Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-02-23
2001-08-28
Richter, Johann (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C564S153000
Reexamination Certificate
active
06281247
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to salt forms of (2E)-5-amino-5-methylhex-2-enoic acid N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide, preparation thereof and use as therapeutic agent.
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 synthethic 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.
The compound, (2E)-5-amino-5-methylhex-2-enoic acid N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide, was disclosed in WO 97/23508. Therein the hydrochloride salt was prepared.
For commercial use it is important to have a physiologically acceptable salt with good stability, good solubility, non-hygroscopicity, good bioavailability, good handling properties, and a reproducible crystalline form.
SUMMARY OF THE INVENTION
The present invention relates to a salt of (2E)-5-amino-5-methylhex-2-enoic acid N-methyl-N-((1)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide having an aqueous solubility of at least about 5 mg/ml, and a hygroscopicity of less than about 8 at 98% RH. In particular the invention relates to the anhydrous hemi fumarate salt of (2E)-5-amino-5-methylhex-2-enoic acid N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide. (The invention also relates to the hydrous hemi fumarate salt of (2E)-5-amino-5-methylhex-2enoic acid N-methyl-N-((1)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide and the L(+)-mandelate salt of (2E)-5-amino-5-methylhex-2-enoic acid N-methyl-N-((1R)-1-(N-methyl-N-((1)-1-(methylcrbamoyl)-2-phenylethyl)carbamoyl)-(naphthyl)ethyl)amide.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a salt of (2E)-5-amino-5-methylhex-2-enoic acid N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide having the structural formula I as shown herein below
having an aqueous solubility of at least about 5 mg/ml, and a hygroscopicity of less than about 8 at 98% relative humidity (RH). Such aqueous solubility and hygroscopicity are measured by methods well-known in the art.
Hereinafter the above compound of formula I is referred to as compound I.
A salt of the compound I is provided in the form of polymorph crystals, which have good stability characteristics, good solubility in e.g. water, good bioavailability, good handling properties, and a reproducible crystalline form.
In one embodiment the salt of compound 1 has an aqueous solubility of at least about 7 mg/ml, preferably at least about 100 mg/ml, more preferably at least about 200 mg/ml, in particular from 5 to 400 mg/ml, such as 150 to 250 mg/ml.
In a further embodiment the salt of compound I has a hygroscopicity of less than about 7 at 98% RH, preferably from 0.1 to 8 at 98% RH, in particular from 0.5 to 7 at 98% RH, such as 1 to 6.5 at 98% RH.
In a further embodiment the salt of compound I is the hemi fumarate salt. In a further embodiment the salt of compound I is the hemi fumarate, monohydrate salt. In a further embodiment the salt of compound I is the L(+)-mandelate salt.
The present invention also provides a process for the preparation of a salt of compound I, which process comprises dissolving compound I in a suitable solvent, and dissolving a specific acid, in the same kind of solvent, and adding the solution of the acid to the solution of compound I, and crystallizing the resulting salt from the solution. Examples of the common solvents include but are not limited to organic solvents in particular lower aliphatic alcohols such as ethanol, 2-propanol, 2-butanol, 1-hexanol and solvents like acetone, isobutylmethylketone and tetrahydrofuran. Preferred solvents are ethanol, 2-propanol and acetone. The mixture of the components are conveniently performed at temperatures from 40° C. to reflux before cooling down to 0-5° C. and collection of the crystals by filtration. The speed of cooling down may have influence on the type of salt obtained. Optionally, seeding crystals are added if precipitation has not occured within 1-2 hours after mixing.
The present invention also provides a pharmaceutical composition comprising a salt of compound I optionally together with a pharmaceutically acceptable carrier or diluent.
A salt of compound I may be used in human and veterinary medicine for stimulating the release of growth hormone. The present invention provides thus according to another aspect a method for stimulating the release of growth hormone in a patient such as a mammal, e.g. a human, comprising administering a therapeutically effective amount of a salt of compound I according to the invention.
A salt of (2E)-5-amino-5-methylhex-2-enoic acid N-methyl-N-((1)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide is useful for stimulation of growth hormone release in the elderly; prevention of catabolic side effects of glucocorticoids, prevention and/or treatment of osteoporosis, treatment of chronic fatigue syndrom (CFS), treatment of acute fatigue syndrom and muscle loss following election surgery, stimulation of the immune system, acceleration of wound healing, accelerating bone fracture repair, accelerating complicated fractures, e.g. disctraction osteogenesis, treatment of wasting secondary to fractures, treatment of growth retardation, treating renal failure or insufficiency resulting from growth retardation, treatment of cardiomyopathy, treatment of chronic liver disease, treatment of thrombocytopenia, treatment of Crohn's disease, treatment of short bowel syndrome, treatment of chronic obstructive pulmonary disease (COPD), treatment of complications associated with transplantation, treatment of physiological short stature including growth hormone deficient children and short stature associated with chronic illness, treatment of obesity and growth retardation associated with obesity, treatment of anorexia, treating growth retardation associated with the Prader-Willi syndrome and Turner's syndrome; increasing the growth rate of a patient having partial growth hormone insensitivity syndrome; accelerating the recovery and reducing hospitalization of burn patients; treatment of intrauterine growth retardation, skeletal dysplasia, hypercortisolism and Cushing's syndrome; induction of pulsatile growth hormone release; replacement of growth hormone in stressed patients, treatment of osteochondrodysplasias, Noonan's syndrome, schizophrenia, depressions, Alzheimer's disease, delayed wound healing and psychosocial deprivation, treatment of pulmonary dysfunction and ventilator dependency, treatment of cardiac failure or related vascular dysfunction, treatment of impai
Davis Brian J.
Green, Esq. Reza
Novo Nordisk A S
Richter Johann
LandOfFree
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