EP2079689A2 - Derives indoliques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent - Google Patents

Derives indoliques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent

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Publication number
EP2079689A2
EP2079689A2 EP07858468A EP07858468A EP2079689A2 EP 2079689 A2 EP2079689 A2 EP 2079689A2 EP 07858468 A EP07858468 A EP 07858468A EP 07858468 A EP07858468 A EP 07858468A EP 2079689 A2 EP2079689 A2 EP 2079689A2
Authority
EP
European Patent Office
Prior art keywords
formula
compound
pharmaceutically acceptable
base
compounds
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07858468A
Other languages
German (de)
English (en)
French (fr)
Inventor
Pascal Marchand
Vincent Badonneau
Sylvie Piessard
Muriel Duflos
Jean Albert Boutin
Valérie Audinot
Philippe Delagrange
Daniel-Henri Caignard
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Laboratoires Servier SAS
Original Assignee
Laboratoires Servier SAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Laboratoires Servier SAS filed Critical Laboratoires Servier SAS
Publication of EP2079689A2 publication Critical patent/EP2079689A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms

Definitions

  • the present invention relates to novel indole derivatives, process for their preparation and pharmaceutical compositions containing them.
  • the compounds of the present invention are novel and have very interesting pharmacological characteristics concerning melatoninergic receptors.
  • melatonin N-acetyl-5-methoxytryptamine
  • melatonin analogues which are metabolically more stable and have an agonist or antagonist character, which can be expected to have a therapeutic effect greater than that of the hormone itself.
  • ligands of brainlatom system have energetic interesting pharmacological properties on the central nervous system, including anxiolytics and antipsychotics (Neuropharmacology of Pineal Secretions, 1990, 8 (3-4), pp. 264-272), analgesics (Pharmacopsychiat., 1987, 20, pp. 222- 223), as well as for the treatment of Parkinson's disease (J. Neurosurg, 1985, 63, pp. 321-341) and Alzheimer's (Brain Research, 1990, 528, pp. 170-174).
  • the compounds of the present invention in addition to their novelty, show a very high affinity for melatonin receptors.
  • the present invention relates more particularly to the compounds of formula (I):
  • R 1 represents a linear or branched (C 1 -C 6 ) alkyl, linear or branched (C 3 -C 8 ) cycloalkyl or linear (C 1 -C 6 ) (C 3 -C 8 ) alkyl (C 1 -C 6 ) cycloalkyl group; branched
  • R 2 and R 3 form together with the nitrogen atom which carries them a heterocycle comprising from 5 to 8 members,
  • n 2, 3, 4, 5 or 6
  • the 5- to 8-membered heterocycle thus defined does not contain any additional heteroatom, and may be optionally substituted with one to three groups, which may be identical or different, linear or branched (C 1 -C 6 ) alkyl, alkoxy (C 1 -C 6 ) linear or branched, OH, carboxy, amino (optionally substituted with one or two linear or branched (C 1 -C 6 ) alkyl groups), or halogen atoms, their enantiomers and diastereoisomers, and their addition salts with an acid or a pharmaceutically acceptable base.
  • groups which may be identical or different, linear or branched (C 1 -C 6 ) alkyl, alkoxy (C 1 -C 6 ) linear or branched, OH, carboxy, amino (optionally substituted with one or two linear or branched (C 1 -C 6 ) alkyl groups), or halogen atoms, their enantiomers and diastereoisomers,
  • hydrochloric hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, methanesulphonic and camphoric acids. , oxalic, etc.
  • n 2 or 3 and more preferably 2.
  • R 1 advantageously represents an alkyl group such as, for example, the methyl, ethyl and propyl groups.
  • the preferred R 2 and R 3 groups are those forming with the nitrogen which carries them a piperidinyl group.
  • the invention relates to the compounds which are N- (2- ⁇ 5- [2- (1-piperidinyl) ethoxy] -1H-indol-3-yl ⁇ ethyl) acetamide, N- (2- ⁇ 5- [2- (1-Piperidinyl) ethoxy] -1H-indol-3-yl ⁇ ethyl) propanamide, N- (2- ⁇ 5- [2- (1-piperidinyl) ethoxy] -1H-indol- 3-yl ⁇ ethyl) butanamide, and N- (2- ⁇ 5- [3- (1-piperidinyl) propoxy] -1H-indol-3-yl ⁇ ethyl) butanamide.
  • the invention also extends to the process for preparing the compounds of formula (I), characterized in that the compound of formula (II) used is the starting material: on which the acid chloride of formula R 1 COCl in which R 1 is as defined in formula (I) or the corresponding symmetrical anhydride is condensed to give the compound of formula (III):
  • R 1 is as defined above, which is placed under demethylation conditions to yield the compound of formula (V): in which R 1 is as defined above, on which the compound of formula (VI) is condensed
  • R 1 , R 2 , R 3 and n are as defined above, which is subjected to the action of magnesium to yield the compound of formula (I), which can be purified according to a conventional separation technique, that it is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and whose enantiomers can be separated on a chiral column according to a conventional separation technique.
  • the pharmacological study of the derivatives of the invention showed that they were atoxic, endowed with a high selective affinity for melatonin receptors and had important activities on the central nervous system and, in particular, were noted.
  • the products of the invention are useful in the treatment of stress, sleep disorders, anxiety, seasonal depression or major depression, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jet lag, schizophrenia, panic attacks, melancholy, disorders of the appetite, obesity, insomnia, psychotic disorders, epilepsy, diabetes, Parkinson's disease, senile dementia, various disorders related to normal or pathological aging, migraine, memory loss, Alzheimer's disease, as well as disorders of the cerebral circulation.
  • the products of the invention can be used in sexual dysfunctions, that they have properties of ovulation inhibitors, immmunomodulators and that they are likely to be used in the treatment of cancers.
  • the compounds will preferably be used in the treatment of major depression, seasonal depression, sleep disorders, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jet lag, appetite disorders and obesity.
  • the compounds will be used in the treatment of major depression, seasonal depression and sleep disorders.
  • the present invention also relates to pharmaceutical compositions containing at least one compound of formula (I) alone or in combination with one or more pharmaceutically acceptable excipients.
  • compositions according to the invention mention may be made of particularly those which are suitable for oral, parenteral, nasal, percutaneous, rectal, perlingual, ocular or respiratory administration and in particular simple or coated tablets, sublingual tablets, sachets, packets, capsules, glossettes, tablets, suppositories, creams, ointments, dermal gels, and oral or injectable ampoules.
  • the dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication, or possibly associated treatments and ranges between 0.01 mg and 1 g per 24 hours. in one or more takes.
  • Step A S-Methoxy-S- ⁇ -nitroethenyl-L-indole
  • Step B 2- (5-Methoxy-l J ⁇ r -indol-3-yl) ethylamine
  • Step E N- (2- ⁇ 5-Hydroxy-l - [(4-methylphenyl) sulfonyl] -l J FF-indol-3-yl ⁇ ethyl) acetamide
  • Step F N- (2- ⁇ l - [(4-Methylphenyl) sulfonyl] -5- [2- (l-piperidinyl) ethoxy] -l J fir- indol-3-yl ⁇ ethyl) acetamide
  • the title product is obtained in the form of a brown paste.
  • the title product is obtained in the form of a brown paste and is then recrystallized.
  • Acute toxicity was assessed after oral administration to batches of 8 mice (26 ⁇ 2 grams). The animals were observed at regular intervals during the first day and daily for two weeks after treatment. The LD 50, resulting in the death of 50% of the animals, was evaluated and showed the low toxicity of the compounds of the invention.
  • the compounds of the invention are tested in a behavioral model, the forced swimming test.
  • the apparatus consists of a Plexiglas cylinder filled with water.
  • the animals are tested individually during a 6-minute session. At the beginning of each test, the animal is placed in the center of the cylinder. The downtime is recorded. Each animal is judged immobile when it ceases to struggle, and remains on the surface of the water, motionless, making only the movements allowing it to keep its head out of the water.
  • MT 1 or MT 2 receptor binding experiments were performed using 2- [ 12 I] -iodomelatonin as a reference radioligand. The retained radioactivity is determined using a liquid scintillation counter.
  • the compounds of the invention have Ki less than 1 ⁇ M.
  • the compound of Example 3 has a Kj (MT 1 ) of 11 nM and a K 1 (MT 2 ) of 19 nM.
  • the effects of the molecules are tested on many parameters and, in particular, on the circadian rhythms of locomotor activity that represent a reliable marker of endogenous circadian clock activity.
  • One-month-old male rats are subjected to a light cycle of 12 hours of light per day as soon as they arrive at the laboratory (LD 12:12). After 2 to 3 weeks of adaptation, they are placed in cages equipped with a wheel connected to a recording system in order to detect the phases of locomotor activity and thus to follow the diurnal (LD) or circadian (DD) rhythms. ).
  • the rats receive a daily administration of the molecule to be tested.
  • the compounds of the invention are tested in a behavioral model, the light / dark cages test, which reveals the anxiolytic activity of the molecules.
  • the device consists of two polyvinyl boxes covered with Plexiglas. One of these boxes is obscure. One lamp is placed on top of the other box sleeping a luminous intensity in the center of it of approximately 4000 lux. An opaque plastic tunnel separates the clear box from the dark box. The animals are tested individually during a 5 min session. The floor of each box is cleaned between each session. At the beginning of each test, the mouse is placed in the tunnel, facing the dark box. The time spent by the mouse in the lighted box and the number of transitions through the tunnel are recorded after the first entry in the dark box. After administration of the compounds 30 min before the start of the test, the compounds of the invention significantly increase the time spent in the illuminated cage and the number of transitions, which shows the anxiolytic activity of the derivatives of the invention.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Diabetes (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Psychology (AREA)
  • Anesthesiology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Emergency Medicine (AREA)
  • Gynecology & Obstetrics (AREA)
  • Nutrition Science (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
EP07858468A 2006-10-18 2007-10-17 Derives indoliques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent Withdrawn EP2079689A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0609113A FR2907451B1 (fr) 2006-10-18 2006-10-18 "nouveaux derives indoliques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent"
PCT/FR2007/001708 WO2008049997A2 (fr) 2006-10-18 2007-10-17 Derives indoliques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent

Publications (1)

Publication Number Publication Date
EP2079689A2 true EP2079689A2 (fr) 2009-07-22

Family

ID=38051392

Family Applications (1)

Application Number Title Priority Date Filing Date
EP07858468A Withdrawn EP2079689A2 (fr) 2006-10-18 2007-10-17 Derives indoliques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent

Country Status (18)

Country Link
US (1) US20100204276A1 (ja)
EP (1) EP2079689A2 (ja)
JP (1) JP2010506890A (ja)
KR (1) KR20090084874A (ja)
CN (1) CN101522616A (ja)
AR (1) AR063328A1 (ja)
AU (1) AU2007310770A1 (ja)
BR (1) BRPI0717528A2 (ja)
CA (1) CA2666522A1 (ja)
EA (1) EA200900481A1 (ja)
FR (1) FR2907451B1 (ja)
GE (1) GEP20115240B (ja)
MA (1) MA30797B1 (ja)
MX (1) MX2009004006A (ja)
NO (1) NO20091779L (ja)
UA (1) UA91645C2 (ja)
WO (1) WO2008049997A2 (ja)
ZA (1) ZA200902414B (ja)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2010306750B2 (en) 2009-10-15 2014-11-13 Children's Medical Center Corporation Sepiapterin reductase inhibitors for the treatment of pain
CN103601683B (zh) * 2010-04-16 2016-03-30 中国科学院上海药物研究所 苯并杂环类化合物及其制备方法和用途
KR20160100998A (ko) 2014-01-14 2016-08-24 아스테라스 세이야쿠 가부시키가이샤 인돌 화합물
CN105085366A (zh) * 2014-05-07 2015-11-25 北京生命科学研究所 一种吲哚骨架化合物及其应用
RU2581711C1 (ru) * 2015-03-10 2016-04-20 Федеральное государственное бюджетное учреждение "Российский научный центр "Восстановительная травматология и ортопедия" имени академика Г.А. Илизарова" Минздрава России ФГБУ "РНЦ "ВТО" им. акад. Г.А. Илизарова" Минздрава России Способ восстановления функции локтевого сустава при неправильно сросшихся переломах мыщелка плечевой кости
CN108299274B (zh) * 2018-02-08 2021-01-15 中国热带农业科学院海口实验站 一种天然吲哚，其制备方法及应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2737725B1 (fr) * 1995-08-08 1997-10-31 Valentonine Nouveaux derives acyles de la melatonine et d'analogues melatoninergiques, leur procede de preparation et leur utilisation en tant que medicament

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2008049997A2 *

Also Published As

Publication number Publication date
UA91645C2 (ru) 2010-08-10
JP2010506890A (ja) 2010-03-04
ZA200902414B (en) 2010-07-28
GEP20115240B (en) 2011-06-10
WO2008049997A8 (fr) 2009-05-22
MA30797B1 (fr) 2009-10-01
AR063328A1 (es) 2009-01-21
WO2008049997A2 (fr) 2008-05-02
MX2009004006A (es) 2009-04-28
FR2907451A1 (fr) 2008-04-25
CN101522616A (zh) 2009-09-02
WO2008049997A3 (fr) 2008-09-12
NO20091779L (no) 2009-05-06
CA2666522A1 (fr) 2008-05-02
BRPI0717528A2 (pt) 2013-10-22
AU2007310770A1 (en) 2008-05-02
KR20090084874A (ko) 2009-08-05
FR2907451B1 (fr) 2008-12-12
EA200900481A1 (ru) 2009-10-30
US20100204276A1 (en) 2010-08-12

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