WO1996016333A1 - PROCEDE PERMETTANT DE SYNTHETISER DIFFERENTES COLLECTIONS DE COMPOSES A BASE DE β-LACTAME - Google Patents

PROCEDE PERMETTANT DE SYNTHETISER DIFFERENTES COLLECTIONS DE COMPOSES A BASE DE β-LACTAME Download PDF

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Publication number
WO1996016333A1
WO1996016333A1 PCT/US1995/015261 US9515261W WO9616333A1 WO 1996016333 A1 WO1996016333 A1 WO 1996016333A1 US 9515261 W US9515261 W US 9515261W WO 9616333 A1 WO9616333 A1 WO 9616333A1
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Prior art keywords
group
compound
lactam
ketene
complementary
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PCT/US1995/015261
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English (en)
Inventor
Mark A. Gallop
Eric Gordon
Beatrice Ruhland
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Affymax Technologies, N.V.
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Priority to AU43688/96A priority Critical patent/AU4368896A/en
Publication of WO1996016333A1 publication Critical patent/WO1996016333A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • This invention is directed to methods for synthesizing very large collections of diverse ⁇ - lactam (2-azetidinones) compounds on solid supports. This invention is further directed to methods for identifying and isolating ⁇ -lactam compounds with useful and diverse activities from such collections. This invention is still further directed to the incorporation of identification tags in such collections to facilitate identification of compounds with desired properties.
  • Compounds having biological activity can be identified by screening diverse collections of compounds (i.e., libraries of compounds) produced through either molecular biological or synthetic chemical techniques. Such screening methods include methods wherein each member of the library is tagged with a unique identifier tag to facilitate identification of compounds having biological activity 1,2 or where the library comprises a plurality of compounds synthesized at specific locations on the surface of a solid substrate wherein a receptor is __ 3 __
  • binding compound appropriately labeled to identify binding to the compound, e.g., fluorescent or radioactive labels.
  • Correlation of the labelled receptor bound to the substrate with its location on the substrate identifies the binding compound.
  • the compounds in the library are typically formed on solid supports wherein the compound is covalently attached to the support via a cleavable or non-cleavable linking arm.
  • libraries of diverse compounds are prepared and then screened to identify "lead compounds" having good binding affinity to the receptor.
  • the compounds are synthesized in si tu on the solid support so that the support can be tagged to identify the synthetic steps employed and/or the derivative incorporated onto the support.
  • relatively simple synthetic methods to produce a diverse collection of such derivatives on the supports are often not available.
  • ⁇ - lactam compounds are also useful for inclusion in screening libraries. These compounds form the basis of an important class of compounds having diverse pharmaceutical and chemical properties. In addition to their great clinical success achieved as antibacterial agents, ⁇ -lactams have also been found to possess other diverse biological activities, including mechanism-based inactivators of serine proteases such as elastase ' and inhibition of acyl- CoA:cholesterol acyltransferase (ACAT) . ⁇ -lactams are also valuable chiral starting materials for the synthesis of other natural and unnatural products.
  • mechanism-based inactivators of serine proteases such as elastase '
  • ACAT acyl- CoA:cholesterol acyltransferase
  • a ketene precursor e.g. a carboxylic acid chloride
  • si tu converted to a ketene in the presence of a base and then, in the presence of an imine, undergoes a [2+2] cycloaddition to provide for a ⁇ -lactam.
  • This invention is directed to general synthetic methods for incorporating a ⁇ -lactam group onto a solid support which methods can be employed in conjunction with known stochastic methods for preparing libraries of compounds comprising one or __ 5 __
  • the ⁇ -lactam compounds generated on the solid support via the methods described below can be further derivatized thereby elaborating the structure of these compounds .
  • the ⁇ -lactam compounds generated on the solid support via the methods of this invention have a substituent at the 3 and/or 4- position thereof which substituent comprises a ketene precursor group or a group convertible to an imine, imidate, thioimidate or amidine functionality thereby permitting synthesis of polymeric ⁇ -lactam compounds or the appendage of a heterocyclic compound.
  • Solid supports containing such ⁇ -lactam groups preferably comprise a linking arm which links the solid support to the group.
  • the linking arm can be either cleavable or non-cleavable and when cleavable, can be used to prepare a library of soluble ⁇ -lactam compounds.
  • the library of ⁇ -lactam compounds, whether soluble or insoluble, can be screened to isolate individual compounds that possess some desired biological activity. In a preferred embodiment, each compound in the library is unique.
  • the invention provides for methods of synthesizing N-unsubstituted- ⁇ -lactams.
  • N-unsubstituted- ⁇ -lactams are useful precursors of chiral ⁇ -amino acids.
  • this invention is directed to a method for synthesizing a ⁇ -lactam group covalently attached to a solid support which method comprises: -- 6 --
  • the ketene precursor compound is converted to the ketene in si tu in the presence of the complementary compound.
  • the ketene precursor compound and the complementary compound are combined into a reaction mixture and the precursor compound is in si tu converted to the ketene compound which then undergoes [2+2] cycloaddition with the complementary compound to provide for the ⁇ - lactam.
  • the ketene precursor compound is a carboxylic acid halide (e.g., acid chloride or acid bromide) or an activated carboxylic acid ester and the ketene precursor is converted in si tu to the ketene by reaction with a base.
  • carboxylic acid halide e.g., acid chloride or acid bromide
  • activated carboxylic acid ester e.g., acid chloride or acid bromide
  • the ketene precursor compound and the complementary compound are not coupled to the same compound and ⁇ -lactam formation is by intermolecular [2+2] cycloaddition.
  • the ketene precursor compound and the complementary compound are coupled to the same compound having at different sites thereon both a ketene precursor functionality and __ 7 ---.
  • ⁇ -lactam formation can proceed by intramolecular [2+2] cycloaddition.
  • the solid supports prepared in the methods described above can be used, for example, in creating libraries of compounds in the manner described in International Patent Application Publication No. WO 93/06121 or in creating solid supports such as those described in U.S. Patent No. 5,143,854 2 , to screen said compounds for biological activity.
  • the disclosures of International Patent Application Publication No. WO 93/06121 and U.S. Patent No. 5,143,854 are incorporated herein by reference in their entirety.
  • this invention is directed to a library of diverse ⁇ - lactam structures comprising a plurality of solid supports having a plurality of covalently bound ⁇ - lactams, wherein the ⁇ -lactams bound to each of said supports is substantially homogeneous and further wherein the ⁇ -lactam bound on one support is different from the ⁇ -lactams bound on selected other supports.
  • this invention is directed to a method for preparing a synthetic ⁇ - lacta compound library produced by synthesizing on each of a plurality of solid supports a single compound wherein each compound comprises at least one ⁇ -lactam group, which library is synthesized in a process comprising: a) apportioning the supports comprising a covalently bound ketene precursor group or a covalently bound complementary group comprising an imine, imidate, thioimidate or amidine functionality ---- 8 ----
  • this method further comprises pooling the supports produced in part b) .
  • this invention is directed to a method for preparing a synthetic polymeric ⁇ -lactam compound library produced by synthesizing on each of a plurality of solid supports a single compound wherein each compound comprises from 2 to 5 ⁇ -lactam groups, which library is synthesized in a process comprising: a) apportioning the supports comprising a covalently bound ketene precursor group or a covalently bound complementary group comprising an imine, imidate, thioimidate or amidine functionality or a group convertible to an imine, imidate, thioimidate or amidine functionality among a plurality of reaction vessels, b) exposing the supports in each reaction vessel under conditions wherein the ketene precursor group or the complementary group is converted to a ⁇ -lactam group wherein said ⁇ -lactam group is different for each of the reaction vessels; c) pooling the supports; d) repeating procedures a) through c) up to about 4 times; with the proviso that the
  • one substituent at the 3 or 4 position thereof having a ketene precursor group or a group convertible to an imine, imidate, thioimidate or amidine functionality.
  • Figure 1 illustrates the synthesis of imine 3. on a solid support, followed by reaction of imine 3 . with a ketene (not shown) formed from ketene precursor compound 4 . by reaction with triethylamine (NEt 3 ) 5 . in dichloromethane (CH 2 C1 2 ) to provide for a ⁇ -lactam, as a mixture of stereoisomers 6 . and 1_, bound to the solid support via a cleavable linking arm.
  • Figure 1 further illustrates cleavage of the ⁇ -lactam isomers, 6 . and 1_, from the solid support to provide for soluble ⁇ -lactam compounds 8. and S_.
  • Figure 2 illustrates the stereoselective synthesis of ⁇ -lactam __ bound to a solid support via a cleavable linking arm and subsequent cleavage of this linking arm to provide for soluble ⁇ -lactam 16.
  • Figure 3 illustrates the stereoselective synthesis of ⁇ -lactam 2_ bound to a solid support via a cleavable linking arm and subsequent cleavage of this linking arm to provide for soluble ⁇ -lactam 23.
  • Figure 4 illustrates the stereoselective synthesis of ⁇ -lactam 2_ bound to a solid support via a cleavable linking arm and subsequent cleavage of this linking arm to provide for soluble ⁇ -lactam 30.
  • Figure 5 illustrates the stereoselective synthesis of ⁇ -lactam 3_6 and subsequent conversion of this compound to carboxyalkyl amine __ , which is an enalapril type metalloprotease inhibitor. 61
  • Figure 6 illustrates the synthesis of a ⁇ -lactam 47 having an amino group at the 3-position thereof which amino group can be converted to an imine and reacted with a ketene to provide for a ⁇ -lactam dimer
  • Figures 7A-7D illustrates several cleavable linking arms for covalently linking compounds comprising at least one ⁇ -lactam group to the solid support.
  • Figure 8 illustrates several photocleavable linking arms for covalently linking compounds comprising at least one ⁇ -lactam group to the solid support.
  • Figure 9 illustrates the synthesis of imine 0 on a solid support from immobilized photolinker 58, followed by reaction of imine joO with a ketene (not shown) formed from phthalimido acetyl chloride by reaction with triethylamine (NEt 3 ) in dichloromethane (CH 2 C1 2 ) to provide for a ⁇ -lactam .61, bound to the solid support via a cleavable linking arm.
  • Figure 9 further illustrates the photolytic cleavage of the ⁇ - lactam jS_l from the solid support to provide for soluble ⁇ -lactam compound 62.
  • This invention is directed to synthetic methods for preparing ⁇ -lactam groups in si tu on solid supports and the use of these methods to incorporate ⁇ -lactam groups in large synthetic compound libraries.
  • substrate or “solid support” refers to a material having a rigid or semi-rigid surface which contain or can be derivatized to contain reactive functionality which covalently links a compound to the surface thereof.
  • materials are well known in the art and include, by way of example, silicon dioxide supports containing reactive Si-OH groups, polyacrylamide supports, polystyrene supports, polyethyleneglycol supports, and the like.
  • Such supports will preferably take the form of small beads, pellets, disks, or other conventional forms, although other forms may be used.
  • at least one surface of the substrate will be substantially flat.
  • a particularly preferred solid support is the acid-labile Sasrin resin.
  • halogen refers to fluorine, chlorine, bromine and iodine and preferably chlorine.
  • ketene precursor refers to any group, substituent or functionality which is convertible to a ketene group.
  • Such precursors are known in the art and include, by way of example only, carboxyl acid halides and activated carboxyl acid esters each having a methine or methylene hydrogen atom ⁇ to the carbonyl atom of the carboxyl acid halide or the activated carboxyl acid ester and the like.
  • an activated carboxyl acid ester having a methine or methylene hydrogen atom ⁇ to the carbonyl atom of the carboxyl group refers to carboxyl groups of the formula -CH n C(0)OR where R is any ester functionality which facilitates conversion to a ketene as compared to the carboxyl group in the absence of such an ester and n is an integer equal to 1 or 2.
  • Such activated carboxyl acid esters are well known in 61
  • a complementary compound comprising an imine, imidate, thioimidate or amidine functionality
  • a complementary compound comprising an imine, imidate, thioimidate or amidine functionality
  • imines can be prepared from a primary amine (e.g., an amino acid) and an aldehyde or ketone; imidates and thioimidates and amidines are conveniently prepared from imino chlorides by reaction with alkoxides or aryl oxides, thiolates or primary and secondary amines respectively.
  • Imino chlorides in turn, can be prepared from amides by reaction with phosphorus pentachloride. See, for example, Patai, The Chemistry of Amidines and Imidates, Wiley, New York, New York (1975) .
  • a complementary compound having a group convertible to an imine, imidate, thioimidate or amidine functionality refers to those compounds which contain a functional group which is convertible to an imine, imidate, thioimidate or amidine functionality by methods known in the art.
  • ketone and aldehyde groups are known to react with primary amines to form imines.
  • compounds having a ketone, an aldehyde, or a primary amine contain a group convertible to an imine.
  • hydroxyl groups can be oxidized to provide for a ketone or an aldehyde group and carboxyl groups can be converted to ketones via reaction with an alkyl lithium reagent . /US95/15261
  • hydroxyl and carboxyl groups comprise groups convertible to an imine.
  • Other groups convertible to imidate, thioimidate or amidine functionalities are well known in the art. Examples of groups convertible to imidate, thioimidate and amidine functionality are recited above.
  • the particular complementary compound and ketene precursor compound employed in the methods described herein are not critical.
  • Particularly preferred groups convertible to an imine functionality are amino acids wherein the amine group of the amino acid is employed to form an imine with the carbonyl group of a ketone or aldehyde.
  • the complementary compound comprising an imine, imidate, thioimidate or amidine functionality is covalently attached directly to the solid support or is attached to the support via a linking arm.
  • subsequent cycloaddition of the complementary compound to a ketene will provide for covalent attachment of the resulting ⁇ -lactam to the solid support regardless of whether the ketene compound is initially bound to the solid support.
  • the ketene precursor compound is covalently attached directly to the solid support or is attached to the support via a linking arm.
  • a linking arm subsequent conversion of this precursor compound to the ketene followed by cycloaddition with the complementary compound comprising an imine, imidate, thioimidate or amidine functionality will provide for covalent attachment of the resulting ⁇ -lactam to the solid support regardless of whether the complementary compound is initially bound to the solid support.
  • Linking arms are well known in the art and include, by way of example only, conventional linking arms such as those comprising ester, amide, carbamate, ether, thio ether, urea, amine groups and the like.
  • the linking arm can be cleavable or non-cleavable.
  • “Cleavable linking arms” refer to linking arms wherein at least one of the covalent bonds of the linking arm which attaches the compound comprising the ⁇ -lactam group to the solid support can be readily broken by specific chemical reactions thereby providing for compounds comprising ⁇ -lactam groups free of the solid support ("soluble compounds") .
  • the chemical reactions employed to break the covalent bond of the linking arm are selected so as to be specific for bond breakage thereby preventing unintended reactions occurring elsewhere on the compound.
  • the cleavable linking arm is selected relative to the synthesis of the compounds to be formed on the solid support so as to prevent premature cleavage of this compound from the solid support as well as not to interfere with any of the procedures employed during compound synthesis on the support.
  • Figures 7A-7D illustrates several embodiments of such linking arms.
  • Figure 7A illustrates a cleavable Sasrin resin comprising polystyrene beads and a cleavable linking arm as depicted therein which linking arm is cleaved by strong acidic conditions such as trifluoroacetic acid. Cleavage results in breakage at the wavy line interposed between the oxygen and carbonyl moieties of the ester so as to provide for a compound terminating in a carboxylic acid.
  • Figures 7B and 7C illustrate cleavable TentaGel AC and TentaGel PHB resins respectively, each comprising a polystyrene bead and the cleavable linking arm depicted therein both of which are cleaved by strong acidic conditions such as trifluoroacetic acid. Cleavage results in breakage at the wavy line interposed between the oxygen and carbonyl moieties of the ester so as to provide for a compound terminating in a carboxylic acid.
  • Figure 7D illustrates a cleavable TentaGel RAM resin comprising a polystyrene bead and a cleavable linking arm depicted therein which is cleaved by strong acidic conditions such as trifluoroacetic acid. Cleavage results in breakage at the wavy line interposed between the nitrogen and the benzhydryl carbon of the linking arm so as to provide for a compound terminating in an amide group.
  • this linking arm facilitates formation of the amide bond by stabilizing the intermediate carbonium ion on the carbon atom between the two aromatic groups . Such stabilization permits selective bond cleavage as compared to bond cleavage for other amide groups of the compound comprising a ⁇ -lactam group.
  • the linker may be attached between the tag and/or the molecule and the support via a non-reversible covalent cleavable linkage.
  • linkers which can be cleaved photolytically can be used.
  • Preferred photocleavable linkers of the invention include 6- nitroveratryloxycarbonyl (NVOC) and other NVOC related linker compounds (see PCT patent publication Nos. WO 90/15070 and WO 92/10092; see also U.S. patent application Serial No. 07/971,181, filed 2 Nov. 1992, incorporated herein by reference) ; the ortho- nitrobenzyl-based linker described by Rich (see Rich and Gurwara (1975) J. Am. Chem. Soc.
  • Non-cleavable linking arms refer to linking arms wherein one or more of the covalent bonds linking the compound comprising a ⁇ -lactam group to the solid support can only be cleaved under conditions which chemically alters unintended parts of the structure of the compound attached thereto.
  • ⁇ -lactam or "2-azetidinone” refers to a saturated 4-member ring heterocyclic compound containing one (1) ring nitrogen atom which can be depicted as follows:
  • Substituents to the ⁇ -lactam group can occur at any of the 1, 3 and 4 positions thereof including the nitrogen atom in the manner depicted above. Such substituents are governed solely by the reagents employed thereby providing flexibility in preparing a large library of ⁇ -lactam compounds.
  • Preferred substituents at the 3 and 4 positions include, by way of example only: alkyl groups of from 1 to 10 carbon atoms optionally substituted with 1 or more (typically up to 5) substituents selected from the group consisting of hydroxyl, halo, cyano, amino, mono- and di-alkylamines of from 1 to 10 carbon atoms in each alkyl group, alkoxy of from 1 to 10 carbon atoms, -SH, -SR where R is alkyl of from 1 to 10 carbon atoms, carboxyl, carboxyl esters of from 1 to 10 carbon atoms in the ester moiety, -NRC(0)R where R and R are independently selected from the group consisting of hydrogen and alkyl of from 1 to 10 carbon atoms, heterocycles having from 2 to 6 carbon atoms and 1 to 3 ring hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, aryl groups of from 6 to 10 carbon atoms optionally substituted with from 1 to 3 substituents on the
  • R 1 and R 2 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 10 carbon atoms, heterocycles having from 2 to 6 carbon atoms and 1 to 3 ring hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, aryl groups of from 6 to 10 carbon atoms optionally substituted with from 1 to 3 substituents on the aryl moiety selected from the group consisting of halo, hydroxyl, amino, cyano, carboxyl, nitro, alkyl of from 1 to 10 carbon atoms, and alkoxy of from 1 to 10 carbon atoms, amino, alkyl and dialkylamino of from 1 to 10 carbon atoms in each alkyl group,
  • R 1 and R 2 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 10 carbon atoms, aryl groups of from 6 to 10 carbon atoms optionally substituted with from 1 to 3 substituents on the aryl moiety selected from the group consisting of halo, hydroxyl, amino, cyano, carboxyl, nitro, alkyl of from 1 to 10 carbon atoms, and alkoxy of from 1 to 10 carbon atoms, and X is selected from the group consisting of a bond, 0, and NR 1 where R is as defined above, halo, hydroxyl,
  • R is selected from the group consisting of alkyl of from 1 to 10 carbon atoms, aryl groups of from 6 to 10 carbon atoms optionally substituted with from 1 to 3 substituents on the aryl moiety selected from the group consisting of halo, hydroxyl, amino, cyano, carboxyl, nitro, alkyl of from 1 to 10 carbon atoms, and alkoxy of from 1 to 10 carbon atoms
  • R-C(O)- groups where R is hydrogen or an alkyl group of from 1 to 10 carbon atoms optionally substituted on the alkyl group with 1 or more (typically up to 5) substituents selected from the group consisting of hydroxyl, halo, cyano, amino, mono- and di-alkylamines of from 1 to 10 carbon atoms in each alkyl group, alkoxy of from 1 to 10 carbon atoms, -SH, -SR where R is alkyl of from 1 to 10 carbon atoms, carboxyl, carboxyl esters of from 1 to 10 carbon atoms in the ester moiety, -NRC(0)R where R 1 and R 2 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 10 carbon atoms, heterocycles having from 2 to 6 carbon atoms and 1 to 3 ring hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, aryl groups of from 6 to 10 carbon atoms optionally substituted with from 1 to 3 substituent
  • Suitable substituents at the 1 position include, by way of example only: alkyl groups of from 1 to 10 carbon atoms optionally substituted with 1 or more (typically up to 5) substituents selected from the group consisting of hydroxyl, halo, cyano, amino, mono- and di-alkylamines of from 1 to 10 carbon atoms in each alkyl group, alkoxy of from 1 to 10 carbon atoms, -SH, -SR where R is alkyl of from 1 to 10 carbon atoms, carboxyl, carboxyl esters of from 1 to 10 carbon atoms in the ester moiety, -NRC(0)R where R and R are independently selected from the group consisting of hydrogen and alkyl of from 1 to 10 carbon atoms, heterocycles having from 2 to 6 carbon atoms and 1 to 3 ring hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, aryl groups of from 6 to 10 carbon atoms optionally substituted with from 1 to 3 substituents on the ary
  • substantially homogeneous refers to collections of molecules wherein at least 80%, preferably at least about 90% and more preferably at least about 95% of the molecules are a single compound or stereoisomer thereof.
  • stereoisomer refers to a chemical compound having the same molecular weight, chemical composition, and constitution as another, but with the atoms grouped differently. That is, certain identical chemical moieties are at different orientations in space and, therefore, when pure, have the ability to rotate the plane of polarized light. However, some pure stereoisomers may have an optical rotation that is so slight that it is undetectable with present instrumentation.
  • the compounds described herein may have one or more asymmetrical carbon atoms and therefore include various stereoisomers. All stereoisomers are included within the scope of the invention.
  • removable protecting group or “protecting group” refers to any group which when bound to a functionality such as hydroxyl, amino, or carboxyl groups prevents reactions from occurring at these functional groups and which protecting group can be removed by conventional chemical or enzymatic steps to reestablish the functional group.
  • the particular removable protecting group employed is not critical.
  • a ketene from a precursor molecule via solution chemistry is documented in the art .
  • one particularly preferred method is the treatment of a carboxylic acid halide (e.g., the chloride or bromide) having a methylene or methine hydrogen atom ⁇ to the carbonyl group with a base which converts the acid halide, in situ, to a ketene.
  • the resulting ketene is then reacted with a complementary compound comprising an imine, imidate, thioimidate or amidine functionality to provide for the ⁇ -lactam.
  • Figure 1 further illustrates the formation of imine compound 3., which serves as the complementary compound for reaction with the ketene, by conventional methods from a suitable aldehyde 2. (ketones can also be used) and amine .
  • the reaction is typically conducted by contacting an amine with a 10-15 fold molar excess of an alkyl, aromatic, or (X, ⁇ -unsaturated aldehyde.
  • the reaction is conducted in an inert solvent under conditions which eliminate water thereby forming imine 3..
  • the water of reaction is removed from the reaction system to facilitate reaction completion.
  • One means for effecting water removal is the use of molecular sieves (e.g., 4A molecular seives) in the reaction medium.
  • Another means is to employ a solvent that will form an azeotrope with water so that water generated during reaction can be readily removed.
  • preferred solvents include by way of example, benzene, toluene, etc.
  • a preferred means to effect water removal is to use a dehydrating solvent such as trimethyl orthoformate to effect imine formation.
  • a base for example, triethylamine
  • the particular base employed is not critical and is selected relative to its ability to extract the methine or methylene hydrogen atom alpha to the carbonyl group of the ketene precursor thereby generating the ketene and to be compatible with both the starting materials and the products formed therefrom.
  • Suitable bases include, by way of example only, triethylamine, trimethylamine, pyridine, and the like.
  • Each procedure in this reaction sequence is preferably conducted in a single reaction medium employing an inert diluent or a mixture of inert diluents.
  • the inert diluent employed in the reaction is not critical and suitable diluents include, by way of example only, acetonitrile, benzene, toluene, methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran and the like.
  • the reaction is typically conducted by contacting the ketene precursor compound with at least a stoichiometric amount of a suitable base to form the ketene.
  • a suitable base Preferably, a large molar excess of ketene (relative to imine) at high concentrations to effect the cycloaddition reaction.
  • the ketene precursor is present at a concentration of about 0.5 to 5 M, preferably, at about 0.5 to 1.5 M, and more preferably, at about 1 M.
  • the base is present at a concentration of about 0.5 to 5 M, preferably, at about 0.7 to 2 M, and more preferably, at about 1.5 M.
  • This reaction is conducted under conditions sufficient to effect formation of the ketene and is preferably conducted at a temperature of from about -78°C to about 100°C, and preferably from about 0°C to about room temperature, for a period of from about 4 to about 24 hours and preferably for from about 5 to about 15 hours.
  • ketene formation is preferably conducted in the presence of the complementary compound comprising an imine, imidate, thioimidate or amidine functionality which, upon in si tu ketene formation, reacts therewith to form a ⁇ -lactam under the conditions recited above.
  • the resulting ⁇ -lactam isomeric compounds 6. and 1_ are recovered by conventional methods, i.e., filtration, centrifugation, etc.
  • Confirmation that the resin (i.e., solid support) contains the desired ⁇ -lactam compound can be accomplished by cleaving the ⁇ -lactam compound from a small portion of the treated resins (if a cleavable linking arm is employed) and subjecting this product to conventional analysis, e.g., nuclear magnetic resonance spectroscopy ( H, C, etc.), high performance liquid chromatography, and the like.
  • the reaction can be monitored by use of appropriate resins using gel-phase C 13 -nuclear magnetic resonance spectroscopy.
  • Suitable resins for this use include those illustrated in Figures 7B-7D attached.
  • the imine carbon of Schiff bases derived from the condensation of benzaldehyde labeled with a l ⁇ C at the carbonyl carbon with various resin-bound amino acids resonates at 160-165 ppm, and upon cycloaddition becomes C-4 of the ⁇ -lactam ring with a corresponding resonance at 63-65 ppm.
  • ⁇ C labeled amino acids such as alanine or valine
  • alanine or valine can be used.
  • the method is sufficiently sensitive to monitor for the presence of isomers.
  • the ketene precursor comprises phthalimidoacetyl chloride or 4- nitrophthalimido glycine.
  • Treatment of the corresponding ⁇ -phthalimido- ⁇ -lactam derivative with hydrazine or methyl hydrazine in an appropriate solvent yields the corresponding 3-amino-2- azetidinone.
  • the reaction is conducted in with about 10% to about 50% methylhydrazine in DMF or ethanol. More preferably, about 20% methyl hydrazine in DMF or ethanol (4M) is used.
  • the phthalimido group serves as a latent amino functionality which can be further modified, for example, through alkylation, acetylation, addition of a carbobenzoyl group, formation of a succinimide group (see, e . g. , Wollenberg et al . U.S. Patent No. 4,612,132), etc., using techniques well known in the art.
  • the free 3-amino functionality can be further modiified through acylation. Acylation with a variety of amino acids, including valine and phenylalanine, using standard peptide coupling reagents proceeds smoothly to afford the desired 3- amido-2-azetidinones in excellent yield and purity upon cleavage from the resin.
  • ketenes from suitable ketene precursor compounds
  • suitable ketene precursor compounds include by way of example, treatment of activated esters of carboxylic acids having a methylene or methine hydrogen atom ⁇ to the carbonyl group with a base and photochemical conversion from metal carbenes.
  • Suitable activating esters and metal carbenes are well known in the art and are described, for example, by Georg and Ravikumar .
  • the particular ketene precursor compound and the method employed to convert this precursor to the ketene employed in the methods of this invention is not critical.
  • alkyl ketenes derived from alkyl carboxylic acid chlorides
  • imines like imino esters or imines derived from phenylglyoxal
  • ⁇ -lactams having 3-alkyl substituents can be employed.
  • the linker is tethered to the solid support via the phenolic hydroxyl, typically through a spacer.
  • the amino group of the linker can participate directly in Schiff base formation and subsequent [2+2] cycloaddition, as exemplified by the synthesis of two 3-phthalimido-2-azetidinones derivatives. See Figure 9.
  • Photocleavage from the support provides a convenient synthesis of N- unsubstituted ⁇ -lactams, important precursors of both monocyclic and bicyclic antibiotics. 12
  • the use of a photolabile support offers opportunities to configure antimicrobial assays in which compounds are photochemically released from the solid supports directly onto a confluent lawn of a test organism.
  • Figure 1 illustrates formation of imine 3 . from an amine covalently attached to a solid support
  • aldehyde 2 or a ketone
  • a soluble amine i.e., not attached to the solid support
  • the ketene precursor compound could be covalently attached to the solid support which can then be reacted with a soluble complementary compound (not attached to the support) to provide for a ⁇ -lactam group covalently attached to the support.
  • this reaction is conducted in the manner to that described above.
  • the stereochemical course of the cycloaddition reaction has been extensively studied for solution chemistry and the stereochemical outcome is dependent on the nature of both the imine and ketene components. As depicted in Figure 1, the reaction of the ketene derived from phenoxyacetyl chloride with the imine 3 . derived from immobilized L-alanine 1 and benzaldehyde 2.
  • the cis diastereomeric ⁇ - lactams are formed in ratios from about 1:1 to about 3:2, depending on the steric bulk of the amino acid substituent.
  • asymmetric syntheses conducted on solid phase resins also give predominantly single products even when sterically hindered amines (e.g., valine) are used.
  • Such asymmetric syntheses are illustrated in Figures 2-4 which syntheses provide for selective preparation of resin bound ⁇ -lactams 1J5/ 2_2, and 2_ respectively. Cleavage of these ⁇ -lactams from the resin provides for soluble ⁇ -lactams __, 23 . and __ respectively.
  • Hydroxy groups for example, can be acylated or oxidized and amine groups can be alkylated or converted to amides by conventional methods .
  • Figure 5 illustrates the formation of a 3-benzyloxy ⁇ - lactam 3_ from a benzyloxyprotected hydroxyketene precursor __ .
  • the protecting benzyloxy group is removed with hydrogen (H 2 ) and subsequently oxidized with phosphorus pentaoxide (P 2 0 5 ) in dimethylsulfoxide (DMSO) to provide for the 3-keto ⁇ -lactam _1_ .
  • N-carboxyanhydride .38 which can be ring opened via either hydroxyl anion to provide for carboxyalkyl amine __ or via an amine to provide amide 40.
  • Figure 6 illustrates a general procedure for the formation of a ⁇ -lactam __ having a 3-protected amino group (Pg is a removable protecting group) which is converted to the free amino compound .47 and subsequently employed to prepare a ⁇ -lactam dimer 51.
  • the 3-amino group of compound _J_ can be used to prepare heterocyclic compounds __ ⁇ and ___ .
  • the 3-amino group can be incorporated into a thiazolidinone or metathiazonone, as described in U.S. Serial No. 08/ , filed July 27, 1995 (Attorney Docket No. 1059.1), which application claims priority from PCT Application Serial No.
  • the 3-amino group on the ⁇ -lactam also serves as a basis for the preparation of ⁇ -lactam dimers and higher polymers by conversion of this amino group to an imine by reaction with a suitable aldehyde or ketone which in turn can be reacted with a ketene in the manner described above to prepare a ⁇ -lactam dimer.
  • substituents at the 3 or 4-positions comprising a ketene precursor functionality can be employed to prepare ⁇ -lactam dimers.
  • each solid support will preferably contain a single compound which compound is different to the compounds found on the other solid supports but each compound will also comprise a ⁇ -lactam group.
  • each compound will also comprise a ⁇ -lactam group.
  • the term "single compound” as used herein includes different regio and stereoisomers of that compound. Also, the term “single compound” does not mean that only one copy of that compound is attached to each support. Rather, multiple copies of that compound can be included on the support.
  • such methods comprise apportioning the supports comprising a covalently bound ketene precursor or a covalently bound complementary compound comprising an imine, imidate, thioimidate or amidine group among a plurality of reaction vessels; exposing the supports in each reaction vessel under conditions wherein the ketene precursor or the complementary compound is converted to a ⁇ -lactam group wherein said ⁇ -lactam group is different for each of the reaction vessels; and then preferably pooling the supports.
  • the ketene precursor is converted to a ⁇ -lactam group by first converting the ketene precursor to the ketene followed by reaction of the ketene with a complementary compound comprising an imine, imidate, thioimidate or amidine group.
  • the complementary group comprising an imine, imidate, thioimidate or amidine group is converted to a ⁇ -lactam group by reaction with a ketene.
  • the library will contain at least about 10 2 compounds, more preferably from about 10 2 to about 10 1 compounds and still more preferably from about 10 3 to about 10 compounds.
  • each solid support is tagged with an identifier tag that can be easily decoded to report the compounds formed on the solid support.
  • the tag can be directly attached either to the solid support or the tag can be included on the compound itself. In this latter embodiment, cleavage of the compound from the solid support will still permit identification of the compound.
  • WO 93/06121 or WO 95/12608 each of which is corporated herein by reference in its entirety.
  • a portion of the same compounds attached to a single support is cleaved and subjected to mass spectroscopy, nuclear magnetic resonance spectroscopy and/or other forms of direct structural analysis so as to identify the compound on the support.
  • the ⁇ -lactam group can be incorporated into each compound in a library of different compounds all of which are covalently linked to the same solid support in the manner described in U.S. Patent No. 5,143,854.
  • a library of different compounds can be simultaneously screened for receptor binding or some other activity.
  • U.S. Patent No. 5,143,854 is incorporated herein by reference in its entirety.
  • FMOC fluorenyl ethyl oxycarbonyl
  • NMP N-methylpyrrolidone
  • TFA trifluoroacetic acid
  • the Sasrin resin described herein is commercially available from Bache Biosciences and the TentaGel Ac resin, TentaGel PHB resin and TentaGel RAM resin are commercially available from Rapp Polymere, Tubigen, Germany. Each of these resins is depicted in Figures 7A-7D respectively.
  • Example 1 illustrates a typical procedure for effecting solid phase synthesis of a ⁇ -lactam.
  • Example 2 illustrates the synthesis of a chiral ketene precursor compound suitable for use in preparing a chiral ketene which induces asymmetry to the ketene- imine cycloaddition reaction.
  • Examples 3-10 illustrate asymmetric ketene-imine cycloaddition reactions using the chiral ketene precursor of Example 2.
  • Examples 11 and 12 illustrate the formation of 3- phthalimido-2-azetidinone compounds wherein the phthalimido group serves as a latent amino functionality.
  • Examples 13-27 illustrate the synthesis of a 25 compound library of different ⁇ - lactam compounds.
  • Examples 28 and 29 illustrate the synthesis of 3-vinyl-2-azetidones.
  • Example 30 illustrates the synthesis of 3-benzyloxy-2- azetidinone.
  • Example 31 illustrates the use of a photolinker.
  • Example 32 illustrates the use of a free amino group to form a heterocyclic compound.
  • FMOC-Ala-Sasrin 200 mg, 0.68 mmol loading
  • 30% piperidine/NMP 5 mL
  • the resin was filtered, washed (4 x 5 mL methylene chloride, 2 x 5 mL methanol, 2 x 5 mL diethyl ether) and dried under high vacuum for 15-20 minutes.
  • the resin was poured into a 10 mL screw capped vial and suspended in methylene chloride (4 mL) .
  • Benzaldehyde (276 ⁇ L, 2.72 mmol) and molecular sieves (4A, 10 pellets) were added to the vial and the mixture was heated to 40° to 42°C for 3 hours by placing the vial into a dry heating block.
  • the resin was transferred into a centrifuge filter unit and washed (4 x 2 mL methylene chloride, 2 x 2 mL methanol, 2 x 2 mL diethyl ether) and dried under high vacuum for 30 minutes .
  • the resulting support bound imine was poured in a 10 mL screw capped vial and suspended in methylene chloride (4 mL) .
  • Triethylamine (379 ⁇ L, 2.72 mmol) was added to the vial and the mixture was cooled to -78°C.
  • phenoxyacetyl chloride (283 ⁇ L, 2.04 mmol) dropwise and the mixture was kept for 10 minutes at -78°C and placed on a shaker table and agitated for 15 hours at 25°C.
  • the resin was transferred into a centrifuge filter unit, washed (4 x 2 mL methylene chloride, 2 x 2 mL methanol, 3 x 2 mL diethyl ether) and dried under high vacuum for 30 minutes.
  • the resin was placed in a vial and treated with 2% TFA in methylene chloride (3 mL) for 45 minutes.
  • the resin was filtered and the filtrate was rotary evaporated to dryness to give the title compound.
  • Sasrin resin pre-loaded with an N-Fmoc-protected amino acid (0.165 mmol, 0.3 g of resin, loading 0.55 mmol/g) was treated with a solution of 30% piperidine in N-methylpyrrolidone (NMP) for 45 minutes.
  • NMP N-methylpyrrolidone
  • the resin was rinsed with NMP or DMP, methylene chloride, methanol, and ether, and dried under reduced pressure.
  • the resin was suspended in a mixture of methylene chloride (1.5 mL) and trimethylorthoformate (1.5 mL) and the aldehyde (2.3 mmol) was added. After agitating for 3 hours, the resin was rinsed with methylene chloride, methanol, and ether and dried under reduced pressure.
  • the resin was transfered to a glass vial, suspended in methylene chloride (3 mL) and cooled to 0°C. To the suspension was added triethylamine (3.3 mmol) followed by a slow addition of the acid chloride (2.5 mmol) . The reaction mixture was left at 0°C for 5 minutes and then agitated overnight at room temperature. The resin was filtered, rinsed with DMF, methylene chloride, methanol and ether and dried under reduced pressure.
  • the product was cleaved from the support by treating the resin with a solution of 3% (v/v) TFA/methylene chloride for 45 minutes.
  • the crude material was subjected to a second TFA treatment (50% TFA/methylene chloride) to remove the protecting groups.
  • the solution was filtered, and after removal of the solvent, the crude product was purified by preparative HPLC.
  • Example 2 using the procedure set forth in Example 1, the (4S-phenyl oxazolidinyl) acetyl chloride of Example 2 and the appropriate amino acid, the ⁇ -lactams of the Table 1 below were prepared, after cleavage of the cleavable linking arm with 1 to 3% TFA in dichloromethane.
  • the following examples illustrate the formation of 3-phthalimido-2-azetidinone compounds.
  • the phthalimido group serves as a latent amino functionality which can, at the appropriate point in the synthesis, be easily removed with N-methyl hydazine without disrupting the ⁇ -lactam ring.
  • Phthalimido acetyl chloride was prepared in the manner consistent with Example 2 above and was converted to the phthalimido ketene with triethylamine, dichloromethane at -78°C in the manner of Example 1 above and then treated with solid phase imines to form ⁇ -lactam compounds.
  • the resulting ⁇ - lactam was cleaved by use of TFA (2%) in dichloromethane.
  • the crude product was purified by preparative HPLC and each fraction analyzed by " " ⁇ -NMR and mass spectroscopy thereby providing the expected cis ⁇ -lactam compounds as set forth in Table 2 below. These compounds were, however, contaminated with the corresponding methyl ester which contamination could be obviated by eliminating the methanol rinse.
  • Methyl hydrazine (0.11 mL, 2.1 mmol) was added to a suspension of Sasrin resin bearing the 3- phthalimido-azetidin-2-one (0.14 mmol based on the initial loading of the resin) in methylene chloride (1.5 mL) at room temperature. After agitating the suspensin overnight, the resin was filtered, washed with DMF, methylene chloride, methanol, and ether and dried under reduced pressure. The product was then suspended in DMF (1 mL) and treated with an N-FMoc- protected amino acid (0.69 mmol), HOBt (0.75 mmol) and DIC (0.75 mmol) .
  • reaction mixture was agitated for 6 hours, filtered, and washed with DMF, methylene chloride, methanol, and ether.
  • the resin was dried and thea resulting ⁇ -lactam was cleaved from the support by exposure to 5% TFA/methylene chloride for 1 hour.
  • this library was formed as follows. FMOC-Val-Sasrin was deprotected with 30% piperidine in NMP. The resin was filtered, rinsed (dichloromethane, diethyl ether) , dried and split equally in 5 flasks and suspended in dichloromethane. To each vial was added an excess of one aldehyde, R 2 - CHO where Rj is as defined in Table 3 below, (15 equivalents) and a small amount of molecular sieves (4A) . This mixture was shaken for 3 hours and the resins were filtered, rinsed, dried and then each reaction vessel was equally divided into three aliquots to provide a total of 15 reaction vessels the resins for each of which were suspended in dichloromethane. To each aliquot was added an excess of triethylamine (20 equivalents) and the mixture was cooled to -78°C, treated with one of three acid chlorides, R 2 -CH 2 C(0)C1 where R 2 is as defined in
  • the library of ⁇ - lactam compounds can be prepared as above provided that at least one of the following conditions is satisfied 1) at least two different ketene precursor groups are used to produce the ⁇ -lactam group; 2) at least two different complementary groups are used to produce the ⁇ -lactam group; and 3) at least two different sets of reaction conditions are used to produce the ⁇ -lactam group.
  • 3-Benzyloxy substituents on the ⁇ -lactam can be obtained by condensing benzyloxyacetyl chloride and an imine derived from alanine (attached to a solid support) and benzaldehyde in the manner described above. The desired ⁇ -lactam is recovered in the manner described above.
  • EXAMPLE 31 Imine formation on photolinker and subsequent cycloaddition A.
  • the resin (300 mg, 0.08 mmol) was treated with 30% piperidine in DMF (1 mL) for 30 minutes, filtered, washed with DMF, methylene chloride, methanol, and ether and dried under high vacuum.
  • the free amino aci resin was then suspended in trimethylorthoformate (1 mL) and treated with aldehyde (1.7 mmol) for 3 hours at room temperature to form resin-bound imine.
  • the resin was washed several times with methanol and ether and dried under high vacuum.
  • the imine resin was suspended in methylene chloride (1 mL) and cooled to 0°C. Triethylamine (1.2 mmol) was added followed by slow addition of phthalimidoacetyl chloride (1.0 mmol) . The reaction mixture was agitated overnight at room temperature, then filtered, washed with DMF, methylene chloride, methanol, and ether and dried. The b-lactam product was cleaved from the resin by photolysis in DMSO at 365 run for 6 hours.
  • the 3-phthalimido-2-azetidinone was prepared by treating the imine with phthalimido acetyl chloride
  • the reaction was conducted at 0°C.
  • the ⁇ -lactam was cleaved from the resin through photolysis in ethanol or DMSO using a 500 W Hg ARC lamp fitted with a 350-450 nm dichroic mirror at a 10 mW/c ⁇ .2 power level measured at 365 nm. After photolysis, the samples were filtered and the filtrate was collected. The samples were analyzed by HPLC, mass spectroscopy and NMR and the data indicated that the desired ⁇ -lactam was produced in high purity. This reaction sequence is shown schematically in Figure 9.
  • the corresponding imine was produce from cinnamaldehyde and valine on Sasrin resin as described above.
  • the ⁇ -lactam was formed from the imine and phthalimido acetyl chloride as described above.
  • the b-lactam was deprotected with methyl hydrazine in methylene chloride as described above.
  • the resulting amine was treated with benzaldehyde (20 eq. , 0.75 M) and mercaptoacetic acid (35 eq. , 2M) in a 1:1 trimethylorthoformate:THF mixture at 70°C for two hours.
  • the reaction was conducted in THF with molecular sieves at 70°C. Both sets of conditions resulted in the production of a thiazolidinone coupled to the b-lactam.
  • the adduct was cleaved from the resin by treatment with 10% TFA in methylente chloride.
  • HPLC showed four peaks representing four isomers, two for each ⁇ -lactam (two cis isomers) .
  • the structures of the compounds were elucidated by NMR and mass spectroscopy.

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Abstract

On décrit des procédés permettant de synthétiser de très grandes collections de différents composés à base de β-lactame sur des supports solides, ainsi que des banques de composés de synthèse qui comprennent ces groupes β-lactame préparés par de tels procédés.
PCT/US1995/015261 1994-11-23 1995-11-22 PROCEDE PERMETTANT DE SYNTHETISER DIFFERENTES COLLECTIONS DE COMPOSES A BASE DE β-LACTAME WO1996016333A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6455263B2 (en) 1998-03-24 2002-09-24 Rigel Pharmaceuticals, Inc. Small molecule library screening using FACS
US6521611B2 (en) * 1996-02-23 2003-02-18 Eli Lilly And Company Non-peptidyl vasopressin V1a antagonists

Citations (1)

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Publication number Priority date Publication date Assignee Title
US5288514A (en) * 1992-09-14 1994-02-22 The Regents Of The University Of California Solid phase and combinatorial synthesis of benzodiazepine compounds on a solid support

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Publication number Priority date Publication date Assignee Title
US5288514A (en) * 1992-09-14 1994-02-22 The Regents Of The University Of California Solid phase and combinatorial synthesis of benzodiazepine compounds on a solid support

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Title
NATURE, Volume 354, issued 07 November 1991, LAM et al., "A New Type of Synthetic Peptide Library for Identifying Ligand-binding Activity", pages 82-84. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6521611B2 (en) * 1996-02-23 2003-02-18 Eli Lilly And Company Non-peptidyl vasopressin V1a antagonists
US6610680B1 (en) * 1996-02-23 2003-08-26 Eli Lilly And Company Non-peptidyl vasopressin V1A antagonists
US6455263B2 (en) 1998-03-24 2002-09-24 Rigel Pharmaceuticals, Inc. Small molecule library screening using FACS

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