WO1997015573A1 - Procede de preparation d'un facteur de secretion d'hormone de croissance - Google Patents

Procede de preparation d'un facteur de secretion d'hormone de croissance Download PDF

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Publication number
WO1997015573A1
WO1997015573A1 PCT/US1996/016954 US9616954W WO9715573A1 WO 1997015573 A1 WO1997015573 A1 WO 1997015573A1 US 9616954 W US9616954 W US 9616954W WO 9715573 A1 WO9715573 A1 WO 9715573A1
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WIPO (PCT)
Prior art keywords
compound
formula
acid
amino
protecting group
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Application number
PCT/US1996/016954
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English (en)
Inventor
Peter G. Houghton
Ioannis Houpis
Audrey Molina
Joseph E. Lynch
Ralph P. Volante
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Merck & Co., Inc.
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Publication date
Priority claimed from GBGB9602949.1A external-priority patent/GB9602949D0/en
Priority to EP96936868A priority Critical patent/EP0863900A1/fr
Priority to CA002235511A priority patent/CA2235511A1/fr
Priority to EA199800337A priority patent/EA199800337A1/ru
Priority to BR9610887A priority patent/BR9610887A/pt
Priority to PL96326428A priority patent/PL326428A1/xx
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to KR1019980703037A priority patent/KR19990067097A/ko
Priority to JP9516736A priority patent/JPH11513984A/ja
Priority to SK511-98A priority patent/SK51198A3/sk
Priority to AU74685/96A priority patent/AU7468596A/en
Priority to US09/051,847 priority patent/US6028196A/en
Publication of WO1997015573A1 publication Critical patent/WO1997015573A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms

Definitions

  • Growth hormone which is secreted from the pituitary, stimulates growth of all tissues of the body that are capable of growing.
  • growth hormone is known to have the following basic effects on the metabolic processes of the body: ( 1 ) Increased rate of protein synthesis in all cells of the body; (2) Decreased rate of carbohydrate utilization in cells of the body; (3) Increased mobilization of free fatty acids and use of fatty acids for energy.
  • a deficiency in growth hormone secretion can result in various medical disorders, such as dwarfism.
  • growth hormone Various ways are known to release growth hormone. For example, chemicals such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and insulin induced hypoglycemia, as well as activities such as sleep and exercise, indirectly cause growth hormone to be released from the pituitary by acting in some fashion on the hypothalamus perhaps either to decrease somatostatin secretion or to increase the secretion of the known secretagogue growth hormone releasing factor (GRF) or an unknown endogenous growth hormone- releasing hormone or all of these.
  • L-DOPA L-3,4-dihydroxyphenylalanine
  • GRF growth hormone releasing factor
  • certain spiro compounds are disclosed in PCT Patent Publication WO 94/13696 and Proc. Natl. Acad. Sci. USA.22, 7001-7005 (July 1995) as being non-peptidal growth hormone secretagogues. These compounds have the ability to stimulate the release of natural or endogenous growth hormone and thus may be used to treat conditions which require the stimulation of growth hormone production or secretion such as in humans with a deficiency of natural growth hormone or in animals used for food or wool production where the stimulation of growth hormone will result in a larger, more productive animal.
  • PCT Patent Publication WO 94/13696 discloses methods for preparing this compound (see Examples 18, 19 and 55). However, the synthesis of the compound was accomplished by using the very expensive amino acid coupling agent EDC ($1100/kg); the use of numerous equivalents of trifluoroacetic acid as the catalyst for the BOC group deprotections; extensive chromatographic purifications; and resulted in "gumming" of the final product.
  • the advantages of the present invention include: a 6-step high yielding non-isolation process providing material of >99.9% purity; decreased expense through the use of DCC [$40/kgl instead of EDC [$1100 kg]; diminished environmental impact through the use of methanesulfonic acid instead of trifluoroacetic acid as the catalyst (as well as lesser equivalents of catalyst) in the deprotections; and ease of isolation of the final product.
  • the instant invention is directed to a process for the preparation of the compound N-[l(R)-[(l,2-dihydro-l-methanesulfonyl- spiro[3H-indole-3,4'-piperdin]-r-yl)carbonyl]-2-(phenylmethyl- oxy)ethyl]-2-amino-2-methyl-propanamide which has the structure:
  • This compound has the ability to stimulate the release of natural or endogenous growth hormone and may be used to treat conditions which require the stimulation of growth hormone production or secretion such as in humans with a deficiency of natural growth hormone or in animals used for food or wool production where the stimulation of growth hormone will result in a larger, more productive animal.
  • the present invention is directed to a novel process for the preparation of the compound N- [1(R)-[(1, 2-dihydro-l -methanesulf onyl- spiro[3H-indole-3,4'-piperdin]- 1 '-yl)carbonyl]-2-(phenylmethyl- oxy)ethyl]-2-amino-2-methyl-propanamide which has the structure:
  • the instant process provides the desired compound from readily available inexpensive and environmentally acceptable starting materials reagents and solvents.
  • the process does not require the use any chromatographic purifications, and it is possible to produce the final product from the intermediate spiroindoline sulfonamide without isolation of any of the intermediates.
  • Acid activating agents suitable for this process include: DCC, EDC, ECAC and BOP, in which the preferred acid activating agent is DCC (N,N'-dicyclohexylcarbodiimide).
  • Catalytic agents suitable for this process include: HOBT and the like in which a preferred catalytic agent is HOBT (hydroxybenzotriazole) .
  • Inert solvents appropriate for this processes include: acetonitrile; iso-propyl acetate; ethyl acetate; propionitrile; water; chlorinated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, ortho-dichlorobenzene; benzene; toluene; xylenes; and the like; and mixtures thereof, in which the preferred solvent is either acetonitrile or isopropyl acetate and water.
  • Suitable amino protecting groups include: benzyl, benzyloxymethyl, benzyloxycarbonyl (carbobenzyloxy), benzylsulfonyl, 2-bromo-ethyloxycarbonyl, t-butoxy-carbonyl, 2-chloro-benzyloxy- carbonyl, 2-chloroethyloxycarbonyl, di-t-amyloxycarbonyl, 9-fluoroenyl- methyloxycarbonyl, isopropoxycarbonyl, 4-methoxy-benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrophenyl-sulfonyl, phthaloyl, 2,2,2- trichloro-t-butyloxycarbonyl, trifluoroacetyl, triphenylmethane, allyloxycarbonyl, and vinyloxycarbonyl groups, and
  • L is an amino protecting group, with an amino deprotecting agent to give the compound of formula II.
  • Suitable amino protecting groups include: benzyl, benzyloxymethyl, benzyloxycarbonyl (carbobenzyloxy), benzylsulfonyl, 2-bromo-ethyloxycarbonyl, t-butoxy-carbonyl, 2-chloro-benzyloxy- carbonyl, 2-chloroethyloxycarbonyl, di-t-amyloxycarbonyl, 9-fluoroenyl- methyloxycarbonyl, isopropoxycarbonyl, 4-methoxy-benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrophenyl-sulfonyl, phthaloyl, 2,2,2- trichloro-t-butyloxycarbonyl, trifluoroacetyl, triphenylmethane, allyloxycarbonyl, and vinyloxycarbonyl groups, and the like
  • the removal of the amino protecting group may be accomplished by use of an appropriate catalytic agent.
  • Removal of a t-butoxycarbonyl protecting group may be carried out in a solvent such as methanol, ethanol, methylene chloride, ethyl acetate, or iso ⁇ propyl acetate, with a strong acid.
  • Such strong acids include methanesulfonic acid, trifluoroacetic acid, hydrochloric acid, hydrogen chloride gas, hydrogen bromide; hydrogen iodide; trifluoromethane- sulfonic acid; camphorsulfonic acid; sulfuric acid; phosphoric acid; and an arylsulfonic acid, such as benzenesulfonic acid, p-toluenesulfonic acid, and p-chlorobenzene-sulfonic acid.
  • Preferred catalytic agents include: trifluoroacetic acid; methanesulfonic acid; camphorsulfonic acid; benzenesulfonic acid, p-toluenesulfonic acid; and p-chlorobenzene- sulfonic acid.
  • the most preferred catalytic agent is methanesulfonic acid.
  • the preferred solvent is methanol or ethanol, and the most preferred solvent is ethanol.
  • the preferred reaction temperature range is between -40 and 150°C, and the most preferred range is between 10 and 40°C.
  • Removal of a benzyloxycarbonyl (carbobenzyloxy) group may be achieved by a number of methods, for example, catalytic hydrogenation with hydrogen in the presence of a noble metal or its oxide such as palladium on activated carbon in a protic solvent such as ethanol.
  • the removal of benzyloxycarbonyl (carbobenzyloxy) group may also be achieved by treatment with a solution of hydrogen bromide in acetic acid, or by treatment with a mixture of TFA and dimethylsulfide.
  • this acid- catalyzed deprotection be conducted in situ without isolation of the compound of formula II following its preparation by the aforementioned process.
  • a third process concerns the preparation of a compound of formula III:
  • Acid activating agents suitable for this process include: DCC, EDC, ECAC and BOP, in which the preferred acid activating agent is DCC (N,N'-dicyclohexylcarbodiimide).
  • Catalytic agents suitable for this process include: HOBT and the like in which a preferred catalytic agent is HOBT (hydroxybenzotriazole).
  • Inert solvents appropriate for this processes include: acetonitrile; isopropyl acetate; ethyl acetate; propionitrile; water; chlorinated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, ortho-dichlorobenzene; benzene; toluene; xylenes; and the like; and mixtures thereof, in which the preferred solvent is a mixture of iso-propyl acetate and water, preferably in a ratio of approximately 40:60 to 60:40 (by volume) and more preferably in a ratio of approximately 50:50 (by volume).
  • Suitable amino protecting groups include: benzyl, benzyloxymethyl, benzyloxycarbonyl (carbobenzyloxy), benzylsulfonyl, 2-bromo-ethyloxycarbonyl, t-butoxy-carbonyl, 2-chloro-benzyloxy- carbonyl, 2-chloroethyloxycarbonyl, di-t-amyloxycarbonyl, 9-fluoroenyl- methyloxycarbonyl, isopropoxycarbonyl, 4-methoxy-benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrophenyl-sulfonyl, phthaloyl, 2,2,2- trichloro-t-butyloxycarbonyl, trifluoroacetyl, triphenylmethane, allyloxycarbonyl, and vinyloxycarbonyl groups, and
  • a fourth process concerns the preparation of a compound of formula IV, or a pharmaceutically acceptable salt thereof:
  • Suitable amino protecting groups include: benzyl, benzyloxymethyl, benzyloxycarbonyl (carbobenzyloxy), benzylsulfonyl, 2-bromo-ethyloxycarbonyl, t-butoxy-carbonyl, 2-chloro-benzyloxy- carbonyl, 2-chloroethyloxycarbonyl, di-t-amyloxycarbonyl, 9-fluoroenyl- methyloxycarbonyl, isopropoxycarbonyl, 4-methoxy-benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrophenyl-sulfonyl, phthaloyl, 2,2,2- trichloro-t-butyloxycarbonyl, trifluoroacetyl, triphenylmethane, allyloxycarbonyl, and vinyloxycarbonyl groups, and the like, in which the preferred ones include benzyloxycarbonyl (carbobenzyloxy),
  • the removal of the amino protecting group may be accomplished by use of an appropriate catalytic agent.
  • Removal of a t-butoxycarbonyl protecting group may be carried out in a solvent such as methanol, ethanol, methylene chloride, ethyl acetate, or iso ⁇ propyl acetate, with a strong acid.
  • Such strong acids include methanesulfonic acid, trifluoroacetic acid, hydrochloric acid, hydrogen chloride gas, hydrogen bromide; hydrogen iodide; trifluoromethane- sulfonic acid; camphorsulfonic acid; sulfuric acid; phosphoric acid; and an arylsulfonic acid, such as benzenesulfonic acid, p-toluenesulfonic acid, and p-chlorobenzene-sulfonic acid.
  • Preferred catalytic agents include: trifluoroacetic acid; methanesulfonic acid; camphorsulfonic acid; benzenesulfonic acid, p-toluenesulfonic acid; and p-chlorobenzene- sulfonic acid.
  • the most preferred catalytic agent is methanesulfonic acid. It is preferred that compound of formula V is isolated in the form of the methanesulfonate salt.
  • the preferred solvent is methanol or ethanol, and the most preferred solvent is ethanol.
  • the preferred reaction temperature range is between -40 and 150°C, and the most preferred range is between 10 and 40°C.
  • Removal of a benzyloxycarbonyl (carbobenzyloxy) group may be achieved by a number of methods, for example, catalytic hydrogenation with hydrogen in the presence of a noble metal or its oxide such as palladium on activated carbon in a protic solvent such as ethanol.
  • the removal of benzyloxycarbonyl (carbobenzyloxy) group may also be achieved by treatment with a solution of hydrogen bromide in acetic acid, or by treatment with a mixture of TFA and dimethylsulfide.
  • this acid- catalyzed deprotection be conducted in situ without isolation of the compound of formula IV following its preparation by the aforementioned process.
  • a fifth process concerns the preparation of a pharmaceutically acceptable salt of a compound of formula IV, in particular, the methanesulfonate salt, i.e. a compound of formula V:
  • compound of formula V is isolated in the form of the methanesulfonate salt.
  • the preferred solvent comprises ethyl acetate and ethanol, and the most preferrred solvent is a mixture of ethyl acetate and ethanol.
  • the formation of the salt be conducted in situ without isolation of the compound of formula V following its preparation by the aforementioned process.
  • the CBZ-Spiroindoline I is treated with Darco (20% by weight) prior to hydrogenation.
  • the hydrogenation is carried out in ethanol at 65°C over 10% Pd C with vigorous stirring.
  • a solution of lb in isopropyl acetate and water is coupled with commercially available N-BOC-O-benzyl-D-serine in the presence of dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBt).
  • DCC dicyclohexylcarbodiimide
  • HOBt 1-hydroxybenzotriazole
  • the BOC-group of li is removed by treatment with methanesulfonic acid (MsOH) (3 eq) in ethanol at 35-40°C. Partitioning between isopropyl acetate and aqueous IM sodium hydroxide solution affords 12.
  • MsOH methanesulfonic acid
  • the coupling of 12 with N-BOC- ⁇ -aminoisobutyric acid is best conducted in a two-phase solvent system, isopropyl acetate/water ( 1 : 1 ) in the presence of DCC and HOBt (1.1 eq. each). Removal of the DCU by filtration, separation of the layers and washing the organic layer successively with IM aqueous sodium hydroxide, 0.5M aqueous hydrochloric acid and saturated aqueous sodium hydrogen carbonate affords ⁇ 4. The mixture is solvent switched to ethanol for the subsequent methanesulfonic acid cleavage of the Boc group.
  • the ethyl acetate solution of the free base 1 is concentrated to low bulk in vacuo and is azeotroped dry (KF ⁇ 500 mgmf ) by "feeding and bleeding" 2x batch volumes of 90/10, ethyl acetate/ethanol followed by 2x batch volumes of ethyl acetate.
  • the resulting dry, slightly hazy solution of the free base 15 in ethyl acetate is treated with Darco G-60 (25 weight %) at room temperature for about 10 hours. Removal of the Darco by filtration with a filtration agent gives the free base 1 .
  • Formation of the methanesulfonic acid salt 16 from 15 is carried out in EtOAc with 1.1 eq of MsOH at about 50°C.
  • Form II The conversion of Form II to Form I is accomplished where the salt is formed in EtOAc-EtOH as above, but instead of cooling the initial solution of the salt (at 55°C) to ambient temperature, it is cooled to 45°C. Crystals should start appearing at that temperature and the slurry should become thicker with time. The temperature is then raised to 51°C and the slurry is aged overnight. Complete conversion to Form I of 16 should be expected.
  • the conversion of Form II to Form I is achieved by adding seed crystals of Form I to a solution of the free base in EtOAc- EtOH at 50-55°C followed by aging.
  • the free base 13 may be treated with 1.1 equivs. of methanesulfonic acid in 8% ethanol in ethyl acetate at 50-55°C.
  • the batch is then seeded with approximately 2% by weight of Form I of the methanesulfonate salt 16, and then aged at 55 °C overnight.
  • the batch is cooled to room temperature and aged for approximately 2-3 hours.
  • the product is isolated by filtration at room temperature under a nitrogen atmosphere, dried at 35 °C in vacuo and sieved to give the methanesulfonate salt J_6.
  • the methanesulfonic acid salt 16 may also be formed by alternating the 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°C, wherein the order of addition of the MsOH and the seed is not critical.
  • peptide coupling reaction is intended to mean the coupling of a carboxylic acid with an amine using an acid activating agent such as EDC, DCC, and BOP in an inert solvent in the presence of a catalyst such as HOBT.
  • Inert solvents appropriate for such couplings include: acetonitrile; iso-propyl acetate; ethyl acetate; propionitrile; water; chlorinated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, ortho- dichlorobenzene; benzene; toluene; xylenes; and combinations thereof; and the like.
  • variable "L” and the term "amino protecting group” is intended to indicate the presence of an appropriate protecting group for amino, such as those described in Greene, T.W., Wuts, P.G.M. Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Sons, Inc., New York, 1991.
  • An appropriate protecting group will be able to withstand the reaction conditions of intermediate processes, prior to being removed when desired.
  • the amino protecting group is independently selected for each process within the entire processes.
  • Suitable amino protecting groups include: benzyl, benzyloxymethyl, benzyloxycarbonyl (carbobenzyloxy), benzylsulfonyl, 2-bromo-ethy loxycarbony 1 , t-butoxy-carbony 1, 2-chloro-benzy .oxy ⁇ carbonyl, 2-chloroethyloxycarbonyl, di-t-amyloxycarbonyl, 9-fluoroenyl- methyloxycarbonyl, isopropoxycarbonyl, 4-methoxy-benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrophenyl-sulfonyl, phthaloyl, 2,2,2- trichloro-t-butyloxycarbonyl, trifluoroacetyl, triphenylmethane, and vinyloxycarbonyl groups, and the like, in which the preferred ones include benzyloxycarbonyl (carbobenzyloxy), t-butoxy-carbon
  • the removal of the amino protecting group may be accomplished by use of an appropriate catalytic agent. Removal of a t- butoxycarbonyl protecting group may be carried out in a solvent such as methanol, ethanol, methylene chloride, ethyl acetate, or iso-propyl acetate, with a strong acid.
  • a solvent such as methanol, ethanol, methylene chloride, ethyl acetate, or iso-propyl acetate
  • Such strong acids include methanesulfonic acid, trifluoroacetic acid, hydrochloric acid, hydrogen chloride gas, hydrogen bromide; hydrogen iodide; trifluoromethane-sulfonic acid; camphorsulfonic acid; sulfuric acid; phosphoric acid; and arylsulfonic acids, such as benzenesulfonic acid, p-toluenesulfonic acid, and p- chlorobenzene-sulfonic acid.
  • Preferred catalytic agents include: trifluoroacetic acid; methanesulfonic acid; camphorsulfonic acid; benzenesulfonic acid, p-toluenesulfonic acid; and p-chlorobenzene- sulfonic acid.
  • the most preferred catalytic agent is methanesulfonic acid.
  • the preferred solvent is methanol or ethanol.
  • Removal of a benzyloxycarbonyl (carbobenzyloxy) protecting group may be achieved by a number of methods, for example, catalytic hydrogenation with hydrogen in the presence of a noble metal or its oxide such as palladium on activated carbon in a protic solvent such as ethanol.
  • the removal of benzyloxycarbonyl (carbobenzyloxy) group may also be achieved by treatment with a solution of hydrogen bromide in acetic acid, or by treatment with a mixture of TFA and dimethylsulfide.
  • the amine compounds employed as starting materials for the process of the present invention may be present as their acid salts, such as the salts derived from using inorganic and organic acids.
  • acids are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic, methane sulfonic and the like.
  • the compounds produced by the processes of the instant invention may be isolated in the form of their pharmaceutically acceptable acid salts.
  • certain compounds containing an acidic function such as a carboxy can be in the form of their inorganic salt in which the counterion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as from organic bases.
  • the preparation of compounds with the process of the present invention may be carried out in sequential or convergent synthetic routes. It is noted that in some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. In general, the process of the present invention is conducted in a sequential manner as presented herein. Many of the starting materials are either commercially available or known in the literature and others can be prepared following literature methods described for analogous compounds. The skills required in carrying out the reaction and purification of the resulting reaction products are known to those in the art. Purification procedures include crystallization, normal phase or reverse phase chromatography.
  • Isonipecotic acid (2) and K2CO3 were dissolved in 40.2 L of water in a 100 L 4 neck flask with mechanical stirring under N2 and the solution was cooled to 10°C.
  • Benzyl chloroformate was added, maintaining the temperature between 9 and 14°C, and the mixture was warmed up to 22°C after the addition was complete and aged for 58 h.
  • the addition was completed in 4 h at which point the pH was 9.0. After aging for 58 h there was no change in the pH.
  • the aqueous phase was acidified with 37% aqueous HCl to pH 1.8. Carbon dioxide was evolved during the addition of HCl, but gas evolution was easily controlled. The addition of HCl took ⁇ 1 h and required 10 L of cone. HCl.
  • the aqueous phase was extracted with 3 x 6.6 L of toluene. The toluene extracts were dried with 2 kg of sodium sulfate and filtered through a pad of Solka-flocTM. The combined filtrates weighed 17.8 kg. The crude yield of carbamate 3 was 7.89 kg (97%) (as obtained by evaporation of weighed aliquots of the filtrates to dryness).
  • the filtrates were transferred through a 10 ⁇ inline filter to a 100 L flask.
  • the extracts were concentrated at 10 mbar at ⁇ 25°C to a volume of 18 L.
  • the final concentration of carbamate 3 was 440 g/L.
  • the product was 99.1 area % pure with 0.9 area % benzyl alcohol as the only impurity.
  • the assay yield of aldehyde 3 was 94% by HPLC analysis.
  • the crude aldehyde 5 solution from the previous step was transferred through a 10 ⁇ inline filter to a 100 L reactor equipped with Teflon coated copper coils for cooling or heating and a mechanical stirrer. Toluene (34.4 kg) and MeCN (7 L) were added, and the resulting solution was cooled to 0°C. Phenylhydrazine was added in portions and the temperature was maintained at -1 to 3°C while nitrogen was continuously bubbled through the reaction mixture.
  • the color change from green to orange corresponds very closely to reaction end point.
  • the quantity of NaBH4 required to complete the reaction is heavily dependent on the temperature and rate of addition of NaBH4, but the yield and quality of the product is virtually unaffected provided that the reaction is complete.
  • the reaction mixture was cooled to 5°C over a period of 30 min.
  • 8 L of 3% aqueous NH4OH (8 L) were added to bring the pH of the aqueous phase to 7.4, the mixture was agitated, and allowed to settle.
  • the temperature rose to 15°C.
  • the cloudy yellow lower aqueous phase was separated.
  • the organic phase was washed with 4 L of 3% aqueous NH4OH, 2 x 4 L of water, and 2 X 4 L of brine.
  • the weight of the organic phase after the washings was 53.5 kg, and the assay yield was 94%.
  • the washed toluene solution was combined with the washed organic phases of two other similarly processed reactions.
  • the total aldehyde used in the three reactions was 5.06 kg, (20.5 mol).
  • the total weight of CBZ-indoline 9 assayed in the combined organic phases was 5.91 kg, (18.3 mol, 90% assay yield).
  • the combined organic phases were dried with 5 kg of sodium sulfate, treated with 250 g of Darco G60 carbon for 30 min, and filtered through Solka-flocTM.
  • the filtrates were vacuum concentrated at 10 mbar at ⁇ 25°C until the residue was near dryness.
  • the solvent switch was completed by slowly bleeding in 30 L of IPAC and reconcentrating to 14 L at 200 mbar at 50-60°C.
  • the mixture was heated to reflux in order to obtain a clear homogeneous deep orange solution. iH NMR analysis indicated that the solution contained ca. 6 mol% of residual toluene after solvent switch.
  • the solution was cooled to 68°C and seeded with 4 g of crystalline CBZ-indoline 9.
  • the solution was allowed to gradually cool to 26°C over 6 h and aged for 9 h at 20-26°C.
  • the slurry was cooled to 2°C over 1 h and aged at 2°C for lh.
  • the product was isolated by filtration, and the filter cake was washed with 2 x 2 L of 5°C IPAC and 2 x 2 L of 5°C MTBE.
  • the product was dried in the vacuum oven at 30°C under a nitrogen bleed to give 4.37 kg (74%) of the title compound 9 as a light tan crystalline powder.
  • HPLC analysis of the product indicated 99.5 area % purity.
  • reaction mixture was warmed to 18°C and aged for 16 h. There was no change in the appearance of the reaction mixture, and HPLC profile between the end of the addition and after the 16 h age.
  • the reaction mixture was slowly transferred over lh into a vigorously stirred solution of 30 L of water and 200 mL of 37% aqueous HCl in a 50 L flask. The temperature in the 50 L flask rose from 22 to 28°C. The product separated as a pale tan gummy solid which changed to a granular solid.
  • the aqueous suspension was cooled to 22°C and aged for 1 h. The suspension was filtered, and the filter cake was washed with 2 x 4 L of MeOH/water (50/50).
  • HPLC analysis indicated that ⁇ 0.1% of the CBZ-Spiroindoline- methanesulfonamidel was in the mother liquors.
  • the filter cake was washed with 4 L of MeOH/water (50/50) to which 50 mL of 28% aqueous NH4OH had been added.
  • the filter cake was washed with 2 x 4 L of MeOH/water (50/50), and the solid was dried in the vacuum oven at 50°C under a nitrogen bleed to give 2.03 kg (97%) of the title product 1 as an off-white powder.
  • HPLC analysis of the solids indicated 93.7 area % 1.
  • the CBZ-aldehyde 5 was dissolved in dichloromethane in a 1 L flask equipped with Teflon coated magnetic stirring bar. The resulting solution was cooled to 0°C. Phenylhydrazine was added via a weighed syringe over 5 min and the temperature was maintained at - 1 to 3°C while nitrogen was continuously bubbled through the reaction mixture.
  • HPLC conditions 25 cm Dupont Zorbax RXC8 column at 30°C with 1.0 mLJmin flow and detection at 254 nm; gradient schedule:
  • the reaction mixture was aged for 10 min at 0-2°C, and TFA was added by syringe maintaining the temperature between 2 and 7°C.
  • the reaction mixture was warmed to 35°C over 30 min, and maintained for 17 h.
  • the nitrogen sparge through the reaction mixture was stopped and a slow stream of nitrogen was maintained over the reaction mixture.
  • the color gradually darkened to a rosy pink then to a deep green, and a relatively small amount of a white crystalline precipitate (ammonium trifluoroacetate) formed.
  • HPLC analysis (same conditions as above) indicated that the reaction mixture contained 93 area % indolenine 8 and ⁇ 0.5% of unreacted phenylhydrazone remained.
  • a 2% (by volume) solution of MeCN in toluene was made up using 654 mL of toluene and 13.3 mL of MeCN.
  • 617 ml of the above solution were degassed by passing a fine stream of nitrogen through the solution for 5 min. Phenylhydrazine and TFA were added to the mixture while still degassing.
  • the CBZ-aldehyde 5 was dissolved in the rest of the solution prepared above (50 mL) and degassed by bubbling nitrogen through the solution while in the addition funnel.
  • the mixture was warmed to 20°C, and 200 mL of IM aqueous HCl was added.
  • the mixture was warmed to 50°C, and the aqueous phase was separated.
  • the organic phase was washed sequentialy with 100 mL water, 100 mL 5% aqueous sodium bicarbonate, and 100 mL water.
  • the organic phase was transferred to a 1 L 3 neck flask equipped for mechanical stirring and distillation.
  • the mixture (ca 400 mL) was distilled at atmospheric pressure until 150 mL of distillate had been collected.
  • the head temperature reached 107°C; the pot temperature was 110°C.
  • the distillation was continued with continuous addition of n-propanol at such a rate as to maintain a constant volume (ca 350 mL) in the pot.
  • the distillation was stopped when a total of 525 mL of n-PrOH had been added and a total of 800 mL of distillate had been collected.
  • n-PrOH crystallized sulfonamide was dissolved in 134 mL of EtOAc at 60°C and treated with 8.0 g of Darco G-60 carbon for 1 h at 60°C. After the addition of 2.0 g SolkaflocTM, the slurry was filtered through a pad of 4.0 g SolkaflocTM, and the pad was washed with 90 mLof EtOAc at 60°C. Prior to the addition of the carbon the solution was a brown color. The filtration proceeded well without plugging to give a golden yellow filtrate.
  • the filtrate was distilled at atmospheric pressure in a 500 mL flask (pot temperature 80-85°C) until 100 g (100 mL) of residue remained. This solution was allowed to cool to 35°C over 3 h. Over a lh period, 116 mL of cyclohexane was added with good agitation at 35°C. The mixture was cooled to 20°C over 1 h and aged at 20°C for 12 h. At 35 °C much of the sulfonamide has crystallized out and the mixture was thick. Addition of cyclohexane at 20°C makes agitation difficult. After the aging period, the supernatant was found to contain 2.5 mg 1/g.
  • the crystalline slurry was filtered and the cake was washed with 77 mL of 2: 1 cyclohexane-EtOAc and 2 x 77 mL of cyclohexane.
  • the mixture was purged with nitrogen and the catalyst was removed by filtration through Solka-flocTM while still warm.
  • the catalyst was washed with 4 L of THF and 2 L of MeOH.
  • the pale yellow filtrates were concentrated to a thick oil at 10 mbar and ⁇ 25°C.
  • the solvent switch was completed by slowly bleeding in 15 L of EtOAc and reconcentrating to dryness.
  • the residue solidified to a hard off-white mass.
  • MeOH (1.5 L) was added and the mixture was heated to 70°C to give a homogenous solution. While the solution was at 70°C, 10.5 L of EtOAc at 20°C was added. The temperature fell to 40°C, and the mixture remained homogenous.
  • the hydrogenation was run three (3) times due to equipment limitations; this procedure refers to a single run.
  • the catalyst loading and reaction time are a function of the purity of starting material 1. This material was unique requiring > 15% catalyst and long reaction time.
  • the initial vessel, the filter, the pump and the lines were rinsed with a hot (60-65 °C) mixture of aqueous ammonia (500 ml) in absolute ethanol (25 L).
  • the filtrate and washings were combined in the two stainless-steel bins.
  • the batch was then transfe ⁇ ed to a vessel using an in-line filter containing a 10 micron cartridge, and then concentrated in vacuo to low bulk (-15 L).
  • the ethanol was replaced by isopropyl acetate by the "feeding and bleeding" of 3x batch volumes of isopropyl acetate (45 L total), while maintaining a batch volume of -15 L.
  • the solvent switch when complete, contained ⁇ 1% residual ethanol by GC.
  • the batch was then diluted to -33 L by the addition of isopropyl acetate (20 L), and this solution of spiroindoline-amine lb (1.855 kg by LC analysis) in isopropyl acetate was used for the next stage of the process.
  • the batch was sti ⁇ ed at room temperature under nitrogen atmosphere for 5 hours when LC showed the ratio of product/starting material to be 99.4/0.6.
  • the mixture was then filtered through an Estrella filter using cloth and cardboard only and utilizing a pump into another vessel.
  • the sending vessel was rinsed with isopropyl acetate (22 L) and this was used to rinse the filter, the pump and the lines into the receiving vessel.
  • the 2-phase mixture in the vessel was stirred for 10 minutes and then allowed to settle for 15 minutes. The lower aqueous layer was separated off and the organic solution was left to stand at room temperature overnight.
  • Methanesulphonic acid (2.006 kg, 1.355 L, -3 equivs.) was added to the sti ⁇ ed solution of Boc-O-benzylserine spiroindoline (11) (3.787 kg) in ethanol (total volume -15 L) in a reaction vessel.
  • the batch was warmed to 35-40°C. After 7 hours, LC showed the absence of starting material and the reaction was allowed to cool to room temperature overnight.
  • water (44 L) was added to the batch with stirring. The batch was cooled to -5°, stirred for 30 minutes and then filtered through an in-line filter (loaded with a lO ⁇ cartridge) into a bin. The batch was then sucked back into the vessel.
  • the solution of the amine 12 in IPAc was diluted to a total volume of 39 L with IPAc and 37 L of H2 ⁇ was added.
  • the biphasic mixture was then treated in sequence with HOBT (827 g) as a solid, DCC (1266.7 g) as a melt, and amino acid 13 at ambient temperature under nitrogen.
  • the reaction mixture was stirred for 2 h upon which time LC analysis indicated dissappearance of the starting material 12 ( ⁇ 0.3 A%).
  • the mixture was filtered through Solka FloeTM and the solids were washed with 13 L of IPAc. The material may be stored at this point as a biphasic mixture overnight.
  • Isopropyl acetate 22 L was used to rinse vessel, the filter , the pump and the lines into the receiving vessel.
  • the 2- phase mixture was then stirred for 5 minutes and the layers were allowed to separate.
  • the organic solution was then washed sequentially with IM aqueous sodium hydroxide (38 L), 0.5M aqueous hydrochloric acid (38 L) and finally, saturated aqueous sodium hydrogen carbonate (38 L) without incident.
  • the Boc spiroindoline 14 was dissolved in 6.2 L of EtOH and treated with MsOH (979 mL). The temperature rose from 20 to 30°C and the reaction was allowed to proceed overnight. After 12 hours at 20°C there was still 15 A% of starting material left so the mixture was heated to 35°C for 6 hours. Upon completion ( ⁇ 0.1 A% 14) the reaction was cooled to 20°C and 30 L of H2 ⁇ were added and the solution was filtered through a glass funnel with a polypropylene filter to filter off residual DCU. The mixture was transferred to a 100 L extractor and 26 L of EtOAc were added. The aqueous layer was basified via addition of chilled IN NaOH (11 L) and 1 L of 50% NaOH. Addition of ice was required to keep the temperature below 14°C. Higher temperatures resulted in significant emulsion problems.
  • the organic layer was distilled at 50°C at ca. 21 " of Hg until KF ⁇ 1000 ⁇ g/mL. Lower KF's result in more efficient carbon treatments and better recovery at the salt formation step. KF's of 160 ⁇ g/mL were achieved at the 700 g scale.
  • the solution was diluted with ethyl acetate to a total volume of 31 L (LC assay 2.40 kg).
  • Activated carbon (Darco G-60) was added and the mixture was stirred for 24 h.
  • the mixture was filtered through Solka FloeTM and the filter cake was washed with ethyl acetate (16 L), assay 2.34 Kg.
  • Methanesulfonic acid (2.017 kg, 1.36 L, -3 equivs.) was added to the stirred solution of the Boc spiroindoline 14 (4.395 kg) in ethanol (total volume -25 L) in a reaction vessel at room temperature.
  • the batch was warmed to 35-40°C, and sti ⁇ ed overnight.
  • the batch contained -1.1 A% of starting material and so the reaction was continued for a further 4 hours, then LC showed ratio of product/ starting material to be 99.6/0.4.
  • the batch was concentrated in vacuo to -15 L volume and then diluted with water (44 L).
  • the batch was cooled to 5°C, sti ⁇ ed for 30 minutes and then filtered through a Sparkler in-line filter (containing a lO ⁇ cartridge) using a pump to another vessel to remove a small amount of residual DCU.
  • the vessel, the pump, the filter and the lines were rinsed with water (10 L), and this was added to the vessel.
  • Ethyl acetate (36 L) was added to the vessel and the stirred mixture was cooled to 10°C.
  • a solution of cold (5-10°C) IM aqueous sodium hydroxide solution (16 L) and cold (5-10°C) 50% aqueous sodium hydroxide solution (2.6 L) were added at 10°C and the temperature rose to 14°C. The resulting mixture was stirred for 15 minutes at ⁇ 14°C and then the lower aqueous layer separated off.
  • the batch was concentrated in vacuo to -20 L volume and then a mixture of ethyl acetate (35 L) and ethanol (5 L) was fed in while maintaining the volume at -20 L. At the end of this distillation the KF was 9160 mgml " .
  • the batch was solvent switched to ethyl acetate by "feeding and bleeding" ethyl acetate (40 L total). At the end of this distillation, KF was 446 mgml " .
  • the batch was diluted with ethyl acetate (10 L).
  • the batch (58 L) had a KF of 2950 mgml " 1 and so was redried by concentrating in vacuo to 20-25 L volume.
  • the batch was diluted to 46 L volume (dipstick) by the addition of ethyl acetate (25 L).
  • the KF was 363 mgml .
  • the batch was diluted to 62 L volume by the addition of ethyl acetate (17 L) and was used for the final stage of the process.
  • the volume of the solution of 15 from the previous step was adjusted to 60 L with ethyl acetate and EtOH (4.8 L) was added.
  • the MsOH (316 mL) was added in 3 L of EtOAc at 45°C.
  • To the deep red homogeneous solution was added 496 g of the title compound Form I seed (10% seed based on the weight of the free amine was employed). The temperature rose to ca. 48°C and the reaction was aged at 52°C for 1.5 hours. Analysis indicated complete conversion to the title compound (Form I). (At less than 10% seed longer age (> 3 hours) was required).
  • Form I (99.9 A% purity; ⁇ 0.1% enantiomer).
  • the conversion of Form II to Form I is also accomplished where the salt is formed in EtOAc-EtOH by addition of MsOH as above and the initial solution of the salt (at 55°C) is cooled to 45°C. Crystals start appearing at that temperature and the slurry becomes thicker with time. The temperature is then raised to 51°C and the slurry is aged ovemight. Complete conversion to Form I of 16 should be expected. This procedure may also be employed to prepare seed crystals of Form I of 16.
  • Absolute ethanol (6.4 L) was added to the solution of the amine (15) (3.1 kg) in ethyl acetate (total volume -62 L) in a reacttion vessel. The batch was warmed to 50°C and a solution of methanesulfonic acid (620 g, 412 ml, 1.1 equivs.) in ethyl acetate (11 L) was added over -5 minutes at 50-54°C.
  • Form I of N-[l(R)-[(l,2-dihydro-l-methanesulfonyl- spiro[3H-indole-3,4'-piperdinl-l'-yl)carbonyl]-2-(phenylmethyl- oxy)ethyl]-2-amino-2-methylpropanamide methanesulfonate is an anhydrous polymorph characterized by the following properties: a melting point of 168- 171 °C and solubility in isopropanol of
  • Form I was characterized by an X-ray powder diffraction pattem with reflections at approximately: 6.5, 14.7, 16.9, 17.1, 17.9, 19.5, 21.1, 21.7, and 22.0° (2 theta). Data collected using a Philips APD3720 Automated Powder Diffraction instmment with copper K ⁇ radiation. Measurements were made from 2° to 40° (2 theta) with the sample maintained at ambient room temperature. HPLC Conditions:

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Abstract

La présente invention se rapporte à un nouveau procédé de préparation du composé N-[1(R)-[1,2-dihydro-1-méthanesulfonylspiro[3H-indole-3,4'-piperdin]-1'-yl)carbonyl]-2-(phénylméthyloxy)éthyl]-2-amino-2-méthyl-propanamide, et de certains de ses sels, ledit composé étant représenté par la formule (1) et pouvant stimuler la libération de l'hormone de croissance naturelle ou endogène. Ce composé peut être utilisé pour traiter des états nécessitant une stimulation de la production ou de la sécrétion de l'hormone de croissance, par exemple chez des sujets humains présentant une carence en hormone de croissance naturelle ou chez des animaux utilisés pour la production alimentaire ou lainière, la stimulation de l'hormone de croissance permettant d'accroître la taille de l'animal et de le rendre plus productif.
PCT/US1996/016954 1995-10-27 1996-10-23 Procede de preparation d'un facteur de secretion d'hormone de croissance WO1997015573A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
US09/051,847 US6028196A (en) 1995-10-27 1996-10-23 Process for the preparation of a growth hormone secretagogue
CA002235511A CA2235511A1 (fr) 1995-10-27 1996-10-23 Procede de preparation d'un facteur de secretion d'hormone de croissance
EA199800337A EA199800337A1 (ru) 1995-10-27 1996-10-23 Способ получения гормона роста, усиливающего секрецию
BR9610887A BR9610887A (pt) 1995-10-27 1996-10-23 Processo para a preparação de um composto
PL96326428A PL326428A1 (en) 1995-10-27 1996-10-23 Method of obtaining a compound stimulating hormonal secretion of a growth hormone
EP96936868A EP0863900A1 (fr) 1995-10-27 1996-10-23 Procede de preparation d'un facteur de secretion d'hormone de croissance
KR1019980703037A KR19990067097A (ko) 1995-10-27 1996-10-23 성장 호르몬 분비 촉진제의 제조 방법
JP9516736A JPH11513984A (ja) 1995-10-27 1996-10-23 成長ホルモン分泌促進剤の製造方法
SK511-98A SK51198A3 (en) 1995-10-27 1996-10-23 Method for producing n-[1(r)-[(1,2-dihydro-1- -methanesulfonylspiro[3h-indole-3,4'-piperidine-1'-yl)carbonyl]- -2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide
AU74685/96A AU7468596A (en) 1995-10-27 1996-10-23 Process for the preparation of a growth hormone secretagogue

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US589895P 1995-10-27 1995-10-27
US60/005,898 1995-10-27
GBGB9602949.1A GB9602949D0 (en) 1996-02-13 1996-02-13 Process for the preparation of a growth hormone secretagogue
GB9602949.1 1996-02-13

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998018815A1 (fr) * 1996-10-25 1998-05-07 Merck & Co., Inc. Procede convergent de preparation d'un secretagogue d'hormone de croissance
US5885999A (en) * 1996-01-29 1999-03-23 Merck Sharp & Dohme Ltd. Serine derivatives and their use as therapeutic agents
EP1159964A2 (fr) 2000-05-31 2001-12-05 Pfizer Products Inc. Compositions et methodes pour stimuler la motilité gastrointestinale
US6329342B1 (en) 1997-08-19 2001-12-11 Eli Lilly And Company Treatment of congestive heart failure with growth hormone secretagogues
US6639076B1 (en) 1998-08-18 2003-10-28 Eli Lilly And Company Growth hormone secretagogues
US6828331B1 (en) 1999-02-19 2004-12-07 Eli Lilly And Company Growth hormone secretagogues
US7125840B2 (en) 2001-10-09 2006-10-24 Eli Lilly And Company Substituted dipeptides as growth hormone secretagogues
WO2007098716A1 (fr) 2006-02-28 2007-09-07 Centro De Ingeniería Genética Y Biotecnología Composés analogues aux sécrétagogues peptidiques de l'hormone de croissance et préparations contenant ceux-ci
US7396846B2 (en) 2002-04-09 2008-07-08 Eli Lilly And Company Growth hormone secretagogues
EP2457893A1 (fr) 2004-06-18 2012-05-30 Tranzyme Pharma, Inc. Intermédiaires pour des modulateurs macrocycliques du récepteur de ghréline
EP2644618A1 (fr) 2007-02-09 2013-10-02 Tranzyme Pharma, Inc. Intermédaires dans la synthese de modulateurs macrocycliques du récepteur de la ghréline
WO2017075535A1 (fr) 2015-10-28 2017-05-04 Oxeia Biopharmaceuticals, Inc. Méthodes de traitement de troubles neurodégénératifs
US10105416B2 (en) 2014-02-05 2018-10-23 The Regents Of The University Of California Methods of treating mild brain injury

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994013696A1 (fr) * 1992-12-11 1994-06-23 Merck & Co., Inc. Spiro-piperidines et homologues favorisant la liberation de l'hormone de croissance

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994013696A1 (fr) * 1992-12-11 1994-06-23 Merck & Co., Inc. Spiro-piperidines et homologues favorisant la liberation de l'hormone de croissance

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5885999A (en) * 1996-01-29 1999-03-23 Merck Sharp & Dohme Ltd. Serine derivatives and their use as therapeutic agents
WO1998018815A1 (fr) * 1996-10-25 1998-05-07 Merck & Co., Inc. Procede convergent de preparation d'un secretagogue d'hormone de croissance
US6329342B1 (en) 1997-08-19 2001-12-11 Eli Lilly And Company Treatment of congestive heart failure with growth hormone secretagogues
US6639076B1 (en) 1998-08-18 2003-10-28 Eli Lilly And Company Growth hormone secretagogues
US6992097B2 (en) 1998-08-18 2006-01-31 Eli Lilly And Company Growth hormone secretagogues
US6828331B1 (en) 1999-02-19 2004-12-07 Eli Lilly And Company Growth hormone secretagogues
EP1159964A2 (fr) 2000-05-31 2001-12-05 Pfizer Products Inc. Compositions et methodes pour stimuler la motilité gastrointestinale
US7125840B2 (en) 2001-10-09 2006-10-24 Eli Lilly And Company Substituted dipeptides as growth hormone secretagogues
US7396846B2 (en) 2002-04-09 2008-07-08 Eli Lilly And Company Growth hormone secretagogues
EP2457925A1 (fr) 2004-06-18 2012-05-30 Tranzyme Pharma, Inc. Procédé pour la préparation d'un modulateur macrocyclique du récepteur de ghréline et intermédiaires
EP2457893A1 (fr) 2004-06-18 2012-05-30 Tranzyme Pharma, Inc. Intermédiaires pour des modulateurs macrocycliques du récepteur de ghréline
WO2007098716A1 (fr) 2006-02-28 2007-09-07 Centro De Ingeniería Genética Y Biotecnología Composés analogues aux sécrétagogues peptidiques de l'hormone de croissance et préparations contenant ceux-ci
EP2644618A1 (fr) 2007-02-09 2013-10-02 Tranzyme Pharma, Inc. Intermédaires dans la synthese de modulateurs macrocycliques du récepteur de la ghréline
US10105416B2 (en) 2014-02-05 2018-10-23 The Regents Of The University Of California Methods of treating mild brain injury
US10617740B2 (en) 2014-02-05 2020-04-14 The Regents Of The University Of California Methods of treating mild brain injury
US11241483B2 (en) 2014-02-05 2022-02-08 The Regents Of The University Of California Methods of treating mild brain injury
WO2017075535A1 (fr) 2015-10-28 2017-05-04 Oxeia Biopharmaceuticals, Inc. Méthodes de traitement de troubles neurodégénératifs

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YU56596A (sh) 1999-09-27
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AR004124A1 (es) 1998-09-30
HUP9902095A2 (hu) 1999-10-28
MX9803316A (es) 1998-09-30
CA2235511A1 (fr) 1997-05-01
JPH11513984A (ja) 1999-11-30
KR19990067097A (ko) 1999-08-16
PL326428A1 (en) 1998-09-14
HRP960494A2 (en) 1998-04-30
AU7468596A (en) 1997-05-15
SK51198A3 (en) 1998-11-04
EP0863900A1 (fr) 1998-09-16
CZ128298A3 (cs) 1998-07-15

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