Patent Grant
8093394
The present invention relates to novel 5-thioxylose compounds, preferably derivatives of 5-thioxylopyranose type, and to their process of preparation and their use as active substance of medicaments, in particular intended for the treatment or inhibition of thrombosis.
D-Xylose derivatives are already known, for example in EP 051 023 B1, U.S. Pat. No. 4,877,808 or EP 421 829 B1 or in the publication J. Med. Chem. Vol. 36, No. 7, pp 898-903. The compounds described in these documents are of use in reducing the risks of venous thrombosis in man. The mechanism of action of these compounds appears to be an effect on glycosaminoglycans (J. Biol. Chem., Vol. 270, No. 6, pp 2662-68, Thromb. Haemost., 1999, 81, pp 945-950). The document WO 2005/030785 describes pyridinyl 5-thio-β-D-xylopyranosides exhibiting an activity in treating venous thrombosis.
Furthermore, it is known that the beneficial effects of a transluminal coronary angioplasty can be compromised due to restenosis of the vessel, thus causing a fresh obstruction of the arterial lumen. Compounds which make it possible to avoid this restenosis are thus of the greatest advantage in maintaining a satisfactory diagnosis following the surgical operation with regard to artherosclerosis.
Novel compounds have now been discovered, and this is the subject matter of the present invention, which exhibit a good effectiveness when they are administered orally with an excellent pharmacological result (generally approximately 100%) against the appearance of arterial or venous thrombosis.
The novel compounds according to the invention are characterized in that they are chosen from:
a) the compounds of formula:
in which:
in which:
b) their addition salts,
c) their metabolites.
The invention also relates to the compounds of formula I for their use as pharmacologically active substance.
In particular, the invention relates to the use of at least one substance chosen from the compounds of formula I and their nontoxic salts for the preparation of a medicament, of use in human or animal therapeutics, intended for the inhibition or treatment of thrombosis, in particular venous thrombosis. The compounds according to the invention are also of use as active substances of medicaments intended for the inhibition of restenosis after transluminal coronary angioplasty. As the compounds according to the invention are active according to a method of action involving glycosaminoglycans, they may also be of use as active substance of a medicament intended for the treatment or inhibition of any other disease in which glycosaminoglycans are involved.
In the formula I, the term “C1-C4 alkyl group” is understood to mean a saturated, linear or branched, hydrocarbon chain having from 1 to 4 carbon atoms or one which is partially or completely cyclized, the cyclized portion having 3 or 4 carbon atoms. Examples of C1-C4 alkyl groups are in particular the methyl, ethyl, propyl, butyl, 1-methylethyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl, cyclopropyl or cyclopropylmethyl groups.
The term “halogen” should be understood as meaning a fluorine, chlorine, bromine or iodine atom and preferably a fluorine or chlorine atom.
The term “C2-C6 acyl group” is understood to mean an R—CO— group in which R represents an alkyl group as defined above having from 1 to 5 carbon atoms. Examples of C2-C6 acyl groups are in particular the acetyl, propanoyl, butanoyl, pentanoyl or hexanoyl groups and their homologs in which the chain can be branched.
The term “C1-C4 alkoxy group” is understood to mean an RO— group in which R represents an alkyl group having from 1 to 4 carbon atoms as defined above. Mention may be made, as examples of C1-C4 alkoxy groups, of the methoxy, ethoxy, propoxy, butoxy, 1-methylethoxy, 1,1-dimethylethoxy, 1-methylpropoxy, 2-methylpropoxy or cyclopropylmethoxy groups.
The term “addition salts” is understood to mean the addition salts obtained by reaction of a compound of formula I with an inorganic or organic acid. Preferably, the addition salts are pharmaceutically acceptable addition salts. The hydrates or solvates of the compounds of formula I or of the salts of the compounds of formula I also form an integral part of the invention.
Preference is given, among the inorganic acids suitable for salifying a basic compound of formula I, to hydrochloric, hydrobromic, phosphoric and sulfuric acids. Preference is given, among the organic acids suitable for salifying a basic compound of formula I, to methanesulfonic, benzenesulfonic, toluenesulfonic, maleic, fumaric, oxalic, citric, tartaric, lactic and trifluoroacetic acids.
The term “active metabolites” is understood to mean the compounds which are produced in the biological medium from the compounds of formula I and which have a pharmacological activity of the same nature as the compounds of formula I which are described in the present patent application. By way of example, the compounds of formula I can be metabolized as the result of a hydroxylation reaction to provide a novel compound (metabolite) which retains a pharmacological activity of the same nature as that of the compounds of formula I.
Mention may be made, as specific examples of fused bicyclic groups represented by A in the case where R1 and R2 together form an aromatic ring comprising 6 carbon atoms, of the benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzimidazolyl, quinolinyl, quinoxalinyl, quinazolinyl, indolyl, benzothiazolyl or indazolyl groups.
Preference is very particularly given, among the compounds according to the present invention, to those in which the thioxyloside group is in the 3 position of a pyridine ring.
Preference is also given, among the compounds according to the present invention, to the compounds in which R is the hydrogen atom or the —COCH3 group.
Other preferred compounds in the context of the present invention are the compounds of abovementioned formula I in which one at least of the following conditions is observed:
The compounds of formula I according to the invention can be prepared by employing the glycosylation methods known to a person skilled in the art, in particular:
a) the Helferich method described in the work “The Carbohydrate, Chemistry and Biochemistry”, 2nd edition, Academic Press, New York-London, 1972, Volume IA, pages 292-294, by condensation of a peracetylated sugar with an aromatic hydroxyheterocycle in the presence of a Lewis acid;
b) the Koenigs-Knorr method (idem, pages 295-299), by condensation of a halogenated acylose with a hydroxyl group having a phenolic nature in the presence of a proton acceptor, such as mercuric cyanide, silver imidazolate or silver trifluoromethanesulfonate;
c) the Schmidt method, by condensation of an osyl trichloroacetimidate with an aromatic hydroxyheterocycle in the presence of a Lewis acid, such as, for example, trimethylsilyl trifluoromethanesulfonate or boron trifluoride etherate.
The compounds of formula I are preferably prepared according to methods derived from the abovementioned processes.
According to a first general process, the stages consisting in:
a) reacting a pyridinol of formula:
in which:
in which:
in which Hal represents a halogen, preferably bromine, and R represents a C2-C6 acyl group, preferably the acetyl group, in an aprotic solvent, such as acetonitrile or toluene, in the presence of a silver salt, in particular silver oxide or imidazolate, or of a zinc salt (in particular the oxide or the chloride), in an anhydrous medium, at a temperature of between 25 and 110° C. and for 1 to 10 hours, in order to obtain the compound of formula:
in which A, R, R′ and R″ retain the same meanings as in the starting compounds;
b) if necessary, reacting the compound of formula I obtained above with a solution of ammonia in methanol in order to bring about the deacylation and thus to replace the acyl group by hydrogen atoms and to obtain the compound of formula:
in which R1 and R2 retain the same meanings as above;
c) if necessary, reacting one of the compounds I or Ia obtained above with an acid according to methods known to a person skilled in the art in order to obtain the corresponding addition salt,
are carried out.
In an alternative form of stage b) described above, the replacement of the acyl group by a hydrogen atom can be brought about by the action of a metal alkoxide, preferably sodium methoxide in a catalytic amount in methanol, at a temperature of between 0 and 30° C. and for 0.5 to 2 hours, in order to obtain the compound of formula Ia from the compound of formula I in which R represents a C2-C6 acyl group.
According to a second process, the compounds of formula I can be obtained by reaction of tetra-O-acetyl-5-thioxylopyranose of formula:
in which Ac represents the acetyl group, with a compound of formula:
in which:
in which:
in which A, R, R′ and R″ retain the same meanings as in the starting compounds.
The compound of formula Ib can subsequently be reacted according to the protocol described in the preceding process in order to obtain the unsubstituted pyranosyl compound and/or a salt with an acid.
According to a third process, the compounds of formula I can be obtained by reacting a thioxylose derivative of formula:
in which Ac represents the acetyl group,
with a compound of formula:
in which:
in which:
in which A, R′ and R″ retain the same meanings as in the starting compounds.
The compound of formula Ib thus obtained can subsequently be reacted as above in order to obtain the unsubstituted pyranosyl compounds and/or the acid salts.
The compounds of formula I according to the invention can also be prepared from halogenated derivatives of a glycosylated pyridine by a Suzuki-type coupling reaction between two aromatic rings.
According to a general process, the stages consisting in:
a) reacting a compound of formula:
in which Hal is a halogen atom, preferably bromine or iodine, R′ and R″ each independently represent a hydrogen atom, a halogen atom (other than bromine or iodine) or a C1-C4 alkyl group, and R represents a hydrogen atom or a C2-C6 acyl group;
with a heteroarylboronic acid or an alkyl heteroarylboronate of formula:
in which:
in which:
For compounds of this type, another similar process consists in reacting a glycosylated pyridineboronic acid or a glycosylated pyridinylboronate of formula:
in which R represents a hydrogen atom or a C2-C6 acyl group, R′ and R″ each independently represent a hydrogen atom, a halogen atom (other than bromine or iodine) or a C1-C4 alkyl group, and Alk represents a hydrogen atom or a C1-C4 alkyl group,
with a heteroaryl halide of formula:
in which Hal represents a halogen, preferably bromine or iodine, and R1, R2 and R3 each independently represent a hydrogen atom, a halogen atom, preferably a fluorine atom, a cyano group, a C1-C4 alkyl group, a C1-C4 alkoxy group or a trifluoromethyl group; or R1 and R2 form, together with the atoms of the heterocycle to which they are attached, an aromatic ring comprising 6 carbon atoms,
under the same conditions as above, in order to obtain the compound of formula:
in which:
Generally, it is preferable to use 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide or tetra-O-acetyl-5-thio-α-D-xylopyranose when it is a matter of obtaining a β-D-5-thioxylopyranose derivative.
The glycosylation reactions described above generally result in a mixture of the isomers of α and β configuration and it is generally necessary to optimize the operating conditions in order to obtain proportions favorable to the isomer of β configuration. For this same reason, it may also be necessary to carry out purifications, either by recrystallization or by chromatography, in order to obtain the pure β isomer.
The aim of the following examples is to illustrate the invention and they should under no circumstances limit the scope thereof. The melting points were measured on a Kofler bench or in a capillary tube and the Nuclear Magnetic Resonance spectral values are characterized by the chemical shift, calculated with respect to TMS, by the number of protons associated with a signal and by the shape of the signal (s for singlet, d for doublet, t for triplet, q for quartet and m for multiplet). The operating frequency and the solvent used are shown for each compound.
The following abbreviations have been used:
mM means millimole (10−3 mol)
DMSO denotes dimethyl sulfoxide
THF denotes tetrahydrofuran
CHCl3 denotes chloroform
DME denotes dimethoxyethane
The “pinacolatoboryl” group means:
5.1 g (37.5 mM) of zinc chloride are melted under reduced pressure, the melt is cooled under an inert atmosphere and then 12 ml of toluene, 12 ml of acetonitrile, 3 g of 4 Å molecular sieve and 2.45 g (15 mM) of 5,6-dichloro-3-pyridinol are added. The temperature of the mixture is brought to 90° C. and 3.78 g (37.5 mM) of triethylamine and 5.86 g (16.5 mM) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide are added. The reaction medium is stirred at 90° C. for 20 minutes and is then cooled and filtered to remove the inorganic salts, which are washed with ethyl acetate. The combined organic phases are washed with a 0.5 N sodium hydroxide solution and then the pH is brought to a value of 3 using a 0.1 N hydrochloric acid solution. The organic phase is subsequently washed with a saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The product is crystallized from ethyl ether and the desired product is obtained in the form of a light brown solid with a yield of 50%.
M.p.=128° C.
[α]D27=−92° (c=0.23; CHCl3).
By carrying out the operation analogously to preparation I, starting from 4-bromo-3-pyridinol, the desired product is obtained in the form of a yellow powder (yield=38%).
M.p.=153° C.
[α]D30=−69° (c=0.31; DMSO).
By carrying out the operation analogously to preparation I, starting from 2-bromo-3-pyridinol, the desired product is obtained in the form of a white powder (yield=41%).
M.p.=156° C.
[α]D24=−78° (c=0.40; CH3OH).
By carrying out the operation analogously to preparation I, starting from 6-bromo-3-pyridinol, the desired product is obtained in the form of a beige powder (yield=43%).
M.p.=145° C.
[α]D29=−20° (c=0.52; DMSO).
By carrying out the operation analogously to preparation I, starting from 2-iodo-6-methyl-3-pyridinol, the desired product is obtained in the form of a white powder (yield=81%).
M.p.=187° C.
[α]D30=−88° (c=0.28; DMSO).
By carrying out the operation analogously to preparation I, starting from 2-chloro-4-methyl-3-pyridinol, the desired product is obtained in the form of a white powder (yield=30%).
M.p.=144° C.
[α]D30=+45° (c=0.37; DMSO).
By carrying out the operation analogously to preparation I, starting from 2-bromo-4-pyridinol, the desired product is obtained in the form of a white solid (yield=37%).
M.p.=162° C. (recrystallized from ether).
[α]D29=−11° (c=0.48; DMSO).
By carrying out the operation analogously to preparation I, starting from 5-bromo-2-fluoro-3-pyridinol, the desired product is obtained in the form of white crystals (yield=39%).
M.p.=120-122° C. (recrystallized from isopropanol).
By carrying out the operation analogously to preparation I, starting from 5-bromo-3-pyridinol, the desired product is obtained in the form of a light brown powder (yield=55%).
M.p.=174° C.
[α]D20=−20° (c=0.23; DMSO).
By carrying out the operation analogously to preparation I, starting from 2-chloro-6-iodo-3-pyridinol, the desired product is obtained in the form of a white powder (yield=53%).
M.p.=188° C. (recrystallized from ethyl ether).
[α]D30=−34° (c=0.39; DMSO).
By carrying out the operation analogously to preparation I, starting from 6-chloro-5-fluoro-3-pyridinol, the desired product is obtained in the form of white flakes (yield=43%).
M.p.=158-162° C. (recrystallized from ethanol).
[α]D27=−21° (c=0.33; DMSO).
By carrying out the operation analogously to preparation I, starting from 2-fluoro-6-iodo-3-pyridinol, the desired product is obtained in the form of a white powder (yield=41%).
M.p.=234° C. (recrystallized from ethyl ether).
[α]D30=−10° (c=0.49; DMSO).
By carrying out the operation analogously to preparation I, starting from 6-chloro-2-pyridinol, the desired product is obtained in the form of a white powder (yield=20%).
M.p.=127° C.
[α]D29=−72° (c=0.33; CHCl3).
By carrying out the operation analogously to preparation I, starting from 5-bromo-2-chloro-3-pyridinol, the desired product is obtained in the form of beige crystals (yield=38%).
M.p.=143-147° C. (crystallized from ethyl ether).
[α]D24=−35° (c=0.15; DMSO).
A solution of 1.7 g (14.17 mM) of 2-cyano-3-pyridinol in 80 ml of acetonitrile is prepared and 4.3 g (18.3 mM) of silver oxide and 3 g of 13× molecular sieve are added with the exclusion of light. The mixture is stirred at 50° C. for 10 min, 6.5 g (18.3 mM) of 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranosyl bromide are then added and the reaction mixture is maintained at 50° C. for 18 hours with stirring. The mixture is subsequently cooled to ambient temperature and filtered through a filtration aid. The filtrate is diluted with ethyl acetate, washed with water, an N sodium hydroxide solution and then water to neutral pH and finally dried over magnesium sulfate and concentrated under reduced pressure. The residual oil is crystallized by addition of ethyl ether. 0.89 g of the expected product is obtained in the form of beige crystals (yield=16%).
1H NMR (300 MHz; CDCl3) δ: 8.43 (m, 1H), 7.53 (m, 2H), 5.49 (t, 1H), 5.30 (d, 1H), 5.19 (m, 2H), 3.18 (m, 1H), 2.76 (m, 1H), 2.10 (m, 9H).
The product comprises a low proportion of α derivative, the anomeric proton of which gives signals at δ=5.76 and δ=5.63.
A solution of 0.354 g (3.34 mM) of sodium carbonate in 3 ml of water, 0.18 g (0.223 mM) of the [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane and 0.68 g (4.46 mM) of 2-methoxy-3-pyridineboronic acid are added to a solution of 1 g (2.23 mM) of 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, in 10 ml of DME. The reaction mixture is heated using microwave radiation at 120° C. for 20 minutes and cooled, water is added and extraction is carried out with ethyl acetate. The organic phase is washed with a 1M sodium carbonate solution and then with water to neutral pH, dried over magnesium sulfate and concentrated under reduced pressure. The evaporation residue is purified by chromatography on a silica column (eluent: toluene/acctone 90/10; v/v) in order to obtain the expected product in the form of a white solid with a yield of 70%.
M.p.=176° C.
[α]D29=+5° (c=0.30; DMSO).
A solution of 0.3 g (0.63 mM) of 6-(2-methoxy-3-pyridinyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to example 1, in 4 ml of a 7M solution of ammonia in methanol is stirred at ambient temperature for 4 hours. The reaction mixture is subsequently concentrated under reduced pressure and the evaporation residue is crystallized from ether. The desired product is obtained in the form of a white solid with a yield of 81%.
M.p.=127° C.
[α]D29=−45° (c=0.26; DMSO).
By carrying out the operation analogously to example 1, starting from 2-chloro-4-methyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VI, and 3-pyridineboronic acid, the desired product is obtained in the form of a white foam (yield=27%).
M.p.=143° C.
[α]D33=+29° (c=0.43; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 3, the desired product is obtained in the form of a white cotton-like product (yield=40%).
M.p.=98° C.
[α]D29=+66° (c=0.20; DMSO).
By carrying out the operation analogously to example 1, starting from 2-iodo-6-methyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to preparation V, and 3-furanboronic acid, the desired product is obtained in the form of a white solid (yield=42%).
M.p.=117° C.
[α]D25=−73° (c=0.10; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 5, the desired product is obtained in the form of a cream white solid (yield=81%).
M.p.=162° C.
[α]D29=−117° (c=0.10; DMSO).
By carrying out the operation analogously to example 1, starting from 2-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation III, and 5-methyl-2-furanboronic acid, the desired product is obtained in the form of a white solid (yield=45%).
M.p.=128° C.
[α]D32=−68° (c=0.27; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 7, the desired product is obtained in the form of a white solid (yield=83%).
M.p.=191° C.
[α]D30=−103° (c=0.28; DMSO).
By carrying out the operation analogously to example 3, starting from 2-chloro-6-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation X, the desired product is obtained in the form of a beige powder (yield=34%).
M.p.=155° C.
[α]D36=−38° (c=0.13; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 9, the desired product is obtained in the form of a beige powder (yield=35%).
M.p.=180° C.
[α]D35=−51° (c=0.11; DMSO).
By carrying out the operation analogously to example 1, starting from 5-bromo-2-fluoro-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VIII, and 4-pyridineboronic acid, the desired product is obtained in the form of a beige foam (yield=53%).
M.p.=143-144° C.
[α]D30=+8° (c=0.26; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 11, the desired product is obtained in the form of a pink foam (yield=59%).
M.p.=98-102° C.
[α]D30=−61° (c=0.28; DMSO).
By carrying out the operation analogously to example 1, starting from 2-chloro-6-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation X, and 2-methoxy-3-pyridineboronic acid, the desired product is obtained in the form of a pink solid (yield=40%).
M.p.=221° C.
[α]D30=−44° (c=0.20; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 13, the desired product is obtained in the form of a white cotton-like product (yield=60%).
M.p.=102° C. (recrystallized from a methanol/water mixture).
[α]D30=−53° (c=0.16; DMSO).
By carrying out the operation analogously to example 1, starting from 2-chloro-6-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation X, and 2-fluoro-3-pyridineboronic acid, the desired product is obtained in the form of a white powder (yield=27%).
M.p.=227° C. (recrystallized from ethanol).
[α]D30=−38° (c=0.61; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 15, the desired product is obtained in the form of a white cotton-like product (yield=80%).
M.p.=153° C. (recrystallized from an ethanol/water mixture).
[α]D30=−28° (c=0.48; DMSO).
By carrying out the operation analogously to example 1, starting from 2-chloro-6-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation X, and 2-fluoro-4-pyridineboronic acid, the desired product is obtained in the form of a white powder (yield=37%).
M.p.=226° C. (recrystallized from a water/acetonitrile mixture).
[α]D32=−34° (c=0.31; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 17, the desired product is obtained in the form of a white powder (yield=27%).
M.p.=195° C. (recrystallized from an isopropanol/water mixture).
[α]D32=−41° (c=0.18; DMSO).
By carrying out the operation analogously to example 1, starting from 2-chloro-6-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation X, and 6-fluoro-3-pyridineboronic acid, the desired product is obtained in the form of a white powder (yield=43%).
M.p.=226° C. (recrystallized from a water/acetonitrile mixture).
[α]D32=−23° (c=0.26; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 19, the desired product is obtained in the form of white needles (yield=27%).
M.p.=199° C. (recrystallized from an ethanol/water mixture).
[α]D32=−33° (c=0.33; DMSO).
By carrying out the operation analogously to example 11, starting from 2-fluoro-6-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation XII, the desired product is obtained in the form of a white cotton-like product (yield=47%).
M.p.=164° C. (recrystallized from a water/acetonitrile mixture).
[α]D30=−2° (c=0.14; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 21, the desired product is obtained in the form of a white powder (yield=34%).
M.p.=196° C. (recrystallized from a methanol/water mixture).
[α]D30=−40° (c=0.38; DMSO).
By carrying out the operation analogously to example 11, starting from 2-chloro-6-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation X, the desired product is obtained in the form of a white solid (yield=13%).
M.p.=179° C. (recrystallized from ethyl ether).
[α]D30=−31° (c=0.30; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 23, the desired product is obtained in the form of a yellow powder (yield=47%).
M.p.=186° C. (recrystallized from a methanol/water mixture).
[α]D30=−36° (c=0.17; DMSO).
By carrying out the operation analogously to example 1, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to preparation IX, and 2-chloro-3-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=21%).
M.p.=162° C.
[α]D29=−16° (c=0.36; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 25, the desired product is obtained in the form of a white solid (yield=79%).
M.p.=215° C.
[α]D29=−47° (c=0.35; DMSO).
By carrying out the operation analogously to example 1, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to preparation IX and 6-methoxy-3-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=72%).
M.p.=172° C.
[α]D29=−9 (c=0.24; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 27, the desired product is obtained in the form of a white solid (yield=57%).
M.p.=189° C.
[α]D30=−47° (c=0.34; DMSO).
By carrying out the operation analogously to example 1, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IX, and 6-chloro-3-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=33%).
M.p.=194° C.
[α]D29=−17° (c=0.30; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 29, the desired product is obtained in the form of a white solid (yield=72%).
M.p.=211° C.
[α]D30=−46° (c=0.45; DMSO).
By carrying out the operation analogously to example 1, starting from 5-bromo-3-pyridinyl 2,3,4-ti-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IX, and 2-methoxy-3-pyridineboronic acid, the desired product is obtained in the form of an ecru solid (yield=63%).
M.p.=167° C.
[α]D29=−13° (c=0.27; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 31, the desired product is obtained in the form of a white solid (yield=77%).
M.p.=209° C.
[α]D29=−90° (c=0.22; DMSO).
By carrying out the operation analogously to example 1, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 5-methyl-2-furanboronic acid, the desired product is obtained in the form of an ecru solid (yield=74%).
M.p.=134° C.
[α]D29=+22° (c=0.23; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 33, the desired product is obtained in the form of a fine ecru solid (yield=71%).
M.p.=168° C.
[α]D30=−38° (c=0.30; DMSO).
By carrying out the operation analogously to example 1, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 6-methyl-3-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=62%).
M.p.=181° C.
[α]D29=+15° (c=0.21; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 35, the desired product is obtained in the form of a white powder (yield=48%).
M.p.=228° C.
[α]D29=−46° (c=0.31; DMSO).
By carrying out the operation analogously to example 1, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 6-chloro-3-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=41%).
M.p.=204° C.
[α]D29=+5° (c=0.22; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 37, the desired product is obtained in the form of a white solid (yield=62%).
M.p.=170° C. (recrystallized from water).
[α]D30=−32° (c=0.34; DMSO).
By carrying out the operation analogously to example 1, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 2-chloro-3-pyridineboronic acid, the desired product is obtained in the form of an ecru solid (yield=43%).
M.p.=180° C.
[α]D29=−8° (c=0.42; DMSO).
0.394 g (0.82 mM) of product obtained according to example 39, 25 ml of methanol and 0.025 ml of an 8% solution of sodium methoxide in methanol are mixed. The mixture is stirred at ambient temperature for 40 minutes and the precipitate obtained is filtered off and dried under reduced pressure at 40° C. The expected product is obtained in the form of an off-white powder with a yield of 93%.
M.p.=203° C.
[α]D28=−51° (c=0.30; DMSO).
0.633 g (1.45 mM) of 5,6-dichloro-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation I, 0.214 g (1.74 mM) of 4-pyridineboronic acid, 0.595 g (3.9 mM) of cesium fluoride and 0.118 g (0.145 mM) of the [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane are mixed in 6 ml of DME. The mixture is heated at 125° C. for 90 minutes using microwave radiation. The cold mixture is filtered, rinsing is carried out with methanol and the combined organic phases are concentrated under reduced pressure. The evaporation residue is purified by chromatography on a silica column, elution being carried out using a dichloromethane/ethyl acetate mixture (80/20 and 50/50; v/v). The expected product is obtained in the form of a light brown solid with a yield of 20%.
M.p.=153° C.
[α]D27=−52° (c=0.10; CHCl3).
0.315 g (0.656 mM) of product obtained according to example 41, 20 ml of methanol and 0.02 ml of an 8% solution of sodium methoxide in methanol are mixed. The mixture is stirred at ambient temperature for 40 minutes and the precipitate obtained is filtered off and dried under reduced pressure at 50° C. The expected product is obtained in the form of a beige powder with a yield of 82%.
M.p.=226° C.
[α]D28=−49° (c=0.15; DMSO).
By carrying out the operation analogously to example 41, starting from 6-chloro-5-fluoro-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation XI, the desired product is obtained in the form of a white powder (yield=38%).
M.p.=165° C.
[α]D29=−28° (c=0.23; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 43, the desired product is obtained in the form of a gray powder (yield=55%).
M.p.=192° C.
[α]D29=−54° (c=0.12; DMSO).
By carrying out the operation analogously to example 41, starting from 6-chloro-2-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation XIII, the desired product is obtained in the form of a cream powder (yield=65%).
M.p.=137° C.
[α]D28=−41° (c=0.32; CHCl3).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 45, the desired product is obtained in the form of a greenish powder (yield=98%).
M.p.=178° C.
[α]D29=−23° (c=0.28; DMSO).
By carrying out the operation analogously to example 41, starting from 6-chloro-2-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation XIII, and 3-pyridineboronic acid, the desired product is obtained in the form of a cream powder (yield=38%).
M.p.=141° C.
[α]D29=−31° (c=0.26; CHCl3).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 47, the desired product is obtained in the form of a cream powder (yield=99%).
M.p.=179° C.
[α]D29=−44° (c=0.22; DMSO).
A mixture composed of 2.5 g (5.59 mM) of 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IX, 9 ml of DME, 0.136 g (0.166 mM) of the [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane, 2.12 g (8.34 mM) of bis(pinacolato)diborane and 1.64 g (16.7 mM) of potassium acetate is heated at 110° C. for 30 minutes using microwave radiation under an inert atmosphere. After cooling, the reaction medium is filtered and 0.52 g (2.97 mM) of 2-bromo-5-fluoropyridine, 0.24 g (0.29 mM) of the [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane and 4.45 ml of a 1M aqueous potassium carbonate solution are added to the filtrate. The mixture is again heated at 120° C. for 20 minutes using microwave radiation. The medium is cooled, diluted with water and extracted with ethyl acetate. The organic phase is washed with an aqueous sodium bicarbonate solution and then with water, dried over magnesium sulfate and concentrated under reduced pressure. The evaporation residue is purified by chromatography on a silica column, elution being carried out using a toluene/acetone mixture (80/20; v/v). The product obtained is triturated from ether and filtered off. The desired product is obtained in the form of white crystals with a yield of 71%.
M.p.=164-166° C.
[α]D22=−16° (c=0.23; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 49, the desired product is obtained in the form of white crystals (yield=69%).
M.p.=166-190° C. (recrystallized from water).
[α]D22=−85° (c=0.59; DMSO).
By carrying out the operation analogously to example 49, starting from 5-bromo-2-fluoro-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VIII and 3-bromopyridine, the desired product is obtained in the form of a gray solid (yield=26%).
M.p.=67-68° C.
[α]D33=−8° (c=1.90; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 51, the desired product is obtained in the form of a white solid (yield=86%).
M.p.=215-216° C.
[α]D33=−70° (c=0.62; DMSO).
By carrying out the operation analogously to example 49, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IX, and 4-chloro-3-methylpyridine, the desired product is obtained in the form of beige crystals (yield=15%).
M.p.=153-174° C. (recrystallized from ether).
[α]D23=−2° (c=0.17; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 53, the desired product is obtained in the form of a beige cotton-like product (yield=50%).
M.p.=194-214° C.
[α]D23=−58° (c=0.20; DMSO).
By carrying out the operation analogously to example 53, starting from 2-bromo-3-methylpyridine, the desired product is obtained in the form of a white solid (yield=17%).
M.p.=148-150° C. (recrystallized from ether).
[α]D32=−22° (c=0.25; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 55, the desired product is obtained in the form of a beige solid (yield=67%).
M.p.=162-175° C.
[α]D32=−44° (c=0.32; DMSO).
By carrying out the operation analogously to example 53, starting from 5-bromo-2,4-dimethylthiazole, the desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 42, starting from the product prepared according to example 57, the desired product is obtained in the form of a white solid (yield=32%).
M.p.=150° C.
[α]D30=−61° (c=0.10; DMSO).
By carrying out the operation analogously to example 53, starting from 4-bromo-1-methyl-3-(trifluoromethyl)-1H-pyrazole, the desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 2, starting from the product prepared according to example 59, the desired product is obtained in the form of a white solid (yield=26%).
M.p.=210° C.
[α]D29=−60° (c=0.24; DMSO).
By carrying out the operation analogously to example 53, starting from 4-bromo-5-methyl-3-(trifluoromethyl)-1H-pyrazole, the desired product is obtained and is used directly in the deacetylation stage.
5-[5-Methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-3-pyridinyl 5-thio-β-D-xylopyranoside
By carrying out the operation analogously to example 2, starting from the product prepared according to example 61, the desired product is obtained in the form of a beige solid (yield=6%).
M.p.=234° C.
[α]D29=−76° (c=0.21; DMSO).
By carrying out the operation analogously to example 53, starting from 4-iodo-5-methylisoxazole, the desired product is obtained in the form of a white solid (yield=28%).
M.p.=127° C.
[α]D28=−28° (c=0.22; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 63, the desired product is obtained in the form of a white solid (yield=79%).
M.p.=209° C.
[α]D28=−87° (c=0.19; DMSO).
5-Pyrazinyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
By carrying out the operation analogously to example 53, starting from iodopyrazine, the desired product is obtained in the form of a white powder (yield=13%).
M.p.=145° C.
[α]D29=−11° (c=0.22; DMSO).
5-Pyrazinyl-3-pyridinyl 5-thio-β-D-xylopyranoside
By carrying out the operation analogously to example 2, starting from the product prepared according to example 65, the desired product is obtained in the form of a white solid (yield=70%).
M.p.=197° C.
[α]D29=−68° (c=0.20; DMSO).
By carrying out the operation analogously to example 53, starting from 2-bromopyrimidine, the desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 2, starting from the product prepared according to example 67, the desired product is obtained in the form of a white powder (yield=31%).
M.p.=201° C.
[α]D29=−69° (c=0.23; DMSO).
By carrying out the operation analogously to example 53, starting from 2-bromothiazole, the desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 2, starting from the product prepared according to example 69, the desired product is obtained in the form of a white powder (yield=26%).
M.p.=204° C.
[α]D29=−93° (c=0.20; DMSO).
By carrying out the operation analogously to example 53, starting from 5-bromo-1-methyl-1H-imidazole, the desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 2, starting from the product prepared according to example 71, the desired product is obtained in the form of a beige powder (yield=25%).
M.p.=213° C.
[α]D29=−83° (c=0.32; DMSO).
By carrying out the operation analogously to example 1, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IX, and 2-chloro-4-pyridineboronic acid, the desired product is obtained in the form of an ecru solid (yield=55%).
M.p.=105-108° C.
[α]D30=−21° (c=0.30; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 73, the desired product is obtained in the form of a white solid (yield=68%).
M.p.=204° C.
[α]D30=−76° (c=0.34; DMSO).
By carrying out the operation analogously to example 73, starting from 3-chloro-4-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=39%).
M.p.=175° C.
[α]D25=−22° (c=0.25; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 75, the desired product is obtained in the form of a white solid (yield=88%).
M.p.=208° C.
[α]D25=−72° (c=0.24; DMSO).
By carrying out the operation analogously to example 1, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 6-methoxy-3-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=65%).
M.p.=74° C.
[α]D29=+10° (c=0.44; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 77, the desired product is obtained in the form of a white solid (yield=30%).
M.p.=167° C.
[α]D28=−27° (c=0.23; DMSO).
By carrying out the operation analogously to example 1, starting from 2-chloro-4-methyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to preparation VI, and 3-furanboronic acid, the desired product is obtained in the form of an ecru solid (yield=77%).
M.p.=164° C.
[α]D33=+61° (c=0.23; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 79, the desired product is obtained in the form of a white cotton-like product (yield=59%).
M.p.=95° C.
[α]D29=+83° (c=0.18; DMSO).
By carrying out the operation analogously to example 79, starting from 3,5-dimethyl-4-isoxazoleboronic acid, the desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 42, starting from the product prepared according to example 81, the desired product is obtained in the form of a white powder (yield=20%).
M.p.=70-100° C.
[α]D25=+115° (c=0.10; DMSO).
By carrying out the operation analogously to example 1, starting from 4-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation II, and 3-pyridineboronic acid, the desired product is obtained in the form of an ecru solid (yield=57%).
M.p.=159° C.
[α]D32=−72° (c=0.25; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 83, the desired product is obtained in the form of a white solid (yield=86%).
M.p.=212° C.
[α]D30=−53° (c=0.35; DMSO).
By carrying out the operation analogously to example 1, starting from 2-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation III, and 2-benzofuranboronic acid, the desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 42, starting from the product prepared according to example 85, the desired product is obtained in the form of a white solid (yield=15%).
M.p.=215° C.
[α]D32=−68° (c=0.26; DMSO).
By carrying out the operation analogously to example 83, starting from 3-furanboronic acid, the desired product is obtained in the form of an ecru solid (yield=36%).
M.p.=167° C.
[α]D31=−77° (c=0.37; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 87, the desired product is obtained in the form of a white solid (yield=64%).
M.p.=231° C.
[α]D32=−112° (c=0.28; DMSO).
By carrying out the operation analogously to example 83, starting from 4-pyridineboronic acid, the desired product is obtained in the form of an ecru solid (yield=55%).
M.p.=185° C.
[α]D31=−114° (c=0.47; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 89, the desired product is obtained in the form of a white solid (yield=84%).
M.p.=212° C.
[α]D32=−54° (c=0.26; DMSO).
By carrying out the operation analogously to example 73, starting from 2-benzothiopheneboronic acid, the desired product is obtained in the form of a beige solid (yield=72%).
M.p.=168° C.
[α]D30=+7° (c=0.36; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 91, the desired product is obtained in the form of an ecru solid (yield=91%).
M.p.=235° C.
[α]D32=−50° (c=0.32; DMSO).
By carrying out the operation analogously to example 85, starting from 2-thiopheneboronic acid, the desired product is obtained in the form of an ecru solid (yield=51%).
M.p.=166° C.
[α]D32=−112° (c=0.20; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 93, the desired product is obtained in the form of an ecru solid (yield=80%).
M.p.=130° C.
[α]D30=−90° (c=0.46; DMSO).
By carrying out the operation analogously to example 73, starting from 5-methyl-2-furanboronic acid, the desired product is obtained in the form of a beige solid (yield=56%).
M.p.=124° C.
[α]D30=+1° (c=0.40; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 95, the desired product is obtained in the form of a white solid (yield=55%).
M.p.=188° C.
[α]D30=−75′ (c=0.40; DMSO).
By carrying out the operation analogously to example 1, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 2-benzofuranboronic acid, the desired product is obtained in the form of an ecru solid (yield=65%).
M.p.=179° C.
[α]D30=+13° (c=0.31; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 97, the desired product is obtained in the form of a white solid (yield=50%).
M.p.=195° C.
[α]D30=−24° (c=0.28; DMSO).
By carrying out the operation analogously to example 97, starting from 3-thiopheneboronic acid, the desired product is obtained in the form of a white foam (yield=66%).
M.p.=158° C.
[α]D35=−9° (c=0.30; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 99, the desired product is obtained in the form of an off-white solid (yield=98%).
M.p.=154° C.
[α]D30=−50° (c=0.28; DMSO).
By carrying out the operation analogously to example 85, starting from 2-furanboronic acid, the desired product is obtained in the form of an ecru solid (yield=46%).
M.p.=160° C.
[α]D28=−60° (c=0.51; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 101, the desired product is obtained in the form of an ecru solid (yield=91%).
M.p.=184° C.
[α]D34=−108° (c=0.30; DMSO).
By carrying out the operation analogously to example 97, starting from 2-furanboronic acid, the desired product is obtained in the form of an off-white solid (yield=64%).
M.p.=133° C.
[α]30=+16° (c=0.30; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 103, the desired product is obtained in the form of a pale pink solid (yield=92%).
M.p.=146° C.
[α]D30=−53° (c=0.30; DMSO).
By carrying out the operation analogously to example 85, starting from 4-pyridineboronic acid, the desired product is obtained in the form of an ecru solid (yield=28%).
M.p.=161° C.
[α]D28=−82° (c=0.30; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 105, the desired product is obtained in the form of a beige solid (yield=97%).
M.p.=129° C.
[α]D30=−56° (c=0.40; DMSO).
By carrying out the operation analogously to example 97, starting from 2-thiopheneboronic acid, the desired product is obtained in the form of an ecru solid (yield=68%).
M.p.=172° C.
[α]D33=−6° (c=0.40; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 107, the desired product is obtained in the form of a beige solid (yield=80%).
M.p.=134° C.
[α]D30=−40° (c=0.38; DMSO).
By carrying out the operation analogously to example 73, starting from 2-furanboronic acid, the desired product is obtained in the form of a beige foam (yield=61%).
M.p.=184° C.
[α]D25=−10° (c=0.28; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 109, the desired product is obtained in the form of a beige solid (yield=66%).
M.p.=215° C.
[α]D30=−68° (c=0.25; DMSO).
By carrying out the operation analogously to example 85, starting from 3-pyridineboronic acid, the desired product is obtained in the form of an ocher solid (yield=28%).
M.p.=70° C.
[α]D24=−70° (c=0.35; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 111, the desired product is obtained in the form of an ocher solid (yield=89%).
M.p.=80° C.
[α]D30=−40° (c=0.44; DMSO).
By carrying out the operation analogously to example 85, starting from 3-furanboronic acid, the desired product is obtained in the form of a white solid (yield=20%).
M.p.=185° C.
[α]D25=−99° (c=0.28; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 113, the desired product is obtained in the form of a white solid (yield=91%).
M.p.=128° C.
[α]D24=−74° (c=0.30; DMSO).
By carrying out the operation analogously to example 73, starting from 2-benzofuranboronic acid, the desired product is obtained in the form of an ecru solid (yield=70%).
M.p.=125° C.
[α]D29=+8° (c=0.40; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 115, the desired product is obtained in the form of a white solid (yield=86%).
M.p.=210° C.
[α]D24=−44° (c=0.30; DMSO).
By carrying out the operation analogously to example 97, starting from 3-furanboronic acid, the desired product is obtained in the form of an ecru solid (yield=66%).
M.p.=187° C.
[α]D29=+3° (c=0.25; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 117, the desired product is obtained in the form of an ecru solid (yield=85%).
M.p.=132° C.
[α]D29=−29° (c=0.27; DMSO).
By carrying out the operation analogously to example 97, starting from 3-pyridineboronic acid, the desired product is obtained in the form of an ecru solid (yield=50%).
M.p.=196° C.
[α]D26=+4° (c=0.27; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 119, the desired product is obtained in the form of a pale pink solid (yield=99%).
M.p.=152° C.
[α]D28=−40° (c=0.30; DMSO).
By carrying out the operation analogously to example 97, starting from 4-pyridineboronic acid, the desired product is obtained in the form of an off-white solid (yield=31%).
M.p.=189° C.
[α]D29=+4° (c=0.40; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 121, the desired product is obtained in the form of an ecru solid (yield=82%).
M.p.=248° C.
[α]D26=−35° (c=0.34; DMSO).
By carrying out the operation analogously to example 73, starting from 4-pyridineboronic acid, the desired product is obtained in the form of an off-white solid (yield=40%).
M.p.=138° C.
[α]D27=−14° (c=0.35; DMSO).
0.41 g (0.92 mM) of product obtained according to example 123 is added to a mixture of 6 ml of THF and 6 ml of water. The medium is cooled using an ice bath, 0.385 g (9.18 mM) of lithium hydroxide (monohydrate) is added and the mixture is stirred for 90 minutes. The reaction medium is partially concentrated under reduced pressure and the resulting aqueous phase is brought to pH 5-6 using a 1N hydrochloric acid solution. The precipitated product is filtered off and dried. The desired product is thus obtained in the form of a white solid with a yield of 88%.
M.p.=213° C.
[α]D27=−48° (c=0.40; DMSO).
By carrying out the operation analogously to example 73, starting from 3-furanboronic acid, the desired product is obtained in the form of a beige solid (yield=32%).
M.p.=127° C.
[α]D27=−20° (c=0.29; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 125, the desired product is obtained in the form of an ecru solid (yield=93%).
M.p.=170° C.
[α]D27=−72° (c=0.31; DMSO).
By carrying out the operation analogously to example 73, starting from 3-pyridineboronic acid, the desired product is obtained in the form of an ecru solid (yield=63%).
M.p.=149° C.
[α]D23=−23° (c=0.25; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 127, the desired product is obtained in the form of an ecru solid (yield=50%).
M.p.=203° C.
[α]D23=−8° (c=0.43; DMSO).
By carrying out the operation analogously to example 1, starting from 2-bromo-4-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VII, and 4-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=53%).
M.p.=185° C.
[α]D29=−27° (c=0.13; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 129, the desired product is obtained in the form of a white solid (yield=42%).
M.p.=170° C.
[α]D29=−49° (c=0.10; DMSO).
By carrying out the operation analogously to example 129, starting from 6-fluoro-3-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=51%).
M.p.=151° C.
[α]D29=−34° (c=0.15; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 131, the desired product is obtained in the form of a white solid (yield=94%).
M.p.=171° C.
[α]D29=−66° (c=0.26; DMSO).
By carrying out the operation analogously to example 129, starting from 3-pyridineboronic acid, the desired product is obtained in the form of beige crystals (yield=22%).
M.p.=185° C. (recrystallized from isopropanol).
[α]D31=−21° (c=0.24; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 133, the desired product is obtained in the form of white crystals (yield=66%).
M.p.=197° C. (recrystallized from water).
[α]D29=−83° (c=0.10; DMSO).
By carrying out the operation analogously to example 73, starting from 2-thiopheneboronic acid, the desired product is obtained in the form of an ecru solid (yield=57%).
M.p.=166° C.
[α]D27=+6° (c=0.25; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 135, the desired product is obtained in the form of an ecru solid (yield=78%).
M.p.=205° C.
[α]D30=−68° (c=0.40; DMSO).
A mixture composed of 1 g (5.32 mM) of 3-bromo-5-methoxypyridine, 10 ml of DME, 2.02 g (7.98 mM) of bis(pinacolato)diborane, 0.13 g (0.16 mM) of the [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane and 1.56 g (15.96 mM) of potassium acetate is heated at 110° C. for 30 minutes using microwave radiation under an argon atmosphere. The mixture is cooled and filtered, and 1.59 g (3.55 mM) of 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IX, 0.29 g (0.355 mM) of the [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane and 0.564 g (5.32 mM) of sodium carbonate dissolved in 5 ml of water are added to the filtrate. The reaction mixture is heated at 120° C. for 20 minutes using microwave radiation. The medium is subsequently cooled, water is added and extraction is carried out with ethyl acetate. The organic phase is washed with an aqueous sodium bicarbonate solution and with water, then dried over sodium sulfate and concentrated under reduced pressure. The evaporation residue is purified by chromatography on a silica column (eluent: toluene/isopropanol 90/10; v/v) and the product obtained is triturated in the presence of ether and filtered off. The expected product is obtained in the form of a white solid with a yield of 28%.
M.p.=181° C.
[α]D28=−7° (c=0.26; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 137, the desired product is obtained in the form of a white solid (yield=33%).
M.p.=193° C.
[α]D27=−71° (c=0.40; DMSO).
A solution of 0.208 g (1 mM) of 4-iodo-5-methylisoxazole in 5 ml of THF is prepared under an argon atmosphere and 0.019 g (0.1 mM) of cuprous iodide and 0.060 g (1.5 mM) of 60% sodium hydride in oil are added. The reaction mixture is stirred at ambient temperature for 5 minutes and 0.192 g (1.5 mM) of bis(pinacolato)diborane is added. The reaction mixture is subsequently stirred at ambient temperature for 1 hour, then 4 ml of a saturated sodium bicarbonate solution are added and extraction is carried out with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and concentrated under reduced pressure. The pinacol ester of 5-methyl-4-isoxazoleboronic acid [1H NMR (250 MHz; d6-DMSO) δ=8.44 (s, 1H), 2.55 (s, 3H), 12.27 (s, 12H)] is obtained in the form of a white solid with a yield of 81%. This compound is again reacted with 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, analogously to the process employed for example 1 and the expected compound is thus obtained in the form of a white solid (yield=43%)
M.p.=165° C.
[α]D30=−4° (c=0.31; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 139, the desired product is obtained in the form of a white solid (yield=39%).
M.p.=184° C.
[α]D30=−69° (c=0.25; DMSO).
By carrying out the operation analogously to example 137, starting from 3-bromo-5-methylpyridine and 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, the desired product is obtained in the form of a white solid (yield=38%).
M.p.=189-190° C.
[α]D25=+9° (c=0.20; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 141, the desired product is obtained in the form of a white solid (yield=49%).
M.p.=165-166° C.
[α]D30=−44° (c=0.25; DMSO).
By carrying out the operation analogously to example 137, starting from 3-bromo-5-methylpyridine, the desired product is obtained in the form of a beige solid (yield=45%).
M.p.=180-182° C.
[α]D25=−17° (c=0.24; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 143, the desired product is obtained in the form of a white solid (yield=83%).
M.p.=119-120° C.
[α]D25=−73° (c=0.27; DMSO).
By carrying out the operation analogously to example 1, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IX, and 3-chloro-5-(pinacolatoboryl)pyridine, the desired product is obtained in the form of a white solid (yield=31%).
M.p.=199° C.
[α]D29=−23° (c=0.29; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 145, the desired product is obtained in the form of a white solid (yield=73%).
M.p.=185-187° C.
[α]D29=−23° (c=0.27; DMSO).
By carrying out the operation analogously to example 1, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IX, and 6-cyano-3-(pinacolatoboryl)pyridine, the desired product is obtained in the form of a mauve solid (yield=22%).
M.p.=142-151° C.
[α]D29=−14° (c=0.26; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 147, the desired product is obtained in the form of a white solid (yield=30%).
M.p.=197-203° C.
[α]D29=−68° (c=0.34; DMSO).
By carrying out the operation analogously to example 1, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 3-fluoro-5-(pinacolatoboryl)pyridine, the desired product is obtained in the form of a white solid (yield=22%).
M.p.=197-198° C.
[α]D29=+1° (c=0.22; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 149, the desired product is obtained in the form of a white solid (yield=66%).
M.p.=207-217° C.
[α]D29=−56° (c=0.21; DMSO).
By carrying out the operation analogously to example 137, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IX, and 2-methyl-3-(pinacolatoboryl)pyridine (obtained from 2-methyl-3-pyridinyl trifluoromethanesulfonate), the desired product is obtained in the form of a beige solid (yield=30%).
M.p.=152-153° C.
[α]D29=−21° (c=0.24; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 151, the desired product is obtained in the form of a white solid (yield=85%).
M.p.=204-207° C.
[α]D29=−81° (c=0.21; DMSO).
By carrying out the operation analogously to example 1, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 3-fluoro-5-(pinacolatoboryl)pyridine, the desired product is obtained in the form of a white solid (yield=26%).
M.p.=175-176° C.
[α]D29=−21° (c=0.30; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 153, the desired product is obtained in the form of a white solid (yield=77%).
M.p.=160-171° C.
[α]D29=−72° (c=0.25; DMSO).
By carrying out the operation analogously to example 137, starting from 3-bromo-5-methoxypyridine and 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, the desired product is obtained in the form of a white solid (yield=48%).
M.p.=155° C.
[α]D29=+1° (c=0.47; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 155, the desired product is obtained in the form of a white solid (yield=93%).
M.p.=193° C.
[α]D28=−31° (c=0.42; DMSO).
By carrying out the operation analogously to example 1, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IX, and 1,3,5-trimethyl-4-(pinacolatoboryl)pyrazole, the desired product is obtained in the form of a white solid (yield=60%).
M.p.=166° C.
[α]D29=−26° (c=0.19; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 157, the desired product is obtained in the form of a white powder (yield=48%).
M.p.=174° C.
[α]D29=−82° (c=0.27; DMSO).
By carrying out the operation analogously to example 1, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IX, and 3,5-dimethyl-4-(pinacolatoboryl)pyrazole, the desired product is obtained in the form of a beige solid (yield=45%).
M.p.=95° C. (crystallized from ether).
[α]D29=−22° (c=0.24; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 159, the desired product is obtained in the form of a white powder (yield=41%).
M.p.=227° C.
[α]D28=−86° (c=0.28; DMSO).
By carrying out the operation analogously to example 1, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 6-cyano-3-(pinacolatoboryl)pyridine, the desired product is obtained in the form of a white solid (yield=41%).
M.p.=247° C.
[α]D29=+15° (c=0.20; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 161, the desired product is obtained in the form of a white solid (yield=49%).
M.p.=167° C.
[α]D27=−43° (c=0.30; DMSO).
By carrying out the operation analogously to example 1, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 1,3,5-trimethyl-4-(pinacolatoboryl)-1H-pyrazole, the desired product is obtained in the form of a white solid (yield=54%).
M.p.=156° C.
[α]D28=0° (c=0.24; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 163, the desired product is obtained in the form of a white powder (yield=57%).
M.p.=132° C.
[α]D28=−41° (c=0.29; DMSO).
By carrying out the operation analogously to example 1, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 1-methyl-4-(pinacolatoboryl)-1H-pyrazole, the desired product is obtained in the form of a white solid (yield=46%).
M.p.=183° C.
[α]D28=+7° (c=0.18; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 165, the desired product is obtained in the form of a white solid (yield=65%).
[α]D28=−50° (c=0.20; DMSO).
By carrying out the operation analogously to example 1, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 3,5-dimethyl-4-(pinacolatoboryl)-1H-pyrazole, the desired product is obtained in the form of a white solid (yield=21%).
M.p.=154° C.
[α]D28=−1° (c=0.26; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 167, the desired product is obtained in the form of a white solid (yield=72%).
M.p.=210° C.
[α]D28=−47° (c=0.24; DMSO).
By carrying out the operation analogously to example 1, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IX, and 6-fluoro-3-pyridineboronic acid, the desired product is obtained in the form of a cream solid (yield=56%).
M.p.=167-169° C.
[α]D27=−18° (c=0.23; DMSO).
By carrying out the operation analogously to example 124, starting from the product prepared according to example 169, the desired product is obtained in the form of a white solid (yield=47%).
M.p.=210-212° C.
[α]D24=−47° (c=0.14; DMSO).
By carrying out the operation analogously to example 1, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IX, and 1-methyl-4-(pinacolatoboryl)-1H-pyrazole, the desired product is obtained in the form of a beige solid (yield=58%).
M.p.=68° C.
[α]D29=−19° (c=0.20; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 171, the desired product is obtained in the form of a white solid (yield=72%).
M.p.=216° C.
[α]D29=−74° (c=0.25; DMSO).
By carrying out the operation analogously to example 1, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 2,4-dimethyl-5-(pinacolatoboryl)thiazole, the desired product is obtained in the form of white crystals (yield=21%).
M.p.=174-177° C. (crystallized from ethyl ether).
[α]D32=+9° (c=0.43; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 173, the desired product is obtained in the form of cream crystals (yield=92%).
M.p.=175° C.
[α]D32=−53° (c=0.41; DMSO).
By carrying out the operation analogously to example 137, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 2-methyl-3-(pinacolatoboryl)pyridine (obtained from 2-methyl-3-pyridinyl trifluoromethanesulfonate), the desired product is obtained in the form of a white solid (yield=11%).
M.p.=198-200° C.
[α]D29=−3° (c=0.21; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 175, the desired product is obtained in the form of a white solid (yield=39%).
M.p.=167-168° C.
[α]D32=−26° (c=0.32; DMSO).
0.2 g (0.45 mM) of 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IX, 66 mg (0.53 mM) of 5-pyrimidineboronic acid, 0.281 g (0.90 mM) of resin grafted with benzyltriethylammonium carbonate and 36 mg (0.044 mM) of the [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane are mixed in 3 ml of DME and 2 ml of methanol. The reaction mixture is brought to 120° C. for 30 minutes by heating under microwave radiation. After filtering and rinsing the solid residue with methanol, the resulting solution is concentrated under reduced pressure. The evaporation residue is purified by chromatography on a silica column (eluent: dichloromethane/methanol 70/30; v/v) and the product is subsequently recrystallized from isopropanol in order to obtain the expected product in the form of pearlescent pink crystals with a yield of 50%.
M.p.=213-217° C.
[α]D30=−4 (c=0.10; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 177, the desired product is obtained in the form of a pink powder (yield=67%).
M.p.=196° C.
[α]D30=−96° (c=0.17; DMSO).
By carrying out the operation analogously to example 177, starting from 3,5-dimethyl-4-isoxazoleboronic acid, the desired product is obtained in the form of white crystals (yield=33%).
M.p.=129-131° C.
[α]D30=−36° (c=0.10; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 179, the desired product is obtained in the form of white crystals (yield=70%).
M.p.=222-223° C.
[α]D24=−51° (c=0.10; DMSO).
By carrying out the operation analogously to example 179, starting from 2-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation III, the desired product is obtained in the form of a pink foam (yield=49%).
M.p.=68-72° C.
[α]D27=−92° (c=0.24; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 181, the desired product is obtained in the form of an off-white powder (yield=65%).
M.p.=112° C.
[α]D27=−53° (c=0.24; DMSO).
By carrying out the operation analogously to example 177, starting from 2-fluoro-3-pyridineboronic acid, the desired product is obtained in the form of beige crystals (yield=52%).
M.p.=169-170° C. (recrystallized from isopropanol).
[α]D24=−37° (c=0.17; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 183, the desired product is obtained in the form of a white solid (yield=46%).
M.p.=193-196° C.
[α]D31=−81° (c=0.11; DMSO).
By carrying out the operation analogously to example 177, starting from 2-fluoro-4-pyridineboronic acid, the desired product is obtained in the form of a beige solid (yield=70%).
M.p.=122-125° C.
[α]D31=−29° (c=0.11; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 185, the desired product is obtained in the form of a white solid (yield=76%).
M.p.=208° C. (recrystallized from methanol).
[α]D28=−92° (c=0.32; DMSO).
By carrying out the operation analogously to example 183, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, the desired product is obtained in the form of a cream powder (yield=38%).
M.p.=153° C.
[α]D26=−7° (c=0.19; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 187, the desired product is obtained in the form of a white powder (yield=88%).
M.p.=181° C. (recrystallized from water).
[α]D27=−48° (c=0.17; DMSO).
By carrying out the operation analogously to example 187, starting from 5-pyrimidineboronic acid, the desired product is obtained in the form of a pink solid (yield=39%).
M.p.=215° C. (crystallized from ethyl ether).
[α]D28=−2° (c=0.18; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 189, the desired product is obtained in the form of a pink powder (yield=77%).
M.p.=188° C.
[α]D27=−45° (c=0.19; DMSO).
By carrying out the operation analogously to example 187, starting from 3,5-dimethyl-4-isoxazoleboronic acid, the desired product is obtained in the form of a white solid (yield=21%).
M.p.=172° C. (recrystallized from ethyl ether).
[α]D28=−13° (c=0.14; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 191, the desired product is obtained in the form of a fluffy white solid (yield=52%).
M.p.=138° C.
[α]D27=−43° (c=0.10; DMSO).
By carrying out the operation analogously to example 187, starting from 6-fluoro-3-pyridineboronic acid, the desired product is obtained in the form of white flakes (yield=30%).
M.p.=185° C. (recrystallized from an ethanol/water mixture).
[α]D28=+3° (c=0.43; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 193, the desired product is obtained in the form of a white powder (yield=98%).
M.p.=143-156° C.
[α]D28=−56° (c=0.26; DMSO).
By carrying out the operation analogously to example 177, starting from 5-bromo-2-fluoro-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VIII, and 2-fluoro-4-pyridineboronic acid, the desired product is obtained in the form of a pink solid (yield=65%).
M.p.=142-144° C.
[α]D30=−9° (c=0.25; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 195, the desired product is obtained in the form of a gray solid (yield=65%).
M.p.=145-146° C.
[α]D30=+8° (c=0.24; DMSO).
By carrying out the operation analogously to example 195, starting from 6-fluoro-3-pyridineboronic acid, the desired product is obtained in the form of a pink solid (yield=35%).
M.p.=135-136° C.
[α]D30=−22° (c=0.28; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 197, the desired product is obtained in the form of a gray solid (yield=71%).
M.p.=158-159° C.
[α]D30=−72° (c=0.30; DMSO).
By carrying out the operation analogously to example 177, starting from 3-thienylboronic acid, the desired product is obtained in the form of a beige solid (yield=25%).
M.p.=175° C.
[α]D27=+6° (c=0.25; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 199, the desired product is obtained in the form of a white solid (yield=32%).
M.p.=212° C.
[α]D27=−113° (c=0.10; DMSO).
By carrying out the operation analogously to example 187, starting from 2-chloro-4-pyridineboronic acid, the desired product is obtained in the form of a pink powder (yield=21%).
M.p.=226° C.
[α]D29=+12° (c=0.20; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 201, the desired product is obtained in the form of a yellow powder (yield=62%).
M.p.=179° C. (recrystallized from water).
[α]D29=−36° (c=0.13; DMSO).
By carrying out the operation analogously to example 177, starting from 4-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation II, and 3,5-dimethyl-4-isoxazoleboronic acid, the desired product is obtained in the form of a pink powder (yield=30%).
M.p.=150-155° C.
[α]D25=−38° (c=0.10; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 203, the desired product is obtained in the form of a beige powder (yield=62%).
M.p.=175-179° C.
[α]D31=−159° (c=0.10; DMSO).
By carrying out the operation analogously to example 177, starting from 2-iodo-6-methyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation V, and 3-pyridineboronic acid, the desired product is obtained in the form of an ocher powder (yield=42%).
M.p.=92-102° C.
[α]D26=−82° (c=0.10; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 205, the desired product is obtained in the form of a yellow powder (yield=72%).
M.p.=160-170° C.
[α]D25−19° (c=0.18; DMSO).
By carrying out the operation analogously to example 205, starting from 4-pyridineboronic acid, the desired product is obtained in the form of a pale pink powder (yield=54%).
M.p.=140-144° C.
[α]D34=−54° (c=0.11; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 207, the desired product is obtained in the form of a beige powder (yield=95%).
M.p.=196-200° C.
[α]D25=−35° (c=0.10; DMSO).
By carrying out the operation analogously to example 187, starting from 2-fluoro-4-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=30%).
M.p.=179° C.
[α]D30=+1° (c=0.82; DMSO).
By carrying out the operation analogously to example 124, starting from the product prepared according to example 209, the desired product is obtained in the form of a white solid (yield=56%).
M.p.=219° C.
[α]D32=−49° (c=0.28; DMSO).
By carrying out the operation analogously to example 181, starting from 5-pyrimidineboronic acid, the desired product is obtained in the form of a cream solid (yield=48%).
M.p.=205° C. (recrystallized from ethyl ether).
[α]D30=−76° (c=0.61; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 211, the desired product is obtained in the form of a pink powder (yield=36%).
M.p.=195° C. (recrystallized from a methanol/ethyl ether mixture).
[α]D30=−38° (c=0.27; DMSO).
A solution of 0.421 g (1 mM) of 6-chloro-5-fluoro-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation XI, in 4 ml of DME is prepared. 0.211 g (1.5 mM) of 6-fluoro-3-pyridineboronic acid, 0.082 g (0.1 mM) of the [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane and then 1.5 ml (1.5 mM) of a 1M potassium carbonate solution are added. The reaction medium is heated at 120° C. for 30 min using microwave radiation. After cooling and separating by settling, the organic phase is withdrawn and the extraction is completed by the addition of ethyl acetate. The combined organic phases are evaporated under reduced pressure and the evaporation product is dissolved in 4 ml of dichloromethane and washed successively with water, a 1M potassium carbonate solution and then water. The organic phase is filtered through a hydrophobic membrane and evaporated under a stream of nitrogen. The desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 2, starting from the product prepared according to example 213, the desired product is obtained in the form of a white solid with a yield of 75%.
M.p.=184° C.
[α]D33=−54° (c=0.10; DMSO).
By carrying out the operation analogously to example 213, starting from 6-methyl-3-pyridineboronic acid, the desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 2, starting from the product prepared according to example 215, the desired product is obtained in the form of a white solid (yield=58%).
M.p.=184° C.
[α]D33=−54° (c=0.24; DMSO).
By carrying out the operation analogously to example 213, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IX, and 2-methoxy-5-pyrimidineboronic acid, the desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 2, starting from the product prepared according to example 217, the desired product is obtained in the form of a white solid (yield=46%).
M.p.=215° C.
[α]D30=−75° (c=0.10; DMSO).
By carrying out the operation analogously to example 213, starting from 2-methyl-4-pyridineboronic acid, the desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 2, starting from the product prepared according to example 219, the desired product is obtained in the form of a white solid (yield=31%).
M.p.=143° C.
[α]D30=−27° (c=0.10; DMSO).
By carrying out the operation analogously to example 213, starting from 2-methoxy-3-pyridineboronic acid, the desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 2, starting from the product prepared according to example 221, the desired product is obtained in the form of a white solid (yield=77%).
M.p.=141° C.
[α]D30=−35° (c=0.10; DMSO).
By carrying out the operation analogously to example 213, starting from 1-methyl-4-(pinacolatoboryl)-1H-pyrazole, the desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 2, starting from the product prepared according to example 223, the desired product is obtained in the form of a white solid (yield=41%).
M.p.=206° C.
[α]D30=−46° (c=0.10; DMSO).
By carrying out the operation analogously to example 213, starting from 3,5-dimethyl-4-isoxazoleboronic acid, the desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 2, starting from the product prepared according to example 225, the desired product is obtained in the form of a white solid (yield=33%).
M.p.=177° C.
[α]D30=−48° (c=0.12; DMSO).
By carrying out the operation analogously to example 213, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 2-methoxy-5-pyrimidineboronic acid, the desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 2, starting from the product prepared according to example 227, the desired product is obtained in the form of a white solid (yield=20%).
M.p.=134° C.
[α]D26=−53° (c=0.10; DMSO).
By carrying out the operation analogously to example 213, starting from 5-pyrimidineboronic acid, the desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 2, starting from the product prepared according to example 229, the desired product is obtained in the form of a white solid (yield=19%).
M.p.=192° C.
[α]D33=−34° (c=0.12; DMSO).
A solution of 0.448 g (1 mM) of 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IX, in 2 ml of DME is used to prepare the boronate according to the method described in example 49. The reaction medium is subsequently filtered and then rinsing is carried out with DME. 0.422 g (1.66 mM) of 2,3-dichloropyridine, 0.020 g (0.025 mM) of the [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane and then 1.5 ml (1.5 mM) of a 1M potassium carbonate solution are added to the resulting solution. The reaction medium is heated at 120° C. for 30 min using microwave radiation. After cooling and separating by settling, the organic phase is withdrawn and the extraction is completed by the addition of ethyl acetate. The combined organic phases are evaporated under reduced pressure and the evaporation product is dissolved in 4 ml of dichloromethane and washed successively with water, a 1M potassium carbonate solution and then water. The organic phase is filtered through a hydrophobic membrane and evaporated under a stream of nitrogen. The desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 2, starting from the product prepared according to example 231, the desired product is obtained in the form of a white solid (yield=50%).
M.p.=193° C.
[α]D30=−46° (c=0.18; DMSO).
By carrying out the operation analogously to example 231, starting from 2-bromo-5-methylpyridine, the desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 2, starting from the product prepared according to example 233, the desired product is obtained in the form of a white solid (yield=33%).
M.p.=199° C.
[α]D29=−64° (c=0.18; DMSO).
By carrying out the operation analogously to example 231, starting from 2-bromo-4-methylpyridine, the desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 2, starting from the product prepared according to example 235, the desired product is obtained in the form of a white powder (yield=20%).
M.p.=166° C.
[α]D29=−80° (c=0.10; DMSO).
By carrying out the operation analogously to example 231, starting from 2-bromo-6-methylpyridine, the desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 2, starting from the product prepared according to example 237, the desired product is obtained in the form of a white powder (yield=49%).
M.p.=188° C.
[α]D29=−68° (c=0.30; DMSO).
0.3 g (0.59 mM) of 2-iodo-6-methyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation V, 0.1 g (0.71 mM) of 3,5-dimethyl-4-isoxazoleboronic acid, 0.384 g (1.17 mM) of cesium carbonate and 0.327 g of tetrakis(triphenylphosphine)palladium grafted to polystyrene resin are mixed in 5 ml of DME and 3.5 ml of methanol. The mixture is heated at 120° C. for 30 minutes using microwave radiation. The reaction mixture is subsequently filtered, the residual solid is rinsed with methanol and the filtrate is concentrated under reduced pressure. The evaporation residue is purified by chromatography on a silica column, elution being carried out using a dichloromethane/methanol mixture (80/20; v/v), to give the expected product in the form of a white powder with a yield of 70%.
M.p.=70-84° C.
[α]D31=−64° (c=0.11; DMSO).
By carrying out the operation analogously to example 239, starting from 2-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation III, and 6-fluoro-3-pyridineboronic acid, the desired product is obtained in the form of a white powder (yield=14%).
M.p.=199° C.
[α]D32=−54° (c=0.26; DMSO).
By carrying out the operation analogously to example 239, starting from 2-bromo-4-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VII, and 3,5-dimethyl-4-isoxazoleboronic acid, the desired product is obtained in the form of white crystals (yield=25%).
M.p.=143-147° C. (recrystallized from water).
[α]D27=−77° (c=0.22; DMSO).
By carrying out the operation analogously to example 239, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IX, and 4-methoxy-3-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=23%).
M.p.=154° C.
[α]D29=−49° (c=0.30; DMSO).
By carrying out the operation analogously to example 239, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 4-methoxy-3-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=37%).
M.p.=207° C.
[α]D27=−11° (c=0.25; DMSO).
By carrying out the operation analogously to example 239, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IX, and 2-methyl-4-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=28%).
M.p.=120° C. (recrystallized from water).
[α]D29=−77° (c=0.17; DMSO).
By carrying out the operation analogously to example 239, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 2-methyl-4-pyridineboronic acid, the desired product is obtained in the form of a white powder (yield=23%).
M.p.=214° C. (recrystallized from water).
[α]D28=−51° (c=0.52; DMSO).
By carrying out the operation analogously to example 1, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 5-chloro-3-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=40%).
M.p.=203-205° C.
[α]D30=+8° (c=0.31; DMSO).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 246, the desired product is obtained in the form of a white solid (yield=28%).
M.p.=171-172° C.
[α]D30=−167° (c=0.24; DMSO).
By carrying out the operation analogously to example 137, starting from 3-bromo-4-methylpyridine, the desired product is obtained in the form of a white solid (yield=9%).
M.p.=165° C.
[α]D30=−9° (c=0.27; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 248, the desired product is obtained in the form of a white solid (yield=49%).
M.p.=201° C.
[α]D26=−75° (c=0.23; DMSO).
By carrying out the operation analogously to example 1, starting from 2-chloro-6-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation X, and 6-fluoro-3-pyridineboronic acid, the desired product is obtained in the form of a beige powder (yield=15%).
M.p.=169° C.
[α]D26=−35° (c=0.45; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 250, the desired product is obtained in the form of a beige powder (yield=30%).
M.p.=209° C. (recrystallized from an ethanol/water mixture).
[α]D26=−19° (c=0.14; DMSO).
A mixture of 0.682 g (1.73 mM) of 2-cyano-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation XV, and 1.24 g (6.05 mM) of azidotrimethyltin in 10 ml of toluene is prepared and this mixture is stirred at 70° C. for 7 days. After cooling, the reaction medium is poured onto a mixture of water and ethyl acetate and brought to pH 1 by addition of an N hydrochloric acid solution. The aqueous phase is extracted, brought to pH 5 by addition of a dilute sodium hydroxide solution and extracted with ethyl acetate. This organic phase is separated, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The crude product obtained is purified by chromatography on silica gel, elution being carried out with a dichloromethane/methanol mixture (95/5;v/v). The expected compound is thus obtained in the form of a white foam (yield=30%).
M.p.=119-127° C.
[α]D25=−147° (c=0.28; CH2Cl2).
By carrying out the operation analogously to example 42, starting from the product prepared according to example 252, the desired product is obtained in the form of a white powder (yield=42%).
M.p.=170° C. (recrystallized from an ethanol/water mixture).
[α]D22=−153° (c=0.24; DMSO).
By carrying out the operation analogously to example 213, starting from 2-fluoro-6-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation XII, and 3,5-dimethyl-4-isoxazoleboronic acid, the desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 2, starting from the product prepared according to example 254, the desired product is obtained in the form of a white powder (yield=56%).
M.p.=101-104° C.
[α]D32=−42° (c=0.12; DMSO).
By carrying out the operation analogously to example 254, starting from 2-fluoro-3-pyridineboronic acid, the desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 2, starting from the product prepared according to example 256, the desired product is obtained in the form of a white powder (yield=53%).
M.p.=186-190° C.
[α]D32=−33° (c=0.12; DMSO).
By carrying out the operation analogously to example 254, starting from 5-pyrimidineboronic acid, the desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 2, starting from the product prepared according to example 258, the desired product is obtained in the form of a white powder (yield=33%).
M.p.=177-179° C.
[α]D32=−106° (c=0.45; DMSO).
By carrying out the operation analogously to example 254, starting from 6-fluoro-3-pyridineboronic acid, the desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 2, starting from the product prepared according to example 260, the desired product is obtained in the form of a white powder (yield=65%).
M.p.=141-144° C.
[α]D32=−38° (c=0.26; DMSO).
By carrying out the operation analogously to example 254, starting from 2-fluoro-4-pyridineboronic acid, the desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 2, starting from the product prepared according to example 262, the desired product is obtained in the form of a white powder (yield=53%).
M.p.=179-182° C.
[α]D32=−37° (c=0.10; DMSO).
By carrying out the operation analogously to example 254, starting from 1-methyl-4-(pinacolatoboryl)-1H-pyrazole, the desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 2, starting from the product prepared according to example 264, the desired product is obtained in the form of a white solid (yield=38%).
M.p.=183-185° C.
[α]D32=−23° (c=0.13; DMSO).
By carrying out the operation analogously to example 254, starting from 6-methyl-3-pyridineboronic acid, the desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 2, starting from the product prepared according to example 266, the desired product is obtained in the form of a pink powder (yield=36%).
M.p.=189-190° C.
[α]D32=−20° (c=0.10; DMSO).
By carrying out the operation analogously to example 254, starting from 2-methyl-4-pyridineboronic acid, the desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 2, starting from the product prepared according to example 268, the desired product is obtained in the form of a white powder (yield=24%).
M.p.=159-162° C.
[α]D32=−23° (c=0.10; DMSO).
By carrying out the operation analogously to example 254, starting from 2-cyano-5-(pinacolatoboryl)pyridine, the desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 2, starting from the product prepared according to example 270, the desired product is obtained in the form of a white powder (yield=37%).
M.p.=158-162° C.
[α]D32=−19° (c=0.14; DMSO).
By carrying out the operation analogously to example 213, starting from 6-chloro-5-fluoro-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation XI, and 3-pyridineboronic acid, the desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 2, starting from the product prepared according to example 272, the desired product is obtained in the form of a white powder (yield=58%).
M.p.=179° C.
[α]D32=−33° (c=0.10; DMSO).
By carrying out the operation analogously to example 272, starting from 2-fluoro-4-pyridineboronic acid, the desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 2, starting from the product prepared according to example 274, the desired product is obtained in the form of a white powder (yield=53%).
M.p.=209-212° C.
[α]D27=−68° (c=0.10; DMSO).
By carrying out the operation analogously to example 259, starting from 5-bromo-2-chloro-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation XIV, the expected product is obtained in the form of a white foam (yield=48%).
M.p.=72-90° C.
[α]D25=−44° (c=0.21; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 276, the desired product is obtained in the form of white flakes (yield=81%).
M.p.=174-189° C.
[α]D25=60° (c=0.22; DMSO).
By carrying out the operation analogously to example 276, starting from 6-fluoro-3-pyridineboronic acid, the expected product is obtained in the form of a white foam (yield=38%).
M.p.=70-90° C.
[α]D24=−26° (c=0.22; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 278, the desired product is obtained in the form of white flakes (yield=84%).
M.p.=176-197° C.
[α]D30=−51° (c=0.15; DMSO).
By carrying out the operation analogously to example 259, starting from 2-chloro-6-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation X, the expected product is obtained in the form of a white foam (yield=37%).
M.p.=168° C.
[α]D36=−41° (c=0.11; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 280, the desired product is obtained in the form of a white powder (yield=20%).
M.p.=100° C.
[α]D26=31° (c=0.11; DMSO).
By carrying out the operation analogously to example 231, starting from 5-bromo-2-fluoro-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VIII, and 2-bromopyridine, the desired product is obtained and is used directly in the deacetylation stage.
By carrying out the operation analogously to example 2, starting from the product prepared according to example 282, the desired product is obtained in the form of a white solid (yield=79%).
M.p.=145-146° C.
By carrying out the operation analogously to the first part of example 137, 5-(pinacolatoboryl)pyrimidine is prepared from 5-bromopyrimidine and is reacted immediately in the same reactor with 5-bromo-2-fluoro-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VIII, under conditions analogous to those applied in the preparation of example 177. The expected product is thus obtained in the form of a yellow solid (yield=40%).
M.p.=96-97° C.
[α]D30=−11° (c=0.24; DMSO).
By carrying out the operation analogously to example 2, starting from the product prepared according to example 284, the desired product is obtained in the form of a white solid (yield=60%).
M.p.=204-205° C.
The structures of the compounds of formula I described in the preceding examples have been combined in the following table:
In the above table:
The antithrombotic activity of the compounds according to the invention was studied in vivo in rats by virtue of a test in which a venous thrombosis is reproduced.
The venous thrombosis was induced according to the protocol described in Thromb. Haemost., 1992, 67(1), 176-179. The activity via the oral route was studied according to the procedure described below.
The experiment is carried out on non-fasting male Wistar rats weighing from 250 to 280 g and divided into groups of 10 animals each. The test products are administered orally (intubation) in solution or in suspension in a 0.5% solution of methylcellulose in water. The concentrations of the compounds are calculated so as to bring about the absorption of an amount of solution of 10 ml/kg orally. A thrombosis is induced at a time T after the administration of the product and the thrombus formed is removed and weighed. In order to induce this thrombosis, a venous stasis is brought about under hypercoagulation, according to the technique described by Wessler (J. Applied Physiol., 1959, 943-946), using a solution of activated factor X (Xa), supplied by Biogenic (Montpellier) and comprising a dose of 7.5 nKat/kg, as hypercoagulant. The venous stasis is brought about 10 seconds exactly after the injection of the hypercoagulant. The activity of the test compounds is monitored at various doses, after they have been administered. The thrombosis is induced 2 hours after the administration of the compound. By way of example, the results of the above tests are given in the following table for a few compounds according to the invention (the activity is expressed by the percentage of inhibition of the formation of the thrombus, observed in the presence of the compound according to the invention, with respect to the weight of the thrombus formed in the absence of the compound).
These results show that the compounds according to the invention exhibit a good antithrombotic activity after administration via the oral route.
The present invention thus includes a compound of formula (I) according to the invention and its salts with an acid, solvates and hydrates which are pharmaceutically acceptable for their use as medicaments. The compound of formula (I) or one of its pharmaceutically acceptable salts, solvates or hydrates can be used in the preparation of an antithrombotic medicament intended in particular for the treatment or inhibition of disorders of the venous or arterial circulation and especially for correcting certain sensitive venous hematological parameters, or for compensating for cardiac insufficiency. The compound of formula (I) or one of its pharmaceutically acceptable salts, solvates or hydrates can also be used in the preparation of a medicament intended for the inhibition of restenosis after transluminal arterial or coronary angioplasty or else to inhibit or treat pathologies of thromboembolic type which risk occurring subsequent, for example, to a surgical action, such as hip or knee arthroplasty. The compounds according to the invention can also be used as active substances of medicaments intended to inhibit strokes or heart attacks.
The present invention thus also includes pharmaceutical compositions comprising a compound of formula (I) or one of its pharmaceutically acceptable salts, solvates or hydrates. These pharmaceutical compositions generally comprise suitable excipients. Said excipients are chosen according to the pharmaceutical form desired and the method of administration desired, in particular oral or injectable.
These pharmaceutical compositions are prepared according to conventional methods well known to a person skilled in the art. For example, the compounds according to the invention can be formulated with physiologically acceptable excipients in order to obtain an injectable form to be used directly, an injectable form to be prepared at the time of use or a solid form for oral administration, such as, for example, a hard gelatin capsule or a tablet.
By way of example, an injectable form can be prepared preferably by lyophilization of a filtered and sterilized solution comprising the compound according to the invention and a soluble excipient in an amount necessary and sufficient to obtain an isotonic solution after addition at the time of use of water for injection. The solution obtained can be administered either in a single subcutaneous or intramuscular injection or in the form of a slow infusion. A form which can be administered orally will preferably be presented in the form of a hard gelatin capsule comprising the finely milled or better still micronized compound of the invention mixed with excipients known to a person skilled in the art, such as, for example, lactose, pregelatinized starch and magnesium stearate.
In order to obtain the desired therapeutic or prophylactic effect, each unit dose can comprise from 10 to 500 mg of at least one compound according to the invention.
The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Since modifications of the described embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, the invention should be construed broadly to include all variations within the scope of the appended claims and equivalents thereof.
| Number | Date | Country | Kind |
|---|---|---|---|
| 06 53961 | Sep 2006 | FR | national |
This application is a continuation of international patent application no. PCT/FR2007/052005, filed Sep. 26, 2007, designating the United States of America, and published in French on Apr. 3, 2008 as WO 2008/037922, the entire disclosure of which is incorporated herein by reference. Priority is claimed based on French patent application no. FR 0653961, filed Sep. 27, 2006.
| Number | Name | Date | Kind |
|---|---|---|---|
| 4432973 | Picart | Feb 1984 | A |
| 4877808 | Samreth et al. | Oct 1989 | A |
| 5101048 | Bajgrowicz et al. | Mar 1992 | A |
| 5169838 | Samreth et al. | Dec 1992 | A |
| Number | Date | Country |
|---|---|---|
| 0 051 023 | May 1982 | EP |
| 0 290 321 | Nov 1988 | EP |
| 0 365 397 | Apr 1990 | EP |
| 421 829 | Apr 1991 | EP |
| 1 609 799 | Dec 2005 | EP |
| WO 2005030785 | Apr 2005 | WO |
| WO 2005030785 | Apr 2005 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 20090182013 A1 | Jul 2009 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/FR2007/052005 | Sep 2007 | US |
| Child | 12411783 | US |
