Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-30
2003-09-02
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S334000, C546S335000
Reexamination Certificate
active
06613784
ABSTRACT:
The present invention relates to new products having anti-inflammatory, analgesic and antithrombotic activity.
Specifically it relates to cyclo-oxygenase (COX) inhibitors.
It is known that the anti-inflammatory and antithrombotic efficacy of NSAIDs (Non steroid antiinflammatory drugs), also known as FANS (non steroid antiinflammatory drugs), but esoecially their tolerability, seem to be considerably affected by their inhibitory activity of the cyclo-oxygenase (COX) both in the inflammatory site and in the healthy tissue. See for example FASEB Journal 1, 89, 1987; Bioch. Biophys. Acta 1083, 1, 1991. The drawback of these products is that they are toxic, as already described in U.S. Pat. No. 5,861,426.
Nitroderivative compounds, described in said patent, are also known, have an high efficacy in the cyclooxygenase inhibition and a low toxicity. However these compounds show some drawbacks connected to the chemical-physical and structural characteristics of the molecules themselves, these latter being highly lipophilic and therefore having a poor solubility in water. It is well known that the solubilization process is decisive for absorption and interaction with the effector. The poor solubility generally involves a variable and unpredictable efficacy whereby it is difficult to set a correct posology. In practice it is necessary to administer higher doses in order to contain the above mentioned variabilities. The drawback is the risks of a higher incidence of side effects. Another disadvantage bound to the poor solubility of the nitroderivatives of said patent application is that they are difficult to be formulated. It is well known that the solubility in water of a molecule is one of the most important properties affecting the pharmacokinetic and pharmacodynamic processes. For example for parenteral administration, particularly by intravenous route, drugs must be formulated in solutions. In order to increase solubility, when it is unsatisfactory for these uses, the choice of suitable solvents and/or excipients is therefore critical, for example, among the latter, surfactants, etc., can be mentioned. This can lead to drawbacks from the toxicological point of view connected to the excipient tolerability; besides there are other drawbacks for example in the intravenous formulation which, as well known, must not cause haemolysis or incompatibility with blood constituents. Besides it is necessary to notice that it is well known that surfactants and apolar solvents can be irritant. See for example J. Pharm. Science 72, 1014, 1983.
Experiments carried out by the Applicant, wherein 0.1% Tween 80 and 1% dimethylsulphoxide have been used to suspend the nitroxy derivatives of the antiinflammatory compounds described in the patent application WO 95/30641 have shown that these substances were irritant towards the gastric mucous membrane.
It has unexpectedly been found that the derivatives of the present invention, differently from the above mentioned compounds of the prior art, can be solubilized without using the substances commonly used in the pharmaceutical technique to obtain solutions or suspensions, maintaining or even improving the activity of the prior art nitroxy derivatives. A further advantage of the compounds of the present invention is that it is possible to avoid adding to the formulation the excipients, such as for example those above mentioned, which cause or can induce irritant effects.
The antiinflammatory products described in the present application have an high cyclo-oxygenase inhibiting activity combined with low toxicity and pharmacokinetic good responses, and have furthermore a better systemic absorption degree.
This is quite surprising and unexpected since the factors affecting the FANS antiinflammatory and antithrombotic efficacy depend on various parameters whereby it is not possible to foresee a priori the pharmacokinetics, for example the absorbed product fraction, the pharmacodynamic activity, the toxicity and the COX inhibiting properties and most of all, no assumptions can be made to predict or limit the response variability.
An object of the present invention are compounds or organic or inorganic salts of compounds of general formula:
A—X
1
—N(O)
z
for use as medicaments, specifically as antiinflammatory and antithrombotic agents, wherein:
z is an integer and is 1 or 2, preferably 2;
A=R(COX
u
)
t
and wherein t is an integer 0 or 1; u is 0 or 1;
X=O, NH, NR
1c
wherein R
1c
is a linear or branched C
1
-C
10
alkyl;
wherein:
nIX is an integer between 0 and 3, preferably 1;
nIIX is an integer between 1 and 3, preferably 1;
R
TIX
, R
TIX′
, R
TIIX
, R
TIIX′
, equal to or different from each other, are H or linear or branched C
1
-C
4
alkyl; preferably R
TIX
, R
TIX′
, R
TIIX
, R
TIIX′
are H;
Y is a ring containing at least one salifiable nitrogen atom;
preferably Y is an heterocyclic ring, saturated or unsaturated or aromatic, having preferably 5 or 6 atoms and containing at least one or two nitrogen atoms, preferably one or two nitrogen atoms;
R is selected from the following groups:
Group I) wherein t=1 and u=1
wherein:
R
1
is the OCOR, group; wherein R
3
is methyl, ethyl or linear or branched C
3
-C
5
alkyl, or the residue of a heterocycle with a single ring having 5 or 6 atoms which may be aromatic, partially or totally hydrogenated, containing one or more hetero-atoms independently selected from O, N and S;
R
2
is hydrogen, hydroxy, halogen, a linear or when possible branched C
1
-C
4
alkyl, a linear or when possible branched C
1
-C
4
alkoxyl; a linear or when possible branched C
1
-C
4
perfluoroalkyl, for example trifluoromethyl; nitro, amino, mono- or di- (C
1-4
) alkylamino;
nI is an integer 0 or 1;
Preferably in the Compounds of Formula Ia) X is Equal to O or NH, R
1
is acetoxy, preferably in ortho position with respect to —CO—, R
2
is hydrogen; in X
1
R
TIX
=R
TIX′
=R
TIIX
=R
TIIX′
H, n
IX
=n
IIX
=1 and Y is an aromatic ring having 6 atoms, containing one nitrogen atom, said aromatic ring having the two free valences in position 2 and 6.
Preferably in the Compounds of Formula Ib) R
3
=CH
3
, nI=0, X is equal to O, X
1
is as above defined for Ia); in this case Ib) is the residue of the acetylsalicylsalicylic acid.
The compounds Ic) of formula Ic
1
) are the 5-amino salicylic acid derivatives (5-amino-2-hydroxybenzoic acid), for example mesalamine, when the valence is saturated with —COOH.
In the compounds of formula Ic
2
) at least one of the two carboxyl groups is reacted for obtaining the invention compounds. When both carboxyl groups react, bifunctional compounds are obtained. When the two valences are saturated with —COOH, the compound known as olsalazine is obtained. When one of the two valences instead of —COOH is saturated with —CONHCH
2
—CH
2
—COOH, the compound is known as balsalazide, wherein —OH which is in ortho position in the same aromatic ring is substituted with H.
The compounds of formula IC
3
) are known as sulphalazine: 2-hydroxy-5-[(2-pyridinylamino)sulphonyl]phenyl]azo] benzoic acid when the free valence is saturated with —COOH.
The preferred Ic) compounds have X=O and u=1;
Group II) wherein t=1, u=1
wherein:
R
II5
is H, a linear or branched when possible C
1
-C
3
alkyl;
R
II6
has the same meaning as R
II5
, or when R
II5
is H it may be benzyl;
R
II1
, R
II2
and R
II3
can independently be hydrogen, a linear or when possible branched C
1
-C
6
alkyl or a linear or when possible branched C
1
-C
6
alkoxy, or Cl, F, Br;
R
II4
is R
II1
or bromine;
the compounds wherein R
II1
, R
II4
are hydrogen and R
II2
and R
II3
are chlorine in ortho position with respect to NH are preferred;
R
II5
and R
II6
are H, X is equal to O, and X
1
is as above defined for the compounds of formula Ia);
IIb) is the residue of the 2-[(2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridincarboxylic] acid and when the —COOH group is present t
Benedini Francesca
Del Soldato Piero
Arent Fox Kintner & Plotkin & Kahn, PLLC
Davis Zinna Northington
Nicox S.A.
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