WO1997029091A1 - Analogues de balanol - Google Patents

Analogues de balanol Download PDF

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Publication number
WO1997029091A1
WO1997029091A1 PCT/DK1997/000058 DK9700058W WO9729091A1 WO 1997029091 A1 WO1997029091 A1 WO 1997029091A1 DK 9700058 W DK9700058 W DK 9700058W WO 9729091 A1 WO9729091 A1 WO 9729091A1
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Prior art keywords
optionally substituted
designates
acid
optionally
alkyl
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PCT/DK1997/000058
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English (en)
Inventor
John Nielsen
Lars Ole Lyngsø
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Phytera Symbion Aps
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Priority to EP97901527A priority Critical patent/EP0880503A1/fr
Priority to JP9528073A priority patent/JP2000504672A/ja
Priority to AU15409/97A priority patent/AU1540997A/en
Publication of WO1997029091A1 publication Critical patent/WO1997029091A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D223/12—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures

Definitions

  • the present invention relates to a novel method for the preparation of balanol analogues using a specially developed combinatorial chemistry scheme
  • the scheme is also especially suited for the preparation of libraries of balanol analogues
  • the present invention gives access to novel classes of compounds which may have interesting and unexpected structural and functional features, and, thus, the present invention also relates to the use of the libraries for screening purposes and to the use of novel compounds as medicaments for the treatment of various diseases
  • Balanol is a fungal metabolite, which has attracted significant attention because it possesses high PKC inhibiting activity Furthermore, balanol has a relatively favourable therapeutic index compared to staurospo ⁇ n, which is another known PKC inhibitor
  • the literature contains several examples of total syntheses of balanol in solution (Lampe, J W , Hughes, P F , Bigger, C K , Smith, S H , Hu, H J Org Chem 1994, 59, 5147-5148, Lampe, J W , Hughes, P F , Bigger, C K , Smith, S H , Hu, H J Org Chem 1996, 61 , 4572-4581, Nicolaou, K C , Bunnage, M E , Koide, K J J Am Chem Soc 1994, 1 16, 8402-8403, Adams, C P , Fairway, S M Hardy C J , Hibbs, D E , Hursthouse, M B , Morley, A D , Sharp, B W
  • the aim of the present invention is to provide a simplified synthetic scheme for the preparation of balanol analogues using solid-phase synthesis methodologies It is believed that a novel solid phase method for the preparation of balanol analogues may provide easier access to known analogues and also provide hitherto unknown balanol analogues The synthetic scheme will also allow for the easy preparation of combinatorial libraries of balanol analogues
  • the present invention provides a method for the preparation of balanol derivatives of the following general formula 1
  • each of A and B designates an organic biradical
  • each of L 1 and L 2 independently designates -NR 5 - or -0-
  • each R 5 independently is selected from hydrogen, optionally substituted Ci 20-alkyl, optionally substituted Ci 20-alkenyl, optionally substituted Ci 20-alkad ⁇ enyl, optionally substituted Ci 20-alkat ⁇ enyl, optionally substituted aryl, and optionally substituted heteroaryl
  • R 3 designates an additional bond to B (whereby B becomes a t ⁇ radical)
  • D designates optionally substituted aryl or optionally substituted heteroaryl
  • the method comprises the following steps
  • the present invention also provides a method for the preparation of a multi-dimensional array of compounds, ⁇ A ⁇ - ⁇ B ⁇ - ⁇ D ⁇ , consisting of at least four compounds, preferably in the range of 6-200 compounds, more preferably in the range of 6-100 compounds, in particular in the range of 8-64 compounds each having the general formula 1 as defined above, comprising the following steps
  • balanol Some of the novel analogues should not at first sight be expected to have any biological effects since they are structurally quite distinct from the original balanol molecule, however it is believed that such compounds may be useful as medicaments in that they are expected to have a higher specificity than balanol itself
  • the present invention also provides the use a compound library for screening purposes and the use of individual compound as a medicament
  • Ci 20-alkyl is intended to mean a linear, cyclic or branched hydrocarbon group having 1 to 20 carbon atoms, such as methyl, ethyl, propyl, iso-propyl cyclopropyl, butyl, (ert-butyl, iso-butyl, cyclobutyl, pentyl cyclopentyl, hexyl, cyclohexyl, hexadecyl, heptadecyl, octadecyl, nonadecyl
  • the term "Ci ⁇ -alkyl” is intended to mean a linear, cyclic or branched hydrocarbon group having 1 to 6 carbon atoms, such as methyl ethyl, propyl iso-propyl, pentyl, cyclopentyl, hexyl, cyclohexyl.
  • Ci 4-alkyl is intended to cover linear, cyclic or branched hydrocarbon groups having 1 to 4 carbon atoms, e g methyl, ethyl, propyl, iso-propyl, cyclopropyl, butyl, iso-butyl, (erf-butyl, cyclobutyl
  • C22o-alkenyl C4 2o-alkadienyl
  • C62o-alkatr ⁇ enyl are intended to mean a linear, cyclic or branched hydrocarbon group having 2 to 20, 4 to 20. and 6 to 20, carbon atoms, respectively, and comprising one, two, and three unsaturated bonds, respectively
  • alkenyl groups are vinyl, allyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, hepta- decaenyl
  • alkadienyl groups are butadienyl, pentadienyl, hexadienyl, heptadienyl, heptadecadienyl
  • alkat ⁇ enyl groups are hexat ⁇ enyl, heptat ⁇ enyl, octat ⁇ enyl, and heptadecatnenyl
  • Preferred examples of alkenyl are vinyl, ally], butenyl, especially allyl
  • C2 20-alkynyl is intended to mean a linear or branched hydrocarbon group having 2 to 20 carbon atoms and comprising a triple bond Examples hereof are ethynyl, propynyl, butynyl, octynyl, and dodecaynyl
  • alkyl in connection with the terms “alkyl”, “alkenyl”, “alkadienyl”, “alka- tnenyl”, and “alkynyl”, the term “optionally substituted” is intended to mean that the group in question may be substituted one or several times, preferably 1-3 times, with group(s) selected from hydroxy (which when bound to an unsaturated carbon atom may be present in the tautomeric keto form), Ci ⁇ -alkoxy (1 e alkyl-oxy), C2 ⁇ -alkenyloxy, carboxy, oxo (forming a keto or aldehyde functionality), Ci ⁇ -alkoxycarbonyl, Ci 6-alkylcarbonyl, formyl, aryl, aryloxycarbonyl aryloxy, arylcarbonyl, heteroaryl, heteroaryloxycarbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and d ⁇ (C ⁇ 6-alkyl)am ⁇ no,
  • aryl is intended to mean a fully or partially aromatic carbocyclic ring or ring system, such as phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracyl phenanthracyl, pyrenyl, benzopyrenyl, fluorenyl and xanthenyl, among which phenyl is a preferred example
  • heteroaryl groups are oxazolyl, isoxazolyl, thiazolyl, ISO- thiazolyl, pyrrolyl, lmidazolyl, pyrazolyl, py ⁇ dmyl, pyrazinyl, pyridazmyl, pipendinyl, coumaryl, furyl, quinolyl, benzothiazolyl, benzot ⁇ azolyl, benzodiazolyl, benzooxozolyl, phthalazinyl, phthalanyl, triazolyl, tetrazolyl, isoquinolyl, ac ⁇ din
  • non-aromatic carbocyclic and heterocyclic group is intended to cover rings comprising carbon atoms only (carbocyclic) or carbon atoms together with heteroatoms (heterocyclic), respectively Heteroatoms are typically selected from nitrogen, oxygen, and sulphur
  • Such groups involve no unsaturated bonds or one or several unsaturated bonds, however, if present, situated in such a way that no aromatic ⁇ -electron system arises It should be understood that the radical positions are situated directly on the ring in case of a biradical arising from such a group
  • non-aromatic carbocyclic and heterocyclic groups are oxazetane, diazetane, thiazetane, oxazolane, lmidazohdine, thiazolane, oxazilane, hexahydropyndazine, thiazilane, oxazepane, diazepane, thiazepane, oxazocane, diazocane, thiazocane, tetrahydrofuran, dihydro- furan, pyrrolidme, tetrahydrothiophen, tetrahydropyran, piperidme, tetrahydrothiopyran , oxepane, azepane, thiepane, oxocane, azocane, thiocane, cyclopropane, oxirane, azindine, cyclopropene, azinne, cyclobutane
  • the term “optionally substituted” is intended to mean that the group in question may be substituted one or several times, preferably 1-5 times in particular 1-3 times) with group(s) selected from hydroxy (which when present in an enol system may be represented in the tautomeric keto form), Ci ⁇ -alkyl Ci ⁇ -alkoxy, oxo (which may be represented in the tautomeric enol form), carboxy, Ci 6-alkoxycarbonyl, Ci 6-alkylcarbonyl, formyl, aryl, aryl- oxy, aryloxycarbonyl, arylcarbonyl, heteroaryl, amino, mono- and d ⁇ (C ⁇ 6-alkyl)am ⁇ no carbamoyl, mono- and d ⁇ (C ⁇ 6-alkyl)ammocarbonyl, armno-Ci
  • organic biradical and "biradical” are intended to have the meaning normally associated therewith
  • biradicals may be derived from practically any organic molecule from which two (non-geminal and theoretical) hydrogen atoms are removed
  • interesting biradicals are either linear or cyclic or comprises two or more domains selected from linear and cyclic sub-biradicals
  • Illustrative examples of combined biradicals comprising domains which have both linear and cyclic character are phenylene-carbonyl-phenylene, methylene-phenylene-methyleneoxy, and methylene-phenylene
  • the biradical may also consist of or comprise one or more cyclic elements, in particular 5- or 6-or 7-membered cyclic elements
  • oxygen or sulphur oxygen or sulphur
  • Examples of cyclic biradicals are biradicals of optionally substituted aryl groups and optionally substituted heteroaryl groups as well as biradicals of optionally substituted non-aromatic carbocyclic and heterocyclic groups
  • the compounds of the general formula I include possible salts thereof, of which pharmaceutically acceptable salts are especially relevant.
  • Salts include acid addition salts and basic salts Examples hereof are hydrochloride salts, sodium salts, calcium salts, potassium salts, etc..
  • Pharmaceutically acceptable salts are, e.g., those described in Remington's Pharmaceutical Sciences, 17. Ed. Alfonso R.Gennaro (Ed ), Mack Publishing Company, Easton, PA, U.S.A., 1985.
  • final products may also be present in hydrate form
  • this may be an aliphatic biradical of the formula
  • n 1-20, preferably 1-12, in particular 2-8, and
  • biradical A are biradicals either comprising or consisting of cyclic biradicals of the following radicals phenyl, naphthyl, anthracyl, pyrenyl, benzopyrenyl, phenoxazonyl, N 8 -phenoxazonyl, quinolyl, benzophenazinyl, ethidium and fluorenyl
  • Especially preferred examples are naphthyl, benzopyrenyl, phenoxazonyl, N 8 -phenoxazonyl, quinolyl benzophenazinyl, ethidium and fluorenyl, and/or comprising or consisting of linear biradicals of the formula -(CR 3 R 4 ) n -, where each of R 3 and R 4 independently are selected from optionally substituted Ci 6-alkyl, optionally substituted C2 ⁇ -alkenyl hydroxy oxo (thereby forming a keto or aldehyde functionality
  • aromatic and heteroaromatic biradicals, A may be substituted with one or more groups selected from the same groups as defined above as substituents for the aryl and heteroaryl groups
  • 2,2'-b ⁇ qu ⁇ nohne-4,4'-d ⁇ carboxyl ⁇ c acid 5-n ⁇ tro- ⁇ sophthal ⁇ c acid, 2-am ⁇ no-terephthahc acid, 2- bromo-terephthahc acid, 2-n ⁇ tro-terephthal ⁇ c acid, 3,6-d ⁇ chloro-phthal ⁇ c acid anhydride, 4,5- dichloro-phthalic acid anhydride, 3-n ⁇ tro-phthal ⁇ c acid anhydride, 4-n ⁇ tro-phthal ⁇ c acid anhydride, homophthahc acid, 4,4'-b ⁇ phenyl-d ⁇ carboxyhc acid, 2,2 -b ⁇ phenyl-d ⁇ carboxyhc acid, 2,3-naphthalene-d ⁇ carboxyhc acid, 2,6-naphthalene-d ⁇ carboxvhc acid, 1,8-naphthalene-d ⁇ - carboxyhc acid anhydride, 3-n ⁇ t
  • R 3 , R 4 and n are as defined above for A
  • biradical B are, e g , biradicals of the following non-aromatic carbocyclic compounds cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cycloheptane and cyclooctane, the following aromatic or non-aromatic heterocyclic compounds epoxides, aziridines, thioepoxides, oxazetane, diazetane, thiazetane, oxazolane, lmidazohdine, thiazolane, oxazilane, hexahydropyridaz e, thiazilane, oxazepane, diazepane, thiazepane, oxazocane, diazocane, thiazocane, tetrahydrofuran, dihydrofuran, pyrro
  • each of L 1 and L 2 independently designates -NR 5 - or -0-, wherein each R 5 independently is selected from hydrogen, optionally substituted Ci 20-alkyl, optionally substituted C220-alkenyl, optionally substituted C 20-alkad ⁇ enyl optionally substituted C ⁇ 20- alkat ⁇ enyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 6 designates an additional bond to B (whereby B becomes a t ⁇ radical)
  • R 5 designates hydrogen, Ci 4-alkyl or an additional bond to B
  • one of L 1 and L 2 is -O- and the other is -NR 5 -, where R 5 designates hydrogen, Ci 4-alkyl or an additional bond to B
  • interesting and highly relevant starting materials for the preparation of the compounds 1 are l-am ⁇ no- ⁇ -hydroxy-(opt ⁇ onally subst ⁇ tuted)-C ⁇ ⁇ -alkylene, where Ci ⁇ -alkylene is the
  • the hydroxy- and amino-function can be positioned 1 ,2-, 1,3-, 1 ,4- or 1,5-, where applicable, to each other as well as the stereochemical environment of the ammo and alcohol groups can be positioned either in a -configuration where the two substituents are on the same side of the ring or could be positioned fr ⁇ ns-configuration where the two substituents are on the different side of the ring system Likewise, different enantiomers (mirror images) and diastereoisomers can exist as an inherent result of the chirahty in such substituted non-aromatic carbocyclic compounds or heterocyclic compounds Thus, especially preferred examples are aminoalcohols derived from non-aromatic carbocyclic and heterocyclic compounds where the hydroxy and amino function are positioned 1,2 or 1,3 relative to each other, especially 1 ,2 to each other
  • aminoalcohols derived from non-aromatic carbocyclic compounds are 2- ammoethanol, l-am ⁇ no-2-propanol, 3-am ⁇ no- l-propanol, 2-am ⁇ no- l-propanol, 2-am ⁇ no-2-methyl- 1-propanol, l-am ⁇ no-2-methyl-2-propanol, 3-am ⁇ no-2-methyl- l-propanol, 2-am ⁇ no-l-butanol, 1 - am ⁇ no-2-butanol, 3-am ⁇ no-3-butanol, 3-am ⁇ no- l-butanol, 4-am ⁇ no-2-butanol, c ⁇ s-2-ammo- l- cyclobutanol, Jr ⁇ ns-2-am ⁇ no- l-cyclobutanol, 5-am ⁇ no-l-pentanol, 2-am ⁇ no- l -pentanol, 2-
  • aminoalcohols derived from heterocyclic compounds are c ⁇ s-4-am ⁇ no-3- hydroxy-pyrolidine, (r ns-4-am ⁇ no-3- hydroxy-pyrrolidine, c ⁇ s-4-am ⁇ no-3-hydroxy-tetrahydro- furan, (rans-4-am ⁇ no-3-hydroxy- tetrahydrofuran, c ⁇ .9-4-am ⁇ no-3-hydroxy-tetrahydroth ⁇ ophen, fr ⁇ n,s-4-am ⁇ no-3-hydroxy-tetrahydroth ⁇ ophen, c ⁇ s-3-am ⁇ no-4-hydroxy-p ⁇ pe ⁇ d ⁇ ne, (r ⁇ ns-3-am ⁇ no- 4-hydroxy-p ⁇ pe ⁇ d ⁇ ne, ci6--4-am ⁇ no-3-hydroxy-p ⁇ pe ⁇ d ⁇ ne, fr ns-4-am ⁇ no-3-hydroxy-p ⁇ per ⁇ d ⁇ ne, cis- 5-am ⁇ no-3
  • the biradical A is shown in the schemes as 2,6-naphthylene and 1,2- phenylene, respectively
  • the biradical B may be an aliphatic or non-aromatic carbocyclic or heterocyclic group or an aromatic or heteroaromatic group
  • the end group K is OH
  • L 1 is -0-
  • L 2 is -NR 5 -
  • D is phenyl
  • the solid phase material symbolised with a box, is a Wang resin
  • the group M 1 preferably designates OH or 0
  • M 1 is OH or 0
  • the group L' 1 of the entity L''-B-L' 2 should end up as L 1 in the compound I
  • L' 1 is, in the case where L 1 designate -0-, a hydroxyl group or a derivative thereof, preferably a hydroxyl group
  • the group L' 1 is preferably the free amino group or a derivative thereof which under the reaction conditions, will liberate a free ammo group
  • L' 1 is the free amino group either a primary am e, I e R 5 is hydrogen, or a secondary amine, I e
  • groups L' 2 should remain unaffected by the reaction conditions, it preferably designates a protected hydroxy group or a protected primary or secondary amme
  • groups L' 2 are - O-P (where L 2 is -0-), where P designate a hydroxy protection groups selected from dimethoxy- t ⁇ tyl (DMT), monomethoxyt ⁇ tyl (MMT), t ⁇ tyl, 9-(9-phenyl)xanthenyl (pixyl), tetraahydro- pyranyl (thp), methoxytetrahydropyranyl (mthp), t ⁇ methylsilyl (TMS), tnisopropylsilyl (TIPS), ferf-butyldimethylsilyl (TBDMS), t ⁇ ethylsilyl, phenyldimethylsilyl, benzyloxycarbonyl, substi- tuted benzyloxycarbonyl ethers such as 2-bromo
  • the reaction typically involves the use of a coupling agent
  • M 2 may designate OH, 0 ⁇ halogen such as fluoro or chloro, or the remainder of an active ester
  • the conditions for cleaving the compound from the solid phase material is described below in connection with the examples of solid phase materials
  • the cleavage step may, where applicable include deprotection of one or more protected functional groups It should be understood that deprotection may be performed before cleavage or after cleavage of the compound from the solid phase material Furthermore, in an interesting instance, deprotection is performed simultaneously to cleavage of the compound from the solid phase material The latter possibility applies when a Wang resin is used In this instance trifluoroacetic acid (TFA) is used for cleavage of the compound and deprotection of any Boc amino protecting groups
  • any of the groups in question e g any or all of A, B, and D
  • such chemical functionalities may be protected Protection of the starting materials may be performed, or protection may be performed prior to the potentially harmful reaction in a separate reaction step or protection may be included in the reaction step Protection of chemical functionalities may also become relevant in the cases where the unprotected variant of the compound in question is difficult or virtually impossible to purify In such cases a protection-pu ⁇ fication-deprotection scheme may be applied
  • Protecting groups were used according to state-in-the-art procedures such as those described by Greene, T W and Wuts, P G M (Protecting Groups in Organic Synthesis)
  • Preferred protecting groups are the protecting groups frequently used in solid-phase syntheses,
  • Possible protection groups comprise, but is not limited to, the ammo protection groups such as Fmoc (fluorenylmethoxycarbonyl), BOC (ter(-butyloxycarbonyl), trifluoroacetyl, allyloxycarbonyl (alloc, AOC), benzyloxycarbonyl (Z, Cbz) or substitued benzyloxycarbonyls such as 2-chloro benzyloxycarbonyl ((2-C1Z), DDE (Bloomberg, G B , et al , Tetrahedron Lett 1993 34, 4709- 4712), monomethoxyt ⁇ tyl (MMT), dimethoxyt ⁇ tyl (DMT), and 9-(9-phenyl)xanthenyl (pixyl), hydroxy protection groups such as dimethoxyt ⁇ tyl (DMT), monomethoxytrityl (MMT), trityl, 9- (9-phenyl)xanthenyl (pix
  • the compounds of the invention may be prepared by any well known methods or coupling reactions for the preparation of amide and ester bonds Such coupling reactions for establishing amide bonds, as well as ester bonds, between an compound fragment immobilised to a solid phase material and a second chemical species are known for the person skilled in the art of solid phase synthesis
  • An example is the well-established Merrifield solid phase synthesis methodo ⁇ logy (e.g Barany, G , and Merrifield, R B in 77 ⁇ e Peptides, Vol. 2, Academic Press, New York, 1979, pp 1-284)
  • solid phase material is intended to comprise solid phase materials know in the art Especially suitable solid phase materials (polymers) are based on polystyrene cross-linked with 0 2-2% divinylbenzene and functionahsed as described in the literature to yield resin of the so-called “Wang-type” (Wang, S -S , J Am.
  • the compound 1 may after cleavage from the solid phase material undergo a further reaction step (E) for the formation of another compound of the general formula I
  • the present invention further provides a method for the preparation of a multi- dimensional array, ⁇ A ⁇ - ⁇ B ⁇ - ⁇ D ⁇ , 1 e a combinatorial library, of compounds consisting of at least four compounds each having the general formula I
  • the total number of compound is depending on the number of fragments, I e m, n, and o
  • These numbers, m, n, and o are all positive integers, and in order for the multi-dimentional array to comprise at least four compound the product nvn «o must be at least 4
  • the combination where one of m, n, and o is four and the other two numbers each are one is possible within the method of the present invention, it is preferred that at least two of the numbers, preferably all three, are at least two, so that the highest degree of diversity of the combinatorial library is obtained Thus,
  • the preparation of a multi-dimensional array/library of compound follows the same principles as for the preparation of single compounds, and, thus, the synthetic scheme comprises the following steps (described for the case where the split-mix synthesis is used)
  • the o different batches from step (C) may be cleaved individually or the batches may be pooled before cleavage Pooling before cleavage may be advantageous seen from an economical and handling point of view
  • the array of m*n«o compound may actually be present in o batches each containing nvn compound These compound may then be pooled, e g before the actual screening is conducted Alternatively, each of the batches may be screened individually
  • the library consisting of
  • library formats could be as single compounds I e one vial would be containing one single compound, small mixtures of lsome ⁇ c compounds where stereoisomer would be included in the form of enantiomers, diastereomers, geometrical or positional isomers, as mixtures of typically 10- 100 compounds per vial to allow fast deconvolution down to the active substance, or as large mixtures of more than 100 compounds per vial to allow for rapid screening of vast combinatorial libraries Screening are performed in assay formats usual for the high throughput mode, typically using 96 well format, 384 well format or other microplate formats compatible with automation in the search of enzyme inhibitors, receptor agonist, partial agonists, as well as neutral antagonists and negative antagonists (inverse agonists) By such screening methods it
  • Biological effects interesting in the treatment of mammals such as human beings anesthetics, central nervous system depressants such as sedative-hypnotics, anticonvulsants neuroleptics and anxiolytic agents, drugs to treat neuromuscular disorders such as antiperkinsomsm agents or skeletal muscle relaxants, analgesics, central nervous system stimulants, local anesthetics, chohnergic agonists, acetylcholinesterase inhibitors or chohnergic antagonists, adrenergic drugs, cardiac agents such as cardiac glycoside analogs, antiangmals, and antiarrhythmic drugs, anticoagulants, coagulants, and plasma extenders, diuretics, antiallergic and antiulcer drugs, antihpidemic drugs, nonsteroidal anti-inflammatory drugs, drugs affecting sugar metabolism, antimycobacterial agents, antibiotics or antimicrobial agents antifungal agents, antiseptics or disinfectants, as hormone antagonists, antineoplastic agents for cancer chemotherapy or photochemotherapy, antiviral agents or as a
  • a further aspect of the invention is to provide novel compounds for the use as a medicament, and to provide the use of novel compounds for the manufacture of a medicament for one or more of the above mentioned
  • a still further aspect is to provide novel compound for the for the use in crop protection
  • FIGS 1 and 2 illustrate various examples of biradicals A The meanings of the symbols are defined above
  • balanol libraries was synthesised using split-synthesis -method After each step the resins was mixed and swollen in a isopycnic mixture of 1,2-d ⁇ chlorethane and DMF (2 l)and the resin was split for the next step in the synthesis To analyse the contents attached to the resin, it was cleaved of the resin using a solution of 50% TFA dichloromethane
  • N-Fmoc-l-amino-2-propanol Procedure as above using 0 238 g (0 8 mmol) N-Fmoc-l-am ⁇ no-2- propanol The two products was identified on HPLC N-Fmoc-2-amino-l-butanol. Procedure as above using 0 249 g (0 8 mmol) N-Fmoc-2-am ⁇ no- l - butanol The two products was identified on HPLC

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

Méthode de préparation en phase solide d'une série combinatoire d'analogues structurels du produit naturel qu'est le balanol (ophiocordine, azépinostatine), cette série étant un inhibiteur de la protéine kinase C (PKC) et de la protéine kinase A (PKA). Cette méthode prévoit la synthèse en phase solide de variants analogues du balanol avec introduction d'une grande diversité moléculaire. Le schéma de synthèse est basé sur une analyse rétrosynthétique de la structure native ayant fait apparaître trois blocs principaux comme modèles appropriés de modification. La fraction dicarboxy-fonctionnelle peut être immobilisée par rapport au support polymère soit comme ester monoallyle ou comme anhydride interne. Les séries obtenues selon ce procédé se révèlent particulièrement appropriées pour une présélection à haut rendement de candidats potentiels pour le traitement de mammifères supérieurs, notamment de l'être humain.
PCT/DK1997/000058 1996-02-09 1997-02-10 Analogues de balanol WO1997029091A1 (fr)

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EP97901527A EP0880503A1 (fr) 1996-02-09 1997-02-10 Analogues de balanol
JP9528073A JP2000504672A (ja) 1996-02-09 1997-02-10 バラノール類似体
AU15409/97A AU1540997A (en) 1996-02-09 1997-02-10 Balanol analogues

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DK13696 1996-02-09

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Cited By (8)

* Cited by examiner, † Cited by third party
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WO1999032660A1 (fr) * 1997-12-19 1999-07-01 Affymetrix Exploitation de genomes pour la recherche de nouveaux medicaments
WO2001023331A1 (fr) * 1999-09-30 2001-04-05 Peptron Inc. Procede de preparation d'une banque chimique a partir d'un produit naturel
EP1147214A1 (fr) * 1999-01-13 2001-10-24 The Research Foundation Of State University Of New York Nouveau procede d'identification d'inhibiteurs de proteines kinase
WO2002081413A2 (fr) * 2001-04-09 2002-10-17 Carlsberg A/S Protection unichemo (ucp) unidimensionnelle en synthese organique
US6542858B1 (en) 1998-09-14 2003-04-01 Lion Bioscience Ag Pharmacokinetic-based drug design tool and method
EP1418244A1 (fr) * 1997-12-19 2004-05-12 Affymetrix, Inc. Exploitation de la génomique pour identifier des médicaments nouveaux
US7772216B2 (en) 2001-10-22 2010-08-10 The Research Foundation Of State University Of New York Protein kinase and phosphatase inhibitors and methods for designing them
US7838542B2 (en) 2006-06-29 2010-11-23 Kinex Pharmaceuticals, Llc Bicyclic compositions and methods for modulating a kinase cascade

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7098060B2 (en) 2002-09-06 2006-08-29 E.I. Du Pont De Nemours And Company Methods for producing full-color organic electroluminescent devices

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993003730A1 (fr) * 1991-08-22 1993-03-04 Sphinx Pharmaceuticals Corporation Inhibition de proteine-kinase c et nouveau compose appele balanol

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993003730A1 (fr) * 1991-08-22 1993-03-04 Sphinx Pharmaceuticals Corporation Inhibition de proteine-kinase c et nouveau compose appele balanol

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, Volume 5, No. 17, 1995, G. ERIK JAGDMANN Jr. et al., "Novel PKC Inhibitory Analogs of Balanol With Replacement of the Ester Functionality", pages 2015-2020. *
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, Volume 5, No. 18, 1995, YEN-SHI LAI et al., "Heteroatom Effect in the PKC Inhibitory Activities of Perhydroazepine Analogs of Balanol", pages 2147-2150. *
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, Volume 5, No. 18, 1995, YEN-SHI LAI et al., "Synthesis and PKC Inhibitory Activities of Balanol Analogs With a Cyclopentane Substructure", pages 2155-2160. *
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, Volume 5, No. 19, 1995, JOSE S. MENDOZA et al., "Synthesis and Biological Evaluation of Conformationally Constrained Bicyclic and Tricyclic Balanol Analogues as Inhibitors of Protein Kinase C", pages 2211-2216. *
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, Volume 6, No. 15, 1996, G. ERIK JAGDMANN Jr. et al., "Potent and Selective PKC Inhibitory 5-Membered Ring Analogs of Balanol With Replacement of the Carboxamide Moiety", pages 1759-1764. *
CHEM. EUR. J., Volume 1, 1995, K.C. NICOLAOU et al., "Total Synthesis of Balanol and Designed Analogues", pages 454-466. *
TETRAHEDRON LETTERS, Volume 37, No. 46, 1996, JOHN NIELSEN et al., "Combinatorial Solid-Phase Synthesis of Balanol Analogues", pages 8439-8442. *

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EP1418244A1 (fr) * 1997-12-19 2004-05-12 Affymetrix, Inc. Exploitation de la génomique pour identifier des médicaments nouveaux
US6333155B1 (en) 1997-12-19 2001-12-25 Affymetrix, Inc. Exploiting genomics in the search for new drugs
WO1999032660A1 (fr) * 1997-12-19 1999-07-01 Affymetrix Exploitation de genomes pour la recherche de nouveaux medicaments
US6524800B2 (en) 1997-12-19 2003-02-25 Affymetrix, Inc. Exploiting genomics in the search for new drugs
US6542858B1 (en) 1998-09-14 2003-04-01 Lion Bioscience Ag Pharmacokinetic-based drug design tool and method
US6996473B2 (en) 1998-09-14 2006-02-07 Lion Bioscience Ag Method for screening and producing compound libraries
US6647358B2 (en) 1998-09-14 2003-11-11 Lion Bioscience Ag Pharmacokinetic-based drug design tool and method
JP2002534132A (ja) * 1999-01-13 2002-10-15 ザ・リサーチ・ファウンデーション・オブ・ステイト・ユニバーシティ・オブ・ニューヨーク タンパク質キナーゼ阻害剤を設計するための新規の方法
EP1147214A1 (fr) * 1999-01-13 2001-10-24 The Research Foundation Of State University Of New York Nouveau procede d'identification d'inhibiteurs de proteines kinase
EP1147214A4 (fr) * 1999-01-13 2008-08-27 Univ New York State Res Found Nouveau procede d'identification d'inhibiteurs de proteines kinase
US7901894B2 (en) 1999-01-13 2011-03-08 The Research Foundation Of State University Of New York Kinase inhibitors
JP4865129B2 (ja) * 1999-01-13 2012-02-01 ザ・リサーチ・ファウンデーション・オブ・ステイト・ユニバーシティ・オブ・ニューヨーク タンパク質キナーゼ阻害剤を設計するための新規の方法
WO2001023331A1 (fr) * 1999-09-30 2001-04-05 Peptron Inc. Procede de preparation d'une banque chimique a partir d'un produit naturel
US7083812B2 (en) 1999-09-30 2006-08-01 Peptron, Inc. Chemical library preparation method from natural product
WO2002081413A2 (fr) * 2001-04-09 2002-10-17 Carlsberg A/S Protection unichemo (ucp) unidimensionnelle en synthese organique
WO2002081413A3 (fr) * 2001-04-09 2004-05-27 Carlsberg As Protection unichemo (ucp) unidimensionnelle en synthese organique
US7772216B2 (en) 2001-10-22 2010-08-10 The Research Foundation Of State University Of New York Protein kinase and phosphatase inhibitors and methods for designing them
US8088768B2 (en) 2001-10-22 2012-01-03 The Research Foundation Of The State University Of New York Protein kinase and phosphatase inhibitors
US7838542B2 (en) 2006-06-29 2010-11-23 Kinex Pharmaceuticals, Llc Bicyclic compositions and methods for modulating a kinase cascade

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