Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-29
2003-01-07
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S271100, C546S273700
Reexamination Certificate
active
06503929
ABSTRACT:
The present invention relates to compositions to be used in the therapy and in the prevention of the ulcer relapses and, in general, of dyspepsias. More particularly it relates to compositions having an improved gastroprotective activity combined with a high acid secretion inhibition activity.
Products known in the art and those commercialized and used in the ulcer therapy are compounds which perform an anti-secretory activity (acid secretion inhibition). See for instance “New Guide to Medicine & Drugs” Brit. Medical Assoc. Editor, 1997, pagg. 108-109. Known products having higher therapeutic efficacy show a high anti-secretory activity and are used, both in the acute and in long-therm (six months and more) therapies. The drawback of these products is that they have a poor gastroprotectve activity, when present. From a practical point of view this means that the gastric protection is not optimal and causes inconveniences above all in the long-term therapy. In this case the presence of frequent relapses due to the enfeeblement of gastric mucosa is noticed.
To overcome these inconveniences it is known in the art to add to above medicines other anti-ulcer medicines having a gastroprotective action: prostaglandins, bismuth salts (e.g. bismuth citrate) and antibiotics. In such way the remission of ulcerous pathology is achieved. However above combinations are not satisfactory as for their tolerability in general. For example it is well known that prostaglandins produce side effects (diarrhoea) towards the intestinal tract; bismuth salts frequently produce nausea and gastric burning. Antibiotics produce unwanted gastrointestinal effects.
The need was felt to have available compositions active in the ulcer and gastric dyspepsia treatment, having improved therapeutic characteristic and tolerability, general and local, in particular having an improved gastroprotective activity combined to a high anti-secretion activity.
The Applicant has unexpectedly and surprisingly found pharmaceutical anti-ulcer compositions having the above mentioned desired properties.
It is an object of the present invention pharmaceutical compositions comprising as essential components nitrate salts of one or more components selected from the following classes of compounds:
where in the (A) class compounds:
R=H, OCH
3
, OCHF
2
;
R
1
=CH
3
, OCH
3
;
R
2
=H, CH
3
;
R
3
=CH
3
, CH
2
—CF
3
, (CH
2
)
3
—OCH
3
;
where in the class (B) compounds:
R
I
3
, R
I
4
equal to or different from each other, are respectively free valence, hydrogen —N=C(NH
2
)
2
, —CH
2
—N(CH
3
)
2
;
Y=S, N—R
I
6
, CR
I
7
R
I
8
;
X=O, S, N—R
I
1
;
R
I
2
=H, CH
3
;
n=0, 1;
Z=N—CN, N—SO
2
NH
2
, CH—NO
2
or
R
I
5
=H, —NH—CH
3
, NH
2
;
R
I
6
, R
I
7
, R
I
8
, R
I
1
, equal to or different from each other, are hydrogen, free valence.
The preferred nitrate salts with the (A) formula precursors are the following:
when R=OCH
3
, R
1
=CH
3
, R
2
=CH
3
, R
3
=CH
3
, Omeprazole residue; as in Omeprazole, but with R=OCHF
2
, R
1
=OCH
3
, R
2
=H, Pantoprazole residue;
as in Omeprazole, but with R=H, R
2
=H, R
3
=(CH
2
)
3
—OCH
3
, Rabeprazole residue;
as in Rabeprazole, but with R
3
=CH
2
—CF
3
, Lansoprazole residue.
In the (A) class compounds also those having the following intramolecular ring are comprised, obtainable by treating the precursors in an acid aqueous environment (rif. “A Textbook of Drug Design and Development”, Harwood Academic Publisher,1991, pag. 140):
wherein N
AI
and C
AII
mean, respectively, the nitrogen and carbon atom in 1 and 2 position of the pyridine ring of formula A and C
B2
and N
B3
the carbon and nitrogen atom, respectively, in 2 and 3 position of the imydazole ring (1 position of the imydazole ring is that of the proton nitrogen).
The preferred nitrate salts with the (B) formula precursors are the following:
when in (B) formula X=N—R
I
1
, with R
I
1
free valence, Y=N—R
I
6
with R
I
6
=H, R
I
3
=H, R
I
4
is a free valence and forms with R
I
1
a double bond, R
I
2
=CH
3
, n=1, R
I
5
=NH—CH
3
, Z=N—CN, Cimetidine residue;
when X=N—R
I
1
with R
I
1
free valence, Y=S, R
I
3
=—N=C(NH
2
)
2
, R
I
4
is a free valence and forms with R
I
1
a double bond, R
I
2
=H, n=1 R
I
5
=H, Z=(VII
A
), Ebrotidine residue;
as in Ebrotidine but with n=0, R
I
5
=NH
2
and Z=N—SO
2
NH
2
, Famotidine residue;
as in Ebrotidine but with R
I
3
=—CH
2
—N(CH
3
)
2
, R
I
5
=—NH—CH
3
and Z=CH—NO
2
, Nizatidine residue;
as in Nizatidine, but with X=oxygen, Y=CR
I
7
R
I
8
with R
I
7
hydrogen and R
I
8
free valence, R
I
4
is a free valence and forms with R
I
8
a double bond, Ranitidine residue.
In the compositions according to the present invention also optical isomers of the compounds belonging to (A) and (B) classes may be used.
In the compositions according to the present invention the compound salts of above classes contain at least one mole of nitrate ion/mole of compounds. Preferably the ratio between the nitrate ion moles and the precursor is equal to one. Salts having a higher molar ratio are obtained when in the molecule other amino groups basic enough to be salified are present.
Salt precursors belonging to the above mentioned classes are prepared according to the methods described in “The Merck Index 12
a
Ed.” (1996), herein completely incorporated by reference.
The salts of the present invention may be prepared according to one of the following methods.
When the substance to be salified is available as free base or as a soluble corresponding salt in an organic solvent, which preferably does not contain hydroxyl groups, for example acetonitrile, ethyl acetate, tetrahydrofuran ecc., the salt is prepared by dissolving the substance in the solvent at a concentration preferably equal or higher than 10% w/v, by adding the amount of concentrated nitric acid corresponding to the moles of salifiable aminic groups present in the compound. The nitric acid is preferably diluted in the same solvent. Preferably during and after the addition the mixture is cooled to temperatures in the range 20°-0° C. The product is generally recovered by filtration and washed with the solvent.
When on the contrary the substance is not much soluble or it is available as a not much soluble salt in the above mentioned solvents, the corresponding mixtures with hydroxylated solvents may be used. Examples of such solvents are methyl alcohol, ethyl alcohol and water. The precipitation can be quickened by diluting then the so obtained mixture, after the addition of nitric acid, with an apolar solvent.
When the starting product is salified with hydrochloric acid it is possible to prepare the salt with nitric acid directing adding silver nitrate to the compound solution. After filtering silver chloride, the solution is concentrated and cooled to recover the nitrate salt.
When the starting product is a salt, it is possible to liberate the corresponding base by a treatment with a sodium or potassium carbonate or bicarbonate saturated solution, or with a sodium or potassium hydroxide diluted solution. The base is then extracted by a suitable organic solvent (e.g. halogenated solvents, esters, ethers) which is then dried. The organic solution is evaporated and then one proceeds according to the preceding preparation methods, by dissolving the base in acetonitrile or in the other above mentioned solvents.
It has now surprisingly been found that the compositions of the present invention allow to improve, compared with the known above mentioned combinations, the comprehensive pharmaco-toxicological situation of precursors, increasing the therapeutic efficacy and their general and local tolerability in the ulcer and gastric dyspepsia treatment with an improved gastroprotective activity.
The compositions of the present invention are formulated in the correspond
Arent Fox Kintner & Plotkin & Kahn, PLLC
Coppins Janet
Nicox S.A.
Rotman Alan L.
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