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WO2005100337A1 - Derives de dioxolane substitues et leur utilisation dans la preparation de neuroregulateurs - Google Patents

Derives de dioxolane substitues et leur utilisation dans la preparation de neuroregulateurs Download PDF

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Publication number
WO2005100337A1
WO2005100337A1 PCT/CN2005/000257 CN2005000257W WO2005100337A1 WO 2005100337 A1 WO2005100337 A1 WO 2005100337A1 CN 2005000257 W CN2005000257 W CN 2005000257W WO 2005100337 A1 WO2005100337 A1 WO 2005100337A1
Authority
WO
WIPO (PCT)
Prior art keywords
dioxolane
dimethyl
carboxylic acid
compound
ethyl ester
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.)
Ceased
Application number
PCT/CN2005/000257
Other languages
English (en)
Chinese (zh)
Inventor
Song Li
Aihua Nie
Lili Wang
Junhai Xiao
Zhibing Zheng
Hongying Liu
Yunde Xie
Chengmai Ruan
Guoming Zhao
Yuandong Hu
Wu Zhong
Hao Cui
Xinbo Zhou
Wei Gu
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.)
Institute of Pharmacology and Toxicology of AMMS
Original Assignee
Institute of Pharmacology and Toxicology of AMMS
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 Institute of Pharmacology and Toxicology of AMMS filed Critical Institute of Pharmacology and Toxicology of AMMS
Publication of WO2005100337A1 publication Critical patent/WO2005100337A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • 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
    • A61P25/28—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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals

Definitions

  • the inventors have discovered through research that compounds having the following general formula I can act on FKBP and promote nerve growth and regeneration under various neuropathy states, and thus can be used to prevent and / or treat neurological diseases related to neurodegeneration, thereby The present invention has been completed.
  • alkyl or alkenyl chain is unsubstituted or substituted by one or more groups selected from the group consisting of: C 3 ⁇ C 8 cycloalkyl, C 5 ⁇ C 7 cycloalkenyl or Ar 2 ; furthermore, A part of the C atoms in the alkyl or alkenyl chain may be substituted by 0 or N.
  • I-R 4 and Z have the same definitions as above.
  • the obtained compound of formula (I) may be converted into a pharmaceutically acceptable salt thereof with a suitable pharmaceutically acceptable acid or base.
  • Y is 0 or s
  • R 3 and R 4 may be the same or different and are independently selected from hydrogen, d ⁇ C 3 alkyl or C 2 ⁇ C 3 alkenyl.
  • a preferred embodiment of the present invention is a compound represented by formula (II) or a pharmaceutically acceptable salt or hydrate thereof:
  • 11 3 and 1 4 may be the same or different, and are independently selected from hydrogen, C ⁇ Cs alkyl, or c 2 to c 3 alkenyl.
  • Another preferred embodiment of the present invention is a compound represented by formula ( ⁇ ) or a pharmaceutically acceptable salt or hydrate thereof, wherein:
  • 1 ⁇ is ( ⁇ ⁇ (: 8 straight or branched alkyl, C 2 ⁇ C 8 straight or branched alkenyl, ( 3 ⁇ (: 8 cycloalkyl, C 5 ⁇ C 7 cycloalkenyl, or Wherein the alkyl or alkenyl chain is unsubstituted, or is substituted by one or more groups selected from: C 3 ⁇ C 8 cycloalkyl, C 5 ⁇ C 7 cycloalkenyl or Ar 2 .
  • Linear or branched alkyl Linear or branched alkenyl, where the alkyl or alkenyl chain is unsubstituted, or is substituted by one or more groups selected from the group: C 3 ⁇ C 8 cycloalkyl, C 5 ⁇ C 7 ring Alkenyl or Ar 2 ; In addition, a part of the C atoms in the alkyl or alkenyl chain may be substituted with 0 or N.
  • compound 5 is dissolved in an organic solvent, Select dioxane and tetrahydrofuran, add an alkaline aqueous solution, preferably sodium hydroxide (concentration of 1N, and a molar ratio of 3 to 1: 1), react at 0 ° C ⁇ room temperature, and then use inorganic Acid, preferably hydrochloric acid (concentration: 1N), and then use an organic solvent, preferably Dichloromethane, diethyl ether and ethyl acetate were used for extraction to obtain compound 6.
  • an organic solvent preferably Dichloromethane, diethyl ether and ethyl acetate were used for extraction to obtain compound 6.
  • the pharmaceutically acceptable carriers include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum proteins, buffer substances such as phosphate, glycerol, sorbic acid, potassium sorbate, A partial glyceride mixture of saturated vegetable fatty acids, Water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose materials, polyethylene glycol , Sodium carboxymethyl cellulose, polyacrylate, beeswax, polyethylene-polyoxypropylene block polymer and lanolin.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum proteins
  • buffer substances such as phosphate, glycerol, sorbic acid, potassium sorbate
  • the compounds of the present invention can be formulated into any orally acceptable formulation including, but not limited to, tablets, capsules, aqueous solutions or aqueous suspensions.
  • the carriers used for tablets generally include lactose and corn starch, and lubricants such as magnesium stearate can also be added.
  • Diluents used in capsule preparations generally include lactose and dried corn starch.
  • Aqueous suspensions are usually prepared by mixing the active ingredient with suitable emulsifying and suspending agents. If necessary, some sweeteners, fragrances, or colorants can be added to the above oral preparations.
  • the compound of the present invention can be prepared in the form of a rectal suppository formulation or a suitable enema formulation as described above, or a topical transdermal patch can be used.
  • the compounds of the invention can also be administered in the form of sterile injectable preparations, including sterile injectable water or oil suspensions, or sterile injectable solutions.
  • carriers and solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution.
  • sterilized non-volatile oils can be used as solvents or suspension media, such as monoglycerides or diglycerides.
  • Figure 1 shows how the compound of Example 16 of the present invention promoted the growth of periganglion ganglia around the dorsal root of chicken embryo at different doses.
  • Figure 2 shows the effect of the compound of Example 10 of the present invention on H 2 0 2 injured NG108 cells. Protection effect
  • the compound (0.279 g, 1 mmol) was reacted with glutamic acid diethyl ester hydrochloride (0.303 g, 1.26 legs ol) according to the method for synthesizing compounds to obtain 0.296 g of the title compound as a yellow oil.
  • the yield was 64.01 'HNMR (400MHz, CDC1 3 ) 5 (ppm):
  • the compound (0.461g, 1.65 ol) was reacted with threonine ethyl ester hydrochloride (0.318g, 1.73 ol) according to the method of synthesizing the compound to obtain 0.206g of the title compound as a yellow oil with a yield of 30.6%. .
  • ⁇ ⁇ ⁇ ⁇ 8 / ' ⁇ ) 8 8 ⁇ ⁇ ' ( ⁇ 5 'ra) igg' L- £ 99Z 'L' (HI '?
  • Example 11 L- (4R, 5R) -5-cyclohexylaminocarbonyl-2, 2-dimethyl-1, 3-dioxolane- 4-carboxylic acid leucine ethyl ester
  • Example 21 L- (4R, 5R) -5-cyclohexylamino-2, 2- Dimethyl-1, 3-dioxolane-4-carboxylic acid-3-phenyl-propyl ester
  • the compound (0.407g, 1.5IMIO1) was reacted with 3- (3-pyridine ⁇ )-propyl alcohol (1.60 legs ol) according to the method of synthesizing the compound to obtain 0.38g of the title compound as a yellow oil with a yield of 63.3 %.
  • Example 30 The neurotrophic activity of the compounds of the present invention can be reflected in a variety of in vitro biological models, such as a chicken embryo dorsal root ganglion ganglion in vitro serum-free culture model. Take the chicken embryos that have been incubated for 8 days. In a sterile environment, expose the spine and ganglion ganglia under a dissecting microscope. Use dorsal forceps to extract the dorsal root ganglia one by one and inoculate them into a culture flask covered with rat tail collagen. Inoculate 5 to 6 bottles, 2 bottles per dose.
  • in vitro biological models such as a chicken embryo dorsal root ganglion ganglion in vitro serum-free culture model. Take the chicken embryos that have been incubated for 8 days. In a sterile environment, expose the spine and ganglion ganglia under a dissecting microscope. Use dorsal forceps to extract the dorsal root ganglia one by one and ino
  • FIG. 1 shows the growth of the ganglion ganglia around the dorsal root ganglia of the chicken embryo under different doses of the compound of Example 16.
  • A indicates that the dorsal root ganglia of chicken embryos caused only a few rare protrusions under the action of NGF (0.15ng / mL) alone.
  • B represents the compound of Example 16 (1 1 enhanced ⁇ 1? ( ) Promoting nerve growth.
  • Example 31 Protective effect of NG108 cells damaged by HA (%): Take NG108-15 cells in logarithmic growth phase, inoculate a 96-well cell culture plate with a cell concentration of lx 107ml, 5% CO 2 incubator, 37 ° C paste Add 24 hours to the wall, add the test compound, and incubate at 37 ° C in a 5% CO 2 incubator for 24 hours. Change the medium. Add 100 L of H 2 0 2 (300 Mmol / L) culture solution to each well. Determination of viable cells.
  • Figure 2 shows the results of the compound of Example 10 at different concentrations. It can be seen from FIG. 2 that the compound of Example 10 has a significant protective effect on NG108 cells damaged by H 2 0 2 .

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurology (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Ophthalmology & Optometry (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des dérivés de dioxolane représentés par la formule générale (I), possédant des effets nutritionnels sur le système nerveux, ou des sels ou hydrates acceptables d'un point de vue pharmaceutique de ceux-ci. Chaque groupe représenté par la formule générale (I) est défini tel que dans les spécifications. La présente invention concerne également une composition pharmaceutique contenant lesdits composés, et l'utilisation de ladite composition pharmaceutique comme inhibiteur de l'activité de la protéase de liaison FK506 dans la préparation de médicaments pouvant prévenir ou traiter les maladies neurodégénératives et d'autres troubles neurologiques causés par des lésions nerveuses ou des maladies associées.
PCT/CN2005/000257 2004-04-13 2005-03-02 Derives de dioxolane substitues et leur utilisation dans la preparation de neuroregulateurs Ceased WO2005100337A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNB200410033624XA CN100378090C (zh) 2004-04-13 2004-04-13 取代的二氧戊环衍生物及其用于制备神经调节剂的用途
CN200410033624.X 2004-04-13

Publications (1)

Publication Number Publication Date
WO2005100337A1 true WO2005100337A1 (fr) 2005-10-27

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WO (1) WO2005100337A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008064218A3 (fr) * 2006-11-21 2008-10-23 Genelabs Tech Inc Composés amido antiviraux

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114890978B (zh) * 2022-04-19 2023-07-25 宿迁医美科技有限公司 酚类化合物及其制备方法和应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07330671A (ja) * 1994-06-07 1995-12-19 Res Dev Corp Of Japan エステル化合物の製造法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07330671A (ja) * 1994-06-07 1995-12-19 Res Dev Corp Of Japan エステル化合物の製造法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BARTON ET AL: "Radical decarboxylative alkylation of tartaric acid.", TETRAHEDRON., vol. 49, no. 21, 1993, pages 4589 - 4602 *
IMAI ET AL: "Novel C2 symmetric chiral bisoxazoline ligands in rhodium(I)-catalyzed asymmetric hydrosilylation.", TETRAHEDRON: ASYMMETRY., vol. 7, no. 8, 1996, pages 2453 - 2462, XP004048305, DOI: doi:10.1016/0957-4166(96)00304-7 *
PORZIEMSKY ET AL: "Complementary use of reverse-phase, normal-phase and chiral high-performance liquid chromatography for the study of the stereoisomers produced in decarboxylative alkylation of tartaric acid.", JOURNAL OF CHROMATOGRAPHY., vol. 440, 1988, pages 183 - 195, XP026503624, DOI: doi:10.1016/S0021-9673(00)94522-9 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008064218A3 (fr) * 2006-11-21 2008-10-23 Genelabs Tech Inc Composés amido antiviraux

Also Published As

Publication number Publication date
CN100378090C (zh) 2008-04-02
CN1683365A (zh) 2005-10-19

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