WO2005113496A1 - Verfahren zur herstellung von 1,4-diphenylazetidinon-derivaten - Google Patents

Verfahren zur herstellung von 1,4-diphenylazetidinon-derivaten Download PDF

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Publication number
WO2005113496A1
WO2005113496A1 PCT/EP2005/005498 EP2005005498W WO2005113496A1 WO 2005113496 A1 WO2005113496 A1 WO 2005113496A1 EP 2005005498 W EP2005005498 W EP 2005005498W WO 2005113496 A1 WO2005113496 A1 WO 2005113496A1
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Prior art keywords
alkyl
aryl
general formula
anion
cation
Prior art date
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Ceased
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PCT/EP2005/005498
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German (de)
English (en)
French (fr)
Inventor
Andreas Lindenschmidt
David William Will
Gerhard Jaehne
Theodor Andreas Wollmann
Wendelin Frick
Bernd Junker
David Rigal
Guenter Billen
Heiner Jendralla
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Sanofi Aventis Deutschland GmbH
Original Assignee
Sanofi Aventis Deutschland GmbH
Aventis Pharma Deutschland GmbH
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
Priority claimed from DE200410025071 external-priority patent/DE102004025071B4/de
Priority claimed from DE102005010770A external-priority patent/DE102005010770A1/de
Priority to MXPA06013456A priority Critical patent/MXPA06013456A/es
Priority to RSP-2007/0483A priority patent/RS50539B/sr
Priority to AU2005245124A priority patent/AU2005245124A1/en
Priority to HR20070570T priority patent/HRP20070570T3/xx
Priority to HK07107318.3A priority patent/HK1103296B/xx
Priority to EP05747892A priority patent/EP1756049B1/de
Priority to NZ551413A priority patent/NZ551413A/en
Priority to CA002567149A priority patent/CA2567149A1/en
Application filed by Sanofi Aventis Deutschland GmbH, Aventis Pharma Deutschland GmbH filed Critical Sanofi Aventis Deutschland GmbH
Priority to BRPI0510150-6A priority patent/BRPI0510150A/pt
Priority to DK05747892T priority patent/DK1756049T3/da
Priority to DE502005001841T priority patent/DE502005001841D1/de
Priority to PL05747892T priority patent/PL1756049T3/pl
Priority to JP2007517094A priority patent/JP2007538042A/ja
Publication of WO2005113496A1 publication Critical patent/WO2005113496A1/de
Priority to IL178991A priority patent/IL178991A0/en
Priority to US11/561,626 priority patent/US7488818B2/en
Anticipated expiration legal-status Critical
Priority to NO20065776A priority patent/NO20065776L/no
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • 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
    • 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
    • A61P3/06—Antihyperlipidemics

Definitions

  • the invention relates to the preparation of 1,4-diphenylazetidinone derivatives by cyclization of ⁇ -substituted aminoamides in the presence of silylating agents and Zyklleiterskatalysatoren.
  • Ezetimibe as a known representative of these compounds, blocks the absorption of cholesterol from the intestine, so that both lower LDL levels and less triglycerides are observed in patients. It is the 1- (4-fluorophenyl) -3 (R) - [3- (4-fluorophenyl) -3 (S) -hydroxypropyl] -4 (S) - (4-hydroxyphenyl) -2-azetidinone of the following formula (see claim 8 in EP 0 720599 Bl).
  • Dialkylchlorophosphate / phase transfer catalyst di- or trichlorobenzoyl chloride / tetra-n-butylammonium hydrogensulfate, or dichlorobenzoyl chloride / NaH.
  • R y , R z are, for example, independently of one another H, -Ce-alkyl, phenyl, benzyl.
  • TMEDA may cause dermatitis after repeated contact and is highly hazardous to water.
  • the cyclization with Na- or bis-bistrirnethylsilylamid must be carried out at low temperatures (-78 ° C), otherwise significant amounts of by-product are formed. Therefore, this synthetic route is not suitable for a large-scale process.
  • a silylating agent and a fluoride ion catalyst as a cyclization agent or a salt of the chiral compound (G + salt), in particular with bis (trimethylsily ⁇ ) acetamide and tetra-n-butylammonium fluoride.
  • LAG alkylene
  • a 1 , A 3 and A are, for example, H, halogen, C 1 -alkyl
  • a 2 is, for example, a C 1 -C 5 -alkylene chain or C 1 -C -alkenylene chain
  • R 3 is OH, OC (O) -R j where R i is, for example H or (C 1 -C 5 ) alkyl
  • n, p, q, r are either zero or a multiple of 1 or 2
  • Y is an optically active sultam derivative) with TBAF and a silylating agent.
  • the object of the invention is to show a further synthesis variant for the abovementioned compounds, which can also be carried out stereospecifically and in high yield, and requires those auxiliary reagents which are as little toxic as possible. With a view to use in a large-scale process, it should also be possible to carry out this process with catalytic amounts of cyclization reagent.
  • One solution is then a process for the preparation of i ⁇ -piphenylazetidinone derivatives from suitably protected ⁇ -substituted aminoamides in the presence of silylating agents and at least one cyclization catalyst, said cyclization catalyst being represented by one of the general formulas below
  • R 16 , R 17 , R 18 , R 19 independently of one another are aryl, (C 1 -C 15 ) -alkyl, benzyl,
  • R 42 (C 1 -C 15 ) alkyl, benzyl, (C 5 -C 8 ) cycloalkyl, aryl, where aryl may be substituted by F, Cl, Br, J, -OH, -O (C 1 -C 3 ) -alkyl, -NH 2 , -NH (dC 3 ) alkyl, -N [(C 1 -C 3 ) alkyl] 2 , -C (O) OH, -C (O) O (C 1 -C 3 ) alkyl, -C (O) NH 2 , -C (O) NH (C 1 -C 3 ) alkyl, -C (O) N [(C 1 -C 3 ) alkyl] 2 , -SO 2 NH 2 , -SO 2 NH (C C3) alkyl, -SO 2 N [(C 1 -C 3 ) alkyl] 2 , -CN, (CC
  • R 20 to R 32 and R 34 to R 38 independently of one another are H, ( CC ⁇ ) alkyl, aryl or heteroaryl and in each case two alkyl radicals together can also form a cycloalkylene radical of at most 6 C-blocks in the ring, which in turn may be substituted with F, Cl, Br, I, CF 3 , NO 2 , COO (-CC 6 ) alkyl, CON [(-CC 6 ) alkyl] 2 , cycloalkyl, (CC 10 ) -alkyl, (C 2 -C 6 ) alkenyl, O- (C 1 -C 6 ) alkyl, O-CO- (CC 6 ) alkyl, O-CO- (CC 6 ) alkylene-aryl, SO 2 N [(CC 6 ) alkyl] 2 , S - (CC 6) alkyl, S- (CH 2 -) ⁇ aryl, SO- (C ⁇ -C6) alkyl, SO-
  • aryl is meant an aromatic hydrocarbon radical having 6 to 14 carbon atoms, e.g. Phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha- or beta-tetralonic, indanyl or indan-1-one-yl radical and is preferably unsubstituted but may also be substituted.
  • Typical substituents are, for example, F, Cl, Br, I, CF 3 , NO 2 , COO (C 1 -C 6 ) alkyl, CON [(CC 6 ) alkyl] 2 , cycloalkyl, (C 1 -C 10 ) alkyl, (C 2 -C 6 ) alkenyl, O- (C 1 -C 6 ) alkyl, O-CO- (CC 6 ) alkyl, O-CO- (dC 6 ) alkylene-aryl, SO 2 N [(dC 6 ) alkyl] 2 , S- (dC 6 ) alkyl, S- (CH 2 -) n aryl, SO- (dC 6 ) alkyl, SO- (CH 2 -) ⁇ aryl, SO 2 - (CC 6 ) alkyl, SO 2 - (CH 2 -) n aryl, SO 2 -N ((CC 6 ) alkyl) (CH 2 -)
  • Heteroaryl is understood as meaning aromatic rings and ring systems which, in addition to carbon, also contain heteroatoms such as nitrogen, oxygen or sulfur. Furthermore, ring systems also belong to this definition, in which the heterocyclic radical is fused with benzene nuclei.
  • the rings are preferably 3- to 7-membered.
  • An alkyl radical is understood as meaning a straight-chain or branched hydrocarbon chain having one or more carbons, preferably 1 to 8 carbons, for example methyl, ethyl, propyl, butyl, hexyl, isopropyl, isobutyl, neopentyl, tert-butyl, hexyl.
  • a cycloalkyl radical is meant a radical consisting of one or more ring-containing ring systems which is saturated or partially unsaturated (having one or two double bonds) composed exclusively of carbon atoms, e.g. Cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl or adamantyl.
  • the rings are preferably 3- to 7-membered. As possible substituents, those mentioned above are typical.
  • a preferred embodiment of the process according to the invention is based on the known process for the preparation of 1,4-diphenylazetidinone derivatives of the general formula (I)
  • X is CH 2 , CHOH, CO or CHOCOR 11
  • R 1, R 2 independently H, OH, OCF 3, or O- (C ⁇ -C ö) alkyl, O- (C 3 -C 7) cycloalkyl, O-COR 11, CN, CH 2 NHR 7, CH 2 NR 7 R 8 , NR 7 R 8 , COR 14 , F or Cl
  • R 3 , R 4 independently of one another H, F, Cl, OH, OCF 3 , O- (CC ö ) alkyl, O- (C 3 -C 7 ) cycloalkyl, O-COR 11 , CN, CH 2 NHR 7 , CH 2 NR 7 R 8 , NR 7 R 8 , COR 14 or (CC 6 ) alkyl
  • R 5 , R 6 _ independently of one another are H, F, Cl, (C 1 -C 6 ) alkyl, CF 3 or OCF 3
  • R 8 H, (dC 6 ) alkyl, or (C 3 -C 7 ) cycloalkyl
  • R y is OH or NHCH 2 [-CH (OH)] m -CH 2 OH or a suitably protected form thereof
  • R 12 (dC 6 ) alkyl or (C 3 -C 7 ) cycloalkyl
  • R 13 (C 1 -C 6 ) alkyl or (C 3 -C 7 ) cycloalkyl, aryl or heteroaryl
  • R ⁇ R ⁇ R 1, R 2 and O-protective group R 3 ', R 4' R 3, R 4, CH 2 NHCO 2 CH 2 (C 6 H 5), CH 2 N [Si (alkyl) 0 ( aryl) p] CO 2 CH 2 (C 6 H 5), CH 2 NHCO 2 -tert.Bu, CH 2 N [Si (alkyl) 0 (phenyl) p] CO 2 -tert.Bu,
  • R 16, R 17, R 18, R 19 independently of one another aryl, (C ⁇ -C15) alkyl, in particular (dC t o) alkyl, benzyl, especially butyl mean
  • R, 1 1 6 0 ' ' , "RI 1 T V , R TJ 1 1 8 0 ' ' , ⁇ R1 1 9 V ' ' are independently aryl, (CC 15 ) alkyl.
  • the process according to the invention is characterized in that compounds of the general formula (II)
  • R 15 aryl or (C 1 -C 10) alkyl
  • R 1 ', R 2 ' R 1 , R 2 and O-protecting group
  • R 15 aryl or (C 1 -C 10) alkyl
  • R 1 ', R 2 ' R 1 , R 2 and O-protecting group
  • R 3 ', R 4 R 3 , R 4 , CH 2 NHCO 2 CH 2 ( C 6 H 5 ), CH 2 N [Si (alkyl) o (aryl) p ] CO 2 CH 2 (C 6 H 5 ), CH 2 NHCO 2 tert.Bu, CH 2 N [Si (alkyl) o ( Phenyl) p] CO 2 -tert.Bu, wherein in the cyclization catalyst, the cation corresponds to the general formula (XII) and the anion R 2 COO " is.
  • diphenylazetidinone compounds which can be prepared according to the invention are frequently used in practice as a pharmaceutically acceptable salt, because they are particularly suitable for medical applications because of their higher water solubility relative to the starting or basic compounds. These salts must have a pharmaceutically acceptable anion or cation.
  • Suitable pharmaceutically acceptable acid addition salts of the compounds which can be prepared according to the invention are salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, sulfonic acid and sulfuric acid and also organic acids, for example acetic acid, benzenesulfonic acid, benzoic acid, citric acid, Ethansulfone, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluene sulfonic, tartaric and trifluoroacetic acid.
  • the chloro salt is used in a particularly preferred manner.
  • Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth salts (such as magnesium and calcium salts).
  • the compounds of the general formula (I) and their pharmaceutically acceptable salts and physiologically functional derivatives are ideal drugs for the treatment of lipid metabolism disorders, in particular hyperlipidemia.
  • the compounds of the general formula (I) are also suitable for influencing the serum cholesterol level and for prevention and treatment arteriosclerotic phenomena.
  • azetidinones of general formula (V) described in the beginning are obtained in particular by dissolving the compounds of general formula (IV) in an organic solvent, e.g. Hexane, heptane, toluene, chlorobenzene, diisopropyl ether, ethyl acetate, dimethoxyethane, dichloromethane or tert-butyl methyl ether, but preferably toluene, diisopropyl ether or tert-butyl methyl ether, and then with a mild silylating agent, e.g.
  • an organic solvent e.g. Hexane, heptane, toluene, chlorobenzene, diisopropyl ether, ethyl acetate, dimethoxyethane, dichloromethane or tert-butyl methyl ether, but preferably toluene, diisopropyl ether or
  • potassium methoxylate (475.5 mg) is suspended under an argon atmosphere in methanol (7 ml). To this is added a methanolic solution (3 ml) of tetrabutylphosphonium chloride (2 g). It is stirred for 2 hours at room temperature, filtered under argon through a syringe filter and the solvent is removed. The residue is weighed and taken up in tetrahydrofuran (THF) (5 ml). There is obtained a 1.35 molar solution of tetrabutylphosphonium methoxide.
  • THF tetrahydrofuran
  • TetrabutyIphosphoniumoxazoIidin-on-2 Tetrabutylphosphonium chloride (300 mg) is dissolved in methanol (3 ml) and silver (I) oxide (203.85 mg) added. At room temperature, it is stirred under argon for 16 hours. The reaction solution is filtered through a syringe filter. To the filtrate is added oxazolidin-2-one (104.4 mg) and stirred for 2 hours at room temperature. The solvent is removed on a rotary evaporator. Tetrabutylphosphonium oxazolidin-2-one (200 mg) is obtained as a colorless oil.
  • 1 H NMR (d 6 -DMSO) 0.9 (m, 12 H), 1.4 (m, 16 H), 2.2 (m, 8 H), 3.4 (t, 2H), 3.85 (t, 2 H).
  • Tetrafuranophosphonium-10,10-dimethyl-3-thia-4-aza-tricyclo [5.2.1.01, 1decane-3,3-dioxide The compound is prepared analogously to the procedure in Example 5 from 2,10-Camphersultam.
  • Tetrabutylphosphonium phthalamate is also represented by the following route.
  • a solution of tetrabutylphosphonium hydroxide (12.5 g, 40% in water) is charged.
  • phthalimide (2.7 g) is added and the reaction solution is stirred overnight at room temperature.
  • the water is removed on a rotary evaporator and the residue taken up in toluene.
  • the toluene is removed on a rotary evaporator and the residue is taken up in toluene again. This procedure is repeated 4-5 times. Thereafter, the solvent is removed to dryness.
  • Example 26 Cyclization of ⁇ 4- [5- (tert -butyldimethylsilanyloxy) -5- (4-fluorophenyl) -1- (4-methoxyphenyl) -2- (2-oxo-4-phenyloxazolidine-3-carbonyl) pentylamino benzyl ⁇ -carbamic acid benzyl ester with tetrabutylphosphonium phthalamate from Example 24 is carried out in an analogous manner to the procedure in Example 25, but in diisopropyl ether and at 50 ° C within 6 hours. By means of LC / MS comparison (Liquid Chromatography / Mass Spectrometry), a conversion to the analogous product from Example 25 is determined.
  • Tetrabutylphosphonium benzoate is also represented by the following route.
  • a solution of tetrabutylphosphonium hydroxide (4.7 g, 40% in water) is charged.
  • benzoic acid (0.8 g) is added and the reaction solution is stirred for 5 hours at room temperature.
  • the water is removed on a rotary evaporator and the residue taken up in toluene.
  • the toluene is removed on a rotary evaporator and the residue is taken up in toluene again. This procedure is repeated 4-5 times. Thereafter, the solvent is removed to dryness.
  • Example 29 Cyclization of ⁇ 4- [5- (tert -butyldimethylsilanyloxy) -5- (4-fluorophenyl) -1- (4-methoxy-2-phenyl) -2- (2-oxo-4-phenyloxazolidine-3-carbonyl) -pentylamino benzyl ⁇ -carbamic acid benzyl ester with tetrabutylphosphonium benzoate from Example 28 is carried out in an analogous manner to the procedure in Example 25, but in diisopropyl ether and at 60 ° C within 3 hours. By means of LC / MS comparison (Liquid Chromatography / Mass Spectrometry), a conversion to the analogous product from Example 25 is determined.

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PCT/EP2005/005498 2004-05-21 2005-05-20 Verfahren zur herstellung von 1,4-diphenylazetidinon-derivaten Ceased WO2005113496A1 (de)

Priority Applications (16)

Application Number Priority Date Filing Date Title
PL05747892T PL1756049T3 (pl) 2004-05-21 2005-05-20 Sposób wytwarzania pochodnych 1,4-difenyloazetydynonu
JP2007517094A JP2007538042A (ja) 2004-05-21 2005-05-20 １，４−ジフェニルアゼチジノン誘導体の製造方法
BRPI0510150-6A BRPI0510150A (pt) 2004-05-21 2005-05-20 processo para preparação de derivados de 1,4-difenilacetidinonas
AU2005245124A AU2005245124A1 (en) 2004-05-21 2005-05-20 Method for producing 1,4-diphenyl azetidinone derivatives
HR20070570T HRP20070570T3 (en) 2004-05-21 2005-05-20 Method for producing 1,4-diphenyl azetidinone derivatives
HK07107318.3A HK1103296B (en) 2004-05-21 2005-05-20 Method for producing 1,4-diphenyl azetidinone derivatives
EP05747892A EP1756049B1 (de) 2004-05-21 2005-05-20 Verfahren zur herstellung von 1,4-diphenylazetidinon-derivaten
NZ551413A NZ551413A (en) 2004-05-21 2005-05-20 Method for producing 1,4-diphenyl azetidinone derivatives
CA002567149A CA2567149A1 (en) 2004-05-21 2005-05-20 Method for producing 1,4-diphenyl azetidinone derivatives
MXPA06013456A MXPA06013456A (es) 2004-05-21 2005-05-20 Metodo para producir derivados de 1,4-difenilazetidinona.
RSP-2007/0483A RS50539B (sr) 2004-05-21 2005-05-20 Postupak proizvodnje derivata 1,4-difenil-azetidinona
DK05747892T DK1756049T3 (da) 2004-05-21 2005-05-20 Fremgangsmåde til fremstilling af 1,4-diphenylazetidinon-derivater
DE502005001841T DE502005001841D1 (de) 2004-05-21 2005-05-20 Verfahren zur herstellung von 1,4-diphenylazetidinon-derivaten
IL178991A IL178991A0 (en) 2004-05-21 2006-11-01 Method for producing 1,4-diphenyl azetidinone derivatives
US11/561,626 US7488818B2 (en) 2004-05-21 2006-11-20 Method for producing 1,4-diphenyl azetidinone derivatives
NO20065776A NO20065776L (no) 2004-05-21 2006-12-13 Fremgangsmate for fremstilling av 1,4-difenylazetidinonderivater

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE200410025071 DE102004025071B4 (de) 2004-05-21 2004-05-21 Verfahren zur Herstellung von Diphenylazetidinon-Derivaten
DE102004025071.5 2004-05-21
DE102005010770A DE102005010770A1 (de) 2005-03-09 2005-03-09 Verfahren zur Herstellung von 1,4-Diphenylazetidinon-Derivaten
DE102005010770.2 2005-03-09

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US11/561,626 Continuation US7488818B2 (en) 2004-05-21 2006-11-20 Method for producing 1,4-diphenyl azetidinone derivatives

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US (1) US7488818B2 (https=)
EP (1) EP1756049B1 (https=)
JP (1) JP2007538042A (https=)
KR (1) KR20070027554A (https=)
AR (1) AR049184A1 (https=)
AT (1) ATE376997T1 (https=)
AU (1) AU2005245124A1 (https=)
BR (1) BRPI0510150A (https=)
CA (1) CA2567149A1 (https=)
CY (1) CY1107425T1 (https=)
DE (1) DE502005001841D1 (https=)
DK (1) DK1756049T3 (https=)
ES (1) ES2294712T3 (https=)
HR (1) HRP20070570T3 (https=)
IL (1) IL178991A0 (https=)
MA (1) MA28635B1 (https=)
MX (1) MXPA06013456A (https=)
NZ (1) NZ551413A (https=)
PL (1) PL1756049T3 (https=)
PT (1) PT1756049E (https=)
RS (1) RS50539B (https=)
RU (1) RU2380361C2 (https=)
TW (1) TW200611896A (https=)
UY (1) UY28912A1 (https=)
WO (1) WO2005113496A1 (https=)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7470678B2 (en) 2002-07-05 2008-12-30 Astrazeneca Ab Diphenylazetidinone derivatives for treating disorders of the lipid metabolism
US7842684B2 (en) 2006-04-27 2010-11-30 Astrazeneca Ab Diphenylazetidinone derivatives possessing cholesterol absorption inhibitor activity
US7863265B2 (en) 2005-06-20 2011-01-04 Astrazeneca Ab 2-azetidinone derivatives and their use as cholesterol absorption inhibitors for the treatment of hyperlipidaemia
US7871998B2 (en) 2003-12-23 2011-01-18 Astrazeneca Ab Diphenylazetidinone derivatives possessing cholesterol absorption inhibitory activity
US7893048B2 (en) 2005-06-22 2011-02-22 Astrazeneca Ab 2-azetidinone derivatives as cholesterol absorption inhibitors for the treatment of hyperlipidaemic conditions
US7906502B2 (en) 2005-06-22 2011-03-15 Astrazeneca Ab 2-azetidinone derivatives as cholesterol absorption inhibitors for the treatment of hyperlipidaemic conditions
WO2011056895A1 (en) * 2009-11-03 2011-05-12 University Of Notre Dame Du Lac Ionic liquids comprising heteraromatic anions
EP2567959A1 (en) 2011-09-12 2013-03-13 Sanofi 6-(4-Hydroxy-phenyl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2013044026A1 (en) * 2011-09-22 2013-03-28 Ut-Battelle, Llc Phosphonium-based ionic liquids and their use in the capture of polluting gases
US10086331B2 (en) 2013-11-05 2018-10-02 University Of Notre Dame Du Lac Carbon dioxide capture using phase change ionic liquids
US10385251B2 (en) 2013-09-30 2019-08-20 University Of Notre Dame Du Lac Compounds, complexes, compositions, methods and systems for heating and cooling

Families Citing this family (4)

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Publication number Priority date Publication date Assignee Title
CN100471835C (zh) * 2003-12-23 2009-03-25 默克公司 抗高胆固醇血症化合物
US20090047716A1 (en) * 2007-06-07 2009-02-19 Nurit Perlman Reduction processes for the preparation of ezetimibe
EP2414529A2 (en) 2009-04-01 2012-02-08 Matrix Laboratories Ltd Enzymatic process for the preparation of (s)-5-(4-fluoro-phenyl)-5-hydroxy- 1morpholin-4-yl-pentan-1-one, an intermediate of ezetimibe and further conversion to ezetimibe
JP6803138B2 (ja) * 2014-10-22 2020-12-23 三星エスディアイ株式会社Samsung SDI Co., Ltd. ホスホニウム系化合物、それを含むエポキシ樹脂組成物、およびそれを用いて製造された半導体装置

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US7470678B2 (en) 2002-07-05 2008-12-30 Astrazeneca Ab Diphenylazetidinone derivatives for treating disorders of the lipid metabolism
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US7863265B2 (en) 2005-06-20 2011-01-04 Astrazeneca Ab 2-azetidinone derivatives and their use as cholesterol absorption inhibitors for the treatment of hyperlipidaemia
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US10259788B2 (en) 2009-11-03 2019-04-16 University Of Notre Dame Du Lac Ionic liquids comprising heteraromatic anions
US10889544B2 (en) 2009-11-03 2021-01-12 University Of Notre Dame Du Lac Ionic liquids comprising heteraromatic anions
EP2567959A1 (en) 2011-09-12 2013-03-13 Sanofi 6-(4-Hydroxy-phenyl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
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BRPI0510150A (pt) 2007-10-02
US20070149776A1 (en) 2007-06-28
TW200611896A (en) 2006-04-16
IL178991A0 (en) 2007-03-08
NZ551413A (en) 2009-07-31
MA28635B1 (fr) 2007-06-01
PT1756049E (pt) 2007-12-17
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US7488818B2 (en) 2009-02-10
JP2007538042A (ja) 2007-12-27
PL1756049T3 (pl) 2008-02-29
RU2380361C2 (ru) 2010-01-27
CA2567149A1 (en) 2005-12-01
CY1107425T1 (el) 2013-03-13
RS50539B (sr) 2010-05-07
AU2005245124A1 (en) 2005-12-01
RU2006145444A (ru) 2008-06-27
ES2294712T3 (es) 2008-04-01
EP1756049B1 (de) 2007-10-31
DK1756049T3 (da) 2008-02-25
HRP20070570T3 (en) 2008-01-31
ATE376997T1 (de) 2007-11-15
UY28912A1 (es) 2005-12-30
HK1103296A1 (zh) 2007-12-14

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