Disaccharides with anti-arthrosic properties

Details Disaccharides with anti-arthrosic properties Disaccharides with anti-arthrosic properties

2003-01-10

2004-01-20

Barts, Samuel (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S025000, C514S825000, C514S886000, C536S004100, C536S021000, C536S115000, C536S118000, C536S124000

Reexamination Certificate

active

06680304

ABSTRACT:

The present invention relates to novel disaccharides, the solvates and pharmaceutically acceptable salts thereof, and to the pharmaceutical compositions containing them. This invention also refers to a process for preparing the novel disaccharides, as well as to the therapeutical use thereof.
STATE OF THE ART IN RELATION TO THE INVENTION
Arthrosis (osteoarthritis) is the most common articular rheumatic disease, affecting most people over 65 years of age, characterised by a gradual degradation of the cartilaginous tissue, together with the presence of inflammation and pain. The term arthrosis describes a disease in which the hyaline cartilage of the articulations is destroyed.
At present, therapy is centred on relieving the symptoms, since no agent has yet been found that provides a proven reduction of the progression of the damage to the cartilage, although there is some clinical evidence for chondroitin sulphate and hyaluronic acid.
The substances that act on the symptoms include: rapid action substances such as analgesics, non steroidal anti-inflammatory drugs (NSAIDS) and corticoids, and substances that have a somewhat slower effect, known as SYSADOA (Symptomatic slow acting drug for osteoarthritis) (M. G. Lequesne,
Rev. Rhum.
(Eng./Ed.), 61, 69-73 (1994)), which include hyaluronic acid, chondroitin sulphate and glucosamine sulphate.
Symptomatic slow acting drugs have the additional advantage that they are safer than NSAIDS (E. Maheu,
European Journal of Rheumatology and Inflammation,
15, 17-24 (1995)), and have longer-lasting effects, which even persist for some months after the cessation of treatment.
Recently, clinical trials conducted with hyaluronic acid (V. Listrat et al.,
Osteoarthritis Cart.,
5, 153-160 (1997)) and with chondroitin sulphate (G. Verbruggen et al.,
Osteoarthritis Cart.,
6 (Supplement A), 37-38 (1998)) have for the first time provided evidence of the possibility that these two compounds, besides acting as SYSADOA, may influence and delay the course of the arthrosic disease, (chondro-protective agents).
Hyaluronic acid is a non-sulphate glycosaminoglycan of natural origin, with a polymeric structure composed of disaccharides of N-acetylglucosamine and glucuronic acid.
Hyaluronic acid is extracted from mammal organs and/or tissues. One known problem lies in the fact that, depending on how it is obtained, the molecular weight of the product can vary, which, together with the fact that it may come from different sources, means that there are several hyaluronic acids that may or may not have the same clinical effects.
The disaccharides of the present invention are structurally related to the dimers present in the polymeric structure of hyaluronic acid, in as much as they are disaccharides with &bgr;-(1→3) unions between the glucuronic acid and the glucosamine, but the disaccharides of the present invention always contain a sulphate group in the C-4 and/or the C-6 of the glucosamine ring.
Some compounds have been described in the bibliography that can also be considered to be structurally related to the compounds of the present invention.
J. R. Couchman et al. (EP 211610) disclose esterified disaccharides that differ from the compounds of the present invention in the nature of the alkyl root of the ester group (—COOR′). These compounds also differ from those of the present invention in that they are useful for stimulating hair growth and for the treatment of baldness.
The disaccharides that are repeated in the structure of chondroitin sulphate, the sulphated derivative both in position 4 and position 6 of the N-acetylgalactosamine, are commercially available, and they are obtained by degradation of the natural polymers or by chemical synthesis (J. C. Jacquinet,
Carbohydrate Research,
199, 153-181 (1990); J. C. Jacquinet et al.
Carbohydrate Research,
314, 283-288 (1998)), but they differ from the compounds of the present invention in that they contain galactosamine instead of glucosamine. The biological activities of these disaccharides have not been described to date.
Hartung et al. (WO 9309766) disclose a method for treating human and horse painful arthopathic conditions, administering parenterally, intramuscularly, or transdermally an effective amount of a composition containing at least one chondroitin sulfate salt. In the same manner, Nocelli et al. (EP 704216) disclose a gel-like pharmaceutical composition containing chondroitin sulfate salts for the treatment of arthrosis by means of an oral administration. The chondroitin derivatives described by Hartung et al. and Nocelli et al. differ from the compounds of the present invention in that they refer to a polymeric structure and that they contain a galactosamine moiety instead of a glucosamine.
Therefore, it is evident that the obtention of new compounds for the treatment of arthrosis and its symptoms, such as inflammation and pain, is still a problem in therapy.
DISCLOSURE OF THE INVENTION
The present invention provides new disaccharides of formula (I),
in which:
R
1
is-selected from the group consisting of: hydrogen, linear or branched (C
1
-C
4
)-alkyl, phenylalkyl of less than ten carbon atoms and —COCH
3
;
R
2
is selected from the group consisting of: hydrogen, —COCH
3
and SO
3
M;
R
3
is selected from the group consisting of: hydrogen, linear or branched (C
1
-C
4
)-alkyl, phenylalkyl of less than ten carbon atoms, —COCH
3
and —COPh, where Ph is phenyl;
G is selected from between —COOR
4
and —COOM, where R
4
is selected from the group consisting of: hydrogen, (C
1
-C
2
)-alkyl and arylalkyl of less than sixteen carbon atoms;
A is selected from the group consisting of: hydrogen, —SO
3
H, —SO
3
M and —COCH
3
; and
B is selected from the group consisting of: hydrogen, —SO
3
H, —SO
3
M, and —COCH
3
, where either A or B is necessarily either —SO
3
H, or —SO
3
M, and where M is an organic or metallic cation.
The invention also includes the solvates and the pharmaceutically acceptable salts of the compounds of formula (I):
The compounds of formula (I) have an anomeric carbon in their structure. This invention includes anomeric forms &agr; and&bgr;, and their mixtures.
In a preferred embodiment, the compounds of formula (i) are those where: G is —COOR
4
, or —COOM, where R
4
is (C
1
-C
2
)-alkyl, or arylalkyl of less than sixteen carbon atoms, and M is a metallic cation.
More preferred are the compounds of formula (I) where: R
1
is hydrogen, R
2
is —COCH
3
and R
3
is hydrogen. Equally preferred are the compounds of formula (I) where: R
1
is methyl, R
2
is —COCH
3
and R
3
is hydrogen.
Even more preferred are the compounds of formula (I) where A is hydrogen and B is —SO
3
M, or where A is —SO
3
M and B is hydrogen, or where A and B are —SO
3
M, and M is a metallic cation.
Especially preferred are the compounds of formula (I) where: M is the sodium cation.
Particularly especially preferred embodiments of this invention are those in which the compounds of formula (I) are one of the following:
methyl 2-acetamido-2-deoxy-3-O-(&bgr;-D-glucopyranosyluronic acid)-6-O-sulfo-&agr;-D-glucopyranoside, disodium salt;
methyl 2-acetamido-2-deoxy-3-O-(&bgr;-D-glucopyranosyluronic acid)4-O-sulfo-&agr;-D-glucopyranoside, disodium salt;
methyl 2-acetamido-2-deoxy-3-O-(&bgr;-D-glucopyranosyluronic acid)4,0-di-O-sulfo-&agr;-D-glucopyranoside, trisodium salt;
2-acetamido-2-deoxy-3-O-(&bgr;-D-glucopyranosyluronic acid)-6-O-sulfo-D-glucopyranose, disodium salt;
2-acetamido-2-deoxy-3-O-(&bgr;-D-glucopyranosyluronic acid)4-O-sulfo-D-glucopyranose, disodium salt;
2-acetamido-2-deoxy-3-O-(&bgr;-D-glucopyranosyluronic acid)4,6-di-O-sulfo-D-glucopyranose, trisodium salt.
Another embodiment of this invention is a process for preparing a compound of formula (I).
According to this invention, compounds of general formula (I) are obtained by a process characterised in that a monosaccharide of formula (II),
where R
5
represents a reactive group that can establish a &bgr;-(1→3) union with the free hydroxyl in the monosaccharide of formula (III), R
6
can be equivalent to group R
4
in (I) or a g

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