BACKGROUND OF THE INVENTION

Field of the Invention

This invention relates to adhesives prepared from metabolicaliy-acceptable polyisocyanate or polyisothiocyanate monomers. More particularly, the present invention is concerned with surgical adhesive polymers derived from these polyisocyanate monomers which do not metabolize to toxic products.

Brief Description of the Prior Art

In recent years there has developed increased interest in replacing or augmenting sutures with adhesive bonds. The reasons for this increased interest are many but those most evident are:

1) the potential speed with which repair might be accomplished;

2) the ability of a bonding substance to effect complete closure, thus preventing seepage of fluids;

3) the possiDility of forming a bond without excessive deformation of tissue, and

4) possible improvement in repair of tissue too weakened by disease or age to permit effective suturing.

Studies in this area, however, have revealed that, in order for surgical adhesives to be accepted by surgeons, they must possess a number ot properties. Pirst, they must exhiDit high initial tack and an ability to bond rapidly to living tissue. Secondly, the strength of the bond should be sufficiently hign to cause tissue failure before bond failure. Thirdly, the adhesive should form a bridge, preferably a permeable flexible bridge. Fourthly, the adhesive bridge and/or its metabolic products should not cause local histotoxic or carcinogenic effects.

A number of adhesive systems such as alkyl cyanoacryiates, poiyacrylates, maleic anhydride/methyl vinyl ethers, epoxy systems, polvinyl alcohols, formaldehyde resins and isocyanates have been investigated as possible surgical adhesives. None has gained acceptance because each tails to meet one or more of the criteria noted above. The principal criticism of these

♦ systems has been the potential toxicity problems they pose. In the case of adhesives based on conventional isocyanates, for example, the production of aromatic and aliphatic diamines by

metaoolism could lead to local histological reactions at minimum, and possibly to even sore serious systemic toxicity.

It is an object ot the invention to provide novel metabolicaliy-acceptable polyisocyanate adhesives, including polyisothiocyanate-based adhesives and in particular metabolically-acceptaole surgical adhesives. ϊet another object of the invention is to provide metabolicaliy-acceptable surgical adhesives which are biodegradable.

A further object of the invention is to provide a method for closing wounds in living tissue by use of novel, metabolicaliy-acceptable surgical adhesives.

An additional object of the invention is to provide metabolicaliy-acceptable adhesives low in toxicity as a consequence of their physical properties.

SIM.MARY OP THE INVENTION

These and other objects of the invention are obtained by using a curaole, surgical adhesive comprised of: λ. a metabolicaliy-acceptable polyisocyanate (including polyisothiocyanates} having the structural formula:

(ZCN)__ - R <0) _q -

wherein

R is a polyvalent aliphatic radical of about 1 to 10 carbon atoms or a polyvalent aromatic radical of 6 to about 24 carbon oms;

A is carbon, sulfur or phosphorus;

Z is oxygen or sulfur; y is 1 when A is carbon or phosphorus, and 2 when A is sulfur; n is 1 or 2; p is at least 1; q is 0 or 1, with the proviso that when A is carbon or sulfur, q is 0; r is 0 or 1, with the proviso that when A is carbon or sulfur, r is 0;

X is a residue of an organic compound having active hydrogen-containing groups,- and

X* is a residue of an organic compound having at least 1 active hydrogen-containing group; or

B. an excess of said polyisocyanate A in admixture with an organic compound containing at least two active hydrogen atoms reactive with isocyanate groups of polyisocyanate A.

The polyisocyanates or polyisothiocyanates of the invention, polymeric products of these monomers per se and polymeric reaction products of the monomers and organic compounds containing reactive hydrogen atoms, are found to be metabolicaliy-acceptable, that is, incapable of breaking down into toxic materials such as aromatic or aliphatic diamines. Rather, the compounds of the invention are characterized by their metabolism into innocuous materials such as amino acids.

It should be understood that for purposes of convenience both the novel polyisocyanates and polyisothiocyanates of the invention will be referred to in the specification and claims simply as "polyisocyanates".

In the structural formula of the polyisocyanates of the invention, illustrative of suitable R radicals are divalent or polyvalent aliphatic radicals, which say be straight-chain or branched, such as methylene, 1,2-ethylene, 1,2-propylene, 1,3-propylene, l-2,butylene, 1,3-butylene, 1,4-butylene, 2,3-butyiene, 1,4-pentylene, 1,5-ρentylene, 2,4-ρentylene, 1,6-hexylene, 1,7-heptylene, 1,8-octylene, 2,6-octylene, 1,9-nonylene, 1,10-decylene, vinylene, propenylene, 2-butenylene, 2-methyl-l-butenylene, 3-methyl-2-pentenylene, butadienylene, etc.; divalent or polyvalent cycloaliphatic radicals, such as 1,3-cyclopentylene, 1,3-cyclohexylene, 1,4-cyclohexylene, 1,2,4-cyclopentylene, 1,3,4-cyclohexylene; divalent and polyvalent aralkyl radicals, such as benzyl, 3-phenylproρyl, diphenylmethyl, etc.; and divalent or polyvalent aromatic radicals, such as para, meta and ortho-phenylene, biphenylene and the like.

The radical "X" in the novel polyisocyanates of the invention can be the residue of any organic compound, which contains active hydrogen-containing groups as determined by the Zerewitinoff method. Such active hydrogen-containing compounds include, for example, compounds having at least hydroxyl groups, thiol groups and the like. Thus, by way of illustration, the radical "X" can be the residue of simple hydroxyl- or thiol-group terminated alkanes, which may be straight-chain or branched, aralkanes, etc., as well as polymeric radicals such as hydroxy or thiol-group terminated polyesters, polyethers, polythioethers, poiyacetais, poly¬ carbonates, poiyanhyd ides, polyphosphates, poiyphosphazines, polypeptides, polydepsipeptides, polyamides, polyester- polyether block copolymers and the like. In most instances, the compounds and/or polymers will contain at least two functional groups, often up to 8 functional groups and will have a molecular weight of bϋ to 10,000, more often about lϋϋ to 1,000.

The hydroxyl-group-containing polyesters may be, tor example, reaction products of polyhydric alcohols, preferably dihydric alcohols and polybasic, preferably dibasic, carboxylic acids. The corresponding polycarboxylic acid anhydride or corresponding polycarboxylic acid esters of lower alcohols or their mixtures may be used instead of the free polycarboxylic acids foe preparing the polyesters. The polycarboxylic acid may be aliphatic, cycloaliphatic, aromatic and/or heterocyclic and may be substituted, e.g. with halogen atoms or may be

unsaturated. Exanplea include succinic acid, adipic acid, suberic acid, azelaic acid, sebacic acid, phthalic acid, cerephthalic acid, isophthalic acid, trimellitic acid, tetrahydrophthalic acid, hexahydrophthalic acid, tetrachlorophthalic acid, glutaric acid, maleic acid, fumaric acid. Any suitable polyhydric alcohol may be used, such as, for example, ethylene glycol; propylene-1,2- and -1,3-glycol; butylene-1,4- and -2,3-glycol; hexane-l,6-diol; octane-i,8-diol; neopentyl glycol; cyclohexanedimenthol; 1,4-bis-hydroxymethylcyclohexane; 2-met yl-propane-l,3-diol; glycerol; trimethylolpropane; hexane-l,2,3-triol; butane-l,2,4-triol; trimethylolethane; pentaerythritol; ribose; erythose; quinitol; mannitol; sorbitol; glucose; starches; fructose; cane sugar; dextrans; castor oil; methylglycoside; diethylβne glycol; triethylene glycol; tetraethylene glycol; polyethylene glycols; dipropylene glycol; polypropylene glycols; dibutylene glycol and polybutylene glycols. The polyesters may also contain a proportion of carboxyl end groups. Polyesters of lactones such as caprolactone, or hydroxycarboxylic acids such as hydroxycaproic acid may also be used. The hydroxyl-terminated polyesters include hydroxyl-terminated polyorthoesters such as are prepared by the melt polymerization of 2,2-diethoxytetrahydrofuran with diols.

Suitable polyhydric polyalkylene ethers (polyethers) include, for example, the polymerization product of an alkylene oxide beginning with any suitable initiator. The initiator may be a difunctional compound, including water, so that the resulting polyether is essentially a chain of repeating alkyleneoxy groups as in polyethylene glycol, polypropylene glycol, polybutylene glycol and the like; or the initiator may be any suitable active hydrogen containing compound which may be a monomer or even a compound having a relatively high molecular weight including other active hydrogen containing compounds as disclosed herein. Any suitable alkylene oxide may be used such as, for example, ethylene oxide, propylene oxide, butylene oxide, amylene oxide, tetrahydrofuran, epihalohydrins such as epichlorohydrin, dioxalane, styrene oxide and the like. Suitable initiators include, for example, water, polyhydric alcohols, preferably having 2 to 8 hydroxyl groups, amines, preferably having 2 to 8 replaceable hydrogen atoms bonded to nitrogen atoms and the like to which the alkylene oxides may be added. The resulting polyhydric polyalkylene ethers may have either primary or secondary hydroxyl groups or

nixtures of primary and secondary hydroxyl groups. It is preferred to use alkylene oxides which contain from ^* 2 to 5 carbon atoms and,- generally speaking, it is advantageous to condense from about 1 to about 30 equivalents of alkylene oxide per functional group of the initiator. Specific examples of initiators are water, ethylene glycol, propylene glycol, glycerol, tri ethylolpropane, pentaerythritol, arabitol, sorbitol, maltose, sucrose, ammonia, diethanolamine, triethanolamine, dipropanolamine, tripropanolamine, diethanolpropanolamine, tributanolamine, 2, 4-tolylenediamine, 4,4'-diphenylmethanediamine, 4,4' ,4' '-triphenylmethanetriamine, ethylenediamine, propylenediamine, propylenetriamine, N,N,N* ,N'-tetrakis-l2-hydroxy-propyl)-ethylene diamine, diethylene triamine and the like. There are many suitable processes for the preparation of polyhydric polyalkylene ethers including O.S. Patents 1,922,459; 3,009,939 and 3,061,625 or by the process disclosed by Wurtz in 1859 and discussed in the Encyclopedia of Chemical Technology, Volume 7, p. 257 to 262, published by Interscience Publishers, Inc. 11951).

By "polythioethers" are meant, in particular, the condensation products of dithioglycol with itself and/or with other glycols, dicarboxylic acids, ormaldehyde, or analogous polymers synthesized from ethylene sulfide, etc. The products obtained are polythio-mixed ethers or polythioether esters, depending on the co-component.

Hydroxyl-terminated polyester-polyether block copolymers can be derived from polyalkylene glycols and hydroxyacids such as glycolic, lactic and hydroxycaproic acid by the melt polymerization of the polyalkylene glycol with the corresponding hydroxyacid or its cyclic lactone (e.g. glycolide, lactide, caprolactone, etc.).

The polyacetais may be, for example, the compounds which may be obtained from glycols, e.g. diethylene glycol, triethylene glycol, 4,4'-dihydroxydiρhenyidimethylmethane, hexanediol, etc. and formaldehyde. Suitable polyacetais may also be prepared by the polymerization of cyclic acetals.

The polycarbonates with hydroxyl groups may be of the known kind, e.g. those which may be prepared by reacting diois, such as proρane-i,3-diol, butane-l,4-diol and/or hexane-l,6-dioϊ or diethylene glycol, triethylene glycol or tetraethylene glycol, with diarylcarbonates such as diphenyicarbonate or with phosgene.

Mixtures of any of the compounds of any of the classes set forth hereinbefore aay be used and such coapounds aay also contain other substituents including halogen atoms such as, for example, chloro, bromo, iodo and the like; nitro groups; alkoxy radicals such as, for example, methoxy, ethoxy, propoxy, butoxy and the like; carboalkoxy groups such as, for example, carbomethoxy, carbethoxy and the like; dialkylamino groups such as, for example, di ethylamino, dipropylaaino, aethylethylamino and the like; carbonyl, thiocarbonyl, phosphoryl, phosphato and like groups.

Of the various monomeric and polymeric residues that can constitute the radical "X" in the isocyanates of the invention those generally preferred are selected froa the following structures: Polyether

Polyester

O u

_f ₀ -R ₄ _o-«?-(R ₅ ) _n -C}^0-R ₄ --O-

-8-

Poiyether/Polyestet Copoiyaers

4- 10~R ₃ ) _£ —0-t— (R ₅ ) _n —Cjy.0—R ₃ ) _k —0-

0 II

+ϊ(0 ₃ ϊ _i -O-.C-(R ₅ ) _n -Cl ₃ - ^■ °- ^,R 3- ^0, -

+°- ⁽ _n - ^C Cθ-R ₃ -0- C-(R ₆ ) _n ~0}-

wherein R,, R., ₅ , and R, are aliphatic radicals ol 1 to 12 carbon atoms, which may be straight-chain or branched, or aromatic radicals of 6 to 12 carbon atoms including oxygen-bridged aliphatic and aromatic radicals;

R, is a polyfunctional active hydrogen-containing aliphatic radical; a, b, c, d, f, g, h, i, j, k, m, p, and q are integers of at least 1 usually up to 10 or more; b, e, 1, and s are integers of at least 2 usually 3 or more; and n is an integer of 0 or 1.

The novel polyisocyanates and polyisothiocyanates of the invention are film-forming materials that may be prepared in numerous ways as, for instance, by the phosgenation or thiophosgenation of polyamine compounds having the structure:

(NI-2 ⁾ __ - R (0) - (O) - R ^{* (N} ). wherein n, R, A, y, q, r, p, X, and X* are as defined above. These polyamine precursors may be prepared by any one of many possioie condensation methods, well-known to someone skilled in the art, of an appropriate carboxylic, phosphorus or sultonic acid derivative with the active hydrogen containing radicals "X", as defined above. A convenient route when R is an aromatic group, involves reacting one mole of a compound having 2 terminal active hydrogen-containing groups with '__ taoles ot a nitro-substituted compound having the structure:

-9-

0 ₂ N-R-C0C1 or

0 ₂ - -S0 ₂ C1 or

wherein R is aromatic and defined as above and q is 0 or 1. These condensation reactions may be carried out "in the melt", i.e. oy heating the mixture of the reactants in the aosence of a solvent; or in an inert solvent such as toluene, tetrahydro- furan, benzene, dioxane, etc. The nitro compounds are then reduced to the corresponding amines which are subjected to phosgenation. These syntheses can be represented as follows, using for purposes of illustration hydroxy-terminated compounds as the organic compound having terminal active hydrogen atoms.

Scheme I

Scheme II riO-X-OH — C» ₂

CN-R—S0 ₂ -0-X-0-S0 ₂ -R-NCO wherein R and X are as defined above.

The reduction and phosgenation or thiophosgenation steps in these syntheses can be carried out using any of the well-known techniques. For instance, the reduction can be effected by simple hydrogenation in the presence of a suitable hydrogenation catalyst such as palladium, or by transfer hydrogenation. The phosgenation or thiophosgenation can be carried out by either a cold phase-hot phase phosgenation or by the hydrochloride process wherein the corresponding amine hydrochloride is phosgenated. The phosgenation can be carried out continuously or intermittently and inert solvents such as dioxane, chlorobenzene, o-dicnlorobenzene, tetrahydrofuran, etc., are preferably employed for the reaction. Phosgene is conveniently stored as a stable solution in most of the above-mentioned solvents.

In an alternate procedure, especially useful for the synthesis of polyammes in which the groups rt are aliphatic, an aaino acid may be condensed with an active ^" hydrogen- terminated compound by suspending the reactants in an inert solvent, such as toluene, chlorobenzene or benzene. The mixture is heated under reflux and hydrogen chloride gas passed in a continuous streaa through the mixture. The water of condensation is removed by azeotropic distillation from the reaction βixture in order to drive the reaction to completion, i.e.,

HO-X-OH + 2Cl ^" H ₃ N ⁺ -R-C0 ₂ H -^^ ClΗ ₃ N ⁺ ~-C0 ₂ - -0 ₂ C- -NH*Cl ^" + 2 H _j O

The hydrochloride salt of the polyamine may be phosgenated or thiophosgenated in the usual manner to give the polyisocyanate or polyisothiocyanate.

An alternate procedure for the synthesis of these polyamine precursors involves the condensation of suitably-protected aaino acid derivatives with an active hydrogen-containing compound, i.e.,

2 Y-NH-R -C0 ₂ H + HO-X-OH ^activation y-NH-R -C0 ₂ -X-0 ₂ C-R -NH-Y + 2 H _j O

Any suitable, selectively-cleavable amine-protecting group Y, well-known to someone skilled in the art, may be used for this purpose. For example, Y may be benzyloxycarbonyl or t-butyloxycarbonyl. In this method, the protected amino acid derivative is condensed with the active hydrogen-containing

-1 T-

co:apound through use of suituole activation techniques. There are many activation methods. inown, for instance, coupling agents such as carbodiiraides, 1 , 1-carbonyldiimidazole, the intermediate formation of symmetrical or «ιxed anyhydrides, active esters and the like, all of which will be well-known to someone skilled in the art. The most preferred methods involve the use. of 1,1-carbonyldiimidazole or mixed carboxylic-carbonic anhydrides, catalyzed by suitable catalysts such as pyridme or 4-dime hy1aminopyri ine.

The protected polyamine precursors may oe eprotected by appropriate procedures. For example, when Y is benzyloxycaroonyl, the compounds may be:

Y-NH-ft -co ₂ -x-o ₂ c-R -NH-Y ϋ -prott-ction

H ₂ N-R -CO ₂ -X-O ₂ C-R -NH.

deprotected by cata lyt ic hydrogenolysi s or under anhydrous , acidic condi tions , for example using solut ions of hydrogen bromi de in glacial acetic acid. Al ternatively, when the t-butyloxycarbonyl group i s used for aaine protection , cleavage may be ef fected selectively using anhydrous acids , such as t r i f luoroacet c aci d or solutions of hydrogen chlor ide in anhydrous d oxane .. The result ing polyamines are phosgenated or thi ophosgenated Dy the usual procedures , as out lined above .

Exemplary of preferred metabolicaliy-acceptable diisocyanates of the invention are those having the structure:

0 0 ^" . O 0

ZCN -(oV C- O-R ₆ -C) __.- (0-R ₃ ) -O- (C-Rg-O) -C- θV NCZ (1) wherein and q are 1 to about 10 or more; p is 1 to 20; R- _j and Rg are aliphatic or aromatic radicals having 1 to 12 carbon atoms and z is oxygen or sulfur. Of these diisocyanates, particularly preferred are those having the structure:

0 0 O O

OCN -(oV-C-(0-CH ₂ -C) -(0-CH ₂ -CH ₂ ) -O-(C-CH ₂ -0) -CYOYNCO (I, preferred

wherein m and q are 2 or 4 and p is 4 to 20. These monomers, for example, will degrade ultimately to the metabolically- acceptabie products, p-aminobenzoic acid, polyethylene glycol, and glycolic acid, all of which are innocuous. Other preferred metabolicaliy-acceptable polyisocyanates include those having the structure:

wherein R _fi is an aliphatic or aromatic radical having 1 to 12 carbon atoms; R- is a pol functional active hydrogen-containing aliphatic radical; c, d, and h are integers of at least 1; and

Z is oxygen or sulfur. Of these polyisocyanates, particularly preferred are those having the structure:

NCO (II, preferred)

wherein a + b + c is at least 3;

R is hydrogen or a lower alkyl;

R' is an alkylene of 1 to 4 carbon atoms; and n is an integer of 0 or 1.

These monomers, for example, will degrade ultimately to the metabolicaliy-acceptable products, p-aminobenzoic acid, glycerol or related triol and glycolic acid, which are innocuous.

A preferred curable adhesive composition of the invention is comprised of a mixture of 5 to 95% by weight of polyisocyanate I and 95 to 51 by weight of polyisocyanate II.

The novel polyisocyanates of the invention have large variations in physical properties and may be used alone or in admixture with dissimilar polyisocyanates of the invention. Consequently, control over the physical properties of the polyisocyanate formulation and the polymer formed after set-up are achieved in three ways:

1) Variations in the parameters a, b, c, m, p, q, R and R';

2) Variations of polyisocyanates, particularly admixtures of polyisocyanates of Structure I with polyisocyanates of Structure II.

3) Using combinations of 1 and 2.

These characteristics allow for control of physical properties of the adhesive bridge which is formed. For instance, the absorption rate of the bridge may be controlled, the flexibility of the bridge may be. controlled {a flexible bridge being preferred) and the porosity of the bridge can be controlled. In many cases, the polyisocyanates of the

invention or Mixtures thereof can be used as tingle component adhesive systems which cure rapidly upon exposure to surface moisture. Alternatively, two component adhesive systems can be formulated with the polyisocyanates of the invention. In the manufacture of trfo component adhesive systems the polyisocyanate or admixture of polyisocyanates and a curing agent are maintained separately until just prior to use. Suitable curing agents including conventional polyfunctional compounds such as glycerol, inositol, 1,4-butane diol, triaethylolpropane, neopentylglycol, methylene dianiline, phenyldiethanolaaine, triisopropanolamine, pentaerythritol and the like. Alternately, the active hydrogen-containing polymeric components, H-X-H, derived from the radical "X" discussed above, may be used as curing agents. Also useful as curing agents are the amines described above.

It nay be desirable in both a single component adhesive system and a two component adhesive system to include a catalyst so as to speed up the curing reaction. Any conventional catalyst used in urethane production can be used as, for example, tertiary amines such as 1,2,4-triroethyl piperazine, N-methylmorpholine, triethylamine, tri-n-butylaaine N-(N,N-dime hylaainoproρyl)-2-ρyrrolidone, 2,4,6-collidine, pyridine, quinaldi ^' ne, triethanolamine, 4-dimethylaιainoρyridine, tris-2,4 6-(diαethylaminomethyl)phenol and the like and tin compounds such as tin hexanoate, tri-n-butyl tin acetonate, di-t-butyl tin dilaurate, stannous-2-ethyl hexanoate and the like. Purther preferred curing agents include diamines of the corresponding polyisocyanate, i.e., compounds of the same structure as the polyisocyanate but possessing a ine groups instead of isocyanate groups. Mixtures of one or more amines, one or more tin compounds and admixtures of both tin compounds and amines can be used as catalysts for the reaction. In fact, in some cases a synergistic result is found when a combination of catalysts is employed. A preferred combination is 1,2,4-trimethyl i erazine/trie anol mine.

Other preferred catalysts for use in the reaction are: I. Pyridine carboxylates having the structure:

(CH ₂ ) _n -C0 ₂ R

wherein

K is lower alkyl; and n is 0 to 6 or more, such as the nicotinate esters (n « 0) and pyridylacetate esters In » l).

Exemplary of such catalysts are 3-aethyl or 3-ethyl nicotinate and ethyl 3-pyridylacetate.

II. Saturated, aliphatic analogs of pryridine carboxylates having the structure:

wherein

R and R' are lower alkyl; and n is 0 to 6 or ωore. Exemplary is ethyl

1-πethylnipeco te.

III. Aliphatic amine catalysts having the structure:

wherein

R, R* and R" are lower alkyl; and

0 n is 1 to 6 or more and R ^» " is H or -C-fi. Exemplary is 2-(N,N-diπ.ethylaιnino)-ethyl acetate.

In all instances, catalyst is used in an amount sufficient to speed the reaction and generally in an amount of from about 0.05 to 30 parts by weight based on 100 parts by weight of the polyisocyanate.

Adhesive solutions of the polyisocyanates of the present invention can be prepared, if desired, by dissolving the polyisocyanate in typical adhesive solvents including ethers having 4-6 carbon atoms such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane and diisopropyl ether; ketones having 3-7 carbon atoms such as acetone, methyl ethyl ketone, methyl isobutyl ketone and diisopropyl ketone; N,N-dialkyl lower

amides containing 3-6 carbon atoms such as dimethyl formamxde, dimethyl aeetaβide, diethylacetamide and N,N-di ethyl forma ide and sulfones and sulfoxides having 2-4 carbon atoas such &s dimethyl sulfoxide and tetramethylene sulfone. Also useful solvents are trif luoroethanol and trimethylphosphate. Alkyl substituted benzenes such as toluene and xylene can be used in admixture with the above solvents. Preferred solvents are methylene chloride and fluorinated halogenated hydrocarbons such as trichlorofluoromethane; dichlorodifluoromethane, chlorotrif luorome thane, chlorodif l oroaethane, 1,1,2-trιfluoroethane and sya-dichlorotetrafluoroethane. Particularly preferred is dichlorof luoromethane.

The polyisocyanates of the invention can De reacted with any of the polyfunctional organic compounds normally used for polyurethane formation to form curable prepoly ers and higher molecular weight adhesives. Generally speaking, any compound having an active hydrogen atom which will react with an -NCO group may be used. Illustrative of such compounds are the simple and polymeric esters, ethers, esterethers, amides, esterasides, thioethers, acetals, carbonates, diaαines, anhydrides, phosphates, phosphazines, peptides, including retro nversopeptides, and the like, and any combination or block copolyαers of the above. In addition, any suitable aliphatic polyol may be used as, for example, alkane diols including, for example, ethylene glycol, butylene glycol, 1,3-butylene glycol, 1,5-pentane diol, 1,4-butane dxol, 1,3-pentane diol, 1,6-hexane diol, 1,7-heptane diol, 2,2-dimethyl-l,3-proρane diol, 1,8-octane diol, 1,20-eicosane diol and the like; alkene diols such as, for example, l-butene-l,4-dιol, 1,3-butadιene- 1,4-diol, 2-pentene-l,5-dιol, 2-hexene-l,δ-diol, 2-heptene-l,7-dιol and the like; alkyne diols such as, for example, 2-butyne-l,4-diol, l,5-hexadyne-l,6-d ol and the like; alkane triols such as, for example, glycerol, 1,3,6-hexanetriol, 1,3,7-heptanetriol, 1,4,8-octane triol, 1,6,12-dodecane triol and the like; alkene triols such as l-hexene-l,3,6-triol and the like; alkyne triols such as 2-hexyne-l,3,6 triol and the like; alkane tetrols such as, for example, 1,2,5,6-hexane tetrol and the like; alkene tetrols such as, for example, 3-heptene-l,2,6,7-tetrol and the like; alkyne tetrols such as, for example, 4-octyne-l,2,7,8-tetrol or any admixtures, block, or random copolymers derived froβ the above.

Also contemplated for use as cuεing agents art dioxiaeβ or polyoxiβes. These compounds ώoth act 4s conventional curing agents and also confer added hydrolytic instability on the adhesives because of the susceptibility of "oxiiiinourethanes" to aqueous hydrolysis (see below). While the isocyanates of the invention normally result in adhesives which are metabolized i vivo in another embodiment of the invention, biodegradable polymers useful as absorbable surgical adhesives can be prepared by selecting for reaction with the metabolicaliy-acceptable polyisocyanates a polyfunctional compound which contains hydrolyzable linkages and/or linkages susceptible to cleavage by enzymes such as endogenous proteolytic enzymes. For example, in the case of a diol monomer, block polyether-polyester copolymers (III) derived from polyethylene or propylene glycols or copolymers, copoly erized with ester monomers such as glycolide, lactide, caprolactone, etc. are useful for preparing urethane adhesives with a range of hydrolysis rates.

R-lO-CH- (CH ₂ ) _n -CO] _χ -[0-CH- CH ₂ ) -0-[OC-(CH ₂ ) _n -C IH-0] _χ -H (III)

The rate of hydrolysis of the resultant adhesive nay be controlled through variation of the hydrophobic/hydrophilic balance in the diol monomers III.

Other diol monomers which can be reacted with the novel isocyanates for the preparation of absorbable adhesives include orthoester monomers of the type (IV), prepared from, for example, the copolyroerization of 2,2-diethoxytetrahydrofuran (n * 3) and a wide variety of diols.

The diols may be simple, such as alkyl diols, or complex structures, such as the block copolymers III. Clearly, a wide, variety of structures are conceivable, leading to a broad range of hydrolysis rates for the adhesives.

Oiol monomers derived froβ peptides (e.g. those containing serine) and depsipeptides (copolymers of aasino and hydroxy acids) are also useful for the preparation of absorbable adhesives. Por example, the peptide diol aonomerβ (V) are susceptible to cleavage by proteolytic enzymes, as would

(V) be simi lar monomers of the depsipeptide type . Adhesives der ived f rom such monomers are therefore susceptible to cleavage by endogenous proteolytic enzymes .

Also useful for reaction with the novel polyisocyanates of the invent ion to produce absorbable adhesives are the simple and complex diox imes having the st ructure:

H-O-N • Q ■ N-O-H wherein 3 is selected f rom substi tuted or unsubstituted al iphatic ( including cycloaliphatic ) or aromat ic radicals of 2 to 12 carbon atoms or a polyester , polyester-polyether block copolymer or polyamide radicals such as described above with reference to the radical "X" . The oximes are excellent nucleophi les which react extremely rapidly with isocyanates to produce "oxi inourethanes" that are water-sensitive. The oximes, therefore, render polyisocyanate adhesives into which they are incorporated biodegradable because of the labili ty of the "oximinourethane" l inkage.

The polymers are water-sensitive and their rate of degradation may be controlled through t he structure of the reactants . In general , polymers which are derived f rom aliphatic dioxime monomers are more labile than those derived f rom aromat ic monomers .

l l lustrat ive of simple oxime monomers are :

CH, CH.

H-O-N ^*** C I — ³ C I - ^J N-O-H; and

-O-N ^« Q ⁼ N-O-H; and

Illustrative of complex dioxime monomers are those prepared by the condensation of a diol with the appropriate methyl keto acid, followed by reaction with hydroxylamine to form the oxime. The following oxime is exemplary:

Another example of a complex oxime is the oxime- terminated polyethers synthesized by oxidation of low molecular weight polyethylene glycols, followed by condensation with hydroxylamine. Such complex oximes are exemplified by the following compounds:

H-O-N -= CH-CH ₂ -lO-(CH ₂ ) ₂ ) _n -0-CH ₂ -CH = N-O-H

The adhesives of the invention can be applied either as a single component system or as a two component system. In the single component procedure the monomer, with or without catalyst, is applied directly to the tissues to be bonded together. In the two component procedure an excess of isocyanate is reacted with the polyfunctional active hydrogen-containing reactant, i.e. curing agent, to prepare an isocyanate-ter inated prepolyroer which may be mixed with a catalyst, if required, immediately prior to application to the tissues to be bonded. The molar ratio of NCO groups to active hydrogen functional groups (e.g. hydroxyl, amino, thio, etc.

and ^β ixtures thereof) is generally on the order of 2:1 to 4:1 but say be as great as 10:1 or βore.

Thus, the invention contemplates an article of manufacture comprised of a two container pack wherein the curaole, sterile polyisocyanate (Component λ) as described above, is placed in a first container and the polyfunctional organic compound (Component B) containing at least two reactive hydrogen atoms reactive with isocyanate groups of said Component A is placed in a second container. The amount of Component λ in the first container will De in excess of Component B in the second container so that the two component system will be ready for mixing and application at the site of the wound-closing. Advantageously, catalysts such as described above for speeding up the curing reaction can be added to the components of either container,, but preferaol.y to the curing agent. It should oe understood that the components in said first and second container are always maintained in a stable condition prior to admixture.

The preferred adhesives of the invention, however, are single component systems of the polyisocyanate monomer, preferably catalyzed, which react with water to fora strong bonding, porous,' adhesive bridges. The reaction mechanise is not understood in its entirety but in large part is believed to. involve the following sequence of reactions:

First, the water reacts with the isocyanate groups to for* a carbaaic acid which is unstaole and immediately breaks down to an amine and caroon dioxide. The amine reacts with isocyanate to form polyurea which foams due to the simultaneous evolution of carbon dioxide thereby forming a porous, polymeric bridge.

This reaction can be represented as follows:

OCN w CO + HOH-i OCN . N —C-OH

H

OCN /W NH, + OCN ^ NCO

O

■

OC z-vV N - C - N ,- ^* W NCO

Exemplary of a preferred adhesive is a formulation comprised of 60* by weight of polyisocyanate (I, preferred) wherein a « 2; q - 2, and p ■ 13 and 401 by weight of polyisocyanate (II, preferred) above wherein a, b, and c are 2 , R ^■ H, and n ^» 0. The adhesive is conveniently used as a solution in dichlorofluoromethane (either as a spray or as concentrated drops) and catalyzed as described above. A strong, porous, flexible bond is formed in one to two minutes after application of the adhesive on living tissue.

It has been found that the foregoing adhesive and other fomulations of polyisocyanate I and polyisocyanate II fore a putty-like bridge which adheres at the wound site and follows and conforas to the movement of tissue without tearing away. The adhesive file or bridge offers no resistance to flexion or change in the tissue to which it adheres Dut rather conforas to the dynanic aovement of the tissue.

The polyisocyanates and polyisothiocyanates of the present invention are preferably sterilized prior to use as surgical adhesives. The sterilization aay be effected by use of conventional gaseous sterilizing agents such as ethylene oxide in the absence of aoisture. Alternatively, the curable adhesives aay be sealed in containers free of aoisture and then sterilized by using heat and radiation including X-rays, gaaaa rays, electrons, neutrons, etc.

The adhesive systea of the invention say be applied in any convenient Banner as by brushing, spraying, pouring and the like, A preferred method of application is spraying either as a two component systea wherein the catalyst and aonoaer are kept separate until just before application or alternatively as a single component systen wherein the catalyst and aonoaer arc preaixed and stored in a stable environsent until spray application. Another preferred method of application is to deliver to the site drops of the catalyst an aonoaer, either preaixed or separately. If desired, the adhesive composition of the invention may be provided with polymerization inhibitors such as sulfur dioxide.

Not only are the polyisocyanates of the invention characterized by their lack of toxicity when used in _, vivo, but they also set up extremely rapidly to give stronger bonds than healthy living tissue. Consequently, the polyisocyanates and polyisothiocyanates fora strong, useful bonds to all kinds of living tissues so that use of conventional sutures nay b« elininated. Also the polyisocyanates of the invention react

ith aoisture on tissue surfaces to fora a carbaaic acid which breaks down during curing to evolve carbon dioxide gas. The carbon dioxide gas evolution that occurs during the polymerization reaction results in a porous foam-like bridge which by its increased permeability and absorbability is not characterized by the toxicity normally associated with solid continuous adhesive films. The porous peraeaole nature of the resulting adhesive bridge facilitates transport of essential nutrients into and through the bridge peraitting tissue ingrowth and thereby accelerating the wound healing process. Thus, if desired, the polyisocyanate of the invention may include as addenda conventional surface active agents to control foam or bubble size formation in the resulting adhesive bridge.

The compounds of the invention also form very strong bonds to other substrates, providing traces of moisture are present. For this reason, model systeαs of hydrated cellulose membrane and rat skin were chosen for the purpose of obtaining comparative i_n vitro data on adhesive monomers and compositions, as set forth in the examples discussed below.

The following examples are included to further illustrate the invention and are not to be considered as limiting the invention in any way.

EXλHPLE 1

Bi«-(4-l8ocyanatobenzoyl)-T-»traethyl'.nt Glycol λ. p-Nitrobentoyl chloride (390 g. 2.1 sole) and tβtraethylene glycol (194 g, 1.0 sole) were dissolved in dry tetrahydrofuran (1 1) and the aixture evaporated under reduced pressure. The resulting thick oil was stirred under high vacuua ( 0.5 ma) overnight, during which tiae the aixture solidified. The aix¬ ture was slowly heated to 60*C and maintained at thif teapera- ture for 5 hours. On cooling, the product was dissovled in ethyl acetate (2 1), saturated aqueous βodiua bicarbonate (2 1) added and the aixture stirred at room teaperature for 24 hours. The phases were separated, the organic phase washed with ^* saturated sodiua bicarbonate (3 x), dried (HgSO.), filtered and the filtrate evaporated to dryness under reduced pressure. The residue was crystallized froα ethyl acetate/hexanes to give bis-(4-nitrobenzoyl)-tetraethylene glycol (406 g), a. . 57.5-58.5*C, which was honogeheous by T C.

B. Bis-(4-nitrobenzoyl)-tetraethylene glycol (130 g, 0.264 sole) was dissolved in dry, redistilled ethyl acetate (1.2 1) in a 3-liter, round-bottoa flask, palladium on carbon (10%, 7 g) added and the aixture stirred under an ataosphere of hydrogen. The gas was taken up at the rate of approximately 15 1 per hour and external ice-cooling was applied periodically to maintain a temperature of 40*C. After hydrogen uptake was complete ( 35 1), the mixture was stirred at room temperature under hydrogen for two hours. The catalyst was removed by filtration and the filtrate concentrated i vacuo. The product was light and 0« sensitive and was therefore crystallized in the absence of both by addition of hexanes to give bis-(4-aminobenzoyl)-tetra- ethylene glycol (105 g), a. . 85- 86.5*C as a white solid which was homogeneous by TLC.

C. Bi*- (4-aminobenzoyl) -tetraethylenβ glycol (120 q, 0. 278 mole) waa. dissolved in dry dioxane (2. 5 1) in a S- liier, 3-nec flask, equipped with a reflux condenser, drying tube and mechanical stirrer. The solution was stirred vigorous ly _v nd purged with argon before adding a solution of phosgene in toluene (3 M, 650 ml) . The mixture was heated slowly to reflux over 2 hours and refluxed for a further 3 hours . The condenser was then rearranged for di t¬ illation and solvent removed by disti llation at atmospheric pressure " unti l the volume of the reaction mixture was reduced to ^• approximately one third. The reaction mixture was allowed to cool to room temperature under argon and then evaporated under reduced pressure. The residue was re-evaporated several times from dry dioxane to give bis- (4-isocyanatoben2oyl) -tetraethylene glycol (125 g) as a pale yellow, viscous oil which crystallized on prolonged standing at -15°C, a. p. 34-35°C.

EXAMPLE 2 In Vitro Testing Procedure for Adhesives Test strips were prepared by cutting regenerated cellulose dialysis membrane into strips (0.5 x 6 inch) which were boiled with aqueous E TA (0.2 M) for 5 hours. On cooling, the βtrip were washed thoroughly with distilled water, excess water removed by mopping and the resulting hydrated cellulose samples stored in a 100% humidity chamber.

Adhesive samples were prepared by thoroughly mixing the components (isocyanate monomer, curing agent, if used and catalyst) in the specified ratio. A thin film of the sample was spread on one side of the test strip, which had been folded in half, and the strip then clamped with a steel spring clip. i .e.

clamp

hydrated cellulose ^< OSL membrane adhesive'

Test samples were returned to the 100% humidity chamber and stored for the specified period before measuring adhesive strengths. Adhesive strength was measured as 'peel strength" — the force required to pull the strip apart when the two ends of the strip were pulled apart in a straight line at a constant rate (1 ft/min).

The results of adhesive testing of the monomer, bis- (4-iso- cyanatobenzoyD-tetraethylene glycol, with a variety of catalysts are summarized in Table 1. The values quoted are the averages of 2-5 determinations in each case.

EXAMPLE 3 Testing of Adhesives Dsing a Rat Sλin Model

Tissue specimens were obtained by ^* excising samples (approx. 4 X inch) from the dorsal region of previously shaved rats. Samples were rinsed to remove animal hair, sealed in plastic bags and sterilized by ⁶⁰ cobalt irradiation. Immediately prior to use, the specimens were cut into strips U ^nch X 1/2 inch).

Adhesive samples were prepared by thoroughly mixing the components in the specified ratio. A thin film of the mixture was applied to a 1 sq. cm. area on one strip of skin, and a second strip laid over the top to provide an area of overlap of l/2_inch containing the adhesive. The strips were clamped under:a..constant load for the specified time before measuring tensile strengths using an Inεtron. The results of these studies using a variety of catalysts are summarized in Table 2.

-25-

TABLB 1 Adhesive Strengths of Bia- -Tetraethylane Glycol-Derived Adhesives as a Function of Catalysts Used

Adhesive Strength (g/0.5 inch) * 1 min. 2 min. 5 min. 60 min.

0.10

4-(N,N-Dimethylamino)- 0.02 pyridine

0.10*

N-Methylmorpholine 0.10

. 0.20

0.30

K-(N,N-Dimethylamino- 0.10 propyl)-2-pyrrolidone

0.20 ^e

2,4,6-Collidine 0.10

0.20 ^e

4-t-Butylpyridine 0.10

0.20 ^β

Pyri idine 0.20

0.30

0.60

Quinaldine 0.20

0.30 ^f

Triethanolamine 0.15

0.30

TABLE 1 (Continued)

Catal st/NCO Adhesive Strength (g/0.5 incnj*

Catalyst (mole/mole) 1 min. 2 min. 5 ain. 60 min. 3-Pyridyl Carbinol 0.05 5 64 46

0.10 5 90 56

0.20 ^b 50 23 20

Di-t-Butyl Tin 0.05 5 124 208 Dilaurate

0.15 8 74 169

0.30 3 43 202

Stannous 2-Ethyl 0.05 3 89 303 Hexanoate

0.15 5 70 328

Tris- (Dime thy lamino- 0.015 24 268 methyl) -phenol

0.03 23 67

0.10 40 15 30

Tetramethyldiamino- 0.03 105 ⁹ 2-propanol

0.125 5*

0.25 34

Pyridine 0.05 95 342

0.50 >500

Triethanolamine/1,2.4- 388 Tri ethylpiperazine

Triethylamine 0.20

Methyl Nicotinate 0.40 255 0.50 209 0.60 405 0.80 291

Ethyl nicotinate 0.30 305 0.50 395 0.70 333

TABLE 1 (Continued)

Treasured using hydrated cellulose as substrate; each value represents the average of 2-5 measurements. pot-life » 5-10 minutes. ^c Catalyst dissolved in dimethylformamide.

Catalyst dissolved in diroethylsulfoxide. ^e Pot-life = 10-20 minutes.

Pot-life » 20-30 minutes. β 'Measurements made at 15 minutes.

Triethanolamine:l,2, -trimethylpiperazine:isocyanate - 0.05;

0.20:1.0 (molar).

TABLE 2 Adhesive Strengths of Bis-(4-Isocyanatobenzoyl) -Tetraethylene Glycol-Derived Adhesives Using Rat Skin as Substrate

Hexa ethylenetetramine Triethylamine

Triethylamine + N,N- diethylaceta ide

Measured using rat skin as substrate (see Example 3) .

Isocyanate and catalyst were mixed in the indicated ratio; one drop of this formulation was mixed with one drop of N,N-diethyl- acetamide and the adhesive mixture applied to the substrate. ^c The tissue was pretreated with 8% aqueous sodium bicarbonate before applying the adhesive.

EXΛMPLE 4 Bi8-(4-l3θcyanatobenzoyl)-Polyethylene Glycol (M.W. ^* » -.00)

A. Polyethylene glycol 400 (100 g, 0.25 mole) was treated with p-nitrobenzoyl chloride (113 g, 0.6 mole), following the procedure described in Example 1, Part A. The residual, thick oil was treated with aqueous sodium bicarbonate, as described, to remove excess acid chloride. The product, bis- (4-nitrobenzoyl) -poly¬ ethylene glycol 400 (148.3 g) was obtained as a thick, yellow oil.

B. Bis-(4-nitrobenzoyl)-polyethylene glycol 400 (130 g) , pre¬ pared in Part A, was hydrogenated over palladium on carbon (10%, 7 g) , as described in Example 1, Part B, to give bis- (4-amino- ben z oyl) -poly ethylene glycol 400 (115 g) as a thick, pale yellow oil.

C. Bis- (4-aminobenzoyl) -polyethylene glycol 400 (100 g, from Part B) was phosgenated by the procedure described in Example 1, Part C, to give bis- (4-isocyanatobenzoyl) -polyethylene glycol 400 in quantitative yield, as a thick, pale yellow oil.

D. Adhesive Testing: The monomer was mixed with ethyl 3-pyr- idylacetate (molar ratio of catalyst to isocyanate * 0.1). The mixture was tested using hydrated cellulose as substrate, as described in Example 2, resulting in an adhesive strength of 113 g m./0.5 inch at 2 minutes.

EXAMPLE 5 Bis- (4-Isocyanatoben2oyl) -Polyethylene Glycol (M.W. = 600) A. Following the procedure described in Example 1, Part A, polyethylene glycol 600 (150 g, 0.25 mole) was treated with p-nitrobenzoyl chloride (113 g, 0.6 mole) to give bis-(4-nitro- benzoyl) -polyethylene glycol 600 (208 g) as a thick, yellow oil.

B. Bit-(4-nitrobenzoyl)-polyethylene glycol 600 (120 g) , from Part A, ^y as hydrogenated in the usual manner to give bis- (4-amino- benzoyl)-polyethylene glycol 600 (115 g) as a pale yellow oil.

C. The product from Part B (50 g) was phosgenated by the pro¬ cedure described in Example 1, Part C, to give bis-(4-isocyanato- benzoyD-polyethylene glycol 600 in quantitative yield, as a thick, pale yellow oil.

D. Adhesive Testing: The monomer was mixed thoroughly with ethyl 3-pyridyl acetate (molar ratio of catalyst to isocyanate ■ 0.2). The resulting adhesive was tested as described in Example 2 adhesive strength « 38 gm/0.5 inch at 2 minutes.

EXAMPLE 6 Bis- (4-Isocyanatobenzoyl)-Triethylene Glycol

A. Triethylene glycol (45 g, 0.3 mole) was treated with excess P--nitrobenzoyl chloride (116 g, 0.62 mole), following the general procedure outlined in Example 1, . Part A. After treating with aqueous sodium bicarbonate to remove excess acid chloride, the product was recrystallized from ethyl acetate to give bis- (4-nitrobenzoyl)-triethylene glycol (115 g) as a pale yellow solid, m.p. 104-105°C. The product was homogeneous by TLC.

B. Bis-(4-nitrobenzyoyl)-triethylene glycol (50 g) was hydro¬ genated in the usual manner over palladium on carbon (10%, 3 g) . The product was recrystallized from ethyl acetate in the dark to give bis-(4-aminobenzoyl)-triethylene glycol (42 g) as a white solid, which was homogeneous by TLC.

C. Bis-(4-aminobenzoyl)-triethylene glycol (25 g) , from Part B, was phosgenated by the procedure described in Example 1, Part C, to give bis-(4-isocyanatobenzoyl)-triethylene glycol in quantit¬ ative yield as a pale yellow solid, m.p. 64.2-65.1 C.

_*

D. Adhesive Testing: The isocyanate monomer, prepared as des¬ cribed in Part A, was mixed in equi olar proportions with bis- (4-isocyanatobenzoyl)-tetraethylene glycol (from Example 1) and the mixture wanned gently to produce a homogeneous mixture. On cooling, ethyl 3-pyridylacetate was mixed thoroughly with the mixture (molar ratio of catalyst to isocyanate • 0.25) and the adhesive tested using hydrated cellulose as substrate, as des¬ cribed in Example 2. Adhesive strength ~ 483 gm/0.5 inch at 2 minutes.

EXAMPLE 7 Bis- (4-Isocyanatobenzoyl)-Diethylene Glycol

A. Diethylene glycol (31.8 g, 0.3 mole) and p-nitrobenzoyl chloride (116 g, 0.62 mole) were reacted under the conditions described in Example 1, Part A. The product was crystallized from ethyl acetate to give bis- (4-nitrobenzoyl)-diethylene glycol (101 g) as a pale yellow solid, m.p. 100-102°C. The product was homogeneous by TLC.

B. The product from Part A (90 g, 0.25 mole) was hydrogenated in the usual manner over palladium on carbon (10%, 5 g) . The product was crystallized from ethyl acetate, in the dark, to give bis-(4-arainobenzoyl)-diethylene glycol (62 g) as a white solid, m.p, 101-104°C which was homogeneous by TLC.

C. The product from Part B (25 g) was phosgenated as described in Example 1, Part C, to give bis-(4-isocyanatobenzoyl)-diethylene glycol in quantitative yield as a pale yellow solid, m.p. 45-48 C.

D. Adhesive Testing: The isocyanate monomer was melted by warming gently and ethyl 3-pyridylacetate mixed thoroughly with the monomer (molar ratio of catalyst to isocyanate ^« • 0.4). The resulting adhesive mixture was tested as described in Example 2, to give an adhesive strength of 118 gm/0.5 inch at 2 minutes.

Alternatively, the monomer, prepared as described in Part C, was mixed in eqimolar proportions with bis-(4-iaocyanatobenz- oyl)-tetraethylene glycol, with gentle warming if necessary to achieve homogeneity. Ethyl 3-pyridylacetate was mixed thoroughly with the adhesive mixture (molar ratio of catalyst to isocyanate ^» 0.5). The mixture was tested as described in Example 2 to give an adhesive strength of >500 gm/0.5 inch at 2 minutes.

EXAMPLE 8 Bis- (4-Isocyanatobenzoyl)-Propane-l, 3-Diol

A. Bis- (4-aminobenzoyl)-propane-l,3-diol (3.14 g, 0.01 mole) was phosgenated as described in Example 1, Part C, to give bis-(4-isocyanatobenzoyl)-propane-l,3-diol (3.2 g) as a pale yellow solid, m.p. 97-102°C.

B. Adhesive Testing: The isocyanate monomer, prepared as des¬ cribed in Part A, was mixed in a molar ratio of 1:9 with bis- (4-isocyanatobenzoyl)-tetraethylene glycol with gentle warming to achieve homogeneity. On cooling, ethyl 3-pyridylacetate was mixed thoroughly with the adhesive mixture (molar ratio of catalyst to isocyanate » 0.5) and the mixture tested as descibed in Example 2. Adhesive strength »• 498 gm/0.5 inch at 2 minutes.

EXAMPLE 9 Bis-(3-Isocyanatobenzoyl)-Tetraethylene Glycol A. Tetraethylene glycol (58.2 g, 0.3 mole) was treated with m-nitrobenzoyl chloride, following the general procedure des¬ cribed in Example 1, Part A. After the usual work-up, the pro¬ duct was crystallized from ethyl acetate/hexanes at -20°C for 3 days to give bis-(3-nitrobenzoyl)-tetraethylene glycol (110 g) as a pale yellow solid, m.p. 38-40°C.

B. Bis-(3-nitrobenzoyl)-tetraethylene glycol (100 g, from Part A) was. hydrogenated. over palladium on carbon (lOδ, β g) , following the usual procedure. When hydrogen uptake was complete (27.95 liters total) the mixture was stirred for two hours at room temperature under hydrogen. After removal of the hydrogen in vacuo, magnesium sulfate was added directly to the mixture which was stirred for a further 2 hours at room .temperature and then filtered. The product was precipitated directly as an oil by addition of hexanes to the filtrate. The supernatent was decanted, the residue redissolved in isopropanol and excess hydrogen chloride/ dioxane (4 N) added. The hydrochloride salt of the desired product crystallized at -20°C and was recrystallized from isopropanol/ tetrahydrofuran to give bis- (3-aninobenzoyl)-tetraethylene glycol dihydrochloride (75 g) as a pale yellow solid, m.p. 100-101.5 C.

The product was homogeneous by TLC.

C. The product from Part B (25 g) was phosgenated in the usual manner, as described in Example 1, Part C, to give bis-(3-iso- cyanatobenzoyl)-tetraethylene glycol in quantitative yield as a thick yellow oil. The product solidified on prolonged storage at -15°C; m.p. 36-39°C.

D. Adhesive Testing: The isocyanate monomer, prepared as des¬ cribed in Part C, was mixed thoroughly with ethyl 3-pyridyl- acetate (molar ratio of catalyst to isocyanate « 0.4). The adhesive mixture was tested as described in Example 2, using hydrated cellulose as substrate. Adhesive strength ^* * ^•* 450 gm/0 ^" .5 inch at 2 minutes.

EXAMPLE 10 Bis- (2-l8θcyanatobenzoyl)-Tetraethylene Glycol

A. Tetraethylene glycol (58.2 g, 0.3 mole) was treated with o-nitrobenzoyl chloride (116 g, 0.625 mole), under the general conditions described in Example 1, Part A. Following the usual work-up procedure, bis-(2-nitrobenzoyl)-tetraethylene glycol (124 g) was obtained as a yellow oil which, was homogeneous by TLC.

B. The product from Part A (32 g, 0.07 mole) was dissolved in redistilled ethyl acetate (200 ml) and hydrogenated over palladium on carbon (10%, 1.5 g) using a Parr hydrogenation apparatus at

50 p.s.i. When hydrogen uptake was complete (4 days), magnesium sulfate was added directly to the mixture, which was stirred at room temperature for 2 hours. After filtration, the filtrate was evaporated to dryness, redissolved in ethanol and treated with excess anhydrous hydrogen chloride/dioxane (4 N) . The mixture was diluted with two volumes of tetrahydrofuran and evaporated to dryness. The solid residue was recrystallized .from methanol/tetrahydrofur n to give bis-(2-aminobenzoyl)-tetra¬ ethylene glycol (23 g) as a white solid, m.p. 98-102°C, which was homogeneous by TLC.

C. The product from Part B (5.1 g, 0.01 mole) was phosgenated in the usual manner to give bis-(2-isocyanatobenzoyl)-tetraethyl¬ ene glycol (4.1 g) as a light brown oil.

D. Adhesive Testing: The isocyanate monomer, prepared as des¬ cribed in Part C, was warmed gently to give a melt which was mixed thoroughly with ethyl 3-pyridylacetate (molar ratio of catalyst to isocyanate = 0.4) and the adhesive mixture tested as described in Example 2. Adhesive strength ■ 0 gm/0.5 inch at ^" 2 minutes.

EXAMPLE 11

Bis-(4-Isocyanatobenzenesu fonyl)-Tetraethylene Glycol

A. p-Nitroben∑enesulfonyl chloride (25 g , 0.113 mole) and tetraethylene glycol (10 g, 0.052 mole) were dissolved in dry tetrahydrofuran and treated with triethylamine (15 al, 0.110 mole) . The mixture was stirred overnight at room temperature when TLC revealed that reaction was incomplete. Further portions of acid chloride (12 g) and triethylamine (7 ml) were therefore added and the mixture stirred for a further 4 hours at room temperature. An equal volume of saturated aqueous sodium bi¬ carbonate was then added, the mixture stirred at room tempera¬ ture for 4 hours and then extracted with ethyl acetate (2 x) .

The combined organic extracts were washed with saturated sodium chloride (4 x) , dried (MgSO.) and evaporated under reduced pressure. The residue was crystallized from ethyl acetate/ hexanes to give bis-(4-nitrobenzenesulfonyl)-tetraethylene glycol (15.5 g) as a pale yellow solid, m.p. 59-62°C, which was homo¬ geneous by TLC.

B. Bis-(4-nitrobenzenesulfonyl)-tetraethylene glycol (10 g, from Part A) was dissolved in distilled ethyl acetate (200 ml) and hydrogenated over palladium on carbon (10%, 0.5 g) at

40 p.s.i. in a Parr hydrogenation apparatus. The solution was filtered and evaporated under reduced pressure to give bis-(4- aminobenzenesulfonyU-tetraethylene glycol in quantitative, yield as a thick, yellow oil which was homogeneous by TLC.

C. The product from Part B (8 g) was phosgenated in the usual manner to give bis-(4-isocyanatobenzenesulfonyl)-tetraethylene glycol (8.3 g) as -a thick yellow oil.

D. Adhesive Testing: The isocyanate monomer, prepared as des¬ cribed in Part C, was mixed thoroughly with triethylamine (molar

ratio of catalyst to isocyanate ■ 0.2) and the adhesive mixture tested, as described in Example 2, using hydrated cellulose as. substrate. Adhesive strength ^*** 50 gm/0.5 inch at 10 minutes.

EXAMPLE 12 Bis-(4-Isocyanatobenzoyl)-Dipropylene Glycol λ. Dipropylene glycol (40.2 g, 0.3 mole) was treated with p-nitrobenzoyl chloride (116 g, 0.625 mole), following the general procedure described in Example 1, Part A. After treat¬ ment with saturated aqueous sodium bicarbonate in the usual manner, the ethyl acetatesolution of the product was dried (MgSO^), filtered and crystallization effected by the addition of hexanes. The product, bis-(4-nitrobenzoyl)-dipropylene glycol (67 g) , was isolated as a pale yellow solid, m.p. 96-100°C-which- was homogeneous by TLC.

B. Bis-(4-nitrobenzoyl)-dipropylene glycol (50 g, 0.134 mole, from Part A) was hydrogenated in the usual manner over palladium on carbon (10%, 4 g) . The product crystallized during drying over MgSO.. The solution was therefore heated to boiling, filtered hot and crystallization effected by addition of hexanes to give bis-(4-aminobenzoyl)-dipropylene glycol (29 g) as an off- white solid, m.p. 163-165 C which was homogeneous by TLC.

C. The product from Part B (3.72 g, 0.01 mole) was phosgenated in the usual manner to give bis-(4-isocyanatobenzoyl)-dipropylene glycol (3.69 g) as a pale yellow solid, m.p. 90-100°C.

D. Adhesive Testing: The isocyanate monomer, prepared as des¬ cribed in Part C, was mixed in a molar ratio of 1:3 with bis-(4- isocyanatobenzoyl)-tetraethylene glycol (Example 1) with gentle warming to achieve homogeneity. On cooling, ethyl 3-pyridy.l-

acetate was mixed thoroughly with the adhesive mixture (molar ratio of catalyst to isocyanate » 0.5) and the adhesive tested as described in Example 2. Adhesive strength ■ >500 gm/0.5 inch at 2 minutes.

EXAMPLE 13 Bis- (4-Isocyanatobenzoyl)-Tripropylene Glycol

A. Tripropylene glycol (57.6 g, 0.3 mole) was treated with p-nitrobenzoyl chloride (116 g, 0.625 mole), following the general procedure described in Example 1, Part A. The product, bis- (4-nitrobenzoyl)-tripropylene glycol (131 g), was obtained as a viscous yellow oil.

B. Bis-(4-nitrobenzoyl)-tripropylene glycol (120 g, 0.28 mole, from Part A) was hydrogenated in the usual manner over palladium on carbon (10%, 5 g) . When hydrogen uptake was complete, mag¬ nesium sulfate was added directly to the mixture which was stirred at room temperature for several hours, filtered and evaporated to dryness under reduced pressure. The residue was redissolved in a minimum volume of isopropanol and the product converted to the dihydrochloride salt by addition of excess, anhydrous hydrogen chloride in dioxane. Crystallization was effected by addition of tetrahydrofuran to the solution, to give bis-(4-aminobenzoyl)- tripropylene glycol dihydrochloride (67 g) as a white solid, m.p. 189-193°C, which was homogeneous by TLC.

C. The product from Part B (2.5 g, 0.005 mole) was phosgenated in the usual manner to give bis-(4-isocyanatobenzoyl)-tripropylene glycol in quantitative yield as a very viscous, yellow oil.

D. Adhesive Testing: The isocyanate monomer, prepared as des¬ cribed in Part C, was mixed thoroughly with ethyl 3-pyridylacetate

(■olar ratio of catalyst to isocyanate ■ 0.4) and the adhesive tested as described in Exaaple 2, to give and adhesive strength of 105 gm/0.5 inch at 2 minutes.

Alternatively, the adhesive aonoaer, prepared as described in Part C, was mixed in equiaolar proportions with bis-(4-iso- cyanatobenzoyD-tetraethylene glycol (froa Exaaple 1). Ethyl 3-pyridylacetate was βixed thoroughly with the mixture of monoaers (oolor ratio of catalyst to isocyanate » 0.3) and the adhesive was tested as described in Exaaple 2. Adhesive strength » 475 gm/0.5 inch at 2 minutes.

EXAMPLE 14 Tris-(4-Isocyanatobenzoyl)-Triaethylolpropane

A. Trimethylolpropane (26.84 g, 0.2 mole) was treated with p-nitrobenzoyl chloride (117 g, 0.63 mole), following the general procedure described in Exaaple 1, Part A. The product was worked up in the usual way, except that precipitation occurred during the treatment with saturated aqueous sodium bicarbonate. The aixture was therefore heated to effect solution, the phases separated, the organic phase washed with saturated sodiua bicarbonate (3 x), and dried over MgSO,. The product crystallized during drying and the aixture was therefore heated to boiling, filtered hot, the solid washed with hot ethyl acetate and hexanes added to the filtrate to induce crystallization. The product, tris-(4-nitro- benzoyl)-triaethylolpropane (67 g) was obtained at a pale yellow solid, a.p. 104-106*C, which was homogeneous by TLC.

B. The product from Part A (15 g, 0.026 mole) was slurried in distilled ethyl acetate (200 ml) and hydrogenated over palladium on carbon (10%, 1 g) in a Parr hydrogenation apparatus at 50 p.s.i.

When hydrogen uptake was complete (20 hours), the solution was filtered and the filtrate dried (M S0 ₄ ). The product crystallized during drying and the mixture was therefore heated to boiling, filtered hot and the solid washed with hot ethyl acetate and hot tetrahydrofuran. The combined filtrates were evaporated to dryness under reduced pressure and the residure triturated with ethyl acetate/tetrahydrofuran. After standing overnight at -15°C. the solid was filtered to give tris-(4-aminobenzoyl)- tri ethylolpropane (9 g) as a white solid, m.p. 210-212°C, which was homogeneous by TLC.

C. The product from Part B (2.5 g, 0.005 mole) was phosgenated in the usual manner to give tris-(4-isocyanatobenzoyl)-trimethyl¬ olpropane in quantitative yield as a viscous, yellow oil.

D. Adhesive Testing: The isocyanate monomer, prepared as des¬ cribed in Part C, was mixed thoroughly with ethyl 3-pyridylacetate (molar ratio of catalyst to isocyanate « 0.2) and the adhesive tested as described in Example 2. Adhesive strength - 93 gm/0.5 inch at 1 minute.

EXAMPLE 15 Bis-(4-Isocyanat(Dbenzoyl)-Dihydroxyethyladipate A. A mixture of p-nitrobenzoic acid (33.4 g, 0.2 mole), ethylene carbonate (19.4 g, 0.22 mole) and tetraethylammoniua iodide (9.6 g, 0.036 mole) was. heated at 140°C for 45 minutes. On cooling, the mixture was dissolved in ethyl acetate (500 ml) and washed with water (3 x) and saturated sodium chloride _* The organic solution was dried (MgSO.) and evaporated to dryness under reduced pressure. The residue was shown to be a mixture of the desired product and a small amount of the diester product,

bis-(4-nitrobenzoyl)-ethylene glycol, by TLC (silica gel, ethyl acetate as mobile phase; R _* 's « _. 8.5 and 0.7 ₃ respectively). The mixture was therefore chro atographed on silica gel, eluting first with benzene and then with chloroform to give hydroxyethyl p-nitrobenzoate (31 g) as a pale yellow solid, m.p. 77-78°C, which was homogeneous by TLC.

B. A solution of hydroxyethyl p-nitrobenzoate (29.5 g, 0.14 mole) in tetrahydrofuran (150 ml) was cooled to 0°C and treated with a solution of adipoyl chloride (12.4 g, 0.068 mole) in tetrahydro¬ furan (50 ml), followed by pyridine (12.9 g, 0.160 mole). The mixture was allowed to warm to room temperature slowly and stirred overnight. The solid pyridine hydrochloride was then removed by filtration, and the fitrate evaporated under reduced pressure to half the volume. The solution was' then diluted with a little methanol, heated to reflux and filtered while hot. The product, bis-C4-nitrobenzoyl)-dihydroxyethyladipate (33 g) crystallized on standing as a pale yellow solid, m.p. 100-101°C, which was homo¬ geneous by TLC.

C. The product from Part B (10.0 g) was hydrogenated in the usual manner over palladium on carbon (10%, 1 g) in a Parr hydro¬ genation apparatus at 50 p.s.i. When hydrogenation was complete (20 hours) magnesium sulfate was added directly to the mixture which was stirred at room temperature for several hours. The mixture was then filtered directly into the phosgenation apparatus under nitrogen. The solvent was evaporated under a stream of nitrogen, the residue redissolved in dry dioxane and phosgenated in the usual manner to give bis-(4-isocyanatobenzoyl)-dihydroxy- ethyladipate in quantitative yield as a pale yellow solid, m.p. 92-96°C.

D. Adhesive Testing: The isocyanate aonoaer, prepared as des¬ cribed in Part C, was mixed in a aolar ratio of 1:3 with bis- (4-isocyanatobenzoyl)-tetraethylene glycol (Exaaple 1), with gentle waraing to achieve homogeneity. On cooling, ethyl 3- pyridylacetate was mixed thoroughly with the adhesive aixture (molar ratio of catalyst to isocyanate » 0.25) and the adhesive tested as described in Exaaple 2.. Adhesive strength - 475 gm/0.5 inch at 2 minutes.

EXAMPLE 16 Bis-(2,4-Dii3θcyanatobenzoyl)-Tetraethylene Glycol

A. 2,4-Dintrobenzoic acid (25 g, 0.11 aole) was suspended in dry dichloromethane (100 al), the mixture cooled to 0*C and treated dropwise with a solution of carbonyl diiaidazole (20.6 g, 0.125 mole) in dry dichloromethane (150 al) over 25 ainutes. The mixture was stirred at 0*C for a further 30 minutes before adding a solution of tetraethylene glycol (9.7 g, 0.05 aole) in dry dichloromethane (100 al) dropwise over 20 minutes. The aixture was allowed to wara to room temperature slowly, stirred at this temperature for 6 days and then evaporated to dryness under reduced pressure. The residue was redissolved in ethyl acetate and washed with 2N hydrochloric acid (3 x), saturated sodiua bicarbonate (3 x), water and dried (mgSo.). Evaporation of the solvent gave the product bis-(2,4-dinitrobenzoyl)-tetraethylene glycol (17.2 g) as a viscous yellow oil which was homogeneous by TLC.

B. The product froa Part A (10 g) was hydrogenated in the usual manner over palladiua on carbon (10%, 1 g) in a Parr hydrogena¬ tion apparatus at 50 p.s.i. When hydrogen uptake was complete (20 hours) magnesium sulfate was added directly to the mixture

which was stirred for several hours at room temperature, then filtered and,.evaporated, to dryness under reduced pressure. The residue was redissolved in a minimum volume of isopropanol and converted to the tetrahydrochloride salt by treatment wit excess, anhydrous hydrogen chloride in dioxane. Crystallization was effected by addition of tetrahydrofuran to the solution to give bis-(2,4-diaminobenzoyl)-tetraethylene glycol tetrahydro¬ chloride (7.4 g) as an off-white solid, _w hich was homogeneous by TLC. c. The product from Part B (5 g) was phosgenate in the usual manner to give bis-(2, -diisocyanatobenzoyl)-tetraethylene glycol in quantitative yield as a viscous, yellow oil. D. Adhesive Testing The isocyanate monomer, prepared as des¬ cribed in Part C, was mixed thoroughly with ethyl 3-pyridyl- acetate (molar ratio of catalyst to isocyanate ■ 0.5) and the adhesive tested as described in Example 2. Adhesive strengt ^**** - 30 gm/0.,5 inch at 2 minutes.

EXAMPLE 17 Bis-(3-Isocyanatopropionyl)-Tetraethylene Glycol A.. N-t-Butyloxycarbonyl-β-alanine (75.fi g, 0.4 mole) was coupled with tetraethylene glycol (36.9 g, 0.19 mole), using carbonyl diimidazole (72.6 g, 0.44 mole), following the general procedure described in Example 16, Part A. When reaction was complete, the reaction mixture was evaporated to dryness under reduced pressure. The residue was redissolved in ethyl acetate and washed with 2 M hydrochloric acid (3 x) , saturated sodium bicarbonate (3 x) , water and dried (MgSO^) . The mixture was filtered and the filtrate evaporated under reduced pressure to give bis-(t-butyloxycarbonyl-β-alanyl)-tetraethylene glycol (.93 g)

as a syrup which failed to crystallize. The product was shown to contain a trace of t-butyloxycarbonyl-g-alanine y TLC.

B. The product from Part A (93 g) was treated with anhydrous hydrogen chloride in dioxane (4 H, 200 ml) for 1 hour at room temperature. The mixture was evaporated to dryness under re¬ duced pressure and the residue crystallized from isopropanol/ tetrahydrofuran to give bis-(β-alanyl)-tetraethylene glycol di¬ hydrochloride as a white amorphous solid which was homogeneous by TLC.

C. The product from Part B (10 g) was phosgenated in the usual manner to give bis-(3-isocyanatopropionyl)-tetraethylene glycol in quantitative yield as a viscous oil.

D. Adhesive Testing: The isocyanate monomer, prepared as des¬ cribed in Part C, was mixed thoroughly with ethyl 3-pyridyl- acetate (molar ratio of catalyst to isocyanate ■ 0.5) and the adhesive tested as described in Example 2. Adhesive strength ■ - 10 gm/0.5 inch at 2 minutes.

EXAMPLE 18 Bis-(4-Isothiocyanatobenzoyl)-Tetraethylene Glycol

A. Bis-(4-aminobenzoyl)-tetraethylene glycol (10 g, 0.023 mole), prepared as described in Example 1, Part B, was dissolved in dry dioxane and thiophosgenated, following the general procedure described in Example 1, Part C, using thiophosgene (85% in carbon tetrachloride, 11.5 ml, 0.125 mole) in place of phosgene. After work-up, the product, bis-(4-isothiocyanatobenzoyl)-tetraethylene glycol, was obtained in quantitative yield as a brown oil.

B. Adhesive Testing: The isothiocyanate monomer, prepared as described in Part A, was mixed thoroughly with pyridine (molar ratio of catalyst to isothiocyanate ■ 0.5) and the adhesive

tested as described in Example 2. Adhesive strength * 0 gm/0. 5 inch at 2 minutes .

EXAMPLE 19 Effect of Curing Agents on Adhesive Strength The isocyanate monomer, bis-(4-isocyanatobenzoyl)-tetra¬ ethylene glycol, prepared as described in Example 1, was mixed thoroughly in various proportions with curing agents, such as glycerol or diethylene glycol. The catalyst, ethyl 3-pyridyl- acetate was added (molar ratio of catalyst to isocyanate ■ 0.4), mixed thoroughly and the adhesives tested using hydrated cellulose as substrate, as described in Example 2. The results of these studies are summarized in Table 3.

TABLE 3 Effect of Curing Agents

Adhesive Strength (g/0.5 inch)

1 min. 2 min.

483 500

500 500

350 470

408 500 330 493

None — ^" 495 470

^a Molar ratio of curing agent (CA.) to isocyanate. M Meeaassuurreedd uussiiing hydrated cellulose as substrate, as described in Example 2.

EXAMPLE 20

Bis( ^• .-isocyanatobenzoyl-polyglycolyl) -diethylene glycol

CN-fo NCO

Where n+m * 4 and x * 2

A. Diethylene glycol (16 g.,0.151 mole), Glycolide (glycolic acid cyclic dimer) (34 g., 0.2928 mole) and lead oxide (ι2 mg.) were placed in a dry 100 ml. 3 neck round bottom flask equipped with an oil bath and magnetic stirrer. The mixture was brought to 140 ^W C with stirring and this temperature was maintained for about 20 hrs. The cooled reaction was evaluated by NMR and IR spectroscopy, which showed complete conversion to Bis-(polyglycolyl) ^* diethylene glycol. The Bis-(polyglycolyl) -diethylene glycol was stored under nitrogen and used in the following step without further purification.

B. Bis-(polyglycolyl)-diethylene glycol (50 g., 0.151 mole) from part A above, and 4-dimethylamino pyridine (44.7 g., 0.332 mole) were dissolved in dry, distilled tetrahydrofuran (800 ml.) in a one liter erlenmeyer flask equipped with a magnetic stirrer. 4-Nitrobenzoylchloride (61.7 g., 0.332 mole) dissolved in dry, distilled tetrahydrofuran (200 mis.) was added in two portions to the vigorously stirred solution above. The reaction was complete about five minutes after the second addition (by TLC in methanol/chloroform; 15/85) . The off-white solid (dimethylaminopyridine hydrochloride) ^* was removed by filtration and washed with a small volume of tetrahydrofuran. The combined filtrate and wash were con¬ centrated under reduced pressure to about 300 ml. Ethyl acetate (1 liter) was added. The resulting solution was stirred vigorously for about 18 hours with one liter of

saturated sodium bicarbonate. The organic phase was separated and washed with 500 ml. of saturated sodium bicarbonate (1 x), 500 ml. water (1 x) , 300 ml. of IN hydrochloric acid (2 x) and 300 ml. of saturated sodium chloride (2 x) . The resulting solution was dried by stirring with MgSO., and the MgS0 ₄ removed by filtration. The product (Bis-(4-nitro- benzoyl-polyglycolyl)-diethylene glycol) was homogeneous by TLC (chlorofor /methanol; 85/15; Silica) . The solvent was removed ^" from a small aliquot under reduced pressure, and the structure confirmed by NMR and IR spectroεcop . The remaining ethyl acetate solution was used "as is" for the next step.

C. Bis-(4-nitrobenzoyl-polyglycolyl)-diethylene glycol in ethyl acetate (the total solution from part B above) was placed in a 3 liter round bottom flask and 10% palladium on carbon (6 g.) added. The mixture was vigorously agitated under an atmosphere of hydrogen until gas uptake ceased. During the hydrogenation, the temperature was kept below 3D ^» C by the periodic cooling of the reaction in an ice bath. After hydrogen uptake had stooped, the mixture was agitated an additional two hours at room temperature. The catalyst was removed by filtration (cautionl product is light and oxygen sensitive) and the filtrate concentrated in vacuo. The product was lyophilized three times from dry, distilled dioxane and used as is" in the following step. The structure of the Bis-(4-aminobenzoyl-polyglycolyl)-diethylene glycol was confirmed by NMR spectroscopy and was shown to be homo¬ geneous on TLC (chloroform/methanol; 85/15; silica gel).

D. Bis-(4-aminobenzoyl-polyglycolyl)-diethylene glycol (the total from part C) was dissolved in dry, distilled, deoxygenated dioxane (500 ml.) in a 2 liter, 3 neck round

bottom flask equipped with a reflux condenser, drying tube, magnetic stirrer, nitrogen purge, and an oil bath for heating. -The solution was purged with nitrogen,and 4N hydrogen chloride in dioxane (30 ml., 0.12 mole) was added while purging continued. Phosgene in dioxane (4M, 60 ml., 0.24 mole) was added to the above stirred slurry via a nitrogen pressure transfer system. The stirred reaction was brought to 80*C over a period of one to two hours and maintained at this temperature until complete solution occurred. Once a clear solution was obtained, the mixture was heated slowly to reflux and very mild reflux maintained for two hours. The condenser was then rearranged for distillation, and solvent removed by distillation at atmospheric pressure until the volume of the reaction mixture was reduced to approximately one third. The reaction mixture was allowed to cool to room temperature and then lyophilized. Extreme care must be taken during all subsequent manipulation to ensure that no moisture contacts the product. The lyophilized material was heated at 80*C under high vacuum with magnetic stirring in order to drive off all traces of dioxane. Bis-(4-isocyanatobenzoyl-polyglycolyl)-diethylene glycol was obtained as an extremely viscous amber oil which was stored without deterioration under dry nitrogen at -2Q ^» C for extended periods of time. The structure was confirmed by IR and NMR spectroscopy.

EXAMPLE 21 Testing of Adhesives Using a Rat Skin Model Two sections of rat skin (obtained as described in Example 3) are placed face to face and cut into 0.5 inch squares. ^" The resulting "sandwiches" are stored at -20-C until needed.

Adhesive samples were prepared by dissolving the isocyanate monomer ^* {in this case, 3is-{isocyanatobenzoyi- polyglycolylϊ-diethylene glycol from Example 20) in dichlorofluoromethane (40-45% by weight) , cooling to ^* •-10*C and adding triethylamine (60μl per gram of monomer) . The pot life of this solution was about 30 minutes. To obtain the adhesives peel strength, a frozen "sandwich" of rat skin was removed from the freezer and immediately clamped on one edge with a ball clamp. The tissues were pulled apart and the fat was removed from both sides. The tissue was then re-clamped on the opposite edge and the rest of the fat removed. The tissues were folded back to the clamp and a few drops of the cold solution prepared above was applied to the interface of the two rat skins. As the solution warmed, the solvent evaporated and the moisture on the tissue started the polymer zation. The two tissues were pressed together several times at the point of appli¬ cation, and then the clamp was moved to exert pressure at this point. After one minute, the clamp was removed and the force required to pull the tissues apart measured (in grams/ 0.5 inch). The peel strength was obtained by averaging the values of from 2-6 of the above experiments. The peel strength of the monomer from Example 20 was 92 grams/0.5 inch at 1 minute.

EXAMPLE 22

Bis-(4-isocyanatobenzoyl-polyglyolyl)-polyethylene glycol 600

Where n+m ^* 4 and xa ^* *13

This material was prepared exactly as per Example 20, except polyethylene glycol 600 (90.6 g.;0.151 mole) was

substituted for diethylene glycol.

Adhesive Testing: The monomer was prepared and tested as described in Example 21. Adhesive strength was ^" v-25 grams/

0.5 inch at 5 minutes.

EXAMPLE 23 Bis-H-isocyanatobenzoyl-polyglycolyl) -polyethylene glycol 200

Where n+m 4 and x ^** } ^" 4

This material was prepared exactly as per Example 20, except polyethylene glycol 200 (30.2 g., 0.151 mole) was substituted for diethylene glyool.

Adhesive Testing: The monomer was prepared and tested as described in Example 21. Adhesive strength v 80 grams/0.5 inch at i minute.

EXAMPLE 24

Bis- (4-isocyanatobenzoyl-polyqlycolyl) -polyethylene glycol 300

0 0 0 0 ^^^

OCN -βS- C- (0-CH ₂ -C) _n -0- (CH ₂ CH ₂ -O) _χ - (C-CH ₂ -O) _ _] .-C --fc - ^NC0

Where n+m at 4 and x & 6 This material was prepared exactly as described in Example 20, except polyethylene glycol 300 (45.3 g., 0.151 mole) was substituted for diethylene glycol. Adhesive Testing: This monomer was prepared and tested as described in Example 21. Adhesive strength ^* y 45 grams/0.5 inch at 1 minute.

EXAMP E 25

Bis- ( 4-i3ocyanatobenzoyl-polyglycolyl) -polyethylene glycol 400

0 0 0 0 ^^

OCN-fcV C- (0-CH ₂ -C) _n -0- (CH ₂ CH ₂ -0) _χ - (C-CH _j -O) _B -C "fcV NCO

Where n+m ^< af 4 and xiJ S This material was prepared exactly as per Example 20, except polyethylene glycol 400 (60.4 g., 0.151 mole) was substituted for diethylene glycol.

Adhesive Testing: This monomer was prepared and tested as described in Example 21. Adhesive strength ^**** . 30 grams/ 0.5 inch at 3 minutes.

EXAMPLE 26

Bis- (4-isocyanatobenzoyl-polyglycolyl)-diethylene glycol

0 0 O 0

OCN -fc/" C-(0-CH ₂ -C) _n -0-(CH ₂ <5H ₂ -0) _χ -(C-CH ₂ -0) _a .-C -fcV NCO

Where n+m &6 and x « 2 This material was prepared exactly as per Example 20, except the glycolide was increased to 5/grams, 0.440 mole. Adhesive Testing: This monomer was prepared and tested aβ described in Example 21. Adhesive strength S^I ^Q O grams/ 0.5 inch at 1 minute.

EXAMPLE 27

Bis- (4-isocyanatobenzoyl-polyqlycolyl3 -polyethylene glycol 600

0 0 0 0 ^.^

OCN -fc C- (0-CH ₂ -C) _n -0- (CH _j CH -0) _χ - (C-CH _j -O) _B -C -fc " CO

Where n+m ^* # 6 and x»13 This material was prepared as per Example 22, except the glycolide was increased by 50%.

Adhesive Testing: This monomer was prepared and tested aβ described in Example 21. Adhesive strength ^β» 25 grams/0.5 inch at 4 minutes.

EXAMPLE 28 Bis-(4-isocyanatobenzoyl-polylactoyl)-diethylene glycol

OCN

Where n+ro s? 4 and x » 2. This material was prepared as per the procedure of Example 20, except that lactide was substituted for glycolide. Adhesive Testing: This monomer was prepared and tested as described in Example 21. Adhesive strength ** 40 grams/0.5 inch after three minutes. With 50% more catalyst ^* , adhesive strength was 100 grams/0.5 inch at 2 minutes.

EXAMPLE 29

Bis- (4-isocγanatobenzoyl-polyglycolyl) -dipropylene glycol

0CN NCO

Where n+m at 4 and x « 2

This material was prepared exactly as described in

Example 20, except that dipropylene glycol was substituted for diethylene glycol.

Adhesive Testing: This monomer was tested as described in

Example 21. Adhesive strength z 118 grams/0.5 inch after one minute.

EXAMPLE 30 Bis-(4-isocyanatobenzoyl-polyglycolyl)-polypropylene glycol 725

Where n+m # 4 and x _ 12 This material was prepared as described in Example 22, except polypropylene glycol 725 was substituted for poly¬ ethylene glycol 600.

Adhesive Testing: This monomer was tested as described in Example 21. Adhesive strength r 40 grams/0.5 inch at 5 minutes.

EXAMPLE 31 Bis-(4-isocyanatoben2oyl-polyglycolyl)-ethylene glycol

Where n+m ϋ 4

This material was prepared according to the procedure of Example 20, sxcept. hat ethylene glycol wa3 substituted for diethylene glycol.

Adhesive Testing: This monomer was prepared and tested as described in Example 21. Adhesive strength a*159 grams/ 0.5 inch at 1 minute.

EXAMPLE 32

Bis-(4-isocyanatobenzoyl-polyglycolyl-lactoyl) -diethylene glycol

NCO

Where n+ra_*4 and R is a 50/50 mixture of H and CH ₃

This material was prepared according to the procedure of Example 20, except that a 50/50 mixture of lactide and glycolide was substituted for the glycolide.

Adhesive Testing: This monomer was prepared and tested as described in Example 21. Adhesive strength a- ^* 90 gram/0.5 inch at 1 minute.

EXAMPLE 33 Tris-(4-isocyanatobenzoyl-polyglycolyl)-glycerol

Where a+b+c zt 5 This material was prepared according to the procedure of Example 20, except that glycolide (83.0 grams, 0.5 mole) and glycerol (7.5 g. , 0.082mole) in place of diethylene

glycol, were used in part A. This product was reacted with 4-nitrobenzoyl chloride- (54.7 g., 0.295.sole) and 4-dimethyl- a ino pyridine (43.2 g. ₍ 0.354 mole) in part B. The tri- isocyanate was obtained as an amber glass. Adhesive Testing: This monomer was prepared and tested as described in Example 21. Adhesive strength _v 85 grams/0.5 inch after one minute.

EXAMPLE 34

Tris- (4-isocyanatobenzoyl-polyglycolyl) -glycerol

0 0

CH ₂ -0- (C-CH ₂ -0) _a -C -fc/~ ^NC0

0

M

CH -0- (C-CH ₂ -0) _b -C -( O >- NC0 0 0 CH ₂ -0- ⁽ C-CH ₂ -0 ⁾ _c -ϊ-<0/- ^NC0

Where a+b+c«*10 This material was prepared as per Example 33, except double the amount of glycolide was used. Adhesive Testing: This monomer was prepared and tested as described in Example 21. Adhesive strength -v 80 grams/0.5 inch at 1 minute.

EXAMPLE 35

Tris-(4-isocyanatobenzoyl-polyglycolyl)-trimethylol propane

Where a+b+c-^6 This material was prepared by the procedure of Example 33, except trimethol propane was substituted for glycerol and the glycolide was increased to give a+b+c ^■ 6.

Adhesive Testing: This monomer was prepared for testing as described in Example 21. Adhesive strength-af-SO grams/ 0.5 inch after one minute.

EXAMPLE 36

Tris- (4-isocyanatobenzoyl-polyglycolyl) -ethylene-glycol- tri ethanol propane

(Where a+b+c

This material was prepared by chain extending trimethol propane with ethylene oxide and reacting the resulting tri¬ ol as described in Example 35. Adhesive strength * 105 grams/0.5 inch at 1 minute.

EXAMPLE 37 Diglycolyl-bis-(ethyl-4-isocyanato benzoate)

A. Ethylene carbonate (20 g., 0.22 mole), 4-Nitrobenzoic acid (38 g., 0.2 mole), and tetraethylammonium chloride (2.0 g., 0.04 mole) were placed in a one liter round bottom flask and heated at 140 ^» C with stirring until evolution of C0 ₂ stopped. The reaction was cooled to room temperature and dissolved in one liter of ethyl acetate. The solution was washed with water and dried over MgSO^. The drying agent was removed by filtration. The volume was reduced in-vacuo and the 2-hydroxyethyl-4-nitrobenzoate obtained as a pale yellow solid. The structure was confirmed by NMR εpectroscopy.

B. Diglycolic acid (13.4 g., o.l mole) was slurried in chloroform- (150 ml.) and phosphorous pentachioride (45 g , 0.22mole)added all at once. The mixture was slowly brought to reflux over about one hour. Reflux was maintained for 1.5 hours. After cooling the chloroform was removed under reduced pressure (20mm) and the phosphorous oxy-chloride, which had formed, was removed by distillation at 0.5mm

Hg {t.25 ^» C) . The product (diglycolyl chloride) was collected at 56-57*C and 0.5 mm Hg. Structure was confirmed by IR and NMR spectroscopy.

C. Diglycolyl chloride (8.5 g., 0.05 mole) and 2-Hydroxyl- ethyl-4-nitrobenzoate were condensed as described in Example 20, part B. The resulting di-nitro material was converted to the di-isocyanate by the procedure of Example 20 (Part C i D).

Adhesive Testing: This monomer was tested as described in Example 21. Adhesive strength « ^* 115 grams/0.5 inch at 1 minute.

EXAMPLE 38

Dimalonyl-bis-(ethyl-4-isocyanato-benzoate)

0 0 0 0

OCN -fc)/~ C-O-CH ₂ -CH ₂ -0-C-CH ₂ -C-O-CH ₂ -CH ₂ -O-C - 0/~ ^NCO This material was prepared according to the procedure of Example 37, except malόnyl dichloride was substituted for diglycolyl dichloride.

Adhesive Testingt This monomer was tested as described in Example 2. Adhesive strength -=165 gram.?/0.5 inch at two minutes(on hydrated cellulose) .

EXAMPLE 39 Oxalylτ ^* -bis-(ethyl-4-isocyanatobenzoate)

OCN -fcV ^NC0

This material was prepared by the procedure of Example 37, except oxalyl chloride was substituted for diglycolyl dichloride.

Adhesive Testing: This monomer was tested according to the procedure of Example 2. Adhesive strength ■ 30 grams/0.5 inch at 4 minutes (on hydrated cellulose) .

EXAMPLE 40 Oxalyl -bis-(propyl-4-isocyanato-benzoate)

This material was prepared according to Example 37, except propylene carbonate was substituted for ethylene carbonate and oxalyl chloride was substituted for diglyolyl dichloride. Adhesive Testing: This monomer was tested by the procedure of Example 21. Adhesive strength (on rat skin) - 83 grams/ 0.5 inch at 1 minute. ^' '

EXAMPLE 41 Bis-(4-isocyanatobenzoyl)-polypropyloxalate

OCN- θV"C-0- (CH ₂ Ϊ ₃ -0-C-C-0 _χ -(CH ₂ ) ₃ -0.-C-fcV CO

Where x* 3 Oxalyl chloride was condensed (without solvent) with 1, 3-propane diol to give the corresponding diol where x . ^* ■ 3. This diol was carried through to the diisocyanate by the procedure of Example 20.

Adhesive Testing: This monomer was tested according to the procedure of Example 21. Adhesive strength ** 38 grams/0.5 inch at 1 minute.

EXAMPLE 42

Bis-(4-isocyanatobenzoyl-hydroxy-ethyl-glycolate)-di- ethylene glycol ether

0 0 0 0

OCM-fcV- C-O-(CH ₂ ⁾ ₂ -0-C-CH ₂ -0- ⁽ CH ₂ -CH ₂ -0 ⁾ ₂ -O-CH ₂ -C-0-(CH ₂ ) ₂ -0-C- θV

Tetraethylene glycol was oxidized to the corresponding diiacid, converted to the acid chloride by the action of thionyl chloride and condensed with 2-hydroxy-ethyl-4- nitrobenzoate. The latter was then converted to the diisocyanate according to the procedures of Example 37. Adhesive Testing: This monomer was tested by the procedure of Example 21. Adhesive strength ^* * ^** 112 grams/0.5 inch at 1 minute.

EXAMPLE 43 Bis-(4-i3θcyanatobenzoyl-glycolyl)-ethylene glycol

4-Aminobenzoic acid was condensed with t-butyloxy- dicarbonate by standard procedure to give t-butyloxycarbonyl- 4-amino-benzoic acid. This was condensed (by the action of carbonyldiimidazole) with glycolic acid benzyl ester. The benzyl ester was removed by hydrogenation (Pd/C) and the resulting acid reacted with 1,2-dichloroethane to give bis-(t-butyloxycarbonyl-4-amino-benzoylglycolyl)-ethylene glycol. The t-butyloxycarbonyl group was removed with HCl/dioxane, and the diamine converted to the diisocyanate. Adhesive Testing: This monomer was tested according to the procedure of Example 21. Adhesive strength » 15 grams/ 0.5 inch at 2 minutes.

EXAMPLE 44

3is-(4-isocyanatobenzoyl-glycolyl) -diethylene glycol

This material was prepared according to the procedure of Example 43, except that 2-chloroethyl ether was sub¬ stituted for 1,2-dichloroethane.

Adhesive Testing: This monomer was tested according to the procedure of Example 21. Adhesive strength * 103 gram/0.5 inch at 1 minute.

EXAMPLE 45 Adhesive Composition An adhesive composition was prepared by mixing 85% by weight of the monomer of Example 20 with 15% by weight of the monomer of Example 33, and performing adhesive testing as described in Example 21. Adhesive strength >200 grams/ 0.5 inch at 1 minute.

EXAMPLE 46 Adhesive Composition An adhesive composition was prepared by mixing 60% by weight of the monomer of Example 22 with 40% by weight of the monomer of Example 33, and performing adhesive testing as described in Example 21. Adhesive strength >200 grams/ 0.5 inch at 1 minute.

EXAMPLE 47 Adhesive Composition An adhesive composition was prepared by mixing 70% by weight of the monomer of Example 24 with 30% by weight of the monomer of Example 33, and performing adhesive testing

as described in Example 21. Adhesive strength >200 grams/ 0.5 inch at 1 minute.

EXAMPLE 48 Adhesive Composition An adhesive composition was prepared by mixing 70% by weight of the monomer of Example 1 with 30% by weight of the monomer of Example 33, and performing adhesive testing as described in Example 21. Adhesive strength 200 grams/ 0.5 inch at 1 minute.

(The monomer from Example 1 under these conditions gives an adhesive strength of 110 grams/0.S inch at 1 minute.)

EXAMPLE 49 Adhesive Composition As Example 45, except dissolve monomer in methylene chloride. Adhesive strength « 175 grams/0.5 inch at 2 minutes.

EXAMPLE 50 Adhesive Composition Spray The monomers from Example 22 and 33 were mixed in a ratio of 60/40 (wt./wt.) and dissolved in cold dichlorofluoromethane at a concentration of 25% (wt./wt.) .60μl of triethylamine per gram of monomer was added and the solution placed in a pressure bottle equipped with an aerosol spray nozzle. The solution was allowed to warm to room temperature and the adhesive solution sprayed onto the substrate. An adhesive strength of greater than 200 grams/0.5 inch at 1 minute (rat skin) was obtained.

EXAMPLE 51 Curing Agents The diol from part A of Example 20 was mixed with the adhesive composition of Example 46 in a molar ratio of 0.2/ 1 (diol/isocyanate) and tested as described in Example 21. Adhesive strength ^* *-175 grams/0.5 inch at 2 minuteβ.

EXAMPLE 52 Absorption of Polymers Derived from Adhesive Monomers (in-vitro)

Each monomer or monomer mixture was prepared as described in Example 20. Each solution was spread over the surface of a glass slide and allowed to polymerize in the presence of 90+% humidity for 24 hours. The resulting polymers are dried under vacuum and scraped off the slides. The polymers are incubated in 0.1 M phosphate buffer pH 7.4 (seal tubes) for various times and temperatures. After each time interval the polymer left unadsorbed' was collected and weighed. The results are given as wt. % of polymer remaining as a function of time and temperature. The results are summarized in Table 4.

TABLE 4 (CONT.)

ABSORPTION STUDIES

Polymer Derived From

Monomer of Example Wt.% Remaining Time Tem .

28 62 85 85

33 1.9 0.0 92 1.4

37 22 92 80 40

39 0.0 8 days 5β ^« C

40

41

42

43

44