CA2180527A1 - Method of making polymers having specific properties - Google Patents

Abstract

A method of making a polymer having specific physiochemical properties by forming a first module having a structure which includes at least two structural diversity elements suitable to impart a desired physical property to a polymer which is made from said monomer; and reacting one or more modules to form a polymer having specific physiochemical properties. The base module can be formed by reacting a first compound having at least one structural diversity element and a first reactive group, with a second compound having at least one structural diversity element and a second reactive group, wherein the first and second groups combine by an addition reaction. Specifically, an aminimide compound, an oxazolone compound or derivatives thereof are useful as base modules in the invention.

Description

~ 2 1 80527 ~F.THOr) OF M~KTl`IG POLYMF.RS IIAVING SPECIFIC PROPERTTES
F rFT n OF T~F INVE~TION
The present invention relates to a novel method of controlled polymerization to produce encoded synthetic polymers, involving the stepwise assembly of discrete modules having selected structural features in a manner so as to produce a polymer having (l) a precisely ordered sequence of structural units; or (2) a precisely ordered sequence of structural units and a specific uniform chain length and molecular weight, depending on the particular strategy chosen; and (3) resultant physioçh~mi~T and biological properties which are the sum of the individual properties of the modules and their specific 5 arrangement in the polymer.
BAcKGRouNr) OF T~TF INVENTION
Existing polymeriztion methods fall into one of two basic 20 types; (1) Addition or Chain Growth Polyllleli~d~ion; and (2) Condensation or Step-Growth Polymerization.
Chain growth polymerizations most commonly utilize monomers possessing reactive carbon-carbon double bonds, although other species, such as cyclic ethers, e.g., ethylene and propylene oxide and aldehydes, e.g., formaldehyde, can be polymerized in this way. These chain-growth polyl,~c~ ions are Illal~ d by the fact that the free radical, ionic or metal complex inferm~Ai~f~s involved in the process are transient alld can not be isolated. A generalized example for a simple free radical initiated vinyl poly~ ion is shown below:

SUBSTlllJTE SHEET

WO 95/18627 ~ 2 1 8 0 5 2 7 PCTNS94/0~222 1. Fonnation Or illitiator (~Coo) ~,Ct~
5 2. Initiation ~- + ~R ~~R

3. Propa~alion ~R ~R ~R
R
( CH2CHR) CH2CHR. ~ by radtcal coup!ingOr chain tralts~er processes POLYMEiR
Step-growth polymerizations involve reactions which occur between molecules containing multiple reactive groups which 25 can react with each other. An example of this is the well-known reaction of a glycol and a dibasic aromatic acid to give a polyester.
It can be readily seen that the use of multiple reactive monomers posessing groups with similar or equivalent 30 reactivities with this method produces a mixture of individual polymer species having random al~angements of monomeric sequences and only statistical control of the resulting stoichiometric make-up.
While many different variations of these two classes of 35 polymerization reaction schemes exist ,e.g. initiation may be . cationic, radical, anionic, s~l, rll aldol, ring-opening or rlicplstt~-~.m~n~, and many different reactive species may be employed, e.g. electron deficient alkenes, epoxides, polyamines, SUBSTlTUTiE SHEET

2 1 8 0 5 2 7 PCTNS94100222 hydroxyesters, etc., all of these variations possess a common limiting feature - they all rely on a statistical or average stoichiometric control of the final polymeric product. This is achieved through the careful selectioD and control of the 5 reaction eonditions, such a concentration of monomers, agitation conditions, catalyst level, time/temperature cycles, etc.. These existing poly~ dtion methods do not have any ability to control the exact constitution or length of any specific individ~al polymer chain. The properties of the polymers produced via these processes are, in fact, a statistical average of the properties of a complex mixture of subtly differing individual polymer species having a range of molecular weights and c~nt~inin~ differing combinations and S~ Ccs of monomers along the chains. .Even in the simplest example of a step growth polymerization involving only two reactants, where the product is a polymer containing a single repeating structural motif, the product obtained will consist of a statistical mixture of a large number of individual molecules each having differing lengths and molecular weights.
In spite of these limitations, those skilled in the art have developed strategies by which these methods ean be exploited.
Average chain length ean be eontrolled roughly by the ratio of initiator to monomer, or by quenching with an additive giving a range of mnlpc~ r weights. Macroscopic properties can be mnd~ d by the addition of comonomers which are ir-- ~.oldtcd randomly into the backbone. However, these methods possess no ability to have discreet or even reproducible ~lCI~ e control, and the "address" of a singular 30 functionality added to the polymerization reaction is statistica~ly determined .
Most natural biological polymers, such as oligonucleotides, proteins and poly~ch~rirl~Ps, on the other hand, contain precise sequences of monomer units which confer the polymer with highly specific functional properties, including a specific three dimensional structure. Recent advances in the understanding of the complex mPrh~ni.~mc of biochemical processes and of the underlying structure-function relationships of biological SUBSmUTE SHEET

WO 95/18627 ' ' 2 1 8 0 5 2 7 PCTIIJS94/00222 polymers involved in the replication (DNA-DNA), storage (DNA), transcription (DNA-RNA), translation (RNA-protein), cl~mmllnic~tion, recognition, control (proteins, peptides, carbohydrates) and function (proteins, oligocz~ ch~ri-1es) of all 5 biological systems have. ill~lmin~fpd the exquisite sensitivity of these polymers to microsequence variations. A classic example of this is sickle cell anemia which has been shown to be due to a single point mutation in the genetic sequence encoding for the beta chain of hemoglobin. As a result of this mutation, the abnormal hemoglobin contains a single valine in place of a glutamine in the sequence of the protein. This results in an abnormal shape for the hemoglobin, producing the characteristic sickle-shaped cells and the resulting tragic pathological consequences The biosynthesis of these biopolymers can be viewed, at a molecular level, to consist of a highly organized series of individual catenation steps, each carried out with specific reactants under highly contl-olled csnrliti~ns and mediated by biocalytic agents, principally enzymes. All of the monomers 2 necessary for the constluction of these biological polymers are present in the vicinity of the reaction area and are carried by cllap~,lune m~ Ps to the site of their incorporation into the growing chain, where they are released and coupled. Since these polymers were designed by nature to carry out their highly specific functions under physiological conditions (water at pH 7 and physit)logi~l temperatures, etc.), and have been programmed by nature to be subject to natural biorhPmical transfr~rm~ti~ nc, such as proteolytic decomposition, they are usually not robust (notable exceptions include structural polymers such as chitin, cotton, skin, silk, hair and other structural materials ) and are easily decomposed or denatured by exposure to non-physiological conditions, such as elevated temperatures, organic solvents, extlemes of pH, etc.. As a result, 35 these mQl~PculPs are generally ill suited for tasks other than their proper biochemical ones.
Simply put, the makers of polymers, while being able to statistically achieve good and consistent macroscopic properties SUBSTITUTE SHEET

WO 95/18627 2 1 8 0 5 2 7 ~DSg4/00~22 in the polymeric materials which they produce, have not had any way, up to this point, to control the microscopic make-up of their product. Nature, in producing biomacromolecules, has eYolved systems which allow exquisite control over both the 5 microscopic make-up and the macro-structure of its functional polymers. However, these polymers are severely limited in the variety of uses to which they may be applied by their chemical constitution, their lack of stability tojwards chemical and bioc~ cAl agents and their sensitivity to changes in ellvil<,nlllcntal conditions; such as temperature. In addition, the nature of natural scaffolds and substituents and theil sensitiv~ty . to the chemical conditions necessary to manipulate and to transform them severely limits their utility in producing new materials from these components.

SUMMARY OF THE INVENTION
This invention relates to a method of making a polymer having specific phyciochPmic Al properties by forming a base module having a structure which includes at least two orthogonal l~,&-,livily or structural diversity elements suitable to impart a desired phycioch~-micAl property to a polymer which is made from said monomer; and reacting one or more modules to form a polymer having specific properties. The module is 25 preferablyan Aminimi~ compound, an oxazolone-compound, or a derivative thereof. The module is prepared from first and second components which provide the orthogonal reactivity elements. The module may contain 2, 3, 4 or more orthogonal reactivity elements, depending on the desired performance `~
properties of the resultant polymer.
The polymer chains are started with a terminus or start~r module containg a single reactivity element and are capped at the desired point in the synthesis with a second terminus or 35 capping module containing a single reactivity element in orde:r to control the length of the chain.
The base module can be formed by reacting a first compound having at least one structural diversity element and a SUBSmUTE SHEET

~ . 21 80527 first reactive group, with a second compound having at least one structural diversity element and a second reactive group, wherein the first and second groups combine by an addition reaction .
Preferably, the first compound is produced by forming an oxazolone cdompound having at least one structural diversity element attached thereto and reacting it with a nucleophile or carbonyl compound which contains at least one structural diversity element to form a base module having one of the o following structures:
N~= H >~11/
O
and wherein at least two of the I - -: ' lines are connf ct~d to structural diversity elements.
Alternatively, it is also preferred to provide the first compound as an :lminimi~l~-forming compound having at least 30 one structural diversity element attached thereto and to react it with an oxazolone or an oxirane compound, which contains at least one structural diversity element to form a base module having one of the following ~I.u~lu.c;s.
SUBSTITUTE SHEET

WO 95/18627 PCr/US94/00222 OH
~/~N)~

H Xl-- /3~
wherein at least two of the unconnected lines are connPctPd to structural diversity elements.
In particular, this method can be used to make polymers having a designed water solubility. This invention still further relates to the polymers produced according to these methods.
Still further, this invention relates to uniform polymers c~mrricin~ a multitude of long chain molecules each of which 20 have the same molecular weight and the same length.
This ability to produce polymeric chains of specific sequence and composition has great utility in the fabrication of a new generation of functional oligomeric and polymeric materials for a wide spectrum of ~rpli~ion~ such as drugs, chiral z5 recognition elements, catalysts, seperations tools, biomaterials, fibers, plastics, membranes, beads and gels.
DETAlr F.n DESCRIEYrION OF TT~F. INVENTION
The present invention discloses a fllntl~mPnt~lly new approach to the f~hric~ n of oligomeric and polymeric mtllPc~ s involving (1) the use of modular units which can contain at least two orthogonally reactive elements and are capable of bearing a wide variety of structural information, such 35 as specific geometry, functionality, substituents, etc. (2) the stepwise assembly of polymers from these modules (a) by carrying out catenation or coupling reactions one step at a time or (b) by constructing "sub assemblies" of modular units one SUBsnTuTE SHEET

` 2180527 WO 95/lgG27 PCT/IJS94/00222 step at a time and connecting them together in a concerted manner in such a way that the resulting polymer has a controlled (encoded) microsequence and a resultant overall functional activity, which is the sum of the functional activities 5 of the constituent modular parts. This approach involves the design and construction of a scaffolding superstructure which sets the basic spacing and geometry of the molecule and serves to arrange and orient the attached s~ stit~llqnt groups in a manner suitable to achieve the desired functional property and, ~imlllt~n~ously~ serves to allow the incorporation of desired pendant s~lbs~ nts in the appropriate positions having the appropriate desired relationships to each other and to the scaffold to produce the desired functional effect in the final polymer.
In this application, the term "polymer" is used to refer to any catenated structure con~:~ining a sufficient number of modules to carry enough structural information to impart the desired property to the resulting polymer, usuallyconsisting of a minimum of three monomers plus two terminus (starter and capping) modules.
A key element of this method is the presence of at least two orthogonal reactivity elements in the modules. Orthagonal reactivity elements are defined as those elements which are either (A) multiple reactive groups which are capable of being "turned on" independently of each other or (B) multiple differing reactive states which may be addressed or brought into being at different times or under different conditions in the catenation sequence. It is highly desirable, although not absolutely 30 necessary, that the individual reactions be high-yielding addition reactions with no by-products, so that isolation and purification steps are not necesary between cycles. The two basic schemes are illustrated below:

A. Multiple Reactive Groups SUBSmUTE SHEET

Slep 1. Coupling of "St2rter Module" with "Extender Module"
~R2 + R,~}R2 1 ~C~FI2 Step 2. Coupling of RExlender Module" with Chain 10 ~O~R2 + R~R [~C~R2 Step 3. Coupling of "Capping Module'' with Chain E¦C~ R2 + Rl ~ ~C~c[~
Where Rl and R2 = groups capable of undergoing addition 20 reactions with each other, and A, B, C, D are either mrnomprir modules or "sub assemblies" crnt:~injn~ multiple modules stitched together in a sequence specific manner.

B. Multiple Reactive States SUBSTITUTE SHEET

i - - 21 80527 St~p i Coupling of "S~lrter Modu~e' v itù '~tend~r Interrne tir te' ~F~ + Rl~
S~ep 2 Tr~nsforrn~Qon of Terr~onal Interrnediate Group to RellcQv~ Group Be~ring Module Step 3 Coupling of "E~teDder loterrnedi~le" v ith Chain E~Pe + Rl--(X) ~(X) Step 4 Tr~nsforn~tioD of Terr onal Int~rrneoiate Gnoup to Rei~cQve Group Be~riDg Module 15 EPE~ ~}
Step 5 Couprng of ~Cr~pp~ng Modub' v iQh Chain 2 0 [~)~ Re + R l--~ 3 Where Rl and R2 ale groups capable of undergoing addition reactions with each other, and A, B, C, D are either monomeric modules or "sub assemblies" ~ ~ ' v multiple modules stitched together in a sequence specific manner.
These reactive orthagonalities allow each discrete addition reaction to be carried to completion before the next individual addition reaction is undertaken. If desired, the in~rm.~
products may be isolated following each individual step. In this critical respect this method is fllnflslm~n~lly different from both chain and step-growth polymerization methods.
In addition to the stepwise sequential construction of polymers one unit at a time as illustrated, this method may be utilized to construct oligomeric "sub assemblies" having designed microsequences, and properties. These may then be connected SUBSTITUTE SHEET

` 2 1 80527 W~ 95118627 PCr/l~sg4loo222 together in a separate step to produce higher order assemblies, which may themselves again be connected together to, ultimately form a polymer having the desired set of properties.
This strategy requires that one of the orthogonal reactivity 5 elements on each sub-unit be either protected with an appropriate removable blocking group or contain a third orthogonally reactive group. These reactions may be carried out with modules c~-nt~ining > ~ orthogonally reactive elements to produce three ~lim-~nci~n~lly cross linked networks and structures. Alternatively these sub ~ccemhlies may be combined with appropriately functionalized "classical" modules to produce hybrid polymers.
A new approach to the stepwise sequential 5 construction of novel oligomeric and polymeric molecules is des~rihed This approach involves the development of a process whereby molecular building blocks which contain appropriate atoms and functional groups and posses at least two orthogonally reactive elements are cc ~ d together in a 20 stepwise s~l. -l fashion to allow the modular assembly of oligomers and polymers with tailored properties; each module contributing to the overall properties of the assembled molecu~e.
This approach to molecular construction is applicable to the synthesis of all types of mol~c~ s~ including but not limited to mimetics of peptides, proteins, oligonll~leotides, oligosacchalide classical polymers, variants, hybrids of these and to fabricated structures and materials useful in materials science. It is analogous to the modular construction of a mpch~nics~l device 30 that performs a specific operation wherein each module performs a specific task contributing to the overall operation of the device.
Examples of suitable modules cont~inin~ appropriate orthogonally reactive elements for utilization in this method are - given below:
Several of the specific modular chemistries chosen to illustrate and exemplify the invention are capable of bearing and nlS~int~inin~ chiral centers throughout the various steps SUBSTITUTE SHEET

involved. Where this is the case, the chirality will be shown. This is not intended to limit the scope of the invention to chiral m~t~.ri~lg, since there are a large number of variations and applications where structural stereocontrol is not required or 5 where achiral materials are employed POL~FR~ PRODU~I~ FROM 0XA70LOI~
07~:l7nlone Modllles A type of o~s~7~10n~ module appropriate for use in the present invention may be represented by the following general structure:

~o 2o ""
where R & R' are the same or different and X ~ sGIlt~ either a group having orthagonal reactivity to the oxazolone ring or a structural moiety, depending on which of two possible assembly 25 strategies is chosen, as outlined below. Rl and R2 differ from one another and taken alone each signifies one of the followng: alkyl including cycloalkyl and substituted forms thereof; aryl, aralkyl, alkaryl, and s l.s(i~ or heterocyclic versions thereof;
preferred forms of Rl and R2 are the side chain s~lhsti~ nts 30 occuring in native polypeptides, oligonucleotides, variants or mimetics of these, carbohydrates. pharmacophores, variants or mimetics of these, or any other side chain sllbstitll~nt which can be attached to a scaffold or a backbone to produce a desired interaction with a target system.

The ~..I.~l;l~ ..l~ R & R' may be of a subset of hydrophilic substitll~ntg such as, but not limited to hydroxymethyl, SUBS~lTUTE SHEET

hydroxyethyl, hydroxypropyl, thioethyl, thiomethyl;carboxymethyl, carboxyethyl, ethylcarboxamido, methylcarboxamido; aminomethyl, aminoethyl, aminopropyl, guanindinylpropyl, guanidinylbutyl; mono-, di-, and 5 triaminobenzyl, mono-, di-, and trinitrobenzyl; mono-, di-, tri-, and tetrahydroxy benzyl, mono- or polyhydroxyaryl (e.g.
pyrogallol); heteroaryl (e.g. alkylpyridines, imidazole, alkyltryptophans); alkyl nucleotides; all substituted pyrimidylalkyl and substituted purinealkyl moieties; mono-, di-, and oligosaccharide (e.g. N-methylfucosamine, maltose and the calicheamicin recognition sequence respectively);
alkylsulfonates, alkylphosphonates; a-polyfluoroketones;
secondary, tertiary and qua~ -yd---i~es; hydrazines and the l~ydl~l~illiulll salts.R and R' may also come from the subset 5 c-~nc;cfin~ of hydrophobic substituents such as, but not limited to: hydrogen; methyl, ethyl propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, iso-, sec-, and neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.; vinyl, propenyl, butenyl or other alkenyl groups; acetylenic side chains; aromatic polycyclics (e. g.
20 biphenyl, binaphthyl, naphthylphenyl, phenylnaphthyl); fused aromatic polycyclics(e.g. anthracene, phenylene, pyrene, Prerl ~rhfh~n~., azulenes); fused polycyclics (e. g. decalin, hy~llir~:lnl~.c steroids); phenyl, alkylphenyl, phenylalkyl; benzyl, mono-, di-, tri-, and tetraalkylbenzyl; mono-, di-, and trialkoxybenzyl; hc~cro.l,yl (e.g. furyl, xanthanyl, quinolyl);
methoxyalkyl, ethoxyalkyl, aryloxy; methylmercaptans, ethylmercaptans, alkyl thioethers and arylthioethers; dyes ancl fluorescent tags (such as rhod~mir~ or IIUU1e~CC;.~); alkyl esters,

3 O aryl esters, aralkyl esters, and alkylaryl esters .
Polymerization Strate~ies These oxazolone modules may be employed to construct 35 oligomers and polymers in two diffel-ent ways:
A. Rin~ Openin~ Reaction/2-Position Substituent Addition-SUBSTITUTE SHEET

Oxazolones with suitable substituents at the 2-position (X = an orthagonally reactive group) may act as orthogonally reactive agents suitable for the construction of the polymers which are the subject of the present invention. This 5 may be acc- mrlicll~d by carrying out Alt~r~ in~ ring opening and 2-position substituent addition reactions with suitable bifunctionally reactive species. One terminus of these reactive elements should contain an SH, OH or NH group capable of underegoing ring-opening addition reaction with the oxazolone 10 ring. The second terminus of the reactive element should contain a group capable of undergoing addition reaction with X. The choice of this second group, obviously, depends on the nature of the specific X group chosen in each case.Appropriate 2-position 6~ C include vinyl groups, which make the oxazolone a 5 Michael acceptor, haloalkyl and alkyl sulfonate esters and epoxide groups. This is shown below for the case of alternating ring opening and Michael additions to the double bond of a 4,4-disubstituted-2-vinyloxazolone by appropriate dinucleophillic 20 species produces pol/meric chains, as shown SU~STITUTE SHEEI-WO 95/18627 ' 2 1 8 0 5 2 7 PCT/US94/00222 H3C y O H3C ~f 5 ZNI ~H R~=
- HNu2ZNu1 (B) /o~O o ~ 4 CH3~ j~ Nu1 ~ NU ~<N~
R3 R~
(C) HNu3ZINu4H
CH3~ Nu~ ~Nu~N?<~N13 Nu~H

tO CH3e~ j~, Nu~ NU~ ~ Nu3 NU; " CH2~CHJ~ N~;~ N1'2 In the above sequence of reactions, HNu1-Z-Nu2H represents a structure containing two differentially reactive nucleophilic groups, such as methylamino-ethylamine, I-amino propane-3-thiol, and so on; groups Nul, Nu2, Nu3 and Nu4 need not be identical and Z is a generalized structural group connecting HNul and HNu2. HNul-Z-Nu2H may contain two nucleophilic groups of ~;UBSrlTUlE SHEET

differential reactivity, as stated above, or if Nul and Nu2 are of comparable reactivity one of the nucleophilic groups is protected to prevent it from competing with the other and deprotected selectively following acylation; protecting groups commonly used 5 in the art of peptide synthesis (e.g., for the nucleophilic groups such as amino, hydroxyl, thio, etc.) are useful in the protection of one of the Nu ,.,~ r.tb of the structure HNul-Z-Nu2H. The product of the acylation reaction with HNul-Z-Nu2H (after Nu-deprotection, if necessary) is further reacted with a new oxazolone unit in a Michael fashion, and this addition is followed by ring opening acylation with an additional dinucleophile;
repetition of this sequence of synthetic steps produces a growing polymeric molecule.
The Michael reaction step is usually calried out using 5 ~ ,.m,~ri~ amounts of n~ r~ le AXH and the oxa2010ne in a suitable solvent, such as toluene, ethyl acetate, dimethyl fr~rm~ . an alcohol, and the like. The selectivities of the Michael and oxazolone ring-opening processes impose certain limitations on the choice of the nucleophiles shown above.
20 Specifically, n~lelPorhil~s of the form ROH tend to add primarily via the ring-opening reaction, and usually require.
acidic catalysts (e.g., BF3); thus, Nu2 should not be OH.
Likewise, primary amines tend to add only via ring-opening, and Nu2 should therefore not be NH2 Secondary amines readily add to the double bond under appropriate reaction conditions.
Nl-"c,' l~s of the form RSH will exclusively add via ring-opening if the sulfhydryl group is ionized (i.e., if the basicity of the reaction mixture co~ undS to pH >9); on the other hand, 30 such nucleophiles will exclusively add via Michael reaction under non-ionizing (i.e., neutral or acidic) conditions. During the Michael addition, it is important to limit the presence of hydroxylic species in the reaction mixture (e.g., moisture) to avoid ring-opening side-reactions.
The ring-opening reactions can be carried out either in an organic solvent such as methylene chloride, ethyl acetate, dimethyl formamide (DMF) or in water at room or higher temperatures, in the presence or absence of acids, such as SUBSTITUTE SHEET

WO 95/18627 PCI~/IJS94/00222 carboxylic, other proton or Lewis-acids, or bases, such as tertiary amines or hydroxides, serving as catalysts.
An example of the application of this strategy is given below for the synthsis of a subunit c~ n~ining four structural 5 modules and the s~sequent assembly of these modules into a polymer containing repeating sequences of these specific subunits:
The required 4,4'-disubstituted oxazolone modules may be prepared from the appropriate N-acyl amino acid using any of a number of standard acylation and cyclization techniques well-known to those skilled in the arl, e.g.:
o XCOCI + x2 ~R1XR2 AL~ O

N

Rt R2 Alternative reactive groups may be introduced at the 2-position of the oxazolone in this way, as shown for a benzyl substituted reactive substituent:
x CH2~c--Cl + R~R
X-CH2~C N~CO H - x-CH2~~'oR' A wide variety of 4-monosubstituted a~lactones may be readily prepared by reduction of the corresponding SUB~i I IrUTE SHEET

`` ` 2180527 WO 9S/18627 PCrlUS94100222 unsaturated derivatives obtained in high yield from the condensation reaction of aldehydes, ketones, or imines with the oxazolone formed from an N-acyl glycine (49 J. Or~. ChPrn 2502 (1984); 418 Synthesis Commllnications (1984)) .
Ph lo ~ x~/ ~H

~Ph 11~' X~ H ~ r ~~O
These may be converted to 4,4'-disubstituted ~ 701~ '- by alkylation of the 4-position, as in the following transformation (Synthesis Commun.. Sept. 1984, at 763; 23 25 Tetr~hPAron l ett. 4259 (1982)):
Ph Ph 3 0 O~O X~
Other important bifunctionally reactive oxazolone dc~ which may be employed in these schemes include:
SUBSmUTE SHEET

/~ ~ Ar.~
B. Alternatin~ Se~u~.~c,~s of Nucleo~hilic 0~7~10ne~ in~-Openin~
Addition Reaction6 Followed by O~rl7-10ne-Forrnin~ Cycli7rltion Reactions Alpha,Alpha'-Disubstituted Sequences According to this approach, oxazolone modules are catenated via ring-opening nucleophilic attack by the amino group of an r~lrh~,~lrh~'-disubstituted amino acid; the resulting adduct is su~ y recyclized to form a terminal o~r~7olo (with retention of chirality). This is then subjected to another n~ ophilic ring-opening catenation reaction, producing a growing polymer as shown below. This ~luC~ lc is repeated 20 until the desired polymer is obtained.

SUBSmUTE SHEET

c2 Y~ ~ + ~ A~
lC H,~:,M
A~ N?~ H~ ~"Rs BHX

~ ~ N~

Wherein M is an alkali metal; each member of the Q~ ' ' ' pairs Rl and R2, R3 and R4, and R5 and R6 differs from the other and taken alone each signifies alkyl, cycloalkyl, 35 or substituted versions thereof, aryl, aralkyl or alkaryl, or substituted and heterocyclic Yersions thereof; these substituent pairs can also be joined into a carbocyclic or heterocyclic ring;
SUBSTITUTE SHEET

preferred forms of Rl and R2 are the side chain substituents occurring in native polypeptides, oli~ n~ otides, variants or mimetics of these, carbohydrates, pharmacophores, variants or mimetics of these, or any other side chain ~ul,~ u~ t which can 5 be attached to a scaffold or a backbone to produce a desired interaction with a target system.; X represents an oxygen, sulfur, or nitrogen atom; and A and B are the substituents desclibed above.
A chiral oxazolone derivative containing a blocked te}minal amino group may be prepared from a blocked, tlicllbsti~ .d dipeptide. that was prepared by standard techniques known to those skilled in the art, as shown:
R~ R2 R' ~R2 ~N~NR~,RCOOH B ~ 50 RJ ~
20 wherein B1 is an appropriate protecting group, such as Boc (t-bu~ y~a~onyl) or Fmoc (fluorenylmethoxycarbonyl). One may then use this oxazolone to acylate an amine, hydroxyl, or sulfhydryl-group in a linker structure or functionalized solid support, represented generically by AXH, using the reaction 25 ~ ~ " nnc described above. This acylation is followed by deblocking, using standard amine deprotection techniques comr~tihl~ with the overall structure of the amide (i.e., the amine protecting group is orthogonal with respect to any other protecting or functional groups that may be present in the 30 molecule), and the resulting amino group is used for reaction with a new bifunctional oxazolone generating a growing chiral polymeric structure, as shown below:
3s SUBSTITUTE SHEET

Wo95/l8627 2 1 8 0 527 rcr~ss4/00222 R~ R2 AXH + B~ ~ B, debloclc R7 R ~2NH2 2 C ~R~
C~Y~
N7~
R~ Rn O ~;4 ~ ~ "`" ~ ~ ~C
In the reaction shown above, Y is a linker 35 (preferably a fl-r^tionslli7~d alkyl group); X is a nitrogen of suitable structure; an oxygen or a sulfur atom; each member of the s~lbsti~ nt pairs Rl and R2, R3 and R4, Rn-l and Rn differs from the other and taken alone each signifies alkyl, cycloalkyl, ~UBSTITUTE SHEET

21 ~0527 WO 9~/18627 PCT/[JS94/00222 or functionalized versions thereof; aryl, aralkyl or alkaryl or functionalized including heterocyclic versions thereof (preferably, these R sl~hst~ ntc mimic the side-chain of naturally occurring amino acids); substituent R can also be par~
5 of a carbocyclic or heterocyclic ring; A is a substituent as described above; and C is a substituent selected from the set of structures for A; and Bl is a blocking or protecting group.
Sub Assemblies Alternatively, modular "sub assemblies" capable of conferring higher order structural properties may be pre-constructed and ~lcc~mhl~d together using these same reaction se~quences in a manner which allows control of the higher order 5 structure. This is illl-s~r~t~d for the case of a polymer formed with a repeating pattern of alternating modules of the type::
so3 25 ~ ~ n This polymer will form 3-10 helices, driven by the conf~rm~tio~l restrictions imposed by the repetitive viscinal ~liell~stitlltion This triadic periodicity results in the formation ~f 30 a helical superstructure which has charged sulfonate groups lined up regularly along one side of the helix:
3s SUBSmUTE SHEET

-~~
10 This "sub assembly" strategy may be used to generate higher order polymers in the following manner:
1. An o~ 7~tlon~ dimer c~t~tstinin~ a blocked terminal amino group may be prepared from a blocked disubstituted peptide, 15 prepared using standard techniques known to those skilled in the art, as shown:
~H B1 ~;~0 2s 2. This oxazolone may be coupled with a suitable c-terminal derivative of a second disubstituted dipeptide, as shown, to give the 4-mer module shown:
Bl~ ~ R2 R
R~ ~ R~
SUBSTITUTE SHEET

3. This process may then be repeated with the 4-mers to produce an 8-mer module; repeated again to form a 16-mer module, and so on, until a molecule having the desired length ~s 5 obtained. At any point in this sequence, the protecting groups - can be removed and the modules can be catenated together to form a polymer with repeating sequences of modules, as shown:
' ' ~ R~'R
, m~ n where m = number of iteratiYe steps In cases where solubility problems are o. ~d as the size of the modules increases, the stability of the linkages allows the use of a broad array of standard or 20 "exotic" reaction solvents, such as hexamethyl phosphoramide. If necessary, solubili~ing groups can be incorporated as side chai substituents or connecting modules.
Other Reactive Elements At any point in the polymer syntheses showr~
above, a structural species, possessing (I) a terminal OH, -SH or -NH2 group capable of ring-opening addition to the oxazolone and (2) another terminal group capable of 30 reacting with the amino group of a chiral alpha, alpha'-hStit--t~d amino acid, may be inserted in the polymer backbone as shown below ~ H N/\/\cooH ~' N~ 2 ~", SUBSTITUTE SHEET

o A~N~N/~/\ HN~C
O

H~ ~ C02 H

~
RZ
R~
This process may be repeated, if desiled, at each step in the synthesis where an 0~ 7oloTl~ ring is produced.
The bifunctional species used may be the same or different in the steps of the synthesis.
The e,~ llcntal procedures described above for o~z~701--n~ formation and use of o~7~ lon~s as acylating agents are expected to be useful in the oxazolone-directed catenations. Solubility and coupling problems that may arise in specific cases can be dealt with effectively by one with ordinary skill in the art of polypeptide and peptide mimetic synthesis.
For example, special solvents such as dipolar aprotic solvents (e.g., dimethyl forms~nifl~., DMF, dimethyl sulfoxide, DMSO, N-methyl pyrollidone, etc.) and chaotropic (molecular ag~l~,gdl~brCdking) agents (e.g., urea) will be very useful as catenations produce progressively larger molecules.
POLYMERS PRODUCED FROM AMINIMIDES
Stepwise sequential Reactions of l,l-Disubstituted Hydrazines or Hydrazine Derivatives with Bifunctionally Reactive elements.
SUBSmUTE SHEET

WO 9~i118627 218 0 5 2 7 Pcr/Us~4loo222 The aminimide monomer structure may be represented by the fo}mula:
X~X' ~o where R & R' are the sarne or different and X & X' are from the same groups as R or R:' and/or represent the extension or remainder of a polymer chain..
The groups R & R' may be of a subset of hydrophilic 5 Sl~stit~onfg such as. but not limited to hydroxymethyl, hydroxyethyl, hydlu~y~JIo~yl, thioethyl, thiomethyl;
carboxymethyl, carboxyethyl, ethylcarboxamido, methylcarboxamido; aminomethyl, aminoethyl, aminopropyl, guanindinylpropyl, guanidinylbutyl; mono-, di-, and 20 triaminobenzyl, mono-, di-, and trinitrobenzyl; mono-, di-, tri-, and tetrahydroxy benzyl, mono- or polyhydroxyaryl (e.g.
pyrogallol); heteroaryl (e.g. alkylpyridines, imidazole, alkyltryptophans); alkyl nucleotides; all substituted pyrimidylalkyl and substituted purinealkyl moieties; mono-, di-, and oligosaccharide (e.g. N-methylf~l~os ~minl~., maltose and the calicheamicin recognition sequence respectively);
alkylsulfonates, alkylphosphonates; a-polyfluoroketones;
secondary, tertiary and quaternaryamines; hydrazines and the lly-lla.silliulll salts. They may also come from the subset 30 concictin~ of hydrophobic s~bs~ nts such as, but not limited to hydrogen; methyl, ethyl propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, iso-, sec-, and neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.; vinyl, propenyl, butenyl or other alkenyl groups; acetylenic side chains; al-omatic polycyclics (e. g.
biphenyl, binaphthyl, naphthylphenyl, phenylnaphthyl); fused aromatic polycyclics(e.g. anthracene, phenylene, pyrene, açen ~ , azulenes); fused polycyclics (e. g. decalin, SUBSmUTE SHEET

WO 95t18627 2 1 8 0 5 2 7 PCT/US94100222 hydrindanes, steroids); phenyl, alkylphenyl, phenylalkyl; benzyl, mono-, di-, tri-, and tetlaalkylbenzyl; mono-, di-, and trialkoxybenzyl; heteroaryl (e.g. furyl, xanthanyl, quinolyl);
methoxyalkyl, ethoxyalkyl, aryloxy; methyimercaptans, 5 ethylmercaptans, alkyl thioethers and arylthioethers; dyes and fluorescent tags (such as rhorl~mi~ o~- fluorescein); alkyl esters, aryl esters, aralkyl esters, and alkylaryl esters; polymeric support surfaces Polym~- ization of Aminimide Subunits via Acylation/Alkylation Cvcles The following steps are inYolved in this synthesis:
1. Acylation of a hyd~ liulll salt with a molecule capable of functioning both as an acylating and as an alkylating agent producing an aminimide; BrCH2COCI and other bifunctional species, such as bromoalkyl isocyanates, 2-bromoalkyl oxazolones, etc., may be used as acylating agents under the reaction conditions given above.

C2H5 `N~'0 + ~ -H2N CH3 1- Br~/~O
2. Reaction of the product of the above reaction with a 1,1-disubstituted llyd~ c to form an ~minimid~ hydrazinium salt.
30 ,~
~ H3 + ~ N--NH2 ' H C~ N~3 3 Acylation of the product from step 2 with a bifunctional acyl derivative similar to those listed in step I above producing a dimer .
SUBSTITUTE SHEET

WO 95/18627 2 1 8 0 5 2 7 p~r~usg4/00222 O H5C2 ~ CH~3 54 Repetition of steps 2 and 4 the required number of times t~
build the desired aminimide polymeric sequence.
6. Capping of the :~ccernh'- i sequence if desired, for example, by reaction with an acylating agent, such as acetyl chloride.
The experimental conditions (e.g. reaction-solvent, temperature and time, and purification procedures for products) for all of the above reactions were described above and are also 5 well-known and practiced in the art. As the molecular weight of the products increases (e.g. in step 5 above) solubility and reaction-rate problems may develop if the reactions are run under the conditions that successfully gave products of much smaller molecular weight. As is well known from the art of peptide synthesis, this is probably due to conformational (folding) effects and to aggregation phenomena, and procedures found to work in the related peptide cases are expected to be very useful in the case of ~rninimiti~ catenations. For example, reaction solvents such as DMF, or N-methyl pyrollidone, and chaotropic (aggregate-breaking) agents, such as urea, are expected to be helpful in alleviating reactivity problems as the molecular-weight of the product increases.
3~ N'~ ", ~ ~ ~ CH~3 Polymerization of Aminimide Subunits via Acylation/Alkylatic~n 35 Ç.~
The following steps are involved in this synthesis;
SlJBSmUTE SHEET

- 2 1 80527 ~
WO 95/1862~ PCTNS94/00222 -3~
1. Alkylation of an asymmetrically disubstituted hydrazide, prepared as outlined above, with a molecule capable of functioning both as an alkylating and an acylating agent to form a racemic mixture of aminimides; as before the use of 5 BrCH2COCI is shown below, but other bifunctional species, such as bromoalkyl isocyanates, 2-bromoalkyl oxazolones, etc. may also be used.
2~ . Reaction of the racemate from above with an asymmetrically disubstituted hydrazine to form the hydrazide:
3. Alkylation of the product from step 3 with a bifunctional molecule capable of alkylation and acylation, which may be the same as that used in step I or different, to form a 5 mixture of diastereomeric aminimid~s

4. Reaction of the product from step 4 with a suitable asymmetrically disubstituted hydrazine to form the hydrazide, as shown:

R ~N,N+RI N--N+' 1~ R7 6. Repetition of steps 4, and 5 to build the desired aminimide polymer sequence.
8. Capping of the sequence, if desired, using e.g.
methyl bromide to produce a sequence such as shown below.
R ~ N' N~ Rl "~ ", "~"~ ~ N' + CH3 Poly ~ dtion of Aminimide Subunits Usin~ Hydra7inolysis of 35 an E~ster in the Presence of an Epoxide The following steps are involved in this synthesis:
SUBSTITUTE SHEET

WO95/18627 2180527 pCT/US94100222 1. Formation of an ~minimim~ from the reaction of an 1,1-asymmetrically disubstituted hydrazine with an epoxide;:

5 ~7 + R3,N NH2 H~--RN~'RNH
2. The ~miniminP is reacted with an ester-epoxide ~o give an ~minimide;

H~OH--R/ R3 ~3 H~/2~R3 COzMe 3. Reaction of the ~minimide with an asymmetrically disubstituted hydrazine to form an ~minimide-~miniminP.
20:
R ~--+N' N ~ 3~/R-~NH

4. Repetition of steps 2 and 3 using the appropriate hydrazines and epoxy-esters in each step to produce the desired ~minimi~le sequence.
5. "Capping" of the final sequence, if desired, by acylation with a simple ester, such as methyl acetate, to produce the designed aminimitl~ ligand shown:
R~ ~N, N~ " ~ R,n O
, SUBSTITUTE SHEET

WO95/18627 2180527 PCT/US94/0~)222 Synthesis of Hydr~l7ides l,l-disubstituted hydrazine with an activated acyl derivative or an isocyanate, in a suitable organic solvent, e.g. methylene chloride, toluene, ether, etc. in the presence of a base such as triethylamine to neutralize the haloacid generated during the acylation .

2,N--NH2 + ,C~ 4 ~ R2~N`N'C`R4 H
Activated acyl derivatives include acid chlorides, chlorocarbonates, chlorothiocarbonates, etc.; the acyl derivative 20 may also be replaced with a suitable carboxylic acid and a contiencing agent such as dicyclohexylcarbo-iiimid~ (DCC).
An example of the latter is the synthesis of the trifluoromethylhydrazides shown below:

+ H2N~ ~N~ ~CH3 In this reaction a solution of 2-trifluoro~e~midoicobutyric acid in dry THF is stirred and an equivalent amount of dicyclohexylcarbodiimide is added. The reaction is subsequently strirred for three minutes, after which 35 an equimolar quantity of thel-substituted-l-methylhydrazine is added neat. Dicyclohexylurea precipitates imm~ f~ly, The resultant suspension is stirred for one hour, filtered to remove SUBSmUTE SHEEI' the insoluble urea and the solvent is removed on a rotary evaporator to afford the crude hydrazide.
The desired 1,1-disubstituted hydrazines may be readily 5 prepared in a number of ways well known in the art; one is th~
reaction of a secondary amine with NH2CI in an inert organic solvent.
Rl Rl o NH + H2N. Cl ~ N--NH2 HCI

A second synthetic route for the preparation of hydrazines is alkylation of monoalkyl hydrazines, shown below for methyl hydrazine:
C 3 (~
neutr, N--NH
2 O N--NH2 + RX ' ,' / 2 H R
This reaction is carried out by reacting a solution of methylhydrazine in THF, cooled at 0 C with a solution of an 25 equimolar amount of the alkyl halide in THF added dropwise with stirring over a period of 30 minutes. The reaction is stirrlod at 0 C for another 15 minutes, then heated to reflux and held at reflux for two hours. A water-cooled downward c~nd~nger is set up and ;tL~Iu~illldl~ly half of the solvent is removed by 30 distillation. The residue is poured into water, which is then made basic by the addition of concentrated aqueous NaOH. The layers are separated, the aqueous phase is extracted with ether and the combined organic phases are washed with water, dried over MgSO4 and Coll~ tl~lt~,~ by distillation. Distillation at reduced 35 pressure affords thel-substituted-1-methylhydrazine as a colorless liquid.
SUBSTITUTE SHEET

Polvmers Pt oduced by Hydrazides Polymers containing designed sequences of substituted hydrazones may be produced using the following steps:
R DCC R
AC02H + H2N~ ~ ACC)NH~
C02Bu-t C025u-t ¦ I,;n.. ,.. , ;.
acid H2NN~
R ~ CO2Bu-t R
. ACONH~ R ~ ACONHl~
CONHN~ C02H
C02Bu -t acid H2NI~_ 2 0 CO2Bu-t etc., etc.
¦ H2NNRB
~ ~
ACO- . --N}1~ ~0 NHNRB ~ ACO- . ~ ~N ~ .-NHNRB
base ~ R R' ' n n Mixed Modules All of the oxazolone, z~minimil1~ and hydrazide modules and monomers illustrated above may be mixed and matched to provide a variety of mixed-backbone polymers having specific properties, functionalities and sequences.

SUBSmUTE SHEET

Substituents Any of the various R and R' groups illustrated in all of the oxazolone, aminimide and hydrazide structures may be selected from among the following list:

I ) Amino acid derivatives of the form (AA)N, which would include, for example, natural and synthetic amino acid residues (N=l ) including all of the naturally occuring alpha amino acids, especially alanine, arginine, asparagnine, aspartic acid, 10 cysteine, ~IIlt:lmin~. glutamic acid, glycine, histidine, isoleucine, leucine, Iysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine; the naturally occuring ~ "hStit~lt~d amino acids, such as amino isobutyric acid, and isovaline, etc.; a variety of synthetic amino acid residues, including 5 alpha-disubstituted variants, species with olefinic substitution at the alpha position, species having derivatives, variants or mirnetics of the naturally occuring side chains; N-Substituted glycine residues; natural and synthetic species known to functionally mimic amino acid residues, such as statine, bestatin, etc. Peptides (N=2-30) constructed from the amino acids listed above, such as angiotensinogen and its family of physiologically important angiotensin hydrolysis products, as well as derivatives, variants and mimetics made from various combinations and permutations of all the natural and synthetic residues listed above. Polypeptides (N=31-70), such as big endothelin, pancreastatin, human growth hormone releasing factor and human pancreatic polypeptide.
Proteins (N>70) including structural proteins such as collagen, functional proteins such as hemoglobin, regulatory proteins such as 30 the lo~qmin~ and thrombin receptors.
2 ) Nucleotide derivatives of the form (NUCL)N, which includes natural and synthetic nucleotides (N=1) such as adenosine, thymine, guanidine, uridine, cystosine, derivatives of these and a variety of variants and mimetics of the purine ring, the sugar ring, 35 the phosphate linkage and combinations of some or all of these.
Nucleotide probes (N=2-25) and oligonucleotides (N>25) including all of the various possible homo and heterosynthetic combinations and permutations of the naturally occuring nucleotides, derivatives SUBSTITUTE SHEET

WO 95/18627 PC'r/US94/00222 and variants containing synthetic purine or pyrimidine species or mimics of these, various sugar ring mimetics, and a wide variety of alternate backbone analogues including but not limited to phosphodiester, phosphorothionate, phosphorodithionate, 5 phosphoramidate, alkyl phosphotriester, sulfamate, 3'-thioformaeetal, methylene(methylimino), 3-N-carbamate, morpholino carbamate and peptide nucleic acid analogues.
3 ) Carbohydrate derivatives of the form (CH)n. This would inelude natural physiologically active carbohydrates such o as including related compounds such as glucose, galactose, sialic acids, beta-D-glucosylamine and nojorimycin which ale both inhibitors of glucosidase, pseudo sugars, such as Sa-carba-2-D-gala~o~,~,.u~ose, which is known to inhibit the growth of l~l~.bgi~
pnPI.monin (n=l), synthetic carbohydrate residues and derivatives 15 of these (n=l) and all of the complex oligomeric permutations of these as found in nature, including high mannose oligosaccharides, the known antibiotic ~ L)tullly~ (n>l).
4 ) A naturally occurring or synthetic organic structural motif. This term is defined as meaning an organic moleeule having a speeifie strueture that has biologieal aetivity, sueh as having a c ~J~ ~ ~r.~ y strueture to an enzyme, for instanee. This term ineludes any of the well known base struetures of pharm~ceutieal eompounds ineluding ph~llllacol~hores or metabolites thereof. These include beta-laetams, sueh as pennieillin, known to inhibit bacterial eell wall biosynthesis; ~ 7~7~ cs. known to bind to CNS receptors, used as antidepressants; polyketide macrolides, known to bind to baeterial ribosymes, etc . These stl uctural motifs are generally 30 known to have specific desirable binding properties to ligand acceptors .
5 ) A reporter element such as a natural or synthetic dye or a residue capable of photographic amplification whieh possesses reactive groups which may be synthetically incorporated into the oxazolone structure or reaction scheme and may be attached through the groups without adv,ersely interfering with the reporting functionality of the group. Preferred reactive groups are amino, thio. hydroxy, carboxylic acid, carboxylic acid ester, .
.

SUBSmUTE SHEEr particulally methyl ester, acid chloride, isocyanate alkyl halides, aryl halides and oxirane groups.

6 ) An organic moiety containing a polymerizable group such as a double bond or other functionalities capable of 5 undergoing condensation polymerization or copolymerization.
Suitable groups include vinyl groups, oxirane groups, carboxylic acids, acid chlorides, esters, amides, lactones and lactams. Other organic moiety such as those defined for R and R' may also be used .

7 ) A macromoleculal component, such as a macromolecular surface or structures which may be attached to the oxazolone modules via the various reactive groups outlined above in a manner where the binding of the attached species to a ligand-receptor molecule is not adversely affected and the 5 interactive activity of the attached functionality is determined or limited by the macr~-mr.l-~cllle. This includes porous and non-porous inorganic macromolecular components, such as, for example, silica, alumina, zirconia, titania and the like, as comrnonly used for various applications, such as normal and reverse phase chromatographic separations, water purification, pigments for paints, etc.; porous and non-porous organic macromolecular components, including synthetic components such as styrene-divinyl benzene beads, various methacrylate beads, PVA beadls, and the like, commonly used for protein puriflcation, water softening and a variety of other applications, natural colllpc,llcl.ts such as native and functionalized celluloses, such as, for example, agarose and chitin, sheet and hollow fiber membranes made from nylon, polyether sulfone or any of the materials mentioned above.
The molecular weight of these macromolecules may range from about 1000 Daltons to as high as possible. They may take the form of nanoparticles (dp=100-lOOOAngstroms ), latex particles (dp=1000-SOOOAngstroms), porous or non-porous beads (dp=O.S-1000 microns), membranes, gels, macroscopic surfaces or 35 functionalized or coated versions or composites of these.

8 ) A structural moiety selected from the group including cyano, nitro, halogen, oxygen, hydroxy, alkoxy, thio, straight or branched chain alkyl, carbocyclic aryl and substituted or SUBSTITUTE SHEET

WO 9~/18627 PCT/US94/00222 heterocyclic derivatives thereof, wherein R and R' may be different in adjacent n units and have a selected ste~eochemic~l arrangement about the carbon atom to which they are attached;
As used herein, the phrase linear chain or branched 5 chained alkyl groups means any substituted or unsubstituted acyclic carbon-containing compounds, including alkanes, alkenes and alkynes. Alkyl groups having up to 30 carbon atoms are preferred. Examples of alkyl groups include lower alkyl, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl; upper alkyl, for example, cotyl, nonyl, decyl, and the like; lower alkylene, for example, ethylene, propylene, propyldiene, butylene, butyldiene; upper alkenyl sùch as l-decene, l-nonene, 2,6-dimethyl-5-octenyl, 6-ethyl-5-octenyl or heptenyl, and the like; alkynyl such as l-ethynyl, 2-butynyl, l-pentynyl and 5 the like. The ordinary skilled artisan is familiar with numerous linear and branched alkyl groups, which are within the scope of the present invention.
In addition, such alkyl group may also contain various substituents in which one or more hydrogen atoms has been 20 replaced by a functional group. Functional groups include but are not limited to hydroxyl, amino, carboxyl, amide, ester, ether, and halogen (fluorine, chlorine, bromine and iodine), to mention but a few. Specific substituted alkyl groups can be, for exarnple, alkoxy such as methoxy, ethoxy, butoxy, pentoxy and the like, polyhydroxy such as l ,2-dihydroxypropyl, l ,4-dihydroxy- l -butyl and the like; methylamino, ethylamino, dimethylamino, diethylamino, triethylamino, cyclopentylamino, benzylamino, dibenzylamino, and the like; propanoic, butanoic or pentanoic acid groups, and the like; formamido, acetamido, but~n~mido, and the like, methoxycarbonyl, ethoxycarbonyl or the like, chloroformyl, bromoformyl, l,l-chloroethyl, bromoethyl ,and the like, or dimethyl or diethyl ether groups or the like.
As used herein, substituted and unsubstituted carbocyclic groups of lp to about 20 carbon atoms means cyclic carbon-containing compounds, including but not limited to cyclopentyl, cyclohexyl, cycloheptyl, admantyl, and the like. such cyclic groups may also contain various s~lbstitl-ents in which one or SUBSTITUTE SHEET

wo gS/18627 2 1 8 0 5 2 7 P~ s94100222 more hydrogen atoms has been replaced by a functional group.
Such functional groups include those described above, and lower alkyl groups as described above. The cyclic groups of the invention may further comprise a heteroatom. For example, in a 5 specific embodiment, R2 is cycohexanol.
As used herein, substituted and unsubstituted aryl groups means a hydrocarbon ring bearing a system of conjugated double bonds, usually comprising an even number of 6 or more (pi) electrons. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anisyl, toluyl, xylenyl and the like. According to the present invention, aryl also includes al yloxy, aralkyl, aralkyloxy and heteroaryl groups, e.g., pyrimidine, morpholine, piperazine, piperidine, benzoic acid, toluene or thiophene and the like. These aryl groups may also be substituted with any number 5 of a variety of functional groups. In addition to the functional groups described above in connection with sllbstitllt~d alkyl groups and carbocylic groups, functional groups on the aryl groups can be nitro groups.
As mentioned above, these structural moieties can also 20 be any c~mhins-tion of alkyl, carbocyclic or aryl groups, for example, 1-cyclohexylpropyl, benzylcyclohexylmethyl, 2-cyclohexyl-propyl, 2,2-methylcyclohexylpropyl, 2,2methylphenylpropyl, 2,2-methylphenylbutyl, and the like.
Reactive Groups Specifically prefened reactive groups to generate the ~minimid~ and oxazolone structures and the resulting base modules are listed below in tables 1, 2 and 3. The bonds in the structures in these figures represent potential points of ~t1~nllln~rlt to the first and second cu-l-poul~ds and to the base modules.
Specifically preferred reactive groups to generate the ~minimill~ and oxazolone structures and the resulting base modules are listed below in tables 1, 2 and 3. The bonds in the ~llLCtU--,s in these figures represent potential points of attachment for the attachment of the structural diversity elements to the first and second compounds and to the base modules.
SUBSmUTE SHEET

Table 1. O~a~nlone Module~
Reaclivily Groups ~rse M~dules ~< (Y - N, S, O) H~/
10 '1--~> c=o '1--O O

(Y = N, S, O) H
2 0 --C02H/CI \~N\
NH2Xco2H (ClC02EI/EaN) o ~<
Z~O ~)< H~ O~X
O (Z = CH2=CH .
elc.) Replesents potenti~l points of ~ttachment SUBSTITUTE SHEET

Table 2. Aminimide Modules Re~ctivi~y Groul)s Bllse Modules -- COOH H2N~< --CONHN
--Nt-O H2NI~ --NHCONHN
--OCOCI H2N~ --OCONHN

--SCOCI H2N~ -- SCONHN
--CONHN -- X --CONN--15 \ (neut[.) --CONHN\ ~7 --CON~
20 --NHCONHN\ (neutr~x) --NHCONN----NHCONHN\ ~ --NHCON~
25 / --X ~3t3 --OCONHN\ (neutr.) --OCON IN----OCONHN\ ~7 --OcON~

-- SCONHN~ -- X --SCONN--(neutr.) --SCONHN\ ~7 --SCON~
Reptesents potential points of attachment SUBSTITUTE SHEET

WO95/18627 2180527 PCllUS94100222 Table 2. Contillued ~ imide Modules Re~ctB/ity Groups Base Modules 3 16) H2~ -- X H2N~ X
(neutr.) I

H2N~ ~~7 HNN
I(E) 3 H~
H2N~ X BASE
HN~ -- COOR --CON IN--~ --COOR N~
1~ ~O ~ ~N~
o CO~H o ~3) OH
~ ~ /~0 -- Represents potential points of lttt~tchment SUBSTITUTE SHEET

Table 3. Am~ mide-Oxa~ololle Modules Reactivi~ Groups sase Modules HNI~ ~1--~ \ll H2NN~ < N
(Base) -- Represents potential points of attachmenL
2 o EXAMPLE l .
This example describes preparation of a tetramer by alternating ring-opening/Michael-addition reactions followed by chain polymerizations.

Step 1.
rHF~ t en TBSCI~ X~5 ~
In the first synthetic step, a solution of b-butyrolactone (8.61 g, O.l mole, 8.15 mL) in THF (150 mL) is cooled at 0 C while a 3~ solution of benzyl 2-aminoisobutyrate (19.3 g, 0.1 mole) in THF
(100 mL) is added. The mixture is stirred at 0 C for two hours , then room temperature for four hours, then is treated with tert-butyldimethylsilyl chloride ( IS.l g, 0.1 mole) and SUBSrlTUTE SHEET

imidazole (13.6 g, 0.2 mole) added in alternating portions as the solids. The mixture is stirled overnight at room temperature, the solids are removed by filtration, and the filtrate is concentrated in vacuo. The residue is dissolved in 5 methanol (100 mL), palladium on carbon catalyst (5 % Pd, 500 mg) is added, and the solution stirred under an ~tmosp2~re of hydrogen gas until the ester is exhausted (reaction is lllo~ olc~ in progress by volume of absorbed H2 gas and by TLC). Following complete removal of the benzyllic 10 functionality, the catalyst is removed by filtration with the aid of celite. The ~ lc is washed with methanol (3 x 100 mL) and the combined filtrates are concentrated in vacuo. The residue is crystallized, then recrystallized from ethyl acetate to afford the protected acid (21.7 g, 0.072 mole, 72 %).
This acid is dissolved in ethyl acetate (300 mL) and cooled at 0 C while ethyl chloroformate (7.77 g, 0.072 mole, 6.85 mL) is added, followed by triethylamine (7.25 g, 0.072 mole, 9.98 mL). After cessation of gas evolution (ca. four hours), the triethylamine hydrochloride is removed by 20 filtration and the filtrate is concentrate to afford crude 2-(2-tert-butyldimethylsilyloxy propyl)-4,4-dimethyl-5-oxazolone as a yellow oil (23.4 g). Recrystallization from ethyl acetate affords the pure product (13.7 g, 67 %, 0.048 mole). The material gave s~ticf~tnry spectral data (300 MHz NMR proton signals corresponding to silyl group butyl: silyl group methyls:
oxazolone gem-dimethyl integrals 9:6:6; IR 1820 cm ~ I
azlactone band).
Stc 2.
P
TBS N~I~O CHC'2.O-C ~ >~2N~~N~
A solution of of 95% N-methylethy!~.n~2i~mine (3.56 g, 48 mmol, 4.23 mL) in methylene chloride (75 mL) is cooled in an ice bath while a solution of 2-(2-tert-butyldimethylsilyloxy propyl)-4,4-dimethyl-5-oxazolone (13.7 SUBSTITUTE SHEET

~ 2 1 80527 ~5-g, 48 mmol) in methylene chloride (100 mL) is added such that the temperature remains below 5 C. The solution is stirred at room temperature for 15 minutes while a white precipitate forms. The mixture is stirred for an additional 2 h at 0 C. The 5 solids are removed by filtration and washed with methylene chloride (25 mL) and air dried to yield the ring-opened adduct (12.87 g, 36 mmol, 75%), identified by nuclear magnetic resonance (NMR) and Fourier transform infrared (FTIR) spectroscopy as follows: NMR (CDC13): CH3-N/gem (CH3)2 ratio o 1:2; tert-butyldimethylsilyl - splitting pattern in 0-1 ppm region, integration ratios and D2O exchange experiments rnos~ir for structure. FTIR (nujol mull): azlactone CO band at 1820 cm~1 absent; strong amide bands present in 1670 - 1700 cm~1 region.

Step 3.
OTBS TBS
~OBn ~
~ ~ o=~ ~ P-nl-mor 1 2 oDJ~N H H N PhH, 7BC-rl N H
7~HfiNH ~= ~N~

A solution of of the ring-opened adduct (8.98 g, 25 rnmol) and 4,4-dimethyl-2-vinyl 171~r~ nl~ ( 3.48 g, 25 mmol) irk benzene (50 mL) is heated to 70 C for 4 hours. The flask is cooled 30 to room temperature and allowed to stand under an inert ,I,cre for 3 days. The solvent is decanted off from the th:ick oil that forms. This oil is dissolved in acetone (ca 50 mL) and concentrated to produce another thick oil, which is concentrated under vacuum at I torr overnight to yield 9.34 g of a white 35 crystalline solid (25 mmol), identified by NMR and FTIR
spectroscopy as 2-(N-(2-(2-(3-tert-butyldimethylsilyloxy butyramido)-isobutyramido)-ethyl)-N-methyl-2-aminoethyl)-4 ,4-dimethyl-5-oxazolone: NMR: CH3-N/gem (CH3)2 ratio 1:4; tert-SUBSmUTE SHEET

21 80527 ~
WO 9~i/18627 - PCT/US94/00222 butyldimethylsilyl - splitting pattern in 0- 1 ppm region , integl-ation ratios and D20 exchange t~ ts diagnostic for structure. FTIR (nujol mull)- strong azlactone CO band at 1820 cm~

Construction of the Poly(pentamer) P-ntam-r ~ ~On~Nx~ N~
Polymerization of the mono(pentamer) -This material is 5 dissolved in THF (500 mL) and cooled at O C while a solution of tetra-n-butylammonium fluoride (I.OM in THF, 25 mL, 25 mmol) is added. The exotherm is controlled by the rate of addition of the fluoride reagent. The mixture is then heated briefly to 70 C and cooled to room temperature. Water 100 mL) is added and the 20 layers aue stirred, then separated. The organic phase is dried (sat'd aq NaCl, MgS04), and co~ in vacuo (18 torr, then 0.1 torr 10 hours) to afford the polymer (9.60 g). This material showed no signals for the tert-butyldimethylsilyl group in the proton NMR spectrum and the azlactone band was absent in the 25 infrared spectrum.
EXAMPLE 2.
This example illustrates the preparation of a tris(penr~mPric) module and its assembly into a polymer.
3s SUBSTITUTE SHEET

~ 2180527 WO 95/18627 PC'r/US94/0022 OTBS OTBS
OBn ;~NH ~ PhH, 7~C-rt ;~NH
H i ~ N~
NH

A solution of of the ring-opened adduct (8.98 g. 25 mmol) and benzyl 3-phenyl-2-methyl-2-acrylamidopropionate ( 8.03 g, 25 mmol) in benzene (50 mL) is heated to 70 C for 4 hours. The flask is cooled to room klllpc~ ulc and allowed to stand under an inert atmosphere for 3 days. The solvent is decanted off from the thick oil that forms. The residue is crystallized, then recrystallized from ethyl acetate. to afford t~le protected benzyl ester adduct (15.34 g, 23 mmol, 90%) 0 Step 2.
v~_~
~OTBS , N H ~N H
,~ 1. TBAF, THF J H
H N O th-n P-nt-m-r 1 ~ J
~ OBn O~NH r ~ ~
l SUBSTITUTE SHEET

2180527 ~

The product is dissolved in THF (250 mL) and a solution of TBAF (I.OM, 23 mmol, 23 mL) is added and the reaction stirred for one hour at room temperatule, then cooled at O C while a solution of 2-(N-(2-(2-(3-tert-butyldimethylsilyloxy 5 butyramido)-isobutyramido)-ethyl)-N-methyl-2-aminoethyl)-4,4-dimethyl-5-oxazolone (11.45 g, 23 mmol) in THF (150 mL) is added with stirring. The reaction is stirred overnight at room temperature, then partitioned between water (200 mL) and THF.
The aqueous phase is separated and extracted with ether (2 x 200 mL) and the combined organics are dried (sat'd aq NaCI, MgS04) and concentrated to afford a solid (22.0 g).
A suspension of this solid and palladium on carbon catalyst (5 % Pd, ~00 mg) in methanol (200 mL) is stirred under an atmosphere of hydrogen gas until the ester is eYh~l-c~rd (reaction 15 is Illo~ cd in progress by volume of absorbed H2 gas and by TLC). Following complete removal of the benzylic functionality, the catalyst is removed by filtration with the aid of celite. The filter pad is washed with methanol (3 x 100 mL) and the combined filtrates are concentrated in vacuo to afford a viscous syrup that is used directly.
This acid is dissolved in ethyl acetate (lOO mL) and cooled at O C while ethyl chlorofolmate (2.32 g, 23 mmol, 2.04 mL) is added, followed by ùiethylamine (2.16 g, 23 mmol, 2.98 mL). After cessation of gas evolution (approximately two hours), the triethylamine hydrochloride is removed by filtration and the filtrate is concentrated to afford the crude product as a yellow oil (23.4 g). A pure sample of this product is obtained Purified by chromatographic purification on RP-Cl 8 silica gel (methanol-water gradient elution) to give 2-(N-(2-(3-(2-(N-(2-(2-(3-tert-butyldimethyl silyloxybutyramido)-isobutyramido)-ethyl)-N-methyl-3-propanamido)-isobutyroxy)-butyramido)-isobutyramido)-ethyl-N-methyl-2-aminoethyl)-ethyl-4,4-dimethyl-5-oxazolone (11.43 g, 61%, 14 mmol) as an amorphous powder. The material gave s~ticf~r~ory spectral data (300 MHz NMR proton signals corresponding to silyl group butyl: silyl group methyls:
SUBS~TUTE SH~t, WO 95/18627 2 1 8 0 5 2 7 Pcr/US94100222 --4~--oxazolone gem-dimethyl integrals 9:6:6; IR 1820 cm - I
azlactone band).
Step 3.
OT~S OT135 Jl` ~ PhH, 70'C.rt ~n O
H ~
INH

A solution of of the ling-opened adduct (8.98 g, 25 mmol) and benzyl 2,4-dimethyl-2-acrylamidopentanoate ( 7.18 g, 25 rnmol) in benzene (S0 rnL) is heated to 70 C for 4 hours. The flask is cooled to room temperature and allowed to stand unde~ an 20 inert atmosphere fo~ 3 days. The solvent is decanted off from the thick oil that forms. The residue is crystallized, then recrystal~ized from ethyl acetate to afford the protected benzyl ester adduct (13.41 g, 21 mmol, 83%) 25 Step 4.

3s SUBSTITUTE SHEET

s ~`!.
0~ ~N H ' J
0 ~ ~ H
Ph o A solution of this product (8.94 g, 14 mmol) in THF
(250 mL) and a solution of TBAF (I.OM, 14 mmol, 14 mL) is added and the reaction stirred for one hour at room temperature` then 20 cooled at O C while a solution of the previously prepared di-pentamer oxazolone (11.43 g, 14 mmol) in THF (150 rnL) is added with stining. The reaction is stirred overnight at room t~l..p.,l~.lul~ then partitioned between water (200 mL) and THF.
The aqueous phase is separated and extracted with ether (2 x 200 5 mL) and the combined organics are dried (sat'd aq NaCI, MgS04) and concentrated to afford a solid (22.0 g).
A suspension of this solid and palladium on carbon catalyst (5 % Pd, 250 mg) in methanol (200 mL) is stirred under an atmosrhPIe of hydrogen gas until the ester is ÇYh~l-ct~d (reaction is monitored in progress by volume of absorbed H2 gas and by TLC). Following complete removal of the benzylic functionality, the catalyst is removed by filtration with the aid of celite. The filter pad is washed with methanol (3 x 100 mL) and the combined 35 filtrates are concentrated in vacuo to afford a viscous syrup that is used directly.
This acid is dissolved in ethyl acetate (100 rnL) and cooled at O C while ethyl chloroformate (1.41 g, 14 mmol, 1.24 SUBSrlTUTE SHEET

WO ~Y18627 2 1 8 0 5 2 7 PCT/US94/00222 mL) is added, followed by triethylamine (1.31 g, 14 mmol, 1.81 mL). After ten hours, the triethylamine hydrochloride is removed by filtration and the filtrate is concentrated to afford the crude product as a tan solid (23.4 g). Purification by 5 column chromatography on RP-CI 8 silica gel (methanol-water gradient elution), pooling of the appropriate fractions and concentration in vacuo affords pure 2-(3-(N-(2-(2-(2-(3-(N-(2-(3-(2-(N-(2-(2-(3-tert-butyldimethylsilyloxybutyramido)-isobutyramido)-ethyl)-N-methyl-2-aminoethyl)-propanoylamido)-isobutyroxy)-butyramido)-isobutyramido)-ethyl)-N-methyl-2-aminoethyl)-propanoylamido)-isobutyroxy)-propanoylamido)-isobutyramido)-N-methyl-ethylamino)-ethyl)-4-isobutyl-4-methyl-5-oxazolone z(3.72 g, 22%, 3 mmol) as an amorphous powder. The material gave 5 s~ticf~tory spectral data (300 MHz NMR proton signals corresponding to silyl group butyl: silyl group methyls:
oxazolone gem-dimethyl integrals 9:6:6; IR 1820 cm -1 azlactone band).

Constructlon of the Polytrls(pentamer) ~IUF. THF ~N~O ~
O~NH O~hH O~NH ~ O~,~RH
l ~ F~O
Poly~ ation of the tris(pentamer) -This material is 35 dissolved in THF (200 mL) and cooled at O C while a solution of tetra-n-butylammonium fluoride (I.OM in THF, 3 mL, 3 mmol) is added. The exotherm is controlled by the rate of addition of the fluoride reagent. The mixture is then heated briefly to 70 C and SUBSTITUTE SHEET

cooled to room t~ d~Ult;. Water (100 mL) is added and the layers are stirred, then separated. The organic phase is dried (sat'd aq NaCI, MgSO4), and concentrated in vacuo (18 torr, then 0.1 ton 10 hours) to afford the polymer (3.38 g). This material 5 showed no signals for the tert-butyldimethylsilyl group in the proton NMR spectrum and the azlactone band was absent in the infrared spectrum.
Further details on the reaction possibilities for the 10 oxazolone and ~minimi-le compounds can be found in two PCT
applications PCT/US93/0--- and PCT/US93/0---, each filed on .December 28, 1993, and entitled Modulal Design And Synthesis of ~minimitl~.-Derived Molecules, ,.,s~e~liv~ly. The content of each of those applications is expressely incorporated herein by reference thereto to the extent necessary to understand the metes and bounds of this invention.

3s SUBSTITUTE SHEET

Claims (30)

THE CLAIMS
What is claimed is:

1. A method of making a polymer having specific physiochemical properties which comprises:
forming a first module having a structure which includes at least two structural diversity elements suitable to impart a desired physical property to a polymer which is made from said module; and reacting one or more modules by means of an addition reaction to form a polymer having specific physiochemical properties.

2. A method according to claim 1 which further comprises forming the base module from an aminimide compound, an oxazolone compound or derivatives thereof.

3. A method according to claim 1 which further comprises forming the base module by reacting a first compound having at least one structural diversity element and a first reactive group, with a second compound having at least one structural diversity element and a second reactive group, wherein the first and second groups combine by an addition reaction.

4. The method according to claim 3 which further comprises producing the first compound by forming an oxazolone compound having at least one structural diversity element attached thereto.

5. The method according to claim 4 which further comprises providing the second compound as a nucleophile or carbonyl compound which is capable of reaction with the oxazolone and which contains at least one structural diversity element.

6. The method according to claim 5 which further comprises combining the first and second compounds to form a base module having one of the following structures:

wherein at least two of the unconnected lines are connected to structural diversity elements.

7. A method of making a polymer having specific physiochemical properties which comprises:
forming a first module having a structure which includes at least two structural diversity elements suitable to impart a desired physical property to a polymer which is made from said monomer by reacting a first compound of an aminimide-forming compound having at least one structural diversity element attached thereto and a first reactive group, with a second compound having at least one structural diversity element and a second reactive group, wherein the first and second groups combine by an addition reaction; and reacting one or more modules to form a polymer having specific physiochemical properties.

8. The method according to claim 7 which further comprises providing the second compound as an oxazolone or ether compound which is capable of reaction with the aminimide-forming compound and which contains at least one structural diversity element.

9. The method according to claim 8 which further comprises combining the first and second compounds to form a base module having one of the following structures:

wherein at least two of the unconnected lines are connected to structural diversity elements.

10. The method of claim 9 which further comprises selecting the first and second structural diversity elements to be one of the following:
an amino acid derivative of the form (AA)n;
nucleotide derivative of the form (NUCL)n;
carbohydrate derivative of the form (CH)n;
an organic moiety of an alkyl, cycloalkyl, aryl, aralkyl or alkaryl group or a substituted or heterocyclic derivative thereof, or of a naturally occurring or synthetic organic structural motif, optionally containing a reporter element, an electrophilic group, a nucleophilic group or a polymerizable group; or a macromolecular component.

11. The method according to claim 3 which further comprises providing at least one of the first and second compounds with at least two structural diversity elements.

12. The method according to claim 1 which further comprises providing each of the first and second with at least two structural diversity elements.

13. A method according to claim 1 which further comprises sequentially reacting modules to form the polymer.

14. A method according to claim 1 which further comprises reacting a plurality of the same modules to form the polymer.

15. A method according to claim 1 which further comprises reacting a plurality of different modules to form the polymer.

16. A method according to claim 1 which further comprises selecting the module to be a derivative or mimic of a peptide, protein, oligonucleotide, oligosaccharide, carbohydrate, pharmaceutical or pharmacophore.

17. A method of making a polymer having a desired water solubility which comprises:
forming a first base module having a having a hydrophobic moiety attached thereto;
forming a second base module having a hydrophilic moiety attached thereto; and reacting one or more of the first and second base modules by means of an addition reaction to form a polymer having a specific molecular weight, a specific length and a particular water solubility.

18. A method according to claim 17 which further comprises sequentially reacting said modules to control the addition of each modules to the polymer.

19. A method of making a polymer having a desired water solubility which comprises:
forming a first base module having a hydrophobic moiety attached thereto, the first base module having the formula or wherein R and R' are the same or different and are alkyl, carboxylic, aryl or an organic moiety exhibiting hydrophobicity, and wherein the unconnected lines signify points of attachment for structural diversity elements;
forming a second base module having a hydrophilic moiety attached thereto, the second base module having the formula or wherein R and R' are the same or different and are alkyl, carbocyclic, aryl or an organic moiety exhibiting hydrophilicity, and wherein the unconnected lines signify points of attachment for structural diversity elements; and reacting one or more of the first and second base modules to form a polymer in a manner which is effective to control the addition of each module to a developing polymer chain until a polymer having a specific molecular weight, a specific length and a particular water solubility is produced.

20. A method according to claim 19 wherein R and R' of the first base module are selected from the group of hydrophobic moieties consisting of long chain alkyl groups.

21. A method according to claim 19 wherein R and R' of the second base module are selected from the group of hydrophilic moieties comprising alkyl, carbocyclic and aryl groups that also contain carboxylic acid groups.

22. A method of making a polymer having a desired water solubility which comprises:
forming a first base module having a hydrophobic moiety attached thereto, the first base module having the formula or wherein R and R' are the same or different and are alkyl, carboxylic, aryl or an organic moiety exhibiting hydrophobicity, and wherein the unconnected lines signify points of attachment for structural diversity elements;
forming a second base module having a hydrophilic moiety attached thereto, the second base module having the formula or wherein R and R' are the same or different and are alkyl, carbocyclic, aryl or an organic moiety exhibiting hydrophilicity, and wherein the unconnected lines signify points of attachment for structural diversity elements;
reacting one or more of the first and second base modules to form a polymer in a manner which is effective to control the addition of each module to a developing polymer chain until a polymer having a specific molecular weight, a specific length and a particular water solubility is produced.

23. A method according to claim 22 wherein R and R' of the first base module are selected from the roup of hydrophobic moieties consisting of long chain alkyl groups.

24. A method according to claim 22 wherein R and R' of the second base module are selected from the group of hydrophilic moieties comprising alkyl, carboxylic and aryl groups that also contain carboxylic acid groups.

25. A polymer comprising at least three connected modules wherein the modules are connected by means of an addition reaction, and at least one module has a structure which includes at least two structural diversity elements.

26. A polymer according to claim 25 wherein each module has a structure which includes at least two structural diversity elements.

27 . A polymer according to claim 25 wherein the first and last modules have less than two structural diversity elements.

28. A polymer made according to the method of claim 17.

29. A polymer made according to the method of claim 19.

30. A polymer made according to the method of claim 22.