ITUB20150109A1 - USEFUL COMPOUNDS FOR THE TREATMENT OF HEPATITIS C - Google Patents

Description

Patent application for industrial invention entitled:

? Compounds useful for the treatment of hepatitis C?

DESCRIPTION

The present invention relates to new compounds useful for the treatment of hepatitis C.

Hepatitis C? an infectious disease caused by the Hepatitis C virus (HCV), which primarily affects the liver. The infection? often asymptomatic, but its chronicity can? lead to scarring of the liver and ultimately to cirrhosis, which is generally evident after many years. In some cases, liver cirrhosis may cause lead to developing liver failure, liver cancer, esophageal and gastric varices. The HCV? transmitted primarily by direct contact with infected blood, often due to intravenous drug use, unsterilized medical devices, and blood transfusions.

The hepatitis C virus leads to chronic infection in 50-80% of people who contract it, of which about 40-80% are treated.

Initially, patients with a? Chronic hepatitis C infection underwent treatment with interferon-? (IFN-?), But such treatment led to a virological response in only 10-15% of treated patients. Subsequently, the combination IFN-? and ribavirin was the primary therapy used, but it turned out? relatively ineffective as only 40% of treated patients manifest? a lasting benefit. Finally, the last therapy adopted for the treatment of chronic hepatitis C infection was the combination of interferon-PEG and ribavirin, which showed? a promising activity? antiviral.

The main problem with therapies involving the use of ribavirin? the appearance of anemia as a side effect, which, added to the neuropsychiatric adverse effects of IFN-?, led in about 10-20% of patients to premature discontinuation of therapy.

? the search for potent and selective antiviral molecules has therefore become necessary; in particular, prodrug molecules have proved to be of great importance which, acting as inhibitors of the NS5B RNA-dependent RNA polymerase of HCV, block its replication and therefore have proved to be effective molecules for the treatment of hepatitis C.

Recently ? was introduced into sofosbuvir therapy (Sovaldi?), a prodrug with activity? NS5B RNA-dependent RNA polymerase inhibitor of HCV having a nucleotide type structure. Other activity molecules? RNA polymerase inhibitor useful for the treatment of hepatitis C are under development. Most of them have a nucleoside, nucleotide or analogue structure.

Given the importance and spread of hepatitis C and the very high costs of current therapy, c ?? a continuing need for new effective molecules for the treatment of hepatitis C.

We have now found a class of antiviral compounds useful for the treatment of hepatitis C which have better chemical-physical characteristics than the known compounds thanks to the presence of an unsaturated chain on the ring of the nucleoside base.

The object of the present invention is a compound of formula I

in which

R1 and R2, the same or different from each other, are a hydrogen atom, an OCOR4 group, a linear or branched C1-18 alkyl group, a linear or branched C2-18 alkenyl group, or a group of formula

R3? a linear or branched C2-18 alkenyl group, preferably an allyl group;

R4? a linear or branched C1-18 alkyl group, a linear or branched C2-18 alkenyl group, preferably an allyl group, or an optionally substituted aryl group;

R5 and R6, the same or different from each other, are an azide group, a halogen, or an OR7 group, or an NR8R9 group, or they can together form a cycle;

R7? a hydrogen atom, a linear or branched C1-18 alkyl group, or an optionally substituted aryl group;

R8 and R9, the same or different from each other, are a hydrogen atom, a linear or branched C1-18 alkyl group optionally substituted with a COOR10 group, a linear or branched C2-18 alkenyl group, or together they can form a cycle;

R10? a hydrogen atom or a linear or branched C1-6 alkyl group; X? a group = O or a group? NH2;

Y? a group = O or a hydrogen atom.

The compounds of formula I represent an object of the present invention in all their possible stereochemical configurations to all the stereogenic atoms present and in all their polymorphic forms which can be obtained by crystallization from various solvents.

A preferred aspect of the present invention are the compounds of formula I-A

in which

R1 and R2, the same or different from each other, are a hydrogen atom, an acetoxy group, or a group of formula

wherein R5 and R6, the same or different from each other, are an azide group, a halogen, or a? OR7 group, or a NR8R9 group, or they can together form a cycle;

R7? a hydrogen atom, a linear or branched C1-6 alkyl, or an optionally substituted phenyl group;

Y? a group = O or a hydrogen atom.

Particularly preferred are the compounds of formula I-A in which R1? a hydrogen atom, an acetoxy group, or a group

wherein R5 and R6, the same or different from each other, are an OR7 group or a NR8R9 group, or they can together form a cycle; R2? a hydrogen atom or an acetoxy group; R7? a linear or branched C1-3 alkyl group or a phenyl group.

A particularly preferred object of the present invention are the compounds of formula I-Aa, I-Ab, I-Ac, I-Ad, I-Ae, I-Af and I-Ag

The compounds of formula I are prepared according to a process which comprises the condensation of a compound of formula IV

in which

R1 and R2, the same or different from each other, are a hydrogen atom, an OCOR4 group, a linear or branched C1-18 alkyl group, a linear or branched C2-18 alkenyl group;

W? a halogen, such as for example chlorine or bromine, or an -OR4 group, or a? OCOR4 group;

R4? a linear or branched C1-18 alkyl group, a linear or branched C2-18 alkenyl group;

with a compound of formula III

in which

R3? a linear or branched C2-18 alkenyl group;

X? a group = O or a group? NH2;

to give compounds of formula I in which R1? a hydrogen atom, a? OCOR4 group, a linear or branched C1-18 alkyl group, a linear or branched C2-18 alkenyl group.

The subsequent reaction with a compound of formula II

in which

LG? a suitable leaving group;

R5 and R6, the same or different from each other, are an azide group, a halogen, or an OR7 group, or an NR8R9 group, or they can together form a cycle;

Y? a group = O or a hydrogen atom;

R7? a hydrogen atom, a linear or branched C1-18 alkyl group, or an optionally substituted aryl group;

R8 and R9, the same or different from each other, are a linear or branched C1-18 alkyl group optionally substituted with a? COOR10 group, a linear or branched C2-18 alkenyl group, or together they can form a cycle;

R10? a hydrogen atom or a linear or branched C1-6 alkyl group; leads to compounds of formula I in which R1? a group

in which

R5 and R6, the same or different from each other, are an azide group, a halogen, or an OR7 group, or an NR8R9 group, or they can together form a cycle;

Y? a group = O or a hydrogen atom;

R7? a hydrogen atom, a linear or branched C1-18 alkyl group, or an optionally substituted aryl group;

R8 and R9, the same or different from each other, are a linear or branched C1-18 alkyl group optionally substituted with a? COOR10 group, a linear or branched C2-18 alkenyl group, or together they can form a cycle;

R10? a hydrogen atom or a linear or branched C1-6 alkyl group. The compounds of formula I-A in which R2? an acetoxy group are prepared according to a preferred process which comprises:

a) the acetylation reaction of the compound of formula IV-B

to give the compound of formula IV-A

b) the reaction of the compound of formula IV-A with allyluracil of formula

III-A

to give the compound of formula I-Aa

c) the mono de-acetylation reaction of the compound of formula I-Aa to give the compound of formula I-Ab

d) the reaction of the compound of formula I-Ab with an intermediate of formula II

where LG? a suitable leaving group, to give a compound of formula I-A where R1? a group of formula

in which R5 and R6 have the meanings reported above.

Step a) of the preferred process object of the present invention is carried out by reaction with acetic anhydride, in an apolar solvent, in the presence of a base and an amidine in quantity. catalytic.

The non-polar solvent? selected from toluene, hexane, dichloromethane, ethyl acetate, tetrahydrofuran. Preferably? used dichloromethane.

The base used? a tertiary amine preferably selected from triethylamine, trimethylamine and N, N-diisopropylethylamine. Pi? triethylamine is preferably used.

Is the amidine preferably used? choice between 1,5-diazabicyclo [5.4.0] undec-5-ene (DBU), diminazene and benzamidine. Even more? DBU is preferably used.

Step b) of the preferred process object of the present invention is carried out according to the conditions reported in the article published in Chem.Ber. 1981, 114, 1279-1286. In particular, step b) is carried out? One-pot ?, in an aprotic polar solvent, such as acetonitrile, or an apolar solvent such as 1,2-dichloroethane, preferably acetonitrile, in the presence of trimethylchlorosilane (TCS) and hexamethyldisilazane (HMDS), such as catalysts, and a Lewis acid or a salt selected from tin chloride, trifluoromethanesulfonic acid, ammonium perchlorate, sodium tetrafluoroborate, preferably trifluoromethanesulfonic acid.

Step c) of the preferred process object of the present invention is carried out enzymatically using resin-supported lipases (CALB) in a polar protic solvent at a temperature of about 40 ° C.

The polar protic solvent used? preferably selected from alcohols, such as for example methanol, ethanol, isopropanol and n-butanol. Pi? preferably ethanol is used.

The compound of formula I-Aa or of formula I-Ab obtained in step c) of the preferred process object of the present invention can? be subjected to a de-acetylation process carried out in the presence of a hydroalcoholic mixture, preferably a mixture of water and methanol, in a base selected from sodium hydroxide and potassium hydroxide. Preferably sodium hydroxide is used at room temperature.

The compound of formula I-Ac is obtained

Step d) of the preferred process object of the present invention is carried out in the presence of a Grignard reagent in tetrahydrofuran or in the presence of N-methylimidazole in dichloromethane.

The compounds of formula I object of the present invention are active as inhibitors of the HCV NS5B RNA-dependent RNA polymerase and are therefore used in therapy, alone or in combination with one or more? antiviral drugs, for the treatment of hepatitis C.

Therefore, the subject of the present invention is pharmaceutical compositions containing a compound of formula I in admixture with a suitable pharmaceutically acceptable carrier, preferably a carrier suitable for the preparation of formulations for oral administration.

Although the invention has been described in its characteristic aspects, modifications and equivalents which are apparent to one skilled in the art are included in the following invention.

The present invention will be now illustrated by means of some examples, which are not to be seen as limiting the scope of the invention.

EXAMPLE 1

Synthesis of (3-acetoxy-5- (3-allyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4fluoro-4-methyltetrahydrofuran-2-yl) methyl acetate (compound I- Aa)

3-fluoro-4-hydroxy-5- (hydroxymethyl) -3-methyltetrahydrofuran-2-yl acetate (2.08 g, 10.00 mmol), allyluracil (1.52 g, 10 .00 mmol), acetonitrile (100ml), hexamethyldisilazane (HMDS, 2.3ml, 11.00mmol), trimethylchlorosilane (TCS, 1.5ml, 12.00mmol), trifluoromethanesulfonic acid (1.05ml, 12, 00 mmol), the reaction mixture? was brought to the reflux temperature of the solvent and maintained under these conditions for about six hours. At the end of the reaction,? been added dichloromethane (150 ml), the organic phase? been washed with a saturated solution of sodium bicarbonate (1 x 100 ml) and the aqueous phase? was extracted with dichloromethane (1 x 100 ml). The combined organic phases were washed again with a saturated sodium chloride solution (1 x 100 ml) and the product? was purified by column chromatography to give about 3.26 g of (3-acetoxy-5- (3-allyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4-fluoro- 4-methyltetrahydrofuran-2-yl) methyl acetate.

1H-NMR (DMSO, 300 MHz):? 8.07 (d, 1H), 6.07 (d, 1H), 5.80 (m, 2H), 5.35 (m, 2H), 5.32 (m, 1H), 5.06 (m , 2H), 4.26 (m, 3H), 2.14 (s, 3H), 2.06 (s, 3H), 1.34 (d, 3H).

EXAMPLE 2

Synthesis of 5- (3-allyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-2- (hydroxymethyl) -4-methyltetrahydrofuran-3-yl acetate (compound I -Ab)

(3-acetoxy-5- (3-allyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-4-methyltetrahydrofuran-2- II) methyl acetate (51.00 g, 0.1325 mol), ethanol (250 ml), CALB lipase (2.5 g), the temperature? was brought to about 35-40 ° C and the reaction mixture? was kept in this condition for about one night. At the end of the reaction, the temperature? been brought to that environment, the mixture? been filtered, the solvent? been removed by vacuum distillation and? methylterbutyl ether (MTBE, 100 ml) was added; you filter and the mixture? was washed with methylterbutyl ether (MTBE, 2 x 20 ml). The combined organic phases were reduced to residue by vacuum distillation to give 42.00 g of 5- (3-allyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4-fluoro- 2- (hydroxymethyl) -4-methyltetrahydrofuran-3-yl acetate.

1H-NMR (DMSO, 300 MHz):? 8.09 (d, 1H), 6.13 (d, 1H), 5.88 (m, 2H), 5.07 (m, 2H), 5.06 (m, 2H), 4.41 (m, 2H) ), 4.12 (m, 1H), 3.80 (m, 1H), 3.60 (m, 1H), 2.14 (s, 3H), 1.29 (d, 3H).

EXAMPLE 3

Synthesis of 3-allyl-1- (3-fluoro-4-hydroxy-5- (hydroxymethyl) -3-methyltetrahydrofuran-2-yl) -pyrimidin-2,4 (1H, 3H) -dione (compound I-Ac)

5- (3-allyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-2- (hydroxymethyl) -4-methyltetrahydrofuran-3 were loaded into a reaction flask - acetate (7.00 g, 20.46 mmol), methanol (30.00 ml), 1N sodium hydroxide (30.7 ml) and the reaction mixture? was kept under stirring for about one night. Once the reaction is over, the solid formed? filtered and washed with water (1x5 ml) and methanol (1x5 ml) to give 5.53 g of 3-allyl-1- (3-fluoro-4-hydroxy-5- (hydroxymethyl) -3-methyltetrahydrofuran-2- II) pyrimidine-2,4 (1H, 3H) -dione.

1H-NMR (CD3OD, 300 MHz):? 8.11 (d, 1H), 6.14 (d, 1H), 5.83 (m, 2H), 5.14 (m, 2H), 4.51 (m, 2H), 3.98 (m , 3H), 3.80 (d, 1H), 1.32 (d, 3H).

EXAMPLE 4

Synthesis of (2S) -isopropyl-2 - (((3-acetoxy-5- (3-allyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-4- methyltetrahydrofuran-2-yl) methoxy) (phenoxy) -phosphorylamino) propanoate (compound I-Ag)

5- (3-allyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-2- (hydroxymethyl) -4-methyltetrahydrofuran-3 were loaded into a reaction flask -yl acetate (10.00 g, 29.23 mmol), dichloromethane (100 ml), (2S) -isopropyl-2 - ((perfluorophenoxy) (phenoxy) phosphorylamino) propanoate (15 g, 33.09 mmol) and temperature ? been brought to about 15? -20? C. The reaction mixture? was maintained under these conditions for approximately thirty minutes and 1,5,7-triazabicyclo [4.4.0] dec-5-ene (TBD, 5 g, 35.91 mmol), dichloromethane (20 ml), and the reaction mixture? was kept in these conditions for about two hours. At the end of the reaction, the mixture? was washed with a 1N hydrochloric acid solution (1x45 ml), a 2% sodium carbonate solution (3x70 ml), a 1N hydrochloric acid solution (1x30 ml) and a 2N sodium chloride solution (1x30 ml). The combined organic phases were reduced to residue by vacuum distillation,? was then added isopropanol (100 ml) and the solid obtained? filtered to give 10.10 g of (2S) -isopropyl-2 - (((3-acetoxy-5- (3-allyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) -phosphorylamino) propanoate.

1H-NMR (CDCl3, 300 MHz):? 7.47 (d, 1H), 7.34-7.29 (m, 2H), 7.25-7.20 (m, 3H), 6.21 (d, 1H), 5.88-5, 79 (m, 1H), 5.56 (d, 1H), 5.22-5.14 (m, 3H), 5.20-4.98 (m, 1H), 4.53-4.49 ( m, 3H), 4.31-4.28 (m, 1H), 4.25-4.18 (m, 1H), 4.02-3.90 (m, 1H), 3.79-3, 72 (m, 1H), 2.17 (s, 3H), 1.37-1.20 (m, 12H).

Claims (10)

CLAIMS 1) A compound of formula I in which R1 and R2, the same or different from each other, are a hydrogen atom, an OCOR4 group, a linear or branched C1-18 alkyl group, a linear or branched C2-18 alkenyl group, or a group of formula R3? a linear or branched C2-18 alkenyl group; R4? a linear or branched C1-18 alkyl group, a linear or branched C2-18 alkenyl group, or an optionally substituted aryl group; R5 and R6, the same or different from each other, are an azide group, a halogen, or a? OR7 group, or an NR8R9 group, or they can together form a cycle; R7? a hydrogen atom, a linear or branched C1-18 alkyl group, or an optionally substituted aryl group; R8 and R9, the same or different from each other, are a hydrogen atom, a linear or branched C1-18 alkyl group optionally substituted with a -COOR10 group, a linear or branched C2-18 alkenyl group, or together they can form a cycle; R10? a hydrogen atom or a linear or branched C1-6 alkyl group; X? a group = O or a group? NH2; Y? a group = O or a hydrogen atom. 2) A compound according to claim 1 wherein R3? an allyl group. 3) A compound according to claim 1 of formula I-A in which R1 and R2, the same or different from each other, are a hydrogen atom, an acetoxy group, or a group of formula wherein R5 and R6, the same or different from each other, are an azide group, a halogen, or a? OR7 group, or a NR8R9 group, or they can together form a cycle; R7? a hydrogen atom, a linear or branched C1-6 alkyl, or an optionally substituted phenyl group; Y? a group = O or a hydrogen atom. 4) A compound according to claim 3 wherein R1? a hydrogen atom, an acetoxy group, or a group wherein R5 and R6, the same or different from each other, are an OR7 group or a NR8R9 group, or they can together form a cycle; R2? a hydrogen atom or an acetoxy group; R7? a linear or branched C1-3 alkyl group or a phenyl group. 5) A compound according to claim 1 of formula I-Aa, I-Ab, I-Ac, I-Ad, I-Ae, I-Af and I-Ag 6) A process for the preparation of the compounds of formula I according to claim 1 which comprises the condensation of a compound of formula IV in which R1 and R2, the same or different from each other, are a hydrogen atom, an OCOR4 group, a linear or branched C1-18 alkyl group, a linear or branched C2-18 alkenyl group; W? a halogen, or an -OR4 group, or a? OCOR4 group; R4? a linear or branched C1-18 alkyl group, a linear or branched C2-18 alkenyl group; with a compound of formula III in which R3? a linear or branched C2-18 alkenyl group; X? a group = O or a group? NH2; to give compounds of formula I in which R1? a hydrogen atom, a? OCOR4 group, a linear or branched C1-18 alkyl group, a linear or branched C2-18 alkenyl group; the subsequent reaction with a compound of formula II in which LG? a suitable leaving group; R5 and R6, the same or different from each other, are an azide group, a halogen, or a? OR7 group, or an NR8R9 group, or they can together form a cycle; Y? a group = O or a hydrogen atom; R7? a hydrogen atom, a linear or branched C1-18 alkyl group, or an optionally substituted aryl group; R8 and R9, the same or different from each other, are a hydrogen atom, a linear or branched C1-18 alkyl group optionally substituted with a -COOR10 group, a linear or branched C2-18 alkenyl group, or together they can form a cycle; R10? a hydrogen atom or a linear or branched C1-6 alkyl group; to give the compounds of formula I in which R1? a group in which R5 and R6, the same or different from each other, are an azide group, a halogen, or a? OR7 group, or an NR8R9 group, or they can together form a cycle; Y? a group = O or a hydrogen atom; R7? a hydrogen atom, a linear or branched C1-18 alkyl group, or an optionally substituted aryl group; R8 and R9, the same or different from each other, are a hydrogen atom, a linear or branched C1-18 alkyl group optionally substituted with a -COOR10 group, a linear or branched C2-18 alkenyl group, or together they can form a cycle; R10? a hydrogen atom or a linear or branched C1-6 alkyl group. 7) A process according to claim 6 for the preparation of the compounds of formula I-A in which R2? an acetoxy group which comprises: a) the acetylation reaction of the compound of formula IV-B to give the compound of formula IV-A b) the reaction of the compound of formula IV-A with allyluracil of formula III-A to give the compound of formula I-Aa c) the mono de-acetylation reaction of the compound of formula I-Aa to give the compound of formula I-Ab d) the reaction of the compound of formula I-Ab with an intermediate of formula II where LG? a suitable leaving group, to give a compound of formula I-A where R1? a group of formula in which R5 and R6 have the meanings reported above. 8) A pharmaceutical composition containing a compound of formula I according to claim 1 in admixture with a pharmaceutically acceptable carrier. 9) Use of a compound of formula I according to claim 1 for the preparation of a composition for the treatment of hepatitis C. 10) Use according to claim 9 wherein the compound of formula I? used in combination with one or more? antiviral drugs.