RU2001134613A

RU2001134613A - Amorphous nitroesters and their pharmaceutical compositions

Info

Publication number: RU2001134613A
Application number: RU2001134613/04A
Authority: RU
Inventors: Франческа Бенедини; Патриция АНТОГНАЦЦА
Original assignee: Никокс С.А.
Priority date: 1999-06-24
Filing date: 2000-06-21
Publication date: 2003-09-27

Claims

1. The compounds of formula (I)

AX ₁ -NO ₂ (I)

where A = R (COX),

X = O, NH, NR _1C , where R _1C is linear or branched C ₁ -C ₁₀ alkyl, R is selected from the following radicals:

where R ₁ means OCOR ₃ group, where R ₃ means methyl, ethyl or linear or branched C ₃ -C ₅ alkyl, or the residue of a saturated heterocyclic ring having 5 or 6 atoms, which may be aromatic or fully or partially saturated, and the aforementioned the heterocyclic ring contains one or more heteroatoms independently selected between O and N and S;

R ₂ means hydrogen, hydroxy, halogen, linear or branched when possible C ₁ -C ₄ alkyl, linear or branched when possible C ₁ -C ₄ alkoxyl, linear or branched when possible C ₁ -C ₄ perfluoroalkyl, e.g. trifluoromethyl, mono - or di- (C ₁ -C ₄ ) alkylamino;

R ₁ and R ₂ together mean a dioximethylene group with the condition that when X = NH, then Y is ethylene and R ₂ = H as defined hereinafter, R ₁ cannot be OCOR ₃ at position 2 when R ₃ is methyl;

n1 = 0 or 1,

preferably in (I) X = O, R ₁ is acetoxy and is in the ortho position with respect to the —CO— group, R ₂ is hydrogen, preferably in Ib) R ₃ is CH ₃ , n1 = 0; X is O, and the bond of the aromatic ring with the COX group is in 1 or 2 positions;

X ₁ means a bivalent binding bridge selected from the following:

YO: Y = linear or branched, when possible C ₁ -C ₂₀ , preferably C ₂ -C ₅ alkylene, or C ₅ -C ₇ cycloalkylene, optionally substituted; or X _{1 is} selected from the following:

where n3 = 0 - 3,

n3 ’= 1 - 3;

where n3 and n3 ’have the following meanings;

where nf ’= 1 to 6, preferably from 1 to 4;

where R _1f = H, CH ₃ and nf 'is as defined above,

moreover, the above compounds of formula (I) are fully or partially in amorphous form, at least 5%, and amorphousity measured by DSC.

2. The compounds according to claim 1, amorphous at least 10%, preferably at least 80%, and amorphousness is measured by DSC.

3. The compounds according to claims 1 and 2, where in the formula (I) R = (Ia).

4. The compound according to claim 3, where in the formula (I) R = (Ia), X = O and X ₁ is an aromatic radical of the formula (PAI), where n3 '= 1 and n3 = 0; moreover, the above compounds have the following General formula (IA1):

where R ₁ and R ₂ are as defined above.

5. Compositions containing compounds according to claims 1 to 4 and excipients belonging to one or more of the classes mentioned hereinafter: C ₅ -C ₆ polyalcohols, mono- and disaccharides and their derivatives, oligosaccharides containing from 3 to 10 monosaccharide residues and their derivatives, polysaccharides, their derivatives, including their salts, cyclodextirins and their derivatives, non-cyclic analogues of cyclodextrin, for example, non-cyclic derivatives of β-cyclodextrin, polymers and copolymers based on vinyl monomer units and / or containing a carboxyl function, and whether methacrylic monomers.

6. The composition according to claim 5, where the mass ratio between the number of nitro derivatives of formula (I) and the amount of fillers is in the range of 1:20 and 1: 0.5, preferably 1: 0.7 and 1:10.

7. A method for producing a compound according to claims 1 to 4, wherein the amorphous state is achieved by the use of co-milling, mixing, spray drying, lyophilization.

8. The method according to claim 7, where the method used to obtain the amorphous state is co-grinding.

9. Pharmaceutical compositions containing compounds and compositions according to claims 1-6.

10. The pharmaceutical compositions of claim 9 for oral administration.

11. The compounds of claims 1 to 4 for use as a medicine.

12. The use of compounds according to claim 11 as anti-inflammatory drugs.