Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-05-19
2001-09-18
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06291509
ABSTRACT:
The present invention relates to a combination preparation containing:
(a) an immunosuppressant agent (A), and
(b) an immunosuppressant 2,2′-bi-1H-pyrrole compound (B), as herein defined.
The preparation has an increased immunosuppressive activity, relative to the sum of the effects produced by immunosuppressant drugs (A) or (B) used alone, allowing greater immunosuppressive activity with reduced toxicity.
BACKGROUND OF THE INVENTION
Presently, the most commonly used agents for preventing and treating rejection phenomena associated with organ and tissue transplantations, graft-versus-host diseases and autoimmune diseases are immunosuppressive drugs, e.g. cyclosporin A (CsA), FK506, azathioprine (AZ), methotrexate (Mtx), rapamycin (R), mycophenolate mofetil (Mac) and glucocorticosteroids (Gluc).
All these drug therapies are limited in effectiveness, in part because the doses needed for effective treatments may increase the patient's susceptibility to infection by a variety of opportunistic invaders and, mainly, because of the side effects caused by its direct toxicity. For instance, despite various successful results, a serious limitation to the wider application of CsA in these indications is the toxicity of this substance. In the first place, its marked nephrotoxicity which in some cases is irreversible has to be mentioned here, but also other phenomena such as hypertension, nausea, diabetes, diarrhoea, tremor, tingling or gingival hypertrophy (Palestine A.R. et al.: Am.J.Med. 77 (1984), 652-656), and lymphomagenesis represent complications to be taken seriously, which usually cannot be avoided even with systematic checking of the serum level. In addition, opportunistic infections have to be considered (Dawson T. et al.: J. Rheumatol. 19 (1992), 997), so that by critical benefit-risk assessment an otherwise advantageous CsA medication in many cases has to be sacrificed. FK506 (Tacrolimus) is a macrolide which exerts largely similar effects as CsA, both with regard to its molecular mode of action and its clinical efficacy (Liu J.: Immunol. Today 14 (1993), 290-295; Schreiber S.L. et al.: Immunol. Today 13 (1992), 136-142); these effects, however, may be found already at doses which are less by the factor 20 to 100 compared to CsA (Peters D.H. et al.: Drugs 46 (1993), 746-794). The same is true for rapamycin (R) which again is a macrolide binding intracellularly to the same immunophilin as FK506, although the following biochemical events are differing somewhat (Morris R.E.: Transplant. Rev. 6 (1992), 39-87).
Accordingly, it would be desirable to have a drug capable of potentiating the action of currently used immunosuppressive agents. Ideally, such a drug would increase the efficacy of such immunosuppressive agents and also decrease deleterious side-effects by allowing administration of lower dosage levels.
After an extensive study on the possibility that the effect of an immunosuppressive agent (A) in the present invention is improved by combining it with a variety of compounds, the present inventor has surprisingly discovered that the effect of an immunosuppressive agent (A) is significantly improved and side-effects can be decreased by co-administering it with at least one 2,2′-bi-1H-pyrrole compound (B), as herein defined.
2,2′-Bi-1H-pyrrole compounds (B), according to the present invention are immunosuppressive agents which are known, e.g., from WO 95/17381. Such description also shows a combined use of an immunosuppressant agent (A) and a 2,2′-bi-1H-pyrrole compound (B), in immunosuppressive therapy. However, WO 95/17381 neither shows, nor suggests, that said combined use cause synergistic increase in effect or decrease side-effects in immunosuppressive therapy. In particular, WO 95/17381 neither shows, nor suggests, that the same therapeutic effect obtainable by the combined use of therapeutically effective amounts of an immunosuppressant agent (A) and a 2,2′-bi-1H-pyrrole compound (B) can be similarly also obtained by co-administration of doses by itself inactive of the same two immunosuppressant agents (A) and (B).
DESCRIPTION OF THE INVENTION
In a first aspect, the present invention provides a product containing: (a) an immunosuppressant agent (A) and (b) at least one immunosuppressant 2,2′-bi-1H-pyrrole compound (B) having the following formula (I)
wherein
R
1
represents hydrogen, phenyl, C
1
-C
20
alkyl or C
2
-C
20
alkenyl, wherein the alkyl and alkenyl groups may be unsubstituted or substituted by 1 to 3 substituents chosen independently from halogen, C
1
-C
6
alkoxy, hydroxy, aryl and aryloxy;
R
2
represents hydrogen, C
1
-C
6
alkyl, cyano, carboxy or (C
1
-C
6
alkoxy)carbonyl;
R
3
represents halogen, hydroxy or C
1
-C
11
alkoxy unsubstituted or substituted by phenyl;
R
4
represent hydrogen, C
1
-C
6
alkyl or phenyl; each of R
5
and R
6
independently represents hydrogen, C
2
-C
20
alkanoyl, C
3
-C
20
alkenoyl, phenyl, C
1
-C
20
alkyl or C
2
-C
20
alkenyl, wherein the alkanoyl, alkenoyl, alkyl and the alkenyl groups may be unsubstituted or substituted by 1 to 3 substituents chosen independently from halogen, C
1
-C
6
alkoxy, hydroxy, aryl, aryloxy, cyano, carboxy, (C
1
-C
6
alkoxy)carbonyl, (C
3
-C
4
alkenyl)carbamoyl, aralkylcarbamoyl, arylcarbamoyl and —CONR
c
R
d
in which each of R
c
and R
d
independently is hydrogen or C
1
-C
6
alkyl or R
c
and R
d
, taken together with the nitrogen atom to which they are linked, form a morpholino or piperidino ring; or two of R
4
, R
5
and R
6
taken together form a C
4
-C
12
polymethylene chain, which can be unsubstituted or substituted by a C
1
-C
12
alkyl, by a C
2
-C
12
alkenyl or by a C
1
-C
12
alkylidene group, wherein the alkyl, alkenyl and alkylidene groups may be in turn unsubstituted or substituted by a substituent chosen from halogen, C
1
-C
6
alkoxy, hydroxy, cyano, carboxy, (C
1
-C
6
alkoxy)carbonyl, aryloxy and aryl; the remaining one being hydrogen or C
1
-C
12
alkyl; or a pharmaceutically acceptable salt thereof; in amounts effective to produce a superadditive immunosuppressant effect, as a combined preparation for simultaneous, separate or sequential use in immunosuppressant therapy. Said preparation having therefore a potentiated immunosuppressive activity with respect to products containing either the immunosuppressive agent (A) or the 2,2′-bi-1H-pyrrole immunosuppressive compound (B).
Also disclosed is a combination preparation containing: (a) an immunosuppressant agent (A) and (b) at least one immunosuppressant 2,2 -bi-1H-pyrrole compound (B) of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, in a quantity producing a superadditive immunosuppressive effect.
The present invention also provides a pharmaceutical composition for use in immunosuppressant therapy in mammals, including humans, comprising:
(a) an immunosuppressant agent (A) in a pharmaceutically acceptable carrier and/or excipient, and
(b) at least one immunosuppressive 2,2′-bi-1H-pyrrole compound (B) of formula (I), as defined above, or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier and/or excipient, in amounts effective to produce a superadditive immunosuppressant effect, said composition having a potentiated immunosuppression activity with respect to a composition containing either the immunosuppressive agent (A) or the 2,2′-bi-1H-pyrrole immunosuppressant compound (B).
A further aspect of the present invention is an immunosuppressant therapy method for use in mammals, including humans, in need thereof, the method comprising administering to said mammal (a) an immunosuppressant agent (A) and (b) at least one immunosuppressant 2,2′-bi-1H-pyrrole compound (B) of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, in amounts effective to produce a superadditive immunosuppressive effect.
The invention also provides a method for lowering the side effects caused by immunosuppressant therapy with an immunosuppressant agent (A) or a 2,2′-bi-1H-pyrrole comp
Colotta Francesco
D′Alessio Roberto
Ferrari Mario
Fornasiero Maria Chiara
Gnocchi Paola
Jones Dwayne C.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Pharmacia & Upjohn SpA
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