AP287A - An-ionic oligomers with anti-hiv activity, their uses and formulations - Google Patents

Abstract

The preferred oligomers of the present invention are polyures, polycarbonates, polyesters or polyamides having a number average molecular weight of < 10 000. These oligomers are water-soluble, have a rigid backbone, have recurring units coupled by carbonyl linking moieties which have anionic groups, display predominantly linear geometry such that regular spacing between anionic groups exist in an aqueous medium, and are pharmaceutically acceptable. The oligomers are useful for the treatment and/or diagnosis of aids and arc.

Description

This invention concerns oligomers. their uses and formulations, as well as processes for their preparation. The present oligomers are anionic compounds that have particularly valuable anti-human immunodeficiency virus activity and these oligomers are thus useful in the treatment of acquired immune deficiency syndrome (AIDS).

A great deal cf research is currently underway to develop treatments and cures for viral infections in humans and in animals. Notably the incidence of AIDS and AIDS related complex (ARC) in humans is increasing at an alarming rate. The five year survival rate for those with AIDS is dispiriting and AIDS patients, whose immune systems have been seriously impaired by the infection, suffer from numerous opportunistic infections including Kaposi's sarcoma and Pneumocystis carninii pneumonia . No cure for AIDS is known and current treatments are largely without adequate proof cf efficacy and have numerous untoward side effects. Fear of the disease has resulted in social ostracism of and discrimination against those having cr suspected cf having the disease.

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bad ORIGINAL 0j

AP Ο Ο Ο 2 8 7

Retroviruses are a class o:' ribonucleic acid (RNA) viruses that replicate cy using reverse transcriptase to form a strand cf complementary DNA (cDNA) from which a double stranded, proviral DNA is produced. This proviral DNA is then randomly incorporated into the chromosomal DNA of the host cell maxing possible viral replication by later translation of viral message frcm the integrated viral genome.

Many of the known retroviruses are oncogenic or ¹⁽³ tumor causing. Indeed, the first two human retroviruses discovered, denoted human T-ceil leukemia viruses I and

II or HTLV-I and II, were found to cause rare leukemias in humans after infection of 7-lymphocytes. The third ,- such human virus to be discovered, KTLV-III, now * o referred to as HIV. was found to cause cell death after infection of T-lymphocytes and has teen identified as the causative agent of AIDS and ARC.

The envelope protein of HIV is a 160 kDa glycoprotein. The protein is cleaved by a protease to give a 120 kDa external protein, gp'2O, and a transmembrane glycoprotein. gp41. The gp120 protein contains the amino acid sequence that recognizes the CD4 antigen on human T-helper (74) cells.

One approach being explored is to prevent the binding of HIV to its target, the ~~ cells in humans. These 74 cells have a specific region, a CD4 antigen, which interacts with gp120. If this interaction can be disrupted, the host cell infection can be inhibited.

Interference with the formation of the viral envelope glyoprotein could prevent the initial virushost cell interaction or supsequent fusion or could

38,537A-r

-2BAD ORIGINAL ft

-3prevent viral duplication ty preventing the construction of the proper glycoprotein required fcr the completion of the vira. membrane. It has teen reported [See H. A.

31cugh et al., Biochem. Biophys. Res. Comm. * 4 i ( 1) . 33 —3c (1986)] that the nonspecific glycosylation inhibitors 2decxy-D-glucose and β-hydroxy-norvaline inhibit expression of HIV glycoproteins and block the formation of syncytia. Viral multiplication of HIV-infected cells treated with these agents is stopped, presumably because of the unavailability cf glycoprotein required for the l J viral membrane formation. In another report [W. McDowell et al., Biochemistry 24.(27), 3145-52 ( 1985)], the glycosylation inhibitor 2-deoxy-2-fluoro-D-mannose was found to inhibit antiviral activity against influenza infected cells by preventing the glycosylation of viral membrane protein. This report also studied the antiviral activity cf 2-decxyglucose and 2-deoxy-2fluoroglucose and found that each inhibited viral protein glycosylation by a different mechanism.

However, other known glycosylation inhibitors have been shewn to have no antiviral activity. Thus the antiviral activity against viruses in general, and the viral activity specifically, of glycosylation inhibitors is

.. quite unpredictable.

It has been disclosed in South African Patent 90/0094, issued October 3’» 1990, that a purified form of heparin, a sulfated polysaccharide, binds through interactions to a viral protein which is responsible for ceil recognition and provides limited inhibition cf host cell infection. However, heparin causes some side effects, notably hemorrhage and increased clot formation time as well as thrombocytopenia. Use of heparin is contraindicated in patients who are actively bleeding.

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-4 or have hemophilia, purpura, thrombocytopenia. intracranial hemorrhage, bacterial endocarditis, active tuberculosis, increased capillary permeability, ulcerative lesions of the gastrointestinal tract, severe hypertension, threatened abortion cr visceral carcinoma.

⁰ The contraindication for use by hemophiliacs is particularly of concern because many such individuals are now HIV positive.

It has icr.g been recognized that certain

0 synthetic, water-soluble polymers exhibit a bread spectrum of¹ biological activity [R. M. Ottenbrite in Siciogicai Activities of Polymers. Amer. Chem. Soc. Symp. Ser. No. “82. pp. 205-220, eds. C. Ξ. Carraher and C. G.

.- Gebelein ('952)1. A copolymer of divinyi ether and maleic anhydride has been shewn to be active against a number of viruses and its use in cancer chemotherapy has been studied for years [3reslow, D. S. Pure and Applied Chem. ^6., 103 (1976)]. Polyacrylic, polymethacryl ic and a variety of other aliphatic backbone water soluble polymers also have been shewn to have a broad spectrum of biological activities [W. Regelson et al..Nature 136, 778 (i960)]. Unfortunately, the extreme toxicity of these polvmers has prevented their clinical use. Also, these polymers have a high molecular weight and are unable to pass through the renal membranes.

Attempts have been made to circumvent the toxicity and excretion problems by synthesis of low

0 ^J molecular weight (1,000 to 10,000) aliphatic polymers ]R. M. Ottenbrite in 3iologicai Activities of Polymers, Amer. Chem. Soc. Symp. Ser. No. 182, pp. 205-220. eds. C. E. Carraher and C. G. Gebelein (1982)]. It has been found that such polymers are less toxic but have much reduced antiviral activity. These low molecular

38.537A-P

weight aliphatic polymers may ce classed as random coil polymers. Such polymers have an unpredictable configuration oecause of the flexibility of the backbone linking groups. The configuration cf random coil polymers in solution may be generally described as globular. Although the mechanism of action of such water-soluble polymers is unknown, one postulate is that the polymer binds to the viral· membrane, e.g. encephelcayocarditis, through an ionic attraction, thus rendering the virus unable to infect host cells.

An additional synthetic polymer approach is to place ionic groups on the backbone cf a polymer which exhibits a more defined geometry. There are numerous examples of nor.-ionie, synthetic polymers which exhibit a mere linear geometry in non-aqueous solution than do the aliphatic polymers described above [J. Macromolecular Sci-Reviews in Macromol. Chem. Phys. C26(M), 551 (1986)]. The factors involved which cause this non-random coil structure are complex and poorly understood. In general, such polymers have either a very limited number of rotatable bcr.cs which are not parallel to the polymer axis, or there is hydrogen bonding cr dipolar interactions which favor linear structures. These polymers are referred fo as having a rigid backbone.

A polyamide derived from terephthalic acid and p-diaminobenzene (known commercially as Kevlar' supplied by DuPont) is a well-known example of such

-_θ polymers.

Synthetic, water-soluble, rigid polymers are much less common, but a few high molecular weight examples are known (e.g. see ’J.S. Patents M,32M ,915 and ^.395,560). The non-random coil structure of this class

23.537A-P

-o-

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-όzi polymer results in high solution viscosities for = giver, molecular weight and concentration.

Clearly, it would te desirable to find a treatment and cure for AIDS and ARC which would display minimal or no side effects and constitute a clear improvement over the polymers previously employed as a pharmaceutical.

It has now teen discovered that anionic oligomers inhibit viral replication without the side effects shown by heparin and known polymers. The oligomers have an ordered anion spacing, have a rigid backbone and are water-soluble.

The novel oligomers of the present invention are anionic, carbor.yl containing compounds. Examples of such oligomers are polyureas, polycarbonates, polyesters or polyamides having a number average molecular weight, M_n, of <10,000 which are water-soluble, have a rigid backbone, and have an ordered anion spacing. The oligomers induce their salts, which are pharmaceutically-acceptable when used as pharmaceutical agents.

Other uses for these anionic oligomers are as effective thickening agents in aqueous solutions, or as mild ionic detergents. In general, water soluble polymers, including those oligomers of the present invention, have a wide spectrum of uses as thickeners, dispersants, and floccular.ts. The present oligomers may be used in applications for oil fields, mining, paper manufacturing, textile manufacturing, cosmetic ingredients and manufacturing, and food processing. Additionally the present low molecular weight polymers, i.e. oligomers, may Pe used as starting materials for

33,537A

-6the preparation of high molecular weight polymers and copolymers.

Thus, this invention concerns a water-soluble, rigid backbone oligomer having a molecular weight less than (<) 10,009 comprising recurring units coupled by carbonyl linking moieties, said oligomer having anionic groups and predominantly linear geometry such that regular spacing between an ion io groups exists in an aqueous medium. Preferably each recurring unit has at θ least two anionic groups.

Any oligomer which meets the aoove criteria can be used i.n this invention. Particularly preferred oligomers are those which are poiyureas. polycarbonates, ’polyesters or polyamides. These oligomers preferably assume a linear geometry.

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Detailed Description cf the invention

The novel oligomers of the present invention are illustrated by polyureas, polycarbonates, polyesters or polyamides having a number average molecular weight M_n of <10,000 which are water-soluble, have a rigid backbone, have an ordered anion spacing and a predominantly linear geometry in an aqueous medium. The oligomers are preferably linear in their backbone and also may be in their salt form, particularly preferred salts are those that are pharmaceutically-acceptable.

The preferred oligomers of this invention are represented by any cr.e of the following formulae:

A) a polyurea of the formula:

H “ 1		Η H 0“ 1 ι 11
-N-C— »1		•N-X-N-C
n —		- —

m

H

-Μη (I) wherein:

H represents a hydrogen atom, a C-|—C4 alkyl group, a phenyl group, or a phenyl group substituted with from 1 to 2 R^ moieties ar.d up to 3 substituents independently selected from a chloro or bromo atom or C-|-Ci4 alkyl group;

R¹ represents -SO3R², -C02R², -?03(R²)₂, or

-OPO₃R²;

R² represents a hydrogen atom or a pharmaceutically-acceptable cation;

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-8-9□ is an integer 3 or with the proviso tha when m is 3. R is a hydrogen aton:

X reoresents

33,587A-F

-9AP Ο Ο Ο 2 8 7

-1C-

38.557A-F

Οi represents -CC

-N = ”

or _C = N_N = C n is an integer from 2 to 50; and represents -3 or -X-NHj, where 3 and X are defined as before:

3) a oolvoaroor.ate of the formula:

; p

X¹-0 c-c-x-c·

X2 (ID w h e r e i n :

X ar.d n are defined as in Formula I aocve;

χ1 represents a HO-X- group, where X is defined as for Formula I above, cr a C^-C^ alkyl group, a phenyl group, cr a pher.yl group substituted with from 1 to 2 3¹ moieties and up to 3 substituents ir.de pen der. t ly selected from a chloro or bromo atom or C-j-Cij alkyl· group: and

X^ represents a hydrogen atom, or -COjX ‘ · where X' is defined as above;

38,237A-F

AP Ο Ο Ο 2 8 7

Ο a polyester cf the formula ,Ί r^uc—> :-:(--0-0-/-04-3³ wherein :

X ar.d n are defined as in Formula 1 above;

R⁴ represents -R², as defined in Formula I, ο»

-X¹, as defined in Formula 1' above;

R³ represents

R^U0 —0 — X³ — C ²⁰ where R¹⁴ is defined as i: where R² is defined as i:

formula III above, cr -R², formula I above;

X^ reDreser.ts

38,537A-F *

33.537A-F

3AP 0 0 0 2 8 7

- 1 43) a polyamide of the formula:

0

Ί II — — C — )

Η⁷ (IV) where;n:

X and n are defined as in Formula I above:

is defined as i.n Formula 111 above;

R^ represents 4_?N-X-NH-. -.²C-. RNH- or R-C(0-NH-X-NH-. where R, R² and X are defined as i.n

R represents a hydrogen atom.

0 ιι ii _r2q _ _C — _;<3 __c

R — C — or

0

H II

RNH— C — χ3 __c _ p

where R ar.d R are defined as in Formula I above; and

X* is defined a3 in Formula 111 above.

3S.057A-F

-1410

The term pharmaoe-o;cally-aoceptable cation means a catior. acceptable for pharmaceutical use. Those cacions o.nat are r.ot substantially toxio at the dosage administered to achieve the desired effect and do not independently possess significant pharmacological activity are included within the term pharmaceuticallyacceptable cation. Illustratively, these salts include those of alkali metals, such as sodium and potassium; alkaline earth metals, such as calcium and magnesium; ammonium; light meoals of Group ΙΣΙΑ including aluminum; ar.d organic primary, secondary and tertiary amines, such as trialkylamines, including triethylamine. procaine, diber.zylamir.e, N. N ¹-diber.zylethyler.ed iamir.e , dihydroabietylamine. (C -Cq ) alky Ipi per idine , and any other suitable amine. Sodium and potassium salts are preferred. The term pharmaceutically-acceptable means suitable for administration to warmblooded animals, especially human beings, and includes being nontoxic, e.g. suitable for pharmaceutical use and is not poisonous to the warm-blooded animal. The pharmaceutically-acceptable cations of the oligomers of the present invention are prepared by conventional ion exchange precesses or by treating the R¹ acid with an appropriate base.

When uses other than for pharmaceuticals are th.e object for the present oligomers, then salts that would otherwise r.ot be as acceptable for pharmaceutical uses may be employed. Examples of such additional salts include barium, zinc and titanium.

The oligomers of the present invention are low molecular weight, rigid backbone, water-soluble polymers. Additionally, the oligomers have ordered anion spacing. 3y ordered anion spacing or regular

38.537A-C

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spacing	between anionic groups	i s	meant that the
anionic	groups (3^) are creser.t	in	the backbone cf the
polymer	at intervals determined	u... -,/	the starting materi	ai
reagent	used and the occurrence	of	the anionic groups	is
control	led in a credictab 1e manner.	While not wishing

to ce bound by any theory, the anionic groups of the oligomers are believed to be the portion that binds to the HIV and/or cell membrane and thereby interrupts the ability of the virus to replicate.

The terms predominantly linear geometry in an aqueous medium refers to the solution configuration cf the oligomer. A method well known in the art for characterization of the solution configuration cf polymer molecules is based on the following formula, referred to as the Mar<-Houwir.k equation [Introduction to Physical Polymer Science, ed. L, H. Sperling, pub. John Wiley i SONS (1985), pp. 81-33], [η] = ΚΜ^α wherein η is intrinsic viscosity; M is weight average molecular weight; X is a constant related to chain bond dimension; and a is a constant determined by polymer configuration. The intrinsic viscosity (η) for a random coil polymer is 0.5<a<0.9; and for a linear polymer is 0.9<= a<1.3. This formula relates the solution viscosity η to the molecular weight M. For this invention linear polymers are defined as having a values greater than or equal to 0.9. For a rigid rod polymer the theoretical upper limit is 1.3. For a given molecular weight, a higher solution viscosity will be obtained from polymers with a linear configuration relative to these polymers which exist as a random coil. An additional consideration is that the a value is a

38,537A-F

-16'3 functicr. of ‘.'.e solver.:, used. The a for a given water soluble polymer may be tifferer.t a: different salt concentrations. For t.n:s invention. the salt concentration is set at tne levels present in serum (approximately 30 g/L MaCl. 4 g/L KC1; .

As usee herein, the term oligomer encompasses all the possible values for n, e.g., 3 through 50. The oligomers are preferably linear with n equal to an integer from 3 to 50, preferably from 3 to 20, more preferably from 3 to '5. Of course, the n value i3 directly related to the molecular weight of the resulting oligomer. It is essential that these oligomers are of sufficiently lew molecular weight in order to pass through the renal excretory membrane, but able tc inhibit the HIV virus. The average molecular weight is governed by the stoichiometry of the reagents. The number average molecular weight (Mr.) is <*0,000, preferably from about 500 to about *0,000, and most preferably from about *1.000 to about 3.000.

For the purpose of the present invention, the oligomers described herein and physiolcg icallyacceptable salts thereof are considered equivalent. Physiologicaily-acceptable salts refer to the salts of those bases which will form a salt with at least one acid group of the R¹ group and which will not cause significant adverse physiological effects when administered as described herein. Suitaole bases include, for example, the alkali metal and alkaline earth metai hydroxides, carbonates, and bicarbcnates such as sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, sodium bicarbonate, magnesium carbonate and the like, ammonia, primary, secondary and tertiary amines and the like.

8,5S7A-F

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Particularly preferred cases are the alkali metal hydroxides, carbonates, and bicarbcr.ates . Physiologically-acceptacle salts may ce prepared by conventional icn exchange processes cr by treating the 3¹ acid with an appropriate case. Examples of additional salts have Peen described herein.

The formulations of the present invention are in the solid or liquid form. These formulations may te in kit form such that the two components are mixed at the appropriate time prior to use. Whether premixed cr as a kit, the formulations usually require a pharmaceutically-acceptacle carrier or adjuvant.

The oligomers cf the present invention are soluble in water and in salt solutions, especially at pr.ys iologi cal pH and in saline solutions. Thus the present oligomers are readily formulated into a suitable aqueous pharmaceutical dosage form. Also, after the present oligomer formulation is administered, the oligomer remains soluble invivo.

Preferred terms for the previously described Formulae 1 to IV are a3 follows:

2~ 3 and 3^ are a 4-methyipher.yl group;

m is 1 : n is 3 to *5;

3*¹ and 3^ are hydrogen;

3⁶ is phenyl;

3? is benzoyl;

X' is a ^-methylphenyl group;

is -C02~(4-methylphenyl) group; χ3 represents

C0’

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-;3- · 3-

or

SO-jR²

-/ ar.d

R²0,S

X represents

R²0;3

It A

In-:

AP Ο Ο Ο 2 8 7

Anti-HIV ar.ionic cligomers can be used to prevent syncytium formation in cells infected with HIV-I

-,5 virus or other related viruses having cpl20 surface protein. Anti-HIV anionic oligomers can be used to treat AIDS and ARC and other diseases caused by the retrovirus HIV-I or other related viruses having gpl20 surface protein. The anionic oligomers of this invention can be used as a pure compound, or as mixtures, such as those of n values of a particular Formula Z to IV, or mixtures of more than one Formula, e.g., Formula I with Formula II compounds, or as mixtures with ether known agents for the present antiviral utilities. However, for all oligomers prepared, n represents the number average repeat length of the di-stributicn through all formulae.

The amount of anti-HIV anionic oligomers which is needed to prevent syncytium formation in HIV infected cells can be any effective amount. Experimentally, it has been determined that anti-HIV anionic oligomers, when employed at a concentration of 10 ug/mL cf aqueous formulation, resulted in complete inhibition of syncytium formation as well as reduced the presence cf

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-20p24 antigen, an indicator cf viral replication, to belcw 300 pg/ml. The amount of anti-HIV anionic oligomers to be administered m order to treat AIDS or ARC or other disease caused by HIV infection can vary widely according to the particular dosage unit employed, the period of treatment, the age and sex of the patient treated, the nature and extent of the disorder treated, and other factors well-known to those practicing the medical arts. Moreover anti-HIV anionic oligomers can be used in conjunction with other agents known to be useful in the treatment cf retroviral diseases ar.d agents known to be useful to treat the symptoms of and complications associated with diseases and conditions caused by retroviruses.

The anti-HIV effective amount of anti-HIV anionic oligomers to be administered according to the present invention will generally rance from about 0.1 mg/kg to 500 mg/kg of body weight cf the patient and can be administered cr.e cr more times per day. Anti-HIV anionic oligomers can be administered with a pharmaceutical carrier using conventional dosage unit forms either orally or parenterally.

For oral administration, anti-HIV anionic oligomers can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions. The solid unit dosage forms can be a capsule which can be of ^w the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, sorbitol, calcium phosphate, and cornstarch. In another embodiment the anionic oligomers of this invention can be tableted with conventional tablet bases such as

38,537A-F

-21AP Ο Ο Ο 2 8 7

-2210 lactose, sucrose, ar.c cornstarch in combination with binders such as acacia, cornstarch, or gelatin, disintegrating agents intended to assist the brea<-up and dissolution cf the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, lubricants intended to improve the flow or tablet granulations and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example, talc, stearic acid, cr magnesium, calcium, cr zinc stearate, dyes, coloring agents, and flavoring agents intended to enhance the aesthetic qualities cf the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include diluents such as water and alcohols, for example, ethanol, benzyl alcchol, and the polyethylene glycols, either with or without the addition cf a pharmaceutically-acceptable surfactant, suspending agent, or emulsifying agent.

The anti-HIV anionic oligomers of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intramuscularly, or i.nterperitor.eally, as injectable dcsaces of the anionic oligomers in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcchol such as ethanol, iscpropar.ol, or hexacecyl alcohol, glycols such as propylene glycol cr polyethylene glycol, glycerol ketals such as 2,2-cimethyl-l, 3-dioxolane-4-n.erhanol, ethers such as poly (ethyleneglycol) 400, an oil, a fatty acid, a fatty acic ester or glyceride, or an acetylatec fatty acic glyceride with or without the addition of a pharmaceutically acceptable surfactant such as a soao cr

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a detergent, suspending agent such as pectin, carbomers, methylcellulose, hycroxyprcpylmethylcellulose, cr carDoxymetnyicellulcse, or emulsifying agent and other pharmaceutical adjuvants.

Illustrative of jus which can oe usee m the and isostearic acid.

parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum, and mineral oil. Suitable fatty acids include oleic acid, stearic acid, Suitable fatty acic esters are, fcr examole, ethyl oleate and isopropyl myristate.

Suitable soaps include fatty alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example, dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamines acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; ncnionic detergents, for example, fatty amine oxides, fatty acid alkanolamices, and polyoxyethyienepolyprcpyle.ne copolymers; and amphoteric detergents, for example, aikyl-beta-amincprcpic.oates, and 2-alkyiimidazoline quarternary ammonium salts, as well as mixtures. The parenteral compositions of this invention will typically contain from about 0.5 to about 25% by weight of anti-HIV anionic oligomer in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a r.cn-ionic surfactant having a hydrophile-lipophile balance (HL3) of frcm about 12 to about 17. The quantity of surfactant in such formulations ranges from

38,537A-F —

AP Ο Ο Ο 2 8 7 about 5 to about 15% by weight. The surfactant car. be a single component having the above HL3 cr can be a mixture of two or mere components having the desired HLB. Illustrative cf surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate.

The oligomers of this invention can also be used prophylactically, that is, to prevent transmission of virus from an infected individual to an uninfected target. Virus is spread proportionally via exchange of blood but may be transmitted via exchange of other bodily fluids as well. Thus the oligomers of this invention can be formulated with standard detergent products for use in cleaning, particularly in research and clinical laboratories and in hospitals where blood products cf infected individuals are handled. Formulations containing the oligomers of the present invention can be used to clean medical/surgical equipment and utensils as well as the hands of and other skin areas of health care workers. The oligomers of this invention can also be applied, as a liquid or powder composition, to the surface of sexual prophylaxis such as concerns by either the user or manufacturer of the prophylaxis prior to sale. The oligomers of this invention can be formulated into a douche composition fpr use by females for use prior to subsequent sexual contact with an infected individual. The oligomers of this invention can also be formulated in lubricants and spermatacidai jellies and lotions. Finally, the oligomers cf this invention can also be formulated as compositions to be added to hot tubs, whirlpool baths and swimming pools to inactivate Doter.tial virus activity,

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-24-25Oef initior.s

T Vi o £ p r» m 2 'J 2 6 d. ** * o ** ** ρ β p r· * defined as follows:

sliest LOΓ. 2Γ“ n represents the number average repeat length of the distribution through ail formulae.

RPMI means a cell culture media.

TC ID50 means tissue culture infectious unit, i.e. the amount of culture fluid effective to infect 50* of the cells.

MTT means 2-i 4,5-dimethy1thiaze1-2-yi)-2,5diphenyltetrazo 1ium bromide.

MT4 means a ceil line.

P24 test-Abbott means an assay of the viral core antigen using the assay kit currently sold by Abbott.

Coulter’'* HIV assay means a radioimmuno assay for P24 viral antigen determination.

ns COu means reccmbi.ner.t soluble COu comprised of the four extracytcplasmic immunoglobulin like variable (V) domains Vi-Vu.

T means 4-methyiani1ine cr toiuidi.ne, except when using the term T4 cells cr T-helper cells.

? means phosgene.

C means p-cnesoi.

M3C means 4-methylbenzoy1 chloride

38,537A-?

-ib-

APO00287

-26T?0 means · , i csrbcr.y 1 chloride or terephthaloyl chloride.

T?OS means sodium 2,5-tis(chlorocarto.nyl)ber.zeresulf orate, having the formula

H30S means dipctassium 2,5-dihydroxy-1,K berzeredisulforate . having the formula

HSrOS means dipotassium 4.4'-dihydrcxy(1.1’biphenyl)-2,2'-disulfonate, having the formula

OK

38,53A-F

-26-Ο?DS means 2.3-biaminc-¹,4-benzenedisuIfonic acid, having the formula in

'0

3?DS means 4,4’-diamino-(1.1'-biphenyl)2,2'disuifonic acid, having the formula

StDS means :rans-2,2 '-( 1,2-ethenediyl) bis (5aminobenzenesulfonic acid), caving the formula

33,537A-?

-27AP 0 0 0 2 8 7

-283P2S/P/T means poiyt iminot.2,2’-d i sulfo( 1 , 1 ' -bipher.y 1) -·*, 41' -diy 1]iminocar bony 1}, alpna-{[ (4-me thyl phenyl) aminojcarbony l}-omega[(4-metr.yiphenyl) amino]- and is represented by Formula I above when 3 is --methyipnenyl, R^ is hydrogen. X is

wherein n is defined as in Formula I.

StOS/F/T means poiyiimir.oi 2-sulf o- i, 4-phenyiene) - 1. 2-ether.ediyi-( 2suif o-1,4-pnenylene) imi r.ocar bony 1], alpha-{[ (4-methy1phenyl) ami r.ocar bony i}-cmega-[( 4-me thyl phenyl) amino- and is represented by Formula I above when R is 4-methylphenyl, R^ £₃ hydrogen, X is

-2333,537A-F

-29PDS/P/T means poly] imino(2,5-disulfo-1.4-phenylene)iminocarbonyl·], alpha-{[( 4-methy ipher.yl jamcrojcarbony i}-cmega-i ( 4-methy1phenyl)amino]- and is represented by Formula I above when R is 4-methylphenyl, R² is hydrogen, X is

and n is defined as in Formula I.

I 5

H3DS/P/C means polyioxy(2,5-disulfo-1,4-phenylene) oxy carbonyl], alpha[(4-methy1phenoxy)carbonyl]-omega-(4-methylphenoxy)- and is represented by Formula II above when X^ is 420 methylpher.yl, R² is hydrogen, X is

33,537A-F

-2?AP Ο Ο Ο 2 8 7

-20K3PDS/P/C means poly{oxy[2,2 ' -disulfο( ’, ' -biphenyl · -4.4 ' -diyl’oxycarccnyl}, alpna-E (4-methylphenoxy) carbony!J-omega-( 4methy Iphe.noxy) - and is represented by Formula ZZ above when X¹ is 4-methylphenyl, is hydrogen, X is

and n is defined as in Formula Z.

K3PDS/TPC means ¹5 poly{oxy[2,2'-disulfo( :, i ' -biphenyl} -4,4 ' -diyl’oxycarbonyl-,4-pher.yler.ecartonyl}- and is represented by Formula III when 3^ and 3^ are hydrogen, X^ i3 ppher.ylene, X is

where n is defined as in Formula I.

33,537A-F

-3CHsDS/TPC means polyfoxy ( 2.5-disulf c- * . 4-pr.er.y ler.e )oxycarbo.nyl- i, 4pnenyier.ecarbor.ylj- ar.d is represented by Formula III when R^ and R⁰ are hydrogen. χ3 ;₃ p-phenylene. X is

where n is defined a3 in Formula I.

3P3S/TPC/M5C means poly{imir.0L2.2' -di su 1 f o ( ¹. 1 ’-cipher./1)-4,4’*5 diyljimir.ocarbor.yl-',4-pnenyler.ecarbonyl}, a!pha-{[(4methylphe.nyl)aminojcarbonyl;-cm.ega-[( 4methylpr.e.nyl )amino]- and is represented by Formula 17 above when R^ is R-C( 3)-NH-X-NH-, R is 4-methyipher.yl. R^ is hydrogen, R? is 4-nethylbenzoyl, X^ is p2 0 phenylene, X is

where n is defined as in Form.’.

a I.

The oligomers procedure of Xershner disclosure cf which is and described further were prepared by modifying the (U.S. Patent Number 4,395,660, the hereby incorporated by reference,

33,537A-r

-31AP 0 0 0 2 8 7

-32cr.e of the difur.ctional monomers with a mono-functional end-capping agent and running the reaction in the absence cf a surfactant. The number average molecular weight (Mn) is governed by the stoichiometry of the reactants.

The oligomers of the present invention are prepared by the various reactions described below.

Polyureas and Polyamides (of Formulae I and III above)

The preferred process for the polyureas and polyamides of Formulae I and III above is described in the art (Xershner U.S. Patent 4,824,916) and is further explained as follows. The various reactants and conditions are also described.

Diamines: A wide variety of aliphatic and aromatic diamines are included. The hydrocarbyler.e diracicals of which the diamines are composed can include methylene, ethylene, butylene, isopropylide.oe, phenylene, biphenylene, and other diradicals. The range of possible substituents is similarly broad, and includes hydroxyl, alkenyl, lower alkyl moieties, carboxylate, sulfonate, and halogens. The substituents are not necessarily anionic at neutral pH in water.

Difuncticr.ai Electrophiles: Phosgene (carbonyl dichlorice), carbonyl dibrcmide, C1₃COCOC1,

C1₃COCO₂CC1₃, diacid halides of aliphatic and aromatic dibasic acids such as oxalic, malonic, succinic, glutaric, adipic, sebacic, phthalic, isophthalic, 2,6r.aohthalic acids.

33,537A-F

-3233Acid Accepters: Several bases have beer, employed, such as sodium carbonate, sodium hydroxide, anc :ributyiamine.

Miscellaneous additives: Various surfactants 5 may be added. Suitaole surfactants may be .non-ionic, such as sorbitan monolaurate, sorbitan mor.ostearate, ethylene glycol distearate, polyethylene oxy/polypropylene cxy polymer. Such surfactants can be difficult to remove from the product, and therefore the

Λ ' use cf surfactants is not preferred.

Solvents: Single solvent process employ polar aprotic solvents suer, as Ν,Ν-dimethylacetamide and N,Ndimethvlformamide. Also applicable are a combination of - 5 water and a second solvent, such as toluene, carbon tetrachloride, benzene, acetone, ethylene dichloride, and the like. Typical ratios cf organic to aqueous solvents are about 3.5 to about 2.

In the precesses described in t diacid halide is added to a stirred sol suspension cf the other starting mater; instances the base is added during the addition. The temperature is maintaine 50^;C, preferably 20 to 30^eC. A reactant ratio of diamine to diacid halide) from may be used, with essentially equimolar :he art, the ution or a1s. In seme carbonyl dihaiide d between 0 and ratio (molar about 0.9 to 1.2 amounts preferred.

The reaction is stirred at a rate sufficient to achieve mixing of the reactants. The reaction rate is dependent in part on the interfacial area between the phases, and therefore vigorous stirring is preferable.

A commercial blender may be employed for this purpose.

38.537A-F

-33AP Ο Ο Ο 2 8 7

-44The process usee co prepared the poiyureas of the present invention is a modification of the process described above.

Diamines: The diamines of the present 5 invention are primarily aromatic, with the formulas described in previous sections. Such diamines are substituted with at least one group which is charged at neutral pH, preferable sulfonate. Monovalent aliphatic substituents are allowable. A small set of aliphatic θ linking groups which tie aromatic radicals together may be used such as trans-substituted ethylene and acetylene. Preferred ciami.nes are those in which the carbon-nitrogen bonds are forced to be parallel, such as .- ?DS, 3?DS, StDS, anc 2,5-cianinobenzensuifenic acid.

Di functional eleotroohiles: For the preparation of poiyureas phosgene (carbonyl dichloride) and carbonyl dibromice, and other urea precursors such as carbonyl diimidazole, hexachlorcacetone,

Cl3COCO₂CCI₃, CCI3COCI, and ClsOCOCl may be used. For the preparation of polyamides, aromatic diacics such as iscphthalic and terephthalic acid (TPC), 2,6napthaler.edioic acid. These ciacics may have neutral or charged substituents, such as monovalent alkyl radical (methyl, ethyl, butyl) and/or charged groups such as sulfonates, phosphates and the like. An example of such a charged difu.nctior.al electrophile is sodium 2,5bis(chlorocarbonyl)benzenesulfonate (TPCS).

Acid Acceptors: A variety of inorganic bases may be used, such as alkali metal or divalent metal hydroxides carbonates, bicar Donates, phosphates. Acid acceptors with buffering capacity are preferred when all of the base is added oricr to the addition cf the

33.537A-F difunctior.al electrophile. Organic bases such as trialkyi amines may re used, out are not preferred.

Monofunctional eno capping agent: A variety of such molecular weight limiting agents may be used. Such agents may be aliphatic or aromatic compounds which react with the diamines or the difunctional electrophiles. Examples of suitable monofunctior.al agents are amines such as aniline, methylaniiir.e, methylamine, ethylamine, butylamine, diethylamine, ' ammonia N-methylaniline, phenol and cresol. Examples of mono:unctional amine reactive agents are benzoyl chloride, methyl benzoyl chloride, acetyl chloride, and phenyl chlcroformate. These end-capping agents may also .- contain charged substituents, for examDle ootassium 2* 0 sulfophencl cr potassium 4-sulfoaniline.

Miscellaneous additives: The addition of surfactants is not necessary or preferred, and can complicate the isolation process.

Solvents: A single solvent, water, is preferred when the difunctic.nal electrophile is a liquid at the reaction temperature. An example of such a difu.ncticnal electrophile is phosgene. When solid, water insoluble reactants are used, a small amount cf a water immiscible cosolvent is desirable. For example, when terephthaloyl chloride is used a minimum amount of methylene chloride is added to improve the contact between the reactants. Example cf such water immiscible cosolvents are chloroform, carbon tetrachloride, toluene, and methylene chloride. Typical ratios cf organic to acueous solvents are 0 to 1, with 0 to 0.1 preferred .

38,5S7A-F

AP 0 0 0 2 8 7

The process is conducted at temperatures which allow the reaction to proceed, typically from about 0 to luO'C. ?referaole temperatures are 0 to 25^OC. When low boiling starting materials are used, for example phosgene (bp 6°C) , it is advantageous to operate at temperatures at cr below the boiling point. The pressure is not important and typically ambient pressure is employed. The pH of the reaction must be carefully maintained for optimum process. At low pH (<6) the reaction is very slew, while at high pH (>10) the difunctional electrophile is unstable to attack by hydroxide or other base. Degradation cf the polyurea can also occur at high pH. The pH is preferably maintained between 7 and 9.

When no end capping agent is used, molecular weight control can be achieved by careful adjustment of the stoichiometry of the reactants. Either the diamine or the difuncticnal electrophile may be used in excess, for example from 1 to 100% molar excess. This stoichiometry must account for any of the difuncticnal electrophile which is destroyed by hydrolysis prior to reaction with the diamine. For example, when phosgene is used at high pH, a large excess is required to compensate for the fast reaction with hydroxide which destroys it. Because the extent of this side reaction is difficult to control, a mor.of u.nct ional end capping agje.nt is preferably used to control the molecular weight. Although the techniques mentioned can be used to control the number average molecular weight, the products are mixtures of polymers with several molecular weights characterized by a distribution.

The order of addition of the reactants is not critical. However, the preferred order is to add the

difunctionai electrophile first. When acic acceptors which are not buffers are used, such as hydroxide, it is most preferaDle to add a portion at the beginning to achieve the desired pH, ar.c then add the remainder concurrently with the difunctional electrophile.

Finally, it is desirable to conduct these polymerizations at high concentrations. This reduces the amount of solvent which must be removed to isolate the product. Also, in certain cases the product precipitates from the reaction solution near the end of the reaction, and may be isolated by simply decanting the solvent. Most cf the inorganic salt which results from reaction of the acid acceptor is removed in this process. The concentration is not critical, and may be from 0.5 to 50 wt%, expressed as weight of diamine to weight of solvent. A preferred range is 5 to 20 wt%.

The product may be isolated by precipitation of the reaction solution into a solvent which is water miscible but is a poor solvent for the product.

Examples of such solvents are acetone, methanol, ethanol, iscpropancl.

Polycarbonates ar.d Polyesters (cf Formulae II and IV above)

The process previously described for the polyureas and polyamides was used, with the following exceptions: Diphenols were used in place of the diamines: Suitable aromatic diphenols containing at least one substituent which is anionic at pH 7. These diphenols have identical structures to these of the diamines except that the amines are replaced with hydroxyl groups. It is possible to pretreat the diols

38,587A-r

AP 0 0 0 2 8 7 with or.e or two moles of case to form the mono- or diphencxides. Some specific examples are cipotassium 4,4' -di hydr oxy (1,1* -biphenyl )-2,2'-disuIfcr.ate (HBPDS) and dipotassium 2,5-dihycroxy-1,4-benzenecisuifonate (H3DS) .

The process conditions are much more critical due to the instability of the products in aqueous solutions. Of particular importance is pH control. At pH levels below 7 the polymerization rate is very slew, while at high pH (>9) the carbonate or ester groups in the polymer undergo hydrolysis. A preferred pH range is 7 to 8, and it is desirable to have an automatic pH controller to maintain it. The useful rance of temperatures under which the polymerization can be conducted is more narrow, 3 to 40^0, and preferably from 0 to 25'C.

After addition of the diacid chloride is complete, it is desirable to wait for a time, typically 15 to 120 minutes to insure that the conversion of starting materials is complete. Additional base may be added during this period, but the pH is never allowed to rise above the previously described limits. The product is isolated as a distribution of products as described above.

The invention will be further clarified by a consideration of the following examples, which are intended to be purely exemplary of the present invention.

38,537A-F

-38-29Ger.eral Experimental

All solvents ar.d reagents were obtained from commercial suppliers and used without further purification, except that 3?DS was purified by recrystallizing from dimethyl sulfoxide under nitrogen atmosphere ,

PDS was prepared by the procedure described in DE 1,393,557 (which disclosure is hereby incorporated by reference), and the product recrystalized from It (v/v) b^SOij.

The inherent viscosity was measured at 0.5 g/'dL in deionized water and Hank's balanced salt solution (HESS) (available from Sigma Chemical) at 25°C, unless noted otherwise.

The water content of the purified diamines was determined by Karl Fischer titration.

²⁰

Proton and carbon nuclear magnetic resonance spectra were recorded on a Varian’ VXR 300 or an Varian’ Gemini 300 spectrometer. Samples were dissolved in D₂0, unless otherwise noted. Where possible the number average molecular weights of the oligomers was confirmed by integrating the area of the resonances from the methyl groups of the end caps relative to the aromatic resonances of the repeat unit. In many cases, particularly the polyamides prepared from BPDS or StDS and TPC, the resonances were too broad to be of value.

High pressure liquid chromatographic analysis (HPLC) were performed on an HP 1090 liquid chromatograph using a 200 mm x 2.1 mm C—18 reverse phase column.

38.537A-E

-29AP Ο Ο Ο 2 8 7

-iO column was eluted with a gradient solution starting initially with of 35% of CH₃CN and 65% of 5 mM tetra-nbutylammonium sulfate and ending with 55% CH₃CN and 45% of tetra-n-butylammonium sulfate.

The phosgene reaction was carried out in a typical phosgenation apparatus having a stainless steel phosgene reservoir connected to a phosgene tank, nitrogen line and reaction feed line. The reservoir was mounted on a scale and could be filled directly from the 'θ phosgene tank when needed. The differential weight of the reservoir before and after the reaction was reported as the amount of phosgene added. Unless otherwise noted, a nitrogen carrier stream of 0.3 mL/min was .- maintained throughout the reaction. Phosgene was introduced at a rate of 0.9 mL/min (total gas flow of

1.2 mL/min during phosgene addition). In general a three-fold excess of phosgene was added to the reaction vessel. A stirring rate of 300 rpm was used and the

2C solution maintained at 10 to 15⁵C throughout the course of the reaction.

The products were routinely dried in a vacuum oven at 40-50°C for a minimum of 15 hours.

STARTING MATERIALS

Example A

Preparation of HBPDS, having the formula _0Ao owe'NM38,587A-?

-KC-4 1-

7o a 2 L flask equipped with an addition funnel and magnetic stir Pan was added ^9-99 g (0.145 mol) of •iq 4,4'-diamino(1,1'-biphenyl)-2,2'-disulfonic acid and 600 mL of water. The diamine was solubilized by the addition of 30 mL (0.15 mol) of 5M NaOH. To the resulting solution was added 20.56 g (0.293 mol) of sodium nitrite. The reaction mixture was then cooled to 0°C and 60 mL of concentrated H₂SO₄ dissolved in 360 mL of water was added over 30 min. A yellow solid was formed. To the mixture was then added 300 mL of water and the mixture maintained at 0°C for one hour. The reaction mixture was then filtered. The yellow solid .

was placed in a 1 L flask dissolved in 800 mL of water, and heated until about 50 mL of water remained.

Nitrogen gas was evolved during heating. To the concentrated solution was added 20.14 g (0.146 mol) of

K₂CO₃, followed by boiling the solution. Absolute ethanol (1.5 L) was then added, and a brown solid precipitated. The solid was filtered and dried overnight in a 50°C oven. The product, HBPDS, was obtained in a yield of 32.33 g (53%), and further

-° characterized by ^}H NMR

56.70 (dd, IH), 7.05 (d, IH), 7.14 (d, IH).

38,537A-F

-41AP 0 0 0 2 8 7

-42Examole 3

Preparation of TPCS, having the formula

A 500 mL flask, equipped with a mechanical stirrer, thermometer and reflux condenser, was charged with 40.49 g (0.143 moi) cf the monosodium salt of 2sulfoterephthalic acid, 160 mL of chlorobenzene, 2.4 mL (0.031 mol) of dimethylformamide, and 23 mL (0.315 mol) of thionyl chloride. The solution was heated to 105’C and stirred for 2 hours under nitrogen. During this time evolution of gas was noted. The solution was cooled to room temperature and a solid precipitated.

The solid was filtered and dried overnight in a vacuum oven at room temperature. The product, as a pale yellow solid, was obtained in a yield of 20.56 g (472).

To confirm the structure of the product, some of the product was converted to its methyl ester.

To a 25 mL flask, equipped with a magnetic stir ba'r and nitrogen bubbler, was added 0.9509 g (3.12 mmol) of the above product, 0.6874 g (6.47 mmol) of Na₂CO₃, and 10 mL of methanol. After stirring the reaction mixture overnight at room temperature under nitrogen, the solid was filtered, dried in a vacuum oven for 6 hours at room temperature, and determined that the

33,587A-r

-42-43dimethyl ester of the product had formed, being characterized by ^XH NMR

53-34 (s, 6H), 7.39 (d. IH), ^.97 (d, IH), 8.25 (s, IH); ¹³C NMR

558.0, 136.0, 139.8, 140.9, 145.2, 146.3, 150.1, 183.5, 186.4.

FINAL PRODUCTS

Example 1

Preparation 0? 5P3S/P/T, having the formula

Olizomer A (r. = 5 ).

To a 1 L flask, equipped with a syringe port, thermometer well, pH electrode, dry-ice condenser, phosgene gas inlet tube, and a mechanical stirring device, was added 10.00 g (23.19 mmol) of 3PDS, 1.35 g (9.40 mmol) of toiuidine hydrochloride, and 400 mL of water. The reaction mixture was stirred and cooled to 12°C. The stirred suspension was then reacted with 13 mL of 5M NaOH until all the solids had dissolved. To the reaction mixture was then added 10.1 g (102 mmol) of phosgene over a 27 min period. During the phosgene addition, 5M NaOH was added with a syringe as necessary

38,537A-P

-43AP Ο Ο Ο 2 8 7

-44to maintain the pH between 7 to 8 (occasional extremes of pH 6 to 9 occurred). A total or 31 mL of NaOH was added. Stirring of the reaction mixture was continued for an additional 30 min, and then the pH was adjusted to 9.5 and the reaction mixture stirred for an additional 30 min. The reaction mixture was transferred to a 2 L flask and the crude product precipitated by the addition of 1000 mL of acetone. The crude product was filtered and air-dried to yield 18.6 g of an off-white powder having an M_n=2500. The inherent viscosity was 0.39 dL/g in H₂0, 0.15 dL/g in HBSS. The product was further characterized by ^ςη nmr ¹⁵ 82.2 (br s), 6.7-7.4 (a), 7.9-8.3 (a).

Oligomer 3 (n=9)·

When the procedure of Example 1A was repeated using the following amounts of reagents:

REAGENT	AMOUNT	mmol
BPDS	'2.C6 g	34.00
T-HCl	1.09 g	7.56
P	11.3 g	111.0
Water	400 mL

the product, as a white powder, was obtained in a yield of 12 g and M_n = 36CC. The inherent viscosity was 0.52 cL/g in H₂0, 0.21 dL/g in H3SS.

O^^G

38,537A-F

-44--5Example 2

Preparation or StDS/P/T, having the formula

Oligomer A (n = 6 ).

When the procedure of Example 1A was repeated using the following amounts of reagents:

REAGENT	AMOUNT	mmol
StDS	10.53 g	23.00
T-HC1	1.34 g	9.33
?	7·- g	74.3
Water	4C0 mL

the product, as a yellow solid, was obtained in a yield of 7.4 g and M_n = 2600. Inherent viscosity was 0.14 dL/g in H2O. The product was further characterized by

NMR 'θ 52.1 (br s), 6.7-8.1 (br m).

38.587A-F

-45AP 0 0 0 2 8 7

-4601i gomer 3 (r. = 9).

The procedure of Example IA was repeated using the following amounts of reagents:

REAGENT	AMOUNT	mmol
StDS	10.58 g	28.00
T-HCl	0.89 g	6.22
a k	9.0 g	91.0
Water	400 mL

About one-half of the suspension obtained after addition of acetone was filtered due to frit clogging problems. The product, as a yellow solid, was obtained in a yield of 3.5 g and = 3300. Inherent viscosity was 0.13 dL/g in H2O.

Example 3

Preparation of P3S/P/T, having the formula

33,587A-c

-46-4701 izor.er A (n = 9) .

When the procecure cf Example 1A was using the following quantifies of reagents;

repeated

REAGENT	AMOUNT	mmol
PDS	3.50 g	13.05
T · HC 1	0.416 g	2.90
P	4.3 g	43.5
Water	225 mL

the product, as a brown powcer, was obtained in a yield of 2.95 g and = 2900. Inherent viscosity was 0.12 ⁵ dL/g in H₂0 and 0.07 dL/g in H3SS.

Oil;or.er 3 (n= 15 ) .

When the procedure of Example 1A was repeated 20 using the following amounts of reagents:

REAGENT	AMOUNT	mmol
PDS	3.50 g	13.05
T-HCl	0.250 g	1.74
p	4.2 g	42.9
Water	225 mL

the product, as a brown powder, was obtained in a yield of 3-83 g and - -650. Inherent viscosity was 0.12 dL/g in H₂0 and 0.1-4 dL/g in H3SS.

38,5S7A-r

-47AP Ο Ο Ο 2 8 7

-ngΞχamole 4

Preparation cf H3DS/?/'C, having the formula

SO₃Na

NaO^S n

Oli zomer A (n = s 1 .

To a 1 L flask, equipped with a syringe port, a thermometer well, mechanical stirrer, pH electrode, dry ice condenser, and a phosgene inlet tube, was added _2Q ¹O.16 g (29.35 mmol) of HBDS, 1.06 g (9.81 mmol) of pcresol, and 4oo mL of water. The reaction mixture was ccoied to 10°C with nitrogen flowing into the flask through the phosgene inlet. The stirred reaction mixture was treated with 5M sodium hydroxide until the ?H of the solution was 8.0. To the reaction mixture was added 10.5 g (106.0 mmol) of phosgene over 35 min along with 42 mL of 5M sodium hydroxide as needed to maintain the pH of the solution between 7.0 to 7.5. After the phosgene addition was complete, the solution was allowed ^;0 to stir for 20 rain at ¹0^sC. The dry ice was then removed from the condenser and the solution stirred an additional 30 min at 1O°C in order to allow the excess phosgene to evaporate. The aqueous solution was transferred to a 2 L flask and 100 mL of water used to rinse the reaction vessel was added. The product was

38.587A-F

-48-49precipitated by the addition of 1000 mL cf acetone, filtered, ar.d dried overnight in a vacuum, oven at room, temperature. The yieid of product was 2.11 g, the inherent viscosity of the solid was 0.30 dL/g in Η£θ, and = 2300.

Example 5

Preparation of HBPDS/P/C, having the formula

S0-;Na

NaO₃S ~(O^~^ch3

01i gomer A (n = 6).

When the procedure cf Example 4 was repeated using the following amounts cf reagents:

REAGENT	AMOUNT	mmol
HBPDS	12.35 g	29.25
p-cresoi	1.07 g	9.91
P	10.1 g	102
Water	400 mL

the pH of the initial solution was 10.0 and was to pH 3.1 with concentrated hydrochloric acid.

adjusted

38,587A-?

-49AP 0 0 0 2 8 7

-5Cphosgene was added over 22 min with 31 mL cf 5M sodium hydroxide to maintain the pH between 7.5 ar.d 8.0. After the phosgene was allowed to evaporate, the reaction mixture was transferred to a 2 L flask and 100 mL of water used to rinse the reaction vessel was added. The product was precipitated by the addition of 1400 mL of acetone, filtered, and dried overnight in a vacuum oven at room temperature. The yield of product was 1.89 g, the inherent viscosity of the solid was 0.17 dL/g in HgO, and M_n = 2700. The product was further characterized ty ¹H NMR

62.2 (s), 7.0 (s), 7.2 (s), 7.5 (hr s ).

Example 6

Preparation of H3PDS/TPC, having the formula

Na0₃S

01i gcrner A (n=4).

A 500 mL flask, equipped with a reflux condenser, addition funnel, and mechanical stirrer, was charged with 7.92 g <18.7 mmol) of KBPDS, 2.16 g (37.5

33.537A-P

-mol) of sodium bicarbonate, 125 mL of water, and 25 mL of methylene chloride. To the stirred reaction mixture was added 3-60 g (16.7 mmol) of T?C in 100 mL cf methylene chloride over one hour. The resulting solution was stirred for 1.5 hours at rocm temperature ⁰ under nitrogen. The solution was then transferred to a 2 L flask and 100 mL of water used to rinse the reaction vessel was added. Acetone was added in 250 mL increments to break the emulsion. After 1000 mL of acetone was added, a solid was formed on the bottom of the flask which looked like beads filled with water.

The solution was filtered, redissolved in 250 mL of water, precipitated with ⁷t0 mL of acetone, filtered, and dried overnight in a vacuum oven at room temperature. The crown solid weighed 4.39 g, the inherent viscosity of the solid was 0.16 dL/g in HjO, and M_n - 21CC. The product was further characterized by ¹H NMR

52.2 (s). 7.C (br s), 7.25 (br s), 7.5 (br s), 3.0 (br s) .

Example ⁷

Preparation of HEDS/TRC, having the formula

38,567A-E

-51AP 0 0 0 2 8 7

-5201 i gomer A (n = 3)·

The procedure o: ixample ό was repeated using the following amounts cf reagents:

REAGENT	AMOUNT	mmol
HBOS	6.51 g	18.8
NaHC03	3. 15 g	37.5
CH2CI2	'25 mL
TPC	3.34 g	18.9
Water	‘25 mL

The resulting solution was stirred for 1.5 hours at room temperature under nitrogen. The solution was then transferred to a 1 L flask and 100 mL of water used to rinse the reaction vessel was added. To the flask was added 450 mL cf acetone to break the emulsion. There was a precipitate formed in the lower water layer. The solution was transferred to a separatory funnel and the lower layer separated. The water solution was then treated with 500 mL of acetone. A beige solid was formed, filtered, and dried over two days in a vacuum oven at room temperature. The product weighed 4.38 g, the inherent viscosity cf the solid was 0.05 dL/g. Analysis by NMR and H?LC revealed significant amounts of starting di phenol.

in order to remove the unreacted starting material. 2.0 g of the above isolated solid was dissolved in 200 mL water. The product was precipitated by the addition of 700 mL of acetone, filtered, and dried overnight in a vacuum oven at room temperature.

38,5S7A-F

-52-53The solid product weighed 0.41 g, the inherent viscositv of the scl.c was 0.1' cL/g in H2O, and M_n = 1300.

Examole 8 0 Preparation of 3PDS/TPC/M3C, having the formula

NaO₃S

NaO₃S

Oligomer A (r. = 6 ).

To a Waring blender was added 200 mL of deionized water and 2.65 g (25.0 mmol) of sodium carbonate and the mixture stirred at low speed until dissolved. To the reaction mixture was added 2.217 g (6.25 mmol) of 3P03 via a powder addition funnel. The funnel was rinsed with 50 mL of water into the mixture.

A clear colorless sodium salt solution was formed.

A second soiution having 1.088 g (5.357 mmcl) of T?C and C.193 mL (236 mg, 1.786 mmol) of MBC in 200 mL of chloroform was prepared. The soiution was immediately added in one portion to the sodium salt solution with vigorous stirring. The resultant white slurry was stirred at low speed for ‘5 min.

After sitting fcr 15 min, the slurry was transferred to a 2 L flask and the blender washed about 200 mL of water which was added to the slurr

38,587A-F

-53AP Ο Ο Ο 2 8 7

-54the slurry was added 200 mL of acetone. The emulsion oroke into a two-phase system with no visible precipitate. The lower layer was removed via separatory funnel; the upper layer was returned to the flask. To the flask was added -50 mL of acetone which effected ⁰ precipitation. The precipitate was filtered through three layers of cheesecloth. The residual solvents were removed from the white gelatinous product by firmly squeezing the cheesecloth. The crude product was dissolved in 600 mL of water and reprecipitated by dilution to a total volume of 1600 mL with acetone. The precipitate was again collected, dissolved in 150 mL of water, and precipitated by adding 850 mL of acetone.

The precipitate was collected as before, dried in a '5 vacuum oven overnight at 35 to 30°C to yield 0.8 g of a fibrous white product.

A second crop of product was obtained from the original mother liquor having a yield of 0.9 g. The combined solids were dissolved in 130 mL of water and precipitated by adding 500 mL of acetone to give 1.26 g, of a off-white solid, M_n = 3450. Inherent viscosity was 3.85 dL/g in H₂0. The product was further characterized by ^:H NMR

52.1 (s), 7.44 (s), 7.78 (s), 8.02 (br s).

33,587A-?

-543).

Oligomer 3 (π =

When the procedure of Example 8A was repeated using the following quantities of reagents:

REAGENT	AMOUNT	mmol
3?0S	2.217 g	6.25
T?C	0.952 g	4.688
M3C	412 mg	3.125
Na2C0-j	2.65 g

the product, = s an off-white powder, was obtained in a yield of 1.53 g and = 2000. Inherent viscosity was 1.83 dL/g in HpO ar.d 2.41 dL/g in H3SS.

Oligomer C (n = 9).

When the procedure of Example 8A was repeated using the following quantities of reagents:

REAGENT	AMOUNT	mmol
S?OS	2.217 g	6.250
:?c	1.142 g	5.625
xsc	i65 mg	i . 250
Na2:o3	2.65 g

fibrous product, was obtained in a yield M_n = 4900. Inherent viscosity was ^.23 the white. 1 . 42 g and in H₂0.

38.587A-F

-ooAP Ο Ο Ο 2 8 7

-00 —

3I0LCGICA1 DATA

Example X

A3ILITY 0? AN ANTI-HIV OLIGOMER TO PREVENT SYNCYTIA

- FORMATION AND EXPRESSION OF P24 VIRAL CORE ANTIGEN USING JM CELLS AND GS8 VIRUS STRAIN

To show that an oligomer of the invention blocks HIV infection, CD4⁺ T-cells (JM) were exposed to a clinical ,- isolate of HIV-I, G38. The virus was first incubated

I J with an oligomer for 15 minutes and then the cells were added. After 2 hours adsorption, the virus innoculum was removed and the cells were washed three times to remove traces cf input virus. Antiviral activity was *5 determined after 3 cays incubation by plotting the mean number cf syncytia found in quadruple cultures against iogio concentration cf anionic polymer or of other test compounds. The potency of an oligomer was also measured by assaying viral core antigen (P24 test-Abbott) in the supernatant fluid. Heparin, dextran sulfate, rs CD4,

ATZ and/or cdC data, when included in any of the following Tables, are provided as positive controls.

33.537A-F

-56-57TA3LE

COMPOUND	C0NC. pg/mL	SYNCYTIA	P24 (pg/mL)	* CONTROL
Control	--		>453600	100
Heparin	5.0	r\ V	2500	<0. 1
	2.5	*'0	25775	<0. 1
	1.25	+ .· 0	N.A.	N.A.
	0.6	+ +	44570	0. 1
Example IA	5.0	0	N.D.	N.A.
	2.5	0	96	<0. 1
	1.25	c	541	<0. 1
	0.6		37355	0.13
Example 13	5.0	c	465	<0. 1
	2.5	0	365	<0.1
	1.25	*	35390	<0. 1
	0.6		32320	0.1

N.O. = not detected N.A. = not assayed

Examole II

Virus infection of JM cells was carried out in the presence cf different concentrations of test compounds. JM cells (IxlO-*) and 50-100 syncytial forming units of virus (GE8) were added to duplicate wells of a tissue culture plate containing 1 ml volumes of growth medium with or without drug. The plate was incubated for 2 days at 37°O and then scored for the presence of syncytia. At the same time the ceils were washed and the growth medium replaced. After a further two days incubation, the cell free supernatant fluids were harvested and assayed for levels of P24 viral core antigen using the Coulter’ HIV Antigen assay. The results are given in Tables TI-IV. In the Tables,

N.D. = not detected and N.A. = not assayed.

38.537A-?

-57AP Ο Ο Ο 2 8 7

-53TA3LE II

COMPOUND	CONC. gg /mL	SYNCYTIA (2 DAYS)	MEAN	t	P24 (unita/mL)
Control		39,27,42,31 42,41.51,13 57,53,56,38 41,47,41,45 52	42	100	3.6x10s	100
rs CD4	5	0	0	0	4.4x104	12
Heparin		10	0, 0	0	0	1.1x104	3
		3	0, 0	0	0	1.7x104	5
		1	2, ’	2	5	2.8x104	8
		0.3	21,22	22	52	4.1x104	1 1
		0. 1	28,20	24	57	N.A.	N.A.
		0.03	39,1?	29	69	N.A.	N.A.
		0.01	33,42	38	90	N.A.	N.A.
Example	1A	10	0, 0	0	0	N.D.	N.D.
		3	0, c	0	0	N.D.	N.D.
		1	0, 0	0	0	9-1x103	3
		0.3	9, 19	•4	33	4.0x104	1 1
		0. 1	21,23	25	58	4.0x10s	100
		0.03	52,52	52	123	4.3x10s	100
		0.01	54,66	60	143	N.A.	N.A.
Example	13	10	0, 0	0	0	N.D.	N.D.
		3	0, 0	0	0	N.D.	N.D.
		1	0, 0	0	0	1.6x103	0.4
		0.3	2, 0	1	2	3.8x104	1 1
		0. 1	36,13	25	58	4.4x105	100
		0.03	43,40	42	100	4.1x105	loo
		0.01	40,54	47	112	N.A.	N.A.
Example	3A	20	9, i	5	12	N.D.	N.D.
		10	4, 2	3	7	4. 1x104	1 1
		5	15, 14	15	36	3.6x105	100
		2.5	37,38	38	90	2.5x105	69
-		1.25	27,13	20	48	4.3x105	100
		0.6	46,55	51	120	N.A.	N.A.
Example	3A	100	0, 0	0	0	N.D.	N.D.
		30	0, 0	0	0	N.D.	N.D.
		10	0, 0	0	0	N.D.	N.D.
		3	0, 0	0	0	4.4x104	12
		1	2, 3	3	7	4.3x104	12

38,537A-F

-58-59TA3LE III

COMPOUND	CONC. pg/mL	SYNCYTIA	MEAN	ί	P24 (pg/mL)	$
Control		46.52,69 79.84,59 31.67,63 71,64,75	69	100	332300	100
rsCD4	10	0, 0	0		5340	1.6
	1 I	15,24	20	28	88700	27
	0.1	35,44	40	57	202000	61
Heparin	100	0, 0	0		989	0.3
	10	0, 0	0		70700	21
	I	9,‘7	1 b	1 Q	21 1000	63
Example 8A	500	0, 0	0		N. A.	N.A.
	50	0, 0	0		1 1600	3.5
	5	39,31	35	51	268599	81

Example III

ABILITY OF VARIOUS ANTI-HIV OLIGOMERS TO PREVENT VIRUSINDUCED CELL DEATH USING MTU CELLS AND STRAIN RF.

Various oligomers were dissolved in RPMI and were then assayed for anti-HIV activity 'ey making doubling dilutions of the solutions across a 96 well microtitre plate. To each well were then added 5x10⁴ cells and '00 TCID50 of virus and the plates incubated at 37°C for days. MTT was added to each well and the elates incubated for a further 2 hours. The blue formaza.n crystals were dissol ved using acidic isoprcpar.ol, and the absorbance measured at 540 nm. The results are given in Table IV.

38.537A-F

-59AP Ο Ο Ο 2 8 7

-60TA3LE 17

COMPOUND	MWa	EDSO pg/mL	TD50 pg/mL
Heparin	10,000 40,000	4.6	> 100
Example 13	4, 168	2.2	>100
Example 1A	2,958	1.6	> 100
Example 8C	5,290	2.2	>100
Example 8A	3,689	1.5	>100
Example 83	2, 180	2. 1	>100
Example 23	4,204	2.5	>100
Example 2A	2.883	1.9	> 100
Example 33	5,314	1.7	>100
Example 3A	3,284	>>10	>100

^ώ Number average molecular weight

Example 17

A3ILITY TO PRETREAT CELLS WITH VARIOUS OLIGOMERS AND 3L0CX HIV-I INFECTION USING JM CELLS AND G38 STRAIN OF HIV-I

JM cells were pretreated overnight at 37’C with different compounds at 20 pg/mL or left untreated. The cells were washed 3 times in RPMI medium and then infected with HIV-I (G28) for 2 hours at room temperature. The cells were again washed 3 times in RPMI med ium and resuspended in fresh medium prior to

3° being distributed into duplicate wells and incubated at 37°C. After 2 days syncytia were scored and the ceil free supernatant fluid harvested and assayed for P24 viral core antigen using the Coulter'¹* HIV antigen assay. The results are given in Table V.

38,587A-F

-61TA3LE 7

COMPCUND	MEAN SYNCYTIA	1 •	P24 (pg/mL)	%
Control	119	100	28290	100
Example Ά	14	12	2623	9
Example B	52	44	2790	10
Example 3A	153	129	26880	95
Heparin	136	1 14	29090	103
Dextran Sulfate	184	155	28710	ιοί

Example V .- ABILITY OF AN ANTI-HI7-I OLIGOMER TO PREVENT SYNCYTIA i P

FORMATION AND P24 VIRAL CORE ANTIGEN EXPRESSION 3Y DIFFERENT VIRAL STRAINS (G38 AND RF) AND CELLS (JM AND C8 166)

2Q Cells were infected with strain RF or GB8 for hours at 37°C at a multiplicity cf infection of 0.001. Ceils were washed three times to remove residual virus and then replated into fresh growth medium. Cells were then treated for 24 and 4 8 hours post-infection (p.i.) with the indicated concentrations of test compounds. Syncytia and P24 antigen levels were determined on the indicated days p.i. by methods described before. Results are presented in Tables VI VIII.

33.587A-F

-61AP Ο Ο Ο 2 8 7

-62TA3LE VI

EFFECT OF TREATING HIV-I (G38) - INFECTED CELLS (JM) 24 HOURS POST-INFECTION

COMPOUND	DOSAGE (μΜ)	TIME OF ADDITION POST- INFECTION (HOURS)	SYNCYTIA/ WELL DAY 3 p.i?	P24 pg/mL DAY 6 p.i?	% CONTROL
Control	0		>100	1.03x106	100.
Example 1A	2.5	0	0	4.2x102	0.04
Example 1A	2.5	24	0	1.21x104	1.2
Example 1A	1.2	24	<10	1.5x104	1.5
Example 1A	0.62	24	<20	5.6x104	5.4
Example 1A	0.31	24	>50	1.65x105	16.0

p.i. means post infection

The results in Table VI above indicate that events associated with viral induced cytopathological changes such as syncytia formation can be inhibited even when compounds are administered to previously infected cells. These results also indicate that the anionic oligomers are working by a mechanism in addition to blocking viral attachment to the CD4 cell surface protein.

bad

ORIGINAL

38,587A-F

-62-63TA3LE VII

EFFECT OF TREATING HIV-I (RF) - INFECTED CELLS (C8166) 24 HOURS POST-INFECTION

COMPOUND	DOSAGE (μΜ)	TIME OF ADDITION POST- INFECTION (HOURS)	SYNCYTIA, WELL	P24 pg/mL DAY 6 p.i?	% CONTROL
DAY 2	DAY 3
Control	0	—	+	+ + +	9 5x105	100.
ddC	10	0	0	0	1.3x104	1.4
ddC	10	24	+	+ + +	4.2x105	44.2
AZT	10	0	0	0	1.0x104	1.1
AZT	10	24	+	+ +	4.4x104	4.6
Example IA	10	0	0	0	1.6x104	1.7
Example 1A	10	24	0	0	9.2x103	1.0
Example 1A	5	24	0	0	9.3x103	1.0
Example 1A	2.5	24	0	0	9.78x104	10.2
Example 1A	1.25	24	0	+ +	1.5x106	100.
Example 1A	0.62	24	+	+ + +	7.0x105	74.

^a p.i. means post infection

The results in Table VII above indicate that the oligomers of this invention are effective against different viral strains and different ceil types even when added 24 hours after virus infection.

38.587A-F

-63AP Ο Ο Ο 2 8 7

-64TA3LE VIII

EFFECT C? TREATING HIV-I (GB8) - INFECTED CELLS (JM)

HOURS POST-INFECTION

COMPOUND	DOSAGE (pM)	TIME OF ADDITION POST- INFECTION (HOURS)	SYNCYTIA/ WELI? DAY 3 p.i.3	DAY 6 p.i.3	P24 pg/'ml	% CON- TROL
Control	0		69 61 70	Cells Degen- erated	1.1x105	100.
Example 1A	1.2	0	0 0 0	0 0 0	4.5x102	0.41
Example 1Ab	1.2	48	19 10 12	2 5 9	2.1x104	19.0 _

“ p.i. means post inrection ^b Approximately 50 syncytia/well p.i. in the virus control wells, received 5 pg/mL of the oligomer 2incubated further. Syncytia wer 4 days p.i. cells were washed in of the oligomer of Example IA an pg/mL cf the oligomer of Example were washed in media as above wi reincubated in parallel. On day media cf all samples were collec 2levels were determined.

were observed at 48 hours At this time, wells of Example IA and were e scored on day 3 p.i. At media containing 5 pg/mL d incubated further in 5

IA. Virus control cells thout test compound and

p.i. the cell-free ted and viral P24 antigen

The results of these studies show that the oligomers of Example IA cleared cultures of syncytia, stabilized the infection and reduced virus antigen levels in cells having preestablished infections.

Λ

38.587A-F

Sxamole 71

ected with HIV (Strain RF) for 1 hour at room temperature to give a multiplicity of infection of approximately 0.01 infectious units per cell. The cells were washed three times and resuspended in fresh medium prior to being distributed into duplicate wells containing different concentrations of test compound. After 2 cays at 37° the cells were observed for the presence of syncytia and the supernatant fluid assayed for p24 viral core antigen using the Coulter HIV antigen assay.

z

38.537A-F

-65AP 0 0 0 2 8 7

-66Table IX

Anti-HIV Activity cf Various Phenyl and Biphenyl Disuifonic Acid Polyester and Polycarbonate Oligomers

COMPOUND	OLIGOMER CONC. pg/ml	SYNCYTIA Day 2	p24(pg/ml) Day 2	% of VIRUS CONTROL
Virus	-	+ + +	3.2xl03	100
Control
Example 6	100	0	neg	0
	50	0	neg	0
	25	ολ	neg	0
	12	o/+	neg	0
Example 4	100	++/+++	1.93xl03	60
	50	++/+++	2.82xl03	88
	25	++/+++	4.82xl03	100
	12	++/+++	3.05xI03	95
Example 7	100	0/+	neg	0
	50	++	8.7xl02	27
	25	++/+++	1.45xl03	45
	12	++/++-	3.14xi03	98
Example 5	100	+ + -	1.06xl03	33
	50	+ + +	2.78xlQ3	87
	25	+ + +	2.32xl03	73
	12	+ + -	3.25xl03	100
AZT	1	0	neg	0
	0.1	0	neg	0
	0.1	0/+	neg	0

Example 71I

JM cells were infected with HIV (Strain GB8) to give approximately 200 syncytia/lxlO⁵ cells after 3 days; virus infection was for 1 hour at room temperature. The ceils were washed and resuspended in fresh medium before being distributed into duplicate wells of a tissue culture plate containing different concentrations of test compound. After 3 days the cells were observed, syncytia counted and the supernatant

38,587A-F

-67fluid assayed far p24 viral core antigen using Coulter HIV Ag assay.

Table X

COMPOUND	OLIGOMER Cone. pg/ml	MEAN SYNCYTIA 3 days p.i.	— p24 pg/ml* 3 days p.i.
Virus	-	>200	5.2xl03
Control
ddC	10	0	neg
	1	0	neg
	0.1	2	neg
	0.01	80	5.4xl03
ExamDle 6	200	0	-
	100	0	neg
	50	12	neg
	25	25	6.8xI03
Example 7	200	0	neg
	100	7	neg
	50	24	neg
	25	43	neg
Example 5	200	14	neg
	100	22	neg
	50	68	neg
	25	>200	6.7X101
ExamDle 4	200	Toxic	-
	100	Toxic	-
	50	64	neg
	25	95	6.5X103

♦supernatant fluids screened at 1/100 dilution.

A

38,587A-F

-67AP Ο Ο Ο 2 8 7 ill be24JUNI99I

-63Other embedimer.ts of the invention apparent to those skilled in the art from a consideration of this specification or prac invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the invention being indicated by the following claims.

38.587A-F

-63'//1 // Ζ>-

Claims (44)

1. A water-soluble, rigid backbone oligomer having a molecular weight less than 10,000 comprising recurring units coupled by carbonyl linking moieties, said oligomer having anionic groups and predominantly linear geometry such that regular spacing between anionic groups exists in an aqueous medium.

2. An oligomer of Claim 1 wherein the oligomer is a poiyurea, polycarbonate, polyester or polyamide.

3. An oligomer of Claim 1 or 2 wherein the recurring unit has two or more anionic groups.

4. An oligomer as claimed in any one of Claims 1, 2 or 3, wherein the oligomer is in the form of its salt.

5. An oligomer of Claim 4, wherein the salt is ph^rmaceutically-acceptable.

6. An oligomer of Claim 2 wherein the number average molecular weight is from 500 to 10,000.

38,587A-r

AP 0 0 0 2 8

7 ⁷. An oligomer of Claim ό wherein the number average molecular weight is from 1,333 to 6,000.

8. An oligomer of Claim 2 which is represented by any one of the following formulae:

A) a polyurea of the formula:

Γ^Η Ί Ή H o' * 1 1 II -N-c-r- •N-X-N-C ^L Λ J _ - —

H

-N-R' n

(I) wherein:

R represents a hydrogen atom, a C-|-Cq alkyl group, a phenyl group, or a phenyl group substituted with from 1 to 2 R¹ moieties and up to 3 substituents independently selected from a chloro or bromo atom or C-j—C^ alkyl group;

r1 represents a -SO^R², -C02R², -PC3(R²)₂i or

-OPO₃R²;

R² represents a hydrogen atom or a pharmaceutically-acceptable cation;

m is an integer 0 or 1, with the proviso that when ra is 0, R is a hydrogen atom;

X represents

38,587A-F

3' Rl R1

3 1

38,537A-F

AP000287

Y represents -CO _C — Ν _

II I

Ο H or — C = N — N = C_ n is an integer from 3 to 50: and r3 represents -R cr -X-NH2, where R and X are defined as before;

3) a polycarbonate of the formula:

X¹-0

1« c-c-x-o— ” n

X² (II) wherein :

X and n are defined as in Formula I in Claim

8(A);

χ1 represents a HC-X- group, where X is defined as in Formula I in Claim 8(A), or a C-j-C^ alkyl group, a phenyl group, or a phenyl group substituted with from 1 to 2 R ¹ moieties and up to 3 substituents independently selected from a chloro or bromo atom or C-,-Cy alkyl group; and

38,587A-F

Ρ 1

X represents a hydrogen atom, or -COjX . where

X¹ is defined as above;

C) a polyester of the formula

R^O— C-X^-C-O-X-Or- R⁵ (ΠΙ) wherein :

X and n are defined as in Formula I in Claim

8(A) ;

R^ represents -R², as defined in Formula I in

Claim 8(A), or -X¹, as defined in Formula II in

1 ** J Ο Z Q \ · d ± in kJ \ D J 9

R-* represents

0 0 »^__C__X3__C_ ;

where R* is defined as in Formula III in Claim 8(0 or R², where R² is defined as in Formula I in Claim 8(A);

X^ represents

38,587A-F

AP Ο Ο Ο 2 8 7

3 1 wherein R and Υ are defined as in Formula I in Claim 3(A); or

38,537A-F

0) a polyamide cf the

II

- X³ — C — N — x — N (IV) wnerem:

X and n are defined as in Formula I in Claim 8(A);

_X3 is defined as in Formula III in Claim 8(C);

represents HjN-X-NH-, R²0-, rnH- or R-C(0)-NH-X-NH-, where R, R² and X are defined as in Formula I in Claim 3(A);

R? represents a hydrogen atom,

0 0

II II a²o — c — χ3 _c o

II

R — c or

II

RNH— C — X 3 _ _c _ where

R and R² are defined as in Formula I in Claim 3(A); and χ3 is defined as in Formula ill in Claim 3(C).

9. An oligomer of Claim 3 wherein n is from 3 to 50.

38,587A-F

AP Ο Ο Ο 2 8 7 '3. An oligomer of Claim 9 wherein n is from 3 to 15 ·

11. An oligomer of Claim 8 which is a polyurea of Formula I wherein 3 and 3^ _{ars a} 4-methylphenyl group; m is 1; n is 3 to *5; X represents and P.2 is defined as in Claim 8.

38,587A-F

I

12. An oligomer of Claim 11 which is StDS/P/T and named as polyiimino(3-sulfo-l,4-phenylene)-1,2e t h e n e d i y 1 - ( 2 — su 1 f o — 1, 4 — phenylene) iminocarbonyl], alpha— {[ ( 4-me thy lphenyl) aminocarbony i}-omega-[ ( 4-methyl phenyl) amino- and is represented by Formula I in Claim 8 when R and R^ is 4-methylphenyl, R^ is hydrogen, X is where n is defined as for Formula I in Claim 8.

13· The oligomer of Claim 12 wherein n is 6.

14. The oligomer of Claim 12 wherein n is 9.

20 15. An oligomer of Claim 11 which is PDS/P/T and named as poly[imino( 2,5-disulfo-1, 4-phe.nylene) iminocarbonyl], alpha-{[( 4-methylphenyl) ami no]car bony l}-cmega[(4-methylphenyl)amino]- and is represented by Formula I in Claim 8 when R and R^ is 4-methylphenyl. R^ is

25 hydrogen, X is

38,587A-F

AP Ο Ο Ο 2 8 7

is defined as for F omul a - in Claim 8. 16. The oligomer of Claim 5 wherein n is 9. 17. The oligomer of Claim 15 wherein n is 15

18. An oligomer of Claim 11 wherein X is

S°3^r2

OHO r²0₃s

19. An oligomer of Claim 18 which is BPDS/P/T, and named as poly{imino[2,2'-disulfo(1,1*-biphenyl)-4,4’diyl] iminocarbonyl}, alpha-{[( 4-methylphenyl )amino]carbcr.yl}-omega-[ (4-methylphenyl )aminoj- and is represented by Formula I in Claim 8 when R is 4methylphe.nyl, R^c is hydrogen, X is wherein n is defined as for Formula I in Claim 3.

20. The oligomer of Claim 19 wherein n is 6.

21. The oligomer of Claim '9 wherein n is 9.

38,587A-F

II

22. An oligomer of Claim 8 which is a polycarbonate of Formula II wherein X¹ is a 4methylphenyl group; X^ is -CC₂-(4-methylpher.yl) group; π is 3 to 15; and X is as defined in Claim 11.

23. An oligomer cf Claim 22 which is HBDS/P/C and named as poly[oxy(2,5-disulfo-1,4-phenyiene)oxycarbonyl], alpha-' ( 4-methyl phenoxy) carbonyl [-omega -( 4methylphenoxy)- and is represented by Formula II in Claim 8 when is 4-methylphenyl, R^ £_S hydrogen, X is \Ο^-0Η₃,

Claim 8.

wherein n is 6, and n is defined as for Formula I in

24. The oligomer of Claim 23

25. An -oligomer of Claim 22 which is HBPDS/P/C and named as poly{oxyi2,2'-disulfo(1,1'-biphenyl)-4,4’diyl]oxycarbonyl}, alpha-[( J-methylphenoxy) carbonyl ]omega-(4-methylphenoxy)- and is represented by Formula II in Claim 8 when X^ is 4-.-n_ethylphenyl, R^ is hydrogen, X is

38,587A-F

AP Ο Ο Ο 2 8 7 and η is defined as for Formula I in Claim 8.

26. The oligomer of Claim 25 wherein n is 6.

27. An oligomer of Claim 8 which is a polyester of Formula III wherein R^ and R^ are hydrogen; n is 3 to 15; and X^ represents /

X represents •ί

38.5S7A-F • ·

0/ ^S03^r; r²o₃s so₃r

28. An oligomer of Claim 27 which is H3PDS/TPC and named as poly{oxy[2,2'-disulfo( 1 , 1 '-biphenyl)-4,4 'diyljoxycarbonyl-1,4-phenyienecarbonyi}- and is represented by Formula III in Claim 8 when R⁴ and FP are hydrogen, X^ is p-phenylene, X is

38,587A-F

AP Ο Ο Ο 2 8 7

ΙΑ where η is defined as for Formula I in Claim 8.

29- The oligomer of Claim 28 wherein n is 4.

30. An oligomer of Claim 27 which is HBDS/TPC and named as poly[oxy(2,5-disulfo-1,4-phenylene)oxycarbonyl-1,4-phenylenecarbonyl]- and is represented by Formula III in Claim 8 when R¹^ and R^ are hydrogen, is p-phenylene, X is where n is defined as for Formula in Claim 8.

31. The oligomer of Claim 30 wherein n is 3·

32. An oligomer of Claim 8 which is a polyamide 30 of Formula IV wherein R^ is phenyl; R⁷ is methyl ber.zoyl; n is 3 to 15; and represents

38,587A-F (5 ίο and X represents

S0₃R‘ 'R²O₃S so₃r sy

38,537A-r

AP 0 0 0 2 8 7

33· An oligomer of Claim 32 which is 3PDS/TPC/MBC and named as poiy{imino[2,2'-disulfo(1,1'biphenyl)-4,4'-diyl] iminocarbony1-1,4-phenylenecarbony1}, a lpha-{[( 4-methylphenyl )amino]carbonyl}-omega-[(4methylphenyl)amino]- and is represented by Formula IV in Claim 8 when R^ is R-C(0)-NH-X-NH-, R is 4-methylphenyl, R² is hydrogen, R? is 4-methylbenzoyl, X^ is pphenylene, X is where n is defined as in Formula I in Claim 8.

34. The oligomer of Claim 33 wherein n is 6.

βΜ⁵

38,587A-F

35. The oligomer of Claim 33 wherein n is 3.

36. The oligomer of Claim 33 wherein n is 9.

37. A pharmaceutical formulation comprising an oligomer as claimed in any one of the preceding Claims with a pharmaceutically-acceptable carrier.

38. A pharmaceutical formulation comprising a mixture of the oligomers as claimed in Claim 8 with a pharmaceutically-acceptable carrier.

39. A pharmaceutical formulation comprising an oligomer as claimed in any one of Claims 1 through 36 with a detergent.

40. A pharmaceutical formulation comprising an oligomer as claimed in any one of Claims 1 through 36 as a liquid, powder, douche, jelly or lotion.

41. An oligomer as claimed in any one of Claims 1 through 36 for use as a pharmaceutically active substance.

42. A formulation as claimed in any one of Claims 37 through 40 for use as a pharmaceutically active substance.

ΑΡΰ4°²⁸⁷

43. A process for preparing a polyamide as claimed in Claim 8D Formula IV which comprises reacting a diamine with a difunctional electrophile, at a molar ratio of diamine to diacid halide of from 0.9 to 1.2, with stirring in the presence of an acid acceptor, in either a polar aprotic solvent or combination solvent of water and an organic solvent, and at a temperature from 0 to 50°C.

44. A process for preparing a polyurea as claimed in Claim 8A Formula I which comprises reacting an aromatic diamine with a difunctional electrophile, in the presence of an acid acceptor, in water as the solvent or water with up to about 1 mole of water immiscible cosolvent, at a temperature of from 0 to 100°C and at a Ph between 7 to 9.

45. A process of Claim 44 wherein a mono-functional end capping agent is used.

46. A process for preparing a polycarbonate or polyester oligomer as defined in Claim 8B and 8C, respectively, Formulae II and III, respectively, which comprises reacting a diphenol with a difunctional electrophile, at a Ph of 7 to 8, at a temperature between 0 to 40°C in a water immiscible solvent.

47. A process of Claim 46 wherein the difunctional electrophile is a diacid chloride and waiting for 15 to 120 minutes after the addition of the diacid chloride, at a Ph of 7 to 8, to ensure conversion.

ΟίβθΛΝΜ- Sj

48. A process of Claim 46 which comprises pretreating the diphenol with one or two moles of base to form the mono- or diphenoxides.