Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1992-03-20
1995-04-11
Hill, Jr., Robert J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530331, C07K 704, A61K 3724, A61K 3743
Patent
active
054058341
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel transient prodrug forms of thyrotropin-releasing hormone (TRH; thyroliberin)(pGlu-L-His-L-ProNH.sub.2), to methods for preparing the prodrug forms, to pharmaceutical compositions containing such prodrug forms, and to methods for using the prodrug forms.
For purposes of this specification, the term "prodrug" denotes a derivative of TRH which, when administered to warm-blooded animals, e.g. humans, is converted into the proven drug, i.e. TRH.
The term "transient" indicates that the conversion ot the prodrug forms proceeds in such a manner that the proven drug form (parent TRH) is released, and the remaining moieties splitt off remain nontoxic or are metabolized so that nontoxic metabolic products are produced.
These novel prodrugs forms of TRH are certain N-alkoxycarbonyl derivatives of TRH which possess a desirable high lipophilicity in comparison to the parent compound, TRH, and which are capable of protecting the parent compound, TRH, against enzymatic degradation or inactivation in vivo, e.g. in the blood.
2. Description of the Prior Art
TRH is the hypothalamic peptide that regulates the synthesis and secretion of thyrotropin from the anterior pituitary gland. Since the discovery of TRH in 1969, the peptide has been shown to have not only a variety of endocrine and central nervous system-related biological activity, but also potential as a drug in the management of various neurologic and neuropsychiatric disorders including depression and schizophrenia (see e.g. Metcalf, 1982; Jackson, 1982; Griffiths, 1986, 1987; Loosen, 1988). However, the clinical utility of TRH has been hampered by its rapid metabolism and clearance and its poor access to the brain (cf. e.g., Metcalf, 1982; Hichens, 1983; Griffiths, 1987). The poor penetration of TRH of the bloodbrain barrier is largely due to its very low lipophilicity (Banks & Kastin, 1985). Intravenous studies in rats and humans have shown that TRH has a plasma half-life of only 4-6 min (Bassin & Utiger, 1973; Morley et al., 1979; Duntas et al., 1988; Iversen, 1988). This short biological half-life is mainly due to rapid degradation of the tripeptide by enzymes endogenous to all body fluids and tissues, in particular by pyroglutamyl aminopeptidases including the so-called TRH-specific pyroglutamyl aminopeptidase serum enzyme (Bauer et al., 1981; Bauer, 1988; Wilk et al., 1988). The latter enzyme plays a major role in the rapid metabolism of TRH in human plasma (Bauer, 1988).
Accordingly, there is a need in the art to circumvent these problems of rapid enzymatic inactivation and poor lipophilicity of TRH.
It has now been found that it is possible to protect TRH against enzymatic inactivation and improve the lipophilicity by the prodrug approach according to the present invention.
SUMMARY OF THE INVENTION
The compounds of the present invention are N-alkoxycarbonyl derivatives of TRH which are more lipophilic than the active parent drug and hence better able to penetrate the blood-brain barrier than TRH, which afford protection of TRH against enzymatic inactivation in vivo and which, upon administration to warm-blooded animals, e.g. humans, are slowly converted into the active parent TRH resulting in enhanced duration of action. These characteristics make the compounds useful as therapeutic agents.
The compounds of the present invention are represented by the following general formula I ##STR1## wherein R.sub.1 is selected from the group consisting of an alkyl group, an aralkyl group, an alkenyl group, a cycloalkyl group, in which the alkyl, aralkyl, alkenyl or cycloalkyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, e.g. Cl or Br, a hydroxyl group or a straight or branched-chain alkoxy group containing from 1 to 6 carbon atoms; and the pharmaceutically acceptable acid addition salts thereof.
In the present context, the term "alkyl" designates C.sub.1-15 alkyl which may be straight or branched, su
REFERENCES:
patent: 4060603 (1977-11-01), Morgan et al.
patent: 4564609 (1986-01-01), Tamura et al.
Banks, W. A. & Kastin A. J.: Brain Res. Bull. 15, 1985, 287-292.
Bassiri, R. M. & Utiger, R. D.; J. Clin. Invest. 52, 1973, 1616-1619.
Bauer, K.: Biochimie 70, 1988, 69-74.
Bauer, K., Nowak, P. & Kleinhauf, H.: Eur. J. Biochem. 118, 1981, 173-176.
Bundgaard, H. & Moss J.: J. Pharm. Sci. 78, 1989, 122-126.
Duntas, L., Keck., F. S. & Pfeiffer, E. F.: Dtsch. med. Wschr. 113, 1988, 1354-1357.
Giralt, E., Ludevid, M. D. & Pedroso, E.: Bioorg. Chem. 14, 1986, 405-416.
Griffiths, E. C.: Nature 322, 1986, 212-213.
Griffiths, E. C.: Clin. Sci. 73, 1987, 449-457.
Gronvald, F. C., et al.: In "Peptides, Structure and Biological Function. Proceed. Amer. Pept. Symp. 7th" (Eds.: Gross, E. & Meinhofer, F.), 1979, 309-312.
Gronvald, F. C., et al.: In "Peptides, Proceed. Dur. Pept. Symp. 16th 1980" (Ed.: Brunfeldt, K.) Scriptor, Copenhagen, 1981, 706-710.
Hichens, M.: Drug Metab. Rev. 14, 1983, 77-98.
Iversen, E.: J. Endocrin, 118, 1988, 511-516.
Jackson, I. M. D.: N. Engl. J. Med. 306, 1982, 145-155.
Loosen, P. T.: Prog. Neuro-Psychopharmacol. & Biol. Psychiat., 12, 1988, S87-S117.
Matzner, M., Kurkjy, R. P. & Cotter, R. J.: Chem. Rev. 64, 1964, 645-687.
Metcalf, G.: Brain Res. Rev. 4, 1982, 389-408.
Morley, J. E., et al.: J. Clin. Endocrin. Metab. 48, 1979, 377-380.
Wilk, S., Suen, C. F. & Wilk, E. K.: Neuropeptides 12, 1988, 43-47.
Bundgaard Hans
Moss Judi
Hill Jr. Robert J.
Salata Carol A.
LandOfFree
Prodrug derivatives of thyrotropin-releasing hormone (TRH) does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Prodrug derivatives of thyrotropin-releasing hormone (TRH), we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Prodrug derivatives of thyrotropin-releasing hormone (TRH) will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1538556