Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-26
2003-06-10
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S201000
Reexamination Certificate
active
06576648
ABSTRACT:
FIELD OF INVENTION
The present invention relates to a new compound, pharmaceutically acceptable salts thereof, compositions containing them, and their use for treating medical disorders resulting from a deficiency in growth hormone.
BACKGROUND OF THE INVENTION
Growth hormone is a hormone, which stimulates growth of all tissues capable of growing. In addition, growth hormone is known to have a number of effects on metabolic processes, e.g., stimulation of protein synthesis and free fatty acid mobilisation and to cause a switch in energy metabolism from carbohydrate to fatty acid metabolism. Deficiency in growth hormone can result in a number of severe medical disorders, e.g., dwarfism.
Growth hormone is released from the pituitary. The release is under tight control of a number of hormones and neurotransmitters either directly or indirectly. Growth hormone release can be stimulated by growth hormone releasing hormone (GHRH) and inhibited by somatostatin. In both cases the hormones are released from the hypothalamus but their action is mediated primarily via specific receptors located in the pituitary. Other compounds which stimulate the release of growth hormone from the pituitary have also been described. For example arginine, L-3,4-dihydroxyphenylalanine (L-Dopa), glucagon, vasopressin, PACAP (pituitary adenylyl cyclase activating peptide), muscarinic receptor agonists and a synthetic hexapeptide, GHRP (growth hormone releasing peptide) release endogenous growth hormone either by a direct effect on the pituitary or by affecting the release of GHRH and/or somatostatin from the hypothalamus.
In disorders or conditions where increased levels of growth hormone is desired, the protein nature of growth hormone makes anything but parenteral administration non-viable. Furthermore, other directly acting natural secretagogues, e.g., GHRH and PACAP, are longer polypeptides for which reason parenteral administration is preferred.
The use of certain compounds for increasing the levels of growth hormone in mammals has previously been proposed, e.g. in EP 18 072, EP 83 864, WO 8302272, WO 8907110, WO 8901711, WO 8910933, WO 8809780, WO 9118016, WO 9201711, WO 9304081, WO 9413696, WO 9517423, WO 9514666, WO 9615148, WO 9622997, WO 9635713, WO 9700894, WO 9722620, WO 9723508, WO 9740023, and WO 9810653.
The composition of growth hormone releasing compounds is important for their growth hormone releasing potency as well as their bioavailability. It is therefore an object of the present invention to provide a novel compound with growth hormone releasing properties. Moreover, it is an object to provide a novel growth hormone releasing compound (growth hormone secretagogue) which are specific and/or selective and have no or substantially no side-effects, such as e.g. release of LH, FSH, TSH, ACTH, vasopressin, oxytocin, cortisol and/or prolactin. It is also an object to provide a compound which has a good oral bioavailability.
SUMMARY OF THE INVENTION
In accordance with the present invention there is provided a novel compound which act directly on the pituitary cells under normal experimental conditions in vitro to release growth hormone therefrom.
The growth hormone releasing compound can be utilized in vitro as unique research tools for understanding, inter alia, how growth hormone secretion is regulated at the pituitary level.
Moreover, the growth hormone releasing compound of the present invention can also be administered in vivo to increase endogenous growth hormone release.
DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to a new compound 2-Amino-N-[(1R)-2-[(3R)-3-benzyl-3-(N,N′,N′-trimethylhydrazinocarbonyl)piperidin-1-yl]-1-(1H-indol-3-ylmethyl)-2-oxoethyl]-2-methylpropionamide, having the following chemical structure
or a pharmaceutically acceptable salt thereof.
Furthermore, the present invention relates to the compound 2-Amino-N-[(1R)-2-[(3R)-3-benzyl-3-(N,N′,N′-trimethylhydrazinocarbonyl)piperidin-1-yl]-1-(1H-indol-3-ylmethyl)-2-oxoethyl]-2-methylpropionamide
or a pharmaceutically acceptable salt thereof.
The structure of the compound obtainable by the procedure as described in example 1 can e.g. be verified by X-ray diffraction analysis (e.g. as described in Remington: The Science and Practice of Pharmacy, 19th Edition (1995), especially pages 160 and 561-562).
Any possible combination of two or more of the embodiments described herein is comprised within the scope of the present invention.
Synthetic Methods in General
The procedure used in this patent is based on peptide couplings well known in the art, and should in no way be interpreted as limiting the invention in any way.
In the procedure, prior to a coupling of amino acid or peptide residues, a suitable protecting group such as tert butyloxycarbonyl (Boc) can be removed with methods well known to those skilled in the art. It is also possible to avoid the use of protecting groups. The appropriate amino acids may be protected and deprotected by methods known in the art and described by e.g. T. W. Green (Protective Groups in Organic Synthesis, 2. Ed., John Wiley and Sons, New York 1991).
Example 1 describes the procedure in details. By resolution of the racemic mixture of 3-benzylpiperidine-1,3-dicarboxylic acid 1-tert-butyl ester to obtain one of the enantiomeric compounds, the final compound obtained by the procedure is the diastereomer 2-Amino-N-[(1R)-2-[(3R)-3-benzyl-3-(N,N′,N′-trimethylhydrazinocarbonyl)piperidin-1-yl]-1-(1H-indo-3-ylmethyl)-2-oxoethyl]-2-methylpropionamide
instead of the mixture of the two diastereomers.
The compound of the present invention exhibits an improved resistance to proteolytic degradation by enzymes because it is non-natural, in particular because the natural amide bonds are replaced by non-natural amide bond mimetics. The increased resistance to proteolytic degradation of the compound of the invention in comparison with known hormone releasing peptides is expected to improve its bioavailability compared to that of the peptides suggested in the prior literature.
Pharmaceutical Composition
The compound of the present invention may optionally be on a pharmaceutically acceptable salt form such as the pharmaceutically acceptable acid addition salts of the compounds of the present invention which include those prepared by reacting the compound of formula I with an inorganic or organic acid such as hydrochloric, hydrobromic, sulfuric, acetic, phosphoric, lactic, maleic, mandelic phthalic, citric, glutaric, gluconic, methanesulfonic, salicylic, succinic, tartaric, toluenesulfonic, trifluoracetic, sulfamic or fumaric acid and/or water.
The compound of the present invention may be administered in pharmaceutically acceptable acid addition salt form or, where appropriate, as a alkali metal or alkaline earth metal or lower alkylammonium salt. Such salt forms are believed to exhibit approximately the same order of activity as the free base forms.
In another aspect, the present invention relates to a pharmaceutical composition comprising, as an active ingredient, a compound of the present invention or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
Pharmaceutical compositions containing a compound of the present invention may be prepared by conventional techniques, e.g. as described in
Remington's Pharmaceutical Sciences,
1985 or in Remington: The Science and Practice of Pharmacy, 19th Edition (1995). The compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
The pharmaceutical carrier or diluent employed may be a conventional solid or liquid carrier. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyet
Agris Cheryl H.
Chang Ceila
Green Reza
Novo Nordisk A S
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