U.S. patent application number 12/715007 was filed with the patent office on 2010-06-17 for use of rapamycin derivatives in chronic rejection.
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 | 20100152105 12/715007 |
Document ID | / |
Family ID | 10791127 |
Filed Date | 2010-06-17 |
United States Patent
Application |
20100152105 |
Kind Code |
A1 |
Schuler; Walter ; et
al. |
June 17, 2010 |
USE OF RAPAMYCIN DERIVATIVES IN CHRONIC REJECTION
Abstract
The present invention is directed to the use of a rapamycin
derivative of formula I in combination with cyclosporin for
preventing or treating manifestations of chronic rejection in a
recipient of an organ or tissue transplant.
Inventors: |
Schuler; Walter;
(Grenzach-Whylen, DE) ; Schuurman; Hendrik J.;
(Basel, CH) ; Weckbecker; Gisbert; (Biel-Benken,
CH) ; Zerwes; Hans-Gunter; (Lorrach, DE) |
Correspondence
Address: |
DILWORTH & BARRESE, LLP
1000 WOODBURY ROAD, SUITE 405
WOODBURY
NY
11797
US
|
Assignee: |
NOVARTIS AG
Basel
CH
|
Family ID: |
10791127 |
Appl. No.: |
12/715007 |
Filed: |
March 1, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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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 |
Sep 23, 1998 |
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09712359 |
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Current U.S.
Class: |
514/1.1 ;
514/1.3 |
Current CPC
Class: |
A61P 9/00 20180101; A61P
9/10 20180101; A61P 37/00 20180101; A61K 31/436 20130101; A61P
43/00 20180101; A61P 35/00 20180101; A61P 37/06 20180101; A61P 7/02
20180101 |
Class at
Publication: |
514/11 |
International
Class: |
A61K 38/12 20060101
A61K038/12; A61P 9/00 20060101 A61P009/00; A61P 37/06 20060101
A61P037/06 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 27, 1996 |
GB |
9606452 |
Claims
1-10. (canceled)
11. A method for treating chronic rejection or preventing
manifestations of chronic rejection in a recipient of an organ or
tissue transplant, said method comprising co-administrating to said
recipient an effective amount of 40-O-(2-hydroxymethyl)-rapamycin
and cyclosporin A.
12. The method of claim 11 wherein the
40-O-(2-hydroxymethyl)-rapamycin and cyclosporin A are administered
concomitantly.
13. The method of claim 11 wherein the
40-O-(2-hydroxymethyl)-rapamycin and cyclosporin A are administered
in sequence.
14. The method of claim 11 wherein the
40-O-(2-hydroxymethyl)-rapamycin is administered in a dosage range
of from about 0.25 to 25 mg.
15. The method of claim 14 wherein the dosage is administered in a
single dose.
16. The method of claim 14 wherein the dosage is administered in
divided doses.
Description
[0001] 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.
[0002] Suitable derivatives of rapamycin include e.g. compounds of
formula I
##STR00001##
wherein
X is (H.H) or O;
Y is (H.OH) or O;
[0003] R.sup.1 and R.sup.2 are independently selected from [0004]
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 [0005] R.sup.4 is
methyl or [0006] R.sup.4 and R.sup.1 together form C.sub.2-6alkyl;
provided that R.sup.1 and R.sup.2 are not both H; and
hydroxyalkoxyalkyl is other than hydroxyalkoxymethyl.
[0007] Such compounds are disclosed in WO 94/09010 the contents of
which, in particular with respect to the compounds, are
incorporated herein by reference.
[0008] 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.
[0009] Examples of such compounds include: [0010] 1.
40-O-Benzyl-rapamycin [0011] 2.
40-O-(4'-Hydroxymethyl)benzyl-rapamycin [0012] 3.
40-O-[4'-(1,2-Dihydroxyethyl)]benzyl-rapamycin [0013] 4.
40-O-Allyl-rapamycin [0014] 5.
40-O-[3'-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2'-en-1'-yl]-rapamycin
[0015] 6.
(2'E,4'S)-40-O-(4',5'-Dihydroxypent-2'-en-1'-yl)-rapamycin [0016]
7. 40-O-(2-Hydroxy)ethoxycarbonylmethyl-rapamycin [0017] 8.
40-O-(2-Hydroxy)ethyl-rapamycin [0018] 9.
40-O-(3-Hydroxy)propyl-rapamycin [0019] 10.
40-O-(6-Hydroxy)hexyl-rapamycin [0020] 11.
40-O-[2-(2-Hydroxy)ethoxy]ethyl-rapamycin [0021] 12.
40-O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin [0022] 13.
40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin [0023] 14.
40-O-(2-Acetoxy)ethyl-rapamycin [0024] 15.
40-O-(2-Nicotinoyloxy)ethyl-rapamycin [0025] 16.
40-O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin [0026] 17.
40-O-(2-N-Imidazolylacetoxy)ethyl-rapamycin [0027] 18.
40-O-[2-(N-Methyl-N'-piperazinyl)acetoxy]ethyl-rapamycin [0028] 19.
39-O-Desmethyl-39,40-O,O-ethylene-rapamycin [0029] 20.
(26R)-26-Dihydro-40-O-(2-hydroxy)ethyl-rapamycin [0030] 21.
28-O-Methyl-rapamycin [0031] 22. 40-O-(2-Aminoethyl)-rapamycin
[0032] 23. 40-O-(2-Acetaminoethyl)-rapamycin [0033] 24.
40-O-(2-Nicotinamidoethyl)-rapamycin [0034] 25.
40-O-(2-(N-Methyl-imidazo-2'-ylcarboxamido)ethyl)-rapamycin [0035]
26. 40-O-(2-Ethoxycarbonylaminoethyl)-rapamycin [0036] 27.
40-O-(2-Tolylsulfonamidoethyl)-rapamycin [0037] 28.
40-O-[2-(4',5'-Dicarboethoxy-1',2',3'-triazol-1'-yl)-ethyl]-rapamycin
[0038] A preferred compound is e.g. 40-O-(2-hydroxy)ethyl-rapamycin
(referred thereafter as Compound A).
[0039] 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.
[0040] 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.
[0041] 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.
[0042] 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.
[0043] 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.
[0044] 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.
[0045] 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.
[0046] 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.
[0047] In accordance with the particular findings of the present
invention, there is provided: [0048] 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.
[0049] In a series of further specific or alternative embodiments,
the present invention also provides: [0050] 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 1. [0051] 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 1. [0052] 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. [0053] 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.
[0054] In a further or alternative embodiment the invention
provides: [0055] 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.
[0056] In a further or alternative embodiment, the present
invention also provides: [0057] 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. [0058] 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.
[0059] As alternative to the above the present invention also
provides: [0060] 5. A compound of formula I for use in any method
as defined under 1 to 4 above; or [0061] 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 [0062] 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.
[0063] 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.
A. Chronic Allograft Rejection
[0064] The kidney of a male DA (RT1.sup.a) rat is orthotopically
transplanted into a male Lewis (RT1.sup.1) recipient. In total 24
animals are transplanted. All animals are treated with cyclosporine
A at 7.5 mg/kg/day per os 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. [0065] 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 crafted 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. B.
Aorta transplantation [0066] 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.
[0067] 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 (RT1.sup.a) rat and transplanted
orthotopically in a male Lewis (RT1.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 crafted aorta and the recipient's own aorta.
[0068] 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. [0069] At autopsy,
weight and histology is performed for thymus, spleen, liver,
kidney, testes and seminal vesicles. [0070] 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. [0071] A second experiment includes 4 groups, each
comprising 4 animals. In all cases allogeneic transplants are
performed, and animals receive per os 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. [0072] In both experiments, the compounds of
formula I, particularly Compound A significantly inhibit graft
infiltration and neointima formation.
C. Angioplasty
[0072] [0073] 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 2F 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 cathether is then removed, a ligature
placed around the external carotid to prevent bleeding and the
animals allowed to recover. [0074] 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. [0075] 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.
[0076] 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 7100according 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. [0077] 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). [0078]
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%, 2.5 mg/kg significant inhibition of 75%.
D. In Vivo Heart Xenotransplantation (Hamster-to-Rat)
[0078] [0079] 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 pan 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. [0080] The heart
of a Syrian hamster is heterotopically transplanted in the abdomen
of a male Lewis (RT1.sup.a 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. [0081] In this assay, compounds of formula I,
e.g. Compound A, result in prolonged graft survival, in both
athymic and euthymic recipients.
[0082] 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.
[0083] 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.
[0084] 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 be 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, immunosuppressive 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. CTLA41g.
[0085] 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:
[0086] 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 [0087] 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
[0088] 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.
* * * * *