Use of 40-O-(2-hydroxy)ethylrapamycin for treatment of...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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Reexamination Certificate

active

06384046

ABSTRACT:

The present invention relates to a new use, in particular a new use for a compound group comprising derivatives of rapamycin, in free form or in pharmaceutically acceptable salt or complex form. Suitable derivatives of rapamycin include e.g. compounds of formula I
wherein
X is (H,H) or O;
Y is (H,OH) or O;
R
1
and R
2
are independently selected from
H,. alkyl, arylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxycarbonylalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, acyloxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, acylaminoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl, dialkyl-dioxolanylalkyl, di(alkoxycarbonyl)-triazolyl-alkyl and hydroxy-alkoxy-alkyl; wherein “alk-” or “alkyl” is C
1-6
alkyl, branched or linear; “aryl” is phenyl or tolyl; and acyl is a radical derived from a carboxylic acid; and
R
4
is methyl or
R
4
and R
1
together form C
2-6
alkyl;
provided that R
1
and R
2
are not both H; and hydroxyalkoxyalkyl is other than hydroxyalkoxymethyl.
Such compounds are disclosed in WO 94/09010 the contents of which, in particular with respect to the compounds, are incorporated herein by reference.
Acyl as may be present in R
1
or R
2
, is preferably R
a
CO— wherein R
a
is C
1-6
alkyl, C
2-6
alkenyl, C
3-6
cycloalkyl, aryl, aryl C
1-6
alkyl (wherein aryl is as defined above) or heteroaryl, e.g. a residue derived from a 5 or 6 membered heterocycle comprising N, S or O as a heteroatom and optionally one or two N as further heteroatoms. Suitable heteroaryl include e.g. pyridyl, morpholino, piperazinyl and imidazolyl.
Examples of such compounds include:
1. 40-O-Benzyl-rapamycin
2. 40-O-(4′-Hydroxymethyl)benzyl-rapamycin
3. 40-O-[4′-(1,2-Dihydroxyethyl)]benzyl-rapamycin
4. 40-O-Allyl-rapamycin
5. 40-O-[3′-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin
6. (2′E,4′S)-40-O-(4′,5′-Dihydroxypent-2′-en-1′-yl)-rapamycin
7. 40-O-(2-Hydroxy)ethoxycarbonylmethyl-rapamycin
8. 40-O-(2-Hydroxy)ethyl-rapamycin
9. 40-O-(3-Hydroxy)propyl-rapamycin
10. 40-O-(6-Hydroxy)hexyl-rapamycin
11. 40-O-[2-(2-Hydroxy)ethoxy]ethyl-rapamycin
12. 40-O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin
13. 40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin
14. 40-O-(2-Acetoxy)ethyl-rapamycin
15. 40-O-(2-Nicotinoyloxy)ethyl-rapamycin
16. 40-O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin
17. 40-O-(2-N-Imidazolylacetoxy)ethyl-rapamycin
18. 40-O-[2-(N-Methyl-N′-piperazinyl)acetoxy]ethyl-rapamycin
19. 39-O-Desmethyl-39,40-O,O-ethylene-rapamycin
20. (26R)-26-Dihydro-40-O-(2-hydroxy)ethyl-rapamycin
21. 28-O-Methyl-rapamycin
22. 40-O-(2-Aminoethyl)-rapamycin
23. 40-O-(2-Acetaminoethyl)-rapamycin
24. 40-O-(2-Nicotinamidoethyl)-rapamycin
25. 40-O-(2-(N-Methyl-imidazo-2′-ylcarboxamido)ethyl)-rapamycin
26. 40-O-(2-Ethoxycarbonylaminoethyl)-rapamycin
27. 40-O-(2-Tolylsulfonamidoethyl)-rapamycin
28. 40-O-[2-(4′,5′-Dicarboethoxy-1′,2′,3′-triazol-1′-yl)-ethyl]-rapamycin
A preferred compound is e.g. 40-O-(2-hydroxy)ethyl-rapamycin (referred thereafter as Compound A).
Compounds of formula I have, on the basis of observed activity, e.g. binding to macrophilin-12 (also known as FK-506 binding protein or FKBP-12), e.g. as described in WO 94/09010, been found to be useful e.g. as immunosuppressants, e.g. in the treatment of acute allograft rejection.
Organ transplants of liver, kidney, lung and heart are now regularly performed as treatment for endstage organ disease. Because of the current shortage of human donors for transplantable allografts, attention has focused on the possibility of using xenografts (transplants between species) in transplantation. One of the major obstacles in transplanting successfully xenografts in humans is immunological.
A further obstacle in allo- and xenotransplantation is the chronic rejection and thus organ transplantation is not yet a clinically viable solution to irreversible organ disease.
Chronic rejection, which manifests as progressive and irreversible graft dysfunction, is the leading cause of organ transplant loss, in some cases already after the first postoperative year. The clinical problem of chronic rejection is clear from transplantation survival times; about half of kidney allografts are lost within 5 years after transplantation, and a similar value is observed in patients with heart allografts.
Chronic rejection is considered as a multifactorial process in which not only the immune reaction towards the graft but also the response of the blood vessel walls in the grafted organ to injury (“response-to-injury” reaction) plays a role. The variant of chronic rejection with the worst prognosis is an arteriosclerosis-like alteration, also called transplant vasculopathy, graft vessel disease, graft arteriosclerosis, transplant coronary disease, etc. This vascular lesion is characterized by migration and proliferation of smooth muscle cells, probably under influence of growth factors that are amongst others synthesized by endothelial cells. This leads to intimal proliferation and thickening, smooth muscle cell hypertrophy repair, and finally to gradual luminal obliteration (vascular remodelling). It appears to progress also through repetitive endothelial injury induced amongst others by host antibody or antigen-antibody complexes; also so-called non-immunological factors like hypertension, hyperlipidemia, hypercholesterolemia etc. play a role.
Chronic rejection appears to be inexorable and uncontrollable because there is no known effective treatment or prevention modality. Thus, there continues to exist a need for a treatment effective in preventing, controlling or reversing manifestations of chronic graft vessel diseases.
There also continues to exist a need to prevent or treat restenosis or vascular occlusions as a consequence of proliferation and migration of intimal smooth muscle cell, e.g. induced by vascular surgeries such as angioplasty.


REFERENCES:
patent: 5362718 (1994-11-01), Skotnicki et al.
patent: 5516781 (1996-05-01), Morris et al.
patent: 5665772 (1997-09-01), Cottens et al.
patent: 551 182 (1993-07-01), None
patent: 568 310 (1993-11-01), None
patent: 691 130 (1996-01-01), None
patent: WO 94/09010 (1994-04-01), None
patent: WO 96/41807 (1996-12-01), None
Ikonen et al., “Sirolimus (Rapamycin) Halts and Reverses Progression of Allograft Vascular Disease in Non-Human Primates”, Transplantation, vol. 70, No. 6, pp. 969-975 (2000).
Matas et al., “Chronic Rejection”, J. Am. Soc. Nephrol., vol. 4, Suppl. 1, pp. S23-S29 (1994).
Kahan, “The Potential Role of Rapamycin in Pediatric Transplantation as Observed from Adult Studies”, Pediatr Transplantation, vol. 3, pp.175-180 (1999).
Sadrani et al., “Chemical Modification of Rapamycin: The Discovery of SDZ RAD”, Transplant. Proc., vol. 30, pp. 2192-2194 (1998).
Fellstrom et al., “Pathogenesis and Treatment Perspectives of Chronic Graft Rejection (CVR)”, Immunological Reviews, No. 134, pp. 83-98 (1993).
Meiser et al., “Effects of Cyclosporin, FK506, and Rapamycin on Graft-Vessel Disease”, Lancet, vol. 388, pp. 1297-1298 (1991).
Gregory et al., “The Use of New Antiproliferative Immunosuppressants is a Novel and Highly Effective Stategy for the Prevention of Vascular Occulusive Disease”, J. Heart Lung Transpl., vol. 11, Pt. 11, p. 197 (1992).
Morris et al., “Immunosuppressive Effects of the Morpholinoethyl Ester of Mycophenolic Acid (RS-61443) in Rat and Nonhuman Primate Recipients of Heart Allografts”, Transplant. Proc., vol. 23, No. 2, Suppl. 2, pp. 19-25 (1991).

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