dissolved in a 250 ml flask pyridine obtained during the previous step in 100 ml of ethanol, then 250 μl (4.38 mmol) of acetic acid and 3.55 ml (4.38 mmol) of an aqueous formaldehyde solution at 37 are added %. Cool to 0 ° C and add 0.275 g (4.38 mmol) of cyano _. sodium borohydride and the mixture is stirred for 3 h. The solvent is evaporated off under reduced pressure and the medium is made alkaline by the addition of concentrated ammonia. The solution obtained is evaporated and the residue is purified by chromatography on a column of silica gel, eluting with a 90/10/1 mixture of dichloromethane, ethanol and ammonia to obtain the product in the form of the base. This is taken up in ethanol and 0.235 g of tartaric acid is added. After evaporation of the solvent under reduced pressure, 0.70 g of product is obtained in the form of a hygroscopic solid. Melting point: 70-71 ° C. [α] ° = -107.3 ° (c = l, H ₂ 0).

The following table illustrates the chemical structures and the physical properties of some compounds of the invention.

Board

For all compounds, the configuration of the atom marked "a" is either R or S, but has not been determined; in the column "b" are indicated the configurations of the atom marked "b" in the above formula.

In the "Salt" column, "-" denotes a compound in the basic state, 2HC1 denotes a dihydrochloride and "Tar." denotes a D-tartrate. The compounds of the invention have been the subject of tests which have demonstrated their therapeutic properties.

Thus, they have been studied as to their affinity for nicotinic receptors according to the methods described by

Anderson and Arneric, Eur. J. Pharmacol (1994) 253 261, and by Hall et al., Brain Res. (1993) 600 127.

Male Sprague Dawley rats weighing 150 to 200 g are decapitated and the whole brain is quickly removed, homogenized in 15 volumes of 0.32 M sucrose solution at 4 ° C and then centrifuged at 1000 g for 10 min. The pellet is removed, and the supernatant is centrifuged at 20,000 xg for 20 min at 4 ° C. The pellet is recovered and homogenized using a Polytron ™ mill in 15 volumes of double-distilled water at 4 ° C., then it is centrifuged at 8000 g for 20 min. The pellet is discarded and the supernatant and the skin layer ("buffy coat") are centrifuged at 4000 g for 20 min, the pellet is recovered, washed with double-distilled water at 4 ° C. and again centrifuged once before storing it at -80 ° C.

On the day of the experiment, the tissue is thawed slowly and suspended in 3 volumes of buffer. 150 μl of this membrane suspension are incubated at 4 ° C. for 120 min in the presence of 100 μl of [ ³ H] 1 nM cytisine in a final volume of 500 μl of buffer, in the presence or absence of the compound to be tested. The reaction is stopped by filtration on hatman GF / B ™ filters previously treated with polyethyleneimine, the filters are rinsed with twice 5 ml of buffer at 4 ° C., and the radioactivity retained on the filter is measured by liquid scintigraphy. The non-specific binding is determined in the presence of (-) -nicotine at 10 μM; non-specific binding represents 75 to 85% of the total binding recovered on the filter. For each concentration of compound studied, the percentage of inhibition of the specific binding of [ ³ H] cytisine is determined, then the IC ₅₀ , the concentration of compound which inhibits 50% of the specific binding, is calculated. The IC ₅₀ values of the compounds of the invention are between 0.01 and 100 μM. The results of biological tests carried out on the compounds of the invention show that they are powerful and selective cholinergic ligands for nicotinic receptors.

These results suggest the use of the compounds in the treatment or prevention of disorders linked to a dysfunction of the nicotinic receptors, in particular in the central nervous system or the gastrointestinal system.

At the level of the central nervous system these disorders include cognitive alterations, more specifically memory impairment, but also attentional alterations, linked to Alzheimer's disease, to pathological aging (Age Associated Memory Impairment, AAMI), to Parkinson's syndrome, to trisomy 21 ( Down's syndrome), alcoholic Korsakoff syndrome, vascular dementia (multi-infarct dementia, MID). The compounds of the invention could also be useful in the treatment of motor disorders observed in Parkinson's disease or other neurological diseases such as Huntington's chorea, Tourette's syndrome, tardive dyskinesia and hyperkinesia. The compounds of the invention can also constitute a curative or symptomatic treatment of cerebrovascular accidents and cerebral hypoxic episodes. They can be used in cases of psychiatric pathologies: schizophrenia, depression, anxiety, panic attacks, compulsive and obsessive behaviors.

They can prevent symptoms due to smoking cessation, alcohol, various addictive substances, such as cocaine, LSD, cannabis, benzodiazepines. Finally they can be useful for the treatment of pain.

In the gastrointestinal system, the compounds of the invention could be useful in the treatment of Crohn's disease, ulcerative colitis, irritable bowel syndrome and obesity.

To this end, the compounds of the invention can be presented in all forms of compositions suitable for enteral, parenteral or transdermal administration, such as tablets, dragees, capsules, capsules, suspensions or oral or injectable solutions such as syrups or ampoules, transdermal patches ("patch"), etc., associated with suitable excipients, and dosed to allow daily administration of 0.01 to 20 mg / kg.

Claims

Claims.

1. Compound, in the form of a pure optical isomer or a mixture of such isomers, corresponding to the general formula (I)

in which

Rτ_ represents a hydrogen atom, a (C ₁ -C ₆ ) alkyl group or a phenyl (C ₁ -C ₄ ) alkyl group, R ₂ represents a hydrogen atom or a (C ₁ -C ₆ ) alkyl group , and

R ₃ , R ₄ and R ₅ each represent, independently of one another, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxy, (C ₁ -C ₆ ) alkyl or (C- _L -Cg) alkoxy, in the basic state or an addition salt with an acid.

2. Compound according to Claim 1, characterized in that R -, _ and R ₂ each represent a hydrogen atom or an alkyl group and R ₃ , R ₄ and R ₅ each represent a hydrogen or halogen atom or a (C _x -C ₄ ) alkyl or ^(c ι ~ ^c 4 ⁾ alkoxy group.

3. Compound according to Claim 1, characterized in that R and R ₂ each represent a hydrogen atom or a methyl group, and R ₃ , R ₄ and R ₅ each represent a hydrogen or chlorine atom or a group methyl or methoxy.

4. Process for the preparation of compounds according to claim 1, characterized in that first reacts a

2-halopyridin-3-ol of general formula (II)

in which R ₃ , R ₄ and R ₅ are as defined in claim 1 and X represents a halogen atom, with 1, 1-dimethylethyl 2-ethynylpyrrolidine-1-carboxylate, to obtain the cyclized derivative of formula general (IV)

whose substituents R ₃ , R ₄ and R ₅ are modified, if desired, by any known method, then nitrogen is deprotected from the pyrrolidine ring to obtain the compound of general formula (V)

then the latter is subjected to catalytic hydrogenation to obtain the compound of general formula (VI)

and finally, and if desired, we carry out an alkylation with nitrogen from the pyrrolidine cycle.

3. Medicament, characterized in that it consists of a compound according to claim 1.

4. Pharmaceutical composition characterized in that it contains a compound according to claim 1, associated with an excipient.