WO1999031507A1 - Banques combinatoires sur la base de matrices peptidomimetiques - Google Patents

Banques combinatoires sur la base de matrices peptidomimetiques Download PDF

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Publication number
WO1999031507A1
WO1999031507A1 PCT/US1998/026387 US9826387W WO9931507A1 WO 1999031507 A1 WO1999031507 A1 WO 1999031507A1 US 9826387 W US9826387 W US 9826387W WO 9931507 A1 WO9931507 A1 WO 9931507A1
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Prior art keywords
alkyl
hydrogen
cycloalkyl
amino acid
membered heterocyclic
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PCT/US1998/026387
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English (en)
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Cynthia Lynn Cwi
William Leonard Scott
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Eli Lilly And Company
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Priority to AU19102/99A priority Critical patent/AU1910299A/en
Publication of WO1999031507A1 publication Critical patent/WO1999031507A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids

Definitions

  • This invention provides a rapid approach for combinatorial synthesis and screening of libraries of mono-, bi- and tricyclic lactam derivatives.
  • the invention also provides a novel resin bound intermediate useful for creating these libraries.
  • Peptides and proteins are known to have bioactivity, functioning as enzymes, drugs, etc.
  • the functional properties of proteins depends upon their three-dimensional structures.
  • the three-dimensional structure arises because particular sequences of amino acids in polypeptide chains fold to generate, from linear chains, compact domains with specific structure.
  • the functional site of the protein is a subsection, or active site, within this larger structure.
  • subsections of these peptides which contain the active site.
  • these subsections are not usually functional equivalents of the larger protein or peptide.
  • the lower energy forms of the isolated subsection do not readily adopt the native conformation of the protein or peptide and thus do not present the active site in a conformation which allows for strong interactions with the target biomolecule
  • the active site in the protein or peptide is formed by non-contiguous amino acids (i.e., the binding unit consists of multiple isolated subsections) and thus cannot not be reproduced in a subsection
  • the subsection is not bioavailable, typically because as a smaller molecule it is more susceptible to degradation than the native protein.
  • U.S. 5,545,568 describes the combinatorial synthesis of benzodiazepines, prostaglandins, ⁇ -turn mimics and a variety of other organic compounds.
  • the resulting libraries of compounds produce by this approach are useful for screening for therapeutically useful compounds.
  • U.S. 5,549,974 teaches combinatorial synthetic methods for the solid phase synthesis of thiazolidinones, metathiazanones, and derivatives thereof.
  • the libraries of compounds produced using these techniques can be screened for therapeutically useful compounds for the treatment of inflammation, hypertension, renal failure, congestive heart failure, uremia and other conditions.
  • the success of the combinatorial chemistry approach is demonstrated by the ever increasing number of combinatorial libraries of derivatives of therapeutically useful compounds.
  • Lactams are therapeutically useful as angiotensin converting enzyme inhibitors.
  • U.S. 4,666,901 describes solution phase synthesis of lactams of the following formula.
  • lactams are useful as angiotensin converting enzyme inhibitors.
  • the available methods for synthesizing these compounds are relatively laborious.
  • methods for synthesizing a combinatorial library for this class of compounds are desirable.
  • one object of this invention is to provide a combinatorial method for the synthesis of mono-, bi- or tricyclic lactams. Such compounds are known angiotension converting enzyme inhibitors and as antihypertensive agents.
  • a second object of the present invention is to provide resin bound amino acid intermediates useful in the above combinatorial method.
  • a third object of the present invention is to provide a method for screening mono-, bi- and tricyclic lactams for biological activity.
  • FIG. 1 illustrates the synthesis of compounds of the formula 4.
  • Figure 2 illustrates the synthesis of compounds of the formula 3.
  • Figure 3 illustrates the synthesis of intermediate 2 from glycine.
  • Figure 4 illustrates the synthesis of intermediate 2 from a natural amino acid.
  • the present invention provides a method of synthesizing libraries of monocyclic lactam derivatives of the formula (3):
  • n 1 , 2, 3, or 4;
  • R 1 is hydrogen or C ⁇ o alkyl
  • R 2 is (i) selected from the group consisting of hydrogen, C M alkyl, C 3 -i 2 cycloalkyl, carbonyl, C 5 -i 2 aryl, and 5-10 membered heterocyclic group containing at least one N, S or O; (ii) an amino acid residue; or (iii) an N-protected peptide with 2-8 amino acid residues;
  • R 3 is (i) selected from the group consisting of hydrogen, C M O alkyl, C 2 - ⁇ 0 alkenyl, C 2 . ⁇ 0 alkynyl, C3-12 cycloalkyl, Cs- ⁇ aryl, and 5-10 membered heterocyclic group containing at least one N, S or O; or (ii) together with the N which it substitutes may comprise an amino acid residue or C- protected peptide containing 2 to 8 amino acid residues;
  • R 4 is hydrogen or d-10 alkyl;
  • R 5 and R 6 are each independently hydrogen, C1-10 alkyl, C3-10 cycloalkyl, halogen, hydroxy, oxo, thiol, sulfinyl, sulfonyl, amino, thiol, carbonyl, C 5 -i2aryl, 5-10 membered heterocyclic group containing at least one N, S or O; and when m is >1 , each R 5 may be different and each
  • each of R 2 , R 3 , R 4 , R 5 , R 6 and R 7 may be substituted one to three times with a substituent selected from the group consisting of C ⁇ . 10 alkyl, C3-10 cycloalkyl, halogen, hydroxy, oxo, thiol, sulfinyl, sulfonyl, C5- 12 aryl, 5-10 membered heterocyclic group containing at least one N, S or O, amino, nitro, cyano, amidino, carbonyl , and wherein said substituents may themselves be further substituted with one to three further substituents.
  • the present invention also provides a method of synthesizing libraries of bicyclic lactam derivatives of the formula (4):
  • m and n are each independently 1 , 2, 3 or 4;
  • X is O, S, NH or CR 7 R 8 ;
  • R 1 is hydrogen or C MO alkyl;
  • R 2 is (i) selected from the group consisting of hydrogen, C MO alkyl, C 3 - 12 cycloalkyl, carbonyl, C 5 -i 2 aryl, and 5-10 membered heterocyclic group containing at least one N, S or O; (ii) an amino acid residue; or (iii) an N-protected peptide with 2-8 amino acid residues;
  • R 3 is (i) selected from the group consisting of hydrogen, C MO alkyl,
  • R 5 , R 6 , R 9 and R 10 are each independently hydrogen, C MO alkyl, C3- 10 cycloalkyl, halogen, hydroxy, oxo, thiol, sulfinyl, sulfonyl, amino, thiol, carbonyl, Cs- ⁇ aryl, 5-10 membered heterocyclic group containing at least one N, S or O; and when m is >1 , each R 5 may be different and each R 6 may be different; and when n is >1 , each R 9 may be different and each R 10 may be different;
  • R 7 and R 8 are each independently hydrogen or an electron withdrawing substituent selected from the group consisting of hydroxyl, alkoxy, amine, thiol, carboxamido and alkyl;
  • R 11 and R 12 are each independently (i) selected from the group consisting of hydrogen, C MO alkyl, C 2 - ⁇ oalkenyl, C 2 -10 alkynyl, C3-12 cycloalkyl, C 5 -i 2 aryl, and 5-10 membered heterocyclic group containing at least one N, S or O; or (ii) together with the nitrogen and C7 ring carbon comprise an amino acid residue or C-protected peptide containing 2 to 8 amino acid residues; wherein each of R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , R 10 , R 11 and R 12 may be substituted one to three times with a substituent selected from the group consisting of C MO alkyl, C 3 - 1 0 cycloalkyl
  • R2 may be a substitutent such as p-methoxy-phenyl-carbonyl.
  • this substituent comprises a carbonyl that is substituted with phenyl (a Cs-i ⁇ aryl) that is further substituted at the para position with an oxo that is further substituted with methyl (a CM O alkyl).
  • peptide mimics can be formed in which the side chain of an amino acid are either conformationally free or constrained.
  • shown below are two compounds of formula (3), which both mimic serine. The bonds forming the serine residue are bolded.
  • R 4 is -CH 2 OH and is conformationally free.
  • R 5 is -OH and is conformationally restricted. free constrained
  • lactam derivatives may have one or more further rings fused along the methylene rings forming the first ring.
  • a tricyclic lactam within the formula 4 can be formed from the following components:
  • the side chains of the amino acid residues composing the ring include glycine and the amino acid derivative 3,4- dihydroxyphenylalanine. Both amino acid side chains are conformational restrained by the ring system.
  • Alkyl as used herein is a branched, cyclic or straight chain alkyl group containing 1-10 carbon atoms. Suitable alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, iso-butyl, tert-butyl, sec-butyl, cyclobutyl, pentyl, hexyl, cyclohexyl, etc.
  • Amino acid is a compound that contains an amino group and a carboxylic acid group. Typically, the phrase refers to oc-amino acids, although other amino acids (such as ⁇ - and ⁇ -amino acids) can be used.
  • Natural amino acids include those which are found in nature. Unnatural amino acids include synthetic amino acid residues. Synthetic amino acids can include oc-amino acids containing aryl or heterocyclic groups attached as side chains. Synthetic amino acids also include oc,oc- disubstituted amino acids such aminoisobuty c acid (AIB) and those described by Scott et al, Tetrahedron Lett. 1997, 38(21 ):3695: incorporated herein by reference.
  • AIB aminoisobuty c acid
  • Suitable amino acids include the naturally encoded amino acids such as alanine (Ala, A), arginine (Arg, R), asparagine (Asn, N), aspartic acid (Asp, D), cysteine (Cys, C), glutamine (Gin, Q), glutamic acid (Glu, E), glycine (Gly, G), histidine (His, H), isoleucine (lie, I), leucine (Leu, L), lysine (Lys, K), methionine (Met, M), ornithine (Orn, O), phenylalanine (Phe, F), proline (Pro, P), serine (Ser, S), threonine (Thr, T), tryptophan (Trp, W), tyrosine (Tyr, Y), and valine (Val, V).
  • any side chain of a synthetic amino acid can be used, including lower alkyl, alkyloxy, alkylamino, alkyl
  • Aryl groups include any monovalent aromatic carbocyclic group of 5-10 carbon atoms in a single ring (i.e. phenyl) or multiple condensed rings (i.e. naphthyl).
  • Combinatorial chemistry is an ordered strategy for parallel synthesis of diverse polymer sequences by sequential addition of monomers.
  • Electron donating groups are those can stabilize an adjacent electron deficiency. Suitable electron donating substituents include hydroxyl, alkoxy, amine, thiol, alkylamine, dialkylamine, amido, alkyl.
  • Halogen is fluorine, chlorine, iodine or bromine.
  • the preferred halogen is fluorine or chlorine.
  • Heterocyclic groups include any monovalent unsaturated or saturated ring system having 3 to 7 carbon atoms in a single ring (i.e. pyridyl or furyl) or multiple fused rings (i.e. quinolinyl or indolzinyl) and having at least one heteroatom, such as N, O or S, within the ring.
  • the group is a five- or six-membered ring.
  • Linkers are any molecule that provides spatial distance between the support and the peptide to be synthesized. Linkers can be covalently attached on the solid phase support prior to coupling with a N ⁇ -Boc or N ⁇ c-Fmoc or otherwise appropriately protected amino acids. Examples of linkers include aminobutyric acid, aminocaproic acid, 7-aminoheptanoic acid, and 8-aminocaprylic acid. In a further embodiment, linkers can additionally comprise ⁇ -alanine or polymeric ⁇ -alanine.
  • “Monomer” is a molecule which is not substantially comprised of repeating molecular subunits.
  • Polymer is a molecule which is composed of monomer units.
  • polymer refers to the polymer resin to which the compounds in the combinatorial library are attached.
  • a linker is first attached to the polymer resin such that the compound of the combinatorial library is linked to the polymer resin via the linker.
  • Suitable polymer resins for use in the present invention must be inert to the reaction conditions for peptide synthesis and include Merrifield type resins, Wang type resins and polyamide type resins.
  • polystyrene e.g., PAM-resin obtained from Bachem Inc.
  • polyamide resin polyamide resin
  • POLYHIPETM resin obtained from Aminotech, Canada
  • p-alkoxybenzyl alcohol resin polystyrene resin grafted with polyethylene glycol or polydimethylacrylamide resin.
  • polystyrene resin is used.
  • a “protecting group” is a material which is chemically bound to a monomer unit and which may be removed upon selective exposure to an activator such as a selected chemical activator such as an acidic or basic environment, or to another selected activator such as electromagnetic radiation, including light.
  • Protecting groups are used to prevent the reactive functional groups (hydroxy, amino, thiol, carboxy, guanidino, etc.) in amino acid monomers from undergoing side reactions during the coupling reactions.
  • N-protecting groups are groups which are designed to protect amino groups.
  • N-protecting groups include carbobenzoyl (Cbz), t-butoxycarbonyl (Boc), fluorenylmethyloxycarbonyl (FMOC), nitropiperonyl, pyrenylethoxycarbonyl, nitroveratryl (NV), nitrobenzyl, etc. These and other protecting groups are discussed in “Solid Phase Peptide Synthesis,” J.M. Sheppard & J.D. Young, 2 nd ed., 1984, Pierce Chemical Co., Illinois.
  • solvents useful in the present invention include both aqueous and organic solvents and mixtures thereof.
  • Suitable organic solvents include halogenated hydrocarbons (chloroform, methylene chloride, carbon tetrachloride), acetonitrile, ether, toluene, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, xylene and benzene.
  • lactams of the present invention can be synthesized from the common intermediate 2:
  • a preferred intermediate 2 has the structure:
  • intermediate 2 can be synthesized as illustrated in Fig. 4.
  • Polymer bound amino acids are commercially available or can be attached to a solid support using conventional methods.
  • the polymer bound amino acid is activated, for example, as an imine with a benzaldehyde derivative (step n in Fig. 4).
  • This intermediate is then reacted with a haloallyl (such as bromoallyl) (step o in Fig. 4). Thereafter the activating group is removed, in the case of an imine with acid (step p in Fig. 4).
  • the N-terminus is then substituted with an appropriate R 3 group (step q in Fig. 4).
  • this resin bound allylic peptide derivative can be directly ozonolyzed to intermediate 2, for example with O 3 in dimethyl sulfoxide (step r in Fig. 4).
  • intermediate 2 can be synthesized as illustrated in Fig. 3. Briefly, the methodology involves activation, deprotonation/alkylation, deprotonation/alkylation and hydrolysis. A resin bound glycine is activated as an benzophenone imine ester.
  • the oc-carbon of the glycine is deprotonated with base, such as the organic-soluble, non- ionic iminophosphorane base, 2-[(1 ,1-dimethylethyl)imino]-N,N-diethyl- 2,2,3,4,5,6-hexahydro-1 ,3-dimethyl-1 ,3,2-diazaphosphorin-2(1 H)-amine (BEMP) and alkylated with an allyl halide.
  • base such as the organic-soluble, non- ionic iminophosphorane base, 2-[(1 ,1-dimethylethyl)imino]-N,N-diethyl- 2,2,3,4,5,6-hexahydro-1 ,3-dimethyl-1 ,3,2-diazaphosphorin-2(1 H)-amine (BEMP) and alkylated with an allyl halide.
  • base such as the organic-soluble, non- ionic imino
  • the second substituent can then be added in either of two ways.
  • the second substituent can be directly added by deprotonating the oc-carbon with a stronger base such as potassium hexamethyldisilazide (KHMDS) (see Griffith et al.,
  • the activating group can be exchanged by replacing the imine activating group with a benzaldehyde derivative. Thereafter a base such as BEMP can be used to deprotonated the ⁇ - carbon, which can then be reacted with an alkyl halide.
  • intermediate 2 can be formed from a unbound amine derivative containing an allyl group by binding the amino acid to a solid support and ozonolyzing, as shown below.
  • the aldehydic group of the resin-bound intermediate 2 is coupled to an amine compound of the formula:
  • H 2 NR is a primary amine
  • H 2 NR can be an amino acid
  • step e Following reduction of the imine (for example, using sodium borohydride; step f), the compound undergoes intramolecular cyclization to a lactam structure with concomitant cleavage from the polymer resin (step g).
  • the final step is performed at elevated temperature (20-80°C).
  • (+/-)-exo-2-aminonorbomane (s)-(+)-2-(aminomethyl)pyrrolidine 3-amino-1 -propanol vinyl ether geranylamine 4-(hexadecylamino)benzylamine (1 r,2r,3r,5s)-(-)- isopinocampheylamine
  • Additional primary amines suitable for the process of the invention include, but are not intended to be limited to, those represented by the following formulae:
  • the resin bound intermediate is coupled to an amine containing compound (step a), forming a monocyclic intermediate.
  • the coupling results in cleavage from the resin as the modified peptidyl unit attached to the resin cyclizes into a bicyclic lactam ring.
  • the coupling is typically performed under acidic conditions (i.e., 1-10% aq. acetic acid) at elevated temperatures (for example, >25°C, preferably from 40 to 80°C).
  • R 1 is hydrogen or phenyl
  • R 2 is hydrogen or an amino acid side chain
  • m is 0-3
  • n is 1-3
  • X is CH 2 or S.
  • Another library of compounds which is accessible using the present methodology is based around the template -X- Cys-, where X is any amino acid. This library could provide leads to inhibitors of influenza polymerase.
  • libraries of the present invention can be modified as shown below:
  • R 2 is an amino acid side chain
  • R 8 is a fatty acid
  • R 9 is hydrogen, alkylcarbonyl (such as acetyl or benzoyl), aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl (the latter three yielding urea derivatives)
  • R 10 is an amino, aminoalkyl or aminodialkyl
  • m is an integer from 1 to 4.
  • Preferred libraries of lactam derivatives according to the present invention have the formulae:
  • R 1 is an amino acid side chain
  • R 3 and R 4 are each, independently, hydrogen, alkyl, alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl
  • R s is hydrogen, alkyl or halogen
  • R 6 is hydroxy, alkoxy, amine, alkylamine, or dialkylamine.
  • the process of the invention may be carried out in any vessel which can hold the resin bound intermediate and which allows for introduction of unbound amine in solution and removal of the lactam product in solution.
  • the library can be assembled by running each reaction sequentially, but is preferably run in parallel.
  • the process of the invention is preferably carried out in containers adaptable to parallel array syntheses.
  • individual reaction products are prepared in physically separated multiple reaction zones.
  • the reaction zone contains at least one type of resin bound intermediate 2 and at least one type of unbound amine.
  • Suitable reaction zones include vessels such as wellplates or supports made from silicone or agar. Resin bound intermediate 2 is either directly attached, absorbed or incorporated into the surface of the vessel or support.
  • a preferred embodiment of the present invention is a diverse lactam compound library in the form of a plurality of wellplates, each wellplate having wells containing a separate reaction product (library compound).
  • the library compounds are conveniently identified by their wellplate number and "x" column and "y" wellplate row coordinates.
  • the process of making the library of lactam compounds may be conveniently carried out in a conventional wellplate apparatus. It is particularly advantageous to carry out the method of the invention in a standard wellplate apparatus such as a plastic 96 well microtiter plate.
  • the wellplate apparatus is in the form of a rigid or semirigid plate, said plate having a common surface containing openings of a plurality of vessels arranged in rows and columns.
  • a standard form of wellplate apparatus is a rectangular plastic plate having 8 rows and 12 columns (total 96) of liquid retaining depressions on its surface.
  • a wellplate apparatus may optionally have other elements of structure such as a top or cover (e.g., plastic or foil), a bottom in a form such as a plate or reservoir, clamping means to secure the wellplate and prevent loss of its contained compounds.
  • resin bound intermediate 2 the amount of resin bound intermediate 2 introduced into each reaction zone will depend on the desired amount of each library compound that is needed for conducting biological assays, archival storage and other related needs. Typically, the desired amount of individual reaction product is from 1 microgram to 50 milligrams.
  • the amount of resin bound intermediate 2 in each reaction zone is represented by the symbol "(n)", where (n) represents the equivalents of resin bound intermediate 2.
  • the resin bound intermediate 2 is the reactant used in stoichiometric excess.
  • An excess of resin bound intemediate 2 is defined as at least 1.1 (n) and preferably a larger excess in the range of from 1.25(n) to 5(n), where the variable (n) is as previously defined.
  • the 1.1 multiplier is used to ensure at least a 10% stoichiometric excess of resin bound intermediate.
  • An excess of resin bound intermediate is used to avoid the need for further purification. That is, as the reaction proceeds, the formed lactam compound is cleaved from the resin. By using an excess of resin bound intermediate, all of the unbound amine should couple to the resin bound intermediate and thereafter cleave from the resin, avoiding the necessity of further purification.
  • an intermediate has a finite lifetime (i.e., it can be isolated)
  • an excess of amine is used and the intermediate is short lived and the product is not cationic at acid pH, then it is still possible to purify lactam product by passing the reaction mixture through a cation exchange resin such as SCX (available from Varian).
  • the reaction zone is maintained at a temperature and for a time sufficient to permit reaction of the resin bound intermediate and the unbound amine, that is, to complete consumption of the resin bound intermediate and form an amount of lactam compound necessary to conduct biological assays to determine the efficacy of the prepared library compounds.
  • the time, temperature, and pressure of the combinatorial reaction zones used for the creation of library compounds are not critical aspects of the invention. Reaction times for a single step of the reaction are generally from 20 minutes to 24 hours, with times of 30 minutes being most often used.
  • the temperature of the reaction may be any temperature between the freezing point and the boiling point of the liquid reaction medium, but is generally room temperature (25°C).
  • Endpoint determination The completion of the reaction between the resin bound intermediate 2 and the unbound amine results in cleavage of the lactam compound from the resin. Cleavage can determined by a number of conventional techniques. One method is to use thin layer chromatography to determine if the lactam is present in solution.
  • the non-reacted resin bound intermediate is separated from the solution and discarded.
  • the separated solution can then be directly screened or further purified.
  • the library of compounds formed using the process of the invention can be used to screen for compounds with biological activity.
  • a myriad of biological assays are known in the art and can be used to screen the library of compounds.
  • biological assay materials are generally in vitro tests known to be predictive of success for an associated disease state.
  • Illustrative of biological assay materials useful in this invention are those required to conduct assays known in the art, which include, but are not intended to be limited to:
  • Colorimetric Biosensors Ca 2+ -EGTA Dyes for Cell-based assays, Reporter Gene Constructs for cell-based assays
  • Cellular reporter assays utilizing, for example, reporters such as luciferase, green fluorescent protein, ⁇ -lactamase, and the like; Electrical cell impedance sensor assays, and the like.
  • the potassium salt of Boc-Allyl glycine was prepared in the following fashion: To 5.37 g (25mmol) of Boc-Allyl glycine dissolved in a mixture of 30 ml 2B ethanol and 20 ml water was added 24.5 ml (24.5 mmol) of 1 N KOH. The pH was ⁇ 6-7. The solution was concentrated to a syrup on the rotary evaporator then repeated, ly taken up in 50 ml of toluene and solvent again removed. A total of 5x250 ml of toluene was used. The resulting white solid was dried overnight at 40° under vacuum to afford 6.09 g (24 mmol) of the potassium salt as a hygroscopic white solid.
  • the resin was collected by filtration and washed successively with 3, 100 ml portions of DMF; 3, 100 ml portions of 75/25 DMF/water; and 4, 100 ml portions of 2B EtOH. The resin was allowed to settle with each wash before filtration. The resin was dried overnight at 40° in the vacuum oven to afford 22.9 g of functionalized resin. Nitrogen analysis was 1.32% indicating 0.94 meq of substitution/g resin. Oxygen analysis was 5.22% indicating 0.82 meq of substitution/g resin.
  • the resin was re-suspended and allowed to settle after each wash. Resin was briefly ( ⁇ 10 seconds) air dried while vacuum filtered, then transferred to a crystallizing dish and further dried in a vacuum oven at 40° for three hours to yield 15.8 g of deprotected amine.
  • the S-trityl and N-Boc groups were removed immediately prior to use by the following procedure: 407mg (0.72 mmol) of the protected cysteine derivative was weighed into a 100 ml round bottom. To this was added 15 ml of a solution of 95%TFA, 2.5% water and 2.5% triethylsilane. A white precipitate formed almost immediately. After stirring at room temperature for 2 h reagents were removed on the rotary evaporator. The residue was triturated with 30 ml of 1 : 1 diethyl ether: petroleum ether giving a gummy residue lining the flask.
  • reaction vial (and remaining resin) was rinsed successively with 1 ml acetic acid and 1 ml 10% isopropyl alcohol in 90% chloroform and filtered through the same pipette.
  • the solvent was allowed to partially evaporate in the back of the hood overnight, then completely removed in a vacuum oven at 40-

Abstract

L'invention concerne des séries combinatoires de dérivés de lactam s'utilisant pour le criblage de composés utiles sur le plan thérapeutique. L'invention concerne également un nouvel intermédiaire à base d'acide aminé aldéhydique lié par la résine et utile dans la synthèse des séries de la présente invention.
PCT/US1998/026387 1997-12-18 1998-12-11 Banques combinatoires sur la base de matrices peptidomimetiques WO1999031507A1 (fr)

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AU19102/99A AU1910299A (en) 1997-12-18 1998-12-11 Peptidomimetic template-based combinatorial libraries

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US6802597P 1997-12-18 1997-12-18
US60/068,025 1997-12-18

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WO1999031507A1 true WO1999031507A1 (fr) 1999-06-24

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Cited By (17)

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Publication number Priority date Publication date Assignee Title
US7932213B2 (en) 1999-05-11 2011-04-26 President And Fellows Of Harvard College Small molecule printing
WO2001094317A3 (fr) * 2000-06-05 2002-04-11 Ortho Mcneil Pharm Inc Procede de synthese de banques d'azoles substitues
US6683191B2 (en) 2000-06-05 2004-01-27 Ortho-Mcneil Pharmaceuticals, Inc. Method for synthesis of substituted azole libraries
WO2001094317A2 (fr) * 2000-06-05 2001-12-13 Ortho-Mcneil Pharmaceutical, Inc. Procede de synthese de banques d'azoles substitues
US6710058B2 (en) 2000-11-06 2004-03-23 Bristol-Myers Squibb Pharma Company Monocyclic or bicyclic carbocycles and heterocycles as factor Xa inhibitors
US6951872B2 (en) 2000-11-06 2005-10-04 Bristol-Myers Squibb Pharma Company Monocyclic or bicyclic carbocycles and heterocycles as factor Xa inhibitors
US7157470B2 (en) 2002-05-06 2007-01-02 Bristol-Myers Squibb Company Sulfonylaminovalerolactams and derivatives thereof as factor Xa inhibitors
US7524863B2 (en) 2002-05-06 2009-04-28 Bristol-Myers Squibb Company Sulfonylaminovalerolactams and derivatives thereof as factor Xa inhibitors
US7008957B2 (en) 2003-07-25 2006-03-07 Sanofi-Aventis Deutschland Gmbh Bicyclic cyanoheterocycles, process for their preparation and their use as medicaments
JP4711959B2 (ja) * 2003-07-25 2011-06-29 サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング 新規なシアノチアゾリド、その製造方法、及びその薬剤としての使用
US7094800B2 (en) 2003-07-25 2006-08-22 Sanofi-Aventis Deutschland Gmbh Cyanopyrrolidides, process for their preparation and their use as medicaments
WO2005012308A1 (fr) * 2003-07-25 2005-02-10 Sanofi-Aventis Deutschland Gmbh Nouveaux cyanopyrrolidides, procedes pour leur production et leur utilisation comme medicament
JP2006528602A (ja) * 2003-07-25 2006-12-21 サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング 新規なシアノチアゾリド、その製造方法、及びその薬剤としての使用
WO2005012312A1 (fr) * 2003-07-25 2005-02-10 Sanofi-Aventis Deutschland Gmbh Nouvelles cyanothiazolides, leur procede de production et leur utilisation comme medicament
US8389279B2 (en) 2004-09-02 2013-03-05 Cambridge Enterprise Limited α-aminocyclolactam ligands for G-protein coupled receptors, and methods of using same
US7662967B2 (en) 2007-08-02 2010-02-16 Cambridge Enterprise Limited Anti-inflammatory compounds and compositions
US7897620B2 (en) 2007-08-02 2011-03-01 Cambridge Enterprise Limited Methods of using anti-inflammatory compounds
US8853200B2 (en) 2007-08-02 2014-10-07 Cambridge Enterprise Limited Treatment of rheumatoid arthritis with 3-amino lactam compounds
US8569341B2 (en) 2010-06-04 2013-10-29 Amgen Inc. Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
US9593129B2 (en) 2010-06-04 2017-03-14 Amgen, Inc. Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
US9296736B2 (en) 2010-06-04 2016-03-29 Amgen Inc. Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer
US9376425B2 (en) 2011-09-27 2016-06-28 Amgen, Inc. Heterocyclic compounds as MDM2 inhibitors for the treatment of cancer
US11407721B2 (en) 2013-02-19 2022-08-09 Amgen Inc. CIS-morpholinone and other compounds as MDM2 inhibitors for the treatment of cancer
US8952036B2 (en) 2013-02-28 2015-02-10 Amgen Inc. Benzoic acid derivative MDM2 inhibitor for the treatment of cancer
US9758495B2 (en) 2013-03-14 2017-09-12 Amgen Inc. Heteroaryl acid morpholinone compounds as MDM2 inhibitors for the treatment of cancer
US9623018B2 (en) 2013-06-10 2017-04-18 Amgen Inc. Processes of making and crystalline forms of a MDM2 inhibitor
US9757367B2 (en) 2013-06-10 2017-09-12 Amgen Inc. Calcium propane-2-sulfinate dihydrate
US9801867B2 (en) 2013-06-10 2017-10-31 Amgen Inc. Processes of making and crystalline forms of a MDM2 inhibitor
US9855259B2 (en) 2013-06-10 2018-01-02 Amgen Inc. Processes of making and crystalline forms of a MDM2 inhibitor
US9376386B2 (en) 2013-06-10 2016-06-28 Amgen, Inc. Processes of making and crystalline forms of a MDM2 inhibitor

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