United States Patent [191 [11] Patent Number: 4,636,387 Allcock et al. [45] Date of Patent: Jan. 13, 1987
[54] ANESTHETIC [56] References Cited POLYORGANOPHOSPHAZENES Us PATENT DOCUMENTS
‘ _ . _ 3,914,283 10/1975 Okamoto et al...... 560/49 [75] Inventors‘ Harry R‘ Allcock’ Paul E’ Austm’ 4,495,174 1/1985 Allcock et al...... 424/78 Thomas X. Neenan, all of State College, Pa. OTHER PUBLICATIONS _ _ ‘ Allcock et 211., Chemical Abstracts, vol. 97, No. 2, Abst. [73] Ass1gnee: Research Corporation, Tucson, Al’lZ. No‘ 6398_Y (Jul‘ 12’ 1982)’ Allcock et a]., Chemical Abstracts, vol. 102, No. 20, [21] Appl. No.: 708,907 Abst. No. 172,651d, (May 20, 1985). _ Primary Examiner-—Alan L. Rotman [22] Flled‘ Sep- 21’ 1984 Attorney, Agent, or Firm-Scully, Scott, Murphy & Presser Related US. Application Data [57] ABSTRACT [62] Division of Ser. No. 390,345, Jun. 21, 1982, Pat. No. A long-acting, local anesthetic, comprising a polymeric 4,495,174- phosphazene backbone, and certain radicals having local anesthetic activity and an amino functional group [51] Int. Cl.4 ...... C08G 79/02; C08G 79/04; On the ring of Said radical through which said radical is A61K 9/58 covalently attached to the phosphazene backbone by a [52] US. Cl...... 514/89; 546/22; phosphorous-nitrogen single bond is disclosed along 560/46; 560/49; 564/12; 564/13; 514/110; with medicaments containing such anesthetics. The 514/118; 514/124; 424/78 radicals employed are 2-amino-4-picoline, benoxinate, [58] Field of Search ...... 546/22; 560/48, 64, naepaine and phenacaine. 560/46, 49; 564/12, 13; 424/78; 514/110, 124, 89, 118 10 Claims, No Drawings 4,636,387 1 2 It is a further object of this invention to provide a ANESTHETIC POLYORGANOPHOSPHAZENES long-acting anesthetic using a small molecule having known anesthetic activity and known toxic side effects This is a divisional of copending application Ser. No. but to provide it in a novel slow-release form. 390,345, ?led on June 21, 1982, now US. Pat. No. These and other objects of the invention, as will here 4,495,174, issued Jan. 22, 1985. inafter become morereadily apparent, have been ac complished by providing a long-acting local anesthetic BACKGROUND OF THE INVENTION comprising a polymeric phosphazene backbone and an 1. Field of the Invention organic radical having local anesthetic activity and an The present invention relates to a long-acting local amino or hydroxyl functional group on an aryl ring anesthetic and more particularly to an anesthetic through which said radical is covalently attached to formed by covalently linking a small molecule having said phosphazene backbone by a phosphorous-nitrogen local anesthetic activity to polyphosphazene. or phosphorous-oxygen single bond. 2. Description of the Prior Art Many useful anesthetics and analgesics, such as co DESCRIPTION OF THE PREFERRED deine and procaine, have been developed for the treat EMBODIMENTS ment of persistent localized pain. However, such medi The present invention arose with the discovery that, caments are not without their own problems. Systemic when proper controls are used, known local anesthetic anesthetics affect the entire nervous system and are not agents having typical short lifetimes can be converted, useful for control of localized pain. Mild analgesics, 20 by covalentingly attaching them to the covalent back such as aspirin, may be ineffective against severe pain < bone of a polyphosphazene, into molecules which while stronger analgesics, such as codeine and the re slowly release the small molecules as anesthetics as the lated narcotics, produce many undesirable side effects. polymeric backbone hydrolyzes. One useful class of anesthetics for the treatment of Local anesthetics are drugs that produce loss of sen localized pain is the local anesthetics. These are drugs 25 sation and motor activity in a restricted area of the body that produce loss of sensation and motor activity in a by reversibly blocking conduction in nerve ?bers. The restricted area of the body by reversibly blocking con ?rst local anesthetic to be introduced into clinical prac duction in nerve ?bers. However, such drugs often tice was cocaine in 1884. However, cocaine was soon have undesirable side effects caused by their high con determined to have undesirable side effects and syn centration in the blood either at the point of injection or 30 thetic analogs were introduced. In order for an anes systemically. Such high concentration are needed ini thetic to be useful as a local anesthetic, it should possess tially since the known local anesthetics are short-lived the following properties: effectiveness whether used and are metabolized in plasma or the liver. Even if only topically or parenterally; inertness to the tissue to which a low dose is needed to‘ produce the desired degree of it is applied except for nerve tissue; rapid onset of anes anesthetic, a higher dose must be administered in order 35 thesia; low systemic toxicity; stability to heat and stor to produce an anesthetic effect of suitable duration, age; and solubility in suitable pharmaceutical carries. since multiple injections traumatize the patient and are No known local anesthetic is ideal. However, many undesirable. Accordingly, there exists a need for a local local anesthetics are known and can be used with the anesthetic in a long-acting, slow-release form. present invention. Some of these, identi?ed by their Various publications have disclosed long-acting med generic names, are the following: 2-amino-4-picoline, icaments of various types. For example, US. Pat. Nos. benoxinate, benzocaine, bupivacaine, butethamine, bu 3,887,699 to Yolles, 3,983,209 to Schmitt, and 4,130,639 tyl-4-amino-benzoate, chloroprocaine, cocaine, cyclo to Shalaby et al have disclosed incorporation of a drug methycaine, dibucaine, dimethisoquin, diperodon, dy into a biodegradable polyester composition. Water-sol clonine, hexylcaine, lidocaine, mepivacaine, mepryl uble or biodegradable polyorganophosphazenes have 45 caine, metabutethamine, naepaine, phenacaine, pipero recently come into use in this area. The use of water-sol caine, pramoxine, prilocaine, procaine, proparacaine, uble polyorganophosphazenes as carriers for coordina propoxycaine, pyrrocaine and tetracaine. Preferred tively bonded platinum-containing anti-cancer drugs is local anesthetics are compounds already having an un disclosed in Allen et al, J. Am. Chem. Soc, 99, 3987 substituted amino group directly attached to an aryl (1977) and Allcock et al, ibid, 3984 (1977). Likewise, ring because of the ease with which these compounds US Pat. No. 4,239,755 to Allcock et al discloses a can be attached to the polyphosphazene backbone. Ex medicament comprising steroidal cyclotriphospha amples of such compounds include procaine, benzo zenes. caine, chloroprocaine, p-aminobenzoic acid butyl ester, The chemistry of polyphosphazene polymers, al and 2-amino-4-picoline. though not established to the extent known for organic Previous approaches for prolonging the activity of polymers, is becoming better known. A recent review procaine-like compounds were based on changes in the in this area indicative of the known chemistry of these molecular skeleton of the molecules, such as increasing macromolecules is Allcock, “High Polymeric Organo the size of the amino alkyl group, lengthening the alka phosphazenes,” Contemporary Topics in Polymer Science, lene chain, or introducing alkyl groups into the 4-amino 3, 55 (1979) which is herein incorporated by reference. 60 unit. In the present invention, the object is to modify the However, none of these references disclose or sug duration of the biological activity by linking the active gest the preparation of a long-acting local anesthetic, molecule to a polyphosphazene skeleton. As will be and the need for such substances still exists. discussed shortly, there are many known methods of attaching small molecules to the backbone of a poly SUMMARY OF THE INVENTION 65 phosphazene polymer. Compounds containing an Accordingly, it is an object of this invention to pro amino aryl or hydroxy aryl functional group are pre duce a local anesthetic in a long-acting, slow-release ferred because of the ease with which these molecules form. can be attached to the polyphosphazene backbone. 4,636,387 3 4 Since most known local anesthetics have one of these -continued functional groups, or they can be modi?ed synthetically to contain such a group by known reactions of organic chemistry, such compound are useful in the practice of this invention. Preferred are compounds already known 5 to have local anesthetic activity and already having an amino functional group attached to an aryl ring, partic ularly a phenyl ring. Of these, those compounds in which at least one, and preferably both, of the positions ortho to the amino group are unsubstituted (i.e., contain hydrogen at those positions) are particularly preferred T“ since such molecules are more easily attached to the phosphazene backbone. Examples of some of the pre NR1 ferred local anesthetics are 2‘amino-4-picoline, benoxi nate, benzocaine, butethamine, butyl 4-aminobenzoate, 5 chloroprocaine, metabutethamine, naepaine, phena eaine, procaine, proparacaine, propoxycaine, and tetra caine. R If a local anesthetic does not contain an aryl amino n group, it may still be used in accordance with this in vention if modi?ed to contain a hydroxy aryl or amino In these macromolecules the group R is an organic aryl group. For example, dyclonine, which is 1-(4 residue and n may be from 3 to 30,000. butoxyphenyl)-3-(l-piperidinyl)-l-propanane, contains The most striking difference between conventional a “hidden” hydroxy group which can be released by polymers and poly(organophosphazenes) is in their cleavage of the butyl ether with HI to free the hydroxy 25 method of synthesis. The normal techniques for the phenyl group. Other anesthetics, such as piperocaine, synthesis of macromolecules—i.e., the polymerization which is Z-methyl-l-piperidinepropanol benzoate, of unsaturated monomers or the condensation reactions which are derivatives of benzoic acid, may be con of difunctional monomeric reagents-are not applicable " verted into compounds capable of being attached to the to polyphosphazene synthesis. Monomers of structure, ' phosphazene backbone by synthesizing them from p 30 NEP(OR)2, NEP(NHR)2, NEP(NR2)2, or NEPR2, aminobenzoic acid rather than benzoic acid. Other syn have not yet been isolated. thetic routes to deserved compounds are equally useful The key to the synthesis of poly(organophospha and are well within the skill of an organic chemist. zenes) is the use of a preformed, linear, high polymeric Examples of suitable synthetic techniques are found in, halogenophosphazene as a highly reactive intermediate for example, Weyhgand et a1, Preparative Organic for substitution reactions. A few organic polymers are Chemistry, John Wiley & Sons, New York, 1972, which prepared by the modi?cation of preformed macromole is herein incorporated by reference. cules (for instance, the formation of poly(vinyl alcohol) The key to synthesizing the compounds of the present from poly(vinyl acetate), or the chloromethylation of invention lies in the chemistry of the polyphosphazene polystyrene), but this method of synthesis cannot be polymer backbone, which will be brie?y reviewed prior applied generally because of the low reactivity of most . to discussing the speci?c embodiments of the invention. organic polymers and the well-known problems that Polyphosphazene polymers possess a highly unusual result from chain-coiling in solution or from the deacti backbone structure composed of an inorganic chain of vation induced by charge generation on nearby repeat alternating phosphorus and nitrogen atoms. Some typi ing units. This modi?cation method, however, forms cal polyorganophosphazene structures are shown in 45 the main synthetic route to the polyorganophospha zenes. The overall synthesis routes for poly(organophospha zenes) are shown in Scheme 1.
Scheme 1. General synthesis routes to poly(organophosphazenes)
V \i/ 250“ 4,636,387
~continued Scheme 1. General synthesis routes to poly(org_anophosphazenes) [ CI Cl l.
RONa —NaCl RNI-Ig —HCl
R0 OR Rl-IN NI-IR ll \ / l l“ VII VIII IX n = 15,000
25 The formation of hexachlorocyclotriphosphazene (V) from phosphorus pentachloride and ammonium choride or ammonia has been known since the work of Liebig and Wohler in 1834. Similarly, the thermal polymeriza tion of V to a rubbery, crosslinked form of polydi chlorophosphazene (VI) was reported by Stokes as early as 1897. However, for over 70 years this polymer was viewed merely as a laboratory curiosity because it is hydrolytically unstable in the atmosphere and is insol uble in all solvents. However, it has since been shown that the polymerization of V to V1 is a two-step reac tion. During the initial stages of the polymerization (up to ~70-75% conversion of _V to VI) an uncrosslinked form of VI is formed. This polymer is soluble in a num Because the chain cleavage reaction is presumably fa vored by a high electron-density in the lone-pair-elec ber of organic solvents, such as benzene, toluene, or 40 tetrahydrofuran. Beyond this stage, the polymer cross tron orbital at skeletal nitrogen, the inventors have used links rapidly. The mechanism of this crosslinking pro the more electronegative ?uorine atoms in poly(di cess is still not fully understood, although traces of fluorophosphazene) to favor halogen substitution at the water will accelerate the process, possibly by yielding expense of chain cleavage. Poly(difluorophosphazene) P-O-P bridging links. (XV) can be prepared by the high pressure, high tem The formation of the uncrosslinked polydichloro perature polymerization of hexa?uorocyclotriphospha phosphazene has been reported in various references zene (XIV). Once again this is a two-step process. In the and is not considered to be part of the present invention. ?rst step the reaction mixture contains only a decreas This synthesis and the synthesis of various polymers ing amount of XIV and an increasing proportion of therefrom, such as I-IV, have been reported in, for 50 uncrosslinked XV. In the second stage, XV crosslinks, example, Allcock and Kugel, J. Am. Chem. Soc, 87, often when the conversion of XIV to polymer has 4216 (1965); Allcock et a1, Inorg. Chem, 5, 1709 (1966); arisen above ~70%. The reactions of XV with organo and Allcock and Kugel, Inorg. Chem, 5, 1716 (1966), metallic reagents yield alkylated or arylated high mo all of which are herein incorporated by reference. lecular weight polymers, although 100% alkylation or In solution, the uncrosslinked form of VI is a highly arylation has not yet been achieved without appreciable reactive species. It reacts rapidly with alkoxides, amines, and some organometallic reagents to yield poly mers, such as I-IV.' Investigators in the laboratories of the present inven tors have recently developed a modi?cation to this 60 general synthesis route, speci?cally for the purpose of preparing polymers of structure, II. Polydichlorophos phazene (VI) reacts with organometallic species such as Grignard or organ'olithium reagents by two different reaction pathways~one favorable and one distinctly 65 unfavorable. These two reactions are alkylation or ary lation (XII) on the one hand, and chaincleavage (XIII) In polyphosphazene chemistry an enormous range of on the other. different polymers can be prepared by relatively simple 4,636,387 7 techniques from one or two preformed polymeric start- ' ing materials. This means that the polymerization prob CH3 XIX lem is a relatively trivial aspect of the synthesis. Differ ent polymers are prepared from the same starting mate rials merely by modifying the side groups. LII This unusual synthetic versatility can, in principle, give rise to an almost unprecedented range of new mac romolecules. However, it is important to note that cer NaO tain restrictions exist with respect to the types and com 10 binations of different substituent groups that can be The crosslinking reactions by difunctional reagents attached to the polyphosphazene chain. are facile processes. Aliphatic or aromatic diamines or First, the nucleophilic substitution reactions of poly( the alkoxides generated from diols readily crosslink the dihalophosphazenes) generally fall into the category of chains, either by halogen replacement or, in some cases, SNZ-type replacements. Hence, they are affected by the by the displacement of organic groups already present. nucleophilicity and steric characteristics of the attack Even ammonia or methylamine can function as cross ing nucleophile and and by the leaving-group ability of linkage agents. However, methylamine does not cross the halogen. Second, restrictions exist when a prospec link the chains at low temperatures, and ethylamine and tive nucleophile possesses two or more potential nu higher alkyl or primary amines function exclusively as cleophilic sites. For example, a difunctional reagent (a mono- rather than di-nucleophiles. Perhaps the most serious restriction to the diversifica diamine or diol) could crosslink the chains. Third, as mentioned previously, the possibility exists that the tion of polyphosphazene structures is found in the ten dency of many reagents to induce chain cleavage. The cleavage of phosphorus-nitrogen skeletal bonds might role of organometallic reagents in chain cleavage has become competitive with phosphorus-halogen bond 25 already been mentioned. However, carboxylic acids cleavage. A few examples will illustrate some of the and their alkali metal salts are particularly effective speci?c restrictions that have been identi?ed. chain-cleavage agents. The mechanisms of these cleav The reactions of amines with poly(dihalophospha age reactions are only partly understood. Nevertheless, . zenes) are, in general, more sensitive to mechanistic this reaction pathway precludes the use of many biolog restrictions than are the substitutions by alkoxides or ically active agents as substituent groups unless special aryloxides. For example, diethylamine replaces only care is taken in attaching such radicals to the backbone. one chlorine per phosphorus in VI to yield polymers of The chemical characteristics of poly(organophospha structure, XVI. zenes) can be understood in terms of two factors—the nature of the backbone and the structure of the side 35 group. The chemistry of the backbone is dominated by the presence of the lone-pair electrons on the skeletal nitrogen atoms. The basicity of these nitrogen atoms facilitates protonation, coordination to metals, or hy drogen bonding to water or other protice solvents. For example, the polymer [NP(NHCH3)2],, forms acid-base “salts” with hydrohalides, functions as a polymeric Diphenylamine apparently undergoes no substitution at ligand for transition metals such as platinum, and at the all. These results reflect the sensitivity of the aminolysis same is soluble in water or alcohols. reaction to steric effects and to the nucleophilicity of An equally powerful in?uence on the chemical prop the amine. Moreover, if poly(di?uorophosphazene) erties is exerted by the side group structure~sometimes (XV) is used as a polymeric intermediate, even primary in opposition to the skeletal in?uence. For example, amines replace only one ?uorine per phosphorus, under although the CH3NH- side group confers water-solubil conditions whre total halogen replacement occurs with ity on the polymer, ?uorinated side groups, such as polydichlorophosphazene. This effect is ascribed partly CF3CH2O— or CF3CF2CH2O—, give rise to hydro to the poor leaving-group ability of ?uorine compared phobicity and water-insolubility. However, these latter to chlorine. Steric effects are particularly side groups provide solubility in ketones or ?uorocar bons. The phenoxy group imparts solubility in hot, aromatic hydrocarbons, but insolubility in nearly all other media. Thus the hydrophobicity or hydrophilicity of a polymer can be varied over a wide range by a choice of suitable side groups. The hydrolytic stability of a polyphosphazene is markedly dependent on the type of side group. Nearly 60 all poly(organophosphazenes) are stable to aqueous media, but the most hydrophobic species are remark noticeable when bulky nucleophiles such as the steroi ably resistant to hydrolytic degradation. The polymers dal anion shown in XIX are employed. Only one of [NP(OCH2CF3)2],, and [NP(OC6H5)2],,, are unaffected these molecules can be introduced every three or four after years of immersion in strong aqueous sodium hy repeating units along the polymer chain, and some diffi 65 droxide solution. However, a limited number of side culty is encountered when attempts are made to replace groups are hydrolytic destabilizing groups. For exam I the remaining halogen atoms by less hindered nucleo ple, polymers that possess ——NH2 or —NHCH2COOR philes. groups hydrolyze slowly with moisture. 4,636,387 9 10 Polymers according to the present invention may be synthesized as cyclic trimers using hexachlorocyclotri phosazene, (NPCl1)3, as the starting material, or as lin ear polymers using polydichlorophophazene, (NPCl2),,, as the starting material. The exact synthetic method will vary with the structure of the polymer being synthe sized but will typically consist of two basic steps: reac tion of the intermediate polyhalophosphazene with the where n is 1 or 2, or molecule having anesthetic activity either preceeding or followed by replacement of the remaining halogens Em with the inactive side groups. Polymers may be synthesized containing only active side groups if desired, but it is preferred to synthesize mixed polymers for ease of control of the physical prop L. erties of the polymers. Inactive side groups can be used The substituents or divalent 'oraganic functional to impart water solubility, water insolubility, or biode groups listed for the C1-C1; alkyl groups may indepen gradability as was previously discussed. When mixed 20 dently appear more than once or more than one such polymers are synthesized, it is preferred to form the substituent or group may be present. inactive side groups ?rst since these generally contain Preferred inactive side groups have —NI-I— or fewer functional groups that may interfer with later —O—- for Q and only halogen atoms or one of two reactions. This is essential if alkyl or aryl groups are divalent functional groups present in the remainder of attached directly to the phosphorous of the backbone the alkyl or aryl side group. Most preferred inactive side groups are —N(CH3)2, because of the reactive organometallic reagents used to carry out this reaction. In general there are few limita tions on the types of functional groups present in possi ble inactive side groups; the only prohibited functional 30 groups are those in which a hydrogen is attached to a where R2 is the side chain of a naturally occuring amino nitrogen, oxygen, or sulfur. Such functional groups can acid, cause crosslinks to form with other polymer chains or cause undesirable chain cleavage. Examples of undesir able functional groups are hydroxyl, carboxylic acid, primary and secondary amino thiol, and sulfonic acid groups. However, —NH; attached to the phosphorous of the backbone is acceptable. Preferred precursors of inactive side groups have the formula HQJ where Q 40 —OCH2CF3 and other fluorinated C2-C4 alkoxy represents —NR- (R is hydrogen or methyl), —O—, groups, or a covalent bond and J represents
45 —(CHm-N ; u D N
and --NH2. Replacement of chlorine atoms in the backbone of the L, where L represents H, a C1-C1; alkyl group, or a 50 polyhalophosphazene is carried out in an aprotic or C2-C1; alkyl group substituted by a halogen atoms or ganic solvent, preferably an aromatic hydrocarbon such -—CN or interrupted by a divalent organic functional as toluene, by reacting the side group percurser HQJ; its group of the formula —O—, —COO—, —CONR1, salt GQJ, where G is an alkali metal ion; or the organo metallic reagent UJ (where Q is a covert bond), where --R1C__—.CR1—, —C=C—, 55 U is a metal ion with the polyhalophosphazene. The ratio of inactive to active side groups is easily con Em trolled by controlling the mole ratio of percursor HQJ to replaceable chlorine atoms. Suitable ratios include from 100:1 to 1:10. Preferred are ratios of 10:1 to 1:2 60 with about 3:1 being most preferred. A trialkylamine may be used as a catalyst when the , reaction is carried out with HQJ. Triethylamine is pre or —-C0—, where each R1 independently represents ferred. This reaction is preferred when Q is NH. When hydrogen or a C1-C4 alkyl group, In is an integer from Q is O, a reaction with GQJ is preferred. 65 The polyorganohalophazene intermediate is gener 0 to 4, and each E independently represents a halogen ally not isolated but is reacted with the small molecule atom, —NOZ, —CN, or R1; or M, where M represents having local anesthetic activity that is to be attached to an aryl radical of the formula the polymer backbone. Since this molecule will have 4,636,387 1111 12 either the functional group H2N—Ar or HO—AR, mixed with auxiliary agents, e.g., lubricants, preserva where Ar is the aryl ring, the reaction is carried out as tives, stabilizers, wetting agents, emulsi?ers, salts for described above for HQJ and GQJ. influencing osmotic pressure, buffers, coloring and/or As has been previously discussed, it is preferred that aromatic substances and the like which do not deleteri the small molecule having local anesthetic activity be ously react with the active compounds. one of the known local anesthetics. However, useful For parenteral application, particularly suitable are long acting local anesthetics can also be prepared from solutions, preferably oil or aqueous solutions, as well as related compounds of slightly different structure having suspension, emulsions, or implants, including supposito an aryl ring and one or more side groups (functional ries. Ampoules are convenient unit dosages. Solutions, group) selected (respectively) from aryl rings and side 0 suspensions, and emulsions are also suitable for topical groups attached to an aryl ring of 2-amino-4-picoline, application. Injections, particularly intramuscular injec benoxinate, benzocaine, bupivacaine, butethamine, bu tions, are preferred for parenteral application. tyl-4-amino-benzoate, chloroprocaine, cocaine, cyclo Generally, the compounds of this invention are dis methycaine, dibucaine, dimethisoquin, diperodon, dy pensed in unit dosage form comprising l0~500 mg of a clonine, hexylcaine, lidocaine, mepivacaine, mepryl pharmaceutical carrier per unit dosage and the amount caine, metabutethamine, naepaine, phenacaine, pipero of active agent of the invention per unit dosage is about caine, pramoxine, prilocaine, procaine, proparacaine, 1 to 50 mg. Dosage rated for known local anesthetics propoxycaine, and tetracaine or any side chain or aryl may be followed, for example, as disclosed in the 35th group in a molecule known to have local anesthetic Edition of the Physician’s Desk Reference (1981), activity, for example as listed in The Merk Index, 9th which is herein incorporated by reference. Edition, Merk & Co., Rahway, N.J., 1981, which is It will be appreciated that the actual preferred herein incorporated by reference. amounts of active compounds being utilized, the partic The resulting polymer may have local anesthetic ular compositions formulated, the mode of application, activity in the polymeric form because of interactions of and the particular situs and organism being treated. the active side groups with nerve tissue. It is also possi 25 Optimal application rates for a given set of conditions ble to design a polymer which will hydrolyze when can be ascertained by those skilled in the art using con contacted with water so that the small active molecules ventional dosage determination tests in view of the ,_ are released by chosing inactive side groups that impart above guidelines. ; hydrolytic instability to the polymer, as has been previ Methods of administering any of the long-acting, " ously discussed. Likewise, the polymers may be de 30 local anesthetics disclosed in this application to a human signed to be either soluble or insoluble in water by or animal, particularly a domesticated animal, by any of correctly chosing the inactive side groups. the means and methods disclosed above in order to Insoluble polymers could be surgically implanted, for produce anesthesia are also considered to be part of the example in oral surgery. Soluble polymers would be present invention. injectable and would diffuse more slowly than the cur Having now generally described this invention, the rently available small molecules, thereby prolonging same will be better understood by reference to certain ' the anesthetic activity by preventing metabolism of the speci?c examples, which are included herein for pur small molecules in the liver. Biodegradable polymers poses of illustration only and are not intended to be ' can also be produced and could be used in sutures and limiting of the invention or any embodiment thereof, the like. Biodegradable (i.e., hydrolizable) phospha~ unless so speci?ed. zenes are discussed in detail in Allcock et al, Inorg. ' Chem, 21, 515 (1982), which is herein incorporated by EXAMPLE 1 reference. The following procedures were used for the reaction Polymers of this invention have been demonstrated to of (NPCl2)3 with procaine, benzocaine, chloroprocaine, release an active local anesthetic by hydrolysis in an 45 p-aminobenzoic acid butyl ester, and 2-amino-4-pico aqueous medium. Once hydrolysis begins, the polymer line. A schematic diagram of these reactions, along with backbone also hydrolyzes to urea and phosphate. The reactions for Examples 2 and 3, is shown in Scheme 2, remaining hydrolysis products depend on the nature of which appears after Example 3. Hexachlorocyclotri the remaining side groups, and may be an amine, amino phosphazene (2) (mp. ll0°~112° C.) was obtained from acid, steroid, alcohol, or other molecule as previously a trimer-tetramer mixture (Ethyl Corp.) after two vac described as suitable side groups. It is possible to release uum sublimitations at 60° C./O.5 Torr, two recrystalliza a second active component in this manner so that two tions from heptane, and two additional vacuum sublima bene?cial effects simultaneously take place, for example tions. by providing a medicament for a joint injury which Hexachlorocyclotriphosphazene (2 g., 5.83 X10-3 releases both a steroid and a local anesthetic. 55 mol) was dissolved in dry toluene (100 mL). To this was The compounds of this invention can be employed in added dropwide a solution of the free amine (4 equiv. mixture with conventional excipients, i.e. pharmaceuti for each chlorine atom) in dry THF (100 mL), and cally acceptable organic or inorganic carrier substances excess freshly distilled triethylamine. The solution was suitable for topical or parenteral application which do heated slowly to re?ux, and heating was continued for not deleteriously react with the active compounds. 96 h. A white precipitate of triethylamine hydrochlo Suitable pharmaceutically acceptable carriers include ride formed slowly. The progress of each reaction was but are not limited to water, salt solutions, alcohols, monitored by 3‘P NMR spectroscopy, with completion vegetable oils, polyethylene glycols, gelatine, lactose, of the substitution being indicated by the appearance of amylose, magnesium stearate, talc, silicic acid, viscous a singlet in the 04 ppm region. The reaction mixture para?n, perfume oil, fatty acid monoglycerides and 65 was then cooled, ?ltered, and solvent was removed diglycerides, pentaerythritol fatty acid esters, hydroxy from the ?ltrate at reduced pressure to leave a yellow methylcellulose, polyvinyl pyrrolidone, etc. The phar oil. Methylene chloride was added and the solution was maceutical preparations can be sterilized and if desired then extracted twice with water, and was dried with 4,636,387 13 14 anhydrous magnesium sulfate. The organic layer was cal shifts were similar when the side group residues then added slowly to n-hexane to bring abuot precipita were derived from 4-8, presumably because of the sepa tion of an adhesive yellow solid. Tritration with hot ration between the variable units and the skeletal phos n-hexane (to remove residual free base) followed by phorus atoms. However, these 31P chemical shifts column chromatography of the residue through silica (2.9-3.8 ppm) were quite different from those for gel (or neutral alumina) (cHz/clz/ethylacetate eluent) (NPCl2)3 (+ 19 ppm). The 1H NMR spectra were com yielded the hexaaminocyclotriphosphazenes as off plicated, but the integrated ratios of aliphatic to aro white needles (30-70% yields). matic protons were consistent with residues derived The synthesis of the chloroprocaine derivative dif from 4-8. fered from the procedure described above because the O Infrared spectra showed evidence for the survival of amine was received as its hydrochloride salt. This was the phosphazene ring in 1,0, with characteristic maxima treated ?rst with an excess of triethylamine in boiling in the 1150-1200 cm”1 region. Aromatic C-H bonds THF, and the solution was then ?ltered through a glass were detected from peaks in the 3000-3100 cm—1 re coarse fritted funnel into the solution fo the cyclotri gion, the amino N-H groups were evident from peaks at phosphazene. The reaction of 2-amino-4-picoline with 3500-3200 cm—1, while P-N or C-N stretching modes (NPCl2)3 required only 48 h at the solvent re?ux tem were detected in the 925-960 cm"1 region. perature. In all of these reactions, the co-solvent ratios were not critical, but a 1:1 ratio of toluene to THF gave EXAMPLE 2 the best results. Melting points and other characteriza The following procedures were used for the reaction tion data are listed in Table I. 20 of high polymeric (NPCl2),, with procaine, benzocaine, Proton decoupled 31P NMR spectra were obtained in chloroprocaine, p-aminobenzoic acid butyl esters, and dioxane at 40 Me with the use of a JEOL-PS 100 FT 2-amino-4-picoline. Polydichlorophosphazene (11) was spectrometer equipped with a Nicolet 1080 data-pro prepared by the thermal polymerization of (NPC12)3 at cessing system and were interpreted as A3 spin systems. 250° C. for an 8-24 h period in a sealed Pyrex tube Ultraviolet spectra were obtained with the use of a (20x25 cm). Typically, less than 25% conversion to Hewlett Packard 8450 A spectrometer. Infrared spectra the high polymer was attempted, and the unreacted of samples as KBr discs or thin ?lms on NaCl plates trimer was then recovered by sublimation at 60° C./0.5 were obtained using a Perkin Elmer 580 spectrometer. Torr during 12-24 h. The polymer was soluble in org Approximate polymer molecular weight estimations fanic media such as toluene or tetrahydrofuran. were made with the use a Waters-Associates ALC-20l Polydichlorophosphazene (15 g, 0.13 mol) was dis gel permeation chromatography instrument ?tted with solved in toluene (900 mL) to yield a clear, viscous a 122 cm X1 cm 105 Styragel column for use with THF solution. Excess triethylamine was distilled directly into solvent at a flow rate of 2.4 ml/min. Approximate cali this reaction mixture. A solution of the free base amine bration of the columns was accomplished by means of (3 equiv. per chlorine atom) in dry THF (400 mL) was narrow molecular weight distribution polystyrene stan added dropwise to the cooled polymer solution. The dards obtained from Waters Associates. Glass transition solution was then heated slowly to re?ux, and heating temperatures were measured with the use of a Perkins was continued for 168 h, with moisture being rigorously Elmer OSC 2O instrument. These instruments were used excluded throughout this time period. Evidence that the in all experimental work unless otherwise noted. reaction was complete was obtained from the appear TABLE I Characterization Data for Cyclotriphosphazenes Infrared Microanalysis UV C=Oband m.p. 31? NMR“ Yield Compounds 10 c H N Am,“ cm"1 ‘c. PPM % where RNl-Iz = 4 Cale. 60.58 5.37 15.59 294 1705 149-151 2.87 33 ~ Found 60.78 5.70 15.70 5 Calc. 57.90 5.36 11.26 240 1675 198-200 2.94 35 ~ Found 57.48 5.35 11.39 ‘ 6 Calc. 53.42 6.16 11.98 310 1708 144-146 3.78 72 ~ Found 53.39 6.33 10.37 7 Cale. 61.53 6.52 9.79 250 1705 204 3.12 68 ~ Found 61.56 7.53 10.14 8 Calc. 55.59 5.40 27.02 255 — 138 3.45 42 ~ Found 54.57 5.50 27.51 “Chemical shift positions were relative to aqueous 85% H3PO4, where positive chemical shifts represent deshielding. A D20 capillary lock was used.
All chlorine atoms were replaced in the ultimate products. However, forcing reaction conditions were needed before complete replacement of the chlorine atoms could be accomplished. The products were crys ance of a singlet at 0-7 ppm in the 31p NMR spectrum. talline materials that were soluble in tetrahydrofuran, 60 The reaction mixture was then cooled to 25° C., ?ltered methylene chloride, or toluene, but insoluble in water. to remove hydrochloride salts and, on some occasions, No residual P-Cl bonds were detected by 31P NMR the polymer. The clear, yellow ?ltrate was concen analysis. trated in a rotary evaporator. The polymer was isolated The substituted trimers were characterized by a com by precipiation of the concentrate into n-hexane or by bination of 31P NMR, 1H NMR, infrared and ultraviolet 65 washing the ?lter cake with water. Two reprecipita spectroscopy, and elemental analysis (see Table I and tions from dioxane into pentane, followed by through the Experimental section). The 31P NMR spectra were Soxhlet extraction with n-pentane, yielded the polymers singlets, indicative of hexa-substitution. The 31P chemi as pale yellow, ?lm-forming materials. For elemental 4,636,387 15 16 analysis, the polymer was reprecipitated one more time tween 1320 and 1100 cm—1 plus carbonyl bands in the from dioxane into pentane. 1675-1708 cm—1 region. Again, the procedures used for the reaction with The GPC average molecular weights were in the chloroprocaine were slightly different. The hydrochlo range of 4>
Preliminary experiments indicate the the procaino- 40 substituted high polymers undergo a slow hydrolysis in compared to the value of 91° C. for [NP-(NHC6I-I5)2],,. buffered aqueous media at pH 7. No evidence was Hydrogen bonding undoubtedly plays a part in reduc found for crosslinking during the high polymer reac ing the torsional mobility of polyphosphazenes of this tions, at least under the dilute reaction conditions em type, compared to, say, [NP(OC6H5)2],, (Tg: ~8° C.). ployed. Thus, it seems clear that arylamines of this type 45 are not subject to the crosslinking side reactions that EXAMPLE 3 can occur with the lower primary alkyl amines. Pre- Mixed substituent polymers containing me~ sumably this re?ects a greater steric shielding by the thylamino/procaino and methylamino/2-amino-4 aryl reagents. All the polymers were soluble in organic picolino side groups were synthesized to produce poly solvents. Only the mixed substitutent polymer (14) was 50 mers having high solubility in aqueous media. Polydi appreciably soluble in neutral aqueous media. Evidence chlorophosphazene (29 g, 0.25 mol) was dissolved in for polyelectrolyte behavior was found when the poly dry toluene (1500 mL) under strictly anhydrous condi mers were dissolved in aqueous acid. As shown in Table tions, in a 3L, 3-necked flask equipped with an overhead II, the elemental microanalyses corresponded to struc stirrer, dry ice condenser, and nitrogen inlet. Triethyl tures 12-14. (The ratios of the different substituent 55 amine (70 mL) was distilled directly into this solution, groups in 14, deduced by microanalysis, are shown in followed by methylamine (16.6 ml, 0.375 mol), previ Table II). ously condensed at —78° C. over sodium spheres. Dur 31P NMR spectra of the homopolymers, 12, showed a ing these additions the temperature of the reaction mix sharp singlet only, with chemical shifts at 2.5 (procaino ture was maintained at 0° C. The mixture was stirred for derivative), 6.8 (benzocaino), 0.7 (picolino), 2.7 (p- 60 2 h. during which time a copious precipitate of triethyl aminobenzoic acid butyl ester), and 2.5 ppm (chloro- amine hydrochloride was formed. procaino). The spectra of the mixed substituent poly The solution was then divided equally into two 3 mers, 14, were remarkably simple. They showed three necked, 3L ?asks, each equipped with condenser, nitro equivalent 31P NMR peaks that were compatible with gen inlet, and mechanical stirrer. To one ?ask was the presence of equal concentrations of P(NHCH3)2, 65 added procaine (free base) (82.3 g, 0.35 mol) in THE P(NHCH3) (NHR), and P(NHR)2 units. (500 mL). The temperature of the reaction mixture was The infrared spectra for all the polymers showed maintained at 2° C. or lower during the addition. The characteristic -—P:N— “stretching” absorptions be mixture was then stirred at 0° C. for 24 h, was allowed 4,636,387 17 18 to warm to 25° C., and was stirred at this temperature analysis. The trace amounts of residual chlorine (<1%) for 180 h. 31P NMR spectroscopy at this point showed that were detected by elemental microanalysis were three distinct sets of resonances, none of which could be attributed to small amounts of hydrogen chloride bound ascribed to P-Cl units. The reaction mixture was ?ltered as a salt to the skeletal or side group nitrogen atoms. No and the ?ltrate concentrated under reduced pressure to evidence was found that the cosubstitution reaction was a volume of 300 mL. The concentrate was added to accompanied by displacement of methylamino groups hexane to precipitate the polymer as an off-white pow already present.
Cl C]
\P/ $1 11 NH / \ ~ N=P -——>c3 2 C] N N Cl E9 | —HCl \I II/ C] P P n / \ / \ 01 N c1 2 L1
RNH; —HCI RNH; —HCl
RHN NHR \ / NHR P l N=P Rl-IN N N NHR \! II/ Nl-IR P P n / \ / \ RI-IN N NHR l2 1_9
Where RNHZ = 13-2 (6 cnzcm HZN COCHQCHQN HZN CH2CH3 5.
C] H CH2CH3 HZN COCHZCHZN HZN CHzCl-Ig, 2 l E der. This was Soxhlet extracted with hexane and was precipitated twice from THF or dioxane into n-pentane. The second half of the initial reaction mixture was The invention now being fully described, it will be treated with 2-amino-4-picoline (35 g, 0.324 mol) in dry apparent to one of ordinary skill in the art that many THF (500 mL). The subsequent steps were similar to 50 changes and modi?cations can be made thereto without those described above. The product was a white pow departing from the spirit or scope of the invention as set der. forth herein. The methylamino side groups were introduced into What is claimed as new and desired to be secured by the mixed substituent system ?rst in order to avoid a Letters Patent of the United States is: possible reaction of the ester function of 41-1 with free 55 1. A long-acting, local anesthetic, consisting of a methylamine. Mild reaction conditions (—50° to +25" polymeric phosphazene backbone, and an organic radi C. in a THF/methylamine co-solvent system at 760 cal having local anesthetic activity and an amino func Torr) allowed roughly 50% of the chlorine atoms in 1,1 tional group on the ring of said radical through which to be replaced by methylamino groups to yield 1;. Es said radical is covalently attached to said phosphazene sentially all of the remaining chlorine atoms in 13 could 60 backgone by a phosphorous-nitrogen signal bond, said then be replaced by treatment with procaine (1) or organic radical being selected from the group consisting 2-amino-4-picoline with the use of the more vigorous of 2-amino-3-picoline, benoxinate, naepaine and phena reaction conditions (40° C.) established earlier for the caine. homopolymers. However, these conditions must not be 2. The local anesthetic of claim 1, wherein said poly so forcing that the methylamino side groups already 65 meric phosphazene backbone is a cyclic trimer. present can generate crosslinks by reaction with P-Cl 3. The local anesthetic of claim 1, wherein said poly groups still present. After completion of the reactions, meric phosphazene backbone is a linear chain contain no residual P-Cl bonds were detected by 31P NMR ing from 3 to 30,000 4,636,387 19 20 6. A long-acting local anesthetic medicament, com prising a local anesthetic effective amount of a com pound of claim 1 in admixture with a pharmaceutically acceptable carrier. 7. The local anesthetic of claim 1 wherein said or ganic radical is a radical of 2-amino-4-picoline. 8. The local anesthetic of claim 1 wherein said or repeating units. ganic radical is a radical of benoxinate. 4. The local anesthetic of claim 3, wherein said back 9. The local anesthetic of claim 1 wherein said or bone contains from 100 to 20,000 repeating units. ganic radical is a radical of naepaine. 10. The local anesthetic of claim 1 wherein said or 5. The local anesthetic of claim 3, wherein said back ganic radical is a radical of phenacaine. bone contains about 15,000 repeating units. * Q I? i It
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65 ,- UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 4, 636,387 Page 1 of 2 DATED January 13, 1987 |NVENTOR(5) 1 Harry R. Allcock et al It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below: . IN THE SPECIFICATION
Column 2, line 20: "covalentingly" should read ——covalently-—
Columns 3, 4 & 7: in structures I to IV, VI, XVI, XV and XVII,
the valences for the nitrogen and phosphorous
atoms should read I
- :N--P: "
Column 9, line 23: "interfer" should read -—interfere-—h'
Column 10, line 5: the subscript "2" should read —-n—
Column 12, line 23: "the" should read -—and the Column 12, line 24: "and the" should read --will depend on
the-— Column 12, line 56: "dropwide" should read ——dropwise-
Column 13, line 2: "abuot" should read -—about——
Column 13, line 14: "f0" should read --of-— UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. : 4,636,387 Page 2 of 2 ‘ DATED ; January 13, 1987 INVENTOR(S) ; Harry R. Allcock et al_ It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:
IN THE CLAIMS Claim 1, column 18, line 60: "backgone" should read --backbone--.
Signed and Sealed this Twenty-ninth Day of December, 1987
\ I Arrest: \
DONALD J. QUIGG
Arresting O?icer Commissioner of Patents and Trademarks