EP1000030A1

EP1000030A1 - Piperidine oligomers and combinatorial libraries thereof

Info

Publication number: EP1000030A1
Application number: EP98933574A
Authority: EP
Inventors: John Nielsen; Mikael Bols; Elisabeth Vang Carstensen; Marianne Willert
Original assignee: Phytera Symbion ApS
Current assignee: Phytera Symbion ApS
Priority date: 1997-07-14
Filing date: 1998-07-14
Publication date: 2000-05-17
Also published as: WO1999003832A1; CA2296428A1; AU8334498A

Abstract

The present invention relates to piperidine oligomers, methods for the preparation of piperidine oligomers and compound libraries thereof, and the use of piperidine oligomers as drug substances. The present invention also relates to the use of combinatorial libraries of piperidine oligomers for screening purposes. The oligomers have one of the general formulas (I) or (II). Each of the monomers (piperidine carboxylic acids) are linked via amide bonds. The piperidine monomers may carry substituents, particularly hydroxy, hydroxymethyl, and carboxy substituents. The oligomers may be prepared in libraries (arrays) of compounds especially suitable for screening purposes.

Description

PIPERIDINE OLIGOMERS AND COMBINATORIAL LIBRARIES THEREOF

FIELD OF THE INVENTION

The present invention relates to piperidine oligomers, methods for the preparation of piperidine oligomers and libraries thereof, and the use of piperidine oligomers as drug substances. The present invention also relates to the use of combinatorial libraries of piperidine oligomers for screening purposes.

BACKGROUND OF THE INVENTION Cell surface oligosaccharides play an important, though often little understood, role in cell recognition and adhesion processes (Keilhauer, K. L. et al; Nature 31 6 ( 1985) 728; Hoffman, S. et al; Proc. Natl. Acad. Sci. USA 80 ( 1 983) 5762; Springer, T. A. et al; Nature 346 ( 1 990) 425; and Brandley, B. K. et al; Cell 63 ( 1 990) 861 ), virus (including HIV) infectivity (Brandley, B. K. et al; Cell 63 ( 1 990) 861 ), lymphocyte homing and migration (Montefiori, D. C. et al; Proc. Natl. Acad. Sci. USA 85 ( 1 988) 9248 and Yednock, T: A. et al; 104 (1987) 71 3), tumor metastasis (Stoolman, L. M. 56 (1 989) 907; Dennis, J. W. et al; 236 ( 1987) 582; and Benedetto, A. et al; 43 ( 1 989) 1 26) and many other disorders. Synthetic oligosaccharides could potentially be of great value both for study of these phenomena but also as therapeutics. Thus, a synthetic oiigosaccharide could be used to, by binding to a certain complementary oiigosaccharide receptor, block cell adhesion, virus infection etc. and do so with very high specificity.

Although this idea is not new, it has been little exploited because oligosaccharides of sufficient size are extremely difficult and laborious to synthesise. Furthermore the oligosaccharides will be susceptible to the glycoside cleaving enzymes present in vivo converting them back into monosaccharides thus reducing their efficiency.

Compounds that would resemble the oligosaccharides in shape and polarity, i.e. oiigosaccharide biomimetics, and thus bind to the same receptors but lack the lability to glycosidases would be a powerful analytical and therapeutic tool, provided such compounds were easier to prepare. DESCRIPTION OF THE INVENTION

Construction of the compounds of the general formula I and II

As mentioned above, oligosaccharides play an important role in a number of biological processes, however, oligosaccharides are first of all difficult to prepare, and secondly susceptible to enzymatic degradation. Thus, the rationale behind the present invention is to provide novel compounds which resemble the spatial configuration of oligosaccharides, but which have superior properties with respect stability towards enzymatic degradation and, not the least important, are easy to prepare. The present invention provides novel piperidine oligomers and a novel method for the preparation of such compounds. Furthermore, the oligomers according to the invention have interesting in vitro properties (see the examples). The oligomers according to the present invention (in combination with the novel method for their preparation) thus solves the problem of enzymatic lability and tedious synthetic protocols associated with oligosaccharides by opening up for a novel class of biologically interesting compounds.

A special class of the oligomers of the present invention is the cyclised oligomers of the general formula II (see below). Such oligomers are believed to possess the same advantageous biological properties as has been outlined for the "linear" oligomers (having the general formula I, see below). Furthermore, it is believed that the cyclised oligomers also can mimic the overall conformation and properties of cyclodextrins (e.g. cyclooligoamyloses). Thus, this feature of the cyclised oligomers constitutes a special aspect of the present invention.

The oligomers according to the present invention are either "linear" oligomers of the general formula I

(in short K-C( = 0)-M₀-...-M_n-T, wherein M₀, ..., M_n designate the individual "piperidine monomers") or "cyclised" oligomers of the general formula II

(in short K-C( = O)-M₀-...-M_n-W, wherein M₀, ..., M_n designate the individual "piperidine monomers" and W designates the biradical -Y^a-Y^b-); including acid addition salts and basic salts of these oligomers.

With reference to the method for the preparation of the oligomers, the piperidine carrying the cumulative substituent X° is called the "first monomer" and the piperidine carrying the substituent T (formula I) or the substituent Y^b (formula II) is called the "last monomer". In general, each of the optionally substituted piperidine fragments in the general formulae I and II are called "monomers" or "monomer fragments" .

In the general formulae I and II, n is a positive integer designating the number of piperidine monomers in excess of one. Typically n is an integer in the range of 1 -25, preferably 1 -15, particular 2-10 such as 2-5 or 3-6. For potential glycosidase inhibitors, n is preferably 2. The length of the oligomer is obviously related to what specific use is selected for the oligomer, thus, it may be envisaged that rather large oligomers (e.g. n in the range of 10-50, or even more) may be applicable in certain instances. With the method according to the present invention in hand, rather large oligomers may be realistic.

The moiety K-C( = 0)- in the general formulae I and II (the substituent on the first monomer) 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 can arise when cleaving the oligomers from a solid phase resin (when the oligomers are 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)₃R'), or is derivatised 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 = OR"), where each of R, R', R", and R"' independently designates optionally substituted C_1-β-alkyl, optionally substituted C₂.₆-alkenyl, optionally substituted aryl, or optionally substituted heteroaryl. Furthermore, the C-terminal carboxylic acid may be reduced to the corresponding aldehyde (K = H) in the cleavage step. Preferably, K designates OH, 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, C₂.₆-alkenyl, phenyl, and benzyl. It should be understood that the situation where K designate 0 is realisable when the oligomer or monomer in question is in the form of a basic salt. Furthermore, the derivatives described above may also be obtained after subsequent modification of the "free" oligomer, see below.

In the general formula I, T (the N-terminal substituent on the last monomer) is selected from hydrogen, optionally substituted C^^-alkyl, optionally substituted C^^-alkoxy, optionally substituted C^o-alkylcarbonyl, optionally substituted aryl, optionally substituted heteroaryl, and amino-protecting groups. Preferred meanings of T are hydrogen, optionally substituted C_1-6-alkyl, optionally substituted C^-alkoxy, optionally substituted C^-alkylcarbonyl, optionally substituted aryl, optionally substituted heteroaryl, tert-butoxycarbonyl (Boc), and fluorenylmethoxycarbonyl (Fmoc), where the Boc and Fmoc groups may be remainders of the protection used in the synthesis of the oligomer. Especially preferred meanings of T are hydrogen; C^-alkyl which may be substituted with 1 -3, preferable 1 -2, substituents selected from hydroxy, C_1-6- alkoxy, carboxy, aryl, heteroaryl, amino, mono- and di(C₁.₆-alkyl)amino, and halogen, where aryl may be substituted 1 -3 times with C_1-4-alkyl, C_1-4-alkoxy, nitro, cyano, amino or halogen; C^-alkoxy; C_1-6-alkylcarbonyl; amino-C₁._β-alkylcarbonyl; aryl which may be substituted with 1 -3, preferably 1 -2 substituents selected from C_1-4-alkyl, C-,_₄- alkoxy, nitro, cyano, amino, and halogen; and heteroaryl which may be substituted with 1 -3, preferably 1 -2 substituents selected from C^-alkyl, C ₄-alkoxy, nitro, cyano, amino, and halogen. Particularly interesting embodiments are those where T is selected from hydrogen; C^-alky!; benzyl, Cvβ-alkylcarbonyl; and aryl which may be substituted with 1 -3, preferably 1 -2 substituents selected from C^-alkyl, C_1-4-alkoxy, nitro, cyano, amino, and halogen.

In the general formula II, Y^a and Y^b together designate a linear biradical (-Y^a-Y^b-, which links the first and the last monomer together) comprising 1 -20 backbone atoms. The term "backbone atoms" is intended to mean that the linear biradical comprises from one atom (e.g. one carbon atom yielding methylene (which may be substituted)) and up to 20 atoms between the radical positions, i.e. the positions where the biradical is attached to the first monomer and the last monomer, respectively. Useful examples of linear biradicals are given further above, however, it is believed that linear biradicals (- Y^a-Y^b-) selected from -C( = 0)-NH-(CH₂)_m-C( = 0)-, -NH-C( = OMCH₂)_m-C{ = 0)-, -C( = 0)- NH-(CH₂)_m-, -NH-C( = 0)-(CH₂)_m-, wherein m is 1 -20, preferably 2-1 2, especially 3-10, in particular 3-8, and wherein any of the methylene groups may be substituted with hydroxy, C_1-β-alkyl, aryl optionally substituted 1 -3 times with C_1- -alkyl, C_1-4-alkoxy, nitro, cyano, amino or halogen, amino, mono- and dKC^e-alkyDamino, and halogen, are especially relevant. An especially preferred linear biradical is-C( = 0)-NH-(CH₂)_m-C( = 0)- , where m is as defined above, which arises when a piperidine dicarboxylic acid is used as the "first monomer" in the oligomer and a ω-amino carboxylic acid is used as a linker between the "last monomer" and the "first monomer" .

In the general formulae I and II, each of the "cumulative" substituents X⁰,..., and Xⁿ independently designates 0-5, preferably 0-4, such as 0-3, substituents. It should be understood that such substituents are further substituents when considering the already carboxy substituted piperidine monomers. As indicated above, each of the "cumulative" substituents X⁰,..., and Xⁿ may designate several substituents, thus, one or both of the meanings (a) and (b) given below may apply for such substituents (however meaning (b) only applies for one set of two substituents):

(a) such optional substituents independently are selected from optionally substituted C_1-20-alkyl, optionally substituted C₂.₂₀-alkenyl, optionally substituted C₄.₂₀-alkadienyl, optionally substituted C₆.₂₀-alkatrienyl, optionally substituted C₂.₂₀-alkynyl, hydroxy, d_. ₂o-alkoxy, C₂.₂₀-alkenyloxy, carboxy, oxo, C^^-alkoxycarbonyl, C^o-alkylcarbonyl, formyl, aryl, aryloxycarbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxycarbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and dKC^e-alkyDamino, carbamoyl, mono- and di(C_1-6-alkyl)aminocarbonyl, amino-C^e-alkyl-aminocarbonyl, mono- and guanidino, carbamido, C _-6-alkanoyloxy, sulphono, Cι_₆-alkylsulphonyloxy, nitro, sulphanyl, C,^- alkylthio, trihalogen-C ₄-alkyl, and halogen, where aryl and heteroaryl may be optionally substituted; and/or

(b) two substituents on two adjacent carbon atoms together with said two adjacent carbon atoms may designate (i) a fused optionally substituted aromatic or non- aromatic carbocyclic or heterocyclic ring, or (ii) a double bond.

In a preferred embodiment, each of X⁰,..., and Xⁿ independently designates 0-3 substituents, where

(a) such optional substituents are selected from optionally substituted C_1-6-alkyl, optionally substituted C₂.₆-alkenyl, hydroxy, C^-alkoxy, C_{2 6}-alkenyloxy, carboxy, oxo, C^-alkoxycarbonyl, Cvβ-alkylcarbonyl, formyl, aryl, aryloxycarbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxycarbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and dKC e-alkyDamino; carbamoyl, mono- and dHC β-alkyDamino- carbonyl, Cι_₆-alkylcarbonylamino, sulphone, and halogen, where aryl and heteroaryl may be optionally substituted with 1 -3, preferably 1 -2 substituents selected from C_1-4-alkyl, C^-alkoxy, nitro, cyano, amino, and halogen; and/or

(b) two substituents on two adjacent carbon atoms together with said two adjacent carbon atoms may designate a double bond.

In an especially preferred embodiment each of X°, ..., and Xⁿ independently designates 0-3 substituents, where such optional substituents are selected from C^-alkyl which may be substituted with 1 -3, preferable 1 -2, substituents selected from hydroxy, C_1-β- alkoxy, carboxy, aryl, heteroaryl, amino, mono- and di(C₁.₆-alkyl)amino, and halogen, where aryl may be substituted 1 -3 times with C_1- -alkyl, C^-alkoxy, nitro, cyano, amino or halogen; C_2-6-alkenyl; hydroxy; C^-alkoxy; C₂.₆-alkenyloxy; carboxy; C_{1 6}- alkoxycarbonyl; Cι_₆-alkylcarbonyl; formyl; amino; mono- and carbamoyl; mono- and d C β-alkyDaminocarbonyl; sulphono, and halogen such as fluoro or chloro. In an even more preferred embodiment, each of X°, ..., and Xⁿ independently designates 0-2 substituents, where such optional substituents are selected from C_1-6-alkyl which may be substituted with a substituent selected from hydroxy, C^-alkoxy, aryloxy, and carboxy, where aryl may be substituted 1 -3 times with C_1- -alkyl, C^-alkoxy, nitro, cyano, amino or halogen; hydroxy; C_1-6-alkoxy; C₂.₆-alkenyloxy; carboxy; C^-alkoxycarbonyl; amino; mono- and difCve-alkyDamino; mono- and dHCve-alkyDaminocarbonyl; and C_{1 6}-alkyl- carbonylamino. A still more preferred embodiment is where each of X°, ..., and Xⁿ independently designates 1 -2 substituents, where such substituents are selected from C^e-alkyl which may be substituted with a substituent selected from hydroxy, C^._β- alkoxy, aryloxy, and carboxy; hydroxy; C,.₆-alkoxy; carboxy; and C^-alkoxycarbonyi.

It is generally believed that the monomers should include one or more polar substituents in order to resemble the electrostatic properties of the carbohydrate they mimic. Thus, in a preferred embodiment of the present invention, at least one of each of X°, ..., and Xⁿ is selected from hydroxy, hydroxymethyl and carboxy, in particular at least one of each of X°, ..., and Xⁿ is selected from hydroxy and hydroxymethyl.

In particular, the monomer fragments constituting the oligomers according to the present invention, can be represented by the following general formulae M^2S, M^2R, M^3R, M^3S and/or M⁴

M 2S

M 3R

M

wherein each of the substituents R², R^2', R³, R^3', R⁴, R^4', R⁵, R^5', R⁶, and R^6' independently is as defined for X°, ..., and Xⁿ.

Particularly interesting variants of the monomer fragments M^2S, M^2R, M^3R, M^3S and M⁴ are those which (with a suitable selection of substituents) resembles the configuration of naturally occurring carbohydrates, such as monosaccharides selected the xylose, fucose, galactose, glucose, mannose, glucosamine, galactosamine, and siaiic acid (neuraminic acid). It should be understood that the oligomers are so constructed that the amide bond between the individual piperidine rings mimics the glycosylic bond between the individual rings in a corresponding oiigosaccharide. Thus, in the case where a dimer according to the invention is intended to mimic, e.g., ( -r- )-maltose (α- anomer), the dimer may, e.g., be selected so that the first monomer is of the type M^3R carrying substituents in at least some of the positions R , R⁵, and R⁶ (with the possibility of a substituent in R² ), and the second (and last) monomer is of the type M^3S carrying substituents in at least some of the positions R², R⁴, R^5', and R⁶ .

As above, preferred embodiments are those where at least one of R², R² , R³, R^3', R⁴, R⁴ , R⁵, R⁵ , R⁶, and R⁶ is selected from hydroxy, hydroxymethyl and carboxy, in particular hydroxy and hydroxymethyl. Interesting monomers within the present invention are illustrated in Figure 8.

Definitions

In the present context, the term "Cι_₂₀-alkyl" is intended to mean a linear, cyclic or branched hydrocarbon group having 1 to 20 carbon atoms, such as methyl, ethyl, propyl, /so-propyl, cyclopropyl, butyl, tert-butyl, /so-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, hexadecyl, heptadecyl, octadecyl, nonadecyl. Analogously, the term "C^-alky!" is intended to mean a linear, cyclic or branched hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, /so- propyl, pentyl, cyclopentyl, hexyl, cyclohexyl, and the term "C^-alkyl" is intended to cover linear, cyclic or branched hydrocarbon groups having 1 to 4 carbon atoms, e.g. methyl, ethyl, propyl, /so-propyl, cyclopropyl, butyl, /so-butyl, tert-butyl, cyclobutyl.

Preferred examples of "C^-alky!" are methyl, ethyl, propyl, /so-propyl, butyl, tert- butyl, /so-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl, in particular methyl, ethyl, propyl, /so-propyl, tert-butyl, /so-butyl and cyclohexyl. Preferred examples of "C^- alkyl" are methyl, ethyl, propyl, /so-propyl, butyl, tert-butyl, and /so-butyl.

Similarly, the terms "C₂.₂₀-alkenyl", "C₄.₂₀-alkadienyl", and "C₆.₂₀-alkatrienyl" are intended to cover linear, cyclic or branched hydrocarbon groups 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, heptadecaenyl. Examples of alkadienyl groups are butadienyl, pentadienyl, hexadienyl, heptadienyl, heptadecadienyl. Examples of alkatrienyl groups are hexatrienyl, heptatrienyl, octatrienyl, and heptadecatrienyl. Preferred examples of alkenyl are vinyl, allyl, 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, i.e. in connection with the terms "alkyl", "alkenyl", "alkadienyl", "alkatrienyl", 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), oxy), C₂.₆-alkenyloxy, carboxy, oxo (forming a keto or aldehyde functionality), C_1-6- alkoxycarbonyl, C^-alkylcarbonyl, formyl, aryl, aryloxycarbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxycarbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and dKC^es-alkyDamino; carbamoyl, mono- and di(C₁.₆-alkyl)aminocarbonyl, amino-Cι_-6- alkyl-aminocarbonyl, mono- and dKC β-alkyDamino-C^e-alkyl-aminocarbonyl, C^-alkyl- carbonylamino, cyano, guanidino, carbamido, C^-alkanoyloxy, sulphono, C^- alkylsulphonyloxy, nitro, sulphanyl, C e-alkylthio, halogen, where any aryl and heteroaryl may be substituted as specifically describe below for "optionally substituted aryl and heteroaryl".

"Halogen" includes fluoro, chloro, bromo, and iodo.

Preferably, the substituents are selected from hydroxy, C^-alkoxy, carboxy, ^._β- alkoxycarbonyl, C_1-6-alkylcarbonyl, formyl, aryl, aryloxycarbonyl, arylcarbonyl, heteroaryl, amino, mono- and dKCve-alkyDamino, carbamoyl, mono- and di(C_1-β-alkyl)- aminocarbonyl, alkyl-aminocarbonyl, C_1-6-alkylcarbonylamino, cyano, carbamido, halogen, where aryl and heteroaryl may be substituted 1 -5 times, preferably 1 -3 times, with C_1-4-alkyl, C_1-4- alkoxy, nitro, cyano, amino or halogen. Especially preferred examples are hydroxy, C,. ₆-alkoxy, carboxy, aryl, heteroaryl, amino, mono- and and halogen, where aryl and heteroaryl may be substituted 1 -3 times with C_1-4-alkyl, C_1-4-alkoxy, nitro, cyano, 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 -NH), sulphur, and/or oxygen atoms. Examples of such heteroaryl groups are oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, piperidinyl, coumaryl, furyl, quinolyl, benzothiazolyl, benzotriazolyl, benzodiazolyl, benzooxozolyl, phthalazinyl, phthalanyl, triazolyl, tetrazolyl, isoquinolyl, acridinyl, carbazolyl, dibenzazepinyl, indolyl, benzopyrazolyl, phenoxazonyl.

In the present context, i.e. in connection with the terms "aryl" and "heteroaryl", 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), C_1-β-alkyl, C^-alkoxy, oxo (which may be represented in the tautomeric enol form), carboxy, C^-alkoxycarbonyl, C_1-6- alkylcarbonyl, formyl, aryl, aryloxy, aryloxycarbonyl, arylcarbonyl, heteroaryl, amino, mono- and di(C_1-6-alkyl)amino; carbamoyl, mono- and difCvβ-alkyDaminocarbonyl, amino-C_1-6-alkyl-aminocarbonyl, mono- and di(C₁_₆-alkyl)amino-C₁.₆-alkyl-aminocarbonyl, C_{1 6}-alkylcarbonylamino, cyano, guanidino, carbamido, C_{1 6}-alkanoyloxy, sulphono, C_1-6- alkylsulphonyloxy, nitro, sulphanyl, dihalogen-C^-alkyl, trihalogen-Cι. -alkyl, halogen, where aryl and heteroaryl representing substituents may be substituted 1 -3 times with C_1- -alkyl, C_1-4-alkoxy, nitro, cyano, amino or halogen. Preferred examples are hydroxy, C e-alkyl, aryl, amino, mono- and dKC^e-alkyDamino, and halogen, wherein aryl may be substituted 1 -3 times with C_1-4-alkyl, C^-alkoxy, nitro, cyano, amino or halogen.

In the present context the term "aromatic or non-aromatic carbocyclic or heterocyclic ring" is intended to mean a non-aromatic or fully or partially aromatic carbocyclic or heterocyclic ring or ring system. A heterocyclic ring or ring system is a carbocyclic ring or ring system where one or more of the carbon atoms have been replaced with heteroatoms, e.g. nitrogen ( = N- or -NH), sulphur, and/or oxygen atoms. Examples of such rings are benzene, naphthalene, 1 ,2,3,4-tetrahydronaphthalene, anthracene, phenanthracene, pyrene, benzopyrene, fluorene, xanthene, oxazole, isoxazole, thiazole, isothiazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyridazine, piperidine, coumarine, furan, quinoline, benzothiazole, benzotriazole, benzodiazole, benzoxozole, phthalazine, phthalane, triazole, isoquinole, acridine, carbazole, dibenzazepine, indole, benzopyrazole, phenoxazone, oxazetane, diazetane, thiazetane, oxazolane, imidazolidine, thiazolane, oxazilane, hexahydropyridazine, thiazilane, oxazepane, diazepane, thiazepane, oxazocane, diazocane, thiazocane, tetrahydrofuran, dihydrofuran, pyrrolidine, tetrahydrothiophen, tetrahydropyran, piperidine, tetrahydrothiopyran, oxepane, azepane, thiepane, oxocane, azocane, thiocane, cyclopropane, oxirane, aziridine, cyclopropene, azirine, cyclobutane, oxetane, azetidine, thietane, pyrolidine, pyroline, pyrrole, cyclopentene, cyclopentadiene, cyclo- hexyl, oxirane, dioxirane, morpholine, piperidine, cyclohexene, cyclohexadiene, tropane, azepine, dihydroazepine, tetrahydroazepine, and hexahydroazepine.

In the present context, i.e. in connection with the term "aromatic or non-aromatic carbocyclic or heterocyclic ring", 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 the same substituents as defined above for "optionally substituted aryl".

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

Useful examples of linear biradicals are 1 -20 carbon atom alkylene chains optionally interrupted and/or terminated by one or more heteroatoms selected from O, S, and NR^N where R^N is selected from hydrogen and C₁₄-alkyl), and optionally substituted one or several times, preferably 1 -5 times, in particular 1 -3 times, with substituent(s) selected from optionally substituted C_1-β-alkyl, optionally substituted C₂.₆-alkenyl, hydroxy, oxo (thereby forming a keto functionality), C^-alkoxy, C₂.₆-alkenyloxy, carboxy, C_1-6-alkoxycarbonyl, C^-alkylcarbonyl, formyl, aryl, aryloxycarbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxycarbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and dKC^e-alkyDamino; carbamoyl, mono- and d Cve-alkyDamino- carbonyl, Cvβ-alkylcarbonylamino, cyano, trihalogen-C_1-4-alkyl, halogen such as fiuoro, chloro, bromo or iodo, where aryl and heteroaryl may be optionally substituted 1 -3 times with C _-4-alkyl, C_1-4-alkoxy, nitro, cyano, amino or halogen.

In the present context, the term "amino protecting group" is intended to cover groups which are introduced in an oligomer or an intermediate therefor, in order to mask an amino group so that the amino group is substantially non-reactive under the given reaction conditions. Examples of such amino protection groups are Fmoc (fluorenyl- methoxycarbonyl), BOC (tert-butyloxycarbonyl), trifluoroacetyl, allyloxycarbonyl (alloc, AOC), benzyloxycarbonyl (Z, Cbz), substitued benzyloxycarbonyls such as 2-chloro benzyloxycarbonyl ((2-CIZ), DDE (Bloomberg, G.B., et al., Tetrahedron Lett. 1993. 34, 4709-471 2), monomethoxytrityl (MMT), dimethoxytrityl (DMT), and 9-(9- phenyDxanthenyl (pixyl), among which the Fmoc (fluorenylmethoxycarbonyl) and BOC (tert-butyloxycarbonyl) protection groups are especially preferred in that they are easy to introduce with standard reagents and are compatible with standardised amide formation reaction conditions, e.g. solid phase peptide synthesis and variants thereof.

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

It should furthermore be understood that the oligomers of the general formulae I and II include possible salts thereof, of which pharmaceutically acceptable salts are especially relevant. Salts include acid addition salts and basic salts. Examples of acid addition salts are hydrochloride salts, sodium salts, calcium salts, potassium salts, etc.. Examples of basic salts are salts where the (remaining) counter ion is selected from alkali metals, such as sodium and potassium, alkaline earth metals, such as calcium, and ammonium ions (⁺N(R)₃R', where R and R' independently designates optionally substituted C_1-β-alkyl, optionally substituted C₂.₆-alkenyl, optionally substituted aryl, or optionally substituted heteroaryl). 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 and more recent editions and in Encyclopedia of Pharmaceutical Technology. Thus, the term "an acid addition salt or a basic salt thereof" used herein is intended to comprise such salts. Furthermore, the oligomers as well as any intermediates or starting materials (e.g. monomers) may also be present in hydrate form.

Preparation of oligomers

The present invention also provides a method for the easy preparation of the "linear" and cyclised oligomers defined above. (Examples hereof are given in the experimental section.)

Thus, the present invention provides a method for the preparation of an oligomer of the general formula I (K-C( = O)-M₀-...-M_n-T) as defined above, comprising the following steps:

(A) providing an optionally functional group protected oligomer -C( = O)-M₀-...-M_n-T immobilised to a solid support material; and

(B) cleaving the oligomer K-C( = 0)-M₀-...-M_n-T from the solid support material, the step optionally including deprotection of one or more functional group(s) of the oligomer.

Step (A):

Since the oligomers according to the present invention are constituted by piperidine rings connected by means amide bonds between a carboxylic acid in one monomer to the ring nitrogen of the previous monomer, the optionally functional group protected oligomer may be provided by sequential coupling of piperidine monomers to a solid phase material. (Segment coupling of lower oligomers may also be applicable.)

Methods and coupling reactions for the preparation of amide bonds are well known in the art, see e.g. Barany, G. and Merrifield, R.B. in The Peptides, Vol. 2, Academic Press, New York, 1979, pp. 1 -284; LlloydWilliams P. et al., Tetrahedron, (1 993) 1 1065-1 1 133; Fields GB. and Noble RL. Int. J. Pep. Prot. Res. (1990), 1 61 -214; and Bodanszky M. and Bednarek, MA., J. Prot. Chem., (1 989), 461 -469.)

In the present context the term "solid phase material" is intended to comprise solid phase materials know in the art of peptide synthesis. Especially suitable solid phase materials (polymers) are based on polystyrene cross-linked with 0.2-2% divinylbenzene and functionalised 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 para- alkoxybenzyl alcohol resin which in the cleavage step 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 trialkoxy-diphenyl-methylester resin which in the cleavage step 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 than the parent polystyrene resins (Bayer, E. Angew. Chem. Int. Ed. Engl., 1991 , 30, 1 13-1 29). PEG-modified resins having similar characteristics 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.). Alternatively, a MBHA polystyrene based resin (4-Methyl Benzhydrylamine resin) from Novabiochem may be use; this resin yields the amide (K = NH₂) after cleavage with HF or, alternatively, a mixture of TFA and TfOH (tetrafluoromethanesulphonic acid) (3: 1 ) for 2 x 1 hours.

The coupling of the first monomer and any of the subsequent monomers (all the way to the last monomer) may be accomplished by means of a coupling reagent, e.g. a reagent which converts the carboxylic acid group of a piperidine (or of the group T, or the group corresponding to the linear biradical where the group in question is a carbonyl functional (bi)radical) into an active derivative, e.g. an active ester or an acid halide. A number of highly effective coupling reagents and activated forms of carboxylic 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, 1 967-1 970), 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, 7 75, 4397-4398; Angell, Y. M.; Garcia-Echeverria, C. and Rich, D. H. Tetrahedron Lett. 1994, 35, 5 5981 -5984, and Angell, Y. M.; Thomas, T. L.; Flenkte, G. R. and Rich, D. R. J. Am. Chem. Soc. 1995, 7 77, 7279-7280), HBTU (Reid, G.E. and R.J. Simpson, Automated Solid-Phase Peptide Synthesis: Use of 2-( 1 H-Benzotriazol-1 yl)-1 , 1 ,3,3,- tetramethyluronium Tetrafluoroborate for Coupling of tert-Butyloxycarbonyl Amino Acids. Anal. Biochem. 200 (1992) 301 -309), PyBOP (Frerot, E., et al.. Tetrahedron, 1 0 1 991 , 47(2), pp 259-270), and CF₃-N0₂-PyBOP (Wijkmans, J.C.H.M., et al, Tetrahedron Lett. 1 995, 36(26), pp 4643-4646).

As it is desirable that any substituents on the monomers (shown with X°, ... , Xⁿ) remain unaffected by the reaction conditions (i.e. the amide bond formation condition 1 5 as well as the conditions for cleavage of the oligomers from the solid phase material), such reactive or susceptible groups are preferably protected. Example of such reactive groups are hydroxy groups, primary or secondary amines, mercapto groups, and carboxyl groups.

20 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 monomer in question 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

25 functionalities may be protected. Protection of the monomers 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 monomer or oligomer in question is difficult or virtually impossible to

30 purify. In such cases a protection-purification-deprotection scheme may be applied.

Protecting groups are 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, IRL Press, 1 989), oligonucleotide synthesis (see e.g. M.J. Gait, Oligonucleotide Synthesis, IRL Press, 1984), oiigosaccharide 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 step (A) and (B). 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 amino protection groups as defined above under "definitions"; hydroxy protection groups such as dimethoxytrityl (DMT), monomethoxytrityl (MMT), trityl, 9-(9-phenyl)xanthenyl (pixyl), tetraahydropyranyl (thp), methoxytetrahydropyranyl (mthp), trimethylsilyl (TMS), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), triethylsilyl, phenyldimethylsilyl, benzyloxycarbonyl or substituted benzyloxycarbonyl ethers such as 2-bromo benzyloxycarbonyl, tert- butylethers, methyl ethers, acetyl or halogen substituted acetyls such as chloroacetyl or fluoroacetyl, isobutyryl, pivaloyl, benzoyl and substituted benzoyls, methoxymethyl (MOM), benzyl ethers or substituted benzyl ethers such as 2,6-dichlorobenzyl (2,6- CI₂Bzl); carboxy protection groups such as allyl esters, methyl esters, ethyl esters, 2- cyanoethylesters, trimethylsilylethylesters, benzyl esters (Obzl), 2-adamantyl esters (O-2-Ada), cyclohexyl esters (OcHex), 1 ,3-oxazolines, oxazoler, 1 ,3-oxazolidines, amides or hydrazides; and mercapto protecting groups such as trityl (Trt), acetamidomethyl (acm), trimethylacetamidomethyl (Tacm), 2,4,6-trimethoxybenzyl (Tmob), tert-butylsulfenyl (StBu), 9-fluorenylmethyl (Fm), 3-nitro-2-pyridinesulfenyl (Npys), and 4-methylbenzyl (Meb).

Thus with reference to the above, it will be evident for the person skilled in the art how to prepare single (as well as multiple) compounds of general formula I and II.

As will also be evident for the person skilled in the art, purification (if necessary or desirable) can be performed by conventional methods, e.g. extraction, crystallisation or chromatography such as flash chromatography, preparative HPLC or by passing through an ion-exchange column.

Step (B):

The conditions for cleaving the oligomers from the solid phase material is described above in connection with the examples of solid phase materials, since cleavage is highly dependant on the character of the selected solid phase material. 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 oligomer from the solid phase material. Furthermore, in an interesting instance, deprotection is performed simultaneously to cleavage of the oligomer 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 oligomer from the solid phase material and deprotection of any Boc amino protecting groups.

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 present invention also provides a method for the preparation of a cyclised oligomer of the general formula II (K-C( = O)-M₀-...-M_n-W) as defined above, comprising the following steps:

(A) providing an optionally functional group protected oligomer -C( = 0)-M₀-...-M_n-W immobilised to a solid support material; and

(B) cleaving the oligomer K-C( = O)-M₀-...-M_n-W from the solid support material, the step optionally including deprotection of one or more functional group(s) of the oligomer.

The preparation of the cyclised oligomers essentially follows the method for the preparation of the "linear" oligomers, however, in addition to the procedures described above, a cyclisation must be applied under step (A). As it is preferred to that the link between the first monomer and the last monomer comprises an amide bond, the cyclisation may be performed by means of the coupling reagents described above.

In a preferred embodiment, the first monomer comprises a further carboxylic acid group (which may be protected in the procedure where the first to the last monomer are coupled to the solid phase material), which becomes a part of the linear biradical otherwise constituted by an co-amino alkyl or alkylcarbonyl substituent on the ring nitrogen of the last monomer. Alternatively, an amino group may be introduced as a further substituent on the first monomer, thereby forming an amide link to the last monomer by means of an ω-carboxy alkyl or alkylcarbonyl substituent. It should be understood that such an amine should be protected due to its higher reactivity towards an activated piperidine carboxyiic acid than the ring nitrogen of the piperidine.

In the case where a dicarboxylic acid substituted piperidine is used as the first monomer, it may be preferred to use the diacid in monoester form, in that use of the free dicarboxylic 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. Furthermore, the coupling reactions may also be disturbed by the presence of a free carboxylic acid. Thus, it is believed, and can also be demonstrated, that use of the dicarboxylic 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. Three different syntheses for the preparation of monoesters of dicarboxylic acids have been described in Tong, G. and Nielsen, J. Bioorg. Med. Chem. 1996, 4, 693-698, namely (a) esterification, in particular allylation, of the monocesium salt of a dicarboxylic acid, (b) 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, 31, 1701 -1704), and the selective deesterification of dicarboxylic acid diesters. A further method for the preparation of monoesters includes phase transfer chemistry (Friedrich-Bochnitschek S., J. Org. Chem. 54, 1989, 751 -756). The monoallyl esters seems especially relevant in the methods according to the invention. An alternative to the use of a mono-protected dicarboxylic acid substituted piperidine as the first monomer is the case where an internal anhydride of a dicarboxylic acid is used. The conditions for coupling the dicarboxylic acid (the first monomer) to the solid phase material is closely connected to the choice of solid phase material and linker, and has thus been described in connection with the solid phase materials.

In a further embodiment of the method according to the present invention, the oligomers I and II may after cleavage from the solid phase material undergo a further reaction step (C) for the formation of another oligomer I or II. This reaction step may be especially relevant when 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 monomers for incorporation into oligomers

As will be clear from the experimental section herein, a number of sources for piperidine monomers are available, e.g. commercially available, available from natural sources, or available by described syntheses via other piperidines, piperidones, pyridines, dihydropyridines, tetrahydropyridines, etc. (see, e.g., Tetrahedron Lett. (1 996), 4827, Tetrahedron Lett. (1996), 2707, Tetrahedron Lett. (1994), 9047, Perkin I (1994), 2621 , Tetrahedron (1987), 979, Tetrahedron (1989), 327, BioOrg. Med. Chem (1997), 519, Tetrahedron (1987), 41 5, Tetrahedron Lett. (1 986), 3205, Tetrahedron Lett (1985), 4981 , Phytochemistry (176), 183, Tetrahedron Lett. (1990), 1 1 9, Tetrahedron Lett. (1990), 1 683, Bull. Kor. Chem. (1995), 985, Biosci. Biotech. Biochem. (1995), 762, Tetrahedron (1987), 423.) As it has been illustrated in the working examples, the piperidine monomers are preferably used as the N-Boc or N- Fmoc protected forms. Furthermore, as discussed above, it may be necessary or desirable to protect other substituents than the mandatory carboxylic acid (optionally in the activated form when the monomers are coupled to the solid phase material or an already immobilised monomer). This can be accomplished by the methods referred to above under "optionally functional group protected" . It should be understood that novel piperidine monomers, as well as methods for the preparation of piperidine monomers (cf. the examples), are considered as further aspects of the present invention.

Preparation of libraries of compounds of the general formula I

The present invention also provides a method for the preparation of an array of oligomers (K-C( = O)-{M₀}-...-{M_n}-{T}), consisting of at least four oligomers each having the general formula I as defined above. The method comprises the following steps:

(A) providing an array of optionally functional group protected oligomers -C( = O)-{M₀}- ...-{M_n}-{T} immobilised to a solid support material; and

(B) cleaving the array of oligomers K-C( = O)-{M₀}-...-{M_n}-{T} from the solid support material, the step optionally including deprotection of one or more functional group(s) of the oligomer.

Furthermore, the present invention provides a method for the preparation of an array of cyclised oligomers (K-C( = O)-{M₀}-...-{M_n}-{W}), consisting of at least four oligomers each having the general formula II as defined in any of the claims 50-99, the method comprises the following steps:

(A) providing an array of optionally functional group protected cyclised oligomers - C( = O)-{M₀}-...-{M_n}-{W} immobilised to a solid support material; and

(B) cleaving the array of cyclised oligomers K-C( = O)-{M₀}-...-{M_n}-{W} from the solid support material, the step optionally including deprotection of one or more functional group(s) of the cyclised.

In the present context, the term "array of oligomers" is intended to mean a plurality of structurally similar oligomers synthesised using combinatorial library principles. Thus, the "array of oligomers" constitutes a combinatorial library of oligomers. The sets {M₀}, ..., {M_n}, and {T} (in case of an oligomer of the general formula I) may each comprise one or more monomer variants, thus the set {M₀} may, e.g., comprise three different monomer fragments and will then contribute to the variability of the array with a factor of 3 (when the split-mix synthesis method is applied). It is envisaged that some of the sets may comprise only one compound, especially in the case where a monomer in a specific position is considered irrelevant for the biological effect, or where a specific monomer in a specific position is considered crucial.

The preparation of combinatorial libraries (arrays) of oligomers follows the same principles as described above for the preparation of single oligomers. In order to ensure that a suitable amount of each of the theoretically obtainable oligomers are formed, the split-mix synthesis method (Furka, A.; Sebestyen, F.; Asgedom, M.; Dibό, G. Int. J. Peptide Protein Res. 1991 , 37, 487-493) is typically applied. Other method may also be applicable within the context of the present invention.

The variability of the arrays can be introduced in each of the sequential coupling steps necessary for establishing the array of oligomers. Thus, the mathematical product of the number of variants within the sets {M₀}, ..., {M_n}, and {T} (in case of the oligomers of the general formula I) defines the number of oligomers within the array. In the case of a cyclised oligomer of the general formula II, oligomer the mathematical product of the number of variants within the sets {M₀}, ..., {M_n}, and {W} defines the number of oligomers within the array. It should be understood that larger amounts of key intermediates for the immobilised oligomers may be prepared leaving material for later experiments.

It is preferred that the combinatorial library of oligomers comprises at least 4, such as in the range of 6-200 different oligomers, more preferably 6-100 different oligomers, and in particular 8-64 different oligomers.

It should be understood that any separate batches from step (A) 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 oligomers within each (sub)array. These (sub)arrays of oligomers may then be pooled before the actual screening is conducted. Alternatively, each of the batches ((sub)arrays) may be screened individually. In a third and most interesting alternative, the library consisting of the combined batches (or a number of these) is screened, and in the case where biological activity is identified, each of the batches ((sub(arrays) are screened individually thereby pointing back to one specific "last monomer" as biologically interesting. The principles of screening are discussed in the following.

Method of screening and potential medical applications

Screening of combinatorial libraries of the oligomers according to the invention may be performed in any of the ways generally used by scientists and technicians skilled in the art (see, e.g., Rogers, MV., Drug Discovery Today, (1997), 156-1 60, 209-209, and 251 -251 ; Janzen, WP. Laboratory Robotics and Automation, (1996), 261 -265; Reichman, M. et al. Laboratory Robotics and Automation, 1996, 267-276 and Kay BK; Paul Jl. Molecular Diversity, (1 996), 1 39-140.). These include but is not limited to screening of individual oligomers, by deconvolution of libraries containing mixtures of oligomers, 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 oligomer, small mixtures of isomeric oligomers where stereoisomer would be included in the form of enantiomers, diastereomers, geometrical or positional isomers, as mixtures of typically 6-200 compounds per vial to allow fast deconvolution down to the active substance, or as large mixtures of more than 200 compounds per vial to allow for rapid screening of vast combinatorial libraries. Screening is 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).

Thus, it is clear from the above that the present invention also provide a the use of arrays of oligomers (of the general formula I or II defined herein or combinations thereof) for screening of the biological activity or biological effect of a plurality of oligomers of the general formula I or II comprised within said array. It should be understood that it is possible to prepare a combinatorial library comprising an array of oligomers of the general formula I as well as an array of oligomers of the general formula II, either by preparing those arrays separately with subsequent mixing or combination, or by preparing the two arrays in the same batch. The latter situation can be accomplished by including piperidine dicarboxylic acids as a part of the piperidine monomers use for the first monomer fragment and then subject the entire array (or a part thereof) to cyclisation conditions so as to obtain cyclised oligomers of the general II in combination with "linear" oligomers of the general formula I. In the case where the linear biradical (-Y°-Yⁿ-) in the cyclised oligmers is, e.g., -C( = 0)- (CH₂)_m-NH-C( = 0)-, the group T in the corresponding "linear" oligmers will be -C( = 0)- (CH₂)_m-NH₂.

By such screening methods it is envisaged that a diverse range of biological activity and biological effects of the oligomers according to the present invention can be demonstrated. Thus, it is believed that biological activity within one of the following fields can be shown: 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, cholinergic agonists, acetylcholinesterase inhibitors or cholinergic antagonists, adrenergic drugs, cardiac agents such as cardiac glycosides, antianginals, and antiarrhythmic drugs, anticoagulants, coagulants, and plasma extenders, diuretics, antiallergic and antiulcer drugs, antilipidemic 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 present invention also provides the use of an oligomer of the general formula I or II as a drug substance, and the use of an oligomer of the general formula I or II for the preparation of a medicament for the treatment of one or more of the above-mentioned diseases or conditions. Furthermore, the oligomers of the present invention may also be used in connection with or as mimics for haptenes for the generation of antibodies (Ragupathi, G. et al. Angew. Chem. Int. Ed. Engl. 1 997, 36, 1 25-1 28); and as marker molecules and detection molecules in diagnostic applications. General and specific methods and principles for the preparation of medicaments and pharmaceutical compositions are described in Remington's Pharmaceutical Sciences and in Encyclopedia of Pharmaceutical Technology, cited above.

BRIEF DESCRIPTION OF THE FIGURES

Fig. 1 : Illustrates the sequential coupling of piperidine oligomers to a first immobilised piperidine monomer. The first piperidine monomer comprises a protected carboxylic acid besides the carboxylic acid used for linking the monomer to the solid phase material.

Fig. 2: Illustrates the coupling of N-Fmoc-6-aminocapronic acid to an oligomer of piperidine carboxylic acid monomers. The ω-aminocapronic acid may together with the carboxylic acid of the first monomer constitute a biradical between the first and the last piperidine monomer.

Fig. 3: Illustrates the a possible deprotection scheme in the case where a carboxylic acid of the first monomer is allyl ester protected and where the secondary amines of the piperidine oligomers are Fmoc protected.

Fig. 4: Illustrates the cyclisation between the first and the last piperidine monomer.

Figs. 5-7: Illustrates various route to piperidine monomers.

Fig. 8: Illustrates particularly interesting monomers for incorporation into oligomers.

EXPERIMENTAL

General. ¹³C NMR and \Λ NMR spectra were recorded a Varian instruments Gemini 200. When CDCI₃ was used as solvent TMS and CDCI₃ (¹³C-NMR: δ 76.93 ppm) were used as references. Mass spectra were obtained on a VG TRIO-2 instrument. Melting points were uncorrected. Optical rotations were measured on a Perkin Elmer 141 polarimeter. Concentrations were performed on a rotary evaporator at a temperature below 40 °C. HPLC was performed on a Chiralcel AD column from Daicel Chemical Industries LTD.

General procedure for the synthesis of N-Boc-piperidine-dicarboxylic acid

5

Ethyl N-tert-butoxycarbonyl-4-piperidone-3-carboxylate (6).

Ethyl 4-piperidone-3-carboxylate, hydrochloride (8, 2.08 g, 10 mmol) was dissolved in 50% aqueous THF (30 mL) and Na₂C0₃ (1 .09 g, 10.2 mmol) was added. At 0 ° C a solution of di-tert-butyl dicarbonate (2.48 g, 1 1 .4 mmol) and Na₂C0₃ (1 .07 g, 1 2

10 mmol) in 50% aqueous THF (20 mL) was added. The solution was kept for 30 min. at 0 °C and then allowed to reach room temperature over 2 h. The mixture was acidified with cone. HCI and water (20 mL) was added. The mixture was extracted with CH₂CI₂ (3 x 20 mL), dried (MgS0 ) and concentrated to give a crystalline product (2.5 g, 92%). Mp: 52-56 °C. TLC: (EtOAc-pentane 10:1 ) R, 0. . H NMR (CDCI₃, 200 MHz): δ

1 5 1 2.1 (s, 1 H, OH), 4.21 (q, 2H, J 7 Hz, CH₂CH₃), 4.04 (s, 2H, H-2), 3.53 (t, J 6 Hz, H- 6), 2.35 (t, 2H, J 6 Hz, H-5), 1 .45 (s, 9 H, (CH₃)₃), 1 .23 (t, 3H, J 7 Hz, CH₂CH₃). ¹³C NMR (CDCI₃, 200 MHz): δ 171 .2 (COOEt), 170.3 (C-4), 155.0 (NCOO), 96.7 (C-3),

80.6 (C(CH₃)₃), 61 .0 (CH2CH3), 40.7, 40.1 , 29.4 (C-2, C-5, C-6), 28.9 (C(CH₃)₃),

14.7 (CH₂CH₃). MS (El): m/z 2 ' 1 (M⁺), 171 (M - C₅H₈0₂). 20

Bakers yeast reduction under fermenting conditions. General procedure. Bakers yeast (10 g) was dissolved in tap water (80 mL) at 30°C, and sucrose (15 g) was added. (Optionally inhibitor (allyl alcohol, 6.3 mmol) was added at this stage and the mixture was incubated 30 min. at this temperature.) After 1 h at 30°C, compound

25 6 or 17 (6.3 mmol) was added, and the reaction was kept at 30 °C for 18 h. More sucrose (10 g) in H₂0 (25 mL) at 40 °C was added, and the mixture was kept for 2 days at 30 °C. Celite (1 g) was added, and the mixture was filtered. The filter was washed with CHCI₃ (3 x 20 mL), which was subsequently used to extract the filtrate. The combined CHCI₃ phase was dried (MgS0₄), concentrated and subjected to flash-

30 chromatography. Eluting with appropriate EtOAc-pentane mixture gave first unreacted ketone then product. Specific details. Ethyl 3,4-cis-N-\eτX-butoxycarbonyl-4- hydroxypiperidine-3-carboxylate (7). Eluting with EtOAc-pentane 1 : 15 gave unreacted 6 (0.93 g, 54%), while eluting with EtOAc gave 7 (0.59 g, 34%, mp: 56-60°C, [α]ζ :

-2 (c 0.75, CH₂CI₂)). Ethyl 3,4-cis-N-tert-butoxycarbony/-3-hydroxypiperidine-4- carboxylate (18). From 17 (0.400 g, 1.48 mmol) was ontained on eluting with EtOAc/pentane 1:10 unreacted 17 (0.039 g, 10 %). Eluting with EtOAc gave 18 (0.150 g, 37 %).[ ]ζ: +1.6 (c 1.61; CHCI₃). 'H NMR (CDCI₃, 200 MHz): δ 4.19 (q,

3H, Jl Hz, CH₂CH₃, H-3), 4.07-3.96 (m, 2H, H-2), 3.01-2.77 (m, 2H, H-6), 2.59- 2.50 (m, 2H, H-4, OH), 2.16-1.77 (m, 2H, H-5), 1.46 (s, 9 H, (CH₃)₃), 1.27 (t, 3H, J 7 Hz, CH₂Ch ).¹³C NMR (CDCI₃, 200 MHz): δ 174.2 (COOEt), 156.1 (NCOO), 80.4 (C(CH₃)₃), 65.9, 61.4 (C-3, CH₂CH₃), 49.5, 45.8, 43.3, 23.1 (C-2, C-4, C-5, C-6), 28.8 (C(CH₃)₃), 14.6 (CH₂CH₃).

3,4-cis-N-tert-butoxycarbonyl-4-hydroxypiperidine-3-carboxylic acid (16).

Ester 7 (0.216 g, 0.79 mmol, e.e.24%) was dissolved in THF (2 mL). 1 M LiOH (1.6 mL) was added. The solution was stirred at 25 °C for 30 min. The solution was acidified with 1 M HCI and water (10 mL) was added. The mixture was extracted with EtOAc (3x 15 mL), dried (MgS0₄) and concentrated to give a crystalline product (0.178 g, 92 %). Mp: 140-144 °C. [α] : + 14.4 (c 4, CHCI₃). 'H NMR(CDCI₃, 200

MHz): δ 4.33 (ddd, 1H, _4βq5ax 3 Hz , J_4βq5βq 3 Hz , _4eq3ax 4 Hz, H-4eq), 3.97 (bdd, 1H,

Jlβ ax.3 HZ, J_2βq2ax 13 Hz, J_2βq6βq 0 Hz, H"2βq), 3.7 (dt, 1H, ι/₆eq5eq 4 HZ, J6βq5ax 4 Hz,

Jββ_qβ_ax 14 Hz, H-6eq), 3.43 (dd, 1H, J_2ax3ax 10 Hz, H-2ax), 3.27 (ddd, 1H, _6ax5ax 11 Hz, H-6ax), 2.66 (ddd, 1H, H-3ax), 1.83 (dddd, 1H,J_5βq5ax 14 Hz, H-5eq), 1.66 (dddd, 1H, H-5ax), 1.45 (s, 9H, (CH₃)₃)).¹³C NMR(CDCI₃, 200 MHz): δ 176.9 (COOH), 155.5

(NCOO), 80.9 (C(CH₃)₃, 65.7 (C-4), 46.2, 41.0, 39.3, 31.9 (C-2, C-3, C-5, C-6), 28.9 (C(CH₃)₃). MS (El): m/z 246 (M+1), 146 (M - C₅H₇0₂).

Ethyl N-tert-butoxycarbonyl-3-piperidone-4-carboxylate (17). Ethyl-N-benzyl-3-piperidon-4-carboxylate (0.503 g, 1.69 mmol) was dissolved in a solution of 50 % aqueous EtOH (10 mL) and 3 M HCI (1 mL) and hydrogenated at 6 atm. for 48 h using 10 % Pd-C (50 mg) catalyst. The mixture was filtred and concentrated to give an oil (0.305 g, 87%). 'H NMR (D₂0, 200 MHz): δ 4.15 (q, 2H, J 6 Hz, CH₂CH₃), 3.42-3.26 (m, 2H, H-2), 3.16-3.0 (m, 2H, H-6), 2.1-1.99 (m, 2H, H- 5), 1.2 (t, 3H, 6 Hz).¹³C NMR (D₂0, 200 MHz): δ 181.4, 178.7, 176.0 (COOEt, C- 3' (enol), C-3 (ketone)), 91.9 (C-4'), 64.9 (CH₂CH₃), 53.1, 52.0, 46.0, 44.1, 25.0, 21.6, 16.0 (C-2, C-2', C-4, C-5, C-5', C-6, C-6'), 11.9 (CH₂CH₃). Ethyl-3-piperidone- 4-carboxylate hydrochloride (0.305 g, 1.47 mmol) was BOC-protected using the same procedure as for 6. Aqueous THF (20 mL), Na₂C0₃ (0.1 76 g, 1 .66 mmol) and a mixture of di-tert-butyl dicarbonate (0.374 g, 1 .72 mmol) and Na₂C0₃ (0.1 81 g, 1 .71 mmol) in aqueous THF (1 0 mL). The solution was acidified with cone. HCI and water (20 mL) was added. The mixture was extracted with CH₂CI₂ (3 x 30 mL), dried 5 (MgS0₄) and concentrated to give an oil (0.395 g, 99 %). TLC: (EtOAc/pentane 10: 1 ) R_f 0. . 'H NMR (CDCI₃, 200 MHz): δ 1 2.08 (s, 1 H, OH), 4.28 (q, 2H, J l Hz, CH₂CH₃), 4.02 (s, 2H, H-2), 3.48 (t, 2H, J 6 Hz, H-6), 2.31 (t, 2H, J 6 Hz, H-5), 1 .46 (s, 9H, (CH₃)₃), 1 .30 (t, 3H, J 7 Hz, CH₂CH₃). ¹³C NMR (CDCI₃, 200 MHz): δ 1 72.3 (COOEt), 1 68.0 (C-3), 1 54.9 (NCOO), 97.4 (C-4), 80.7 (C(CH₃)₃), 61 .1 (CH₂CH₃), 10 45.5, 40.7, 40. 4 (C-2, C-5, C-6), 28.9 (C(CH₃)₃), 1 4.7 (CH₂CH₃).

3,4-cis-N-tert-butoxycarbonyl-3-hydroxypiperidine-4-carboxylic acid (20).

Ester 18 (88 mg, 0.32 mmol) was dissolved in THF (0.7 mL). 1 M LiOH (0.7 mL) was added. The solution was stirred at 25 °C for 30 min. The solution was acidified with 1

1 5 M HCI and water ( 10 mL) was added. The mixture was extracted with EtOAc (3 x 10 mL), dried (MgS0₄) and concentrated to give an oil (50 mg, 63 %). ¹H NMR (CDCI₃, 200 MHz): δ 4.28-4.00 (m, 3H, H-3, H-2), 3.02-2.77 (m, 2H, H-6), 2.62-2.53 (m, 1 H, H-4), 2.1 5-1 .68 (m, 2H, H-5), 1 .45 (s, 9H, (CH₃)₃. ¹³C NMR (CDCI₃, 200 MHz): δ 177.6 (COOH), 156.4 (NCOO), 81 .0 (C(CH₃)₃, 65.9 (C-3), 49.5, 45.6, 30.2, 22.8 (C-

20 2, C-4, C-5, C-6), 28.9 (C(CH₃)₃).

(cis)-(±)-piperidine-2, 6-dicarboxylic acid

1 .67 g ( 10 mmol) pyridine-2,6-dicarboxylic acid is suspended in H₂0/MeOH ( 1 : 1 ) (20 mL). 109 mg 5% Rh/C is added. The mixture is hydrogenated at rt. and 20 bar until 25 disappearance of UV-absorbing material (20 h). The mixture is filtered through celite and the celite is thoroughly washed with water and MeOH. The filtrate is evaporated to give white crystals (1 .22 g, 71 %). Mp > 210 °C. 'H NMR (D₂0) δ 3.6 (dd, 2H), 2.1 (dd, 2H), 1 .9 (m, 1 H), 1 .5 (m, 3H). ¹³C NMR (D₂0) δ 1 75.0, 60.2, 27.8, 24.6.

30 Sodium salt of (cis)-(±)-piperidine-2,5-dicarboxylic acid

8.32 g (50 mmol) pyridine-2,5-dicarboxylic acid is suspended in H₂0 (50 mL). 5.3 g Na₂C0₃ (50 mmol) is added as well as 500 mg 5% Rh/C is added. The mixture is hydrogenated at rt. and 750 psi until disappearance of UV-absorbing material (2 days). The mixture is filtered through celite, and the filtrate is evaporated to give a clear syrup. (100%). NMR shows traces of piperidine-2-carboxylic acid. NMR (D₂0) δ 3.2 (1H), 3.K1H), 2.9 (1H), 2.6 (1H), 2.2 (1H), 1.6 (3H).¹³C NMR (D₂0) δ 183.8, 181.5, 59.1, 45.9, 42.9, 27.3, 26.7.

(cis)-(±)-piperidine-2A-dicarboxylic acid [84229-40-3]

3.7g (20 mmol) pyridine-2,4-dicarboxylic acid monohydrate is suspended in H₂0 (50 mL).207 mg 5% Rh/C is added. The mixture is hydrogenated at rt. and 20 bar until disappearance of UV-absorbing material (3 days). The mixture is diluted (300 mL) and filtered through celite. The filtrate is evaporated to give white crystals (3.6 g, 100%). Mp 293 °C (decomp.).¹H NMR (D₂0) δ 3.5 (dd, 1H), 3.35 (m, 1H), 2.85 (dt, 1H), 2.6 (tt, 1 H), 2.4 (m, 1 H), 2.0 (m, 1 H), 1.45-1.65 (m, 2H).¹³C NMR (D₂0) δ 179.9, 175.4, 58.9, 43.5, 40.3, 29.6, 25.0.

General procedure for the synthesis of N-Fmoc-piperidine-dicarboxylic acid

(cis)-(±)-N-Fmoc-piperidine-2_r 6-dicarboxylic acid

2.49 g (14.4 mmol) (cis)-Piperidine-2,6-dicarboxylic acid is suspended in DCM (35 ml). 8.1 mL DIPEA (47.5 mmol) is added and the mixture is heated to reflux. Under Ar, 6 mL trimethylsilylchloride (47.4 mmol) is added and the mixture is refluxed for 1 y₂ hour. After cooling on ice, 4.1 g (15.8 mmol) FmocCI is added. The temperature is rised to rt. over 1 Vi hour. The mixture is evaporated to a syrup, redisolved in NaHC0_3(βat)/Et₂0 and the aqueous phase is washed with Et₂0. The aqueous phase is made acid with 4 N HCI (pH 2) and extracted with EtOAc. The organic phase is washed with NaCI,_6at), dried over Na₂S0 and evaporated to give a white foam (3.78 g, 66%).¹H NMR (CDCI₃) δ 7.2-7.9 (8H), 4.9 (dd, 1H), 4.7 (dd, 1H), 4.5 (t, 1H), 4.4 (t, 1H), 4.2 (m, 1H), 2.2 (m, 2H), 1.8 (m, 2H), 1.4-1.7 (m, 2H).¹³C NMR (CDCI₃) δ 177.3, 176.5, 156.4, 147.0, 143.0, 127.7, 127.1, 124.8, 119.9, 68.9, 54.3, 53.6, 46.9, 26.1, 25.7, 16.5.

(cis)-(±)-N-Fmoc-piperidine-2,5-dicarboxylic acid

Procedure as above. White foam (82.7%).¹H NMR (CDCI₃) δ 10.8 (2H), 7.2-7.8 (8H), 4.7-5.2 (1H), 4.1-4.6 (4H), 3.0-3.3 (1H), 2.2-2.5 (2H), 1.5-1.9 (2H).¹³C NMR (CDCI₃) δ 178.5, 176.6, 156.0, 143.6, 141.1, 127.6, 127.0, 124.9, 119.9, 68.0, 53.3, 47.0, 42.6, 40.6, 25.3, 23.7. (cis)-(±)-N-Fmoc-piperidine-2_r4-dicarboxylic acid

Procedure as above. White crystals (82.7%). Mp 209 °C (decomp.). NMR (DMSO- d_β) δ 12.5 (1H), 7.2-8.0 (8H), 4.1-4.6 (4H), 3.7 (1H), 3.3 (1H), 2.7 (1H), 2.4 (1H), 1.8-2.1 (2H), 1.6 (1H).¹³C NMR (DMSO-d₆) δ 174.9, 172.7, 155.4, 143.8, 140.8,

127.7, 127.2, 125.1, 120.2, 67.0, 52.6, 46.7, 38.8, 35.0, 26.6, 25.2.

General procedure for the synthesis of N-Fmoc-piperidine-dicarboxylic acid mono allylester

(cis)-(±)-N-Fmoc-piperidine-2,6-dicarboxylic acid mono allylester

To a solution of 1.19 g (3 mmol) N-Fmoc-(cis)-Piperidine-2,6-dicarboxylic acid in 30 ml DMF is added 0.12 g (0.35 mmol) Cs₂C0₃ and after 30 min.0.25 ml (3 mmol) allylbromide. The reaction mixture is stirred 24 h and 0.12 g (0.35 mmol) Cs₂C0₃ is added. This procedure is continued until a total of 0.49 g (1.5 mmol) Cs₂C0₃ has been added. After additional 24 h the reaction mixture is filtered and evaporated to yield a syrup. The syrup is redisolved in NaHC0_3(8at) and extracted with Et₂0. The aqueous phase is made acidic with 1 N HCI and extracted with EtOAc. Dried over Na₂S0₄ and evaporated to give a syrup (1.05 g, 80.5%). 'H NMR (DMSO-d₆) δ 7.2-7.9 (8H), 5.9 (1H), 5.1-5.3 (2H), 4.2-4.8 (7H), 2.1 (2H), 1.4-1.8 (4H).¹³C NMR (DMSO-d₆) δ

173.8, 170.4, 162.0, 143.9, 141.0, 132.3, 127.5, 126.9, 125.0, 119.9, 117.4, 67.2, 65.2, 53.7, 46.8, 42.8, 40.4, 25.5, 23.7.

(cis)-(±)-N-Fmoc-piperidine-2,5-dicarboxylic acid mono allylester Procedure as above. The syrup is chromatographed in 2% AcOH/CHCI₃ to give a syrup (54%).¹H NMR (CDCI₃) δ 10.1 (1H), 7.2-7.8 (8H), 5.9 (1H), 5.3 (2H), 4.2-4.8 (8H), 2.9-3.3 (1H), 2.1-2.6 (2H), 1.4-1.9 (2H).¹³C NMR (CDCI₃) δ 177.9, 170.3, 155.0, 156.0, 144.0, 141.0, 131.4, 127.5, 126.9, 124.9, 119.8, 118.6, 67.9, 65.8, 53.6, 46.9, 42.6, 40.6, 25.5, 23.6.

(cis)-(±)-N-Fmoc-piperidine-2,4-dicarboxylic acid mono allylester Procedure as above. The syrup is chromatographed in a gradient of CHCI₃ and 2% AcOH/CHCI₃ to give a syrup (33%). 'H NMR (CDCI₃) δ 11.3 (1 H), 7.3-7.9 (8H), 5.9 (1H), 5.3 (2H), 4.2-5.0 (5H), 4.0 (1H), 3.5 (1H), 2.7 (1H), 2.6 (1H), 2.1 (2H), 1.8 (1H).¹³C NMR (CDCI₃) δ 179.3, 170.8, 143.6, 141.1, 131.5, 127.5, 126.9, 124.8, 119.8, 118.4, 67.6, 65.8, 52.3, 47.0, 35.2, 26.6, 25.2.

(cis)-(±)-N-Boc-piperidine-2,5-dicarboxylic acid mono allylester Procedure as above. (15%).¹H NMR (CDCI₃) δ 9.7 (1H), 5.9 (1H), 5.2 (2H), 4.7-4.9 (1H), 4.6 (2H), 4.1-4.4 (1H), 3.7 (1H), 3.0 (1H), 2.2-2.5 (2H), 2.0 (1H), 1.7 (1H), 1.4 (9H).¹³C NMR (CDCI₃) δ 177.7, 170.7, 155.4, 131.4, 118.4, 80.6, 65.5, 52.8, 42.8, 40.7, 28.0, 25.5, 23.7.

General procedure for the synthesis of N-Fmoc-piperidine-carboxylic acid

(±)-N-Fmoc-piperidine-2-carboxylic acid [105751-19- 7]

1.29 g (10 mmol) piperidine-2-carboxylic acid is suspended in DCM (50 ml).3.42 mL

DIPEA (20 mmol) is added and the mixture is heated to reflux. Under Ar, 3.16 mL trimethylsilylchloride (25 mmol) is added and the mixture is refluxed for 1¹Λ hour. After cooling on ice, 2.86 g (11 mmol) FmocCI is added. The temperature is rised to rt. over 1 V2 hour. The mixture is evaporated to a syrup, redisolved in NaHC0_3(εat)/Et₂0 and the aq. phase is washed with Et₂0. The aqueous phase is made acidic with 1 N HCI (pH 2) and extracted with EtOAc. The organic phase is washed with NaCI_(sat), dried over Na₂S0 and evaporated to give a white foam (3.32 g, 94%).¹H NMR (CDCI₃) δ 7.2-7.9 (8H), 4.7-5.1 (dd, 1H), 4.0-4.6 (m, 4H), 2.9-3.3 (dt, 1H), 2.3 (t, 1H), 1.1-1.8 (5H).¹³C NMR (CDCI₃) δ 177.2, 143.8, 141.2, 127.6, 127.0, 125.0, 124.8, 119.9, 67.7, 54.1, 47.1, 41.8, 26.5, 24.6, 20.6.

(±)-N-Fmoc-piperidine-2-carboxylic acid fluoride

0.35 g (1 mmol) (±)-N-Fmoc-piperidine-2-carboxylic acid is dissolved in DCM (2.5 mL). The mixture is cooled to -15°C. Pyridine (80 μL, 1 mmol) and cyanuric fluoride (180 μL, 2 mmol) is added. After 1 hour at -15°C, DCM (10 mL) and icewater (10 mL) is added. The phases are separated, and the organic phase is washed with H₂0, dried over Na₂S0₄and evaporated to give a syrup (0.35 g, 100%). HPLC of the methylester (reaction with MeOH the overnight) gives 95.5% yield.¹H NMR (CDCI₃) δ 7.3-7.9 (8H), 4.8-5.3 (1H), 4.4-4.6 (2H), 4.0-4.3 (2H), 2.9-3.2 (1H), 2.1-2.3 (1H), 1.7-1.9 (3H), 1.2-1.6 (2H).¹³C NMR (CDCI₃) δ 143.5, 141.2, 127.6, 126.9, 124.8, 119.9, 67.8, (53.6, 52.7: C1), 47.0, 41.6, 26.0, 24.3, 20.6. ( + )-N-Fmoc-piperidine-2-carboxylic acid [101555-63-9] Procedure as above. (60%). [α] = +26.6° (CHCI₃).

(-)-N-Fmoc-piperidine-2-carboxylic acid [86069-86-5] Procedure as above. (85%). [α] = -18.5° (CHCI₃).

(±)-N-Fmoc-piperidine-3-carboxylic acid [148928-02-3]

Procedure as above. White crystals recrystallized in EtOAc/Hexane (2:3) (65 %). Mp 135-139 °C. 'H NMR (CDCI₃) δ 7.2-7.9 (8H), 4.5 (d, 1H), 3.8-4.4 (3H), 2.8-3.3 (2H),

2.5 (1H), 2.1 (d, 1H), 1.3-1.9 (3H).¹³C NMR (CDCI₃) δ 178.4, 155.1, 144.0, 141.3, 127.6, 127.0, 124.9, 119.9, 67.3, 47.3, 45.5, 44.1, 40.9, 26.9, 23.9.

N-Fmoc-piperidine-4-carboxylic acid [148928-15-8] 1.09 g (10.3 mmol) Na₂C0₃is dissolved in H₂0 (10 mL). THF (10 mL) is added.1.3 g (10 mmol) piperidine-4-carboxylic acid is dissolved and the mixture is cooled on ice. 2.86 g (11.1 mmol) FmocCI dissolved in THF (10 mL) is added dropwise together with 1.9 mL (11.1 mmol) DIPEA. The temperature is rised to rt. After 2 hours the reaction mixture is acidified with 10% citric acid (aq.) and extracted with EtOAc. The EtOAc layer is washed with water, dried with Na₂S0 and evaporated. The residue is triturated with hexane to afford white crystals (3.6 g 100%). Mp 178-180 °C. \Λ NMR (DMSO-d₆) δ 7.2-7.9 (8H), 4.4 (2H), 4.2 (1H), 4.0 (2H), 3.0 (2H), 2.5 (1H), 1.9 (2H),

1.6 (2H).¹³C NMR (DMSO-d₆) δ 175.5, 154.3, 143.9, 140.8, 127.6, 127.1, 124.9, 120.1, 66.4, 46.8, 42.8, 39.8, 27.6.

N-Fmoc-6-amino-capronic acid

Procedure as above. (81.7%). Mp 113.5-115°C.¹H NMR (CDCI₃) δ 10.7 (1H), 7.2-7.9 (8H), 4.9 (1 H), 4.2-4.6 (3H), 3.0-3.3 (2H), 2.4 (2H), 1.2-1.7 (6H).¹³C NMR (CDCI₃) δ 179.0, 157,0, 143.8, 141.2, 127.5, 126.9, 124.9, 119.8, 66.4, 47.1, 40.7, 33.7, 29.4, 26.0, 24.1. General procedure for the synthesis of N-Boc-piperidine-carboxylic acid

l±)-N-Boc-piperidine-2-carboxylic acid

1.29 g (10 mmol) piperidine-2-carboxylic acid is dissolved in a solution of 10% Et₃N/MeOH. Under vigorously stirring, 4.4 g (20 mmol) BOC₂0 is added. The mixture is heated to reflux for 5 min. The mixture is concentrated to give a syrup which is treated for 10 min. with ice cold 0.01 M HCI. Additional acid (1M HCI) is added (pH 4) and the mixture is rapidly extracted with EtOAc. The organic phase is dried over Na₂S0₄and evaporated to give white crystals, which are triturated with pentane (2.04 g, 89 %). Mp 121.5-122.5 °C. 'H NMR (CDCI₃) δ 11.5 (1H), 4.9 (1H), 4.0 (1H), 3.0 (1H), 2.3 (1H), 1.7 (3H), 1.1-1.6 (11H).¹³C NMR (CDCI₃) δ 177.7, 154.3, 80.2, 55.0, 54.0, 43.0, 41.9, 28.2, 26.5, 24.6, 20.6.

( + )-N-Boc-piperidine-2-carboxy/ic acid Procedure as above. (80.6%). Mp 115.5-117 °C. [α] = +49.8° (CHCI₃).

f-)-N-Boc-piperidine-2-carboxylic acid [28697-17-8]

Procedure as above. (87.3%). Mp 115-118°C. [α] = -50.6° (CHCI₃).

(±)-N-Boc-piperidine-3-carboxylic acid [71381-75-4]

Procedure as above. (90 %). Mp 155-156°C. 'H NMR (CDCI₃) δ 11.6 (1H), 4.1 (1H), 3.9 (1H), 3.1 (1H), 2.8 (1H), 2.5 (1H), 2.0 (1H), 1.3-1.8 (12H).¹³C NMR (CDCI₃) δ 178.7, 154.6, 79.8, 45.3, 43.7, 41.0, 28.2, 27.0, 24.0.

N-Boc-piperidine-4-carboxylic acid [84358- 13-4]

Procedure as above. (81 %). Mp 143.5-145.5 °C. 'H NMR (CDCI₃) δ 11.0 (1H), 4.0 (2H), 2.9 (2H), 2.5 (1H), 1.9 (2H), 1.7 (2H), 2.6 (9H).¹³C NMR (CDCI₃) δ 180.2, 155.0, 79.7, 42.8, 40.7, 28.3, 27.6.

cis-(±)-(3R_f4R)-N-Boc-3-hydroxy-piperidine-4-carboxylic acid Procedure as above. (47%). Mp 146-148 °C. (cis)-(±)-N-Boc-Piperidine-2,5-dicarboxylic acid [188345-84-8]

Procedure as above. (100 %). 'H NMR (CDCI₃) δ 9.4 (1 H), 4.8-5.0 (1 H), 4.2-4.5 (1 H),

3.0 (1 H), 2.4 (2H), 2.1 (1 H), 1 .7 (1 H), 1 .5 (9H).

Solid-phase synthesis

Synthesis of a library (3 sub-libraries) of 27 members using BOC-protected piperidine carboxylic acids

The three monomer used are: N-Boc-piperidine-4-carboxylic acid, (-)-N-Boc-piperidine- 2-carboxylic acid and (±)-N-Boc-4-hydroxypiperidine-3-carboxylic acid.

MBHA-resin (4-Methyl Benzhydrylamine resin from Novabiochem with a substitutionlevel of 0.46 mmole/g) is split into three portions. Each portion is coupled for two hours with a monomer (3eq) using HATU (2.5 eq) and DIPEA (6eq) in

DMF/DCM (1 : 1 ). The monomer is prereacted with HATU and DIPEA for 2 min. After reaction, the resin is washed with DMF and DCM. The three portions of resin are mixed, treated with 50% TFA/DCM (2x10min) to remove the BOC protecting group and split into three. The three fractions are reacted as described above with the three monomers, washed, mixed, deprotected, split and reacted a last time. The 3 sub- libraries of each 9 members thus obtained are cleaved from the resin using HF (45 min., rt.) yielding the amide and are extracted with TFA (2χ3min.).

Each of the sub-libraries are reacted with Sanger 's reagent and analysed by LC- UV/MS. As two of the monomers have the same mass in total 4 different masses (516.23, 532.23, 548.22 and 564.22) are expected, with 3 different masses in each sub-library. Within the three chromatograms the peaks are identified by one of the above masses.

Coupling of N-Fmoc-piperidine-carboxylic acid to 4-(2 ^'A ^' -Dimethoxyphenyl-Fmoc- amino-methyU-phenoxy resin (Rink-resin)

Rink-resin from Novabiochem with a substitution level of 0.43 mmole/g is used. The Rink-resin is first deprotected using 20% piperidine in DMF for 2x 1 0 min. The resin is washed with 3χDMF before further reaction. Both N-Fmoc-piperidine-2- carboxylic acid, N-Fmoc-piperidine-3-carboxylic acid and N-Fmoc-piperidine-4- carboxylic acid are coupled to Rink-resin to give each of the 5-mers. Each of the couplings are performed using 2 eq of N-Fmoc-piperidine-carboxylic acid, 1 .8 eq of HBTU and 4 eq of DIPEA in DMF. The monomers are prereacted with HBTU and DIPEA for 2 min. Only traces of unreacted product (HPLC) can be seen after 2 hours at rt.

Coupling of of (cis)-(±)-N-Fmoc-piperidine-dicarboxylic acid mono allylester to Rink- resin

The Rink-resin is first deprotected using 20% piperidine in DMF for 2x 10 min. The resin is washed with 3^χDMF before further reaction. The (cis)-(±)-N-Fmoc-piperidine- dicarboxylic acid mono allylester (syrup) is dissolved in DCM to a known concentration. To this solution (corresponding to 2 eq) is added 1 .8 eq HBTU dissolved in DMF and 4 eq of DIPEA. After 2 min. the mixture is added to the resin. After 2 hours, the coupling is quantitative.

Coupling of (cis)-(±)-N-Fmoc-piperidine-dicarboxylic acid mono allylester to PEGA Rink- resin

Rink amide PEGA-resin from Novabiochem with a substitution level of 0.37 mmole/g is used. The resin is provided wet (MeOH) and is to be weighed off as such. The resin is washed with 3χDMF.

The (cis)-(±)-N-Fmoc-piperidine-dicarboxylic acid mono allylester (syrup) is dissolved in DCM to a known concentration. To this solution (corresponding to 2 eq) is added 1 .8 eq HBTU dissolved in DMF and 4 eq of DIPEA. After 2 min. the mixture is added to the resin. After 2 hours, the coupling is quantitative according to Fmoc-test. The resin is washed with 3^χDMF and 3^χDCM. Synthesis of 6-carbamoyl-1-(N-Fmoc-4-piperidylcarbonyl)-2-piperidine-allylic- carboxylate

Rink-coupled (cis)-(+)-N-Fmoc-piperidine-2,6-dicarboxyiic acid mono allylester is deprotected with 20% piperidine in DMF for 2x10 min. The resin is washed with 3xDMF and 3χDCM and flushed with Ar. DCM is added and BSA (N,0-bis- (trimethylsilyl)-acetamide) (4 eq). After 24 h, N-Fmoc-piperidine-2-carboxylic acid (4 eq), TFFH (tetramethyluronium hexafluorophosphate) (4 eq) and DIPEA (8 eq) are added. After 21 h, the reaction is run to 88% of maximum, according to Fmoc-test. The resin is washed with 3^χDMF and 3χDCM. The product is cleaved from the resin with 20 % TFA/DCM for 2x5 min.

Synthesis of 6-carbamoyl-1-(N-Fmoc-3-piperidylcarbonyl)-3-piperidine-allylic- carboxylate

Rink-coupled (cis)-(±)-N-Fmoc-piperidine-2,5-dicarboxylic acid mono allylester is deprotected with 20% piperidine in DMF for 2x10 min. The resin is washed with 3χDMF. The coupling is performed using N-Fmoc-piperidine-3-carboxylic acid (2 eq), 1 .8 eq of HATU and 4 eq of DIPEA in DMF for 3x2 h with inbetween wash with DMF. The monomer is prereacted with HATU and DIPEA for 2 min. The reaction is followed by Fmoc-test. The product is cleaved from the resin with 20 % TFA/DCM for 2x5 min.

Synthesis of 6-carbamoy/-1-{1-[1-(1-{1-[1-(N-Fmoc-3-piperidy/carbony/)-3- piperidylcarbonyl]-3-piperidylcarbonyl}-3-piperidylcarbonyl)-3-piperidylcarbonyl]-3- piperidylcarbonyl}-3-piperidine-allylic-carboxylate

Rink-coupled 6-carboxy-1 -(N-Fmoc-3-piperidylcarbonyl)-3-piperidine-allylic-carboxyiate is deprotected with 20% piperidine in DMF for 2x 10 min. The resin is washed with 3^χDMF. Each coupling is performed using 2 eq of N-Fmoc-piperidine-3-carboxylic acid, 1 .8 eq of HBTU and 4 eq of DIPEA in DMF for 2 h. or overnight. The monomer is prereacted with HBTU and DIPEA for 2 min. After each coupling, the resin is washed with 3^χDMF and 3^χDCM. A sample is cleaved for HPLC by reaction with 20% TFA/DCM for 2x5 min. The rest of the resin is deprotected before the next coupling with 20% piperidine in DMF for 2x 1 0 min. and washed with 3^χDMF. The final product is cleaved from the resin with 20 % TFA/DCM for 2x5 min.

Synthesis of 6-carbamoyl-1 -{1 -[1 -(1 -{1 -[N-Fmoc-4-piperidylcarbonyl]-4- pipe dylcarbonyl}-4-piperidylcarbonyl)-4-piperidylcarbonyl]-4-piperidylcarbonyl}-4- piperidine-allylic carboxylate (6mer) and the corresponding 7mer and 8mer (Figure 1)

PEGA-Rink-coupled (cis)-(±)-N-Fmoc-piperidine-2,4-dicarboxylic acid mono allylester is deprotected with 20% piperidine in DMF for 2x 10 min. The resin is washed with 3χDMF. Each of the couplings are performed in one of the two following ways. Either by using 2 eq of N-Fmoc-piperidine-4-carboxylic acid, 1 .8 eq of HBTU and 4 eq of DIPEA in DMF for 2x2 h with inbetween wash with DMF, or by using 4 eq of N-Fmoc- piperidine-4-carboxylic acid, 3.8 eq of HBTU and 8 eq of DIPEA in DMF overnight. The monomer is prereacted with HBTU and DIPEA for 2 min. After each complete coupling, the resin is washed with 3^χDMF and 3^χDCM. A sample is cleaved for HPLC by reaction with 95% TFA/DCM for 30 min. The rest of the resin is deprotected before the next coupling with 20% piperidine in DMF for 2x 10 min. and washed with 3xDMF.

Synthesis of 1 -(1 -{1 -[1 -(1 -{1 -[1 -(N-Fmoc-2-aminoacetyl)-4-piperidylcarbonyl]-4- piperidylcarbonyl}-4-piperidylcarbonyl)-4-piperidylcarbonyl]-4-piperidylcarbonyl}-6- carbamoyl-4-piperidine-allylic carboxylate

Rink-PEGA-bound 6-carboxy-1 -{ 1 -[1 -( 1 -{ 1 -[N-Fmoc-4-piperidylcarbonyl]-4- piperidylcarbonyl}-4-piperidylcarbonyl)-4-piperidylcarbonyl]-4-piperidylcarbonyl}-4- piperidine-allylic carboxylate is deprotected with 20% piperidine in DMF for 2x 1 0 min. The resin is washed with 3^χDMF. 4 eq N-Fmoc-Gly-OH, 3.8 eq HBTU and 8 eq DIPEA is prereacted before added to the resin. After 1 9 hours, the resin is washed with 3^χDMF and 3^χDCM. The product is cleaved from the resin with 95 % TFA/DCM in 30 min.

Synthesis of 1 -{1 -[1 -(1 -{1 -[1 -(N-Fmoc-6-aminohexanoyl)-4-piperidylcarbonyl]-4- piperidylcarbonyl}-4-piperidylcarbonyl)-4-piperidylcarbonyl]-4-piperidylcarbonyl}- 6carbamoyl-4-piperidine-allylic carboxylate and 1 -(1 -{1 -[1 -(1 -{1 -[1 -(N-Fmoc-6- aminohexanoyl)-4-piperidylcarbonyl]-4-piperidylcarbonyl}-4-piperidylcarbonyl)-4- piperidylcarbonyl]-4-piperidylcarbonyl}-4-piperidylcarbonyl)-6carbamoyl-4-piperidine- a Hylic carboxylate (Figure 2)

Rink-PEGA-bound 6-carboxy-1 -{ 1 -[ 1 -( 1 -{ 1 -[N-Fmoc-4-piperidylcarbonyl]-4- piperidylcarbonyl}-4-piperidylcarbonyl)-4-piperidylcarbonyl]-4-piperidylcarbonyl}-4- piperidine-allylic carboxylate or 1 -{1 -[1 -(1 -{ 1 -[1 -(N-Fmoc-4-piperidylcarbonyl)-4- piperidylcarbonyl]-4-piperidylcarbonyl}-4-piperidylcarbonyl)-4-piperidylcarbonyl]-4- piperidylcarbonyl}-6-carbamoyl-4-piperidine-allylic carboxylate is deprotected with

20% piperidine in DMF for 2x 10 min. The resin is washed with 3xDMF. 2 eq N-Fmoc- 6-aminocapronic acid, 1 .8 eq HATU and 4 eq DIPEA is prereacted before added to the resin. After 1 9 hours, the resin is washed with 3^χDMF and 3^χDCM. The product is cleaved from the resin with 95 % TFA/DCM in 30 min.

Deprotection of the acid and the amine of the linear Rink-bound or Rink-PEGA-bound polymer (Figure 3)

The resin is washed twice with 2.5%NMM/5%AcOH/CHCI₃ and flushed with Ar. 1 .2 eq Pd(Ph₃)₄ is added under Ar. After 1 h, the resin is washed with 7^χ0.5%DIPEA/- 0.5%sodiumdiethyldithiocarbamate/DMF. The resin is reacted with 20% piperidine in DMF for 2x 10 min. and washed with 3^χDMF. MALDI of linear deprotected 7mer of piperidine-3-carboxylic acid gives the right mass of 842.5.

Attempt to cyclise the linear deprotected Rink-bound or Rink-PEGA-bound n-mer

The linear deprotected Rink-bound or Rink-PEGA-bound n-mer is washed with NMP. 1 6 eq DIPEA, 8 eq PyBOP and 8 eq HOBT is added. After 17 hours, the resin is washed with 3xNMP and 3xDCM.

Attempt to cyclise 1-(1-{1-[1-(1-{1-[1-(2-aminoacetyl)-4-piperidylcarbonyl]-4- piperidylcarbonyl}-4-piperidylcarbonyl)-4-piperidylcarbonyl]-4-piperidylcarbonyl}-6- carboxy-4-piperidine-carboxylic acid The linear deprotected Rink-PEGA-bound Gly-6-mer is washed with NMP. 1 6 eq DIPEA, 8 eq PyBOP and 8 eq HOBT is added. After 17 hours, the resin is washed with 3χNMP and 3^χDCM. The Kaiser-test was negative. The product is cleaved off the resin, but MS-UV/HPLC do not show the expected product.

Attempt to cyclise Rink-PEGA-bound 1-{1-[1-(1-{1-[1-(6-aminohexanoy/)-4- piperidylcarbonyl]-4-piperidylcarbonyl}-4-piperidylcarbonyl)-4-piperidylcarbonyl]-4- piperidylcarbonyl}-6-carboxy-4-piperidine-carboxylic acid and 1-(1-{1-[1-(1-{1-[1-(6- aminohexanoyl)-4-piperidylcarbonyl]-4-piperidylcarbonyl}-4-piperidylcarbonyl)-4- piperidylcarbonyl]-4-piperidylcarbonyl}-4-piperidylcarbonyl)-6-carboxy-4-piperidine- carboxylic acid

The Rink-PEGA-bound 1 -{ 1 -[1 -(1 -{ 1 -[1 -(6-aminohexanoyl)-4-piperidylcarbonyl]-4- piperidylcarbonyl}-4-piperidylcarbonyl)-4-piperidylcarbonyl]-4-piperidylcarbonyl}-6- carboxy-4-piperidine-carboxylic acid and 1 -(1 -{ 1 -[1 -( 1 -{ 1 -[1 -(6-aminohexanoyl)-4- piperidylcarbonyl]-4-piperidylcarbonyl}-4-piperidylcarbonyl)-4-piperidylcarbonyl]-4- piperidylcarbonyl}-4-piperidylcarbonyl)-6-carboxy-4-piperidine-carboxylic acid is washed with NMP. 1 6 eq DIPEA, 8 eq PyBOP and 8 eq HOBT is added. After 17 hours, the resin is washed with 3^χNMP and 3^χDCM. The Kaiser-test is negative. MS- UV/HPLC do not show the expected mass.

Novel piperidine carboxylic acid monomers

Still further monomers have been prepared as illustrated in Figure 7 (all numerals refer to Figures 7 and 8). The synthesis takes advantage of the commercially available

Dieckman adduct 4. Thus 4 was protected as the BOC derivative ((^tBuO)₂CO, THF/aq. Na₂C0₃ ( 1 : 1 ), 25 °C, 1 h, 95 %), and then converted into the dianion 5 by treatment with first NaH (1 .1 5 eq.) and then Buϋ ( 1 .1 eq.). The solution of 5 was now treated with various alkylating agents. Addition of 1 .1 5 eq. of chloromethyl methyl ether gave 95 % of the 5-alkylated product 6^6"8 while treatment with 1 .1 5 eq. of chloromethyl benzyl ether gave 96 % of the corresponding product 7. Both compounds were enols in unpolar solvent probably due to the formation of an intaramolecular hydrogen bond. In polar solvent slow conversion to the stereoisomeric ketones was observed. Reduction of enols 6 and 7 were performed with a number of reducing agents to obtain the desired stereoselectivity (Table 1 ). In general two or more stereoisomers were obtained. Best result was obtained using catalytic hydrogenation catalysed by Raney Ni or palladium on carbon which gave mainly s π-reduction from the less hindered face to give the cis isomers 8 or 9, respectively. Rhodium and platinum catalysts under a number of conditions gave also formation of the trans isomers 8a, 8b or 9a. A number of metal hydride reduction agents were also investigated: Sodium borohydride gave a mixture of stereoisomers consisting of 8, 8a and a third stereoisomer 8b presumably the 3,4-trar/s-4,5-c/s isomer. The bakers yeast reduction gave mainly allo isomer 8a. Since 8 and 9 could be separated the stereoisomers these products could be efficiently prepared using hydrogenation. Thus 6 on treatment with Pd/C and H₂ at 40 atm. in EtOH was converted to pure 8 in 50 % yield while 1 8% of the allo isomer 8a was isolated. 7 under the same conditions gave 9 in good yield.

Table 1. Reduction conditions for reduction of 6 and 7. Reagent Solvent Starting Pressure Yield Ratio 8/8a/8b material (bar) (or 9/9a)

H₂/Rh EtOH 6 35 74% ϊϊϊϊ

H₂/Pd EtOH 6 40 94% 6:3:1

H₂/Pd + Et₃N EtOH 6 40 95% 7:3:0

H₂/Ni MeOH 6 33 88% 4: 1 :2

H₂/Pt EtOH 6 30 60% 1 : 1 : 1

H₂/Pt + KOH EtOH 6 30 90% 3:2:1

H₂/Pt *BuOH 6 30 66% 1 : 1 : 1

NaBH₄ 6 67% mix

Bakers yeast H₂0 6 23% 0: 1 :0

(no sugar) (65% *)

Bakers yeast H₂0 6 35% 3:4:0

(sugar/0₂)

H₂/Pd + Et₃N EtOH 7 40 100% 1 :0

H₂/Ni MeOH 7 42 93% 4:3

* Yield based on recovered starting material. Both 8 and 9 were deprotected. Methyl ether 8 was hydrolysed with LiOH in THF/H₂0 to give 10 in 57 % yield. Similarly 9 gave 11 in 79 % yield. Acid hydrolysis of 8 gave hydroxyamino acid 1a in good % yield. Compounds 8a, 8b and 9a are ethyl esters of the Boc-protected functionalized piperidine carboxylic acids and hydrolysis of such 5 ethyl groups to yield the free Boc-protected functionalized piperidine carboxylic acids building blocks can be performed in high to quantitative yields by a series of methods. Especially preferred is the LiOH mediated hydrolysis.

¹³C NMR-data (d6-DMSO, 100 °C): 6, δ 171.2 (C3'), 169.8 (br, C4), 155.2 (Boc),

10 97.8 (br, C3), 80.4 (Boc), 71.1 (C6), 61.1 (Et), 59.4 (OMe), 44-40 (C2, C5, C5'), 28.8 (3C, Boc) and 14.6 ppm (Et).7, δ 171.0 (C3'), 169.8 (br, C4), 155.0 (Boc), 138.3, 128.6, 128.2 (Ph), 97.8 (br, C3), 80.3 (Boc), 73.8 (Bn), 68.8 (C6), 60.5 (Et); 43.0-40.5 (all br, C2, C5, C5'), 28.7 (3C, Boc), 14.7 ppm (Et).8, δ 171.4 (C3'), 154.3 (Boc), 78.9 (Boc), 71.9 (C6), 66.8 (C4), 59.8 (Et), 58.5 (OMe), 43.9, 41.9,

15 40.9 (C2, C3, C5), 28.4 (Boc) and 14.2 ppm (Et). 10, δ 176.3 (C3'), 155.3 (Boc), 80.6 (Boc), 73 (br, C6), 59.6 (OMe), 46.2, 44.0, 42.9, 40.4 (C2, C3, C5, C5'), 28.8 ppm (Boc).1a, δ 177.2 (C3'), 74.3 (C6), 68.7(C4), 61.4 (OMe), 45.6, 44.6, 43.6, 40.0 ppm (C2, C3, C5, C5'). 'H NMR: 6, δ 12.02 (w s, enol OH), 4.08 (q, 2H, Et); 4.0-3.1 (m, 7H), 3.16 (s, 3H, OMe); 1.12 (t, 3H, Et).8, δ 4.55 (t, 2H, Et), 3.99 (dd,

20 1H, J_3,4 4.0 Hz, ₄₅5.3 Hz, H-4), 3.65 (dd, 1H, J_2βq,2ax 13.6 Hz, _2βq34.65 Hz, H- 2eq), 3.42 (dd, 1H, _5βq,5ax 13 Hz, _5,5eq 4.0 Hz, H-5'eq), 3.4-3.28 (3H, H-6'ax, 2 x H-6), 3.29 (s, 3H, OMe), 2.60 (m, 1H, H-3), 2.11 (m, 1H, H-5ax), 1.43 (s, 9H, t- butyl), 1.25 (t, 3H, Et). 1a, δ 4.20 (dd, 1H, J_3A 3.8 Hz, J₄₅5.6 Hz, H-4), 3.64 (dd, 1H, J_6a,6b 10.5 Hz, _5,6a 5.2 Hz, H-6a), 3.57 (dd, _6a,6b 10.5 Hz, _6b56.0 Hz, H-6b),

25 3.42 (dd, 1H, _2βq,2ax 10 Hz, J_2βq3 3.7 Hz, H-2eq), 3.39 (dd, 1H, J_5βq,5ax 13.4 Hz,

J_5βq,54.1 Hz), 3.31 (s, 3H, OMe), 3.29 (dd, 1H, J_2ax,2βq 10 Hz, J_2ax39.8 Hz), 3.23 (dt, 1H, _3,2ax 9.8 Hz, _3,2βq 3.7 Hz, ₃₄3.8 Hz), 3.15 (dd, 1H, J_5ax,5eq 13.4 Hz, ₅._ax,56.4 Hz), 2.25 (sxt, 1H, H-5ax, J ^"5 Hz). MS (El): 6, 316 (M + 1) ⁺ .

30

Routes to piperidine carboxylic acid monomers

Preparation of some of the above-mentioned monomers have been described in Byrgesen, E.; Nielsen, J; Willert, M.; Bols, M. Tetrahedron Lett. 1997385697-5700. It is envisaged that further piperidine monomers can be prepared as outlined in Figure 5 (all numerals below refer to Figure 5):

Thus, the monomers 4 and 5 can be prepared as follows: known epoxide 7 is converted into a N-Boc protected derivative of 4 (4a), using a scheme closely related to the procedure for synthesis of isofagomine (Jespersen, T. M.; Bols, M.; Sierks, M.R.; Skrydstrup,T. "Synthesis of Isofagomine, a Novel Glycosidase Inhibitor." Tetrahedron 50 (1994) 13449-13460.). Reaction of 7 with benzylmagnesiumbromide gives regioselective epoxide opening, followed by acidic hydrolysis of the 1 ,6-acetal and periodate cleavage of the 5,6-diol gives dialdehyde 8. Reductive amination of 8 using ammonia and hydrogen leads to a piperidine, that is then protected on the nitrogen with (Boc)₂0 and subjected to ozone to give 4a. A derivative of 5 (5a) is prepared by a similar sequence from known epoxide 9 that is subjected to regioselective epoxide-cleavage with PhTMS and Lewis acid followed by base- treatment to a 2,3-epoxide that is then cleaved regioselectively with allylmagnesium chloride to give 10. Acetal hydrolysis, Nal0₄-cleavage of 5,6-diol and reductive amination of the resulting dialdehyde gives 1 1 . Protection of the amine with a Fmoc- group, cleavage of the double bond with Lemieux's reagent, esterification of the resulting acid and ozonolysis gives 5a.

The monomer 1 8 can be prepared as follows (see Figure 6): Amine 1 8 is to be made from cinnamic aldehyde, which is reacted with a chiral amine to form an optical active Schiff-base, which is to be cyclo added to tert-Butyl acrylate. The resulting enamine 23 is condensed with chloromethylbenzyl ether giving, after hydrogenation of the benzyl group, piperidinol 24. Protection with (Boc)₂0 and ozonolysis gives 1 8.

Methods for determining the biological activity of the oligomers

Protein binding assay: A colometric assay can be used to screen the resin-bound oligomers as well as libraries of oligomers for binding to proteins such as lectins. The assay is performed essentially as described in Liang et al. Science 274 (1 996) 1520-2. Glucosidase assay: Enzymes (α-glucosidase from yeast, β-glucosidase from almonds, isomaltase from yeast, α-fucosidase from human placenta, β-mannosidase from snail, and β-galactosidas from E.coli) and substrates therefor can be obtained from Sigma. As substrates are employed p-nitrophenyl-α-glucopyranoside for α-glucosidase and p- nitrophenyl-β-glucopyranoside for β-glucosidase. The experiments are performed in 0.05 M phosphate buffer at 22°C. The enzyme assays were performed essentially as described by H. Halvorson Methods Enzym. 8 (1966) 559-62.

1 . An oligomer of the general formula I

(in short K-C( = O)-M₀-...-M_n-T, wherein M₀, ..., M_n designate "piperidine monomers")

wherein n is a positive integer;

K-(C = 0)- is a carboxylic acid or a derivative thereof;

T is selected from hydrogen, optionally substituted C_1-20-alkyl, optionally substituted C_1-20-alkoxy, optionally substituted C^o-alkylcarbonyl, optionally substituted aryl, optionally substituted heteroaryl, and amino-protecting groups; and

each of X⁰,..., and Xⁿ independently designates 0-5, preferably 0-4, such as 0-3, substituents, where

(a) such optional substituents independently are selected from optionally substituted C_1-20-alkyl, optionally substituted C₂.₂₀-alkenyl, optionally substituted C₄.₂₀-alkadienyl, optionally substituted C₆.₂₀-alkatrienyl, optionally substituted C₂.₂₀-alkynyl, hydroxy, C^o-alkoxy, C₂.₂₀-alkenyloxy, carboxy, oxo, C^o-alkoxycarbonyl, C^o-alkylcarbonyl, formyl, aryl, aryloxycarbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxycarbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and dUCvβ-alkyDamino, carbamoyl, mono- and d C^-alkyDaminocarbonyl, amino-Cvg-alkyl-aminocarbonyl, mono- and di(C₁_₆-alkyl)amino-C₁.₆-alkyl-aminocarbonyl, Cve-alkylcarbonylamino, guanidino, carbamido, C^-alkanoyloxy, sulphono, C^-alkylsulphonyloxy, nitro, sulphanyl, C-,.₆- alkylthio, and halogen, where aryl and heteroaryl may be optionally substituted; and/or (b) two substituents on two adjacent carbon atoms together with said two adjacent carbon atoms may designate (i) a fused optionally substituted aromatic or non- aromatic carbocyclic or heterocyclic ring, or (ii) a double bond;

or an acid addition salt or a basic salt thereof.

2. An oligomer according to claim 1 , wherein n is in the range of 1 -25, preferably 1 - 15, in particular 2-10 such as 2-5 or 3-6.

3. An oligomer according to any of the preceding claims, wherein K- is selected from hydrogen, NH₂, NHR, NRR', N(OH)H, NHNH₂, NHNHR'", and OR", where each of R, R', R", and R'" independently designates optionally substituted C,_₆-alkyl, optionally substituted C₂__β-alkenyl, optionally substituted aryl, or optionally substituted heteroaryl.

4. An oligomer according to any of the preceding claims, wherein K- designates OH, OR", NH₂, NHR, or NRR', where R and R' are selected from C^-alkyl and benzyl, and R" is selected from C_1-β-alkyl, C₂._β-alkenyl, phenyl, and benzyl; in particular K- designates OH, methoxy, or NH₂.

5. An oligomer according to any of the preceding claims, wherein T is selected from hydrogen, optionally substituted C_1-β-alkyl, optionally substituted C^-alkoxy, optionally substituted Cvβ-alkylcarbonyl, optionally substituted aryl, optionally substituted heteroaryl, tert-butoxycarbonyl (Boc), and fluorenylmethoxycarbonyl (Fmoc).

6. An oligomer according to any of the preceding claims, wherein T is selected from hydrogen; which may be substituted with 1 -3, preferable 1 -2, substituents selected from hydroxy, C^-alkoxy, carboxy, aryl, heteroaryl, amino, mono- and di(C_1-6- alkyDamino, and halogen, where aryl may be substituted 1 -3 times with C_1-4-alkyl, C_1-4- alkoxy, nitro, cyano, amino or halogen; C^e-alkoxy; C e-alkylcarbonyl; amino-C_1-β- alkylcarbonyl; aryl which may be substituted with 1 -3, preferably 1 -2 substituents selected from C₁.₄-alkyl, C,.₄-alkoxy, nitro, cyano, amino, and halogen; and heteroaryl which may be substituted with 1 -3, preferably 1 -2 substituents selected from C_1- - alkyl, C_1-4-alkoxy, nitro, cyano, amino, and halogen. 7. An oligomer according to any of the preceding claims, wherein T is selected from hydrogen; C_1-β-alkyl; benzyl, Cvβ-alkylcarbonyl; and aryl which may be substituted with 1 -3, preferably 1 -2 substituents selected from C_1-4-alkyl, C_1- -alkoxy, nitro, cyano, amino, and halogen.

8. An oligomer according to any of the preceding claims, wherein each of X⁰,..., and Xⁿ independently designates 0-3 substituents, where

(a) such optional substituents are selected from optionally substituted C_1-6-alkyl, optionally substituted C₂.₆-alkenyl, hydroxy, C^-alkoxy, C₂.₆-alkenyloxy, carboxy, oxo, formyl, aryl, aryloxycarbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxycarbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and dKC^-alkyDamino; carbamoyl, mono- and dKC^e-alkyDamino- carbonyl, C e-alkylcarbonylamino, sulphono, C^-alkanoyloxy, and halogen, where aryl and heteroaryl may be optionally substituted with 1 -3, preferably 1 -2 substituents selected from C_1- -alkyl, C^-alkoxy, nitro, cyano, amino, and halogen; and/or

9. An oligomer according to any of the preceding claims, wherein each of X°, ..., and X" independently designates 0-3 substituents, where such optional substituents are selected from C_1-e-alkyl which may be substituted with 1 -3, preferable 1 -2, substituents selected from hydroxy, C_1-6-alkoxy, carboxy, aryl, heteroaryl, amino, mono- and di(C_1-β-alkyl)amino, and halogen, where aryl may be substituted 1 -3 times with C_1-4-alkyl, C_1- -alkoxy, nitro, cyano, amino or halogen; C₂.₆-alkenyl; hydroxy; C^- alkoxy; C₂.₆-alkenyloxy; carboxy; C ₆-alkoxycarbonyl; C₁_₆-alkylcarbonyl; formyl; amino; mono- and d C^-alkyDamino; carbamoyl; mono- and di(C₁.₆-alkyl)amino- carbonyl; Cve-alkylcarbonylamino; sulphono, C^-alkanoyloxy; and halogen such as fluoro or chloro. 10. An oligomer according to claim 8, wherein each of X°, ..., and X" independently designates 0-2 substituents, where such optional substituents are selected from C_{1 6}- alkyl which may be substituted with a substituent selected from hydroxy, C_1-6-alkoxy, aryloxy, and carboxy, where aryl may be substituted 1 -3 times with C_1- -alkyl, C^- alkoxy, nitro, cyano, amino or halogen; hydroxy; C^-alkoxy; C_{2 β}-alkenyloxy; carboxy; amino; mono- and mono- and di(C_1-β-alkyl)- aminocarbonyl; and C_1-6-alkylcarbonylamino.

1 1 . An oligomer according to claim 8, wherein each of X°, ..., and Xⁿ independently designates 1 -2 substituents, where such substituents are selected from C^-alkyl which may be substituted with a substituent selected from hydroxy, C^-alkoxy, aryloxy, and carboxy; hydroxy; C^-alkoxy; carboxy; and Cvβ-alkoxycarbonyl.

1 2. An oligomer according to any of the preceding claims, wherein in at least one of each of X°, ..., and Xⁿ is selected from hydroxy, hydroxymethyl and carboxy.

1 3. An oligomer according to any of the preceding claims, wherein in at least one of each of X°, ..., and X" is selected from hydroxy and hydroxymethyl.

14. An oligomer according to any of the preceding claims, comprising monomer fragments (M₀, ... , M_n) of the general formulae M^2S, M^2R, M^3R, M^3S and/or M⁴

M^2S M^3R M⁴

1 5. An oligomer according to claim 14, wherein each of the monomer fragments resembles a substitution pattern similar to that of a monosaccharide selected the xylose, fucose, galactose, glucose, mannose, glucosamine, galactosamine, and sialic acid (neuraminic acid).

1 6. An oligomer according to claim 14 or 1 5, wherein at least one of R², R² , R³, R³ , R⁴, R⁴ , R⁵, R⁵ , R⁶, and R⁶ is selected from hydroxy, hydroxymethyl and carboxy.

17. A cyclised oligomer of the general formula II

(in short K-C( = 0)-M₀-...-M_n-W, wherein M₀, ..., M_n designate "piperidine monomers" and W designates the biradical -Y^a-Y -)

wherein n is a positive integer;

K-(C = 0)- is a carboxylic acid or a derivative thereof;

Y^a and Y together designate a linear biradical (-Y^a-Y -) comprising 1 -20 backbone atoms;

(a) such optional substituents independently are selected from optionally substituted Cvao-alkyl, optionally substituted C_2-20-alkenyl, optionally substituted C₄.₂₀-alkadienyl, optionally substituted C₆.₂₀-alkatrienyl, optionally substituted C₂.₂₀-alkynyl, hydroxy, d. ₂o-alkoxy, C₂.₂₀-alkenyloxy, carboxy, oxo, C^o-alkoxycarbonyl, C^o-alkylcarbonyl, formyl, aryl, aryloxycarbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxycarbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(C₁.₆-alkyl)amino; carbamoyl, mono- and dKCve-alkyDaminocarbonyl, amino-C^e-alkyl-aminocarbonyl, mono- and dKC^e-alkyDamino-C^e-alkyl-aminocarbonyl, C_{1 6}-alkylcarbonylamino, guanidino, carbamido, C^e-alkanoyloxy, sulphono, C^e-alkylsulphonyloxy, nitro, sulphanyl, C_1-e- alkylthio, and halogen, where aryl and heteroaryl may be optionally substituted; and/or

(b) two substituents on two adjacent carbon atoms together with said two adjacent carbon atoms may designate (i) a fused optionally substituted aromatic or non- aromatic carbocyclic or heterocyclic ring, or (ii) a double bond;

or an acid addition salt or a basic salt thereof.

1 8. A cyclised oligomer according to claim 17, wherein the linear biradical (-Y^a-Y^b-) is selected from -C( = 0)-NH-(CH₂)_m-C( = 0)-, -NH-C( = 0)-(CH₂)_m-C( = 0)-, -C( = 0)-NH- (CH₂)_m-, -NH-C( = 0)-(CH₂)_m-, wherein m is 1 -20, preferably 2-1 2, especially 3-10, in particular 3-8, and wherein any of the methylene groups may be substituted with hydroxy, C^-alkyl, C^-alkoxy, carboxy, C^-alkoxycarbonyl, C_{1 6}-alkylcarbonyl, aryl optionally substituted 1 -3 times with C_1-4-alkyl, C^-alkoxy, nitro, cyano, amino or halogen, amino, mono- and di(C_1-6-alkyl)amino, and halogen.

19. A cyclised oligomer according to claim 18, wherein the linear biradical is -C( = 0)- NH-(CH₂)_m-C( = 0)-.

20. A cyclised oligomer according to any of the claims 17-1 9, wherein n is in the range of 1 -25, preferably 1 -1 5, in particular 2-10 such as 2-5 or 3-6.

21 . A cyclised oligomer according to any of the claims 17-20, wherein K- is selected from hydrogen, NH₂, NHR, NRR', N(OH)H, NHNH₂, NHNHR'", and OR", where each of R, R', R", and R'" independently designates optionally substituted C_1-6-alkyl, optionally substituted C₂.₆-alkenyl, optionally substituted aryl, or optionally substituted heteroaryl. 22. A cyclised oligomer according to any of the claims 17-21 , wherein K designates OH, 0^~, OR", NH₂, NHR, or NRR', where R and R' are selected from C^-alkyl and benzyl, and R" is selected from C,._β-alkyl, C₂.₆-alkenyl, phenyl, and benzyl; in particular K designates OH, methoxy, or NH₂.

23. A cyclised oligomer according to any of the claims 17-22, wherein each of X⁰,..., and X" independently designates 0-3 substituents, where

(a) such optional substituents are selected from optionally substituted C_1-6-alkyl, optionally substituted C₂.₆-alkenyl, hydroxy, C^-alkoxy, C₂.₆-alkenyloxy, carboxy, oxo, C β-alkoxycarbonyl, Cvβ-alkylcarbonyl, formyl, aryl, aryloxycarbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxycarbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(C₁.₆-alkyl)amino; carbamoyl, mono- and carbonyl, Cvβ-alkylcarbonylamino, sulphono, C^e-alkanoyloxy, and halogen, where aryl and heteroaryl may be optionally substituted with 1 -3, preferably 1 -2, substituents selected from C_1- -alkyl, C_1-4-alkoxy, nitro, cyano, amino, and halogen; and/or

24. A cyclised oligomer according to any of the claims 17-23, wherein each of X°, ..., and Xⁿ independently designates 0-3 substituents, where such optional substituents are selected from C^-alkyl which may be substituted with 1 -3, preferable 1 -2, substituents selected from hydroxy, C^-alkoxy, carboxy, aryl, heteroaryl, amino, mono- and di(C_1-e-alkyl)amino, and halogen, where aryl may be substituted 1 -3 times with C_1-4-alkyl, C_1-4-alkoxy, nitro, cyano, amino or halogen; C₂.₆-alkenyl; hydroxy; C_1-6- alkoxy; C₂.₆-alkenyloxy; carboxy; formyl; amino; mono- and di(C_1-β-alkyl)amino; carbamoyl; mono- and di(C_1-β-alkyl)amino- carbonyl; sulphono, C_1-6-alkanoyloxy; and halogen such as fluoro or chloro. 25. An oligomer according to claim 24, wherein each of X°, ..., and Xⁿ independently designates 0-2 substituents, where such optional substituents are selected from C_halky! which may be substituted with a substituent selected from hydroxy, C^-alkoxy, aryloxy, and carboxy, where aryl may be substituted 1 -3 times with C_1-4-alkyl, C ₄- alkoxy, nitro, cyano, amino or halogen; hydroxy; C^-alkoxy; C₂.₆-alkenyloxy; carboxy; C_1-6-alkoxycarbonyl; amino; mono- and mono- and di(C_1-6-alkyl)- aminocarbonyl; and Cvβ-alkylcarbonylamino.

26. An oligomer according to claim 24, wherein each of X°, ..., and X" independently designates 1 -2 substituents, where such substituents are selected from C_1-6-alkyl which may be substituted with a substituent selected from hydroxy, C^-alkoxy, aryloxy, and carboxy; hydroxy; C^e-alkoxy; carboxy; and C^-alkoxycarbonyl.

27. An oligomer according to any of the claims 1 7-26, wherein in at least one of each of X°, ..., and Xⁿ is selected from hydroxy, hydroxymethyl and carboxy.

28. An oligomer according to any of the claims 17-27, wherein in at least one of each of X°, ..., and X" is selected from hydroxy and hydroxymethyl.

29. A cyclised oligomer according to any of the claims 17-28, comprising monomer fragments (M₀, ..., M_n) of the general formulae M^2S, M^2R, M^3R, M^3S and/or M°⁴ as defined in claim 9.

30. An oligomer according to claim 29, wherein each of the monomer fragments resembles a substitution pattern similar to that of a monosaccharide selected the xylose, fucose, galactose, glucose, mannose, glucosamine, galactosamine, and sialic acid (neuraminic acid).

31 . An oligomer according to claim 29 or 30, wherein at least one of R², R^2', R³, R^3', R⁴, R , R⁵, R⁵ , R⁶, and R⁶ is selected from hydroxy, hydroxymethyl and carboxy. 32. A method for the preparation of an oligomer of the general formula I (K-C( = 0)-M₀- ...-M_n-T, where M₀, ..., M_n designate "piperidine monomers") as defined in any of the claims 1 -10, comprising the following steps:

(B) cleaving the oligomer K-C( = O)-M₀-...-M_n-T from the solid support material, the step optionally including deprotection of one or more functional group(s) of the oligomer.

33. A method for the preparation of a cyclised oligomer of the general formula II (K- C( = O)-M₀-...-M_n-W, where M₀, ..., M_n designate "piperidine monomers" and W designates the biradical -Y^a-Y^b-) as defined in any of the claims 1 1 -20, comprising the following steps:

(A) providing an optionally functional group protected oligomer -C( = O)-M₀-...-M_n-W immobilised to a solid support material; and

(B) cleaving the oligomer K-C( = O)-M₀-..--M_n-W from the solid support material, the step optionally including deprotection of one or more functional group(s) of the oligomer.

34. A method for the preparation of an array of oligomers (K-C( = O)-{M₀}-...-{M_n}-{T}), consisting of at least four oligomers each having the general formula I as defined in any of the claims 1 -1 6, the method comprises the following steps:

(B) cleaving the array of oligomers K-C( = O)-{M₀}-...-{M_n}-{T} from the solid support material, the step optionally including deprotection of one or more functional group(s) of the oligomer. 35. A method for the preparation of an array of cyclised oligomers (K-C( = O)-{M₀}-...- {M_n}-{W}), consisting of at least four oligomers each having the general formula II as defined in any of the claims 17-32, the method comprises the following steps:

(B) cleaving the array of cyclised oligomers K-C( = 0)-{M₀}-...-{M_n}-{W} from the solid support material, the step optionally including deprotection of one or more functional group(s) of the cyclised oligomer.

36. The use of an array of oligomers of the general formula I for screening of the biological activity or effect of a plurality of oligomers of the general formula I comprised within said array, wherein the oligomers are as defined in any of the claims 1 -1 6.

37. The use according to claim 36, wherein the array comprises 6-200 oligomers of the general formula I, preferably 6-100 different oligomers, and in particular 8-64 different oligomers.

38. The use of an array of oligomers of the general formula II for screening of the biological activity or effect of a plurality of oligomers of the general formula II comprised within said array, wherein the oligomers are as defined in any of the claims 17-32.

39. The use according to claim 38, wherein the array comprises 6-200 oligomers of the general formula II, preferably 6-100 different oligomers, and in particular 8-64 different oligomers.

40. A composition comprising at least two compounds of the general formula I and/or II as defined in the claims 1 -32.

41 . The use of an oligomer of the general formula I, as defined in any of the claims 1 - 1 6, as a drug substance 42. The use of a cyclised oligomer of the general formula II, as defined in any of the claims 1 7-32 as a drug substance.

43. A composition comprising a compound of the general formula I as defined in any of the claims 1 -1 6.

44. A composition comprising a compound of the general formula II as defined in any of the claims 1 7-32.

45. A composition according to claim 43 or 44, further comprising a pharmaceutically acceptable carrier and one or more pharmaceutically acceptable excipients.

Claims

AMENDED CLAIMS

[received by the International Bureau on 30 November 1998 (30.11.98); original claims 1-45 replaced by amended claims 1-43 (7 pages)] 1. An oligomer ofthe general formula I

(in short K-C(=O)-M₀-...-M_n-T, wherein M₀, ..., MΓÇ₧ designate "piperidine monomers") wherein n is a positive integer;

K-(C=0)- is a carboxylic acid or a derivative thereof;

T is selected from hydrogen, optionally substituted C|_-2o-alkyl, optionally substituted C╬╣_-2o- alkoxy, optionally substituted C╬╣.₂o-alkylcarbonyl, optionally substituted aryl, optionally substituted heteroaryl, and amino-protecting groups; and each of X⁰,..., and X" independently designates 1 -5, preferably 1-4, such as 1-3, substituents, where

(a) such optional substituents independently are selected from optionally substituted C╬╣_-2o- alkyl, optionally substituted C₂-₂o-alkenyl, optionally substituted C₄_₂o-alkadienyl, optionally substituted C₆.₂o-alkatrienyl, optionally substituted C₂-₂o-alkynyl, hydroxy, C╬╣.₂₀-alkoxy, C₂-₂₀- alkenyloxy, carboxy, oxo, C╬╣.₂o-alkoxycarbonyl, C|.₂o-alkylcarbonyl, formyl. aryl, aryloxycarbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxycarbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(C╬╣_₆-alkyl)amino, carbamoyl, mono- and di(C|.₆- alkyl)aminocarbonyl, amino-C╬╣.₆-alkyl-aminocarbonyl, mono- and di(C╬╣_₆-alkyl)amino-C]_₆- alkyl-aminocarbonyl, C╬╣_-6-alkylcarbonylamino, guanidino, carbamido, C╬╣_₆-alkanoyloxy, sulphono, C╬╣.₆-alkylsulphonyloxy, nitro, sulphanyl, C╬╣_6-alkylthio, and halogen, where aryl and heteroaryl may be optionally substituted; and/or

(b) two substituents on two adjacent carbon atoms together with said two adjacent carbon atoms may designate (i) a fused optionally substituted aromatic or non-aromatic carbocyclic or heterocyclic ring, or (ii) a double bond; provided that at least one of each X⁰,... and Xⁿ is selected from hydroxy, hydroxymethyl and carboxy or an acid addition salt or a basic salt thereof.

2. An oligomer according to claim 1, wherein n is in the range of 1-25, preferably 1-15, in particular 2-10 such as 2-5 or 3-6.

3. An oligomer according to any of the preceding claims, wherein K- is selected from hydrogen, NH₂, NHR, NRR', N(OH)H, NHNH₂, NHNHR"^*, and OR", where each of R, R', R", and R'" independently designates optionally substituted C╬╣.₆-alkyl, optionally substituted C₂-₆-alkenyl, optionally substituted aryl, or optionally substituted heteroaryl.

4. An oligomer according to any of the preceding claims, wherein K- designates OH, OR", NH , NHR, or NRR', where R and R' are selected from C╬╣_₆-alkyl and benzyl, and R" is selected from C╬╣_₆-alkyl, C₂.6-alkenyl, phenyl, and benzyl; in particular K- designates OH, methoxy, or NH₂.

5. An oligomer according to any of the preceding claims, wherein T is selected from hydrogen, optionally substituted C╬╣-₆-alkyl, optionally substituted C╬╣-₆-alkoxy, optionally substituted C].6-alkylcarbonyl, optionally substituted aryl, optionally substituted heteroaryl, tert-butoxycarbonyl (Boc), and fluorenylmethoxycarbonyl (Fmoc).

6. An oligomer according to any of the preceding claims, wherein T is selected from hydrogen; C╬╣.6-alkyl which may be substituted with 1-3, preferable 1-2, substituents selected from hydroxy, C_]-6-alkoxy, carboxy, aryl, heteroaryl, amino, mono- and di(C₁.₆-alkyl)amino, and halogen, where aryl may be substituted 1-3 times with C_1-4-alkyl, C^-alkoxy, nitro, cyano, amino or halogen; Q-╬▓-alkoxy; C╬╣.₆-alkylcarbonyl; amino-C╬╣_₆-alkylcarbonyl; aryl which may be substituted with 1-3, preferably 1-2 substituents selected from C_]-4-alkyl, C_]-4- alkoxy, nitro, cyano, amino, and halogen; and heteroaryl which may be substituted with 1-3, preferably 1-2 substituents selected from C_M-alkyl, C].₄-alkoxy, nitro, cyano, amino, and halogen.

7. An oligomer according to any of the preceding claims, wherein T is selected from hydrogen; C╬╣.6-alkyl; benzyl, C╬╣.₆-alkylcarbonyl; and aryl which may be substituted with 1-3, preferably 1-2 substituents selected from C^-alkyl, C^-alkoxy, nitro, cyano, amino, and halogen.

8. An oligomer according to any of the preceding claims, wherein each of X⁰,..., and X" independently designates 1 -3 substituents, where

(a) such optional substituents are selected from optionally substituted C╬╣_-6-alkyl, optionally substituted C₂.6-alkenyl, hydroxy, C╬╣_₆-alkoxy, C₂-₆-alkenyloxy, carboxy, oxo, C╬╣.₆-alkoxy- carbonyl, C╬╣.₆-alkylcarbonyl, formyl, aryl, aryloxycarbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxycarbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(C|_6- alkyl)amino; carbamoyl, mono- and di(C╬╣-₆-alkyl)aminocarbonyl, C╬╣.₆-alkylcarbonylamino, sulphono, C╬╣.₆-alkanoyloxy, and halogen, where aryl and heteroaryl may be optionally substituted with 1-3, preferably 1-2 substituents selected from C_M-alkyl, C╬╣-₄-alkoxy, nitro. cyano, amino, and halogen; and/or

9. An oligomer according to any of the preceding claims, wherein each of X┬░, ..., and X" independently designates 1-3 substituents, where such optional substituents are selected from C╬╣.₆-alkyl which may be substituted with 1-3, preferable 1-2, substituents selected from hydroxy, C╬╣.₆-alkoxy, carboxy, aryl, heteroaryl, amino, mono- and di(C╬╣.₆-alkyl)amino, and halogen, where aryl may be substituted 1-3 times with C_M-alkyl, C╬╣.₄-alkoxy, nitro, cyano, amino or halogen; C₂-₆-alkenyl; hydroxy; C╬╣.₆-alkoxy; C₂-₆-alkenyloxy; carboxy; C|.₆- alkoxycarbonyl; C╬╣_₆-alkylcarbonyl; formyl; amino; mono- and di(C╬╣.₆-alkyl)amino; carbamoyl; mono- and di(C╬╣.6-alkyl)aminocarbonyl; C╬╣.₆-alkylcarbonylamino; sulphono, C_1-6- alkanoyloxy; and halogen such as fluoro or chloro.

10. An oligomer according to claim 8, wherein each of X┬░, ..., and X" independently designates 1-2 substituents, where such optional substituents are selected from C_1-6-alkyl which may be substituted with a substituent selected from hydroxy, C╬╣.₆-alkoxy, aryloxy, and carboxy, where aryl may be substituted 1-3 times with C╬╣_₄-alkyl, C╬╣_₄-alkoxy, nitro, cyano, amino or halogen; hydroxy; C╬╣.₆-alkoxy; C₂-6-alkenyloxy; carboxy; C╬╣_₆-alkoxycarbonyl; amino; mono- and di(C|.₆-alkyl)amino; mono- and di(C╬╣_₆-alkyl)aminocarbonyl; and C|.₆- alkylcarbonylamino.

1 1. An oligomer according to claim 8, wherein each of X┬░, ..., and Xⁿ independently designates 1-2 substituents, where such substituents are selected from C╬╣_-6-alkyI which may be substituted with a substituent selected from hydroxy, C╬╣.₆-alkoxy, aryloxy, and carboxy; hydroxy; C].₆-alkoxy; carboxy; and C].₆-alkoxycarbonyl.

12. An oligomer according to any of the preceding claims, wherein in at least one of each of X┬░, ..., and Xⁿ is selected from hydroxy and hydroxymethyl.

13. An oligomer according to any of the preceding claims, comprising monomer fragments (Mo, .... MΓÇ₧) of the general formulae M^2S, M^2R, M ^R, M^3S and/or M⁴

M 2S

M 3R ur

M^2R _M S wherein each of the substituents R², R^2', R³, R^3', R⁴, R^4', R⁵, R⁵, R⁶, and R^6' independently is as defined for X┬░, ..., and Xⁿ.

14. An oligomer according to claim 13, wherein each of the monomer fragments resembles a substitution pattern similar to that of a monosaccharide selected the xylose, fucose, galactose, glucose, mannose, glucosamine, galactosamine, and sialic acid (neuraminic acid).

15. A cyclised oligomer of the general formula II

(in short K-C(=O)-M₀-...-M_n-W, wherein Mo, ..., MΓÇ₧ designate "piperidine monomers" and W designates the biradical -Y^a-Y^b-) wherein n is a positive integer;

K-(C=0)- is a carboxylic acid or a derivative thereof;

Y^a and Y^b together designate a linear biradical (-Y^a-Y^b-) comprising 1-20 backbone atoms; each of X⁰,..., and X" independently designates 0-5, preferably 0-4, such as 0-3, substituents, where

(a) such optional substituents independently are selected from optionally substituted C|.₂₀- alkyl, optionally substituted C₂-₂o-alkenyl, optionally substituted C₄. o-alkadienyl, optionally substituted C₆.₂o-alkatrienyl, optionally substituted C₂-₂o-alkynyl, hydroxy, C^o-alkoxy, C_2-2o- alkenyloxy, carboxy, oxo, C╬╣.₂o-alkoxycarbonyl, C|.₂o-alkylcarbonyl, formyl, aryl, aryloxycarbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxycarbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(C|.₆-alkyl)amino; carbamoyl, mono- and di(C|_6- alkyl)aminocarbonyl, amino-C╬╣_-6-alkyl-aminocarbonyl, mono- and di(C╬╣_6-alkyl)amino-C╬╣.₆- alkyl-aminocarbonyl, C|_6-alkylcarbonylamino, guanidino, carbamido, C╬╣.6-alkanoyloxy, sulphono, C╬╣-₆-alkylsulphonyloxy, nitro, sulphanyl, C╬╣_₆-alkylthio, and halogen, where aryl and heteroaryl may be optionally substituted; and/or

(b) two substituents on two adjacent carbon atoms together with said two adjacent carbon atoms may designate (i) a fused optionally substituted aromatic or non-aromatic carbocyclic or heterocyclic ring, or (ii) a double bond; or an acid addition salt or a basic salt thereof.

16. A cyclised oligomer according to claim 15, wherein the linear biradical (-Y^a-Y^b-) is selected from -C(=0)-NH-(CH₂)_m-C(=0)-, -NH-C(=0)-(CH₂)_m-C(=0)-, -C(=0)-NH-(CH₂)_m- , -NH-C(=0)-(CH2)m-, wherein m is 1-20, preferably 2-12, especially 3-10, in particular 3-8, and wherein any of the methylene groups may be substituted with hydroxy, C╬╣.₆-alkyl, C^- alkoxy, carboxy, C╬╣.₆-alkoxycarbonyl, C╬╣.₆-alkylcarbonyl, aryl optionally substituted 1-3 times with C|.₄-alkyl, C -alkoxy, nitro, cyano, amino or halogen, amino, mono- and di(C]_₆- alkyl)amino, and halogen.

17. A cyclised oligomer according to claim 16, wherein the linear biradical is -C(=0)-NH- (CH₂)_m-C(=0)-.

18. A cyclised oligomer according to any of the claims 15-17, wherein n is in the range of 1- 25, preferably 1-15, in particular 2- 10 such as 2-5 or 3-6.

19. A cyclised oligomer according to any of the claims 15-18, wherein K- is selected from hydrogen, NH₂, NHR, NRR', N(OH)H, NHNH₂, NHNHR"*, and OR", where each of R, R', R", and R'" independently designates optionally substituted C╬╣_₆-alkyl, optionally substituted C₂-₆-alkenyl, optionally substituted aryl, or optionally substituted heteroaryl.

20. A cyclised oligomer according to any of the claims 15-19, wherein K. designates OH, 0^~, OR", NH₂, NHR, or NRR', where R and R' are selected from C,.₆-alkyl and benzyl, and R" is selected from C|_₆-alkyl, C₂-₆-alkenyl, phenyl, and benzyl; in particular K designates OH, methoxy, or NH .

21. A cyclised oligomer according to any of the claims 15-20, wherein each of X⁰,.--, and X" independently designates 0-3 substituents, where (a) such optional substituents are selected from optionally substituted C|.₆-alkyl, optionally substituted C₂-₆-alkenyl, hydroxy, C╬╣_₆-alkoxy, C₂-6-alkenyloxy, carboxy, oxo, C╬╣.₆- alkoxycarbonyl, C].₆-alkylcarbonyl, formyl, aryl, aryloxycarbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxycarbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(C╬╣.₆-alkyl)amino; carbamoyl, mono- and di(C╬╣.₆-alkyl)aminocarbonyl, C|.₆-alkylcarbony- la ino. sulphono, C╬╣.₆-alkanoyloxy, and halogen, where aryl and heteroaryl may be optionally substituted with 1-3, preferably 1-2, substituents selected from C -alkyl, C_M- alkoxy. nitro, cyano, amino, and halogen; and/or

22. A cyclised oligomer according to any of the claims 15-21, wherein each of X┬░, .... and Xⁿ independently designates 0-3 substituents, where such optional substituents are selected from C|.₆-alkyl which may be substituted with 1-3, preferable 1-2, substituents selected from hydroxy, C|.₆-alkoxy, carboxy, aryl, heteroaryl, amino, mono- and di(C|.₆-alkyl)amino, and halogen, where aryl may be substituted 1-3 times with C╬╣-₄-alkyl, C|_₄-alkoxy, nitro, cyano, amino or halogen; C₂-6-alkenyl; hydroxy; C╬╣.₆-alkoxy; C₂.6-alkenyloxy; carboxy; C╬╣.₆- alkoxycarbonyl; C╬╣.₆-alkylcarbonyl; formyl; amino; mono- and di(C╬╣.₆-alkyl)amino; carbamoyl; mono- and di(C╬╣.₆-alkyl)aminocarbonyl; C╬╣.₆-alkylcarbonylamino; sulphono, C|_₆- alkanoyloxy; and halogen such as fluoro or chloro.

23. An oligomer according to claim 22, wherein each of X┬░, ..., and X" independently designates 0-2 substituents, where such optional substituents are selected from C|.₆-alkyl which may be substituted with a substituent selected from hydroxy, C].₆-alkoxy, aryloxy, and carboxy, where aryl may be substituted 1-3 times with C^-alkyl, C -alkoxy, nitro, cyano, amino or halogen; hydroxy; C|_6-alkoxy; C₂-₆-alkenyloxy; carboxy; C╬╣.₆-alkoxycarbonyl; amino: mono- and di(C|.₆-alkyl)amino; mono- and di(C╬╣_₆-alkyl)aminocarbonyl; and C|_₆- alkylcarbonylamino.

24. An oligomer according to claim 22, wherein each of X┬░, ..., and X" independently designates 1-2 substituents, where such substituents are selected from C|.₆-alkyl which may be substituted with a substituent selected from hydroxy, C╬╣.₆-alkoxy, aryloxy, and carboxy; hydroxy; C╬╣_₆-aIkoxy; carboxy; and C╬╣_₆-alkoxycarbonyl.

25. An oligomer according to any of the claims 15-24, wherein in at least one of each of X┬░, ..., and X" is selected from hydroxy, hydroxymethyl and carboxy.

26. An oligomer according to any of the claims 15-25, wherein in at least one of each of X┬░, ..., and X" is selected from hydroxy and hydroxymethyl.

27. A cyclised oligomer according to any of the claims 15-26, comprising monomer ffrraaggmmeenntts (M₀, ..., M_n) of the general formulae M^2S, M^2R, M^3R, M^3S and/or M^c4 as defined in claim 9.

28. An oligomer according to claim 27, wherein each of the monomer fragments resembles a substitution pattern similar to that of a monosaccharide selected the xylose, fucose, galactose, glucose, mannose, glucosamine, galactosamine, and sialic acid (neuraminic acid).

29. An oligomer according to claim 27 or 28, wherein at least one of R², R² , R³, R³ , R⁴, R⁴ , R⁵, R\ R⁶, and R⁶ is selected from hydroxy, hydroxymethyl and carboxy.

30. A method for the preparation of an oligomer of the general formula I (K-C(=0)-Mo-...- M_n-T, where Mo, ..., M_n designate "piperidine monomers") as defined in any of the claims 1- 10, comprising the following steps:

(a) providing an optionally functional group protected oligomer -C(=O)-M₀-...-M_n-T immobilised to a solid support material; and

(b) cleaving the oligomer K-C(=O)-M₀-...-M_n-T from the solid support material, the step optionally including deprotection of one or more functional group(s) of the oligomer.

31. A method for the preparation of a cyclised oligomer of the general formula II (K-C(=0)- M₀-...-M_n-W, where M₀, ..., M_n designate "piperidine monomers" and W designates the biradical -Y^a-Y^b-) as defined in any of the claims 1 1-18, comprising the following steps:

(a) providing an optionally functional group protected oligomer -C(=O)-M₀-...-M_n-W immobilised to a solid support material; and

(b) cleaving the oligomer K-C(=O)-M₀-...-M_n-W from the solid support material, the step optionally including deprotection of one or more functional group(s) of the oligomer.

32. A method for the preparation of an array of oligomers (K-C(=O)-{M₀}-...-{M_n}-{T}), consisting of at least four oligomers each having the general formula I as defined in any of the claims 1-14, the method comprises the following steps:

(a) providing an array of optionally functional group protected oligomers -C(=0)-{Mo}-...- {M_n}-{T} immobilised to a solid support material; and

(b) cleaving the array of oligomers K-C(=O)-{M₀}-...-{M_n}-{T} from the solid support material, the step optionally including deprotection of one or more functional group(s) of the oligomer.

33. A method for the preparation of an array of cyclised oligomers (K-C(=O)-{M₀}-...-{M_n}- { W}), consisting of at least four oligomers each having the general formula II as defined in any of the claims 15-30, the method comprises the following steps:

(a) providing an array of optionally functional group protected cyclised oligomers -C(=0)- {Mo}-...-{M_n}-{W} immobilised to a solid support material; and

(b) cleaving the array of cyclised oligomers K-C(=O)-{M₀}-...-{M_n}-{W} from the solid support material, the step optionally including deprotection of one or more functional group(s) of the cyclised oligomer.

34. The use of an array of oligomers of the general formula I for screening of the biological activity or effect of a plurality of oligomers of the general formula I comprised within said array, wherein the oligomers are as defined in any of the claims 1-14.

35. The use according to claim 34, wherein the array comprises 6-200 oligomers of the general formula I, preferably 6-100 different oligomers, and in particular 8-64 different oligomers.

36. The use of an array of oligomers of the general formula II for screening of the biological activity or effect of a plurality of oligomers of the general formula II comprised within said array, wherein the oligomers are as defined in any of the claims 15-30.

37. The use according to claim 36. wherein the array comprises 6-200 oligomers of the general formula II, preferably 6-100 different oligomers, and in particular 8-64 different oligomers.

38. A composition comprising at least two compounds of the general formula I and/or II as defined in the claims 1-30.

39. The use of an oligomer of the general formula I, as defined in any of the claims 1-14, as a drug substance

40. The use of a cyclised oligomer of the general formula II, as defined in any of the claims 15-30 as a drug substance.

41. A composition comprising a compound of the general formula I as defined in any of the claims 1-14.

42. A composition comprising a compound of the general formula II as defined in any of the claims 15-30.

43. A composition according to claim 41 or 42, further comprising a pharmaceutically acceptable carrier and one or more pharmaceutically acceptable excipients.