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WO1999033431A2 - Procedes de preparation et de selection de composes a noyaux biaromatiques et triaromatiques pontes a partir d'une bibliotheque universelle a diversite structurelle - Google Patents

Procedes de preparation et de selection de composes a noyaux biaromatiques et triaromatiques pontes a partir d'une bibliotheque universelle a diversite structurelle Download PDF

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WO1999033431A2
WO1999033431A2 PCT/US1998/027695 US9827695W WO9933431A2 WO 1999033431 A2 WO1999033431 A2 WO 1999033431A2 US 9827695 W US9827695 W US 9827695W WO 9933431 A2 WO9933431 A2 WO 9933431A2
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alkyl
chch
independently
compounds
alkylnr
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PCT/US1998/027695
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WO1999033431A3 (fr
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Michael R. Pavia
Harold V. Meyers
Guy Milot
Mark E. Hediger
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Pavia Michael R
Meyers Harold V
Guy Milot
Hediger Mark E
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Application filed by Pavia Michael R, Meyers Harold V, Guy Milot, Hediger Mark E filed Critical Pavia Michael R
Priority to AU20175/99A priority Critical patent/AU2017599A/en
Publication of WO1999033431A2 publication Critical patent/WO1999033431A2/fr
Publication of WO1999033431A3 publication Critical patent/WO1999033431A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/20—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C219/22—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
    • C40B50/14—Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/11—Compounds covalently bound to a solid support

Definitions

  • the invention relates to methods for preparing bridged biaromatic and triaromatic ring compounds having desired pharmaceutical or other biological utility. More particularly, the invention relates to structurally diverse libraries of bridged biaromatic and triaromatic ring compounds, methods for preparing such libraries, and an apparatus for storing such libraries and for use as a component of assay systems for identifying compounds for drug development .
  • angiotensin II antagonists include several imidazopyridine and tetrazole-substituted biphenyl compounds (E.M. Naylor et al . , Medicinal Chemistry Abstract #76 (1993) ACS Meeting-Chicago) and a series of carbon-tethered biphenyl pyrrole compounds (J.M. Hamby et al . , Medicinal Chemistry Abstract #72 (1993) ACS Meeting-Chicago) . Others recently have reported that certain orthobiphenylphenols are leukotriene antagonists (M.J. Sofia et al . , Medicinal Chemistry Abstract #5 (1993) ACS Meeting-Chicago) .
  • the present invention provides methods for preparing and selecting bridged biaromatic and triaromatic ring compounds having desired pharmaceutical or other biological utility, libraries prepared by such methods, and a system which utilizes such libraries for rapidly generating large rationally designed libraries of structurally diverse small molecule compounds to explore multiparameter space that overcomes many of the disadvantages associated with using currently available libraries as a basis for identifying and selecting new pharmaceutical agents.
  • the present invention makes possible preparation of libraries of low molecular weight organic chemical compounds which have diverse chemical structures that are known and can be controlled. Additionally, other characteristics of the compounds that are important for pharmaceutical utility, such as solubility, can be controlled.
  • One embodiment of the present invention provides an assay kit for the identification of pharmaceutical lead bridged biaromatic and triaromatic ring compounds, said kit comprising assay materials and a well plate apparatus or equivalent apparatus providing a two-dimensional array of defined reservoirs.
  • the well plate apparatus provides a diverse combinatorial library, wherein each well (reservoir) contains a unique member of the bridged biaromatic and triaromatic ring compound library.
  • the well plate apparatus is used to provide multiple reaction zones for making the library and to store and provide a readily accessible source of library member compounds .
  • the method of the invention includes a multiple combinatorial approach to prepare structurally diverse libraries of biaromatic and triaromatic ring compounds which contain biologically useful compounds .
  • Combinatorial chemistry takes advantage of the nature of the interaction between biological ligates such as antibodies, receptors, enzymes, ion channels, and transcription factors, and their ligands such as antigens, hormones, neurotransmitters, and pharmaceutical agents. It generally is agreed that ligate/ligand affinity and interaction results from binding or interaction between at least three functional groups or chemical functionalities on the ligand and complementary sites on the ligate. Strong interactions between ligates and ligands are dependent upon the properties and three dimensional spacial orientation of the functional groups or chemical functionalities on the ligands. High affinity specific ligands for a given ligate have functional groups that:
  • scaffold moieties are an invariable region or core of the compounds which are members of the combinatorial libraries of the present invention, onto which functional groups can be attached in a manner that when two or more scaffold moieties are attached results in the desired spacial orientation of the functional groups.
  • Scaffold moieties preferably are selected such that they can be prepared from available materials by known chemical reactions and readily allow for attachment of desired functional groups and/or other scaffold moieties in a variety of positions on the molecule. In this specification and claims, as indicated by the context, "scaffold” may also refer to two or more attached scaffold moieties.
  • Suitable scaffolds are compounds of the following formula:
  • M-. and M 2 independently are CH(NRR') or CH(OR) , wherein R and R' independently are H, C 0 - C 6 alkylCOR 15 , C 1 . 6 al ylOR 24 , C 1 . 6 alkylNR 2S R 26 , C 0 _ s alkylNR 80 C(NR 81 )NR 82 R 83 , C ⁇ alkylindole, C 0 _ 6 alkyl-D, C ⁇ 6 alkylCN, C 0 . ⁇ alkylSOR 15 , C 0 . 6 alkylC (0) R 16 , S00R 16 , or C x _
  • X 17 Y-. and Z x are any accessible combination of CH, CHCH, 0, S, N, and NH provided that at least one is CH or CHCH and not more than one is CHCH;
  • X 2 , Y 2 and Z 2 are any accessible combination of CH, CHCH, 0, S, N, and NH provided that at least one is CH or CHCH and not more than one is CHCH;
  • V is H, halo, (C 0 . 4 alkyl) OH, (C 0 _ alkylSH, (C 0 _ 4 alkyl) NR 22 R 23 , (C 0 . 4 alkyl) C0 2 R 76 , or C 0 _ 4 alkylOR 7 ;
  • W is H or
  • X 3 , Y 3 , and Z 3 are any accessible combination of CH, CHCH, 0, S, N, and NH provided that at least one is CH or CHCH and not more than one is CHCH.
  • Preferred scaffolds are: (1) bisphenyl, (2) trisphenyl, (3) bispyridyl, and (4) pyridyl-phenyl wherein the bridging group between the rings is as defined for M x and M 2 above.
  • Useful functional groups include the side chains of the 19 naturally occurring L-amino acids and the side chains of nucleotides found in nature. Additionally, non-natural occurring mimics of these groups are useful.
  • Preferred compounds of the invention which are prepared by combining preferred scaffold moieties with preferred functional groups are shown in Formula I below:
  • X 1 , Y x and Z are any accessible combination of CH, CHCH, 0, S, N, and NH provided that at least one is CH or CHCH and not more than one is CHCH;
  • X 2 , Y 2 and Z 2 are any accessible combination of CH, CHCH, 0, S, N, and NH provided that at least one is CH or CHCH and not more than one is CHCH;
  • W is H or
  • X 3 , Y 3 and Z 3 are any accessible combination of CH, CHCH, 0, S, N, and NH provided that at least one is CH or CHCH and not more than one is CHCH; x and M 2 independently are CH(NRR') or CH(OR) , wherein R and R' independently are H, C 0 -
  • C 6 alkylCOR 15 C 1 . 6 alkylOR 24 , C 1 . 6 alkylNR 25 R 26 , C 0.6 alkylNR 80 C(NR 81 )NR 82 R 83 , C ⁇ alkylindole, C 0 _ 6 alkyl-D, C x _ 6 alkylCN, C 0 . 6 alkylSOR 15 , C 0 . 6 alkylC (0) R 16 , S00R 16 , or C x . g alkylOC ⁇ g alkylR ⁇ ; V is H, C ⁇ alkyl, halo, (C 0 . 4 alkyl) OH, (C 0 .
  • a ⁇ / A 2 , A 3 , A 4 , A 5 , and A 6 independently are absent or present as 0, S, NR 60 ; or C 0 . 6 alkylC (0) NR 21 , provided that at least two are present ;
  • R 17 R 2 , R 3 , R 4 , R 5 , and R s independently are H, C 0.6 alkylCOR 15 , C 1 . 6 alkylR 1g R 17 , C 1 . 6 alkylOR 24 except methoxymethyl , C 0 _ 6 alkylNR 80 C (NR 81 ) NR 82 R 83 , C ⁇ g alkylindole, C 0 . 6 alkyl-D, C ⁇ alkylCN, C 0 . 6 alkylSOR 15 , or C ⁇ g alkylOC ⁇ g alkylR ⁇ ;
  • D is one or multiple fused saturated or unsaturated five or six membered cyclic hydrocarbon or heterocyclic ring system containing one or two 0, N, or S atoms that is unsubstituted or substituted by an accessible combination of 1 to 4 substituents selected from C ⁇ g alkyl, NR 7 R 8 , 0R 9 , SR 10 , COR ⁇ , halogen, CF 3 , or 0;
  • R 81 , R 82 , and R 83 independently are H or
  • R ?g independently are H, C 1 . 6 alkyl, phenyl, or substituted phenyl ;
  • R 1X is 0R 12 or NR 13 R 14 ;
  • R 15 is 0R 18 or NR 19 R 20 ; or any pharmaceutically useful salt thereof.
  • the compounds of Formula I constitute a universal library of compounds that includes pharmaceutically useful compounds. As used in Formula I and elsewhere in this specification and the claims, "C x .
  • y alkyl is a straight chain or branched, saturated or unsaturated alkyl group containing x to y carbons atoms wherein x and y are integers and "halo” includes bromo, chloro, fluoro, and iodo, and "substituted phenyl” is a phenyl group substituted by any accessible combination of halo, CF 3 , OH, C ⁇ alkyl, C ⁇ alkoxy, COOH, COOC 1 _ 6 alkyl , NRR', CONRR', CN, O, N0 2 , C 0 . 6 alkylCOR ls , or C 0 . 6 alkylC (O) R 16 , wherein R and R' independently are H or C h alky1.
  • X x to X 3 , Y-. to Y 3 , and Z ⁇ to Z 3 are selected so that one or more of the ring systems is pyrrole, furan, thiophene, pyridine, pyrazole, pyrimidine or isoxazole with phenyl being most preferred.
  • D is one of the following ring systems substituted as described above: pyrrole, furan, imidazole, thiophene, pyridine, pyrazole, pyrimidine, pyridazine, or isoxazole with phenyl being most preferred.
  • Mi is CH(O(C 0 . 4 alkyl)R) , wherein R is H, C x _ 6 alkyl, D, COOH, COOC ⁇ alkyl , OH, OC ⁇ alkyl, NH 2 , N(C X . 6 alkyl) 2 , or CN;
  • V x is H, CH 3 , OH, or CH 2 OH;
  • a 7 , A 8 , A 9 , and A 10 independently are absent or present as 0 provided that three are O; and
  • R 30 , R 31 , R 32 , and R 33 independently are H, C _ 6 alkyl, D, COOH, COOC ⁇ alkyl, OH, OC ⁇ alkyl, NH 2 , N(C 1 . 6 alkyl) 2 , or CN.
  • Pharmaceutically useful salts of the above compounds include, for example, sodium, potassium, trialkyl ammonium, calcium, zinc, lithium, magnesium, aluminum, diethanolamine, ethylenediamine, megulmine, acetate, maleate, fumarate, lactate, oxalate, methansulfonate, ethanesulfonate, benzenesulfonate, tartrate, citrate, hydrochloride, hydrobromide , sulfate, phosphate, and nitrate.
  • Other pharmaceutically useful salts are readily apparent to skilled medicinal chemists.
  • Formula I Some of the compounds included in Formula I can exist in more than one chiral form and thus exhibit stereoisomerism.
  • Formula I includes all purified stereoisomers and racemic mixtures of the compounds within its scope.
  • a preliminary step in preparing and selecting compounds having desired pharmaceutical or other biologic utility is preparation of a universal library.
  • medicinal chemists and pharmacologists generally agree that interactions between biological ligates and ligands require that the ligand contain at least three functional groups in a spacial orientation that is complementary to the binding sites on the ligate. It also is known that the distance between the binding sites on ligates is determined by the conformation of the ligate as it exists in its native environment and that effective ligands are those that have functional groups positioned to be complementary to such conformation. Because ligates are three dimensional in their natural setting, for any selected intramolecular distance between binding sites an essentially infinite number of possible specific positions for the binding sites exist .
  • a universal library is a collection of related small molecular weight compounds that with respect to spacial orientation of functional groups effectively samples a large segment of the possible specific positions with a selected distance and a sub-universal library is a universal library that is targeted to a particular biological ligate.
  • the number of compounds in the library can vary.
  • the library includes at least ten compounds, more preferably at least about 100 compounds , or more .
  • bradykinin antagonists provide an example of the general approach to designing a sub-universal library.
  • Bradykinin is a naturally-occurring nonapeptide (Arg-Pro-Pro-Gly-Phe- Ser-Pro-Phe-Arg) that is formed enzymatically in the blood and extracellular fluids after injury (a review covering all aspects of bradykinin has appeared (M. Hall, Pharmac. Ther. 56 . (1992) 131) .
  • Bradykinin is a major pain producing substance that excites and sensitizes sensory nerves following trauma, burns, injury and infection.
  • Peptide bradykinin antagonists block bradykinin-induced pain in animal models suggesting that a bradykinin antagonist would be effective for the treatment of a variety of painful disorders. Bradykinin has also been found in plasma exudates taken from the scalp of migraneurs and has been shown to cause severe vascular head pain upon intravenous injection suggesting that bradykinin antagonists would be useful for the treatment of headache .
  • Bradykinin is a potent vasodilator of most peripheral arteries and also causes neurogenic inflammation by the peripheral release of substance P, neurokinin A, and CGRP from sensory nerve fibers. Bradykinin has also been found in fluid from arthritic joints. These results suggest that bradykinin antagonists might have an important role as antiinflammatory agents. Bradykinin has been proposed to play a role in the pathogenesis of asthma as well. While an orally-active bradykinin antagonist is likely to be of immense therapeutic benefit, the potent bradykinin agonists and antagonists reported to date have been peptide derivatives similar in size to bradykinin (which like bradykinin are expected to be rapidly degraded in body fluids) .
  • bradykinin has shown that in general, replacement of Pro 7 with D-He or conformationally-constrained analogues as well as replacement of the Phe 5 and 8 with thienylalanine or conformationally-constrained phenyl analogues affords competitive and selective antagonists of bradykinin.
  • the C-terminal arginine is crucial for receptor activity. It appears that the N-terminal amino groups is not necessary for activity since it can be acylated or removed without significant loss of activity.
  • Bl selective antagonists are obtained by making the des-9 Arg analogues .
  • D-Arg°-Hyp 3 -Thi 5 -D-Tic 7 -Oic 8 - bradykinin is a specific, potent, and long-lasting bradykinin antagonist being developed by Hoechst (Hoe- 140) for allergic rhinitis and asthma.
  • Hoechst Hoe- 140
  • Kyle et . al . have incorporated unnatural amino acids in the C-terminus of bradykinin which introduce B-turn stability and conclude that a B-turn in the four C- terminal amino acid residues might be a prerequisite for high receptor affinity (D.J. Kyle et . al . , J. Med. Chem (1991) 3_4 (3) : 1230-33) .
  • bradykinin antagonists are not fully extended at the receptor and likely occupy a distance of 10-18A. This is an ideal size to be mimicked by a bisphenyl scaffold and the size, shape, and group variations are explored by preparing a large library of compounds guided, or limited, by previously reports SAR studies on bradykinin receptor antagonists. This approach can be carried over to B 1 receptors by leaving out the arginine mimic on the A-ring.
  • the following compounds of Formula III are expected to include bradykinin antagonists:
  • M j. and M 2 independently are CH(NRR') or CH(OR) , wherein R and R" independently are H, C 0 - C 6 alkylCOR 15 , C 1 . 6 alkylNR 25 R 2fi , C 0.6 alkylNR 80 C(NR 81 )NR 82 R 83 , C 0 . 6 alkyl-D, C ⁇ alkylCN, C 0 _ 6 alkylSOR 15 , C 0 . 6 alkylC (0) R 16 , SOOR 16 , or 6 alkylR 15 ;
  • B and B ' are H, O (CH 2 ) n NR 40 C (NR 41 ) NR 42 R 61 , or O (CH 2 ) n ,NR 43 R 44 wherein R 40 , R 41 , R 42 , R 43 , R 44 , and R 61 , independently are H or C ⁇ alkyl, n and n' are 2 or 3; provided one of B and B' is H; E is
  • X is CH, N, NH, 0, S; n is 1-3; n' is 1 when X is 0,S, or NH; and n' is 2 when X is CH or N;
  • F, F', and F" are H, 0 (CH 2 ) n NR 45 C (NR 46 ) NR 47 R 62 , or 0(CH 2 ) n ,NR 48 R 49 wherein R 4S , R 46 , R 47 , R 48 , R 49 , and R 62 independently are H or C ⁇ alkyl, and n and n' are 2 or 3; provided two of F, F ' , and F" are H;
  • G and G' are H, O(CH 2 ) n OR 50 , or
  • X' is CH, N, NH, 0, or S';
  • R 50 is H or C ⁇ alkyl;
  • R 51 is H, C 1 . 3 alkyl, halogen, OH, or OC- ⁇ alkyl ; n is 1-3; and n 1 is 1 or 2; provided one of G and G' is
  • B or B' is OCH 2 CH 2 NHC(NH)NH 2 ;
  • F 1 and F" are OCH 2 CH 2 NHC (NH) NH 2 ; and G and G' are H.
  • rat B2 receptor For potential use in rapid mass screening, a rat B2 receptor has been cloned by Jarnagin et. al . IPNAS (1991) ' 7724) . It appears to be a 7- transmembrane domain G-protein coupled receptor with a molecular weight of 42 kD and 366 amino acids. Furthermore, human B2 receptor was cloned by Hess et al. (Biochem. Biophys. Res. Comm. (1992) 184, 260) and has a molecular weight of 41.1 kD and 364 amino acids with 81% sequence homology to the rat B2 receptor. The binding assays are followed by examination of the compound in an in vitro smooth muscle preparation. Functional activity is assessed by examining in vitro PI turnover. In vivo models include bradykinin paw pressure in rate, both IP and PO.
  • GPCR transmembrane G- protein coupled receptors
  • Such receptors include, but are not limited to, CCK, angiotensin, bombesin, bradykinin, endothelin, neuropeptide Y, neurotensin, opiod, somatostatin, tachykinin (NK-1, NK- 2, NK-3) , thromboxane A 2 , and vasopressin.
  • the angiotensin-2 receptor might be of particular interest as a test case in light of the recently reported activity of a number of functionalized bisphenyl molecules.
  • the ligands for many of the GPCRs range from small-medium sized organics to small-medium peptides (4-35 amino acids) . Most of these ligands are expected to occupy a 10-30 cubic A volume making them ideal candidates for the libraries described herein.
  • An increasing number of modeling and mutagenesis studies are not only indicating the appropriate approximate size but are also giving specific information on important residues of the receptor that interact with the ligand. This information can be readily applied to the design of receptor specific sub-universal libraries .
  • TXA 2 receptor (Yamamoto et, al . , J. Med. Chem (1993) 3_6, 820-25) . These workers propose the TXA 2 binding site and suggest specific residues of the receptor that are important for ligand binding, including Ser-201, Arg-295, and Trp-258. Groups that are complimentary to these residues would be built into the sub-universal library.
  • the NK 1-3 receptors have been cloned and expressed and mutational studies are ongoing which suggest the binding site for NK-1 antagonists is likely to be around the junction of extracellular loop 2 and the top of TMV and TMV1.
  • NK-1 receptor suggests some groups that allow initial selection of groups for a sub-universal library (Watling, TIPS (1993) 14, 81) . It is believed that NK- 1 antagonists will be useful for treating pain, inflammation, arthritis, and asthma.
  • Ion channels are proteins which span cell membranes providing pathways for the flow of ions such as chloride or potassium. These channel proteins are involved in many cellular functions such as nerve signaling, muscle contraction and hormone secretion. Over the past several years there has been an explosive growth in the number of cloned and expressed ion channels, as well as in discoveries which link channels to disease.
  • Potassium channels can be divided into at least 6 major classes, and 15 subclasses, each with its own distinct biophysical and pharmacological identity. Agents which modulate specific potassium channels in specific tissues are expected to target select disease states withoutaltering normal functions. Potassium channels are largely responsible for maintenance functions like establishing the membrane potential in unstimulated cells, or in switching on, or off, a cell's electrical activity. Thus, these channels in part control the cell ' s capacity for nervous transmissions, muscle contraction and secretion. Due to their integral roles in almost all normal signal processing, agents which modulate potassium channels are likely to be useful for treating conditions such as diabetes and muscular sclerosis, cardiac arrhythmias and vascular hyperactivity.
  • ligand-activated and voltage-activated ion channels have now been cloned and functionally expressed. Sequence comparisons and hydropathy analyses have revealed a great deal of structural homology among these channels. Each channel sequence is composed of a repeating motif of transmembrane spanning domains which combine in various ways to form channels (For a recent review of the field, see Andersen and Koeppe, II, Physiological Reviews (1992) Vol. 72) . Site-directed mutagenesis has allowed researchers to probe the primary structure of ion channel proteins for critical amino acid residues involved in the binding sites of drug molecules. These studies will allow for the development of agents targeted for specific channel subtypes and binding sites. To date, several classes of ion channels, including potassium and chloride, have received intensive characterization leading to a basis on which to consider structure-based drug design.
  • Toxins such as those from scorpion venoms, have proven useful in defining potential drug interaction sites on ion channels as well as defining physiological roles for channels.
  • These peptide toxins which are 36-38 residues long, contain three disulfide bridges, and share strong sequence similarity among isoforms, block both voltage-gated and Ca-activated K channels with nanomolar affinity.
  • ther are specific subtypes which bind to specific subtypes of potassium channels.
  • Electrostatic interactions between charybdotoxin (CTX, a specific peptide pore blocker of K channels and a Ca-activated K channel have been extensively investigated.
  • Charybdotoxin has eight positively charged residues (four lysines, three arginines, and one histidine) .
  • CTX The solution structure of CTX has been recently determined (Bontems et al ⁇ , Biochemistry (1992) 3_1, 7756) and it has been shown that Arg 25 and Lys34 are located within A of Lys 37 and each is crucial for high affinity binding of CTX.
  • the receptor site in the channel's mouth must be wide (>22A) and flat to accommodate the CTX molecule.
  • the wide mouth must narrow abruptly into an ion-selective pore in order to provide a selective K binding site with which lys27 interacts (Miller and
  • a sub-universal library targeted to K channels which mimics the three important binding residues both electronically (three positive charges) and spatially (6-18A total spearation) is designed.
  • Such a library is expected to identify non-peptide CTX mimics with therapeutic potential.
  • the compounds of Formula IV represent a sub-universal library targeted to potassium channels :
  • M x and M 2 independently are CH(NRR') or CH(OR), wherein R and R' independently are H, C 0 - C 6 alkylCOR 15 , C 0 . 6 alkylNR 80 C(NR 81 )NR 82 R 83 , C ⁇ alkylindole, C 0 . s alkyl-D, C x . 6 alkylCN, C 0 . 6 alkylSOR 15 , C 0 . 6 alkylC (0) R 16 , S00R 16 , or C x .
  • J, J', and M independently are O(CH 2 ) n NR 50 C(NR sl )NR 52 R 65 or 0 (CH 2 ) n ,NR 53 R 54 wherein R 50 , R 51 , R 52 ' R 53 ' R 54 ' R 65 independently are H or and n and n' independently are 2-3;
  • Q and Q' are H or 0 (C 1 . 4 alkyl) T wherein T is C ⁇ alkyl, C0 2 R 55 , OR 56 , or
  • X 7 is CH, N, NH, S, or 0; n* ' ' is 1 or 2;
  • U is H, C ⁇ g alkyl, halogen, CF 3 , or OR 57 ; and R 55/ R 56 , and R 57 independently are H or C x .
  • a multiple combinatorial method is a method for preparing compounds that uses two or more scaffold molecules each carrying functional group (s) that have been attached in a combinatorial fashion.
  • compounds comprising two scaffold moieties are used for ligates of about 12 to 20A and compounds having three scaffold moieties yield ligands for ligates of about 20 to 35A.
  • the power of the invented multiple combinatorial method is demonstrated by the numbers of compounds that can be prepared quickly and efficiently. Libraries with greater number of compounds can be readily prepared in accordance with the invention.
  • the compounds of Formula I are an example of a universal library of compounds that are prepared according to the invention.
  • the invention is used to prepare large quantities of a desired target compound rather than small amounts of multiple compounds as is the case in preparing universal or sub-universal libraries.
  • multiple compounds are prepared by simultaneously conducting different chemical reactions in multiple reaction vessels, as discussed below.
  • the process of the invention may be carried out in any vessel capable of holding the reaction medium.
  • the process of the invention is carried out in containers adaptable to parallel array synthesis.
  • the process can be conducted in an apparatus providing multiple reaction zones, typically a two-dimensional array of defined reservoirs, wherein one member of the libraries of the invention is prepared in each reservoir.
  • the library of the invention comprises a plurality of reservoir arrays, e.g., well plates or equivalent apparatus, each reservoir or well containing a unique member of the library. Accordingly the library compounds are typically identified by reference to their well plate number and their x column and y row well plate coordinates.
  • the compounds can be transferred in whole or in part to other reservoir arrays to prepare multiple copies of the library apparatus or to subject the library to additional reaction conditions.
  • Copies of the library apparatus (each comprising a two-dimensional array of defined reservoirs with each reservoir containing a predetermined member of the library) are useful as replaceable elements in automated assay instruments.
  • the apparatus of the invention allows convenient access to a wide variety of structurally related compounds.
  • One preferred reservoir array for use in making and using this invention is a multi-well titer plate, typically a 96 -well microtiter plate.
  • the compounds and libraries of the invention preferably are prepared according to Scheme I below. In Scheme I the preferred method of synthesizing the compounds on a solid support is depicted.
  • the libraries and compounds of the invention also can be prepared using solution phase chemistry.
  • Scheme I demonstrates the invented method of preparing universal libraries of compounds.
  • functional groups are attached to a first scaffold moiety to yield a compound comprising a scaffold and one or two functional groups (Compound 3) .
  • a second scaffold molecule (Compound 4) is added with the formation of M followed by addition of functional group (s) to the second scaffold moiety to yield Compound 6 which can have three or four functional groups.
  • Compounds of Formula I then are prepared by cleaving Compound 6 from the solid support .
  • Compounds of the invention wherein M x is -CH(OR)- are prepared as described in Example 1.
  • SS is a solid support material such as the cross-linked polystyrene resin known as the Merrifield resin (R.S. Merrifield, J. Am. Chem. Soc. (1963) 15 . , 2149) .
  • any other suitable polymeric resin or other support material such as, for example, silica, glass, cotton, and cellulose is used.
  • AG is any suitable group for attachment to the linker such as, for example, OH, NH 2 , COOH, CH 2 OH, CH 2 Br, CHO, CH 2 Cl, CH 2 SH, SH and V is the same as in Formula I .
  • the linker group shown in Scheme I is any group that hold the first scaffold (Compound I) onto the solid support and is formed by reaction of AG with the solid support, is stable to the reaction conditions necessary to complete the synthesis, and is easily cleavable upon completion of the synthesis.
  • Suitable linkers are, for example, an OH, NH 2 , halogen, SH or COOH group.
  • An olefin group also is used as a linker. In such case, for example, AG in Compound 1 is CHO and it is attached to the solid support using a Wittig-like reaction. When an olefin group is used the final product is cleaved from the linker by treatment with ozone or other known methods. A sulfide or oxygen bond is another suitable linker.
  • a sulfide or oxygen bond is the desired linker AG in Compound 1 is CH 2 halogen, preferably CH 2 Br, and the bond between the solid support and Compound 1 is formed by reaction between the AG on Compound 1 and an SH or OH group on the solid support.
  • a sulfide or oxygen bond linker is cleaved by, for example, treatment with hydrogenolysis, Raney nickel, or dissolving metal reduction.
  • a benzyl ester group is the desired linker AG in Compound 1 is CH 2 OH and the bond between the solid support and Compound 1 is formed by reaction between the AG on Compound 1 and a C0 2 H group on the solid support .
  • the benzyl ester group is cleaved by, for example, hydrogenolysis conditions.
  • P and P' in Scheme I are protecting groups for aromatic hydroxy groups.
  • P and P' can be the same or different to allow for selective deprotection.
  • Choice P and P' also is influenced by compatibility with the chemistry to be used in the remainder of the synthesis.
  • Preferred protecting groups are C(0)CH 3 and Ph-Co wherein "Ph” is phenyl. Deprotection of a C(0)CH 3 is performed by treatment with an amine according to known procedures and deprotection of a Ph-CO group is accomplished by treatment with a nucleophile such as methoxide using known conditions and procedures.
  • X' and Y' are groups that allow for formation of M r
  • a preferred method for joining the rings is through reaction of a trimethylstannyl group on Compound 1 wherein X' is SnMe 3 , with an acid chloride on Compound 4 wherein Y' is C0 2 C1.
  • a preferred method for joining the rings is through reaction of an OH group on Compound 1 wherein X' is OH with an acid chloride, I, or CH 2 Br.
  • the procedure of Scheme I is modified by repeating the steps needed to add one or more additional scaffolds before cleaving from the solid support.
  • the general procedure shown in Scheme I is used when scaffolds other than phenyl rings are used.
  • any of the compounds included in Formula I can be prepared using Scheme I modified as may be necessary to accommodate different scaffold moieties. Any such necessary modifications are apparent to those skilled in the organic chemical synthetic arts.
  • "FG" is a functional group which may be the same or different at different positions on the compounds. Suitable functional groups are the R through R 6 groups as defined in Formula I above.
  • Scheme I shows preparation of compounds having two scaffold moieties and four functional groups such compounds having three functional groups are prepared by using a scaffold having one functional group in place of Compound 1 or Compound 4.
  • Compounds 1 and 4 provide for attachment of functional groups through an oxygen. By suitable replacement of these compounds a sulfur atom, a nitrogen atom, or an N-alkylamide group can be used in place of one or more of the oxygens .
  • Procedures for introducing functional groups onto scaffolds are included in the examples below.
  • Scheme II is a modification of Scheme I procedure that is used to prepare compounds wherein the functional group is attached to the scaffold moiety using a (CH 2 ) n ,C (0) NR' and n' is O and R' is H or C x _ 6 alkyl .
  • X', Y', and FG have the same meanings as in Scheme I .
  • a scaffold molecule having two cyano groups attached (Compound 8) first is attached to a solid support via a linker and then is hydrolyzed to yield free carboxylic acid groups (Compound 10) . Then, functional groups are attached by treatment with HN(CH 3 )FG to yield a scaffold with two functional groups (Compound 11) . Next a second scaffold moiety with two cyano groups is attached as described in Scheme I followed by addition of functional groups to yield Compound 13.
  • Compounds to be included in the libraries of the invention then are prepared by adjusting the M x group as needed, deprotecting and cleaving Compound 13 from the solid support as described in Scheme I .
  • Scheme III describes an alternate method of producing compounds wherein the functional groups are linked to the scaffold moieties via a C(0)N(CH 3 ) residue.
  • X', Y', P, P', and FG have the same meanings as in Scheme I .
  • Compound 14 is prepared by adding HN(CH 3 )P or HN(CH 3 )P' to the COOH functionalities of Compound 10 from Scheme II.
  • Compound 15 is then prepared by deprotecting, differentially if desired, and introducing functional groups onto Compound 14.
  • Compound 16 then is added to Compound 15 using the procedure for attaching scaffold moieties described in Scheme I to yield Compound 17.
  • Compound 18 next is prepared by deprotecting, differentially if desired, and introducing functional groups onto Compound 17.
  • Compounds included in the invented libraries are prepared by adjusting the M group as needed, and deprotecting and cleaving Compound 18 from the solid support as described in Scheme I.
  • Scheme IV describes an alternate method of producing compounds wherein the functional groups are linked to the scaffold moieties via a C(0)N(CH 3 ) residue.
  • X', Y', P, P' and FG have the same meanings as in Scheme I .
  • the starting compound in Scheme IV (Compound 19) is prepared by standard procedures.
  • Compounds included in the invented libraries are prepared by cleaving Compound 23 from the solid support.
  • two or more scaffolds are independently derivatized with one or two functional groups, then are combined in a convergent approach.
  • two scaffolds are independently attached through a separate linker to a separate solid support material.
  • the linkers and solid supports can be the same or different .
  • the scaffolds can have handles for introducing side chains that are optionally protected or differentiated as described herein.
  • one derivatized scaffold can be cleaved from its solid support, then reattached to the other scaffold through an appropriate coupling reaction.
  • any additional desired or needed synthetic transformations, e.g., side chain protecting group removal
  • the functionalized scaffold (s) is cleaved from the remaining solid support to give compounds of the invented libraries.
  • two scaffolds can be prepared independently with desired functional groups attached thereto.
  • the functionalized scaffolds can then be attached to each other through an appropriate coupling reaction, and the coupled scaffolds attached to a solid support material and manipulated as desired (e.g., side chain protecting group removal, derivatization of linking group of the scaffolds) .
  • the resultant scaffold can then be cleaved from the solid support to give compounds of the libraries of the invention.
  • a third scaffold can be independently functionalized, then coupled in the desired manner to one or both of the other scaffolds attached to a solid support or a combination of the two strategies can be employed whereby two scaffolds are attached together on a solid support in the manner described in the Schemes herein (a linear approach) , then a third functionalized scaffold derived from a separate solid support is attached.
  • two or more scaffolds can be separately functionalized in a parallel, simultaneous fashion.
  • the disclosed invention includes the following Formula V compounds which are useful as intermediates in preparing the invented libraries and compounds :
  • W is H or
  • X 3 , Y 3 , Z 3 , A 5 , and A 6 are as defined in Formula I ;
  • R' lf R'j, R' 3 , R' 4 , R' 5 , and R' 6 are a protecting group or R ⁇ r R 2 , R 3 , R 4 , R 5 , and R s as defined in Formula I, provided that at least one R 1 1 to R' ⁇ is a protecting group;
  • V is V as defined in Formula I or a bond to a solid support; and the remaining variables are as defined in Formula I .
  • a protecting group is any of the well known protecting groups that is suitable in view of the synthetic conditions used. Preferred protecting groups are C(0)CH 3 and Ph-CO.
  • Preparation of libraries of Formula I compounds is the first step in the invented method of preparing and selecting compounds having pharmaceutical or other biologic utility.
  • an assay kit for the identification of pharmaceutical lead compounds.
  • the assay kit comprises, as essential parts, (1) a well plate apparatus (containing one of the compounds of the present invention in each of its individual wells) , and (2) biological assay materials.
  • the biological assay materials are generally known to be predictive of success for an associated disease state.
  • Illustrative of biological assay materials useful in the kit of this invention are those required to conduct assays known in the art, which include, but are not limited to: in vitro assays such as enzymatic inhibition, receptor- ligand binding, protein-protein interaction, protein- DNA interaction, and the like; cell-based, functional assays such as transcriptional regulation, signal transduction/second messenger, viral infectivity, and the like; and add, incubate & read assays such as scintillation proximity assays, fluorescence polarization assays, fluorescence correlation spectroscopy, colorimeric biosensors, receptor gene constructs for cell based assays, cellular reporter assays utilizing, for example, reporters such as luciferase, green fluorescent protein, B-lactamase, and the like; electrical cell impedance sensor assays; and the like.
  • in vitro assays such as enzymatic inhibition, receptor- ligand binding, protein-protein interaction, protein- DNA interaction, and the like
  • the compounds of Formula I that are useful as pharmaceutical agents can be incorporated into convenient dosage unit forms such as capsules, tablets, or injectable preparations.
  • Pharmaceutical carriers which can be employed include, among others, syrup, peanut oil, olive oil, and water.
  • the carrier or diluent may include any time delay material, such as glycerol monostearate or glycerol distearate, alone or with a wax.
  • the amount of solid carrier will very widely but, preferably, will be from about 25 mg to about 1 g per dosage unit. If a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin, capsule, sterile injectable liquid such as an ampule, or an aqueous or non-aqueous suspension.
  • compositions are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling, and dissolving the ingredients, as appropriate, to give the desired oral or parenteral end products.
  • Doses of the pharmaceutically useful compounds of the invention will be an effective amount, that is, an amount necessary to produce the desired effect without producing untoward toxicity selected from the range of 0.1-1000 mg/kg of active compound, preferably 10-100 mg/kg.
  • the selected dose is administered to a patient in need of treatment from 1-5 times per day, orally, rectally, by bolus injection, or by infusion.
  • the acetal (3_) (5.03 g, 16.4 mmol) was dissolved in dry THF (50 mL) under argon. Phenethyl alcohol (2.0 mL, 16.4 mmol) and triphenylphosphine (4.30 g, 16.4 mmol) were added and the solution cooled to 0°C. Diisopropyl azodicarboxylate (3.3 mL, 16.4 mmol) was added dropwise with stirring. The solution wa allowed to come to room temperature over 10 hours. The reaction mixture was diluted with Et 2 0 (150 mL) , washed with 3 x 100 mL portions of water and dried over MgS0 4 . After concentrating, the crude product was purified by column chromatography to give 5.96 g (89% yield) of 4 . .
  • the acetal (4.) (5.96 g, 14.5 mmol) was dissolved in 50 mL of THF prior to slow addition of 40 mL deionized water and 15 mL of cone. HCl. The mixture was vigorously stirred for 8 hours, extracted with 100 mL of Et 2 0 and washed with 3 x 100 mL portions of deionized water. The organic layer was dried with MgS0 4 and concentrated and the crude product purified by column chromatography to give 4.57 g (90% yield) of the aldehyde 5_.
  • the iodo compound 6. (4.57 g, 13 mmol) was dissolved in 50 mL of toluene under argon. Hexamethyl ditin (2.8 mL, 13 mmol) and the tetrakis (triphenylphosphine) palladium (0) catalyst (0.72 g, 0.6 mmol) were added and the mixture brought to reflux. After 20 minutes a palladium mirror formed on the inside of the flask and the reaction was allowed to cool prior to filtration through a pad of Celite and evaporation to dryness . The crude product was purified by column chromatography on silica gel to give 3.95 g (86% yield) of the stannane.
  • 3-Hydroxybenzoic acid (24.86 g, 180 mmol) was dissolved in 600 mL of dry CH 2 C1 2 under argon and cooled to 0°C. Triethylamine (56 mL, 400 mmol) was added. A solution of t-butyldimethylsilyl chloride (56.0 g, 370 mmol in 200 mL of dry CH 2 C1 2 ) was added dropwise with stirring using a pressure equalized addition funnel and the reaction stirred for 12 hours. The mixture was the evaporated to dryness, redissolved in 400 mL of Et 2 0, and washed with 3 x 100 mL portions of deionized water. The organic layer was dried with Na 2 S0 4 , concentrated, and used without further purification.
  • the silyl ester 8 . (11.3 g, 30 mmol) was dissolved in 100 mL of dry CH 2 C1 2 containing 5 drops of DMF under argon. The solution was cooled to 0°C prior to dropwise addition of oxalyl chloride (10.5 mL, 120 mmol) . The reaction was allowed to warm to room temperature over 12 hours . The crude product was evaporated to approximately 25 mL and filtered through a plug of silica gel using 25 mL of CH 2 C1 2 as a wash. The product was concentrated and used without further purification.
  • the stannane (6 . ) (3.95 g, 10.1 mmol) was dissolved with stirring in 100 mL of dry THF under argon prior to addition of oven dried K 2 CO 3 (0.71 g, 5.0 mmol). Hunig's base (2.4 mL, 13.5 mmol) was then added with stirring.
  • the acid chloride ( 9_) (2.70 g, 10 mmol) was dissolved in 50 mL of dry THF and slowly added to the stannane solution.
  • Tris (dibenzylidene acetone) dipalladium (0) (0.50 g, 0.6 mmol) was added in one portion and the mixture was stirred at room temperature until formation of a palladium mirror was observed (approximately 20 minutes) .
  • Diethyl ethyl ether (100 mL) was added and the mixture filtered through a pad of Celite. The solution was evaporated under reduced pressure and purified by column chromatography over silica gel to give 2.16 g (4.7 mmol, 47% yield) of benzophenone 10.
  • Carboxylated polystyrene resin (30.0 g, 3.0 mmol/g) was heated to reflux in dry toluene (200 mL) under argon with excess oxalyl chloride (39.0 mL, 1.455 g/mL, 450 mmol) for 26 hours. The slurry was cooled, filtered under dry nitrogen, and washed with toluene (3 x 100 mL portions) . The resin was dried under high vacuum for 12 hours (2.57 mmol Cl by elemental analysis) .
  • the benzyl alcohol 3L (1.94 g, 4.2 mmol), triethylamine (1.1 mL, 8.0 mmol), acid chloride resin (1.44 g, 2.57 mmol/g) and a catalytic amount of N,N- dimethylaminopyridine (15 mg) were combined with 50 mL of dry methylene chloride under argon in a resin ' reactor and shaken for 18 hours.
  • the resin was filtered and sequentially washed with 2 x 20 mL portions of methylene chloride, THF, DMF, THF, and finally methylene chloride.
  • the resin was then dried under high vacuum to 2.46 g of Y2_ (1.0 mmol/g) .
  • the resin ( ⁇ 2 . ) was deprotected in 10 hours using a stock TBAF solution (0.25 mL of a 1.0 M TBAF/THF solution) , drained, and washed with 1 mL portions of CH 2 C1 2 (3), THF (3), DMF (3), THF (3), and CH 2 C1 2 (3) to give the phenolic resin 13.
  • This was then treated with 0.4 mL of a stock methyl alcohol solution (49 mL in 1.75 mL toluene) and 0.5 mL of freshly prepared Merck reagent (6.50 g suspended in 32 mL of CH 2 C1 2 ) .
  • the well was capped and rotated for 4 days prior to draining and washing with 1 mL portions of CH 2 C1 2 (3), THF (3), DMF (3), THF (3), and CH 2 Cl 2 (3) to give 14.
  • a stock solution of NaOMe was prepared by dissolving sodium methoxide (0.47 g, 8.8 mmol) in methanol (12 mL) and diluting with THF (52 mL) .
  • the resin was treated with the methoxide solution (0.95 mL) for hours without agitation.
  • the well was drained and the filtrate evaporated to dryness.
  • Protein Kinase C Activity Determination Compounds of the invention are tested for ability to inhibit protein kinase C using rat brain as the enzyme source accordingly to widely used procedures such as described by A.C. McArdle and P.M. Conn, Methods in Enzymology (1989) 168, 287-301, and by U. Kikkawa et al . , Biochem. Biophys. Res. Commun. (1986), 135 , 636-634.
  • protein kinase C activity is determined using purified human protein kinase C isozymes by methods such as described in P. Basta et al. , Biochim. Biophys. Acta. (1992) 1132, 154-160.
  • bradykinin receptor affinity of compounds prepared according to this invention is determined for ability to displace [ 3 H] bradykinin binding from guinea pig ileal membrane as described in S.G. Farmer et al . , J.Pharmacol. Exp. Ther. (1989) 248, 677.
  • Phospholipase A A procedure useful to test efficacy of the invented compounds in inhibiting phospholipase A 2 is described by J. Reynolds et al . , Methods in Enzymology (1991) 197, 3-23.

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Abstract

L'invention porte sur de nouvelles bibliothèques combinatoires de composés à noyaux biaromatiques et triaromatiques pontés, sur des procédés de préparation de ces bibliothèques, et sur un appareil de stockage de ces bibliothèques destiné à être utilisé comme composant de systèmes de dosage pour identifier des composés dans le développement de médicaments.
PCT/US1998/027695 1997-12-30 1998-12-29 Procedes de preparation et de selection de composes a noyaux biaromatiques et triaromatiques pontes a partir d'une bibliotheque universelle a diversite structurelle WO1999033431A2 (fr)

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