SK9062002A3 - Benzophenone alpha-d-glycopyranosides, preparation and therapeutic use - Google Patents

Abstract

The invention concerns (i) [4-(4-cyanobenzyl)phenyl] alpha -D-glycopyranosides of formula (I) wherein: the group alpha -D-glycopyranosyl R represents a alpha -D-glycopyranosyl, alpha -D-galactopyranosyl, alpha -D-mannopyranosyl, alpha -D-arabinopyranosyl, alpha -D-lyxopyranosyl, or alpha -D-ribopyranosyl group; (ii) their esters resulting from the esterification of at least a OH function of each pyranosyl group with a C2-C4 alkanoic or a cycloalkanoic acid, as novel industrial products. Said novel [4-(4-cyanobenzyl)phenyl] alpha - D-glycopyranosides are useful in therapy for fighting against atheromatous plaque.

Description

BENZOPHENONE-α-D-GLYCOPYRANOSIDES, METHOD OF PREPARATION

PHARMACEUTICAL APPLIANCE AND THERAPEUTIC USE * ·

Technical field

The invention relates to 4-cyano-4'-hydroxybenzophenone derivatives of the following general formula I, which are benzophenone-α-D-glycopyranosides and which are novel industrial products according to the invention. The invention further relates to a process for the preparation of these substances and to their use as therapeutic agents, in particular in the form of compositions in which they are present as active ingredients.

BACKGROUND OF THE INVENTION

EP-A-0 051 023 discloses compounds containing a beta-D-xyloyl substituted hydroxybenzophenone moiety, which compounds exhibit valuable pharmacological activity in the treatment or prevention of venous thrombosis.

EP-A-0 133 103 also discloses derivatives of the benzylphenyl-beta-Dxylozide type which exhibit hypocholesterolemic and hypolipidemic properties. It is also known in the art that derivatives in which the beta-D-xylosyl residue has been replaced by the beta-D-thioxylozyl residue described in EP-A-0 365 397 and EP-A-0 290 321 are compounds. useful due to their antithrombotic activity.

Last but not least, F. Bellamy et al., J. Med. Chem., 1993, 36, no. 7, p. 898-903 disclose compounds derived from benzophenone substituted with glycosyl groups, of which only the beta-configuration derivatives exhibit antithrombotic activity. Studies of these substances have shown that these compounds, especially those containing the beta-D-xyloyl group, are good substrates for

PP 0906-2002

31961 / T rr galactosyltransferase I, and therefore these compounds are capable of initiating the synthesis of glycosaminoglycans (CAG). This mode of action, achieved after oral administration of the product, is most likely related to antithrombotic activity, with respect to therapeutic utility only those derivatives in which D-xylose is in the beta-configuration show this activity. Thus, it is apparent that there is a link between the effect on CAG synthesis and antithrombotic activity, meaning that compounds other than those derived from beta-D-xylose have no utility in this therapeutic field.

SUMMARY OF THE INVENTION

According to the present invention, a new technical solution has been found for obtaining new, therapeutically valuable substances as regards atheromatous plaques, which are useful not only in the treatment of said atheromatous plaque, but also to prevent this phenomenon.

The present invention is based on the discovery that the novel compounds of the present invention, i.e., [4- (4-cyanobenzoyl) phenyl] -? the knowledge resulting from the above-cited publications.

In a first aspect, the present invention provides novel compounds which may be selected from the group consisting of:

(i) [4- (4-Cyanobenzoyl) phenyl] -α-D-glycopyranoside compounds of formula I:

PP 0906-2002

31961 / T e ** c c r.

n r r * r f r <

· 'R

r.

wherein said α-D-glycopyranosyl group R is α-D-glucopyranosyl, α-D-galactopyranosyl, α-Dmanopyranosyl, α-D-arabinopyranosyl, α-Dlyxopyranosyl or α-D-ribopyranosyl α, (ii) esters of these compounds obtained by esterifying at least one OH group on each of the glycopyranosyl groups with an alkanoic acid having 2 to 4 carbon atoms or a cycloalkanoic acid.

A second aspect of the present invention is a process for preparing the compounds of formula (I) and esters thereof.

The present invention also includes a therapeutic composition comprising a therapeutically effective amount of at least one compound of Formula I or one of its esters in combination with a physiologically acceptable excipient.

The present invention also includes the use of a compound of formula (I) or one of its esters as an active ingredient for the preparation of a medicament for use as a therapeutic agent for suppressing atheromatous plaque, particularly for preventing or treating it.

The new compounds of the present invention are the products of formula (I) and esters thereof, which are pyranoside derivatives of 4-cyano-4'-hydroxybenzophenone (or 4- (4-hydroxybenzoyl) benzonitrile). Preferred products of the present invention in which the glycoside residue is in pyranose form have the following general formulas, which are given according to the structure of the glycopyranosyl group R α -D-configuration as:

(a) α-D-glucose structure (α-D-Glc) of general formula _IA :

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r e e - - <<<((((((((((((((((((

(c) α-D-mannose structure (α-D-Man) of general formula Iq:

(d) the α-D-arabinose structure (α-D-Ara) of the general formula Id:

(i _d ) (e) the α-D-lyxose structure (α-D-Lyx) of formula Ie:

(f) α-D-ribose structure (α-D-Rib) of general formula If:

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C '

In the above formulas, R 1 is hydrogen or COR 2, where R ₂ is an alkyl group having 1 to 3 carbon atoms selected from methyl, ethyl, propyl, isopropyl and cyclopropyl.

The process for the preparation of the compounds of the formula I or one of their esters according to the invention consists of:

(i) reacting the peracetylated pentose or hexose of the pyranosyl structure of formula II:

wherein Z represents a hydrogen atom or a CH ₂ OAc group selected from the group consisting of

1,2,3,4,6-pentaacetyl-D-glucose,

1.2.3.4.6- pentaacetyl-D-galactose,

1.2.3.4.6- pentaacetyl-D-mannose,

1.2.3.4-tetraacetyl-D-arabinose,

1,2.3,4-tetraacetyl-D-lyxose and 1,2,3,4-tetraacetyl-D-ribose, with 4- (4-hydroxybenzoyl) benzonitrile of formula III:

(III)

I

CN to give, after appropriate purification, the corresponding ozide compound of formula IV:

(Iv)

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c. r ⁶ , ¹ , ^1: 1? · 'in which Z has the same meaning as above, and then follows:

(ii) if desired, carrying out a substitution reaction on the acetyl groups of the resulting resulting ozide compound of formula IV to replace them with hydrogen atoms to give the corresponding compound of formula I wherein R 1 is hydrogen, but other esters may also be obtained ( wherein R 1 is a group other than Ac) by esterifying a compound of formula I wherein R 1 is represents a hydrogen atom with an acid having 3 to 4 carbon atoms.

In a preferred embodiment of the invention, the reaction of the compound of formula II with the compound of formula III inlet (i) is carried out in an organic solvent (in particular dichloromethane may be used) in the presence of Lewis acid (e.g. tin tetrachloride). ° C to the boiling point of the solvent used for 10 to 30 hours.

In step (ii), the replacement of the Ac groups with hydrogen atoms is preferably carried out as follows. Compound of formula. IV is reacted with ammonia NH ₃ in an anhydrous alcohol solution (mainly methanol may be used) to remove the Ac groups and replace them with hydrogen.

In an alternative embodiment, a reaction is possible

Replace II + III -> IV in step (i) by reaction

V + III -> IV wherein the compound of formula V is the corresponding peracetylated halopentose or halohexose. Under these conditions, step (i) must then be replaced by step (i '), namely:

(i ') reacting a peracetylated halopentose or halohexose of a pyranosyl structure of formula V:

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(V) in which:

X is a halogen atom (i.e. fluorine, chlorine, bromine or iodine, preferably halogen is bromine), and

Z is hydrogen or CH 2 OAC, selected from the group consisting of:

1-bromo-2,3,4,6-tetraacetyl-D-glucose, 1-bromo-2,3,4,6-tetraacetyl-D-galactose, 1-bromo-2,3,4,6-tetraacetyl- D-mannose,

1-bromo-2,3,4-triacetyl-D-arabinose,

1-bromo-2,3,4-triacetyl-D-lyxose, and 1-bromo-2,3,4-triacetyl-D-ribose, with 4- (4-hydroxybenzoyl) benzonitrile of formula III:

(III) to give, after purification, the corresponding ozide compound of formula IV:

(IV) wherein Z has the same meaning as previously defined.

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r. c · r c e ςrc

IC C r 'rr

Preferably, the reaction of a compound of formula V with a compound of formula III to give a compound of formula IV is carried out in an anhydrous solvent such as dichloromethane, 1,2-dichloroethane or acetonitrile in the presence of an addition agent such as trifluoromethanesulfonate silver or silver oxide, at a temperature ranging from -10 to +10 ° C, and the reaction is carried out for 5 to 40 hours.

The above reactions:

II + III -> IV a

V + III -> IV can be used to prepare all compounds of formula IV of the present invention.

Other advantageous features and characteristics of the present invention will be more apparent from the following examples and pharmacological tests. It is to be understood that all details herein are not intended to limit the invention.

DETAILED DESCRIPTION OF THE INVENTION

The process of the invention and the characteristic products will be explained in more detail below with reference to specific examples, which are illustrative only and are not intended to limit the scope of the invention in any way.

Example 1 (Formula Ia, R 1 = COCH 3) [4- (4-cyanobenzoyl) phenyl] -2,3,4-tetra-O-acetyl-α-D-glucopyranoside

A suspension containing 12.17 g (31.10 ^-3 moles) of 1,2,3,4,6-penta-O-acetyl-beta-D-glucose and 10.36 g (46.10 ^-3 moles) was used according to this example. - (4-hydroxy-benzoyl) -benzonitrile in 500 ml of dichloromethane, taking as follows

PP 0906-2002

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C r r <

^: . The prepared suspension was gradually added at 0 ° C with stirring, while stirring 8.5 ml (72.6 x 10 ^-3 mol) of anhydrous tin (II) chloride. After stirring the mixture for 20 hours at room temperature, an additional 4.25 mL (36.3 x 10 ^-3 mol) of anhydrous tin (II) chloride was added and the reaction mixture was then gently heated at reflux for 24 hours. After cooling, the reaction medium was poured onto ice. The organic phase was separated and then washed with water, extracted with 1 N sodium hydroxide solution, then washed with water until the washings were neutral and finally dried over magnesium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel chromatography, eluting with a toluene / ethyl acetate mixture (8/2 by volume) to give the desired product as an amorphous white solid.

Yield: 918 mg (5.3%).

Melting point: 63 ° C.

[α] _D ²⁹ = + 83.2 ° (c = 0.25, DMSO).

Example 2 (Formula Ia, R 1 = H) [4- (4-cyanobenzoyl) phenyl] -α-D-glucopyranoside

A solution containing 575 mg (1.06.10 ^-3 mol) of the compound of Example 1 in 50 ml of methanol was used, and 5.6 ml of saturated solution were added to the solution at 0 ° C while stirring. solution of ammonia in methanol. The reaction mixture was then stirred for 6 hours at room temperature, and the solvent was removed under reduced pressure. The crude product thus obtained was purified by silica gel chromatography, eluting with dichloromethane / methanol (9/1 by volume) to give the desired product as a fine white solid.

· 'R

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Yield: 137 mg (34%).

Melting point: 130 ° C. [α] _D ²³ = + 145 ° (c = 0.33, DMSO).

Example 3 (general formula 1c, R 1 = COCH 3) [4- (4-cyanobenzoyl) phenyl] -2,3,4,6-tetra-O-acetyl-α-D-manopyranoside

A solution containing 9.9 g (144.10 ^-3 mol) of 4- (4-hydroxybenzoyl) benzonitrile and 26 g (63.10 ^-3 mol) of 2,3,4,6-tetra-O-acetyl-α-Dmanopyranosyl bromide was used according to this example. in 300 ml 1,2-dichloroethane, this solution was prepared in the presence of about 4 g of molecular sieve. The mixture was then cooled to -20 ° C and 34 g (132.10 ³ mol) of silver trifluoromethanesulfonate were added at this temperature. The reaction mixture was stirred for 24 hours at 0 ° C and then filtered to remove solids. The organic phase was then washed with dilute hydrochloric acid solution and then with water, then with dilute sodium hydroxide solution and finally with water. After drying over magnesium sulfate, the solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography using toluene / ethyl acetate as the eluent to give the desired product as a pale yellow solid. substances.

Yield: 19 mg (77%).

Mp .: 60 ° C.

[α] _D ²⁷ = + 64 ° (c = 0.62, DMSO).

Example 4 (general formula 1c, R 1 = H) [4- (4-cyanobenzoyl) phenyl] - α -D-manopyranoside

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16.7 g (30 * 10 &^lt; ^{-3 &gt;} mol) of the product of Example 3 were dissolved in 50 ml of methanol and 100 ml of a saturated solution of ammonia in methanol was added at 0 [deg.] C. The reaction mixture was stirred for 6 hours at 0 to 10 ° C and then concentrated under reduced pressure. The crude product thus obtained was purified by silica gel chromatography using a mixture of dichloromethane and methanol as eluent (15/1 by volume). The pure product fraction was then crystallized from acetone to give the desired product as fine light beige crystals.

Yield: 7.9 g (68%).

Melting point: 145 ° C.

[α] _D ²⁷ = + 102 ⁰ (c = 0.17, DMSO).

Example 5 (Formula Ib, R 1 = COCH 3) [4- (4-cyanobenzoyl) phenyl] -2,3,4,6-tetra-O-acetyl-α-D-galactopyranoside

The desired product was obtained in the form of an amorphous solid, following a similar procedure to that described in Example 1 and starting with 1,2,3,4,6-penta-O.-acetylgalactose.

Yield: 4%.

Melting point: 64 - 66 ° C.

[α] _D ²⁹ = + 156 ⁰ (c = 0; 26, DMSO).

Example 6 (Formula Ib, R 1 = H) [4- (4-cyanobenzoyl) phenyl] - α -D-galactopyranoside

The desired product was obtained in the form of a white solid and was prepared in a similar manner as described above

PP 0906-2002

31961 / T r • r f f f r>>>

• r. c c r r r. r. r. r.

e f c r. o r r - · (r,

Γ C <R _t fi - _ς -, Γ Γ H of Example 2 and starting from the compound obtained according to Example fifth

Yield: 90%.

Mp .: 240 ° C.

[α] _D ²⁹ = + 173 ⁰ (c = 0.25, DMSO).

Example 7 (Formula Id, R 1 = COCH 3) [4- (4-cyanobenzoyl) phenyl] -2,3,4-tri-O-acetyl-α-D-arabinopyranoside

The desired product was obtained in the form of a yellow oil using a similar procedure to that described in Example 3 and starting with 2,3,4-tri-O-acetyl-D-arabinopyranosyl bromide.

Yield: 15%.

[α] D ²⁴ = -10.7 ° (c = 0.38, CH ₂ Cl ₂ ).

Example 8 (Formula Id, R 1 = H) [4- (4-cyanobenzoyl) phenyl] -α-D-arabinopyranoside

The desired product was obtained in the form of a beige solid, following a procedure similar to that of Example 4 and starting from the compound of Example 7.

Yield: 75%.

Melting point: 160 ° C.

[α] ^{26 =} - 66 ⁰ (c = 0.32, DMSO).

Example 9 (Formula Ie, R 1 = COCH 3)

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[4- (4-cyanobenzoyl) phenyl] -2,3,4-tri-0-acetyl-a-D-lyxopyranozid

The desired product was obtained in the form of an oil using a similar procedure to that described in Example 1 and starting with 1,2,3,4-tetra-O-acetyl-D-lyxopyranose. Yield: 60%.

[a] _D ²⁴ = + 40.3 ⁰ (c = 0.67, CH ₂ Cl _2).

Example 10 (Formula Ie, R 1 = H) [4- (4-cyanobenzoyl) phenyl] -α-D-lyxopyranoside

The desired product was obtained as a white solid, following a procedure similar to that of Example 2 and starting from the compound of Example 9.

Yield: 90%.

Melting point: 173 ° C.

[cx] _D ²⁸ = + 12 5 ⁰ (c = 0.175, DMSO).

Example 11 (general formula If, R 1 = H) [4- (4-cyanobenzoyl) phenyl] -α-D-ribopyranoside

In the procedure of this example, [4- (4-cyanobenzoyl) phenyl] -2,3,4-tri-O-acetyl-α-D-ribopyranoside was obtained as a yellow solid, following a procedure analogous to Example 1 and as a starting material. 1,2,3,4-tetra-O-acetylribopyranose was used. This material was treated with a solution of ammonia in methanol following the same procedure as in Example 2 to give the desired product as a white powder.

Yield: 6%.

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Melting point: 164 ° C.

[α] _D ²⁶ = + 77.7 ° (c = 0.21, DMSO).

Pharmacological tests

The anti-atheromatic activity of the compounds of the present invention was evaluated as a function of these compounds to lower serum cholesterol levels in mice on a fat diet. Several prior art publications have already demonstrated a close relationship between lipid excess and a significant increase in atheroma risk (see Lancet, 1996, 348, pp. 1339 - 1342, Lancet, 1990, 335, pp. 1233 - 1235). This correlation allows you to run a test that is faster than direct experiments on)

atheromatous plaque, requiring lengthy animal handling and costly histological study of the aortic arch walls.

The assays used consisted of administering a single dose of the compound of the invention to C57BL / 6J mice using the following protocol. On day 1 (DO), mice were fasted from 9am to 5pm, with a blood sample taken at 2pm. At 5 pm, a given amount of food was given (a fat diet containing 1.25% cholesterol and 0.5% cholic acid). On the second day (D1), the remainder of the food was weighed at 9am and the mice were fasted from 9am to 2pm. Blood samples were collected at 2pm. For the treated group of mice, the compound of the invention was administered at 9 am the next day (D1) by tube as a suspension in a 3% aqueous resin solution. The control group received only an aqueous resin solution.

The test dose of the compounds of the invention was 100 mg / kg. Total serum cholesterol was determined and the results were expressed as percent inhibition of cholesterolemia compared to the control group. The results obtained are shown in the column "potency" in the table below. It should further be noted that analysis of the cholesterol content of the various serum lipoprotein groups showed a beneficial effect of the compounds of the invention on the HDL cholesterol / total cholesterol ratio.

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· · rc r n r y r

r. r r r '· r r r e ·'

It has also been noted that the compounds of formula (I) of the present invention do not induce CAG synthesis.

The compounds of formula (I) of the present invention and an ester thereof may be administered orally in the form of tablets or gelatin capsules, each containing 20 to 500 mg of a compound of formula I or one of its esters as active ingredient in combination with suitable excipients. Dosages typically range from about 1 to about 4 units per day. The compounds of the present invention are preferably prescribed on an atheromatous plaque and in particular for the prevention or treatment of atheroma risk.

Table I

Example R ri Efficiency (%) 1 a-D-Glc COCH ₃ -27 2 a-D-Glc H -23 3 and D-Man COCH3 -10 4 and D-Man . H -38 5 a-D-Gala COCH3 -32 6 a-D-Gala H -35 7 a-D-Ara COCH3 -25 8 a-D-Ara H -29 9 a-D-Lyx COCH3 - 10 a-D-Lyx H -48 11 a-D-Rib H -26

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ΡΡ 106-02.

r e c c y y y y y y y y y y y y y y y y y y - - (y y y y y y y ~ y y y y y y y y y y y y y y y y y y - <c

Claims (10)

PATENT CLAIMS 1. An α-D-glycopyranoside compound which is selected from the group consisting of: (i) [4- (4-Cyanobenzoyl) phenyl] -α-D-glycopyranoside compounds of general formula formula I: ? CN R i 1 (I) 0 in which α-D-glycopyranosyl group R is α-D- a glucopyranosyl group, an α-D-galactopyranosyl group, an α-D-manopyranosyl group, an α-D-arabinopyranosyl group, an α-Dlyxopyranosyl group, or an α-D-ribopyranosyl group α, (ii) esters of these compounds obtained by esterifying at least one OH group on each The groups are alkanoic acid having 2 to 4 carbon atoms or cycloalkanoic acid. 2. [4- (4-Cyanobenzoyl) phenyl] -α-D-glucopyranoside compound and its peracetylated derivative. 3. [4- (4-Cyanobenzoyl) phenyl] -α-D-galactopyranoside compound and its peracetylated derivative. 4. [4- (4-Cyanobenzoyl) phenyl] -α-D-mannopyranoside compound and its peracetylated derivative. 5. [4- (4-Cyanobenzoyl) phenyl] -α-D-arabinopyranoside compound and its peracetylated derivative. 6. [4- (4-Cyanobenzoyl) phenyl] -α-D-lyxopyranoside compound and peracetylated derivative thereof. PP 0906-2002 31961 / T 7. [4- (4-Cyanobenzoyl) phenyl] -α-D-ribopyranoside compound and its peracetylated derivative. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula I or one of its esters according to claim 1 in combination with a physiologically acceptable excipient. Use of a product selected from the group consisting of compounds of formula I and esters thereof according to claim 1 for the preparation of an anti-atheromatic drug for use as a therapeutic agent for suppressing atheromatous plaque. A process for the preparation of a [4- (4-cyanobenzoyl) phenyl] -? - D-glycopyranoside compound of formula I or a peracetylated derivative thereof according to claim 1, wherein the process comprises: (i) reaction of (a) the peracetylated pentose or hexose of the pyranosyl structure of formula II: wherein Z represents a hydrogen atom or a CH ₂ OAc group selected from the group consisting of: 1.2.3.4.6- pentaacetyl-D-glucose, 1.2.3.4.6- pentaacetyl-D-galactose, 1.2.3.4.6-pentaacetyl-D-mannose,. 1.2.3.4-tetraacetyl-D-arabinose, 1,2.3.4-tetraacetyl-D-lyxose a PP 0906-2002 31961 / T 1,2,3,4-tetraacetyl-D-ribose, or (b) peracetylated halopentose or structure of formula V: pyranosyl halide hexhexose zx γ ° γ ^χ And what ^0Ac OAc (in) in which: X is a halogen atom (i.e. fluorine, chlorine, bromine or iodine, preferably halogen is bromine) _; and Z is hydrogen or CH 2 OAC, selected from the group consisting of: 1-bromo-2,3,4,6-tetraacetyl-D-glucose, 1-bromo-2,3,4,6-tetraacetyl-D-galactose, 1-bromo-2,3,4,6-tetraacetyl-D-mannose, 1-bromo-2,3,4-triacetyl-D-arabinose, 1-bromo-2,3,4-triacetyl-D-lyxose, and 1-bromo-2,3,4-triacetyl-D-ribose, with 4- (4-hydroxybenzoyl) benzonitrile of formula III: to give, after appropriate purification, the corresponding ozide compound of formula IV: PP 0906-2002 31961 / T (IV) wherein Z has the same meaning as above, and then follows: (ii) if desired, carrying out a substitution reaction on the acetyl groups of the resulting resulting ozide compound of formula (IV) to replace it with hydrogen atoms to give the corresponding compound of formula (I) wherein R 1 is hydrogen.