Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1999-04-02
2003-08-26
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S179000, C514S825000
Reexamination Certificate
active
06610676
ABSTRACT:
This application is a 371 of PCT/EP97/05426 filed Oct. 2, 1997.
The present invention relates to preparation of new corticoid compounds.
In particular it relates to steroid-structured compounds having anti-inflammatory, immunodepressive and angiostatic activities (the so-called steroid anti-inflammatory drugs).
The compounds according to the present invention are therapeutically useful in the treatment of pathologic conditions where generally corticosteroid (corticoids) preparations are used, but with increased benefits.
This represents an unexpected advantage over the known corticoids products. In fact, by taking into account the various defined therapeutic uses of a specific product, it is always possible, with the new products of the present invention, to find a better combination of results with respect to the known corticoids. Contrary to any expectation the products of the present invention are characterised by the fact that they show an improved therapeutic profile: high activity combined with low side-effects.
Corticoids are well known as a first-choice pharmacological measure in the treatment of inflammatory disease. Drugs in this category—which include, for example, hydrocortisone, cortisone, prednisolone, prednisone, fludrocortisone, desoxycorticosterone, methylprednisolone, triamcinolone, paramethasone, betametasone, dexamethasone, triamcinolone acetonide, fluocinolone acetonide, beclomethasone, acetoxypregnelone, etc.—have marked pharmacotoxicological effects on various organs. Because of this, the clinical use and discontinued use thereof cause a series of side effects some of which are very severe. See for example Goodman & Gilman: “The Pharmaceutical Basis of Therapeutics”, 9th Ed., pages 1459-1465, 1996.
These toxic effects include:
those on bone which lead to changed cell metabolism and a high frequency of osteoporosis;
those on the cardiovascular system which cause hypertensive reactions;
those on the gastrointestinal tract which cause gastric damage.
See for instance Martindale: “The Extrapharmacopoeia”, 30th Ed., pages 712-723, 1993.
According to the above mentioned art it appears to be almost impossible for therapeutic activities to be separated from side effects, see Goodman et al., as mentioned above, at page 1474.
Known in the art are non-steroid anti-inflammatory drugs either with or without acidic ending see patents WO 94/04484, WO 94/12463, WO 95/09831, WO 95/30641 for non-acidic ending and the patents therein mentioned for those with acidic ending.
DE-A-2222491 (1) discloses pregnane derivatives having at position 21 the group
Said compounds are said to be endowed of antiinflammatory, antiallergic and cardiotropic activity. The single compounds are vasodilators.
U.S. Pat. No. 3,494,941 (2) discloses steroid derivatives from estrane-3-ol or estr-4-en-3-one useful as vasodilators in the treatment of heart conditions, such as coronary insufficiency and angina pectoris. Said compounds have at position 17 an ether linker attached to a nitrate radical. Nitrate groups can be also at positions 3 and 16 of the steroid ring.
Arzneimittel Forschung, vol. 19, n. 4, 1969, pp. 584-685 (3) discloses 3- and 17-nitrate ester of androstane derivatives, 3, a 17-dinitrate derivative of androstene, 17-nitrate esters of testosterone derivatives and 21-nitrate esters derivatives of desoxicortisone, cortisone and prednisone. In the paper it is stated that desoxicorticosterone nitrate promotes protein anabolism in different organs.
WO-A-97/34871 (4) discloses (i) compounds comprising a steroid, a &bgr;-agonist, an anticholinergic, a mast cell stabilizer or a PDE (phosphodiesterase) inhibitor to which is directly or indirectly linked at least one NO or NO
2
group or a group which stimulates the endogenous production of NO or EDRF (endothelium-derived relaxing factor) in vivo, said group linked through sites such as oxygen, sulfur, carbon and nitrogen; (ii) compositions comprising a therapeutically effective amount of a steroid, a &bgr;-agonist, an anticholinergic, a mast cell stabilizer or a PDE inhibitor, optionally substituted with at least one NO or NO
2
moiety or a group which stimulates endogenous production of NO or EDRF in vivo, in combination with a compound that donates, transfers, or releases nitric oxide and/or a compound that stimulates endogenous production of NO or EDRF in vivo.
However, it should be toted that steroid compounds are completely different from non-steroid compounds chemically, pharmacologically and biochemically as the pharmaco-toxicological mechanism of action of non-steroid products is based on inhibition of one or more cyclo-oxvgenases (COX), while steroid products have nothing to share with COX and have more complex pharmaco-toxicological mechanisms of action which have not yet been fully explained.
It is well known that these two groups of compounds are listed in completely separate categories in international pharmacopoeias.
The applicant has surprisingly and unexpectedly found corticosteroids (corticoids) which are very effective, even superior to those in the known art, and have, at the same time, a higher tolerance than the known corticoids as unexpectedly they do not cause the above side effects, or when they do, these are lower.
An object of the present invention are corticosteroids and their use as anti-inflammatory, immunosuppressive and angiostatic agents having the general formula:
B—X
1
—NO
2
or their esters or salts, where:
B has the following structure:
where, in place of the hydrogens H in the CH group or two hydrogens H
2
in the CH
2
group shown in the general formula, there may be the following substituents:
at position 1-2: there may be a double bond;
at position 2-3: there may be the following substituent:
at position 2: there may be Cl, Br;
at position 3: there may be CO, —O—CH
2
—CH
2
—Cl, OH;
at position 4-5: there may be a double bond;
at position 5-6: there may be a double bond;
at position 6: there may be Cl, F, CH
3
, —CHO;
at positicn 7: there may be Cl;
at position 9: there may be Cl, F;
at position 11: there may be OH, CO, Cl;
at position 16, there may be CH
3
, OH, ═CH
2
;
at position 17: there may be OH, CH
3
, OCO(O)
ua
(CH
2
)
va
CH
3
, or
where ua is an integer equal to 0 or 1, va is an integer from 0 to 4;
at positions 16-17: there may be the following groups
R and R′ are eaual or different one from the other and may be hydrogen or linear or branched alkyls having from 1 to 4 carbon atoms, preferably R=R′=CH
3
;
B being a carticasteraid residue;
(1) when at position 9 there is F, at position 11 there is OH, at positions 1-2 and at positions 4-5 there are two double bonds, at positions 3 and 20 two groups CO, at positions 16 and 17 there cannot be the group:
R″ is —(CO—L)
t
—(X)
t1
—
where t and t
1
are integers equal to 1; the bivalent bridging group L is selected from:
(CR
4
R
5
)
na
(O)
nb
(CR
4
R
5
)
n′a
(CO)
n′b
(O)
n″b
(CO)
n′″b
(CR
4
R
5
)
n″a
where na, n′a and n″a are equal or different one from the other and are integers from 0 to 6, preferably from 1 to 3; nb, nb′, n″b and n′″b are equal or different one from the other and are integers eorual to 0 or 1; R
4
and R
5
are equal or different one from the other and are chosen from H, linear or branched alkyl having from 1 to 5 carbon atoms, preferably from 1 to 3;
X is equal to X
0
=0, NH, NR
1C
where R
1C
is a linear or branched alkyl having from 1 to 10 C atoms;
X
1
is a bivalent connecting bridge chosen from:
YO
where Y is a linear or whenever possible branched C
1
-C
20
alkylene, preferably having from 2 to 5 carbon atoms, or an optionally substituted cycloalkylene having from 5 to 7 carbon atoms;
Y
1
selected from
where n
3
is an integer from 0 to 3;
where nf′ is an integer from 1 to 6, preferably from 2 to 4;
where R
1f
═H, CH
3
and nf is an integer from 1 to 6, preferably from 2 to 4.
The compounds which can be mentioned, and which are those preferred, are the ones listed below where B can be obtai
Arent Fox Kintner Plotkin & Kahn
Badio Barbara P.
Nicox S.A.
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