WO1994000509A9 - Matieres derivees d'oxazolone - Google Patents
Matieres derivees d'oxazoloneInfo
- Publication number
- WO1994000509A9 WO1994000509A9 PCT/US1993/006240 US9306240W WO9400509A9 WO 1994000509 A9 WO1994000509 A9 WO 1994000509A9 US 9306240 W US9306240 W US 9306240W WO 9400509 A9 WO9400509 A9 WO 9400509A9
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- different
- chemical bond
- oxazolone
- same
- Prior art date
Links
- SJHPCNCNNSSLPL-UHFFFAOYSA-N 4-(ethoxymethylene)-2-phenyloxazol-5-one Chemical compound O1C(=O)C(=COCC)N=C1C1=CC=CC=C1 SJHPCNCNNSSLPL-UHFFFAOYSA-N 0.000 title claims abstract description 105
- 239000000463 material Substances 0.000 title abstract description 48
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- 239000003446 ligand Substances 0.000 claims description 47
- 238000006243 chemical reaction Methods 0.000 claims description 44
- XYVMOLOUBJBNBF-UHFFFAOYSA-N 3H-1,3-oxazol-2-one Chemical group OC1=NC=CO1 XYVMOLOUBJBNBF-UHFFFAOYSA-N 0.000 claims description 42
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 41
- 239000000047 product Substances 0.000 claims description 36
- 238000007142 ring opening reaction Methods 0.000 claims description 35
- -1 isocyanate alkyl halide Chemical class 0.000 claims description 34
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 26
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- 229910052717 sulfur Inorganic materials 0.000 claims description 19
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- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 18
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
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- DODCBMODXGJOKD-UHFFFAOYSA-N hydron;methyl 2-amino-4-methylpentanoate;chloride Chemical compound Cl.COC(=O)C(N)CC(C)C DODCBMODXGJOKD-UHFFFAOYSA-N 0.000 description 1
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Definitions
- the present invention relates to the logical development of biochemical and biopharmaceutical agents and of new materials, including fabricated materials such as fibers, beads, films and gels. Specifically, the invention relates to the development of molecular modules derived from oxazolone (azlactone) and related
- the molecular modules of the invention are preferably chiral, and can be used to synthesize new compounds and
- nucleotides can form complementary base pairs so that complementary single-stranded molecules hybridize resulting in double- or triple-helical
- a biologically active molecule binds with another molecule, usually a macromolecule referred to as ligand-acceptor (e.g. a receptor or an enzyme), and this binding elicits a chain of molecular events which
- the binding between ligand and ligand-acceptor is geometrically characteristic and extraordinarily
- oligonucleotides that can be used to block or suppress gene expression via an antisense, ribozyme or triple helix mechanism.
- sequence of the native target DNA or RNA molecule is characterized and standard methods are used to synthesize oligonucleotides representing the complement of the desired target
- the gangliosides are examples of the versatility and effect with which organisms can use saccharide structures. These molecules are glycolipids (sugar-lipid composites) and as such are able to position themselves at strategic locations on the cell wall:
- ganglioside GM a potent inhibitor of the toxin secreted by the cholera organism, featuring a branched complex pentameric structure is shown below.
- glycoproteins responsible for the human blood-group antigens (the A, B, and O blood classes) are shown below.
- incompatible blood classes cause formation of aggregates, or clusters and are the cause for failed transfusions of human blood.
- glycosylation i.e., the covalent linking with sugars.
- glycosylation of erythropoetin causes loss of the hormone's biological activity; deglycosylation of human gonadotropic hormone increases receptor binding but results in almost complete loss of biological activity (see Rademacher et al., Ann. Rev. Biochem 57. 785 (1988); and glycosylation of three sites in tissue plasminogen activating factor (TPA) produces a glycopolypeptide which is 30% more active than the polypeptide that has been glycosylated at two of the sites.
- TPA tissue plasminogen activating factor
- a currently favored strategy for development of agents which can be used to treat diseases involves the discovery of forms of ligands of biological receptors, enzymes, or related macromolecules, which mimic such ligands and either boost, i.e., agonize, or suppress, i.e., antagonize, the activity of the ligand.
- boost i.e., agonize
- suppress i.e., antagonize
- proteins for specific acceptors, e.g. receptors or enzymes, which is in the subnanomolar range.
- peptide mimetics which bind tightly, preferably in the nanomolar range, and can withstand the chemical and biochemical rigors of coexistence with biological fluids.
- peptidase inhibitor design using the enzyme substrate as a lead cannot be transferred for use in another area, e.g. tyrosine-kinase inhibitor design using the kinase substrate as a lead.
- the peptidomimetics that result from a peptide structural lead using the "rational" approach comprise unnatural ⁇ -amino acids. Many of these mimetics exhibit several of the troublesome features of native peptides (which also comprise ⁇ -amino acids) and are, thus, not favored for use as drugs.
- nonpeptidic scaffolds such as steroidal or sugar structures, to anchor specific receptor-binding groups in fixed geometric relationships have been described (see for example Hirschmann, R. et al., 1992 J. Am. Chem. Soc. 114:9699-9701; Hirschmann, R. et al., 1992 J. Am. Chem. Soc.. 114:9217-9218);
- Huebner and D.V. Santi utilized functionalized polystyrene beads divided into portions each of which was acylated with a desired amino acid; the bead portions were mixed together and then split into portions each of which was subjected to acylation with a second desirable amino acid producing dipeptides, using the techniques of solid phase peptide synthesis.
- This synthetic scheme exponentially increasing numbers of peptides were produced in uniform amounts which were then separately screened for a
- Protein Res. 91:1 also have developed similar methods for the synthesis of peptide libraries and applied these methods to the automation of a modular synthetic
- Crystallization can be valuable as a separation technique but in the majority of cases, especially in cases involving isolation of a biomolecule from a complex biological milieu, successful separation is
- Chromatographic separations are the result of reversible differential binding of the
- macromolecules e.g. reverse-phase silica frequently used to perform high pressure liquid chromatography can denature hydrophobic proteins and other polypeptides.
- hydrocarbons, polysaccharide and other types of beads or gels, etc. which in order to attain their maximum separating efficiency need to be used under conditions that are damaging to biomolecules, e.g. conditions involving high pressure, use of organic solvents and other denaturing agents, etc.
- Oxazolones, or azlactones are structures of the general formula:
- A is a functional group and n is 0 or 1 and
- Oxazolones containing a five-membered ring and a single substituent at position 4 are typically encountered as transient intermediates which cause problematic racemization during the chemical synthesis of peptides.
- An oxazolone can in principle contain one or two substituents at the 4-position.
- Chiral oxazolones possessing a single 4-substituent also known as 5 (4H)-ooazolones
- derived from (chiral) natural amino acid derivatives, including activated acylamino acyl structures have been prepared and isolated in the pure, crystalline state (Bodansky, M.; Klausner, Y.S.; Ondetti, M.A. in "Peptide Synthesis", Second Edition, John Wiley & Sons, New York, 1976, p. 14 and references cited therein).
- the facile, base-catalyzed racemization of several of these oxazolones has been studied in connection with investigations of the serious racemization problem confronting peptide
- the oxazolone derivative building blocks of the invention can be used to synthesize novel molecules designed to mimic the three-dimensional structure and function of native ligands, and/or interact with the binding sites of a native receptor.
- This logical approach to molecular construction is applicable to the synthesis of all types of molecules, including but not limited to mimetics of peptides, proteins, oligonucleotides, carbohydrates, lipids, polymers and to fabricated materials useful in materials science. It is analogous to the modular construction of a mechanical device that performs a specific operation wherein each module performs a
- the invention is based, in part, on the
- All ligands share a single universal architectural feature: they consist of a scaffold structure, made e.g. of amide, carbon-carbon, or phosphodiester bonds which support several functional groups in a precise and relatively rigid geometric arrangement.
- Binding modes between ligands and receptors share a single universal feature as well: they all involve attractive interactions between complementary structural elements, e.g., charge- and ⁇ -type interactions, hydrophobic and van der Waals forces, hydrogen bonds.
- a continuum of fabricated materials exists spanning a dimensional range from about 100 A to 1 cm in diameter comprising various materials of
- Oxazolone derivative structures heretofore regarded as unwanted intermediates which form during the synthesis of peptides, would be ideal building blocks for constructing backbones or scaffolds bearing the appropriate functional groups that either mimic desired ligands, and/or interact with appropriate
- the invention is also based, in part, on the further recognition that such derivatives of ozaxolones, which do not racemize, can be used as universal building blocks for the synthesis of such novel molecules.
- oxazolone derivatives may be utilized in a variety of ways across the continuum of fabricated materials
- derivatives may be chirally pure and used to synthesize molecules that mimic a number of biologically active molecules, including but not limited to peptides,
- carbohydrates and lipids and a variety of other polymers as well as fabricated materials that are useful as new materials, including but not limited to solid supports useful in column chromatography, catalysts, solid phase immunoassays, drug delivery vehicles, films, and
- oxazolone-derived modules in the modular assembly of a variety of molecular structures are given.
- the molecular structures include functionalized silica surfaces useful in the optical resolution of racemic mixtures; peptide mimetics which inhibit human elastase, protein-kinase, and the HIV protease; and polymers formed via free-radical or condensation polymerization of oxazolone-containing monomers.
- the oxazolone-derived molecules of interest possess the desired stereochemistry and, when required, are obtained enantiomerically pure.
- the synthesis of libraries of oxazolone-derived molecules using the techniques
- oxazolone-derived molecules possess enhanced hydrolytic and enzymatic stabilities, and in the case of
- chiral oxazolones in which the asymmetric center is a
- 4-disubstituted carbon, as well as synthetic nonchiral oxazolones may be synthesized readily and used as
- oxazolones may also be linked together, using
- the 4 position of the oxazolone precursor does not need to be chiral, e.g., the construction of certain polymeric materials
- the use of oxazolones in the construction of linkers for the joining of two or more pharmaceutically useful or, simply, biologically active ligands, etc., symmetric or nonchiral oxazolones are used in chemical syntheses.
- the oxazolone-derived product does not need to
- oxazolone precursors which are not enantiomerically pure may be used for syntheses.
- Chiral 4,4'-disubstituted oxazolones may be prepared from the appropriate N-acyl amino acid using any of a number of standard acylation and cyclization
- X S or NR and A' is a functionalized alkyl group.
- chiral amino acid precursors for oxazolone synthesis may be produced using stereoselective reactions that employ chiral auxiliaries.
- An example of such a chiral auxiliary is (5)-(-)-1-dimethoxymethyl-2- methoxymethylpyrrolidine (SMPD) (Liebig's Ann. Chem. 1668 (1983)) as shown below,
- R 2 CH 3 , i-Bu, or benzyl
- R 3 CH 3 , CHF 2 , C 2 H 5 , n-Bu, or benzyl.
- a second example involves 5H,10bH- oxazolo[3,2-c][1,3]benzoxazine-2(3H),5-diones (55 J. Org. Chem. 5437 (1990)),
- the desired chiral amino acid may be obtained using stereoselective biochemical transformations carried out on the racemate, synthesized via standard reactions, as shown below for a case involving a commercially-available organism (53 J. Org. Chem. 1826 (1988)),
- oxazolones may be prepared from monosubstituted oxazolones by alkylation of the 4-position, as in the following transformation (Synthesis Commun., Sept. 1984, at 763; 23 Tetrahedron Lett. 4259 (1982)):
- Racemic mixtures of oxalolones may be effected using chromatography or chiral supports under suitable conditions which are well known in the art; using fractional crystallization of stable salts of oxazolones with chiral acids; or simply by hydrolyzizing the racemic oxazolone to the amino acid derivative and resolving the racemic modification using standard
- a wide variety of 4-monosubstituted azlactones may be readily prepared by reduction of the corresponding unsaturated derivatives obtained in high yield from the condensation reaction of aldehydes, ketones, or imines with the oxazolone formed from an N-acyl glycine (49 J. Org. Chem. 2502 (1984); 418 Synthesis Communications
- Chiral oxazolones may be subjected to ring- opening reactions with a variety of nucleophiles
- Y represents an oxygen, sulfur, or nitrogen atom.
- R 1 and R 2 differ from one another and taken alone each signifies one of the followng: alkyl including cycloalkyl and substituted forms thereof; aryl, aralkyl, alkaryl, and substituted or heterocyclic
- the above ring-opening reaction can be carried out either in an organic solvent such as methylene chloride, ethyl acetate, dimethyl formamide (DMF) or in water at room or higher temperatures, in the presence or absence of acids, such as carboxylic, other proton or Lewis-acids, or bases, such as tertiary amines or
- a and B shown may be of a variety of structures and may differ markedly in their physical or functional properties, or may be the same; they may also be chiral or symmetric.
- a and B are preferably selected from:
- oligonucleotides including both deoxyribose (DNA) and ribose (RNA)
- a reporter element such as a natural or synthetic dye or a residue capable of photographic amplification which possesses reactive groups which may be synthetically incorporated into the oxazolone structure or reaction scheme and may be attached through the groups without adversely interfering with the reporting functionality of the group.
- Preferred reactive groups are amino, thio, hydroxy, carboxylic acid, acid chloride, isocyanate alkyl halides, aryl halides and oxirane groups.
- Suitable groups include vinyl groups, oxirane groups, carboxylic acids, acid chlorides, esters, amides, lactones and
- a macromolecular component such as a macromolecular surface or structures which may be attached to the oxazolone modules via the
- weight of these macromolecules may range from about 1000 Daltons to as high as possible.
- a and/or B may be a chemical bond to a suitable organic moiety, a hydrogen atom, an organic moiety which contains a suitable electrophilic group, such as an aldehyde, ester, alkyl halide, ketone, nitrile, epoxide or the like, a suitable nucleophilic group, such as a hydroxyl, amino, carboxylate, aminde, carbanion, urea or the like, or one of the R groups defined below.
- a and B may join to form a ring or structure which connects to the ends of the repeating unit of the compound defined by the preceding formula or may be separately connected to other moeities.
- composition of the invention is defined by the structure wherein:
- a and B are as defined above and A and B are optionally
- X and Y are the same or different and each represents a chemical bond or one or more atoms of carbon, nitrogen, sulfur, oxygen or
- R and R' are the same or different
- each is an alkyl, cycloalkyl, aryl, aralkyl or alkaryl group or a substituted or
- R 1 may be different in adjacent n units and
- G is a connecting group or a chemical bond which may be different in adjacent n
- n 1, and X and Y are chemical bonds, A and B are different and one is other than a chemical bond, H or R; (2) if n is 1 and Y is a chemical bond, G includes a NH, OH or SH terminal group for connection to the carbonyl group and G-B is other than an amino acid residue or a peptide; (3) if n is l and X, Y, and G each is a chemical bond, A and B each is other than a chemical bond, an amino acid residue or a peptide; and (4) if n is 1, either X or A has to include a CO group for direct connection to the NH group.
- compositions may be used to mimic various compounds such as peptides, nucleotides, carbohydrates, pharmaceutical compounds, reporter compounds,
- composition is defined by the formula:
- A, B, X, Y and G are as defined above.
- At least one of A and B represents an organic or inorganic
- macromolecular surface functionalized with hydroxyl, sulfhydryl or amine groups.
- preferred macromolecular surfaces include ceramics such as silica and alumina, porous or nonporous beads, polymers such as a latex in the form of beads, membranes, gels,
- group A or B in the above structure is an aminimide moiety.
- This moiety may be introduced, for example by reacting the oxazolone with an asymmetrically substituted hydrazine and alkylating the resulting hydrazide, (e.g., by reaction with an alkyl halide, or epoxide).
- An example of such a surface is shown below.
- aminimides are described in a PCT application entitled MODULAR DESIGN AND SYNTHESIS OF AMINIMIDE-BASED MOLECULES USEFUL AS MOLECULAR RECOGNITION AGENTS AND NEW POLYMERIC MATERIALS (attorney docket no.: 5925-005-228) and filed of even date herewith, the content of which is expressly incorporated herein by reference thereto.
- Y is a chemical bond [see claim 36]. This ring is useful for preparing the desired oxazolone derivatives.
- a further embodiment of the invention exploits the capability of oxazolones with suitable substituents at the 2-position to act as alkylating agents.
- substituents include vinyl groups, which make the oxazolone a Michael acceptor, haloalkyl and alkyl sulfonate-ester and epoxide groups.
- Michael addition to the double bond of a chiral 2-vinyloxazolone followed by a ring opening reaction results in a chiral conjugate structure.
- substituents A and B may adopt a variety of structures, differing markedly in their physical or functional properties or being the same, may be chiral or achiral, and may be preferably selected from amino acids, oligopeptides, polypeptides and proteins, nucleotides, oligonucleotides, ligand mimetics,
- therapeutic agents metabolites, dyes, photographically active chemicals, or organic molecules having desired steric, charge, hydrogen-bonding or hydrophobicity characteristics, or containing polymerizable vinyl groups.
- the Michael reaction described above is usually carried out using stoichiometric amounts of nucleophile AXH and the oxazolone in a suitable solvent, such as toluene, ethyl acetate, dimethyl formamide, an alcohol, and the like.
- a suitable solvent such as toluene, ethyl acetate, dimethyl formamide, an alcohol, and the like.
- the product of the Michael addition is preferably isolated by evaporating the reaction solvent in vacuo and purifying the material isolated using a technique such as recrystallization or chromatography.
- Gravity- or pressure-chromatography on one of a variety of supports, e.g., silica, alumina, under normal- or reversed-phase conditions, in the presence of a suitable solvent system, may be used for purification.
- nucleophiles of the form ROH tend to add primarily via the ring-opening reaction, and often require acidic catalysts (e.g., BF 3 ); thus, X should not be oxygen.
- acidic catalysts e.g., BF 3
- primary amines tend to add only via ring-opening, and X should therefore not be NH.
- nucleophiles will exclusively add via Michael reaction under non-ionizing (i.e., neutral or acidic) conditions.
- non-ionizing i.e., neutral or acidic
- AXH can be a secondary amine or thiol
- BYH can be a primary or secondary amine or thiol, or an alcohol.
- A is a substituent selected from the foregoing list and BXH comprises an organic or inorganic macromolecular surface, e.g., a ceramic, a porous or non-porous bead, a polymer such as a latex in the form of a bead, a membrane, a gel or a composite, or hybrid of these; the macromolecular surface is
- reaction sequence is carried out under conditions similar to those given for the nonpolymeric cases; purification of the final product involves
- reactive groups may be
- a suitable protecting group shown as Bl below, may be used to block an existing benzylic amino group in the oxazolone; subsequent to the ring-opening addition of BYH the protected group is removed using standard techniques (e.g., if the protecting group is Boc, it is removed by using dilute TFA in CH 2 Cl 2 ), and the resulting product is reacted with an appropriate electrophile, e.g., A-CH 2 -Br, thus introducing substituent A into the molecule.
- an appropriate electrophile e.g., A-CH 2 -Br
- the oxazolones selected for catenation contain functional groups which, when part of the oxazolone-derived
- a hybrid molecule may be produced which has improved stability properties.
- a and B represent the polypeptide sequences flanking the inserted oxazolonederived unit or units.
- sequences may be constructed in one of three ways as outlined below.
- the oxazolone ring is opened via nucleophilic attack by the amino group of a chiral ⁇ , ⁇ '-disubstituted amino acid; the resulting amide may be recyclized to the oxazolone, with retention of chirality, and subjected to a further nucleophilic ring-opening reaction, producing a growing chiral polymer as shown below:
- M is an alkali metal
- substituent pairs R 1 and R 2 , R 3 and R 4 , and R 5 and R 6 differs from the other and taken alone each signifies alkyl, cycloalkyl, or substituted versions thereof, aryl, aralkyl or alkaryl, or substituted and heterocyclic versions thereof; these substituent pairs can also be joined into a carbocyclic or heterocyclic ring; preferred versions of these substituents are those mimicking side-chain structures found in naturally-occurring amino acids; X represents an oxygen, sulfur, or nitrogen atom; and A and B are the substituents described above.
- a structural species possessing (1) a terminal -OH, -SH or -NH 2 group capable of ring-opening addition to the oxazolone and (2) another terminal group capable of reacting with the amino group of a chiral ⁇ , ⁇ '-disubstituted amino acid, may be inserted in the polymer backbone as shown below:
- This process may be repeated, if desired, at each step in the synthesis where an oxazolone ring is produced.
- the bifunctional species used may be the same or different in the steps of the synthesis.
- a chiral oxazolone derivative containing a blocked terminal amino group may be prepared from a blocked, disubstituted dipeptide, that was
- B is an appropriate protecting group, such as Boc (t-butoxycarbonyl) or Fmoc (fluorenylmethoxycarbonyl).
- Boc t-butoxycarbonyl
- Fmoc fluorenylmethoxycarbonyl
- acylation is followed by deblocking, using standard amine deprotection techniques compatible with the overall structure of the amide (i.e., the amine protecting group is orthogonal with respect to any other protecting or functional groups that may be present in the molecule), and the resulting amino group is used for reaction with a new bifunctional oxazolone generating a growing chiral polymeric structure, as shown below:
- Y is a linker (preferably a functionalized alkyl group);
- X is a nitrogen of suitable structure; an oxygen or a sulfur atom; each member of the substituent pairs R 1 and R 2 , R 3 and R 4 , R n-1 and R n differs from the other and taken alone each signifies alkyl, cycloalkyl, or functionalized versions thereof; aryl, aralkyl or alkaryl or functionalized including
- substituent R can also be part of a
- A is a substituent as described above; and C is a substituent selected from the set of structures for A; and B, is a blocking or
- a preliminary step may be carried out with a suitable amino acid derivative as shown below, prepared via standard synthesis.
- the addition reaction may be combined with a ring-opening acylation to produce chiral polymeric sequences. This is shown for the case of alkenyl azlactones below.
- A denotes a structure of the form described above and HNu 1 -Z-Nu 2 H represents a structure containing two differentially reactive
- nucleophilic groups such as methylamino-ethylamine, 1-amino propane-3-thiol, and so on; groups Nu 1 , Nu 2 , Nu 3 and Nu 4 need not be identical and Z is a linker structure as described above.
- Structure HNu 1 -Z-Nu 2 H may contain two nucleophilic groups of differential reactivity, as stated above, or if Nu 1 and Nu 2 are of comparable reactivity one of the nucleophilic groups is protected to prevent it from competing with the other and deprotected selectively following acylation; protecting groups commonly used in the art of peptide synthesis (e.g., for the nucleophilic groups such as amino, hydroxyl, thio, etc.) are useful in the protection of one of the Nu substituents of the structure HNu 1 -Z-Nu 2 H.
- oligomers are highly useful biochemically because of their structural similarity to polypeptides.
- the substituents R can be chosen to tailor the steric, charge or hydrophobicity characteristics of the oligomer such that a versatile polypeptide mimetic results.
- nucleophilic ring-opening of asymmetrically disubstituted oxazolones may be utilized to introduce a chiral residue or sequence in selected positions in peptides or proteins to produce hybrid molecules with improved hydrolytic stability or other properties.
- the oxazolone used in the above aminolysis may contain a blocked amino terminus which, after the
- polypeptide synthesis may be continued, if desired, using standard peptide-synthesis techniques.
- the structure below illustrates a short polymer containing nine subunits prepared as above and detached from the solid phase synthesis support.
- each of the R groups signifies alkyl, cycloalkyl, or substituted version thereof; aryl, aralkyl, alkaryl, or substituted including heterocyclic versions thereof; the R groups can also define a carbocyclic or heterocyclic ring; preferred structures for the R groups are those mimicking the structures of the side-chains of naturally-occurring amino acids.
- disubstituted chiral azlactones may be utilized to introduce a variety of novel,
- each of the R groups signifies alkyl, cycloalkyl, aryl, aralkyl or alkaryl, or
- R groups may also define a carbocyclic or
- heterocyclic ring preferably the R groups are structural mimetics of the side-chains of naturally-occurring amino acids.
- oxazolone peptide produced in step (b) above may be reacted with a variety of bifunctional nucleophilic molecules to give acylation products as shown below:
- the above acylation product may be coupled with a peptide to produce novel chiral hybrids; two coupling routes may be used.
- A is a group which can be condensed with an amino group, the condensation reaction is used for coupling. For example, if A is a carboxyl group, condensation with a peptide amine using DCC or similar reagent produces the desired product. Reaction
- A is a suitable nucleophilic group (e.g., hydroxyl, amino, thio, etc.) it may be used to open a peptide oxazolone containing a protected amino terminus.
- residues may be attached to or inserted into peptide chains using oxazolones with reactive groups attached at the 2-position of the ring. This may be accomplished in either of two ways, as illustrated below for the case of 2-alkenyl azlactones.
- oxazolone molecular building blocks may be utilized to construct new macromolecular structures capable of recognizing specific molecules ("intelligent macromolecules").
- R is a structure capable of molecular
- L is a linker
- P is a macromolecular structure serving as a supporting platform
- C is a polymeric structure serving as a coating which surrounds P.
- Structure R may be a native ligand of a
- Linker L may be a chemical bond or one of the linker structures listed above, or a sequence of subunits such as amino acids, aminimide monomers, oxazolonederived chains of atoms or the like.
- Polymeric coating C may be attached to the supporting platform either via covalent bonds or "shrink wrapping," i.e., the bonding that results when a surface is subjected to coating polymerization well known to those skilled in the art.
- This coating element may be 1) a thin crosslinked polymeric film 10 - 50 A in
- the support platform is a microporous particle or a membrane, as described below, the controlled microporosity gel may be engineered to completely fill the porous structure of the support platform.
- the polymeric coatings may be constructed in a controlled way by carefully controlling a variety of reaction parameters, such as the nature and degree of coating crosslinking, polymerization initiator, solvent, concentration of reactants, and other reaction
- the support platform P may be a pellicular material having a diameter (dp) from 100 A to 1000 ⁇ , a latex particle (dp 0.1 - 0.2 ⁇ ) , a microporous bead
- polymeric materials such as silica, polystyrene, polyacrylates, polysulfones,
- the multisubunit recognition agents above are expected to be very useful in the development of targeted therapeutics, drug delivery systems, adjuvants,
- the azlactone ring-opening addition reaction discussed above may be used to directly produce a wide variety of chiral vinyl monomers. These may be polymerized or
- copolymerized to produce chiral oligomers or polymers may be further crosslinked to produce chiral beads, membranes, gels, coatings or composites of these
- Other useful monomers which may be used to produce chiral crosslinkable polymers, may be produced by nucleophilic opening of a chiral 2-vinyl oxazolone with a suitable amino alkene or other unsaturated nucleophile.
- Vinyl polymerization and polymer-crosslinking techniques are well-known in the art (see, e.g., U.S. Patent No. 4,981,933) and are applicable to the above preferred processes.
- the bead-staining technique of Lam may be used.
- the technique involves tagging the ligand-candidate acceptor, e . g. , an enzyme or cellular receptor of interest, with an enzyme (e . g. , alkaline phosphatase) whose activity can give rise to color prodution thus staining library support particles which contain active ligands-candidates and leaving support particles containing inactive ligand-candidates colorless. Stained support particles are physically removed from the library (e . g.
- combinatorial library is the encoded combinatorial library, which involves the synthesis of a unique chemical code (e.g., an oligonucleotide or peptide), that is readily
- decipherable e.g., by sequencing using traditional analytical methods
- the structure of the code is fully descriptive of the structure of the ligand and used to structurally characterize biologically active ligands whose structures are difficult or impossible to elucidate using traditional analytical
- such particle contains a single ligand-canditate type.
- This library can be constructed and screened for
- a suitable solid phase synthesis support e .g. , the chloromethyl resin of Merrifield, is split into three equal portions.
- R 1 ,R 2 H, CH 3 , CH 2 CH 3 , (CH 3 ) 2 CH
- acyl amino acid resin is treated with ethyl chloroformate as described above producing the oxazolone resin.
- the amide product is deprotected as described above, for each of the resin portions and cyclized to the oxazolone using the reaction with ethyl chloroformate.
- Each of the resin portions is coupled to a different glycine, containing a carboxyl protected as the t-butyl ester, and the product is deprotected using TFA as described above; the resin portions are mixed producing a library containing 27 types of resin beads, each type containing a single oxazolone- derived tripeptide analog linked to the support via a succinoyl linker; this linker may be severed using acidolysis to produce a "solution-phase" library of peptides whose N-terminus is succinoylated.
- polysaccharide structural motifs incorporating oxazolone-derived structures are contemplated including but not limited to the following.
- carbohydrate chemistry describes numerous sugars of variety of sizes with selectively blocked functional groups, which allows for selective reactions with
- unblocked can be used selectively as described above to derivatize a desired oxazolone structure.
- a suitable oxazolone can also be ring-opened by a sugar containing reactive amino substituents, i.e., an aminosaccharide or polyaminosaccharide.
- reaction with muramic acid is expected to proceed as follows.
- oxazolone to produce an alkene oxazolone; this can then be ring-opened, by e .g. , the anomeric hydroxyl of a sugar to give a novel saccharide after deprotection.
- oxazolone-derived structures are contemplated including, but not limited to, the following. (1) For the synthesis of oligonucleotides containing peptidic oxazolone-derived linkers in place of the phosphate diester groupings found in native
- oligonucleotides the following approach is one of many that is expected to be useful.
- the (S)-isomer of p-hydroxyphenylglycine is an effective therapeutic agent for promoting the oxidation of carbohydrates when this process is depressed by high fatty acid utilization levels (such as occurs in ischemic heart disease), and is also an important chiral intermediate in the production of penicillin, amoxicillin and several other
- enantiomers to be characterized in methanol and the temperature of the mixture kept between 10 and 20°C with ice cooling. The reaction was allowed to proceed at room temperature for 1 hour. The methanol was then removed at room temperature under aspirator vacuum (10 torr) on a rotary evaporator and a solid was obtained. This solid was dissolved in 10 ml of deionized water and the pH adjusted to 9.2 with 0.88 M ammonium hydroxide. The solution was then stirred for 1 hour at 10°C and the precipitated solid ester mixture was filtered off, washed with deionized water and dried at 45°C under vacuum to give 0.41 g of product (94%).
- enantiomeric amide conjugates were then quantitated using a calibration curve generated with a series of synthetic mixtures containing varying ratios of the two pure enantiomers.
- the pure L-isomer was purchased from
- the pure D-isomer was prepared from the commercially available D,L-racemate obtained from MTM Research Chemicals/Lancaster Synthesis Inc. by the method of Clark, Phillips and Steer (J. Chem. Soc.. Perkins Trans. I at 475 [1976]).
- the silica was then washed twice with 50 ml toluene, sucked dry, reslurried in 250 ml toluene, refiltered, reslurried in 250 ml methanol and refiltered a total of three times.
- the resulting methanol wet cake was dried in a vacuum oven set for 30" at 60°C to yield 196.4 g aminopropyl silica.
- the mixture was then cooled, the silica collected on a Buechner filter and washed with 100 ml benzene.
- the wet cake was reslurried in 100 ml methanol and refiltered a total of four times.
- the product was dried in a vacuum oven set for 30" and 60°C to give 9.72 g functionalized silica.
- the bonded phase was packed into a 25 cm ⁇ 0.46 cm stainless-steel HPLC column from methanol and successfully used to separate a series of ⁇ -acceptor amine derivatives using standard conditions described in the Chromatography Catalog distributed by Regis Chemical, Morton Grove, 111. 60053 (e.g., the 3,5-dinitro benzoyl derivatives of racemic 2- amino-1-butanol + alpha methyl benzye amine).
- Buechner filter washed with 50 ml benzene, sucked dry, reslurried in 100 ml of methanol and refiltered a total of four time.
- the resulting methanol wet cake was dried in a vacuum oven set for 30" at 60°C to yield 19.45 g oxazolone-functionalized silica.
- NMR 9CDC1) chemical shifts
- CH 2 CH - splitting pattern in 6 ppm region + integration ratios diagnostic for structure.
- FTIR + (mull) strong azlactone CO band in
- thermometer and a vertical condenser set up with a Dean- Stark trap through a claisen adaptor The slurry was stirred, heated to a bath temperature of 140°C and the water was azeotropically removed by distillation and collected in the Dean-Stark trap. The loss in toluene volume was measured and compensated for by the addition of incremental dry toluene. 110.0 g of 3-mercaptopropyltrimethoxysilane was added carefully through a funnel and the mixture was stirred and refluxed for 3 hours with the bath temperature set at 140oC. The reaction mixture was then cooled to about 40°C. The resulting functionalized silica was collected on a
- Buechner filter washed twice with 50 ml toluene, sucked dry, reslurried in 250 ml toluene, refiltered, reslurried in 250 ml methanol and refiltered a total of three times.
- the resulting methanol wet cake was dried in a vacuum oven set for 30" at 60oC to yield 196.4 g of
- Chiral azlactone conjugates may similarly be produced using a variety of azlactone derivatives
- This example teaches the synthesis of a
- N-trifluoroacetyl-(S)-2-methylleucyl-(S)-2-methylphenylalanine lithium salt is slurried in 50 ml of an appropriate solvent, such as dry benzene, in a three-necked round-bottomed flask equipped with a stirrer, heating bath, claisen head, downward condenser, thermometer and dropping funnel.
- an appropriate solvent such as dry benzene
- FTIR (mull) Strong azlactone CO band in 1820 cm -1 region. N-trifluoracetyl-(S)-2-methylleucyl-(S)-2-methylphenylalanine.
- This mimetic is useful as a competitive inhibitor for proteases inhibited by pepstatin.
- the Boc-protected lithium salt prepared as described below simultaneously converted to the acid form and deprotected by treatment with acid under standard deprotection conditions.
- 5.17 g (0.01 mol) of N-isovaleryl-(S)-2-methy derivative added to 100 ml dry acetonitrile, stirred at room temperature and 3.17 g (0.01 mol) of the valyl-(S)-4-methyl-4-isopropyl-5-oxazolone was added with cooling. Once addition was complete, the mixture was heated to reflux and held at reflux for 1 hour.
- Boc-protected (3S,4S)-statine, [(3S,4S)-4-amino-3-hydroxy-6- methylheptanoic acid] was produced from the commercially available amino acid, coupled with 2-methylalanine using standard peptide synthesis methods and converted to the lithium salt using the method described below. 18.30 g (0.05 mol) of this derivative was stirred in 150 ml dry acetonitrile at room
- 2-(S)-methylvaline was prepared from (S)-valine by the method described by Kolbe and Barth .Liebigs Ann. Chem. at 1668 (1983)), and was acylated with isovaleryl chloride using standard acylation methods to produce N-isovaleryl-(S)-methylvaline, this was subsequently treated with one equivalent of LiOH in ethanol, followed by removal of the solvent in vacuo to yield the N-isovaleryl-(S)-methylvaline lithium salt. 22.3 g (0.1 mol) of this Li salt was stirred in 150 ml of dry
- This example teaches the synthesis of a competitive inhibitor for the HIV protease, based on the insertion of a chiral azlactone residue into a
- This example teaches the synthesis of another competitive inhibitor for the HIV protease.
- the phenyl substituent is replaced with a uracil
- the DMF is then removed under high vacuum and the
- A. 74.08 g (1 mol) of N-methyl urea and 216.2 g (1 mol) of diethylethoxymethylenemalonate are heated together at 122 oC for 24 hours, followed by 170°C for 12 hours to yield the 3-methyluracil-5-carboxylic acid ethyl ester in 35% yield, following recrystallization from ethyl acetate.
- 3-methyluracil-5-carboxylic acid was treated with HCL and CH 2 O using standard chloromethylation conditions to yield 3-methyl-5-chloromethyluracil in 52% yield, following standard work-up and recrystallization from ethyl acetate.
- norcodeine (I) dissolved in 50 ml of the appropriate solvent, such as benzene, is added a solution of 0.139 g (0.001 mol) of 4,4'-dimethylvinylazlactone (II) in 10 ml of the same solvent.
- the resulting solution is heated to 70 °C and held at this temperature for 10 hours. At the end of this time the solvent is removed under vacuum to yield 0.42 g of the Michael adduct (III).
- Cibacron Blue F3 GA 40.0 g (0.05 mol) of Cibacron Blue F3 GA is dissolved in 1 liter of DMF at 40 °C with stirring. To this solution is added 26.5 g (0.23 mol) of hexamethylene diamine with stirring, followed by 4.0 g (0.05 mol) of pyridine. The reaction mixture is allowed to stir
- functionality is a photographic developer, capable of photographic amplification by means of standard
- FTIR (mull) azlactone CO band at 1820 cm' 1 absent.
- This example describes preparation of an affinity coating from compound (III) as prepared in the previous example.
- the coated silica was then collected by filtration and washed three times in 50 ml methanol, and air dried. Finally, the silica was heated at 120 for two hours to cure the coating and yield 5.4 g of coated silica.
- the silica contained the following attached groups:
- a one-cm glass column was packed with the
- Protein-A functionalized material and loaded with human IgG from PBS buffer (pH - 7.4) at a flow rate of 1.6 ml/min.
- the IgG was then collected and the amount measured spectrophotometrically using standard calibration curves.
- the measured capacity of the packing was 12 mg IgG per ml of column volume.
- the azlactone-functional support is slurried in a suitable solvent, such as CHCl 3 , and cooled to 0 oC.
- a suitable solvent such as CHCl 3
- the mixture is then shaken at 0 °C for 6 hours, allowed to come to room temperature, and shaken at room temperature overnight.
- the support is collected by filtration, washed with fresh solvent, re-slurried in an appropriate solvent and one equivalent of vinylazlactone, dissolved in the same solvent, is added thereto.
- the mixture is then shaken, heated to 70 °C and held at this temperature for 12 hours. At the end of this time, the mixture is cooled and the support
- the functional beads prepared as above are suspended in pH 7.5 aqueous phosphate buffer.
- the beads are concentrated by centrifugation, the supernate decanted off and the beads washed five times with pH 7.5 aqueous phosphate buffer. The beads are then loaded into a 0.46 cm inner-diameter glass column and used to purify human IgG from serum using standard affinity-purification techniques.
Abstract
L'invention concerne la conception et la synthèse de nouveaux modules moléculaires dérivés d'oxazolone, ainsi que l'utilisation des modules dans l'élaboration de nouvelles molécules et de nouvelles matières fabriquées. Les nouvelles molécules et les nouvelles matières fabriquées constituent des agents de reconnaissance moléculaires utiles dans la conception et la synthèse de médicaments, et elles présentent des applications dans les sciences de séparation et des matières.
Priority Applications (5)
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KR1019940704824A KR950702216A (ko) | 1992-06-30 | 1993-06-30 | 옥사졸론 유도물질(oxazlone derived materials) |
JP6502661A JPH08500576A (ja) | 1992-06-30 | 1993-06-30 | オキサゾロンから誘導される物質 |
BR9306656A BR9306656A (pt) | 1992-06-30 | 1993-06-30 | Composição mimético de peptídeo de núcleotídeo e de carboidrato composto substrato e processo para sintetizar um composto |
AU46591/93A AU678168B2 (en) | 1992-06-30 | 1993-06-30 | Oxazolone derived materials |
EP93916883A EP0649443A4 (fr) | 1992-06-30 | 1993-06-30 | Matieres derivees d'oxazolone. |
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US041,562 | 1987-04-23 | ||
US90675692A | 1992-06-30 | 1992-06-30 | |
US906,756 | 1992-06-30 | ||
US4156293A | 1993-04-02 | 1993-04-02 |
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JP (1) | JPH08500576A (fr) |
KR (1) | KR950702216A (fr) |
AU (1) | AU678168B2 (fr) |
BR (1) | BR9306656A (fr) |
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JPH09507852A (ja) * | 1994-01-05 | 1997-08-12 | アーキュール,インコーポレーテッド | 特定の性質を有するポリマーの製造方法 |
DE19714343A1 (de) * | 1997-04-08 | 1998-10-15 | Bayer Ag | Chromatographische Enantiomerentrennung von Lactonen |
GB9812675D0 (en) * | 1998-06-11 | 1998-08-12 | Univ Edinburgh | Peptides |
WO2000064845A1 (fr) * | 1999-04-22 | 2000-11-02 | Sankyo Company, Limited | Cetoamides porteurs de resine et leur procede de preparation |
EP2113510A1 (fr) | 2008-04-30 | 2009-11-04 | Freie Universität Berlin | Dérivés de pepstatine A |
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US4125519A (en) * | 1976-10-13 | 1978-11-14 | Murray Goodman | Polypeptides containing 3,4-dihydroxyphenylalanine |
DE2819277A1 (de) * | 1977-05-16 | 1978-11-23 | Sandoz Ag | Neue polypeptidderivate, ihre herstellung und verwendung |
DE2834607A1 (de) * | 1978-08-07 | 1980-02-28 | Basf Ag | Verfahren zur herstellung von indoleninen |
US4485236A (en) * | 1982-09-27 | 1984-11-27 | Minnesota Mining And Manufacturing Company | Azlactone-functional compounds |
JPS60215657A (ja) * | 1984-04-10 | 1985-10-29 | Mitsui Toatsu Chem Inc | N−アシルフエニルアラニン類の製造法 |
US4910277A (en) * | 1988-02-09 | 1990-03-20 | Bambury Ronald E | Hydrophilic oxygen permeable polymers |
US4996292A (en) * | 1989-06-30 | 1991-02-26 | Fox Sidney W | Self-sealing artificial skin comprising copoly-alpha-amino acid |
US5157108A (en) * | 1989-12-12 | 1992-10-20 | Minnesota Mining And Manufacturing Company | Thermally sensitive linkages |
US5149806A (en) * | 1990-03-28 | 1992-09-22 | Minnesota Mining And Manufacturing Company | Azlactone michael adducts |
US5039813A (en) * | 1990-06-29 | 1991-08-13 | Polaroid Corporation | 2-(4-alkenylphenyl)-5-oxazolones and polymers thereof |
JP3190431B2 (ja) * | 1991-07-01 | 2001-07-23 | 三菱化学株式会社 | ケトン誘導体 |
US5219731A (en) * | 1991-11-01 | 1993-06-15 | Wisconsin Alumni Research Foundation | Method for preparing optically-active amino acid derivatives |
-
1993
- 1993-06-30 BR BR9306656A patent/BR9306656A/pt not_active Application Discontinuation
- 1993-06-30 AU AU46591/93A patent/AU678168B2/en not_active Ceased
- 1993-06-30 JP JP6502661A patent/JPH08500576A/ja active Pending
- 1993-06-30 KR KR1019940704824A patent/KR950702216A/ko not_active Application Discontinuation
- 1993-06-30 CA CA002139350A patent/CA2139350A1/fr not_active Abandoned
- 1993-06-30 EP EP93916883A patent/EP0649443A4/fr not_active Ceased
- 1993-06-30 WO PCT/US1993/006240 patent/WO1994000509A1/fr not_active Application Discontinuation
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