 Polymorph of Growth Hormone Secretagogue
专利摘要:
The present invention relates to a method of treating a physiological or medical condition characterized by the fact that in edible animals, the growth of these substances is promoted to make the production of edible meat products more efficient and the lack of secretion of growth hormone in humans, (R) - [(1,2-dihydro-1-methanesulfonylsulfi [3H-indole-3,4 ' Yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate compound. The instantaneous polymorphs can be used in combination with other known forms of N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] -Yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate in terms of thermodynamic stability and suitability for inclusion in pharmaceutical formulations. The present invention also relates to methods of preparing such polymorphs, pharmaceutical compositions comprising these polymorphs as active ingredients, polymorphs of the compounds in the treatment of certain diseases, and uses of these compositions. 公开号:KR19990067098A 申请号:KR1019980703038 申请日:1996-10-23 公开日:1999-08-16 发明作者:제롬 피. 드레이퍼；데이빗 씨. 두보스트；마이클 제이. 카우프만；제임스 에이. 맥컬리；제니퍼 엘. 반드릴라；리차드 제이. 바솔로나 申请人:폴락 돈나 엘.；머크 앤드 캄파니 인코포레이티드； IPC主号:
专利说明:
Polymorph of Growth Hormone Secretagogue BACKGROUND OF THE INVENTION Growth hormone secreted from the pituitary gland stimulates the growth of all tissues of an organism that can grow. Growth hormone is also known to have the following basic effects on the metabolism of an organism: (1) increased protein synthesis rate in all cells of an organism; (2) the reduced use rate of carbohydrates in the cells of the organism; (3) increased utilization of fatty acids for increased mobilization energy of free fatty acids. Deficiencies in growth hormone secretion can cause a variety of medical conditions such as dwarfism. The manner in which growth hormone is released is known in a number of ways. Activities such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin and chemicals such as insulin that causes hypoglycemia, as well as activities such as sleep and exercise, It has been shown to decrease the secretion of growth hormone from the pituitary gland by decreasing hormone secretion or secretion of a known secretion promoter of the growth hormone releasing factor (GRF) or by increasing the known endogenous growth hormone-releasing hormone, Secretion. When it is desired to increase the concentration of growth hormone, the problem is generally solved by administering a protein-based compound that provides exogenous growth hormone or stimulates the formation and / or release of GRF or growth hormone. In this case, the peptide compound of the compound should be administered by injection. First, the source of growth hormone is the pituitary gland extract of the dead body. This is a very expensive product and there is a risk that a disease associated with the source of the pituitary gland may be delivered to the implant of growth hormone. Recombinant growth hormone is still on the market as a very expensive product that should no longer be delivered by injection or nasal spray, while there is no risk of disease transmission. Other compounds have been developed to stimulate the release of endogenous growth hormone. Particular spiro compounds are described in U.S. Patent No. 5,536,716, International Patent Application No. WO 94/13696, and Proc. Natl. Acad. Sci. USA, 92, 7001-7005 (July 1995)] as secretagogues for the secretion of non-peptide growth hormone. These compounds have the ability to stimulate the release of natural or endogenous growth hormone and are used in the production of edible or wool products which are capable of stimulating larger or more productive animals by stimulating growth hormone or a person deficient in natural growth hormone Can be used for treatment conditions that require stimulation of the production or secretion of growth hormone, such as in animals. Among the preferred compounds described in this document are spiro [3H-indole-3,4'-piperidine] 1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] Methyl propanamide methanesulfonate are: < RTI ID = 0.0 > U.S. Patent No. 5,536,716 and International Patent Application No. WO 94/13696 describe the preparation of this compound (see Examples 18, 19 and 55). In particular, Example 55 shows that the melting point of a compound prepared by recrystallization from ethyl acetate-ethanol-water is " 166 to 168 占 폚. &Quot; Such compounds are defined in the literature as polymorphic forms designated as " Form II ". Proc. Natl. Acad. Sci. USA, 92, 7001-7005 (July 1995) describes a very general method for preparing compounds, although the melting point of the compounds to be separated as monohydrate is 168-170 ° C, but does not describe how this compound crystallizes. The morphological form of the pharmaceutical compound is such that when the morphological form is not kept constant during clinical studies and stability studies, the exact dosage used or measured can not be compared with one split and the next split, The interest in the form associated with the development of. Once a pharmaceutical compound is a product for use, it is important to recognize the morphological form in each formulation so that the manufacturing process uses the same form and the same amount of drug is included in each formulation. Thus, it is inferred that there is a single morphological form or a combination of some known morphological forms. In addition, certain morphological forms may exhibit improved thermodynamic stability or hydraulic stability and may be more stable than other morphological forms for inclusion in pharmaceutical formulations. As used herein, a "polymorph" of a compound is the same in chemical composition but different in crystal arrangement. Gist of invention The present invention relates to a process for the preparation of N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] 2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate compound and a process for producing such a polymorph. The present invention also relates to pharmaceutical formulations comprising these polymorphs as active ingredients and to the use of these polymorphs and compositions in treating certain diseases. The polymorph of the present invention promotes the growth of edible animals, thereby making the production of edible meat products more efficient. In a person who is characterized by a deficiency of growth hormone secretion, the polymorph is useful for treating physiological or medical diseases, It is a growth hormone secretagogue useful for treating medical diseases that are improved by the assimilation effect of growth hormone. Such polymorphs may also be used in combination with other known forms of N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] Yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate in terms of thermodynamic stability and suitability for inclusion in pharmaceutical compositions. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel polymorphs of N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidin] ) Carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate compound and a process for preparing such a polymorph. Spiro [3H-indole-3,4'-piperidine] -l'-yl) carbonyl] -2 (2S) - (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide Methanesulfonate is a growth hormone secretagogue containing the release of growth hormone in humans and animals as follows. Such properties can be used to promote the growth of edible animals, make the production of edible meat products more efficient, treat the physiological or medical disorders in persons characterized by a deficiency of growth hormone secretion, RTI ID = 0.0 > a < / RTI > Such a particular polymorph (herein referred to as "Form I", "Form II", "Form III", "Form IV", "Form V", "Form VI", "Form VII" IX ", " Form X ") have superior properties that are more suitable for inclusion in pharmaceutical formulations than other crystalline compounds. Preferred crystalline forms for pharmaceutical compositions are Form I based on thermodynamic stability and non-hygroscopicity. Another preferred crystalline form for pharmaceutical formulation is Form IV, in particular based on its formulation characteristics in relation to compression on tablet formulations. Form IV has been found to have a higher bulk density than other forms. The present invention also relates to a process for the preparation of N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole- -Propyl) -piperidin] -l'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide in methanesulfonic acid (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H) -quinolinone < / RTI > - indole-3,4'-piperidine] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2- methylpropanamide methanesulfonate will be. Optionally, the temperature is sequentially raised to about 51 캜 and maintained for 2 to 24 hours. The present invention further relates to a process for the preparation of N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole- -Propyl) -piperidine] -l'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide in methanol -1,1-dihydro-1-methanesulfonylpyrazolo [3H-indole-3, 4 ' -piperidine] -1 & Methylphenyl) methane sulfonate (where the relative order of addition is not important), about 2 to 15 [1 (R) - [(1, 2-dihydro-1-methanesulfo < / RTI > Yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide Methanesulfonamide Lt; RTI ID = 0.0 > Nate. ≪ / RTI > Further, the present invention relates to a process for the preparation of N- [1 (R) - [(1,2-dihydro-1-methanesulfonyl-spiro [3H-indole-3,4'-piperidine] 2-methylpropanamide methanesulfonate at about 25 < 0 > C for about 2-24 hours, I] N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidin] -1'- yl) carbonyl] -2 - (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate. The present invention also relates to a process for the preparation of N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole- (Approx. 1.1 eq.) Was treated with a solution of the free base of methanesulfonic acid (approx. 1.1 eq.) In dry dichloromethane (R) - [(1, 2-dihydro-1-methanesulfonylpyrazolo [3H-indole < / RTI > -3,4'-piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2- methylpropanamide Methanesulfonate will be. The present invention further relates to the use of a composition comprising an effective amount of the N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [ -Yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide Methanesulfonate was dissolved in a solution of ethanol / water (preferably 25:75 v / v); Evaporating the solvent from this solution, preferably at 40 < 0 >C; Pulverizing the solid to be produced into fine powder; 1 - (1, 2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3, 4 ' - Piperidin] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate. The present invention further relates to the use of a composition comprising an effective amount of the N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [ (Preferably 24.8 / 1.6 / 1.95 v / v / v) of 2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide Methanesulfonate was dissolved in ethyl acetate / ethanol / water - [(1, 2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] -1'- Yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate. In addition, the present invention relates to the use of the N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidin] ) Carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate at a relative humidity of at least about 75%, preferably at least about 88% 1 > - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] Yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate. In addition, the present invention provides N- [1 (R) - [(1,2-dihydro-1- (methylsulfanyl) Yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate (R) - [(1, 2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3 Carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate. In addition, the present invention relates to the use of the N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidin] ) Carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate at ambient temperature to a relative humidity of less than about 30% at ambient temperature. (R) - [(1,2-dihydro-1 -methanesulfonylpyrazolo [3H-indole-3,4'-piperidin] -1'- yl) carbonyl] -2- (phenylmethyloxy) Ethyl] -2-amino-2-methylpropanamide methanesulfonate. The present invention further relates to a process for the preparation of N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] ) Carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate was added to a solution of nitrogen sieved at about room temperature without moisture, -1,2-dihydro-1-methanesulfonylpyrazo [3H-indole-3,4'-piperidine] -1 ' -Yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate. In addition, the present invention relates to the use of N- [1 (R) - [(1,2-dihydroxyphenyl) -1- Yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide Methanesulfonylpyrro [3H-indole-3, 4 ' -piperidine < / RTI > ] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate. The present invention further provides N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] ) Carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate in a suitable inert gas such as anhydrous nitrogen for a sufficient period of time. 1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidin] -1'- yl) carbonyl] -2- ) Ethyl] -2-amino-2-methylpropanamide methanesulfonate. In addition, the present invention relates to the use of an optionally morphological composition of N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] 1-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate was prepared and then formed by evaporation controlled at a relative humidity of 20% 1 ' - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4 ' -piperidine] -1 & -Yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate. In addition, the present invention relates to the use of the N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidin] ) N- (1 (R) -carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate at ambient temperature and humidity for a sufficient time. ) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] Amino-2-methylpropanamide methanesulfonate. ≪ / RTI > In addition, the present invention relates to the use of the N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidin] ) Carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate in 100% relative humidity for about 1 to 4 days. 1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidin] -1'- yl) carbonyl] -2- ) Ethyl] -2-amino-2-methylpropanamide methanesulfonate. Similarly, the present invention also encompasses any of the methods mentioned herein, including morphologically uniform N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [ Yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate. The compound of the present invention, N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] ] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate in a new polymorphic edible animal to promote their growth, making the production of edible meat products more efficient, Is a growth hormone secretagogue useful in treating a physiological or medical disease and treating a medical condition that is improved by the assimilation effect of growth hormone in a person characterized by a deficiency of hormone secretion. The invention thus further relates to pharmaceutical compositions comprising polymorphs as active ingredients and to the use of such polymorphs and their formulations in the treatment of certain diseases. Differential scanning calorimetry cell [DSC] Spiro [3H-indole-3,4'-piperidine] -l'-yl) carbonyl] - lH- The DSC curves of the methanesulfonate were determined by melting at 10 [deg.] C / min in an open cup under a nitrogen flow to a peak temperature of about 180 [deg.] C and about 53 J / lt; RTI ID = 0.0 > 170 C. < / RTI > - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] -1'- yl) carbonyl] - The DSC curve of 2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate has a peak temperature of about 174 DEG C and a melting point of about 37 J / g Lt; RTI ID = 0.0 > 165 C. < / RTI > (1 H) - (1, 2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] -1'- yl) carbonyl] - The DSC curve of the 2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate was found to be about 45 DEG C due to melting at 10 DEG C / min in an open cup under nitrogen flow, And an extrapolated onset temperature (melting point) of about 129 占 폚 due to melting of the heat-related Form VI of about 23 J / g. DSC data [samples are heated under a nitrogen atmosphere (extrapolated onset temperature) at a rate of 10 캜 / min] Form I: 170 占 폚 (melt endotherm) Form II: 165 占 폚 (melt endotherm) Form VI: 129 占 폚 (melt endotherm) (I) - (1, 2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidin] -1'- yl) carbonyl] - 2- (Methylphenyl) ethyl] -2-amino-2-methylpropanamide methanesulfonate is a relatively anhydrous polymorph characterized by the following characteristics: melting point 169 DEG C and solubility in isopropanol 4.6 mg / mL . - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] -1'- yl) carbonyl] - 2- (Methylphenyl) ethyl] -2-amino-2-methylpropanamide methanesulfonate is a relatively anhydrous polymorph characterized by the following characteristics: melting point 158 DEG C and solubility in isopropanol 12.3 mg / mL. - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] -1'- yl) carbonyl] - 2- (Methylphenyl) ethyl] -2-amino-2-methylpropanamide Methanesulfonate is an anhydride characterized by the following properties: a water loss at a peak temperature of 46 DEG C, A small amount of molten / decomposed endotherm with an internal temperature of 123 ° C. (1 H) - (1, 2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] -1'- yl) carbonyl] - 2- (Methylphenyl) ethyl] -2-amino-2-methylpropanamide methanesulfonate is an anhydride characterized by the following properties: a water loss at a peak temperature of 45 DEG C, A small amount of molten / decomposed endotherm with an onset temperature of 129 ° C (estimated due to melting / decomposition of Form VI). (1 H) - (1, 2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] -1'- yl) carbonyl] - Methanesulfonylpyrro [3H-indole < RTI ID = 0.0 > (3H) < / RTI > -3,4'-piperidine] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide To a solution containing 3.5 mol of water per mole of methanesulfonate It appears to be a hygroscopic anhydride. (1 H) - (1, 2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] -1'- yl) carbonyl] - Methanesulfonylpyrro [3H-indole < RTI ID = 0.0 > (3H) < / RTI > -3,4'-piperidine] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methane sulfonate Lt; / RTI > (1 H) - (1, 2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] -1'- yl) carbonyl] - 2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate is an anhydrous polymorph and is characterized by a melting point of 129 占 폚. - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] -l'-yl) carbonyl] - 2- (Methylphenyl) ethyl] -2-amino-2-methylpropanamide methanesulfonate is an anhydride characterized by the following characteristics: extensive water loss at peak temperature 60 ° C, followed by extrapolation onset A small amount of molten / cracked endotherm with a temperature of 144 ° C (presumably due to melting / decomposition of Form VIII). [0154] The compound of formula VIII, N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] 2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate is an anhydrous polymorph and is characterized by a melting point of 144 占 폚. (1 H) - (1, 2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidin] -1'- yl) carbonyl] - 2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate is characterized by a broad water loss endotherm at a peak temperature of 49 占 폚. X-ray powder diffraction (XRPD) X-ray powder diffraction studies are widely used to reveal molecular structure, crystallinity and polymorphism. The X-ray powder diffraction (XRPD) pattern is collected using a Philips APD3720 automated powder diffractometer using copper K Radiation. The measured value is 2 [deg.] To 40 [deg.] (2 [Theta]) for a sample held at ambient room temperature. Form I is characterized by an X-ray powder diffraction pattern having major reflections at about 6.5, 14.7, 16.9, 17.1, 17.9, 19.5, 21.1, 21.7 and 22.0 degrees (2 ). Form II is characterized by an X-ray powder diffraction pattern having major reflections at about 4.8, 11.8, 17.5, 19.4, 21.6, 21.9, 22.5 and 22.7 degrees (2 ). Form III is characterized by an X-ray powder diffraction pattern having major reflections at about 13.8, 14.1, 18.0, 18.8, 19.5, 20.1, 20.6, 21.8 and 25.7 degrees (2 ). Form IV is characterized by an X-ray powder diffraction pattern having major reflections at about 16.0, 16.2, 18.3, 20.1, 21.0, and 24.0 DEG (2 ). Form V is characterized by an X-ray powder diffraction pattern having major reflections at about 14.8, 17.1, 17.6, 19.0, 19.1, 19.4, 20.6, 21.5 and 21.8 degrees (2 ). Form VI is characterized by an X-ray powder diffraction pattern having major reflections at about 9.8, 14.0, 14.8, 17.1, 17.6, 19.0, 19.5, 20.6 and 21.6 degrees (2 ). Form VII is characterized by an X-ray powder diffraction pattern having major reflections at about 9.1, 11.3, 17.1, 17.4, 20.0, 22.1 and 24.5 degrees (2 ). Form VIII is characterized by an X-ray powder diffraction pattern having major reflections at about 11.5, 11.6, 18.1, 19.6, 22.5, 24.7 and 24.8 DEG (2 ). Form IX is characterized by an X-ray powder diffraction pattern having major reflections at about 8.0, 12.1, 15.3, 15.8, 19.6, 19.7, 21.1, 22.3 and 23.7 degrees (2 ). Form X is characterized by an X-ray powder diffraction pattern having major reflections at about 15.5, 15.8, 18.0, 18.4, 18.6, 19.4, 20.7, 20.8, 23.9 and 24.8 degrees (2 ). This XRPD pattern confirms that all Forms I-X are clear crystals. Microscope analysis Polymorphism experiments are performed at magnification 100 under normal light and polarization. Forms I and II are acicular particles. Both Form I and Form II exhibit double refraction under polarized light. Hygroscopic The overall volatile content (as set by TGA analysis) of the solid samples of Forms I, II, III and IV when exposed to various controlled humidity is as shown in the following table. Lt; RTI ID = 0.0 > I < / RTI > Form II contains 0.56 weight% water; 4.5 to 5.0% by weight of water of Form III; And Form IV is comprised between 9.5 and 10.0% by weight of water. Hygroscopicity is measured by storing the solid compound in a chamber of constant relative humidity. Contrasting the anhydrous Forms I and II at room temperature, Form II exhibits hygroscopicity and shows a significant increase in humidity at 65% RH. In Form I, there is virtually no increase in humidity except in the case of storage above 76% RH. The results are shown in the following Tables 1 and 2. Room temperature (48 hours)Form IForm II RH% Absorption / loss% Absorption / loss% 0-0.02+0.08 11-0.05+0.02 33-+0.33 47+0.21+0.39 65+0.37> 10.0 a76+0.12> 10.0 a100> 12.0> 10.0 a, b (a = sample becomes a gummy semi-solid) (b = converted to Form IV if exposed to ambient humidity) Room temperature (48 hours)Form I RH% Absorption / loss% 0+0.4 22+0.3 47+0.5 68+0.6 88+12.9 *100+23.9 * (* = Deliquescent substance) Hydrated forms III and IV of N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] Carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide Methanesulfonate is measured by storage at room temperature for 48 hours in a relative humidity chamber. Form III shows an increase in humidity after storage for 48 hours at 33% RH. Form IV absorbs a small amount of moisture until it is stored at 100% RH, but loses water of the hydrate when stored at less than 11% RH. The results are shown in Table 3 below. Room temperature (48 hours)Form IIIForm IV RH% Absorption / loss% Absorption / loss% 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 above 100 mg / mL. The water solubility (RT) of Form II in the buffered solution (pH 4 to 9) is at least 100 mg / mL. The solubility of Form I in the ethanol / water mixture is as follows: Ethanol / H 2O Solubility (mg / mL) 25/75> 100 50/50> 100 75/25> 90 100% ethanol> 90 Thermal Stability - Pure Compound The solid state stability of pure compounds is measured by storing the drug in the dark in a vial with a screw-cap made of glass. Samples are analyzed by HPLC and the compounds are quantitatively analyzed. The isocratic method used is summarized as follows: Column: Beckman Ultrasphere ODS (250 x 4.6mm, 5μ) Fluid phase: 0.1% TEA, H 3 PO 4 : pH 4.0 using acetonitrile (65:35) Flow rate: 1.0 mL / min Detection wavelength: 228 nm Duration: 14 minutes Column temperature: Ambient temperature [0157] Injection volume: [0158] N- [1 (R) - [(1,2- 2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide Methanesulfonate (50 占 퐂 / mL) The results are shown below for Forms I and II calculated as weight percent. Form I Early% ℃ 6 weeks 17 weeks 40 100.1 98.7 60 100.7 101.3 80 100.7 99.4 Form II Early% ℃ 1 week 2 weeks 4 weeks 8 weeks 12 weeks 24 weeks 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 the thermal stability of pure solid Forms I and II is good. The method for preparing the desired compound is summarized as follows: PhNHNH 2 The CBZ-spiroindole of formula 1 is treated with Darco (20% by weight) prior to hydrogenation as shown in Schemes Ia and Ib. Hydrogenation is carried out with vigorous stirring at 65 [deg.] C in ethanol at 10% Pd / C. Isopropyl acetate and a solution of the compound of formula (Ib) in water is reacted with commercially available N-BOC-O-benzyl-D-serine in the presence of dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole Lt; / RTI > After filtering off the dicyclohexylurea (DCU) byproduct, the 2-phase filtrate is separated and the organic phase is washed successively with 1M aqueous sodium hydroxide solution, 0.5M aqueous hydrochloric acid and finally with saturated aqueous sodium hydrogen carbonate solution. In this coupling, improved results are obtained when a solution of free amino in iPrPAc / H 2 O is treated with DCC, HOBT and then the amino acid is added at ambient temperature and allowed to react for 3 to 5 hours. The batch is concentrated in vacuo and the solvent is changed from isopropyl acetate to ethanol. Such a change of solvent is generally carried out by three times of "feeding and bleeding" three times to remove isopropyl acetate. The BOC-group of the compound of formula 11 is removed by treatment with methanesulfonic acid (MsOH) (3 equivalents) in ethanol at 35-40 <0> C. And partitioned between isopropyl acetate and a 1 M aqueous sodium hydroxide solution to give the compound of formula 12. Coupling of the compound of formula 12 with N-BOC- alpha -aminoisobutyric acid gave the best results in the presence of DCC and HOBt (1.1 equivalents each) in a two phase solvent system, isopropyl acetate / water (1: 1) . The solution of DCU by filtration, separation of layers and washing the organic layer successively with aqueous 1M sodium hydroxide solution, 0.5M aqueous hydrochloric acid and finally saturated aqueous sodium hydrogen carbonate solution yields the compound of formula 14. The mixture is subsequently a solvent that has been changed to ethanol to cleave the Boc group to methanesulfonic acid. Deprotection of the compound of formula 14 is much more difficult than the deprotection of the compound of formula 11 and requires a solution of concentrated ethanol / methanesulfonic acid and heating to 35-40 < 0 > C. After treatment by extraction (EtOAc-NaOH), the free amine of formula (15) is isolated. The organic layer is washed with 1N NaOH to completely remove methanesulfonic acid. The ethyl acetate solution of the free base of formula (15) was concentrated in vacuo to a low volume and azeotroped with ethyl acetate / ethyl acetate twice of the eluent of "feeding and bleeding" three times of 90/10 ethyl acetate / ethanol (KF < 500 mg ml -1 ). The dry, slightly cloudy solution of the free base of formula 15 in ethyl acetate is treated with Darco G-60 (25% by weight) at room temperature for about 10 hours. Removal of the diko by filtration using filter paper yields the free base of formula (15). From the free base of formula 15 the methanesulfonic acid salt of formula 16 is prepared in EtOAc at about 50 < 0 > C with 1.1 equivalents of MsOH. The free base of formula (15) is treated with 8 vol% EtOH and 1 equivalent of H 2 O and is heated to 55 ° C until decomposition is complete. Cooling to ambient temperature and stirring the resulting slurry for 4 hours gives crystalline material 16 designated Crystalline Form II [solubility in IPA 12 mg / mL]. The conversion from Form II to Form I is accomplished when a salt is formed in EtOAc-EtOH as above, but the solution of the salt (at 55 ° C) is cooled to 45 ° C instead of cooling to ambient temperature. The crystals must start to precipitate at this temperature and the slurry becomes thicker with time. The temperature is then raised to 51 DEG C and the slurry aged overnight. Complete conversion to form I, a compound of formula 16, must be achieved. Preferably from Form II to Form I is accomplished by adding the crystals of Form I to a solution of the free base in EtOAc-EtOH at 50-55 占 폚 and aging. Thus, the free base of formula (15) is treated with 1.1 equivalents of methanesulfonic acid in ethyl acetate at 8-8% at 50-55 [deg.] C. The batch is then fed with about 2% by weight of the methanesulfonate salt Form I of Formula 16 and stirred at 55 [deg.] C overnight. The batch is cooled to room temperature and aged for about 2 to 3 hours. The product is isolated by filtration at room temperature under a nitrogen atmosphere, dried in vacuo at 35 < 0 > C and then cried to give the methanesulfonate salt of formula (16). The methanesulfonate salt of formula 16 is also formed by stepwise 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 < 0 > C, The order is not important. The use of the polymorphic compounds of the present invention as growth hormone secretagogues can be carried out as described in the method described in Snith, et al., Science 260, 1640-1643 (1993) (see text of Figure 2 therein) Can be represented by the type analysis known in the prior art. In particular, all of the polymorphs of the present invention possess activity as growth hormone secretagogues in the above-mentioned analysis. These results indicate the intrinsic activity of the polymorph of the present invention as a growth hormone secretagogue. The compounds of the present invention that release growth hormone are useful as a unique mechanism for understanding how secretion of growth hormone is regulated in the pituitary gland in vitro. This includes use in assessing a number of factors known to affect growth, such as age, sex, nutritional factors, glucose, amino acids, fatty acids, as well as secretion of growth hormones such as fixed and non-steady state. The compounds of the present invention may also be used to assess how other hormones alter the growth hormone releasing activity. For example, somatostatin is known to inhibit the release of growth hormone. Other hormones that are important and necessary in relation to the effects on the release of growth hormones include reproductive hormones such as testosterone, estradiol and progesterone; Adrenal hormones such as cortisol and other corticoids, epinephrine and norepinephrine; Pancreas and gastrointestinal hormones such as insulin, glucagon, gastrin, secretin; Vasoactive peptides such as bombesin, neurokinin; And thyroid hormones, such as thyroxine and triiodothyronine. The compounds of the present invention may also be used to investigate possible negative or positive feedback effects, such as growth hormone and endorphin peptides, against some pituitary hormones, such as growth hormone, that alter the release of growth hormone. Of particular interest in science is the use of these compounds to explain the mechanism of the cell that regulates the release of growth hormone. The compounds of the present invention can be administered to animals, including humans, to release growth hormone in vivo. For example, the compounds can be administered to commercially important animals such as pigs, cows, sheep, etc. to enhance the rate and rate of growth, improve feed efficiency and increase milk production in animals . In addition, these compounds can be administered to a human in vivo to directly determine whether the pituitary gland is capable of releasing growth hormone as a diagnostic tool. For example, the compounds of the present invention may be administered to children in vivo. Serum samples taken before and after administration can be analyzed for growth hormone. By comparing the amount of growth hormone in each of these samples, one can directly determine the ability of the patient's pituitary gland to release growth hormone. Accordingly, the present invention includes within its scope pharmaceutical compositions comprising one or more compounds of the present invention as active ingredients in conjunction with a pharmaceutical carrier or diluent. Optionally, the active ingredient of the pharmaceutical composition may contain, in addition to one or more compounds of the invention, an anabolic agent or a different activity, such as an antibiotic growth-permissive substance or an osteoporosis therapeutic agent, or a combination with a corticosteroid to minimize degenerative side effects or other pharmacological activity Other compositions that exhibit a combination with a substance, where the combination improves efficiency and minimizes side effects. Growth promoting agents and anabolic agents include, but are not limited to, TRH, diethylstilbene sterol, estrogen, beta-agonists, theophylline, anabolic steroids, enkephalin, E-series prostaglandins, compounds described in U.S. Patent No. 3,239,345 (E.g., Geranol), the compounds described in U.S. Pat. No. 4,036,979 (eg, Sulbecox), or the peptides described in U.S. Patent No. 4,411,890. In addition, the compounds of the present invention may further comprise growth hormone releasing peptides GHRP-6, GHRP-1 as described in U.S. Patent 4,411,890 and International Application Nos. WO 89/07110, WO 89/07111 and B- As well as growth hormone secretagogues such as GHRP-2 or growth hormone releasing hormone (designated GHRP or GRF) and their analogs as described in WO 93/04081, or growth hormone and its analogs or IGF-1 and IGF -2 or an alpha-adrenergic agonist such as clonidine or a thermotropic agent such as serotonin 5HTID agonists and somatomedin including pyridostigmine. In particular, the compounds of the present invention may be used in combination with growth hormone releasing factors, growth hormone releasing factor homologues, IGF-1 or IGF-2. For example, the compounds of the present invention may be used in combination with IGF-1 for the treatment and prevention of obesity. The compounds of the present invention can also be used in combination with retinoic acid to improve the state of muscles and skin caused by inherent aging. The invention also relates to a method for the preparation of a medicament for stimulating the release of growth hormone in humans and animals, comprising combining the polymorph of the invention with a pharmaceutical carrier or diluent. As is known to those skilled in the art, the known and potential uses of growth hormones are varied and varied. Administration of the compounds of the present invention for the purpose of stimulating the release of endogenous growth hormone can exhibit the same effects and uses as the growth hormone itself. Accordingly, various uses of such compounds of the present invention can be summarized as follows; Treatment of growth hormone deficient adults; Prevention of degenerative side effects of glucocorticoids; Treatment of osteoporosis; Stimulation of the immune system; Promotion of wound healing; Promotion of fracture restoration; Treatment of growth retardation; Treatment of acute or chronic kidney disease or deficiency; Physiologic monotherapy including children with growth hormone deficiency; Short-term therapy associated with clinical disease; Obesity and obesity; Growth retardation therapy associated with Frieder-Willie syndrome and Turner syndrome; Promoting recovery of burn patients and reducing hospitalization or promoting subsequent surgical recovery such as gastrointestinal surgery; Treatment of intrauterine growth retardation and treatment of skeletal disorders, peripheral neuropathy; Replacement of growth hormone in stress patients; Osteoarthritis, schizophrenia, schizophrenia, depression, Alzheimer's disease, delayed wound healing and psychosocial induction; Pulmonary dysfunction and ventilatory dependence therapy; Weakening of protein degenerative response after major surgery; Reduction of cachexia and protein loss due to chronic diseases such as cancer or AIDS; Promoting weight gain and protein adhesion in TPN (total parenteral nutrition) patients; Treatment of hyperinsulinemia with islet cell depletion; Adjunctive therapy for the induction of ovulation and adjuvant therapy for the treatment and prevention of gastric and duodenal ulcers; Promotion of thymus development and prevention of age-related thymus dysfunction; Adjuvant therapy for chronic hemodialysis patients; Treatment of immunosuppressed patients and improvement of antibody response to vaccine; A person associated with an increase in the total lymphocyte count of a person, particularly with consequences of a T 4 / T 8 -cell ratio inhibited from physical trauma, such as on a line near the head, or from a bacterial or viral infection, particularly a human immunodeficiency virus infection The ratio of T 4 / T 8 -cells in the cells; Improvement in muscular strength, motility, maintenance of skin thickness, homeostasis of metabolism, and homeostasis of kidneys in weakened middle-aged and elderly persons; Osteoblasts, bone remodeling and cartilage growth stimulation; Stimulation of the immune system in pets and treatment of old age in pets; Growth promotion in livestock; And stimulation of wool growth in sheep. In addition, the compounds of the present invention are useful for increasing breeding efficiency, for growing and growing, for increasing milk production, and for improving the quality of livestock carcasses. Likewise, the compounds of the present invention are useful in methods of treating diseases or disorders that are ameliorated by the anabolic effects of enhanced growth hormone concentrations, including administration of the compounds of the present invention. In particular, the compounds of the present invention are useful for the prevention or treatment of diseases selected from the group consisting of: osteoporosis; Degenerative disease; An immune deficiency, including those associated with individually suppressed T 4 / T 8 -cell ratios; Hip fracture; Musculoskeletal disorders for elderly people; Growth hormone deficiency in adults or children; Obesity; Cachexia and protein loss due to chronic diseases such as AIDS or cancer; And treatment of recovering patients requiring them from major surgery, wounds or fires. The compounds of the invention may also be used in the treatment of stress-related and anxiety-related disorders, such as diseases induced or promoted by a corticotropin releasing factor or stress-induced depression and headache, abdominal obesity syndrome, immunosuppression, HIV infection, Alzheimer ' , Gastrointestinal diseases, anorexia nervosa, hemorrhagic stress, drug and alcohol withdrawal syndromes, drug addiction and pregnancy disorders. A number of compounds used in an effort to treat a disease or therapeutic use listed above may be known to those skilled in the art. The combination of some of the above-mentioned therapeutic agents with the growth hormone secretagogue of the present invention is further preferable, and a synergistic effect of improving the growth promoting agent, assimilating action and desirable characteristics of these various therapeutic agents often occurs. In such formulations, the therapeutic agent and the growth hormone secretagogue of the present invention may be independently present at a dosage level of 1/100 to 1 times the effective dose when these compounds and the secretagogue are used alone. Combination therapy for the inhibition of bone resorption, prevention of osteoporosis and improvement of treatment of fracture can be represented by the combination of bisphosphonate and the growth hormone secretagogue of the present invention. The use of bisphosphonates for such applications is described, for example, in Hamdy, N. A. T., Role of Bisphosphonates in Metabolic Bone Diseases, Trends in Endocrinlo. Metab., 4, 19-25 (1993). Bisphosphonates having such uses include allendonate, tyluronate, dimethyl-APD, risedronate, etidronate, YM-175, claudronate, pamidronate and BM-210995. Depending on their performance, effective treatment of osteoporosis is achieved by administering 0.1 mg to 5 g of bisphosphonate at a daily oral dose and from 0.01 mg / kg to 20 mg / kg of body weight per day of the growth hormone secretagogue of the present invention. In the case of alendronate, a daily oral dose of 0.1 mg to 50 mg is combined with 0.01 mg / kg to 20 mg / kg of the growth hormone secretagogue of the present invention for the treatment of effective osteoporosis. Osteoporosis and other bone diseases can also be treated using the compounds of the present invention in combination with calcium supplements such as calcitonin, estrogen, raloxifene and calcium citrate. An anabolic effect, in particular in the treatment of male elderly patients, is obtained by using the compounds of the invention in combination with anabolic steroids such as oxymetolone, methyltosterone, fluoxymasterone and stannosol. The compounds of the present invention may be administered by oral, parenteral (e.g. intramuscular, intraperitoneal, intravenous, subcutaneous injection or transplantation), nasal, vaginal, rectal, sublingual or topical routes of administration, ≪ / RTI > Formulations for oral administration include capsules, tablets, pills, powders and granules. In such solid formulations, the active compound is mixed with one or more pharmaceutically suitable carriers, for example sucrose, lactose or starch. Such formulations may also include additional substances that are not typically inert diluents, for example lubricants such as magnesium stearate. In the case of capsules, tablets and pills, the formulations may comprise buffering agents. Tablets and pills may additionally be prepared with enteric coating materials. For oral administration, liquid formulations include inert diluents commonly used in the art such as pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs containing water. In addition to these inert diluents, the compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents and sweetening agents, flavoring agents and flavoring agents. Formulations according to the invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of non-aqueous solvents or excipients are injectable organic esters such as propylene glycol, polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin and ethyl oleate. Such dosage forms may also contain adjuvants such as preservatives, hygroscopic agents, emulsifiers and dispersing agents. They may be sterilized, for example, by filtration through a filter containing bacteria, incorporation of a sterilizing agent into the composition, irradiation of the composition, or heating of the composition. They may also be prepared in the form of sterile solid compositions which can be dissolved immediately prior to use in sterile water or some other injectable sterile medium. Compositions for rectal administration or enamel are preferably suppositories containing excipients such as cocoa butter or suppository waxes other than the active ingredient. Compositions for non-administration or sublingual administration are prepared by standard experiments known in the art. The compounds of the present invention may be administered at a dosage that will provide optimal pharmaceutical efficacy to patients (animals and humans) in need of such treatment. The dosage required for use in any particular application will depend upon the particular compound or composition selected, as well as the route of administration, the nature of the disease to be treated, the age and condition of the patient, the drugs used together, or the particular diet , And other factors known to those skilled in the art, and may eventually be varied according to the physician's instructions. The dosage of the active ingredient in the compositions of the present invention may vary; The amount of active ingredient is required to be such that it is sufficient to obtain a suitable formulation. The dose chosen will depend on the desired therapeutic effect, route of administration and duration of treatment. Generally, a daily dose of 0.0001 to 10 mg / kg of body weight is administered to patients and animals, such as mammals, to obtain effective release of growth hormone. Preferably the dosage is from about 0.001 to about 25 mg / kg per day; More preferably about 0.01 to about 10 mg / kg per day. The method for producing the polymorph of the present invention is shown in the following examples. The following examples are provided for the purpose of describing the present invention and are not to be construed as limiting the scope or spirit of the present invention. Example 1 1'-yl) carbonyl ] 2- (phenyl) -1,2 -dihydro-1 -methanesulfonylpyrazolo [3H-indole-3,4'-piperidin] Methyloxy) ethyl] -2-amino-2-methylpropanamide Step A: 1,2- dihydro-1-methanesulfonate Nils fatigue [3H- indole-3,4'-piperidin] hydrochloric fluoride 3-methyl-1,2-dihydro-spiro [3H-indole-3,4'-piperidine] (H. Ong. Et al., J. Med. Chem., 23, (0.90 mL; 6.4 mmol) and methanesulfonyl chloride (0.49 mL; 6,35 mmol) at 0 < 0 > C were added to a solution of 1.20 g (5.8 mmol) And stirred for 30 minutes. The reaction mixture is poured into 15 mL of a saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (2 x 10 mL). The combined organics were washed with brine (20 mL), dried over anhydrous potassium carbonate, filtered and the solvent removed under reduced pressure to yield 1.44 g of the methanesulfonamide derivative as a pale yellow oil, which was used without purification. To a solution of the above crude product in 20 mL of anhydrous 1,2-dichloromethane was added 1.0 mL (9.30 mmol) of 1-chloroethyl chloroformate at 0 ° C, stirred at room temperature for 30 minutes and finally stirred under reflux for 1 hour . The reaction mixture is concentrated to about 1/3 volume, diluted with 20 mL of anhydrous methanol and refluxed for 1.5 hours. The reaction is cooled to room temperature and concentrated to about 1/2 volume. The precipitate is filtered off and washed with a small amount of cold methanol. This gives 1.0 g of piperidine HCl as a white solid. The filtrate is concentrated, a small amount of methanol is added, and ether is added. The precipitated material is filtered once more, washed with cold methanol and dried. This gives an additional 0.49 g of the desired product. Overall yield 1.49 g (70%). 1 H NMR (CDCl 3, 200MHz ) δ 7.43-7.20 (m, 3H), 7.10 (dd, 1H), 3.98 (bs, 2H), 3.55-3.40 (bd, 2H), 3.35-3.10 (m, 2H) , 2.99 (s, 3H), 2.15 (t, 2H), 2.00 (t, 2H) Step B : Synthesis of N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] 2- (phenylmethyloxy) ethyl] -2 - [(1,1-dimethylethoxy) carbonyl] amino-2 -methylpropanamide To a solution of (2R) -2 - [(1,1-dimethylethoxy) carbonyl] amino-3- [2- (phenylmethyloxy) ethyl] -1-propanoic acid in 13 mL of dichloromethane was added 1,2- (0.325 g; 1.07 mmol), N-methylmorpholine (0.18 mL, 1.63 mmol), 1-hydroxybenzaldehyde 0.159 g (1.18 mmol) of triazole (HOBT) was added and stirred for 15 minutes. EDC (0.31 g; 1.62 mol) was added and stirring was continued for 1 hour. Add 60 [mu] L of N-methylmorpholine and stir for 45 minutes. The reaction mixture is poured into 5 mL of water and the organic layer is separated. The organic layer is washed with 5 mL of 0.5N aqueous hydrochloric acid and 5 mL of a saturated aqueous sodium bicarbonate solution. The combined organics were dried over anhydrous potassium carbonate, filtered and concentrated to give 0.627 g of product as a yellow foam which was used without purification. 1.0 mL of trifluoroacetic acid was added to a solution of 0.627 g (1.07 mmol) of the above product in 5 mL of dichloromethane, and the mixture was stirred at room temperature for 75 minutes. Add 1.00 mL of additional trifluoroacetic acid and stir for 10 minutes. The reaction mixture is concentrated, diluted with 5.0 mL of dichloromethane and carefully basicized with 10 mL of 1% aqueous sodium carbonate solution. The organic layer was separated and the aqueous layer was further extracted with 2 X 15 mL of dichloromethane. The combined organics were washed with 5 mL of water, dried over anhydrous potassium carbonate, filtered and concentrated to give 0.486 g of amine as a pale yellow foam which was used without purification. (1.28 mmol) of 2 - [(1,1-dimethylethoxy) carbonyl] amino-2-methyl-propanoic acid, 1-hydroxybenzotriazole (1.28 mmol) of EDTA (HOBT) and EDC (0.245 g; 1.28 mol), and the mixture was stirred at room temperature overnight. The reaction mixture is poured into 5.0 mL of water and the organic layer is separated. The aqueous layer is extracted with 5 mL of dichloromethane. The combined organics were washed with 0.5N aqueous hydrochloric acid, 5 mL saturated aqueous potassium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated to give 0.751 g crude product as a yellow foam. A solution of this crude product in dichloromethane is chromatographed on silica gel (25 g) and eluted with hexanes / acetone / dichloromethane (70/25/5) followed by hexane / acetone / dichloromethane (65/30/5). 0.63 g of the title compound was obtained as a white solid. 1 H NMR (CDCl 3 , 400 MHz) The compound is present as a mixture of 3: 2 rotamers. (m, 6H), 7.06 (d, 1/3H), 7.02 (t, 1/3H), 6.90 (t, 1/3H), 6.55 (Bd, 1H), 4.95 (bs, 1H), 4.63 (bd, 1/3H), 4.57-4.40 (s, 1H), 2.86 (s, 1H), 2.80-2.60 (m, 2H), 3.78-3.62 1H), 1.45 (s, 4H), 1.42 (s, 2H), 1.90 (bs, 1H), 2.85-2.75 (m, 1H), 1.82-1.60 ), 1.39 (s, 9H) Step C : Preparation of N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] 2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide hydrochloride To a solution of 0.637 g (0.101 mmol) of intermediate from Step B in 5 mL dichloromethane was added 2.5 mL of trifluoroacetic acid and stirred at room temperature for 30 minutes. The reaction mixture is concentrated to an oil, treated with 10 mL of ethyl acetate and washed with 8 mL of 10% aqueous sodium carbonate solution. The aqueous layer is further extracted with 5 mL of ethyl acetate. The combined organics were washed with 10 mL water, dried over anhydrous magnesium sulfate, filtered and concentrated to give 0.512 g of the free base as a white foam. To 0.512 g of the free base in 5 mL of ethyl acetate is added 0.2 mL of saturated hydrochloric acid in ethyl acetate at 0 DEG C and the mixture is stirred for 1.5 hours. 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 H NMR (400 MHz, CD 3 OD) compound exists as a mixture of 3: 2 rotamers. 3H), 6.80 (d, 1/3H), 5.16 (ddd, 1 H), 7.30-7.28 (m, 4H), 7.25-7.17 1H), 2.97 (s, 1H), 4.60-4.42 (m, 3H), 4.05 , 2.95 (s, 2H), 2.90-2.78 (m, 1H), 1.96 (t, 1/3H), 1.85-1.65 Example 2 Carbonyl] -2- ((4 -methylpiperazin-1-yl) -1H -pyrazolo [ Phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide Step A: (2R) - [[ [- 2- (1,1- dimethyl-ethoxy) carbonyl] amino] -2,2-dimethyl-1-oxyethyl] Oh diamino-2- (phenylmethyl) ethyl ] -1-propanoic acid allyl ester A propanoyl acid and allyl CH 2 Cl 2 of the coupling reaction in the presence of EDC DMAP from alcohols - (2R) -2 [(1,1- dimethyl-ethoxy) carbonyl] amino-3- (phenylmethyl) ethyl . 1 H NMR (400MHz, CDCl 3 ) δ 7.25 (s, 5H), 5.8 (m, 1H), 5.2 (dd, 2H), 5.0 (bs, 1H), 4.7 (m, 1H), 4.6 (m, 2H ), 4.4 (dd, 2H), 3.9 (dd, 1H), 3.6 Step B: (2R) - [[ [- 2- (1,1- dimethyl-ethoxy) carbonyl] amino] -2,2-dimethyl-1-oxyethyl] Oh diamino-2- (phenylmethyl) ethyl ] -1-propanoic acid To a stirred solution of the crude intermediate obtained in Step A (6.7 g 15.9 mmol), tetrakis (triphenylphosphine) -palladium (1.8 g 0.1 equiv) and triphenylphosphine (1.25 g 0.3 equiv) -Ethyl hexanoate (35 mL, 0.5 M in EtOAc) is added. The reaction mixture is stirred at room temperature under a nitrogen atmosphere for 1 hour, diluted with ether (100 mL) and poured into cold water. The organic layer is separated and the aqueous fraction is acidified with citric acid (20%) and extracted with EtOAc. The EtOAc extract is washed with brine, dried over magnesium sulphate, filtered and evaporated to give the title compound as a solid. 1 H NMR (400MHz, CD 3 OD) δ 7.3 (s, 5H), 4.7 (m, 1H), 4.5 (s, 2H), 4.0 (m, 1H), 3.6 (m, 1H), 1.4 (d, 6H), 1.3 (s, 9H) Step C : Preparation of N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] 2- (phenylmethyloxy) ethyl] -2 - [(1,1-dimethylethoxy) carbonyl] amino-2 -methylpropanamide To a solution of 1.0 g (3.44 mmol) of 1-methanesulfonylpyrro [indoline-3,4 ' piperidine] hydrochloride in 50 mL of dichloromethane, (2R) -2 - [(1,1-dimethylethoxy) carbonyl] (3.78 mmol), N-methylmorpholine (0.58 mL; 5.20 mmol), and N, N-dimethylformamide EDC (1.03 g; 5.20 mmol) was added to a solution of 1-hydroxybenzotriazole (HOBT) (0.58 g; 3,78 mmol) and stirred at room temperature for 16 hours. The reaction mixture is diluted with 50 mL of dichloromethane, washed with saturated aqueous potassium bicarbonate (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The crude oil residue was purified by flash chromatography (silica gel 50 g) to give 2.148 g (90%) of the title compound as a colorless foam. 1 H NMR (400 MHz, CD 3 OD) compound exists as a mixture of 3: 2 rotamers. (m, 6H), 7.06 (d, 1/3H), 7.02 (t, 1/3H), 6.90 (t, 1/3H), 6.55 (Bd, 1H), 4.95 (bs, 1H), 4.63 (bd, 1/3H), 4.57-4.40 (s, 1H), 2.86 (s, 2H), 2.80-2.60 (m, 2H), 3.78-3.62 1H), 1.45 (s, 2H), 1.42 (s, 2H), 1.90 (bs, 1H), 2.85-2.75 (m, 1H), 1.82-1.60 ), 1.39 (s, 9H) Step D : Synthesis of N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] 2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide hydrochloride To a solution of 2.148 g (3.41 mmol) of the intermediate from Step C in 10 mL dichloromethane is added 5 mL trifluoroacetic acid and stirred for 1 hour. The reaction mixture is concentrated, basified with 100 mL of 5% aqueous sodium carbonate solution and extracted with dichloromethane (3X50 mL). The combined organics were washed with brine (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 is added 4 mL of 1 M hydrochloric acid in ethyl acetate at 0 < 0 > C. The precipitate was filtered and washed first with ethyl acetate followed by ethyl acetate-ether (1: 1) and dried to give 1.79 g (93%) of the title compound as a colorless solid. 1 H NMR (400 MHz, CD 3 OD) compound exists as a mixture of 3: 2 rotamers. 3H), 6.80 (d, 1/3H), 5.16 (ddd, 1 H), 7.30-7.28 (m, 4H), 7.25-7.17 1H), 2.97 (s, 1H), 4.60-4.42 (m, 3H), 4.05 , 2.95 (s, 2H), 2.90-2.78 (m, 1H), 1.96 (t, 1/3H), 1.85-1.65 Example 3 Carbonyl] -2- ((4 -methylpiperazin-1-yl) -1H -pyrazolo [ Phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide mesylate This compound is prepared by treating the free base obtained in Step D of Example 5 with methanesulfonic acid. The title compound is obtained by recrystallization from ethyl acetate-ethanol-water. The melting point is 166 to 168 占 폚. This sample is subsequently defined as polymorph II. It is characterized by an X-ray powder diffraction pattern having major reflections at about 4.7, 11.6, 17.4, 19.2, and 21.6 degrees (2 &thetas;). (Melting temperature) relating to heat of about 174 DEG C and about 37 J / g due to single melting by DSC at 10 DEG C / min in an open cup under nitrogen flow. . Example 4 (3) Isocyanic acid-N-benzylcarbamate (3) material: Isonipecotic acid (2) T.C.I. 4.02 kg (31.1 mol) 6.91 kg (40.5 mol) of benzyl chloroformate (Schweitzerhall) K 2 CO 3 10.1 kg (72.9 mol) Water 40.2L Isonipecotic acid of formula (2) and K 2 CO 3 are dissolved in 40.2 L of water under N 2 with mechanical stirring in a 100 L four-necked flask and the solution is cooled to 10 ° C. Benzyl chloroformate is added while maintaining the temperature at 9-14 [deg.] C and the mixture is warmed to 22 [deg.] C after addition is complete and aged for 58 hours. The addition is complete after 4 hours of pH of 9.0. After aging for 58 hours, there is no change in pH. The reaction mixture is transferred to an extractor of 200 L capacity and washed with 3 x 13 kg of IPAC (15 L) and 12 L of EtOAc. The aqueous layer is extracted with 8 L of toluene. After washing, the benzyl alcohol content is reduced from 3.8% to 1.4% by HPLC analysis. HPLC analysis: a DuPont gore-box 25 cm RXC8 column detected at a flow rate of 1.5 mL / min and 254 nm; An isocratic mixture of MeCN 35%, 0.1% aqueous H 3 PO 4 65%; Retention time: compound of formula 3 = 6.9 min, benzyl alcohol = 3.3 min, toluene = 17.3 min. The aqueous phase is acidified to pH 1.8 with 37% aqueous HCl. Carbon dioxide is released during the application of HCl, but evaporation of the gas is easily controlled. HCl is added for less than 1 hour and 10 L of concentrated HCl is needed. The aqueous phase is extracted with 3 x 6.6 L of toluene. The toluene extract is dried with 2 kg of sodium sulfate and filtered through a pad of Solka-floc ( TM ). The weight of the combined filtrate is 17.8 kg. The crude yield of the carbamate of formula (3) is 7.89 kg (97%) (as obtained by evaporating the metered fraction of the filtrate to anhydrous). The filtrate is transferred to a 100L flask through a 10 mu inline filter. The extract is concentrated at a volume of 18 L at less than 25 ° C at 10 mbar. The final concentration of the carbamate of formula (3) is 448 g / L. The toluene filtrate concentrate is then slurried to azeotropically remove the final traces of water (final KF = 170 mg / L). The product is 99.1% by area, which is 0.9% by area of benzyl alcohol as an impurity. Example 5 Formula 4 Isonipecotic acid chloride-N-benzylcarbamate (4) material: 7.93 kg (30.0 mol) of isonipecotic acid N-benzylcarbamate (3) 17.9 L of toluene (MW-263.30) Oxalyl chloride (MW = 126.93) 3.94ZL (31.0mol) DMF (MW = 73.10) 10 mL 12 L of toluene To the toluene solution of the benzyl carbamate of formula (3) from the preceding step is added 5 mL of DMF and 10 L of toluene. Oxalyl chloride is added over 20 minutes. The reaction mixture is aged under a slow stream of nitrogen at < RTI ID = 0.0 > 18 C < / RTI > HPLC analysis of the reaction mixture shows that 1,3% of the carboxylic acid of formula (III) still remains unreacted. The reaction mixture is heated to 26 DEG C and 5 mL of DMF is added. The mixture is aged for 2.5 hours. 1.0 mL of the reaction mixture was quenched with 5.0 mL of tert-butylamine and analyzed by evaporation followed by HPLC: a DuPont gore box 25 cm RXC8 column, detected at a flow rate of 1 mL / min and 220 nm; An isocratic mixture of MeCN 42%, 0.1% aqueous H 3 PO 4 58%. This method shows that the acid of formula (3) remains less than 0.05% (determined as the compound of formula (A)) and represents 3% by area or more of the compound of formula (B) (1 mol% or more (COCl) 2 ). The mixture is concentrated at 10 mbar and at a temperature of 20-25 < 0 > C until 5 L of the solvent is removed. Typical HPLC characteristics of a concentrated toluene solution after quenching with t-BuNH 2 as described above are as follows: Retention time (minutes) area% matter 2.1 < 0.5% < RTI ID = 0.0 > 7.8 < 0.5% benzyl chloride 11.0 > 99% Cbz-t-butyl carboxamide of formula A 12.1 NA toluene 12.7 < 0.5% Di-tert-butyloxamide of formula (B) Example 6 Formula 5 Piperidine-4-carboxaldehyde-1-benzylcarbamate (5) material: Isonipecotic acid chloride 3.38 kg (12.0 mol) of N-benzylcarbamate (4) 5.54 kg of toluene (MW-281.74) 1.55 kg (15.0 mol) of DIEA (KF = 18 mg / L) Pd / C 10% (KF < 20mg / g) 101g Thioanisole (MW = 124.21, d = 1.058) 0.56 g DIEA and thioanisole are added to a solution of the compound of formula 4 in toluene from the preceding step and the crystals are suspended in this mixture. The mixture is immediately placed in a 5- gallon autoclave and hydrogenated at 20 < 0 > C and H240 at 40 pci. After 18 hours, the reaction product was treated with 70% of the theoretical amount of hydrogen and quenched with tert-butylamine. HPLC analysis showed that 14.2% by area of the acid chloride of formula (2) remained. The HPLC conditions are as above. Retention time: compound of formula 5 = 8.1 min. The catalyst (101 g) and thioanisole (0.54 g) in the second charge are added to the hydrator as a slurry in 1375 mL of toluene. HPLC analysis of the fraction quenched with tert-butylamine after 23 hours shows 1.8 area% of the acid chloride of formula (2) remained. The mixture is purged with nitrogen and the catalyst and precipitated DIEA 占 Cl HCl are removed by filtration through a Socar-floc. The filter cake is washed with 10 L of toluene. The filtrate is transferred via a 10μ inline filter to a 50L capacity extractor and washed with 1M aqueous HCl 2 x 7.2L and water 2 x 7.2L. The mixture is concentrated at 10 mbar and a temperature of 25-30 < 0 > C until 5 L of residue remains. Retention time (minutes) area% matter 2.1 < 2 carboxylic acid 3 6.6 < 1 dimer 21 8.1> 95% Aldehyde 5 The analytical yield of the aldehyde of formula (3) is 94% by HPLC analysis. Example 7 Formula 9 CBZ-Spiroindoline (9) material: Piperidin-4-carboxaldehyde-1-benzyl 1.71 kg (6.89 mol) 21.4 kg of carbamate (5) in toluene solution 900 mL of phenylhydrazine, 981 g (9.15 mol) 2.20 L of trifluoroacetic acid (TFA), 3.26 kg (28.6 mol) 300 g of NaBH 4 , (7.93 mol) 34.4 kg of toluene MeCN 7.0L 7.0 L of MeOH From the preceding step, the crude aldehyde solution of formula 5 is transferred via a 10 micron inline filter to a 100 L capacity reactor equipped with a Teflon coated copper coil for cooling or heating and equipped with a mechanical stirrer. Toluene (34.4 kg) and MeCN (7 L) were added and the resulting solution was cooled to 0 < 0 > C. The phenylhydrazine is aliquoted and the temperature is maintained at 1-3 ° C while continuously bubbling nitrogen through the reaction mixture. TLC and HPLC analysis of the phenylhydrazine showed complete consumption of the aldehyde of formula 5 and added until a slight excess (<5%) of phenylhydrazine appeared. TLC conditions: silica E. Merck Kieselgel G60 F254 0.25 mm; Diethyl ether / pentane (4/1); And developing agent 0.5% cerium sulfate, 14% ammonium molybdate in 10% aqueous sulfuric acid; Room temperature; Aldehyde of Formula 5 = 0.52, phenylhydrazone of Formula 7 = 0.61, phenylhydrazine of Formula 6 = 0.21. HPLC conditions: a DuPont gore box 25 cm RXC8 column detected at a flow rate of 1.0 mL / min and 254 nm; Gradient Schedule: Time (minutes) Acetonitrile: water 0 57:43 10 65:35 15 75:25 18 75:25 Retention time: phenylhydrazine of Formula 6 = 4.5 minutes, toluene = 7.2 minutes, phenylhydrazone of Formula 7 = 11.4 minutes The reaction mixture is aged at 0-2 < 0 > C for 30 min and TFA is added maintaining the temperature at 2-7 [deg.] C. The reaction mixture is warmed to 50 < 0 > C over 30 minutes and maintained for 17 hours. The nitrogen sparge is stopped through the reaction mixture and a slow stream of nitrogen is maintained throughout the reaction mixture. The color gradually darkens to dark green at 5 ° C for 1 hour and forms a relatively small amount of white crystalline precipitate (ammonium trifluoroacetate). After 17 hours, HPLC analysis (same conditions as above) shows that 91.6% of indolenine of formula 8 and 1.5% of unreacted phenylhydrazone remain in the reaction mixture. Aging the mixture for a longer period of time does not increase the analytical yield of indolenine of formula (8). The reaction mixture is cooled to 12 [deg.] C and 7.0 L of MeOH is added. Add NaBH 4 to a small fraction (< 20 g) while keeping the temperature below 15 ° C. The addition is carried out for 30 minutes. Evaporation of mild hydrogen is observed during the addition, but this is easily controlled and virtually non-bubbling. When the addition is almost complete, the color rapidly changes from green to brown to light orange. Separate a small amount (<200 mL) of the heavier phase (presumable aqueous salt). HPLC analysis (conditions as before) indicates that all indolenines of formula 8 are consumed (CBZ-indoline 90.4 area% of formula 9); Retention time: indolenine of formula (8) = 7.5 minutes, indoline of formula (9) = 8.2 minutes. TLC: ethyl ether, cerium sulfate, ammonium molybdate stain or 1% anisaldehyde stain as solvent; Maintenance factor: indolenine of formula (8) = 0.18, CBZ-indoline of formula (9) = 0.33). The color change from green to orange corresponds to the final point of the reaction which is very close. The amount of NaBH 4 to the need to complete the reaction depends mainly on the temperature and rate of addition of NaBH 4, but the yield and quality of the product is not subject to little effect on the condition that the reaction is complete. The reaction mixture is cooled to 5 < 0 > C over 30 minutes. 8 L of 3% aqueous NH 4 OH (8 L) is then added to bring the pH of the aqueous phase to 7.4 and the mixture is stirred and fixed. The temperature is raised to 15 占 폚. Separate low aqueous phase on yellow cloud. The organic phase is washed with 4 L of aqueous 3% NH 4 OH, 2 x 4 L of water and 2 x 4 L of brine. After washing, the weight of the organic phase is 53.5 kg and the analysis yield is 94%. The toluene solution to be cleaned is combined with the washed organic phase of the two reactants, which are similarly prepared. The total aldehyde used in the three reactions is 5.06 kg (20.5 mol). The total weight of the CBZ-indoline of formula (9) analyzed in the combined organic phase is 5.91 kg (18.3 mol, 90% analytical yield). The combined organic phases are dried with 5 kg of sodium sulfate, treated with 250 g of Darco G60 carbon for 30 min, and filtered through a Solka floc. The filtrate is concentrated in vacuo at <10 mbar and <25 <0> C until the residue is almost anhydrous. Solvent switching is completed by slowly bleaching in 30 L of IPAC and re-concentrating at 200 mbar and 50-60 占 폚. The mixture is heated under reflux to obtain a clear, homogeneous dark green solution. The 1 H MNR analysis shows that after the solvent change the solution contained about 6 mol% residual toluene. The solution is cooled to 68 [deg.] C and seeded with 4 g of CBZ-indoline of crystalline formula 9. The solution is slowly cooled over 6 hours and aged at 20-26 < 0 > C for 9 hours. The slurry is cooled to 2 DEG C over 1 hour and aged at 2 DEG C for 1 hour. The product is separated by filtration and the filter cake is washed with 2 x 2 L of IPAC at 5 [deg.] C and 2 x 2 L of MTBE at 5 [deg.] C. The product was dried in a vacuum oven at 30 < 0 > C under nitrogen bleeding to give 4.37 kg (74%) of the title compound of formula 9 as a slightly browned crystalline powder. HPLC analysis of the product shows a purity of 99.5 area%. The mother liquor (11L) and wash water contain 1.15 kg (19%) of the product of formula (9) and about 3% of Cbz-isonipecotic acid phenylhydrazide (retention time = 4.8 min). Example 8 Formula 1 CBZ-Spiroindoline-methanesulfonamide (1) < RTI ID = 0.0 > material: 1.69 kg (5.23 mol) of CBZ-spiroindoline (9) Methanesulfonyl chloride (599 g, 5.23 mol) Et 3 (KF = 151) 635 g 96.27 mol) THF (KF = 41) 12 L A 22 L flask was charged with CBZ-spiroindoline of solid formula 9 and 11.5 L of THF and Et 3 N were transferred to the flask via a 10 micron inline filter. The resulting homogeneous solution is cooled to 0 < 0 > C. A 1 L dropping funnel is charged with 500 mL of methanesulfonyl chloride and THF. A solution of MsCl in THF is added to the reaction mixture while maintaining the temperature at 0-4 < 0 > C. The addition takes 5 hours and is endothermic. A white precipitate is formed which is believed to be triethylammonium hydrochloride. HPLC analysis indicates that the reaction is terminated at the end of the addition (the compound of formula 9 is not detected). HPLC conditions: a DuPont gore-box 25 cm RXC8 column detected at a flow rate of 1.5 mL / min and 254 nm; Gradient Schedule: Time (minutes) 0.1% aqueous H 3PO 4: MeCN 0 70:30 3 70:30 12 20:80 25 20:80 Retention time: compound of formula 9 = 7.6 min, 1 = 13.6 min. After the addition is complete, the reaction mixture is warmed to 18 < 0 > C and aged for 16 hours. There is no change in the HPLC characteristics between the end of the reaction mixture and the end of the addition and after 16 hours of aging. The reaction mixture is slowly added over a period of 1 hour in a 50 L capacity flask in a solution of 30 L of water and 200 mL of 37% aqueous HCl stirred vigorously. In a 50 L flask, the temperature is raised from 22 to 28 占 폚. The product is separated into a slightly soaked gonadal solid which turns into a granular solid. The aqueous suspension is cooled to 22 [deg.] C and aged for 1 hour. The suspension is filtered and the filter cake is washed with 2 x 4 L MeOH / water (50/50). HPLC analysis indicates that < 0.1% of CBZ-spiroindoline methanesulfonamide of formula 1 is the mother liquor. The filter cake is washed with 4 L of MeOH / water (50/50) with 50 mL of 28% aqueous NH 4 OH. The filter cake was washed with 2 x 4 L MeOH / water (50/50) and the solids were dried under nitrogen bleeding in a vacuum oven at 50 < 0 > C to yield 2.03 kg (97%) of the title compound as a white powder as a white powder. HPLC analysis of the solid gives 93.7% area by weight of Compound 1. [ Example 9 8 Any process for the separation of intermediates CBZ-Spiroindolenine (8) material: (0.050 mol) of piperidine-4-carboxaldehyde-1-benzylcarbamate (5) Phenylhydrazine 5.45 (0.050 mol) 11.56 mL of trifluoroacetic acid (TFA), 17.10 g (0.150 mol) Methylene chloride 500 mL The CBZ-aldehyde of formula (5) is dissolved in dichloromethane in a 1 L capacity flask equipped with a Teflon coated magnetic stirrer bar. The resulting solution is cooled to 0 < 0 > C. The phenylhydrazine is added via a weighing syringe over a period of 5 minutes and the temperature is maintained at 1-3 ° C while continuously bubbling nitrogen through the reaction mixture. TLC and HPLC analysis showed complete consumption of the aldehyde of formula 5 and continued until a slight excess (<2%) of phenylhydrazine appeared. TLC conditions: silica E. Merck Kieselgel G60 F254 0.25 mm; Diethyl ether / pentane (4/1); And developing agent 0.5% cerium sulfate, 14% ammonium molybdate in 10% aqueous sulfuric acid; Room temperature; Aldehyde of Formula 5 = 0.52, phenylhydrazone 7 = 0.61, phenylhydrazine of Formula 6 = 0.21. HPLC conditions: a DuPont gore-box 25 cm RXC8 column, detected at a flow rate of 1.0 mL / min at 30 DEG C and at 254 nm; Gradient Schedule: Time (minutes) Acetonitrile: water 0 57:43 10 65:35 15 75:25 18 75:25 Retention time: phenylhydrazine of Formula 6 = 4.5 minutes, toluene = 7.2 minutes, phenylhydrazone of Formula 7 = 11.4 minutes The reaction mixture is aged at 0-2 < 0 > C for 10 min and TFA is added maintaining the temperature at 2-7 [deg.] C. The reaction mixture is allowed to warm to 35 [deg.] C over 30 minutes and maintained for 17 hours. The nitrogen sparge is stopped through the reaction mixture and a slow stream of nitrogen is maintained throughout the reaction mixture. At 1 hour at 35 ° C, the color gradually rose to rosy pink and dark green to form a relatively small amount of white crystalline precipitate (ammonium trifluoroacetate). After 17 hours, HPLC analysis (same conditions as above) shows that 93% by area of indolenine of formula 8 and 0.5% of unreacted phenylhydrazone remain in the reaction mixture. Aging the mixture for a longer period of time does not increase the analytical yield of indolenine of formula (8). The reaction mixture is cooled to 10 DEG C and a mixture containing 28 to 30% ammonium hydroxide 60 mL, water 90 mL and crushed ice 150 g is added with good stirring. The color of the mixture changes to light blue. The organic phase is separated and washed twice with 400 mL water and 100 mL aqueous saturated NaCl. The organic phase is dried over magnesium sulfate and filtered through a plug of 5 g of silica. The filtrate is evaporated to give 15.84 g (99%) of indolenine of formula 8 as a pale orange oil. Example 10 Formula 1 Preparation of CBZ-spiroindoline-methanesulfonamide of formula (1) without separation of CBZ-spiroindoline of intermediate 9 Step 1: CBZ-Spiroindoline (9) material: (0.20 mol) of piperidine-4-carboxaldehyde-1-benzylcarbamate (5) 23.7 g (0.22 mol) of phenylhydrazine (Aldrich) 75.4 g (0.66 mol) of trifluoroacetic acid (TFA) 654 mL of toluene (KF < 250 mg / L) MeCN (KF < 250 mg / L) 13.3 mL NaBH 4 11.3g (0.30mol) 20 mL of toluene MeOH 50 mL A 2% (by volume) solution of MeCN in toluene is prepared using 654 mL of toluene and 13.3 mL of MeCN. A nitrogen stream is passed through the solution in a 2 L three-necked flask equipped with a mechanical stirrer for 5 minutes to remove 617 ml of the above solution. Phenylhydrazine and TFA are added to this mixture while degassing. The CBZ-aldehyde 5 is dissolved in the remainder (5 mL) of the solution prepared above and degassed by bubbling nitrogen through the solution in the addition funnel. In the flask the solution is heated to 35 DEG C and the aldehyde solution is slowly added to the phenylhydrazine-TFA over 2 hours. The mixture is aged at 35 < 0 > C for 16 hours. HPLC conditions: DuPont Gore Box 25 cm RXC8 column detected at flow rate 1 mL / min and 220 nm at 50 < 0 >C; Isocyclic 55% MeCN, 0.1% aqueous H 3 PO 4 45%. Typical HPCL after aging for 16 hours Features: Retention time (minutes) area% matter 1.6 0.1-0.5 The phenylhydrazine of formula 6 4.1 <0.1 dimer 21 4.7 <0.1 Aldehyde of formula (5) 5.0 NA Spiroindoline of formula (9) 6.3 NA toluene 6.9 97 Spiroindolenine of formula 8 10.3 < 0.2 phenylhydrazone of formula (7) 2-3tot other impurities <each 0.2% The mixture is cooled to -10 < 0 > C and MeOH is removed. A suspension of sodium borohydride in 20 mL of toluene is added to a small portion (1 mL) over 30 minutes, taking care not to let the temperature fall below -2 ° C. area% matter 0.1-1 phenylhydrazine of formula 6 85-90 CBZ-spiroindoline of formula 9 <0.1 CBZ-Spiroindolenine of Formula 8 10-15tot other impurities (<3% each) The temperature is raised to 10 < 0 > C over 1 hour and 6% aqueous ammonia (200 mL) is added. The mixture is stirred for 10 minutes and held for a further 10 minutes and the lower aqueous phase is removed. Add acetonitrile (20 mL) and MeOH (20 mL) to the organic phase and wash it with 150 mL of 15% brine. The organic phase shows an analysis yield of 92% of CBZ-spiroindoline of formula (9). Step 2 : CBZ-Spirooindol-methanesulfonamide (1) material: CBZ-Spiroindoline 9 (MW = 322.51) (0.184 mol) 21.1 g (0.184 mol) of methanesulfonyl chloride, DIEA (KF = 150 mg / L), 40.1 mL (0.230 mol) THF (KF = 41 mg / L) 150 mL The crude CBZ-spiroindoline crude solution of Formula 9 from Step 1 above is concentrated in a 1 L three-necked flask (60-70 占 폚 150-200 Torr) until 250 g of residue remains. THF and DIEA are added and the remaining homogeneous solution is cooled to 0 < 0 > C. A 125 mL dropping funnel is charged with 50 mL of methanesulfonyl chloride and THF. A solution of MsCl in THF is added to the reaction mixture over 2 hours maintaining the temperature at 0-4 < 0 > C and the mixture is aged at 5-8 [deg.] C for 2 hours. The addition reaction is slightly endothermic. A white precipitate, presumably DIEA-hydrochloride, is formed during the addition. The HPLC conditions are as above. HPLC analysis showed that the reaction was complete after 1 hour and the analytical yield was 94% from the compound of formula 9 after the addition was terminated (no compound of formula 9 was detected). Retention time: compound of formula 1 = 7.8 min. Typical HPLC characteristics of the reaction mixture after 2 hours of aging: area% matter <0.1 CBZ-Spiroindoline of Formula 9 90-92 CBZ-sulfonamide of formula 1 8-10tot other impurities (<2% each) The mixture is warmed to 20 < 0 > C and 200 mL of 1 M aqueous HCl are added. The mixture is warmed to 50 < 0 > C and the aqueous phase is separated. The organic phase is washed successively with 100 mL of water, 100 mL of 5% aqueous sodium bicarbonate and 100 mL of water. The organic phase is transferred to a 1 L three-necked flask equipped for mechanical stirring and distillation. The mixture (about 400 mL) is distilled at atmospheric pressure until 150 mL of distillate is collected. The temperature of the head reaches 107 ° C and the temperature of the port is 110 ° C. Continuously, n-propanol is added to continue distillation while maintaining a constant volume (about 350 mL) in the pot. Add 525 mL of total n-PrOH and stop distillation when 800 mL of the total distillate is collected. The temperature of both the head and the port is increased from 94 to 98 占 폚 while changing the solvent. Toluene and n-PrOH form an azeotropic point at 97.2 ° C and consist of 47.5% toluene and 52.5% n-PrOH. The mixture is gradually cooled to 20 [deg.] C over 3 hours and aged for 2 hours. The mother liquor appears to contain 2% toluene and 4 mg / mL of sulfonamide. The solubility of the sulfonamide in various mixtures of toluene and n-PrOH is determined by HPLC analysis. The toluene (%) in n-PrOH 1 solubility (mg / mL) 0 2.36 5 3.02 10 4.02 20 7.51 25 10.3 The crystalline slurry is filtered and washed with 100 mL of n-PrOH 3 x. The product was dried in a vacuum oven under nitrogen bleeding at 50 ° C for 16 hours to give 65.5 g (82% from aldehyde 5) of the compound of formula 6 as a tan solid with 93.5% by weight of impurities. Typical HPLC characteristics of solids: area% matter <0.1 CBZ-Spiroindoline of Formula 9 > 99 CBZ-sulfonamide of formula 1 <1tot other impurities (<0.2% each) For further purification, 40.0 g of a sample of n-PrOH, the crystallized sulfonamide is dissolved in 134 mL of EtOAc at 60 DEG C and treated with 8.0 g of Doral G-60 carbon for 1 hour at 60 DEG C. [ After 2.0 g of Solka flock is added, the slurry is filtered through a pad of 4.0 g of Solka flock and the pad is washed with 90 mL of EtOAc at 60 < 0 > C. The solution is brown before adding carbon. The filtration is preferably performed without flushing to obtain a golden yellow filtrate. The filtrate is distilled under atmospheric pressure in a 500 mL flask (pot temperature 80-85 DEG C) until the residue remains 100 g (100 mL). The solution is cooled to 35 占 폚 over 3 hours. 116 ml of cyclohexane are added with stirring at 35 < 0 > C for 1 hour. The mixture is cooled to 20 [deg.] C over 1 hour and aged at 20 [deg.] C for 12 hours. Most of the sulfonamide is crystallized at 35 DEG C and the mixture is concentrated. Addition of cyclohexane at 20 DEG C makes stirring difficult. After the aging period, the supernatant indicates that the compound of formula (I) contains 2.5 mg / g. The crystalline slurry is filtered and the cake is 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 < 0 > C with bleeding for 16 h to yield the compound of formula (1) as a white crystalline solid (85% yield from crude 1, 70% = 400.3). Example 11 (1a) < / RTI > of < RTI ID = 0.0 & material: 941 g (2.35 mol) of CBZ-spiroindoline-methanesulfonamide (1) Perlman Catalyst 20% Pd (OH) 2 / C 188 g THF 8L MeOH 7L The catalyst is suspended in 7 L of MeOH and transferred to a 5 gal autoclave and a solution of the compound of formula 1 in 8 L of THF is added. The mixture was then hydrogenated at 25 ℃ at 80psi H 2. The temperature is raised to 35 [deg.] C over a period of 30 minutes for 2.5 hours. HPLC analysis shows complete consumption of Cbz-spiroindoline-methanesulfonamide. HPLC conditions: a DuPont gore-box 25 cm RXC8 column detected at a flow rate of 1.5 mL / min and 254 nm; Gradient Schedule: Time (minutes) 0.1% aqueous H 3PO 4: MeCN 0 70:30 3 70:30 12 20:80 25 20:80 Time of stay: Surprising = 7.6 minutes Cbz-Spiroindoline-methanesulfonamide = 13.6 min. The mixture is purged with nitrogen and the catalyst is filtered off through a Solka floc while warming the catalyst. The catalyst is washed with 4 L of THF and 2 L of MeOH. The pale yellow filtrate is concentrated to a thick oil at less than 10 mbar and < RTI ID = 0.0 > 25 C. < / RTI > Solvent changes are completed by slowly bleaching in 1 L of EtOAc and drying with copious water. Solidify the residue into a solid, non-white material. MeOH (1.5 L) was added and the mixture was heated to 70 DEG C to obtain a homogeneous solution. Add 10.5 L of EtOAc at 20 < 0 > C to the solution maintained at 70 < 0 > C. The temperature is lowered to 40 占 폚 and the mixture remains uniformly. Continuous experiments indicate that it is more convenient to solvent change the MeOH-THF filtrate to MeOH, concentrate to the desired volume and then add EtOAc. This prevents solidification of the residue due to concentration of the EtOAc solution. Pour approximately equal volumes of hydrogen chloride diluted in nitrogen into the solution. The temperature is raised to 60 < 0 > C over 15 minutes and a white precipitate of the hydrochloride salt is formed. Dilute HCl with nitrogen to prevent absorption of the reaction mixture and may not be necessary. The mixture is cooled in an ice bath and hydrogen chloride is added continuously for 1 hour. The temperature is gradually lowered to 20 占 폚. The suspension is aged for 2 hours while the temperature is lowered to 10 占 폚. The crystalline product is separated by filtration and the filter cake is washed with 3 L of EtOAc. This was dried at 35 [deg.] C in a vacuum oven to give 1.18 kg (86%) of the title product of formula Ia as a non-white crystalline solid having a purity of 99.5 area% or greater by HPLC analysis. HPLC conditions: Dupont Gorebox 25 cm RXC8 column detected at a flow rate of 1.5 mL / min and 230 nm; Isocratic 35% MeCN, 0.1% aqueous ammonium acetate 65%. Retention time: Compound of formula (I) = 5.4 min. Example 12 1b Spiroindoline-methine sulfonamide (free base form) (1b) Concentrate 250 mL of the filtrate from the Cbz-hydrolyzate containing 4.67 g of the compound of formula 1b (free base) to about 10 mL. The residue is dissolved in 20 mL of EtOAc and the solution is re-concentrated to about 10 mL. This is repeated once more and 10 mL of EtOAc are added to the residue. Crystalline precipitate begins to form. MTBE (20 mL) is added in one portion. Additional crystalline solids precipitate but the supernatant still contains the most amount of dissolved product that is not precipitated when settled. Hexane (70 mL) is added dropwise to the mixture with vigorous stirring over 2 hours. It is necessary to gradually add hexane to prevent the oil from removing the amine. The stirred mixture is aged for 1 hour and filtered. The filter cake is washed with 20 mL of 1: 1 MTBE-hexane followed by 20 mL of hexane. The product was dried under a stream of nitrogen to give 3.86 g (82%) of the title product of formula Ib as an off-white crystalline solid with a purity of 99.5 area% or more. HPLC conditions: a DuPont gore-box 25 cm RXC8 column, detected at a flow rate of 1.5 mL / min and 230 nm; Isocratic 35% MeCN, 0.1% aqueous ammonium acetate 65%. Retention time: Compound of formula (I) = 5.4 min. Example 13A 1b Spiroindoline-methine sulfonamide (free base form) (1b) material: 833.5 g (2.08 mol) of CBZ-spiroindoline-methanesulfonamide (1) Pd (OH) 2 / C (20% by weight of Pd (OH) 2 ) 124.5 (15% THF 6.5L 19.5 L of MeOH NH 4 OH (dark) 60 mL The hydrogenation reaction is carried out three times due to limitations on the apparatus; This process is seen as a single action. The CBZ-spiroindoline sulfonamide of Formula 1 was dissolved in THF (6.5 L, KF = 53 μg / μL), MeOH (KF = 18 μg / mL, 4 L) was added and the catalyst was added and the slurry was transferred to a 5 gal autoclave . Remaining MeOH (2.5 L) is used for washing. The mixture is heated to 40 < 0 > C at 50 psi for 24 hours. The amount of catalyst added and the reaction time are the contents of the purity of the starting material of formula (1). This material uniquely requires more than 15% of the catalyst and requires a long reaction time. Pure batching of spiroindoline requires only 5% of catalyst and 4 to 6 hours of reaction time. When complete (<0.1 A% of the compound of formula 1 by LC), the mixture is filtered through a Solka floc and the carbon cake is washed with MeOH (13 L) containing NH 4 OH (0.5%, 60 mL). The combined filtrate (1518 g of spiroindoline amine of formula 1b according to the analysis) was concentrated in vacuo and the solid produced was bred between 40 L of toluene: THF (3: 1) and 0.5 N NaOH (18 L). Despite the easy separation of the layers, heavy sediments can appear as an aqueous layer. The aqueous suspension is extracted with CH 2 Cl 2 (15 L). The aqueous layer and the organic layer are slowly separated. THF is added to the aqueous layer with sufficient NaCl to saturate the layer before adding CH 2 Cl 2 . However, the product is not distilled, so CH 2 Cl 2 should be used. The combined toluene, THF and CH 2 Cl 2 layers are combined in a batch concentrator and concentrated. Flush the residue with CH 3 CN 7L. Finally, 10 L of CH 3 CN is added and the solution is allowed to stand overnight under a N 2 atmosphere. Example 13B 1b Spiroindoline-methanesulfonamide (free base form) (1b) material: 3 kg (7.49 mol) of CBZ-spiroindoline-methanesulfonamide (1) Darco G-60 600g Ethyl acetate 36L 189L of anhydrous ethanol 10% Pd / C 450g Ammonia solution 500ml Solka flock 2.5kg Isopropyl acetate 65L A mixture of CBZ-spiroindoline (1 kg) and Darco G-60 (200 g) in ethyl acetate (9 L) is stirred and heated at 60-65 ° C for 8 hours under a nitrogen atmosphere. Darco is removed by filtration at 60-65 [deg.] C and the solid is washed with hot ethyl acetate (3 L) and combined with filtration and washing. The LC wt / wt analysis confirms the negligible loss for Darko. The ethyl acetate solution is evaporated in vacuo to an anhydride using a 20 L Buchi apparatus and flushed with absolute ethanol (2 x 5 L). The material is slurried in anhydrous ethanol (8 L) warmed to 65-70 < 0 > C and placed in a 20 L autoclave. The batch is washed with absolute ethanol (1 L). A slurry of 10% platinum on charcoal (75 g, 7.5 wt%) in anhydrous ethanol (750 ml) is added to the autoclave and rinsed with additional anhydrous ethanol (250 ml) fractions. The batch is hydrogenated at 65 < 0 > C for 3 h at 40 psi hydrogen pressure and the second fraction of 10% platinum on charcoal (75 g, 7.5 wt%) and the batch is hydrogenated for an additional 2 h and sealed overnight. Batch (still hot at 60-65 ° C) is transferred to a 20L Buchi apparatus and degassed in vacuo to remove formic acid by "feeding and bleeding" anhydrous ethanol (total 18L). This process is repeated at least twice, and three batches are combined in a glass-lined container having a capacity of 10 gal, and the combined batches are again degassed by adding anhydrous ethanol (2 x 10 L) and distilling (in vacuo). Solka floc (0.5 kg) was added to the batch and rinsed with ethanol (10 L). The Estrella filter is combined with Solka floc (2 kg) as a slurry in ethanol (20 L). The resulting mixture is allowed to warm to 60-65 占 폚 and transferred at this temperature through a heated filter using a pump to two tared stainless steel bins. The first vessel, filter, pump and line is rinsed with a hot (60-65 ° C) mixture of aqueous ammonia (500ml) in anhydrous ethanol (25L). Combine the filtrate and wash solution in two stainless steel beads. The batch is transferred to a vessel using an in-line filter containing a 10 mu cartridge and concentrated in vacuo to a low bulk (15 L or less). The ethanol is replaced with isopropyl acetate by " feeding and bleeding " triplicate isopropyl acetate (total 45L) while keeping the batch volume below 15L. When complete, the change in solvent will contain less than 1% of residual ethanol by GC. The batch is diluted with less than 33 L of isopropyl acetate (20 L) and this solution of spiroindoline-amine 1b (1.855 kg by LC analysis) in isopropyl acetate is used in the next step of the process. Example 14 Formula 11 Boc-O-Benzylserine Spiroindoline (11) material: 1587g (5.966mol) of spiroindoline-amine (Formula Ib) 1938 g (6.563 mol) 10 DCC 1334.5 g (6.563 mol) HOBT 884 g (6.563 mol) CH 3 CN 25L 0.5 N NaOH 18 L NaHCO 3 < / RTI > iPrOAc 28L HOBT (884 g; 1.1 eq.) As a solid, DCC (1334.5 g, 1.1 eq.) As a liquid under N 2 at ambient temperature was added to a solution of the spiroindoline- amine of formula Ib in CH 3 CN or iPrOAc: H 2 O (Heated at 60 < 0 > C in hot water for about 1 hour) and finally treated with the amino acid of formula 10 (1938 g) as a solid. Stirring the mixture for 3 h gives rise to a heavy precipitate of DCU and shows that approximately 0.5% of the amine of formula Ib is retained by LC analysis. IPAc (9L) is added, the slurry is filtered through a Solka floc and the cake is washed with IPAc (19L). The combined organic solution is washed successively with 0.5 N NaOH (18 L), 0.5 N HCl (18 L) and saturated NaHCO 3 (18 L). At this time, finally washing with water forms a milky lotion and is removed. The organic layer is concentrated in vacuo and the residue is dissolved in MeOH or EtOH (final volume 10 L). The analytical yield is 3026 g (89%). The compound of formula 11 and / or the compound of formula 14, which has a high degree of epimerization in the case of the preceding compound, and / or the compound of formula 14, which is another peptide coupling agent such as carbonyldiimidazole, or a mixed anhydride such as sec- A poor yield is obtained. Other peptide coupling agents are very expensive. Example 14B Formula 11 Boc-O-Benzylserine Spiroindoline (11) material: 1.815 kg (6.96 mol) of spiroindoline-amine (Formula Ib) Isopropyl acetate 29L 1.58 kg (7.65 mol) of dicyclohexylcarbodiimide (DCC) 1.03 kg (7.62 mol) of 1-hydroxybenzotriazole (HOBt) 2.26 kg (7.65 mol) of N-Boc-O-benzyl-D- 1M aqueous sodium hydroxide 26L 0.5 M aqueous hydrochloric acid 26 L Saturated aqueous sodium bicarbonate 26L Anhydrous ethanol 50 L Water (20 L) is added to a stirred solution of spiroindoline-amine (1.855 kg) of formula (Ib) in isopropyl acetate (33 L) in a reaction vessel. The following chemicals are successively added under nitrogen atmosphere at room temperature: DCC (1.58 kg, 1.1 eq.), HOBt (1.03 kg, 1.1 eq.) And finally N-Boc-O-benzyl- 1.1 eq.). The preparation is washed with isopropyl acetate (7 L). When the batch is stirred at room temperature under a nitrogen atmosphere for 5 hours, LC shows a ratio of product / starting material of 99.4 / 0.6. The mixture is then filtered through an ester filter using cloth and cardboard and using a pump into the other vessel. The vessel is cleaned with isopropyl acetate (22 L) and used to clean the filter, pump and line into the collection vessel. The two-phase mixture is stirred in the vessel for 10 minutes and held for 15 minutes. The lower aqueous layer is separated and the organic solution is allowed to stand overnight at room temperature. The next day, the organic solution is washed with 1 M aqueous sodium hydroxide solution (26 L) followed by 0.5 M aqueous hydrochloric acid (26 L) and finally saturated aqueous sodium bicarbonate solution (26 L). LC analysis showed an overall yield of 93% from an analytical yield of 3.787 kg and 7.49 mol (3 kg) of starting CBZ-spiroindole of formula (1). The batch was " fed and bleached " by concentrating in vacuo (internal temperature = 13-15 째 C, jacket temperature = 40 째 C vacuum = 29 째) low bulk (-15 L) and volume at -15 L Solvents are changed with ethanol GC shows less than 1% isopropyl acetate remaining This solid is used for the next step in the process. Example 15A Formula 12 O-Benzylserine Spiroindoline (free base form) (12) material: 3026 g (5.57 mol) of Boc-O-benzyl serine spiroindoline (11) Methanesulfonic acid (MsOH) (1.16 L, 17.9 mol) MeOH 10 L iPrOAc 24L 0.5 N NaOH 35 L Boc-O-benzylserine spiroindoline of formula 11 in 10 L of MeOH (or EtOH) is treated with pure MsOH (1.16 L) added over about 30-40 minutes (initial temperature 16 [deg.] C, final temperature 28 [deg.] C). The dark red solution is aged under N 2 overnight. The mixture is then pumped into a 100 L extractor containing 24 L of iPrOAc and 35 L of 0.5 N NaOH. The pH of the aqueous layer is 7. Add NaOH (6M) until the pH is above 10.5. As the pH increases, the color changes from red to yellow. The layers were separated and the organic layer (24 L) was analyzed by NMR to show 13 mol% MeOH in iPrOAc [5 vol%]. LC analysis 2.48 kg. Example 15B Formula 12 O-Benzylserine Spiroindoline (free base form) (12) material: 3.787 kg (6.96 mol) of Boc-O-benzylserine spiroindoline (11) Methanesulfonic acid (2.006 kg, 20.87 mol) Isopropyl acetate 38L 1M aqueous sodium hydroxide 16L 50% aqueous sodium hydroxide 1.6 L Methanesulfonic acid (2.006 kg, 1.355 L, 3 equiv. Or less) is added to a stirred solution of Boc-O-benzylserine spiroindoline of formula 11 in ethanol (total volume 15 L or less) in a reaction vessel. The batch is allowed to warm to 35-40 < 0 > C. After 7 hours, LC indicates no starting material and the reaction is allowed to cool to room temperature overnight. The next day, water 44L is added to the batch while stirring. The batch is cooled to -5 ° C and stirred for 30 minutes and filtered through an in-line filter (with a 10μ cartridge) into the beaker. Bleach is sucked into the container. The water 10L is used to clean the vessel and line in the bin, which is used to be rinsed back into the vessel. Isopropyl acetate (38 L) followed by 1 M aqueous sodium hydroxide (16 L) was added. The batch is cooled to 10 to 15 占 폚, the pH of the lower aqueous layer is adjusted to 7 or less, and a 50% aqueous solution of sodium hydroxide (1.6 L) is added (in excess of pH 10). The batch is stirred at 10 to 15 占 폚 for 25 minutes and fixed for 10 to 15 minutes. The lower aqueous layer is separated (78.1 kg). LC analysis indicated that 28.4 g of 12 (0.85% of theory) was contained in the aqueous liquid. Volume of organic solution = 51L. LC analysis yielded 3.057 kg of an overall yield of 92% from 3 kg, 7.49 mol of CBZ-spiroindole sulfonamide of formula (1). This solution is used for the next step. Example 16A Formula 14 Boc-aminoisobutyryl O-benzylserine Spiroindole (14) material: 2481 g (5.57 mol) of spiroindoline-amine (Formula 12) 1247.1 g (6.16 mol) of amino acid peptide Formula 13 DCC 1266.7 g (6.16 mol) HOBT 827 g (6.16 mol) IPAc 52L H 2 O 37L 0.5 N NaOH 36 L 0.5N HCl 36L NaHCO 3 < / RTI > An amine solution of formula 12 in IPAc is diluted with IPAc to a total volume of 39 L and 37 L of H 2 O is added. The above mixture is treated with HOBT (827 g) as a solid, DCC (1266.7 g) as a melt and the amino acid of formula (13) under nitrogen at ambient temperature. When the reaction mixture was stirred for 2 hours, LC analysis indicated absence of starting material 12 (less than 0.3 A%). The mixture is filtered through a Solka floc and the solid is washed with 13 L of IPAc. The material is stored as an abnormal mixture at this temperature overnight. The mixture is transferred to a 100 L extractor and the aqueous layer is separated and the organic layer is washed successively with 36 L of 0.5 N NaOH, 0.5 N HCl and saturated NaHCO 3 . Analysis yield: 3160 g (volumetric measurement error ± 5% from spiroindole 81%). The solution is concentrated to small volume and flushed with ethanol (2 x 4 L). If desired, the intermediate compound of formula 14 is separated by crystallization with water. Another peptide coupling agent such as carbonyldiimidazole is used or a mixed anhydride such as sec-butyl carbonate is formed to obtain a poor yield of the compound of formula (14) having a high degree of epimerization. Other peptide coupling agents are very expensive. Example 16B Formula 14 Boc-Amiazoisobutyryl O-benzylserine Spiroindoline (14) material: 3.058 kg (6.89 mol) of spiroindoline amine (12) 1.56 kg (7.56 mol) of dicyclohexylcarbodiimide (DCC) 1.02 kg (7.55 mol) of 1-hydroxybenzotriazole (HOBt) 1.54 kg (7.58 mol) of Boc-2-aminoisobutyric acid (13) Isopropyl acetate 32L 1M aqueous sodium hydroxide 38 L 0.5 M aqueous hydrochloric acid 38 L Saturated aqueous sodium bicarbonate 38L Anhydrous ethanol 45 L Water (49 L) is added to a stirred solution of spiroindoline-amine (3.057 kg) of formula 12 in isopropyl acetate (total volume 51 L or less) at room temperature and under a nitrogen atmosphere in a reaction vessel. The following chemicals are successively added at room temperature under a nitrogen atmosphere: DCC (1.56 kg, 1.1 eq.), HOBt (1.02 kg, 1.1 eq.) And finally N-Boc-2-aminoisobutyric acid 1.54 kg, 1.1 equivalents or less). When the mixture is vigorously stirred at room temperature for 2 hours, LC indicates that the reaction is complete. The mixture is filtered through another pump through an Esterella filter. The vessel, filter, pump and line are cleaned in a collection vessel using isopropyl acetate (22L). The biphasic mixture is stirred for 5 minutes and the layers are separated. The low aqueous layer is separated accidentally (weight of aqueous liquid = 51.1 kg). The organic solution is washed successively with 1 M aqueous sodium hydroxide (38 L), 0.5 M aqueous hydrochloric acid (38 L) and finally saturated aqueous sodium bicarbonate (38 L). The organic solution is then transferred to another vessel via an in-line filter (containing 10μ cartridge) using a pump to change the solvent to ethanol. The vessel is washed with isopropyl acetate (10 L) and used to clean the pump, filter and line in the collection vessel. Combine the filtrate and wash. Total volume = 75L (by dipstick). LC analysis provided 4.395 kg of Boc-aminoisobutyryl O-benzylserine spiroindoline of formula 14, 93% overall from 7.49 mol of starting CBZ-spiroindoline sulfonamide of formula (1). The batch is concentrated in vacuo to a low bulk (15 L or less) and the isopropyl acetate is changed to ethanol by " feeding and bleeding " of anhydrous ethanol (total 45 L). At the end of the solvent change, GC indicates that less than 1% of isopropyl acetate remains. This solution (25 L) containing 4.395 kg of 14 is used for the next step. If desired, the intermediate compound of formula 14 can be crystallized by separating it with water. Example 17A Formula 15 Amino isobutyryl O-benzyl serine spiroindoline (15) material: 3160 g (5.03 mol) of Boc spiroindoline (14) Methanesulfonic acid (MsOH) 979 mL (15.1 mol) 6.2 L of EtOH H 2 O 30L 1N NaOH 11 L EtOAc 26L Darko 60 activated carbon 1Kg Boc spiroindoline of formula 14 is dissolved in 6.2 L of EtOH and treated with MsOH (979 mL). The temperature is raised from 20 to 30 < 0 > C and the reaction is allowed to proceed overnight. After 12 hours at 20 < 0 > C, the starting material of formula (15) remains A% and the mixture is heated at 35 [deg.] C for 6 hours. When complete (<0.1 A% compound of formula 14), the reaction is cooled to 20 ° C, 30 L of H 2 O is added and the solution is filtered through a glass funnel with a polypropylene filter to remove residual DCU. The mixture is transferred to a 100 L extractor and 26 L of EtOAc are added. The aqueous layer is basified by adding cold 1N NaOH (11 L) and 1 L of 50% NaOH. It is necessary to add ice to keep the temperature below 14 ° C. Higher temperatures result in serious fluid problems. The organic layer is distilled at 50 DEG C in Hg DIR 21 " until KF is 1000 [mu] g / mL at 50 DEG C. Lower KF causes better recovery in more efficient carbon treatment and salt formation steps. The solution is diluted with ethyl acetate to a total volume of 31 L (LC analysis 2.40 kg) Activated carbon (Darko G-60) is added and the mixture is stirred for 24 hours The mixture is passed through a Solka flock Filter and wash the filter cake with ethyl acetate (16 L). Example 17B Formula 15 Amino isobutyryl O-benzyl serine spiroindoline (15) material: Boc Spiroindoline (14) 4.395 kg (6.99 mol) 2.017 kg (20.99 mol) of methanesulfonic acid, Ethyl acetate < RTI ID = 1M aqueous sodium hydroxide 16L 50% aqueous sodium hydroxide 2.6 L Darco G-60 900g Solskloof 2.5kg Methanesulfonic acid (2.017 kg, 1.36 L, 3 equiv. Or less) is added to a stirred solution of Boc spiroindoline (4.395 kg) of formula 14 in ethanol (total volume 25 L or less) in a reaction vessel. The batch is warmed to 35-40 < 0 > C and stirred overnight. The next day, the batch contains 1.1 A% or less of starting material and the reaction is continued for an additional 4 hours, then the LC indicates that the ratio of product / starting material is 99.6 / 0.4. The batch is concentrated in vacuo to 15 L and diluted with water (44 L). The batch is cooled to 5 ° C and stirred for 30 minutes and filtered through an in-line filter (with a 10μ cartridge) using a pump for another vessel to remove a small amount of residual DCU. Clean the vessel, pump, filter and line with water (10L) and add it to the vessel. Ethyl acetate (36 L) is added to the vessel and the stirred mixture is cooled to 10 < 0 > C. A solution of 1 M sodium hydroxide aqueous solution (16 L) and cold (5 to 10 캜) 50% sodium hydroxide aqueous solution (2.6 L) in cold (5 to 10 ° C) was added at 10 ° C and the temperature was raised to 14 ° C. The resulting mixture is stirred at <14 ° C for 15 minutes and the lower aqueous layer is separated. The batch is concentrated in vacuo to a volume of 20 L or less and a mixture of ethyl acetate (35 L) and ethanol (5 L) is fed while keeping the volume below 20 L. At the end of this distillation, KF is 9160 mg ml -1 . The batch is changed to ethyl acetate by " feeding and bleeding " ethyl acetate (total 40 L). At the end of this distillation, KF is 446 mg ml -1 . The batch was diluted with ethyl acetate (10 L). Darco G-60 (900 g) is added to the opacifying mixture. This is washed with ethyl acetate (6 L). The mixture is stirred at room temperature overnight. The following day, Solka floc (0.5 kg) was added to a batch which was stirred in a vessel, and Solka floc (2.0 kg) was stirred in a small amount of ethyl acetate and added to an ester filter. Excess solvent is pumped through a sparkler in-line filter containing a 10μ cartridge. The slurry is delivered from the vessel through a pump-using filter and through another filter 2 x 40L stainless steel bean. Visual inspection indicates that the liquid is transparent. The vessel is rinsed with ethylacetate (22 L) and rinsed through the route outlined above for the stainless steel can using it. Move the contents of both cans into the reaction vessel and mix the solution thoroughly. The KF of the batch (58 L) is 2950 mg ml -1 and is concentrated to a volume of 20-25 L in vacuo and re-dried. The batch is diluted with 46 L volume (dip stick) by adding ethyl acetate (25 L). KF is 363 mg ml -1 . The batch is diluted to 62 L volume by adding ethyl acetate (17 L) and used for the final step of the process. Example 18A Formula 16 Yl) carbonyl] -2- (phenylmethyl-oxy) ethyl] -2-amino -2- methylpropanamide methanesulfonate (16 < ) material: Amine (15) 2340 g (4.43 mol) (4.88 mol) of methanesulfonic acid (MsOH) EtOAc 60 L EtOH 4.8 L EtOAc in EtOAc 8% 20 L A solution of the compound of formula 15 from the preceding step is adjusted to 60 L of ethyl acetate and added EtOH (4.8 L). MsOH (316 mL) is added to 3 L of EtOAc at 45 < 0 > C. A homogeneous solution of core is added to 496 g of the title compound Form I seed (10% seed is used based on the weight of the free amine). The temperature is raised to about 48 ° C and the reaction is aged at 52 ° C for 1.5 hours. The assay shows complete conversion to the title compound (Form I) (long aging of seed less than 10% (more than 3 hours) is required). Cooling the slurry to 20 ℃ overnight and is filtered by centrifugation under N 2. The cake is washed with 20 L of 8% EtOH in EtOAc. N 2 is essential during filtration because hygroscopic crystals are highly hygroscopic. The batch is dried in vacuo at 35 [deg.] C to give 2.7 Kg (overall yield, 56%) of the title compound (Form I) (purity 99.9 A%; less than 0.1% enantiomer). Also, the conversion of Form II to Form I occurs when MsOH is added as above to form salts in EtOAc-EtOH and the initial solution (55 占 폚) of the salt is cooled to 45 占 폚. The crystals begin to appear at this temperature and the slurry becomes thicker over time. The temperature is then raised to 51 DEG C and the slurry aged overnight. Full conversion to Form I of 16 is expected. This process is also used to produce seed crystals of Form I of 16 or 16. Example 18B Formula 16 Yl) carbonyl] -2- (phenylmethyl-oxy) ethyl] -2-amino -2- methylpropanamide methanesulfonate (16 < ) material: 3.1 kg (5.86 mol) of amine (15) Methanesulfonic acid (620 g, 6.45 mol) Ethyl acetate 37 L 8.7 L of anhydrous ethanol Spiro [3H-indole-3,4 ' -piperidin] -l'-yl) Carbonyl] -2- (phenylmethyl-oxy) ethyl] -2-amino- 70 g (0.11 mol) of 2-methylpropanamide methanesulfonate (Form I) Anhydrous ethanol (6.4 L) is added to a solution of the amine (3.1 kg) in ethyl acetate (62 L total volume or less) in a reaction vessel. The batch was allowed to warm to 50 < 0 > C and methanesulfonic acid (620 g, 412 ml, 1.1 eq.) In ethyl acetate (11 L) was added at 50-54 C over 5 min. The batch was carried out in the same manner as in Example 1 except that spiro [3H-indole-3,4'-piperidine] -1'-yl) carbonyl] -2- (phenylmethyl- oxy) ethyl] -2- (Form I) (70 g) and stirred at 55 < 0 > C under nitrogen atmosphere overnight. The next day, the slurry is cooled to 15-20 DEG C and held for 2 hours and then added dropwise to a 50 cm polypropylene filter under a nitrogen atmosphere. The solid product is washed with a mixture of absolute ethanol (2.3 L) in ethyl acetate (26 L). The white solid product is collected and dried in an Apex oven at 36 [deg.] C for a suitable time (approximately 2 days) in vacuo. Yl) carbonyl] -2- (phenylmethyl-oxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate (3.352 kg) was sieved using a Jackson-Crockett sheave to yield 3.347 kg (including 70 g seed). Yield 3.277 kg. HPLC conditions; LC retention time on a Gorebox RT-C8 (4.6 mm x 25 cm), λ = 210 nm, flow rate 1.5 ml / min. The compounds of formula 1: 60:40 CH 3 CN-H 2 O (1% H 3 PO 4) RT = 5.0min Compound of the formula 1b: 35:65 CH 3 CN-H 2 O (0.1% by weight of NH 4 OAc) RT = 6.2min The compounds of formula 10: 60:40 CH 3 CN-H 2 O (0.1% H 3 PO 4) RT = 2.9min The compounds of formula 11: 60:40 CH 3 CN-H 2 O (0.1% H 3 PO 4) RT = 5.4min The compounds of formula 12: 40:60 CH 3 CN-H 2 O [H 5.25 NaH 2 PO 4 (H 2 O 6.9g / L) (PH adjusted with NaOH)] RT = 5.6 min The compounds of formula 14: 60:40 CH 3 CN-H 2 O (0.1% H 3 PO 4) RT = 4.65min The compounds of formula 15: 40:60 CH 3 CN-H 2 O [H 5.25 NaH 2 PO 4 (H 2 O 6.9g / L) (PH controlled with NaOH)] RT = 4.9 min LC = residence time, = 210 nm, flow rate 1.2 ml / min, column temperature = 48 占 폚, solvent A = 005% phosphoric acid + 0.01% triethylamine in solvent + B, solvent B (4.6 mm x 25 cm) = Acetonitrile Change system: time A% B% 0 min 95 5 35 minutes 10 90 38 minutes 95 5 40 minutes 95 5 Retention time (minutes) Compound 25.2 Compound of Formula 1b 8.5 Compound 10 (20.5 Compound 26.3 (11) Compound 14.8 (12) Compound 14 of Formula 14 Compound 15 (15) Example 19 (I) - (1, 2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidin] -1'- yl) carbonyl] - 2- (phenylmethyl) ethyl] -2-amino-2-methylpropanamide methanesulfonate Conversion from Form II to Form I takes place when MsOH is added by the procedure of Example 18A to form the salt in EtOAc-EtOH and the initial solution of the salt (55 占 폚) is cooled to 45 占 폚. The crystals begin to appear at this temperature and the slurry becomes thicker over time. The temperature is then raised to 51 DEG C and the slurry aged overnight. Complete conversion to Form I is expected. Example 20 (I) - (1, 2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidin] -1'- yl) carbonyl] - 2- (phenylmethyl) ethyl] -2-amino-2-methylpropanamide methanesulfonate Conversion from Form II to Form I is accomplished by dissolving N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] -1'-yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate is stirred at about 25 ° C for about 2-24 hours. Example 21 (1 H) - (1, 2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] -1'- yl) carbonyl] - 2- (phenylmethyl) ethyl] -2-amino-2-methylpropanamide methanesulfonate Any of the morphological forms of N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidin] Ethyl] -2-amino-2-methylpropanamide Methanesulfonate A sample of 8.4 g was dissolved in a mixture of 24.8 ml of ethyl acetate, 1.6 ml of ethanol and 1.95 ml of water at 42 DEG C with stirring Dissolve. The solvent is evaporated from the solution at a temperature of 40 DEG C and the solids produced are pulverized into fine powder in a motor and the fine powder is exposed to about 75% relative humidity to obtain Form IV. Example 22 (1 H) - (1, 2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] -1'- yl) carbonyl] - 2- (phenylmethyl) ethyl] -2-amino-2-methylpropanamide methanesulfonate Any of the morphological forms of N- [1 (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidin] Ethyl] -2-amino-2-methylpropanamide methanesulfonate A sample was recrystallized from a solution of ethyl acetate / ethanol / water (24.8 / 1.6 / 1.95) do. Example 23 (1 H) - (1, 2-dihydro-1-methanesulfonylpyrazolo [3H-indole-3,4'-piperidine] -1'- yl) carbonyl] - 2- (phenylmethyl) ethyl] -2-amino-2-methylpropanamide methanesulfonate (R) - [(1,2-dihydro-1-methanesulfonylpyrazolo [3H) -quinolinecarboxylic acid methyl ester of Form I in isopropyl acetate / ethanol (90:10 v / v) containing about 2.8% Yl) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate was stirred at about 25 < 0 > C ≪ / RTI > overnight and the resulting solid is isolated. While the invention has been described and illustrated with reference to specific embodiments thereof, those skilled in the art will recognize that various modifications, alterations, alterations, substitutions, deletions or additions to such processes and protocols may be made without departing from the spirit and scope of the invention . For example, an effective dosage other than the specific dosage as set forth herein may be applied as a result of various responses of the mammal being treated for any indication using the above mentioned compounds of the present invention. The particular pharmacological response similarly observed may vary depending on and depending on the particular active compound selected or the form of the formulation as well as the pharmaceutical carrier, as well as the mode of administration employed and the resulting expected variation or difference, May be supplemented with regard to implementation. Accordingly, the present invention is defined by the claims appended hereto, and such claims should be interpreted as broadly as is appropriate.
权利要求:
Claims (28) [1" claim-type="Currently amended] Spiro [3H-indole-3, 4 ' -piperidine] -l ' -yl) carbonyl ] -2- (phenylmethyl-oxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate. [2" claim-type="Currently amended] The polymorph according to claim 1 characterized by a melt endotherm with an extrapolated onset temperature of about 170 ° C when heated at 10 ° C / min under a nitrogen atmosphere in a differential scanning calorimetry cell. [3" claim-type="Currently amended] The polymorph according to claim 1, characterized by an X-ray powder diffraction pattern having major reflections at about 6.5, 14.7, 16.9, 17.1, 17.9, 19.5, 21.1, 21.7 and 22.0 degrees (2 ). [4" claim-type="Currently amended] Spiro [3H-indole-3,4'-piperidine] -1'-yl) carbonyl ] -2- (phenylmethyl-oxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate. [5" claim-type="Currently amended] 5. A method according to claim 4, characterized in that when heating in a differential scanning calorimetry cell under a nitrogen atmosphere at a rate of 10 캜 / min, a water loss endotherm at about 45 캜, followed by a polymorph . [6" claim-type="Currently amended] 5. The compound of claim 4 which is N- [1 (R) - [(1,2-dihydro-1-methanesulfonyl- spiro [3H- indole- 3,4'- piperidin] Carbonyl] -2- (phenylmethyl-oxy) ethyl] -2-amino-2-methylpropanamide Polymorph containing about 3.5 moles of water per mole of methanesulfonate. [7" claim-type="Currently amended] 5. A polymorph according to claim 4 characterized by an X-ray powder diffraction pattern having major reflections at 16.0, 16.2, 18.3, 20.1, 21.0 and 24.0 degrees (2 ). [8" claim-type="Currently amended] A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a polymorph of claim 1. [9" claim-type="Currently amended] A pharmaceutical composition useful for the treatment of osteoporosis, comprising a combination of a bisphosphonate compound and the polymorph of claim 1. [10" claim-type="Currently amended] 10. The pharmaceutical composition according to claim 9, wherein the bisphosphonate compound is alendronate. [11" claim-type="Currently amended] A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a polymorph of claim 4. [12" claim-type="Currently amended] A pharmaceutical composition useful for the treatment of osteoporosis, comprising a combination of a bisphosphonate compound and the polymorph of claim 4. [13" claim-type="Currently amended] 13. The pharmaceutical composition according to claim 12, wherein the bisphosphonate compound is alendronate. [14" claim-type="Currently amended] A method for increasing the concentration of endogenous growth hormone in a human or animal, comprising administering to the human or animal an effective amount of the polymorph of claim 1. [15" claim-type="Currently amended] A method for increasing the concentration of endogenous growth hormone in a human or animal, comprising administering to the human or animal an effective amount of the polymorph of claim 1 and an additional growth hormone secretagogue. [16" claim-type="Currently amended] 16. The method of claim 15, wherein the additional growth hormone secretagogue is selected from the group consisting of a growth hormone releasing peptide GHRP-6, a growth hormone releasing peptide GHRP-2, a growth hormone releasing peptide GHRP-1, B-HT920, a growth hormone releasing factor, ≪ / RTI > IGF-1, and IGF-2. [17" claim-type="Currently amended] A method for improving the efficiency of raising livestock, promoting growth, enhancing milk production, and improving meat quality, comprising administering an effective amount of the polymorph of claim 1 to the livestock. [18" claim-type="Currently amended] The polymorph effective amount of claim 1 is used for the treatment of osteoporosis, metabolic disease, immune deficiency in individuals with reduced T 4 / T 8 cell ratio, high fracture, musculoskeletal damage in the elderly, growth hormone deficiency in adults or children, , Patients suffering from cachexia and protein loss due to chronic diseases such as AIDS or cancer, and patients in therapy who are recovering from major surgery, injury or burn, need treatment thereof ≪ / RTI > wherein said disease is treated or prevented. [19" claim-type="Currently amended] A method of treating osteoporosis, comprising administering to a patient suffering from osteoporosis a combination of a bisphosphonate compound and the polymorph of claim 1. [20" claim-type="Currently amended] 20. The method of claim 19 wherein the bisphosphonate compound is alendronate. [21" claim-type="Currently amended] A method of increasing the concentration of endogenous growth hormone in a human or animal, comprising administering to the human or animal an effective amount of the polymorph of claim 4. [22" claim-type="Currently amended] A method for increasing the concentration of endogenous growth hormone in a human or animal, comprising administering to the human or animal an effective amount of the polymorph of claim 1 and an additional growth hormone secretagogue. [23" claim-type="Currently amended] 23. The method of claim 22, wherein the additional growth hormone secretagogue is selected from the group consisting of a growth hormone releasing peptide GHRP-6, a growth hormone releasing peptide GHRP-2, a growth hormone releasing peptide GHRP-1, a B-HT920, a growth hormone releasing factor, A homolog of the factor, IGF-1 and IGF-2. [24" claim-type="Currently amended] A method for improving the efficiency of raising livestock, promoting growth, enhancing milk production, and improving meat quality, comprising administering an effective amount of the polymorph of claim 4 to the livestock. [25" claim-type="Currently amended] The polymorph effective amount of claim 4 is used for the treatment of osteoporosis, metabolic diseases, immune deficiency in individuals with reduced T 4 / T 8 cell ratio, high fracture, musculoskeletal damage in the elderly, growth hormone deficiency in adults or children, , Patients suffering from cachexia and protein loss due to chronic diseases such as AIDS or cancer, and patients in therapy who are recovering from major surgery, injury or burn, need treatment thereof ≪ / RTI > wherein said disease is treated or prevented. [26" claim-type="Currently amended] A method for treating osteoporosis, comprising administering to a patient suffering from osteoporosis a combination of a bisphosphonate compound and the polymorph of claim 4. [27" claim-type="Currently amended] 27. The method of claim 26, wherein the bisphosphonate compound is alendronate. [28" claim-type="Currently amended] A solution of N- [1 (R) - [(1,2-dihydro-1-methanesulfonyl- spiro [3H- indole- 3,4- piperidin] Ethyl] -2-amino-2-methylpropanamide methanesulfonate in methanol at about 25 < 0 > C for about 2-24 hours, Lt; / RTI >
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同族专利:
公开号 | 公开日 PL327511A1|1998-12-21| SK51398A3|1998-12-02| NO310556B1|2001-07-23| NZ321370A|1999-11-29| BG102476A|1999-04-30| JPH10512295A|1998-11-24| BR9611229A|1999-05-25| JP3204266B2|2001-09-04| MX9803351A|1998-09-30| HU9902208A3|2001-05-28| YU56696A|1999-09-27| IS4721A|1998-04-21| HU9902208A2|1999-10-28| CN1205703A|1999-01-20| EE9800147A|1998-12-15| NO981867L|1998-06-29| EA000528B1|1999-10-28| HK1017894A1|2001-09-28| CO4770956A1|1999-04-30| TR199800726T2|1998-08-21| CN1067687C|2001-06-27| AU707946B2|1999-07-22| CA2235371A1|1997-05-01| CZ128098A3|1998-09-16| WO1997015574A1|1997-05-01| EA199800335A1|1998-12-24| EP1019402A1|2000-07-19| AU7468696A|1997-05-15| NO981867D0|1998-04-24|
引用文献:
公开号 | 申请日 | 公开日 | 申请人 | 专利标题
法律状态:
1995-10-27|Priority to US590095P 1995-10-27|Priority to US60/005,900 1996-02-16|Priority to GBGB9603361.8A 1996-02-16|Priority to GB9603361.8 1996-10-23|Application filed by 폴락 돈나 엘., 머크 앤드 캄파니 인코포레이티드 1996-10-23|Priority to PCT/US1996/016955 1999-08-16|Publication of KR19990067098A
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申请号 | 申请日 | 专利标题 US590095P| true| 1995-10-27|1995-10-27| US60/005,900|1995-10-27| GBGB9603361.8A|GB9603361D0|1996-02-16|1996-02-16|Polymorphic forms of a growth hormone secretagogue| GB9603361.8|1996-02-16| PCT/US1996/016955|WO1997015574A1|1995-10-27|1996-10-23|Polymorphic forms of a growth hormone secretagogue| 相关专利
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