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WO1993010127A1 - Procede de production d'un ester de prolineboronate - Google Patents

Procede de production d'un ester de prolineboronate Download PDF

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Publication number
WO1993010127A1
WO1993010127A1 PCT/US1992/009845 US9209845W WO9310127A1 WO 1993010127 A1 WO1993010127 A1 WO 1993010127A1 US 9209845 W US9209845 W US 9209845W WO 9310127 A1 WO9310127 A1 WO 9310127A1
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WO
WIPO (PCT)
Prior art keywords
formula
pinanediol
yield
group
ester
Prior art date
Application number
PCT/US1992/009845
Other languages
English (en)
Inventor
Roger Snow
Terence A. Kelly
Julian Adams
Simon Coutts
Clark Perry
Original Assignee
Boehringer Ingelheim Pharmaceuticals, Inc.
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 Boehringer Ingelheim Pharmaceuticals, Inc. filed Critical Boehringer Ingelheim Pharmaceuticals, Inc.
Priority to JP5509442A priority Critical patent/JPH07501078A/ja
Priority to EP92925238A priority patent/EP0641347A1/fr
Priority to SK592-94A priority patent/SK59294A3/sk
Priority to AU31368/93A priority patent/AU661362B2/en
Publication of WO1993010127A1 publication Critical patent/WO1993010127A1/fr
Priority to FI942345A priority patent/FI942345A0/fi
Priority to NO941905A priority patent/NO941905L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a method for making optically active prolineboronate esters. These are useful as intermediates in the production of peptides which incorporate prolineboronic acid instead of proline. These peptides, in turn, are useful for inhibiting various biologically important proteases.
  • Peptides which incorporate the ⁇ -aminoboronic acid analog of proline (BoroPro) at the C-terminus are of special interest because they have been shown to be potent inhibitors of certain post-proline cleaving enzymes.
  • Bachovchin et al. J. Biol. Chem. 265, 3738 (1990)] have reported that such peptides are inhibitors of IgA proteinases from certain bacteria. These enzymes are strongly implicated in bacterial virulence.
  • Flentke et al. Proc. Natl. Acad. Sci.
  • a first broad aspect of the present invention comprises three closely related methods for the synthesis of prolineboronic acid esters. Two of these syntheses commence from pyrrole. The third commences from pyrrolidine. Included within the scope of this first aspect of the invention are certain novel intermediates. Prolineboronic acid has a chiral center a to the boron atom. A second broad aspect of the invention comprises a method for resolving the enantiomers of prolineboronic acid, if desired. According to this method, the prolineboronic ester is formed through reaction with a chiral alcohol, with the use of pinanediol being particularly preferred.
  • prolineboronic acid esters can be easily coupled to activated carboxylic acid groups, such as are typically used in peptide synthesis, to yield peptides having a prolineboronic acid ester, instead of an amino acid, at the C-terminus.
  • the ester protecting group can be removed to yield the free boronic acid peptide.
  • the ester protecting group is pinanediol, it is not easily removed by known per se techniques.
  • a third aspect of the invention comprises several methods for removing the pinanediol protecting group.
  • Figure 1 illustrates a reaction scheme which is a preferred embodiment of the invention.
  • a first synthesis according to the invention commences with pyrrole, which is reacted with an activated derivative of carbonic acid, in order to protect the nitrogen atom with a group of the formula -COOR, wherein R is C- .alkyl, C_ --cycloalkyl, benzyl, phenyl, phenyl substituted with one or more C 1.—D-- alkyl groups, or trimethylsilylethyl, in order to yield a compound of the formula I.
  • R is tert-butyl, benzyl, trimethylsilylethyl, phenyl, methyl or ethyl.
  • the most preferred protecting group is tert-butyloxycarbonyl, or Boc.
  • the protecting group is applied using well known techniques. A specific synthesis for 1-Boc-pyrrole has been described by Grehn et al. [Angew. Chem. Int. Ed. Engl. 23, 296 (1984)].
  • R is defined as before.
  • Lithiation of the compound of formula I can be accomplished by treatment with lithium tetramethylpiperidide in a known per se manner, such as that described by Hasan et al. [J. Org. Chem. 46, 157 (1981)], or with other hindered lithium amides such as lithium diisopropyl amide or lithium dicyclohexylamide, or with n-butyl lithium in the presence of tetra ethyl ethylenediamine.
  • This reaction is conveniently carried out in an inert solvent, preferably an ether such as THF, diethyl ether, dimethoxyethane, or methyl t-butyl ether at a temperature between -78°C and -40°C.
  • pyrrole can be brominated at the 2-position, in a known per se manner, such as that described by Chen et al. r [Org. Syn. , 70, 151 (1991)], and the resulting product can be protected and then lithiated, using other less expensive lithiating agents, such as n-butyl lithium, using known per se techniques.
  • each alkyl group may be straight, branched or cyclic and contains 1 to 6 carbon atoms, preferably tri ethyl or triethyl borate, followed by acid-catalyzed hydrolysis, using a weak acid such as citric or acetic acid, or potassium hydrogen sulfate, in order to yield a protected pyrrole-2-boronic acid of formula III
  • R is defined as before.
  • R is defined as before.
  • the catalytic hydrogenation of the intermediate of formula III may be carried out in an organic solvent, such as ethyl acetate or tetrahydrofuran, using a catalyst such as 5% platinum on carbon, platinum oxide, rhodium on carbon, rhodium on alumina, palladium on carbon, or Raney nickel, either at atmospheric pressure, or at about 50 psi.
  • organic solvent such as ethyl acetate or tetrahydrofuran
  • a catalyst such as 5% platinum on carbon, platinum oxide, rhodium on carbon, rhodium on alumina, palladium on carbon, or Raney nickel, either at atmospheric pressure, or at about 50 psi.
  • R is defined as before.
  • the protecting group is chosen to allow activation of the pyrrolidine to lithiation adjacent to the nitrogen, and it should contain a bulky moiety which hinders attack on the carbonyl by the lithiating agent. It is preferred to use a carbamoyl protecting group of the formula -COOR, for example, groups wherein R is tert-butoxy or 2,4,6-tri-tert- butylphenoxy. However, certain acyl or aroyl groups can also be used, for example tert-butylcarbonyl or triphenylmethylcarbonyl. Other suitable activating groups are outlined in Beak et al. , [Chem. Rev., 84, 471-523, (1984)]. The most preferred protecting group is tert-butyloxycarbonyl, or Boc. The protecting group may be applied to pyrrolidine by well known techniques.
  • R is defined as before.
  • Lithiation of the compound of formula VIII can be accomplished by treatment with sec-butyl lithium and tetramethyl ethylenediamine in a known per se manner, such as that described by Beak et al. [Tet. Lett. 30, 1197 (1989)].
  • This reaction is conveniently carried out in an inert organic solvent, preferably an ether such as diethyl ether, methyl tert-butyl ether or THF at a temperature between about -78°C and 0°C, preferably -78°C to -40°C.
  • Lithiation may be achieved with a reactive alkyl lithium such as sec-butyl lithium or tert-butyl lithium, preferably in the presence of a coordinating additive such as tetramethyl ethylenediamine, hexamethyl phosphoramide or N,N'-dimethylpropyleneurea (DMPU) .
  • a reactive alkyl lithium such as sec-butyl lithium or tert-butyl lithium
  • a coordinating additive such as tetramethyl ethylenediamine, hexamethyl phosphoramide or N,N'-dimethylpropyleneurea (DMPU) .
  • the intermediate of formula IX which is not isolated, is next reacted with a trialkyl borate wherein each alkyl group may be straight, branched or cyclic and contains 1 to 6 carbon atoms, preferably trimethyl or triethyl borate, followed by hydrolysis with water and extraction into aqueous alkali such as sodium hydroxide or potassium hydroxide to aid puri ication. Acidification of the alkali solution to about pH 3 and extraction yields the protected prolineboronic acid of formula IV. In order to form a boronic acid ester, the free boronic acid intermediate of formula IV, is next esterified by reaction with a diol of the formula V,
  • the ester group thus formed is intended to function only as a removable protecting group.
  • the structures, syntheses, and methods for attachment and removal of such ester protecting groups are generally known in the chemical art. Accordingly, those skilled in the chemical art will appreciate that the structure of the linking group X is not critical.
  • the linking group X can be, by way of non-limiting examples, a saturated 2- to 3-membered hydrocarbon chain; a saturated 2- to 3-membered hydrocarbon chain which constitutes part of a C j .
  • carbocyclic system which may optionally contain unsaturations or ring fusions; a 2- to 3-membered hydrocarbon chain which constitutes part of an aromatic ring system; or, a group of the formula -(CH2,,)'n-NH-(CH2_,) ; m-,' wherein n and m are each 2 or 3; wherein such groups may be unsubstituted or substituted by one or more C alkyl or phenyl groups.
  • suitable diols of formula V are, for example, ethylene glycol, pinacol, catechol, pinanediol, butan-2, 3-diol, 2,2-dimethyl propan 1,3-diol, diethanolamine and 1, 2-diphenylethan- 1,2-diol.
  • the protecting group on the nitrogen is next removed using known per se techniques, such as those described by Greene in “Protective Groups in Organic Synthesis” (J. Wiley & Sons, 1981) , to yield the hydrochloride of the desired prolineboronic acid ester of the formula VII.
  • the protecting group is Boc
  • it may be easily removed with dry hydrogen chloride in ethyl acetate.
  • the isomers of the hydrochloride of the compound of formula VII, with the same boron protecting group may be separated by fractional crystallization in a solvent such as ethyl acetate, or a dichloromethane/ethyl acetate mixture, isopropanol, or ethanol to give compound Vllb as a single isomer with the R configuration at the carbon attached to boron.
  • a solvent such as ethyl acetate, or a dichloromethane/ethyl acetate mixture, isopropanol, or ethanol
  • pinanediol A further advantage of using pinanediol is that the boronate esters so formed are more stable than those derived from other diols, for example, pinacol, with which significant loss of the protecting group is often observed during chromatography. This is useful in both purification and isomer separation by chromatography on silica gel, since better recovery of the desired material is achieved.
  • a derivatized pyrrole of formula III can be directly esterified with a diol of the formula V.
  • prolineboronic acid esters thus produced are easily coupled to activated carboxylic acids such as those typically used in peptide synthesis, for example a nitrogen-protected amino acid to yield a compound of the formula X
  • -COOR 2 i.s an ammo protecting group of the sort commonly used in peptide synthesis, so that R 2 is, for example, tert-butyl, benzyl, or fluorenylmethyl
  • R 3 i.s the side chain of a naturally occurring amino acid, optionally with appropriate protecting groups of the sort commonly used in peptide synthesis.
  • Compounds of formula X contain protecting groups both on the boronate and on the amino acid nitrogen. It may be necessary to remove either or both protecting groups for biological activity or for further chemical manipulation. The protecting groups may be removed in either order. Various methods for removing these protecting groups are described below.
  • Removal of the nitrogen protecting group may be achieved by known methods to yield a compound of the formula XI.
  • hydrolysis is known to be difficult, and special conditions are required for removal of the pinanediol. See for example Matteson et al. [J. Am. Chem. Soc, 102, 7590 (1980)] and Brown et al. [J. Organometallic Chem., 385, 15 (1988)].
  • pinanediol is not suitable for the removal of pinanediol from a compound of formula VI, X, or XI.
  • a boronate such as compound VI, X or XI.
  • removal of the pinanediol may be achieved under mild conditions using an oxidizing agent capable of cleaving 1,2 diols to remove the pinanediol from the equilibrium and hence drive it in the direction of the free boronic acid.
  • This reaction is conveniently carried out in water, optionally with an added buffer such as ammonium acetate or disodium hydrogen phosphate, at a pH between 3 and 10, preferably 6 to 8, and a temperature of 0 to 80 °C, preferably 20 to 40 ° C , in the presence of a water miscible organic cosolvent such as acetone, methanol, ethanol, THF, or acetonitrile.
  • a water miscible organic cosolvent such as acetone, methanol, ethanol, THF, or acetonitrile.
  • the oxidizing agent is a non-nucleophilic oxidant capable of cleaving 1,2-diols such as periodic acid or its salts or permanganate salts. Under these conditions oxidative cleavage of the carbon-boron bond is not observed.
  • this method is applicable to any boronic acid protected with pinanediol. Furthermore, it is applicable to any boronate protecting group which is a 1,2-diol, although it is particularly useful for protecting groups where simple aqueous hydrolysis is slow or incomplete.
  • a pinanediol boronate ester of a compound containing an unprotected amine such as a compound of formula XI
  • the method described above may also be employed, but a second new method is preferable for compounds of this type.
  • This method consists of applying an aqueous solution of a compound of formula XI, at pH 4 or lower, to a column of a cation exchange resin, and eluting the column with water or dilute acetic acid to remove the pinanediol. This removes the pinanediol from the equilibrium, and thus drives the reaction in the direction of hydrolysis.
  • the column is then eluted with dilute aqueous ammonium hydroxide to remove the product, which after evaporation and acidification is obtained as a salt of the compound of formula XIII.
  • a strongly acidic cation exchange resin for example a sulfonic acid type of resin is used, such as, for example, Dowex 50.
  • the pinanediol eluted from the resin may be recovered from the water solution and reused. This is most conveniently achieved by passing the water solution through a column of a nonionic polymeric adsorbent, such as Amberlite XAD-200, which adsorbs pinanediol almost quantitatively.
  • the pinanediol is removed from the column by elution with methanol or ethanol.
  • the two operations of ion exchange and pinanediol adsorption may be combined in a single process in which water is recycled from one column to the other using a pump. This has the advantage of requiring much smaller amounts of water, and allows the process to be continued long enough to achieve a high conversion to the product.
  • a third method is also applicable to pinanediol esters of compounds containing an unprotected amine, such as a compound of the formula XI.
  • This method consists of transesterification of the pinanediol boronate with
  • R represents a C hydrocarbon group, which may be composed of straight, branched or cyclic alkyl chains and phenyl rings.
  • R is preferably phenyl.
  • One of the phases is water adjusted to a pH below 7, preferably pH 1-4, and the other is a hydrocarbon organic solvent such as hexane, petroleum ether, or toluene.
  • a compound of formula XI with phenylboronic acid in a mixture of water at pH 1 and hexane, followed by separation of the phases, produces the pinanediol ester of phenylboronic acid in the organic phase, which may be recovered simply by evaporation, and a solution of the free boronic acid of formula XIII in the aqueous phase, which may be isolated using an ion exchange resin in a similar manner to that described above.
  • the only component which is soluble in the organic phase is the pinanediol phenylboronate, thus removing the pinanediol from the equilibrium.
  • the reaction may be carried out with any boronic acid with a hydrocarbon sidechain, providing its pinanediol ester is soluble in hydrocarbon solvents.
  • the fully deprotected compound of formula XIII may also be prepared by removal of the nitrogen protecting group from a compound of the formula XII using known methods. It will be appreciated that compounds of formula X, XI, XII, and XIII generally posess two chiral centers. One is adjacent to the boron atom, and the other is present in the amino acid moiety, except when that moiety is glycine. It will be further appreciated that the pure single diastereoisomers of these compounds are more desirable for biological use than mixtures of diastereoisomers. Accordingly it is important to be able to produce these compounds as pure single isomers.
  • reaction mixture was diluted with ether (500 mL) and washed with 1M aqueous KHSO (3 x 100 mL) followed by 1M aqueous NaHCO (1 x 100 L) . Drying over MgSO and rotary evaporation produced a brown solid which was purified by flash chromatography over silica gel (1:9 EtOAc:Hexane) to yield 8.7 g (82%) of a white crystalline solid (mp 101.0 - 101.5 °C) .
  • 1-(1,1-dimethylethoxycarbonyl)-pyrrolidine-2R-boronate could be produced in an analogous manner, starting with (1R,2R,3S,5R)-(-)-pinanediol.
  • the aqueous phase was isolated and the organic phase was reextracted with 2M NaOH (150 mL) .
  • the combined basic extracts were acidified to pH 3 using 2M HC1 and extracted using EtOAc (5 x 200 mL) .
  • the combined organic extracts were dried (Na_SO ) and concentrated to afford the desired product as a white crystalline solid (I5.49g, 72%) , identical with the material produced in Example 2.
  • Example 7 To a stirred solution of the material obtained in Example 7 (15.49 g, 72.0 mmol) in chloroform (250 mL) was added (IS, 2S, 3R, 5S) -(+) -pinanediol (12.77 g, 75 mmol) . After stirring at room temperature under a nitrogen atmosphere for 16 h, the solvent was removed and the residue purified via flash chromatography over silica gel (hexane/EtOAc 9:1, 4:1) to give the desired product as a 1:1 mixture of diastereomers as an oil (23.62 g, 67.7% based on 1-(1,1-dimethyl ⁇ ethoxycarbonyl)-pyrrolidine) . This was identical with the mixture of isomers produced in Example 3.
  • a reagent solution of 0.2 M phenyl isothiocyanate in dichloromethane-triethylamine (9:1) was prepared.
  • the sample to be analyzed (1-5 mg) was treated with 10 ⁇ L of the reagent solution per / xmole of analyte and the clear solution was allowed to stand at room temperature for 15 min.
  • the phenylthiourea derivative of the R isomer of proline boronic acid elutes at about 6.4 min, its epi er elutes at about 7.8 min, and unreacted phenyl isothiocyanate, which serves as an internal standard, elutes at 12.2 min.
  • Example 10 The 60:40 isomeric mixture obtained in Example 10 (1.18 g 4.13 mmol) was dissolved in CH Cl (65 mL) with slight warming, and the solution filtered. The filtrate was diluted with EtOAc (65 mL) and crystallization began within a minute. The suspension was stirred for 1-2 h at room temperature and the first crop of solid was collected and the diastereomeric ratio determined as described in Example 9 (540 mg, 46%, R:S ratio 97.1:2.9) . Solvent was distilled from the filtrate until most of the CH2C12 was removed, then the residual EtOAc solution was stirred at room temperature overnight to afford a second crop of off-white solid (346 mg, 29%, R:S ratio 39.2:60.8) .
  • Pinacol 1- (1, 1-dimethylethoxycarbonyl) - pyrrolidine-2RS-boronate
  • N-(1, 1-Dimethylethoxycarbonyl) -L-valylpyrrolidine-2R- boronate (IS, 2S, 3R, 5S) -pinanediol ester (248 mg, 0.553 mmol) was added to a stirred solution of dry hydrogen chloride in ethyl acetate. After 1.5 h the solvent was evaporated to leave the deprotected hydrochloride. The residue was partitioned between CH-.C1 and sodium carbonate solution, and the organic layer dried over magnesium sulfate. The organic layer contains the free base of the title compound, which exists as a cyclic form containing a nitrogen-boron bond, but reverts to the open form on adding acid.
  • a solution of the maleate salt obtained in Example 15 (5.0 g, 10.8 mmol) in dilute acetic acid (1.0%, 60 mL) was loaded on to a column (3.5 cm deep x 4 cm dia.) of Dowex 50X2-200 ion exchange resin in the H+ form. The column was then eluted with acetic acid (1.0%, 14 L) , water (42 L) and ammonium hydroxide solution (1:100 dilution of commercial 0.880 solution) . Pinanediol could be recovered from the neutral and acidic fractions. The product was found in early basic fractions, which were collected and washed with CH Cl (2 x 100 mL) .
  • N-(l,1-Dimethylethoxycarbonyl)-L-valylpyrrolidine-2R- boronic acid, obtained in Example 17 was stirred with HCl/ether (4.5M, 20 mL) at room temperature under nitrogen for 1.5 h. The solvent was then evaporated and the residue triturated with diethyl ether (3 x 10 L) and each time the ether was decanted. The residue was dried to yield the title compound as a white powdery solid (172 mg, 86%) (mp 211-213°C) .

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyrrole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Procédé de production d'esters d'acide prolineboronique. Un pyrrole N-protégé (I) est lithiné en position 2. On fait réagir l'espèce lithinée (II) avec du trialkylborate, de manière à obtenir un acide pyrrole-2-boronique protégé (III). On réduit ce composé pour former un acide prolineboronique protégé (IV), que l'on fait réagir, à son tour, avec un diol pour obtenir un ester (VI). La fraction d'acide boronique étant protégée par le groupe ester, on élimine le groupe de protection sur l'azote, afin d'obtenir l'ester d'acide prolineboronique désiré (VII). Dans une variante de synthèse, une pyrrolidine protégée (VIII) est lithinée en position 2 pour obtenir une 2-lithio-pyrrolidine protégée (IX). On fait réagir ce composé avec du trialkylborate pour obtenir le composé intermédiaire (IV). Les esters d'acide prolineboronique ainsi produits présentent un centre chiral à l'atome de bore. On décrit également des procédés de résolution d'énantiomères. Les produits finals peuvent être couplés à des acides carboxyliques activés, afin d'obtenir des peptides comportant un ester d'acide prolineboronique, au lieu d'un acide aminé, à la terminaison C. Ces analogues peptidiques de l'acide boronique sont utilisés pour inhiber des protéases biologiquement importantes. On décrit également plusieurs procédés d'élimination de pinanediol d'esters de boronate de pinanediol.
PCT/US1992/009845 1991-11-22 1992-11-19 Procede de production d'un ester de prolineboronate WO1993010127A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
JP5509442A JPH07501078A (ja) 1991-11-22 1992-11-19 プロリンボロネートエステルの製法
EP92925238A EP0641347A1 (fr) 1991-11-22 1992-11-19 Procede de production d'un ester de prolineboronate
SK592-94A SK59294A3 (en) 1991-11-22 1992-11-19 Method of making a prolineboronate ester
AU31368/93A AU661362B2 (en) 1991-11-22 1992-11-19 Method for making a prolineboronate ester
FI942345A FI942345A0 (fi) 1991-11-22 1994-05-20 Menetelmä proliiniboronaattiesterin valmistamiseksi
NO941905A NO941905L (no) 1991-11-22 1994-05-20 Fremgangsmåte for fremtilling av en prolinboronat-ester

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US79614891A 1991-11-22 1991-11-22
US07/796,148 1991-11-22
US93619892A 1992-08-26 1992-08-26
US07/936,198 1992-08-26

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EP (1) EP0641347A1 (fr)
JP (1) JPH07501078A (fr)
CN (1) CN1073946A (fr)
AU (1) AU661362B2 (fr)
CA (1) CA2123128A1 (fr)
CZ (1) CZ124494A3 (fr)
FI (1) FI942345A0 (fr)
HU (1) HUT67937A (fr)
IL (1) IL103817A0 (fr)
MX (1) MX9206628A (fr)
NO (1) NO941905L (fr)
NZ (1) NZ245207A (fr)
PT (1) PT101079A (fr)
SI (1) SI9200332A (fr)
SK (1) SK59294A3 (fr)
TW (1) TW232697B (fr)
WO (1) WO1993010127A1 (fr)

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* Cited by examiner, † Cited by third party
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US5965532A (en) * 1996-06-28 1999-10-12 Trustees Of Tufts College Multivalent compounds for crosslinking receptors and uses thereof
WO1999062914A1 (fr) * 1998-06-05 1999-12-09 Point Therapeutics, Inc. Composes cycliques de boroproline
US6100234A (en) * 1997-05-07 2000-08-08 Tufts University Treatment of HIV
US6258597B1 (en) 1997-09-29 2001-07-10 Point Therapeutics, Inc. Stimulation of hematopoietic cells in vitro
US6300314B1 (en) 1998-05-04 2001-10-09 Point Therapeutics, Inc. Hematopoietic stimulation
WO2001062266A3 (fr) * 2000-02-25 2002-05-02 Novo Nordisk As Inhibition de la degenerescence des cellules beta
US6692753B2 (en) 1997-05-07 2004-02-17 Trustees Of Tufts College Potentiation of the immune response
US6825169B1 (en) 1991-10-22 2004-11-30 Trustees Of Tufts College Inhibitors of dipeptidyl-aminopeptidase type IV
US6890904B1 (en) 1999-05-25 2005-05-10 Point Therapeutics, Inc. Anti-tumor agents
US6979697B1 (en) 1998-08-21 2005-12-27 Point Therapeutics, Inc. Regulation of substrate activity
WO2005105817A3 (fr) * 2004-04-27 2006-01-12 Wyeth Corp Proceder de couplage pour generer des derives reactifs contenant du bore de pyrrole-2-carbonitriles n-substitues afin de produire des bi-aryles
EP1743676A1 (fr) * 2003-11-12 2007-01-17 Phenomix Corporation Dérivés d'acide boronique hétérocycliques, inhibiteurs de dipeptidyl peptidase IV
WO2003063903A3 (fr) * 2002-02-01 2007-12-21 Probiodrug Ag Modulation des lymphocytes t au moyen d'inhibiteurs de la dp iv
US7317109B2 (en) 2003-11-12 2008-01-08 Phenomix Corporation Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
US7399869B2 (en) 2005-05-19 2008-07-15 Genentech, Inc. Fibroblast activation protein inhibitor compounds and methods
WO2007100374A3 (fr) * 2005-12-19 2008-11-13 Tufts College Inhibiteurs legers de proteases et leurs pro-formes legeres
US7576121B2 (en) 2003-11-12 2009-08-18 Phenomix Corporation Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
EP2116235A1 (fr) 2005-01-10 2009-11-11 Arena Pharmaceuticals, Inc. Thérapie combinée pour le traitement des diabètes et des conditions associées, et pour le traitement des conditions améliorées par l'augmentation du niveau de sang GLP-1
EP2165703A2 (fr) 2004-01-20 2010-03-24 Novartis Pharma AG. Formule de compression directe et procédé
US7767828B2 (en) 2003-11-12 2010-08-03 Phenomix Corporation Methyl and ethyl substituted pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
US7825139B2 (en) 2005-05-25 2010-11-02 Forest Laboratories Holdings Limited (BM) Compounds and methods for selective inhibition of dipeptidyl peptidase-IV
EP2253311A2 (fr) 2006-04-11 2010-11-24 Arena Pharmaceuticals, Inc. Utilisation d'agonistes du récepteur de GPR119 dans des procédés d'augmentation de la masse osseuse et de traitement de l'ostéoporose, et thérapie de combinaison associée
WO2011005929A1 (fr) 2009-07-09 2011-01-13 Arena Pharmaceuticals, Inc. Dérivé de pipéridine et son utilisation pour le traitement du diabète et de l'obésité
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WO2012040279A1 (fr) 2010-09-22 2012-03-29 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement des troubles qui lui sont liés
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Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1331835C (zh) * 2005-10-18 2007-08-15 武汉大学 光活性β－羟基酮的制备方法
EP1971862B1 (fr) 2006-04-11 2010-11-10 Arena Pharmaceuticals, Inc. Procédés d'utilisation du récepteur gpr119 pour identifier des composés utiles pour augmenter la masse osseuse chez un individu
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989003223A1 (fr) * 1987-10-06 1989-04-20 Bachovchin William W Inhibiteurs de protease
WO1991016339A1 (fr) * 1990-04-14 1991-10-31 New England Medical Center Hospitals, Inc. Inhibiteurs de dipeptidyl-aminopeptidase de type iv
EP0471651A2 (fr) * 1990-08-13 1992-02-19 Sandoz Ltd. Dérivés de l'acide boronique peptidique ayant une activité inhibante de protéase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989003223A1 (fr) * 1987-10-06 1989-04-20 Bachovchin William W Inhibiteurs de protease
WO1991016339A1 (fr) * 1990-04-14 1991-10-31 New England Medical Center Hospitals, Inc. Inhibiteurs de dipeptidyl-aminopeptidase de type iv
EP0471651A2 (fr) * 1990-08-13 1992-02-19 Sandoz Ltd. Dérivés de l'acide boronique peptidique ayant une activité inhibante de protéase

Cited By (72)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7230074B2 (en) 1991-10-22 2007-06-12 Trustees Of Tufts College Inhibitors of dipeptidyl-aminopeptidase type IV
US6825169B1 (en) 1991-10-22 2004-11-30 Trustees Of Tufts College Inhibitors of dipeptidyl-aminopeptidase type IV
US5965532A (en) * 1996-06-28 1999-10-12 Trustees Of Tufts College Multivalent compounds for crosslinking receptors and uses thereof
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US6503882B2 (en) 1997-05-07 2003-01-07 Trustees Of Tufts College Treatment of HIV
US6100234A (en) * 1997-05-07 2000-08-08 Tufts University Treatment of HIV
US6703238B2 (en) 1997-09-29 2004-03-09 Point Therapeutics, Inc. Methods for expanding antigen-specific T cells
US6258597B1 (en) 1997-09-29 2001-07-10 Point Therapeutics, Inc. Stimulation of hematopoietic cells in vitro
US7276371B2 (en) 1997-09-29 2007-10-02 Point Therapeutics, Inc. Stimulation of hematopoietic cells in vitro
US6300314B1 (en) 1998-05-04 2001-10-09 Point Therapeutics, Inc. Hematopoietic stimulation
US7067489B2 (en) 1998-05-04 2006-06-27 Point Therapeutics, Inc. Hematopoietic stimulation
US6770628B2 (en) 1998-05-04 2004-08-03 Point Therapeutics, Inc. Hematopoietic stimulation
US6355614B1 (en) 1998-06-05 2002-03-12 Point Therapeutics Cyclic boroproline compounds
WO1999062914A1 (fr) * 1998-06-05 1999-12-09 Point Therapeutics, Inc. Composes cycliques de boroproline
US7265118B2 (en) 1998-08-21 2007-09-04 Point Therapeutics, Inc. Regulation of substrate activity
US6979697B1 (en) 1998-08-21 2005-12-27 Point Therapeutics, Inc. Regulation of substrate activity
US7259138B2 (en) 1999-05-25 2007-08-21 Point Therapeutics, Inc. Anti-tumor agents
US6890904B1 (en) 1999-05-25 2005-05-10 Point Therapeutics, Inc. Anti-tumor agents
US7282484B2 (en) 1999-05-25 2007-10-16 Point Therapeutics, Inc. Anti-tumor agents
US6949514B2 (en) 1999-05-25 2005-09-27 Point Therapeutics, Inc. Anti-tumor agents
WO2001062266A3 (fr) * 2000-02-25 2002-05-02 Novo Nordisk As Inhibition de la degenerescence des cellules beta
WO2003063903A3 (fr) * 2002-02-01 2007-12-21 Probiodrug Ag Modulation des lymphocytes t au moyen d'inhibiteurs de la dp iv
US8415295B2 (en) 2003-11-12 2013-04-09 Phenomix Corporation Heterocyclic boronic acid compounds
US7767828B2 (en) 2003-11-12 2010-08-03 Phenomix Corporation Methyl and ethyl substituted pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
US7317109B2 (en) 2003-11-12 2008-01-08 Phenomix Corporation Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
US7906658B2 (en) 2003-11-12 2011-03-15 Phenomix Corporation Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
US7884217B2 (en) 2003-11-12 2011-02-08 Phenomix Corporation Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
US7576121B2 (en) 2003-11-12 2009-08-18 Phenomix Corporation Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
EP1743676A1 (fr) * 2003-11-12 2007-01-17 Phenomix Corporation Dérivés d'acide boronique hétérocycliques, inhibiteurs de dipeptidyl peptidase IV
US7674913B2 (en) 2003-11-12 2010-03-09 Phenomix Corporation Heterocyclic boronic acid compounds
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EP3023095A1 (fr) 2004-01-20 2016-05-25 Novartis AG Formulation et procede pour compression directe
EP2165703A2 (fr) 2004-01-20 2010-03-24 Novartis Pharma AG. Formule de compression directe et procédé
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EP3738585A1 (fr) 2004-01-20 2020-11-18 Novartis Ag Formulation de compression directe et procédé
US7446211B2 (en) 2004-04-27 2008-11-04 Wyeth Coupling process for generating reactive boron-containing derivatives of N-substituted pyrrole-2-carbonitriles to produce biaryls
US8129523B2 (en) 2004-04-27 2012-03-06 Wyeth Llc Coupling process for generating reactive boron-containing derivatives of N-substituted pyrrole-2-carbonitriles to produce biaryls
WO2005105817A3 (fr) * 2004-04-27 2006-01-12 Wyeth Corp Proceder de couplage pour generer des derives reactifs contenant du bore de pyrrole-2-carbonitriles n-substitues afin de produire des bi-aryles
EP2116235A1 (fr) 2005-01-10 2009-11-11 Arena Pharmaceuticals, Inc. Thérapie combinée pour le traitement des diabètes et des conditions associées, et pour le traitement des conditions améliorées par l'augmentation du niveau de sang GLP-1
US7399869B2 (en) 2005-05-19 2008-07-15 Genentech, Inc. Fibroblast activation protein inhibitor compounds and methods
US7825139B2 (en) 2005-05-25 2010-11-02 Forest Laboratories Holdings Limited (BM) Compounds and methods for selective inhibition of dipeptidyl peptidase-IV
US8933056B2 (en) 2005-12-19 2015-01-13 Trustees Of Tufts College Soft protease inhibitors and pro-soft forms thereof
WO2007100374A3 (fr) * 2005-12-19 2008-11-13 Tufts College Inhibiteurs legers de proteases et leurs pro-formes legeres
AU2006339348B2 (en) * 2005-12-19 2013-01-17 Trustees Of Tufts College Soft protease inhibitors and pro-soft forms thereof
US8268880B2 (en) 2005-12-19 2012-09-18 Trustees Of Tufts College Soft protease inhibitors and pro-soft forms thereof
US9192646B2 (en) 2005-12-19 2015-11-24 Trustees Of Tufts College Soft protease inhibitors and pro-soft forms thereof
US8563533B2 (en) 2005-12-19 2013-10-22 Trustees Of Tufts College Soft protease inhibitors and pro-soft forms thereof
EP2253311A2 (fr) 2006-04-11 2010-11-24 Arena Pharmaceuticals, Inc. Utilisation d'agonistes du récepteur de GPR119 dans des procédés d'augmentation de la masse osseuse et de traitement de l'ostéoporose, et thérapie de combinaison associée
US8883714B2 (en) 2008-04-07 2014-11-11 Arena Pharmaceuticals, Inc. Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues
US10526351B2 (en) 2008-06-17 2020-01-07 Millennium Pharmaceuticals, Inc. Boronate ester compounds and pharmaceutical compositions thereof
US10604538B2 (en) 2008-06-17 2020-03-31 Millenium Pharmaceuticals, Inc. Boronate ester compounds and pharmaceutical compositions thereof
US11485746B2 (en) 2008-06-17 2022-11-01 Millennium Pharmaceuticals, Inc. Boronate ester compounds and pharmaceutical compositions thereof
WO2011005929A1 (fr) 2009-07-09 2011-01-13 Arena Pharmaceuticals, Inc. Dérivé de pipéridine et son utilisation pour le traitement du diabète et de l'obésité
WO2011127051A1 (fr) 2010-04-06 2011-10-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur de gpr119 et traitement de troubles associés
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TW232697B (fr) 1994-10-21
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HU9401350D0 (en) 1994-08-29
PT101079A (pt) 1994-02-28
JPH07501078A (ja) 1995-02-02
NZ245207A (en) 1994-07-26
AU661362B2 (en) 1995-07-20
CA2123128A1 (fr) 1993-05-27
CN1073946A (zh) 1993-07-07
AU3136893A (en) 1993-06-15
CZ124494A3 (en) 1995-07-12
EP0641347A1 (fr) 1995-03-08
HUT67937A (en) 1995-05-29
IL103817A0 (en) 1993-04-04
SK59294A3 (en) 1995-02-08
SI9200332A (en) 1993-06-30
FI942345A0 (fi) 1994-05-20

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