MXPA00008576A - New 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-naphtyl)ethyl)amide - Google Patents

Abstract

This invention relates to salt forms of (2E)-5- amino-5methylhex-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.

Description

NEW SALINE FORMS OF N-METHYL-N - ((1R) -1- (N-METHYL-N- ((lR) -l- (METILCARBAMOÍL) -2-FENILETIL) CARBAMOÍL) -2- (2-NAFTIL) ETHYL) AMID OF ACID (2E) -5-AMINO-5-METILHEX-2-ENOIC.

FIELD OF THE INVENTION This invention relates to the salt forms of N-methyl-N - ((1 R) -l- (N-methyl-N ((1 R) -1- (methylcarbamoyl) -2-phenylethyl) carbamoyl) -2- (2-E) -5-amino-5-methyl-1-hexen-2-enoic acid (2-naphthyl) ethyl ester, the preparation thereof and their use as therapeutic agents.

BACKGROUND OF THE INVENTION The hormone. Growth is a hormone that stimulates the growth of tissues capable of growing. Furthermore, it is known that growth hormone has various effects on metabolic processes, e.g., stimulation of protein synthesis and mobilization of free fatty acids; and that causes the change in the energy metabolism of carbohydrates to the metabolism of fatty acids. Deficiency in growth hormone can result in various medical disorders, e.g., dwarfism.

KEF : 121969 Growth hormone is released from the pituitary. The release is under a rigid control of several hormones and neurotransmitters either directly or indirectly. The release of growth hormone can be stimulated by the hormone that releases growth hormone (GHRH) and is inhibited by somatostatin. In both cases, the hormones are released by him. hypothalamus, but its action is mediated mainly via specific receptors that are located in the pituitary. Other compounds that stimulate the release of growth hormone by the pituitary have also been described. For example, arginine, L-3,4-dihydroxyphenyl-alanine (L-Dopa), glucagon, vasopressin, PACAP (adenylyl cyclase activation peptide, pituitary peptide), muscarinic receptor agonists and a synthetic hexapeptide, GH RP (growth hormone release peptide) releases the endogenous growth hormone either by means of a direct effect on the pituitary or by affecting the release of GHRH and / or somatostatin from the hypothalamus. The compound N-methyl I - N - ((1 R) - 1 - (N-methyl I - N ((1 R) -1 - (methylcarbamoyl) -2-phenylethyl) carbamoyl) -2- (2-naphthyl I ) eti I) amide of! (2 E) - 5 - a m i n o - 5 - m e t i I h e x - 2 - enoic acid was described in WO 97/23508. In this document the hypochloride salt was prepared. For commercial use, it is important to have a physiologically acceptable salt with good stability, that is not hygroscopic and that has good bioavailability, with good handling properties and a crystalline form p e r o d u c i b i e.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a salt of N-methyl-N - ((lR) -l- (N-methyl-N ((lR) -l- (metM-carbamoyl) -2-phenylethyl ) (2E) -5-amino-5-methylhex-2-enoic acid camobamo) -2- (2-naphthyl) ethyl) amide having a solubility in water of at least about 5 mg / mL, and a hygroscopicity less than about 8, at a RH (relative humidity) of 98%. In particular, the invention relates to the hemifumarate anhydrous salt of N-methyl-N - ((lR) -l- (N-methyl-N ((lR) -l- (methylcarbamoyl) -2-phenylethyl) carbamoyl ) -2- (2-naphthyl) ethyl) to (2 E) -5-amino-5-methy1 hex-2-acid mixture in or. The invention also relates to the hydrated salt of hemifumarate of N-metii-N - ((lR) -l- (N-methyl-N ((lR) -l- (methylcarbamoyl) -2-phenylethyl) carbamoyl) 2- (2-E) -5-amino-5-methylhex-2-enoic acid (2-naphthyl) ethyl ester and with the N-methyl-N- (-) - salt ((1R) -l- (N-methyl-N ((lR) -l- (methylcarbamoyl) -2-phenylethyl) carbamoyl) -2- (2-naphthyl) ethyl) amide of (2E) -5- amino-5-methylhex-2-enoic.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a salt of N-methyl-N - ((lR) -l- (N-methyl-N ((lR) -l- (methylcarbamoyl!) - 2-phenylethyl) (2E) -5-amino-5-methylhex-2-enoic acid carbamoyl) -2- (2-naphthyl) ethyl) amide having the structural form I, as shown below: Formula I having a solubility in water of at least about 5 mg / m L and a h i g r o s c o p i c a d d less than about 8, at a relative humidity (RH) of 98%. Water solubility and hygroscopicity are measured by methods well known in the art. Hereinafter, the compound of formula I is called Compound I. A salt of Compound I is provided in the form of polymorph crystals, which have good characteristics of stability, good solubility, eg, in water, good bioavailability, good handling properties and a reproducible crystalline form. In one embodiment, the salt of Compound I has a solubility in water 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 from 150 to 250 mg / m L. In a further embodiment, the salt of Compound I has a hygroscopicity less than about 7, at a RH of 98%, preferably from 0.1 to 8, at a RH of 98. %, in particular from 0.5 to 7, at a RH of 98%, such as from 1 to 6.5, at a RH of 98%. 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 monohydrated hem fumarate salt. In a further embodiment the salt of Compound I is the salt of L (+) - m a n d and I a t o. The present invention also provides a process for the preparation of a salt of Compuest I, wherein the process comprises dissolving the compound in a suitable solvent and dissolving a specific acid in the same type of solvent, and adding the solution of the acid to the solvent. Compound I solution; and the resulting salt of the solution crystallizes. Examples of common solvents include, without limitation, organic solvents, in particular, lower aliphatic alcohols such as ethanol, 2-propanol, 2-butanol, 1-hexanol and acetone-like solvents isobutylmethyl ketone and tetrahydrofuran. The preferred solvents are ethanol, 2-propanol and acetone. The mixture of the components is conveniently carried out at temperatures from 40 ° C to the reflux temperature, before cooling to a temperature of 0 to 5 ° C and recovering the crystals by filtration. The cooling rate may have influence on the type of salt obtained. Optionally, seed crystals are added if the precipitation has not been effected in a time of 1 to 2 hours after mixing.

The present invention also comprises a pharmaceutical composition comprising a salt of Compound I, optionally together with a pharmaceutically acceptable carrier or diluent. A salt of Compound I can be used in human and veterinary medicine to stimulate the release of growth hormone in a patient such as a mammal, eg, human, which comprises administering a therapeutically effective amount of a salt of Compound I, according to the invention. A salt of N-methyl-N - ((lR) -l- (N-methyl-N ((lR) -l- (methylcarbamoyl) -2-phenylethyl) carbamoyl) -2- (2-naphthi I) eti I) (2 E) -5-amino-5-methyl-1-hexen-2-enoic acid amide is useful for estimating the release of growth hormone in old age; prevention of catabolic side effects of glucocorticoids, prevention and / or treatment of osteoporosis, treatment of chronic fatigue syndrome (CFS), treatment of acute fatigue syndrome and muscle loss after surgery of choice, stimulation of the immune system , acceleration of wound healing, acceleration of bone fracture repair, acceleration of complicated fractures, eg, distraction osteogenesis, treatment of secondary wear to fractures, treatment of growth retardation, treatment of failure or renal failure resulting from the retardation in growth, treatment of cardiomyopathy, treatment of chronic liver diseases, treatment of thrombocytopenia, treatment of Crohn's disease, treatment of small bowel syndrome, treatment of chronic obstructive pulmonary disease (COPD), treatment of complications associated with transplant, treatment of physiological short stature including children with growth hormone deficiency and low stature associated with chronic diseases, treatment of obesity and growth retardation associated with obesity, treatment of anorexia, treatment of delayed growth associated with Prader-Willi syndrome and Tu rner syndrome; increase in the growth rate of a patient who has partial growth hormone insensitivity syndrome; acceleration of recovery and reduction of hospitalization of burned patients; treatment of intrauterine growth retardation, skeletal dysplasia, hypercortisolism and Cushi syndrome ng; induction of intermittent release of growth hormone; growth hormone replacement in patients with nervous tension, treatment of osteochondrodysplasias, Noonan syndrome, schizophrenia, depressions, Alzheimer's disease, delayed wound healing and psychosocial deprivation, treatment of pulmonary dysfunction and ventilator dependence, treatment of treatment of cardiac disorders or related vascular dysfunction, treatment of reduced cardiac function, treatment or prevention of myocardial infarction, reduction of blood pressure, protection against ventricular dysfunction or prevention of reperfusion events; treatment of adults with chronic dialysis; attenuation of protein catabolic responses after major surgery, reduction of cachexia and loss of protein due to chronic diseases such as cancer or AIDS; treatment of hyperinsulinemia, including nesidioblastosis, auxiliary treatment for the induction of ovulation; to stimulate the development of the thymus and to prevent the reduction, associated with age, of thymus function, treatment of immu- nised patients; treatment of sarcopenia, treatment of wear in connection with AIDS; improvement in muscle strength, mobility, maintenance of skin thickness, metabolic homeostasis, renal homeostasis in the elderly weak, stimulation of osteoblasts, remodeling of bone and cartilage growth, regulation of food intake; stimulation of the immune system in companion animals and treatment of the aging disorder in companion animals, growth promoter in cattle and stimulation of wool growth in sheep, and treatment of the metabolic syndrome (syndrome X); treatment of insulin resistance, including NIDDM, in mammals, eg, humans, and improvement of sleep quality and correction of hyposomatology of senescence due to a high increase in REM sleep and a network in the REM latency. The treatment is also intended to include prophylactic treatment. For use in the present invention, a salt of Compound I with a pharmaceutically acceptable carrier or excipient may be formulated to provide a medicament for parenteral, either oral, nasal, rectal, subdermal or intradermal, or transdermal administration, in accordance with conventional methods, The formulations may also include one or more diluents, relievers, emulsifiers, preservatives, buffers, excipients, etc., and may be provided in forms such as liquids, powders, emulsions, suppositories, liposomes, transdermal patches, controlled release, dermal implants, tablets, et c. Anyone skilled in the art can formulate the compound in a suitable manner, and in accordance with accepted practices, such as those described in Remington's Pharmaceutical Sciences, Gennaro, eds., Mack Publishing Co., Easton, PA, 1990; or in Rem ington: The Science and Practice of Pharmacy, 19th Edition (19.95). The compositions may appear in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions or topical applications. The pharmaceutical carrier or diluent employed can be a conventional solid or liquid vehicle. Examples of solid carriers are lactose, alba earth (almost pure calcium sulfate), sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose. Examples of liquid vehicles are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water. Similarly, the carrier or diluent can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The compositions of this invention are usually adapted for oral administration. For oral administration, a Compound I salt is prepared in the form suitable for oral administration, such as a tablet or a capsule. Typically, Com Item I is combined with a vehicle and molded into a tablet. Suitable carriers in this regard include starch, sugars, dicalcium phosphate, calcium stearate, magnesium stearate and the like. These compositions may also include one or more auxiliary substances, such as wetting agents, emulsifiers, preservatives, stabilizers, coloring additives, etc. The pharmaceutical compositions are administered one or more times per day or per week. An effective amount of this pharmaceutical composition is the amount that provides a clinically important effect. These amounts will depend, in part, on the particular condition to be treated, the age, weight and general health of the patient, and other factors evident to those trained in the art. The pharmaceutical compositions can be administered in unit dosage forms one or more times per day or per week. Alternatively, they can be provided as controlled release formulations suitable for a dermal implant. The implants are formulated to provide the release of the active compound during the desired period of time, which may be up to several years. Controlled release formulations are described in, for example, Sanders et al., I_ Pharm. Sci. 73 (1964), 1294-1297, 1984; in Patent North erica No. 4,489,056; and in U.S. Patent No. 4,210,644, which are incorporated herein by reference. The composition usually comes in the form of a unit dose composition containing 0.01 to 1000 mg of a salt of Compound I, according to the invention, for oral dosing. The typical dose for the effect of release of growth hormone would vary between 0.1 to 500 mg, preferably between 0.1 to 280 mg per day, either once or divided into 2 or 3 doses, when administered orally, or 2 or 3 times a week, once a week, or once every 14 days. Preferred dosage unit forms include in solid form, tablets or capsules; in liquid form, solutions, suspensions, emulsions, elixir or capsules filled therewith; or in the form of sterile injectable solutions, or patches, vagitorio (ovules), vaginal rings or implants of long duration. The composition of this invention can be formulated by conventional galenic pharmacy methods. Conventional excipients are pharmaceutically acceptable organic or inorganic carrier substances for parenteral or oral application, which react noxiously with the active Compound. Examples of these vehicles are water, saline solutions, alcohols, polyethylene glycols, castor oil, hydroxyethoxy, syrup, peanut oil, olive oil, gelatin, lactose, terry alba, sucrose, agar, pectin, acacia, magnesium stearate, talc, silicic acid, stearic acid monoglycerides and diglycerides of fatty acid, fatty acid esters of pentaerythritol, hydroxymethyl ether and polyvinylpyrrolidone and calcium phosphates. The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, such as binders, lubricants, preservatives, disintegrants, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers and / or coloring substances, and the like; that do not react in a harmful way with the active com ponent. For parenteral application, particularly acceptable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil. For oral administration, particularly suitable are tablets, dragees or capsules having talc and / or a carbohydrate carrier or binder, or the like, the carrier preferably being lactose or calcium phosphate and / or corn starch and / or starch. dad. A syrup, elixir or the like may be used when a sweetened vehicle can be used.

A typical tablet, which can be prepared by means of tableting techniques, contains: Active Compound 10 mg Lactosum 67.8 mg Ph. Eur. Avicel® 31.4 mg Talcum 1.0 mg Magnesii stearas 0.25 mg Ph. Eur.

The present invention is further illustrated by the following examples, which, however, were not elaborated as limiting the scope of the protection. The features described in the foregoing description and in the following examples may, both separately and in any combination thereof, be taken as material for effecting the invention in various forms thereof. The salts of Compound I, according to the invention, were synthesized, purified and crystallized as described in the following examples.

EXAMPLES The compound N-methyl-N- ((lR) -l- (N-metii-N ((lR.) - l- (methylcarbamoyl) -2-phenylethyl) carbamoyl) -2- (2-naphthi I) eti I) (2 E) -5-amino-5-methyl I h ex-2-enoic acid amide has the structural formula I, as shown below: Formula I and can be prepared as described in Example 1 of WO. 97/23508. Preparation of the hydrochloride salt of N-methyl-N- ((1 R) -l- (N-methyl-N ((1 R) -l- (methylcarbamoyl) -2-phenylethyl) carbamoyl) -2- (2- (2E) -5-Amino-5-methylhex-2-enóic acid naphthyl) ethyl) amide Tert-butyl ester of 3-h id roxy-1,1-dimethylpropylcarbamic acid: Step A: At 0 ° C, ethyl chloroformate (1.10 mL, 11.5 mmol) was added, dropwise, to a solution of 3-tert-butoxycarbonylamino-3-methylbutanoic acid. (2.50 g, 11.5 mmol) and triethylamine (1.92 mL, 13.8 mmol) in tetrahydrofuran (10 mL). The solution was stirred for 40 minutes at 0 ° C. The formed precipitate was filtered and washed with tetrahydrofuran (20 mL). The liquid was immediately cooled to 0 ° C. A 2M solution of lithium borohydride in tetrahydrofuran (14.4 mL, 28.8 mmol) was added dropwise. The solution was stirred at 0 ° C for 2 hours, and then warmed to room temperature, for a period greater than 4 hours. It was cooled to 0 ° C. Methanol (5 mL) was added carefully. IN hydrochloric acid (100 mL) was added. The solution was extracted with ethyl acetate (2 x 100 mL, 3 x 50 mL). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (100 mL) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was subjected to chromatography on silica (110 g) with ethyl acetate / hepta no 1: 2, to give 1.84 g of the tert-butyl ester of 3-hydroxy, l imeti I propi ca r bá my co. H-NMR (CDCl 3): d 1.33 (s, 6H); 1.44 (s, 9H); 1.88 (t, 2H); 1.94 (br, 1H); 3.75 (q, 2H); 4.98 (br, ÍH). 3- (tert-butoxycarbonylamino) -3-methylbutanal Step B: DMSO (1.22 L, 17.2 mmol) was added to a solution of oxalyl chloride (1.1 μL, 12.9 mmol), at -78 ° C, in dichloromethane (15 mL). The mixture was stirred for 15 minutes at -78 ° C. A solution of the tert-butyl ester of 3-hydroxy, l-dimethylpropylcarbamic acid (1.75 g, 8.6 mmol) in dichloromethane (10 mL) was added dropwise over a period of 15 minutes. The solution was stirred at -78 ° C for an additional 15 minutes. Triethylamine (6.0 mL, 43 mmol) was added. The solution was stirred at -78 ° C for 5 minutes and then warmed to room temperature. The solution was diluted with dichloromethane (100 mL) and extracted with IN hydrochloric acid (100 mL). The aqueous phase was extracted with dichloromethane (50 mL). The combined organic layers were washed with sodium hydrogen carbonate solution (100 mL) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by column chromatography on silica (140 g) with ethyl acetate (1: 3) to give 1.10 g of 3- (tert-butoxycarbonylamino) -3-methylbutanal. MHz -'H-NMR (CDCl 3): d 1.39 (s, 6H); 1.45 (s, 9H); 2.85 (d, 2H); 4.73 (br, ÍH); 9.80 (t, ÍH). (2E) -5- (Tert-butoxycarbonyl amine) -5-methylhex-2-enoate ethyl: Stage C: T r i e t i I f o n a c e t t a t o r (1.96 mL, 9.8 m mol) was dissolved in tetrahydrofuran (30 mL). T e r t-b u t or x potassium (1.10 g, 9.8 mmol) was added. The solution was stirred for 40 minutes at room temperature. A solution of 3- (tert-b u t t i c a r b o n i i a m i n o) - 3 - m e t i I b u ta n a I (1.10 g, 5.5 mmol) in tetrahydrofuran (6 mL) was added. The solution was stirred at room temperature for 75 minutes. It was diluted with ethyl acetate (100 mL) and IN hydrochloric acid (100 mL). The phases separated. The aqueous phase was extracted with ethyl acetate (2 x 5 mL). The combined organic phases were washed with saturated sodium carbonate hydrogen solution (60 mL) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by chromatography on silica (90 g) with ethyl acetate / heptane (1: 4) to give 1.27 gd (2E) -5- (tert-butoxycarbonylamino) -5-methylhex-2-enoate. ethyl. 'H-NMR (CDCl 3): d 1.30 (s, 6H); 1.30 (t, 3H); 1.46 (s 9H); 2.62 (d, 2H); 4.27 (q, 2H); 4.42 (br, ÍH); 5.8 (d, 1 H); 6.94 (td, 1 H).

Acid (2E) -5- (tert-butoxycarbonylamino) -5-methylhex-2 e n o 1 c o Step D (2E) -5- (tert-butoxycarbonylamino) -5 m e t i I h ex- 2 - ethyl ethoxide (1,233 g4.54 m mol) was dissolved in dioxane (20 mL). Lithium hydroxide (0.120 g, 5.00 mol) was added in solid form. Water (10 mL) was added, until a clear solution was obtained. The solution was stirred for 16 hours at room temperature. The solution was diluted with water (70 mL) and extracted with tert-butyl methyl ether (2 x 100 mL). The aqueous phase was acidified with a solution of sodium hydroxide (pH = 1) and extracted with tert-butyl methyl ether (3 70 mL). The organic phases were combined and dried over magnesium sulfate. The solvent was removed in vacuo to give 1.05 g of (2 E) -5 (tert-butoxycarbonylamino) -5-methylhex-2-enoic acid. The crude product was used for subsequent syntheses. XH-NMR (DMSO d6): d 1.15 (s, 6H); 1.35 (s, 9H); 2.53 (d, 2H); 5.75 (d, ÍH); 6.57 (br, ÍH); 6.75 (td, ÍH); 12.15 (s, ÍH).

N-methyl-N - ((R) -l- (methylcarbamoyl) -2-phenylethyl) carbamic acid tert-butyl ester: Stage E: N-tert-butoxycarbonyl-N-methyl-D-phenylalanine (1.22 g, 4.4 m mol), 1-hydroxybenzotriazo hydrate I (0.59 g, 4.4 mmol) and l-ethyl-3- (3-dimeti I-aminopropy I) hydrochloride) carb bo diimide (0.88 g, 4.6 mmol) were dissolved in N, N-dimeti I formamide (25 mL), and stirred for 30 minutes. Methylamine (0.51 g of a 40% solution in methanol, 6.6 mmol) was added and the mixture was stirred overnight. Methylene chloride (80 mL) and water (100 mL) were added and the phases were separated. The organic phase was washed with a solution of sodium hydroxide (20 mL, IN), sodium hydrogen sulfate (50 mL, 10%) and water (50 mL). The organic phase was dried (magnesium sulfate) and the solvent was removed in vacuo to give 1.39 g of the N-methyl-N- ((R) l- (methylcarbamoyl) -2-phenylethyl) carbamic acid tert-butyl ester. . XH-RM N (CDCl 3): d 1.25, 1.35 (two s (br), 9H); 2.73-2.94 (m, 7H); 3.30-3.50 (m, ÍH); 4.68, 4.90 (two m, ÍH); 5.90, 6.12 (two s (br); ÍH); 7.12-7.25 (m, 5H).

(R) -N-methyl! -2-methylamido-3-phenylpropionamide Step F: The tert-butyl ester of N-methyl-N - ((R) -l- (methylcarbamoyl) -2-pheny! Ethyl) carbamic acid (1.39 g, 7.23 mmol) was dissolved in a mixture of trifluoroacetic acid. (5 mL) and methylene chloride (10 mL), and stirred for 45 minutes. The volatiles were removed in vacuo and the residue was stirred with a mixture of ethyl acetate (100 mL) and water (100 mL). Sodium hydrogen carbonate (50 mL, saturated solution) was added and the phases were separated. The organic phase was dried (magnesium sulfate) and the solvent was removed in vacuo to obtain 330 mg of the (R) -N-m e t i I-2-m e t i I a m i n o -3-phenylpropionam ida. 1 H - R M N (C D C 13): d 2.1 (s (br), 3H); 2.32 (s, 3H); 2.77 (dd, ÍH); 2.81 (two s, 3 H); 3.21 (dd, ÍH); 3.32 (dd, 1H); 7.12 (s (br), ÍH); 7.20-7.34 (m, 5H).

Tert-butyl ester of N-methyl-N- acid. { (1 R) -l- (N-methyl-N - ((1 R) -l- (methylcarbamoyl) -2-phenylethyl) carbamoyl) -2- (2-naphthyl) ethyl} carbamic Step G: acid (R) -tert-butoxycarbonyl-N m e t i I a m i n o - 3 - (2 - n a f t i I) p r o p i n i co (548 g, 1.66 mmol) was dissolved in methylene chloride (5 μL); 1 - h i d r ox i - 7 - a za b e n z o t r i a zo I (227 mg, 1.66 mmol) was added together with N, -dimet and Iformamide (2 mL). Hydrochloride of 1-e t i I-3 - (3-d i m e t i i a m i n -propyl) carbodiimide (351 mg, 1.83 mol) was added and the solution was stirred for 15 minutes. (R) - N -methyl-2-methylamino-3-phenylpropionamide (320 mg, 1.66 m mol), dissolved in methylene chloride (4 m L), and diisopropy I eti amine (0.28 mL, 1.66 mmol) were added, and the mixture was stirred overnight. Methylene chloride (50 mL) was added and the organic phase was washed with water (100 mL), sodium hydrogensulfate (50 μL, 5%) and sodium hydrogen carbonate (50 mL, saturated). The organic phase was dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was subjected to chromatography (silica, 2 x 45 cm) using ethyl acetate / methylene chloride (1: 1), to obtain 604 mg of the tert-butyl ester of N-methyl-N- acid. { (1 R) -l- (N-methy! -N - ((1R) -l- (methylcarbamoyl) -2-phenylethyl) carbamoyl) -2- (2-naphthyl) ethyl} carbamic H-NMR (CDCl 3): d 1.05, 1.31, 1.56 (three s, 9H); 2.28- 3-37 (several m, 13H); 5.04, 5.17, 5.29, 5.48 (four dd, 2H); 7.05-7.79 (m, 12H). (2R) -N-methyl-2-methylamino-N - ((lR) -l- (methylcarbamoyl) 2-phenylethyl) -3- (2-naphthyl) propionam ida: Step H: The tert-butyl ester of N-methyl-N- acid. { (1 R) -l- (N-methyl-N- ((1 R) -l- (methylcarbamoyl) -2-phenylethyl) carbamoyl) -2- (2-naphthyl) ethyl} The carbamate (600 mg, 1.19 mmoi) was stirred in methylene chloride (1: 1, 5 m L) for 10 minutes and volatile compounds were removed in vacuo. The residue was washed with diethyl ether (2 x 5 mL) and dissolved in methanol (2 mL), and mixed with sodium hydrogen carbonate (10 mL) and ethyl acetate (15 mL). The organic phase was separated and dried (magnesium sulfate) to provide 420 mg of (2 R) -N-methyl I-2-methylamino-N- ((1 R) -l- (methylcarbamoyl) -2-phenylethyl ) -3- (2-naphthl) propiopam ida. XH-NMR (CDCI3): (selected values) d 1.69 (s, 3H); 2.08 (d, 3H); 2.54 (s, 3H); 2.76 (dd, ÍH); 2.92 (dd, ÍH), 3.12 (dd, ÍH), 3.31 (dd, ÍH); 3.72 (dd, ÍH), 4.95 (q (br), ÍH); 5.50 (dd, ÍH).

Tert-butyl ester of ((3E) -l, l-dimethyl-4- (N-methyl-N - ((lR) -l- (methylcarbamoyl) -2-phenylethyl) carbamoyl) -2- (2-naphthyl) ester ethyl) carbamoyl) but-3-enyl) carbamic: Stage I: The acid (2 E) -5- (tert-buti I oxycarboni I amino) -5-methyl I he x- 2 -en or co (200 mg, 0.82 mmol), l-hydroxy-7-aza benzotriazole (112 mg, 0.82 mmol) and 1-ethi hydrochloride I-3 - (3-dimethylaminopropyl I) -carbodiimide (173 mg, 0.90 mmol) were dissolved in a mixture of methylene chloride (10 mL) and N, N-Dimeti I formamide (1 mL) and stirred for 15 minutes. The N-methyl I-2-methylamino -N- ((lR) -l- (methylcarbamoyl) -2-phenylethii-3- (2-naphthyl) propionamide (332 mg, 0.82 mol), dissolved in chloride of methylene (5 μL) and diisopropy I and amine (0.14 mL) were added and the mixture was stirred overnight under nitrogen atmosphere.The mixture was diluted with methylene chloride (50 μL), washed with Water (50 mL), sodium hydrogen carbonate (30 mL, saturated), sodium hydrogen carbonate (30 mL, 5%) .The phases were separated and the organic phase was dried with magnesium sulfate and evaporated at room temperature. The residue was subjected to chromatography (silica, 2 x 40 cm) to obtain 450 mg of the tert-butyl ester of ((3 E) -1,1-dimeti I-4 - (- methyl I - N - ( (1 R) - 1 - (N -methyl-N - ((lR) -l- (methylcarbamoyl) -2-phenylethyl) carbamoyl) -2- (2-naphthyl) ethyl) carbamoyl) but-3-enyl) carbamic. 'H-NMR (CDCI3): (selected values) d 1.20, 1.22, 1.24, 1.30, 1. 41, 1.55 (six s, 15H), 4.30, 4.40 (two s (br), 1H); 5.08, 5.18, 5.32, 5.60, 5.87 (five dd, 2H); 6.05 (dd, Í H); 6.75 (m, Í H).

Step 3: ((3 E) -1,1-dimethyl-4- (methyl- ((lR) -l- (methyl- ((lR) -l- (methyl-carbamoyl) -2 tert -butyl ester) phenylethyl) carbamoyl) -2- (2-naphthyl) ethyl) carbamoyl) but-3-enylcarbamic acid (403 mg, 0.63 mmol was stirred in a mixture of trifluoroacetic acid (mL) and methylene chloride (4 mL) for 10 minutes The volatile compounds were removed in vacuo, the crude product was subjected to chromatography on silica (400 g) using a mixture of methylene chloride, ethanol and ammonia (25% in water) (80/18/2 as eluent. The isolated product was dissolved in 3M hydrochloric acid and ethyl acetate and evaporated, then redissolved in methyl chloride and evaporated twice to obtain 140 mg of the title compound 1 H-NMR (CDCl 3): d 1.05, 1.10, 1.15, 1.16 (four S 6H), 2.07 (s (br), 3H), 5.12, 5.32, 5.40, 5.60, 5.9 (five dd, 2H), 6.05, 6.14 (two d, Í H); 6.80 (m, 1H) HPLC: Rt = 29.02 minutes (Method Al) ESMS: m / z = 529 (100%) (M + H) *.

Example 1 Synthesis of the hemi fumarate of compound I (referred to as Compound I, hfum). 20.5 g (MW: 528.7 g) of the crude product of compound I (containing approximately 10-20% residual solvent), are dissolved in 200 μl of 2-propanol at 45 ° C and the temperature rises to 75 °. C. 2.0 g of fumaric acid (MW: 116.1 G, 17 mmol) are dissolved in 100 mL of 2-propanol, at 75 ° C and added slowly. The temperature of the reaction is maintained at 75 ° C. It is important that the amount of fumaric acid is not too high, as this would have a negative effect on yield and purity. Crystals are sown if precipitation has not occurred in. l h. Stirring is continued overnight at a temperature of 70-75 ° C. The next day, the reaction mixture is equilibrated for more than about 4 h at room temperature by removing the heating equipment. The mixture is cooled to 0-5 ° C and maintained for 2 h at that temperature. The suspension is filtered easily and the filter cake is washed with cold 2-propanol. The product is dried overnight at 40 ° C in a vacuum drying oven, leaving 18.1 g (89%, calculated from fumaric acid) of compound I, hfum (MW: 586.7), as white crystals.

Example 2 Synthesis of hemi fumarate monohydrate of compound l. 50.8 g of the crude product of compound I (containing approximately 10-20% residual solvent) are dissolved in 500 mL of ethanol (or 2-propanol) at 70 ° C and 5.4 g of fumaric acid (47 mmol) dissolved are added. in 250 mL of ethanol (or 2-propanol), at 70 ° C. The heating equipment is removed and the mixture is allowed to equilibrate at room temperature overnight. The precipitation occurs around 60 ° C, after the planting of crystals. The next day, the suspension is cooled to a temperature of 0-5 ° C, for 2 h and filtered to give small crystals which are very difficult to filter. The filter cake is washed with cold ethanol (or 2-propanol) and dried overnight at 40 ° C, in a vacuum drying oven, leaving 35.3 g (66%, calculated from fumaric acid) of the compound I, monohydrated hfum, as white crystals.

A similar experiment was performed on 2-propanol, giving the same result. Exposure of the anhydrous form of compound I, hfum, at high humidity, e.g., 10 weeks at 98% RH, produced the hydrated form.

Example 3 Synthesis of L - (+) m a n d I I t of compound I. 2.0 g of the crude product of compound I (containing approximately 10-20% residual solvent), are dissolved in 10 mL of acetone. 0.58 g of L-mandeleic acid (MW: 152.2, 3.8 mmol) dissolved in 10 mL of acetone are added. The mixture is heated to reflux. The precipitation occurs at 5 m inutes after the planting of crystals. The reflux is maintained for 2 h. The heating device is removed and the suspension is balanced at ambient temperature. The suspension is filtered. The filter cake is washed with acetone. The product was filtered overnight, at 40 ° C, in a vacuum drying oven, leaving 1.5 g (58%, calculated from the acid L - (+) mande ion) of the L- (+) mandelate. compound I (MW: 680.8 g), as white crystals.

E em plo 4 Synthesis of the D - (-) mandelate of compound I. 7.9 g of the crude product of compound I (containing approximately 10-20% residual solvent) are dissolved in 160 mL of acetone. 2.3 g of D-m acid are added to the mixture, dissolved in 40 μL of acetone. The mixture is heated to reflux. The precipitation occurs at 10 m inutes after the planting of crystals. The reflux is maintained for 3 h. The heating device is removed and the suspension is equilibrated at room temperature. The suspension is filtered. The filter cake is washed with acetone. The product is dried overnight at 40 ° C in a drying oven, under vacuum, leaving 6.6 g (65%, calculated from the acid D - (-) mande Iico) of the D - (-) mande I ato of compound I (MW: 680.8 g), as white crystals.

Example 5 Synthesis of Maleate of Compound I. 0.44 g of maleic acid are dissolved in 10 μL of refluxing acetone. 2.0 g of the crude product of compound I (containing approximately 10-20% residual solvent) dissolved in 10 mL of acetone are added. The mixture is stirred overnight at 45 ° C. Crystallization occurs during the night. The heating device is removed and the mixture is allowed to equilibrate at room temperature. The suspension is filtered. The filter cake is washed with acetone. The product is dried overnight at 40 ° C, in a drying oven, under vacuum, leaving 1.57 g (65%, calculated from maleic acid), of the maleate of compound I (MW: 644.8 g), as crystals whites.

It is noted that, in relation to this date, the best method known to the applicant to carry out the aforementioned invention is the conventional one for the manufacture of the objects or substances to which it refers.

Claims (11)

1. CLAIMS Having described the invention as above, the contents of the following indications are claimed as property. 1. A salt of the - methi I - N - ((1 R) - 1 - (N - methyl I - N - ((1 R) -1 (methylcarbamoyl) -2-phenylethyl) carbamoyl) -2- (2 (2 E) -5-amino-5-methyl-h-ex-2-enoic acid amine, characterized in that it has a water solubility of at least about 5 mg / mL and a hygroscopicity of less than about 8, to 98 by R. R.
2. 2. A salt of N-metM-N - ((lR) -l- (N-methyl-N- ((lR) -l (methylcarbamoyl) -2-phenylethyl) carbamoyl) -2 (2E) -5-amino-5-methylhex-2 enoic acid (2-naphthyl) ethyl) amide, characterized in that it is the hemi fumarate.
3. 3. A salt of N-methyl-N- ((lR) -l- (N-metii-N- ((lR) -l (methylcarbamoyl) -2-phenylethyl) carbamoyl) -2- (2-naphthi) ethyl) amide of (2 E) -5-amino-5-methyl-I hex-2 enoic, characterized in that it is hemi fumarat monohydrate.
4. 4. A salt of the N-meti I - N - ((1 R) - 1 - (N - methyl I - N - ((1 R) - 1 (methiicarbamoyl) -2-phenylethyl) carbamoyl) -2- ( 2-Naphthyl) ethyl) amide of (2E) -5-amino-5-methylhex-2 enoic acid, characterized in that it is the L- (+) mande I ato.
5. 5. A process, for the preparation of the salt, according to any of claims 4, characterized in that it comprises dissolving the N-methyl-N- ((lR) -l- (N-methyl-N- ((lR) -l - (Methylcarbamoyl) -2-phenylethyl) carbamoyl) -2- (2-naphthyl) ethyl) amide of the acid (2 E) -5-amino-5-methyl-2-methyl ester in a suitable solvent; Dissolve a specific acid, in the same type of solvent; add the solution of the acid to the solution of the - meti I - N - ((1 R) - 1 - (N - methyl I - N - ((1 R) - 1 (methylcarbamoyl) -2-phenylethyl) carbamoyl) -2 (2E) -5-amino-5-methylhex-2 enoic acid (2-naphthyl) ethyl) amide; and crystallize the salt resulting from the solution.
6. 6. A pharmaceutical composition, characterized in that it comprises a salt, according to any of claims 1 to 4, together with a pharmaceutically acceptable diluent carrier.
7. 7. The pharmaceutical composition, according to claim 6, characterized in that it is in a unit dose form containing approximately 0.01 to 1000 mg per day.
8. 8. A pharmaceutical composition for stimulating the release of growth hormone, in a patient, characterized in that it comprises a therapeutically effective amount of a salt, according to any of claims 1 to 4, together with a pharmaceutically acceptable carrier or diluent. .
9. 9. The composition according to claim 8, characterized in that it is for use in the treatment of children with growth hormone deficiency.
10. 10. The use of a salt, according to any of claims 1 to 4, characterized in that it is for the preparation of a pharmaceutical composition for stimulating the release of growth hormone in a patient.
11. 11. A method for stimulating the release of growth hormone, in a patient, characterized in that it comprises the administration, to a patient, of an effective amount of a salt, according to any of claims 1 to 4.