Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-05-17
2001-08-14
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
06274629
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 alky,
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
1-6
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.
REFERENCES:
patent: 627 406 (1994-12-01), None
patent: 812 588 (1997-12-01), None
Y.Hoshino et al., Transplantation Proceedings, “FTY720, A Novel Immunosuppressant Possessing Unique Mechanisms. II.”, vol. 28, No. 2, pp. 1060-1061 (1996).
S.Suzuki et al., Transplant Immunology, “Immuynosuppressive effect of a New Drug, FTY720, on Lymphocyte Responses in Vitro and Cardiac Allograft Survival in Rats”, vol. 4, No. 3, pp. 252-255 (1996).
S.Suzuki et al., Transplantation Proceedings, “Long Term Graft Acceptance in Allografted Rats and Dogs by Treatment with a Novel Immunosuppressant FTY720”, vol. 28, No. 3, pp. 1375-1376 (1996).
S.Suzuki et al., Transplantation, “A Novel Immunosuppressant, FTY720, with a Unique Mechanism of Action, Induces Long-Term Graft Acceptance in Rat and Dog Allotransplantation”, vol. 61, No. 2, pp. 200-205 (1996).
K.Chiba et al., Transplantation Proceedings, “FTYY720, A Novel Immunosuppressant Possessing Unique Mechanisms”, vol. 28, No. 2, pp. 1056-1059 (1996).
T.Kawaguchi et al., Transplantation Proceedings, “FTY720, A Novel Immunosuppressant Possessing Unique Mechanisms III.” vol. 28, No. 2, pp. 1062-1063 (1996).
Y.Hoshino et al., 9th International Congress of Immunology, “FTY720, A Novel Immunosuppressant, Possessing Unique Mechanisms. II”, p. 864 (1995).
K.Adachi et al. Bioorganic & Medicinal Chemistry Letters, “Design, Synthesis, and Structure-Activity Relationship of 2-Substituted-2-Amino-1,3-Propanediols: Discovery of a Novel Immunosuppressant, FTY720”, vol. 5, No. 8, pp. 853-856 (1995).
Cottens Sylvain
Hof Robert Paul
Wenger Roland
Criares Theodore J.
Furman Diane E.
Kim Jennifer
Novartis AG
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