Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2001-01-19
2003-06-03
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C562S013000, C562S453000, C562S456000, C562S457000, C514S567000
Reexamination Certificate
active
06573252
ABSTRACT:
The present invention relates to compositions to be used in the therapy and prevention of bony disorders, such as those of the bony tissue and articulations. More specifically it relates to compositions having an improved therapeutic activity and improved gastrointestinal tolerability.
It is known in the art that the pharmacologic treatment of bony disorders implies therapies directed to control pathophysiologic processes such as those concerning the bony tissue and articulations.
Among the compounds known in the art for the pharmacologic treatment of the muscle skeletal and articular system disorders the following ones can be mentioned (see “New Guide to Medicine & Drugs”, Brit. Med. Association 1997, pag. 115; “Martindale, The Extra Pharmacopeia” vol. 31, 1996 pages 11-13):
diphosphonates (Alendronate, Pamidronate, Risedronate, etc.);
“oxicams”, i.e. Piroxicam, Tenoxicam; Aminopyrine; Tomoxiprol; Penicillamine; Methotrexate; etc.
They are medicines having a limited efficacy and having the inconvenience of causing lesions of the gastrointestinal duct, in particular of the stomach. Diphosphonates cause also lesions in the esophagus.
Other compounds used in the bony disorder therapy are anti-leukotriene medicines, for intance Ibudilast, Pranlukast, etc.; aminosalicylates. The efficacy and the gastrointestinal tolerability of these medicines is not optimal.
Compounds suitable to overcome the drawbacks shown by the medicines used in the bony disorder treatment have not yet been available in the art.
The need was felt to have available compounds for use in the bony disorder treatment with improved therapeutic features and tolerability and/or having an higher efficay.
The Applicant has unexpectedly and surprisingly found compounds and their compositions having improved pharmacotherapeutic properties.
It is an object of the present invention nitrate salts of compounds having a therapeutic activity in bony disorders, or their pharmaceutical compositions, said compounds being characterized in that they contain at least a reactive group capable to be salified with nitric acid, said compounds being selected from the following classes:
Class. F1):
Class F2A:
Class F2B:
The nitrate salts of the present invention can be obtained also by using the above mentioned compounds of the described classes, which optionally contain one or more —ONO
2
groups covalently bound to the molecule by one of the following bivalent linking bridges
YO wherein Y is a C
1
-C
20
alkylene linear or branched when possible, preferably from 2 to 5 carbon atoms, or an optionally substituted cycloalkylene from 5 to 7 carbon atoms;
Y
1
selected from:
wherein n
3
is an integer from 0 to 3;
wherein nf′ is an integer from 1 to 6 preferably from 2 to 4;
wherein R
1f
=H, CH
3
and nf is an integer from 1 to 6; preferably from 2 to 4.
Said compounds containing a —ONO
2
group covalently bound to the molecule through one or more of said bivalent linking bridges, or spacers, are prepared as described in the European patent application 759,899 in the name of the Applicant, herein incorporated by reference.
Preferably these compounds containaing —ONO
2
groups covalently bound to the molecule by said spacers are selected from the compounds of class F2A (in the Ampiroxicam (F2AII) case by previously hydrolising the ethyl ester) and Montelukast of class F3.
It has been found by the Applicant that the nitrate salts of compounds containing at least a nitrate group covalently bound to the molecule by one or more of the above spacers, show an higher pharmacological activity. For instance the nitrate salt of the 5-aminosalicylic acid derivative (mesalamine) containing a nitrate group covalently bound to the molecule by a butyl spacer, has resulted more active than the unsalified compound in the pharmacological model indicated in the examples.
The precursors to obtain the salts of the present invention are preferably selected from the following:
class F1: Alendronate;
class F2A: Piroxicam, Diclofenac, Etodolac, Flufenamic acid;
class F2B: Tomoxiprole;
class F3: Pranlukast.
In the compositions according to the present invention also the isomers, when they are available, of the compounds belonging to the above described classes, can be used.
Examples of isomers are cis-, trans-, optical isomers D and L or the racemic, enantiomer. In general one isomeric form has higher activity with respect to the other, e.g. D form with respect to L form or viceversa.
The compound salts belonging to above classes contain at least one nitrate ion mole/compound mole. Preferably the ratio between the nitrate ion moles and the precursor moles is unitary. Salts with higher molar ratio are obtained when in the molecule other aminic groups basic enough to be salified, are present.
The salts of the present invention are formulated in the corresponding pharmaceutical compositions according to well known techniques in the field, together with the usual excipients; see for instance the “Remington's Pharmaceutical Sciences 15a Ed.” volume.
The invention salt dosages in their pharmaceutical compositions are the same, and generally lower than those of their precursors of the mentioned classes. However since they are generally more tolerated, it is possible to use them also in dose higher than those of the precursors without having the side effects appearing with the precursors at high doses.
The precursors of the salts belonging to the above mentioned classes are prepared according to the methods described in the following references:
Class F1:
disodic Alendronate, disodic Pamidronate, sodic Risedronate: see the “Index Merck 14
a
Ed.” volume, herein incorporated by reference; disodic Ibandronate EP 252,502, formula (F1e) compound EP 325,482, formula (F1f) compound: EP 531,253, formula (F1g) compound: EP 592,488, formula (F1h) compound: EP 522,576, formula (P1i) compound: EP 546,548, formula (F1l) compound: EP 561,296, formula (F1m) compound: JP 93032684 (C.A. ref. Vol.119 226194d), formula (F1n) compound: JP 93222073 (C.A. ref. Vol.120 134926m), formula (F1o) compound: JP 92356496 (C.A. ref. Vol.119 095828p), formula (F1p) compound: WO 93/12122;
Class F2A:
Tenoxicam, Ampiroxicam, Lornoxicam, Piroxicam, Meloxicam, Flufenamic acid, Meclofenamic acid, Mefenamic acid, Niflumic acid, Aceclofenac, Diclofenac, Etodolac, Mesalamine, Methotrexate, Penicillamine, Tramadol: see “Index Merck volume, 14
a
Ed.”, herein incorporated by reference;
Class F2B:
Tomoxiprole: EP 12,866; Droxicam: “Index Merck 14
a
Ed.”; Celecoxib: WO 94/2,798, formula (F2BIV) compound WO 95/15,315; the compounds of formula F2BV (7-nitro indazol) and F2BVI (1,2-(trifluoromethylphenyl)imydazol) are commercialized by Lancaster Synthesis, Morecam—England.
Class F3:
Sodic salt Pranlukast, Ibudilast, Montelukast: see the “Index Merck volume, 14
a
Ed.”.
The salts of the present invention are obtainable according to one of the following methods.
If the substance to be salified is available as free base or as a corresponding salt soluble in an organic solvent, which preferably does not contain hydroxyl groups, for example acetonitrile, ethyl acetate, tetrahydrofuran, etc., the salt is prepared by dissolving the substance in the solvent at a concentration preferably equal or higher than 10% w/v, adding the amount of concentrated nitric acid corresponding to the moles of salifiable minic 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 at temperatures between 20° C. and 0° C. The product is generally recovered by filtration and washed with the solvent.
When on the contrary the substance is not very soluble, or it is available as a not very soluble salt in the above mentioned solvents, the corresponding mixtures with hydroxylated solvents can be used. Examples of such solvents are methyl alcohol, ethyl alcohol and water. Precipitation can be quickened by diluting the so obtained mixture, after the addition of nitric acid, with an apolar solvent.
When the starting product is salified
Arent Fox Kintner Plotkin & Kahn
Habte Kahsay
Nicox S.A.
Raymond Richard L.
LandOfFree
Medicine nitrate salts does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Medicine nitrate salts, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Medicine nitrate salts will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3140909