WO1997029091A1

WO1997029091A1 - Balanol analogues

Info

Publication number: WO1997029091A1
Application number: PCT/DK1997/000058
Authority: WO
Inventors: John Nielsen; Lars Ole Lyngsø
Original assignee: Phytera Symbion Aps
Priority date: 1996-02-09
Filing date: 1997-02-10
Publication date: 1997-08-14
Also published as: AU1540997A; JP2000504672A; EP0880503A1

Abstract

The present invention relates to a solid phase methodology for the preparation of a combinatorial library of structural analogues of the natural product balanol (ophiocordin, azepinostatin), which is a protein kinase C (PKC) and protein kinase A (PKA) inhibitor. The method comprises solid-phase synthesis of the analog variants of balanol whereby a high molecular diversity is introduced. The synthetic scheme is based on a retrosynthetic analysis of the native structure which revealed three main building blocks suitable as templates for modification. The dicarboxy-functional moiety can be immobilised to the polymer support either as the monoallyl ester or as the internal anhydride. The libraries produced by the method are especially suited for high throughput screening of potential drug candidates for the treatment of mammals, especially humans.

Description

BALANOL ANALOGUES

FIELD OF THE INVENTION

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

BACKGROUND OF THE INVENTION

In traditional medicinal chemistry, an average of 10,000 different compounds are synthesised and tested during the process of finding the one active component with the right pharmacological and toxicological properties (the drug) The combined experiences from a series of analytical, crystallographic, synthetic organic and computational chemistry techniques have been collected and generated a whole new field often termed "Rational Drug Design" These methods have been expected to speed up and facilitate the search for new lead compounds and drugs, but have so far not proven very effective Today the average cost for a new drug still runs around US$ 250- 350,000,000 and it takes an average of 12 years for a new drug to reach the market place Furthermore, in spite of obvious scientific progress during the last couple of decades, many diseases are still threatening mankind because of no or insufficient treatment These obviously include AIDS, cardiovascular diseases and human cancers but also diseases related to neuro- degenerative disorders (e g Alzheimer's disease), metabolic disorders (Type 2 Diabetes) and other diseases affecting not only the quantity but also the quality of life

To facilitate this search for novel biologically active compounds, a new chemical/analytical technique has emerged This research area is often termed combinatorial chemistry and it is one of the fastest growing research areas in modern organic chemistry The synthesis and screening of vast and diverse libraries of small molecules might lead not only to new drugs but might also have a great importance for the discovery of novel synthetic receptors, new materials or new catalysts Most of the reported literature in this field have been concerned with libraries consisting of small peptides and oligonucleotides because synthetic protocols for solid-phase synthesis of these molecules have been optimised for decades However, small molecules represent a larger challenge for the synthetic organic chemist as well hold the potential for finding possible leads for the drug discovery process The generation of chemical diversity using combinatorial chemistry is one of the most active fields of modern organic chemistry Initially research was focused on the generation on peptide and nucleotide libraries but more recently - due to the dubious drug-potential for finding molecules with activities in other areas such as anesthetics central nervous system depressants such as sedative-hypnotics, anticonvulsants neuroleptics and anxiolytic agents drugs to treat neuromuscular disorders such as antiperkinsonism agents or skeletal muscle relaxants, analgesics, central nervous system stimulants, local anesthetics, chohnergic agonists, acetylcholmesterase inhibitors or chohnergic antagonists, adrenergic drugs cardiac agents such as cardiac glycosides, antiangmals, and antiarrhvthmic 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, as pesticides, antiseptics or disinfectants, as hormone antagonists, antineoplastic agents for cancer chemotherapy or photochemotherapy antiviral agents or as a potential drugs against HIV-infections and AIDS - the generation of non- peptidic small molecule libraries have attracted most of the attention and resources in this field

Protein kinase C (PKC) belongs to a family of serin e/threomne specific kinases which are involved in a variety of processes including signal transduction, cell proliferation and cell differentiation Agents that inhibit PKC may have wide ranging therapeutic potential since activated PKC has been implicated in numerous disease processes These include some widespread and severe diseases such as cancer, inflammation, cardiovascular dysfunctions, diabetic complications, asthma, central nervous system disorders and HIV infection

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 staurospoπn, 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 , Vicker, N , Warner, I J Chem Soc Perkin Trans I, 1995, 2355-2362) and some analogues with improved selectivity (Lai, Y -S , Stamper, M Bworg Med Chem Lett 1995, 5, 2147-2150, Lai, Y -S , Menaldino, D S , Nichols J B , Jagdmann, G E J , Mylott, F , Gillespie, J , Hall, S E Bworg Med Chem Lett 1995, 5, 2151-2154, Nicolaou, K C , Koide, K , Bunnage, M E Chem Eur J 1995, 1 , 454-466) However, all these syntheses involve numerous synthetic steps and a level of complication in the applied chemistry that is not compatible with solid-phase organic synthesis and combinatorial chemistry SUMMARY OF THE INVENTION

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

Thus, the present invention provides a method for the preparation of balanol derivatives of the following general formula 1

K-C(=0)-A-C(=0)-L>-B-L²-C(=0)-D I

wherein K-C(=0)- designates a carboxy group or a derivative thereof, each of A and B designates an organic biradical, each of L¹ and L² independently designates -NR⁵- or -0-, wherein each R⁵ independently is selected from hydrogen, optionally substituted Ci 20-alkyl, optionally substituted Ci 20-alkenyl, optionally substituted Ci 20-alkadιenyl, optionally substituted Ci 20-alkatπenyl, optionally substituted aryl, and optionally substituted heteroaryl, or R³ designates an additional bond to B (whereby B becomes a tπradical), and D designates optionally substituted aryl or optionally substituted heteroaryl, the method comprises the following steps

(A) providing an optionally functional group protected moiety -C(=0)-A-C(=0)-M' immobilised to a solid support material, wherein -C(=0)-M¹ designates a carboxy group or a derivative thereof,

(B) coupling an optionally functional group protected difunctional entity L'^!-B-L'² to the -C(=0)- M¹ end of the immobilised moiety -C(=0)-A-C(=0)-M¹ for the formation of an optionally functional group protected immobilised fragment -C(=0)-A-C(=0)-L'-B-L'²,

(C) coupling an optionally functional group protected entity D-C(=0)-M² wherein C(=0)-M² designates a carboxy group or a derivative thereof, to the L'² end of the immobilised fragment - C(=0)-A-C(=0)-L¹-B-L'² for the formation of an optionally functional group protected immobilised compound -C(=0)-A-C(=0)-L¹-B-L²-C(=0)-D, the step optionally including deprotection of any protection group involved in L'², and

(D) cleaving the compound K-C(=0)-A-C(=0)-L¹-B-L²-C(=0)-D from the solid support material the step optionally including deprotection of one or more functional group(s) attached to A, B, and/or D 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

(A) providing an array {A} of m optionally functional group protected moieties -C(=0)-A-C(=0)- M¹ immobilised to a solid support material, wherein -C(=0)-M¹ designates a carboxy group or a derivative thereof,

(B) coupling an array {B} of n optionally functional group protected difunctional entities L'-B-L'² to the -C(=0)-M¹ end of the immobilised moieties -C(=0)-A-C(=0)-M¹ for the formation of an array {A}-{B} of m*n optionally functional group protected immobilised fragments -C(=0)-A- C(=0)-L'-B-L'²,

(C) coupling an array {D} of o optionally functional group protected entities D-C(=0)-M², wherein -C(=0)-M² designates a carboxy group or a derivative thereof, to the L'² end of the immobilised fragments -C(=0)-A-C(=0)-L¹-B-L'² for the formation of an array {A}-{B}-{D} of m*n*o optionally functional group protected immobilised compounds -C(=0)-A-C(=0)-L¹-B-L²-C(=0)-D, the step optionally including deprotection of any protection group involved in L'², and

(D) cleaving the array {A}-{B}-{D} of compounds K-C(=0)-A-C(=0)-L'-B-L -C(=0)-D from the solid support material, the step optionally including deprotection of one or more functional group(s) attached to individual As, Bs, and/or Ds

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

Thus, the present invention also provides the use a compound library for screening purposes and the use of individual compound as a medicament

DETAILED DESCRIPTION OF THE INVENTION

Definitions

In the present context, the term "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 Analogously, the term "Ci β-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. and the term "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

Preferred examples of "Ci β-alkyl" are methyl, ethyl, propyl, iso-propyl, butyl, (erf-butyl, iso- butyl, pentyl, cyclopentyl, hexyl, cyclohexyl, in particular methyl, ethyl, propyl, iso-propyl, tert- butyl, iso-butyl and cyclohexyl Preferred examples of "Ci 4-alkyl" are methyl, ethyl, propyl, iso- propyl, butyl, (erf-butyl, and iso-butyl

Similarly, the terms "C22o-alkenyl", "C4 2o-alkadienyl", and "C62o-alkatrιenyl" 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

Examples of alkenyl groups are vinyl, allyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, hepta- decaenyl Examples of alkadienyl groups are butadienyl, pentadienyl, hexadienyl, heptadienyl, heptadecadienyl Examples of alkatπenyl groups are hexatπenyl, heptatπenyl, octatπenyl, and heptadecatnenyl Preferred examples of alkenyl are vinyl, ally], butenyl, especially allyl

Similarly, the term "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

In the present context, 1 e 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 β-alkoxy (1 e alkyl-oxy), C2 β-alkenyloxy, carboxy, oxo (forming a keto or aldehyde functionality), Ci β-alkoxycarbonyl, Ci 6-alkylcarbonyl, formyl, aryl, aryloxycarbonyl aryloxy, arylcarbonyl, heteroaryl, heteroaryloxycarbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and dι(Cι 6-alkyl)amιno, carbamoyl, mono- and dι(Cι 6-alkyl)amιnocarbonyl, a ino- Cι 6-alkyl-amιnocarbonyl, mono- and di(Cι 6-alkyl)amιno-Cι β-alkyl-aminocarbonyl, Ci β-alkyl- carbonylamino, guanidino, carbamido, Ci 6-alkanoyloxy, sulphono, Ci β-alkylsulphonyloxy, nitro, sulphanyl, Ci 6-alkylthιo, tπhalogen-Ci 4-alkyl, halogen such as fluoro, chloro, bromo or lodo, where aryl and heteroaryl may be substituted as specifically describe above for "optionally substituted aryl and heteroaryl" Preferably, the substituents are selected from hydroxy, Ci 6-alkoxy, carboxy, Ci 6-alkoxvcarbonyl Ci 6-alkylcarbonyl, formyl, aryl, aryloxycarbonyl, arylcarbonyl, heteroaryl, amino, mono- and dι(Cι 6-alkyl)amιno, carba oyl, mono- and dι(Cι 6-alkyl)amιnocarbonyl, amino-Ci 6-alkyl-amιno- carbonyl, mono- and dι(Cι 6-alkyl)ammo-Cι 6-alkyl-amιnocarbonyl, Ci β-alkylcarbonylamino, carbamido, tπhalogen-Ci 4-alkyl, halogen such as fluoro, chloro, bromo or lodo, where aryl and heteroaryl may be substituted 1-5 times, preferably 1-3 times, with Ci 4-alkyl, Ci 4-alkoxy, nitro, ammo or halogen Especially preferred examples are hydroxy, Ci β-alkoxy, carboxy, aryl heteroaryl, amino, mono- and dι(Cι 6-alkyl)amιno, and halogen such as fluoro, chloro, bromo or lodo, where aryl and heteroaryl may be substituted 1-3 times with Ci 4-alkyl, Ci 4-alkoxy, nitro amino or halogen

In the present context the term "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

The term "heteroaryl" is intended to mean a fully or partially aromatic carbocyclic ring or ring system where one or more of the carbon atoms have been replaced with heteroatoms, e.g nitrogen (=N- or -NR⁵-, where R^δ is selected from hydrogen and Ci 4-alkyl), sulphur, and/or oxygen atoms Examples of such heteroaryl groups are oxazolyl, isoxazolyl, thiazolyl, ISO- thiazolyl, pyrrolyl, lmidazolyl, pyrazolyl, pyπdmyl, pyrazinyl, pyridazmyl, pipendinyl, coumaryl, furyl, quinolyl, benzothiazolyl, benzotπazolyl, benzodiazolyl, benzooxozolyl, phthalazinyl, phthalanyl, triazolyl, tetrazolyl, isoquinolyl, acπdinyl, carbazolyl, dibenzazepinyl, mdolyl, benzopyrazolyl, phenoxazonyl Preferred heteroaryl groups are pyridinyl, benzopyrazolyl, and lmidazolyl

In the present context the term "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 π-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

Specific examples of 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 oxetane, azetidine, thietane, 2-azetιdιnone 1 3-lactone, pyrohdine, pyrohne, pyrrole, cyclopentene, cyclopentadiene, pyrolhdione, pvrollidone cyclohexyl oxirane, dioxirane, morpholine, pipeπdme, 1,5-lactone, 1,5-lactam, cyclohexene yclohexadiene, pipeπdione, tropane, 1,6-lactone (tropolone), 1 ,6-lactam azepine, dihydroazepine, tetrahydroazepine, and hexahydroazepine Especially preferred examples are oxirane, azindine, azinne, oxetane, 2-azetιdιnone, 1,3-lactone, pyrohdine, pyrohne, pyrrole, pyrolhdone, pyrol¬ hdione, oxirane, dioxirane, morpholine, pipeπdine, δ-valerolactam (2-pιpendone), 1 5-lactone, pipeπdione, tropolone, 1,6-lactam, azepine, dihydroazepine, tetrahydroazepine, and hexahydroazepine Particularly preferred examples are 2-azetιdιnone, 1,3-lactone, pyrolhdone 1,5-lactam, 1,5-lactone, tropolone, 1,6-lactam, azepine, dihydroazepine, tetrahydroazepine, and hexahydroazepine

In the present context, I e in connection with the terms "aryl", "heteroaryl", and "non-aromatic carbocyclic and heterocyclic group", 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 β-alkyl Ci β-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 dι(Cι 6-alkyl)amιno carbamoyl, mono- and dι(Cι 6-alkyl)ammocarbonyl, armno-Ci 6-alkyl-ammocarbonyl, mono- and dι(Cι β-alkyl)- amino-Ci 6-alkyl-amιnocarbonyl, Ci 6-alkylcarbonylamιno, guamdmo, carbamido, Ci 6-alkanoyl- oxy, sulphono, Ci 6-alkyIsulphonyloxy, nitro, sulphanyl, dihalogen-Ci 4-alkyl, tnhalogen-Ci 4- alkyl, halogen such as fluoro, chloro, bromo or lodo, where aryl and heteroaryl representing substituents may be Preferred examples are hydroxy, Ci β-alkyl, Ci β-alkoxy, carboxy, Ci e- alkoxycarbonyl, Ci 6-alkylcarbonyl, aryl, amino, mono- and dι(Cι 6-alkyl)amιno and halogen such as fluoro, chloro, bromo or lodo, wherein aryl and heteroaryl may be substituted as above

In the present context the synonymous terms "organic biradical" and "biradical" are intended to have the meaning normally associated therewith Thus, such biradicals may be derived from practically any organic molecule from which two (non-geminal and theoretical) hydrogen atoms are removed In the present context, 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

Examples of linear biradicals or domains of a combined biradical are 1-20 carbon atom alkylene chain optionally interrupted and/or terminated by one or more heteroatoms selected from O, S and NR⁵, and optionally substituted one or several times, preferably 1-δ times, in particular 1-5 times, with substιtuent(s) selected from optionally substituted Ci β-alkyl optionally substituted C2 e-alkenyl, optionally substituted C4 β-alkadienyl, optionally substituted Cβ a-alkatπenyl hydroxy oxo (thereby forming a keto or aldehyde functionality), -O-R⁶, formyl, -C(=0)-R⁶ -0-C(=0)-R⁶, carboxy, -C(=0)-0-R⁶, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted aryl, optionally substituted aryloxy, halogen such as fluoro chloro, bromo, and lodo, nitro, cyano, -N(R^B)2, -NC O-CO-R⁶, carbamoyl, mono- or dι(Cι β-alkyl)- aminocarbonyl, sulphanyl, optionally substituted Ci β-alkylthio, optionally substituted Ci β-alkyl- thio-Ci 6-alkyl, (optionally substituted aryl)thιo, guamdino, sulphono (-SO3H), sulphino (-SO₂H), halosulphonyl, -OS(0)m-R⁶ where m is 2 or 3, -N(R⁷)S(0)_m-R⁶ where m is 2 or 3, -S(0)m-N(R⁷)₂ where m is 2 or 3, -S(0)m-NH(R⁷) where m is 2 or 3, -S(0)_m-NIi2 where m is 2 or 3, isocyano, isothiocyano, thiocyano, -OP(0)_P(R⁶) where p is 1, 2, or 3, q is 1 or 2, and p+q is 3, 4, or 5, and -N(R⁷)P(0)_P(R⁶)q where p is 1, 2, or 3, q is 1 or 2, and p+q is 3, 4, or 5, wherein each R⁵ and each R⁶ independently is selected from hydrogen, optionally substituted Ci 20-alkyl, optionally substituted C220-alkenyl, optionally substituted C42o-alkadιenyl, optionally substituted C6₂0- alkatrienyl, optionally substituted aryl, and optionally substituted heteroaryl, and each R⁷ is selected from hydrogen and Ci 4-alkyl

Especially preferred examples of linear biradicals or domains of a combined biradical are substituents are 1-6 carbon atom alkylene chain optionally interrupted and/or terminated by one or two heteroatoms selected from 0, S, and NR⁶, and optionally substituted 1-3 times with substιtuent(s) selected from optionally substituted Ci β-alkyl, optionally substituted C2 β-alkenyl, hydroxy, oxo (thereby forming a keto or aldehyde functionality), -O-R⁶, formyl, -C(=0)-R⁶, -0-C(=0)-R⁶, carboxy, -C(=0)-0-R⁶, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted aryl, optionally substituted aryloxy, halogen such as fluoro chloro, bromo, and lodo, cyano, -N(R⁶)2, -N(R⁷)-C0-R⁶, carbamoyl, mono- or dι(Cι 6-alkyl)amιno- carbonyl, Ci 6-alkylthιo, wherein each R⁵ and R⁷ independently is selected from hydrogen and Ci 4-alkyl, and each R⁶ independently is selected from hydrogen, optionally substituted Ci 6-alkyl, optionally substituted C2 β-alkenyl, optionally substituted aryl, and optionally substituted heteroaryl

The biradical may also consist of or comprise one or more cyclic elements, in particular 5- or 6-or 7-membered cyclic elements Each such cyclic element may independently be saturated, unsaturated or fully or partially aromatic, it may be carbocyclic, or it may be heterocyclic by incorporating 1, 2, 3, or 4 heteroatoms, typically selected from nitrogen (=N- or -NR⁵-, where R⁵ is as defined above for the linear biradicals), oxygen or sulphur In the case of several cyclic elements being present, these may be connected through single or double bonds, or they may be fused, or combinations thereof 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

As it will be evident from the general formula I and the definitions associated therewith, there may be one or several asymmetric carbon atoms present in the compound I depending on the nature of the biradicals and the possible substituents, cf below. The compounds prepared according to the method of the invention, as well as the compound I per se, are intended to include all stereoisomers arising from the presence of any and all isomers of the individual moieties as well as mixtures thereof, including racemic mixtures

It should furthermore be understood that 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. Furthermore, final products may also be present in hydrate form

Construction of the compounds of the general formula I

The rationale for the method according to invention is illustrated in Scheme 1, where a retrosynthetic analysis of balanol lead to the identification of three main building blocks or synthons which are mono-protected aromatic diacids, aminoalcohols and benzoic acid derivatives, respectively

Scheme 1 Thus, with reference Scheme 1, a number of modification are possible and also realistic within the scope of the present invention For example, the balanol molecule comprises one amide bond and one ester bond, corresponding to -L²-C(=0)- and -C(=0)-L'-, respectively However, the analogues which are possible within the present invention may comprise two amide bond or two ester bonds, or the bonds may be interchanged, so that the ester bond corresponds to -L²-C(=0)- and the amide bond corresponds to -C(=0)-L'- It is furthermore believed that the benzoic acid building block may be represented by any aromatic and heteroaromatic carboxylic acid, and that the diacid may be any other dicarboxylic acid of linear, cyclic, non-aromatic or aromatic origin

The moiety K-C(=0)- in the general formula I designates a carboxylic acid (K=OH) or a derivative thereof It should be understood that any of the carboxylic acid derivatives known in the art are possible within the definition of the present invention However, since the moiety -C(=0)-K arises when cleaving the compound I from a solid phase resin (when the compound I is prepared according to the present invention), the moiety is typically in the free acid form

(-COOH, K=OH) or in the carboxylate form (-COO , K=0 ), where the counter ion is selected from alkali metals, such as sodium and potassium, alkaline earth metals, such as calcium, and ammonium ions (N(R)₂R'), or is deπvatised as the amide (-CONH2, -CONHR, -CONRR', K= NH2, NHR, NRR', respectively), the hydroxylamide (-CON(OH)H, K=N(OH)H), the hydrazide (- CONHNH2, CONHNHR'", K= NHNH2, NHNHR'", respectively) or the ester (-COOR", K=R"), where each of R, R', R", and R'" independently designates optionally substituted Ci 20-alkyl, optionally substituted C22o-alkenyl, optionally substituted C4 20-alkadιenyl, optionally substituted C620-alkatrιenyl, optionally substituted aryl, or optionally substituted heteroaryl Furthermore, the C-terminal carboxylic acid may be reduced to the corresponding the corresponding aldehyde (K=H) in the cleavage step Preferably, K designates OH, O , OR", NH2, NHR, or NRR', in particular OH, methoxy, or NH2, where R and R' are selected from Ci 6-alkyl and benzyl, and R" is selected from Ci β-alkyl, C26-alkenyl, phenyl, and benzyl

With respect to the biradical A, this may be an aliphatic biradical of the formula

-(CR³RV

(1 e an alkylene chain with no interrupting or terminating heteroatoms) wherein n is 1-20, preferably 1-12, in particular 2-8, and

where each of R³ and R⁴ independently is selected from hydrogen, optionally substituted Ci 6- alkyl, optionally substituted C2 β-alkenyl, optionally substituted C4 β-alkadienyl optionally substituted Cβ β-alkatπenyl, hydroxy, oxo (thereby forming a keto or aldehyde functionality), -O-R⁶, formyl, -C(=0)-R⁶, -0-C(=0)-R⁶, carboxy, -C(=0)-0-R⁶, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted aryl, optionally substituted aryloxj halogen such as fluoro, chloro, bromo, and lodo, nitro, cyano -N(R⁵)2, -N(R⁷)-CO-R⁶, carbamoyl mono- or dι(Cι 6-alkyl)amιnocarbonyl, sulphanyl, optionally substituted Ci 6-alkylthιo, optionally substituted Ci β-alkylthio-Ci β-alkyl, (optionally substituted aryl)thιo, guanidino, sulphono (-SOsH), sulphino (-SO2H), halosulphonyl, -OS(0)_m-R⁶ where m is 2 or 3, -N(R⁷)S(0)_m-R⁶ where is 2 or 3, -S(0)_m-N(R⁷)₂ where m is 2 or 3, -S(0)m-NH(R⁷) where m is 2 or 3, -S(0)_m-NH₂ where m is 2 or 3, isocyano, isothiocyano, thiocyano, -OP(0)_P(R⁶)_q where p is 1, 2, or 3, q is 1 or 2 and p+q is 3, 4, or 5, and where p is 1, 2, or 3, q is 1 or 2, and p+q is 3 4, or 5, wherein each R^& and each R⁶ independently is selected from hydrogen, optionally substituted Ci 20-alkyl, optionally substituted C220-alkenyl, optionally substituted C4 20-alkadιenyl, optionally substituted C620-alkatπenyl, optionally substituted aryl, and optionally substituted heteroaryl, and each R⁷ is selected from hydrogen and Ci 4-alkyl, where at the most 5, preferably at the most 3 of the substituents R³ and R⁴ are different from hydrogen

The substituents R³ and R⁴ are preferably independently selected from optionally substituted Ci 6-alkyl, optionally substituted C26-alkenyl, hydroxy, oxo (thereby forming a keto or aldehyde functionality), -O-R⁶, formyl, -C(=0)-R⁶, -0-C(=0)-R⁶, carboxy, -C(=0)-0-R⁶, optionally substi¬ tuted heteroaryl, optionally substituted heteroaryloxy, optionally substituted aryl, optionally substituted aryloxy, halogen such as fluoro, chloro, bromo, and lodo, cyano, -N(R⁵)s, -N(R⁷)-CO- R⁶, carbamoyl, mono- or dι(Cι 6-alkyl)amιnocarbonyl, Ci 6-alkylthιo, wherein each R⁵ and R⁷ independently is selected from hydrogen and Ci 4-alkyl, and each R⁶ independently is selected from hydrogen, optionally substituted Ci 6-alkyl, optionally substituted C2 β-alkenyl, optionally substituted aryl, and optionally substituted heteroaryl

Alternatively, the biradical A, illustrated as the fragment -C(=0)-A-C(=0)-, could be derived from an aliphatic or aromatic dicarbonyl functionahsed moiety, e g , as illustrated in Figure 1 and 2, wherein X is selected from the group consisting of >NR⁵, >NH, -0-, -S-, -Se-, -Te-, -CR'R²- >C=0, >C=S, and Y¹, Y², R¹, and R² each independently designate substituents as defined as optional substituent for aryl and heteroaryl (see above), or Y¹ together with Y² may form a biradical which together with the atoms located between these substituents, form(s) a 4-, 5-, 6-, 7- or 8-membered ring which may be an optionally substituted non-aromatic carbocyclic or heteroaromatic ring or an optionally substituted aromatic or heteroaromatic rings, and each Z¹ and Z² independently designates =N-, =N⁺R⁵-,

Preferred examples of the biradical A are biradicals either comprising or consisting of cyclic biradicals of the following radicals phenyl, naphthyl, anthracyl, pyrenyl, benzopyrenyl, phenoxazonyl, N⁸-phenoxazonyl, quinolyl, benzophenazinyl, ethidium and fluorenyl Especially preferred examples are naphthyl, benzopyrenyl, phenoxazonyl, N⁸-phenoxazonyl, quinolyl benzophenazinyl, ethidium and fluorenyl, and/or comprising or consisting of linear biradicals of the formula -(CR³R⁴)_n-, where each of R³ and R⁴ independently are selected from optionally substituted Ci 6-alkyl, optionally substituted C2 β-alkenyl hydroxy oxo (thereby forming a keto or aldehyde functionality), -O-R⁶, formyl, -C(=0)-R⁶, -0-C(=0)-R⁶, carboxy, -C(=0)-0-R⁶, optio¬ nally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted aryl, optionally substituted aryloxy, halogen such as fluoro, chloro, bromo and lodo, cyano -N(R⁵)₂, -N(R⁷)-C0-R⁶, carbamoyl, mono- or dι(Cι 6-alkyl)amιnocarbonyl, Ci β-alkylthio, sulphono (-SOsH), sulphino (-SO2H), wherein each R⁵ and R⁷ independently is selected from hydrogen and Ci ₄- alkyl, and each R⁶ independently is selected from hydrogen, optionally substituted Ci β-alkyl, optionally substituted C2 β-alkenyl, optionally substituted aryl, and optionally substituted heteroaryl

These 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

With respect to the carbonyl groups neighbouring A in formula I, it should be understood that these carbonyl groups may be an integral part of a starting material for the preparation of the compound I or libraries of the compound I Thus, in most cases, it is advantageous to use, as a starting material, a cyclic entity carrying two carboxylic acid groups, one of these groups optionally in protected form, and the other group in the free acid form or in activated form, or alternatively the two carboxy groups in internal anhydride form In this way, A may easily be linked to the solid phase material

Illustrative examples of dicarboxyhc acid functional compounds, which after incorporation into the compound 1 will represent the fragment -C(=0)-A-C(=0)-, are

Aromatic and heteroaromatic

2,2'-bιquιnohne-4,4'-dιcarboxylιc acid, 5-nιtro-ιsophthalιc acid, 2-amιno-terephthahc acid, 2- bromo-terephthahc acid, 2-nιtro-terephthalιc acid, 3,6-dιchloro-phthalιc acid anhydride, 4,5- dichloro-phthalic acid anhydride, 3-nιtro-phthalιc acid anhydride, 4-nιtro-phthalιc acid anhydride, homophthahc acid, 4,4'-bιphenyl-dιcarboxyhc acid, 2,2 -bιphenyl-dιcarboxyhc acid, 2,3-naphthalene-dιcarboxyhc acid, 2,6-naphthalene-dιcarboxvhc acid, 1,8-naphthalene-dι- carboxyhc acid anhydride, 3-nιtro-l,8-naphthalene-dιcarboxyhc acid anhydride, 1,2-phenylen- dioxy-diacetic acid, embonic acid, 5,5'-dιthιobιs-(2-nιtrobenzoιc acιd)(3,3'-6), 2,2'-dιthιobenzoιc acid, glutamic acιc-5-(3-carboxy-4-nιtro-anιhde), ahzaπn-3-methylιmιnodιacetιc acid, 1,4- phenylene-diacetic acid, 2,4'-benzophenone-dιcarboxyhc acid, 2 4 -benzophenyl-dιcarboxyhc acid chehdamic acid, 2,3-pyrιdιne-dιcarboxyhc acid, 2,4-pyπdιne-dιcarboxylιc acid, 2,5-pyπdιne-dι- carboxyhc acid, 2,6-pyrιdιne-dιcarboxylιc acid, 3,4-pyrιdιne-dιcarboxyhc acid, 3,5-pyπdιne-dι- carboxyhc acid, 4,5-pyrιdιne-dιcarboxyhc acid, ιmιdazole-4,5-dιcarboxyhc acid, 3,4,5,6-tetra- chloro-phthahc acid, 2-amιno-4,6-pyπmιdιne-dιcarboxyhc acid 9 10-anthracene-dιcarboxvhc acid, l,4-dιhydroχy-naphthalene-2,3-dιcarboxyhc acid, benzιmιdazol-5,6-dιcarboxyhc acid benzo phenone-4,4'-dιcarboxylιc acid, 4-methoxy-phthalιc acid, naphtιdιne-3,3'-dιcarboxyhc acid, naphthalene- 1,2-dιcarboxyhc acid, naphthalene- 1 3-dιcarboxylιc acid, naphthalene- 1 4-dι- carboxylic acid, naphthalene-l,5-dιcarboxyhc acid, naphthalene- 1 6-dιcarboxyhc acid naphthalene- 1 ,7-dιcarboxyhc acid, naphthalene- 1 8-dιcarboxyhc acid, naphthalene-2 3-dι- carboxyhc acid, naphthalene-2,4-dιcarboxyhc acid, naphthalene-2,5-dιcarboxyhc acid, naphthalene-2,7-dιcarboxyhc acid, naphthalene-2,8-dιcarboxyhc acid, pyπmιdιne-4,6-dιcarboxyhc acid, pyrrazole-3,6-dιcarboxyhc acid, and l, 10-phenanthrohne-5,6-dιcarboxyhc acid, especially preferred examples are phthalic acid, isophthalic acid, terphthahc acid, 5-nιtro-ιsophthalιc acid 2,6-naphthalene dicarboxyhc acid, 1,2-naphthalene dicarboxyhc acid, 2,3-naphthalene di- carboxylic acid, bιphenyl-4,4'-dιcarboxyhc acid, bιphenyl-2,4'-dιcarboxyhc acid, 4-methoxy- bιphenyl-2,4'-dιcarboxyhc acid, 2,2'-benzophenonedιcarboxyhc acid, 3,3'-benzophenonedι- carboxyhc acid, 4,4 -benzophenonedιcarboxyhc acid, Benzophenone-2 4'-dιcarboxylιc acid, 2- methoxy-benzophenone-2'-5-dιcarboxyhc acid, 2-methoxy-benzophenone-4'-ό-dιcarboxyhc acid 6,2',6'-tπhydroxy-2,4'-dιcarboxy-bιsphenylmethane, l, l-(6',2 ',6'-tπhydroxy-2',4"-dιcarboxy- dιphenyl)-ethene, 6,2',6'-trιhydroxybenzophenone-2,4'-dιcarboxyhc acid, 6 2',6'-tπmethoxy- benzophenone-2,4'-dιcarboxylιc acid, 2-carboxamιdo-6, 2', 6 -tπhydroxybenzophenone-4' -carboxylic acid, 2-carboxyethyl-6,2',6'-tnhydroxybenzophenone-4'-carboxvlιc acid, 2-carboxymethyl-6,2',6 - tπhydroxybenzophenone-4' -carboxylic acid, 6,2',6'-trιfluorobenzophenone-2,4'-dιcarboxylιc acid, 2 ,6'-dιmethoxy-6-hydroxybenzophenone-2,4'-dιcarboxyhc acid

and

Linear and non-aromatic oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimehc acid, suberic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, tetradecanedioic acid, hexadecanedioic acid docosanedioic acid, trans, trans-muconic acid, methylmaleic acid, methylmaleic acid anhydride, (+)- and (-)-camphonc acid, 1,3-acetone dicarboxyhc acid, N- (acetamιdo)-ιmιnodιacetιc acid, L-aspartic acid, S-carboxymethyl-L-cysteine, 2,2'-(ethylendιthιo)- diacetic acid, malic acid (+ and -), D-penicillamme, phenylsuccinic acid, N-(phosphonomethyl)- lminodiacetic acid, tetrahydrofohc acid, (+ or -) 0,0'-dιbenzyI-2-tartarιc acid, (3-thιenyl)-malonιc acid, N-phtaloyl-1-glutamιc acid, diphenyl maleic anhydride, cιs-l,2,3,6-tetrahydrophthahc acid 3,4,5,6-tetrahydrophthalιc acid, pyrazιne-2,3-dιcarboxyhc acid, ticarcillin, chelidomc acid, glycine cresol red, cyclopropane- l, l'-dιcarboxylιc acid, cyclobutane-l '-dicarboxyhc acid, 1-cyclopentene- 1,2-dιcarboxyhc acid anhydride, l, l'-azobιs-(cyclohexane-carboxyhc acid), cyclopropane- 1,2- dicarboxyhc acid, (cιs+trans)- l,4-cyclohexandιcarboxylιc acid, pyrazιne-2,5-dιcarboxyhc acid pιpeπdιne-2,6-dιcarboxylιc acid, pιpeπdιne-3,3-dιcarboxylιc acid, pyrrohne-N-oxιde-5,δ- dicarboxyhc acid, γ-pyrone-2,6-dιcarboxylιc acid and pιperazιne-2,6-dιcarboxyhc acid With respect to the biradical B, it is believed that this can be an aliphatic biradical of the formula

where R³, R⁴ and n are as defined above for A

Alternatively, B could be derived from an aliphatic or aromatic amino alcohol, e g , as illustrated in Figure 3 wherein X is selected from the group consisting of >NR⁶, >NH, -0-, -S-, -Se-, -Te-, - CR'R²-, >C=0, >C=S, and Y¹, Y², R¹, and R² each independently designates substituents as defined as optional substituent for aryl and heteroaryl (see above), or Y¹ together with Y² may form a biradical which together with the atoms located between these substituents, form(s) a 4- 5-, 6-, 7- or 8-membered ring which may be an optionally substituted non-aromatic carbocyclic or heteroaromatic ring or an optionally substituted aromatic or heteroaromatic rings, and each Z¹ and Z² independently designates =N-, =N⁺R⁵-,

Preferred examples of the 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, pyrrohdine, tetrahydrothiophen, tetrahydropyran, piperidme, tetrahydrothiopyran, oxepane azepane, thiepane, oxocane, azocane, thiocane, cyclopropane, oxirane aziridine, cyclopropene, azinne cyclobutane, oxetane, azetidme, thietane, 2-azetιdιnone, 1,3-lactone, pyrrohdine pyrrohne pyrrole, pyrrohdione, pyrrohdone, oxirane, dioxirane, morpholine, piperidine, 1 ,5-lactone, 1,5- lactam, cyclohexene, cyclohexadiene, piperidione, tropane, 1,6-lactone (tropolone), 1,6-lactam azepine, dihydroazepine, tetrahydroazepine, and hexahydroazepine

As appears from the above, each of L¹ and L² independently designates -NR⁵- or -0-, wherein each R⁵ independently is selected from hydrogen, optionally substituted Ci 20-alkyl, optionally substituted C220-alkenyl, optionally substituted C 20-alkadιenyl optionally substituted Cβ 20- alkatπenyl, optionally substituted aryl, and optionally substituted heteroaryl, or R⁶ designates an additional bond to B (whereby B becomes a tπradical) Preferably R⁵ designates hydrogen, Ci 4-alkyl or an additional bond to B In particular, one of L¹ and L² is -O- and the other is -NR⁵-, where R⁵ designates hydrogen, Ci 4-alkyl or an additional bond to B Thus, interesting and highly relevant starting materials for the preparation of the compounds 1 are l-amιno-ω-hydroxy-(optιonally substιtuted)-Cι β-alkylene, where Ci β-alkylene is the biradical of the radicals defined for Cι-6-alkyl and optional substituents are as defined for "alkyl"

When the ammoalcohol is selected from the group of non-aromatic carbocyclic compounds or heterocyclic compounds 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 frαns-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

Specific examples of aminoalcohols derived from non-aromatic carbocyclic compounds are 2- ammoethanol, l-amιno-2-propanol, 3-amιno- l-propanol, 2-amιno- l-propanol, 2-amιno-2-methyl- 1-propanol, l-amιno-2-methyl-2-propanol, 3-amιno-2-methyl- l-propanol, 2-amιno-l-butanol, 1 - amιno-2-butanol, 3-amιno-3-butanol, 3-amιno- l-butanol, 4-amιno-2-butanol, cιs-2-ammo- l- cyclobutanol, Jrαns-2-amιno- l-cyclobutanol, 5-amιno-l-pentanol, 2-amιno- l -pentanol, 3-amιno-2- pentanol, 2-amιno-3-pentanol, l-amιno-2-pentanol, cιs-2-amιno- l-cyclopentanol, (rαπ.s-2-amιno- l- cyclopentanol, 6-ammo- l-hexanol, fr rιs-4-amιno- l-cyclohexanol, cιs-4-amιno- l-cyclohexanol, trαns-2-amιno- l-cyclohexanol, cιs-2-amιno- l-cyclohexanol, -2-amιno- l-cyclohexanol, cιs-2- amιno-4-methyl- l-cyclohexanol, c«-2-amιno-5-methyl- l-cyclohexanol, (rατιs-2-amιno- l- cycloheptanol, cιs-2-ammo-l-cycloheptanol, (rαns-2-amιno- l-cyclooctanol, cιs-2-amιno- 1 - cyclooctanol

Specific examples of aminoalcohols derived from heterocyclic compounds are cιs-4-amιno-3- hydroxy-pyrolidine, (r ns-4-amιno-3- hydroxy-pyrrolidine, cιs-4-amιno-3-hydroxy-tetrahydro- furan, (rans-4-amιno-3-hydroxy- tetrahydrofuran, cι.9-4-amιno-3-hydroxy-tetrahydrothιophen, frαn,s-4-amιno-3-hydroxy-tetrahydrothιophen, cιs-3-amιno-4-hydroxy-pιpeπdιne, (rαns-3-amιno- 4-hydroxy-pιpeπdιne, ci6--4-amιno-3-hydroxy-pιpeπdιne, fr ns-4-amιno-3-hydroxy-pιperιdιne, cis- 5-amιno-3-hydroxy-pιperιdιne, (rans-5-amino-3-hydroxy-pipendine, cιs-4-amιno-3-hydroxy- tetrahydro-2H-pyrane, frαns-4-amιno-3-hydroxy-tetrahydro-2H-pyrane, cιs-4-amιno-3-hydroxy- tetrahydro-2H-thιopyrane, (rαn.s-4-amιno-3-hydroxy-tetrahydro-2H-thιopyrane, cιs-5-amιno-4- hydroxy-2-pιpeπdone, frα/ιs-5-amιno-4-hydroxy-2-pιperιdone, /r /ιs-3-amιno-4-hvdroxy-azepane cis-3-ammo-4-hydroxy-azepane, (rαns-4-amιno-3-hydroxy-azepane, cιs-4-amιno-3-hydroxy - azepane, frαns-5-amιno-4-hydroxy-azepane cιs-5-amιno-4-hydroxy-azepane frαπs-3-amιno-4- hydroxy-oxepane, cιs-3-amιno-4-hydroxy-oxepane (rx s-3-amιno-4-hydroxv-azocane cιs-' - amιno-4-hydroxy-azocane

The fragment D-C(=0) in the formula I is obviously derived from an aromatic carboxylic acid or a derivative thereof Thus, it is believed that a huge number of readily (and also commercially) available starting materials for the preparation of the compound I can be utilised Furthermore, the chemistry of aromatic compound is quite developed, so the group of accessible compound may be further supplemented

Preparation of the compounds of the general formula I

The synthesis of the compounds I is exemplified in the following Scheme 2 With reference to the general formula I, 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, L¹ is -0-, L² is -NR⁵-, and D is phenyl Furthermore, the solid phase material, symbolised with a box, is a Wang resin

Pd(PPh_ay NMM

moc piperidme

Scheme 2

The example illustrated in Scheme 2 represents two possible embodiments of the method according to the invention. Thus, in each of the steps (A)-(D), variations are possible In the following general guidelines for each of the steps of the method according to invention are given

Step (A)- an optionally functional group protected moiety -C(=0)-A-C(=0)-M^! immobilised to a solid support material, wherein -C(=0)-M> designates a carboxy group or a derivative thereof, is provided.

As illustrated in Scheme 2, various possibilities for the immobilisation are comprised within the scope of the present invention. Normally, it is preferred to use the diacid in monoester form, in that use of the dicarboxyhc acid may lead to side product formation due to the lack of mono- selectivity in the reaction between the activated solid phase material and the diacid Thus, it is believed, and can also be demonstrated, that used of the dicarboxyhc acid in the free acid form will lead to a lower yield, such a lower yield may, however, compensate for the resources used when preparing, e.g. , the monoester. Another example is the case where an internal anhydride of a dicarboxyhc acid is used In the cases where the dicarboxyhc acid is mono-protected, the protecting group is preferably removed in order to provide the carboxy functionality in a form, C(=0)-M>, ready for coupling in step (B) Thus, the group M¹ preferably designates OH or 0 The conditions for coupling the dicarboxyhc acid to the solid phase material is closely connected to the choice of solid phase material and linker, and will be described further below

Step (B) an optionally functional group protected difunctional entity L''-B-L'² is coupled to the -C(=0)-M' end of the immobilised moiety -C(=0)-A-C(=0)-M> for the formation of an optionally functional group protected immobilised fragment -C(=0)-A-C(=0)-L⁾-B-L'²

First of all, the group -C(=0)-M' should be present in a form susceptible to reaction with the entity L -B-L'², thus, as described above, -C(=0)-M' is preferably a carboxy group or a carboxylate group, or, alternatively, in reactive form, e g in active ester form Preferably M¹ is OH or 0 It is clear that the group L'¹ of the entity L''-B-L'² should end up as L¹ in the compound I Thus, L'¹ is, in the case where L¹ designate -0-, a hydroxyl group or a derivative thereof, preferably a hydroxyl group In the case where L¹ designate -NR⁵-, 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 Preferably L'¹ is the free amino group either a primary am e, I e R⁵ is hydrogen, or a secondary amine, I e R^B is, e g , an Ci 4-alkyl group or designates an additional bond to B

As the group L'² should remain unaffected by the reaction conditions, it preferably designates a protected hydroxy group or a protected primary or secondary amme Examples of groups L'² are - O-P (where L² is -0-), where P designate a hydroxy protection groups selected from dimethoxy- tπtyl (DMT), monomethoxytπtyl (MMT), tπtyl, 9-(9-phenyl)xanthenyl (pixyl), tetraahydro- pyranyl (thp), methoxytetrahydropyranyl (mthp), tπmethylsilyl (TMS), tnisopropylsilyl (TIPS), ferf-butyldimethylsilyl (TBDMS), tπethylsilyl, phenyldimethylsilyl, benzyloxycarbonyl, substi- tuted benzyloxycarbonyl ethers such as 2-bromo benzyloxycarbonyl, (erf-butylethers, methyl ethers, acetyl, halogen substituted acetyls such as chloroacetyl and fluoroacetyl, isobutery], pivaloyl, benzoyl, substituted benzoyls, methoxymethyl (MOM), benzyl ethers, and substituted benzyl ethers such as 2,6-dιchlorobenzyl (2,6-Ci2Bzl), and -NR⁶-P (where L¹ is -NR⁵-), where P designates an amino protection groups selected from Fmoc (fluorenylmethoxycarbonyl), BOC (terf-butyloxycarbonyl), trifluoroacetyl, allyloxycarbonyl (alloc, AOC), benzyloxycarbonyl (Z, Cbz), substitued benzyloxycarbonyls such as 2-chloro benzyloxycarbonyl ((2-C1Z), DDE (Bloomberg, G B , et al , Tetrahedron Lett 1993 34, 4709-4712), monomethoxytπtyl (MMT), dimethoxytπtyl (DMT), and 9-(9-phenyl)xanthenyl (pixyl) The coupling reaction in step (B) will often include a coupling reagent, e g a reagent which converts the group -C(=0)-M> into an active derivative, e g an active ester or an acid hahde A number of highly effective coupling reagents and activated forms of carboxvhc acids are know by the person skilled in the art of amide bond formation (peptide chemistry) Illustrative examples include the use of PyBrOP (Coste, J , Frerot, E , Jouin, P and Castro, B Tetrahedron Lett 1991, 32, 1967- 1970), amino acid fluorides (Carpino, L A , Sadat-Aalaee, D , Chao H G and DeSelms, R H J. Am. Chem. Soc.) and HATU (Carpino, L A J. Am Chem Soc , 1993, 115, 4397-4398, Angell, Y M , Garcia-Echeverπa, C and Rich, D H Tetrahedron Lett 1994 35, 5981-5984, and Angell, Y M , Thomas, T L , Flenkte, G R and Rich, D R J Am Chem. Soc 1995, 117, 7279- 7280), PyBOP (Frerot, E , et al , Tetrahedron, 1991 , 47(2), pp 259-270), and CFs-NOz-PyBOP (Wijkmans, J C H M , et al, Tetrahedron Lett 1995, 36(26), pp 4643-4646) A coupling reagent will be equally applicable for the formation of an amide bond as for the formation of an ester bond

Step (C) an optionally functional group protected entity D-C(=0)-M², wherein C(=0)-M² designates a carboxy group or a derivative thereof, is coupled to the L'² end of the immobilised fragment -C(=0)-A-C(=0)-L'-B-L'² for the formation of an optionally functional group protected immobilised compound -C(=0)-A-C(=0)-L¹-B-L²-C(=0)-D, the step optionally including deprotection of any protection group involved in L'²

As described under step (B), the group L'² typically includes a protecting group, thus in that case, such a group should preferably be removed before coupling of the entity D-C(=0)-M² to the immobilised fragment With respect to the group -C(=0)-M² it may be a carboxy group or derivative thereof In one variant the group -C(=0)-M² is a reactive derivative of a carboxylic acid, e g an active ester or the acid hahde, e g. the acid chloride or fluoride In another variant, the group -C(=0)-M² is the free acid or the carboxylate thereof In the latter case, the reaction typically involves the use of a coupling agent Thus, M² may designate OH, 0^~ halogen such as fluoro or chloro, or the remainder of an active ester

Step (D) the compound K-C(=0)-A-C(=0)-L'-B-L²-C(=0)-D is cleaved from the solid support material, the step optionally including deprotection of one or more functional group(s) attached to A, B, and/or D

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

In the present context the term "optionally functional group protected" and similar terms are intended to mean that in the case where any of the groups in question, e g any or all of A, B, and D, comprises a chemical functionality (or several chemical functionalities) which is/are susceptible to reaction, alteration or degradation under the reaction conditions in question or due to the lack of regioselectivity of the reagents used, 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-puπfication-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, peptide synthesis (see e g Steward, J M & Young, J D , Solid Phase Peptide Synthesis, Pierce Chemical Company (1984) or Robert C Sheppard E Atherton, Solid-Phase Peptide Synthesis, 1RL Press, 1989), ohgonucleotide synthesis (see e g M J Gait, Ohgonucleotide Synthesis, IRL Press, 1984), ohgosaccharide synthesis, organic synthesis and during synthesis of natural products Protection groups are especially relevant for the amino groups, hydroxy and mercapto groups, and carboxy groups in that they may directly interfere with the reactions performed in the steps (B) and (C) Thus, protection groups, among numerous are well know to the person skilled in the art, may not just be desirable but also necessary in order to suppress side product formation

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), monomethoxytπtyl (MMT), dimethoxytπtyl (DMT), and 9-(9-phenyl)xanthenyl (pixyl), hydroxy protection groups such as dimethoxytπtyl (DMT), monomethoxytrityl (MMT), trityl, 9- (9-phenyl)xanthenyl (pixyl), tetraahydropyranyl (thp), methoxytetrahydropyranyl (mthp), tπ- methylsilyl (TMS), trnsopropylsilyl (TIPS), (er(-butyldιmethylsιlyl (TBDMS), tπethylsilyl, phenyldimethylsilyl, benzyloxycarbonyl or substituted benzyloxycarbonyl ethers such as 2-bromo benzyloxycarbonyl, (erf-butylethers, methyl ethers, acetyl or halogen substituted acetyls such as chloroacetyl or fluoroacetyl, isobutyryl, pivaloyl, benzoyl and substituted benzoyls, methoxy- methyl (MOM), benzyl ethers or substituted benzyl ethers such as 2,6-dιchlorobenzyl (2,6- CbBzl), carboxy protection groups such as allyl esters, methyl esters, ethvl esters 2-cvanoethyl- esters, tπmethylsilylethylesters, benzyl esters (Obzl), 2-adamantyl esters (O-2-Ada), cyclohexyl esters (Ocllex), 1,3-oxazohnes, oxazoler, 1,3-oxazohdιnes, amides or hydrazides, or in the form of an activated ester such as an N-hydroxysuccimmide or an symmetric or asymmetric anhydride, and mercapto protecting groups such as trityl (Trt), acetamidomethyl (acm), tπmethylacetamido- methyl (Tacm), 2,4,6-tπmethoxybenzyl (Tmob), ferf-butylsulfenyl (S(Bu), 9-fluorenylmethyl (Fm), 3-nιtro-2-pyπdιnesulfenyl (Npys), and 4-methylbenzyl (Meb)

Deprotection of any "optionally protected functional groups" is performed by methods known by the person skilled in the art, e g as described in Greene, T W and Wuts, P G M (Protecting Groups in Organic Synthesis)

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 77ιe Peptides, Vol. 2, Academic Press, New York, 1979, pp 1-284)

In the present context the term "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. Chem Soc 1973 94, 1328- 1333) a pαrα-alkoxybenzyl alcohol resin which yields the free acid upon treatment and cleavage with trifluoroacetic acid/dichloromethane (1 1, v/v) for 30 minutes at room temperature or a resin of the so-called "Rink-type" (Rink, H Tetrahedron Lett , 1987 28, 3787-3790) ) a tnalkoxy-diphenyl-methylester resin which yields the acid amide upon treatment and cleavage with trifluoroacetic acid/dichloromethane (3 7, v/v) for 60 minutes at room temperature Likewise, the resins can be based on polystyrene cross-linked with 0 2-2% divinylbenzene and grafted with polyethyleneglycol (PEG) to yield the so-called "TentaGel resin" which have better and more uniform swelling characteristics in polar solvents that the parent polystyrene resins (Bayer, E Angew Chem. Int Ed Engl , 1991, 30, 113- 129) Resins of similar characteristics given from PEG-modified are commercial available with many different functionalities and are sold under trade names such as ArgoGel, PEGA resin or PEG-PS from various different vendors (e g Argonaut Inc , Peptide Laboratories, NovaBiochem, etc )

In a further embodiment of the methods of present invention, 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 This reaction step may be especially relevant yvhen modification of the group K-C(=0)- is desired due to the fact that the variability of this group is governed by the applicable method for cleavage of the compound from the resin

Preparation of monoesters of dicarboxylic acids

As the first step in the preparation of the compounds I involves the moiety -C(=0)-A-(=0)-, it is evident that a diacid HOOC-A-COOH, e g in the free acid monoester, or internal anhydride form may be used when providing the immobilised moiety -C(=0)-A-C(=0)-M'

In order to be able to utilise a wide range of bifunctional aromatic and heteroaromatic molecules in the synthesis of compounds I, the accessibility to synthetic routes towards, e g , aromatic dicarboxyhc acid monoesters are advantageous Three different syntheses have been described in Tong, G and Nielsen, J Bworg Med Chem 1996, 4, 693-698 The first method is based on the esterif ication, in particular the allylation, of the monocesium salt of a dicarboxyhc acid, exemplified herein as esterification of naphthalene-2,6-dιcarboxyhc acid with allyl bromide (Example 3) The second one is based on the use of anion exchange resins to block off one of the carboxylic acid groups while the other undergoes esterification (Blankemeyer-Menge, B , Nimtz, M and Frank, R Tetrahedron Lett 1990, 57, 1701- 1704) A third possible route it the selective deesterification of dicarboxyhc acid diesters A further possibility is using phase transfer chemistry (Friednch-Bochnitschek S , J Org Chem 54, 1989, 751-756) Advantageous conditions for the production of the monoester with a minimum yield of the diester were an equimoiar amount of CS2CO3 added in small portions over an extended period such as 16 h, and 2 equivalents of allyl bromide Obtainable yields of the purified monoester are at least 30% An alternative method based on the adsorption of the naphthalene diacid onto an anion exchange resin followed by reaction with mesithylenesulphonylmtrotriazohde (MSNT), N-methyhmidazole and allyl alcohol produces the desired monoester The third method is based on the possibility of mono-deesterification of certain aromatic dimethyl esters Synthesis of the mixed methyl-allyl- diester followed by selective demethylation (NaCN/HMPAOiexamethylphosphoramide)) yields the corresponding monoallyl ester

Preparation of libraries of compounds of the general formula I

The preparation of compound libraries of balanol analogues follows the same principles as described above for the preparation of single analogues In order to ensure that a suitable amount of each of the theoretically obtainable compound were formed in a suitable amount, the split-mix synthesis method (Furka, A , Sebestyen, F , Asgedom, M , Dibό G Int Peptide Protein Res 1991 37, 487-493) was applied Other method may also be applicable within the context of the present invention

Thus, 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

K-C(=0)-A-C(=0)-L'-B-L -C(=0)-D I

as defined above Such an array is constructed by combining an array {A} consisting of m compounds corresponding to the biradical -C(=0)-A-C(=0)- with an array {B} consisting of n compound corresponding to the biradical -L'-B-L²- and an array {C} consisting of o compound corresponding to the radical -C(=0)-D 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 Although 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, it also is preferred that the combinatorial library comprises in the range of 6-200 different compound, more preferably 6- 100 different compounds, and in particular 8-64 different compounds

As mentioned above, 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)

Step (A) an array {A} of m optionally functional group protected moieties -C(=0)-A-C(=0)-M' immobilised to a solid support material, wherein -C(=0)-M' designates a carboxy group or a derivative thereof, is provided Following the split-mix synthesis, each of the types of immobilised moieties are synthesised individually, thus, each solid phase particle or entity, comprises only one type of moiety After this step the solid phase material is pooled and split into n (see below) portions ready for the step (B) It should be understood that larger amounts of the immobilised moieties may be prepared leaving material for later experiments

Step (B) an array {B} of n optionally functional group protected difunctional entities L''-B-L'² is coupled to the -C(=0)-M> end of the immobilised moieties -C(=0)-A-C(=0)-M¹ for the formation of an array {A}-{B} of nvn optionally functional group protected immobilised fragments -C(=0)-A- C(=0)-L^I-B-L'² Also in this step to coupling is preferably performed in n different batches where the reacted material is pooled and split for the next coupling step, I e step (C) Step (C) an array {D} of o optionally functional group protected entities D-C(=0)-M² wherein - C(=0)-M² designates a carboxy group or a derivative thereof, is coupled to the L'² end of the immobilised fragments -C(=0)-A-C(=0)-L¹-B-L'² for the formation of an array {A}-{B}-{D} of nvn-o optionally functional group protected immobilised compounds -C(=0)-A-C(=0)-L¹-B-L²-C(=0)-D, the step optionally including deprotection of any protection group involved in L'² Also in this step the coupling is preferably performed in o different batches The reacted material need not necessarily to be pooled before cleavage in step (D)

Step (D) cleaving the array {A}-{B}-{D} of compounds K-C(=O)-A-C(=O)-L¹-B-L²-C(=0)-D from the solid support material, the step optionally including deprotection of one or more functional group(s) attached to individual As, Bs, and/or Ds It should be understood that 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 However, in the case where an analysis of the prepared library is to be performed, it is (of course) advantageous to operate with a relatively low number of compounds Thus, 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 In a third and most interesting alternative the library consisting of the combined batches (or a number of these) containing (up to) nvn«o compound is screened, and in the case where biological activity is identified, each of the o batches are screened individually thereby pointing back to one specific moiety D as biologically interesting The principles of screening are discussed in the following

Method of screening

Screening of combinatorial libraries may be performed in any of the ways generally used by scientists and technicians skilled in the art These include but is not limited to screening of individual compounds, by deconvolution of libraries containing mixtures by positional scanning of libraries of mixtures or by screening sub-libraries in an index library mode Therefore, library formats could be as single compounds I e one vial would be containing one single compound, small mixtures of lsomeπc 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 is envisaged that biological activity of the compound 1 prepared according to the present invention will be demonstrated Thus it is believed that biological activity within one of the following fields can be shown

(a) 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 potential drugs against HIV-infections and AIDS

(b) Biological effects interesting in the field of crop protection compounds affecting sugar metabolism, antibiotics or antimicrobial agents, antifungal agents, such as pesticides, disinfectants, and hormone antagonists

Thus, 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

DESCRIPTION OF THE DRAWINGS

Figures 1 and 2 illustrate various examples of biradicals A The meanings of the symbols are defined above

Figure 3 illustrates various examples of biradicals B The meanings of the symbols are defined above EXAMPLES

Example 1

Procedure for the synthesis of N-Fmoc-aminoalcohols

N-Fmoc-l-amino-2-propanol. Procedure as above starting from l-amιno-2-propanol White solid (100%) Mp 120- 123°C Η NMR (CDC1₃) d 7 8 (d, 2H, J = 6 5 Hz), 7 6 (d, 2H J = 6 5 Hz), 7 3 (m, 4H), 5 2 (m, IH), 4 5 (d, 2H, J = 6 8), 4 2 (t, IH, J = 6 8), 3 9 (m, IH), 3 3-3 1 (m, 2H), 2 5 (m, IH), 1 2 (d, 3H, J = 6 0) ¹³C NMR (CDCI3) d 156 0 143 8 141 2 127 6 127 0 124 9 1 19 9 67 3 66 7 48 2 47 2 20 6

N-Fmoc-2-amino-l-butanol. Procedure as above starting from 2-amιno-l-butanol White solid (96%) Mp 127- 131°C 'H-NMR (CDCI3) d 7 8 (d, 2H, J = 6 5 Hz), 7 6 (d, 2H. J = 6 5 Hz), 7 4 (m, 4H), 4 9 (m, IH), 4 5 (d, 2H, J = 7 Hz), 4 2 (t, IH, J = 7 Hz), 3 6 (m, 3H), 1 9 (m, IH), 1 5 (m 2H) 1 0 (t, 3H), '³C-NMR (CDCI3) dl56 0 144 0 142 0 127 6 127 0 124 9 119 9 66 5 65 0 54 7 47 3 24 3 10 4

N-Fmoc-3-amino-l-propanol. Procedure as above starting from 3-amιno- l-propanol White solid (95%) Mp 115-118°C Η-NMR (CDCb) d 7 8 (d, 2H, J=6 5 Hz), 7 6 (d, 2H, J=6 5 Hz), 7 4

(m, 4H), 5 1 (m, IH), 4 5 (d, 2H, J=7 Hz), 4 2 (t, IH, J=7 Hz), 3 7 (m, 2H), 3 4 (q, 2H), 2 6 (m, IH), 1 7 (p, 2H) '³C-NMR (CDCI3) d 142 136 128 127 125 120 67 60 48 38 33

trαnβ-N-Fmoc-4-amino-cyclohexanol. Procedure as above starting from (rαns-4-amιno- cyclohexanol White sohd (37%) Mp 208-210°C Η-NMR (DMSO-dβ) d 7 9 (d, 2H), 7 7 (d, 2H), 7 4 (m, 4H), 4 3 (m, 3H), 3 9 (m, 6H), 3 3 (s, IH), 1 7 (m, 2H), 1 2 (m, 2H) ¹³C-NMR (DMSO-de) d 155 3 143 9 140 7 127 6 127 0 125 2 120 0 68 1 65 1 49 2 46 8 34 0 30 5

Example 2

Procedure for the synthesis of aromatic dicarboxylic acid

(a) Methylation of phenolic alcohol

2-Nitro-5-methyl-anisole. To a suspension of 4 6 g (30 mmol) 2-nιtro-5-methyl-phenol and 20 7 g (150 mmol) dry K2CO3 in 150 ml acetone was added 42 6 g (300 mmol) Mel The reaction mixture was stirred at reflux 16 h, then cooled, filtered and concentrated in vacua The residue was redissolved in EtOAc filtered and concentrated in vacuo to afford light yellow solid 4 9 g (98%) Mp 56-57°C >H NMR (CDCls) d 7 8 (d, IH, J = 8 4 Hz), 6 9 (s, IH), 6 8 (d 111 J = 8 4 H/) 4 0 (s, 3H), 2 4 (s, 3H) >³C NMR (CDCls) d 153 1 145 9 125 8 120 8 1 13 9 108 5 56 2 21 8

2-Methyl-3-nitro-anisole. Procedure as above starting from 2-methyl-3-nιtro-phenol Yellow solid (91%) Mp 51-52°C Η NMR (CDCls) d 7 3 (d, IH, J = 8 0 Hz), 7 2 (t, IH, J = 8 0 Hz), 7 0 (d IH, J = 8 0 Hz), 3 9 (s, 3H), 2 3 (s, 3H) ¹³C NMR (CDCls) d 158 2 150 8 132 1 126 5 115 4 113 6

55 9 11

2-Nitro-3-methyl-anisole. Procedure as above starting from 2-mtro-3-methyl-phenol Yellow sohd (98%) Mp 46-48°C >H NMR (CDCls) d 7 3 (t, IH, J = 8 5 Hz), 6 9 (d, IH, J = 8 5 Hz), 6 8 (d IH, J = 8 5Hz), 3 9 (s, 3H), 2 3 (s, 3H) '³C NMR (CDCla) d 150 6 130 7 130 5 122 4 110 0 109 8

56 1 16 7

(b) Hydrogenation of the nitro group

2-methoxy-4-methyl-aniline. To a solution of 4 9 g (29 3 mmol) 2-nιtro-5-methyl-anιsole in 100 ml EtOH and 5 ml cone HCI under an N2 atmosphere was added 250 mg 5% Pd on charcoal The solution was hydrogenated at 200 psi and room temperature After 16 h the reaction mixture was filtered through Cehte and concentrated in vacuo The residue was chromatographed in hexane- EtOAc 1 1 to afford red oil 2 8 g (70%) 'H NMR (CDCla) d 6 7 (m, 3H), 3 9 (s, 3H), 3 7 (s, 2H), 2 4 (s, 311) ¹³C NMR (CDCls) d 147 0 133 2 127 7 120 9 114 8 111 1 55 1 20 7

2-methyl-3-methoxy-aniline. Procedure as above starting from 3-nιtro-2-metbyl-anιsole Red oil (60%) 'H NMR (CDCls) d 7 1 (t, IH, J = 8 0 Hz), 6 5 (dd 2H, J = 8 0 Hz) 3 9 (s, 3H), 3 8 (s 2H), 2 2 (s, 2H) >³C NMR (CDCls) d 157 8 145 4 126 2 109 9 108 1 100 7 55 1 8 5

(c) Diazotation of an ammo group to a nitπle group (Sandmeier)

2-methyl-3-methoxy-benzonitrile. A solution of 2 5 g (18 mmol) 2-methyl-3-methoxy-anιhne in 55 ml 2N HCI was cooled to -5°C in a ice/salt bath and stirred for 30 min A solution of 1 37 g (19 8 mmol) NaNO∑ m 28 ml H2O was added dropwise at -5°C The reaction mixture was stirred 30 min and neutralised carefully with approximately 3 7 g Na2Cθ3, then a solution of 1 8 g (19 8 mmol) CuCN and 1 9 g (39 6 mmol) NaCN in 28 ml H2O was added in one portion After 18 h the reaction mixture was extracted with 3*100 ml CHCI3 The combined organic phases was extrac- ted with H2O, dried with Na2SU4 and concentrated in vacuo to afford dark red oil 2 0 g (75%) IR- data 2222 cm ' (CN) >H NMR (CDCla) d 7 2 (q IH, J = 7 7 Hz), 7 15 (dd, IH, J = 7 7 Hz, J = 1 5 Hz), 7 0 (dd, IH, J = 7 7 Hz, J = 1 5 Hz), 3 9 (s, 3H), 2 4 (s, 3H) ¹³C NMR (CDCla) d 157 5 130 8 127 1 123 7 117 9 113 9 113 5 55 4 14 1 (d) Synthesis of benzophenone

3,3'-dimethyl-benzophenone. To 3 6 g (110 mmol) Mg-turmngs under 10 ml THF was added a Iodme Crystal and 'A of 17 1 g (100 mmol) 3-bromotoluene The mixture was heated to 40°C and after a while the Gngnard reaction started The rest (3/4) of the 3-bromotoluene in THF was added in such a rate to maintain reflux After addition the reaction mixture was reflux for 1 h cooled to room temperature and added dropwise to a solution of 7 3 g (63 mmol) 3-methyl-benzo- nitnle in 40 ml toluene at room temperature, then kept at 70°C for 16 h The reaction mixture was cooled on an ice bath and 33 ml cone HCI was added dropwise followed by 170 ml MeOH and refluxed 7 h The reaction mixture was cooled, 100 ml H2O was added and extracted with EtOAc The combined organic phases was dried with MgS04, filtered and concentrated in vacuo The residue was chromatographed (hexane/EtOAc 19 1) to afford colourless oil 10 5 g (80%) >H NMR (CDCls) d 7 6 (m, 2H), 7 3 (m, 2H), 2 4 (s, 3H) ¹³C NMR (CDCla) d 196 7 137 8 137 5 132 8 130 1 127 7 127 0 21 0

2,4'-dimethyl-benzophenone. Procedure as above starting from 2-bromotoluene and 4-methyl- benzonitnle Colourless oil (77%) 'H NMR (CDCls) d 7 7 (d, 2H, J = 8 2 Hz), 7 4-7 2 (m, 6H), 2 4 (s, 3H), 2 3 (s, 3H) >³C NMR (CDCla) d 198 0 143 8 138 7 136 2 134 9 130 7 130 1 129 8 129 0 128 0 124 9

2-methoxy-2\5-dimethyl-benzophenone. Procedure as above starting from 2-bromo-4- methyl-anisole and 2-methyl-benzonιtrιle THF used instead of toluene Colourless oil (36%) 'H NMR (CDCls) d 7 4-7 1 (m, 6H), 6 8 (d, IH, J = 8 0), 3 6 (s, 3H), 2 5 (s, 3H), 2 3 (s, 3H) >³C NMR (CDCla) d 198 3 156 0 139 2 137 7 133 0 130 9 130 6 130 0 129 5 129 0 126 0 124 9 11 1 7 55 6 20 5 20 1

2-methoxy-4\5-dimethyl-benzophenone. Procedure as above starting from 2-bromo-4- methyl-anisole and 4-methyl-benzonιtπle Chromatographed in φexane/EtOAc 9 1) colourless oil (56%) 'H NMR (CDCls) d 7 7 (m, 2H), 7 3-7 1 (m, 4H), 6 9 (d, IH, J = 8 4 Hz), 3 7 (s, 3H), 2 4 (s, 3H), 2 3 (s, 3H) >³C NMR (CDCla) d 196 8 155 0 143 6 135 1 131 9 129 9 129 6 128 8 111 3 108 7 55 6 21 6 20 2

(e) Synthesis of benzophenone via benzhydrole

4,4'-dimethyl-benzhydrole. To 3 6 g (150 mmol) Mg-turnings under 10 ml THF was added a Iodine Crystal and V* of 17 1 g (100 mmol) 4-bromotoluene The mixture was heated to 40°C and after a while the Gngnard reaction started The rest (3/4) of the 4-bromotoluene in THF was added in such a rate to maintain reflux After addition the reaction mixture was reflux for 1 h, cooled to 0°C and the remaining Mg-turmngs was removed A solution of 12 3 g (103 mmol) 4- methyl-benzaldehyde in 20 ml THF at 0°C was dropwise added After 2 h the reaction mixture was quenched with 200 ml ice, temperature allowed to rise to room temperature and 25% H₂SO₄ was added until solution was clear The reaction mixture was extracted with DCM The com¬ bined organic phases was dried with MgSθ4, filtered and concentrated in vacuo The residue was recrystahsed in heptane to afford white solid 10 6 g (50%) Mp 64-65°C 'H NMR (CDCI3) d 7 2 (d 4H, J = 8 1 Hz), 7 1 (d, 411, J = 8 1 Hz), 5 8 (s, 111), 2 3 (s, 6H) >³C NMR (CDCh) d 141 1 137 1 129 1 126 4 77 5 21 1

4,4'-dimethyl-benzophenone. To a suspension of 12 96 g (60 mmol) pyπdinium chloro chromate 60 ml DCM was added 6 36 g (30 mmol) 4 4 -dιmethyl-benzhvdrole The mixture was stirred 24 h and 240 ml diethylether was added The reaction mixture was filtered 3X through silica gel and concentrated in vacuo to afford white solid 3 7 g (59%) Mp 92-94°C >H NMR (CDCh) d 7 7 (d, 4H, J = 7 9 Hz), 7 3 (d, 4H, J = 7 9 Hz), 2 4 (s, 6H) ' C NMR (CDCla) d 196 2 142 8 135 1 130 1 128 8 21 5

(f) Procedure for the Synthesis of methyl-methylphenyl-benzene

2-methyl-(4-methylphenyl)-benzene. To a solution of 5 2 g (24 mmol) 2-Iodotoluene in 12 ml diethylether under an atmosphere of N2 at -78°C was dropwise added 32 ml 1 5 M (48 mmol) tert- BuLi in hexane The reaction mixture was stirred 1 h at -78°C and 1 h at room temperature followed by concentration m vacuo To the residue was added 16 ml THF at 0°C and the reaction mixture was dropwise added to a solution of 3 3 g (24 mmol) dry ZnCk in 12 ml THF under an atmosphere of N2 at 0°C The reaction mixture was stirred 1 h at room temperature, then added to a solution of 3 4 g (20 mmol) 4-bromo-toluene 0 23 g (0 2 mmol) Pd(PPh₃)4 in 20 ml THF under an atmosphere of N2 cooled in a water bath The reaction mixture was stirred 16 h at 50°C cooled and poured in a solution of 20 ml diethylether and 60 ml 4N HCI The mixture was extrac¬ ted with 2*40 ml ether The combined organic phases was washed with NaHCOa (sat ), dried with MgSθ4 and concentrated m vacuo to afford colourless oil 2 0 g (47%) >H NMR (CDCI3) d 7 2 (m, 8H), 2 3 (s, 3H), 2 2 (s, 3H)

(g) Aromatic Side Chain Oxidation of methyl-groups

Biphenyl-2,4'-dicarboxylic acid. To a solution of 5 2 g (33 mmol) KMn0₄ in 48 ml 50% pyridine (aq ) at 100°C was added 0 6 ml cone NaOH and a solution of 2 0 g (1 1 mmol) 2-methvl- (4-methylphenyl)-benzene in 15 ml pyridine followed by 15 ml H2O The reaction mixture was stirred 1 h and 5 2 g (33 mmol) KMnθ4 was added This procedure was continued to a total of 41 6 g (264 mmol) KMnθ4 was added The hot reaction mixture was filtered and the filter cake was washed with 4*30 ml H2O and 10 ml pyridine The filtrate was cooled in a ice bath and acidified to pH = 1 with cone HCI Brine was added and the reaction mixture was extracted with 4* 150 ml EtOAc The combined organic phases was concentrated in vacuo to afford white solid 0 9 g (33%) Mp 270°C Η NMR (DMSO-de) d 109 (broad, 2H), 8 0 (d, 2H, J = 8 0 Hz), 7 8 (d, IH J = 8 0 Hz), 7 6 (t, IH, J = 8 0 Hz), 7 5 (t, IH, J = 8 0 Hz) 7 45 (d, 211, J = 8 0 Hz), 7 4 (d, 111, J = 8 0 Hz) ¹ C NMR (DMSO-de) d 169 3 167 3 145 5 140 4 132 1 131 2 130 5 129 5 129 1 128 6 128 6 127 9

Benzophenone-2,2'-dicarboxylic acid. Procedure as above starting from 2,2'-dιmethyl- benzophenone White solid (69%) Mp 208-210°C 'H NMR (DMSO-de) d 8 7 (broad, 2H), 7 8 (d, 2H, J = 6 6 Hz), 7 6 (m, 4H), 7,4 (d, 2H, J = 6,6 Hz) ' C NMR (DMSO-de) d 168 6 138 6 132 8 131 1 130 8 129 3 128 9

Benzophenone-3,3'-dicarboxylic acid. Procedure as above starting from 3,3 -dιmethyl- benzophenone White solid (56%) Mp 330°C (decomp ) 'H NMR (DMSO-de) d 8 25 (s, 2H), 8 25 (m, IH), 8 1-7 85 (m, 3H), 7 7 (m, 2H) '³C NMR (DMSO-de) d 194 8 166 6 137 0 133 8 133 4 131 2 130 2 129 3

Benzophenone-4,4'-dicarboxylic acid. Procedure as above starting from 4,4 -dιmethyl- benzophenone White solid (66%) Mp 355°C (decomp ) Η NMR (DMSO-de) d 8 1 (d 4H, J = 8 0 Hz), 7 8 (d, 4H, J = 8 0 Hz) ¹ C NMR (DMSO-de) d 195 0 166 6 140 0 134 3 129 8 129 5

Benzophenone-2,4'-dicarboxylic acid. Procedure as above starting from 2,4'-dιmethyl- benzophenone White solid (72%) Mp 241-243°C »H NMR (DMSO-de) d 8 0 (m, 3H), 7 7 (m, 4H), 7 5 (d, IH, J = 7 6 Hz) ' C NMR (DMSO-de) d 166 9 166 7 141 5 140 5 134 5 132 7 130 1 129 6 129 6 128 9 127 5 127 5

2-Methoxy-benzophenone-2',5-dicarboxylic acid. Procedure as above starting from 2- methoxy-2,5'-dιmethyl-benzophenone White solid (64%) Mp 224-227°C 'H NMR (DMSO-de) d 8 2-8 0 (m, 2H), 7 9-7 8 (m, IH), 7 7-7 5 (m, 2H), 7 3 (m, IH), 7 2 (m, IH), 3 6 (s, 3H) ' C NMR (DMSO-dβ) d 195 0 167 5 166 5 143 5 135 2 132 9 132 4 130 8 129 6 129 1 126 3 122 6 112 9 56 1

Example 3

Procedure for the synthesis of mono-allylated aromatic diacids

Benzophenone-2,2'-dicarboxylic acid monoallyl ester. To a solution of 1 08 g (4 mmol) Benzophenone-2,2'-dιcarboxyhc acid m 90 ml DMF was added 0 16 g (0 5 mmol) CS2CO3 After 30 min 0 34 ml (0,484 g, 4 mmol) allyl bromide The reaction mixture was stirred 24 h and 0 16 g (0 5 mmol) CS2CO3 was added This procedure was continued until a total of 0 64 g (2 mmol) CS2CO3 was added After additional 24 h the reaction mixture was filtered and chromatographed (CHCls/AcOH 99 1) to afford 0 52 g (42%) Mp 205-207°C Unreacted benzophenone-2,2'-dι- carboxylic acid 0 312 g (29%) was isolated for reuse 'II NMR (CDCls) d 8 8 (broad, IH), 8 0-7 3 (m, 8H), 6 0-5 7 (m, IH), 5 3-5 1 (m, 2H), 4 7 (d, 2H, J = 7 0) ¹³C NMR (CDCls) d 171 0 167 4 139 3 138 8 135 0 131 9 131 4 131 4 131 1 130 2 129 7 129 3 129 2 128 0 125 9 118 7 66 4

Benzophenone-3,3'-dicarboxylic acid monoallyl ester. Procedure as above starting from benzophenone-3,3'-dιcarboxyhc acid White solid (42%) Mp 140- 143°C >H NMR (CDCla) d 8 5 (m, 2H), 8 4-8 3 (m, 2H), 8 1-7 8 (m, 2H), 7 7-7 5 (m, 2H), 6 1-5 9 (m, IH), 5 5-5 2 ( , 2H), 4 9 (d, 2H, J = 7 0 Hz) ¹ C NMR (CDCla) d 194 6 170 6 165 3 137 5 137 3 134 8 134 0 133 6 131 8 131 5 130 9 130 6 130 2 129 8 129 7 128 9 128 8 118 6 65 9

Benzophenone-4,4'-dicarboxylic acid monoallyl ester. Procedure as above starting from benzophenone-4,4'-dιcarboxyhc acid White solid (5%) Mp 263°C (decomp ) 'H NMR (DMSO-de) d 11 7 (broad, IH), 8 2 (m, 4H), 7 9 (m, 4H), 6 2-6 0 (m, IH), 5 5-5 3 (m. 2H), 4 9 (d, 211, J = 7 0 Hz)

Benzophenone-2,4'-dicarboxylic acid monoallyl ester. Procedure as above starting from benzophenone-2,4'-dιcarboxyhc acid White solid (64%) of the 2 isomers in ratio 7 1 (2- allylester/4'-allylester) Chromatographed (CHCb/ MeOH/ triethylamine 8 1 1) to afford pure white sohd of 2-allylester (39%) (Mp 125-127°C) and pure white solid of 4'-allylester (6%) (mp 119-120°C) 2-allylester >H NMR (CDCla) d 10 8 (broad, IH), 8 2-8 1 (m, 3H), 7 8 (d 2H, J = 8 4 Hz), 7 4 (dd, IH, J = 7 4 Hz, J = 1 6 Hz), 5 7 (m, IH), 5 2 (m, 2H), 4 5 (d, J = 7 0 Hz) '³C NMR (CDCla) d 196 2 170 8 165 3 141 0 140 9 132 8 132 6 131 2 131 0 130 8 130 2 129 9 129 0 128 9 127 6 125 2 118 7 66 1 4'-allylester 'H NMR (CDCls) d 9 2 (broad, IH), 8 1 (d, 3H, J - 8 2 Hz), 7 75 (d, 2H, J = 8 2 Hz), 7 7 (dt, IH, J = 7 5 Hz, J = 1 2 Hz), 7 6 (dt, IH, J = 7 5 Hz, J = 1 2 Hz), 7 4 (d, IH, J = 7 5 Hz), 6 1-5 9 ( , IH), 5 5-5 3 (m, 2H), 4 8 (d, J = 7 0 Hz) ¹³C NMR (CDCls) d 196 3 170 1 165 3 141 9 140 2 133 7 133 3 131 7 130 8 129 8 129 8 129 6 129 0 127 8 127 5 127 4 118 5 65 9

Biphenyl-2,2'-dicarboxylic acid monoallyl ester. Procedure as above starting from bιphenyl-2,2'-dιcarboxyhc acid Colourless oil (35%) Bιphenyl-2 2'-dιcarboxyhc acid (40%) was isolated for reuse Η NMR (CDCls) d 8 0 ( , 2H), 7 6-7 4 (m, 4H). 7 2 (d, 2H, J = 7 2 Hz), 5 7-5 6 (m, IH), 5 2-5 0 (m, 2H), 4 5 (d, 2H J = 5 9 Hz) ' C NMR (CDCls) d 171 5 166 7 143 7 142 8 134 0 132 0 131 7 131 4 130 5 130 3 130 1 129 9 129 2 128 4 127 2 118 0 65 4 Naphthoic-2,6-dicarboxylic acid monoallyl ester. C 2CO3 (1 60g, 5 00 mmol) was added in two equal portions over 0 5 h to a solution of naphthoιc-2 6-dιcarboxyhc acid (2 16g, 10 0 mmol) in anhydrous DMF (97 mL) Allyl bromide (17 3 L, 200 mmol) was then added and the reaction mixture stirred vigorously for 24 h The same amount of CS2CO3 was then added in two equal portions over 8 h and the reaction allowed to proceed for a further 17 h The precipitate was filtered and rinsed with DMF (3 x 20 mL) The combined filtrate was then concentrated in vacuo and extracted with hot 50% MeOH/acetone (2 x 100 mL) After evaporation of the solvent, residual starting material was removed by silica gel chromatography (acetone/hexane/HOAc, 50/48/2) The resulting fractions which contained a mixture of the monoester and the diester was concentrated, redissolved in 10 % MeOH/dichloromenthane, and treated with Amberlyst A-26 (hydroxide form) resin (24 0 g, 96 meq) for 17 h The resin was then filtered and washed with fresh solvent (about 3 L) until no diester was detected in the effluent by TLC (CHCla/MeOH, HOAc, 94/4/2) The monoallyl ester was then eluted with MeOH/dichloromethane/acetic acid (10 80 10) After solvent removal, recrystalhsation from acetone gave 3 as a fine colourless solid (0 77 g, 30 %), Mp 217-218°C δ (250 MHz, DMSO-dβ) 4 88 (d, 2H, CH₂-CH=CH₂, J = 5 1 Hz), 5 30 (m, 1 H, CH₂-CH=CH2), 5 45 (m, 1 H, CH₂-CH=CH2), 6 10 (m, IH CH₂-CH=CH₂), 805 (m, 2H, H4 and H8), 8 25 (d, 2H, H I and H3, J=8 4 Hz), 8 70 (dd, 2H, H5 and H7, =15 5, 3 9 Hz) Elemental analysis (C15H12O4) C 69 77% (calcd 70 3%) H 4 51% (calcd 4 72%) EIMS calculated for C15H12O4 256, found 256

Example 4

Solid Phase Synthesis of Balanol Analogues

The balanol libraries was synthesised using split-synthesis -method After each step the resins was mixed and swollen in a isopycnic mixture of 1,2-dιchlorethane 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

Two dicarboxyhc acids were used in step (A) (m=2), four aminoalcohols were used in step (B) (n=4), and four aromatic carboxylic acid were used in step (C) (o=4) Thus a library having 2*4*4=32 compounds was prepared

(A) Coupling of aromatic acids to a Wang resin (corresponding to step (A) in the general scheme)

Phthalic acid and naphthalene-2,6-dιcarboxyhc acid as the internal anhydride and the monoallyl esters, respectively, were coupled to a Wang resin using 2 different methods Coupling of phthalic acid to a Wang Resin. 1 6 g (0 87 meq/g) Wang resin (poh styrene cross-linked with 1% divinylbenzene from NovaBiochem) was swollen in 10 ml dry DMF and 2 83 g (1 6 mmol) phthahc-anhydride, 1 95 ml (1 425 g (14 1 mmol) EtsN and 0 2346 g ( 1 92 mmol) DMAP was added The reaction mixture was shaken for 4 days, then washed with 2*10 ml 30% MeOH in dichloromethane and 4* 10 ml dichloromethane The res was dried and analysed on HPLC Loading L = 0 66 meq/g

Coupling of naphthalene-2,6-dicarboxylic acid monoallyl ester on Wang resin. 0 8 g (0 87 meq/g) Wang resin was swollen in 8 ml dry DMF and 0 321 g (1 25 mmol) naphthalene-2,6- dicarboxyhc acid monoallyl ester, 0 412 g (1 39 mmol) MSNT and 0 443 ml (5 57 mmol) 1 -methyl- lmidazole (NMI) was added The reaction mixture was shaken 4 days and washed with 2* 10 ml 30% MeOH in dichloromethane and 4*10 ml dichloromethane The resin was dried and analysed on HPLC Loading L = 0 87 meq/g

Deallylation of the immobilised naphthalene-2,6-dicarboxylic acid allyl ester. To a 5% HOAc and 2,5% NMM solution in 15 ml CHCls was added 2,4 g (2 09 mmol) Pd(PPhs)₄ under Argon The mixture was shaken 10 mm and 0 8 g (0 87 meq/g, 0 696 mmol) mono-allylated resin was added under Argon The reaction mixture was shaken 18 h and washed with 6* 15 ml 0 5% DIPEA, 0 5 sodium-diethyl-dithio-carbamate in DMF for each 10 min and 3*15 ml dichloromethane The resin was dried and analysed on HPLC Loading L = 0 83 meq/g

Coupling of N-Fmoc-aminoalcohols on -COOH functionalised resin (corresponding to step (B))

Four different N-Fmoc-aminoalcohols were used

frcms-N-Fmoc-4-amino-l-cyclohexanol. 0 4 g (0 87-0 66 meq/g) -COOH functionalised resin was swollen in 5 ml dry dichloromethane and a solution of 0 27 g (0 8 mmol) trans-N-Fmoc-4- amino- 1 -cyclohexanol in 5 ml dry dichloromethane was added The reaction mixture was shaken 2 min and 0 237 g (0 8 mmol) MSNT and 0 254 ml (3 2 mmol) NMI was added After 4 days the reaction mixture was washed with 10 ml dichloromethane, 10 ml of 30% MeOH in DCM, 10 ml DMF and 2*10 ml DCM The resin was dried and analysed on HPLC to identify the two products

N-Fmoc-l-amino-2-propanol. Procedure as above using 0 238 g (0 8 mmol) N-Fmoc-l-amιno-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-amιno- l - butanol The two products was identified on HPLC

N-Fmoc-3-amino-l-propanol. Procedure as above using 0 238 g (0 8 mmol) N-Fmoc-3-amιno- l - propanol The two products was identified on HPLC

Coupling of benzoic acid derivatives on -NH2 functionalised resin (corresponding to step (C))

Four different benzoic acids was used

Diisopropylethylammonium salt of 4,4'-Dimethoxytrityl-oxymethyl-benzoic acid. 0 4 g (approx 0 6 meq/g) -NH-Fmoc functionalised resin was washed with 2*10 ml 20% piperidine in DMF 2*40 mm and 3*10 ml DMF The resin was swollen in 7 ml dry DMF and 0 584 g (1 0 mmol) diisopropylethylammonium salt of 4,4'-Dιmethoxytπtyl-oxymethyl-benzoιc acid was added followed by addition of 0 520 g (1 0 mmol) PyBOP, 0 135 g (1 0 mmol) HOBT and 0 33 ml (2 0 mmol) DIPEA After 4 days the resin was washed with 2*10 ml DMF, 2*10 ml 30% MeOH in DCM and 2*10 ml DCM for each 10 min

4-nitro-benzoic acid. 0 4 g (approx 0 6 meq/g) -NH-Fmoc functionalised resin was washed with 2*10 ml 20% pipendme in DMF 2*40 mm and 3*10 ml DMF The resin was swollen m 7 ml dry DMF and 0 167 g (1 0 mmol) 4-nιtrobenzoιc acid was added followed by addition of 0 520 g (1 0 mmol) PyBOP, 0 135 g (1 0 mmol) HOBT and 0 33 ml (2 0 mmol) DIPEA After 4 days the res was washed with 2*10 ml DMF, 2*10 ml 30% MeOH in DCM and 2*10 ml DCM for each 10

4-methoxy-benzoic acid. Procedure as above using 0 152 g (1 0 mmol) 4-methoxy-benzoιc acid

3-fluoro-benzoic acid. Procedure as above using 0 140 g (1 0 mmol) 3-fluoro-benzoιc acid

Cleavage of the combinatorial library from the Wang resin (corresponding to step (D))

In order to implement this synthesis on solid-phase, the outcome and optimisation of the key coupling reactions were followed by a cleave-&-analyse technique Following this cleave-&- analyse technique, approximately 5 mg resin was weighted on an analytical balance and cleaved by trifluoroacetic acid (TFA)/dιchloromethane (DCM) (1 1, v/v), evaporated (Speed- Vac™), redissolved and quantified by reverse-phase HPLC pre-cahbrated using minimum three standard concentrations The products were cleaved by TF.VDCM (1 1 v/v) when a W ang-typp resin was applied for the synthesis of the combinatorial library and analysed using diode-array HPLC-UV (Hitachi) and HPLC-MS (Perkm-Elmer, Sciex) to identify the constituents of each of the four sub-libraries

The 4,4'-Dimethoxytrityl-oxymethyl-benzoic acid batch. The DMT protecting group was removed by washing with 4*10 ml 3% dichloroacetic acid in DCM followed by wash with 4*10 ml DCM The resin was dried and analysed on HPLC (LC-MS) and 6 of the 8 theoretically obtainable balanol analogues were identified

The 4-nitro-benzoic acid batch. The resin was dried and analysed on HPLC (LC-MS) and 7 of the 8 theoretically obtainable balanol analogues were identified

The 4-methoxy-benzoic acid batch. The resin was dried and analysed on HPLC (LC-MS) and 7 of the 8 theoretically obtainable balanol analogues were identified

The 3-fluoro-benzoic acid batch. The resin was dried and analysed on HPLC (LC-MS) and 7 of 8 theoretically obtainable balanol analogues

In the sub-libraries above, I e the 4,4'-Dιmethoxytπtyl-oxymethyl-benzoιc acid batch, the 4-nιtro- benzoic acid batch, the 4-methoxy-benzoιc acid batch, and the 3-fluoro-benzoιc acid batch, 6 7, 7, and 7 balanol-structures, respectively, were identified as distinct peaks in the LC-UV/MS analyses The remaining five balanol analogues containing either one of the isomeπc building blocks l-amιno-propan-2-ol or 3-ammo-propan- l-ol were not observed the analysis of the library Several reasons can be proposed to account for this observation where precipitation of individual library members or co-elution in HPLC are very likely possibilities

Claims

1. A method for the preparation of a compound of the following general formula I: K-C(=O)-A-C(=O)-L¹-B-L²-C(=O)-D

wherein

K·C(=O)- designates a carboxy group or a derivative thereof; each of A and B designates an organic biradical; each of L¹ and L² independently designates -NR⁵- or -O-, wherein each R⁵ independently is selected from hydrogen, optionally substituted C_1-20-alkyl, optionally substituted C_1-20- alkenyl, optionally substituted C_1-20-alkadienyl, optionally substituted C_{1 -20}-alkatrienyl, optionally substituted aryl, and optionally substituted heteroaryl, or R³ designates an additional bond to B (whereby B becomes a triradical);

D designates optionally substituted aryl or optionally substituted heteroaryl; comprising the following steps

(A) providing an optionally functional group protected moiety -C(=O)-A-C(=O)-M¹ immobilised to a solid support material, wherein -C(=O)-M¹ designates a carboxy group or a derivative thereof, (B) coupling an optionally functional group protected difunctional entity L'¹-B-L'² to the

-C(=O)-M¹ end of the immobilised moiety -C(=O)-A-C(=O)-M¹ for the formation of an optionally functional group protected immobilised fragment -C(=O)-A-C(=O)-L¹-B-L'²,

(C) couphng an optionally functional group protected entity D-C(=O)-M², wherein C(=O)- M² designates a carboxy group or a derivative thereof, to the L'² end of the immobilised fragment -C(=O)-A-C(=O)-L¹-B-L'² for the formation of an optionally functional group protected immobilised compound -C(=O)-A-C(=O)-L¹-B-L²-C(=O)-D the step optionally including deprotection of any protection group involved in L'², and (D) cleaving the compound K-C(=O)-A-C(=O)-L¹-B-L²-C(=O)-D from the solid support material, the step optionally including deprotection of one or more functional group(s) attached to A, B, and/or D

2. A method according to claim 1, w herein the organic biradical -C(=O)-A-C(=O)- is an aliphatic biradical of the formula

-C(=O)-(CR³R⁴)_n-C(=O)- wherein n is 1-20, preferably 1- 12, in particular 2-8, and where each of R³ and R⁴ independently is selected from hydrogen, optionally substituted C_{1 -6}-alkyl, optionally substituted C_2-6-alkenyl, optionally substituted C_4-8-alkadienyl, optionally substituted C_6-8-alkatrienyl, hydroxy, oxo (thereby forming a keto or aldehyde functionality), -O-R⁶, formyl, -C(=O)-R⁶, -O-C(=O)-R⁶, carboxy, -C(=O)-O-R⁶, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted aryl, optionally substituted aryloxy, halogen such as fluoro, chloro, bromo, and lodo nitro, cyano, -N(R⁵)₂, -N(R⁷)-CO-R⁶, carbamoyl, mono- or di(C_{1 -6}-aIkyl)aminocarbonyl, sulphanyl, optionally substituted C_1-6-alkylthio, optionally substituted C_1-6-alkylthio-C_1-6-alkyl, (optionally substituted aryl)thio, guanidino, sulphono

(-SO₃H), sulphino (-SO₂H), halosulphonyl, -OS(O)_m-R⁶ where m is 2 or 3, -N(R⁷)S(O)_m-R⁶ wherein is 2 or 3, -S(O)_m=N(R⁷)₂ where m is 2 or 3, -S(O)_m-NH(R⁷) where m is 2 or 3, -S(O)_m-NH₂ wherein is 2 or 3, isocyano, isothiocyano, thiocyano, -OP(O)_P(R⁶)_q where p is 1, 2, or 3, q is 1 or 2, and p+q is 3, 4, or 5, and -N( R⁷)P(O)_p(R⁶) _q where p is 1, 2, or 3, q is 1 or 2, and p+q is 3,

4, or 5, wherein each R⁵ and each R⁶ independently is selected from hydrogen, optionally substituted C_1-20-alkyl, optionally substituted C_2-20-alkenyl, optionally substituted C_4-20-aIkadienyl, optionally substituted C_6-20-alkatrienyl, optionally substituted aryl, and optionally substituted heteroaryl, and each R⁷ is selected from hydrogen and C_1-4-alkyl, where at the most 5, preferably at the most 3, of the substituents R³ and R⁴ are different from hydrogen, or a biradical as illustrated in Figure 1 and 2, wherein X is selected from the group consisting of >NR⁵, >NH, -O-, -S-, -Se-, -Te-, -CR¹R²-, >C=O, >C=S, and Y¹, Y², R¹, and R² each independently designate substituents as defined as optional substituent for aryl and heteroaryl (see above), or Y¹ together with Y² may form a biradical which together with the atoms located between these substituents, form(s) a 4-, 5-, 6-, 7- or 8-membered ring which may be an optionally substituted non-aromatic carbocyclic or heteroaromatic ring or an optionally substituted aromatic or heteroaromatic rings, and each Z¹ and Z² independently designates =N-, =N⁺R⁵- 3. A method according to claim 1 or 2, wherein the organic biradical -L¹-B-L²- is an aliphatic biradical of the formula

-L¹-(CR³R⁴)_n-L²- where L¹, L², R³, R⁴ and n are as defined in claims 1 and 2, or an aliphatic or aromatic amino alcohol as illustrated in Figure 3, wherein X is selected from the group consisting of >NR⁶, >NH, -O-, -S-, -Se-, -Te-, -CR¹R²-, >C=O, >C=S, and Y¹ Y² R¹, and R² each independently designates optional substituents, or Y¹ together with Y² may form a biradical which together with the atoms located between these substituents, form(s) a 4-, 5-, 6-, 7- or 8-membered ring which may be an optionally substituted non-aromatic carbocyclic or

heteroaromatic ring or an optionally substituted aromatic or heteroaromatic rings, and each Z¹ and Z² independently designates =N-, =N⁺R⁵-^. 4. A method according to any of the preceding claims wherein one of L¹ and L² designates -O- and the other designates -NR⁵-, wherein R^B designates hydrogen, C_1-44alkyl or an additional bond to B.

5. A method according to any of the preceding claims, wherein K designates OH, O- OR", NH₂ NHR, or NRR', in particular OH, methoxy, or NH₂, where R and R' are selected from C_{1 -6}-alkyl and benzyl, and R" is selected from C_1-6-alkyl, C_2-6-alkenyl, phenyl, and benzyl.

6. A method according to any of the preceding claims, further comprising a step (E) performed after the step (D), where the step (E) comprises conversion of one compound of the general formula 1 to another compound of the general formula I.

7. A method for the preparation of a multi-dimensional array of compounds, {A}-{B}-{D} consisting of at least four compounds each having the general formula I K-C(=O)-A-C(=O)-L¹-B-L²-C(=O)-D I wherein

K-C(=O)- designates a carboxy group or a derivative thereof, each of A and B designates an organic biradical, each of L¹ and L² independently designates -NR⁵- or -O-, wherein each R⁵ independently is selected from hydrogen, optionally substituted C_1-20-alkyl, optionally substituted C_1-20- alkenyl, optionally substituted C_1-20-alkadienyl, optionally substituted C_1-20-alkatrienyl, optionally substituted aryl, and optionally substituted heteroaryl, or R³ designates an additional bond to B (whereby B becomes a triradical);

D designates optionally substituted aryl or optionally substituted heteroaryl; comprising

(A) providing an array {A} of m optionally functional group protected moieties -C(=O)-A- C(=O)-M¹ immobilised to a solid support material, wherein -C(=O)-M¹ designates a carboxy group or a derivative thereof; (B) couphng an array {B} of n optionally functional group protected difunctional entities

L'¹-B-L'² to the -C(=O)-M¹ end of the immobilised moieties -C(=O)-A-C(=O)-M¹ for the formation of an array {A}-{B} of m*n optionally functional group protected immobilised fragments -C(=O)-A-C(=O)-L¹-B-L'²; (C) coupling an array {D} of o optionally functional group protected entities D-C(=O)-M², wherein -C(=O)-M² designates a carboxy group or a derivative thereof, to the L'² end of the immobilised fragments -C(=O)-A-C(=O)-L¹-B-L'² for the formation of an array {A}-{B}-{D} of m*n*o optionally functional group protected immobilised compounds -C(=O)-A-C(=O)-L¹-B- L²-C(=O)-D, the step optionally including deprotection of any protection group involved in L'², and

(D) cleaving the array {A}-{B}-{D} of compounds K-C(=O)-A-C(=O)-L¹-B-L²-C(=O)-D from the solid support material, the step optionally including deprotection of one or more functional group(s) attached to individual As, Bs, and/or Ds; with the proviso that m*n*o is at least 4, preferably in the range of 6-200, more preferably in the range of 6- 100, in particular in the range of 8-64.

8. A method according to claim 7. wherein the organic biradical -C(=O)-A-C(=O)- is as defined in claim 2.

9. A method according to claim 7 or 8, wherein the organic biradical -L¹-B-L²- is as defined in claim 3.

10. A method according to any of the claims 7-9, wherein one of L¹ and L² designates -O- and the other designates -NR⁵-, wherein R⁵ designates hydrogen, C_1-4-alkyl or an additional bond to B.

11. A method according to any of the claims 7-10, wherein K designates OH, O-, OR", NH₂, NHR, or NRR', In particular OH, methoxy, or NH₂, where R and R' are selected from C_1-6-alkyl and benzyl, and R" is selected from C_1-6-alkyl, C_2-6-alkenyl, phenyl, and benzyl.

12. A method according to any of the claims 7- 1 1, further comprising a step (E) performed after the step (D), where the step (E) comprises conversion of at least some of the compounds in the array of compounds of the general formula I to other compounds of the general formula I.

13. The use of an array of compounds according to any of the claims 7- 13 for screening purposes.

14. The use of a compound prepared according to a methods defined in any of the claims 1-6 or 7¬

13 as a medicament.