+

WO1995004277A1 - Methode de preparation et selection de composes non peptidiques a usage pharmacologique a partir d'une bibliotheque universelle d'elements de structures diverses - Google Patents

Methode de preparation et selection de composes non peptidiques a usage pharmacologique a partir d'une bibliotheque universelle d'elements de structures diverses Download PDF

Info

Publication number
WO1995004277A1
WO1995004277A1 PCT/US1994/007780 US9407780W WO9504277A1 WO 1995004277 A1 WO1995004277 A1 WO 1995004277A1 US 9407780 W US9407780 W US 9407780W WO 9504277 A1 WO9504277 A1 WO 9504277A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
chch
independently
compounds
compound
Prior art date
Application number
PCT/US1994/007780
Other languages
English (en)
Inventor
Michael Raymond Pavia
George Mcclelland Whitesides
David Garry Hangauer, Jr.
Mark Edward Hediger
Original Assignee
Sphinx Pharmaceuticals Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sphinx Pharmaceuticals Corporation filed Critical Sphinx Pharmaceuticals Corporation
Priority to EP94923427A priority Critical patent/EP0712493A4/fr
Priority to AU73293/94A priority patent/AU7329394A/en
Priority to JP7505836A priority patent/JPH09504511A/ja
Publication of WO1995004277A1 publication Critical patent/WO1995004277A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/08—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic

Definitions

  • the invention relates to a method for preparing and selecting low molecular weight non-peptide compounds having desired pharmaceutical or other biological utility. More particularly, the invention is a method for preparing a structurally diverse library of low molecular weight compounds and then selecting from the library those compounds having the desired pharmacologic activity.
  • a key step in preparing and selecting pharmaceutically or other biologically useful compounds is identification of structurally-unique lead compounds.
  • Traditionally and currently mass screening of large numbers of compounds and mixtures of compounds has been and is the most successful method for identifying chemical leads.
  • Recent availability of robotic, rapid, high throughput biological screens is beginning to make possible efficient screening of hundreds of thousands of compounds per year.
  • Most screening libraries consist of a historical collection of compounds synthesized in the course of pharmaceutical research, natural products, and, more recently, peptide libraries. Each of these libraries has limitations. Historical pharmaceutical collections of synthesized compounds contain a limited number of diverse structures which represent only a small fraction of total structural diversity possibilities. Limitations of natural products libraries include the structural complexity of the leads identified and the difficulty of reducing these leads to useful pharmaceutical agents. Peptide libraries are limited to peptides or peptide mimics; to date conversion of peptide chemical leads into pharmaceutically useful, orally active, non-peptide drug candidates in the absence of a small molecule chemical lead has been met with limited success.
  • Some of the peptide and peptide mimic libraries referred to above were prepared using combinatorial chemistry.
  • the challenge facing medicinal chemists is to translate the success using combinatorial chemistry to prepare peptide and peptide-like compounds into technology suitable for efficiently preparing large libraries of low molecular weight non-peptide compounds.
  • Solid phase chemistry for preparing low molecular weight compounds is desirable to effect such a translation.
  • the following references are examples of the types of solid phase chemistry methods that may be useful in low molecular weight compound combinatorial chemistry.
  • biphenyl and triphenyl compounds that have been prepared by well known synthetic organic chemical methods.
  • A. A. Patchett et al. recently reported that certain biphenyl acylsulfonamides and biphenyl sulfonylcarbamates are orally active antagonists of the angiotensin II receptor (Medicinal Chemistry Abstract #80 (1993) ACS Meeting-Chicago).
  • Other recently reported angiotensin II antagonists include several imidazopyridine and tetrazole-substituted biphenyl compounds (E. M.
  • the presently invented method for preparing and selecting low molecular weight non-peptide compounds having desired pharmaceutical or other biological utility includes a system 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 disclosed 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. Most importantly, however, because the compounds prepared using this invention are low molecular weight non-peptide compounds they are expected to be useful in a much broader spectrum of therapeutic applications than peptides which generally can only be administered by injection or inhalation.
  • the presently invented method for preparing and selecting low molecular weight compounds having desired pharmaceutical or other biologic utility includes a multiple combinatorial approach to prepare structurally diverse libraries 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: (1) bind tightly to the binding sites on the ligate and (2) are positioned to bring the functional groups into close proximity with the ligate binding sites in the biological milieu where the interactions occur.
  • scaffold moieties are compounds of the following formula:
  • X 1 , Y 1 and Z 1 are any accessible combination of CH, CHCH, O, 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, O, 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, O, S, N, and NH provided that at least one is CH or CHCH and not more than one is CHCH;
  • V is H, C 1-6 alkyl, halo, (C 0-4 alkyl)OH, (C 0-4 alkyl)SH, or (C 0-4 alkyl)NRR, or (C 0-4 alkyl)CO 2 R wherein each R independently is H or C 1-6 alkyl.
  • 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-naturally 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 1 and Z 1 are any accessible combination of CH, CHCH, O, 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, O, 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, O, S, N, and NH provided that at least one is CH or CHCH and not more than one is CHCH;
  • V is H, C 1-6 alkyl, halo, (C 0-4 alkyl)OH, (C 0-4 alkyl)SH, (C 0-4 alkyl)NR 22 R 23 , or (C 0-4 alkyl)CO 2 R 76 ;
  • a 1 , A 2 , A 3 , A 4 , A 5 , and A 6 independently are absent or present as O, S, NR 60 ; or C 0-6 alkylC(O)NR 21 , provided that at least three are present;
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 independently are H, C 0-6 alkylCOR 15 , C 1-6 alkylR 16 R 17 , C 1-6 alkylOR 24 except methoxymethyl, C 1-6 alkylNR 25 R 26 , C 0-6 alkylNR 80 C(NR 81 )NR 82 R 83, C 1-6 alkylindole, or C 0-6 alkyl-D;
  • D is any one or multiple fused saturated or unsaturated five or six membered cyclic hydrocarbon or heterocyclic ring system containing one or more O, N, or S atoms that are unsubstituted or substituted by any accessible combination of 1 to 4 substituents selected from C 1-6 alkyl, NR 7 R 8 , OR 9 , SR 10 , or COR 11 , halogen, CF 3 ;
  • R 7 , R 8 , R 9 , R 10 , R 19 , R 20 , R 21 , R 22 , R 23 , R 60 , R 80 , R 81 , R 82 , R 83 , R 84 and R 85 independently are H or C 1-6 alkyl;
  • R 12 , R 13 , R 14 , R 16 , R 17 , R 18 , R 24 , R 25 , R 26 , and R 76 independently are H, C 1-6 alkyl, phenyl, or substituted phenyl;
  • R 11 is OR 12 or NR 13 R 14 ;
  • R 15 is OR 18 or NR 19 R 20 ; or
  • the compounds of Formula I constitute a universal library of compounds that includes pharmaceutically useful compounds.
  • C x-y alkyl is a straight chain or branched, saturated or unsaturated alkyl group containing x to y carbon 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 1-6 alkyl, C 1-6 alkoxy, COOH, COOC 1-6 alkyl, NRR', or CONRR' wherein R and R' independently are H or 1-6 alkyl.
  • 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.
  • V 1 is H, CH 3 , OH, or CH 2 OH;
  • a 7 , A 8 , A 9 , and A 10 independently are absent or present as O provided that three are O;
  • R 30 , R 31 , R 32 , and R 33 independently are OH, NH 2 , CO 2 H, phenyl, substituted phenyl, CONH 2 , NR 80 C(NR 81 )NR 82 R 83 , C 1-6 alkyl, imidazole, or indole wherein R 80 to R 83 are H or C 1-4 alkyl.
  • 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 within a selected distance and a sub-universal library is a universal library that is targeted to a particular biological ligate.
  • bradykinin antagonists provides an example of the general approach to designing a sub-universal library.
  • Bradykinin is a namrally-occurring nonapeptide (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) that is formed enzymatically in the blood and extracellular fluids after injury.
  • 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.
  • bradykinin antagonists 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 Peptide analogs of bradykinin have shown that in general, replacement of Pro 7 with D-Phe or conformationally-constrained analogues as well as replacement of 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 group is not necessary for activity since it can be acylated or removed without significant loss of activity.
  • B1 selective antagonists are obtained by making the des-9 Arg analogues.
  • D-Arg 0 -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.
  • 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 reported 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:
  • 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 1-3 alkyl, n and n' are 2 or 3; provided one of B and B' is H;
  • E is wherein X is CH, N, NH, O, or S; n is 1-3; and n' is 1 or 2;
  • F, F', and F" are H, O(CH 2 ) n NR 45 C(NR 46 )NR 47 R 62 , or O(CH 2 ) n ,NR 48 R 49 wherein R 45 , R 46 , R 47 , R 48 , R 49 , and R 62 independently are H or C 1-3 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, O, or S
  • R 50 is H or C 1-3 alkyl
  • R 51 is H, C 1-3 alkyl, halogen, OH, or OC 1-3 alkyl; n is 1-3; and n' is 1 or 2; provided one of G and G' is H.
  • B or B' is OCH 2 CH 2 NHC(NH)NH 2 ;
  • F or F" are OCH 2 CH 2 NHC(NH)NH 2 ;
  • G and G' are H.
  • 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 subuniversal libraries.
  • TXA 2 receptor (Yamamoto et al., J. Med. Chem. (1993) 36, 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.
  • NK 1-3 receptors have been cloned and expressed and mutational studies are ongoing which suggest the binding site for NK, antagonists is likely to be around the junction of extracellular loop 2 and the top of TMV and TMVI. Furthermore, the identification of non-peptide leads for the 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, 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.
  • ions such as chloride or potassium.
  • These channel proteins are involved in many cellular functions such as nerve signaling, muscle contraction and hormone secretion.
  • there are many subtypes of ion channels differentially distributed throughout the body the possibilities for selective targeting of specific channels in specific tissues are unlimited. This selective targeting will reduce unwanted drug-related side effects and toxicities.
  • the plasma membrane localization of ion channels eliminates the need for complex delivery systems required for drugs directed at intracellular or intranuclear targets.
  • 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 without altering 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 transmission, 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.
  • 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 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.
  • Within this group of toxins there 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.
  • CX charybdotoxin
  • Charybdotoxin has eight positively charged residues (four lysines, three arginines, and one histidine). Electrostatic forces are known to favor CTX binding to the negatively charged mouths of K channels. However, only replacement of Arg25, Lys27, or Lys34 with a Gin residue strongly decreased the affinity of the toxin for the channel. These three residues are located close to one another on one side of the CTX molecule and make direct contact with the channel mouth. On the opposite side are five charged residues whose neutralization show little effect. Therefore the positively charged groups on CTX promote toxin channel interaction in two ways; by weak through space electrostatic influences and by direct and intimate contact with the channel on one side of the toxin molecule.
  • CTX The solution structure of CTX has been recently determined (Bontems et al., Biochemistry (1992) 31, 7756) and it has been shown that Arg25 and Lys34 are located within 10 ⁇ of Lys27 and each is crucial for high affinity binding of CTX.
  • the receptor site in the channel's mouth must be wide (>22 ⁇ ) 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 Park, Biochemistry (1992) 31, 749, and Neuron (1992) 9, 307).
  • These studies reveal a molecular surface of CTX which makes direct contact with the extracellular mouth of the K channel and a single CTX molecule physically occludes the K conduction pathway by binding to a receptor located in the externally-facing mouth of the channel protein.
  • a sub-universal library targeted to K channels which mimics the three important binding residues both electronically (three positive charges) and spatially (6-18 ⁇ total separation) 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.
  • J, J', and M independently are O(CH 2 ) n NR 50 C(NR 51 )NR 52 R 65 or O(CH 2 ) n ,NR 53 R 54 wherein R 50 , R 51 , R 52 , R 53 , R 54 , and R 65 independently are H or C 1-3 alkyl, and n and n' independently are 2-3;
  • Q and Q' are H or O(C 1-4 alkyl)T wherein T is C 1-6 alkyl, CO 2 R 55 , OR 56 , or
  • X 7 is CH, N, NH, S, or O;
  • n'" is 1 or 2;
  • U is H, C 1-6 alkyl, halogen, CF 3 , or OR 57 ;
  • R 55 , R 56 , and R 57 independently are H or C 1-6 alkyl; provided that Q or Q' is H.
  • a multiple combinatorial method is a method for preparing compounds that uses two or more scaffold molecules each carrying functional groups that have been attached in a combinatorial fashion.
  • compounds comprising two scaffold moieties are used for ligates of about 12 to 20 A and compounds having three scaffold moieties yield ligands for ligates of about 20 to 35 A.
  • the power of the invented multiple combinatorial method is demonstrated by the numbers of compounds that can be prepared quickly and efficiently. For example, using two scaffold molecules each containing two of twenty possible functional groups arranged in four different orientations yields more than 1,000,000 compounds. Using the same parameters with a third scaffold molecule allows for preparation of a universal library containing more than 1,000,000,000 compounds.
  • 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.
  • reactions are conducted simultaneously in about 25 reaction vessels, more preferably in about 100 reaction vessels, and most preferably in standard 96 well plates.
  • To prepare large quantities of a selected compound the same reaction is carried out simultaneously in multiple reaction vessels.
  • 2',4,5'-trimethoxybiphenyl-4'-carboxylic acid a compound known to exhibit estrogenic activity, (CA54: 19584c (1959)) is prepared according to the invention as described in the Examples below.
  • the compounds and libraries of the invention preferably are prepared according to Scheme I below.
  • 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 followed by addition of functional group(s) to the second scaffold moiety to yield Compound 6 which can have 3 or 4 functional groups.
  • Compounds of Formula I wherein M, is a bond then are prepared by cleaving Compound 6 from the solid support.
  • SS is a solid support material such as the crosslinked polystyrene resin known as the Merrifield resin (R. S. Merrifield, J. Am. Chem. Soc. (1963) 85, 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 Br, CHO, CH 2 Cl, CH 2 SH, SH, V and M, are the same as in Formula I.
  • the linker group shown in Scheme I is any group that can be reacted with the first scaffold (Compound 1) to attach it to a 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 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 reductions.
  • 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 of 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(O)CH 3 and Ph-CO wherein "Ph” is phenyl. Deprotection of a C(O)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 attachment of the scaffold rings and introduction of the appropriate M, group.
  • a preferred method for joining the rings is the method of Stille (J. Am. Chem. Soc. (1987) 109, 5478-5486) wherein X' and Y' are an organotin group and a halogen or triflate, respectively. The following is an example of using this method:
  • Scheme I When compounds having more than two scaffold moieties are desired 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. Also, the general procedure shown in Scheme I is used when scaffolds other than phenyl rings are used. Thus, 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 I-L, 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 the scaffolds are included in the examples below.
  • Scheme II is a modification of the 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(O)NR' and n' is 0 and R' is H or C 1-6 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 1 group as needed, deprotecting and cleaving Compound 13 from the solid support as described in Scheme I.
  • Scheme III is a variation of Scheme II wherein the scaffold moiety substituents are protected prior to addition of the functional groups.
  • 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 then is 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, 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(O)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.
  • 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
  • R' 1 , R' 2 , R' 3 , R' 4 , R' 5 , R' 6 are a protecting group or R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 as defined in Formula I, provided that at least one of R' 1 to R' 6 is a protecting group;
  • V' is V as defined in Formula I or a bond to a solid support
  • 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(O)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. After the libraries are prepared they are tested in a wide variety of in vitro and in vivo assays that are predictive of biologic activity and generally involve contacting the compounds with biological targets of interest and determining the strength of the interaction between the compounds and the biological target.
  • assays are well known and include, without limitation, enzyme inhibition assays, such as protein kinase C and angiotensin converting enzyme, receptor binding assays, such as serotonin and excitatory amino acids, ion channel blocking, such as calcium, potassium and chloride, and transcription factor interaction.
  • enzyme inhibition assays such as protein kinase C and angiotensin converting enzyme
  • receptor binding assays such as serotonin and excitatory amino acids
  • ion channel blocking such as calcium, potassium and chloride
  • transcription factor interaction such as calcium, potassium and chloride
  • any activity identified in vitro is confirmed by evaluation in a
  • 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 glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier will vary 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 resin-bound material (8.3 mmol) was placed in a mixture of 100mL CHCl 3 , 50mL MeOH and anhydrous powdered potassium carbonate (5.0g, 36.18 mmol) was added (18-crown-6 can be added if solubility is a problem).
  • the reaction was heated at 50oC for 15 min, then side chain bromide (9.24 mmol) was added and the mixture refluxed for 4h. After filtration, the residue was washed.
  • the phenol triflate (0.5 mmol), anhydrous LiCl (0.171g, 4.2 mmol), triphenylphosphine (0.079g, 0.30 mmol), and PdCl 2 (PPh 3 ) (0.037g, 0.06 mmol) is suspended in DMF (4.5mL).
  • the resin-bound organostannane was added and a crystal of inhibitor (2,6-di-tert-butyl-4-methylphenol) was added, and the mixture was then heated under an inert atmosphere of argon at 120°C for 2-8h. The resin was filtered and washed.
  • Steps a, b, and d are carried out as described above. Removal of the benzoate is carried out as described by Bell (Tet. Lett. (1986) 27, 2263).
  • the resin-bound material (0.005 mol) was placed in toluene (20 mL) and n-butylamine (3.65 g, 0.05 mol) was added. The mixture was stirred at room temperature for 3 h followed by filtration and washing of the resin.
  • the reaction was cooled to 0°C and PMCCl (3.66g, Raylo Chemicals, Alberta, Canada) was added in acetone (8mL). After stirring for 1h at 0oC the reaction was diluted with ethyl acetate, washed one time each with 25mL sat'd NH 4 Cl, water, and sat'd NaCl, dried and evaporated. The product was purified by flash chromatography (silica, hexane/ethyl acetate 1:1) to afford 1.71g (46%) of desired product.
  • the product (0.57g, 1.23 mmol) was dissolved in THF (10mL), cooled to 0°C and tetrabutylammomumfloride (371mg, 1.42 mmol) added. After 30 min the reaction was worked up by diluting with ethyl acetate, washing one time each with 25mL sat'd NH 4 Cl, water, and sat'd NaCl, dried and evaporated. The product was purified by flash chromatography (silica, CH 2 Cl 2 /methanol; 19:1) to afford 0.43g (94%) of desired product.
  • Steps a, b, and d are carried out as described above with step d using side chain bromide (D). Removal of the benzoate is carried out as described by Bell (Tet. Lett. (1986) 27, 2263).
  • the resin-bound material (0.005 mol) was placed in toluene (20 mL) and n-butylamine (3.65 g, 0.05 mol) was added. The mixture was stirred at room temperature for 3 h followed by filtration and washing of the resin.
  • 2-Methoxy methyl phenylacetate was prepared by refluxing 2-methoxy phenylacetate (10.2 g, 61.3 mmole), 70 mL of anhydrous methanol and 1.5 mL of concentrated sulfuric acid for 17 hours. The solvent was removed and the oil was dissolved in 100 mL of diemyl ether, washed with saturated NaHCO 3 , dried, filtered and evaporated to give 9.26 grams (83%) of 2-methoxymethyl phenylacetate.
  • This material (10.0 g, 55.0 mmole) dissolved in 6 mL of tetrachloroethane was added over a period of 25 minutes ( making sure that the temperature of the reaction mixture did not exceed 50°C) to AlCl 3 (15 g, 112 mmole) in 50 mL of tetrachloroethane to which was added 2-bromopropionyl chloride (5.7 mL, 56.5 mmole) and the mixture heated at 45oC for 20 minutes. The reaction was allowed to stir at 50°C for 5 hours then at room temperature for 10 hours, poured onto 150 mL ice and 0.5 mL of concentrated HCl was added.
  • Coupling of this material to TentaGel ® resin was accomplished by placing TentaGel ® (3.0g, 0.87 mmole of amine), 50 mL CH 2 CL 2 and 1 mL DIE A (6.46 mmole) in a peptide synthesis vessel and the mixture shaken for 5 minutes followed by washing with CH 2 Cl 2 . To this was added 20 mL CH 2 Cl 2 followed by 3-[2-[(2-nitrophenyl)dithio]propionyl]-6-methoxyphenyl acetic acid from above (0.9 g, 2.2 mmole) dissolved in 30 mL of CH 2 Cl 2 and mixture shaken for 30 seconds.
  • the mono- or di-oxygen substituted bromobenzyl bromides, 32 can be prepared by methods well known to those skilled in the art . For an example see Example 5 below.
  • the trimethylstannyl group can be introduced if needed to afford 53, by reacting the penultimate intermediate to bromobenzene 32, the tolyl compound, (8.78 mmol) with Pd(PPh 3 ) 4 (71 mg, 0.061 mmol) in toluene (8.8 mL) to which was added hexamethylditin (5 g, 15.26 mmol). The reaction was heated to 120°C for 1.5h which after work-up and purification afforded the desired product. Conversion to the benzylbromide occurs with NBS under standard conditions.
  • the required bromides are either commercially available as needed, or as the bromide having side chains which require protection with standard acid labile protecting groups.
  • the alcohols are available which require conversion to the corresponding bromides or mesylates by methods known to those skilled in the art.
  • the materials were prepared by a several step synthetic sequence as described in the specific example below.
  • the resin-bound material (46.0g, 8.3 mmol) was placed in a mixture of 300mL CHCl 3 , 150mL MeOH and anhydrous powdered potassium carbonate (5.0g, 36.18 mmol) was added (18-crown-6 can be added if solubility is a problem).
  • the reaction was heated at 50°C for 15 min, then side chain bromide (9.24 mmol) was added and the mixture refluxed for 4h. After filtration, the residue was washed.
  • the resin-bound material (46.0g, 8.3 mmol) was placed in a mixture of 300mL CHCl 3 , 150mL MeOH and anhydrous powdered potassium carbonate (5.0g, 36.18 mmol) was added (18-crown-6 can be added if solubility is a problem).
  • the reaction was heated at 50°C for 15 min, then side chain bromide (9.24 mmol) was added and the mixture refluxed for 4h. After filtration, the residue was washed.
  • the substituted phenylacetylene 35 was prepared from the corresponding iodobenzene compound by the general procedure described by Lau et al. described below (J. Org. Chem., 1981, 46, 2280).
  • the differentially protected dihydroxyiodobenzene was prepared from the dimethoxyaniline (Aldrich) by diazotization and iodine introduction followed by demethylation of the methoxy groups all under standard conditions. Differential protection was accomplished from the iodophenol (16.0 mmol) which was dissolved in CH 2 Cl 2 (30mL). Triethylamine (11.15mL, 80 mmol), acetic anhydride (4.55 mL, 48 mmol) and DMAP (390 mg, 3.2 mmol) were added and the reaction stirred for 16 h.
  • the resin bound bromobenzene 34 (16.5g, 3 mmol) was suspended in DMF (30 mL) and triethylamine (6 mL) added along with the acetylene 35 (8 mmol), Pd(II)acetate (20 mg), and triphenylphosphine (40 mg) in dry triethylamine (5 mL). The mixture was heated at reflux for 4 h, cooled, filtered, and washed in the standard fashion to afford 36.
  • benzylbromide 56 Preparation of benzylbromide 56 and conversion of 55 to 57:
  • the substituted benzy l b romide 56 was prepared from the c orre sp ond ing monoacetoxy-monobenzyloxytoluene by reaction with N-bromosuccinimide under standard conditions.
  • the monoacetoxy-monobenzyloxy toluene was in turn prepared from the corresponding dihydroxytoluene by the same protection scheme used to prepare the phenylacetylene 35, above.
  • the required bromides are either commercially available or as the bromide having side chains which require protection with standard acid labile protecting groups.
  • the alcohols are available which require conversion to the corresponding bromides or mesylates by methods known to those skilled in the art.
  • the bromides or mesylates were prepared via several step synthetic procedures such as that described in the specific example below.
  • the resin-bound material (4.6g, 0.83 mmol) was placed in a mixture of 20mL CHCl 3 , 10mL MeOH and anhydrous powdered potassium carbonate (3.6 mmol) was added (18-crown-6 can be added if solubility is a problem).
  • the reaction was heated at 50°C for 15 min, then side chain bromide (0.92 mmol) was added and the mixture refluxed for 4h. After filtration, the residue was washed.
  • the resin-bound material (4.6g, 0.83 mmol) was placed in a mixture of 20mL CHCl 3 , 10mL MeOH and anhydrous powdered potassium carbonate (3.6 mmol) was added (18-crown-6 can be added if solubility is a problem).
  • the reaction was heated at 50oC for 15 min, then side chain bromide (0.92 mmol) was added and the mixture refluxed for 4h. After filtration, the residue was washed.
  • Resin 31 is prepared as described in Example 3 above.
  • the starting materials 60 and 81 are prepared from commercially available materials by reactions well known to those skilled in the art of organic synthesis.
  • 2-acetoxy-4-bromobenzyl bromide is prepared from 2-methyl-5-nitroaniline (Aldrich) by diazotization under standard conditions.
  • the diazo compound is thermolyzed in acetic acid for 1 h at 80°C as described in Chem. Lett., 1991, 459 to afford the corresponding acetoxy compound.
  • the bromo group is introduced via nitro reduction, diazotization, and bromide displacement all under standard conditions and finally, the desired product is obtained by benzylic bromination with N-bromosuccinimide under standard conditions.
  • the corresponding trimethylstannyl derivative 81 is prepared from the penultimate intermediate above, 2-acetoxy-4-bromotoluene.
  • the trimethyl stannyl group is introduced by placing the bromotoluene (2.0g, 8.78 mmol) in a dry flask with Pd(PPh 3 ) 4 (71 mg, 0.061 mmol). Toluene (8.8 mL) was added then hexamethylditin (5 g, 15.26 mmol) was added via syringe. The reaction was heated to 120°C for 1.5h. The reaction was cooled, filtered through Celite, and evaporated. The residue was dissolved in ether and washed with 3 x 50mL of 50% KF. The organic layers were dried (Na 2 SO 4 ) and evaporated which after purification afforded the desired product (77% yield). Finally, the benzylic bromide is introduced by reaction with NBS under standard conditions.
  • the resin, 31 (2.3 g, 0.43 mmol) was suspended in 45 mL of anhydrous DMF. 15 mL DMF, b-mercaptoethanol (0.25 mL, 3.5 mmole) and diisopropylethylamine (0.4 mL, 2.3 mmole) were added and the mixture shaken for 2-3 minutes, filtered and the process repeated two more times using the same quantities of BME and DIEA. The resin was then washed five times with DMF, three times with methanol, four times with CH 2 Cl 2 and then three times with DMF.
  • the resin bound material 61 (4.6g. 0.83 mmol) was placed in acetone (30mL) and excess 2N ammonium hydroxide was added and the solution left at room temperature for 24 h (Haslam et al., J. Chem. Soc, 2137 (1964)). The resin was filtered, washed, and subjected to the following general alkylation scheme of Venuti et al. (J. Med. Chem. 1988, 31, 2132).
  • the resin-bound material (4.6g, 0.83 mmol) was placed in a mixture of 30mL CHCl 3 , 15mL MeOH and anhydrous powdered potassium carbonate (0.5g, 3.62 mmol) was added. The reaction was heated at 50oC for 15 min, then
  • the product (0.57g, 1.23 mmol) was dissolved in THF (10mL), cooled to 0°C and tetrabutylammoniumfluoride (371mg, 1.42 mmol) added. After 30 min the reaction was worked up by diluting with ethyl acetate, washing one time each with 25mL sat'd NH 4 Cl, water, and sat'd NaCl, dried and evaporated. The product was purified by flash chromatography (silica, CH 2 Cl 2 /methanol; 19:1) to afford 0.43g (94%) of desired product.
  • the substituted phenylacetylene 63 was prepared from this iodobenzene by the general procedure described by Lau et al. (J. Org. Chem., 1981, 46, 2280).
  • This material was converted to the free acetylene by dissolving in THF (8 mL) and adding tetrabutyl ammonium fluoride (3 mL of 1M in THF) and stirring for 3h at room temperature. After standard workup and chromatographic purification the desired substituted phenylacetylene 63 was obtained.
  • the resin bound bromobenzene 62 (5.5g, 1 mmol) was suspended in DMF (10 mL). To this suspension was added the acetylene 63 (0.85g, 3 mmol), Pd(II)acetate (10 mg), and triphenylphosphine (15 mg) in dry triethylamine (5 mL). The mixture was heated at reflux for 4 h, cooled, filtered, and washed in the standard fashion to afford 64.
  • benzylbromide 84 was prepared from the corresponding 3-acetoxy-5-benzyloxytoluene by reaction with N-bromosuccinimide under standard conditions .
  • 3-Acetoxy-5-benzyloxytoluene was in mm prepared from orcinol (Aldrich) by the same protection scheme used to prepare the phenylacetylene 63, above.
  • the resin-bound material (4.6g, 0.83 mmol) was placed in a mixture of 30mL CHCl 3 , 15mL MeOH and anhydrous powdered potassium carbonate (0.5g, 3.6 mmol) was added. The reaction was heated at 50°C for 15 min, then (2-bromoethyl)benzene (171mg, 0.92 mmol, Aldrich) was added and the mixture refluxed for 4h. After filtration, the residue was washed.
  • the resin-bound material (4.6g, 0.83 mmol) was placed in a mixture of 30mL CHCl 3 , 15mL MeOH and anhydrous powdered potassium carbonate (0.5g, 3.6 mmol) was added.
  • the reaction was heated at 50oC for 15 min, then (2-N-PMC-guanidino)-(1-methanesulfonyl)ethanol, (0.92 mmol, see preparation above) was added and the mixture refluxed for 4h. After filtration, the residue was washed in the standard fashion.
  • Reduction of the acetylene 65 to the olefin 67 This selective reduction of the acetylene to the corresponding olefin is accomplished with Lindlar catalyst prepared as described in Org. Syn. Coll., Vol. V, 880. To the resin-bound 65 (5.5g, 1 mmol) suspended in 10 mL hexane was added 10mg of Lindlar catalyst and 50mL of quinoline. The reaction vessel is evacuated and placed under a slight positive pressure of hydrogen gas for 3 h, filtered, and washed to afford 67 (expected to be exclusively the Z-olefin).
  • the bradykinin receptor affinity of compounds prepared according to this invention is determined by testing 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.
  • Xenopus oocytes are well known as tools for studying ion channels and receptors.
  • J. M. Gottesfeld is an example of a reference describing a procedure suitable for analyzing the ability of the invented compounds to influence transcription factor function.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Méthodes rapides de production de grandes bibliothèques, de conception rationnelle, de composés de structures diverses et de faible poids moléculaire par un processus multicombinatoire. Sont également présentés des composés de formule (I).
PCT/US1994/007780 1993-08-03 1994-07-07 Methode de preparation et selection de composes non peptidiques a usage pharmacologique a partir d'une bibliotheque universelle d'elements de structures diverses WO1995004277A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP94923427A EP0712493A4 (fr) 1993-08-03 1994-07-07 Methode de preparation et selection de composes non peptidiques a usage pharmacologique a partir d'une bibliotheque universelle d'elements de structures diverses
AU73293/94A AU7329394A (en) 1993-08-03 1994-07-07 A method for preparing and selecting pharmaceutically useful non-peptide compounds from a structurally diverse universal library
JP7505836A JPH09504511A (ja) 1993-08-03 1994-07-07 構造的に多様なユニバーサルライブラリーから医薬として有用な非ペプチド化合物を製造するためのおよび選択するための方法

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US10107493A 1993-08-03 1993-08-03
US23954294A 1994-05-08 1994-05-08
US08/101,074 1994-05-08
US08/239,542 1994-05-08

Publications (1)

Publication Number Publication Date
WO1995004277A1 true WO1995004277A1 (fr) 1995-02-09

Family

ID=26797874

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1994/007780 WO1995004277A1 (fr) 1993-08-03 1994-07-07 Methode de preparation et selection de composes non peptidiques a usage pharmacologique a partir d'une bibliotheque universelle d'elements de structures diverses

Country Status (6)

Country Link
EP (1) EP0712493A4 (fr)
JP (1) JPH09504511A (fr)
AU (1) AU7329394A (fr)
CA (1) CA2168886A1 (fr)
PE (1) PE14895A1 (fr)
WO (1) WO1995004277A1 (fr)

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997010222A1 (fr) * 1995-09-13 1997-03-20 Cortech, Inc. Procede de preparation de piperazines
WO1998005671A1 (fr) * 1996-08-07 1998-02-12 Oxford Asymmetry International Plc. Composes organosilicies et leur utilisation en chimie combinatoire
US5840500A (en) * 1996-07-11 1998-11-24 Trega Biosciences, Inc. Quinoline derivatives and quinoline combinatorial libraries
WO1999000669A1 (fr) * 1997-06-30 1999-01-07 Isis Pharmaceuticals, Inc. Combinatorique heterocyclique de nucleobases
US5874443A (en) * 1995-10-19 1999-02-23 Trega Biosciences, Inc. Isoquinoline derivatives and isoquinoline combinatorial libraries
US5916899A (en) * 1996-10-18 1999-06-29 Trega Biosciences, Inc. Isoquinoline derivatives and isoquinoline combinatorial libraries
WO1999064039A1 (fr) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. Antagonistes de bradykinine
WO2000032773A1 (fr) 1998-11-27 2000-06-08 Darwin Discovery Ltd. Compositions et methodes d'augmentation de la mineralisation de la substance osseuse
US6080587A (en) * 1998-01-23 2000-06-27 Eli Lilly And Company Method for preparing and selecting pharmaceutically useful sulfur-bridged bi- and triaromatic ring compounds from a structurally diverse universal library
WO2000056724A1 (fr) * 1999-03-22 2000-09-28 The Board Of Governors For Higher Education, State Of Rhode Island And Providence Plantations Banques combinatoires d'oxazole et de thiazole
US6127381A (en) * 1998-04-28 2000-10-03 Basu; Amaresh Isoquinoline compound melanocortin receptor ligands and methods of using same
US6284735B1 (en) 1998-04-28 2001-09-04 Lion Bioscience Ag HP-3228 and related peptides to treat sexual dysfunction
US6534503B1 (en) 1998-04-28 2003-03-18 Lion Bioscience Ag Melanocortin receptor-3 ligands to treat sexual dysfunction
WO2004009531A1 (fr) * 2002-07-24 2004-01-29 Janssen Pharmaceutica N.V. Composes acetyleniques utiles pour traiter des troubles inflammatoires
WO2004048552A2 (fr) 2002-11-21 2004-06-10 Celltech R & D, Inc. Modulation de reponses immunitaires
US6864235B1 (en) 1999-04-01 2005-03-08 Eva A. Turley Compositions and methods for treating cellular response to injury and other proliferating cell disorders regulated by hyaladherin and hyaluronans
US6878557B1 (en) 1995-01-20 2005-04-12 Arqule, Inc. Logically ordered arrays of compounds and methods of making and using the same
US6911429B2 (en) 1999-04-01 2005-06-28 Transition Therapeutics Inc. Compositions and methods for treating cellular response to injury and other proliferating cell disorders regulated by hyaladherin and hyaluronans
US7022703B2 (en) 2003-07-24 2006-04-04 Janssen Pharmaceutica, N.V. Acetylenic compound useful in treating inflammatory disorders
EP1967525A2 (fr) 2001-05-08 2008-09-10 Darwin Molecular Corporation Méthode de régulation de la fonction immune chez les primates à l'aide de la protéine foxp3
EP2338906A1 (fr) 2003-06-16 2011-06-29 UCB Manufacturing, Inc. Compositions et méthodes pour l'augmentation de la mineralisation des os
US20120077863A1 (en) * 2009-02-27 2012-03-29 Ucl Business Plc Guanidino-substituted bi-and polyphenyls as small molecule carriers
US8242145B2 (en) 2008-02-14 2012-08-14 Panmira Pharmaceuticals, Llc Cyclic diaryl ether compounds as antagonists of prostaglandin D2 receptors
US8383654B2 (en) 2008-11-17 2013-02-26 Panmira Pharmaceuticals, Llc Heterocyclic antagonists of prostaglandin D2 receptors
US8426449B2 (en) 2008-04-02 2013-04-23 Panmira Pharmaceuticals, Llc Aminoalkylphenyl antagonists of prostaglandin D2 receptors
WO2022235929A1 (fr) 2021-05-05 2022-11-10 Radius Pharmaceuticals, Inc. Modèle animal ayant une recombinaison homologue du récepteur pth1 de souris

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5218124A (en) * 1989-10-27 1993-06-08 American Home Products Corporation Substituted benzoylbenzene-, biphenyl- and 2-oxazole-alkanoic acid derivatives as inhibitors of pla2 and lipoxygenase
US5250548A (en) * 1990-09-10 1993-10-05 Abbott Laboratories Angiotensin II receptor antagonists

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5218124A (en) * 1989-10-27 1993-06-08 American Home Products Corporation Substituted benzoylbenzene-, biphenyl- and 2-oxazole-alkanoic acid derivatives as inhibitors of pla2 and lipoxygenase
US5250548A (en) * 1990-09-10 1993-10-05 Abbott Laboratories Angiotensin II receptor antagonists

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
AUSTRALIAN JOURNAL OF CHEMISTRY, Volume 45, issued 1992, BANWELL et al.: "Synthesis and Tubilin-Binding Properties of Some AC- and ABC-Analogues of Allocolchicine", pages 1967-1982, see pages 1968, 1969. *
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, Volume 114, issued 1992, BUNIN et al.: "A General and Expedient Method for the Solid-Phase Synthesis of 1,4-Benzodiazepine Derivatives", pages 10997-10998, see entire article. *
See also references of EP0712493A4 *

Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6878557B1 (en) 1995-01-20 2005-04-12 Arqule, Inc. Logically ordered arrays of compounds and methods of making and using the same
US5811241A (en) * 1995-09-13 1998-09-22 Cortech, Inc. Method for preparing and identifying N-substitued 1,4-piperazines and N-substituted 1,4-piperazinediones
WO1997010222A1 (fr) * 1995-09-13 1997-03-20 Cortech, Inc. Procede de preparation de piperazines
US5874443A (en) * 1995-10-19 1999-02-23 Trega Biosciences, Inc. Isoquinoline derivatives and isoquinoline combinatorial libraries
US6143895A (en) * 1996-07-11 2000-11-07 Trega Biosciences, Inc. Quinoline derivatives and quinoline combinatorial libraries
US5840500A (en) * 1996-07-11 1998-11-24 Trega Biosciences, Inc. Quinoline derivatives and quinoline combinatorial libraries
WO1998005671A1 (fr) * 1996-08-07 1998-02-12 Oxford Asymmetry International Plc. Composes organosilicies et leur utilisation en chimie combinatoire
US5916899A (en) * 1996-10-18 1999-06-29 Trega Biosciences, Inc. Isoquinoline derivatives and isoquinoline combinatorial libraries
WO1999000669A1 (fr) * 1997-06-30 1999-01-07 Isis Pharmaceuticals, Inc. Combinatorique heterocyclique de nucleobases
US6893815B1 (en) * 1997-06-30 2005-05-17 Isis Pharmaceuticals, Inc. Nucleobase heterocyclic combinatorialization
US6080587A (en) * 1998-01-23 2000-06-27 Eli Lilly And Company Method for preparing and selecting pharmaceutically useful sulfur-bridged bi- and triaromatic ring compounds from a structurally diverse universal library
US6608082B1 (en) 1998-04-28 2003-08-19 Lion Bioscience Ag Treatment of erectile dysfunction using isoquinoline compound melanocortin receptor ligands
US6127381A (en) * 1998-04-28 2000-10-03 Basu; Amaresh Isoquinoline compound melanocortin receptor ligands and methods of using same
US6284735B1 (en) 1998-04-28 2001-09-04 Lion Bioscience Ag HP-3228 and related peptides to treat sexual dysfunction
US6534503B1 (en) 1998-04-28 2003-03-18 Lion Bioscience Ag Melanocortin receptor-3 ligands to treat sexual dysfunction
WO1999064039A1 (fr) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. Antagonistes de bradykinine
EP1721979A1 (fr) 1998-11-27 2006-11-15 Ucb, S.A. Compositions et méthodes pour augmenter la minéralisation des os
EP2261335A1 (fr) 1998-11-27 2010-12-15 UCB Pharma S.A. Compositions et méthodes pour augmenter la minéralisation des os.
WO2000032773A1 (fr) 1998-11-27 2000-06-08 Darwin Discovery Ltd. Compositions et methodes d'augmentation de la mineralisation de la substance osseuse
WO2000056724A1 (fr) * 1999-03-22 2000-09-28 The Board Of Governors For Higher Education, State Of Rhode Island And Providence Plantations Banques combinatoires d'oxazole et de thiazole
US6864235B1 (en) 1999-04-01 2005-03-08 Eva A. Turley Compositions and methods for treating cellular response to injury and other proliferating cell disorders regulated by hyaladherin and hyaluronans
US6911429B2 (en) 1999-04-01 2005-06-28 Transition Therapeutics Inc. Compositions and methods for treating cellular response to injury and other proliferating cell disorders regulated by hyaladherin and hyaluronans
EP1967525A2 (fr) 2001-05-08 2008-09-10 Darwin Molecular Corporation Méthode de régulation de la fonction immune chez les primates à l'aide de la protéine foxp3
WO2004009531A1 (fr) * 2002-07-24 2004-01-29 Janssen Pharmaceutica N.V. Composes acetyleniques utiles pour traiter des troubles inflammatoires
WO2004048552A2 (fr) 2002-11-21 2004-06-10 Celltech R & D, Inc. Modulation de reponses immunitaires
EP2258724A1 (fr) 2002-11-21 2010-12-08 Celltech R & D, Inc. Modulation de réponses immunitaires utilisant des anticorps anti-CD83 multimerisés
EP2338906A1 (fr) 2003-06-16 2011-06-29 UCB Manufacturing, Inc. Compositions et méthodes pour l'augmentation de la mineralisation des os
EP2341071A1 (fr) 2003-06-16 2011-07-06 UCB Manufacturing, Inc. Compositions et méthodes pour l'augmentation de la minéralisation des os
US7022703B2 (en) 2003-07-24 2006-04-04 Janssen Pharmaceutica, N.V. Acetylenic compound useful in treating inflammatory disorders
US8242145B2 (en) 2008-02-14 2012-08-14 Panmira Pharmaceuticals, Llc Cyclic diaryl ether compounds as antagonists of prostaglandin D2 receptors
US8426449B2 (en) 2008-04-02 2013-04-23 Panmira Pharmaceuticals, Llc Aminoalkylphenyl antagonists of prostaglandin D2 receptors
US8383654B2 (en) 2008-11-17 2013-02-26 Panmira Pharmaceuticals, Llc Heterocyclic antagonists of prostaglandin D2 receptors
US20120077863A1 (en) * 2009-02-27 2012-03-29 Ucl Business Plc Guanidino-substituted bi-and polyphenyls as small molecule carriers
WO2022235929A1 (fr) 2021-05-05 2022-11-10 Radius Pharmaceuticals, Inc. Modèle animal ayant une recombinaison homologue du récepteur pth1 de souris

Also Published As

Publication number Publication date
EP0712493A4 (fr) 1997-01-15
PE14895A1 (es) 1995-06-08
CA2168886A1 (fr) 1995-02-09
JPH09504511A (ja) 1997-05-06
EP0712493A1 (fr) 1996-05-22
AU7329394A (en) 1995-02-28

Similar Documents

Publication Publication Date Title
WO1995004277A1 (fr) Methode de preparation et selection de composes non peptidiques a usage pharmacologique a partir d'une bibliotheque universelle d'elements de structures diverses
JP3943593B2 (ja) Ｎ−置換オリゴマーの合成
Hirschmann et al. De novo design and synthesis of somatostatin non-peptide peptidomimetics utilizing. beta.-D-glucose as a novel scaffolding
JP5005865B2 (ja) 創薬に有用な大環状化合物ライブラリーのコンビナトリアル合成
Dailler et al. Divergent Synthesis of Aeruginosins Based on a C (sp3) H Activation Strategy
JP2002517420A (ja) 新規アンギオテンシンレセプタモジュレーターおよびそれらの用途
EP2999483A2 (fr) Synthèse chimique et criblage de banques de peptides bicycliques
KR20040015797A (ko) 펩티드계 화합물
Chang et al. . kappa. Opioid Receptor Selective Affinity Labels: Electrophilic Benzeneacetamides as. kappa.-Selective Opioid Antagonists
EP3820842B1 (fr) Acide (r)-4-(1-(1-(1-(4-(4-(trifluorométhyl)benzyl)pyrrolidine-2-carboxamide)cyclopropyl)-benzoïque comme antagoniste du récepteur ep4
US5750506A (en) Bradykinin antagonists with extended hydrophobic side chains
Smith et al. Structure-activity studies of a novel bicyclic oxytocin antagonist
TW202210498A (zh) 高難度序列之有效率的胜肽縮合法
Lee et al. Peptide ligation via the suzuki–miyaura cross-coupling reaction
US6080587A (en) Method for preparing and selecting pharmaceutically useful sulfur-bridged bi- and triaromatic ring compounds from a structurally diverse universal library
US5017689A (en) Dynorphin analogs specific for kappa opioid receptors
JP2008505183A (ja) Ｐｄｚ−ドメイン相互作用阻害小分子
JP2002517461A (ja) ブラジキニンアンタゴニスト
WO1993012084A1 (fr) Peptidomimetisme aromatique
Hruby et al. Design of nonpeptides from peptide ligands for peptide receptors
WO1999033431A2 (fr) Procedes de preparation et de selection de composes a noyaux biaromatiques et triaromatiques pontes a partir d'une bibliotheque universelle a diversite structurelle
CN117229291B (zh) 内体-溶酶体转运靶向嵌合体降解剂及其制备方法与应用
Derdowska et al. New analogues of bradykinin containing a conformationally restricted dipeptide fragment in their molecules: Authors' affiliations
CN114437174B (zh) 一种用于抗雌激素受体α的氮杂稳定肽、其制备方法及其用途
Illuminati Exploring the potential of Pd-catalyzed CH activation reaction for the synthesis of non-natural amino acid 2, 6-dimethyl tyrosine-like (Dmt-like) analogues

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AM AT AU BB BG BR BY CA CH CN CZ DE DK ES FI GB GE HU JP KE KG KP KR KZ LK LT LU LV MD MG MN MW NL NO NZ PL PT RO RU SD SE SI SK TJ TT UA UZ VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE MW SD AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2168886

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 1994923427

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 1994923427

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1994923427

Country of ref document: EP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载