WO1997022594A1

WO1997022594A1 - Combinatorial libraries

Info

Publication number: WO1997022594A1
Application number: PCT/DK1996/000534
Authority: WO
Inventors: John Nielsen
Original assignee: PHYTERA SYMBION APS
Current assignee: PHYTERA SYMBION APS
Priority date: 1995-12-15
Filing date: 1996-12-16
Publication date: 1997-06-26
Anticipated expiration: 1998-06-15
Also published as: AU1093197A

Abstract

The invention provides a method for the production of a combinatorial library of compound of general formula (I) using solid phase methodologies. The cleavage of the array of immobilised compounds of the phthalimido type from the solid support matrix is accomplished by using an array of dinucleophiles, e.g. hydrazines (hydrazinolysis) or N-hydroxylamines, whereby a combinatorial dimension is introduced in the cleavage step. The invention also provides a compound library.

Description

FIELD OF THE INVENTION

COMBINATORIAL LIBRARIES The present invention relates to a method for producing a combinatorial library of compounds of the general formula I defined herein The method involves the use of a support material on which an array of intermediates is covalently attached Such intermediates may undergo reactions before cleavage for the support units In the cleavage step, an array of different reagent species may be used, thereby introducing a combinatorial dimension in the cleavage step The present invention also relates to a library of two or more compound of the general formula I

BACKGROUND OF THE INVENTION

In traditional medicinal chemistry, an average of 10,000 different compounds are synthesised and tested durmg the process of finding the one active component with the right pharmacological and toxicological properties (the drug) The combmed 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, m spite of obvious scientific progress durmg 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 m 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 hterature 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 usmg combinatorial chemistry is one of the most active fields of modern organic chemistry Initially, research was focused on the generation on peptide and nucleotide hbraries but more recently - due to the dubious drug-potential of these compounds - the generation of non-peptidic small molecule libraries have attracted most of the attention and resources m this field ^{] 3}

Recently some reports on the generation of small molecule hbraries in solution appeared,^{4 E} but still, the majority of the published work in the area of generating combinatorial small molecule libraries are performed using sohd-phase chemistry The original reason for this was the fact that using a sohd-phase approach, the spht-mix-recombine method^{6 7} could be used as a way of generating truly vast libraries Now, when many people are focusing on fewer (or even single compounds) per vial ("sub -library"), the sohd-phase methods have retamed its popularity - most probably due to lls ease of automation of sohd-phase chemistry as compared to standard solution organic synthesis

Therefore, combinatorial hbraries are generally synthesised using sohd-phase synthesis which leave the individual members with one specific functional group in common (typically a phenol, a carboxylic acid, an amide, etc ) after deprotection and cleavage from the solid support ⁸ Thus, this functionality is required for linking the group of molecules covalently to the sohd-support durmg the course of synthesis

SUMMARY OF THE INVENTION

The present invention relates to a method for producing a combinatorial library of chemical compound following solid phase methodology, where a combinatorial dimension can, and often will, be introduced in the step where the chemical entities are liberated from the support mateπal

Thus, the present invention provides a method for producmg a combinatorial library of compounds of the general formula

wherein each of A and B independently is selected from the group consisting of -NfR¹)-, -0-, -S-, Se-, and -Te-, wherem each R¹ independently designates hydrogen, optionally substituted Ci 20-alkyl, optionally substituted C22o-alkenyl, optionally substituted C420-alkadιenyl, optionally substituted Cβ ∑o-alkatπenyl, optionally substituted C22o-alkynyl, optionally substituted aryl, optionally substituted heteroaryl, and each of Yi, Y2, Y3, and Y4 mdependently designates hydrogen, optionally substituted Ci 20-alkyl, optionally substituted C220-alkenyl, optionally substituted C420-alkadιenyl, optionally substituted Ce 20-alkatrιenyl, optionally substituted C220-alkynyl, hydroxy, optionally substituted aryl, optionally substituted aryl-Ci 6-alkyl, optionally substituted aryloxy-Ci 6-alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-Ci 6-alkyl, optionally substituted heteroaryloxy-Ci 6-alkyl, halogen such as fluoro, chloro, bromo, and iodo, cyano, nitro, O-R², formyl, carboxy, -CO-O-R², -CO-R², -O-CO-R², ammo, -N(R )H, mono- or dι(Cι e-alkyl)amιno-Cι ₆- alkyl, -N(R²)R^J, -N(R³)-C0-R², (Ci 2o-alkyl)carbonylammo-Ci β-alkyl, carbamoyl, ammocarbonyl- Ci 6-alkyl, mono- or dι-(Cι 2o-alkyl)amιnocarbonyl, mono- or dι(Cι 6-alkyl)amιnocarbonyl-Cι β- alkyl, sulphanyl, optionally substituted Ci 2o-aIkylthιo-Cι.6-alkyl, optionally substituted alkylthio, (optionally substituted aryl)thιo, guamd o, guanidino-Ci β-alkyl, sulphono (-SO3H), sulphmo (-SO2H), halosulphonyl, -S(0)m-N(R²)₂ where is 2 or 3, -S(0)_m-NH(R²) where m is 2 or 3, -S(0)m-NH2 where m is 2 or 3, isocyano, isothiocyano, thiocyano, -OP(0)_P(R²)_q where p is 1, 2, or 3, q is 1 or 2, and p+q is 3, 4, or 5, and -N(R³)P(0)_P(R²)_q where p is 1, 2, or 3, q is 1 or 2, and

wherem each R² mdependently designates a group selected from hydrogen, optionally substituted Ci 20-alkyl, optionally substituted C220-alkenyl, optionally substituted C< 20- alkadienyl, optionally substituted Cβ 20-alkatrιenyl, optionally substituted C220-alkynyl, optionally substituted aryl, optionally substituted heteroaryl, and R³ mdependently designates a group selected from hydrogen and Ci 6-alkyl, or one or two of the substituent pairs, Yι Y2, Y2 Y3, Y3/Y4, may each form a biradical which, together with the atoms located between the substituents in question, form(s) either a 4-, 5-, 6-, 7- or 8-membered rmg, where the biradical is a 2-, 3-, 4-, 5-, or 6-membered partially or fully saturated carbon chain optionally interrupted and/or termmated by one or more heteroatoms selected from nitrogen, oxygen, and sulphur, and where the biradical may be substituted with one, two, three, or several substituents as defined for Y^Y⁴,

comprismg

(a) providing an array {P} of at least two different support-immobihsed phthalimido moiety species of the general formula II

wherem "Support" indicates a polymeric support unit to which the phthalimido moiety species are covalently bound, and Yi Y2, Yi, and Y are as defmed above

and (b) cleaving the support-immobihsed phthalimido moiety species, or a least a part thereof, from the support units to which they are immobilised by reactmg the support units with an array {D} of at least one, preferably at least two, dinucleophde species of the general formula A ■ B' (correspondmg to A-B m formula I) wherem each of A' and B' mdependently is selected from the group consisting of -N(R')H, -OII, -SH, -SeH, -TeH wherein each R¹ is as defmed above, whereby the 5-membered ring of the phthalimido moiety (formula II) is converted to a 6- membered rmg (formula I), the identity of which is dependent of the identity of the dinucleophile (A'-B') with which the moiety species has been reacted

Thus, the method give rise to a series of new structurally diverse compounds Furthermore, the linking, deprotection and cleavage schemes are potentially very useful for the generation of different attractive combinatorial library formats

DETAILED DESCRIPTION OF THE INVENTION

In the present context, the term "Ci 20-alkyl" is mtended to mean a hnear, cychc or branched hydrocarbon group havmg 1 to 20 carbon atoms, such as methyl, ethyl, propyl, iso-propyl, cyclopropyl, butyl, tert-butyl, iso-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, hexadecyl, heptadecyl, octadecyl, nonadecyl Analogously, the term "Ci β-alkyl" is mtended to mean a hnear, cychc or branched hydrocarbon group havmg 1 to 6 carbon atoms, such as methyl ethyl, propyl, iso-propyl, cyclopropyl, butyl, iso-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl

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

Similarly, the terms "Cϊ ∑o-alkenyl", "C420-alkadιenyl", and "C62o-alkatπenyl" are mtended to mean a hnear, cychc or branched hydrocarbon group havmg 2 to 20, 4 to 20, and 6 to 20, carbon atoms, respectively, and comprismg one, two, and three unsaturated bonds, respectively Examples of alkenyl groups are vmyl, allyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, heptadecaenyl Examples of alkadienyl groups are butadienyl, pentadienyl, hexadienyl, heptadienyl, heptadecadienyl Examples of alkatπenyl groups are hexatrienyl, heptatnenyl, octatrienyl, and heptadecatnenyl Preferred examples of alkenyl are vmyl, allyl, butenyl, especially allyl Similarly, the term "C220-alkynyl" is mtended to mean a hnear or branched hydrocarbon group havmg 2 to 20 carbon atoms and comprismg a triple bond Examples hereof are ethynyl propynyl butynyl octynyl, and dodecaynyl

In the present context 1 e connection with the terms "alkyl", "alkenvl", "alkadienyl", "alkatπenyl", 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, Ci 6-alkoxy (1 e alkyl-oxy), carboxy, Ci β-alkoxycarbonyl, Ci 6- alkylcarbonyl formyl, aryl, aryloxycarbonyl, arylcarbonyl, heteroaryl, ammo, mono- and dι(Cι 6-alkyl)ammo, carbamoyl, mono- and dι(Cι 6-alkyl)ammocarbonyl, amino-Ci β-alkyl-ammocarbonyl, mono- and dι(Cι 6-alkyl)ammo-Cι 6-alkyl-amιnocarbonyl, Ci 6-alkylcarbonylamιno, guanidino, carbamido, Ci 6-alkanoyloxy, sulphono, Ci β-alkylsulphonyloxy, nitro, sulphanyl, Ci 6-alkylthιo, trihalogenalkyl, halogen such as fluoro, chloro, bromo or iodo, where aryl and heteroaryl may be substituted with methyl, methoxy, nitro or halogen

Preferably, the substituents are selected from hydroxy, Ci β-alkoxy, carboxy, Ci 6-alkoxycarbonyl, Ci 6-alkylcarbonyl, formyl, aryl, aryloxycarbonyl, arylcarbonyl, heteroaryl, ammo, mono- and dι(Cι 6-alkyl)ammo, carbamoyl, mono- and dι(Cι 6-alkyl)amιnocarbonyl, amino-Ci 6-alkyl- aminocarbonyl, mono- and dι(Cι 6-alkyl)ammo-Cι 6-alkyl-amιnocarbonyl, Ci β-alkylcarbonylammo, guanidino, carbamido, trihalogenalkyl, halogen such as fluoro, chloro, bromo or iodo, where aryl and heteroaryl may be substituted with methyl, nitro or halogen Especially preferred examples are hydroxy, Ci 6-alkoxy, carboxy, aryl, heteroaryl, ammo, sulfanyl, mono- and dι(Cι 6- alkyl)ammo, mono- and dι(Cι 6-alkyl)amιno, and halogen such as fluoro, chloro, bromo or iodo

In the present context the term "aryl" is mtended to mean an aromatic carbocychc rmg or rmg system, such as phenyl, naphthyl, anthracyl, phenanthracyl, pyrenyl, benzopyrenyl, fluorenyl and xanthenyl, among which phenyl is a preferred example

The term "heteroaryl" is mtended to mean an aryl group where one or more of the carbon atoms have been replaced with heteroatoms, e g nitrogen, sulphur, and/or oxygen atoms Examples of such heteroaryl groups are oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridmyl, pyrazinyl, pyndazmyl, pipeπdmyl, coumaryl, furyl, qumolyl, indolyl, benzopyrazolyl, phenoxazonyl Preferred heteroaryl groups are pyrid yl, benzopyrazolyl, and imidazolyl

In the present context, 1 e m connection with the terms "aryl" and "heteroaryl", the term "optionally substituted" is mtended to mean that the group in question may be substituted one or several times, preferably 1-5 times, with group(s) selected from hydroxy (which when present in an enol system may be represented in the tautomeπc keto form), Ci β-alkoxy, carboxy Ci 6- alkoxycarbonyl, Ci β-alkylcarbonyl, formyl, aryl, aryloxycarbonyl, arylcarbonyl, heteroaryl, ammo, mono- and dι(Cι 6-alkyl)amιno, carbamoyl, mono- and dι(Cι 6-alkyl)ammocarbonyl, amino- Ci 6-alkyl-amιnocarbonyl, mono- and dι(Cι 6-alkyl)ammo-Cι 6-alkyl-ammocarbonyl, Ci e- alkylcarbonylamino, guanidmo, carbamido, Ci 6-alkanoyloxy sulphono, Ci 6-alkylsulphonyloxv nitro, sulphanyl, trihalogenalkyl, halogen such as fluoro, chloro, bromo or iodo Preferred examples are hydroxy, Ci β-alkoxy, carboxy, Ci 6-alkoxycarbonyl, Ci β-alkylcarbonyl, aryl am o, mono- and dι(Cι β-alkyl)ammo, aryl and halogen such as fluoro, chloro, bromo or iodo

In a preferred embodiment of the present mvention each of Yi, Y2, Ys, and Y mdependently designates hydrogen, optionally substituted Ci 6-alkyl, hydroxy, optionally substituted aryl, optionally substituted aryl-Ci β-alkyl, optionally substituted aryloxy-Ci β-alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-Ci β-alkyl, optionally substituted heteroaryloxy-Ci e-alkyl, halogen, cyano, nitro, O-R², formyl, carboxy, -CO-O-R², -CO-R², -O-CO- R², ammo, -N(R²)H, mono- or dι(Cι ₆-alkyl)ammo-Cι β-alkyl, -N(R²)R³, -N(R³)-CO-R², (Ci 20- alkyl)carbonylammo-Cι β-alkyl, carbamoyl, ammocarbonyl-Ci β-alkyl, mono- or dι-(Cι β- alkyl)amιnocarbonyl, mono- or dι(Cι β-alkyl)ammocarbonyl-Cι β-alkyl, sulphanyl, sulphono (-SO3H), sulphmo (-SO2H), halosulphonyl, -S(0)m-N(R )2 where m is 2 or 3, -S(0)m-NH(R²) where m is 2 or 3, -S(0)m-NH2 where m is 2 or 3, isocyano, isothiocyano, thiocyano, -OP(0)_P(R²)_q where p is 1, 2, or 3, q is 1 or 2, and p+q is 3, 4, or 5, and -N(R³)P(0)_P(R²)_q where p is 1, 2, or 3, q is 1 or

wherem each R² mdependently designates a group selected from hydrogen, optionally substituted Ci 6-alkyl, optionally substituted C220-alkenyl, optionally substituted C 20- alkadienyl, optionally substituted Cβ 20-alkatπenyl, optionally substituted aryl, optionally substituted heteroaryl, and R³ mdependently designates a group selected from hydrogen and Ci β-alkyl, or one or two of the substituent pairs, Y1 Y2, Y2/Y3, Ys Y₄, may each form a biradical which, together with the atoms located between the substituents m question, form(s) either a 4-, 5-, 6-, 7- or 8-membered rmg, where the biradical is a 2-, 3-, 4-, 5-, or 6-membered partially or fully saturated carbon cham optionally mterrupted and/or termmated by one or more heteroatoms selected from with from nitrogen, oxygen, and sulphur, and where the biradical may be substituted with one, two, three, or several substituents as defmed for Y^Y⁴

In an especially preferred embodiment of the present mvention, each of Yi, Y2, Y3, and Y4 mdependently designates hydrogen, optionally substituted Ci β-alkyl, hydroxy, optionally substituted aryl, optionally substituted aryl-Ci β-alkyl, optionally substituted aryloxy-Ci β-alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-Ci β-alkyl, optionally substituted heteroaryloxy-Ci β-alkyl, halogen, cyano, nitro, O-R², formyl, carboxy, -CO-O-R², -CO- R², -O-CO-R², ammo, -N(R²)H, mono- or dι(Cι β-alkyl)amιno-Cι β-alkyl -N(R )R³, -N(R³)-CO-R² (Ci ₂θ-alkyl)carbonylamιno-Cι β-alkyl, carbamoyl, ammocarbonyl-Ci 6-alkyl mono- or dι-(Cι 20- alkyl)ammocarbonyl, mono- or dι(Cι 6-alkyl)ammocarbonyl-Cι β-alkyl, sulphanyl, sulphono (-SO3H), sulphmo (-SO2H), wherein each R² mdependently designates a group selected from hydrogen, optionally substituted Ci β-alkyl, optionally substituted heteroaryl, and R³ independently designates a group selected from hydrogen and Ci β-alkyl

In an alternative embodiment, one of the substituent pairs, YιΛ^r2, Y2 Y3, Y3 Y4 may each form a biradical which, together with the atoms located between the substituents in question form(s) either a 4-, 5-, 6-, 7- or 8-membered rmg, where the biradical is a 2-, 3-, 4-, 5-, or 6-membered partially or fully saturated carbon cham optionally interrupted and or termmated by one or more heteroatoms selected from with from nitrogen, oxygen, and sulphur, and where the biradical may be substituted with one, two, three, or several substituents as defmed for Y'-Y⁴

It is envisaged that when any of the substituent pairs Y1/Y2, Y2/Y3, and Y3/Y4 form(s) a biradical, this biradical, together with the atoms located between the substituents question, represents a rmg fused to the bicychc rmg system represented by the formula I, the rmg bemg selected from benzene, furane, 2,3-dιhydrofuran, 2,5-dιhydrofuran, isoxazole, oxazole, thiazole, isothiazole, imidazole, triazole, cyclobutene, pyrohne, pyrrole, cyclopentene, cyclopentadiene, cyclohexene, and cyclohexadiene These fused rmgs may m themselves be substituted by one or more substituents as defined for Yⁱ-Y

As it will be evident from the definition of possible substitutent in formula I, there may be one or more asymmetric carbon atoms present m the molecule depending on the nature of the substituents The compounds of the mvention are mtended to mclude all stereoisomers arismg from the presence of any and all isomers as well as mixtures thereof, including racemic mixtures Also, the compounds may be in the form of alkali metal salts or acid addition salts

With respect to the dmucleophile A'-B' correspondmg to A-B the general formula I, it should be understood that N-substituted hydrazmes, N-hydroxylammes and the S, Se, and Te analogues of N-hydroxylammes are especially relevant Thus m the general formula I, one of A and B is preferably -NCR¹)- and the other is selected from the group consisting of -NCR¹)-, -0-, -S-, -Se-, and -Te-, preferably -NCR¹)- and -0-, m particular -NCR¹)-, wherein each R¹ mdependently designates hydrogen, optionally substituted Ci 20-alkyl, optionally substituted C220-alkenyl, optionally substituted C₄20-alkadιenyl, optionally substituted Cβ 20-alkatrιenyl, optionally substituted C220-alkynyl, optionally substituted aryl, optionally substituted heteroaryl Preferably R¹ designates hydrogen, Ci β-alkyl, optionally substituted aryl, optionally substituted heteroaryl It should be understood that the dmucleophile A'-B' corresponds to A-B m formula I In the cases where the phthalimido group is asymmetrical, and where the dmucleophile is not a symmetrically substituted hydrazine, it is envisaged that the cleavage reaction will result m two different compounds of the general formula I Thus, m this way a further diversity of the combmatoπal library can be mtroduced The reaction between the dmucleophile and the support-immobdised phthalimido moiety is illustrated m Figure 1

In the trivial case, the array of dmucleophdes consists of only one type of dmucleophile However it is preferred (in order to fully exploit the principles of the present mvention) that the array {D} of dmucleophdes consists of at least two, preferably three, such as four, different dinucleophde species In a special variant, 2-6 different dinucleophiles constitute the array {D}

The array {P} preferably consists of at least three, preferably four, such as five, different support- lmmobihsed phthalimido moiety species In a special variant of the present invention, the array {P} is constituted by 4-15 different phthalimido moieties of the general formula II

Thus, the present mvention provides a method for producmg a combinatorial library {D}={P} comprises at least 10, such as from 10 to 100, different species of the formula I

In the present context, the term "support umt" is mtended to mean the individual physical particles of a support material Such support units may be provided as spheres, sheets, pellets, etc

The array {P} of support-immobilised phthalimido moiety species of the general formula II may be provided by immobihsmg an array {Pab} of phthalimido moieties of the general formula Ila or lib

wherem Yi, Y2, Y3, and Y4 designate the same groups as defmed for the support-immobihsed phthalimido moieties of the formula II constitutmg the array {P} of support-immobilised phthalimido moieties of the general formula II, to a sohd support material As is illustrated m Figure 1, the immobilisation of Ila and lib requires that the support material comprises an alkyl halide group or an ammo alkyl group, respectively In the case of Ila, an alkali metal salt, e g the sodium or potassium salt, may be used It is envisaged that any of number of readily avadable, e g commercially available, support material may be used, and that the immobilisation of the compound of the general formula Ila may be attached the support material following method generally known to the person skilled m the art The methods for immobihsmg a compound to a support material are well-described for peptides but also apply for the compounds of the general formula Ila and lib, see e g the well- established Merrifield sohd phase synthesis methodology ¹⁴ method derived thereof, and the general methodologies described m references 1-7

As described above and illustrated m the following, a compound library {D}={P} of compounds of the formula I may be performed simply by attachmg an array {Pab} of compound of the general formula Ila and or lib to a support material followed by cleavage of the immobilised moieties of the formula II from the sohd support material However, in order to exploit the full scope of the present mvention, one or more reactions may be performed on the support-immobi sed moieties before cleavage

Thus, in an mterestmg embodiment of the present invention, the method comprises attachmg phthalimido moieties to units of a support to obtam an array {P} of support-immobihsed phthalimido moiety species of the general formula III

m which "Support" indicates a polymeric support to which the phthalimido moieties are covalently bound, and each of Xi, X2, Xs, and X4 mdependently designate substituents or biradicals as defined for Yi, Y2, Yβ, and Y , and

performing one or several chemical reactions by contactmg the support units carrymg the immobilised phthalimido moieties, either together or divided mto subgroups of units, with one or several reagents, the contactmg the case of several reagents bemg performed simultaneously or sequentially, or by usmg combmations of simultaneous contactmg and sequential contactmg, whereby an array of support-immobihsed phthalimido moiety species of the general formula II is provided Any necessary protection and deprotection steps should be considered mcluded by the term "one or several chemical reactions"

It is clear that when performing a number of reaction steps, which may be performed on a subgroup of support units only, offers the possibility of mtroducmg further combinatorial dimensions the combinatorial hbraries The individual reactions performed will be the reactions normally performed for, or especially adapted to support-immobihsed compounds, of course with due consideration to the support material used

The present mvention furthermore provides a composition comprismg at least two different compounds of the general formula 1 defmed above The composition preferably comprises at least four, preferably at least six, in particular at least ten such as between 10 and 100 different compounds of the general formula I The composition is preferably obtained by the method accordmg to the present mvention however compound libraries which are produced by methods which differs from this method, but which result in a simdar combmatonal library should also be considered as falhng withm the present mvention

Such as composition which typically is the crude product of the cleavage reaction, optionally obtained after a simple chromatographic process, e g fdtermg through silica gel, may, if desirable for the reason of solubihty, may comprise the compounds of the formula I m the form of salts or acid addition salts thereof It is naturally desirable that the compound are soluble m the solvent chosen The solvent used for the composition may be any solvent suitable for screening purposes, such as water ethanol, methanol, chmethylsulphoxidc (DMSO), DMF, and mixtures thereof, etc The solvent need not necessardy be the same as for the reactions performed on the immobilised moieties or for the cleavage reaction For screenmg purposes it may be essential that the composition according to the present mvention, except for any solvents, is substantially free of compounds not being of the formula I, so that any positive response unambiguously can be related to a compound comprised m the composition

Discussion of the illustrative experiments

The present mvention is illustrated m the following where the dinucleophde is illustrated by various hydrazides A more specific description of the experiments can be found m the experimental section

The applicants have for some time been interested m new strategies for the generation of molecular diversity These mclude the introduction of a combmatonal cleavage and deprotection scheme I e a strategy where a number of different compounds are created durmg the cleavage and/or deproteclion step from the sohd-support ⁹ Usmg this strategy, multiple functionalities can be generated systematically such that large numbers of structurally diverse compounds can be created from one common synthon (see Figure 1) In this approach, the small organic moiety is linked to the solid phase through a phthahmide function The phthahmide function is a fairly stable linkage which still allows for selective cleavage by hydrazmes under mdd conditions - a reaction known as the Ing-Manske procedure ¹⁰ (Scheme 1) The products of these reactions are phthalhydrazides (2 3-dιhydro-phthalazιne-l 4-dιones) which are known to posses a wide range of different biological activities and at the same time phthalhydrazides comprise a rather unexplored group of potentially new drug leads.^{11 12}

Scheme 1. The Ing-Manske procedure for cleavage of the phthahmide linkage by a hydrazine.

As a model study for the above combinatorial cleavage and deprotection scheme, a systematic study of the reaction between a series of hydrazines (the dinucleophde) and phthahmide has been performed. In these experiments, a number of di-aromatic, mono-aromatic and aUphatic hydrazines were investigated as well as a series of different reaction conditions such as variation of solvent, temperature and the addition of a series of possible catalysts. These reaction optimisations were aU carried out in a fashion we have termed "experimental design" using a 2D- matrix having e.g. the solvents in one dimension and the different catalysts in the other dimension. An illustrative example employing 2-hydroxyethylhydrazine as the dmucleophile, 4 different solvents (MeOH, EtOH, N,N-dimethylformamide (DMF) and HOAc) and 6 different catalytic conditions (none, N,N-dusopropylethylamine (DIPEA) (1 and 2 eq.), 4-dimethylamino- pyridine (DMAP) (0.1 and 1 eq.) and trifluoroacetic acid (TFA)) is shown in Scheme 2. From this and the other reaction schemes (which are not included) it was found that exceUent reaction conditions were reactions at room temperature, methanol (or ethanol) as the solvent and catalysing the reaction with 2-3 eq. of N,N-diisopropylethylamine (Some hydrazmes are available only as the mono- or dihydrochloride, for which reason 3 eq. of catalyst (N,N-diisopropylethyl- amine) is preferable). It was also found that aUphatic hydrazides were more Ukely to lead to a complete and smooth conversion of the phthalimide into the corresponding end product. Scheme 2 (see Figure 3) shows an experimental design optimisation of solution reaction between phthahmide and 2-hydroxyethylhydrazme (2 hours reaction time, room temperature, determined by RP-HPLC) HO Ac* For acetic acid, the catalysts were different (1 eq NaOAc, 2 eq NaOAc, 1 eq TFA 2 eq TFA and H2Sθ [catalytic amount, 2 drops/1 m ole], respectively)

In order to expand the scope of this reaction, 5 different hydrazmes were set up to react with 5 different phthahmides m a 6 x 6 matrix format yielding 25 individual compounds (plus 8 isomers), 10 indexed subhbrarιes^6a and 1 full hbrary contammg a mixture of all 33 different compounds (Scheme 3) The reactions were carried out m the 1 mmole scale and m aU cases with the 25 individual compounds we obtamed a high yield of the expected phthalhydrazides including 8 isomers (from B2-E2 and B5-E5) Likewise, us g reversed-phase HPLC (RP-HPLC), we were able to resolve all individual compounds the indexed hbraries whereas the full 33- member library did not allow resolution and identification of individual compounds

B

H,N NH, H,N NHMe eHN — NHMe EtHN — NHEt H_? N'

H

Scheme 3a The 5 different phthahmides (A-E) and 5 different hydrazmes (1-5) tested m the 6 6 matrix solution experiment

Scheme 3b The schematic format of the 6 x 6 matrix (IKA-Vibrax-VXR shaker equipped with an Janke & Kunkel VX2 rack)

Finally, to test this approach on sohd-phase, phthahmides A and C were immobilised to a chloro- methylated polystyrene resin (Merrifield resm) usmg a known procedure ¹³ The resultmg resms contamed the expected substituted phthahmide structures accordmg to IR spectroscopy However, deprotection of phthahmides A and C usmg hydrazme 5 m EtOH at room temperature was sluggish whereas the expected products A5 and C5 were obtamed after reflux for 16 h When the deprotection was performed in dichloromethane at room temperature the expected products were obtamed in high yields under mdd conditions Likewise, when the resm contammg C was reacted with hydrazme 1 in 1,2-dιchloroethane (DCE) led to Cl m nearly quantitative ^yield Reactions performed m N,N-dιmethylformamιde did not provide us with any product m the cases tested, indicating a sluggish reaction m dipolar, aprotic solvents _just as the solution experiments, although the resin is well solvated

The synthetic scheme for the generation of diverse hbraries of phthalhydrazides both by sohd- phase synthesis, by solution synthesis and m several different combmatonal formats (smgle compounds, mdexed hbraries and full hbraries) has proved useful Likewise, usmg this synthetic scheme as a combmatonal deprotection method combmed with sohd-phase synthesis of structures linked via a phthahmide linkage, yields another diversity mtroducmg step m a hitherto unknown fashion The reactions are solvent dependent and durmg the sohd-phase synthesis depend furthermore on the swelling and solvatisation of the resm The synthetic schemes for the sohd-phase reactions to mclude more complicated structures, optionally involving one or more chemical reactions before cleavage, can be estabhshed for the person skilled in the art by using method generally described for sohd phase chemistry The study of sev ral strategies for generating combmatonal hbraries of new small organic molecules (MW < 700 D) has resulted in the present mvention The invention may mcludes the introduction of a combmatonal cleavage and deprotection scheme Combmatonal libraries are generally synthesised usmg sohd-phase synthesis and because of this most smaU molecule hbraries leave the mdividual members with one specific functional group (typicaUy a phenol, a carboxyhc acid, an amide, etc ) after deprotection and cleavage from the sohd support Accordmg to the strategy o the present invention, multiple functionalities are generated systematicaUy such that large numbers of structuraUy diverse compounds can be created from one common synthon

Because of the inherited stability of the phthahmide linkage, this hnkage aUows a wide range of chemistries to be performed as exemplified m Scheme 3 Functionahsed phthahmide derivatives are coupled to ammo acids (e g the 20 naturaUy encoded ammo acids and a range of unnatural ammo acids β-Amino acids could be used as weU and would thus form a product havmg a 7- membered rmg) The resultmg acid function can then either be reduced to the corresponding alcohol function and may be further converted to the corresponding alkyl hahde or converted directly to the correspondmg acyl hahde These alkyl and acyl hahde are the rmg closed by the Friedel-Craft procedure (see Figure 2)

REFERENCES

1 Nielsen, J Chemistry & Industry 1994, 902-905

2 GaUop, M A , Barrett, R W , Dower, W J , Fodor, S P A , Gordon, E M J Med Chem 1994 37, 1233-1251 3 Gordon, E M , Barrett, R W , Dower, W J , Fodor, S P A , GaUop, M A J Med Chem 1994 37, 1385-1401

4 (a) Pirrung, M C , Chen, J J Am Chem Soc 1995 117, 1240-1245 (b) Pirrung, M C , Chau, J H -L , Chen, J Chemistry & Biology 1995, 2, 621-626

5 CareU, T , Wmtner, E A , Sutherland, A J , Rebek, J , Dunayevskiy, Y M , Vouros, P Chemistry & Biology 1995 2, 171-183

6 (a) Furka A , Sebestyen, F , Asgedom, M , Dibo, G In 14th Int Congr Biochem 1988 Praque, Czechchoslovakia W de Gruyter Berlin/New York 1989 (b) Furka, A , Sebestyen, F , Asgedom, M , Dibo, G In 10th Int Symp Med Chem 1988 Budapest, Hungary Elsevier Amsterdam/New York 1989 7 Lam, K S , Salmon, S E , Hersh, E M , Hruby, V J , Kazmierski, W M , Knapp, R J Nature, 1991, 354, 82-84

8 See e g (a) Bunm, B A and Ellman, J A J Am Chem Soc 1992, 114, 10997- 10998 (b) Bunm, B A , Plunkett, M J and Ellman, J A Proc Natl Acad Sci USA 1994, 91, 4708-4712 9 Ley, S V , Mynett, D M , Koot W -J Synlett 1995 1017- 1020

10 Ing, H R , Manske, R H F J Chem Soc 1926, 2348-2351

11 Murthy, A R K , HaU, I H , Chapman J M Rhyne K A Wyrick, S D Pharm Res 1986, 3, 93-101 12 HaU I II , Hall, E S , Wong, O T Anti-Cancer Drugs 1992, 3, 55-62

13 Wemshenker, N M, Shen, C M , Wong, J Y Org Synth 1988, CoU Vol 6, 951-954

14 e g Barany, G , and Merπfield, R B in The Peptides Vol 2, Academic Press, New York 1979, pp 1-284

EXPERIMENTAL

Synthesis of 4-mtrophthalhvdrazιde

4-nιtrophthaUmιde (221 mg) was suspended m ethanol (5 ml) and hydrazme (73 μl, approx 74 mg) was added and the reaction mixture was shaken over night at 1000 rpm HPLC analysis of reaction mixture showed complete conversion of startmg material to 4-nιtrophthaUιydrazιde product (UVmax = 248 nm)

Synthesis of N-methyl-4-nιtrophthaIhvdrazιde

4-nιtrophthahmιde (229 mg) was suspended m ethanol (5 ml) and methylhydrazine (73 μl, approx 74 mg) was added and the reaction mixture was shaken over night at 1000 rpm HPLC analysis of reaction mixture showed complete conversion of startmg material to two isomers of N-methyl-4-nιtrophthalhydrazιde product (UVma_* = 248 nm)

Synthesis of N-(2-hvdroxyethyl)-phthalhvdrazιde 2-Hydroxyethylphthahmιde (192 mg) was suspended m ethanol (5 ml) and 2-hydroxyethyl- hydrazine (163 mg) was added and the reaction mixture was shaken over night at 1000 rpm HPLC analysis of reaction mixture showed 70% conversion of startmg after 18 hours

Synthesis of N-(2-hvdroxyethyl)-4-nιtrophthalhydrazιde 4-Nιtrophthahmιde (193 mg) was suspended m ethanol (5 ml) and 2-hydroxyethylhydrazme (163 mg) was added and the reaction mixture was shaken over night at 1400 rpm HPLC analysis of reaction mixture showed 70% conversion of startmg after 18 hours

Synthesis of a solution-phase 5 phthalhvdrazide-member Ubrarv A vial was loaded with phthalhydrazide (74 mg) and 4-nιtrophthalιmιde (94 mg) and suspended m ethanol (3 ml) An ethanohc stock solution of hydrazme (1 eq ) and methylhydrazine (1 eq ) was added and the reaction mixture was shaken over night at 1000 rpm HPLC analysis of reaction mixture showed conversion of startmg after 16 hours Products were isolated by precipitation from addition of hexane (10 ml) and refrigeration Centrifugation and washmg with hexane (5 ml) Dried m vacuo Library was dissolved in DMSO/H2O (1/9 v/v) and was ready for analysis and or screenmg

Synthesis of a solution-phase 33 phthalhvdrazide-member hbrarv

5 different phthahmides (phthahmide, 4-nιtrophthahmιde, 3-nιtrophthahmιde 4-chlorophthal- lmide and 4-fluorophthahmιde) was reacted with 5 different hydrazmes Chydrazme, methyl¬ hydrazine, N,N'-dιmethylhydrazιne N N'-diethylhydrazme and 2-hydroxyethylhydrazme) m a 6 x 6 matrix format yielding 25 individual compounds (plus 8 isomers) 10 mdexed sub-hbraries and 1 full hbrary contammg a mixture of all 33 different compounds The reactions were carried out on the 1 mmole scale in the foUowmg way (as exemplified for phthahmide) Phthahmide (1 mmole) was placed in each of six 16 mm screw-capped reaction vials and dissolved/suspended in ethanol (or methanol) One of each of the different hydrazmes (1 mmole) was added to vial 1 through 5 To vial 6 was added an equimolar mixture (1 e 0 2 mmole) of each of the five different hydrazines to >ιeld a sub-library The base (N N-dusopropylethylamme, 2-3 mmole) was added and reaction mixtures were fitted mto an IKA-Vibrax-VXR shaker equipped with an Janke & Kunkel VX2 6 x 6-rack and was shaken for 1000-1400 rpm In all cases with the 25 mdividual compounds we obtamed a high yield of the expected phthalhydrazides including 8 isomers (HPLC analysis) Likewise, usmg reversed-phase HPLC (RP-HPLC) we were able to resolve aU mdividual compounds m the mdexed hbraries The resultmg compounds could be isolated either by evaporation of solvent and base or by precipitation with hexane (10 ml), cooling and centrifugation

Phthahmide functionahsation of chloromcthylated polystyrene resin CM ernfield resin) A chloromethylated polystyrene resin (930 mg, 0 88 mmole, Merπfield Peptide Resm, 1% cross- linked, loading 0 95 mmol eq /g) was suspended m N,N-dιmethylformamιde (12 ml) and stirred for 15 mmutes at 100°C Potassium phthahmide (310 mg, 1 67 mmol) was added and the reaction mixture stirred over night at 100°C After cooling to room temperature, the resm was isolated by filtration and washed with N,N-dιmethylformamιde, dichloromethane and methanol Dried m a vacuum dissicator Yield 1 026 g

4-Nιtrophthahmιde functionahsation of chloromethylated polystyrene resm (Merπficld resm) A chloromethylated polystyrene resm (920 mg, 0 87 mmole, Mernfield Peptide Resm, 1% cross- linked, loading 0 95 mmol eq /g) was suspended m N,N-dιmethyUormamιde (12 ml) and stirred for 15 mmutes at 100°C Potassium 4-mtrophthahmιde (370 mg, 1 6 mmol) was added and the reaction mixture stirred for 24 hours at 100°C After cooling to room temperature, the resm was isolated by filtration and washed with N,N-dιmethylformamιde, dichloromethane and methanol Dried m a vacuum dissicator Yield 1 102 g

Claims

1 A method for producing a combmatonal hbrary, {D}={P}, of compounds of the general formula I

wherem each of A and B independently is selected from the group consisting of -NCR¹)-, -0-, -S-, - Se-, and -Te-, wherem each R¹ mdependently designates hydrogen, optionally substituted Ci 20-alkyl, optionaUy substituted C220-alkenyl, optionaUy substituted C 20-alkadιenyl, optionaUy substituted Cβ 20-alkatπenyl, optionaUy substituted C220-alkynyl, optionaUy substituted aryl, optionaUy substituted heteroaryl, and each of Yi, Y2, Y3, and Y4 mdependently designates hydrogen, optionaUy substituted Ci 20-alkyl, optionally substituted C22o-alkenyl, optionaUy substituted C 20-alkadιenyl, optionaUy substituted Cβ 20-alkatπenyl, optionaUy substituted C220-alkynyl, hydroxy, optionaUy substituted aryl, optionaUy substituted aryl-Ci 6-alkyl, optionaUy substituted aryloxy-Ci β-alkyl, optionaUy substituted heteroaryl, optionaUy substituted heteroaryl-Ci β-alkyl, optionaUy substituted heteroaryloxy-Ci 6-alkyl, halogen such as fluoro, chloro, bromo and iodo, cyano, nitro, O-R², formyl, carboxy, -CO-O-R*, -CO-R², -O-CO-R², ammo, -N(R )H, mono- or dι(Cι 6-alkyl)amιno-Cι β- alkyl, -N(R²)R³, -N(R³)-CO-R², (Ci 2o-alkyl)carbonylammo-Cι 6-alkyl, carbamoyl, ammocarbonyl- Ci 6-alkyl, mono- or dι-(Cι 2o-alkyl)amιnocarbonyl, mono- or dι(Cι 6-alkyl)amιnocarbonyl-Cι 6- alkyl, sulphanyl, optionaUy substituted Ci 20-alkylthιo-Cι β-alkyl, optionally substituted alkylthio, (optionaUy substituted aryl)thιo, guanidmo, guanidino-Ci β-alkyl, sulphono (-SO3H), sulphmo (-SO2H), halosulphonyl, -S(0)m-N(R²)₂ where m is 2 or 3, -S(0)m-NH(R²) where m is 2 or 3, -S(0)m-NH2 where is 2 or 3, isocyano, isothiocyano, thiocyano, -OP(0)_P(R²)_q where p is 1, 2, or 3, q is 1 or 2, and p+q is 3, 4, or 5, and -N(R³)P(0)p(R²)_q where p is 1, 2 or 3, q is 1 or 2, and

wherem each R² mdependently designates a group selected from hydrogen, optionaUy substituted Ci 20-alkyl, optionaUy substituted C220-alkenyl, optionaUy substituted C420- alkadienyl, optionaUy substituted Cβ 20-alkatπenyl, optionally substituted C220-alkynyl, optionaUy substituted aryl, optionaUy substituted heteroaryl, and R³ mdependently designates a group selected from hydrogen and Ci 6-alkyl, or one or two of the substituent pairs, Y1 Y2, Y2I 3, Y3 Y4, may each form a biradical which, together with the atoms located between the substituents question, form(s) either a 4-, 5-, 6-, 7- or 8-membered rmg, where the biradical is a 2-, 3-, 4-, 5-, or 6-membered partiaUy or fully saturated carbon chain optionally mterrupted and/or termmated by one or more heteroatoms selected from nitrogen, oxygen, and sulphur and where the biradical may be substituted with one two, three, or several substituents as defmed for Y^[-Y ,

comprismg

wherem "Support" mdicates a polymeric support unit to which the phthahmido moiety species are covalently bound, and Yi, Y2, Y3, and Y4 are as defined above,

and (b) cleavmg the support-immobihsed phthahmido moiety species, or a least a part thereof, from the support units to which they are immobilised by reactmg the support units with an array {D} of at least one, preferably at least two, dinucleophde species of the general formula A- B' (corresponding to A-B m formula I), wherem each of A' and B' independently is selected from the group consistmg of -NCR^H, -OH, -SH, -SeH, -TeH, wherem each R¹ is as defmed above, whereby the 5- embered rmg of the phthahmido moiety (formula II) is converted to a 6- membered ring (formula I), the identity of which is dependent of the identity of the dinucleophde (A'-B¹) with which the moiety species has been reacted

2 A method accordmg to claim 1, wherein one of A and B is -NCR¹)- and the other is selected from the group consistmg o -NCR¹)-, -0-, -S-, -Se-, and -Te-, wherem each R¹ mdependently designates hydrogen, optionally substituted Ci 20-alkyl, optionaUy substituted C220-alkenyl, optionaUy substituted CΛ 20-alkadιenyl, optionaUy substituted Cβ∑o-alkatnenyl, optionaUy substituted C220-a kynyl, optionaUy substituted aryl, optionaUy substituted heteroaryl, and wherem A' and B' corresponds to A and B formula I

3 A method accordmg to claim 2, wherem one of A and B is -NCR¹)- and the other is selected from the group consistmg of -NCR¹)- and -0-, preferably -NCR¹)- wherem each R¹ mdependently designates hydrogen, optionaUy substituted Ci 20-alkyl, optionaUy substituted C220-alkenyl, optionaUy substituted C 20-alkadιenyl, optionally substituted Ce 20-alkatπenyl, optionaUy substituted C220-alkynyl, optionaUy substituted aryl, optionally substituted heteroaryl 4 A method accordmg to any of the claims 1-3 wherein R¹ designates hydrogen, Ci β-alkyl optionaUy substituted aryl, optionally substituted heteroaryl

5 A method accordmg to any of the preceding claims wherein each of Yi, Y2, Y3, and Y mdependently designates hydrogen, optionally substituted Ci 6-alkyl, hydroxy, optionaUy substituted aryl, optionally substituted aryl-Ci 6-alkyl, optionally substituted aryloxy-Ci β-alkyl, optionally substituted heteroaryl, optionaUy substituted heteroaryl-Ci 6-alkyl, optionaUy substituted heteroaryloxy-Ci 6-alkyl halogen, cyano, nitro, O-R², formyl, carboxy, -CO-O-R², -CO- R², -O-CO-R², ammo, -N(R²)I1, mono- or dι(Cι ₆-alkyl)amιno-Cι β-alkyl, -N(R²)R³, -N(R³)-CO-R², (Ci 2o-aUcyl)carbonylammo-Cι 6-alkyl, carbamoyl, ammocarbonyl-Ci 6-alkyl, mono- or dι-(Cι 6- alkyl)amιnocarbonyl, mono- or dι(Cι 6-alkyl)ammocarbonyl-Cι 6-alkyl, sulphanyl, sulphono (-SOsH), sulphmo (-SO2H), halosulphonyl, -S(0)_m-N(R²)2 where m is 2 or 3, -S(0)m-NH(R²) where m is 2 or 3, -S(0)m-NH2 where m is 2 or 3, isocyano, isothiocyano, thiocyano -OP(0)_P(R²)_q where p is 1, 2 or 3, q is 1 or 2, and p+q is 3, 4, or 5, and -N(R³)P(0)_P(R²)_q where p is 1, 2, or 3, q is 1 or

wherem each R² mdependently designates a group selected from hydrogen optionaUy substituted Ci 6-alkyl, optionally substituted C220-alkenyl optionaUy substituted C420- alkadienyl, optionally substituted Cδ2o-alkatπenyl, optionaUy substituted aryl, optionaUy substituted heteroaryl, and R³ mdependently designates a group selected from hydrogen and Ci β-alkyl, or one or two of the substituent pairs, Y1/Y2, Y2 Y3, Y3/Y4, may each form a biradical which, together with the atoms located between the substituents m question, form(s) either a 4-, 5-, 6-, 7- or 8-membered ring, where the biradical is a 2-, 3-, 4-, 5-, or 6-membered partially or fuUy saturated carbon cham optionaUy mterrupted and/or termmated by one or more heteroatoms selected from with from nitrogen, oxygen, and sulphur, and where the biradical may be substituted with one, two, three, or several substituents as defined for Y'-Y⁴

6 A method according to claim 5, wherem each of Yi, Y2, Y3, and Y4 mdependently designates hydrogen, optionaUy substituted Ci β-alkyl, hydroxy, optionaUy substituted aryl, optionaUy substituted aryl-Ci 6-alkyl, optionaUy substituted aryloxy-Ci 6-alkyl, optionaUy substituted heteroaryl, optionally substituted heteroaryl-Ci β-alkyl, optionaUy substituted heteroaryloxy-Ci 6- alkyl, halogen, cyano, nitro, O-R², formyl, carboxy, -CO-O-R², -CO-R², -O-CO-R², ammo, -N(R²)H, mono- or dι(Cι e- alkyl) ammo- Ci e-alkyl -N(R²)R³, -N(R³)-CO-R², (Ci 2o-alkyl)carbonylammo-Cι e- alkyl, carbamoyl, ammocarbonyl-Ci 6-alkyl, mono- or dι-(Cι 2o-alkyl)amιnocarbonyl, mono- or dι(Cι 6-alkyl)amιnocarbonyl-Cι 6-alkyl, sulphanyl, sulphono (-SO3H), sulphmo (-SO2H), wherem each R² independently designates a group selected from hydrogen, optionaUy substituted Ci 6-alkyl, optionaUy substituted heteroaryl, and R³ mdependently designates a group selected from hydrogen and Ci 6-alkyl 7 A method accordmg to claim 5 or 6, wherein in one of the substituent pairs, Y1 Y2, Y2 Y3, Y3/Y4, may each form a biradical which, together with the atoms located between the substituents m question, form(s) either a 4-, 5-, 6-, 7- or 8-membered rmg where the biradical is a 2- 3-, 4-, 5-, or 6-membered partiaUy or fuUy saturated carbon cham optionaUy mterrupted and/or termmated by one or more heteroatoms selected from with from nitrogen, oxygen, and sulphur, and where the biradical may be substituted with one, two, three, or several substituents as defmed for Y^Y⁴

8 A method accordmg to any of the precedmg claims, wherem, when any of the substituent pairs Y1 Y2, Y2/Y3, and Y3/Y4 form(s) a biradical, this biradical, together with the atoms located between the substituents m question, represents a rmg fused to the bicyclic rmg system represented by the formula I, the rmg bemg selected from benzene, furane, 2,3-dιhydrofuran, 2,5-dιhydrofuran lsoxazolc, oxazole, thiazole, isothiazole, imidazole, triazole, cyclobutene, pyrohne, pyrrole, cyclopentene, cyclopentadiene, cyclohexene, and cyclohexadiene

9 A method according to any of the precedmg claims, wherem the array {P} consists of at least three, preferably four, such as five, different support-immobihsed phthahmido moiety species

10 A method accordmg to any of the preceding claims, wherem the array {D} consists of at least two, preferably three, such as four, different dinucleophde species

11 A method accordmg to any of the preceding claims, wherem the combmatonal hbrary {D}={P} comprises at least 10, such as between 10 and 100, different species o the formula I

12 A method according to any of the precedmg claims, wherem the array {P} of support- immobihsed phthahmido moiety species of the general formula II is provided by immobihsmg an array {Pab} of phthahmido moieties of the general formula Ila or lib

wherein Yi, Y2, Y3, and Y4 designate the same groups as defined for the support-immobihsed phthahmido moieties of the formula II constitutmg the array {P} of support-immobihsed phthahmido moieties of the general formula II, to a sohd support material 13 A method according to any of the claims 1- 1 1 , comprising attachmg phthahmido moieties to units of a support to obtam an array {P} of support-immobilised phthahmido moiety species of the general formula III

which "Support" mdicates a polymeric support to which the phthahmido moieties are covalently bound, and each of Xi, X2, X3, and X4 mdependently designate substituents or biradicals as defined for Yi, Y2, Y3, and Y4, and

performing one or several chemical reactions by contactmg the support units carrying the immobdised phthahmido moieties, either together or divided mto subgroups of units, with one or several reagents, the contactmg m the case of several reagents bemg performed simultaneously or sequentially, or by usmg combmations of simultaneous contactmg and sequential contactmg, whereby an array of support-immobihsed phthahmido moiety species of the general formula II is provided

14 A composition comprismg at least two different compounds of the general formula I

wherem each of A and B mdependently is selected from the group consistmg of -N(R')-, -0-, -S-, - Se-, and -Te-, wherem each R¹ mdependently designates hydrogen, optionaUy substituted Ci 20-alkyl, optionaUy substituted C220-alkenyl, optionaUy substituted C420-alkadιenyl, optionally substituted Cβ 20-alkatrιenyl, optionaUy substituted C220-alkynyl, optionally substituted aryl, optionaUy substituted heteroaryl, and each of Yi, Y2, Y3, and Y4 mdependently designates hydrogen, optionally substituted Ci 20-alkyl, optionaUy substituted C22o-alkenyl, optionaUy substituted C420-alkadιenyl, optionally substituted Cβ 20-alkatrιenyl; optionally substituted C220-alkynyl, hydroxy, optionaUy substituted aryl, optionally substituted aryl-Ci 6-alkyl, optionaUy substituted aryloxy-Ci 6-alkyl, optionaUy substituted heteroaryl, optionaUy substituted heteroaryl-Ci 6-alkyl, optionally substituted heteroaryloxy-Ci 6-alkyl, halogen such as fluoro, chloro, bromo, and iodo, cyano, nitro, O-R², formyl, carboxy, -CO-O-R², -CO-R², -O-CO-R- amino, -N(R²)H, mono- or ώ(Cι 6-alkyl)amιno-Cι ₆- alkyl, -N(R )R³, -N(R³)-CO-R², (Ci 20-alkyl)carbonylammo-Cι β-alkyl, carbamoyl aminocarbonyl- Ci 6-alkyl, mono- or dι-(Cι 2o-alkyl)ammocarbonyl, mono- or dι(Cι e-alkyl)ammocarbonyl-Cι β- alkyl, sulphanyl, optionaUy substituted Ci 20-aUcylthιo-Cι β-alkyl, optionally substituted alkylthio, (optionaUy substituted aryl)thιo, guanidino, guamdino-Ci 6-aL yl, sulphono (-SO3H), sulphmo (-SO2H), halosulphonyl, -S(0)_m-N(R²)₂ where m is 2 or 3, -S(0)_m-NH(R²) where m is 2 or 3, -S(0)m-NH2 where m is 2 or 3, isocyano, isothiocyano, thiocyano, -OP(0)_P(R²)_q where p is 1 , 2, or 3, q is 1 or 2, and p+q is 3, 4, or 5, and -N(R³)P(0)_P(R²)_q where p is 1, 2 or 3, q is 1 or 2, and

wherein each R² mdependently designates a group selected from hydrogen, optionaUy substituted Ci 20-alkyl, optionaUy substituted C220-alkenyl, optionaUy substituted C420- alkadienyl, optionaUy substituted Cβ 20-alkatπenyl, optionally substituted C220-alkynyl, optionaUy substituted aryl, optionally substituted heteroaryl, and R³ mdependently designates a group selected from hydrogen and Ci e-alkyl, or one or two of the substituent pairs, Y1 Y2, Y2 Y3, Y3 Y4, may each form a biradical which together with the atoms located between the substituents in question, form(s) either a 4-, 5-, 6-, 7- or 8-membered rmg, where the biradical is a 2-, 3-, 4-, 5-, or 6-membered partiaUy or fuUy saturated carbon cham optionally mterrupted and/or terminated by one or more heteroatoms selected from nitrogen, oxygen, and sulphur, and where the biradical may be substituted with one, two, three, or several substituents as defmed for Y^Y

15 A composition accordmg to claim 14, comprismg at least four, preferably at least six, in particular at least ten, such as between 10 and 100, different compounds of the general formula I

16 A composition according to claim 14 or 15, which comprises a solvent wherein the compounds, or salts or acid addition salts thereof, are dissolved

17 A composition accordmg to any of the claims 14- 16, which, except for any solvents, is substantiaUy free of compounds not bemg of the formula I

18 A composition according to any of the claims 14- 17, which is obtamable by the method defined m any of the claims 1-13

19 A composition accordmg to any of the claims 14- 17, which is obtamed by the method defmed m any of the claims 1-13