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WO2006029575A1 - Nouveaux acides $g(a)-alkyloxy propioniques, leurs procedes de preparation, compositions pharmaceutiques les contenant et leurs utilisations - Google Patents

Nouveaux acides $g(a)-alkyloxy propioniques, leurs procedes de preparation, compositions pharmaceutiques les contenant et leurs utilisations Download PDF

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Publication number
WO2006029575A1
WO2006029575A1 PCT/CN2005/001483 CN2005001483W WO2006029575A1 WO 2006029575 A1 WO2006029575 A1 WO 2006029575A1 CN 2005001483 W CN2005001483 W CN 2005001483W WO 2006029575 A1 WO2006029575 A1 WO 2006029575A1
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group
compound
ethoxy
hydrogen
phenyl
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PCT/CN2005/001483
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English (en)
Chinese (zh)
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Zongru Guo
Jun Feng
Fengming Chu
Yanshen Guo
Ying Lu
Piaoyang Sun
Yunshu Zhou
Kaihong Yuan
Yongjiang Chen
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Institute Of Mataria Medica, Chinese Academy Of Medical Sciences
Jiangsu Hengrui Medicine Co., Ltd.
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Publication of WO2006029575A1 publication Critical patent/WO2006029575A1/fr

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    • 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
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • 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
    • C07D471/04—Ortho-condensed systems

Definitions

  • Novel ⁇ -alkoxypropionic acid compound, preparation method thereof and pharmaceutical composition and use thereof Novel ⁇ -alkoxypropionic acid compound, preparation method thereof and pharmaceutical composition and use thereof
  • This invention relates to novel ⁇ -alkoxypropionic acids of the general formula I, as well as their tautomers, enantiomers, diastereomers and physiologically acceptable salts.
  • the use of these compounds in the treatment of diabetes also relates to methods for their use, and pharmaceutical compositions containing the compounds. Background technique
  • Type I diabetes insulin-dependent diabetes mellitus, IDDM
  • IDDM insulin-dependent diabetes mellitus
  • Type II diabetes non-insulin-dependent diabetes mellitus, NIDDM
  • NIDDM non-insulin-dependent diabetes mellitus
  • PPAR peroxisome proliferator-activated receptor
  • thiazolidinediones have a high affinity for PPAR/y and act by activating ⁇ after entering the body (Shao D et al. J Biol Chem, 1997, 272, 21473).
  • PPAR is in the nucleus and is a member of the nuclear receptor superfamily. After entering the nucleus, the TZDS compound binds to the ligand binding region of the PPARY C-terminus (Ligand Binding Domin, LBD), activates PPARy, and activates factor II at the end of the sequence.
  • LBD Ligand Binding Domin
  • Activatingtreatment-2 changes in conformation, and activated PPARy and activated RXR (retinoic acid X receptor) bind to form a heterodimer and then recognize its peroxisome proliferator-responsive element (PPRE)
  • PPRE peroxisome proliferator-responsive element
  • DBD DNA Binding Domain
  • AAGACT target gene-specific DNA sequence
  • the first commercially available thiazolidinedione anti-type 2 diabetes drug was troglitazone, which was marketed by Sankyo in 1996. Takeda's pioglitazone and Sike's rosiglitazone were also marketed in 1999.
  • a typical dual agonist such as AZ242 which is an et-substituted phenylpropionic acid compound, binds to PPAR and ⁇ with EC 5Q of ⁇ . ⁇ and 0.2 ⁇ , respectively, and promotes gene transcription with ED 5 o of 1.2 ⁇ and 1.3 ⁇ , respectively. . It is effective in reducing blood fat and losing weight when treating diabetes. It has now entered the clinical phase III study.
  • the present invention is directed to the design of dual agonists that synthesize PPAR Y and c.
  • a virtual compound library was constructed by computer simulation using virtual simulation method. The DOCK virtual screening was used to screen out the theoretically strong compounds from the virtual database, and the compounds were synthesized and evaluated. Its activity. Summary of the invention
  • An object of the present invention is to provide a novel ⁇ -nonoxypropionic acid compound of the formula I.
  • Another object of the present invention is to provide a process for producing an ⁇ -pyroxypropionic acid compound represented by Formula I and an analog thereof.
  • a further object of the invention is to provide the use of a compound of formula I for stimulating a peroxisome proliferator-activated receptor (PPAR) and for use in a medicament for the treatment of a disease associated with PPAR.
  • PPAR peroxisome proliferator-activated receptor
  • the present invention employs the following technical solutions:
  • the present invention relates to a compound of formula I and its racemate, enantiomer, physiologically acceptable salt, solvate And crystalline form,
  • B is selected from the group consisting of a carbocyclic ring having 5 or 6 carbon atoms and a heterocyclic ring number 1-4 (wherein the hetero atoms may be the same or different, and the hetero atom is selected from oxygen, nitrogen or sulfur).
  • Preferred B is selected from the group consisting of a carbon ring of 6 carbon atoms and a heterocyclic ring containing a hetero atom, '
  • B is selected from the group consisting of a benzene ring and a hetero ring containing a nitrogen atom; n is selected from an integer of 1 to 4,
  • n is selected from 2 or 3
  • n is selected from 2;
  • Preferred X is selected from the group consisting of 0, S, NH, CO
  • X is selected from O;
  • Rl is selected from the group consisting of hydrogen, halogen, cyano, -6 alkyl, C 6 methoxy, Q- 6 alkylthio, carboxy, alkoxycarbonyl, R7NHCO-
  • R7 is selected from H, C 1-6 fluorenyl), CF 3 ,
  • R1 is selected from the group consisting of hydrogen, halogen, cyano, -6 alkyl, d- 6 methoxy, carboxy, R7NHCO- (R7 is selected from C1-4 fluorenyl), more preferably R1 is selected from hydrogen, halogen, Cyano, alkyl, C 1-4 alkoxy, carboxy,
  • R1 is selected from the group consisting of hydrogen, bromine, cyano, C 1-3 fluorenyl, C 1-3 alkoxy, carboxy,
  • R2 is selected from the group consisting of hydrogen, halogen, d. 6 alkyl, C 1-6 alkoxy, d- 6 alkylthio, CF 3 , Preferred R2 is selected from the group consisting of hydrogen, CM alkyl, d. 4 alkoxy,
  • R2 is selected from the group consisting of hydrogen, methyl, -3 alkyl,
  • YR3 is located in the ortho, meta or para position and is different from A.
  • Y is selected from the group consisting of 0, S, C 1-6 alkyl
  • Y is selected from the group consisting of 0, S, C 1-3 thiol, .
  • Y is selected from 0, s,
  • Y is selected from 0;
  • R3 is selected from the group consisting of hydrogen, d- 6 alkyl, -6 alkoxy, d- 6 thiol
  • Preferred R3 is selected from the group consisting of hydrogen, d- 3 fluorenyl, C 1-3 alkoxy, C W thiol
  • R3 is selected from the group consisting of hydrogen, methyl, methoxy
  • R4 is selected from H, C r6 fluorenyl, and preferably R4 is selected from H;
  • R5 is selected from the group consisting of H, C 12 alkyl, . 12 decyloxy, -12 12 cyclodecyl, C 3-12 cyclodecyloxy, halogen substituted alkoxy or cyclodecyloxy, or various substitutions and positions Different aryloxy or aryloxyoxy groups,
  • Preferred R5 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkoxy, C 3-12 cyclodecyl, C 3. 12 cycloalkoxy,
  • R5 is selected from methoxy, ethoxy, phenoxy, naphthoxy, tetrahydronaphthalene group, tolyl group, methoxyphenyl, CF 3,
  • R6 is selected from the group consisting of hydrogen, hydroxy, -6 alkoxy, C 3 -8 cycloalkoxy, H 2 , NHR7, R8R9, NHOH, NHORIO (R7-10 is selected from the group consisting of 4 fluorenyl).
  • Preferred R6 is selected from hydroxy, NHOH, C 1-4 alkoxy, C 3 - 8 cycloalkyl group,
  • R6 is selected from the group consisting of hydroxyl, NHOH, for the purpose of the present invention
  • preferred compounds include, but are not limited to, compounds of formula IA
  • R1 is selected from the group consisting of hydrogen, -6 alkyl, d- 6 alkoxy, cyano, carboxy, halogen;
  • R2 is selected from the group consisting of hydrogen, halogen, .6 alkyl, d. 6 alkoxy;
  • Y is selected from S, 0
  • R3 is selected from the group consisting of hydrogen, -6 alkyl, d- 6 methoxy
  • R4 is selected from the group consisting of H, Q-6 alkyl
  • R5 is selected from a 6 -alkoxy group, a substituted or unsubstituted phenoxy group (the substituent on the benzene ring is selected from a C 6 fluorenyl group, a Q 6 fluorenyloxy group), a naphthyloxy group, a tetrahydronaphthyloxy group;
  • R6 is selected from hydroxy, hydroxy, NHOH, C 6 alkoxy, C 3 - 8 cycloalkyl group.
  • more preferred compounds include, but are not limited to, the compounds of formula IAA-
  • R1 is selected from the group consisting of hydrogen, methyl, methoxy, cyano, carboxyl, halogen;
  • R2 is selected from the group consisting of hydrogen and methyl
  • Y is selected from S, 0;
  • R3 is selected from the group consisting of hydrogen and methoxy
  • R5 is selected from -6 alkoxy, substituted or unsubstituted phenoxy (substituents on the phenyl ring are selected from -6 fluorenyl, -6 alkoxy), naphthyloxy, tetrahydronaphthyloxy;
  • R6 is selected from the group consisting of hydroxyl groups and NHOH;
  • R11 is selected from the group consisting of d-3 alkyl and -3 alkoxy.
  • more preferred compounds include, but are not limited to, the compounds of formula IAB: among them,
  • Rl is selected from the group consisting of hydrogen, methyl, methoxy, cyano, carboxyl, halogen;
  • R2 is selected from the group consisting of hydrogen and methyl
  • Y is selected from S, 0;
  • R3 is selected from the group consisting of hydrogen and methoxy
  • R5 is selected from the group consisting of d- 6 methoxy, substituted or unsubstituted *oxy (substituents on the phenyl ring are selected from - 6 fluorenyl, d- 6 alkoxy), naphthyloxy, tetrahydronaphthyloxy;
  • R6 is selected from the group consisting of hydroxyl groups and NHOH;
  • R11 is selected from the group consisting of fluorenyl and -3 alkoxy.
  • preferred compounds include, but are not limited to, compounds as shown in Formula IB.
  • R1 is selected from the group consisting of hydrogen, C 6 fluorenyl, - 6 decyloxy, cyano, carboxy, halogen;
  • R2 is selected from the group consisting of hydrogen, halogen, Q. 6 alkyl, d. 6 methoxy;
  • Y is selected from S, 0
  • R3 is selected from the group consisting of hydrogen, -6 fluorenyl, and d- 6 alkoxy;
  • R4 is selected from the group consisting of H and d-6 fluorenyl
  • R5 is selected from the group consisting of d- 6 alkoxy, substituted or unsubstituted phenoxy (substituents on the phenyl ring are selected from -6 alkyl, Q- 6 methoxy), naphthyloxy, tetrahydronaphthyloxy;
  • R6 is selected from hydroxyl, hydroxyl, d- 6 embankment group, C 3 - 8 cycloalkyl group.
  • preferred compounds include, but are not limited to, compounds as shown in Formula IC
  • R1 is selected from the group consisting of hydrogen, -6 alkyl, d- 6 alkoxy, cyano, carboxy, halogen;
  • R2 is selected from the group consisting of hydrogen, halogen, C 6 fluorenyl, C W alkoxy;
  • Y is selected from S, 0
  • R3 is selected from the group consisting of hydrogen, Q- 6 alkyl, Q- 6 methoxy;
  • R4 is selected from the group consisting of H, Ct- 6 alkyl
  • R5 is selected from the group consisting of d- 6 alkoxy, substituted or unsubstituted phenoxy (substituents on the phenyl ring are selected from -6 alkyl, d- 6 alkoxy), naphthyloxy, tetrahydronaphthyloxy;
  • R6 is selected from hydroxyl, hydroxyl, Ci- 6 alkoxy, C 3 - 8 cycloalkyl group embankment.
  • preferred compounds include, but are not limited to, compounds of the formula ID
  • R1 is selected from the group consisting of hydrogen, C 6 alkyl, - 6 decyloxy, cyano, carboxy, halogen;
  • R2 is selected from the group consisting of hydrogen, halogen, Ci.6 alkyl, .6 methoxy;
  • Y is selected from S, 0
  • R3 is selected from hydrogen, - 6 alkyl with, -6 alkoxy
  • R4 is selected from the group consisting of H, -6 alkyl
  • R5 is selected from the group consisting of d- 6 methoxy, substituted or unsubstituted phenoxy (substituents on the phenyl ring are selected from C 6 alkyl, -6 alkoxy), naphthyloxy, tetrahydronaphthyloxy;
  • R6 is selected from hydroxy, hydroxy, - 6 alkoxy, C 3 - 8 cycloalkyl group embankment.
  • preferred compounds include, but are not limited to, compounds as shown in Formula IE
  • R1 is selected from the group consisting of hydrogen, Q- 6 fluorenyl, d- 6 alkoxycyano, carboxy
  • R2 is selected from the group consisting of hydrogen, halogen, C w fluorenyl, C w decyloxy; Y is selected from s, o
  • R3 is selected from the group consisting of hydrogen, - 6 fluorenyl, - 6 alkoxy;
  • R4 is selected from the group consisting of H, d-6 alkyl
  • R5 is selected from the group consisting of d- 6 alkoxy, substituted or unsubstituted phenoxy (substituents on the phenyl ring are selected from - 6 fluorenyl, d- 6 alkoxy), naphthyloxy, tetrahydronaphthyloxy;
  • R6 is selected from hydroxyl, hydroxyl, d- 6 alkoxy, C 3 - 8 cycloalkyl group embankment.
  • Preferred compounds include, but are not limited to, compounds of formula IF for the purposes of the present invention.
  • R1 is selected from the group consisting of hydrogen, -6 alkyl, - 6 decyloxy, cyano, carboxy, halogen;
  • R2 is selected from the group consisting of hydrogen, halogen, C ⁇ fluorenyl, CL 6 decyloxy;
  • Y is selected from S and 0.
  • R3 is selected from the group consisting of hydrogen, C R6 alkyl, d- 6 methoxy;
  • R4 is selected from the group consisting of H, C R6 alkyl
  • (Substituted on the benzene ring is selected from Q-6 alkyl with, Q- 6 embankment yloxy) -6 embankment group selected from R5, a substituted or unsubstituted phenoxy, naphthyloxy, tetrahydronaphthalene group;
  • R6 is selected from hydroxyl, hydroxyl, d- 6 alkoxy, C 3 - 8 cycloalkyl group embankment.
  • preferred compounds include, but are not limited to, the compounds of formula IG:
  • R1 is selected from the group consisting of hydrogen, d- 6 fluorenyl, -6 fluorenyloxy, cyano, carboxy, halogen;
  • R2 is selected from the group consisting of hydrogen, halogen, .6 fluorenyl, Ci. 6 alkoxy;
  • Y is selected from S, 0
  • R3 is selected from the group consisting of hydrogen, d- 6 alkyl, -6-decyloxy;
  • R4 is selected from the group consisting of H, -6 alkyl
  • R5 is selected from - 6 methoxy, substituted or unsubstituted phenoxy (substituents on the phenyl ring are selected from C 6 fluorenyl, Q-6 fluorenyloxy), naphthyloxy, tetrahydronaphthyloxy;
  • R6 is selected from hydroxyl, hydroxyl, d- 6 alkoxy, C 3 - 8 cycloalkyl group.
  • preferred compounds include, but are not limited to, the compounds of formula IH:
  • R1 is selected from the group consisting of hydrogen, d- 6 alkyl, -6 methoxy, cyano, carboxy, halogen;
  • R2 is selected from the group consisting of hydrogen, halogen, .6 alkyl, C decyloxy;
  • Y is selected from S, 0
  • R3 is selected from the group consisting of hydrogen, d- 6 alkyl, d- 6 alkoxy;
  • R4 is selected from the group consisting of H and -6 fluorenyl
  • R5 is selected from a 6 -alkoxy group, a substituted or unsubstituted phenoxy group (the substituent on the benzene ring is selected from the group consisting of Q- 6 -yl, Q- 6 alkoxy), naphthyloxy, tetrahydronaphthyloxy;
  • R6 is selected from hydroxyl, hydroxyl, d-6 alkoxy, C 3 - 8 cycloalkyl group.
  • the halogens described in the present invention are fluorine, chlorine and bromine.
  • the invention also provides a process for the preparation of a compound of the invention, which comprises reacting a compound of the formula IV with a compound of the formula V, a compound of the formula VI, and a compound of the formula W to form a compound of the formula ffl, which is subsequently reacted by hydrolysis, reduction or the like.
  • a compound of formula K or X; or a compound of formula VI and a compound of formula W are first condensed, followed by a compound of formula IV and a compound of formula V to form a compound of formula Vff1, followed by a reaction of hydrolysis, reduction or the like to form a compound of formula ⁇ or X.
  • ⁇ , ⁇ , X, Y, Rl, R2, R3, R4, R5, R6, n are as defined in claim 1, and ⁇ , Q represent Departing group
  • the P and Q are selected from the group consisting of -OH and halogen.
  • V and VI The condensation of V and VI is carried out by the action of a base using tetrabutylammonium bromide as a catalyst.
  • the hydroxamic acid derivative is prepared by reacting the corresponding acid with isobutyl chloroformate in the presence of triethylamine, followed by the addition of a hydroxylamine methanol solution.
  • the reduction reaction is hydrogenation using Pd/C.
  • Optically pure isomers of the compound of formula I can be prepared using racemic unresolved or optically active starting materials in the synthesis.
  • the invention therefore also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as an active ingredient a compound of the invention and a conventional pharmaceutical excipient or adjuvant.
  • the pharmaceutical composition of the present invention usually contains 0.1 to 95% by weight of the compound of the present invention.
  • compositions of the compounds of the invention can be prepared according to methods well known in the art.
  • the compounds of the invention may be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants, if desired, in a suitable form or dosage for use as a human or veterinary drug. form.
  • the compound of the present invention or a pharmaceutical composition containing the same may be administered in a unit dosage form, which may be enterally or parenterally, such as orally, muscle, subcutaneous, nasal, oral mucosa, skin, peritoneum or rectum.
  • injections include intravenous, intramuscular, subcutaneous, intradermal, and acupoint injections.
  • the dosage form can be a liquid dosage form or a solid dosage form.
  • the liquid dosage form may be a true solution type, a colloid type, a microparticle dosage form, an emulsion dosage form, or a suspension dosage form.
  • Other dosage forms such as tablets, capsules, pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, lyophilized powders, and the like.
  • the compounds of the present invention can be formulated into common preparations, sustained release preparations, controlled release preparations, targeted preparations, and various microparticle delivery systems.
  • a carrier for example, a diluent and an absorbent such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid.
  • a diluent and an absorbent such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid.
  • wetting agent and binder such as water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, sugar, honey, glucose solution, gum arabic, gelatin, carboxymethyl cellulose Sodium, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.
  • disintegrating agents such as dried starch, alginate, agar powder, brown algae Powder, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium dodecyl sulfate, methyl cellulose, ethyl cellulose, etc.
  • disintegration inhibitors such as sucrose, Tristearate, cocoa butter, hydrogenated oil, etc.
  • absorption enhancers such as quaternary ammonium salts, sodium decyl sulfate, etc.
  • lubricants such as talc, silica, corn starch, stearates, Boric
  • a carrier for example, a diluent and an absorbent such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talc, etc.; binders such as gum arabic, tragacanth, Gelatin, ethanol, honey, liquid sugar, rice paste or batter; etc.; disintegrating agents, such as agar powder, dried starch, alginate, sodium dodecylsulfonate, methyl cellulose, ethyl cellulose, and the like.
  • a diluent and an absorbent such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talc, etc.
  • binders such as gum arabic, tragacanth, Gelatin, ethanol, honey, liquid sugar, rice paste or batter
  • disintegrating agents such as agar powder, dried starch, alginate
  • the active ingredient compound of the present invention is mixed with the various carriers described above, and the resulting mixture is placed in a hard gelatin capsule or soft capsule.
  • the active ingredient of the compound of the present invention can also be formulated into a microcapsule, suspended in an aqueous medium to form a suspension, or can be enclosed in a hard capsule or used as an injection.
  • the compound of the present invention is formulated into an injectable preparation such as a solution, a suspension solution, an emulsion, or a lyophilized powder injection, which may be aqueous or non-aqueous, and may contain one and/or more drugs.
  • a pharmaceutically acceptable carrier, diluent, binder, lubricant, preservative, surfactant or dispersing agent may be selected from the group consisting of water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid ester, and the like.
  • an appropriate amount of sodium chloride, glucose or glycerin may be added to the preparation for injection, and a conventional cosolvent, a buffer, a pH adjuster or the like may be added. These excipients are commonly used in the field.
  • coloring agents may also be added to the pharmaceutical preparations as needed.
  • the pharmaceutical or pharmaceutical composition of the present invention can be administered by any known administration method for the purpose of administration and enhancing the therapeutic effect.
  • the dosage of the pharmaceutical composition of the compound of the present invention depends on many factors such as the nature and severity of the disease to be prevented or treated, the sex, age, weight, personality and individual response of the patient or animal, the route of administration, the number of administrations, For therapeutic purposes, the therapeutic dose of the present invention can vary widely. In general, the dosages of the pharmaceutical ingredients employed in the present invention are well known to those skilled in the art.
  • the prophylactic or therapeutic effect of the present invention can be accomplished by appropriately adjusting the amount of the actual drug contained in the final formulation of the compound composition of the present invention to achieve its therapeutically effective amount.
  • a suitable dosage range per day of the compound of the present invention is from 0.
  • 001 to 150 mg/kg body weight preferably from 0.1 to 100 mg/kg body weight, more preferably from 1 to 60 mg/kg body weight, most preferably 2 — 30mg/Kg body weight.
  • the above dosages may be in the form of a single dose or divided into several, for example Administration in two, three or four dosage forms is limited by the clinical experience of the administering physician and the dosing regimen including the use of other therapeutic means.
  • the total dose required for each treatment can be divided into multiple or single dose administrations.
  • the compounds or compositions of this invention may be administered alone or in combination with other therapeutic or symptomatic agents and adjusted in dosage.
  • Pharmacological studies have shown that the compound of the formula I of the present invention has an activity of activating PPAR, and for type II diabetes caused by insulin resistance, the compound can improve the body's sensitivity to insulin, thereby achieving therapeutic purposes.
  • PPAR agonists have been found to have effects on many diseases such as hypertension, hyperlipidemia, atherosclerosis, inflammation, and tumors, and PPAR agonists can treat diseases associated with them.
  • diseases such as hypertension, hyperlipidemia, atherosclerosis, inflammation, and tumors
  • PPAR agonists can treat diseases associated with them.
  • the invention is further illustrated by the following examples, but these examples do not limit the scope of the invention.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS) or high resolution mass spectrometry (HRMS).
  • NMR shift ( ⁇ ) is given in parts per million (ppm). Mp is the defect given by ⁇ , and the temperature is not corrected.
  • Column chromatography generally uses 200-300 mesh silica gel as a carrier.
  • the NMR measurement was performed using INOVA-500, the solvent was determined to be CDC1 3 , DMSO-D 6 , the internal standard was TMS, and the chemical shift was given in ppm.
  • the measurement of MS was carried out using a VG-ZAB-2F 200C mass spectrometer.
  • DMSO dimethyl sulfoxide
  • Methoxyacetic acid 38.4 ml, 0.5 mol was dissolved in 200 ml of ethanol, 2% (calculated by methoxyacetic acid) of 4 g of crystalline ferric sulfate and 0.5 ml of concentrated sulfuric acid were added, and the mixture was heated to reflux for 20 hours, and the reaction was monitored by TLC. end. Stop the reaction, concentrate to remove most of the 005 001483 Ethanol, distilled under reduced pressure, afforded 32 g of colorless liquid, yield 54%. (Acros: 44-45.4 ° C / 9mraHg)
  • Phenol (9.882 g, 105 mmol) and anhydrous potassium carbonate (20.73 g, 150 mmol) were dissolved in 50 ml of acetone, and ethyl chloroacetate (10.75 ml, 100 ml) was slowly added dropwise at room temperature, and the reaction was continued at room temperature. After 8 hours, TLC monitored the reaction completely. The reaction mixture was filtered, and the solvent was evaporated, evaporated, evaporated, evaporated. (136°C/19ramHg) N2005/001483 b) 2-phenoxy-3- ⁇ 4-[2-(1-indolyl)ethoxy]phenyl ⁇ acrylic acid
  • Hydroxylamine hydrochloride (139 mg, 2 mmol) was dissolved in 5 ml of anhydrous methanol, and an equivalent of potassium hydroxide solid was added. After stirring at room temperature for 10 minutes, the precipitated solid was filtered off and the filtrate was taken.
  • ⁇ -naphthol (47.58 g , 330 mmol) of a white solid ⁇ -naphthylacetate 54 g was obtained in a yield of 7 U.
  • 2-Ethoxy-3-(4-hydroxyphenyl) was obtained by the method described in Example 10 using 4-benzyloxybenzaldehyde (10.61 g, 50 mmol) and ethyl ethoxyacetate (6.872 g, 52 mmol). Ethyl propionate, a colorless liquid of 3.575 g, a two-step yield of condensation and reduction of 30.2%.
  • the obtained new compound was assayed with human PPAR ⁇ , PPAR Y by Biacore 3000 instrument (Biacore AB, Rapsgatan 7, S-754 50 Uppsala, Sweden) using surface plasmon resonance (SPR, Surface Plasmon Resonance) analysis method.
  • the binding constant Kd of the body binding region (Table 1).
  • SPR Surface Plasmon Resonance
  • the resulting compound is screened for activity to activate the PPARy receptor.
  • a screening model for screening PPARy activators in live cells was designed using the principle that PPARY activation activates its downstream gene transcription.
  • a reporter gene plasmid was constructed, and the PPARY receptor DNA-binding sequence (PPRE) was inserted upstream of the luciferase gene, and the expression of the luciferase gene was regulated by the PPARY receptor.
  • the reporter gene plasmid and the PPARY receptor are simultaneously transferred into a cell.
  • the PPARy receptor is activated, and the activated receptor can induce the expression of the luciferase gene.
  • the yield of luciferase can be detected by its luminescent substrate.
  • the intensity of activation of the PPARy receptor by the compound can be seen by observing the intensity of the luminescence.
  • GFP plasmid was also co-transfected as an internal reference.
  • the luminescence values of all the test wells were corrected by GFP value in the analysis of the experimental results.
  • the positive control in the trial used the international anti-type 2 diabetes "standard" drug rosiglitazone.
  • the test results are expressed as relative activation multiples, and the solvent control has a value of 1, and the larger the value, the higher the activation ability.
  • Liver cancer cell line 20000 / well lOOul system.
  • the plasmid was transferred to the cells with FUGENE6.
  • the original lOOul medium was aspirated and replaced with 190 ul of fresh medium.
  • volume of culture medium (ul) 49 Add the amount of cells after mixing (ul) 10 Corresponding final concentration (M) 10
  • Example 1 4.861
  • Example 19 2.6302
  • Example 2 5.176
  • Example 20 ND
  • Example 17 ND
  • Example 35 2.3906
  • Example 18 5.1066
  • Example 36 ND
  • PPAR agonists have effects on many diseases such as hypertension, hyperlipemia, atherosclerosis, inflammation, tumors, and the like, and some of the compounds of the present invention are selected for screening for anticancer activity.
  • the selection of drugs for killing cancer cells was determined by MTT assay in vitro.
  • the MTT assay is based on the metabolic reduction of 3-(4, 5-dimethylthiazol-2-yl)-2, 5-dipHenyl tetrazol iura bromide (MTT).
  • MTT 5-dipHenyl tetrazol iura bromide
  • human colon cancer cells, human fibrosarcoma cells, human prostate cancer cells, human breast cancer cells, and the like, which are highly expressed by PPAR were selected.
  • Example 4 has a good inhibitory effect on human colon cancer cells, human fibrosarcoma cells, and human prostate cancer cells.
  • Human colon cancer cell line HT29 was selected for in vivo experiments.
  • Example 6 has an inhibitory effect on the growth of HT29 in vivo -
  • the method is as described above.
  • a screening model for screening PPARa activators in live cells was designed using the principle that PPARa binds to a ligand to activate its downstream gene transcription.
  • the ligand binding domain (LBD) of the PPARa receptor was ligated together with the DNA binding domain (DBD) of the GAL4 protein to construct a fusion plasmid.
  • the fusion protein expressed by the plasmid can activate GAL4 DNA in the presence of PPARa ligand. Binding to the expression of genes downstream of the sequence.
  • the activated receptor can induce the expression of the luciferase gene, and the luciferase production can pass through the luminescent substrate. detected.
  • the intensity of activation of the PPARa receptor by the compound can be known by observing the intensity of the luminescence.
  • GFP plasmid was also co-transfected as an internal reference. The luminescence values of all the test wells were corrected by GFP value in the analysis of the experimental results.
  • the positive control in the trial used the internationally accepted control drug WY14643.
  • the test results are expressed as relative activation multiples, and the value of the solvent control is 1. The higher the value, the higher the activation capacity.
  • Example 11 2.24 Off 4.07 14
  • Example 12 ND ND ND II
  • the gray part of the table indicates that the EC 5 o of this value is less than ⁇ or the maximum activation intensity is greater than 50% of the positive drug.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne de nouveaux acides a-alkyloxy propioniques de la formule (I), leurs stéréo-isomères et racémates optiques, ainsi que leurs sels, solvates et formes cristallines physiologiquement acceptables, leurs procédés de préparation, des compositions pharmaceutiques les contenant ainsi que les utilisations des composés pour traiter des états cliniques associés à l'insulinorésistance.
PCT/CN2005/001483 2004-09-17 2005-09-16 Nouveaux acides $g(a)-alkyloxy propioniques, leurs procedes de preparation, compositions pharmaceutiques les contenant et leurs utilisations WO2006029575A1 (fr)

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JP2016531111A (ja) * 2013-07-22 2016-10-06 メタボリック ソリューションズ ディベロップメント カンパニー， エルエルシー 代謝疾患を処置するためのｐｐａｒ節約化合物
US9745253B2 (en) 2015-03-13 2017-08-29 Forma Therapeutics, Inc. Alpha-cinnamide compounds and compositions as HDAC8 inhibitors

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CN1312795A (zh) * 1998-06-04 2001-09-12 阿斯特拉曾尼卡有限公司 新的3－芳基丙酸衍生物和其类似物
WO2003059864A2 (fr) * 2002-01-15 2003-07-24 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Derives d'acide pheny(alkyl)carboxylique et derives phenylalkylheterocycliques dioniques et leur utilisation comme medicaments a activite d'abaissement de niveau de glucose serique et/ou lipides seriques

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CN1312795A (zh) * 1998-06-04 2001-09-12 阿斯特拉曾尼卡有限公司 新的3－芳基丙酸衍生物和其类似物
WO2003059864A2 (fr) * 2002-01-15 2003-07-24 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Derives d'acide pheny(alkyl)carboxylique et derives phenylalkylheterocycliques dioniques et leur utilisation comme medicaments a activite d'abaissement de niveau de glucose serique et/ou lipides seriques

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016531111A (ja) * 2013-07-22 2016-10-06 メタボリック ソリューションズ ディベロップメント カンパニー， エルエルシー 代謝疾患を処置するためのｐｐａｒ節約化合物
US9745253B2 (en) 2015-03-13 2017-08-29 Forma Therapeutics, Inc. Alpha-cinnamide compounds and compositions as HDAC8 inhibitors
US10266487B2 (en) 2015-03-13 2019-04-23 Forma Therapeutics, Inc. Alpha-cinnamide compounds and compositions as HDAC8 inhibitors
US10508077B2 (en) 2015-03-13 2019-12-17 Forma Therapeutics, Inc. Alpha-cinnamide compounds and compositions as HDAC8 inhibitors
US10988441B2 (en) 2015-03-13 2021-04-27 Valo Early Discovery, Inc. Alpha-cinnamide compounds and compositions as HDAC8 inhibitors
US11919839B2 (en) 2015-03-13 2024-03-05 Valo Health, Inc. Alpha-cinnamide compounds and compositions as HDAC8 inhibitors

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