Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2001-07-03
2002-11-26
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S741000
Reexamination Certificate
active
06486209
ABSTRACT:
The present invention relates to a new use for a compound group comprising 2-amino-1,3-propanediol derivatives.
Compounds for use according to the invention are compounds of formula I
wherein
R
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
2
, R
3
, R
4
and R
5
, independently, is H or lower alkyl, in free form or in pharmaceutically acceptable salt form.
When the carbon chain as R
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.
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.
Preferred compounds of formula I are those wherein R
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
1
is phenylalkyl substituted by a straight or branched C
6-14
alkyl chain optionally substituted by halogen and the alkyl moiety is a C
6-14
alkyl optionally substituted by hydroxy. More preferably, R
1
is phenyl-C
1-6
alkyl substituted on the phenyl by a straight or branched, preferably straight, C
6-14
alkyl chain. The C
6-14
alkyl chain may be in ortho, meta or para, preferably in para.
Preferably each of R
2
to R
5
is H.
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.
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.
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.
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.
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.
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.
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.
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.
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:
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;
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;
In a series of further specific or alternative embodiments, the present invention also provides:
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.
As alternative to the above the present invention also provides:
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
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
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.
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.
A. Prevention of Graft Vessel Disease
Experimen
Cottens Sylvain
Hof Robert Paul
Wenger Roland
Criares Theodore J.
Kim Jennifer
Novartis AG
Savitsky Thomas R.
LandOfFree
Use for 1,3-propanediol derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Use for 1,3-propanediol derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Use for 1,3-propanediol derivatives will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2993120