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WO1998046569A1 - Derives de benzene - Google Patents

Derives de benzene Download PDF

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Publication number
WO1998046569A1
WO1998046569A1 PCT/JP1998/001629 JP9801629W WO9846569A1 WO 1998046569 A1 WO1998046569 A1 WO 1998046569A1 JP 9801629 W JP9801629 W JP 9801629W WO 9846569 A1 WO9846569 A1 WO 9846569A1
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Prior art keywords
group
optionally substituted
added
pharmaceutically acceptable
acceptable salt
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PCT/JP1998/001629
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English (en)
Japanese (ja)
Inventor
Yasuyuki Ueki
Kazuhiko Okazaki
Hitoshi Seki
Jun Nagamine
Kazuo Kumagai
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Sumitomo Pharmaceuticals Co., Ltd.
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Application filed by Sumitomo Pharmaceuticals Co., Ltd. filed Critical Sumitomo Pharmaceuticals Co., Ltd.
Priority to AU67474/98A priority Critical patent/AU6747498A/en
Publication of WO1998046569A1 publication Critical patent/WO1998046569A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems

Definitions

  • the present invention relates to a benzene derivative or a pharmaceutically acceptable salt useful as a growth hormone release enhancer or the like.
  • growth hormone is the most important for growth, since excessive growth hormone secretion causes giantosis and acromegaly, and growth hormone deficiency causes dwarfism. It is clear that this is a factor.
  • growth hormone is known to have basic effects on the body's metabolic processes, such as increasing the rate of protein synthesis, decreasing the rate of carbohydrate utilization, increasing the distribution of free fatty acids, and increasing fatty acid utilization.
  • L-DOPA L-3,4-dihydroxyphenylalanine
  • glucagon glucagon
  • vasopretinsin insulin that induce hypoglycemia.
  • activities such as sleep and movement are known to have the effect of releasing growth hormone.
  • GRF growth hormone-releasing factor
  • GRF growth hormone-releasing factor
  • growth hormone is derived from pituitary pituitary gland or used recombinantly, but these are very expensive, and pituitary gland extract is a source-related disease that causes growth hormone acceptance. With the danger of transmission to the elderly. Because growth hormone is difficult to administer orally, it is administered by injection or nasal spray. Was needed.
  • a second method for increasing the concentration of growth hormone in the body is to use GRF or its derivatives ( ⁇ ⁇ choen WR et al., “Growth hormone secretagogues” m Annual Reports in Medicinal Chemistry; Academic Press, Vol. 28, Chapter 19, 1993) or a method of administering a peptide that stimulates growth hormone production and release (US Pat. No. 4,411,890) is known. Although these peptides are quite small compared to growth hormone, they are still poorly bioavailable on oral administration because they are degraded by various proteases.
  • UK Patent 2,297,972 describes non-peptidic compounds useful as growth hormone release enhancers.
  • the compound is stable in various physiological environments and can be administered by parenteral, nasal, or oral routes, but has not reached clinical application.
  • the problem to be solved by the invention is to provide a non-peptidic compound which is useful as a growth hormone release enhancer applicable as a pharmaceutical.
  • the present inventors have studied various non-peptidic compounds and have found that a benzene derivative or a pharmaceutically acceptable salt thereof is useful as a growth hormone release enhancer applicable as a pharmaceutical.
  • the present invention has been completed.
  • the present invention relates to the following [1] to [13].
  • ring A represents an optionally substituted benzene ring or an optionally substituted naphthalene ring. Represents —CO— or one S 0 2 —. Y represents an oxygen atom or a single bond You.
  • R 3 represents a single bond or alkylene having 1 to 3 carbon atoms.
  • R 4 represents a single bond or an alkylene having 1 to 2 carbons.
  • R 5 represents a hydrogen atom, an alkyl group optionally substituted with a hydroxyl group, an alkenyl group optionally substituted with a hydroxyl group, or an alkynyl group optionally substituted with a hydroxyl group.
  • R 6 is an optionally substituted amino group, an optionally substituted aminoalkyl group, an optionally substituted, saturated nitrogen-containing heterocyclic group, or an optionally substituted saturated nitrogen-containing heterocyclic group. Represents a substituted alkyl group.
  • R 1 and R 2 are as described in (1), (2) or (3) below.
  • R 1 represents a group represented by the formula: Ar—R 7 —, and R 2 represents a hydrogen atom or a lower alkyl group.
  • Ar represents an optionally substituted phenyl group, an optionally substituted naphthyl group, an optionally substituted tetrahydronaphthyl group, an optionally substituted indenyl group, an optionally substituted indanyl group or an optionally substituted Represents a good benzoheterocyclic group.
  • R 7 represents unsubstituted or good having 1 to 4 carbon atoms in the alkylene, substituted carbon atoms which may be 2-4 alkenylene, alkynylene or cycloalk Kanjiiru of optionally substituted carbon atoms 2 be 4.
  • R 1 and R 2 taken together with a nitrogen atom represent a saturated nitrogen-containing heterocyclic group substituted with an optionally substituted phenyl group.
  • (E represents an optionally substituted ethylene, an optionally substituted vinylene, _CH 2 NR 9 — or —NR 9 CH 2 —.
  • R 8 represents a substituent.
  • R 9 represents a hydrogen atom, Represents a lower alkyl group, a lower alkanol group or a lower alkylsulfonyl group. ) Represents a group represented by ]
  • R 1 and R 2 are joined together with a nitrogen atom, optionally substituted spiro (indane-1,4′-piperidine) monoyl group, optionally substituted 1,2-dihydrospiro (3 H —Indole—3,4,1-piperidine) 1-yl group, optionally substituted 4-1-phenylbiperazine-11-yl group, optionally substituted 4-phenylphenylperidine—1-yl group, Optionally substituted 3-phenylpropyl group, optionally substituted 1-naphthylmethyl group, optionally substituted 2-naphthylmethyl group, optionally substituted 2- (2,3-dihydro-
  • W is an optionally substituted indanilidene group, an optionally substituted phenylimino Represents a phenylmethylene group or an optionally substituted phenylmethylene group.
  • n represents 1 or 2.
  • a medicament comprising the benzene derivative according to any one of [1] to [10] or a pharmaceutically acceptable salt thereof.
  • aryl group examples include an aryl group having 6 to 10 carbon atoms, and specific examples include phenyl, 1-naphthyl, and 2-naphthyl.
  • heterocyclic group examples include a monocyclic or bicyclic 5- to 7-membered saturated or unsaturated heterocyclic group containing 1 to 3 nitrogen atoms, oxygen atoms, and sulfur or a sulfur atom.
  • a saturated heterocyclic group examples include piperidyl, piperazinyl, morpholyl, piperidyl, pyrazolidyl, tetrahydrofuryl and the like.
  • unsaturated heterocyclic groups include pyridyl, virazyl, indolyl, isoindolyl, isothiazolyl, isobenzofuranyl, chromenyl, pyrrolyl, furyl, phenyl, quinolyl, isoquinolyl, thiazolyl, imidazolyl, pyrimidinyl, and thiaziridyl.
  • the saturated nitrogen-containing heterocyclic group includes, for example, one nitrogen atom, and may further contain one or two nitrogen atoms, oxygen atoms and / or sulfur atoms. And a 7-membered saturated heterocyclic group.
  • a monocyclic or bicyclic saturated heterocyclic group containing 1 to 3 nitrogen atoms is exemplified.
  • More preferred saturated nitrogen-containing heterocyclic groups include a 5- to 7-membered monocyclic saturated heterocyclic group containing one nitrogen atom, more preferably piperidyl, and particularly preferably 3- And piperidyl.
  • the benzoheterocyclic group refers to a heterocyclic group in which a benzene ring is condensed, and includes, for example, a monocyclic heterocyclic group in which a benzene ring is condensed. Specifically, for example, a monocyclic 5- to 7-membered saturated or unsaturated heterocyclic group containing 1 to 3 nitrogen, oxygen, Z or sulfur atoms condensed with a benzene ring may be mentioned.
  • Can be Preferred benzo heterocyclic groups include one or two nitrogen atoms in which a benzene ring such as 2,3-dihydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, tetrahydroquinoxanyl, and tetrahydrophthalazyl is fused.
  • a benzene ring such as 2,3-dihydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, tetrahydroquinoxanyl, and tetrahydrophthalazyl is fused.
  • 5-7 membered monocyclic saturated heterocyclic group containing 1 to 5 nitrogen atoms containing 1 or 2 nitrogen atoms fused with a benzene ring such as indolyl, isoindolyl, quinolyl, isoquinolyl, etc.
  • unsaturated heterocyclic groups such as indolyl,
  • substituents may be substituted by other substituents described herein.
  • Preferred examples of the substituent include a hydroxyl group, an amino group, an alkyl group, a heterocyclic group, a carbamoyl group, a carboxyl group, an alkylsulfonyl group, a hydroxyalkyl group, a dihydroxyalkyl group, a trihydroxyalkyl group, and a carbamoylalkyl group.
  • Examples of more preferred substituents include a hydroxyl group, a 1 H-tetrazol-5-yl group, a carboxyl group, a hydroxyethyl group, a hydroxypropyl group, a dihydroxypropyl group, a methylsulfonylamino group and the like.
  • a hydroxyl group a 1 H-tetrazol-5-yl group, a carboxyl group, a hydroxyethyl group, a hydroxypropyl group, a dihydroxypropyl group, a methylsulfonylamino group and the like.
  • Preferred examples of the substituent in substituted benzene and substituted naphthalene include, for example, chlorine atom, bromine atom, methylenedioxy, methoxy, ethoxy, benzyloxy, phenyl and the like.
  • examples of the substitution position of Y and R 4 in the optionally substituted benzene represented by ring A include 1, 2, 1, 3, and 1, 4, and preferably 1, 2, and 1, 3, and particularly preferably 1.
  • Examples of the substitution position of Y and R 4 in the optionally substituted naphthalene represented by ring A include 1, 2, 2, 3, 1, 3, 1, 4, and the like, and preferably 2, 3 and the like.
  • alkyl group examples include a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples include methyl, ethyl, propyl, 1-methylethyl, butyl, 2-methylpropyl, and 1,1-dimethylethyl. , Pentyl, 3-methylbutyl, hexyl, 4-methylpentyl and the like. Examples of the lower alkyl group include a linear or branched alkyl group having 1 to 3 carbon atoms.
  • alkenyl group examples include a linear or branched alkenyl group having 2 to 6 carbon atoms, and specific examples thereof include vinyl, aryl, crotyl, methacryl, butadienyl, 2-pentenyl, and 3-hexenyl. .
  • alkynyl group examples include a linear or branched alkynyl group having 2 to 6 carbon atoms, and specific examples include ethynyl and 1-propynyl.
  • alkyl group which may be substituted with a hydroxyl group the alkenyl group which may be substituted with a hydroxyl group, and the alkynyl group which may be substituted with a hydroxyl group, one or more hydroxyl groups may be replaced.
  • alkoxy group include straight-chain or branched-chain alkoxy groups having 1 to 6 carbon atoms. Specifically, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylpropoxy, 1, 1-dimethylethoxy, pentoxy, 3-methylbutoxy, hexoxy, 4-methylpentoxy and the like.
  • alkanoyl group examples include a linear or branched alkanol group having 1 to 6 carbon atoms, and specific examples include formyl, acetyl, propanol, butanol, pentanol, hexanoyl, and the like.
  • Examples of the lower alkanoyl group include a straight or branched alkanoyl group having 1 to 3 carbon atoms.
  • Examples of the cycloalkyl group include a cycloalkyl group having 3 to 8 carbon atoms, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Examples of the alkylene having 1 to 4 carbon atoms include linear or branched alkylene having 1 to 4 carbon atoms, and specific examples thereof include methylene, ethylene, ethylidene, propylene, trimethylene, tetramethylene, and 2-methyltrimethylene. And the like.
  • Examples of the alkylene having 1 to 3 carbon atoms include linear or branched alkylene having 1 to 3 carbon atoms. Is mentioned.
  • Examples of the alkylene having 1 to 2 carbon atoms include linear or branched alkylene having 1 to 2 carbon atoms.
  • C 2-4 alkenylene examples include straight-chain or branched-chain alkenylene having 2 to 4 carbon atoms, and specific examples thereof include vinylene, vinylidene, propenylene, butenylene and the like. No.
  • alkynylene having 2 to 4 carbon atoms examples include straight-chain or branched alkynylene having 2 to 4 carbon atoms, and specific examples include ethinylene, propynylene, and petinylene.
  • cycloalkanediyl examples include cycloalkanediyl having 3 to 7 carbon atoms, and specifically, 1,2-cyclopropanedyl, 1,3-cyclobutanedyl, 1,3-cyclopentanedyl, 1, 3-cyclohexanediyl, 1,4-cyclohexanediyl, 1,4-cycloheptandiyl and the like.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the substituted aminoalkyl group also includes, for example, a residue obtained by removing a carboxyl group from amino acid.
  • the present invention provides a method for separating the same as a pure optical isomer, a partially purified optical isomer, a racemic mixture, or a diastereomer. Any of the mixtures thereof includes all such optical isomers.
  • Pharmaceutically acceptable salts of the benzene derivatives include, for example, salts with inorganic or organic acids.
  • the inorganic acids include hydrochloric acid, nitric acid, sulfuric acid, and phosphoric acid
  • examples of the organic acids include formic acid, acetic acid, trifluoroacetic acid, propionic acid, maleic acid, citric acid, malonic acid, and methanesulfonic acid.
  • an acidic functional group such as a carboxyl group
  • a salt with a base can be used.
  • the salt with a base examples include a salt with a basic amino acid such as arginine and lysine, an alkali metal salt such as a sodium salt and a potassium salt, and an alkaline earth metal such as a calcium salt and a magnesium salt.
  • the present invention also includes solvates such as hydrates of benzene derivatives or pharmaceutically acceptable salts thereof.
  • the benzene derivative of the present invention can be produced, for example, as follows.
  • the compound of formula 4 can be obtained by reacting the compound of formula 3 with the amine of formula 2.
  • Examples of the method for reacting the compound of Formula 3 with the amine of Formula 2 include a conventional peptide bond formation method (for example, “Peptide Synthesis” Maruzen Co., Ltd. 1975; “Basic and Experimental Peptide Synthesis” Maruzen Co., Ltd.) 1985).
  • X is —SO 2 — in Formula 3
  • a sulfonyl chloride or the like and an amine of the formula 2 can be reacted in an inert solvent such as acetonitrile in the presence of an aprotic organic base such as triethylamine.
  • the amine of formula 2 can be produced, for example, in the same manner as described in British Patent 2,297,972.
  • the compound of Formula 5 By reducing the compound of Formula 4, the compound of Formula 5 can be produced.
  • the reduction method include a hydrogenation reaction (for example, a hydrogenation reaction using a palladium catalyst in a solvent such as methanol) and a hydride reduction reaction (for example, sodium borohydride and a chloride in a solvent such as ethanol). Hydride reduction reaction using tin).
  • a hydrogenation reaction for example, a hydrogenation reaction using a palladium catalyst in a solvent such as methanol
  • a hydride reduction reaction for example, sodium borohydride and a chloride in a solvent such as ethanol. Hydride reduction reaction using tin).
  • the benzene derivative of the present invention can be produced by reacting the compound of the formula 5 with the compound of the formula 6 according to a general peptide bond formation method and, if necessary, introducing a substituent as R 5. it can.
  • Examples of the method for introducing a substituent include a reductive amination reaction and the like.
  • the compound of formula 6 is commercially available or can be prepared by a known method (Williams RM "Synthesis of Optically Active a-ammo Acids" Pergamon Press, Vol. 7, 1989).
  • the functional group can be protected if necessary.
  • the protecting group include known groups, which can be protected and deprotected by a known method (Greene T., Wuts PGM “Protective Groups in organic synthesis” John Wiley & Sons Inc., 1991). Since the benzene derivative of the present invention can enhance endogenous growth hormone release, it has the same effects and uses as growth hormone. Uses for growth hormone For example, the following may be mentioned.
  • the dose and frequency of administration vary depending on the animal species, administration route, severity of the symptoms, body weight, etc., and are not particularly limited.In humans, however, usually about 1 ⁇ g to 1 g per adult day, preferably about l ⁇ 500 mg is administered once or more times a day.
  • Examples of the dosage form include powders, fine granules, granules, tablets, capsules, suppositories, injections, nasal preparations and the like. At the time of formulation, it can be manufactured by a usual method using a usual formulation carrier. When preparing oral preparations, excipients and, if necessary, binders, disintegrants, lubricants, coloring agents, etc. are added to the active ingredient, and then tablets, granules, dispersion II are prepared in the usual manner , Capsules and the like. When preparing an injection, a pH adjuster, a buffer, a stabilizing agent, a solubilizing agent, and the like can be added as necessary, and the injection can be prepared by a conventional method.
  • Example 1 Example 1
  • amino acids protecting groups, active groups, solvents and the like may be represented by abbreviations based on IUPAC-IUB and commonly used abbreviations in the art.
  • B oc means t-butyroxycarbonyl
  • HPLC conditions used in the following examples are as follows.
  • Piperidine-1-3-carboxylic acid (4- (2-oxo _2-spiro (indane-1,4_ (Piperidine)-1-yluetyl)-phenyl) monoamide hydrochloride (18)
  • Example 11 In the same manner as described in 11, instead of 1,3-phenylenediacetic acid, 1 Using 2-phenylenediacetic acid, 0.053 g of compound (42) was obtained.
  • the obtained residue was dissolved in dimethylformamide (20 ml), and 0.024 g of the intermediate (13) described in Example 1, 0.014 g of HOBt, 0.020 g of EDC-HC1, and 0.014 ml of triethylamine were added, followed by stirring overnight.
  • Ethyl acetate was added to the reaction solution, and the mixture was washed successively with a saturated saline solution, a 10% aqueous solution of citric acid, a saturated sodium bicarbonate solution, and a saturated saline solution.
  • the organic layer is dried over anhydrous magnesium sulfate and is dried under reduced pressure.
  • Piperidine-1-3-Rubonic acid (2-oxo-1-_2- (1,2-dihydro-1-1-methanesulfonylspiro) (3H-indole-3-, 4-piperidine) 1-1-1 Le) Chill) monophenyl) monoamide hydrochloride (82)
  • the obtained demethylated product was dissolved in 30 ml of dioxane / aqueous solution (2: 1), 5.6 ml of 1N aqueous sodium hydroxide solution and 1.036 g of di-tert-butyldicarbonate were added under ice cooling, and the mixture was stirred overnight.
  • phthalide (91) 2. OOOg and phthalimide potassium (92) 3.000 g were dissolved in dimethylformamide (10 ml) and heated under reflux for 5 hours. After cooling, 6 ml of acetic acid and 10 ml of water were further added, and the mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration and recrystallized (ethanol / water) to obtain 3.384 g (81%) of the intermediate (93).
  • Piperidine-3-carboxylic acid 3- (spiro (indane-1,4-piperidine) monocarbonyl) -benzylamide hydrochloride (103)
  • Piperidine-3-carboxylic acid 4 _ (spiro (indane-1,4-piperidine) monocarbonyl) -benzylamide hydrochloride (109)
  • the obtained residue was dissolved in 30 ml of dimethylformamide, and 0.091 g of the intermediate (13) described in Example 1, 0.054 g of HOBt, 0.076 g of EDC-HC1, and 0.055 ml of triethylamine were added, followed by stirring overnight.
  • Ethyl acetate was added to the reaction solution, and the mixture was washed successively with a saturated saline solution, a 10% aqueous solution of citric acid, a saturated sodium bicarbonate solution and a saturated saline solution.
  • the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the pituitary gland excised from a 7-week-old male Wistar / ST rat was washed three times with HBSS (-), and then the tissue was minced with scissors so as to be about one thigh angle.
  • the tissue was transferred to a 15 ml round-bottom centrifuge tube and washed three times with 10 ml HBSS (-).
  • 0.1 ml of the enzyme solution per pituitary gland was added, and enzyme digestion was started in a 37 ° C water bath. Pipetting was performed every 5 minutes on the way, and the cells were treated for about 20 to 30 minutes until they became dispersed cells.
  • the mixture was centrifuged at 1200 rpm for 2 to 3 minutes at room temperature, the supernatant was removed, and 8 m of the culture solution was added. The same operation was repeated twice to wash the dispersed cells.
  • 96 well plate - with bets on 1 X 10 4 cells number / ⁇ ⁇ / wel l in narrowing the cells were plated 37 ° C, 5% C0 2 culture was started. After 3 days from the start of the culture, discard the culture supernatant, add the Acetate solution, and incubate for 1.5 hours. After washing once, a test compound solution was added and reacted at 37 ° C. in a 5% CO 2 incubator for 15 minutes. After collecting the supernatant, the GH concentration in the supernatant was measured by the RIA method.
  • the EC5Q value (B) was determined by regression calculation by substituting the compound concentration XnM used in the test and the measured GH concentration Yng / ml in the test supernatant into the following formula.
  • a and C both represent the values obtained from the regression calculation, C represents the GH concentration in the supernatant when no compound was added, and A represents the value in the culture supernatant when the compound concentration X was infinite.
  • the difference between the GH concentration and C in Fig. 3 is shown.
  • the composition of the culture solution was 10% serum serum, 2.5% fetal serum, 1% non-essential amino acids, 1% antibiotic / DMEM, and the composition of the Atsey solution was 25 mM HEPES / culture solution ( ⁇ 7.3) Met.
  • the test compound solution was prepared by adding 1 n1 of the compound solution prepared at a 1000-fold concentration using DMS0 to 1 ml of Atsushi solution.
  • a novel benzene derivative useful as a growth hormone release enhancer can be provided.

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Abstract

Dérivés de benzène représentés par la formule générale (1) ou sels pharmaceutiquement acceptables de ces dérivés, utiles comme promoteurs de la libération de l'hormone de croissance, etc. Le cycle A représente un cycle benzénique éventuellement substitué etc.; X représente -CO- ou -SO2-; Y représente oxygène ou une liaison simple; R3 représente une liaison simple ou alkylène C¿1-3; R?4 représente une liaison simple ou alkylène C¿1-2; R?5 représente hydrogène, alkyle éventuellement hydroxylé, etc.; et R6 représente un hétérocycle azoté saturé éventuellement substitué, etc.; ou R1 et R2 associés à l'atome d'azote peuvent former (a), où E représente éthylène éventuellement substitué, vinylène éventuellement substitué, -CH¿2NR?9- ou -NR9CH2- (où R9 représente hydrogène, alkyle inférieur, alcanoyle inférieur ou alkylsulfonyle inférieur); et R8 représente un substituant.
PCT/JP1998/001629 1997-04-11 1998-04-08 Derives de benzene WO1998046569A1 (fr)

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JP9/110153 1997-04-11

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Cited By (11)

* Cited by examiner, † Cited by third party
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WO2000071519A3 (fr) * 1999-05-21 2001-04-26 Lilly Co Eli Agents immunostimulants
EP1159964A2 (fr) 2000-05-31 2001-12-05 Pfizer Products Inc. Compositions et methodes pour stimuler la motilité gastrointestinale
US7045527B2 (en) 2002-09-24 2006-05-16 Amgen Inc. Piperidine derivatives
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
EP1930021A2 (fr) 1999-02-18 2008-06-11 Kaken Pharmaceutical Co., Ltd. Nouveaux dérivés d'amide en tant que secrétagogues d'hormone de croissance
WO2008123017A1 (fr) * 2007-03-09 2008-10-16 Daiichi Sankyo Company, Limited Nouveau derivé de diamide
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
CN104292213A (zh) * 2014-09-08 2015-01-21 湖南华腾制药有限公司 一种嘧啶衍生物的制备方法
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

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WO1994007496A1 (fr) * 1992-10-07 1994-04-14 Merck & Co., Inc. Antagonistes recepteurs d'oxytocine tocolytique
GB2297972A (en) * 1995-02-17 1996-08-21 Merck & Co Inc Camphor compounds promote release of growth hormone
WO1998017625A1 (fr) * 1996-10-22 1998-04-30 Daiichi Pharmaceutical Co., Ltd. Nouveaux remedes pour des maladies infectieuses

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994007496A1 (fr) * 1992-10-07 1994-04-14 Merck & Co., Inc. Antagonistes recepteurs d'oxytocine tocolytique
GB2297972A (en) * 1995-02-17 1996-08-21 Merck & Co Inc Camphor compounds promote release of growth hormone
WO1998017625A1 (fr) * 1996-10-22 1998-04-30 Daiichi Pharmaceutical Co., Ltd. Nouveaux remedes pour des maladies infectieuses

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1930021A2 (fr) 1999-02-18 2008-06-11 Kaken Pharmaceutical Co., Ltd. Nouveaux dérivés d'amide en tant que secrétagogues d'hormone de croissance
US6664271B1 (en) 1999-05-21 2003-12-16 Eli Lilly And Company Immunopotentiator agents
WO2000071519A3 (fr) * 1999-05-21 2001-04-26 Lilly Co Eli Agents immunostimulants
EP1159964A2 (fr) 2000-05-31 2001-12-05 Pfizer Products Inc. Compositions et methodes pour stimuler la motilité gastrointestinale
US7045527B2 (en) 2002-09-24 2006-05-16 Amgen Inc. Piperidine derivatives
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
WO2008123017A1 (fr) * 2007-03-09 2008-10-16 Daiichi Sankyo Company, Limited Nouveau derivé de diamide
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
CN104292213A (zh) * 2014-09-08 2015-01-21 湖南华腾制药有限公司 一种嘧啶衍生物的制备方法
WO2017075535A1 (fr) 2015-10-28 2017-05-04 Oxeia Biopharmaceuticals, Inc. Méthodes de traitement de troubles neurodégénératifs

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