U.S. patent application number 10/261536 was filed with the patent office on 2003-04-10 for new use for 1,3-propanediol derivatives.
Invention is credited to Cottens, Sylvain, Hof, Robert Paul, Wenger, Roland.
Application Number | 20030069315 10/261536 |
Document ID | / |
Family ID | 10803173 |
Filed Date | 2003-04-10 |
United States Patent
Application |
20030069315 |
Kind Code |
A1 |
Cottens, Sylvain ; et
al. |
April 10, 2003 |
New use for 1,3-propanediol derivatives
Abstract
Use of a compound of formula I 1 wherein R.sub.1 is an
optionally substituted straight- or branched carbon chain having 12
to 22 carbon atoms which may be optionally interrupted by an
optionally substituted phenylene, and each of R.sub.2, R.sub.3,
R.sub.4 and R.sub.5, independently, is H or lower alkyl, in free
form or in pharmaceutically acceptable salt form, in the prevention
or treatment of chronic rejection in a recipient of organ or tissue
allo- or xenotransplant, or of acute rejection in a xenograft
transplant recipient.
Inventors: |
Cottens, Sylvain;
(Witterswil, CH) ; Hof, Robert Paul;
(Gelterkinden, CH) ; Wenger, Roland; (Riehen,
CH) |
Correspondence
Address: |
THOMAS HOXIE
NOVARTIS, PATENT AND TRADEMARK DEPARTMENT
ONE HEALTH PLAZA 430/2
EAST HANOVER
NJ
07936-1080
US
|
Family ID: |
10803173 |
Appl. No.: |
10/261536 |
Filed: |
September 30, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10261536 |
Sep 30, 2002 |
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09898143 |
Jul 3, 2001 |
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6486209 |
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09898143 |
Jul 3, 2001 |
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09308098 |
May 17, 1999 |
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6274629 |
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Current U.S.
Class: |
514/651 ;
514/668 |
Current CPC
Class: |
A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 2300/00 20130101; A61K 31/133 20130101; A61K 31/133
20130101; A61K 31/131 20130101; A61P 43/00 20180101; A61K 31/137
20130101; A61P 35/04 20180101; A61P 37/00 20180101; A61K 39/395
20130101; A61P 37/06 20180101; A61K 39/395 20130101; A61K 31/436
20130101; A61K 31/131 20130101; A61K 31/137 20130101; A61K 31/13
20130101; A61K 31/436 20130101 |
Class at
Publication: |
514/651 ;
514/668 |
International
Class: |
A61K 031/137; A61K
031/13 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 19, 1996 |
GB |
9624038.7 |
Claims
1. Use of a compound of formula I 3wherein R.sub.1 is an optionally
substituted straight- or branched carbon chain having 12 to 22
carbon atoms which may be optionally interrupted by an optionally
substituted phenylene, and each of R.sub.2, R.sub.3, R.sub.4 and
R.sub.5, independently, is H or lower alkyl, in free form or in
pharmaceutically acceptable salt form, in the preparation of a
pharmaceutical composition for preventing or treating
manifestations of chronic rejection in a recipient of organ or
tissue allo- or xenotransplant.
2. Use of a compound of formula I 4wherein R.sub.1 is an optionally
substituted straight- or branched carbon chain having 12 to 22
carbon atoms which may be optionally interrupted by an optionally
substituted phenylene, and each of R.sub.2, R.sub.3, R.sub.4 and
R.sub.5, independently, is H or lower alkyl, in free form or in
pharmaceutically acceptable salt form, in the preparation of a
pharmaceutical composition for preventing or treating graft vessel
diseases in a recipient of organ or tissue allo- or
xenotransplant.
3. Use of a compound of formula I 5wherein R.sub.1 is an optionally
substituted straight- or branched carbon chain having 12 to 22
carbon atoms which may be optionally interrupted by an optionally
substituted phenylene, and each of R.sub.2, R.sub.3, R.sub.4 and
R5, independently, is H or lower alkyl, in free form or in
pharmaceutically acceptable salt form, in the preparation of a
pharmaceutical composition for preventing or controlling acute
rejection in a xenograft transplant recipient.
4. Use of a compound of formula I as defined in claim 1, in free
form or in a pharmaceutically acceptable salt form, for preventing
or treating manifestations of chronic rejection in a recipient of
organ or tissue allo- or xenotransplant.
5. Use of a compound of formula I as defined in claim 1, in free
form or in a pharmaceutically acceptable salt form, for preventing
or controlling acute rejection in a xenograft transplant
recipient.
6. Use according to any one of the preceding claims, wherein the
compound of formula I is
2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol, in free form or
in pharmaceutically acceptable salt form.
7. A pharmaceutical composition for preventing or treating
manifestations of chronic rejection in a recipient of organ or
tissue allo- or xenotransplant, or for preventing or controlling
acute rejection in a xenograft transplant recipient, comprising a
compound of formula I as defined in claim 1, in free form or in a
pharmaceutically acceptable salt form, together with one or more
pharmaceutically acceptable diluents or carriers therefor.
8. A kit or package for preventing or treating manifestations of
chronic rejection in a recipient of organ or tissue allo- or
xenotransplant, or for preventing or controlling acute rejection in
a xenograft transplant recipient, comprising a compound of formula
I, in free form or in a pharmaceutically acceptable salt form, with
a pharmaceutical composition comprising an immunosuppressant or
immunomodulatory drug.
9. A composition according to claim 7 or a kit or package according
to claim 8, wherein the compound of formula I is
2-amino-2-[2-(4-octylphenyl- )ethyl]-1,3-propanediol, in free form
or in pharmaceutically acceptable salt form.
10. A method of preventing or treating manifestations of chronic
rejection in a recipient of organ or tissue allo- or
xenotransplant, or of preventing or controlling acute rejection in
a xenograft transplant recipient, comprising the step of
administering to said recipient a therapeutically effective amount
of a compound of formula I as defined in claim 1 in free form or in
pharmaceutically acceptable salt form.
Description
[0001] The present invention relates to a new use for a compound
group comprising 2-amino-1,3-propanediol derivatives.
[0002] Compounds for use according to the invention are compounds
of formula I 2
[0003] wherein
[0004] R.sub.1 is an optionally substituted straight- or branched
carbon chain having 12 to 22 carbon atoms which may be optionally
interrupted by an optionally substituted phenylene, and
[0005] each of R.sub.2, R.sub.3, R.sub.4 and R.sub.5,
independently, is H or lower alkyl, in free form or in
pharmaceutically acceptable salt form.
[0006] When the carbon chain as R.sub.1 is substituted, it is
preferably substituted by halogen, nitro, amino, hydroxy or
carboxy. When the carbon chain is interrupted by an optionally
substituted phenylene, the carbon chain is preferably
unsubstituted. When the phenylene moiety is substituted, it is
preferably substituted by halogen, nitro, amino, methoxy, hydroxy
or carboxy.
[0007] Such compounds are disclosed in EP-A1-627,406 the relevant
disclosure of which, in particular with respect to the compounds,
is incorporated herein by reference.
[0008] Preferred compounds of formula I are those wherein R.sub.1
is a straight or branched, preferably straight, chain alkyl having
13 to 20 carbon atoms, optionally substituted by nitro, halogen,
amino, hydroxy or carboxy, and, more preferably those wherein
R.sub.1 is phenylalkyl substituted by a straight or branched
C.sub.6-14 alkyl chain optionally substituted by halogen and the
alkyl moiety is a C.sub.1-6 alkyl optionally substituted by
hydroxy. More preferably, R.sub.1 is phenyl-C.sub.1-6 alkyl
substituted on the phenyl by a straight or branched, preferably
straight, C.sub.6-14 alkyl chain. The C.sub.6-14 alkyl chain may be
in ortho, meta or para, preferably in para.
[0009] Preferably each of R.sub.2 to R.sub.5 is H.
[0010] Examples of the pharmaceutically acceptable salts of the
compounds of the formula (I) include salts with inorganic acids,
such as hydrochloride, hydrobromide and sulfate, salts with organic
acids, such as acetate, fumarate, maleate, benzoate, citrate,
malate, methanesulfonate and benzenesulfonate salts, and when a
carboxy group is present, salts with metals such as sodium,
potassium, calcium and aluminium, salts with amines, such as
triethylamine and salts with dibasic amino acids, such as lysine.
The compounds and salts of the present invention encompass hydrate
and solvate forms.
[0011] When the compounds of formula I have one or more asymmetric
centers in the molecule, the present invention is to be understood
as embracing the various optical isomers, as well as racemates,
diastereoisomers and mixtures thereof are embraced.
[0012] Particularly preferred compounds of formula I are
2-amino-2-tetradecyl-1,3-propanediol and especially
2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol, (hereinafter
Compound A) e.g. in hydrochloride form.
[0013] Compounds of formula I have, on the basis of observed
activity, e.g. as described in EP-A1-627,406 been found to be
useful e.g. as immunosuppressant, e.g. in the treatment of acute
allograft rejection.
[0014] Organ transplants of liver, kidney, lung and heart are now
regularly performed as treatment for endstage organ disease.
Allograft as well as xenograft transplants have been performed.
However, because of problems with long-term chronic rejection,
organ transplantation is not yet a permanent 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 a heart allograft.
[0015] 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 wall 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 atherosclerosis,
transplant coronary disease, etc. This vascular lesion is
characterized by migration and proliferation of smooth muscle cells
under influence of growth factors, that are amongst others
synthesized by endothelium. It appears to progress also through
repetitive endothelial injury induced amongst others by host
antibody or antigen-antibody complexes, through intimal
proliferation and thickening, smooth muscle cell hypertrophy
repair, and finally to gradual luminal obliteration. Also so-called
non-immunological factors like hypertension, hyperlipidemia,
hypercholesterolemia etc. play a role.
[0016] 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.
[0017] In accordance with the present invention, it has now
surprisingly been found that compounds of formula I in free form or
in pharmaceutically acceptable salt form inhibit graft vessel
disease and are particularly indicated to prevent or treat chronic
rejection in a transplanted organ.
[0018] Furthermore, it has also been found that compounds of
formula I in free form or in pharmaceutically acceptable salt form
suppress xenograft rejection. In accordance with the particular
findings of the present invention, there is provided:
[0019] 1.1. A method of preventing or treating manifestations of
chronic rejection, e.g. to avoid, reduce or restrict chronic
rejection, in a recipient of organ or tissue allo- or
xeno-transplant, e.g. heart, lung, combined heart-lung, liver,
kidney or pancreatic transplant, comprising the step of
administering to said recipient a therapeutically effective amount
of a compound of formula I in free form or in pharmaceutically
acceptable salt form;
[0020] 1.2. A method of preventing or treating graft vessel
diseases, e.g. transplant vasculopathy, arteriosclerosis or
atherosclerosis, in a recipient of organ or tissue allo- or
xeno-transplant, e.g. heart, lung, combined heart-lung, liver,
kidney or pancreatic transplants, comprising the step of
administering to said recipient a therapeutically effective amount
of a compound of formula I in free form or in pharmaceutically
acceptable salt form;
[0021] In a series of further specific or alternative embodiments,
the present invention also provides:
[0022] 2. A method of preventing or controlling acute rejection in
a xenograft transplant recipient, e.g. a patient receiving a heart,
lung, combined heart-lung, kidney, liver, bone marrow, pancreatic
bowel, skin or corneal xenotransplant, comprising administering to
said recipient a therapeutically effective amount of a compound of
formula I in free form or in pharmaceutically acceptable salt
form.
[0023] As alternative to the above the present invention also
provides:
[0024] 3. A compound of formula I in free form or in
pharmaceutically acceptable salt form for use in any method as
defined under 1 or 2 above; or
[0025] 4. A compound of formula I in free form or in
pharmaceutically acceptable salt form for use in the preparation of
a pharmaceutical composition for use in any method as defined under
1 or 2 above; or
[0026] 5. A pharmaceutical composition for use in any method as
defined under 1 or 2 above comprising a compound of formula I in
free form or in pharmaceutically acceptable salt form together with
one or more pharmaceutically acceptable diluents or carriers
therefor.
[0027] Utility of the compounds of formula I in free form or in
pharmaceutically acceptable salt form in chronic rejection, as well
as utility in treating diseases and conditions as hereinabove
specified, may be demonstrated in animal tests for example in
accordance with the methods hereinafter described, as well as in
clinic where e.g. the transplanted organ or tissue may be submitted
to regular biopsy controls and in the case of heart transplant
additionally to ultrasound scanning.
[0028] A. Prevention of Graft Vessel Disease
[0029] Experimental Animals:
[0030] Inbred rat strains DA (RT1.sup.a, donors) and Lewis
(RT1.sup.1, recipients of allografts), weighing between 200 and 350
grams are used. The animals are allowed unrestricted access to food
and water before and after the operation.
[0031] Carotid Artery Transplantation:
[0032] The rats are anaesthetised with isofluorane (Abbott), (4-5%
for induction, 1.5-2% for maintenance) and 300 .mu.g atropin
sulphate is injected subcutaneously following the induction. The
left carotid artery is dissected free. The artery is clamped
proximally and distally and a segment of about 7-10 mm is removed.
The gap is bridged by an allograft which had also been subjected to
45 min cold ischemia. Ethilon 10/o sutures are used. Finally the
skin is closed with 4/0 sutures. If needed, an Alzet osmotic
minipump (Alza Corp. Palo Alto, Calif.) is then implanted
subcutaneously over the back (alternatively the animals are treated
orally).
[0033] The rats are subject to one of the following treatments: A
compound of formula I alone at the doses of 0.1 to 10 mg/kg, or in
combination with Cyclosporin A at the dose of 0.03, 0.3, or 1
mg.kg.sup.-1.day.sup.-1 is administered for 8 weeks either by using
Alzet osmotic minipumps implanted subcutaneously or alternatively
by oral administration. At 8 weeks the rats are sacrificed, the
carotid arteries are perfused 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 carotid
arteries are then excised and stained in Giemsa solution for
histological evaluation.
[0034] Morphometric analysis includes the measurement of the
thickness of the media and intima. A qualitative analysis of the
morphological changes includes a scoring on an 0-3 scale for
adventitial infiltration of mononuclear cells and necrosis
(vacuolar degeneration, hypertrophy of cells), the number of smooth
muscle cells (SMC) nuclei in the media (0-10, <100, >100 and
>>100 nuclei for scores, 0, 1, 2 and 3 respectively, SMC
necrosis (vacuolar degeneration and hypertrophy of SMC) and the
intimal infiltration of mononuclear cells (13).
[0035] In both experiments, the compounds of formula 1,
particularly Compound A in hydrochloride form, significantly
inhibit graft infiltration and neointima formation.
[0036] B. In vivo Heart Xenotransplantation (Hamster-to-Rat)
[0037] 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 polymorphonuclear
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
macro-phages, and destruction of the myocyte parenchyma. The
inhibition of cellular rejection requires more immuno- suppression
than that of allografts. Congenitally athymic (rnu/rnu) 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.
[0038] The heart of a Syrian hamster is heterotopically
transplanted in the abdomen of a male Lewis (RT1') 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.
[0039] Compounds are dissolved in water and administered daily
orally in a volume of 2 ml/kg body weight. Administration of 5-30
mg/kg/day, of a compound of Formula I, e.g. Compound A in
hydrochloride form, results in prolonged graft survival, in both
athymic and euthymic recipients.
[0040] 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, the severity of the condition to be treated, and
the optionally concomitantly used immunosuppressive drug e.g. CysA.
A preferred daily dosage range is about from 0.03 to 2.5 mg/kg per
day, particularly 0.1 to 2.5 mg/kg per day, e.g. 0.5 to 2.5 mg/kg
per day as a single dose or in divided doses. Suitable daily
dosages for patients are on the order of from e.g. 1 to 100 mg p.o.
Suitable unit dosage forms for oral administration comprise from
ca. 1 to 50 mg, usually 5 to 30 mg active ingredient, e.g. Compound
A, e.g. in hydrochloride form, together with one or more
pharmaceutically acceptable diluents or carriers therefor. As an
alternative, the compound of formula I in free form or in
pharmaceutically acceptable salt form may also be administered
twice or three times a week, e.g. at a dosage as indicated
above.
[0041] The compounds of formula I may be administered by any
conventional route, in particular enterally, e.g. orally, for
example in the form of solutions for drinking, tablets or capsules
or parenterally, for example in the form of injectable solutions or
suspensions. Pharmaceutical compositions comprising the compounds
of formula I may be manufactured in conventional manner, e.g. as
described in EP-A1-627,406.
[0042] The compounds of formula I may be administered as the sole
active ingredient or together with other drugs in immunomodulating
regimens or other anti-inflammatory agents. For example, the
compounds of formula I may be used in combination with
cyclosporins, rapamycins or ascomycins, or their immunosuppressive
analogs, e.g. cyclosporin A, cyclosporin G, FK-506, rapamycin,
40-O-(2-hydroxy)ethyl-rapamycin, etc.; corticosteroids;
cyclophosphamide; azathioprene; methotrexate; brequinar;
leflunomide; mizoribine; mycophenolic acid; mycophenolate mofetil;
15-deoxyspergualine; immuno-suppressive monoclonal antibodies,
e.g., monoclonal antibodies to leukocyte receptors, e.g., to MHC,
CD2, CD3, CD4, CD7, CD25, CD28, B7, CD40, CD45, or CD58 or to their
ligands; or other immunomodulatory compounds, e.g. CTLA4-lg.
[0043] Where the compounds of formula I are administered in
conjunction with other immunosuppressive/immunomodulatory therapy,
e.g. for preventing or treating chronic 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:
[0044] 6. 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 set forth above.
[0045] 7. A kit or package for use in any method as defined under 1
or 2 above, comprising a compound of formula 1, in free form or in
pharmaceutically acceptable salt form, with at least one
pharmaceutical composition comprising an immunosuppressant or
immunomodulatory drug. The kit or package may comprise instructions
for its administration.
FORMULATION EXAMPLE
Soft Capsules
[0046]
1 Compound of formula I, e.g. Compound A 30 mg Polyethylene glycol
300 300 mg Polysorbate 80 20 mg Total 350 mg
[0047] Compounds of formula I in free form or in pharmaceutically
acceptable salt form are well tolerated at dosages required for use
in accordance with the present invention. For example, the acute
LD.sub.50 is >10 mg/kg p.o. in rats and monkeys.
* * * * *