ORALLY ACTIVE HEPARIN MULTIPLETS

Abstract: Novel orally active ion multiplets of formula (I) in which <SIGN> is the skeleton of a polyol, n is the number of OH's in the polyol (3 to 24); p is >= 3 and <= n; r is the available valence of the heparin unit and is >= 3 and <= 7; sr is equal to pv; and R<+> is (a), (b), (c), (d) or (e), in which R<iv> is C1-C3 alkyl; R' and R" are C1-C7 alkyl, the same or different, or combined so that -NR'R" represents the residue of a saturated monocyclic secondary amine; R''' is identical to the corresponding portion of a natural amino acid; the alkylene groups contain 1 to 3 carbon atoms; and R<v> is H, -CONH2 or -COO(C1-C7 alkyl). The multiplets are stable lipoidal "ion-pairs" or complexes which can be absorbed through the gastrointestinal wall and which slowly release heparinic acid to achieve long-lasting anticoagulant activity. Novel quarternary salts which are intermediates to the multiplets of the invention are also disclosed.

Description: ORALLY ACTIVE HEPARIN MULTIPLETS Field of the -Invention: The present invention provides novel orally active ionic multiplets of polyanionic heparinic acid with selected polycationic materials ' . " The multiplets are stable lipoidol "ion-pairs" or salts which can be absorbed through the gastrointestinal wall and which slowly release heparinic acid to achieve long-lasting anticoagulant activity. Background of the Invention: Since the initial reports about heparin [Howell et al, Am. _ . Physiol. 47, 328 (1918)] and bishydroxy- coumarin or dicumarol [Link, Harvey Lect. , 39, 162- 216(1944)], anticoagulants have become the object of extensive biological investigation. Heparin is still considered by many as the drug of choice, despite the fact that it is not well absorbed orally and must be administered by a parenteral route. Tcxic side effects are uncommon, but parenteral administra¬ tion, whether as intermittent injections or continuous infusion, precludes its long term use. Therapy employ¬ ing the clinically used oral anticoagulants, on the other hand, is difficult to control between desired limits because of the considerable variability in their rates of metabolism under differing conditions. In addition to undesirable delay in onset of activity after ad¬ ministration, drug interaction problems and side effects make the oral anticoagulants which are now available poor substitutes for heparin itself. The possibility of administering heparin by routes other than injection while obtaining results comparable to those obtained by injection has aroused the interest of many investigators. See, for example, Windsor et al , Nature, London, , 190., 263(1961); Teow Yan Koh, United States Patents -Nos. 3,482,014, 3,510,561 and 3,548,052; and Teow Yan Koh et al , United States Patents Nos. 3,506,642 and 3,577,534. Notably, orally active heparin salts and complexes have been described in the patent literature, e.g. amines, amides (the aforementioned Teow Yan Koh patents) and acid salts such as Na, K, Li etc. (the aforemen¬ tioned Teow Yan. Koh et al patents). Attempts have also been made to enhance oral absorption using sul- foxides and sulfones. Nevertheless, serious need exists in this art for improved oral del very of heparin. Summary and Objects of the Invention: Accordingly, a major object of the present invention is to provide improved delivery of heparin by the oral route. Another object of this invention is provide a form of heparin which will be readily ab- sorbable from the intestine. Another object of this invention is to provide an orally active form of heparin which will be highly stable and which will have a long duration of anticoagulant activity as compared to heparin sodium. These and other objects are achieved by the use of novel orally active ionic multiplets of polyanionic heparinic acid with selected polycationic materials. These multiplets are stable lipoidol "ion-pairs" or salts which can be absorbed through the gastrointestinal wall and which slowly release heparinic acid to achieve long-lasting anti¬ coagulant activity. These novel ionic multiplets or salts result from combination of multivalent cationic units-with the multivalent anionic heparin entity. Brief Description of the Drawings: FIGURE 1 is a graph plotting the amount of time required for clotting, in minutes, against the time elapsed since oral administration to rats, in hours, for Compound 4_ [heparin inositol hexa-(l-methyl- 3-pyridiniumcarboxylate) multiplet], Compound 5_ [heparin N,N-dimethyl-N-dodecyl-N-(β-hydroxy)ethylammonium multiplet] and heparin sodium; FIGURE 2 is a graph plotting the amount of time required for clotting, in hours, against the time elapsed since jejuna! administration to rats, in hours, for Compound £ [heparin inositol hexa-(l- methyl-3-pyridiniumcarbpxylate) multiplet] and heparin sodium; and FIGURE 3 is a graph plotting the amount of time required for clotting, in minutes, against the time elapsed since jejuna! administration to rabbits, in hours, for Compound 4_ [heparin inositol hexa- (l-methyl-3-pyridiniumcarboxylate) multiplet] and heparin sodium. Detailed Description of the J Invention: "Heparin", or " heparinic acid, as used herein refers to a mucopolysaccharide present in mammalian tissue which has strong anticoagulant activity. The polysaccharide ' is a dextrorotatory, highly sulfated, negatively charged, strongly acidic polymer mixture of disaccharides or the corresponding tetrasaccharides. The precise chemical formula, structure and molecular weight are not yet fully elucidated and appear to vary with biological source. Goodman and Gilman's The Pharmacological Basis of Therapeutics, sixth edition, Macmillian Publishing Co., Inc., New York, New York, Chapter 58, pp. 1348-1351, indicates that heparin has an average molecular weight of 15,000 daltons and that commercial heparin is composed of polymers of two repeating disaccharide units, namely, a D-glucosamine-L-iduronic acid unit and a D-glucosamine- D-glucuronic acid unit. According to Goodman and Gilman, most samples, of heparin sodium contain from 8 to 15 repeats of each unit, although they may hot be in equal proportions.- A structure for heparin sodium as depicted by Goodman and Gilman is shown below. See also Cutting's Handbook of Pharmacology, seventh edition, ed. T.Z. Cseiky, M.D. and Byron A. Barnes, Ph.D., Appleton-Century-Crofts , Norwalk, Connecticut, Chapter 27, pp. 318-319; The Merck Index, tenth edition, Merck & Co., Inc., Rahway, New Jersey, 1983, pages 672-673; and The Condensed Chemical Dictionary, eighth edition, revised by Gessner G. Hawley, Van Nostrand Reinhold Company, New York, page 436. Heoαriπ Sodium Unit The chain lengths and potency of heparin samples vary widely. Consequently, heparin is prescribed on a unit basis. The U.S.P. unit of heparin is the amount required to prevent 1.0 ml of citrated sheep plasma from clotting for one hour after addition of 0.2 ml of a 1:100 calcium chloride solution. Heparin Sodium, U.S.P., must contain at least 120 U.S.P. units/mg. The heparin multiplets or complexes of the present invention can be represented by the structural formula .heparin unit] (I) wherein ( ) is the. skeleton of a polyol , said skeleton being the portion of said polyol which would remain after removal of all hydroxy substituents therefrom; n is a number from 3 to about 24 which represents the total number of hydroxy groups in said polyol; p is a number 3 and > ^ n; ' r is the available valence of the heparin unit and is >_ 3 and <_ 7; s is the number which when multiplied by r is equal to pv; v is the number which when multiplied by p is equal to rs; R + is (α) ( b) (C) * -αlkyleπe-COO- or QV-αlkyleπe-COO- ( ) (e) wherein the -C00-, -CH 2 C00-, -CH 2 0C00- and R ring substituents can each be in the 2-, 3- or 4- position of the pyridinium ring; R 1V is C,-C 3 alkyl; R' and R*', which can be the same or different, are each C.- Cy alkyl, or R' and R' ' are combined with the adjacent .R' nitrogen atom such that -N I represents the residue \ R' ' of a saturated monocyclic secondary amine; R 1 ' 1 is a radical identical to the corresponding portion of a natural amino acid; the alkylene groups can be straight or branched and contain ! to 3 carbon atoms; and R V is H, -C0NH 2 or -COOfC j -C alkyl). The expression "[heparin unit]" as used herein is intended to indicate the basic tetrasaccharide unit which makes up heparin sodium itself except that from 3 to 7 of the sodium ions are removed, leaving a polyanion having an available or effective valence of from 3 to 7 which can then be "ion-paired" to the desired polycations to form the multiplets of formula (I). While a typical heparin sodium tetrasaccharide unit would contain one each of the D-glucosamine- L-iduronic acid disaccharide unit and the D-glucosamine- D-glucuronic acid disaccharide unit, the exact identity of the tetrasaccharide unit will vary with source, as already explained hereinabove, as will the number of repeats of each disaccharide unit (typically 8 to 15 of each, but not necessarily in equal proportion) in a given sample. Thus,, for example, a given heparin sodium tetrasaccharide unit may well be composed of two D-glucosamine-L-iduronic acid disaccharide units or two D-glucosamine-D-glucuronic acid disaccharide units rather than one of each disaccharide, and a particular heparin sample may well contain tetra¬ saccharide units of each of these three types. The expression "[heparin unit]" as used herein is in- tended to encompass any such units, save of course for the absence of some or all of the sodium cations, as explained above; in any given multiplet of this invention, the heparin units will be identical to those in the heparin sodium sample from which the multiplet is derived except for the difference in sodium content. The expression "polyol" as used herein is intended to indicate a monosaccharide, ol igosaccharide, Cr- C j8 alicyclic polyhydroxy compound or aliphatic polyhydroxy compound, i.e. a compound of the formula wherein ( ) and n are defined as before. The hydroxy groups are usually situated on the carbon atoms in the polyol backbone or skeleton, but in some cases are located on pendant methyl radicals, particularly in the case of the onosaccharides and ol igosaccharides. When the polyol is an aliphatic polyol, it is preferably a Cg-Cg alkyl polyol such as glycerol, erythritol (tetrahydroxybutane) or 1,2,6-trihydroxy- hexane- When the polyol is an alicyclic polyol, it is preferably a C 5 -C 1Q cycloalkyl or fused fully hydro- genated aromatic polyol (e.g. a cyclohexane or decahydronaphthalene polyol). A particularly preferred cycloalkyl polyol is inositol, a non-toxic substance which is widely distributed in plants and microorganisms. Inositol, which has the empirical formula a nutηDer °f possible stereo- isomers. Shown below is the structure for cis-1,2,3,5* trans-4,6-cyclohexanehexol , the prevalent natural form: •9- When the polyol is a monosaccharide, it is pre¬ ferably a pentose, hexose or heptose. Suitable such simple sugars include aldopentoses such as ribose, arabinose, xylose and lyxose; ketopentqses such as ribulose and xylulose; aldohexoses such as glucose, galactose and mannose; ketohexoses such as fructose, sorbose and tagatose; and ketoheptoses such as manno- heptulose and sedoheptulose. Structures for some typical monosaccharides contemplated by the present invention are as follows: β -L-αrαolnose β -D-rlbofurαnose β -D-xylose CH 2 0H CH 2 0H CO CO HCOH HCOH CH 2 0H HJQJH HOCH CH 2 0H «-D- lyxose D-rlbulose L-xylulose -D-glucose α-D-gαlαctose β -D-mαnnose β-D-fructose L-sorbose D-tαgαtose When the polyol is an oligosaccharide, i.e. a carbohydrate which yields 2 to 8 monosaccharide units upon acid hydrolysis, it is preferably a di= saccharide, a trisaccharide or a cyclodextrin. Re¬ presentative disaccharides are sucrose, lactose and maltose. A representative trisaccharide is raffinose. The cyclodextrins , or cycloamyloses, are homogeneous cyclic α-(l→-4) linked D-glucopyranose units. o-Cyclo- dextrin contains 6 units, β-cyclodextrin contains 7 and γ-cyclodextrin contains 8. Structures for representative oligosaccharides contemplated by the present invention are as follows: maltose raff inose 11 - ■ •-cyclodextrin The expression "C j -^ alkyl" and "C j -C- alkyl" as used herein indicate straight or branched-chain groups containing the indicated number of carbon atoms, e.g. methyl, ethyl, propyl , isopropyl, as well as the higher homologues when the alkyl radical contains more than 3 carbon atoms, e.g. butyl, pentyl, hexyl and heptyl and the corresponding branched- chain isomers, e.g. isobutyl and tert-butyl. The expression "R' '' is a radical identical to the corresponding portion of a natural amino acid" is believed to be self-explanatory. Thus, for example, -R' ' ' can be hydrogen, as in glycine; methyl, as in alanine; -CH(CH 3 ) 2 , as in valine; -CH 2 -CH(CH 3 ) 2 , as in leucine; - , as in as in trypto- phan ; • CH 2 0H as in serine; -CHOH-CHo, as in threonine 12- -(CH 2 ) 2 -SCH 3 , as in ethionine; -CH 2 -C0NH 2 , as in asparagine; -CH CH -C0NH 2 » as in glutamine; -CH 2 — ' -OW, as in tyrosine; -CH 2 SH, as in cysteine; -CH 2 C00H, as in aspartic acid; and -CH 2 CH 2 C00H, as in glutamic acid. When R' and R' 1 are combined with the adjacent / R ' nitrogen atom such that -N represents the residue of a saturated monocyclic secondary amine, such mono- cycles preferably have 5 to 7 ring atoms, optionally contain another hetero ring atom (-0-, -S- or -N-) in addition to the indicated nitrogen atom, and optionally bear one or more substituents such as methyl. Illustrative of residues of saturated mono- cyclic secondary amines which are encompassed by the -N term are orpholino, 1-pyrrolidinyl , per- V R" hydro-l,2,4-oxathiazin-4-yl , 1- or 4-piperazinyl , 4-methyl-l-piperazinyl , piperidino, hexamethylene- imino, 2-methyl-l-pyrazolidinyl , 1- or 2-pyrazoli- dinyl, 3-methyl-l-imidazol dinyl and 1- or 3- i idazol idinyl . When R in formula (I) is structure (a), R 1V is preferably methyl and the -COO- group is pre¬ ferably located in the 3-position. When R in formula (I) is structure (b), R lv is preferably methyl and the -CH 2 C00- group is preferably located in the 3- 13- position. When R in formula (I) is structure (c), R 1V is preferably methyl and the -CH 2 0C00- group is preferably located in the 3-position. When R in formula (I) is structure (d), preferably R* and R'' are both methyl or both ethyl, or R'R' 'Nr re¬ presents morpholino, piperidino, lrpyrrol idinyl or 1-piperazinyl ; R 1V is preferably methyl; alkylene is preferably -CH-; and R' 1 ' is preferably H, -CH 3 , -CH(CH 3 ) 2 , -CH 2 -CH(CH 3 ) 2 - -(CH 2 ) 2 -SCH 3 , -CH 2 -C0NH 2! -CH 2 CH 2 -C0NH 2 o-r© -CH- ■ O OH. When R in formula (I) is structure (e), alkylene is preferably -CH 2 CH 2 -; arid R v is pre¬ ferably H or -C0NH 2 . Structures (a), (d), and (e) are particularly preferred, especially when one or more of the structural variables therein are as set forth in this paragraph. In formula (I)., it is also preferred that p be equal to n so that n minus p equals zero, in which case the heparin multiplets can be represented by the formula Ihepαrln unltl. (Iα) wherein the structural variables -are as generally defined above. Especially preferred multiplets of formula (la) are those in which one or more of the structural variables are. selected from the preferred variables set forth in the preceding paragraph. It is also preferred that there be at least four R groups in the multiplets of formulas (I) and (la). Moreover, it is preferred " that r in formulas (I) and (la) be 5, 6 or 7. In one preferred embodiment of this invention, in formula (I), f j is the skeleton of inositol, n is 6 and p is 6. In one especially preferred em¬ bodiment of this invention, in formula (I), ( J is the skeleton of inositol, n is 6, p is 6, v is 5, r is 5 and s is 6. The "ion-paired" complex or multiplet formed by this interaction of the heparinic acid anion and the quaternary ammonium cation is expected to be hydro- phobic and absorbable from the intestine. The strong ionic interaction is expected to give high stability to the ion pairs. The complexity and high hydrophobicity of the products are expected to reflect slow dis¬ sociation, whether before, after of during absorption and, hence, slow release of heparinic acid and longer duration of action. The multiplets of formula (I) can be prepared by a variety of conventional synthetic methods. One general method comprises coupling the selected polyol of formula (II) hereinabove with a quaternary acid salt of the formula (a') (b*) (C) t. + -αlkylene-C00H X " »lv ( d' ) <e') wherein the structural variables are as hereinbefore defined in connection with structures (a), (b), (c), (d) and (e), respectively, and X " is the anion of a pharmaceutically acceptable organic or inorganic acid. The coupling, or esterification , is typically carried out in the presence of a suitable coupling agent such as dicyclohexylcarbodiimide, in an ap¬ propriate organic solvent, using excess acid reactant so that as many as possible of the hydroxy groups in the polyol will be esterified. Other esterifi¬ cation procedures will be readily apparent to the skilled organic chemist, e.g. use of a mixed anhydride. The resultant novel intermediates can be represented by the structural formula wherein C J , n, p and R + are as defined in con¬ nection with formula (I); X " is the anion of a pharmaceutically acceptable acid (e.g. an inorganic acid such as hydrochloric acid, sulfuric acid or hydrobromic acid, or an organic acid such as acetic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, malonic acid, methanesulfonic acid or benzoic acid); t is the valence of ' the acid anion and q is the number which when multiplied by t is equal to p. Thus, when X is a monovalent anion, q will be equal to p; when the anion is divalent, q will be equal to -δ*; and when the anion is trivalent, q will be equal to -&. Further, it is preferred that p be equal to n so that n-p = 0, the quaternary intermediate in such case being repre¬ sented by the formula wherein the structural variables are defined as above. Preferred polycationic quaternary intermediates are those which lead to the preferred formula (I) ion pairs already discussed above. Especially preferred formula (III) intermediates are derived from non- toxic naturally-occurring substances, and are them¬ selves non-toxic and will be metabolized to non-toxic moieties. Presently preferred quaternaries can be con¬ sidered to be derived from inositol as the polyol and trigonelline (which occurs in the seeds of many plants and is excreted in the urine after taking nicotinic acid) and betaine (which is widely distributed in plants and animals) as the quatemized acid portion The structures of trigonelline and betaine are as follows: trlgonelllne betαlne The novel quaternary ester intermediates of formula (III) are then conveniently reacted with heparin sodium, in aqueous medium, to afford the desired multiplets of formula (I). Typically, equiva lent amounts of reactants are employed in this step. As many sodium ions as possible will be replaced with quaternary ester groupings in this step, i.e. at least 3, but more typically 5 to 7. While not wishing to be bound by this interpretation, it is believed that when heparin sodium has the structure depicted earlier in this specification, of the seven sodium cations per tetrasaccharide unit, those Na 's associated with the C0 2 groupings are more tightly held than those associated with S0 3 " groupings and are consequently easier to replace with the instant cationic entities; and that generally at least the five S0 3 " anions will become associate with the new cations. Nevertheless, other synthetic routes to the instant multiplets are presently preferred. Thus, the presently preferred process for the preparation of the multiplets of formula (I) wherein R is structure (a), (b), (c) or (d) is to first couple the selected polyol of formula (II) with a tertiary acid of the formula (α" ) (b") ( c" ) (d") or the corresponding acid halide ( e.g. chloride) or anhydride, wherein the structural variables are as previously defined in connection with structures (a), (b), (c) and (d), respectively. When the ester- ifying agent is an acid, the process is typically carried out in the presence of a suitable coupling agent such as dicyclohexylcarbodimide (DCC) in an appropriate organic solvent such as pyridine, ace- tonitrile or dichloromethane, the solvent of choice depending upon the particular reactants employed. When the esterifying agent is an acid anhydride (pre¬ pared, for example, by reacting the corresponding acid with phosgene), an organic solvent such as pyridine can be employed. When the esterifying agent is an acid chloride (prepared, for example, by re¬ acting the corresponding acid with a chlorinating agent such as thionyl chloride or phosphorous oxy- chloride), choice of solvent wil-1 vary not only with the particular reactants used but also with whether or not the acid chloride is isolated prior to the esterification step. For example, when the acid chloride is isolated as the hydrochloride, then that salt can be conveniently reacted with the polyol in chloroform. On the other hand, if the acid is first reacted with POCl., and the- polyol subsequently added to the reaction mixture, both steps can be conveniently conducted in pyridine. Whatever the esterifying agent, it will be used in excess so as to esterify as many of the hydroxy groups in the polyol as possible, e.g. when inositol is used as the polyol, a six-fold or greater excess of mono- carboxylic acid or acid chloride will be used (i.e. 6 or more moles of acid or acid chloride per mole of polyol). When a starting acid of structure (d 11 ) or the corresponding acid chloride or anhydride is used, the R 1 1 ' group therein preferably does not contain free hydroxy, thiol or carboxy functions which could interfere with coupling with the polyol structure. However, such functions can be con¬ veniently protected, if desired, e.g. with ester groupings (for example, C,-C 7 lower alkyl esters) prior to acylation and subsequently deprotected. Also, carboxy functions contained in the R' 1 ' grouping need not be protected if the polyol contains suf¬ ficient hydroxy groups; e.g., if R' ' 1 is -CH 2 CH 2 C00H, then each amino acid could combine with two hydroxy groups and at least six hydroxy groups would need to be present in the polyol in order to give an acylated derivative in which there are sufficient R groups, i.e. at least three. The products of the above-described first step of the presently preferred process for the prepara¬ tion of the formula (I) multiplets in which R + is structure (a), (b), (c) or (d) can be represented by the structural formula wherein n ani<d p are as defined in connection with formula (I) and R is the residue of one of the aforementioned acids (a 11 ) to (d' 1 ), i.e. R is or N-αlkyjene-COO- R" R'" ( d"') wherein the structural variables are as defined in con* nection with structures (a), (b), (c) and (d) here- inabove. Preferably, p is equal to n in formula (IV) so that n-p =0, the acylate in such case being represented by the formula wherein R and n are defined as above. The acylates of formula (IV) are then quater- nized, typically by treatment with a C -^ -C^ alkyl halide, R 1v -Hal, preferably methyl iodide, in an appropriate solvent such as dimethylformamide. Pre¬ ferably, the formula (IV) acylate is heated (e.g. at about 50°C) with excess of the alkylating agent in dimethylformamide for at least forty-eight hours. The resultant quaternized acylate wherein the anion is I " or other halide can then be subjected to anion exchange when an anion is desired which is different from the one obtained; such anion exchange may be accomplished via an anion exchange resin or, more conveniently, by use of the method of Kaminski et al, Tetrahedron, Vol. 34, pp. 2857-2859 (1978). Ac¬ cording to the . Kaminski et al method, a methanolic solution of a pharmaceutically acceptable organic or inorganic acid HX will react with a quaternary ammonium halide to produce the methyl halide and the corresponding quaternary 'X salt. The quater- nization and when desired the subsequent anion exchange afford the novel chemical intermediates of formula (III) hereinabove wherein R is structure (a). (b) » (c) or (d) as defined with formula (I). Again, the preferred compounds of formula (III) are as discussed in connection with the first synthetic -22 - route discussed above. And again, those novel inter¬ mediates can then be reacted with heparin sodium as already described above to afford the corresponding heparin multiplets of formula (I). A presently preferred process for the prepara¬ tion of the multiplets of formula (I) wherein R is structure (e) utilizes a starting material of the formula Z-αlkyleπe-COOH (v) or Z-σlkylene-COr (VI) wherein Z is Cl, Br or I; the alkylene group can be straight or branched and contains 1 to 3 carbon atoms; and Y is Cl or Br. The formula (V) or (VI) starting material is first reacted with a polyol of formula (II) above to afford an intermediate poly- ester of the formula wherein _ , n and p are as defined in connection with formula (I) above (i.e. ( is the skeleton of a polyol, n is a number from 3 to about 24 which represent the total number of hydroxy gfoups in the polyol, and p is a number •> 3 and < n); and alkylene and Z are defined as in connection with formulas (V) and (VI) above. When a formula (V) starting material is used, the reaction is conducted in the presence of suitable coupling agent such as dicyclohexylcarbodiimide. Alternatively, a mixed anhydride or activated ester may be used. When a formula (VI) starting material is used, the reaction is typically conducted in the presence of a an acid scavenger such as triethyl- amine, in a halogenated hydrocarbon solvent, e.g. chloroform. The resultant polyester of formula (VII) is then converted to the desired quaternary ester intermediate of formula (III) wherein R is structure (e) by contacting said polyester with excess reactant of the formula (VIII) <@" wherein R v is located in the 2-, 3- or 4-position and is H, -C0NH 2 or -C00(C j -C 7 alkyl), in a polar solvent such as nitromethane, dimethylformamide, ace- tonitrile, acetone, tetrahydrofuran or ethyl ether, followed by isolation by crystallization. The novel quaternary intermediate thus obtained wherein the anion is Cl " , Br " or I " can then be subjected to anion exchange (via an anion exchange resin or the Kaminski et al method described hereinabove), when an intermediate is desired in which a different anion is present. Any of these novel quaternary inter¬ mediates can then reacted with sodium heparin as already described above to give the corresponding heparin multiplets of formula (I). A highly desirable alternate process for the pre- paration ' of the multiplets of formula (I), particularly for the multiplets wherein R + has structure (a) as defined in connection with formula (I), utilizes an activated ester, quaterπized activated ester or quater- nized anhydride as a starting material. In order to prepare a multiplet of formula (I) wherein R + has structure (a) using an activated ester starting material, an activated sϋccini idyl ester or phthali idyl ester of the formula or similar activated ester (prepared, for example, by reacting the appropriate acid such as nicotinic acid with N-hydroxysuccinimide or N-hydroxyphthal imide, respectively), is first reacted with the selected polyol of formula (II). The resultant intermediate of formula (IV) is then converted to a formula (I) deri¬ vative by methods fully described hereinabove (i.e. quaternization with R lv -Hal, followed by ion exchange (if desired), and then reaction of the novel formula (III) salt thus obtained with sodium heparin). In order to prepare a multiplet of formula Cl) wherein R has structure (a) using a quaternized activated ester starting material, an activated ester such as the succ nimidyl or phthalim d l ester depicted above is first quaternized with R lv -Hal ; the resultant quaternized activated ester is then subjected to ion exchange (if desired), and subsequently reacted with the selected polyol of formula (II) to give the desired formula (III) intermediate, which is then reacted with sodium heparin to give the formula (I) multiplet. To prepare a multiplet of formula. (I) wherein R has structure (a) using a quaternized anhydride start¬ ing material , a quaternized anhydride of the formula is first prepared by reacting the desired anhydride, e.g. nicotinic anhydride, with a 2 molar excess of R lv - Hal in an appropriate solvent, e.g. acetonitri 1 e, the structural variables in the general formula being defined as hereinabove. The reaction mixture typically is stirred at reflux for 48 hours. The resultant quaternized anhydride is then reacted with the selected polyol of formula (II), in a suitable solvent such as pyridine or pyridine/dimethyl forma ide, to give the desired formula (III) intermediate, which is then reacted with sodium heparin to give the formula (I) multiplet . In all of the various alternate process schemes described above, the final step comprises reacting a novel quaternary intermediate of formula (III) with sodium heparin to give the corresponding heparin multi¬ plets of formula (I). In any of these schemes, that final step can -be replaced with a two step procedure comprising first subjecting the formula (III) quater¬ nary intermediate to ion exchange to replace the X " anions with OH " anions, and then reacting the resultant compound with heparin acid to give " the formula (I) derivative. In the first step, a strongly basic anion exchange resin is employed to exchange the I " or other X " groups for OH " groups; the formula (III) inter¬ mediate is typically dissolved in water and applied to a column of the resin, and the column is washed with water to elute the corresponding compound of the formul a DOH " (R τ) , wherein^ ), n, p and R are as defined with formula (I) and (II) hereinabove. The resultant intermediate is then reacted with heparinic acid, typically in water or water/alcohol, to afford the corresponding compound of formula (I) wherein the heparin unit has a valence r of 7. The final products and intermediates prepared by the synthetic procedures detailed above can be readily isolated and purified by usual separation means, for example, solvent extraction, dilution, recrystall ization, column chromatography or pre¬ parative thin-la.yer chromatography. The multiplets of formula (I) can be conveniently ad¬ ministered to warm-blooded animals via conventional oral, nasal or pulmonary (i.e. oral inhalation) administration, preferably by combining the active ingredient of formula (I) with a suitable non-toxic pharmaceutically acceptable inert oral, nasal or pulmonary carrier material , respectively. Such carrier materials are well-known to those skilled in the art of pharma- ceutical formulations. For those not skilled in the art, reference is made to the text- entitled REMINGTON'S PHARMACEUTICAL SCIENCES, fourteenth edition, 1970. In a typical, unit dosage form for oral administra¬ tion, e.g. tablet or capsule, any one of the multi- plets of formula (I) is combined, in an effective anti¬ coagulant amount, with an oral non-toxic pharmaceu¬ tically acceptable inert carrier such as lactose, starch (pharmaceutical grade), dicalcium phosphate, calcium sulfate, kaolin, annitol or powdered sugar. Additionally, when required or desired, suitable binders, lubricants, wetting agents, surface-active agents, disintegrating agents, coloring agents, flavoring agents and preserva¬ tives can also be included. Typical binders include starch, gelatin, sugars such as sucrose, molasses and lactose, natural and synthetic gums such as acacia, sodium alginate, extract of Irish Moss, carboxymethyl cellulose, methyl cellulose, pol vinyl pyrrol idione , poly- ethylene glycol, ethyl cellulose and waxes. Typical lubricants for use in these dosage forms can include, without limitation, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine and polyethylene glycol. Suitable disintegrators can include, without limitation, starch, methyl cellulose, agar, bentonite, cellulose, wood products, alginic acid, guar gum, citrus pulp, carboxymethyl cellulose and sodium lauryl sulfate. The amount of active ingredient present in the composition will generally be from about 1 to about 70% by weight of the total composition. Typical dosage forms and carriers for nasal and oral inhalation therapy will obviously depend on the exact nature of the particular dosage form desired, e.g. whether the ion pair is to be formulated into a nasal solution or suspension (typically for use as nose drops or nasal spray), a nasal ointment, cream or gel, or a formulation for oral inhalation. Pre¬ ferred dosage forms for nasal administration ace solutions, which contain a major amount of water in addition to the active ingredient. Minor amounts of other ingredients such as pH adjusters (e.g. a base such as NaOH), emulsifiers or dispersing agents, buffering agents, preservatives, wetting agents and jelling agents (e.g. methylcellulose) may also be present. Most preferably, the nasal composition is a sterile, isotonic, buffered aqueous solution or suspension in polyethylene glycol. The amount of multiplet in the nasal composition will of course vary with the particular multiplet employed and the type of for¬ mulation selected. Generally speaking, the com¬ position will contain 0.01 to 5% of a multiplet of formula (I), preferably 0.25 to 2:5%; in. other words, each ml of solution or suspension will contain 0.1 to 50 mg, preferably 2.5 to 25 mg. of the formula (I) multiplet. In the case of oral inhalation therapy, compositions typically formulated for such route of administration may be used, a preferred dosage form being an oral inhalation aerosol containing the desired multiplet of formula (I) and fluόrochlorohydrocarbons as propellants. Most preferably, the aerosol is pro- vided with a metering mechanism to make accurate dosing possible. Each inhalation will typically deliver 0.1 to 50 mg, preferably 2.5 to 25 mg of the multiplet of formula (I). The therapeutic dosage range for the multiplets of the instant invention will vary with the size and needs of the animal and the particular multiplet selected for administration. Generally speaking, the present "ion-pairs" can be orally administered in much smaller amounts by weight (e.g. less than one- half) and less frequently than would be necessary for orally administered sodium heparin itself. Admin¬ istration as infrequently as once every 24 to 48 hours may be possible using selected ion pairs of this in¬ vention. When nasal or inhalation administration is used, dosages and frequency of administration may be similar to oral dosages and frequency of the instant ion pairs, although smaller, more frequent doses may be preferred for nasal or inhalation therapy. In any case, amounts to be administered by the selected route can be calculated on a unit basis, based on the potency of the heparin sodium used to prepare - 30- the instant multiplets, the new unit/mg potency being calculated based on the increase in molecular weight. The number of units given will approximate 2 to 10 times those currently used parenterally in the case of heparin sodium. In order to further illustrate the present in¬ vention and the advantages thereof, specific examples are given below, it being understood that these examples are intended only as illustrative and in no way limitative. In the examples to follow, all melting points are uncorrected and were obtained by using electrothermal capillary melting point apparatus, Elemental analyses were performed at Atlantic Micro- labs, Inc., Atlanta, Georgia. In all cases where Anal, C, H, N is indicated, the elementary analysis of the material was found to be within ±0.4 of the calculated value. EXAMPLE 1 To a suspension of 50 g (0.41 mol) of dry nic- otinic acid in 135 ml of dry distilled pyridine were added 34 g of phosphorus oxychloride (POCK). The reaction mixture was stirred for one hour at 60°C, then 12.3 g (0.068 mol) of myo-inositol were added. The resultant mixture was maintained at 80°C, with stirring, for 3 hours, then was poured into 200 ml of ice cold water. The fine yellowish-white solid which separated was removed from the dark brown mother liquor by filtration, washed well with water and dried in a vacuum oven at 150°C. The solid was crystal- lized from a chloroform/ether solvent pair to afford 45 g (82% yield) of inositol hexanicotinate (J.). The product melts at 258-260°C and can be represented by the structural formula EXAMPLE 2 To a solution of 20 g (2.5 mmol) of inositol hexanicotinate Q) in 200 ml of dimethylformamide were added 11.2 g (0.08 mol) of methyl iodide. The mixture was heated at 50°C, under reflux, with stir- r ing, for 48 hours. The fine yellow solid which separated was removed by filtration, washed with acetone and dried in a vacuum at 100°C. The pro¬ duct, obtained in 78% yield (3.2 g), was inositol hexa(l-methyl-3-pyridinium carboxylate)hexaiodide (<2), melting at 250-253°C with decomposition. NMR (D 2 0) <S 9.6-7.96 (ms, 24H, pyridinium protons), 6.7-6.6(m, 6H, inositol protons), 4.4 (s, 18H, 6 CH 3 -N + ). Anal. (C 48 H 48 IgN 6 0 12 ) C, H, N. The pro¬ duct can be represented by the structural formula -32- and can also be called hexa(N-methylnicotinoyloxy) Cj - i .p3 3.5-trans-4,6-cyclohexane hexaiodide. EXAMPLE 3 To a solution of 2.0 g (2.5 mmol) of inositol hexanicotinate Q.) in 200 ml of-dimethylformamide were added 6.6 g (0.053 mol) of dimethylsulfate. The mixture was heated, with stirring, at 60°C for forty-eight hours. The sticky, yellowish residue which separated on addition of ether was repeatedly washed with acetone and then dried in a vacuum oven at 50°C for twenty-four hours. There were thus ob¬ tained 2.5 g (64% yield) of inositol hexa(l-methyl- 3-pyridinium carboxylate) hexa(methylsulfate) (3_) as a yellow, highly hygroscopic solid. NMR (D 2 0)δ9.60- 8.03 ( s, 24H, pyridinium protons), 6.6-6.5 (m, 6H, inositol protons), 4.46 (s, 18H, 6 CH 3 -N), 3.56 (s, 18H, 6 CH 3 -0S0 3 ). Anal. ( 54 H 66 g0 36 S-6H 2 0) C, H, N. The product, which can also be named hexa(N- methylnicotτnoyloxy)-cis-l,2,3,5-trans-4,6-cyclo- hexane hexa( ethylsuTfate), can be represented by the structural formula 6CH 3 S0^ •33- EXAMPLE 4 A solution of 1 mmol of the quaternary salt (2) or (_3) in 10 ml of water was added, with stir¬ ring, to a solution of 1.149 of heparin sodium (178.6 USP units/mg, 12% Na) in 10 ml of water. No pre¬ cipitate was observed. On dilution with 100 ml of water, yellow oil droplets separated. The aqueous layer was removed by decantation and the residual oil was washed thoroughly several times with water. The well-drained oil was triturated with 50 ml of acetone. The oil solidified into a glistening yellow solid which was practically insoluble in organic solvents. The product weighed 1.6 g (84% of theore¬ tical) and decomposed at 210°C. Use of the hexa- iodide quaternary (j2) gave a purer, easier to work with product than use of the hexa(methylsulfate) quaternary (_3). Results of microanalysis for C, * N, 5:01; S, 8:19. Found: C, 39:14; H, 4.72; N, 5.60; S, 7:64. The resultant heparin hexa(N-methyl- nicotinoyloxy)-cis-1,2,3,5-tra_ns-4,6-cyc1ohexane multiplet (4_) can also be represented by the structural formula Cheparin unit .CH-, 0 /-\ + <* 2 " O) The anticoagulant activity of the. product was cal¬ culated in relation to the sodium content of heparin sodium to be 107.6 units/mg. EXAMPLE 5 A solution of 6 mmol of N,N-dimethyl-N-dodecyl- N-(β-hydroxyethyl)ammonium bromide in 10 ml of water was added, with stirring, to a solution of 1.14 g of heparin sodium (178.6 άnit/mg, 12% Na) in 10 ml of water. A white precipitate was obtained. The mixture was centrifuged and the residue was washed thoroughly with water, then dried in a vacuum desiccator. The white mass was thus converted to a transparent, colorless plastic-like mass of heparin N,N-dimethyl- N-dodecyl-N-(β-hydroxyethyl )ammonium ion pair ( _ ) _ which was soluble in methahol and ethanol , but in¬ soluble in water, ether, chloroform or dichloromethane. EXAMPLE 6 Substitution of an equivalent quantity of each of the starting materials listed below for the nico- tinic acid employed in Example 1 and substantial repetition of the procedures there detailed affords, after suitable isolation, the indicated products of the formula <_.! r-J oa ft σ* STARTING MATERIAL PRODUCT acid with dlmethylamlne) I prepared by react ing 2-bromo- 3-phenylproplonlc acid with dlmethylamlne) STARTING MATFRfAI PRODUCT ( the morphollno analogue of glyclne, prepared by reacting bromoacetlc acid with morphollne) I ( the pyrrolldln-1-yl analogue of alanlne, prepared by reacting 2- bromoproplonlc acid with pyrrolIdlne) ( the 1-methylplperazln- 1 reacting 2-bromo-3-methylbutanolc a d with N-methylplperazlne) STARTING HATFRIAI PRODUCT ( N. N-dlmethylglyclne, prepared by reacting bromoacetlc acid with dlethylamlne) I c LO I EXAMPLE 7 Substitution of an equivalent quantity of each of the starting materials listed below for the ins ositol employed in Example 1 and substantial repeti¬ tion of the procedures there detailed affords, after appropriate isolation, the indicated products: STARTING MATERIAL PROPUCT ( o-D-glucose) ( e Sl STARTING MATf A . PRODUCT ( loctose) *• -© ( 21) • When using this polyol, the molar ration of nlcotlnlc add to polyol Is at least 12:1. EXAMPLE 8 Substitution of an equivalent quantity of each of the starting materials listed in Column A below for the inositol used in Example 1 and substitution of an equivalent quantity of each of the starting materials listed in Column B below for the nicotinic acid used in Example 1 affords, by the procedures of that Example, the following products: SI SI o o υ SI COLUMN A COLUMN B PRODUCT (o-D-rlbofurαnose) (thepyrrolldln- 1-yl analogue of vallne) P ( 2S> (lactose) (N.N-dlethylglyclne) (β -cyclodextrln)* • When using this polyol. the molar ratio of Column B starting material to polyol Is ot least 12:1. COLUMN A COLUMN B PROPUCT to polyol Is at least 12:1. EXAMPLE 9 Quaternization of each of the products of Examples 6, 7 and 8 according the the general procedure of Example 2 affords, after appropriate isolation, the following products: SI vt I to « SI SI ft §1 I to 3 STARTING MATFRIAI PRODUCT Example 6, Compound (JJ) 61" Exom p le 6. Compound (1.) 61" Example 6, Compound (15) 61" STARTING MATERIAL PRODUCT Example 6, Compound ( lfi ) 61" Example 7, Compound (__) Example 7, Compound <li) S. ~i SI SI Sf SI STARTING MATFRIAI RODUC Exom p le 7, Compound (22)' • When using this polyester as the storting material..on even greater excess of methyl Iodide Is pre¬ ferably used tnan Is employed In Example 2. STARTIW. MATERIAL PROPUCT Example 8. Compound (2j) 51" Example 8, Compound Example 8, Compound (25) 51 " STARTING MATERIAL PROPUCT Example 8, Compound (2fi) 41" CD 1 (5|) Rj « Example 8, Compound (.__) 51" STARTING MATFRIAI PRODUCT Example 8, Compound (2__) Example 8, Compound (23) 5 Example 8, Compound (3ft) 6 STARTING MATF IAI, PRODUCT Example 8. Compound {__)* • When using this polyester as the starting material, on even greater excess of methyl Iodide Is preferably used than Is employed In Exomple 2. Example 8, Compound (32) 61" STARTING MATFRJAI PRODUCT Example 8, Compound (__) • 'When using this polyester as the starting material , an even greater excess of methyl Iodide Is preferably used than Is empl oyed In Example 2 , EXAMPLE 10 The general procedure of Example 4 is repeated, using an equivalent quantity of each of the quater¬ nary salts prepared in Example 9 in place of the quaternary salt (__) or (_3) used in Example 4 and vary¬ ing reaction conditions appropriately when ion pairs of heparin or heparin are desired. After suit¬ able isolation, the following heparin multiplets of the invention are obtained: STARTING MATERIAL Example 9, Compound ( 3 ) Exa i i p ie 9, Compound (25) Exaple 9, Compound (2£) STARTING MATERIAL, PRODUCT Exαnple 9, Cαnpound (29) Exαnple 9, Compound (ϋQ) STARTING MATERIAL Exαnple 9. Compound (__l) I Exanple 9, Canpound STAR I G MATF IAI , Exαn p le 9, Cαnpound (_i_>) Exαn p le 9, Cαnpound (_i£) Exanple 9, Compound ( / > SI ~\ STARTING MATERIAL Exαnple 9, Ccmpound (g;) I Exanple 9, Canpound (55) heparin unit] a SI 53 SI SI EXAMPLE 1 1 1.0 Mol of erythritol and 5.0 mol of Br-CH 2 CH 2 C0C1 are combined in chloroform (25 ml chloroform per 1.0 g erythritol) and 5.0 mol of triethylamine are added. The mixture is heated to the boiling point of chloro¬ form and maintained at that temperature for approx¬ imately 4 hours, then washed successively with water, aqueous sodium bicarbonate solution and water and evaporated. The residue, which is the fully bromo- acetylated intermediate of the formula is then dissolved in dimethylformamide (25 ml dimethyl¬ formamide per 1.0 g of above intermediate) and excess nicotinamide (8.0 mol per 1.0 mol of above intermediate) is added. The mixture is warmed to 60°-70°C and maintained at that temperature for about 24 hours. Acetonitrile is added to complete precipitation and the precipitate is removed by filtration and dried. The resultant novel intermediate of the formula can then be reacted with heparin sodium according to the procedure of Example 4 to afford the following multiplet of the invention: [Heparin unit] Substantial repetition of the foregoing general procedure utilizing an equivalent quantity of α-D- ribofuranose in place of the erythritol affords, in the first step, the bromoacetylated intermediate of the formula in the second step, the novel quaternary intermediate of the formula and, in the third step, the following multiplet of the invention: jhepαrln unit] EXAMPLE 12 1.0 Mol of inositol, 6.6 mol of pyridinium acetic acid bromide (prepared by reacting pyridine with bromo- acetic acid) and 6 mol of dicyclohexylcarbodiimide are combined in pyridine (30 ml per 1.0 g inositol). The mixture is stirred for approximately 4 to 6 hours at room temperature. After appropriate isolation and purification, the following novel quaternary intermediate is obtained: 6 Br- - 2 -»Q> Reaction of that novel intermediate with heparin sodium according to the procedure of Example 4 affords the following multiplet of the invention: Jhepαrln unit] ' 3 - -^ δ EXAMPLE 13 Substitution of equivalent quantities of the starting materials listed below for the inositol and pyridiniu acetic acid bromide used in Example 12 and repetition of the general procedure described in the first paragraph of that example affords the indicated products: PRODUCT Inositol an bromoacetlc acid) o-D-glucose QV-CH 2 CH 2 COOH ( prepared form pyridine and 3-brcmoproplonlc acid) lactose (prepared from nlcotlnomlde and 3-bromoproplonlc acid) EXAMPLE 14 Reaction of each of the products of Example 13 with heparin sodium according to the procedure of Example 4 affords the following multiplets of the in¬ vention: -ej EXAMPLE 15 Stability Studies A solution of (3_) in D 2 0 was maintained at room temperature in an NMR sample tube and an NMR run was taken daily. The only observed di-fference was a broadening of the multiplet at 6 6.6-6.5 corresponding to the protons of the inositol ring which started three days after preparing the solution for study. The broadening increased and the absorption shifted upfield until it lost its characteristic shape (within 12 days). EXAMPLE 16 Pharmacological Testing Determination of Clotting Time Blood was withdrawn from the treated or control animals, rat or rabbit, by cardiac puncture. Each blood sample was divided into three 1.5 ml polypropy¬ lene microceπtrifuge tubes. The tubes were capped and the tube containing the first blood withdrawn was inverted once every 30 sec until the blood clotted. At this time, the next tube was inverted in the same way followed by the third tube, which contained the last blood withdrawn. The clotting time taken was the time the blood in the third tube coagulated. Testing of Anticoagulant Activity by Oral Administration to Rats Male Sprague-Oawley rats with an average weight of 450 g were used. The rats were anesthetized with ether and either the test drug or heparin sodium,with a dose of 9000 USP unit/rat, was given orally through a stomach tube as a suspension in 1 ml polyethylene glycol 400. A group of rats were treated in the same way with 1 ml polyethylene glycol 400 only and was used as control. At selected time intervals, a sample of blood was withdrawn by cardiac puncture and the clotting time was determined as described previously . Testing of Anticoagulant Activity of Jejuna! Administration to Rats and Rabbits Male Sprague-Dawley rats with an average weight of 450 g and New Zealand white rabbits of average weight 3.0 kg were used for this mode of administra¬ tion. The animals were fasted for twenty-four hours before the test. The abdomen of the anesthetized animal was entered and the jejunum identified. The finely powdered ion pair compound or heparin sodium, adjusted to contain a dose of 20,000 USP unit/kg, was suspended in polyethylene glycol 400 and injected directly into the jejunum. Blood samples were taken by cardiac puncture at selected time intervals after administration and the clotting time determined as described previously. With rats, no samples could be taken at more than four hours after administration because of the death of rats from internal bleeding. Results The jji vitro anticoagulant activity of the heparin complexes ( ) and (5_) was tested. Their j_n v tro activity was found to be comparable to their cor¬ responding content of heparin. Their in vivo anti¬ coagulant activity was tested compared to heparin sodium on rats using oral , rectal and jejuna! ad- ministration and on rabbits using jejuna! administra¬ tion. The compounds and heparin sodium were each administered as a suspension in polyethylene glycol 400. [Compound ( ) changed into a sticky semisol d when it came in contact with water.] Blood samples were taken by .heart puncture and the clotting time was determined using the method described above. With rectal administration to rats, no activity was shown, whether for the complexes or for the heparin sodium. With oral administration to rats (Figure 1), compound (5_) showed no activity while ^ compound ( ),a represen¬ tative multiplet of this invention, showed higher activity than heparin, almost twice, after twenty-four hours. In the case of jejunal administration to rats (Figure 2), compound (5_) showed no activity while compound (4J, the representative multiplet of this invention, showed a larger AUC (area under the curve) within the four hours of the experiment. No data could be collected for longer time periods for administra¬ tion, since the rats died from internal hemorrhage due to the operation. With jejunal administration to rabbits (Figure 3), it is shown that, although compound < ) has slower onset of action than heparin sodium, it is more active and has a much longer duration of action. The clotting time does not return back to the normal value except after about 90 hours from administration. One rabbit was sacrificed and dis- sected after 48 hours from administration. The in¬ ternal organs looked normal, except the internal wall ° f the jejunum which was colored yellow; this in¬ dicated still the existence of the drug within the villi. While the invention has been described in terms of various preferred embodiments, the skilled artisan will appreciate that various modifications, substi¬ tutions, omissions and additions may be made without departing from the spirit thereof. Accordingly, it is intended that the scope of the present invention be limited solely by the scope of the following claims

Claims: WHAT IS CLAIMED IS: 1. A multiplet of the structural formula hepαrln unltj (I) wherein j is the skeleton of a polyol, said skeleton being the portion of said polyol remaining after re¬ moval of all hydroxy substituents therefrom; n is a number from 3 to 24 which represents the total number of hydroxy groups in said polyol; p is a number > 3 and < n; r is the available valence of the heparin unit and is > 3 and < 7; s is the number which when multi¬ plied by r is equal to pv; v is the number which when multiplied by p is equal to rs; R + is (α) (b) (c) or QV-αlkylene-C00- (d) (e) wherein the -C00-, -CH 2 C00-, -CH 2 0C00- and R v ring substituents can each be in the 2-, 3- or 4- position of the pyridiniu r ng; R i v is c ι" c 3 alk l; R' an R 1 ' , which can be the same or different, are each C^-Cy alkyl , or R* and R' ' are combined with the adjacent nitrogen atom such that -N represents the residue of a saturated monocyclic secondary amine; R' 1 ' is a radical identical to the correspomdi ng portion of a natural amino acid; the alkylene groups can be straight or branched and contain 1 to 3 carbon atoms; and R v is H, -C0NH 2 or -C00(C 1 -C 7 alkyl). 2. A multiplet as claimed in Claim 1 wherein the polyol is a onosaccharide, particularly when the mono- saccharide is a pentose, hexose or heptose. 3. A multiplet as claimed in Claim 1 wherein the polyol is an ol igosaccharide, particularly when the ol igosaccharide is a disaccharide, a trisaccharide or a cycl odextrin . 4. A multiplet as claimed in Claim 1 wherein the polyol is ribose, arabinose, xylose, lyxose, ribulose, xylulose, glucose, galactose, mannose, fructose, sor¬ bose, tagatose, mannoheptulose, sedoheptul ose , sucrose, lactose, maltose, raffinose, α-cyclodextrin, 8-cyclo- dextrin or γ-cycl odextri n . 5. A multiplet as claimed in Claim 1 wherein the polyol is a Cg-C**^ aliphatic polyhydroxy compound or a Cg-C g alicyclic polyhydroxy compound. 6. A multiplet as claimed in Claim 5 wherein the aliphatic polyhydroxy compound is a C 3 -Cg alkyl polyol, particularly when the C 3 -Cg alkyl polyol is glycerol , erythritol or 1 ,2 ,6-t i hydroxyhexane. 7. A multiplet as claimed in Claim 5 wherein the alicyclic polyhydroxy compound is a C -C1 Q cycloalkyl polyol , particularly a cyclohexane polyol , or wherein the alicyclic polyhydroxy compound is a fused fully hydrogenated aromatic polyol , particularly a decahydro- naphthalene polyol . 8. A multiplet as claimed in Claim 7 wherein the cyclohexane polyol is inositol . 9. A multiplet as claimed in Claim 1 wherein R' 1 ' is H, -CH3, -CH(CH 3 ) 2 , -CH 2 -CH(CH 3 ) 2 , -CH0H-CH 3 , -(CH 2 0NH 2 , -CH 2 SH, -CH 2 C00H or -CH 2 CH 2 C00H 10. A multiplet as claimed in Claim 1 wherein R' and R' ' are combined with the adjacent nitrogen atom such .R' that -N I represents the residue of a saturated mono- \ R . , cyclic secondary amine having 5 to 7 ring atoms, optionally containing another hetero ring atom -0-, -S- or -N- in addition to the indicated nitrogen atom, and optionally bearing 1 to 3 methyl substituents; R' particularly when -N I is morphol ino, 1-pyrroli- R" dinyl , perhydro-1 ,2 ,4-oxathi azi n-4-yl , 1- or 4-piper- azinyl , 4-methyl -1-piperazi nyl , piperidino, hexamethyl- eneimino, 2-methyl -1-pyrazol dinyl , 1- or 2-pyrazoli- dinyl , 3-methyl-l-imidazol idi nyl or 1- or 3-imidazoli- 10 inyl . 11. A multiplet as claimed in Claim 1 1 wwhee-r*e*-i' " "n D+ structure (a), (b) or (c); R 1V is methyl; and tlhe -C00-, -CH 2 C00- or -CH 2 0C00- group is located iin the 3- ) o s i t i o n . 15 . s • 20 —CH(CH ) , —CH -CH(CH 3 )2 » -CH-C Hc, -CHp- / W -(CH 2 ) 2 -SCH 3 , -CH 2 -C0NH 2 , -CH 2 CH 2 -C0NH 2 or 13. A multiplet as claimed in Claim 1 wherein R + is structure (e) and alkylene is -CH 2 - or -CH 2 CH 2 -, 25 particularly when R v is H or -C0NH 2 . 14. A multiplet as claimed in Claim 1 wherein p is equal to n, particularly when p is at least 4. 15. A multiplet as claimed in Claim 1 wherein r is 5, 6 or 7. 16. A multiplet as claimed in Claim 1 wherein C J is the skeleton of inositol, n is 6 and p is 6, particularly when v is 5, r is 5 and s is 6. 17. A multiplet as claimed in Claim 16 having the structural formula heparin uni wherein R 2 + is - 18. A pharmaceutical composition of matter compris¬ ing a multiplet of formula (I) as defined by Claim 1 and a non-toxic pharmaceutically acceptable carrier therefor. 19. A pharmaceutical composition of matter, in unit dosage form, for use in eliciting an anticoagulant response in a warm-blooded animal , said composition comprising, per dosage unit, an effective unit anti- coagulant amount of a multiplet of formula (I) as defined by Claim 1 and a non-toxic pharmaceutically acceptable carrier therefor, said composition being suitable for nasal administration, for oral inhalation therapy or for other oral administration. 20. A salt of the structural formula wherein C J i s the skeleton of a polyol , said skeleton being the portion of said polyol remaining after removal of all hydroxy substituents therefrom; n is a number from 3 to 24 which represents the total number of hydroxy groups in said polyol; p is a number > 3 and < n; R + is (b) (c) (e) wherein the -C00-, -CH 2 C00-, -CHgOCOO- and R v ring substituents can each be in the 2-, 3- or 4- position of the pyridinium ring; R lv is C j -C 3 alkyl; R' and R' which can be the same or different, are each C- C** / alkyl, or R* and R' ' are combined with the adjacent ,R' nitrogen atom such that -N I represents the residue \ R .. of a saturated monocyclic secondary amine; R' *' is a radical identical to the corresponding portion of a natural amino acid; the alkylene groups can be straight or branched and contain 1 to 3 carbon atoms; R v is H, -C0NH 2 or -000(^-0-;); X" is the anion of a pharmaceutically acceptable organic or inorganic acid; t is the valence of the acid anion; and q s. the number which when multiplied by t is equal to p. 21. A salt as claimed in Claim 20 wherein the polyol is a onosaccharide, particularly when the monosac- charide is a pentose, hexose or heptose. 22. A salt as claimed in Claim 20 wherein the polyol is an ol igosaccharide, particularly when the oligosac- charide is a disaccharide, a trisaccharide or a cyclo- dextrin. 23. A salt as claimed in Claim 20 wherein the polyol is ribose, arabinose, xylose, lyxose, ribulose, xyl u- lose, glucose, galactose, mannose, fructose, sorbose, tagatose, mannoheptulose, sedoheptul ose, sucrose, lactose, maltose, raffinose, α-cyclodextrin, S-cyclo- dextrin or γ-cyclodextrin . 24. A salt as claimed in Claim 20 wherein the polyol is a C 3 -C j 5 aliphatic polyhydroxy compound or a Cg-C-ig alicyclic polyhydroxy compound. 25. A salt as claimed in Claim 24 wherein the aliphatic polyhydroxy compound is a C 3 -Cg alkyl polyol , particularly when the C 3 -Cg alkyl polyol is glycerol , erythritol or 1,2 ,6-trihydroxyhexane. 26. A salt as claimed in Claim 24 wherein the alicyclic polyhydroxy compound is a cycloalkyl polyol , particularly a cyclohexane polyol , or wherein the alicyclic polyhydroxy compound is a fused fully hydrogenate ' d aromatic polyol , particularly a decahydro- naphthalene polyol . 27. A salt as claimed in Claim 26 wherein the cyclohexane polyol is inositol . 28. A salt as claimed in Claim 20 wherein R' ' ' is H, —CH , —CH(CH /p, —CHp—CH(CH ) , -(CH 2 ) 2 -SCH 3 -CH 2 -C0NH 2 , -CH 2 CH 2 -C0NH 2 , -C OH, -CH 2 SH, -CH 2 C00H or -CH 2 CH 2 C00H 29. A salt as claimed in Claim 20 wherein R* and R* ' are combined with the adjacent nitrogen atom such that -N represents the residue of a saturated mono- \ R " cyclic secondary amine having 5 to 7 ring atoms, optionally containing another hetero ring atom -0-, -S- or -N- in addition to the indicated nitrogen atom, and optionally bearing 1 to 3 methyl substituents; particu- larly when -N ' is morpholino, 1-pyrrol idinyl , perhydro-1 ,2 ,4-oxathiazin-4-yl , 1- or 4-piperazi nyl , 4- methyl-1-piperazinyl , piperidino, hexamethyl eneimino, 2-methyl -1-pyrazol dinyl , 1- or 2-pyrazol idinyl , 3- methyl-1-imidazol idinyl or 1- or 3-imidazol idinyl . 30. A salt as claimed in Claim 20 wherein R + is structure (a), (b) or (c); R 1V is methyl; and the -C00-, -CH 2 C00- or -CH 2 0C00- group is located in the 3- position. 31. A salt as claimed in Claim 20 wherein R + is structure (d); R' is methyl or ethyl and R' * is identi¬ cal to R' , or R'R^N- represents morpholino, piperi- dino, 1-pyrrol idi nyl or 1-piperazinyl ; R IV s methyl ; and alkylene is -CH-; particularly when R 1 1 is H, -CH 3 , -CH(CH 3 ) 2 , -CH 2 -CH(CH 3 ) 2 -(CH 2 ) 2 -SCH 3 , -CH 2 -C0NH 2 , -CH 2 CH 2 -C0NH 2 or 32. A salt as claimed in Claim 20 wherein R is structure (e) and alkylene is -CH 2 or -CH 2 CH 2 -, particularly when R v is H or -C0NH 2 . 33. A salt as claimed in Claim 20 wherein p is equal to n, particularly when p is at least 4. 34. A salt as claimed in Claim 20 wherein t is 1. 35. A salt as claimed in Claim 20 wherein X " is I " , Br " or Cl " . 36. A salt as claimed in Claim 20 wherein f J i s the skeleton of inositol , n is 6 and p is 6. 37. A salt as claimed in Claim 36, having the structural formula wherein X- 38. A 39. A process for the preparation of a multiplet of formula (I) as defined in Claim 1 which comprises: (a) reacting the corresponding salt of formula (III) as defined in Claim 20 with sodium heparin-; or (b) subjecting the corresponding salt of formula (III) as defined in Claim 20 to anion exchange to replace X" anions in the salt with OH" anions, followed by reacting the resultant intermediate with heparinic acid.

Inventors: BODOR NICHOLAS S, BODOR, NICHOLAS, S.
Applicants: BODOR NICHOLAS S, BODOR, NICHOLAS, S.
Application year: 1985
Main classification: C08B37
IPC codes: C07C67, C07C227, C07D213, C07D295, C07H1, C07H3, C07H13, C08B1, C08B37