MXPA98003351A - ot. POLYMORPHIC FORMS OF A GROWTH HORMONE SECRETAGOGUE - Google Patents

Abstract

This invention relates to polymorphic forms of the methanesulfonate compound of N- [1 (R) - [1,2-dihydro-methanesulfonyl-spiro [3 H -indo l-3,4'-piperidin] -1'yl) -carbonyl] -2- (Phenylmethyloxy-ethyl) -2-amino-2-methylpropanamide, which is a growth hormone secretagogue, useful in food-producing animals to promote its growth, thus making the production of edible meat products more efficient, and in humans, to treat physiological or medical conditions that are characterized by a deficiency of growth hormone secretion, and to treat medical conditions that are enhanced by the anabolic effects of growth hormone, the polymorphic forms present have advantages over others known forms of N- [1 (R) - [1,2-dihydro-methanesulfonyl-spiro [3H-indo-l, 3,4'-piperidin] -1'-yl) -carbonyl] -2- (phenylmethyl) methanesulfonate -o xi) -ethyl] -2-amino-2-methylpropanamide, in terms of thermodynamic stability and adaptability for its inclusion In pharmaceutical formulations, the present invention also relates to processes for preparing these polymorphic forms, pharmaceutical formulations comprising these polymorphic forms as active ingredients and to the use of the polymorphic form of the compound and its formulations in the treatment of certain disorders.

Description

POLYMORPHIC FORMS OF A GROWTH HORMONE SECRETAGOGUE BACKGROUND OF THE INVENTION Growth hormone, which is secreted from the pituitary, stimulates the growth of all the tissues in the body that are able to grow. In addition, it is known that growth hormone has the following basic effects on the metabolic processes of the body: (1) increased speed of protein synthesis in all cells of the body; (2) decreased speed of carbohydrate utilization in body cells; (3) increased mobilization of free fatty acids and use of fatty acids to obtain energy. A deficiency in the secretion of growth hormone can result in several medical disorders, such as dwarfism. Several pathways that release growth hormone are known. For example, chemical compounds such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin and insulin-induced hypoglycemia, as well as activities such as sleep and exercise, indirectly cause growth hormone is released from the pituitary acting in some way on the hypothalamus, perhaps to decrease the secretion of somatostatin or to increase the secretion of the known secretagogue, growth hormone releasing factor (GRF), or an unknown endogenous hormone hormone-releasing hormone growth, or all of them. In cases where increased levels of growth hormone were desired, the problem was usually solved by providing exogenous growth hormone or by administering GRF or a peptide compound that stimulated the production and / or release of growth hormone. In any case, the peptide nature of the compound required that it be administered by injection. Initially, the source of growth hormone was the removal of the pituitary glands from corpses. This resulted in a very expensive product and brought with it the risk that a disease associated with the source of the pituitary gland could be transmitted to the growth hormone receptor. The recombinant growth hormone has now been obtained and, although it does not entail any further risk of disease transmission, it is still a very expensive product that must be administered by injection or by nasal spray. Other compounds that stimulate the release of endogenous growth hormone have been developed. In particular, certain spiro compounds are described in the US patent. No. 5,536,716, PCT Patent Publication WO 94/13696 and Proc. Nati Acad. Sci. USA. _92, 7001-7005 (July 1995) as non-petidic secretagogues of growth hormone. These compounds have the ability to stimulate the release of natural or endogenous growth hormone, and can thus be used to treat conditions that require stimulation of the production or secretion of growth hormone, such as in humans with a growth hormone deficiency. natural, or in animals used for the production of food or wool, where the stimulation of growth hormone will result in a larger and more productive animal. Among the preferred compounds described in the present invention, there is spiro methanesulfonate [3H-indol-3, '-piperidin] -l' -i1) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide , which has the structure: The patent of the U.S.A. No. 5,536,716 and PCT Patent Publication WO 98/13696 describe methods for preparing this compound (see examples 18, 19 and 55). In particular, Example 55 indicates that the compound prepared by recrystallization from ethyl acetate-ethanol-water, has a melting point of "166-168ßC". Subsequently, it was identified that this compound is of the poly orphic form designated as "form II" herein. In Proc. Nati Acad. Sci. USA, 92, 7001-7005 (July 1995) it is noted that the compound isolated as a monohydrate has a melting point of 168-170 * 0, but only describes very general methods for preparing the compound, and does not describe how the compound crystallized. The morphological forms of the pharmaceutical compounds may be of interest for those interested in the development of a suitable dosage form, since if the morphological form is not kept constant during clinical studies and stability, the exact dosage used or measured may not be comparable from one batch to the other. Once a pharmaceutical compound is produced to be used, it is important to recognize the morphological form released in each dosage form to ensure that the production procedure uses the same form and that the same amount of drug is included in each dosage. Therefore, it is imperative to ensure that it is present, be it a single morphological form or some known combination of morphological forms. In addition, certain morphological forms may exhibit increased thermodynamic or hygroscopic stability, which may be more suitable than the other morphological forms for inclusion in pharmaceutical formulations. As used herein, a "polymorphic form" of a chemical compound is the same chemical entity, but in a different crystalline arrangement.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to poly orphic forms of the methanesulfonate compound of N- [1 (R) - [(1,2-dihydro-l-methanesulfonyl-pyrro [3H-indol-3,4'-piperidin] -l'-il) -carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide, as well as with the processes for the preparation of said poly-formal forms. The present invention also relates to pharmaceutical formulations comprising these polymorphic forms as an active ingredient, and to the use of these polymorphic forms and their formulations in the treatment of certain disorders. The polymorphic forms of this invention are growth hormone secretagogues, which are useful in food producing animals to promote their growth, thereby making the production of edible meat products more efficient, and in humans, to treat physiological or medical conditions characterized by a deficiency in the secretion of growth hormone, and to treat medical conditions that are enhanced by the anabolic effects of growth hormone. These polymorphic forms have advantages over the other known forms of methanesulfonate of N- [1 (R) - [(1,2-dihydro-l-methanesulfonyl-pyrro [3H-indol-3,4'-piperidin] -l'-il) -carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide, in terms of thermodynamic stability and convenience for inclusion in pharmaceutical formulations.

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to novel polymorphic forms of the methanesulfonate compound of N- [1 (R) -C (1,2-dihydro-1-methanesulfonyl-lespiro [3H-i ndol -3,4'-pipe ridin] - l '-i 1) carbonyl] -2- (phenylethyloxy) ethyl] -2-amino-2-methylpropanamide, and to the processes for the preparation of these polymorphic forms. The methanesulfonate compound of N- [1 (R) - [(1,2-dihydro-l-methanesulfonyl-spiro [3H-indol-3,4'-piperidin] -l'-yl) carbonyl] -2- (phenylmethyloxy) ) ethyl] -2-amino-2-methylpropanamide has the structure: and it is a secretagogue of growth hormone that induces the release of growth hormone in humans and animals. This property can be used to promote the growth of food-producing animals, to make the production of edible meat products more efficient, and in humans, it can be used to treat physiological or medical conditions characterized by a deficiency in the secretion of growth hormone, and to treat medical conditions that are improved with the anabolic effects of growth hormone. These particular polymorphic forms (designated herein as "Form I", "Form II", "Form III", "Form IV", "Form V", "Form VI", "Form VII", "Form VIII", "Form IX", "Form X",) have superior properties over other crystalline forms of the compound, since they are more suitable for inclusion in pharmaceutical formulations. A preferred crystalline form for pharmaceutical development is Form I, for its thermodynamic stability and non-hygroscopic properties. Another preferred crystalline form for pharmaceutical development is Form IV, for its formulation properties, particularly with respect to compression for the preparation of tablets. It has been found that form IV has a higher bulk density than the other forms. The present invention also relates to a process for the preparation of Form I methanesulfonate N- [l (R) - [(1,2-dihydro-l-methanesulfonyl-spiro [3H-indole-3,4 ' -piperidin] -l'-yl) carbonyl] -2- (phenylmethyl-oxy) ethyl] -2-amino-2-methylproparvamide, which comprises: Treat a solution of the free base of N-Cl (R) -C (1,2-dihydro-l-methanesulfonyl-spiro [3H-indol-3,4'-piperidin] -1 '-i 1) c rbonil] -2- (phenylethyloxy) ethyl] -2-amino-2-methyl-propanamide in ethyl acetate with alcohol (about 8 vol%) with methanesulfonic acid (about 1.1 equivalents) at about 50 ° C; heat to approximately 55 ° C, and cool to approximately 45 ° C. Optionally, the temperature can subsequently rise to approximately 51 ° C, where it is maintained for 2 to 24 hours. The present invention also relates to an alternative process for the preparation of Form I methanesulfonate N- [l (R) - [(1,2-dihydro-l-methanesulfonyl-spiro [3H-indole-3,4 ' -pipe ridi n] -1 '-i 1) carbonyl] -2- (feni lme ti 1-oxy) ethyl] -2-amino-2-methylpropanamide, comprising: Adding alternatively to a solution of the free base of N - [l (R) - [(1,2-dihydro-l-methanesulfonyl-spiro [3H-indol-3,4 '-pipe ridin] -l' -i 1) carbonyl] -2- (feni lmeti loxi) ethyl] -2-amino-2-methylpropanamide in ethyl acetate with ethanol, (about 8 vol%) at about 50-55 ° C, methanesulfonic acid (about 1.1 equivalents), and methane form I of N- [1] (R) - [(1,2-dihydro-l-methanesulfonyl-spiro [3H-indol-3,4'-piperidin] -l'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino- 2-methylpropanamide (where the relative order of addition is not critical), followed by heating to about 55 ° C for about 2 to 15 hours, cooling to about 25-30 ° C, and leaving to age for about 2 to 3 hours. The present invention relates to an alternative process for the preparation of the form I of methanesulfonate of N- [l (R) - [(1,2-dihydro-l-methanesulfonyl-spiro [3H-i ndol -3,4] '-pipe ridin] -l' -i 1) carboni l] -2- (phenylmethyl-1-oxy) ethyl] -2-amino-2-methylpropanamide, comprising: stirring a solution of NC methanesulfonate form II l (R) - [(1,2-dihydro-1-methanesulfonyl -spiro [3H-i ndol -3,4'-pipe ridi] -l'-yl) carbonyl] -2- (phenylmethyl-oxy) ethyl] -2-amino-2-methylpropanamide in isopropanol at about 25 ° C for about 2 to 24 hours. The present invention also relates to a process for the preparation of N- [1 (R) - [(1,2-dihydro-l-methanesulfonyl-spiro [3H-i ndol-3, 4 methanesulfonate] methanesulfonate. '-pipe ridi n] -l' -i 1) carbonyl] -2- (phenylmethyl-oxy) ethyl] -2-amino-2-methylpropanamide, which comprises: Treating a solution of the free base of N- [ 1 (R) -C (1,2-dihydro-l-methanesulfonyl-spiro [3H-indol-3,4'-piperidine] -1'-1) carbonyl] -2- (phenylethyloxy) ethyl] -2-amino-2-methyl-propanamide in ethyl acetate with ethanol (approximately 8 vol%), with methanesulfonic acid (approximately 1.1 equivalents) at about 50 ° C, heat to about 55 ° C, and cool to room temperature. The present invention also relates to a process for the preparation of form IV methanesulfonate of N- [l (R) - [(1,2-dihydro-l-methanesulfonyl-spiro [3H-i ndol -3,4] '-pipe ridin] -l'-yl) carbonyl] -2- (phenylmethyl-oxy) ethyl] -2-amino-2-methylpropanamide, which comprises: dissolving methanesulfonate of N- [l (R) - [(1, 2-dihydro-l-methanesulfonyl-spiro [3H-indole-3,4-pipe ridin] -l '-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide, of composition optional morphological, in an ethanol / water solution (preferably 25:55 v / v); evaporate the solvent from the solution, preferably at a temperature of 40 ° C; grinding the resulting solid to a fine powder; and exposing the fine powder to a relative humidity of about 75%. The present invention further relates to an alternative process for the preparation of form IV methanesulfonate of N- [l (R) - [(1,2-dihydro-l-methanesulfonyl-spiro [3H-i ndol -3, 4 '-pipe ridin] -l'-yl) carbonyl] -2- (phenylmethyl-1-oxy) ethyl] -2-amino-2-methylpropanamide, comprising: Recrystallization of N- [1 (R) - methanesulfonate - [(1,2-dihydro-l-methanesulfonyl-spiro [3H-indol-3,4'-piperidin] -l'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide, of optional morphological composition, of an ethyl acetate / ethanol / water solution (preferably 24.8 / 1.6 / 1.95 v / v / v). The present invention also relates to an alternative process for the preparation of form IV methanesulfonate of N- [l (R) - [(1,2-dihydro-l-methanesulfonyl-spiro [3H-indole -3,4] '-pipe ridi n] -l' -i 1) carboni l] -2- (phenylmethyl-oxy) ethyl] -2-amino-2-methylpropanamide, which comprises: exposing form I of methanesulfonate of N- [1] (R) - [(1,2-dihydro-l-methanesulfonyl-spiro [3H-indol-3,4'-piperidin] -1'-1) carbonyl] -2- (phenylethyloxy) ethyl] -2 -amino-2-methyl-propanamide at a relative humidity of more than about 75%, preferably a relative humidity of about 88%, at room temperature, for a sufficient time. The present invention also relates to an alternative process for the preparation of form IV methanesulfonate N- [l (R) - [(1,2-dihydro-l-methanesulfonyl-spiro [3H-i ndol -3, 4 '-pipe ridi n] -1' -i 1) carbonyl] -2- (feni lmeti 1-oxy) ethyl] -2-amino-2-methylpropanamide, which comprises: isolation from a suspension of the form I N- [l (R) - [(1,2-Dihydro-l-methanesulfonyl-spiro) methanesulfonate [3H-i ndol -3,4 '-pipe ridin.] -l' -i 1) carbonyl] -2- (feni lmeti 1-oxy) ethyl] -2-amino-2-methylpropanamide in isopropyl acetate / ethanol (90:10 v / v), containing about 2.8% by weight of water at about 25 ° C. The present invention also relates to a process for the preparation of the V-form of methanesulfonate of N- [l (R) - [(1,2-dihydro-l-methanesulfonyl-spiro [3H-i ndol -3,4] '-pipe ridin] -l'-yl) carbonyl] -2- (phenylmethyl-1-oxy) ethyl] -2-amino-2-methylpropanamide, which comprises: exposing form IV of methanesulfonate of N- [1 (R ) - C (1,2-dihydro-l-methanesulfonyl-spiro [3H-indol-3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylimethyl) ethyl] -2-amino- 2-methyl-propanamide at a relative humidity of less than 30% at room temperature. The present invention also relates to a process for the preparation of form VI of methanesulfonate of N- [l (R) - [(1,2-dihydro-l-methanesulfonyl-spiro [3H-indole-3,4'- piperidin] -l'-yl) carbonyl] -2- (phenylmethyl-oxy) ethyl] -2-amino-2-methylpropanamide, which comprises: drying form V of methanesulfonate of N- [1 (R) - [(1 , 2-dihydro-l-methanesulfonyl-spiro [3H-indol-3,4'-piperidin] -l'-yl) -carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide in the absence of humidity, at about room temperature, such as under a nitrogen atmosphere dried through a sieve at about 25 ° C. The present invention also relates to a process for the preparation of form VII of N- [l (R) - [(1,2-dihydro-l-methanesulfonyl-spiro [3H-indole-3,4] methanesulfonate. -pipe ridin] -l '-i 1) carboni l] -2- (feni lmeti 1-oxy) ethyl] -2-amino-2-methylpropanamide, which comprises: isolation from a suspension of form I or form IV of N- [l (R) - [(1,2-dihydro-l-methanesulfonyl-is-iro [3H-i ndol -3,4 '-pipe-ridin] -l'-yl) carbonyl methanesulfonate ] -2- (Phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide in isopropyl acetate / ethanol (90:10 v / v) containing about 1. 5% by weight of water.

The present invention also relates to a process for the preparation of form VIII of methanesulfonate of N- [l (R) - [(1,2-dihydro-l-methanesulfonyl-spiro [3H-indole-3,4'- piperidin] -l'-yl) carbonyl] -2- (phenylmethyl-oxy) ethyl] -2-amino-2-methylpropanamide, which comprises: dehydrating form VII of methanesulfonate of N- [l (R) - [(l , 2-dihydro-l-methanesulfonyl-spiro [3H-indole-3,4 '-pipe ridin] -l' -i 1) carbonyl -2- (phenylethyloxy) ethyl] -2-ami no- 2-methylpropanamide under a dry inert gas, such as dry nitrogen, for a sufficient time. The present invention also relates to a process for the preparation of N- [l (R) - [(1,2-dihydro-l-methanesulfonyl-spiro [3H-indole-3, 4 'methanesulfonate] -pipe ridin] -l '-i 1) carbonyl] -2- (phenylmethyl-1-oxy) ethyl] -2-amino-2-methylpropanamide, which comprises: preparing a solution in water of methanesulfonate of N- [1 ( R) -C (1,2-dihydro-1-methanesulfonyl-spiro [3H-indol-3,4 '-pipe ridin] -l' -i 1) carbonyl] -2- (feni lme i loxi) ethyl] -2-amino-2-methylpropanamide, of optional morphological composition, followed by isolation of the solid formed by controlled evaporation at % relative humidity, approximately at room temperature. The present invention also relates to a process for the preparation of the X-form of methanesulfonate of N- [l (R) - [(1,2-dihydro-l-methanesulfonyl-spiro [3H-i ndol -3,4] '-pipe ridi n] -1' -yl) carbonyl] -2- (phenylmethyl-oxy) ethyl] -2-amino-2-methylpropanamide, which comprises: drying form IX of methanesulfonate of N- [1 (R ) - [(1,2-di-idro-1-methanesulfonyl-spiro [3H-i ndol -3,4 '-pipe ridin] -1' -i 1) carboni l] -2- (phenylmethyl) ethyl ] -2-ami no-2-me til -propanamida, at room temperature and humidity, for a sufficient time. The present invention also relates to an alternative process for the preparation of the X-form of methanesulfonate of N- [l (R) - [(1,2-dihydro-l-methanesulfonyl-spiro [3H-i ndol -3, 4 '-pipe ridin] -l' -i 1) carboni l] -2- (phenylmethyl-oxy) ethyl] -2-amino-2-methylpropanamide, which comprises: exposing the N-form of methanesulfonate I (R) - [(1,2-dihydro-1-methanesulfonyl -spyro [3H-i ndol -3,4 '-pipe ridin] -1' -i 1) carbonyl] -2- (feni lmeti loxi) ) ethyl] -2-amino-2-methyl-propanamide at 100% relative humidity for about 1 to 4 days. Similarly, the present invention is also directed to a process for the preparation of N- [l (R) - [(1,2-dihydro-l-methanesulfonyl-spiro [3H-i ndol -3,4 '- methanesulfonate. morphologically homogeneous piperidine] -l '-i 1) carbonyl] -2- (phenolmethyl-1-oxy) ethyl] -2-amino-2-methylpropanamide, which comprises any of the processes mentioned herein. The compounds of this invention, the novel polymorphic methanesulfonate forms of N- [1 (R) - [(1,2-dihydro-l-methanesulfonyl-spiro [3H-indol-3,4 '-pipe ridin] -!' - il) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropane ida, are growth hormone secretagogues which are useful in food-producing animals to promote their growth, thereby making production more efficient of edible meat products, and are useful in humans to treat physiological or medical conditions characterized by a deficiency in the secretion of growth hormone, and to treat medical conditions that are enhanced by the anabolic effects of growth hormone. Therefore, the present invention also relates to pharmaceutical formulations comprising a polymorphic form as an active ingredient, and to the use of this polymorphic form and its formulations in the treatment of certain disorders.

Differential Scanning Calorimetric Cell (DSC) The DSC Curve of Form I Methanesulfonate N- [1 (R) - [(1,2-dihydro-1-methanesulfonyl-spiro [3H-indole-3,4 '- piperidin] -l '-i1) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide at 10 ° C / min in an open cup under nitrogen flow, exhibits a single endotherm, due to melting, with a peak temperature of about 180 ° C and an extrapolated onset temperature (melting point) of about 170 ° C with an associated heat of about 53 J / g. The DSC curve for N- [l (R) - [(1,2-dihydro-l-methanesulfonyl-spiro [3H-indol-3,4'-piperidin] -1 '-yl) carbonyl methanesulfonate form II ] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide at 10 ° C / min in an open cup under nitrogen flow, exhibits a single endotherm, due to fusion, with a peak temperature of approximately 174 ° C and an extrapolated onset temperature (melting point) of about 165 ° C with an associated heat of about 37 J / g. The DSC curve for form IV methanesulfonate N- [l (R) - [(1,2-dihydro-l-methanesulfonyl-spiroC3H-indole-3,4'-pipe ridin] -l '-i 1) carbonyl ] -2- (phenylethyloxy) ethyl] -2-amino-2-methylpropanamide at 10 ° C / min in an open cup under nitrogen flow, exhibits an endotherm with water loss at approximately 45 ° C, followed by an endotherm with a peak temperature of about 134 ° C, and an extrapolated onset temperature (melting point) of about 129 ° C, due to the fusion of the VI form, with an associated heat of about 23 J / g.

DSC data [the samples were heated at a speed of 10 ° C / min under a nitrogen atmosphere (start temperature extrapolated)]: Form I: 170 ° C (melting endotherm) Form II: 165 ° C (endotherm of fusion) Form VI: 129 ° C (fusion endotherm) Form I methanesulfonate N- [l (R) - [(1,2-dihydro-l-methanesulfonyl-spiro [3H-indol-3,4'-piperidin] -l'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methyl? ropanamide is a relatively anhydrous polymorph characterized by the following properties: a melting point of 169 ° C and solubility in isopropanol of 4.6 mg / ml. Form II methanesulfonate of N- [1 (R) - [(1,2-dihydro-1-methanesulfonyl-spiro [3H-indol-3,4'-piperidin] -l '-il) ca rboni 1] -2- (phenyl tymol i) useful] -2-amino-2-methyl propanamide is an anhydrous polymorph characterized by the following properties: a melting point of 158 ° C and solubility in isopropanol of 12.3 mg / ml. Form III methanesulfonate N- [1 (R) - [(1,2-dihydro-1-methanesulfonyl-spiro [3H-indol-3,4'-piperidin] -l '-yl) carbonyl] -2 - (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide is a hydrate characterized by the following properties: an endotherm of water loss at a peak temperature of 46 * C, followed by a lower endotherm of melting / decomposition with a temperature of extrapolated start of 123 ° C. Form IV methanesulfonate N- [1 (R) - [(1,2-dihydro-1-methanesulfonyl-spiro [3H-i ndol -3,4 '-pipe ridin] -l' -il) carbonyl] -2- (feni lmeti loxi) ethyl] -2-amino-2-methylpropanamide is a hydrate characterized by the following properties: an endotherm with water loss at a peak temperature of 45 * C, followed by a melting endotherm / decomposition with an extrapolated start temperature of 129 ° C (presumably due to the melting / decomposition of form VI). Form IV methanesulfonate of N- [1 (R) - [(1,2-dihydro-1-methanesulphon 1 -spyro [3H-indole-3,4'-pipe ridin n] -1 ' - il) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide appears to be a hygroscopic hydrate containing 3.5 moles of water per mole of N- [(R) - [(1, 2) methanesulfonate] -dihydro-l-methanesulfonyl-spiro [3H-indole-3,4'-pipe ridin] -l '-i 1) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide. The V-form of methanesulfonate of N- [l (R) - [(1,2-dihydro-1-methanesulfonyl-spiro [3H-i ndol-3, '-pipe ridin] -l' -il) carbonyl ] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide appears to be a hygroscopic hydrate containing 1 mole of water per mole of methane sulfonate of N- [l (R) -C (1,2-dihydro-l) -methanesul f onyl -spi ro [3 H -indole-3,4 '-pipe ridin] -l'-yl) carbonyl] -2- (phenylethyloxy) ethyl] -2-amino-2-methylpropanamide. Form VI methanesulfonate N- [1 (R) - [(1,2-dihydro-1-methanesulfonyl-spiro [3H-i ndol -3,4 '-pipe ridin] -l'-il) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide appears to be an anhydrous polymorph, and is characterized by a melting point of 129 ° C. Form VII methanesulfonate of N- [1 (R) - [(1,2-dihydro-l-methanesulfonyl-spiro [3H-indol-3,4'-piperidin] -l '-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide is a hydrate characterized by the following properties: a broad endotherm with water loss at a peak temperature of 60 ° C, followed by a melting / decomposition endotherm with a temperature of start extrapolated from 144 ° C (presumably due to the fusion / decomposition of form VIII). Form VIII methanesulfonate of N- [l (R) - [(1, 2-dihydro-1-methanesulfonyl-spiro [3H-i ndol-3, 4 '-pipe ridin] -l' -il) carbonyl] -2- (phenylethyloxy) ethyl] -2-amino-2-methylpropanamide is an anhydrous polymorph characterized by a melting point of 144'C. Form X of methanesulfonate of N- [1 (R) - [(1,2-dihydro-1-methanesulfonyl-spiro [3H-i ndol -3, 4 '-pipe ridi n] -l' -il) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide is characterized by a broad endotherm with water loss at a peak temperature of 49 ° C.

Diffraction of X-ray powder (XRPD) X-ray powder diffraction studies are widely used to elucidate molecular structures, crystallinity and polymorphism. Powder X-ray diffraction patterns (XRPD) were collected using an APD3720 automatic powder diffraction instrument, with Koc copper radiation. The measurements were made from 2 ° to 40 ° (2 theta) with the sample kept at room temperature. Form I was characterized by a powder X-ray diffraction pattern with principal reflections at approximately: 6.5, 14.7, 16.9, 17.1, 17.9, 19.5, 21.1, 21.7 and 22.0 ° (2 theta). Form II was characterized by a powder X-ray diffraction pattern with principal reflections at approximately: 4.8, 11.8, 17.5, 19.4, 21.6, 21.9, 22.5 and 22.7 ° (2 theta). Form III was characterized by a powder X-ray diffraction pattern with principal reflections at approximately: 13.8, 14.1, 18.0, 18.8, 19.5, 20.1, 20.6, 21.8 and 25.7 ° (2 theta). Form IV was characterized by a powder X-ray diffraction pattern with principal reflections at approximately: 16.0, 16.2, 18.3, 20.1, 21.0 and 24.2 * (2 theta). Form V was characterized by a powder X-ray diffraction pattern with principal reflections at approximately: 14.8, 17.1, 17.6, 19.0, 19.1, 19.4, 20.6, 21.5 and 21.8 ° (2 theta). Form VI was characterized by a powder X-ray diffraction pattern with principal reflections at approximately: 9.8, 14.0, 14.8, 17.1, 17.6, 19.0, 19.5, 20.6 and 21.6 ° C (2 theta). Form VII was characterized by a powder X-ray diffraction pattern with principal reflections at approximately: 9.1, 11.3, 17.1, 17.4, 20.0, 22.1 and 24.5 ° (2 theta). Form VIII was characterized by a powder X-ray diffraction pattern with principal reflections at approximately: 11.5, 11.6, 18.1, 19.6, 22.5, 24.7 and 24.8 ° (2 theta). Form IX was characterized by a powder X-ray diffraction pattern with principal reflections at approximately: 8.0, 12.1, 15.3, 15.8, 19.6, 19.7, 21.1, 22.3 and 23.7 ° (2 theta). Form X was characterized by a powder X-ray diffraction pattern with principal reflections at approximately: 15.5, 15.8, 18.0, 18.4, 18.6, 19.4, 20.7, 20.8, 23.9 and 24.8 ° (2 theta). These XRPD patterns confirm that all I-X forms are distinct crystalline forms.

Microscopy The polyformic forms were examined at a magnification of 100X under flat and polarized light. Form I and form II were needle-shaped particles. Both Form I and Form II appeared birefringent under polarized light.

Bigroscopicity The following are the contents of total volatile substances (established by TGA analysis) of solid samples of forms I, II, III and IV by exposure to several controlled humidities. It was found that Form I possesses 0.79% by weight of water; Form II has 0.56% by weight of water; Form III has 4.5-5.0% by weight of water; and Form IV has 9.5-10.0% by weight of water. The hygroscopicity was determined by storing the solid compound in chambers of constant relative humidity. A comparison of the anhydrous forms I and II at room temperature indicates that Form II is hygroscopic and exhibits a large increase in humidity starting at 65% RH. No substantial increase in moisture is exhibited by Form I, except when stored above 76% RH. The results are shown below in Tables I and II.

TABLE I Ambient temperature (48 Hrs) Form I Form II% HR% Loss / Gain% Loss / Gain 0 -0.02 +0.08 11 -0.05 +0.02 33 - +0.33 47 +0.21 +0.39 65 +0.37 > 10.0 »76 +0.12 > 10.0 «100 > 12.0 > 10.0 «.b (• = the sample becomes a gummy semisolid) (b = converted to form IV by exposure to ambient humidity).

TABLE 2 Ambient temperature (96 Hrs) Form I% RH% Loss / Gain 7 +0.4 22 +0.3 47 +0.5 68 +0.6 88 + 12.9 * 100 + 23.9 * (* = deliquescent material) The hydrated forms III and IV of N- [l (R) - [(1,2-dihydro-l-methanesulfonyl-spiro [3H-indol-3,4'-piperidin] -1 '-i1) carbonyl methanesulfonate] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide were also evaluated after storage in relative humidity chambers for 48 hours at room temperature. Form III shows an increase in humidity after 48 hours of storage at 33% RH. Form IV, although it does not gain an appreciable amount of moisture until storage at 100% RH, loses its hydration water when stored at 11% RH or less. The results are shown below in table 3.

TABLE 3 Tempera your ambient anger (48 Hrs) Form III Form IV% HR% Loss / Gain% Loss / Gain 0 - -7.8 11 -0.15 -4.9 33 +2.23 +0.3 47 +3.99 +0.7 66 - +1.4 76 +3.76 +1.5 100 - +5.3 These data indicate that Form I is relatively anhydrous.

Solubility The solubility of Form I in distilled water at room temperature is > 100 mg / ml. The aqueous solubility (TA) of form II in buffered solutions (pH 4-9) is > 100 mg / ml. The solubility of Form I in ethanol / water mixtures is shown below: Solubility% Ethanol / teO (mg / ml) 25/75 > 100 50/50 > 100 75/25 > 90 100% ethanol > 90 Thermal Stability - Pure Compound The solid state stability of the pure compound was determined by storing the drug in screw-capped glass vials in the dark. Samples were analyzed by HPLC and the original compound was analyzed quantitatively. The isocratic method that was used is shown below: Column: ODS Beckman Ultrasphere (250x4.6 mm, 5μ) Mobile phase: 0.1% TEA, pH 4.0 with H3PO4: ketonitrile (65:35). Flow rate: 1.0 ml / min. Detection wavelength: 228 n. Run time: 14 minutes. Column temperature: Environment. Injection volume: 20 μl of N- [1 (R) - [(1,2-dihydro-l-methanesulfonyl-spiro [3H-indol-3,4'-piperidin] -1 '-i1) carbonyl methanesulfonate] -2- (Phenylmethyloxy) ethyl] -2-amino-2-methyl-propanamide (50 μg / ml). The results shown below for forms I and II were calculated as percentages by weight.

FORM I% Initial 1C 6 Sem 17 Sem 40 100.1 98.7 60 100.7 101.3 80 100.7 99.4 FORM II! £. 1 Sem 2 Sem 4 Sem 8 Sem 12 Sem 24 Sem 40 99.7 100.7 99.5 - 100.1 100.1 60 99.4 99.6 100.3 100.0 101.0 100.8 80 99.2 100.3 99.2 99.8 100.4 __ These results indicate that pure solid form I and form II have good thermal stability. The process for preparing the present compound is outlined as follows: SCHEME I: SCHEME I (CONT) As depicted in scheme I, CBZ-spiroindoline 1 is treated with Darco (20% by weight) before hydrogenation. The hydrogenation is carried out in ethanol at 65 ° C over 10% Pd / C with vigorous stirring. A solution of lb in isopropyl acetate and water is coupled with commercially available N-BOC-0-benzyl-D-serine in the presence of dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBt). After filtration of the secondary product of dicyclohexylurea (DCU), the filtrate of phase 2 is separated and the organic layer is washed successively with aqueous sodium hydroxide solution, 0.5 M aqueous hydrochloric acid and finally aqueous sodium carbonate solution. saturated. Better results are achieved in this coupling when a solution of the free amine in iPrOAc / H2? it is treated with DCC, HOBT, followed by the addition of the amino acid at room temperature and followed by reaction for 3 to 5 hours. Then, the batch is concentrated under vacuum and the solvent is changed from isopropyl acetate to ethanol. In general, this change of solvent proceeds promptly by "loading and extracting" 3x volumes per batch to remove isopropyl acetate. The BOC group of 11 is removed by treatment with methanesulfonic acid (MsOH) (3 eq) in ethanol at 35-40 ° C. The partition between isopropyl acetate and aqueous sodium hydroxide solution ÍM produces 12. The coupling of 12 with N-BOC-α-aminoisobutyl acid is best performed in a two phase solvent system, isopropyl acetate / water (1 : 1) in the presence of DCC and HOBt (1.1 equivalents each). The removal of DCU by filtration, separation of the layers and washing of the organic layer successively with aqueous sodium hydroxide, M, 0.5 M aqueous hydrochloric acid and saturated aqueous solution of sodium hydrogen carbonate, produces 14. The solvent of the mixture is changed to ethanol for the subsequent breakdown of methanesulfonic acid from the Boc group. The deprotection of 14 is more difficult than that of 11 and requires a concentrated ethanol / methanesulfonic acid solution and heating at 35-40 ° C. The free amine 15 is isolated after extractive treatment (EtOAc-NaOH). The organic layer is washed well with IN NaOH to ensure complete removal of methanesulfonic acid. The ethyl acetate solution of the free base 15 is concentrated at low volume in vacuo and dried azeotropically (F < 500 gml-1) by means of "loading and extraction" of volumes 2x batch of ethyl acetate / ethanol 90 / 10, followed by volumes 2x batch of ethyl acetate. The slightly cloudy, dry solution resulting from the free base in ethyl acetate is treated with Darco G60 (25% by weight) at room temperature for 10 hours. Removal of the Darco by filtration with a filtration agent gives the free base 15. The formation of the methanesulfonic acid salt 16 from 15, is carried out in ethyl acetate with 1.1 eq of MsOH at about 50 ° C. The free base 15 is treated with 8 volumes percent EtOH and 1 eq H 2 O, and heated at 55 ° C until complete dissolution. Cooling to room temperature and stirring the resulting suspension for 4 hours gives a crystalline material of 16 designated as crystal form II [solubility in IPA = 12 mg / ml]. The conversion of form II to form I takes place where the salt is formed in EtOAc-EtOH, as above, but instead of cooling the initial solution of the salt (at 55 ° C) to room temperature, it is cooled to 45 ° C. Crystals should start to appear at that temperature and the suspension should get thicker with time. Afterwards, the temperature rises to 510C and the suspension is left to age overnight. The complete conversion of form I of 16 can be expected. Preferably, the conversion of form II to form I, is achieved by adding seed crystals of form I to a solution of the free base in EtOAc-EtOH at 50-55 ° C, followed by aging. Therefore, the free base 15 can be treated with 1.1 equivalents of methanesulfonic acid in 8% ethanol in ethyl acetate at 50-55 ° C. The batch is then seeded with approximately 2% by weight of Form I of the methanesulfonate salt 16, and then allowed to age at 55 ° C overnight. The batch is cooled to room temperature and left to age for about 2 to 3 hours. The product is isolated by filtration at room temperature under a nitrogen atmosphere, dried at 35 ° C under vacuum and sieved to give the methanesulfonate salt 16. The methanesulfonic salt 16 can also be formed by alternating the gradual addition of MsOH (1.1 eq. ) and seed crystals of Form I to a solution of the free base in EtOAc-EtOH, at about 50 ° C, where the order of addition of NsOH and seed is not critical. The utility of the polymorphic compounds of the present invention as growth hormone secretagogues can be demonstrated by methodology known in the art, such as a test described by Smith et al.

Science, 260. 1640-1643 (1993) (see the text of Figure 2 in it). In particular, all the polymorphic forms of the present invention have activity as growth hormone secretagogues in the aforementioned test. Said result is indicative of the intrinsic activity of the polymorphic forms of the present invention, such as growth hormone secretagogues. The growth hormone releasing compounds of the present invention are useful in vitro as unique tools for understanding how growth hormone secretion is regulated at the level of the pituitary. This includes the use in the evaluation of many factors that are thought or known to influence the secretion of growth hormone, such as age, sex, nutritional factors, glucose, amino acids, fatty acids, as well as fasting states and of not fasting. In addition, the compounds of this invention can be used to evaluate how other hormones modify the growth hormone releasing activity. For example, it has already been established that somatostatin inhibits the release of growth hormone. Other hormones that are important and require study in regard to their effect on the release of growth hormone, include the gonadal hormones, for example, testosterone, estradiol and progesterone; adrenal hormones, for example, cortisol and other corticosteroids, epinephrine and norepinephrine; pancreatic and gastrointestinal hormones, for example, insulin, glucagon, gastrin, secretin; the vasoactive peptides, for example, bombesin, the neuroquines; and thyroid hormones, for example, thyroxine and triiodothyronine. The compounds of the present invention can also be used to investigate the possible effects of negative or positive feedback of some pituitary hormones, for example, growth hormone and endorphin peptides, on the pituitary to modify the release of growth hormone. Of particular scientific importance is the use of these compounds to elucidate the subcellular mechanisms that mediate the release of growth hormone. The compounds of the present invention can be administered to animals, including man, to release growth hormone in vivo. For example, the compounds can be administered to commercially important animals such as pigs, cattle, sheep and the like to accelerate and increase their speed and magnitude of growth, to improve feed efficiency and to increase milk production in said animals. In addition, these compounds can be administered to humans in vivo as a diagnostic tool to directly determine whether the pituitary is capable of releasing growth hormone. For example, the compounds of the present invention can be administered live jji to children. Serum samples taken before and after said administration can be analyzed for growth hormone. Comparison of the amounts of growth hormone in each of these samples would be a means to directly determine the ability of the patient's pituitary to release growth hormone. Therefore, the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of the present invention in association with a pharmaceutical carrier or diluent. Optionally the active ingredient of the pharmaceutical compositions may comprise an anabolic agent, in addition to one of the compounds of the present invention or another composition exhibiting a different activity, for example an antibiotic growth promoter or an agent for treating osteoporosis or in combination with a corticosteroid to minimize catabolic side effects or with other pharmaceutically active materials where the combination increases efficacy and minimizes side effects. Growth promoting and anabolic agents include, but are not limited to, TRH, diethylstilbesterol, estrogen, β-agonists, theophylline, anabolic steroids, enkephalins, prostanglandins of the E series, the compounds described in US Pat. No. 3,239,345, e.g., zeranol, and the compounds described in the U.S.A. No. 4,036,979, for example, sulbenox or the peptides described in the patent of E.U.A. No. 4,411,890. A further use of the compounds of this invention is in combination with other growth hormone secretagogues such as the growth hormone releasing peptides GHRP-6, GHRP-1, as described in US Pat. No. 4,411,890 and publications W089 / 07110, W089 / 07111 and B-HT920, as well as hexarelin and GHRP-2, as described in W093 / 04081 or growth hormone releasing hormone (GHRH, also referred to as GRF) and its analogs, or growth hormone and its analogs or somatomedins including IGF-1 and IGF-2 or α-adrenergic agonists such as 5H agonists TID of clonidine or serotonin such as sumatriptan or agents that inhibit somatostatin or its release such as physostigmine and pirodostigmine. In particular, the compounds of this invention can be used in combination with the growth hormone releasing factor, an analogue of the growth hormone releasing factor, IGF-1, or IGF-2. For example, a compound of the present invention can be used in combination with IGF-1 for treatment or prevention of obesity. In addition, a compound of this invention can be used in conjunction with retinoic acid to improve the condition of the musculature and the skin that originates from intrinsic aging. The present invention is also directed to a method for the manufacture of a medicament for stimulating the release of growth hormone in humans and animals, which comprises combining a polymorphic form of the present invention with a pharmaceutical carrier or diluent. As is well known to the person skilled in the art, the known and potential uses of growth hormone are varied and multiple. The administration of the compounds of this invention for the purpose of stimulating the release of endogenous growth hormone may have the same effects or uses as the growth hormone itself. These varied uses of the present compounds can be summarized in this manner as follows: stimulation of growth hormone release in elderly humans; treatment of adults deficient in growth hormone; prevention of the catabolic effects of glucocorticoids; osteoporosis treatment; stimulation of the immune system, acceleration of wound healing; acceleration of bone fracture repair; treatment of growth retardation; treatment of acute or chronic renal failure or failure; treatment of short physiological stature, including children deficient in growth hormone; short stature treatment associated with chronic disease; treatment of obesity and growth retardation associated with obesity; treatment of growth retardation associated with Prader-Willi syndrome and Turner syndrome, acceleration of recovery and reduction of hospitalization of burned patients, or after major surgery such as gastrointestinal surgery; treatment of intrauterine growth retardation, and skeletal dysplasia, treatment of peripheral neuropathies, replacement of growth hormone in pensioned patients; treatment of osteochondrodies-splasias, Noonans syndrome, schizophrenia, depression, Alzheimer's disease, delayed wound healing, psychosocial deprivation; treatment of pulmonary malfunction and ventilator dependence; attenuation of the protein catabolic response after a major operation; treatment of malabsorption syndromes; reduction of cachexia and loss of proteins due to chronic diseases such as cancer or AIDS; Acceleration of weight gain and protein increase in patients on TPN (total parenteral nutrition); treatment of hyperinsulinemia including nesidioblastosis; auxiliary treatment for ovulation induction and for prevention and treatment of gastric and duodenal ulcers; for stimulation of thymic development and to avoid the age-related decline in thymic function; auxiliary therapy for chronic hemodialysis patients; treatment of immunosuppressed patients to increase the antibody response after vaccination; increase the total lymphocyte count of a human, in particular, increase the ratio of T4 / T8 cells in a human with a depressed T4 / T8 cell ratio, resulting for example from physical trauma such as head injury, or injection, such as bacterial or viral infection, especially infection with the human immunodeficiency virus; improvement in muscle endurance, mobility, maintenance of skin thickness, metabolic homeostasis, renal homeostasis in frail elderly adults; osteoblast stimulation, bone remodeling and cartilage growth; stimulation of the immune system in companion animals and treatment of aging disorders in pets; promotion of growth in livestock; and stimulation of wool growth in sheep. In addition, the present compounds are useful for increasing feed efficiency, promoting growth, increasing milk production and improving carcass quality. Also, the present compounds are useful in a method of treating diseases or conditions that benefit from the anabolic effects of the increased levels of growth hormone, which comprises the administration of a compound present. In particular, the present compounds are useful in the prevention or treatment of a condition selected from the group consisting of: osteoporosis; catabolic disease; immunodeficiency, including that of individuals with a depressed T4 / T8 cell ratio; hip fracture; musculoskeletal impairment in the elderly; Growth hormone deficiency in adults or children; obesity; cachexia and protein loss due to chronic disease such as AIDS or cancer; and treatment of patients recovering from major surgery, injuries or burns, in a patient in need of the same. In addition, the present compounds may be useful in the treatment of diseases induced or facilitated by corticotropin releasing factor or disorders related to stress or anxiety, including depression induced by stress and headache, abdominal bowel syndrome, immunosuppression, infections of HIV, Alzheimer's disease, gastrointestinal disease, anorexia nervosa, hemorrhagic tension, withdrawal symptoms of drugs and alcohol, drug addiction, and fertility problems. It will be known to one skilled in the art that there are numerous compounds currently used in an effort to treat the diseases or therapeutic indications listed above. Combinations of these therapeutic agents, some of which have been mentioned above with the growth hormone secretagogues of this invention, will bring additional, complementary and often synergistic properties to enhance the growth promoting, anabolic and convenient properties of these different therapeutic agents. . In these combinations, the therapeutic agents and secretagogues of the growth hormone of this invention can be presented independently at dose scales from one hundredth to one time the dose levels that are effective when these compounds and secretagogues are used individually. Combination therapy to inhibit bone resorption, prevent osteoporosis and increase healing of bone fractures can be illustrated by combinations of bisphosphonates and the growth hormone secretagogues of this invention. The use of bisphosphonates for these utilities has been analyzed, for example, by Hamdy, N.A.T., Role of Bisphosphonates in Metabolic Bone Diseases, Trends in Endocrinol. Metab. , 4, 19-25 (1993). Bisphosphonates with these utilities include alendronate, tiludronate, dimethyl-APD, risedronate, etidronate, YM-175, clodronate, pamidronate and BM-210995. According to their potency, the daily oral dose levels of the bisphosphonate of between 0.1 mg and 5 g and the daily dose levels of the secretagogues of growth hormones of this invention of between 0..01 mg / kg and 20 mg / kg of body weight are administered to patients to obtain effective treatment of osteoporosis. In the case of alendronate, daily oral dose levels of 0.1 mg to 50 mg are combined for effective therapy of osteoporosis with 0.01 mg / kg to 20 mg / kg of the growth hormone secretagogues of this invention. Osteoporosis and other bone disorders can also be treated with compounds of this invention in combination with calcetonin, estrogens, raloxifene and calcium supplements such as calcium citrate. Anabolic effects are obtained especially in the treatment of geriatric male patients, with compounds of this invention in combination with anabolic steroids such as oxymetholone, methyltesterone, fluoxymesterone and stanozolol. The compounds of this invention may be administered by oral, parenteral (eg, intramuscular, intraperitoneal, intravenous or subcutaneous injection or subcutaneous injection), nasal, vaginal, rectal, sublingual or local routes and may be formulated in appropriate dosage forms for each day of administration. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dose forms, the active compound is shown at least with an inert pharmaceutically acceptable carrier, such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances which are not inert diluents, for example, lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise pH regulating agents. The tablets and pills can be prepared further with enteric layers. Liquid dosage forms for oral administration include emulsions, solutions, suspensions, syrups, pharmaceutically acceptable, elixirs containing inert diluents commonly used in the art, such as water. In addition to such inert diluents, the compositions may also include adjuvants, such as wetting agents, emulsifiers and suspensors, and sweetening, flavoring and perfuming agents. Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Some examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters, such as ethyl oleate. Such dosage forms may also contain adjuvants, such as preservatives, humectants, emulsifiers and dispersants. They can be sterilized, for example, by filtration through a filter that retains the bacteria by incorporating sterilizing agents into the compositions, by irradiating the compositions or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable medium immediately before use.

Compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as cocoa butter or suppository wax. The compositions for nasal or sublingual administration are also prepared, with normal excipients well known in the art. The compound of this invention can be administered to patients (animals and humans) in need of such treatment in doses that will provide optimum pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age of the condition of the patient, the concurrent medication and the special diets that are then being followed by the patient, and other factors that those skilled in the art will recognize, the appropriate dose being finally at the discretion of the attending physician. The dose of the active ingredient of the compositions of this invention can be varied; however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The dose selected depends on the desired therapeutic effect, the route of administration and the duration of treatment. Generally, dose levels of between 0.0001 to 10 mg / kg of body weight are administered daily to patients and animals, e.g., mammals, to obtain effective release of growth hormone. Preferably, the level of the dose will be from about 0.001 to about 25 mg / kg per day; most preferably from about 0.01 to about 10 mg / kg per day. The methods for preparing the polymorphic forms of the present invention are illustrated in the following examples. The following examples are given for the purpose of illustrating the present invention and will not be construed as limitations on the scope or spirit of the present invention.

EXAMPLE 1 N- [l (1,2-Dihydro-l-me-ansulfonyl-pyrro [3 H -indol-3,4'-pipridin-3-l-yl] carbonyl-3- (phenyl-methyloxy) -ethyl-2-amino-2-methylpropanamide Step A: 1,2-Dihydro-l-methanesulfonylpihydrochloride [3G-indole-3,4'-piperidine] To a solution of 1.20 g (5.8 mmol) of l-methyl-l, 2-dihydro-spiro [3G] -indol-3-, 4'-piperidine] (prepared as described by H. Ong, et al., J. Med. Chem., 23, 981-986 (1983) in 20 ml of dry dichloromethane at O'C was added triethylamine (0.90 ml, 6.4 mmol) and methanesulfonyl chloride (0.49 ml, 6.35 mmol, and stirred for 30 min.) The reaction mixture was poured into 15 ml of a saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (2 × 10 ml). The combined organics were washed with saline (20 ml), dried over anhydrous potassium carbonate, filtered and the solvent removed under reduced pressure to provide 1.44 g of the ethanesulfonamide derivative as pale yellow oil which was it was used without purification.To a solution of the above crude product in 20 ml of dry 1,2-dichloroethane at 0 ° C was added 1.0 ml (9.30 mmoles) of chlorine. 1-Chloroethyl roformate and was then stirred at room temperature for 30 minutes and finally refluxed for 1 hour. The reaction mixture was concentrated to about one third volume and then diluted with 20 ml dry methanol and refluxed for 1.5 hours. The reaction was cooled to room temperature and concentrated to about one-half the volume. The precipitate was filtered and washed with a small volume of cold methanol. This provided 1.0 g of the hydrochloric salt of piperidine as a white solid. The filtrate was concentrated and a small volume of methanol was added followed by ether. The precipitated material was filtered once more, washed with cold methanol and dried. This gave 0.49 g more of the desired product. Total yield 1.49 g (70%). 1 H NMR (CDCla, 200 MHz) d 8-43-7.20 (m, 3H), 7.10 (dd, 1H), 3.98 (bs, 2H), 3.55-3.40 (bd, 2H), 3.35-3.10 (m, 2H ), 299 (s, 3H), 2.15 (t, 2H, 2.00 (t, 2H).

Step B: N- [l (R) - [(1,2-Dihydro-l-methanesulfonyl-pyrro [3 H -indol-3,4'-piperidin] -l'yl) carbonyl] -2- (phenylmethyloxy) ethyl] 2- [ll- dimethylethoxy) carbonyl] amino-2-methyl-propanamide. At 0.35 g (1.5 mmol) of (2H) -2- (1, 1-dimethyl-toxy) -carbonyl-1] anubi-3- [2- (phenylethyloxy) ethyl] -1-propanoic acid in 13 ml of dichloromethane was added 1,2-dihydro-l-methanesulfonyl-pyrro- [3H-indole-3,4'-piperidine] hydrochloride (0.325 g, 1.07 mmol), 0.18 ml (1.63 mmol of N-methylmorpholine, 0.159 g (1.18 mmoles) of 1-hydroxybenztriazole (HOBT) and stirred for 15 minutes EDC (0.31 G; 1. 62 moles and stirring was continued for 1 hour. Another 60 μl of N-methylmorpholine was added to and stirred for 45 minutes. The reaction mixture was poured into 5 ml of water and the organic layer was separated. The organic layer was washed with 5 ml of aqueous hydrochloric acid at 0.5 N and 5 ml of saturated aqueous sodium bicarbonate solution. The combined organics were dried over anhydrous magnesium sulfate and concentrated to provide 0.627 g of the product as a yellow foam that was used without purification. To 0.627 g (1.07 mmol) of the above product in 5 mL of dichloromethane was added 1.0 mL of trifluoroacetic acid and it was stirred at room temperature for 75 minutes. An additional 1.00 ml of trifluoroacetic acid was added and it was stirred for 10 minutes. The reaction mixture was concentrated, diluted with 5.0 ml of dichloromethane and basified carefully by pouring into 10 ml of a 10% aqueous solution of sodium carbonate. The organic layer was separated and the aqueous extracted further with 2x15 ml of dichloromethane. The combined organics were washed with 5 ml of water, dried over potassium carbonate, filtered and concentrated to give 0.486 g of the amine as a light yellow foam which was used without purification. To 0.486 g (1.01 mmol) of the amine and 10 mL of dichloromethane was added 0.26 g (1.28 mmol) of 2 - [(1, 1-dimethyl-ethoxy) carbonyl] amino-2-methyl-propanoic acid, 0.17 g. (1.28 mmoles) of 1-hydroxybenzotriazole (HOBT) and EDC (0.245 g; 1. 28 moles) and stirred at room temperature overnight. The reaction mixture was poured into 5.0 moles of water and the organic layer was separated. The aqueous layer was extracted again with 5 ml of dichloromethane. The combined organics were washed with 5.0 ml of aqueous hydrochloric acid at 0.5N, dried 5 ml of saturated aqueous sodium bicarbonate solution over anhydrous magnesium sulfate and concentrated to provide 0.751 g of the crude product as a yellow foam. A solution of this crude product in dichloromethane was chromatographed on 25 g of silica gel and eluted with hexanes / acetone / dichloromethane (70/25/5) and then with hexanes / acetone / dichloromethane (65/30/5). This gave 0.63 g of the title compound as a white solid. iH NMR (CDCI3, 400MHz). The compound exists as a rotary mixture at 3: 2. d 7.40-7.10 (m, 6H), 7.06 (d, 1 / 3H), 7. 02 (t, 1 / 3H), 6.90 (t, 1 / 3H), 6.55 (d, 1 / 3H), 5.15 (m, 1H), 4.95 (bs, 1H), 4.63 (bd, 1 / 3H), 4.57-4.40 (m, 2 2 / 3H), 4.10 (bd, 1 / 3H), 4.00 (bd, 1 / 3H), 3.82 (t, 1H), 3.78-3.62 (m, 2H), 3. 60-3.50 (m, 1H), 3.04 (q, 1H), 2.87 (s, 1H), 2.86 (s, 2H), 2. 80-2.60 (m, 1H), 1.90 (bs, 1H), 2.85-2.75 (m, 1H>, 1.82-1.60 (, 3H), 1.55-1.45 (m, 1H), 1.45 (s, 4H), 1.42 (s, 2H), 1.39 (s, 9H.

Step C: N- [l (R) - [(1,2-Dihydro-l-methanesulfonylpyro [3H-indol-3,4 '-pipe-ridin] -!' -iDcarbonyl] -2- (phenylmethyloxy) ethyl] hydrochloride] -2-amino-2-methylpropanamide To 0.637 g (0.101 mole) of the intermediate from Step B in 5 ml of dichloromethane was added 2.5 ml of trifluoroacetic acid and it was stirred at room temperature for 30 min. The reaction was made up to an oil, taken up in 10 ml of ethyl acetate and washed with 8 ml of 10% aqueous sodium carbonate solution, and the aqueous layer was further extracted with 5 ml of ethyl acetate. washed the combined organic compounds with 10 ml of water, it was dried over magnesium sulfate, filtered and concentrated to give 0.512 g of this free base as a white foam. To 0.512 g of the free base in 5 ml of ethyl acetate at 0 ° C was added 0.2 ml of saturated hydrochloric acid in ethyl acetate and it was stirred for 1.5 h. The white precipitate was filtered under nitrogen, washed with ether and dried to give 0.50 g of the title compound as a white solid. 1 NMR (400MHz, CD3OD). The compound exists as a mixture of rotamers at 3: 2. d 7.40-7.28 (m, 4H), 7.25-7.17 (, 2H), 7.08 (t, 1 / 3H), 7.00 (t, 1 / 3H), 6.80 (d, 1 / 3H), 5.16 (ddd, 1H ), 4.60-4.42 (m, 3H), 4.05 (t, 1H), 3.90 (bs, 2H), 3.83-3.70 (m, 2H), 3.30-3.15 (, 1H0, 2.97 (s, 1H), 2.95 (s, 2H), 2.90-2.78 (m, 1H), 1.96 (t, 1 / 3H), 1.85-1.65 (m , 4H), 1.63 (s, 2H), 1.60 (s, 4H).

EXAMPLE 2 N- [1 (R) - [(1,2-dihydro-l-methanesulfonyl lspiro [3H-i ndol -3.4 '- pipe ridin] -1' -i 1) carbonyl] -2- (f enylmethyloxy) ethyl ] -2-amino-2- me i lp clothes out Step A: (2R) - [[[2- (II-Dimethylethoxy) carbonyl] amino] -2,2-dimethyl-1-oxyethyl] amino-2- (phenyl-methoxy) ethyl] -l- allyl ether propanoic Prepared from (2R) -2- [(1,1-dimethylthoxy) ca rboni 1] -amino-3- (phenylethyloxy) ethyl-propanoic acid and allyl alcohol and carrying out the reaction of coupling in CH2CI2 in the presence of EDC and DMAP. * H NMR (400MHz, CDCl 3) d 7.25 (s, 5H), 5.8 (m, 1H), 5.2 (dd, 2H), 5.0 (bs, 1H), 4.7 (m, 1H), 4.6 (, 2H), 4.4 (dd, 2H), 3.9 (dd, 1H), 3.6 (dd, 1H), 1.45 (d, 6H), 1.39 (s, 9H).

Step B: Acid (2R) - [[[2- (1, 1-dimethylethoxy) carbonyl] amino] -2,2-dimethyl-l-oxoethyl] amino-2- (phenylmethyloxy) tyl) -l-propanoic A a stirred solution of the crude intermediate obtained in Step A (6.7 g, 15.9 mmol), tetrakis- (triphenylphosphine) -paladium (1.8 g, 0.1 eq) and phenyl-phosphine (1.25 g, 0.3 eq) was added to a solution of potassium-2-ethyl hexanoate (35 ml, 0.5M solution in EtOAc). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 1 h and was diluted with ether (100 ml) and poured into ice water. The organic layer was separated and the aqueous fraction was acidified with citric acid (20%), then extracted with EtOAc. The EtOAc extracts were washed with saline, dried over magnesium sulfate, filtered and evaporated to give the title compound as a solid. 1 H NMR (400 Hz, CD 3 OD) d 7.3 (s, 5 H), 4.7 (m, 1 H), 4.5 (s, 2 H), 4.0 (, 1 H), 3.6 (m, 1 H), 1.4 (d, 6 H), 1.3 (s, 9H).

Step C: N- [1 (R) - [(1,2-dihydro-1-methanesulfonyl-phenyl [3H-indol-3,4'-piperidin] -l'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2- [(II-dimethyl-ethoxy) carbonyl] amino-2-methyl-propanamide To a solution of 1.0 g (3.44 mmol) of l-methanesulfonylpyrrochloride [indolin-3,4'-piperidine], 1.44 g (3.78 mmol) (2R) - [[2- (1, 1-dimethyethoxy) carbonyl) -amino] -2,2-dimethyl-1-oxo-ethyl] -amino-2- (phenylmethyloxy) ethyl) -l-propanoic acid , N-methyl-morpholine (0.58 ml, 5.20 mmol) and 1-hydroxybenztriazole (HOBT) (0.58 g, 3.78 mmol) in 50 ml of dichloromethane was added EDC (1.03 g, 5.20 mmol) and stirred at room temperature. for 16 h. The reaction mixture was diluted with an additional 50 ml of dichloromethane and washed with aqueous sodium bicarbonate solution (50 ml), dried over magnesium sulfate, filtered and concentrated. Evaporation chromatography (50 g of silica gel) of the crude oily residue and 2.148 g (90%) of the desired material as a colorless foam. 1 NMR (CDCI3, 400MHz). The compound exists as a rotary mixture at 3: 2 d 7.40-7.10 (m, 6H), 7.06 (d, 1 / 3H), 7.02 (t, 1 / 3H), 6.90 (t, 1 / 3H), 6.55 (d, 1 / 3H), 5.15 (m, 1H), 4.95 (bs, 1H), 4.63 (bd, 1 / 3H), 4.57-4.40 (m, 2 2 / 3H), 4.10 (bd, 1 / 3H), 4.00 (bd, 1 / 3H), 3.82 (t, 1H), 3.78-3.62 (m, 2H), 3.60-3.50 (m, 1H), 3.04 (q, 1H), 2.87 (s, 1H) , 2.86 (s, 2H), 2.80-2.60 (, 1H), 1.90 (bs, 1H), 2.85-2.75 (m, 1H), 1.82-1.60 (m, 3H), 1.55-1.45 (m, 1H), 1.45 (s, 4H), 1.42 (s, 2H), 1.39 (s, 9H).

Step D: Hydrochloride N- [l (R) - [(1,2-dihydro-l-methanesul f oni lspiro [3H-i ndol -3,4 '-pipe ridin] -1' -i 1) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide To a solution of 2.148 g (3.41 mmol) of the intermediate from Step C in 10 ml of dichloromethane was added 5 ml of trifluoroacetic acid and it was stirred for 1 h. The reaction mixture was concentrated and basified with 100 ml of 5% aqueous sodium carbonate solution and extracted with dichloromethane (3X50 ml). The organic compounds were washed with saline (50 ml), dried over anhydrous potassium carbonate, filtered and concentrated to give a colorless foam. To a solution of the foam in 25 ml of ethyl acetate at 0 ° C was added 4 ml of a solution of INM hydrochloric acid in ethyl acetate. The precipitate was filtered and washed first with ethyl acetate and then with ethyl acetate-ether (1: 1), was dried to provide 1.79 g (93%) of the title compound as a colorless solid. iH NMR (400MHz, CD3OD). The compound exists as a mixture of rotamers at 3: 2 d 7.40-7.28 (m, 4H), 7.25-7.17 (m, 2H), 7.08 (t, 1 / 3H), 7.00 (t, 1 / 3H), 6.80 (d, 1 / 3H), 5.16 (ddd, 1H), 4.60-4.42 (m, 3H), 4.05 (t, 1H), 3.90 (bs, 2H), 3.83-3.70 (m, 2H), 3.30-3.15 (m, 1H0, 2.97 (s, 1H), 2.95 (s, 2H), 2.90-2.78 (m, 1H), 1.96 (t, 1 / 3H), 1.85-1.65 (m, 4H), 1.63 (s, 2H), 1.60 (s, 4H).

EXAMPLE 3 N- [l (R) - [(1,2-Dihydro-l-m-methanesulfoniIspi roC3H-indol-3, '-pipe ridin] -' -yl) ca-rbonyl 3-2-C-phenylmethyloxy) ethyl 3 - mesylate 2- amine-2-methyl-propanamide This was prepared by compounding the free base obtained in Example 5, Step D, with methanesulfonic acid. The title compound was obtained by recrystallization from ethyl acetate-ethanol-water. p. f. = 166 ° -168ßC. It was subsequently identified that this sample was a polymorphic form II. It was characterized by a dust diffraction pattern and X-rays with main referents approximately: 4.7, 11.6, 17.4, 19.2 and 21.6a (2 theta). It was further characterized by a DSC at 10 ° C / min in an open cup under nitrogen flow and exhibited a single endotherm, due to fusion, with a maximum temperature of approximately 174 ° C and an initial extrapolated temperature (melting point) of about 165 ° C with an associated heat of about 37 J / g.

EXAMPLE 4 N-benzyl carbamate of isonipecotic acid (3) Materials Isonipecotic acid (2) T.C.I. 4.02 kg (31.1 moles) Benzyl chloroformate (Schweitzerhall) 6.91 Kg (40.5 moles) K2CO3 10.1 kg (72.9 moles) Water 40.2 1 Isonipecotic acid (2) and K2CO3 were dissolved in 40.2 1 of water in a 4-neck flask of 100 1, with mechanical stirring under N2, and the solution was cooled to 10 ° C. Benzyl chloroformate was added, maintaining the temperature between 9 and 14 ° C, and the mixture was heated to 22 ° C after the addition was complete, and was aged for 58 h. The addition was concluded at 4 h, at which point the pH was 9.0. After aging for 58 h, there was no change in pH. The reaction mixture was transferred to a 200 1 extractor, and washed with 3 x 13 kg (15 1) of IPAC and 1 x 12 1 of EtOAc. The aqueous layer was extracted with 8 1 of toluene. After the washings, the benzyl alcohol content was reduced from 3.8% to 1.4% by CLAP analysis. Analytical CLAP: Zorbax Dupont 25 cm RXC8 column with 1.5 ml / min flow and detection at 254 nm; isocratic mixture with 35% MeCN, 65% aqueous H3PO4 at 0.1%; Retention times: 3- = 6.9 min, benzyl alcohol = 3.3. min, toluene = 17.3 min. The aqueous phase was acidified with 37% aqueous HCl to pH 1.8. Carbon dioxide was produced during the addition of HCl, but gas production was easily controlled. The addition of HCl took < 1 h, and required 10 1 of concentrated HCl. The aqueous phase was extracted with 3 x 6.61 of toluene. The toluene extracts were dried with 2 kg of sodium sulfate, and filtered through a pad of Solka-floc ™. The combined filtrates weighed 17.8 kg. The crude yield of carbamate 3 was 7.89 kg (97%) (as obtained by evaporation of heavy aliquots of the filtrates to dryness). The filtrates were transferred through a lOμ in-line filter to a 100 1 flask. The extracts were concentrated at 10 mbar at < 25 ° C to a volume of 18 1. The final concentration of carbamate 3 was 440 g / 1. The concentration of the toluene filtrate served to azeotropically remove the final traces of water (final KF = 170 mg / l). The product was 99.1% pure in area with 0.9% in benzyl alcohol area as the only impurity.

EXAMPLE 5 N-benzyl carbamate of isonipecotic acid chloride (4) Materials: N-benzyl isonipecotic acid carbamate (3) 7.89 kg (30.0 moles) in toluene (P.M. = 263.30) 17.9 1 Oxalyl chloride (MW = 126.93) 3.94 kg (31.0 moles) DMF (PM = 73.10) 10 ml Toluene 12 1 To the toluene solution of benzyl carbamate 3 from the previous step, 5 ml of DMF and 10 1 of toluene were added. The oxalyl chloride was added over a period of 20 min. The reaction mixture was aged for 16 h at 18 ° C under a slow stream of nitrogen. The CLAP analysis of the reaction mixture showed that 1.3% of the unreacted carboxylic acid 3 remained. The reaction mixture was heated to 26 ° C, and 5 ml of DMF was added. The mixture was aged for 2.5 hours. A 1.0 ml aliquot of the reaction mixture was warmed with 5.0 ml of tert-butylamine, and analyzed after evaporation by CLAP: 25 cm RXC8 column Zorbax Dupont at 50 ° C with 1 ml / min flow and detection 220 nm; Isocratic MeCN at 42%, 58% aqueous H3PO4 at 0.1%. This method showed that < 0.05% of acid 3 (estimated by A), and showed > 3% in area of B (> 1 mol% (C0C1) 2).

A B The mixture was concentrated at 10 mbar and at a temperature of 20 to 25 ° C until 5 1 of the solvent had been removed.

The typical CLAR profile of the concentrated toluene solution after annealing with t-BuNH2, descd above, is as follows: Retention time% in. Identity area (min) 2.1 < 0.5% carboxylic acid 3 7.8 < 0.5% Benzyl chloride 11.0 > 99% Cbz-t-butylcarboxamide A 12. 1 NA Toluene 12.7 < 0.5% Diter-butyloxamide B EXAMPLE 6 4-carboxyaldehyde-1-benzyl carbamate piperidine (5) Materials: N-benzyl carbamate of isonipecotic acid chloride (4) 3.38 kg (12.0 moles) in toluene (mp = 281.74) in 5.54 kg DIEA (KF = 18 mg / 1) 1.55 kg (15.0 moles) Pd / C a 10% (KF <20 mg / g) 101 g Thioanisole (mp = 124.21, d = 1.058) 0.56 g DIEA and thioanisole were added to the solution of (4) in toluene from the previous step, and the catalyst was suspended in this mixture. The mixture was immediately placed in the 18.925 1 autoclave, and hydrogenated at 20aC and 2812 Kg / cm2 of H2. After 18 hours, the reaction had captured 70% of the theoretical amount of hydrogen, and the CLAP analysis of an aliquot that was quenched with tert-butylamine indicated that 14.2% remained in the area of acid chloride 2. CLAP conditions They were identical as descd above. Retention time: 5 = 8.1 min. A second load of catalyst (101 g) and thioanisole (0.54 g) was added to the hydrogenator as a suspension in 1375 ml of toluene. After 23 hours of CLAP analysis of an aliquot that was quenched with tert-butylamine, it indicated that 1.8% remained in the area of acid chloride 2. The mixture was purged with nitrogen, and the precipitated catalyst and DIEA * HC1 were removed by filtration through Solka-floc ™. The filter cake was washed with 10 1 of toluene. The filtrates were transferred through a 10 μl in-line filter to a 50 1 extractor, and washed with 2 x 7.2 1 of 1 M aqueous HCl and 2 x 7.2 1 of water. The mixture was concentrated at 10 mbar, and at a temperature of 25 to 30 ° C until 5 liters of residue remained.

Retention time% in area Identity (min) 2.1 < 2 carboxylic acid 3 6.6 < 1 dimer 21 8.1 > 95 aldehyde 5 The test yield of aldehyde 3 was 94% by CLAP analysis.

EXAMPLE 7 CBZ-Spiroindoline (9) Materials: 4-carboxyaldehyde-l-benzyl-ca rbama to piperidine (5) 1.71 kg (6.89 moles) in toluene solution in 21.4 kg Phenylhydrazine 900ml, 981g (9.15 moles) Trifluoroacetic acid (TFA) 2.201, 3.26kg (28.6 moles) NaBH 300 g, (7.93 moles) Toluene 34.4 kg MeCN 7.0 1 MeOH 7.0 1 The crude solution of the aldehyde 5 from the previous step was transferred through a 10 μl in-line filter to a 100 1 reactor equipped with Teflon-coated copper coils for cooling or heating and a mechanical stirrer. Toluene (34.4 kg) and MeCN (7 1) were added, and the resulting solution was cooled to 0 ° C. The phenylhydrazine was added in portions, and the temperature was maintained at -1 to 3 ° C, while nitrogen was continuously bubbled through the reaction mixture. Phenylhydrazine was added until the TLC and CLAP analysis indicated complete consumption of aldehyde 5 and the appearance of a slight excess (< 5%) of phenylhydrazine. TLC conditions: Silica, Kieselgel G60 F254 0.25 mm E. Merck; diethyl ether / pentane (4/1); and development agent, 0.5% serum sulfate, 14% ammonium molybdate in 10% aqueous sulfuric acid, and subsequent heating; Rf: aldehyde 5 = 0.52, phenylhydrazone 7 = 0.61, phenylhydrazine 6 = 0.21. CLAP conditions: Zorba 25 cm RXC8 column? Dupont at 30 * C with flow at 1.0 ml / min, and detection at 254 nm; Gradient program: Time (min) acetonitrile: water 0 57:43 10 65:35 15 75:25 18 75:25 retention times: phenylhydrazine 6 = 4.5 min, toluene = 7.2 min, phenylhydrazone 7 = 11.4 min. The reaction mixture was aged for 30 minutes at 0 to 2 ° C, and TFA was added maintaining the temperature between 2 and 7 ° C. The reaction mixture was heated at 50 ° C for 30 minutese. , and it was maintained for 17 hours. The nitrogen mist was stopped through the reaction mixture, and a slow stream of nitrogen was maintained during the reaction mixture. During the first hour at 5 ° C, the color gradually darkened to a dark green, and a relatively small amount of a crystalline white precipitate formed (ammonium trifluoroacetate). After 17 hours, the CLAP analysis (identical conditions as described above) indicated that the reaction mixture contained 91.6% area of indolenin 8, and that 1.5% of unreacted phenylhydrazone remained. Aging the mixture for longer periods did not increase the test yield of indolenin 8. The reaction mixture was cooled to 12 ° C, and 7.0 1 of MeOH was added. NaBH * was added in small portions (<20 g), keeping the temperature below 15 ° C. The addition took 30 minutes. Moderate hydrogen production was observed during the addition, but was easily controlled, and virtually no foam formation occurred. Near the end of the addition, the color changed rapidly from green to brown, and then to bright orange. A small amount (< 200 ml) of a heavier phase had separated (possibly aqueous salts). The CLAP analysis (identical conditions as described above) indicated that all indolenine 8 had been consumed (90.4% in CBZ-indoline 9 area); retention times: indolenin 8 = 7.5 min, indoline 9 = 8.2 min. TLC: ethyl ether as a solvent, ceric sulfate dye-ammonium molybdate or 1% anisaldehyde dye; Retention factors: indolenine 8 = 0.18, CBZ-indoline 9 = 0.33. The color change from green to orange corresponds very closely to the end point of the reaction. The amount of NaBH 'necessary to conclude the reaction depends to a large extent on the temperature and rate of NaBH addition, but the yield and quality of the product are virtually unaffected, provided that the reaction is over. The reaction mixture was cooled to 5 ° C over a period of 30 minutes. Then, 8 1 of 3% aqueous NH 4 OH was added to bring the pH of the aqueous phase to 7.4, and the mixture was stirred and allowed to settle. The temperature rose to 15 ° C. The lower aqueous phase was turbid yellow colored. The organic phase was washed with 4 1 of 3% aqueous NHJJOH, 2 x 4 1 of water, and 2 x 4 1 of brine. The weight of the organic phase after washing was 53.5 kg, and the test yield was 94%. The washed toluene solution was combined with the washed organic phases of two other reactions processed in the same way. The total amount of aldehyde used in the three reactions was 5.06 kg (20.5 moles). The total weight of CBZ-indoline 9 tested in the combined organic phases was 5.91 kg (18.3 moles, 90% test yield). The combined organic phases were dried with 5 kg of sodium sulfate, treated with 250 g of Darco G60 charcoal for 30 minutes, and filtered through Solka-floc «R. The filtrates were concentrated in vacuo at 10 bars at < 25 ° C until the residue was close to drying. The change of solvent was concluded very slowly by extracting 30% IPAC, and reconcentrating up to 14 1 to 200 mbar at 50-60 ° C. The mixture was heated to reflux to obtain a clear homogenous, bright orange solution. The 1 H NMR analysis indicated that the solution contained approximately 6 mole% residual toluene after solvent exchange. The solution was cooled to 68 ° C, and seeded with 4 g of crystalline CBZ-indoline 9. The solution was allowed to cool gradually to 26 ° C for 6 hours, and was aged for 9 hours at 20-26 ° C. The suspension was cooled to 2 ° C for 1 hour, and aged at 2 ° C for 1 hour. The product was isolated by filtration, and the filter cake was washed with 2 2 1 IPAC at 5 ° C, and 2 x 2 1 MTBE at 5 ° C. The product was dried in the vacuum oven at 30 ° C under a nitrogen charge to give 4.37 kg (74%) of the title compound 9 as a light brown crystalline powder. The CLAP analysis of the product indicated 99.5% in area of purity. The stock solution (11 1) and the washings contained 1.15 kg (19%) of the additional product 9, and approximately 3% Cbz-phenylhydrazide of isonipecotic acid (retention time = 4.8 min).

EXAMPLE 8 CBZ-espi roindoline methanesulfonamide (1) Materials: CBZ-Spiroindoline (9) 1.69 kg (5.23 moles) Methanesulfonyl chloride 599 g (5.23 moles) Et3N (KF = 151) 635 g (6.27 moles) THF (KF = 41) 12 1 A mat of 22 1 with the solid CBZ-espi roindoline 9 was placed, and then 11.5 1 of THF and Et 3 of the flask were transferred through a 10 μ filter in line. The resulting homogeneous solution was cooled to 0 ° C. A 1 1 dropping funnel was charged with the methanesulfonyl chloride and 500 ml of THF. The solution of the MsCl in THF was added to the reaction mixture maintaining the temperature between 0 and 4 ° C. The addition took 5 hours, and was exothermic. A white precipitate, probably triethylammonium hydrochloride, was formed during the addition. The CLAP analysis indicated that the reaction ended at the end of the addition (9 was undetectable). CLAP conditions: Zorbax Dupont 25 cm RXC8 column with 1.5 ml / min flow and detection at 254 nm. Gradient program: Time (min) H3PO4 aqueous at 0.1%: MeCN 0 70:30 3 70:30 12 20:80 25 20:80 Retention times: 9 = 7.6 min, 1 = 13.6 min.

After the addition was complete, the reaction mixture was heated to 18 * C and aged for 16 hours. There was no change in the appearance of the reaction mixture and the CLAP profile between the end of the addition and after 16 hours of aging. The reaction mixture was transferred slowly for 1 hour in a vigorously stirred solution of 30 1 of water and 200 ml of 37% aqueous HCl in a 50 1 flask. The temperature in the 50 1 flask was raised from 22 to 28 ° C. The product separated as a pale tan gummy solid which changed to a granular solid. The aqueous suspension was cooled to 22 ° C and aged for 1 hour. The suspension was filtered, and the filter cake was washed with 2 x 4 1 MeOH / water (50/50). The CLAP analysis indicated that < 0.1% of the methanesulfonamide of CBZ-spiroindoline 1 was in the stock solution. The filter cake was washed with 4 1 MeOH / water (50/50) to which 50 ml of 28% aqueous NH 0 H had been added. The filter cake was washed with 2 x 4 1 MeOH / water (50/50), and the solid was dried in the vacuum oven at 50 ° C under nitrogen loading to give 2.03 kg (97%) of the product 1 of the title as a white powder. The CLAP analysis of solids indicated 93.7% in area of 1.

EXAMPLE 9 Optional procedure for the isolation of the intermediary CBZ-spiroindolenin (8) Materials: 4-carboxyaldehyde-l -benzyl - 12.37 g (0.050 moles) piperidine carbamate (5) Phenylhydrazine 5.41 g (0.050 moles) Trifluoroacetic acid (TFA) 11.56 ml, 17.10 g (0.150 mol) Methylene chloride 500 ml The CBZ-aldehyde 5 was dissolved in dichloromethane in a flask of 11 equipped with magnetic stirring bar coated with Teflon. The resulting solution was cooled to 0 ° C. Phenylhydrazine was added via a heavy syringe for 5 minutes, and the temperature was maintained at -1 to 3 ° C, while nitrogen was continuously bubbled through the reaction mixture. The analysis of TLC and CLAP indicated the complete consumption of CBZ-aldehyde 5, and the appearance of a slight excess (< 2%) of phenylhydrazine. TLC conditions: Silica, Kieselgel G60 F254 0.25 mm E. Merck; diethyl ether / pentane (4/1); and development agent, 0.5% ceric sulfate, 14% ammonium molybdate in 10% aqueous sulfuric acid, and subsequent heating; Rf: aldehyde 5 = 0.52, phenylhydrazone 7 = 0.61, phenylhydrazine 6 = 0.21. CLAP conditions: Zorbax Dupont 25 cm RXC8 column at 30 ° C with flow of 1.0 ml / min, and detection at 254 nm; Gradient program: Time (min) acetonitrile: water 0 57:43 10 65:35 15 75:25 18 75:25 retention times: phenylhydrazine 6 - 4.5 min, toluene = 7.2 min, phenylhydrazone 7 = 11.4 min.

The reaction mixture was aged for 10 minutes at 0 to 2 ° C, and TFA was added by syringe keeping the temperature between 2 and 7 ° C. The reaction mixture was heated at 35 ° C for 30 minutes, and it was maintained for 17 hours. The nitrogen mist through the reaction mixture was stopped, and a slow stream of nitrogen was maintained on the reaction mixture. During the first hour at 35 ° C, the color gradually darkened to a pink color and then to a deep green color, and a relatively small amount of a crystalline white precipitate formed (ammonium trifluoroacetate). After aging for 17 hours, the CLAP analysis (identical conditions as described above) indicated that the reaction mixture contained 93% in indolenin 8 area and that it remained <0.5% unreacted phenylhydrazone. Aging the mixture for longer periods did not increase the test yield of indolenin 8. The reaction mixture was cooled to 10 ° C, and a mixture containing 60 ml of ammonium hydroxide at 28 ° C was added with vigorous stirring. 30%, 90 ml of water and 150 g of crushed ice. The color of the mixture changed to a salmon color. The organic phase was separated and washed twice with 400 ml of water and then with 100 ml of saturated aqueous NaCl. The organic phase was dried over magnesium sulfate and filtered through a plug of 5 g of silica. The filtrate was evaporated to give 15.84 g (99%) of indolenine 8 as a pale orange oil.

EXAMPLE 10 Procedure for the preparation of CBZ-Espi roindoline-methanesulfonamide (1) without isolation of intermediate CBZ- Espi roi ndol i na (9) Step 1: CBZ-Espi roindoline (9) Mate rials: Ca rbamate of pipe ridin-4- ca rboxaldehí do-1-belo 49.5 g (020 moles) Feni lhid razi na (Ald ri ch) 23.7 g (0.22 mol) Trifluoroacetic acid (TFA) 75.4 g (0.66 mol) Tol uene (KF <250 mg / 1 654 ml MeCN (KF <250 mg / 1 13.3 ml NaBH4 11.3 g, (0.30 moles) Toluene 20 ml MeOH 50 ml A 2% (by volume) solution of MeCN in toluene was made using 654 ml of toluene and 1.3 ml of MeCN. In a 2-liter 3-necked flask equipped with a mechanical stirrer, 617 ml of the above solution was degassed by passing a fine stream of nitrogen through the solution for 5 minutes. Phenylhydrazine and TFA were added to the mixture while degassing. The CBZ-aldehyde 5 was dissolved in the rest of the solution prepared above (50 ml) and degassed by bubbling nitrogen through the solution while it was in the addition funnel. The solution in the flask was heated to 35 ° C and the adehide solution was slowly added to the phenylhydrazine-TFA for 2 hours. The mixture was aged at 35 ° C for 16 hours. CLAR conditions: a Dupont Zorbax RXC8 column of 25 cm at 50 ° C with 1 ml / min flow and detection at 220 nm; 55% isocratic MeCN, 45% aqueous H3PO4 at 0.1%. Typical CLAR profile after 16 hours of aging: Retention time (min)% of area Identity 1.6 0.1-0.5 phenylhydrazine 6 4.1 < 0.1 díme ro 21 4.7 < 0.1 aldehyde 5 5.0 NA spiroindoline 9 6.3 NA toluene 6.9 97 spiroinindole 8 20.3 < 0.2 peni 1 hid reasons 7 2-3 tot. Other impurities < 0.2% each The mixture was cooled to -10 ° C and MeOH was added. A suspension of sodium borohydride in 20 ml of toluene was added in small portions (1 ml) for 30 minutes taking care that the temperature did not exceed -2 ° C.

% Identity Area 0.1-1 phenylhydrazine 6 85-90 CBZ-spiroindoline 9 < 0.1 CBZ-Spiroindolenin 8 10-15 tot. Other impurities (< 3% c / u) The temperature was raised to 10 ° C for 1 hour, and 6% aqueous ammonia (200 ml) was added. The mixture was stirred for 10 minutes, allowed to stand for another 10 minutes and the lower aqueous phase was separated. Acetonitrile was added (20 ml) and MeOH (20 ml) were added to the organic phase and washed with 150 ml of 15% brine. It was found that the organic phase contained a test yield of 92% CBZ-spiroindoline 9.

Step 2: CBZ-Spiroindoline-methanesulfonamine (1) Materials: CBZ-Spiroindoline (9 = (MW = 322.51) (0.184 moles) Methanesulfonyl chloride 21.1 g (0.184 moles) DIEA (KF = 150 mg / 1) 29.7 g, 40.1 ml (0.230 mol) THF (KF = 41 mg / 1) 150 ml The crude solution of the CBZ-spiroindoline 9 solution from Step 1 above was concentrated in a 3-necked flask of 1 1 (60-70 ° C, 150-200 Torr) until they remained 250 grams of residue. The THF and DIEA were added, and the resulting homogeneous solution was cooled to 0 ° C. A 125 ml dropping funnel was charged with methanesulfonyl chloride and 50 ml of THF. The solution of MsCl in THF was added for 2 hours to the reaction mixture maintaining the temperature between 0 and 4 ° C and the mixture was aged for 2 hours at 5-8 * C. The addition was slightly exothermic. A white precipitate, presumably DIEA hydrochloride, was formed during the addition. The conditions of CLAR were the same as before. The CLAR analysis indicated that the reaction was completed 1 hour after the end of the addition (9 was undetectable) and the test yield was 94% from 9. Retention time: 1 = 7.8 min. Typical CLAR profile of reaction mixture after 2 hours of aging: % Identity Area < 0.1 CBZ-Spiroindoline 9 90-92 CBZ-sulfone gone 1 8-10 tot. other impurities (< 2% each) The mixture was heated to 20 ° C and 200 ml of Aqueous HCl at 1 M. The mixture was heated to 50 ° C, and the aqueous phase was separated. The organic phase was washed sequentially with 100 ml of water, 100 ml of 5% aqueous sodium bicarbonate and 100 ml of water. The organic phase was transferred to a 1-liter 3-necked flask equipped for mechanical stirring and distillation. The mixture (approximately 400 ml) was distilled at atmospheric pressure until 150 ml of distilled product had been collected. The temperature of the distillation head reached 107 ° C; the temperature of the vessel was 110 ° C. The distillation was continued with continuous addition of n-propanol at a rate such that a constant volume (about 350 ml) was maintained in the vessel. The distillation was stopped when 525 ml of n-PrOH had been added and a total of 800 ml of distillate had been collected. The temperature of both the distillation head and the vessel was raised from 94 ° C to 98 ° C during the change of solvent. Toluene and n-PrOH form an azeotrope that boils at 97.2 ° C composed of 47.5% toluene and 52.5% n-PrOH. The mixture was allowed to cool gradually to 20 ° C for 3 hours and aged for 12 hours. It was found that the stock solution contained 2% toluene and 4 rag / ml sulfonamide. The solubility of the sulfonamide in various mixtures of toluene and n-PrOH has been determined by HPLC test: % of Toluene in n-PrOH Solubility of 1 in mg / ml 0 2.36 5 3.02 10 4.23 20 7.51 25 10.3 The crystalline suspeneion was filtered and washed with 3 x 100 ml of n-PrOH. The product was dried in a vacuum oven at 50 ° C with a nitrogen purge for 16 hours to yield 65.5 g (82% of aldehyde 5) of 6 as a tan solid with a purity of 93.5% by weight.

Typical solid CLAR profile:% Identity Area < 0.1 CBZ-Spiroindoline 9 > 99 CBZ-sulfonamide 1 1 tot. other impurities (< 0.2% each) For further purification, 40.0 g of the sulfonamide sample crystallized with n-Pr-OH in 134 ml of EtOAc at 60 ° C was dissolved and treated with 8.0 g of Darco G-60 carbon for 1 hour at 60 ° C. After the addition of 2.0 g of Solkafloc ™, the suspension was filtered through a 4.0 g pad of Solkafloc ™, and the pad was washed with 90 ml of EtOAc at 60 ° C. Before the carbon addition, the soon had a brown color. The filtration proceeded well without covering to give a filtered yellow gold product. The filtrate was distilled at atmospheric pressure in a 500 ml flask (vessel temperature 80-85 ° C) until 100 g of residue remained. The soon was allowed to cool to 35 ° C for 3 hours. During a period of 1 hour, 116 ml of hexane cycle was added with good agitation at 35 ° C. The mixture was cooled to 20 ° C for 1 hour and aged at 20 ° C for 12 hours. At 35 ° C, a large part of the sulfonamide had crystallized and the mixture had thickened.Addition of cyclohexane at 20 ° C made agitation difficult.After the aging period, the supernatant was found to contain 2.5 mg 1 / g. The crystalline suspension was filtered and the cake was washed with 77 ml of 2: 1 cyclohexane-EtOAc and 2 x 77 ml of cyclohexane The product was dried in a vacuum oven at 50 ° C with nitrogen purge for 16 hours to give 34.2 g of 1 (MW = 400.3) as a white crystalline solid (85% recovery of crude 1, 70% of 5 with a purity of> 99.9 weight percent).

EXAMPLE 11 Spiroylindoline-methanesulfonamide hydrochloride salt (la) Materials: CBZ-Spiroindolinesulfonamide (1) 941 g (2.35 moles) Pearlman Catalyst Pd (0H) 2 at 20% / C 188 g THF 8 1 MeOH 7 1 The catalyst was suspended in 7 1 MeOH and transferred to the autoclave of 18.9 1 followed by the soon of 1 in 8 1 of THF . The mixture was hydrogenated at 25 ° to 5.6 kg * of H2. After 2.5 hours, the temperature was raised to 35 ° C for 30 minutes. The CLAR analysis indicated complete consumption of Cbz-spiroindoline-methanesulfonamide. CLAR conditions: with a Zorbax RXC8 25cm dupont with 1.5 ml / min flow and detection at 254 nm.

Gradient Scheme: Time (min) H3PO4: 0.1% aqueous MeCN 0 70:30 3 70.30 12 20:80 25 20:80 Retention times: Espi roindoline = 7.6 min, Cbz -spiroindoline-ethanesulfonamide = 13.6 min.

The mixture was purged with nitrogen and the catalyst was removed by filtration through Solka-floc ™ while heating. The catalyst was washed with 4 1 THF and 2 1 MeOH. The pale yellow filtered products were concentrated to a thick oil at 10 m bar and < 25PC. The solvent change was completed by purging slowly in 15 1 of EtOAc and reconcentrating to dryness. The residue solidified to a hard whitish mass. MeOH (1.5 1) was added and the mixture was heated to 70 ° C to give a homogeneous soon. Although the soon was at 70 ° C, 10.5 1 EtOac was added at 20 ° C. The temperature dropped to 40 ° C, and the mixture remained homogeneous. Subsequent experiments suggested that it is more convenient to solvent change the MeOH-THF-filtered products to MeOH, concentrate to the desired volume and then add the EtOAc. This prevents the solidification of the residue under the concentration of the EtOAc soon. Did hydrochloric acid with approximately equal volume of nitrogen was passed to the soon. The temperature was raised to 60 ° C over the course of 15 minutes, and a white precipitate of the hydrochloride salt formed. Ding the HCl with nitrogen only prevents the reaction mixture from being retrosulated and may not be necessary. The mixture was cooled in an ice bath and the addition of hydrochloric acid was continued for one hour. The temperature fell gradually to 20 ° C. The suspension was aged for 2 hours while the temperature was reduced to 10 ° C. The crystalline product was isolated by filtration, and the filter cake was washed with 3 1 EtOAc. It was dried in the vacuum oven at 35 ° C to give 1.18 kg (86%) of the title product as a whitish crystalline solid of% area purity.; 99.5 by CLAR analysis. The CLAR conditions were: a 25 cm Duppont Zorbax RXC8 column with a flow of 1.5 ml / min and the detection at 230 nm; 35% isocratic MeCN, 65% aqueous 0.1% ammonium acetate. Retention time: la = 5.4 min.

EXAMPLE 12 Espi roindolina-me anosulfonamida (free base form) lb) A 250 ml aliquot of the filtrate from the hydrogenolysis of Cbz- containing 4.67 g of lb (free base) was concentrated to approximately 10 ml. The residue dissolved in ml EtOAc and the solution was reconcentrated to approximately 10 ml. This was repeated one more time, and 10 mL of EtOAc was added to the residue. A crystalline precipitate began to form. MTBE (20 ml) was added in one portion.

The additional crystalline solid was precipitated, but the supernatant still contained a substantial amount of dissolved product that did not precipitate during rest. Hexane (70 ml) was added dropwise during 2 hours to the mixture with vigorous stirring. Slow addition of hexanes is necessary to avoid separation of the amine.

The stirred mixture was aged for 1 hour and filtered. The filter cake was washed with 20 ml of 1: 1 MTBE-hexane and then with 20 ml of hexane. The product was dried under a stream of nitrogen to give 3.86 g (82%) of the lb free amine as a whitish crystalline solid of% area purity. 99.5. The CLAR conditions were: Dupont Zorbax RXC8 25 cm column with a flow of 1.5 ml / min and detection at 230 nm; MechaN at 35% isocratic, 65% aqueous ammonium acetate at 0.1%. The retention time: lb = 5.4 min.

EXAMPLE 13A Espi roindolina-methanesulfonamide (free base form) (Ib) Materials: CBZ-espi roindoline-eulfonamide (1) 833.5gr (2.08 moles) Pd (0H) 2 / C (20% by weight of Pd (0H) 2) 124.5 (15%) THF 6.5 1 MeOH 19.5 1 NH4OH (conc) 60 ml Hydrogenation was performed 3 times due to equipment limitations; this procedure refers to a single operation. The CBZ-spiroindoline-sulfonamide 1 was dissolved in THF (6.5 1, KF = 53 μg / μl) and then MeOH (KF = 18 μg / gml, 4 1 was added followed by the addition of the catalyst and the suspension was transferred to an autoclave of 18.9 1. The rest of the MeOH (2.5 1) was used for rinsing.The mixture was heated at 40 ° C to 3.5 k / cm2 for 24 hours.The catalyst loading and the reaction time are a function of the purity of the starting material 1. This material was unique requiring> .15% catalyst and a long reaction time The purest lots of spiroindoline required only 5% catalyst and a reaction time of 4 to 6 hours. (< 0.1 A% 1 by LC) the mixture was filtered through Solka Floc ™ and the carbon cake was washed with MeOH (13 1) containing NH 4 OH (0.5%, 60 ml). sample shows 1587 g of spiroindoline-amine lb) were concentrated in vacuo and the resulting solids were divided between 40 1 (of toluene: THF (3: 1) and 0.5N NaOH (18 1). Although the layers separated easily, a strong precipitate could be seen in the aqueous layer. The aqueous suspension was therefore extracted with CH2C1-2 (15 1). The aqueous and organic layer separated slowly. Prior to the addition of CH2Cl2, THF was added to the aqueous layer together with sufficient NaCl to saturate the layer. However, the dissolution of the product was not achieved, which necessitated the use of CH2CI2. The combined toluene layers THF and CH2Cl2 were combined and concentrated in the intermittent concentrator. The residue was flushed with 7 1 CH 3 CN. Finally, 10 1 of CH 3 CN was added and the solution was allowed to stand overnight under N 2.

EXAMPLE 13B Espi roindolina-methanesulfonamide (free base form) (lb) Materials: CBZ-espi roindoline-sulfonamide (1) 3kg (7.49 moles) Darco G-60 600 g Ethyl acetate 36 1 Absolute ethanol 189 1 10% Pd / C 450 g Ammonia solution 500 ml Solka Floc ™ 2.5 kg Isopropyl acetate 65 1 A mixture of CBZ-espi roindonila (1) (1 kg) and Darco G-60 (200 g) in ethyl acetate (9 1) was stirred and heated to 60-65 ° C under an atmosphere of nitrogen for 8 hours . The Darco was removed by filtration at 60-65 ° C, the solid was washed with hot ethyl acetate (3 1) and the filtrate and the washings were combined. The LC p / p test confirmed negligible loss for Darco. The ethyl acetate solution was evaporated to dryness in vacuo using a 20 1 Buchi apparatus and then jet washed with absolute ethanol (2 x 5 1). This material was then suspended in absolute ethanol (8 1) heated to 65-70 ° C and placed in the autoclave of 20 1. The batch was rinsed in absolute ethanol (11). A 10% suspension of palladium on carbon (75g, 7.5% by weight) in absolute ethanol (750 ml) was then added to the autoclave and rinsed with an additional portion of absolute ethanol (250 ml). The batch was hydrogenated at 65 ° C with vigorous stirring under hydrogen pressure of 2.8 kg / cm2 for 3 hours, a second portion of 10% palladium on charcoal (75 g) the batch was hydrogenated for an additional 2 hours and then sealed during the night. The batch was transferred (still hot, 60-65 * C) to a 20 1 Buchi apparatus and vacuum degassed to remove formic acid by "feeding and purging" absolute ethanol (a total of 18 1). This procedure was repeated 2 more times and the three batches were combined in a 37.8 1 glass lined vessel and the combined batch was degassed again by the addition and distillation (vacuum) of absolute ethanol (2 x 10 1). Solka floc ™ (0.5 kg) was added to the batch and rinsed with ethanol (10 1). A star filter was loaded with Solkafloc ™ (2 kg) as a suspension in ethanol (20 1). The resulting mixture was heated to 60-65 ° C and then transferred at this temperature through a heated filter using a pump to 2 stainless steel tanks that had been tared. The initial vessel, filter, pump and liners were rinsed with a hot mixture (60-65 ° C) of aqueous ammonia (500 ml) in absolute ethanol (25 1). The filtered product and the washes were combined in the two stainless steel tanks. The batch was then transferred to a vessel using an in-line filter containing a 10-micron cartridge, and then concentrated in vacuo to reduce the volume ("15 1. Ethanol was replaced by isopropyl acetate by" feed and purge "of batch volumes 3 x of isopropyl acetate (45 1 in total), while maintaining a batch volume of 15 1. The change of solvent, when completed, contained <1% residual ethanol by gas chromatography. The batch was diluted to ~ 33 1 by the addition of isopropyl acetate (20 1), and this solution of spiroindoline-amine lb (1855 kg by liquid chromatography analysis) in isopropyl acetate was used for the next step of the process.

EXAMPLE 14A Boc-0-Benzyl Serine-Spiroid Nolol (11) Materials Spiroinoline-Amine (Lb) 1587 g (5,966 moles) Amino Acid (10) 1938 g (6,563 moles) DCC 1334.5 g (6,563 moles) HOBT 884 G (6,563 moles) CH3CN 25 1 0.5N N, 0H 18 1 0.5N HCl 181 N.HC03 sat, 18 1 iPrOAc 28 1 Spi roi ndol i na -ami na Ib in CH3CN or iPrOAc H2? (25 1) at room temperature under N2 was treated in sequence with HOBT (884 g; 1.1 eq) as a solid, DCC (1334.5 g, 1.1 eq) as the molten bath (heating in hot water at 60 ° C for about 1 hour) and finally amino acid 10 (1938 g) as the solid . The mixture was stirred for 3 hours, time after which the heavy precipitation of DCU occurred and the liquid chromatography analysis showed approximately 0.5 A% remaining amine lb. IPAc (9 1) was added, the suspension was filtered through Solka Floc ™ and the cake was washed with IPAc (19 1). The combined organic solution was washed in sequence with NaOH at 0.5N (18 1), HCl at 0.5N (18 1) and saturated NaHC 3 (18 1). A final wash with water at this point resulted in an emulsion and then was removed. The organic layer was concentrated in vacuo and the residue was dissolved in MeOH or EtOH (final volume of 10 1). The test produced 3026 gr (89%). The use of alternative peptide coupling agents such as carbonyldimidazole or the formation of mixed anhydrides, such as sec-butyl carbonate, gave lower yields of 11 and / or 14 with a high degree of epimerization in the case of the first compound. Other peptide coupling reagents were prohibitively expensive.

EXAMPLE 14B Materials: Spiroindoline-amine (lb) 1,855 kg (6.96 moles) Isopropyl acetate 29 1 Dicyclohexylcarbodiimide (DCC) 1.58 kg (7.65 moles) 1-Hydroxybenzotriazole (HOBt) 1.03 kg (7.62 moles) N-Boc-O-benz 1 - D-Se 2.26 kg (7.65 moles) Aqueous sodium hydroxide at MM 26 1 Aqueous hydrochloric acid at 0.5M 26 1 Bi carbonate of Sodium Aqueous Saturated 261 Absolute ethanol 50 1 Water (20 1) was added to the stirred solution of the spiroindoline-amine lb (1855 kg) in isopropyl acetate (33 1) in a reaction vessel. The following chemical compounds were added sequentially at room temperature under a nitrogen atmosphere: DCC (1.58 kg, 1.1 equiv.), HOBt (1.03 kg, 1.1 equiv.) And finally N-Boc-O-benzyl-D-Serine ( 2.26 kg, 1.1 equiv.). The reagents were rinsed with isopropyl acetate (7 1). The batch was stirred at room temperature under nitrogen atmosphere for 5 hours when liquid chromatography showed that the product / starting material ratio was 99.4 / 0.6. The mixture was then filtered through a star filter using cloth and cardboard alone and using a pump to pump into another container. The container from which it was sent was rinsed with isopropyl acetate (22 1) and this was used to rinse the filter, pump and lines in the receiving container. The mixture of two phases in the vessel was stirred for 10 minutes and allowed to settle for 15 minutes. The lower aqueous layer was separated and the organic solution was allowed to stand at room temperature overnight. The next day, the organic solution was washed with an aqueous solution of sodium hydroxide to IM (261) and then aqueous hydrochloric acid to 0.5M (26 1) and finally saturated aqueous sodium bicarbonate (26 1). Liquid chromatography analysis gave a test yield of 3,787 kg, overall yield of 93% of 7.49 moles (3 kg) of starting CBZ-spiroindoline (1). The batch was concentrated under vacuum (internal temperature = 13-15 ° C., Jacket temperature = 40 ° C, Vacuum = 29") at low volume (~ 15 1) and the solvent was changed to ethanol" feeding and purging " ethanol (50 1) while maintaining the volume at ~ 15 1. Gas chromatography showed <1% remaining isopropyl acetate The solution was used for the next stage of the process.

EXAMPLE 15A O-Benzyl Serine-Espi Roindoline (free base form) (12) Materials: Boc-O-Bencilse rina-espi roindoline (11) 3026 g (5.57 moles) Methanesulfonic acid (MsOH) 1.16 1 (17.9 moles) MeOH 10 1 iPrOAc 24 1 0.5N NaOH 35 1 Boc-O-benzyl serine-spiroindoline 11 in 10 1 of Me0h (or EtOH) was treated with net MsOH (1.16 1) added for approximately 30-40 minutes (initial temperature of 16 ° C final temperature of 28 ° C). The dark red solution was aged overnight under N2. The mixture was then pumped into a 100 1 extractor containing 24 1 iPrOAc and 35 1 0.5 N NaOH. The pH of the aqueous layer was 7. NaOH (6M) was added until pH L0.5. As the pH increased the color changed from red to yellow. The layers were separated and the organic layer (241) was shown by NMR containing 13 mol% MeOH in iPrOAc [5% by volume]. The liquid chromatography test was 2.48 kg.

O-Benzyl Serine-Spiroindoline (free base forrea) (12) Materials: Boc-O-Benzyl serine-spiroindoline (11) 3,787 kg (6.96 moles) Methanesulfonic acid 2,006 kg (20.87 moles) Isopropyl acetate 38 1 Aqueous sodium hydroxide at M 16 1 1 50% aqueous sodium hydroxide 1.6 1 Methanesulfonic acid (2,006 kg, 1355 1, ~ 3 equiv.) Was added to the stirred solution of Boc -0-benzyl kidney (811) (3,787 kg) in ethanol (total volume of ~ 15 1). In a reaction vessel, the batch was heated to 35-40 ° C. After 7 hours, liquid chromatography showed the absence of starting material and the reaction was allowed to cool to room temperature overnight. Water (441) was added to the batch with stirring The batch was cooled to ~5 °, stirred for 30 minutes and then filtered through an inline filter (loaded with a 10 μm cartridge) to a reservoir. Then it was retrosed back to the container, a water rinse (10 1) was used to rinse the container and the lines to the tank and then used to rinse the container again.The isopropyl acetate (38 1) was added followed by aqueous sodium hydroxide to IM (16 1) .The batch was cooled to 10-15 ° C, the pH of the layer Lower aqueous was confirmed as ~7 and an aqueous 50% sodium hydroxide solution (0.6) was added (pH > 10). The batch was stirred at 10-15 ° C for 25 minutes and then allowed to settle for 10-15 minutes. The lower aqueous layer was separated (78.1 kg). The LC test indicated 28.4 g of 12 (0.85% theory) contained in the aqueous solutions. The volume of the organic solution = 51 1. The liquid chromatography test indicated 3.057 kg, 92% overall yield from 3 kg, 7.49 moles of CBZ-spiroindoline-sulfonamide (1). This solution was used for the next stage.

EXAMPLE 16A Boc-Aminoisobutyryl-O-Benzyl Serine-Spiroindoline (14) Materials: Spiroindoline-amine (12) 2481 g (5.57 moles) Amino acid peptide (13) 1347.1 g (6.16 moles) DCC 1266.7 g (6.16 moles) HOBT 827 g (6.16 moles) IPAc 52 1 H2O 37 1 0.5N NaOH 36 1 0.5N HCl 36 1 Sat. NaHC? 3 361 The solution of the amine in 12 in IPAc was diluted to a total volume of 39 1 with IPAc and 37 1 of H2O was added. The biphasic mixture was then treated in sequence with HOBT (827 g) as a solid, DCC (1266.7 g) as a molten bath, and amino acid 13 at room temperature under nitrogen. The reaction mixture was stirred for 2 hours, after which the liquid chromatography analysis indicated the disappearance of starting material 12 (< 0.3 A%). The mixture was filtered through Solka Floc ™ and the solids were washed with 13 1 of IPAc. The material was stored at this point as a two-phase mixture at night. The mixture was transferred to a 100 1 extractor, the aqueous layer was separated and the organic layer was washed successively with 36 1 of NaOH at 0.5N, HCl at 0.5N and saturated NaHC 3. The test gave 3160 g (81% from spiroindoline + 5% for volume measurement error). The solution was concentrated to a small volume and flushed with ethanol (2 x 4 1). If desired, intermediate compound 14 can be isolated by adding water to crystallize it. The use of alternative peptide coupling agents such as carbonyldiimidazole or formation of mixed anhydrides, such as sec-butyl carbonate gave the lower yields of 14 with a high degree of epimerization. Other peptide coupling reagents were prohibitively expensive.

EXAMPLE 16B Boc-Aminoisobutyryl-O-Benzyl Serine-Spiroindoline (14) Materials: Spiroindoline-amine (12) 3.057 kg (6.89 mol) Dicyclohexylcarbodiimide (DCC) 1.56 kg (7.56 mol) 1-Hydroxybenzotriazole (HOBt) 1.02 kg (7.55 mol) 2-aminoisobutyl acid (13) 1.54 kg (7.58 mol) Isopropyl acetate 32 1 Aqueous sodium hydroxide at MM 38 1 Aqueous hydrochloric acid at 0.5M 38 1 Saturated aqueous sodium bicarbonate 38 1 Absolute ethanol 45 L Water (491) was added to the stirred solution of spiroindoline-amine 12 (3057 kg) in isopropyl acetate (total volume ~ 51 1) in a reaction vessel at room temperature under a nitrogen atmosphere. The following chemical compounds were added sequentially: DCC (1.56 kg, ~ 1.1 equiv.), HOBt (1.02 kg, ~ 1.1 equiv.) And finally N-Boc-2-aminoisobutyl acid 13 (1.54 kg, ~ 1.1 equiv.). The mixture was stirred vigorously at room temperature for 2 hours when liquid chromatography showed that the reaction was complete. The mixture was filtered to another vessel through a Star filter using a pump. Isopropyl acetate (22 1) was used to rinse the container, filter, pump and lines to the receiving container. The two-phase mixture was then stirred for 5 minutes and the layers were allowed to separate. The lower aqueous layer was separated without incident (weight of aqueous solutions = 51.1 kg). The organic solution was then washed sequentially with aqueous sodium hydroxide to IM (381), aqueous hydrochloric acid to 0.5M (381) and finally saturated aqueous sodium bicarbonate (381) without incident. The organic solution was then transferred using a pump through an in-line filter (containing an IOμ cartridge) to another vessel for the change of solvent to ethanol. The vessel was rinsed with isopropyl acetate (10 1) and this was used to rinse the pump, filter and lines to the receiving vessel. The filtrate and the washings were combined. Total volume = 75 1 (by immersion rod). The liquid chromatography test gave 4,395 kg of Boc-aminoisobutyryl-O-benzyl serine espi roindoline (14), ie 93% of the total of 7.49 moles of starting CBZ-spiroindoline-sulfonamide (1). The batch was concentrated in vacuo to a lower volume (^ 15 1) and the isopropyl acetate was changed to ethanol "feeding and purging" with absolute ethanol (45 1 total). At the end of the solvent change, the gas chromatography showed < 1% remaining isopropyl acetate. This solution (25 L) containing 4395 kg of 14 was used for the next step. If desired, intermediate compound 14 can be isolated by adding water to crystallize it.

EXAMPLE 17A Aminoisobutyryl-O-benzyl-serine-spiroindoline (15) Materials: Boc espi roindolina (14) 3160 g (5.03 moles) Methanesulfonic acid (MsOH) 979 mL (15.1 moles) EtOH 6.2 1 H2O 30 1 1N NaOH 11 1 EtOAc 26 1 Charcoal activated Darco 60 1 Kg The bovine spiroindoline 14 was dissolved in 6.2 1 EtOH and treated with MsOH (979 ml). The temperature rose from 20 to 30 ° C and the reaction was allowed to proceed overnight. After 12 hours at 20 ° C there was still 15% A of starting material left, so the mixture was heated at 35 ° C for 6 hours. Upon completion (<0.1% A 14) the reaction was cooled to 20 ° C and 30 1 of H2O was added and the solution was filtered through a glass funnel with a polypropylene filter to filter DCU reeidual. The mixture was transferred to a 100 1 extractor and 26 1 EtOAc was added. The aqueous layer was basified by the addition of cooled IN NaOH (11 1) and 1 1 50% NaOH. The addition of ice was required to maintain the temperature below 14 ° C. Higher temperatures were obtained in significant emulsion problems. The organic layer was distilled at 50 ° C to about 53.34 cm Hg to KF < 1000 μg / ml. Lower KFs resulted in more efficient carbon treatments and better recovery in the salt formation step. KF of 160 μg / ml were achieved at the 700 gram scale. The solution was diluted with ethyl acetate to a total volume of 31 1 (liquid chromatography test gave 2.40 kg). Activated charcoal (Darco G-60) was added and the mixture was stirred for 24 hours. The mixture was filtered through Solka Floc ™ and the filter cake was washed with ethyl acetate (16 1), the test giving 2.34 kg.

EXAMPLE 17B Aminoisobutyl Ril-0-Benzyl Serine-Spiroindoline (15) Materials: Boc espi roindolina (14) 4.395 kg (6.99 mol) Methanesulfonic acid 2.017 kg (20.99 moles) Ethyl acetate 1851 Aqueous sodium hydroxide at IM 16 1 50% aqueous sodium hydroxide 2.6 1 Darco G-60 900 g Solka Floc ™ 2.5 kg Methanesulfonic acid (2017 kg, 1.36 1, ~ 3 equiv.) Was added to the stirred solution of Boc spiroindoline 14 (4395 kg) in ethanol (total volume ~ 25 1) in a reaction vessel at room temperature. The batch was heated to 35-40 ° C, and stirred overnight. The next day, the batch contained "1.1 A% of the starting material and in this way the reaction was continued for an additional 4 hours, then the liquid chromatography showed a product / material starting ratio of 99.6 / 0.4. it was concentrated in vacuo to a volume of ~ 15 1 and then diluted with water (44 1) The batch was cooled to 5 ° C, stirred for 30 minutes and then filtered through a Sparkler in-line filter (which contained a 10μ cartridge) using a pump to pump to another container in order to remove a small amount of residual DCU.

The container, the pump and the filter as well as the lines were rinsed with water (10 1), and this was added to the container. Ethyl acetate (361) was added and the vessel and the stirred mixture were cooled to 10 ° C. A solution of cold aqueous sodium hydroxide (5-10 ° C) (16 1) and a cold 50% aqueous sodium hydroxide solution (5-10 ° C) (2.6 1) were added to 10PC and the temperature rose to 14 ° C. The resulting mixture was stirred for 15 minutes at < 14 ° C and then the lower aqueous layer was separated. The batch was concentrated in vacuo to a volume of ~20 1 and then a mixture of ethyl acetate (351) and ethanol (51) was fed while maintaining the volume at ~20 1. At the end of the distillation, the KF was 9160 mgml -1 .The batch was solvent changed to ethyl acetate "feeding and purging" ethyl acetate (total of 40 1) At the end of this distillation, KF was 446 mgml -1. diluted with ethyl acetate (10 1) Darco G-60 (900 g) was added to the cloudy mixture, which was rinsed with ethyl acetate (6 1) .The mixture was stirred at room temperature overnight. Next, Solka Floc ™ (0.5 kg) was added to the stirred batch in the vessel and then the Solka Floc ™ (2.0 Kg) was stirred in a little ethyl acetate and loaded onto a Star filter.Excess solvent was pumped away. through a Sparkler in-line filter that contained a 10 μm cartridge, the suspension was transferred from the container through a filter using a bo mba and then through another filter to 2 x 40 stainless steel tanks 1. Visual inspection showed that the solutions were clear and clean. The vessel was rinsed with ethyl acetate (22 1) and this was used to rinse through the route previously delineated to the stainless steel cans. The contents of both cans were transferred to the reaction vessel and the solution was mixed uniformly. The batch (58 1) had a KF of 2950 mgml-1 and in this way was dried again by concentrating in vacuo at a volume of 20-25 1. The batch was diluted to a volume of 46 1 (immersion rod) by the addition of ethyl acetate (25 1). The KF was 363 mgml-1. The batch was diluted to a volume of 62 1 by the addition of ethyl acetate (17 1) and used for the final stage of the process.

EXAMPLE 18A 3.4'-piperidinyl] -l '' - il) carbonyl3-2- methanesulfonate. (phenylmethyloxy) ethyl 3-2-amino-2-methylpropanamide (16) Materials: Amine (15) 2340 g (4.43 moles) Methanesulfonic acid (MsOH) 316 mL (4.88 moles) EtOAc 60 1 EtOH 4.8 1 8% EtOH in EtOAc The volume of the solution of 15 from the previous step was adjusted to 60 1 with ethyl acetate and added EtOH (4.8 1). MsOH (316 ml) was added in 3 l of EtOAc at 45 ° C. To the homogeneous deep red solution 496 g of the seed of form I of the title compound were added (10% of seed was used based on the weight of the free amine) the temperature was raised to approximately 48 ° C and the reaction was aged at 52ttC for 1.5 hours. The analysis indicated complete conversion to the title compound (form I). (Less than 10% of seed was required greater than the aging time (> 3 hours)). The euepeneion was allowed to cool to 20 ° C overnight and was filtered in a centrifuge under N2. The cake was washed with 20 L of EtOH at 8% in EtOAc. N2 is essential during filtration because the wet crystals are very hydroscopic. The lot was dried ° C under vacuum to give 2.7 Kg (56% overall yield) of the title compound (form I) (purity 99.9 A%; <0.15 enantiomer). The conversion of form II to form I is also achieved where the salt is formed in EtOAc-EtOH by the addition of MsOH as before and the initial solution of the salt (at 55 ° C) is cooled to 45 ° C . The crystals begin to appear at that temperature and the suspension becomes thicker with time. The temperature is then raised to 51 ° C and the suspension is aged overnight. Complete conversion to form I of 16 would be expected. This procedure can also be used to prepare seed crystals of Form I of 16.

EXAMPLE 18B Spiral methanesulfonate [3H-i ndol -3. '-pipe ridin 3-1' - il) carbonyl 3-2- (phenylmethyloxy) ethyl 3-2-amino-2-methylpropanamide (16) Materials: Amine (15) 3.1 Kg (5.86 moles) Methanesulfonic acid 620 g (6.45 moles) Ethyl acetate 37 1 Absolute ethanol 8.7 1 Spiro methanesulfonate [3 H -indole-3,4'-piperidin] -l'-il) - carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide (Form I) 70 g (0.11 moles) Absolute ethanol (6.4 1) was added to the solution of the amine (15) (3.1 kg) in ethyl acetate (total volume ~62) in a reaction vessel. The batch was heated to 50 ° C and a solution of methanesulfonic acid (620 g, 412 ml, 1.1 equiv.) In ethyl acetate (11 1) was added for ~ 5 minutes at 50-54 ° C. The batch was seeded with spiro methanesulfonate [3H-indol-3,4'-piperidin] -1 '-i1) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide (form I) ( 70 g) and the resulting suspension was stirred and heated to 55 ° C under nitrogen atmosphere overnight. The next day, the suspension was cooled to 15-20 ° C, maintained for 2 hours and then dropped to 50 cm of polypropylene filter under a nitrogen atmosphere. The solid product was washed with a mixture of abeolute ethanol (2.3 1) in ethyl acetate (26 1). The white solid product was excavated and dried in an Apex vacuum oven at 35 ° C for an appropriate time of about two days). Spiro methanesulfonate [3H-indol-3,4'-piperidin] -l '-yl) -carbonyl] -2- (phenylmethyl-oxy) ethyl] -2-amino-2-methylpropanamide (3.352 kg) dry was screened using a Jackson Crockatt sieve to give 3.347 kg (including seed, 70 g)} yield = 3,277 kg.

CLAR conditions: The retention times of liquid chromatography on Zorbax RX-C8 (4.6 mm x 25 cm), wavelength = 210 nm, flow rate = 1.5 ml / min. Compound 1: 60:40 CH3CN-H2O (1% H3PO4), RT = 5.0 min. Compound lb: 35:65 CH3CN-H2Q (0.1% NhUOAc), RT = 6.2 min. Compound 10: 60:40 CH3CN-H2O (H3PO., 0.1%), RT = 2.9 min.

Compound 11: 60:40 CH3CN-H2O (0.1% H3PO4), RT = 5.4 min. Compound 12: 40:60 CH3CN-H2O [pH 5.25 NaH? PO ^ (6.9 g / 1 H 2 O) is adjusted with NaOH)], RT = 5.6 min. Compound 14: 60:40 CH3CN-H2O (0.1% H3PO4), RT = 4.65 min. Compound 15: 40:60 CH3CN-H2? [PH = 5.25 NaH2P0 < v (6.9 g / 1 H2O is adjusted with NaOH), TR = 4.9 min.

Retention time of liquid chromatography on Zorbax RX-C8 (4.6 mm x 25 cm), wavelength = 210 nm, flow rate = 1.2 ml / min, column temperature = 48 C. Solvent A = 0.05% phosphoric acid + 0.01% triethylamine in water. Solvent B = acetonitrile Identification system: Time% A% B 0 min 95 5 35 min 10 90 38 min 95 5 40 min 95 5 Retention time (minutes) Compound 1 25.2 Compound lb 8.5 Compound 10 20.5 Compound 11 26.3 Compound 12 14.8 Compound 14 25.6 Compound 15 15.7 EXAMPLE 19 Preparation of Form I N- [1 (R) - [1,2-dihydro-methanesulfonyl-spiro [3H-indol-3,4 '-piperidin] -l' -yl) -carbonyl] -2- methanesulfonate phenylmethyloxy) -ethyl] -2-amino-2-methylpropanamide. The conversion of form II to form I can be carried out by the procedure of Example 18A, where the salt is formed in EtOAc-EtOH by the addition of MsOH and the initial solution of the salt (at 55 ° C) is cooled to 45 ° C. * C. The crystals should begin to appear at that temperature and the suspension should become thicker over time. Then, the temperature is raised to 51 ° C and the solution is aged overnight. A total conversion to form I must be expected.

EXAMPLE 20 Preparation of Form I Methanesulfonate N- [1 (R) - [1,2-dihydro-me tanosulfonyl-spiro [3H-i ndol -3. '-pipe ridin3-l'-il) - carbonil3-2- (phenylmethyloxy) -ethyl-3-2-areino-2-methylpropanamide The conversion of form II to form I is carried out by stirring a solution of form II methanesulfonate of N- [1 (R) - [1,2-dihydro-methanoeul fonyl-eepi ro [3H-indol-3, 4 '-pipe ridin] -1' -i 1) carbonyl] -2- (phenylethyloxy) -ethyl] -2-amino-2-ethylpropanamide in isopropanol at about 25 ° C, for about 2-24 hours.

EXAMPLE 21 Preparation of Form IV methanesulfonate of N-CKR) -C1.2- dihydro-methanesulfonyl-spiroC3H-indol-3.4 * piperidin-3-yl) -carbonyl -2- (phenylmethyloxy) -ethyl-2-amino -2-methylpropanamide A sample of 8.4 g of N- [l (R) - [1,2-dihydro-methanesulfonyl-spiro [3H-indol-3,4'-piperidin] -l'-yl) carbonyl] -2 methanesulfonate is dissolved. - (Phenylmethyloxy) -ethyl] -2-amino-2-methylpropanamide optionally morphologically in a mixture of 24. 8 ml of ethyl acetate 9, 1.6 ml of ethanol and 1.95 ml of water with stirring at 42 ° C. The solvent is evaporated from the solution at a temperature of 40 ° C, the resulting solid is ground in a mortar to make it a fine powder and it is exposed to a relative humidity of about 75% to give the name of form IV.

EXAMPLE 22 Preparation of Form IV of N- [1 (R) - [1,2-dihydro-methanesulfonyl-spiro [3H-indol-3,4'-pipe-ridin-3-1-yl] carbonyl -2- (phenylmethyloxy) -ethyl-3-2-amino-2-methylpropanamide A sample of methanesulfonate of N- [1 (R) - [1,2-dihydro-methanoe-sulfonyl-spiro [3H-indol-3,4'-piperidin] -1'-yl) ca rboni 1] is recrystallized. 2- (f nor lmeti loxi) -ethyl] -2-ami non-2-methylpropanamide in an optional morphological form in an ethyl acetate / ethanol / water solution (24.8 / 1.6 / 1.95 v / v / v) to give the name form IV.

EXAMPLE 23 Preparation of Form IV methanesulfonate of N-CKR) - [1,2- dihydro-methanesulfonyl -spyroC3H-i ndol -3. '-pipe ridin] -! * -il) - ca rboni 1 -2- (feni lme i loxi) -ethyl 3 -2-ami no-2-me ilo clothes nami da A suspension of the form I of methanesulfonate of N- [1 (R) - [1,2-dihydro-methanesulfonyl-eepiro [3H-i ndol -3,4'-pipe ridin] -l'-il) ca rboni l] -2- (phenylethyloxy) -ethyl] -2-ami-2-methylpropanamide in isopropyl acetate / ethanol (90:10 v / v) containing about 2.8% by weight of water is stirred throughout the night at about 25 ° c and the resulting solid is separated. Although the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, eubstitutions, omissions or additions of procedures and protocols can be made without departing from the spirit and scope. of the invention. For example, effective doses other than the particular doses discussed here may be applicable as a variation variant in the eensibility of the mammalian being that was treated by any of the indications with the above-mentioned component of the invention. Also, the specific pharmacological responses observed may vary according to the particular active component that was selected or depending on it, or whether there are pharmaceutical vehicles present, and the type of formulation and mode of administration used, and said variations. or differences that are expected in the results are contemplated in accordance with the objects and practices of the present invention. Therefore, it is intended that the invention be defined by the scope of the following claims and that said claims be interpreted as widely as is reasonable.

Claims (28)

NOVELTY OF THE INVENTION CLAIMS

1. A polymorphic form of the methanesulfonate compound of N- [l (R) - [1,2-dihydro-methanesulfonyl-eepi ro [3H-indol -3,4 '-pipe ridin] -1' -i 1) -carboni 1] -2- (phenyl-methyl-oxy) -ethyl] -2-amino-2-methylpropanamide, designated form I, which is characterized by an X-ray powder diffraction pattern with main lessons at approximately: 6.5,

14. 7, 17.1, 17.9, 21.1, 21.7 and 22.0 ° (2 theta).

2. The polymorphic form according to claim 1, characterized by a melting endotherm with an extrapolated onset temperature of about 170 ° C when heated in a differential scanning calorimetric cell at a speed of 10 ° C / min under a nitrogen atmosphere.

3. The polymorphic form according to claim 1, which exhibits a solubility in isopropanol of 4.6 mg / ml.

4. The polymorphic form according to claim 1, which appears birefrin under polarized light.

5. A polymorphic form of the methanesulfonate compound of N- [l (R) - [1,2-dihydro-methane-sulfonyl-spiro] [3H-indol-3,4 '-pipe-ridin] -l'-yl) -carbonyl ] -2- (phenyl-methyloxy) -ethyl] -2-amino-2-methylpropanamide, designated form IV, which is characterized by an X-ray powder diffraction pattern with main lessons at approximately: 16.0, 16.2, 18.3 , 20.1 and 24.2 ° (2 theta).

6. The polymorphic form according to claim 5, characterized by an endotherm of water loss at a temperature of about 45 ° C followed by an endotherm with an extrapolated start temperature of about 129 ° C when heated in a calorimetric cell of differential scanning at a speed of 10 ° C / min under a nitrogen atmosphere.

The polymorphic form according to claim 5, which contains about 3.5 moles of water per mole of N- [l (R) - [1,2-dihydro-methanesulfonyl-spiro [3H-indole-3,4 methanesulfonate]. '-piperidin] -l'-yl) -carbonyl] -2- (phenylmethyloxy) -ethyl] -2-amino-2-methylpropanamide.

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of the polymorphic form according to claim 1.

9. A pharmaceutical composition useful for the treatment of osteoporosis comprising a combination of a bisphosphonate compound and the polymorphic form of according to claim 1.

10. The pharmaceutical composition according to claim 9, further characterized in that the bisphosphonate compound is alendronate.

11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of the polymorphic form according to claim 5.

12. A pharmaceutical composition useful for the treatment of oeteoporosis comprising a combination of a bisphosphonate compound and the polymorphic form of compliance with claim 5.

13. The pharmaceutical composition according to claim 12, characterized in that the bisphosphonate compound is alendronate.

14. The use of an effective amount of the polymorphic form of the compound according to claim 1, for preparing a composition for raising the levels of endogenous growth hormone in a human or an animal.

15. The use of an effective amount of the polymorphic form of the compound according to claim 1, in combination with an additional growth hormone secretagogue to prepare a composition for raising the levels of endogenous growth hormone in a human or an animal .

16. The use according to claim 15, further characterized in that the additional growth hormone secretagogue is selected from the group consisting of: growth hormone releasing peptide GHRPD-6; growth hormone releasing peptide GHRPD-2; growth hormone releasing peptide GHRPD-1; B-HT920; growth hormone releasing factor; an analog of growth hormone releasing factor; IGF-1 and IGF-2.

17. The use of an effective amount of the polymorphic form of the compound according to claim 1, to prepare a composition to raise the levels of feed efficiency, promote growth, increase milk production and improve the quality of the milk channel. won.

18. The use of an effective amount of the polymorphic form of the compound according to claim 1 for preparing a composition for treating or preventing a condition selected from the group consisting of: oeteoporosis, catabolic disease, immunodeficiency, including that of individuals with a reduced T¿ Tß cell ratio; hip fracture, musculoskeletal impairment in the elderly; Growth hormone deficiency in adults or children; obesity, cachexia and protein loss due to a chronic disease such as AIDS or cancer; and treat patients recovering from major surgery, injured or burned, in patients who need it.

19. The use of the polymorphic form of the compound according to claim 1 in combination with a biophosphonate compound to prepare a composition for the treatment of osteoporosis in a patient.

20. The use according to claim 19, characterized in that the bisphosphonate compound is alendronate.

21. The use of an effective amount of the polymeric form of the composition according to claim 5 for preparing a composition for raising the levels of endogenous growth hormone in a human or an animal.

22. The use of an effective amount of the polymeric form of the compound in accordance with claim 5, in combination with an additional growth hormone secretagogue to prepare a composition for raising the levels of endogenous growth hormone in a human or animal.

23. The use according to claim 22, characterized in that the additional growth hormone secretagogue is selected from the group consisting of: growth hormone releasing peptide GHRPD-6; growth hormone releasing peptide GHRPD-2; growth hormone releasing peptide GHRPD-1; B-HT920; growth hormone releasing factor; an analogue of the growth hormone releasing factor; IGF-1 and IGF-2.

24. The use of an effective amount of the polymorphic form of the compote according to claim 5 for preparing a composition for raising the levels of feed efficiency, promoting growth, increasing milk production and improving the quality of livestock carcass. .

25. The use of an effective amount of the polymorphic form of the compound according to claim 5 for preparing a composition for treating or preventing a. condition selected from the group consisting of: osteoporosis, catabolic disease, immunodeficiency, including that of individuals with a decreased ratio of hip fracture cells, musculoskeletal impairment in the elderly; Growth hormone deficiency in adults or children; obesity, cachexia and protein loss due to a chronic disease such as AIDS or cancer; and treat patients recovering from major surgery, injured or burned, in patients who need it.

26. The use of an effective amount of the polymorphic form of the compound in accordance with claim 5, in combination with a bisphosphonate compound to prepare a composition for the treatment of osteoporosis in a patient.

27. The use according to claim 26, characterized in that the bisphosphonate compound is alendronate.

28. A process for the preparation of the polymer form according to claim 1 designated form I comprising: stirring a solution of N- [1 (R) - [1,2-dihydro-methanesulfonyl- methanesulfonate form II) espi ro [3 H -indole-3,4 '-piperidin] -l'-yl) -carbonyl] -2- (phenylmethyl-oxy) -ethyl] -2-amino-2-methylpropanamide in isopropanol at about 25 ° C during around 2-24 hours.