U.S. patent application number 13/357199 was filed with the patent office on 2012-07-12 for use of rapamycin derivatives in vasculopathies and xenotransplantation.
This patent application is currently assigned to Novartis AG. Invention is credited to Walter Schuler, Hendrik J. Schuurman, Gisbert Weckbecker, Hans-Gunter Zerwes.
Application Number | 20120177690 13/357199 |
Document ID | / |
Family ID | 10791127 |
Filed Date | 2012-07-12 |
United States Patent
Application |
20120177690 |
Kind Code |
A1 |
Schuler; Walter ; et
al. |
July 12, 2012 |
USE OF RAPAMYCIN DERIVATIVES IN VASCULOPATHIES AND
XENOTRANSPLANTATION
Abstract
Use of a rapamycin derivative of formula I as defined in the
claims for preventing or treating vasculopathies and manifestations
of xenotransplantation.
Inventors: |
Schuler; Walter;
(Grenzach-Whylen, DE) ; Schuurman; Hendrik J.;
(Basel, CH) ; Weckbecker; Gisbert; (Biel-Benken,
CH) ; Zerwes; Hans-Gunter; (Lorrach, DE) |
Assignee: |
Novartis AG
Basel
CH
|
Family ID: |
10791127 |
Appl. No.: |
13/357199 |
Filed: |
January 24, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12715007 |
Mar 1, 2010 |
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13357199 |
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10092639 |
Mar 7, 2002 |
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12715007 |
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09712359 |
Nov 14, 2000 |
6384046 |
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10092639 |
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09155210 |
Sep 23, 1998 |
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PCT/EP97/01548 |
Mar 26, 1997 |
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09712359 |
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Current U.S.
Class: |
424/278.1 |
Current CPC
Class: |
A61K 31/436 20130101;
A61P 7/02 20180101; A61P 9/10 20180101; A61P 35/00 20180101; A61P
37/06 20180101; A61P 37/00 20180101; A61P 9/00 20180101; A61P 43/00
20180101 |
Class at
Publication: |
424/278.1 |
International
Class: |
A61K 31/436 20060101
A61K031/436; A61P 35/00 20060101 A61P035/00; A61P 37/06 20060101
A61P037/06 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 27, 1996 |
GB |
9606452 |
Claims
1. A method for preventing or treating: vascular surgery induced
neointimal proliferation and thickening and/or restenosis and/or
vascular occlusion comprising administering to a subject in need
thereof an effective amount of 40-O-(2-hydroxy)ethyl-rapamycin.
2. A method according to claim 1 for preventing or treating
neointimal proliferation and thickening.
3. A method according to claim 1 for preventing or treating
restenosis and/or vascular occlusion.
4. A method according to claim 1 for preventing or treating
vascular occlusion.
5. A method according to claim 1, wherein the vascular surgery is
angioplasty.
Description
[0001] This application is a continuation of U.S. patent
application Ser. No. 12/715,007 filed Mar. 1, 2010, which is a
continuation of U.S. patent application Ser. No. 10/092,639, filed
Mar. 7, 2002, which is a divisional of U.S. patent application Ser.
No. 09/712,359, filed Nov. 14, 2000, now U.S. Pat. No. 6,384,046,
which is a continuation of Ser. No. 09/155,210, filed Sep. 23,
1998, abandoned, which is a 371 of PCT/EP97/01548, filed Mar. 26,
1997, which claims priority from GB Application No. 9606452.2 which
are herein incorporated by reference.
[0002] 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.
[0003] Suitable derivatives of rapamycin include e.g. compounds of
formula I
##STR00001##
wherein
[0004] X is (H.H) or O;
[0005] Y is (H.OH) or O;
[0006] R.sup.1 and R.sup.2 are independently selected from [0007]
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.sub.1-6alkyl,
branched or linear; "aryl" is phenyl or tolyl; and acyl is a
radical derived from a carboxylic acid; and [0008] R.sup.4 is
methyl or [0009] R.sup.4 and R.sup.1 together form C.sub.2-6,alkyl;
provided that R.sup.1 and R.sup.2 are not both H; and
hydroxyalkoxyalkyl is other than hydroxyalkoxymethyl.
[0010] Such compounds are disclosed in WO 94/09010 the contents of
which, in particular with respect to the compounds. are
incorporated herein by reference.
[0011] Acyl as may be present in R.sub.1 or R.sub.2, is preferably
R.sub.aCO-- wherein R.sub.a is C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.3-6cycloalkyl, aryl, aryl C.sub.1-6alkyl (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.
[0012] Examples of such compounds include:
[0013] 1. 40-O-Benzyl-rapamycin
[0014] 2. 40-O-(4'-Hydroxymethyl)benzyl-rapamycin
[0015] 3. 40-O-[4'-(1,2-Dihydroxyethyl)]benzyl-rapamycin
[0016] 4. 40-O-Allyl-rapamycin
[0017] 5.
40-O-[3'-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2'-en-1'-yl]-r-
apamycin
[0018] 6.
(2'E,4'S)-40-O-(4',5'-Dihydroxypent-2'-en-1'-yl)-rapamycin
[0019] 7. 40-O-(2-Hydroxy)ethoxycarbonylmethyl-rapamycin
[0020] 8. 40-O-(2-Hydroxy)ethyl-rapamycin
[0021] 9. 40-O-(3-Hydroxy)propyl-rapamycin
[0022] 10. 40-O-(6-Hydroxy)hexyl-rapamycin
[0023] 11. 40-O-[2-(2-Hydroxy)ethoxy]ethyl-rapamycin
[0024] 12.
40-O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin
[0025] 13. 40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin
[0026] 14. 40-O-(2-Acetoxy)ethyl-rapamycin
[0027] 15. 40-O-(2-Nicotinoyloxy)ethyl-rapamycin
[0028] 16. 40-O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin
[0029] 17. 40-O-(2-N-Imidazolylacetoxy)ethyl-rapamycin
[0030] 18.
40-O-[2-(N-Methyl-N'-piperazinyl)acetoxy]ethyl-rapamycin
[0031] 19. 39-O-Desmethyl-39,40-O,O-ethylene-rapamycin
[0032] 20. (26R)-26-Dihydro-40-O-(2-hydroxy)ethyl-rapamycin
[0033] 21. 28-O-Methyl-rapamycin
[0034] 22. 40-O-(2-Aminoethyl)-rapamycin
[0035] 23. 40-O-(2-Acetaminoethyl)-rapamycin
[0036] 24. 40-O-(2-Nicotinamidoethyl)-rapamycin
[0037] 25.
40-O-(2-(N-Methyl-imidazo-2'-ylcarboxamido)ethyl)-rapamycin
[0038] 26. 40-O-(2-Ethoxycarbonylaminoethyl)-rapamycin
[0039] 27. 40-O-(2-Tolylsulfonamidoethyl)-rapamycin
[0040] 28.
40O-[2-(4',5'-Dicarboethoxy-1',2',3'-triazol-1'-yl)-ethyl]-rapa-
mycin
[0041] A preferred compound is e.g. 40-O-(2-hydroxy)ethyl-rapamycin
(referred thereafter as Compound A).
[0042] Compounds of formula 1 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.
[0043] 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.
[0044] 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.
[0045] 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.
[0046] 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.
[0047] 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.
[0048] 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.
[0049] In accordance with the present invention, it has now
surprisingly been found that compounds of formula I inhibit
vasculopathies such as vascular remodelling and are particularly
indicated to prevent or combat chronic rejection in a transplanted
organ.
[0050] In accordance with the particular findings of the present
invention, there is provided:
[0051] 1. A method for preventing or treating neointimal
proliferation and thickening in a subject in need thereof,
comprising administering to said subject a therapeutically
effective amount of a compound of formula I.
[0052] In a series of further specific or alternative embodiments,
the present invention also provides:
[0053] 2.1. A method for preventing or combating manifestations of
chronic rejection in a recipient of organ or tissue transplant
comprising the step of administering to said recipient a
therapeutically effective amount of a compound of formula I.
[0054] 2.2. A method for preventing or combating graft vessel
diseases, e.g. transplant vasculopathies, arteriosclerosis or
atherosclerosis, in a recipient of organ or tissue transplant,
comprising the step of administering to said recipient a
therapeutically effective amount of a compound of formula I.
[0055] By manifestations of chronic rejection are meant the
conditions resulting from the immune reaction towards the graft and
the response of the blood vessel walls in the grafted organ or
tissue as indicated above. Compounds of formula I are useful for
reducing chronic rejection manifestations or for ameliorating the
conditions resulting from chronic rejection.
[0056] The organ or tissue transplantation may be performed from a
donor to a recipient of a same or different species. Among such
transplanted organs or tissues and given illustratively are heart,
liver, kidney, spleen, lung, small bowel, and pancreas, or a
combination of any of the foregoing.
[0057] In a further or alternative embodiment the invention
provides:
[0058] 3. A method for preventing or treating intimal smooth muscle
cell proliferation and migration, e.g. restenosis, and/or vascular
occlusion following vascular injury, e.g. angioplasty, in a subject
in need thereof, comprising administering to said subject a
therapeutically effective amount of a compound of formula I.
[0059] In a further or alternative embodiment, the present
invention also provides:
[0060] 4. A method for preventing or combating acute or chronic
rejection in a recipient of organ or tissue xenograft transplant
comprising administering to said recipient a therapeutically
effective amount of a compound of formula I.
[0061] Xenograft organ or tissue transplants include e.g. heart,
liver, kidney, spleen, lung, small bowel, pancreatic (complete or
partial, e.g. Langerhans islets), skin and bone marrow
xenografts.
[0062] As alternative to the above the present invention also
provides:
[0063] 5. A compound of formula I for use in any method as defined
under 1 to 4 above; or
[0064] 6. A compound of formula I for use in the preparation of a
pharmaceutical composition for use in any method as defined under 1
to 4 above; or
[0065] 7. A pharmaceutical composition for use in any method as
defined under 1 to 4 above comprising a compound of formula I
together with one or more pharmaceutically acceptable diluents or
carriers therefor.
[0066] Utility of the compounds of formula I in treating diseases
and conditions as hereinabove specified, may be demonstrated in
animal tests, for example in accordance with the methods
hereinafter described.
[0067] A. Chronic Allograft Rejection
[0068] The kidney of a male DA (RTI.sup.a) rat is orthotopically
transplanted into a male Lewis (RTI.sup.1) recipient. In total 24
animals are transplanted. All animals are treated with cyclosporine
A at 7.5 mg/kg/day per as for 14 days starting on the day of
transplantation, to prevent acute cellular rejection. Contralateral
nephrectomy is not performed. Each experimental group treated with
a distinct dose of a compound of formula I or placebo comprises six
animals.
[0069] Starting at day 53-64 after transplantation, the recipient
animals are treated per os for another 69-72 days with a compound
of formula I or receive placebo. At 14 days after transplantation
animals are subjected to graft assessment by magnetic resonance
imaging (MRI) with perfusion measurement of the kidneys (with
comparison of the grafted kidney and the own contralateral kidney).
This is repeated at days 53-64 after transplantation and at the end
of the experiment. The animals are then autopsied. Rejection
parameters such as MRI score, relative perfusion rate of the
grafted kidney and histologic score of the kidney allograft for
cellular rejection and vessel changes are determined and
statistically analyzed. Administration of a compound of formula I,
e.g. Compound A, at a dose of 0.5 to 2.5 mg/kg in this rat kidney
allograft model yields a reduction in all above mentioned rejection
parameters. In this assay, animals treated per os with 2.5
mg/kg/day of Compound A have a significantly lower MRI score of
rejection, histologic score for cellular rejection and vessel
changes and a significantly lower reduction in perfusion rate
assessed by MRI than the animals of the placebo group.
[0070] B. Aorta Transplantation
[0071] In this model of aorta transplantation in the rat, an
allogeneic response to the graft does not destroy the graft, but it
evokes pathological changes resembling those of chronic rejection
in clinical transplantation. These include infiltration into the
adventitia of mononuclear cells (lymphocytes, macrophages, some
plasma cells), and thickening of the intima.
[0072] Donor aorta between the branch of the renal artery and the
start of the caudal mesenteric aorta, about 1 cm in length, is
harvested from a male DA (RTI.sup.a) rat and transplanted
orthotopically in a male Lewis (RTI.sup.1) rat. Weekly after
transplantation, the body weight is recorded. At autopsy, the graft
with part of the aorta of the recipient just above and below the
transplant is removed. It is perfused ex vivo with
phosphate-buffered saline supplemented with 2% paraformaldehyde and
2.5% glutaraldehyde for about 2 minutes, then for 24 hours fixed by
immersion fixation in the same solution, and thereafter fixed in 4%
buffered formalin. Pieces of the graft are embedded in paraffin, in
such a way that both a transversal section and a longitudinal
section is made of the grafted aorta and the recipient's own
aorta.
[0073] Sections of 4 .mu.m thickness are stained by
hematoxylin-eosin, elastica-von-Gieson and periodic-acid-Schiff.
Apart from conventional light microscopy, images are recorded by
confocal laser scanning microscopy. From each section, four areas
are scanned, and from each area the thickness of the intima and
intima+media is measured at five locations.
[0074] At autopsy, weight and histology is performed for thymus,
spleen, liver, kidney, testes and seminal vesicles.
[0075] A first experiment includes 4 groups, each comprising 4
animals. In one group isogeneic transplantations (Lewis to Lewis)
are performed, and animals receive a placebo microemulsion; the
other groups comprise allogeneic transplantations, and animals
receive per os either placebo microemulsion or a compound of
formula I in microemulsion at 2.5 mg/kg/day. The experiment is
terminated at 7 weeks after transplantation.
[0076] A second experiment includes 4 groups, each comprising 4
animals. In all cases allogeneic transplants are performed, and
animals receive per as either placebo microemulsion or a compound
of formula I in microemulsion at 0.63, 1.25, 2.5 or 5.0 mg/kg/day.
The experiment is terminated 11 weeks after transplantation.
[0077] In both experiments, the compounds of formula I,
particularly Compound A significantly inhibit graft infiltration
and neointima formation.
[0078] C. Angioplasty
[0079] Studies on angioplasty are done in the model of balloon
catheter injury: Balloon catheterization is performed on day 0,
essentially as described by Powell et al. (1989). Under Isofluorane
anaesthesia, a Fogarty 2 F catheter is introduced into the left
common carotid artery via the external carotid and inflated
(distension.apprxeq.10 .mu.l H2O). The inflated balloon is
withdrawn along the length of the common carotid three times, the
latter two times whilst twisting gently to obtain a uniform
de-endothelialization. The cathethcr is then removed, a ligature
placed around the external carotid to prevent bleeding and the
animals allowed to recover.
[0080] 2 groups of 12 RoRo rats (400 g. approximately 24 weeks old)
are used for the study: one control group and one group receiving
the compound of formula I. The rats are fully randomized during all
handling, experimental procedures and analysis.
[0081] The compound to be tested is administered p.o. (gavage)
starting 3 days before balloon injury (day -3) until the end of the
study, 14 days after balloon injury (day +14). Rats are kept in
individual cages and allowed food and water ad libidum.
[0082] The rats are then anaesthetized with Isofluorane, a
perfusion catheter inserted through the left ventricle and secured
in the aortic arch, and an aspiration cannula inserted into the
right ventricle. Animals are perfused under a perfusion pressure of
150 mmHg, firstly for 1 min. with 0.1 M phosphate buffered saline
solution (PBS, pH 7.4) and then for 15 min. with 2.5%
glutaraldehyde in phosphate buffer (pH 7.4). The perfusion pressure
is 150 mmHg at the tip of the cannula (.apprxeq.100 mmHg in the
carotid artery), as determined in a preliminary experiment by
introducing a cannula attached to a pressure transducer into the
external carotid). Carotid arteries are then excised, separated
from surrounding tissue and immersed in 0.1 M cacodylate buffer (pH
7.4) containing 7% saccharose and incubated overnight at 4.degree.
C. The following day the carotids are immersed and shaken for 1 h
at room temperature in 0.05% KMnO4 in 0.1 M cacodylate. The tissues
are then dehydrated in a graded ethanol series; 2.times.10 min in
75%, 2.times.10 min in 85%, 3.times.10 min in 95% and 3.times.10
min in 100% ethanol. The dehydrated carotids are then embedded in
Technovit 7100 according to the manufacturers recommendation. The
embedding medium is left to polymerize overnight in an exsiccator
under argon, since oxygen is found to inhibit proper hardening of
the blocks.
[0083] Sections 1-2 .mu.m thick are cut from the middle section of
each carotid with a hard metal knife on a rotary microtome and
stained for 2 min with Giemsa stain. About 5 sections from each
carotid are thus prepared and the cross-sectional area of the
media, neointima and the lumen morphometrically evaluated by means
of an image analysis system (MCID, Toronto, Canada).
[0084] In this assay, the compounds of formula I inhibit myointimal
proliferation when administered per os at a daily dose of from 0.5
to 2.5 mg/kg. Intimal thickening is significantly less in the
vessels of the rats that receive Compound A compared to the control
animals. e.g. at 0.5 mg/kg statistical inhibition of neointima
formation of 50%, at 2.5 mg/kg significant inhibition of 75%.
[0085] D. In vivo Heart Xenotransplantation (Hamster-to-Rat)
[0086] The hamster-into-rat xenograft combination is a so-called
difficult concordant combination. Rats do not have natural
anti-hamster antibody in sufficient amounts to yield immediate
hyperacute rejection as observed in concordant combinations;
however, rejection in untreated recipients occurs within 3-4 days,
by antibodies in combination with complement. This is visualized in
histology by destruction of blood vessels, exsudation and
extravasation of erythrocytes, and influx by polymorpho- nuclear
granulocytes: often there are signs of hemorrhage and thrombosis.
Once this rejection has been overcome by effective inhibition of
antibody synthesis or complement inactivation, a cellular rejection
can emerge later on. This is visualized in histology by influx of
mononuclear cells, including lymphocytes, lymphoblastoid cells, and
macrophages, and destruction of the myocyte parenchyma. The
inhibition of cellular rejection requires more immuno-suppression
than that of allografts. Congenitally athymic (mu/mu) rats lack a
competent (thymus-dependent) cellular immune system and generally
are unable to reject allografts. Such animals do reject a hamster
xenograft within 3-4 days in a similar fashion as euthymic rats,
indicative that at least part of) anti-hamster antibody synthesis
in rats occurs following a thymus-independent B-cell response. Such
recipients are useful in hamster xenografting to evaluate rejection
by thymus-independent antibody-mediated rejection.
[0087] The heart of a Syrian hamster is heterotopically
transplanted in the abdomen of a male Lewis (RTI.sup.1) rat with
anastomoses between the donor and recipient's aorta and the donor
right pulmonary artery to the recipient's inferior vena cava. The
graft is monitored daily by palpation of the abdomen. Rejection is
concluded in case of cessation of heart beat. Animals are weighed
weekly. In the present series of experiments, the endpoint is set
to 28 days. Animals are subjected to autopsy; apart from the graft,
weight and histology is assessed for thymus, spleen, liver, seminal
vesicles and testes. Blood is taken and processed to serum for the
determination of cytolytic anti-hamster erythrocyte antibody and
hemolytic complement activity.
[0088] In this assay, compounds of formula I, e.g. Compound A,
result in prolonged graft survival, in both athymic and euthymic
recipients.
[0089] Daily dosages required in practicing the method of the
present invention will vary depending upon, for example, the
compound of formula I employed, the host, the mode of
administration and the severity of the condition to be treated. A
preferred daily dosage range is about from 0.25 to 25 mg as a
single dose or in divided doses. Suitable daily dosages for
patients are on the order of from e.g. 0.2 to 25 mg p.o. preferably
5 to 25. The compounds of formula I may be administered by any
conventional route, in particular enterally, e.g. orally. e.g. in
the form of tablets, capsules, drink solutions, nasally. pulmonary
(by inhalation) or parenterally, e.g. in the form of injectable
solutions or suspensions. Suitable unit dosage forms for oral
administration comprise from ca. 0.05 to 12.5 mg, usually 1 to 10
mg active ingredient. e.g. Compound A, together with one or more
pharmaceutically acceptable diluents or carriers therefor.
[0090] When used to prevent or treat chronic rejection or
xenotransplant rejection as hereinabove specified the compounds of
formula I may be administered as the sole active ingredient or
together with other drugs in immunomodulating regimens. For
example. the compounds of formula I may he used in combination with
cyclosporins or ascomycins, or their immunosuppressive analogs,
e.g. cyclosporin A, cyclosporin G, FK-506, etc.: corticosteroids;
cyclophosphamide; azathioprene; methotrexate; brequinar;
leflunomide; mizoribine; mycophenolic acid; mycophenolate mofetil;
15-deoxyspergualine, immunosuppresive monoclonal antibodies, e.g..
monoclonal antibodies to leukocyte receptors, e.g., MHC, CD2, CD3,
CD4, CD7, CD25, CD28, B7, CD45, or CD58 or their ligands; or other
immunomodulatory compounds, e.g. CTLA4Ig.
[0091] Where the compounds of formula I are administered in
conjunction with other immunosuppressive/immunomodulatory therapy.
e.g. for preventing or treating chronic rejection or xenotransplant
rejection as hereinabove specified, dosages of the co-administered
immunosuppressant or immuno-modulatory compound will of course vary
depending on the type of co-drug employed, e.g. whether it is a
steroid or a cyclosporin, on the specific drug employed. on the
condition being treated, and so forth. In accordance with the
foregoing the present invention provides in a yet further
aspect:
[0092] 8. A method as defined above comprising co-administration,
e.g. concomitantly or in sequence, of a therapeutically effective
amount of a compound of formula I and a second drug substance, said
second drug substance being an immunosuppressant or
immunomodulatory drug, e.g. as indicated above.
FORMULATION EXAMPLE
Capsules
TABLE-US-00001 [0093] Ethanol 20.0 mg 1.2-propylene glycol 81.0 mg
Refined oil 121.5 mg Cremophor RH40 202.5 mg Compound A 20.0 mg
Total 500 mg
[0094] Compounds of formula I are well tolerated at dosages
required for use in accordance with the present invention. For
example, the NTEL for Compound A in a 4-week toxicity study is 0.5
mg/kg/day in rats and 1.5 mg/kg/day in monkeys.
* * * * *