AU8334498A - Piperidine oligomers and combinatorial libraries thereof - Google Patents

Description

WO 99/03832 PCT/DK98/00330 1 PIPERIDINE OLIGOMERS AND COMBINATORIAL LIBRARIES THEREOF FIELD OF THE INVENTION The present invention relates to piperidine oligomers, methods for the preparation of 5 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 10 Cell surface oligosaccharides play an important, though often little understood, role in cell recognition and adhesion processes (Keilhauer, K. L. et al; Nature 316 (1985) 728; Hoffman, S. et al; Proc. Natl. Acad. Sci. USA 80 (1983) 5762; Springer, T. A. et al; Nature 346 (1990) 425; and Brandley, B. K. et al; Cell 63 (1990) 861), virus (including HIV) infectivity (Brandley, B. K. et al; Cell 63 (1990) 861), lymphocyte 15 homing and migration (Montefiori, D. C. et al; Proc. Natl. Acad. Sci. USA 85 (1988) 9248 and Yednock, T: A. et al; 104 (1987) 713), tumor metastasis (Stoolman, L. M. 56 (1989) 907; Dennis, J. W. et al; 236 (1987) 582; and Benedetto, A. et al; 43 (1989) 126) and many other disorders. Synthetic oligosaccharides could potentially be of great value both for study of these phenomena but also as therapeutics. Thus, a 20 synthetic oligosaccharide could be used to, by binding to a certain complementary oligosaccharide 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 25 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. 30 oligosaccharide 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.

WO 99/03832 PCT/DK98/00330 2 DESCRIPTION OF THE INVENTION Construction of the compounds of the general formula I and II 5 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 10 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 15 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 20 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 25 aspect of the present invention. The oligomers according to the present invention are either "linear" oligomers of the general formula I O/

X

0 K Xn N I NT n WO 99/03832 PCT/DK98/00330 3 (in short K-C(= O)-Mo-...-Mn-T, wherein M 0 , ... , Mn designate the individual "piperidine monomers") or "cyclised" oligomers of the general formula II /0 X 0 K 0 Xn N N Y ° N- II Ya n 5 (in short K-C(= O)-Mo-...-Mn-W, wherein M 0 , ... , Mn designate the individual "piperidine monomers" and W designates the biradical -Ya-Yb-); including acid addition salts and basic salts of these oligomers. With reference to the method for the preparation of the oligomers, the piperidine 10 carrying the cumulative substituent X 0 is called the "first monomer" and the piperidine carrying the substituent T (formula I) or the substituent yb (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". 15 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 20 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(= O)- in the general formulae I and II (the substituent on the first 25 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(= O)-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 30 acid form (-COOH; K=OH) or in the carboxylate form (-COO-; K= 0-), where the WO 99/03832 PCT/DK98/00330 4 counter ion is selected from alkali metals, such as sodium and potassium, alkaline earth metals, such as calcium, and ammonium ions (N(R) 3 R'), or is derivatised as the amide (-CONH 2 , -CONHR, -CONRR'; K= NH 2 , NHR, NRR', respectively), the hydroxylamide (-CON(OH)H; K=N(OH)H), the hydrazide (-CONHNH 2 , CONHNHR"'; 5 K= NHNH 2 , NHNHR"', respectively) or the ester (-COOR"; K=OR"), where each of R, R', R", and R'" independently designates optionally substituted C 1

_

6 -alkyl, optionally substituted C 2

-

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, 10 OR", NH 2 , NHR, or NRR', in particular OH, methoxy, or NH 2 , where R and R' are selected from Cl 6 -alkyl and benzyl, and R" is selected from Cl6-alkyl, C 2

-

6 -alkenyl, phenyl, and benzyl. It should be understood that the situation where K designate O- 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 15 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 1

-

20 -alkyl, optionally substituted C 1

-

2 0 -alkoxy, optionally substituted C 1

-

20 -alkylcarbonyl, optionally substituted aryl, optionally 20 substituted heteroaryl, and amino-protecting groups. Preferred meanings of T are hydrogen, optionally substituted C_ 6 -alkyl, optionally substituted C, 6 -alkoxy, optionally substituted Cl 6 .e-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 25 of the oligomer. Especially preferred meanings of T are hydrogen; C 1

-

6 -alkyl which may be substituted with 1-3, preferable 1-2, substituents selected from hydroxy, C 1

,

alkoxy, carboxy, aryl, heteroaryl, amino, mono- and di(Cl_ 6 -alkyl)amino, and halogen, where aryl may be substituted 1-3 times with Cl 4 -alkyl, Cl_ 4 -alkoxy, nitro, cyano, amino or halogen; Cl_ 6 -alkoxy; Cl_ 6 -alkylcarbonyl; amino-C.

6 -alkylcarbonyl; aryl which 30 may be substituted with 1-3, preferably 1-2 substituents selected from Cl 4 -alkyl, C 14 alkoxy, nitro, cyano, amino, and halogen; and heteroaryl which may be substituted with 1-3, preferably 1-2 substituents selected from C.

4 -alkyl, C 1

-

4 -alkoxy, nitro, cyano, amino, and halogen. Particularly interesting embodiments are those where T is selected from hydrogen; Cl-e-alkyl; benzyl, C 1 6 -alkylcarbonyl; and aryl which may be WO 99/03832 PCT/DK98/00330 5 substituted with 1-3, preferably 1-2 substituents selected from C1- 4 -alkyl, C 1

_

4 -alkoxy, nitro, cyano, amino, and halogen. In the general formula II, ya and yb together designate a linear biradical (-ya yb-, which 5 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 10 linear biradicals are given further above, however, it is believed that linear biradicals ( ya._yb_) selected from -C(= O)-NH-(CH2)m-C(= O)-, -NH-C(= O)-(CH 2 )m-C(= O)-, -C(= O)

NH-(CH

2 )m-, -NH-C(=0O)-(CH 2 )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, C1- 6 -alkyl, C1- 6 -alkoxy, carboxy, C.

6 -alkoxycarbonyl, C 1 ~ -6-alkylcarbonyl, aryl 15 optionally substituted 1-3 times with C.

4 -alkyl, C 1

_

4 -alkoxy, nitro, cyano, amino or halogen, amino, mono- and di(Cl_ 6 -alkyl)amino, and halogen, are especially relevant. An especially preferred linear biradical is-C(= O)-NH-(CH 2 )m-C(= O)-, where m is as defined above, which arises when a piperidine dicarboxylic acid is used as the "first monomer" in the oligomer and a o-amino carboxylic acid is used as a linker between 20 the "last monomer" and the "first monomer". In the general formulae I and II, each of the "cumulative" substituents Xo,..., 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 25 already carboxy substituted piperidine monomers. As indicated above, each of the "cumulative" substituents Xo,..., 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): 30 (a) such optional substituents independently are selected from optionally substituted

C

1

-

20 -alkyl, optionally substituted C 2

-

20 -alkenyl, optionally substituted C 4

-

20 -alkadienyl, optionally substituted C 6

-

20 -alkatrienyl, optionally substituted C 2

-

20 -alkynyl, hydroxy, C 1 20 -alkoxy, C 2

-

20 -alkenyloxy, carboxy, oxo, C 1

-

20 -alkoxycarbonyl, C 1

-

20 -alkylcarbonyl, formyl, aryl, aryloxycarbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxycarbonyl, WO 99/03832 PCT/DK98/00330 6 heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(C 1

-

6 -alkyl)amino, carbamoyl, mono- and di(Cl_ 6 -alkyl)aminocarbonyl, amino-Cl_ 6 -alkyl-aminocarbonyl, mono- and di(Cl_ 6 -alkyl)amino-Cl_ 6 -alkyl-aminocarbonyl, Cl_ 6 -alkylcarbonylamino, guanidino, carbamido, Cl 6 -alkanoyloxy, sulphono, C 1

.

6 -alkylsulphonyloxy, nitro, sulphanyl, C 16 5 alkylthio, trihalogen-C 1

-

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 10 aromatic carbocyclic or heterocyclic ring, or (ii) a double bond. In a preferred embodiment, each of Xo..... and X n independently designates 0-3 substituents, where 15 (a) such optional substituents are selected from optionally substituted C1- 6 -alkyl, optionally substituted C 2

-

6 -alkenyl, hydroxy, C1- 6 -alkoxy, C 2

-

6 -alkenyloxy, carboxy, oxo, Cl- 6 -alkoxycarbonyl, C_ 6 -alkylcarbonyl, formyl, aryl, aryloxycarbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxycarbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(Cl.

6 -alkyl)amino; carbamoyl, mono- and di(Cl_ 6 -alkyl)amino 20 carbonyl, Cl_ 6 -alkylcarbonylamino, sulphone, C 1 6 -alkanoyloxy, and halogen, where aryl and heteroaryl may be optionally substituted with 1-3, preferably 1-2 substituents selected from C 1

-

4 -alkyl, C 1

.

4 -alkoxy, nitro, cyano, amino, and halogen; and/or (b) two substituents on two adjacent carbon atoms together with said two adjacent 25 carbon atoms may designate a double bond. In an especially preferred embodiment each of X 0 , ..., and X"independently designates 0-3 substituents, where such optional substituents are selected from C 1 .6-alkyl which may be substituted with 1-3, preferable 1-2, substituents selected from hydroxy, C1- 6 30 alkoxy, carboxy, aryl, heteroaryl, amino, mono- and di(Cl 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 2

-

6 -alkenyl; hydroxy; C 1

_

6 -alkoxy; C 2

-

6 -alkenyloxy; carboxy; C 1 6 alkoxycarbonyl; Cl_ 6 -alkylcarbonyl; formyl; amino; mono- and di(Cle-alkyl)amino; carbamoyl; mono- and di(C 1 l 6 -alkyl)aminocarbonyl; Cl_ 6 -alkylcarbonylamino; sulphono, WO 99/03832 PCT/DK98/00330 7 Cl 6 -alkanoyloxy; and halogen such as fluoro or chloro. In an even more preferred embodiment, 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 5 may be substituted 1-3 times with C 1

-.

4 -alkyl, C 1

.

4 -alkoxy, nitro, cyano, amino or halogen; hydroxy; Cl_ 6 -alkoxy; C 2

-

6 -alkenyloxy; carboxy; C 1

.

6 -alkoxycarbonyl; amino; mono- and di(C.

6 -alkyl)amino; mono- and di(C 1

-

6 -alkyl)aminocarbonyl; and C- 6 -alkyl carbonylamino. A still more preferred embodiment is where each of X 0 , ... , and Xn independently designates 1-2 substituents, where such substituents are selected from 10 C 1

_

6 -alkyl which may be substituted with a substituent selected from hydroxy, C 6 alkoxy, aryloxy, and carboxy; hydroxy; C 1

.

6 -alkoxy; carboxy; and C 1 6 -alkoxycarbonyl. 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 15 mimic. Thus, in a preferred embodiment of the present invention, at least one of each of X, ... , and X" is selected from hydroxy, hydroxymethyl and carboxy, in particular at least one of each of X 0 , ... , and Xn is selected from hydroxy and hydroxymethyl. In particular, the monomer fragments constituting the oligomers according to the 20 present invention, can be represented by the following general formulae M 2 S, M 2 R, M 3 R,

M

3 S and/or M 4 WO 99/03832 PCT/DK98/00330 8 R3 R3' O O0 R22' R3 3 2 2'

R

3

R

3

R

3 R R 4' N--- R4' R4R O Rs: 5 6 R 5 R, Re 5 R

M

2 S M 3 R M 4 3 '-O O R 2

R

3 , R 2 4- 'N_...R R4

R

5 R R 5 R

M

2 R M3S wherein each of the substituents R 2 , R 2 , R 3 , R 3 ', R 4 , R 4 ', R, R 5' , R 6 , and R 6 ' independently is as defined for Xo, ... , and X n. 5 Particularly interesting variants of the monomer fragments M 2 S, M 2 R, M 3 R, M3S and M 4 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 sialic acid (neuraminic acid). It should be understood that the oligomers are so constructed that 10 the amide bond between the individual piperidine rings mimics the glycosylic bond between the individual rings in a corresponding oligosaccharide. Thus, in the case where a dimer according to the invention is intended to mimic, e.g., (+)-maltose (u anomer), the dimer may, e.g., be selected so that the first monomer is of the type M 3 R carrying substituents in at least some of the positions R 4 ' , R 5 , and R 6' (with the 15 possibility of a substituent in R2'), and the second (and last) monomer is of the type

M

3 S carrying substituents in at least some of the positions R 2 , R 4 , R 1 5' , and R 6' . As above, preferred embodiments are those where at least one of R 2 , R 2 , R, R, R ,

R

4' , R5, R 5 ', R 6 , and R 6 " is selected from hydroxy, hydroxymethyl and carboxy, in 20 particular hydroxy and hydroxymethyl.

WO 99/03832 PCT/DK98/00330 9 Interesting monomers within the present invention are illustrated in Figure 8. Definitions 5 In the present context, the term "C 1

-

2 0 -alkyl" is intended to mean a linear, cyclic or branched hydrocarbon group having 1 to 20 carbon atoms, such as methyl, ethyl, propyl, iso-propyl, cyclopropyl, butyl, tert-butyl, iso-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, hexadecyl, heptadecyl, octadecyl, nonadecyl. 10 Analogously, the term "Cl_ 6 -alkyl" is intended to mean a linear, cyclic or branched hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, iso propyl, pentyl, cyclopentyl, hexyl, cyclohexyl, and the term "Cl.

4 -alkyl" is intended to cover linear, cyclic or branched hydrocarbon groups having 1 to 4 carbon atoms, e.g. methyl, ethyl, propyl, iso-propyl, cyclopropyl, butyl, iso-butyl, tert-butyl, cyclobutyl. 15 Preferred examples of "C 1

.

6 -alkyl" are methyl, ethyl, propyl, iso-propyl, butyl, tert butyl, iso-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl, in particular methyl, ethyl, propyl, iso-propyl, tert-butyl, iso-butyl and cyclohexyl. Preferred examples of "C 1

-

4 alkyl" are methyl, ethyl, propyl, iso-propyl, butyl, tert-butyl,,and iso-butyl. 20 Similarly, the terms "C 2

-

20 -alkenyl", "C 4

-

20 -alkadienyl", and "C 6

-

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, 25 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. 30 Similarly, the term "C 2

-

2 0 -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.

WO 99/03832 PCT/DK98/00330 10 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 5 carbon atom may be present in the tautomeric keto form), C 1

.

6 -alkoxy (i.e. C 1

.

6 -alkyl oxy), C 2

-

6 -alkenyloxy, carboxy, oxo (forming a keto or aldehyde functionality), C 1

-

6 alkoxycarbonyl, C 1

_

6 -alkylcarbonyl, formyl, aryl, aryloxycarbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxycarbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono and di(Cl_ 6 -alkyl)amino; carbamoyl, mono- and di(Cl- 6 -alkyl)aminocarbonyl, amino-C 1

,

6 10 alkyl-aminocarbonyl, mono- and di(C_ 6 e-alkyl)amino-Cie-alkyl-aminocarbonyl, C 1 -6-alkyl carbonylamino, cyano, guanidino, carbamido, Cl 6 -alkanoyloxy, sulphono, C 1 6 alkylsulphonyloxy, nitro, sulphanyl, C 1

-

6 -alkylthio, halogen, where any aryl and heteroaryl may be substituted as specifically describe below for "optionally substituted aryl and heteroaryl". 15 "Halogen" includes fluoro, chloro, bromo, and iodo. Preferably, the substituents are selected from hydroxy, C 1

,

6 -alkoxy, carboxy, C16 alkoxycarbonyl, Cl 6 -alkylcarbonyl, formyl, aryl, aryloxycarbonyl, arylcarbonyl, 20 heteroaryl, amino, mono- and di(Cl.

6 -alkyl)amino, carbamoyl, mono- and di(C 1

.

6 -alkyl) aminocarbonyl, amino-C 1

.

6 -alkyl-aminocarbonyl, mono- and di(C 1 6 -alkyl)amino-C.

6 alkyl-aminocarbonyl, Cl 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 1 25 6 -alkoxy, carboxy, aryl, heteroaryl, amino, mono- and di(Cl.

6 -alkyl)amino, and halogen, where aryl and heteroaryl may be substituted 1-3 times with Cl 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 30 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.

WO 99/03832 PCT/DK98/00330 11 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, 5 imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, piperidinyl, coumaryl, furyl, quinolyl, benzothiazolyl, benzotriazolyl, benzodiazolyl, benzooxozolyl, phthalazinyl, phthalanyl, triazolyl, tetrazolyl, isoquinolyl, acridinyl, carbazolyl, dibenzazepinyl, indolyl, benzopyrazolyl, phenoxazonyl. 10 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), C1-6-alkyl, C 1 6 -alkoxy, oxo (which may be 15 represented in the tautomeric enol form), carboxy, C 1

-

6 -alkoxycarbonyl, C 1

_

6 alkylcarbonyl, formyl, aryl, aryloxy, aryloxycarbonyl, arylcarbonyl, heteroaryl, amino, mono- and di(Cl_ 6 -alkyl)amino; carbamoyl, mono- and di(C.

6 -alkyl)aminocarbonyl, amino-C 1

_

6 -alkyl-aminocarbonyl, mono- and di(C,- 6 -alkyl)amino-Cl 6 -alkyl-aminocarbonyl, Cl- 6 -alkylcarbonylamino, cyano, guanidino, carbamido, C_ 6 -alkanoyloxy, sulphono, C 1

.

6 20 alkylsulphonyloxy, nitro, sulphanyl, dihalogen-Cl_ 4 -alkyl, trihalogen-C 1

.

4 -alkyl, halogen, where aryl and heteroaryl representing substituents may be substituted 1-3 times with

C

1

_

4 -alkyl, C 1

-

4 -alkoxy, nitro, cyano, amino or halogen. Preferred examples are hydroxy, Cl- 6 -alkyl, Cl- 6 -alkoxy, carboxy, C 1

.

6 -alkoxycarbonyl, C.6-alkylcarbonyl, aryl, amino, mono- and di(Cl_ 6 -alkyl)amino, and halogen, wherein aryl may be substituted 1-3 times 25 with C,- 4 -alkyl, Cl.

4 -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 30 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, WO 99/03832 PCT/DK98/00330 12 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, 5 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 10 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 15 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 20 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 25 interrupted and/or terminated by one or more heteroatoms selected from O, S, and NRN where RN is selected from hydrogen and C 14 -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

-

6 -alkyl, optionally substituted C 2 -6-alkenyl, hydroxy, oxo (thereby forming a keto functionality), Cl_ 6 -alkoxy, C 2

-

6 -alkenyloxy, 30 carboxy, Cl 6 -alkoxycarbonyl, Cl 6 -alkylcarbonyl, formyl, aryl, aryloxycarbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxycarbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(Cl.

6 -alkyl)amino; carbamoyl, mono- and di(C 1

-

6 -alkyl)amino carbonyl, Cl_ 6 -alkylcarbonylamino, cyano, Cl_ 6 -alkanoyloxy, trihalogen-C 1

_

4 -alkyl, halogen such as fluoro, chloro, bromo or iodo, where aryl and heteroaryl may be WO 99/03832 PCT/DK98/00330 13 optionally substituted 1-3 times with Cl_ 4 -alkyl, Cl_ 4 -alkoxy, nitro, cyano, amino or halogen. In the present context, the term "amino protecting group" is intended to cover groups 5 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 10 benzyloxycarbonyl ((2-CIZ), DDE (Bloomberg, G.B., et al., Tetrahedron Lett. 1993. 34, 4709-4712), monomethoxytrityl (MMT), dimethoxytrityl (DMT), and 9-(9 phenyl)xanthenyl (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 15 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. 20 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. 25 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 30 from alkali metals, such as sodium and potassium, alkaline earth metals, such as calcium, and ammonium ions (+N(R) 3 R', where R and R' independently designates optionally substituted Cl_ 6 -alkyl, optionally substituted C 2

-

6 -alkenyl, optionally substituted aryl, or optionally substituted heteroaryl). Pharmaceutically acceptable salts are, e.g., those described in Remington's Pharmaceutical Sciences, 17. Ed.

WO 99/03832 PCT/DK98/00330 14 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 5 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" 10 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)-Mo-...-Mn-T) as defined above, comprising the following 15 steps: (A) providing an optionally functional group protected oligomer -C(=O)-Mo-...-Mn-T immobilised to a solid support material; and 20 (B) cleaving the oligomer K-C(= O)-Mo-...-M,-T from the solid support material, the step optionally including deprotection of one or more functional group(s) of the oligomer. Step (A): 25 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 30 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, (1993) WO 99/03832 PCT/DK98/00330 15 11065-11133; Fields GB. and Noble RL. Int. J. Pep. Prot. Res. (1990), 161-214; and Bodanszky M. and Bednarek, MA., J. Prot. Chem., (1989), 461-469.) In the present context the term "solid phase material" is intended to comprise solid 5 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 10 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. 15 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, 113-129). PEG-modified resins having similar characteristics are 20 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= NH 2 ) after cleavage with HF or, alternatively, a 25 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 30 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, WO 99/03832 PCT/DK98/00330 16 E.; Jouin, P. and Castro, B. Tetrahedron Lett. 1991, 32, 1967-1970), amino acid fluorides (Carpino, L. A.; Sadat-Aalaee, D.; Chao, H. G. and DeSelms, R. H. J. Am. Chem. Soc.) and HATU (Carpino, L. A. J. Am. Chem. Soc., 1993, 115, 4397-4398; Angell, Y. M.; Garcia-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, 117, 7279-7280), HBTU (Reid, G.E. and R.J. Simpson, Automated Solid-Phase Peptide Synthesis: Use of 2-(1H-Benzotriazol-1lyl)-1,1,3,3, tetramethyluronium Tetrafluoroborate for Coupling of tert-Butyloxycarbonyl Amino Acids. Anal. Biochem. 200 (1992) 301-309), PyBOP (Fr6rot, E., et al., Tetrahedron, 10 1991, 47(2), pp 259-270), and CF 3

-NO

2 -PyBOP (Wijkmans, J.C.H.M., et al, Tetrahedron Lett. 1995, 36(26), pp 4643-4646). As it is desirable that any substituents on the monomers (shown with X 0 ... Xn) remain unaffected by the reaction conditions (i.e. the amide bond formation condition 15 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 WO 99/03832 PCT/DK98/00330 17 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, 1989), oligonucleotide synthesis (see e.g. M.J. Gait, Oligonucleotide Synthesis, IRL Press, 5 1984), oligosaccharide 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 10 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 15 (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 20 (MOM), benzyl ethers or substituted benzyl ethers such as 2,6-dichlorobenzyl (2,6

CI

2 Bzl); 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), 25 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 30 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 WO 99/03832 PCT/DK98/00330 18 or chromatography such as flash chromatography, preparative HPLC or by passing through an ion-exchange column. Step (B): 5 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 10 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 15 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, 20 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)-Mo-...-Mn-W) as defined above, comprising the following steps: 25 (A) providing an optionally functional group protected oligomer -C(=O)-Mo-...-Mn-W immobilised to a solid support material; and (B) cleaving the oligomer K-C(=O)-Mo-...-Mn-W from the solid support material, the 30 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 WO 99/03832 PCT/DK98/00330 19 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. 5 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 o-amino alkyl or alkylcarbonyl substituent on the ring nitrogen of the last monomer. Alternatively, an amino group may be introduced as a 10 further substituent on the first monomer, thereby forming an amide link to the last monomer by means of an o-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 carboxylic acid than the ring nitrogen of the piperidine. 15 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 20 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, 25 693-698, 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 30 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.

WO 99/03832 PCT/DK98/00330 20 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, 5 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 10 be especially relevant when modification of the group K-C(= O)- 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 15 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. 20 (1996), 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), 415, Tetrahedron Lett. (1986), 3205, Tetrahedron Lett (1985), 4981, Phytochemistry (176), 183, Tetrahedron Lett. (1990), 119, Tetrahedron Lett. (1990), 1683, Bull. Kor. Chem. (1995), 985, Biosci. Biotech. 25 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 30 an already immobilised monomer). This can be accomplished by the methods referred to above under "optionally functional group protected".

WO 99/03832 PCT/DK98/00330 21 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. 5 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)-{Mo}-..----{Mn}-{T}), consisting of at least four oligomers each having the general formula I as defined above. The method comprises the following 10 steps: (A) providing an array of optionally functional group protected oligomers -C(= O)-{Mo ...- {Mn}-{T} immobilised to a solid support material; and 15 (B) cleaving the array of oligomers K-C(= O)-{Mo}-...-{M,}-{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 20 of cyclised oligomers (K-C(=O)-{Mo}-...-{Mn}-{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 25 C(= O)-{Mo}-...-{Mn}-{W} immobilised to a solid support material; and (B) cleaving the array of cyclised oligomers K-C(= O)-{Mo}-...-{Mn}-{W} from the solid support material, the step optionally including deprotection of one or more functional group(s) of the cyclised. 30 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 {Mo}, ... , {M}, and {T} (in case of an oligomer of the general formula I) may each WO 99/03832 PCT/DK98/00330 22 comprise one or more monomer variants, thus the set {Mo} 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 5 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 10 ensure that a suitable amount of each of the theoretically obtainable oligomers are formed, the split-mix synthesis method (Furka, A.; Sebesty6n, F.; Asgedom, M.; Dib6, 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. 15 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 {Mo), ... , {Mn}, 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 20 product of the number of variants within the sets {Mo}, ... , {MJ}, 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. 25 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 30 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 WO 99/03832 PCT/DK98/00330 23 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 5 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 10 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), 156-160, 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; 15 Paul JI. Molecular Diversity, (1996), 139-140.). 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 20 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, 25 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 30 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 WO 99/03832 PCT/DK98/00330 24 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 5 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 (-yOyn-) in the cyclised oligmers is, e.g., -C(=O)

(CH

2 )m-NH-C(= O)-, the group T in the corresponding "linear" oligmers will be -C(= O)

(CH

2 )m-NH 2 . 10 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 15 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, 20 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 25 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 30 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. EngI. 1997, 36, 125-128); and as marker molecules and detection molecules in diagnostic applications.

WO 99/03832 PCT/DK98/00330 25 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. 5 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 10 material. Fig. 2: Illustrates the coupling of N-Fmoc-6-aminocapronic acid to an oligomer of piperidine carboxylic acid monomers. The co-aminocapronic acid may together with the carboxylic acid of the first monomer constitute a biradical between the first and the 15 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. 20 Fig. 4: Illustrates the cyclisation between the first and the last piperidine monomer. Figs. 5-7: Illustrates various route to piperidine monomers. 25 Fig. 8: Illustrates particularly interesting monomers for incorporation into oligomers. EXPERIMENTAL General 30 13C NMR and 1 H NMR spectra were recorded a Varian instruments Gemini 200. When

CDCI

3 was used as solvent TMS and CDCI 3

(

1 3 C-NMR: 5 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.

WO 99/03832 PCT/DK98/00330 26 Concentrations were performed on a rotary evaporator at a temperature below 40 oC. 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 Na 2

CO

3 (1.09 g, 10.2 mmol) was added. At 0 oC a solution of di-tert-butyl dicarbonate (2.48 g, 11.4 mmol) and Na 2

CO

3 (1.07 g, 12 10 mmol) in 50% aqueous THF (20 mL) was added. The solution was kept for 30 min. at 0 oC and then allowed to reach room temperature over 2 h. The mixture was acidified with conc. HCI and water (20 mL) was added. The mixture was extracted with CH 2

CI

2 (3 x 20 mL), dried (MgSO 4 ) and concentrated to give a crystalline product (2.5 g, 92%). Mp: 52-56 oC. TLC: (EtOAc-pentane 10:1) Rf 0.5. 1 H NMR (CDCI 3 , 200 MHz): 8 15 12.1 (s, 1H, OH), 4.21 (q, 2H, J7 Hz, CH 2

CH

3 ), 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, (CH 3

)

3 ), 1.23 (t, 3H, J 7 Hz, CH 2

CH

3 ). 1 3 C NMR (CDCI 3 , 200 MHz): 8 171.2 (COOEt), 170.3 (C-4), 155.0 (NCOO), 96.7 (C-3), 80.6 (C(CH 3

)

3 ), 61.0 (CH2CH3), 40.7, 40.1, 29.4 (C-2, C-5, C-6), 28.9 (C(CH 3

)

3 ), 14.7 (CH 2

CH

3 ). MS (El): m/z 271 (M ), 171 (M - C 5

H

8 0 2 ). 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 30oC, compound 25 6 or 17 (6.3 mmol) was added, and the reaction was kept at 30 oC for 18 h. More sucrose (10 g) in H 2 0 (25 mL) at 40 oC was added, and the mixture was kept for 2 days at 30 oC. Celite (1 g) was added, and the mixture was filtered. The filter was washed with CHCl 3 (3 x 20 mL), which was subsequently used to extract the filtrate. The combined CHCI 3 phase was dried (MgSO 4 ), 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-tert-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 0 C, [a] : -2 (c 0.75, CH 2

CI

2 )). Ethyl 3,4-cis-N-tert-butoxycarbonyl-3-hydroxypiperidine-4- WO 99/03832 PCT/DK98/00330 27 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 %).[a]2: +1.6 (c 1.61; CHCI 3 ). '1H NMR (CDCI 3 , 200 MHz): 8 4.19 (q, 3H, J 7 Hz, CH 2

CH

3 , H-3), 4.07-3.96 (m, 2H, H-2), 3.01-2.77 (m, 2H, H-6), 2.59 5 2.50 (m, 2H, H-4, OH), 2.16-1.77 (m, 2H, H-5), 1.46 (s, 9 H, (CH 3

)

3 ), 1.27 (t, 3H, J 7 Hz, CH 2

CH

3 ). 1 3 C NMR (CDCI 3 , 200 MHz): 8 174.2 (COOEt), 156.1 (NCOO), 80.4

(C(CH

3 3 ), 65.9, 61.4 (C-3, CH 2

CH

3 ), 49.5, 45.8, 43.3, 23.1 (C-2, C-4, C-5, C-6), 28.8 (C(CH 3

)

3 ), 14.6 (CH 2

CH

3 ). 10 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 oC for 30 min. The solution was acidified with 1 M HCI and water (10 mL) was added. The mixture was extracted with EtOAc (3 x 15 mL), dried (MgSO 4 ) and concentrated to give a crystalline product 15 (0.178 g, 92 %). Mp: 140-144 °C. [a]": + 14.4 (c 4, CHCI 3 ). '1H NMR(CDCI 3 , 200 MHz): 5 4.33 (ddd, 1H, J4eq5ax 3 Hz , J4oq5eq 3 Hz , J 4 eq 3 ax 4 Hz, H-4eq), 3.97 (bdd, 1 H, J2eq3ax 3 Hz, J2eq2ax 13 Hz, J2eq6eq ~ 0 Hz, H-2eq), 3.7 (dt, 1H, J6eq5eq 4 Hz, J6eq5ax 4 Hz,

J

6 eq 6 ax 14 Hz, H-6eq), 3.43 (dd, 1H, J 2 ax 3 ax 10 Hz, H-2ax), 3.27 (ddd, 1H, J 6 ax 5 ax 11 Hz, H-6ax), 2.66 (ddd, 1H, H-3ax), 1.83 (dddd, 1H, Jeq 5 sx 14 Hz, H-5eq), 1.66 (dddd, 1H, 20 H-5ax), 1.45 (s, 9H, (CH 3

)

3 )). 13 C NMR(CDCI 3 , 200 MHz): 8 176.9 (COOH), 155.5 (NCOO), 80.9 (C(CH 3

)

3 , 65.7 (C-4), 46.2, 41.0, 39.3, 31.9 (C-2, C-3, C-5, C-6), 28.9

(C(CH

3

)

3 ). MS (El): m/z 246 (M + 1), 146 (M - C 5

H

7 0 2 ). Ethyl N-tert-butoxycarbonyl-3-piperidone-4-carboxylate (17). 25 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 (D 2 0, 200 MHz): 8 4.15 (q, 2H, J 6 Hz, CH 2

CH

3 ), 3.42-3.26 (m, 2H, H-2), 3.16-3.0 (m, 2H, H-6), 2.1-1.99 (m, 2H, H 30 5), 1.2 (t, 3H, J6 Hz). 13C NMR (D 2 0, 200 MHz): 5 181.4, 178.7, 176.0 (COOEt, C 3' (enol), C-3 (ketone)), 91.9 (C-4'), 64.9 (CH 2

CH

3 ), 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 (CH 2

CH

3 ). Ethyl-3-piperidone 4-carboxylate hydrochloride (0.305 g, 1.47 mmol) was BOC-protected using the same WO 99/03832 PCT/DK98/00330 28 procedure as for 6. Aqueous THF (20 mL), Na 2

CO

3 (0.176 g, 1.66 mmol) and a mixture of di-tert-butyl dicarbonate (0.374 g, 1.72 mmol) and Na 2

CO

3 (0.181 g, 1.71 mmol) in aqueous THF (10 mL). The solution was acidified with conc. HCI and water (20 mL) was added. The mixture was extracted with CH 2

CI

2 (3 x 30 mL), dried 5 (MgSO 4 ) and concentrated to give an oil (0.395 g, 99 %). TLC: (EtOAc/pentane 10:1) Rf 0.5. 1 H NMR (CDCI 3 , 200 MHz): 8 12.08 (s, 1H, OH), 4.28 (q, 2H, J7 Hz,

CH

2

CH

3 ), 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, (CH 3

)

3 ), 1.30 (t, 3H, J 7 Hz, CH 2

CH

3 ). 13C NMR (CDCI 3 , 200 MHz): 8 172.3 (COOEt), 168.0 (C-3), 154.9 (NCOO), 97.4 (C-4), 80.7 (C(CH 3

)

3 ), 61.1 (CH 2

CH

3 ), 10 45.5, 40.7, 40. 4 (C-2, C-5, C-6), 28.9 (C(CH 3

)

3 ), 14.7 (CH 2

CH

3 ). 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 oC for 30 min. The solution was acidified with 1 15 M HCI and water (10 mL) was added. The mixture was extracted with EtOAc (3 x 10 mL), dried (MgSO 4 ) and concentrated to give an oil (50 mg, 63 %). 'H NMR (CDCI 3 , 200 MHz): 8 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), 2.15-1.68 (m, 2H, H-5), 1.45 (s, 9H, (CH 3

)

3 . 13C NMR (CDCI 3 , 200 MHz): 8 177.6 (COOH), 156.4 (NCOO), 81.0 (C(CH 3

)

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(CH 3

)

3 ). (cis)- (+)-piperidine-2,6-dicarboxylic acid 1.67 g (10 mmol) pyridine-2,6-dicarboxylic acid is suspended in H 2 0/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 oC. 'H NMR (D 2 0) 8 3.6 (dd, 2H), 2.1 (dd, 2H), 1.9 (m, 1H), 1.5 (m, 3H). 1 3 C NMR (D 2 0) 8 175.0, 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 H 2 0 (50 mL). 5.3 g Na 2

CO

3 (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 WO 99/03832 PCT/DK98/00330 29 syrup. (100%). NMR shows traces of piperidine-2-carboxylic acid. 'H NMR (D20) 8 3.2 (1H), 3.1(1H), 2.9 (1H), 2.6 (1H), 2.2 (1H), 1.6 (3H). 13C NMR (D20) 5 183.8, 181.5, 59.1, 45.9, 42.9, 27.3, 26.7. 5 (cis)-(±)-piperidine-2,4-dicarboxylic acid [84229-40-3] 3.7g (20 mmol) pyridine-2,4-dicarboxylic acid monohydrate is suspended in H 2 0 (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%). 10 Mp 293 oC (decomp.). 'H NMR (D20) 8 3.5 (dd, 1H), 3.35 (m, 1H), 2.85 (dt, 1H), 2.6 (tt, 1H), 2.4 (m, 1H), 2.0 (m, 1H), 1.45-1.65 (m, 2H). ' 3 C NMR (D 2 0) 8 179.9, 175.4, 58.9, 43.5, 40.3, 29.6, 25.0. General procedure for the synthesis of N-Fmoc-piperidine-dicarboxylic acid 15 (cis)- (±)-N-Fmoc-piperidine-2,6-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 2 20 hour. After cooling on ice, 4.1 g (15.8 mmol) FmocCI is added. The temperature is rised to rt. over 1 hour. The mixture is evaporated to a syrup, redisolved in NaHCOa(at)/Et 2 0 and the aqueous phase is washed with Et 2 0. The aqueous phase is made acid with 4 N HCI (pH 2) and extracted with EtOAc. The organic phase is washed with NaCl.,, dried over Na 2

SO

4 and evaporated to give a white foam (3.78 g, 25 66%). 'H NMR (CDCl 3 ) 5 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 (CDCl 3 ) 6 177.3, 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. 30 (cis)- (±)-N-Fmoc-piperidine-2,5-dicarboxylic acid Procedure as above. White foam (82.7%). 'H NMR (CDCI 3 ) 8 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 (CDCI 3 ) 6 178.5, 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.

WO 99/03832 PCT/DK98/00330 30 (cis)-(_)-N-Fmoc-piperidine-2,4-dicarboxylic acid Procedure as above. White crystals (82.7%). Mp 209 oC (decomp.). 'H NMR (DMSO d 6 ) 8 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), 5 1.8-2.1 (2H), 1.6 (1H). 13 C NMR (DMSO-d 6 ) 5 174.9, 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 10 (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) Cs 2

CO

3 and after 30 min. 0.25 ml (3 mmol) allylbromide. The reaction mixture is stirred 24 h and 0.12 g (0.35 mmol) Cs 2

CO

3 is 15 added. This procedure is continued until a total of 0.49 g (1.5 mmol) Cs 2

CO

3 has been added. After additional 24 h the reaction mixture is filtered and evaporated to yield a syrup. The syrup is redisolved in NaHCO 3 (Se) and extracted with Et 2 0. The aqueous phase is made acidic with 1 N HCI and extracted with EtOAc. Dried over Na 2

SO

4 and evaporated to give a syrup (1.05 g, 80.5%). 'H NMR (DMSO-d 6 ) 8 7.2-7.9 (8H), 5.9 20 (1H), 5.1-5.3 (2H), 4.2-4.8 (7H), 2.1 (2H), 1.4-1.8 (4H). ' 3 C NMR (DMSO-d 6 ) 5 173.8, 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 25 Procedure as above. The syrup is chromatographed in 2% AcOH/CHCI 3 to give a syrup (54%). 'H NMR (CDCI 3 ) 8 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). ' 3 C NMR (CDCI 3 ) 6 177.9, 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. 30 (cis)- (±)-N-Fmoc-piperidine-2,4-dicarboxylic acid mono allylester Procedure as above. The syrup is chromatographed in a gradient of CHCI 3 and 2% AcOH/CHCI 3 to give a syrup (33%). 'H NMR (CDCI 3 ) 8 11.3 (1H), 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 WO 99/03832 PCT/DK98/00330 31 (1H). ' 3 C NMR (CDCl 3 ) 8 179.3, 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 alylester 5 Procedure as above. (15%). 'H NMR (CDCl 3 ) 5 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 (CDCI 3 ) 5 177.7, 170.7, 155.4, 131.4, 118.4, 80.6, 65.5, 52.8, 42.8, 40.7, 28.0, 25.5, 23.7. 10 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 15 trimethylsilylchloride (25 mmol) is added and the mixture is refluxed for 1 /2 hour. After cooling on ice, 2.86 g (11 mmol) FmocCI is added. The temperature is rised to rt. over 1 Y2 hour. The mixture is evaporated to a syrup, redisolved in NaHCO 3 .sat,/Et 2 0 and the aq. phase is washed with Et 2 0. The aqueous phase is made acidic with 1 N HCI (pH 2) and extracted with EtOAc. The organic phase is washed with NaC(at), 20 dried over Na 2

SO

4 and evaporated to give a white foam (3.32 g, 94%). 'H NMR

(CDCI

3 ) 8 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 (CDCI 3 ) 5 177.2, 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. 25 (-)-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 oC. Pyridine (80 pL, 1 mmol) and cyanuric fluoride (180 PiL, 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 H 2 0, dried 30 over Na 2

SO

4 and evaporated to give a syrup (0.35 g, 100%). HPLC of the methylester (reaction with MeOH the overnight) gives 95.5% yield. 'H NMR (CDC 3 ) 8 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). '3C NMR (CDC1 3 ) 5 143.5, 141.2, 127.6, 126.9, 124.8, 119.9, 67.8, (53.6, 52.7: Cl), 47.0, 41.6, 26.0, 24.3, 20.6.

WO 99/03832 PCT/DK98/00330 32 (+)-N-Fmoc-piperidine-2-carboxylic acid [101555-63-9] Procedure as above. (60%). [a] = +26.60 (CHCI 3 ). 5 (-)-N-Fmoc-piperidine-2-carboxylic acid [86069-86-5] Procedure as above. (85%). [a] = -18.50 (CHCI 3 ). (-)-N-Fmoc-piperidine-3-carboxylic acid [148928-02-3] Procedure as above. White crystals recrystallized in EtOAc/Hexane (2:3) (65 %). Mp 10 135-139 oC. 'H NMR (CDCI 3 ) 5 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 (CDCI 3 ) 8 178.4, 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] 15 1.09 g (10.3 mmol) Na 2

CO

3 is dissolved in H 2 0 (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 20 layer is washed with water, dried with Na 2

SO

4 and evaporated. The residue is triturated with hexane to afford white crystals (3.6 g 100%). Mp 178-180 0 C. 'H NMR (DMSO-d 6 ) 6 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-d 6 ) 5 175.5, 154.3, 143.9, 140.8, 127.6, 127.1, 124.9, 120.1, 66.4, 46.8, 42.8, 39.8, 27.6. 25 N-Fmoc-6-amino-capronic acid Procedure as above. (81.7%). Mp 113.5-115oC. 'H NMR (CDCI 3 ) 6 10.7 (1H), 7.2-7.9 (8H), 4.9 (1H), 4.2-4.6 (3H), 3.0-3.3 (2H), 2.4 (2H), 1.2-1.7 (6H). 13C NMR (CDCI 3 ) 5 179.0, 157,0, 143.8, 141.2, 127.5, 126.9, 124.9, 119.8, 66.4, 47.1, 40.7, 33.7, 30 29.4, 26.0, 24.1.

WO 99/03832 PCT/DK98/00330 33 General procedure for the synthesis of N-Boc-piperidine-carboxylic acid ()-N-Boc-piperidine-2-carboxylic acid 1.29 g (10 mmol) piperidine-2-carboxylic acid is dissolved in a solution of 10% 5 Et3N/MeOH. Under vigorously stirring, 4.4 g (20 mmol) BOC 2 0 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 0.01M HCI. Additional acid (1M HCI) is added (pH 4) and the mixture is rapidly extracted with EtOAc. The organic phase is dried over Na 2

SO

4 and evaporated to give white crystals, which are triturated with pentane (2.04 10 g, 89 %). Mp 121.5-122.5oC. 1 H NMR (CDCI 3 ) 8 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 (CDCI 3 ) 5 177.7, 154.3, 80.2, 55.0, 54.0, 43.0, 41.9, 28.2, 26.5, 24.6, 20.6. (+)-N-Boc-piperidine-2-carboxylic acid 15 Procedure as above. (80.6%). Mp 115.5-117 oC. [a] = +49.80 (CHCI 3 ). (-)-N-Boc-piperidine-2-carboxylic acid [28697-17-8] Procedure as above. (87.3%). Mp 115-118 0 C. [a] = -50.60 (CHCI 3 ). 20 (-)-N-Boc-piperidine-3-carboxylic acid [71381-75-4] Procedure as above. (90 %). Mp 155-156 0 C. 1 H NMR (CDCI 3 ) 5 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). 13 C NMR (CDCI 3 ) 6 178.7, 154.6, 79.8, 45.3, 43.7, 41.0, 28.2, 27.0, 24.0. 25 N-Boc-piperidine-4-carboxylic acid [84358-13-4] Procedure as above. (81 %). Mp 143.5-145.5 oC. 1 H NMR (CDCI 3 ) 8 11.0 (1H), 4.0 (2H), 2.9 (2H), 2.5 (1H), 1.9 (2H), 1.7 (2H), 2.6 (9H). 13 C NMR (CDCI 3 ) 5 180.2, 155.0, 79.7, 42.8, 40.7, 28.3, 27.6. 30 cis- ()- (3R,4R)-N-Boc-3-hydroxy-piperidine-4-carboxylic acid Procedure as above. (47%). Mp 146-148 oC.

WO 99/03832 PCT/DK98/00330 34 (cis)- (±)-N-Boc-Piperidine-2,5-dicarboxylic acid [188345-84-8] Procedure as above. (100 %). 1 H NMR (CDCI 3 ) 8 9.4 (1H), 4.8-5.0 (1H), 4.2-4.5 (1H), 3.0 (1H), 2.4 (2H), 2.1 (1H), 1.7 (1H), 1.5 (9H). 5 Solid-phase synthesis Synthesis of a library (3 sub-libraries) of 27 members using BOC-protected piperidine carboxylic acids 10 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 15 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 (2xl0min) to remove the BOC protecting group and split into three. The three fractions are reacted as described above with the three 20 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 (2x3min.). Each of the sub-libraries are reacted with Sanger's reagent and analysed by LC 25 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. 30 Coupling of N-Fmoc-piperidine-carboxylic acid to 4-(2 ',4 '-Dimethoxypheny-Fmoc amino-methyl)-phenoxy resin (Rink-resin) Rink-resin from Novabiochem with a substitution level of 0.43 mmole/g is used.

WO 99/03832 PCT/DK98/00330 35 The Rink-resin is first deprotected using 20% piperidine in DMF for 2x10 min. The resin is washed with 3xDMF 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 5 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. 10 Coupling of of (cis)-(±)-N-Fmoc-piperidine-dicarboxylic acid mono ally/ester to Rink resin The Rink-resin is first deprotected using 20% piperidine in DMF for 2x10 min. The resin is washed with 3xDMF before further reaction. The (cis)-(+)-N-Fmoc-piperidine 15 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. 20 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 25 washed with 3xDMF. 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 30 the resin. After 2 hours, the coupling is quantitative according to Fmoc-test. The resin is washed with 3xDMF and 3xDCM.

WO 99/03832 PCT/DK98/00330 36 Synthesis of 6-carbamoyl-1-(N-Fmoc-4-piperidylcarbonyl)-2-piperidine-allylic carboxylate Rink-coupled (cis)-(±)-N-Fmoc-piperidine-2,6-dicarboxylic acid mono allylester is 5 deprotected with 20% piperidine in DMF for 2x10 min. The resin is washed with 3xDMF and 3xDCM and flushed with Ar. DCM is added and BSA (N,O-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. 10 The resin is washed with 3xDMF and 3xDCM. 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 15 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 3xDMF. 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. 20 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-carbamoyl- 1-{1-[1-l-{-[1-(N-Fmoc-3-piperidylcarbonyl)-3 piperidy/carbonylJ-3-piperidy/carbonyl}-3-piperidy/carbonyl)-3-piperidy/carbonylj-3 25 piperidylcarbonyl}-3-piperidine-allylic-carboxylate Rink-coupled 6-carboxy-1-(N-Fmoc-3-piperidylcarbonyl)-3-piperidine-allylic-carboxylate is deprotected with 20% piperidine in DMF for 2x10 min. The resin is washed with 3xDMF. Each coupling is performed using 2 eq of N-Fmoc-piperidine-3-carboxylic acid, 30 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 3xDMF and 3xDCM. 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 WO 99/03832 PCT/DK98/00330 37 with 20% piperidine in DMF for 2x10 min. and washed with 3xDMF. The final product is cleaved from the resin with 20 % TFA/DCM for 2x5 min. Synthesis of 6-carbamoyl- 1-{1-[l-(1-{1-[N-Fmoc-4-piperidylcarbonyl]-4 5 piperidylcarbonyl}-4-piperidycarbonyl)-4-piperidycarbonyl]-4-piperidycarbonyl}-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 2x10 min. The resin is washed with 10 3xDMF. 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 15 coupling, the resin is washed with 3xDMF and 3xDCM. 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 2x10 min. and washed with 3xDMF. 20 Synthesis of 1-((1-1-( l-{l-[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 25 piperidylcarbonyl}-4-piperidylcarbonyl)-4-piperidylcarbonyl]-4-piperidyl carbonyl}-4 piperidine-allylic carboxylate is deprotected with 20% piperidine in DMF for 2x10 min. The resin is washed with 3xDMF. 4 eq N-Fmoc-Gly-OH, 3.8 eq HBTU and 8 eq DIPEA is prereacted before added to the resin. After 19 hours, the resin is washed with 3xDMF and 3xDCM. The product is cleaved from the resin with 95 % TFA/DCM in 30 30 min. Synthesis of 1-{ l-[1-l-({1-[1-(N-Fmoc-6-aminohexanoyl)-4-piperidylcarbonyl]-4 piperidylcarbonyl}-4-piperidylcarbonyl)-4-piperidylcarbonyl-4-piperidycarbonyl)}- WO 99/03832 PCT/DK98/00330 38 6carbamoyl-4-piperidine-aflylic carboxylate and 1-(1-{1-[1-(1-(1- [1-(N-Fmoc-6 aminohexano y)-4-piperidylcarbonyl-4-piperidylcarbonyl})-4-piperidycarbonyl)-4 piperidylcarbonyl]-4-piperidylcarbonyl)-4-piperidylcarbonyl)-6carbamo yl-4-piperidine alylic carboxylate (Fiqure 2) 5 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 10 piperidylcarbonyl}-6-carbamoyl-4-piperidine-allylic carboxylate is deprotected with 20% piperidine in DMF for 2x10 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 19 hours, the resin is washed with 3xDMF and 3xDCM. The product is cleaved from the resin with 95 % TFA/DCM in 30 min. 15 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/CHCI 3 and flushed with Ar. 1.2 20 eq Pd(Ph 3

)

4 is added under Ar. After 1 h, the resin is washed with 7x0.5%DIPEA/ 0.5%sodiumdiethyldithiocarbamate/DMF. The resin is reacted with 20% piperidine in DMF for 2x10 min. and washed with 3xDMF. MALDI of linear deprotected 7mer of piperidine-3-carboxylic acid gives the right mass of 842.5. 25 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. 16 eq DIPEA, 8 eq PyBOP and 8 eq HOBT is added. After 17 hours, the resin is washed with 3xNMP and 3xDCM. 30 Attempt to cyclise 1-(f-{1-[l-(l-{1-[1-(2-aminoacetyl)-4-piperidylcarbonyl]-4 piperidylcarbony}-4-piperidylcarbony)-4-piperidycarbony-4-piperidycarbony)}-6 carboxy-4-piperidine-carboxylic acid WO 99/03832 PCT/DK98/00330 39 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 3xNMP and 3xDCM. The Kaiser-test was negative. The product is cleaved off the resin, but MS-UV/HPLC do not show the expected product. 5 Attempt to cyclise Rink-PEGA-bound 1-{1-f -(1 -{l-[1-(6-aminohexanoyl)-4 piperidylcarbonyl]-4-piperidycarbonyl}-4-piperidycarbonyl)-4-piperidycarbonyl]-4 piperidylcarbonyl}-6-carboxy-4-piperidine-carboxylic acid and 1-(1 -1-1- -{ -[1-(6 aminohexano yl)-4-piperidylcarbonyl]-4-piperidylcarbonyl)-4-piperidylcarbon yl)-4 10 piperidylcarbonyl]-4-piperidycarbonyl}-4-piperidycarbonyl)-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 15 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. 16 eq DIPEA, 8 eq PyBOP and 8 eq HOBT is added. After 17 hours, the resin is washed with 3xNMP and 3xDCM. The Kaiser-test is negative. MS 20 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 25 to Figures 7 and 8). The synthesis takes advantage of the commercially available Dieckman adduct 4. Thus 4 was protected as the BOC derivative (( t BuO) 2 CO, THF/aq. Na 2

CO

3 (1:1), 25 oC, 1 h, 95 %), and then converted into the dianion 5 by treatment with first NaH (1.15 eq.) and then BuLi (1.1 eq.). The solution of 5 was now treated with various alkylating agents. Addition of 1.15 eq. of chloromethyl methyl ether gave 30 95 % of the 5-alkylated product 668 while treatment with 1.15 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.

WO 99/03832 PCT/DK98/00330 40 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 syn-reduction from the less 5 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-trans-4,5-cis isomer. The bakers yeast reduction 10 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 H 2 at 40 atm. in EtOH was converted to pure 8 in 50 % yield while 18% of the allo isomer 8a was isolated. 7 under the same conditions gave 9 in good yield. 15 Table 1. Reduction conditions for reduction of 6 and 7. Reagent Solvent Starting Pressure Yield Ratio 8/8a/8b material (bar) (or 9/9a) ....................... ......................................................................................................

H

2 /Rh EtOH 6 35 74% 1:1:1

H

2 /Pd EtOH 6 40 94% 6:3:1

H

2 /Pd + Et 3 N EtOH 6 40 95% 7:3:0

H

2 /Ni MeOH 6 33 88% 4:1:2

H

2 /Pt EtOH 6 30 60% 1:1:1

H

2 /Pt + KOH EtOH 6 30 90% 3:2:1

H

2 /Pt t BuOH 6 30 66% 1:1:1 NaBH 4 6 67% mix Bakers yeast H 2 0 6 1 23% 0:1:0 (no sugar) (65% *) Bakers yeast H 2 0 6 1 35% 3:4:0 (sugar/O 2 )

H

2 /Pd + Et 3 N EtOH 7 40 100% 1:0

H

2 /Ni MeOH 7 42 93% 4:3 * Yield based on recovered starting material.

WO 99/03832 PCT/DK98/00330 41 Both 8 and 9 were deprotected. Methyl ether 8 was hydrolysed with LiOH in THF/H 2 0 to give 10 in 57 % yield. Similarly 9 gave 11 in 79 % yield. Acid hydrolysis of 8 gave hydroxyamino acid la 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. 13 C NMR-data (d6-DMSO, 100 oC): 6, 5 171.2 (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, 8 171.0 (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, 6 171.4 (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, 5 176.3 (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). la, 5 177.2 (C3'), 74.3 (C6), 68.7(C4), 61.4 (OMe), 45.6, 44.6, 43.6, 40.0 ppm (C2, C3, C5, C5'). 1 H NMR: 6, 8 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, 8 4.55 (t, 2H, Et), 3.99 (dd, 20 1H, J 3

,

4 4.0 Hz, J4,5 5.3 Hz, H-4), 3.65 (dd, 1H, J2eq,2ax 13.6 Hz, J 2 eq, 3 4.65 Hz, H 2eq), 3.42 (dd, 1H, J5'sq,5'ax 13 Hz, J,s5,eq 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). la, 8 4.20 (dd, 1H, J3,4 3.8 Hz, J 4 ,5 5.6 Hz, H-4), 3.64 (dd, 1H, J6a,6b 10.5 Hz, J5,6, 5.2 Hz, H-6a), 3.57 (dd, J6a,6b 10.5 Hz, J6b,5 6.0 Hz, H-6b), 25 3.42 (dd, 1H, J2eq,2ax 10 Hz, J2eq,3 3.7 Hz, H-2eq), 3.39 (dd, 1H, J5'.q,,'ax 13.4 Hz, J5'eq,5 4.1 Hz), 3.31 (s, 3H, OMe), 3.29 (dd, 1H, J2ax,2oq 10 Hz, J 2 ,x, ~ 3 9.8 Hz), 3.23 (dt, 1H, J3,2ax 9.8 Hz, J3,2eq 3.7 Hz, J3,43.8 Hz), 3.15 (dd, 1H, J5'a,,x,5'eq 13.4 Hz, Js,ax,5 6.4 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. 1997 38 5697-5700.

WO 99/03832 PCT/DK98/00330 42 It is envisaged that further piperidine monomers can be prepared as outlined in Figure 5 (all numerals below refer to Figure 5): 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 10 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) 2 0 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 15 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, NalO 4 -cleavage of 5,6-diol and reductive amination of the resulting dialdehyde gives 11. Protection of the amine with a Fmoc group, cleavage of the double bond with Lemieux's reagent, esterification of the 20 resulting acid and ozonolysis gives 5a. The monomer 18 can be prepared as follows (see Figure 6): Amine 18 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 25 23 is condensed with chloromethylbenzyl ether giving, after hydrogenation of the benzyl group, piperidinol 24. Protection with (Boc) 2 0 and ozonolysis gives 18. Methods for determining the biological activity of the oligomers 30 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 (1996) 1520-2.

WO 99/03832 PCT/DK98/00330 43 Glucosidase assay: Enzymes (c-glucosidase from yeast, P-glucosidase from almonds, isomaltase from yeast, c-fucosidase from human placenta, -mannosidase from snail, and P-galactosidas from E.coli) and substrates therefor can be obtained from Sigma. As substrates are employed p-nitrophenyl-x-glucopyranoside for x-glucosidase and p 5 nitrophenyl-p-glucopyranoside for -glucosidase. The experiments are performed in 0.05 M phosphate buffer at 22 0 C. The enzyme assays were performed essentially as described by H. Halvorson Methods Enzym. 8 (1966) 559-62.

WO 99/03832 PCT/DK98/00330 44 CLAIMS 1. An oligomer of the general formula I O Xo K O Xn N I NT n (in short K-C(=O)-Mo-...-Mn-T, wherein Mo, ... , Mn designate "piperidine monomers") 5 wherein n is a positive integer; K-(C = 0)- is a carboxylic acid or a derivative thereof; 10 T is selected from hydrogen, optionally substituted C 1

-

20 -alkyl, optionally substituted Cl- 20 -alkoxy, optionally substituted C 1

-

20 -alkylcarbonyl, optionally substituted aryl, optionally substituted heteroaryl, and amino-protecting groups; and each of Xo,..., and Xn independently designates 0-5, preferably 0-4, such as 0-3, 15 substituents, where (a) such optional substituents independently are selected from optionally substituted Cl- 20 -alkyl, optionally substituted C 2

-

20 -alkenyl, optionally substituted C 4

-

20 -alkadienyl, optionally substituted C 6

-

20 -alkatrienyl, optionally substituted C 2

-

20 -alkynyl, hydroxy, 20 C 1

-

20 -alkoxy, C 2

-

20 -alkenyloxy, carboxy, oxo, C 1

-

20 -alkoxycarbonyl, C 1

-

20 -alkylcarbonyl, formyl, aryl, aryloxycarbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxycarbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(C1.

6 -alkyl)amino, carbamoyl, mono- and di(C, 6 -alkyl)aminocarbonyl, amino-C 1

.

6 -alkyl-aminocarbonyl, mono- and di(C 1

-

6 -alkyl)amino-Cl.6-alkyl-aminocarbonyl,

C

1

-

6 -alkylcarbonylamino, guanidino, 25 carbamido, Cl.

6 -alkanoyloxy, sulphono, C 1 6 -alkylsulphonyloxy, nitro, sulphanyl, C 1

_

alkylthio, and halogen, where aryl and heteroaryl may be optionally substituted; and/or WO 99/03832 PCT/DK98/00330 45 (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; 5 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. 10 3. An oligomer according to any of the preceding claims, wherein K- is selected from hydrogen, NH 2 , NHR, NRR', N(OH)H, NHNH 2 , NHNHR"', and OR", where each of R, R', R", and R"' independently designates optionally substituted C 1

_

6 -alkyl, optionally substituted C 2

-

6 -alkenyl, optionally substituted aryl, or optionally substituted heteroaryl. 15 4. An oligomer according to any of the preceding claims, wherein K- designates OH, OR", NH 2 , NHR, or NRR', where R and R' are selected from C 1

.

6 -alkyl and benzyl, and R" is selected from C 1 6 -alkyl, C 2 -6-alkenyl, phenyl, and benzyl; in particular K designates OH, methoxy, or NH 2 . 20 5. An oligomer according to any of the preceding claims, wherein T is selected from hydrogen, optionally substituted C 1 .6-alkyl, optionally substituted C 1 -6-alkoxy, optionally substituted Cl 6 -alkylcarbonyl, optionally substituted aryl, optionally substituted heteroaryl, tert-butoxycarbonyl (Boc), and fluorenylmethoxycarbonyl (Fmoc). 25 6. An oligomer according to any of the preceding claims, wherein T is selected from hydrogen; Cl- 6 -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

.

6 alkyl)amino, and halogen, where aryl may be substituted 1-3 times with C 1

.

4 -alkyl, C 1

.

4 30 alkoxy, nitro, cyano, amino or halogen; C 1

.

6 -alkoxy; C 1

-

6 -alkylcarbonyl; amino-Cl.

6 alkylcarbonyl; aryl which may be substituted with 1-3, preferably 1-2 substituents selected from C 1

-

4 -alkyl, C1- 4 -alkoxy, nitro, cyano, amino, and halogen; and heteroaryl which may be substituted with 1-3, preferably 1-2 substituents selected from C 1

.

4 alkyl, C1- 4 -alkoxy, nitro, cyano, amino, and halogen.

WO 99/03832 PCT/DK98/00330 46 7. An oligomer according to any of the preceding claims, wherein T is selected from hydrogen; C 1

-

6 -alkyl; benzyl, C 1

-

6 -alkylcarbonyl; and aryl which may be substituted with 1-3, preferably 1-2 substituents selected from C 14 -alkyl, C1- 4 -alkoxy, nitro, cyano, 5 amino, and halogen. 8. An oligomer according to any of the preceding claims, wherein each of Xo,..., and Xn independently designates 0-3 substituents, where 10 (a) such optional substituents are selected from optionally substituted C 1

_

6 -alkyl, optionally substituted C 2

-

6 -alkenyl, hydroxy, C 1

.

6 -alkoxy, C 2

-

6 -alkenyloxy, carboxy, oxo, Cl 6 -alkoxycarbonyl, C 1 6 -alkylcarbonyl, formyl, aryl, aryloxycarbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxycarbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(C 1

-

6 -alkyl)amino; carbamoyl, mono- and di(Cl_ 6 -alkyl)amino 15 carbonyl, C.

6 -alkylcarbonylamino, sulphono, Cl 6 -alkanoyloxy, and halogen, where aryl and heteroaryl may be optionally substituted with 1-3, preferably 1-2 substituents selected from C 1

-

4 -alkyl, C 1

.

4 -alkoxy, nitro, cyano, amino, and halogen; and/or (b) two substituents on two adjacent carbon atoms together with said two adjacent 20 carbon atoms may designate a double bond. 9. An oligomer according to any of the preceding claims, wherein each of X 0 , ..., and

X

n independently designates 0-3 substituents, where such optional substituents are selected from C 1

.

6 -alkyl which may be substituted with 1-3, preferable 1-2, 25 substituents selected from hydroxy, CI- 6 -alkoxy, carboxy, aryl, heteroaryl, amino, mono- and di(Cl_ 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 2 -6-alkenyl; hydroxy; C-e alkoxy; C 2 -6-alkenyloxy; carboxy; Cle-alkoxycarbonyl; C 6 _e-alkylcarbonyl; formyl; amino; mono- and di(C 1

.

6 -alkyl)amino; carbamoyl; mono- and di(C 1

.

6 -alkyl)amino 30 carbonyl; C 1 l 6 -alkylcarbonylamino; sulphono, C.

6 -alkanoyloxy; and halogen such as fluoro or chloro.

WO 99/03832 PCT/DK98/00330 47 10. An oligomer according to claim 8, wherein each of X 0 , ... , and X n 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, C1-6-alkoxy, aryloxy, and carboxy, where aryl may be substituted 1-3 times with C 14 -alkyl, C 1

-

4 5 alkoxy, nitro, cyano, amino or halogen; hydroxy; C1- 6 -alkoxy; C 2

-

6 -alkenyloxy; carboxy; ClG 6 -alkoxycarbonyl; amino; mono- and di(C1.

6 -alkyl)amino; mono- and di(Cl_ 6 -alkyl) aminocarbonyl; and Cl 6 -alkylcarbonylamino. 11. An oligomer according to claim 8, wherein each of X 0 , ..., and Xn independently 10 designates 1-2 substituents, where such substituents are selected from C1- 6 -alkyl which may be substituted with a substituent selected from hydroxy, Cl 6 -alkoxy, aryloxy, and carboxy; hydroxy; C 1

-

6 -alkoxy; carboxy; and C 1

.

6 -alkoxycarbonyl. 12. An oligomer according to any of the preceding claims, wherein in at least one of 15 each of Xo, ... , and X" is selected from hydroxy, hydroxymethyl and carboxy. 13. 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. 20 14. An oligomer according to any of the preceding claims, comprising monomer fragments (Mo, ... , Mn) of the general formulae M 2 S, M 2 R, MaR, MaS and/or M 4 R33' O 2 R2' R 3 2 3 R 3 R 3

R

2 ' R4',N--- R 4 "'* N--- N-- 4 R 4 O Rs',,' gR6e R s' ' 6 ' 6 Rs R R ~R R R 5

R

6 R 5

RR

5 15, 6 RR,R R

M

2 s M 3 R 4 N / R5. -' R 4 " ... - 6

R

5 R R 5 1 R

M

2 R

M

3

S

WO 99/03832 PCT/DK98/00330 48 wherein each of the substituents R 2 , R 2 ', R 3 , R 3 ', R 4 , R 4 ', R 5 , R 1 5 ', R 6 , and R 6 ' independently is as defined for Xo, ..., and X n . 5 15. 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). 10 16. An oligomer according to claim 14 or 15, wherein at least one of R 2 , R 2' , R 3 , R ' ,

R

4 , R 4 ', R 5 , R 5 ', R 6 , and R 6 ' is selected from hydroxy, hydroxymethyl and carboxy. 17. A cyclised oligomer of the general formula II / 0X 0 o xo K O1 Xn N N- II N Y, Va n 15 (in short K-C(=O)-Mo-...-Mn-W, wherein Mo, ... , Mn designate "piperidine monomers" and W designates the biradical -Y"-Yb) wherein n is a positive integer; 20 K-(C= O)- is a carboxylic acid or a derivative thereof; ya and yb together designate a linear biradical (_ya_yb_) comprising 1-20 backbone atoms; 25 each of Xo,..., 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 C 2

-

20 -alkenyl, optionally substituted C 4

-

20 -alkadienyl, WO 99/03832 PCT/DK98/00330 49 optionally substituted C 6

-

20 -alkatrienyl, optionally substituted C 2

-

20 -alkynyl, hydroxy, C 1 , 20o-alkoxy, C 2

-

20 -alkenyloxy, carboxy, oxo, C 1

-

20 -alkoxycarbonyl, C 1

-

20 -alkylcarbonyl, formyl, aryl, aryloxycarbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxycarbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(C 1

-

6 -alkyl)amino; carbamoyl, 5 mono- and di(Cl_ 6 -alkyl)aminocarbonyl, amino-C,_ 6 -alkyl-aminocarbonyl, mono- and di(Cl_ 6 -alkyl)amino-Cl_ 6 -alkyl-aminocarbonyl, C 1

_

6 -alkylcarbonylamino, guanidino, carbamido, C 16 -alkanoyloxy, sulphono, C.

6 -alkylsulphonyloxy, nitro, sulphanyl, C 1 6 alkylthio, and halogen, where aryl and heteroaryl may be optionally substituted; and/or 10 (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. 15 18. A cyclised oligomer according to claim 17, wherein the linear biradical (_ya_yb_) is selected from -C(= O)-NH-(CH 2 )m-C(= O)-, -NH-C(= O)-(CH 2 )m-C( O)-, -C(= O)-NH

(CH

2 )m-, -NH-C(= O)-(CH 2 )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 20 hydroxy, C 1

.

6 -alkyl, C 1

.

6 -alkoxy, carboxy, Cl.

6 -alkoxycarbonyl, C 1

-

6 -alkylcarbonyl, aryl optionally substituted 1-3 times with C 1

,

4 -alkyl, C 1

.

4 -alkoxy, nitro, cyano, amino or halogen, amino, mono- and di(C 16 .- alkyl)amino, and halogen. 19. A cyclised oligomer according to claim 18, wherein the linear biradical is -C(=O) 25 NH-(CH 2 )m-C(= O)-. 20. A cyclised oligomer according to any of the claims 17-19, wherein n is in the range of 1-25, preferably 1-15, in particular 2-10 such as 2-5 or 3-6. 30 21. A cyclised oligomer according to any of the claims 17-20, wherein K- is selected from hydrogen, NH 2 , NHR, NRR', N(OH)H, NHNH 2 , NHNHR"', and OR", where each of R, R', R", and R'" independently designates optionally substituted C 1 6 -alkyl, optionally substituted C 2

-

6 -alkenyl, optionally substituted aryl, or optionally substituted heteroaryl.

WO 99/03832 PCT/DK98/00330 50 22. A cyclised oligomer according to any of the claims 17-21, wherein K designates OH, 0-, OR", NH 2 , NHR, or NRR', where R and R' are selected from C1- 6 -alkyl and benzyl, and R" is selected from C 1

.

6 -alkyl, C 2

-

6 -alkenyl, phenyl, and benzyl; in particular 5 K designates OH, methoxy, or NH 2 . 23. A cyclised oligomer according to any of the claims 17-22, wherein each of Xo,..., and X n independently designates 0-3 substituents, where 10 (a) such optional substituents are selected from optionally substituted C 1

_

6 -alkyl, optionally substituted C 2

-

6 -alkenyl, hydroxy, C,.

6 -alkoxy, C 2

-

6 -alkenyloxy, carboxy, oxo, Cl 6 -alkoxycarbonyl, C.

6 -alkylcarbonyl, formyl, aryl, aryloxycarbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxycarbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(Cl.

6 -alkyl)amino; carbamoyl, mono- and di(C 1

.

6 -alkyl)amino 15 carbonyl, C 1

-

6 -alkylcarbonylamino, sulphono, Cl.

6 -alkanoyloxy, and halogen, where aryl and heteroaryl may be optionally substituted with 1-3, preferably 1-2, substituents selected from C 1

_

4 -alkyl, C1 4 -alkoxy, nitro, cyano, amino, and halogen; and/or (b) two substituents on two adjacent carbon atoms together with said two adjacent 20 carbon atoms may designate a double bond. 24. A cyclised oligomer according to any of the claims 17-23, wherein each of Xo, and Xn independently designates 0-3 substituents, where such optional substituents are selected from C 1

_

6 -alkyl which may be substituted with 1-3, preferable 1-2, 25 substituents selected from hydroxy, C 1

_

6 -alkoxy, carboxy, aryl, heteroaryl, amino, mono- and di(Cl 6 -alkyl)amino, and halogen, where aryl may be substituted 1-3 times with C 1

-

4 -alkyl, C 14 -alkoxy, nitro, cyano, amino or halogen; C 2

-

6 -alkenyl; hydroxy; C 1

.

alkoxy; C 2

-

6 -alkenyloxy; carboxy; C 1

.

6 -alkoxycarbonyl; Cl_ 6 -alkylcarbonyl; formyl; amino; mono- and di(Cl.

6 -alkyl)amino; carbamoyl; mono- and di(C 1

.

6 -alkyl)amino 30 carbonyl; Cl_ 6 -alkylcarbonylamino; sulphono, C_ 6 -alkanoyloxy; and halogen such as fluoro or chloro.

WO 99/03832 PCT/DK98/00330 51 25. An oligomer according to claim 24, wherein each of Xo, ..., and X n independent ly 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

.

4 -alkyl, C 1

-

4 5 alkoxy, nitro, cyano, amino or halogen; hydroxy; Cz.e-alkoxy; C 2

-

6 -alkenyloxy; carboxy; Cle-alkoxycarbonyl; amino; mono- and di(C_ 6 -alkyl)amino; mono- and di(C 6 .e-alkyl) aminocarbonyl; and Cl_ 6 -alkylcarbonylamino. 26. An oligomer according to claim 24, wherein each of X 0 , ... , and X n independently 10 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 1 6 _e-alkoxy, aryloxy, and carboxy; hydroxy; C 1

,

6 -alkoxy; carboxy; and Cz_ 6 -alkoxycarbonyl. 27. An oligomer according to any of the claims 17-26, wherein in at least one of each 15 of X 0 , ... , and X n 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 0 , ... , and Xn is selected from hydroxy and hydroxymethyl. 20 29. A cyclised oligomer according to any of the claims 17-28, comprising monomer fragments (Mo, ... , Mn) of the general formulae M 2 S, M 2 R, M 3 R, M 3 S and/or Mc 4 as defined in claim 9. 30. An oligomer according to claim 29, wherein each of the monomer fragments 25 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 R 2 , R 2 ', R 3 , R', 30 R 4 , R 4' , R 5 , R 5 ', R 6 , and R' is selected from hydroxy, hydroxymethyl and carboxy.

WO 99/03832 PCT/DK98/00330 52 32. A method for the preparation of an oligomer of the general formula I (K-C(=O)-Mo ...- Mn-T, where Mo, ... , Mn designate "piperidine monomers") as defined in any of the claims 1-10, comprising the following steps: 5 (A) providing an optionally functional group protected oligomer -C(= O)-Mo-...-Mn-T immobilised to a solid support material; and (B) cleaving the oligomer K-C(= O)-Mo-...-Mn-T from the solid support material, the step optionally including deprotection of one or more functional group(s) of the 10 oligomer. 33. A method for the preparation of a cyclised oligomer of the general formula II (K C(= O)-Mo-...-M,-W, where Mo, ... , Mn,, designate "piperidine monomers" and W designates the biradical -Ya-yb-) as defined in any of the claims 11-20, comprising the 15 following steps: (A) providing an optionally functional group protected oligomer -C(= O)-Mo-...-M,-W immobilised to a solid support material; and 20 (B) cleaving the oligomer K-C(=O)-Mo-...-Mn-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)-{Mo}-...-{Mn}-{T}), 25 consisting of at least four oligomers each having the general formula I as defined in any of the claims 1-16, the method comprises the following steps: (A) providing an array of optionally functional group protected oligomers -C(= O)-{Mo} ...- {Mn}-{T} immobilised to a solid support material; and 30 (B) cleaving the array of oligomers K-C(= O)-{Mo}-...-{Mn}-{T} from the solid support material, the step optionally including deprotection of one or more functional group(s) of the oligomer.

WO 99/03832 PCT/DK98/00330 53 35. A method for the preparation of an array of cyclised oligomers (K-C(= O)-{Mo}-...

{Mn}-{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: 5 (A) providing an array of optionally functional group protected cyclised oligomers C(= O)-{Mo}-...-{Mn}-{W} immobilised to a solid support material; and (B) cleaving the array of cyclised oligomers K-C(= O)-{Mo}-...-{Mn}-{W} from the solid support material, the step optionally including deprotection of one or more functional 10 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 15 1-16. 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. 20 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. 25 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. 30 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 16, as a drug substance WO 99/03832 PCT/DK98/00330 54 42. The use of a cyclised oligomer of the general formula II, as defined in any of the claims 17-32 as a drug substance. 5 43. A composition comprising a compound of the general formula I as defined in any of the claims 1-16. 44. A composition comprising a compound of the general formula II as defined in any of the claims 17-32. 10 45. A composition according to claim 43 or 44, further comprising a pharmaceutically acceptable carrier and one or more pharmaceutically acceptable excipients.

Claims (43)

1. An oligomer of the general formula I O Xo K 0 X 0 K n N NT n (in short K-C(=O)-M 0 -...- Mn-T, wherein M 0 , ... , Mn designate "piperidine monomers") wherein n is a positive integer; K-(C=O)- is a carboxylic acid or a derivative thereof; T is selected from hydrogen, optionally substituted Cl- 2 0 -alkyl, optionally substituted Cl- 2 0 alkoxy, optionally substituted C]- 2 0 -alkylcarbonyl, optionally substituted aryl, optionally substituted heteroaryl, and amino-protecting groups; and each of X 0 ,..., and Xn independently designates 1-5, preferably 1-4, such as 1-3, substituents, where (a) such optional substituents independently are selected from optionally substituted Cl- 2 0 alkyl, optionally substituted C 2 - 20 -alkenyl, optionally substituted C 4 -20-alkadienyl, optionally substituted C 6 . 20 -alkatrienyl, optionally substituted C 2 . 2 0 -alkynyl, hydroxy, C 1- 2 0 -alkoxy, C 2 - 20 alkenyloxy, carboxy, oxo, C 1 - 20 -alkoxycarbonyl, C 1 - 2 0 -alkylcarbonyl, formyl, aryl, aryloxy carbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxycarbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(C_ 6 -alkyl)amino, carbamoyl, mono- and di(CI. 6 alkyl)aminocarbonyl, amino-C _ 6 -alkyl-aminocarbonyl, mono- and di(C_ 6 -alkyl)amino-Ci-6 alkyl-aminocarbonyl, C 1 . 6 -alkylcarbonylamino, guanidino, carbamido, C 1 _ 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 X 0 ,... and X n 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, NH 2 , NHR, NRR', N(OH)H, NHNH 2 , NHNHR'", and OR", where each of R, R', R", and R"' independently designates optionally substituted C. 6 -alkyl, optionally substituted C 2 - 6 -alkenyl, optionally substituted aryl, or optionally substituted heteroaryl. WO 99/03832 PCT/DK98/00330 56

4. An oligomer according to any of the preceding claims, wherein K- designates OH, OR", NH 2 , NHR, or NRR', where R and R' are selected from C 1 6 -alkyl and benzyl, and R" is selected from C 1 6 -alkyl, C 2 . 6 -alkenyl, phenyl, and benzyl; in particular K- designates OH, methoxy, or NH 2 .

5. An oligomer according to any of the preceding claims, wherein T is selected from hydrogen, optionally substituted CI_ 6 -alkyl, optionally substituted CI_ 6 -alkoxy, optionally substituted Ci- 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; CI. 6 -alkyl which may be substituted with 1-3, preferable 1-2, substituents selected from hydroxy, Ci- 6 -alkoxy, carboxy, aryl, heteroaryl, amino, mono- and di(Ci-. 6 -alkyl)amino, and halogen, where aryl may be substituted 1-3 times with CI4-alkyl, C1.4-alkoxy, nitro, cyano, amino or halogen; C 1 6 -alkoxy; Cl. 6 -alkylcarbonyl; amino-C 1 6 -alkylcarbonyl; aryl which may be substituted with 1-3, preferably 1-2 substituents selected from C 1 4 -alkyl, C 1 4 alkoxy, nitro, cyano, amino, and halogen; and heteroaryl which may be substituted with 1-3, preferably 1-2 substituents selected from CI4-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; Ci. 6 -alkyl; benzyl, C 1 . 6 -alkylcarbonyl; and aryl which may be substituted with 1-3, preferably 1-2 substituents selected from C14-alkyl, C 1 4 -alkoxy, nitro, cyano, amino, and halogen.

8. An oligomer according to any of the preceding claims, wherein each of X 0 ,..., and Xn independently designates 1-3 substituents, where (a) such optional substituents are selected from optionally substituted C 1 . 6 -alkyl, optionally substituted C 2 . 6 -alkenyl, hydroxy, CI- 6 -alkoxy, C2. 6 -alkenyloxy, carboxy, oxo, CI. 6 -alkoxy carbonyl, CI. 6 -alkylcarbonyl, formyl, aryl, aryloxycarbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxycarbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(C 1 _ 6 alkyl)amino; carbamoyl, mono- and di(CI_ 6 -alkyl)aminocarbonyl, CI. 6 -alkylcarbonylamino, sulphono, Cl. 6 -alkanoyloxy, and halogen, where aryl and heteroaryl may be optionally substi tuted with 1-3, preferably 1-2 substituents selected from C 14 -alkyl, C 1 4 -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.

9. An oligomer according to any of the preceding claims, wherein each of X, ..., and Xn independently designates 1-3 substituents, where such optional substituents are selected from CI 6 -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(Ci. 6 -alkyl)amino, and halogen, where aryl may be substituted 1-3 times with C-4-alkyl, Cl- 4 -alkoxy, nitro, cyano, amino or halogen; C 2 . 6 -alkenyl; hydroxy; Ci. 6 -alkoxy; C 2 - 6 -alkenyloxy; carboxy; C 1 . 6 alkoxycarbonyl; C 1 . 6 -alkylcarbonyl; formyl; amino; mono- and di(C 1 .6-alkyl)amino; carbamoyl; mono- and di(CI. 6 -alkyl)aminocarbonyl; Cl. 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 0 , ..., and X n independently designates 1-2 substituents, where such optional substituents are selected from CI- 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 4 -alkyl, Cl- 4 -alkoxy, nitro, cyano, amino or halogen; hydroxy; C 1. 6 -alkoxy; C 2 6 -alkenyloxy; carboxy; C 1 . 6 -alkoxycarbonyl; AMENDED SHEET (ARTICLE 19) WO 99/03832 PCT/DK98/00330 57 amino; mono- and di(CI 6 -alkyl)amino; mono- and di(Cl- 6 -alkyl)aminocarbonyl; and C- 6 alkylcarbonylamino.

11. An oligomer according to claim 8, wherein each of X 0 , ..., and Xn independently designates 1-2 substituents, where such substituents are selected from Cs_ 6 -alkyl which may be substituted with a substituent selected from hydroxy, C 1 . 6 -alkoxy, aryloxy, and carboxy; hydroxy; Ci- 6 -alkoxy; carboxy; and Ci. 6 -alkoxycarbonyl.

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

13. An oligomer according to any of the preceding claims, comprising monomer fragments (M 0 , ... , Mn) of the general formulae M 2 S, M 2 R, M 3 R, M 3 s and/or M 4 3/ R3 R3 " R 2 R 3 R 3 ' R22' R R, R R 4 '". N---N R 4 R O R 5 '6 R... W R6 R. R6 R R R 5 R 6 R 5 R6R R 5 ' R 6 M 2 S M 3 R M 4 / 3 R3 ' O O- R 2 R -,-R IR 4"""N--- R'N-- R 4 R4 R *" R6 R R 5 R 6 R R M 2 R M 3 S wherein each of the substituents R 2 , R2', R 3 , R 3 , R 4 , R 4' , R 5 , R 5 ' , R 6 , and R 6' independently is as defined for X 0 , ..., and X.

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 O Xo oox K O Xn N II n (in short K-C(=O)-M 0 -...- Mn-W, wherein M 0 , ..., Mn designate "piperidine monomers" and W designates the biradical _yayb_) WO 99/03832 PCT/DK98/00330 58 wherein n is a positive integer; K-(C=0)- is a carboxylic acid or a derivative thereof; ya and yb together designate a linear biradical (_ya_yb_) comprising 1-20 backbone atoms; each of X 0 ,..., 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]. 2 0 alkyl, optionally substituted C 2 -20-alkenyl, optionally substituted C 4 - 2 0 -alkadienyl, optionally substituted C6- 2 0 -alkatrienyl, optionally substituted C 2 . 2 -alkynyl, hydroxy, C 1 - 20 -alkoxy, C 2 -2 0 alkenyloxy, carboxy, oxo, C 1 - 20 -alkoxycarbonyl, C 1 . 2 0 -alkylcarbonyl, formyl, aryl, aryloxy carbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxycarbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(CI. 6 -alkyl)amino; carbamoyl, mono- and di(CI- 6 alkyl)aminocarbonyl, amino-C _ 6 -alkyl-aminocarbonyl, mono- and di(CI- 6 -alkyl)amino-C_6 alkyl-aminocarbonyl, C 1 _ 6 -alkylcarbonylamino, guanidino, carbamido, C 1 . 6 -alkanoyloxy, sulphono, CI. 6 -alkylsulphonyloxy, nitro, sulphanyl, C 1 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 (_ya_yb_) is selected from -C(=O)-NH-(CH 2 )m-C(=O)-, -NH-C(=O)-(CH 2 )m-C(=O)-, -C(=O)-NH-(CH 2 )m , -NH-C(=O)-(CH 2 )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 1 . 6 -alkyl, CI-6 alkoxy, carboxy, C 1 .6-alkoxycarbonyl, C 1 . 6 -alkylcarbonyl, aryl optionally substituted 1-3 times with Cl- 4 -alkyl, C] 4 -alkoxy, nitro, cyano, amino or halogen, amino, mono- and di(Ci- 6 alkyl)amino, and halogen.

17. A cyclised oligomeraccording to claim 16, wherein the linear biradical is -C(=O)-NH (CH 2 )m-C(=O) - .

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, NH 2 , NHR, NRR', N(OH)H, NHNH 2 , NHNHR"', and OR", where each of R, R', R", and R'" independently designates optionally substituted C_ 6 -alkyl, optionally substituted C 2 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, O, OR", NH 2 , NHR, or NRR', where R and R' are selected from CI- 6 -alkyl and benzyl, and R" is selected from Cl- 6 -alkyl, C 2 - 6 -alkenyl, phenyl, and benzyl; in particular K designates OH, methoxy, or NH 2 .

21. A cyclised oligomer according to any of the claims 15-20, wherein each of Xo,..., and X n independently designates 0-3 substituents, where AI1%TfHVfH QHWWT ADToTr V Im WO 99/03832 PCT/DK98/00330 59 (a) such optional substituents are selected from optionally substituted C. 6 -alkyl, optionally substituted C 2 . 6 -alkenyl, hydroxy, C 1 - 6 -alkoxy, C 2 - 6 -alkenyloxy, carboxy, oxo, C 1 . 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 1 - 6 -alkyl)aminocarbonyl, CI. 6 -alkylcarbony lamino, sulphono, C 1 -. 6 -alkanoyloxy, and halogen, where aryl and heteroaryl may be optionally substituted with 1-3, preferably 1-2, substituents selected from C- 4 -alkyl, C 1 - 4 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.

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

23. An oligomer according to claim 22, wherein each of X 0 , ..., and Xn independently designates 0-2 substituents, where such optional substituents are selected from CI. 6 -alkyl which may be substituted with a substituent selected from hydroxy, Cl- 6 -alkoxy, aryloxy, and carboxy, where aryl may be substituted 1-3 times with Cl 4 -alkyl, C 1 - 4 -alkoxy, nitro, cyano, amino or halogen; hydroxy; C 1 _ 6 -alkoxy; C 2 . 6 -alkenyloxy; carboxy; C 1 . 6 -alkoxycarbonyl; amino; mono- and di(CI. 6 -alkyl)amino; mono- and di(CI. 6 -alkyl)aminocarbonyl; and C- 6 alkylcarbonylamino.

24. An oligomer according to claim 22, wherein each of X 0 , ... , and Xn independently designates 1-2 substituents, where such substituents are selected from Ci. 6 -alkyl which may be substituted with a substituent selected from hydroxy, C . 6 -alkoxy, aryloxy, and carboxy; hydroxy; C 1 _ 6 -alkoxy; carboxy; and Cl- 6 -alkoxycarbonyl.

25. An oligomer according to any of the claims 15-24, wherein in at least one of each of X 0 , ... and X n 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 0 , ..., and X n is selected from hydroxy and hydroxymethyl.

27. A cyclised oligomer according to any of the claims 15-26, comprising monomer fragments (M 0 , ..., Mn) of the general formulae M 2S , M 2 R, M 3 R, M 3s and/or Mc 4 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 R 2 , R 2' , R 3 , R", R', R 4', R', R', R 6 , and R 6' is selected from hydroxy, hydroxymethyl and carboxy. AM XWNDl RIFT (A TT T11 . 1I WO 99/03832 PCT/DK98/00330 60

30. A method for the preparation of an oligomer of the general formula I (K-C(=O)-M 0 -... Mn-T, where M 0 , ..., M, 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)-M 0 -...- Mn-T immobilised to a solid support material; and (b) cleaving the oligomer K-C(=O)-M 0 -...- Mn-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(=O) M 0 -...- Mn-W, where M 0 , ... , M, designate "piperidine monomers" and W designates the biradical _ya_yb_) as defined in any of the claims 11-18, comprising the following steps: (a) providing an optionally functional group protected oligomer -C(=O)-M 0 -...- M,-W immobilised to a solid support material; and (b) cleaving the oligomer K-C(=O)-M 0 -...- M,-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)- {M 0 }-...-{Mn}- {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(=O)-{M 0 }-... {Mn}-{T} immobilised to a solid support material; and (b) cleaving the array of oligomers K-C(=O)-{Mo 0 }-...-{Mn}-{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)-{M 0 }-...-{Mn) {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(=O) {M 0 }-...-{Mn}-{W} immobilised to a solid support material; and (b) cleaving the array of cyclised oligomers K-C(=O)-{M 0 }-...- {M,}-{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. A JtXVTTrIMI CTTEI' d A -~'A~ -. -1 WO 99/03832 PCT/DK98/00330 61

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.