EP1144434A2

EP1144434A2 - Combinatorial process for preparing polyamines

Info

Publication number: EP1144434A2
Application number: EP99936759A
Authority: EP
Inventors: Lloyd James Payne; Neal David Hone
Original assignee: Millennium Pharmaceuticals Ltd
Current assignee: Millennium Pharmaceuticals Ltd
Priority date: 1998-12-16
Filing date: 1999-06-16
Publication date: 2001-10-17
Also published as: CA2355880A1; EP1144434A3; WO2000035941A2; WO2000035941A3

Abstract

A process for preparing polyamines of, for example, formula (A) includes a step (a) of treating a compound which incorporates a moiety of formula: (I) SS-NR-Rc-NH- with a compound which incorporates a moiety of formula: (II) -NR1-Rb-L and optionally derivatising the product of the reaction, wherein SS represents a solid support and linking means for linking the group -NR- of moiety (I) to the support, R represents a hydrogen atom or an optionally-substituted alkyl or aryl group, R1 represents a hydrogen atom or an optionally-substituted alkyl or aryl group, R?b and Rc¿ each independently represents an optionally-substituted alkylene or alkenylene group and L represents a leaving group and wherein A1 is a substituent group.

Description

PROCESS FOR PREPARING POLYAMINES

This invention relates to a process for preparing polyamines and particularly, although not exclusively, relates to a solid phase process and/or a process which can readily be used in a combinatorial or parallel array technique-

Several naturally occurring polyamine amide compounds have shown neurological activity and have glutamate receptor antagonist activity. Hitherto, they have been considered for use in the treatment of neurological disorders such as Alzheimer's disease, Huntingdon's chorea, stroke and brain trauma.

Traditionally, the compounds have been isolated from natural sources such as spider and wasp venom's; however, isolation and purification of the compounds can be problematical.

Attempts have been made to synthesise polyamine amides, for example as discussed in Pharmaceutical Sciences (1997), 3,223-233, Chem Letts (1993) 929-932, Chem Pharm Bull 44(5) 972-979 (1996) and by I.R. March and M. Bradley in Tetrahedron 1997, Vol 53, pages 17317 to 34. In the latter reference, a protected polyamine is prepared in solution and is then attached to a resin and used in a solid phase process. However, the solution preparation is hard, tedious and time-consuming and it is difficult to prepare polyamines in a parallel manner. Consequently, desired amines tend to be made one at a time, using the known art. It is an object of the present invention to provide an advantageous process for preparation of symmetrical and unsymmetrical polyamines.

According to a first aspect of the invention, there is provided a process for preparing a polyamine compound which includes a step (a) of treating a compound which incorporates a moiety of formula:

SS-NR-R^C-NH- I

with a compound which incorporates a moiety of formula:

-NR¹-R^b-L II

and optionally derivatising the product of the reaction, wherein SS represents a solid support and linking means for linking the group -NR- of moiety I to the support, R represents a hydrogen atom or an optionally-substituted alkyl or aryl group, R¹ represents a hydrogen atom or an optionally-substituted alkyl or aryl group, R^b and R^c each independently represents an optionally-substituted alkylene or alkenylene group and L represents a leaving group.

Unless otherwise stated in this specification, where any group is stated to be optionally-substituted, it may be substituted by one or more substituents. Suitably, it may be substituted by up to 4, preferably up to 3, more preferably up to 2, especially up to 1 substituent. Unless otherwise stated in this specification, where any group is stated to be optionally-substituted, optional substituents may be selected from halogen (preferably fluorine, chlorine or bromine) atoms and optionally substituted, preferably unsubstituted, alkyl, acyl, aryl, nitro, cyano, alkoxy, alkoxyalkyl, hydroxy, amino, alkylamino (including dialkylamino) , sulphinyl, alkylsulphinyl, carbamoyl (including alkylcarbamoyl and dialkylcarbamoyl) , sulphonyl, alkylsulphonyl, sulphonate, amido, alkylamido, alkoxycarbonyl, halocarbonyl (especially chlorocarbonyl) , haloalkoxy, and haloalkyl (especially fluoroalkyl or chloroalkyl) , groups.

Unless otherwise stated in this specification, an alkyl, alkenyl, alkylene or alkenylene group may have up to 12, suitably up to 10, preferably up to 8, more preferably up to 6, especially up to 4, carbon atoms.

Unless otherwise stated in this specification, an aryl group is suitably an aromatic or heteroaromatic group which preferably has 6 to 10 ring atoms and, more preferably, has 6 or 10 ring atoms. Examples of aromatic groups include phenyl, 1-naphthyl and 2-naphthyl groups of which the phenyl group is preferred. Heteroaromatic groups may include one or more 0, N or S atoms or combinations thereof.

The process suitably produces a compound which incorporates a moiety: WO 00/35941 _- _Δ4 _- PCT/GB99/01719

which may subsequently be optionally derivatized and/or a compound prepared may be detached from said SS moiety and/or said compound prepared may be optionally derivatized after detachment.

Preferably, R represents a hydrogen atom or an optionally-substituted, preferably an unsubstituted, alkyl group. More preferably, R represent a hydrogen atom.

R^b and R^c may independently have up to 10, suitably up to 8, preferably up to 6, more preferably up to 4, carbon atoms in a straight chain. R^b and R^c may have the same number of carbon atoms in a straight chain in which case compounds which include moiety III (and compounds moieties produced in downstream processes) may be symmetrical polyamines. However, R^b and R^c may have a different number of carbon atoms in a straight chain in which case compounds which include moiety III (and compounds/moieties produced in downstream processes) may be unsymmetrical polyamines. Unsymmetrical polyamines can be quite difficult to prepare by known processes; however, the process described herein can relatively easily be used to make such compounds. Preferably, R and R^c independently have 3 or 4 carbon atoms in a straight chain. More preferably, R^c has 4 carbon atoms and R^b has 3 carbon atoms in a straight chain. R^b and R^c may independently be optionally substituted by 1 or 2 optionally-substituted, preferably unsubstituted, alkyl groups, wherein each alkyl group suitably has 1 to 3 carbon atoms.

R¹ suitably represents a hydrogen atom or a Cι-ιo, preferably Cι-₈, more preferably Cι_₆, especially Cι-₄, alkyl group or an aryl group, said alkyl or aryl group being optionally-substituted, preferably by one or more substituents selected from halogen atoms, amino groups, alkylamino groups, dialkylamino groups, cyano groups, hydroxy groups, alkyl groups (except when the substituted group is alkyl) , aryl groups, carbamoyl groups, alkylcarbamoyl groups, dialkylcarbamoyl groups and carboxy groups and esters thereof.

Suitably, in said moiety II (and suitably in other moieties which include R¹) , R¹ represents a hydrogen atom or an optionally-substituted, preferably an unsubstituted, alkyl or aryl group. Preferably, R¹ represents a hydrogen atom or an optionally-substituted alkyl group.

Said moiety of formula I may be part of a structure of formula:

SS-NR-R^C-NHP¹ IV

wherein P¹ represents a protecting/activating group. P¹ is preferably an electron-withdrawing group. It is preferably adapted to increase the acidity of the hydrogen atom of the group -NHP¹. P¹ preferably forms a sulphonamide group with moiety I. Thus, P¹ preferably represents a moiety: -SO2-X¹ V

wherein X¹ represents an optionally-substituted aryl, especially phenyl, group. Said optionally-substituted aryl group may include one or more substituents. Preferred substituents are electron-withdrawing groups. A nitro group is a preferred optional substituent. A 4- nitro or a 2,4-nitro is especially preferred. Preferably, X¹ represents a di-nitrophenyl group.

The mechanism of the reaction of moieties I and II is believed to involve attack of the nucleophilic nitrogen atom of moiety -NH- of moiety I with a carbon atom adjacent to leaving group L in moiety II. L is preferably an electron-withdrawing group. Consequently, the leaving group L is displaced.

L may need to be activated to act as a leaving group in the reaction. L may be any leaving group which may be electronegative and/or be capable of functioning in the mechanism referred to. L may be a halogen atom, preferably a bromine or chlorine atom, especially a bromine atom, or a hydroxy group. The ability of the hydroxy group to act as a leaving group may be caused and/or enhanced by other reagents used in the reaction.

Said moiety of formula II may be part of a structure of formula:

P²NR^X-R^b-L VI wherein P² represents a protecting group. Preferred protecting groups include N-l- (4, 4-dimethyl-2, 6- dioxocyclohex-1-ylidene) ethyl and Triethlsilyloxycarbonyl (TEOC) . The former is preferred.

Preferably, SS represents a solid support resin which includes linking means. Said linking means may include a -O-CO- moiety, the carboxy end of which is suitably bonded to the nitrogen atom of the moiety -NR- of moiety I. The alkoxy end of the -0-CO- moiety may be bonded to the resin by suitable means which is preferably an alkylene group, especially a -CH₂- group. Said solid support resin may be any suitable resin, for example a polystyrene resin. Suitably, the linking means is a Wang linker.

In Step (a) , swollen resin of formula I (which may suitably be swollen in anhydrous tetrahydrofuran) , triphenylphosphine and a said compound which incorporates moiety II (especially compound VI) may be stirred together and, subsequently, a coupling agent, suitably diethylazodicarboxylate, is added, slowly. The mixture may be stirred for about 12 hours, filtered, washed and dried. The product of the reaction suitably incorporates moiety III and is suitably protected by groups P² and P¹ and is, therefore, of formula:

Said compound VI may be prepared by a reaction known to a person skilled in the art, wherein P² is a protecting group.

Said compound IV may be prepared in a step (-b) which comprises reaction of a compound of general formula:

SS-NR-R^C-NH₂ VIII

with a compound of formula P¹---² wherein L² is a leaving group, especially a chlorine atom. The reaction is preferably carried out in the presence of a base, for example 2,6-lutidine and in an organic solvent.

Said compound of formula VIII may be prepared in a step (-c) by reaction of a compound of formula

HRN-R^C-NH₂ IX

with a structure SS-L³ wherein L³ represents a leaving group which may include an imidazole moiety.

Compound VII and/or said compound incorporating moiety II can readily be derivatised to produce a wide range of compounds, suitably in a parallel array or combinatorial chemistry technique. In a first embodiment, compound VII and/or said compound incorporating moiety III may be treated with a further compound which incorporates a moiety of formula II (which moiety may include R¹, R^b and L which are the same as or different to such groups used in Step (a) ) as described above thereby to prepare a compound which incorporates the moiety

or is of formula

wherein R^b(2), R^x(2) and P²(2) may be any group described herein for R^b, R¹ and P² respectively except that they may be the same or different to groups R^b and R¹ used in Step (a) and P² as described above.

In the derivatisation reaction of the first embodiment, said compound of formula VII may be reacted to remove P¹ and replace it with, for example another protecting group (e.g. Boc) and P² may be removed and replaced with a protecting/activating group of type P¹ discussed above. The derivatised compound VII prepared may then be treated, for example with a structure of formula:

P²NR¹(2)-R^b(2)-L

wherein P² and L are as described above (although they could be different from P² and L used in Step (a) ) . The reaction may be carried out under conditions as described above for Step (a) .

The derivatisation of the first embodiment may be further repeated to add successive groups -NR¹ (3) -R^b(3) - etc.

Compound VII (or derivatives thereof prepared as described in said first embodiment) may be derivatized by a range of compounds, for example amino acids, may be coupled to moiety -NR¹- (or -NR¹ (2), -NR¹ (3) if provided) , thereby replacing protecting group P² and, in turn, other compounds, for example further amino acids, may be coupled to said compounds initially coupled to moiety -NR¹- (or -NR¹ (2), -NR¹ (3), if provided) and/or derivatisation reactions effected. Further coupling reactions may also be effected by techniques known to those skilled in the art.

In general terms, a suitably deprotected compound VII and/or said compound incorporating moiety III may be treated with a first reagent (which may be protected) to replace group P² in compound VII with a residue of said first reagent. The product (or a derivative), suitably deprotected, may be treated with a second reagent (which may be protected) so that said second reagent becomes bonded to a said residue of said second reagent. Such treatments may be repeated to react further reagents with the derivative of compound VII.

Suitably, said first reagent is di-functional. Said first reagent preferably includes an aryl group (or a precursor thereof) . Said first reagent preferably includes an amine group (or a precursor thereof) . Thus, suitably said first reagent (and a or any subsequent reagent) is an amino acid (or a precursor thereof, for example a protected version or derivative thereof) .

Suitably, said second reagent is di-functional. Said second reagent preferably includes an aryl group (or a precursor thereof) . Said second reagent preferably includes an amine group (or a precursor thereof) . Thus, suitably said second reagent is an amino acid (or a precursor thereof, for example a protected version or derivative thereof) . Further reagents which may be reacted with said second reagent may have any feature of said second reagent as described above.

More specifically, said compound of formula VII may be reacted in a step (b) to substitute the group P¹ with another group which may be another protecting group P³ or an electrophilic reagent. Group P³ may be an acyl, -Boc, alkyl, or sulphonyl group. Thus, the product of step (b) may be a compound of formula

Protecting group P² may next be removed from compound

(X) in a step (c) so that P² is replaced by a hydrogen atom (such a compound being referred to as compound XI) .

Step (c) may involve reaction in hydrazine and an organic solvent or may involve any suitable deprotection reaction.

Next, in Step (d) , a compound may be coupled to the free -NH₂ group of compound XI. For example, an amino acid, suitably an amino acid which is protected by a protecting group orthogonal to the group binding portions of compound X to the solid support of SS, such as an Fmoc protected amino acid (i.e. "Fmoc AA") , may be coupled to said free -NH₂ group. Suitably, an amino acid selected from those shown in Summary 1 or Summary 2 hereinafter, especially those in Summary 1, may be coupled to said group. Thereafter, other compounds, for example other amino acids, may be coupled, for example to the aforementioned amino acid, in order to produce more complex compounds using procedures know to those skilled in the art. Suitably, an amino acid selected from those shown in Summary 1 or Summary 2 hereinafter, especially those in Summary 2, may be coupled.

Subsequently, the desired compound prepared may be cleaved from the resin and/or optionally derivatised as may be desired.

Such a compound may incorporate a moiety

Preferably such a compound is of general formula

wherein A¹ is a substituent group which may comprise one or more optionally derivatised amino acid residues or is a salt of the aforementioned compound.

More preferably, such a compound may be of formula

wherein R, R^c, R^b and R¹ are as described in any statement herein; W is a hydrogen atom or an optionally- substituted, preferably unsubstituted, alkyl or aryl group; Z is an amino acid residue, especially an aromatic amino acid residue; n is zero or a positive integer, preferably in the range 0-10, more preferably 0-4, especially 0 to 1; R² and R³ are the same or different from each other and each represents a hydrogen atom or a group of formula R⁶, R⁶CO-, R⁶OCO- or R⁶NHCO- where R⁶ represents an optionally-substituted alkyl group, suitably a Ci-io, preferably a Ci-e, more preferably a Ci-β, especially a Cι- , alkyl group, or an optionally- substituted aryl group, wherein preferred optional substituents of said alkyl and aryl groups are selected from halogen atoms, amino groups, alkylamino groups, dialkylamino groups, cyano groups, hydroxy groups, alkyl groups (except when the substituted group is alkyl) , aryl groups, carbamoyl groups, alkylcarbamoyl groups, dialkylcarbamoyl groups and carboxy groups and esters thereof; R^a represents an optionally-substituted straight or branched chain alkylene or alkenylene group, preferably an alkylene or alkenylene group having 1 to 6 carbon atoms each optionally-substituted by from 1 to 4 alkyl groups each having from 1 to 3 carbon atoms; and Q represents an amidino group, a cyano group or a group of formula XYN-, wherein X and Y are the same or different, and each may represent a hydrogen atom, an alkyl group, (suitably a Ci-io, preferably a Cι_₈, more preferably a Cι-₆, especially a Ci_₄ alkyl group) or a simple heteroatom-containing group or, together with the nitrogen atom to which they are attached, form a nitrogen-containing heterocyclic group.

The process described according to said first aspect may be used to prepare any of the polyamine compounds described in any of the documents cited in the introduction of this specification; and any of the polyamine compounds described in PCT/GB89/03775 and the polyamine compounds described in each of the aforementioned documents are incorporated herein by reference. According to a second aspect of the invention, there is provided a process for preparing a plurality of different polyamine compounds which includes a step of:

(a) selecting a plurality of different compounds of general formula I or a plurality of different compounds of formula II or a plurality of different compounds of both formulas I and II and reacting compounds of formula I with compounds of formula II, for example in a combinatorial or parallel array technique, followed by optional derivatisation, thereby to prepare a plurality of different polyamine compounds; OR

(b) derivatising a product of a reaction of a compound of general formula I with a compound of general formula II with a plurality of different compounds, followed by optional derivatisation of the product thereof, thereby to prepare a plurality of different polyamine compounds.

According to a third aspect of the invention, there is provided a library of compounds prepared in a process according to said second aspect.

According to a fourth aspect of the invention, there is provided a product of a process according to said first or second aspect.

According to a fifth aspect of the invention, there is provided any novel intermediate described in any statement herein.

Any feature of any aspect of any invention or embodiment described herein may be combined with any feature of any aspect of another invention described herein.

Specific embodiments of the invention will now be described, by way of example. In the Examples, the following abbreviations are used:

Arg arginine;

Boc t-butoxycarbonyl;

DCM dichloromethane

Dde N-l, 4 (4, 4-dimethyl-2, 6-dioxocyclohex-l- ylidine) ethyl; DEAD diethyl azodicarboxylate; DIC di-isopropylcarbodiimide; DMF dimethylformamide; Fmoc N-fluorenylmethoxycarbonyl; HOBt Nl-hydroxybenzotriazole; Lys lysine; Pbf 2,2,4, 6, 7-pentamethyldihydrobenzofuran-5- sulfonyl; Phe phenylalanine; RP-HPLC reverse phase high performance liquid chromatography; THF tetrahydrofuran; TFA trifluoracetic acid; TBTU 2 (lH-benzotriazole-1-yl) -1,1, 3,3- tetramethyluronium tetrafluoroborate TEOC 2- (Trimethylsilyl) ethoxycarbonyl. Example 1 - Preparation of Arginine-L-phenylalanine- spermidine - an unsymmetrical polyamine.

Wang resin (0.03 mmol, 50 mg) was swollen in anhydrous tetrahydrofuran (1.0 ml) and carbonyl diimidazole ( 4 equivalents, 0.12 mmol, 19 mg) was added. The resulting mixture was then stirred at ambient temperature for 16 hours, after which it was filtered and washed with tetrahydrofuran, ethanol and dichloromethane. The resin was then dried in vaci-o.

The resin was re-swollen in anhydrous dichloromethane (1.0 ml), and 1, 4-diaminobutane (10 equivalents, 0.3 mmol, 25 mg) were added. The resulting mixture was stirred for 2 hours and then filtered and washed (dimethylformamide, methanol, dichloromethane) , after which it was dried in vacuo.

The resin was again swollen in anhydrous dichloromethane (1.0 ml), and 2,6-lutidine (5 equivalents, 0.15 mmol, 16 mg) were added, followed by the careful addition of 2, 4-dinitrobenzenesulfonyl chloride (4 equivalents, 0.12 mmol, 32 mg) . The mixture was stirred under an inert atmosphere for 2 hours and then washed (dimethylformamide, methanol, dichloromethane) and dried in vacuo.

The resulting resin was then swollen in anhydrous tetrahydrofuran (1.0 ml) and triphenylphosphine (4 equivalents, 0.12 mmol, 32 mg) . Dde-protected aminoalcohol (4 equivalents, 0.12 mmol, 29 mg) (prepared as described below) were added and dissolved with stirring. Diethyl azodicarboxylate (4 equivalents, 0.12 - ID —

mmol, 21 mg) was added dropwise and the mixture was stirred for 12 hours and then filtered and washed (dimethylformamide, methanol, dichloromethane) . It was then dried in vacuo.

The resin was then swollen in dichloromethane (1.0 ml), and propylamine (5 equivalents, 0.15 mmol, 13 mg) was added. The mixture was then stirred for 1 hour after which it was filtered and washed (dimethylformamide, methanol, dichloromethane) and then dried in vacuo.

The resin was again swollen in dichloromethane (1.0 ml), and di-t-butyl dicarbonate (10 equivalents, 0.3 mmol, 33 mg) and N,N-dimethylaminopyridine (5 mol%, 0.0015 mmol, 0.2 mg) were added, and the mixture was stirred for 16 hours. The resin was then filtered and washed (dimethylformamide, methanol, dichloromethane) , and then dried in vacuo.

The resin was then stirred in 2% hydrazine hydrate/dimethylformamide (1.0 ml) for 1 hour and then washed (dimethylformamide, methanol, dichloromethane) , after which it was dried in vacuo.

Fmoc-Phe-OH (4 equivalents, 0.12 mmol, 46 mg) , TBTU (4 equivalents, 0.12 mmol, 39 mg) and diisopropylethylamine (8%, 0.48 mmol, 62mg) were dissolved in anhydrous dimethylformamide (1.0 ml), and the mixture was added to the resin. The whole was then stirred for 12 hours, and then filtered and washed (dimethylformamide, methanol, dichloromethane) and dried in vacuo. To the resin was added 20% piperidine/dimethylformamide (1.0 ml) and the mixture was stirred for 0.5 hour. It was then filtered and washed

(dimethylformamide, methanol, dichloromethane) and then dried in vacuo.

Boc-Arg(Pbf) -OH (4 equivalents, 0.12 mmol, 63 mg) , TBTU (4 equivalents, 0.12 mmol, 39 mg) , and diisopropylethylamine (8 equivalents, 0.48 mmol, 62 mg) were dissolved in dimethylformamide (1.0 ml) and the mixture was added to the resin. The whole was then stirred for 12 hours and then filtered and washed

(dimethylformamide, methanol, dichloromethane) . It was then dried in vacuo.

50%TFA/45%dichloromethane/2.5%H₂0/2.5% triisopropylsilane (1.0 ml) was added to the resin and the mixture was stirred for 1 hour. The resin was filtered and washed with dichloromethane (1.0 ml) and the filtrate was concentrated in vacuo. The resulting viscous yellow oil was triturated with anhydrous diethyl ether (3x2 ml) to yield the title compound as shown below as its tetrakis TFA salt (19 mg, 70%) :

Analysis :

LCMS - 90% (ELS detection) . M/z 449 (ES⁺) NMR:- H NMR was found to be in accordance with the above structure

In the above described process, the following Dde protected aminoalcohol was used:

The Dde protected aminoalcohol was prepared as follows: To a solution of 3-amino-l-propanol (1.5 g, 20 mmol) in ethanol was added 2-acetyl dimedone (1.1 equivalents, 22 mmol, 4.0 g) and the mixture was heated to

50°C for 1 hour. The resulting solution was concentrated in vacuo to yield a red crystalline solid that was triturated with hexane to afford an off-white solid

(4.74g, 95%).

Examples 2 - Preparation of other polyamines

Polyamines having the general structure :

[Po_rti n2_HPo_rtion1 _N^_N^ _N

H H

E-I

wherein Portions 1 and 2 are amino acid residues as described hereinafter and wherein n represents 3 or 4 and m represents 4 were prepared using the following general method which is summarised in Scheme 1. Step 1

Wang resin (0.03 mmol) was swollen in anhydrous THF (1.0 ml) and carbonyl diimidazole (4 eq, 0.12 mmol) added portionwise. The resulting mixture was stirred at ambient temperature for 16 hours then filtered and washed with THF, Et₂0 and DCM. The resin was then dried in vacuo (Step 1) .

Step 2

The resin was re-swollen in anhydrous DCM (1.0 ml) and a symmetrical diamine (NH₂- (CH₂)_m-NH₂) (10 eq, 0.3 mmol) added portionwise. The resulting mixture was stirred for

2 hours then filtered and washed (DMF, MeOH, DCM) then dried in vacuo.

Step 3

The resin was again re-swollen in anhydrous DCM (1.0 ml) and 2,6-lutidine (5 eq, 0.15 mmol) added followed by the careful addition of 2, 4-dinitrobenzenesulfonyl chloride (4 eq, 0.12 mmol). The mixture was stirred under an inert atmosphere for 2 hours then washed (DMF, MeOH, DCM) and dried in vacuo.

Step 4

The resulting resin was then swollen in anhydrous THF (1.0 mol) and triphenylphosphine (4 eq, 0.12 mmol), Dde- protected aminoalcohol (DdeHN- (CH₂)_n-OH) (4 eq, 0.12 mmol) were added and dissolved with stirring. Diethylazodicarboxylate (4 eq, 0.12 mmol) was added dropwise and the mixture stirred for 12 hours then filtered and washed (DMF, MeOH, DCM) then dried in vacuo.

Step 5

The resin was then swollen in DCM (1.0 ml) and n- propylamine (5 eq, 0.15 mmol) added and the mixture stirred for 1 hour then filtered and washed (DMF, MeOH, DCM) then dried in vacuo.

The resin was again swollen in DCM (1.0 ml) and di-t- butyldicarbonate (10 eq, 0.3 mmol) and N,N- dimethylaminopyridine (5 mol%, 0.0015 mmol) added and the mixture stirred for 16 hours. The resin was then filtered and washed (DMF, MeOH, DCM) then dried in vacuo.

Step 6

The resin was then stirred in 2% hydrazine hydrate/DMF (1.0 ml) for 1 hour then washed (DMF, MeOH, DCM) and dried in vacuo.

Step 7

The Fmoc derivatives of the amino acids shown in Summary 1 (wherein residues thereof are destined to become Portion 1 in the polyamines) were prepared (hereinafter referred to, generally, as "Fmoc AA1") . Then, Fmoc AA1 (4 eq, 0.12 mmol), TBTU (4 eq, 0.12 mmol) and diisopropylethylamine (8 eq, 0.48 mmol) were dissolved in anhydrous DMF (1.0 ml) and the mixture added to the resin. The whole was then stirred for 12 hours then filtered and washed (DMF, MeOH, DCM) and dried in vacuo.

Step 8

To the resin was added 20% piperidine/DMF (1.0 ml) and the mixture stirred for 0.5 hours then filtered and washed (DMF, MeOH, DCM) then dried in vacuo.

The Boc derivatives of the amino acids shown in Summary 2 (wherein residues thereof are destined to become Portion 2 in the polyamines) were prepared (hereinafter referred to, generally, as "Boc AA") . Then, Boc AA (4 eq, 0.12 mmol), TBTU (4 eq, 0.12 mmol), and diisopropylethylamine (8 eq, 0.48 mmol) were dissolved in DMF (1.0 ml) and the mixture added to the resin. The whole was then stirred for 12 hours then filtered and washed (DMF, MeOH, DCM) then dried in vacuo.

Step 9

50%TFA/45%DCM/2.5%H₂O/2.5% triisopropylsilane (1.0 ml) was added to the resin and the mixture stirred for 1 hour to remove the compound from the resin (Step 9) . The resin was filtered and washed with DCM (1.0 ml) and the filtrate concentrated in vacuo. The resulting viscous yellow oil was triturated with anhydrous diethylether (3x2 ml) to yield the required compound.

A wide range of compounds were prepared using the general method described and using the amino acids in Summary 1 to provide Portion 1 and the amino acids in Summary 2 to provide Portion 2. It will be appreciated that amino acid residues incorporated into compound E-I comprise the amino acids shown in Summary I and II but excluding hydrogen atoms from the -NH₂ and -C0₂H groups.

Table 1 summarises a 4, 4-polyamine library prepared - that is, a library wherein n and m represent 4; the left column in the table details respective Portion l's (identified by their letters in Summary 1) used to prepare the compounds; and the top row details respective Portion 2's (identified by their numbers in Summary 2) used to prepare the compounds. Table 2 summarises a 3, 4-polyamine library - that is, wherein n represents 3 and m represents 4 with Portions 1 and 2 being identified as before.

In tables 1 and 2, each box in the table represents a particular compound prepared and the Mass Spec (ES⁺) and HPLC Retention Time in minutes are provided in each box (where available) .

Summary 1 - amino acids used to form "Portion 1" amino acid residues.

B

H_j CO_jH

F Portion 1 absent Summary 2 - amino acids used to form "Portion 2' amino acid residues.

00

TABLE 2 - 3, -Polyamine Library.

Wang resin

Step 7 Fmoc AA1

Step θ

acid side chain of AA1 acid side chain of AA2 Example 3 - Alternative reagent for Step 4

As an alternative to the use of Dde-protected aminoalcohols in Step 4, TEOC may be used.

Example 4 - Derivatives of polyamines

Derivatives of the amines prepared in Examples 1 and 2 may be prepared by reaction with a compound having an electrophilic specie such as an acid chloride, sulphonyl chloride etc. In a specific example, the starting material of Step 5 may be acylated, instead of using di-t- butyldicarbonate to give a Boc protecting group. Acylation may be carried out using a standard technique, using an acid chloride or another activated acid, to produce peptidomimetics . Sulphonyl chlorides may be used to sulphonylate amine groups to produce derivatives.

Example 5

Step 4 in Example 4 may be repeated more than once in order to add further moieties -NH-(CH₂)_n- to the polyamine chain. To this end, after Step 5 in Scheme 1, the Dde group may be removed and the resultant free amine group re-sulphonated in a process analogous to that described in Step 3. The re-sulphonated product may then be treated with a Dde-protected amine alcohol in a process analogous to that described in Step 4. Step 5 may be repeated. Subsequently, further moieties -NH-(CH₂)_n- may be added in the manner described or Step 6 and subsequent steps described may be carried out. Thus, the product of Step 6 may be of formula

wherein N is an integer of 1 or greater and wherein n may be the same or different for each repeat unit N.

The reader' s attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

All of the features disclosed in this specification

(including any accompanying claims, abstract and drawings) , and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive.

Each feature disclosed in this specification (including any accompanying claims, abstract and drawings), may be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features.

The invention is not restricted to the details of the foregoing embodiment (s) . The invention extend to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings) , or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

Claims

1. A process for preparing a polyamine compound which includes a step (a) of treating a compound which incorporates a moiety of formula:

SS-NR-R^C-NH- I

with a compound which incorporates a moiety of formula:

-NR¹-R^b-L II

and optionally derivatising the product of the reaction, wherein SS represents a solid support and linking means for linking the group -NR- of moiety I to the support, R represents a hydrogen atom or an optionally-substituted alkyl or aryl group, R¹ represents a hydrogen atom or an optionally-substituted alkyl or aryl group, R and R^c each independently represents an optionally-substituted alkylene or alkenylene group and L represents a leaving group.

2. A process according to claim 1, wherein said process produces a compound which incorporates a moiety:

3. A process according to claim 1 or claim 2, wherein said moiety of formula I is part of a structure of formula:

SS-NR-R^C-NHP¹ IV

wherein P¹ represents a protecting and/or activating group.

4. A process according to any preceding claim, wherein said moiety of formula II is part of a structure of formula:

P²NR¹- ^b-L

wherein P² represents a protecting group.

5. A process according to any preceding claim, wherein the product of the reaction of moieties of formula I and II is of formula

wherein P¹ represents a protecting and/or activating group and P² represents a protecting group.

6. A process according to any preceding claim, wherein the polyamine prepared by reacting moieties I and II and/or moiety III and/or moiety VII are derivatised in a subsequent process step.

7. A process according to claim 6, wherein derivatisation involves treatment with a first reagent in order to incorporate a residue of said first reagent into said polyamine.

8. A process according to claim 7, wherein said first reagent is difunctional.

9. A process according to claim 7 or claim 8, wherein said first reagent includes an amine group or a precursor of an amine group.

10. A process according to any of claims 7 to 9, wherein said first reagent is an amino acid or a precursor thereof.

11. A process according to any of claims 7 to 10, wherein said polyamine is derivatised with a second reagent.

12. A process according to any preceding claim, wherein R represents a hydrogen atom or an optionally-substituted alkyl group; R and R^c independently have up to 10 carbon atoms in a straight chain; R¹ represents a hydrogen atom or an optionally-substituted Ci-io alkyl group or an optionally-substituted aryl group.

13. A process according to any preceding claim, wherein L is an electron-withdrawing group.

14. A process according to any preceding claim, wherein L represents a halogen atom or an hydroxy group.

15. A process according to any preceding claim, wherein the compound prepared in the process is of general formula

wherein A¹ is a substituent group.

16. A process for preparing a plurality of different polyamine compounds which includes a step of:

(a) selecting a plurality of different compounds which include moiety I and/or a plurality of different compounds which include moiety II and reacting compound (s) of formula I with compound (s) of formula II, followed by optional derivatisation thereby to prepare a plurality of different polyamine compounds; OR

(b) derivatising a product of a reaction of a moiety I with a moiety II with a plurality of different compounds, followed by optional derivatisation of the product thereof, thereby to prepare a plurality of different polyamine compounds;

wherein moieties I and II are as described in any preceding claim.

17. A library of compounds prepared in a process according to claim 16.

18. A product of a process described in any of claims 1 to 16.

19. Any novel intermediate of a process described in any of claims 1 to 16.